stem cell research controversy article

May 1, 2014

Dispute over Stem Cells: A Timeline

For more than 40 years government officials have grappled with how to regulate and fund the controversial research   

By Roni Jacobson

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Despite its promise, stem cell research in the U.S. has been stymied, time and again, by bioethical landmines. The explosive debate revolves around the fact that, until recently, the only way to get pluripotent stem cells was to extract them from human embryos left over from in-vitro fertilization—a process that destroyed the five-day-old embryo. The ongoing debate about when life begins has led many to oppose stem cell research on the grounds that it is immoral to destroy something that could eventually grow into a person. On the other hand, promoters argue that the potential to help millions of people with stem cell therapies outweighs the sanctity of cells that are not viable outside the womb and that often go unused. Arguments on both sides are based on personal beliefs that may never be reconciled, so the debate hinges on whether the federal government should fund research that many citizens find morally objectionable. The following box chronicles stem cell research regulation in the U.S.  1970s The Supreme Court legalizes abortion in 1973. The ensuing debate on the ethics of experimenting on fetal tissue prompts Congress to issue a moratorium on federal funding for research on human embryos the following year. 1990s In 1995 President Clinton lifts the ban on funding for study of stem cells left over from in-vitro fertilization, but leaves other restrictions in place. In response, Congress passes the Dickey-Wicker Amendment, prohibiting funding for all research “in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death,” regardless of the source of the embryo. 2000s  

President George W. Bush announces that federal funding will be made available for research on the approximately 60 existing embryonic stem cell lines, but not new ones. Congress twice votes to loosen the restrictions on funding for research using embryonic stem cells left over from in-vitro fertilization but President Bush vetoes the legislation both times.

In 2009, early in his first term, President Barack Obama removes the ban on federal funding for new stem cell lines but signs an omnibus bill preserving the Dickey-Wicker Amendment. The move retains restrictions against federal funding for the direct creation of new stem cell lines, but opens up funding for research on newly created lines developed with private or state money.  2010s In 2012 stem cell biologist Shinya Yamanaka wins the Nobel Prize in Physiology or Medicine for discovering how to reprogram adult skin cells into pluripotent stem cells. Going forward, policy makers will have to determine whether Yamanaka’s induced pluripotent stem cells (iPS) will face the same regulations as human embryonic stem cells or if new legislation is needed.  

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From “The Troubled Hunt for the Ultimate Cell” (1998), by Antonio Regalado: “If awards were given for the most intriguing, controversial, underfunded and hush-hush of scientific pursuits, the search for the human embryonic stem (ES) cell would likely sweep the categories. It’s a hunt for the tabula rasa of human cells—a cell that has the potential to give rise to any of the myriad of cell types found in the body. If this mysterious creature could be captured and grown in the lab, it might change the face of medicine, promising, among other remarkable options, the ability to grow replacement human tissue at will … [but] these cells are found only in embryos or very immature fetuses, and pro-life forces have targeted the researchers who are hunting for ES cells, hoping to stop their science cold. In addition, the federal government has barred federal dollars for human embryo research, pushing it out of the mainstream of developmental biology. To make matters worse, human ES cells could conceivably provide a vehicle for the genetic engineering of people, and the ethical dilemmas surrounding human cloning threaten to spill over onto this field.”

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The Stem Cell Debate: Is it Over?

Stem cell therapies are not new. Doctors have been performing bone marrow stem cell transplants for decades. But when scientists learned how to remove stem cells from human embryos in 1998, both excitement and controversy ensued.

The excitement was due to the huge potential these cells have in curing human disease. The controversy centered on the moral implications of destroying human embryos. Political leaders began to debate over how to regulate and fund research involving human embryonic stem (hES) cells.

Newer breakthroughs may bring this debate to an end. In 2006 scientists learned how to stimulate a patient's own cells to behave like embryonic stem cells. These cells are reducing the need for human embryos in research and opening up exciting new possibilities for stem cell therapies.

Both human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells are pluripotent: they can become any type of cell in the body. While hES cells are isolated from an embryo, iPS cells can be made from adult cells.

The Ethical Questions

Until recently, the only way to get pluripotent stem cells for research was to remove the inner cell mass of an embryo and put it in a dish. The thought of destroying a human embryo can be unsettling, even if it is only five days old.

Stem cell research thus raised difficult questions:

• Does life begin at fertilization, in the womb, or at birth?
• Is a human embryo equivalent to a human child?
• Does a human embryo have any rights?
• Might the destruction of a single embryo be justified if it provides a cure for a countless number of patients?
• Since ES cells can grow indefinitely in a dish and can, in theory, still grow into a human being, is the embryo really destroyed?

Problem Solved?

With alternatives to hES cells now available, the debate over stem cell research is becoming increasingly irrelevant. But ethical questions regarding hES cells may not entirely go away.

For now, some human embryos will still be needed for research. iPS cells are not exactly the same as hES cells, and hES cells still provide important controls: they are a gold standard against which the "stemness" of other cells is measured.

Some experts believe it's wise to continue the study of all stem cell types, since we're not sure yet which one will be the most useful for cell replacement therapies.

An additional ethical consideration is that iPS cells have the potential to develop into a human embryo, in effect producing a clone of the donor. Many nations are already prepared for this, having legislation in place that bans human cloning.

Stem Cell Research Legislation

Regulations and policies change frequently to keep up with the pace of research, as well as to reflect the views of different political parties. Here President Obama signs an executive order on stem cells, reversing some limits on federal research funding. (White House photo by Chuck Kennedy)

Governments around the globe have passed legislation to regulate stem cell research. In the United States, laws prohibit the creation of embryos for research purposes. Scientists instead receive "leftover" embryos from fertility clinics with consent from donors. Most people agree that these guidelines are appropriate.

Disagreements surface, however, when political parties debate about how to fund stem cell research. The federal government allocates billions of dollars each year to biomedical research. But should taxpayer dollars be used to fund embryo and stem cell research when some believe it to be unethical? Legislators have had the unique challenge of encouraging advances in science and medicine while preserving a respect for life.

U.S. President Bush, for example, limited federal funding to a study of 70 or so hES cell lines back in 2001. While this did slow the destruction of human embryos, many believe the restrictions set back the progress of stem cell research.

President Obama overturned Bush's stem cell policy in 2009 to expand the number of stem cell lines available to researchers. Policy-makers are now grappling with a new question: Should the laws that govern other types of pluripotent stem cells differ from those for hES cells? If so, what new legislation is needed?

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Article Contents

Public attention to stem cell research, public understanding of research and regulation, moral dimensions of embryonic stem cell research, reproductive and therapeutic cloning.

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Public Opinion About Stem Cell Research and Human Cloning

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Matthew C. Nisbet, Public Opinion About Stem Cell Research and Human Cloning, Public Opinion Quarterly , Volume 68, Issue 1, March 2004, Pages 131–154, https://doi.org/10.1093/poq/nfh009

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Few science and technology–related issues have sparked as much survey attention as the public controversy over human embryonic stem cell research and therapeutic cloning. Interest groups, advocates, and policymakers on both sides of the debate have taken advantage of poll results to support their claims that the public backs their preferred policy outcomes, and the competing camps have staged ongoing public communication campaigns in an effort to shape public opinion. Journalists have also highlighted the results of these surveys, using poll figures to complement their coverage of who is ahead and who is behind in the competition to decide stem cell–and cloning-related policy ( Nisbet, Brossard, and Kroepsch 2003 ).

The study of survey trends detailing public responses to genetic engineering and biotechnology is not new. For example, Singer, Corning, and Lamias (1998) reviewed poll trends specific to genetic testing, gene therapy, and early public reactions to animal and human reproductive cloning. Shanahan, Scheufele, and Lee (2001) examined trends related to agricultural biotechnology, and the National Science Foundation’s Science and Engineering Indicators surveys have tracked public opinion about genetic engineering (broadly defined) since the 1980s (for an overview, see Miller and Kimmel 2001 ). These previous analyses, however, have not focused specifically on surveys measuring public reactions either to stem cell or therapeutic cloning research.

“Stem cells” are utility and repair units of the body that serve a central function in the maintenance and regeneration of organs and tissues throughout life. Adult stem cells, derived mostly from bone marrow and umbilical cord blood, have been used in research since the 1960s, with applications focused primarily on treatments for cancer. Stem cells from human embryos were not isolated for the first time until 1998. Unlike their adult tissue counterparts, embryonic stem cells are “undifferentiated,” meaning these repair units of the human body have yet to be programmed to be specific to the brain, the skin, the heart, the lungs, or other bodily tissues. Research on embryonic stem cells is therefore considered by many scientists to be instrumental in developing a diverse supply of tissues to be used in the treatment of a variety of health problems including AIDS, diabetes, Alzheimer’s, Parkinson’s, spinal cord injuries, and heart disease ( Johnson 2001 ).

The prized potential of embryonic stem cells has led to urgent pleas from the scientific community and research advocates for U.S. government funding. Scientists argue that they have been prevented from making significant advances in the treatment of health problems because of a long-standing moratorium on using cells from human embryos in federally funded projects, limiting work to private and for-profit ventures ( Rowley et al. 2002 ). Opponents of research counter that the derivation of stem cells from human embryos requires the embryos’ destruction, and therefore it would be morally wrong for the government to support the research ( National Bioethics Advisory Committee [NBAC] 1999) .

In July and August 2001 the controversy over human embryonic stem cell research reached the top of the U.S. political agenda. On August 9, President George W. Bush, in his first nationally televised address, announced a compromise solution that would limit federal funding to research that used only existing stem cell lines. As outlined by the Bush decision, funding could only move forward if it meant that new human embryos would not be destroyed. Despite pressing domestic and international political concerns, the issue remained on the political agenda in late 2001 as pro-research advocates contested the suitability of the allocated stem cell lines and as the controversy moved into a new stage when it was linked to the unresolved matter of human cloning regulation.

The beginning of the redefinition of the stem cell issue went relatively unnoticed in July 2001 as the House passed a ban (pending Senate approval) of both reproductive and therapeutic cloning ( Weiss and Elperin 2001 ). The latter procedure was closely linked to stem cell research, as one of its central applications involves the creation of cloned embryos for use in the extraction of stem cells. Despite decisive House approval of a comprehensive ban on cloning, to date there has been little or no movement on legislation in the Senate, as neither side appears to have the votes needed for passage ( Dewar 2002 ). One bipartisan coalition of senators has proposed legislation that would ban reproductive cloning but would allow therapeutic cloning. Another bipartisan coalition of senators has proposed a total ban similar to the House legislation ( Weiss 2002 ). Policy conflict has not been limited to the federal level, as legislation related to stem cell research and/or cloning has been passed in more than a dozen states ( Stolberg 2002 ). As the policy deadlock continues, the issue has been accompanied by a sizable amount of sensationalism. In one leading example, the year 2002 ended with a clone hoax perpetrated by Clonaid, a company affiliated with the Raëlian religion ( Grady and Pear 2002 ). In addition, press reports have chronicled a handful of maverick fertility scientists and doctors who claim to be making progress toward the birth of a human clone ( Nerlich and Clarke 2003 ).

Given that significant media attention to the stem cell issue did not occur until the summer of 2001 ( Nisbet 2003 ; Nisbet, Brossard, and Kroepsch 2003 ), it is not surprising that when surveyed in the fall of 2000, only 20 percent of Americans reported following the issue either “very closely” or “fairly closely.” Even in early July 2001, only a month before Bush’s nationally televised address, the proportion of Americans following the issue had only increased to 38 percent. By early August, however, this number had risen to slightly more than a majority of respondents, and polls indicate that in the days after Bush’s announcement, between 40 percent and 60 percent of respondents reported that they were following the issue at least somewhat closely. Public attention to the issue remained steady even several weeks after the terrorist attacks of September 11 (table 1 ).

In an alternative measure of public awareness, 25 percent of Americans reported that they had either seen, read, or heard “a lot” about the issue in the weeks immediately following the Bush decision (table 2 ). A few months later, in February 2002, this figure remained relatively stable at 27 percent, though a precise trend is difficult to observe because of slightly different question wording. However, in September 2002, a little more than a year after Bush’s decision, only 13 percent of respondents reported having seen, read, or heard “a lot” about the issue, whereas 46 percent of respondents reported “not much” or “nothing at all.” These percentages suggest that overall public attention to the issue had declined from 2001 levels, with this drop in public attention paralleling a drop in media attention.

In terms of issue importance, in the summer of 2001 during the peak of the debate, more than 60 percent of respondents reported that the issue was either “very important” or “somewhat important” to them (table 3 ). Indeed, roughly a third of Americans reported that they had tuned in for Bush’s August 9 televised address (table 4 ). Bush’s televised speech and the sizable audience should not be overlooked in terms of its potential significance for public understanding of the issue. At least one historian viewed Bush’s speech as remarkable for a presidential address since Bush spent an unusual amount of time outlining the background of the issue and the competing points of view that fueled the controversy ( Cmiel 2001 ).

Relative to indicators of public attention to the issue of cloning, the available survey data is fairly nonspecific to therapeutic cloning applications; instead, survey items tracked public attention to reproductive cloning starting with the 1997 announcement of the cloned sheep named Dolly. Through the end of 1998, roughly half of respondents reported following developments related to cloning or having an interest in the issue, with the exception of the announcement of cloned mice by scientists in Hawaii. However, despite the sensationalism surrounding the human cloning claims announced by the Raëlians during Christmas week of 2002, less than half of respondents reported that they were following the issue either “very closely,” or “fairly closely.” (table 5 ) 1

In the early stages of the controversy, given the low levels of media attention to the issue, the public should not be faulted for a lack of knowledge relative to the specifics of the emerging policy debate. For example, when asked in the fall of 2000, only 17 percent of respondents reported that they knew that the National Institutes of Health (NIH) had recently announced that the agency would begin accepting applications for federal funding of embryonic stem cell research, and close to two-thirds of respondents either reported “don’t know” or refused the question (table 6 ). (George W. Bush put the NIH decision on hold shortly after taking office in early 2001.)

Yet by August 2001, despite considerable media coverage and despite an increase in self-reported attention to the issue, the public still scored relatively low in terms of knowledge. For example, although in one August 10–12 poll, 60 percent of respondents reported having a “good understanding” of the issue (table 7 ), a few weeks later only 28 percent of respondents could correctly identify the criteria under which Bush’s decision would allow a stem cell line to be eligible for funding (table 8 ). A majority of respondents, however, were at least familiar with the crux of the debate, naming the destruction of human embryos as the major reason for the controversy (table 9 ). However, a year later, in September 2002, when asked in an open-ended question to answer what kinds of stem cells came to mind when thinking about stem cell therapy, more than half answered “don’t know,” and only 17 percent answered embryonic stem cells (table 10 ).

Specific to public knowledge of cloning, the available survey items are somewhat limited. As early as 1986, 69 percent of the public indicated that they understood the meaning of the term “cloning.” However, the recent debate whether to ban all forms of cloning, or to allow cloning only for medical research purposes appears to have complicated matters for the public. In 2002, for example, a VCU Life Sciences survey indicated that only 41 percent of respondents reported they were either “very clear” or “somewhat clear” on the differences between “reproductive” and “therapeutic” cloning procedures. In terms of knowledge of cloning policy, as of October 2002, according to a survey conducted by The Genetics and Public Policy Center, more than half of respondents incorrectly assumed that the government already regulated the cloning of humans.

As previously mentioned, much of the opposition to embryonic stem cell research from religious and conservative elites derives from the necessary destruction of human embryos. At the base of this elite opposition are the beliefs that a human embryo is equivalent to a human life and that embryos are deserving of the same protections as other human beings. To destroy embryos would therefore be morally wrong, essentially equivalent to murder ( NBAC 1999 ). Where does the public weigh in on this matter? Previous surveys that have asked Americans about when life begins indicate that a slight majority of respondents have consistently indicated that life begins at “conception” (table 11 ).

Important to note is a recent 2003 Newsweek poll (table 12 ). This is the lone poll to explore more carefully the public’s definition of “conception,” distinguishing in response categories between a fertilized egg and an embryo. Given this additional precision in measurement, the important implication for embryonic stem cell research is that a combined 58 percent of the public appears to believe that life begins either at the earliest stage of a fertilized egg or as an embryo.

Given this outlook on when life begins, it would not be surprising to find that embryonic stem cell research might be morally problematic for many respondents. In July 2001, 54 percent of respondents agreed that embryonic stem cell research was morally wrong, but among those same respondents an ambivalent majority said that although the research may be morally wrong, it might also still be necessary. As of early August 2001, this finding remained virtually unchanged, but by May 2002, and later in May 2003, the percentage regarding embryonic stem cell research as morally wrong was 39 percent and 38 percent, respectively (tables 13a , 13b ).

There is also evidence that the type of embryo used in research matters to respondents (tables 14a , 14b ). The first poll listed in table 14a asked specifically about research using stem cells obtained from “extra embryos” created at fertility clinics. From June 2001 to just after the Bush decision in August 2001, polls indicate that a strong majority of Americans supported research using “extra” embryos, and this support appears to have increased slightly from June to just after the Bush decision (table 14a ). Differences in question wording should be noted. Second, when the source of the embryos is left unspecified, it is apparent that public support drops, as indicated in the 2001 Virginia Commonwealth University (VCU) poll (table 14b ). In this particular case only 48 percent of respondents indicated that they either “strongly favored” or “somewhat favored” the research. Importantly, when the same exact question was asked a year later in September 2002, there appears to have been a drop in public support over the twelve-month period, with only 35 percent of respondents indicating that they favored research. Yet as of September 2003, when VCU asked the same question of respondents again, support appears to have climbed back to approximately the level in 2001.

Additional evidence that opinion varies based on the type of embryo used as a source for stem cells is provided by the survey results detailed in tables 15a and 15b . In the May 2001 poll that asked about unspecified embryos (but mentioned possible medical benefits of research) (table 15a ), 58 percent of respondents indicated that research should be allowed. Alternatively, the Gallup and Harris Interactive polls—conducted within days of each other in July—showed strikingly different results. In the Gallup poll, only 38 percent of respondents indicated that research should be allowed using embryos created specifically for research purposes. The Harris poll asked specifically about extra embryos left over from fertilization and found support to be much higher at 61 percent (table 15b ). This suggests that public support for research depends on the type of embryo used, with generalized public support greatest for “discarded” or “extra embryos.”

The importance of how prospective research is framed is illustrated by the first two polls detailed in table 16 , the first sponsored by the Juvenile Diabetes Research Foundation (JDRF) and the second by the National Council of Catholic Bishops (NCCB). Both poll items present strong examples of just how sensitive respondents may be to question-wording effects, especially when public attention to an issue is relatively low. The JDRF poll mentions as the source of stem cells extra embryos “donated to research” and then includes as background information a list of eight high-profile diseases or injuries for which stem cell research might provide “cures.” Not surprisingly, public support for funding is measured at 65 percent. In the NCCB poll, respondents are told, “Congress is considering whether to provide funding for experiments using stem cells from human embryos. The live embryos would be destroyed in their first week of development to obtain these cells.” The respondents are then asked, “Do you support or favor using your federal tax dollars for such experiments ?” (emphasis added). Given this information, 70 percent of respondents voiced their opposition to funding.

Across other polls taken in 2001 and featured in table 16 , public support appears highest for funding of stem cell research that uses either adult cells (68 percent) or extra embryos (greater than 50 percent support across all polls). Public support for funding is lowest, by far, for stem cell research that uses cloned embryos as sources (28 percent). Important to note is that in the July 2001 Gallup poll, when respondents were prompted with the response categories “Do you think the federal government should or should not fund this type of research, or don’t you know enough to say?” more than half of the respondents chose the “don’t know enough to say” response. Considering possible changes in support for funding between 2001 and 2002, the limited number of available measures makes a determination somewhat difficult. The lone 2002 poll asking about support for funding is nonspecific to the embryo source and lacks any background information in the question. This poll registers support at 43 percent but includes a strong 18 percent “don’t know.”

The surveys taken in the days and weeks after Bush’s August 9, 2001, announcement indicate that the president’s decision appears to have been received favorably by a majority of Americans, as the polls were fairly consistent in showing between 50 percent and 60 percent support (table 17 ). This level of support is somewhat surprising given that many scientists, pro-research advocates, and news organizations publicly questioned and criticized the suitability of the existing stem cell lines outlined by Bush.

As previously described, highly relevant to the issue of federal funding for embryonic stem cell research has been the debate over regulation of reproductive and therapeutic cloning. Public opinion is fairly clear when it comes to support for reproductive cloning. (Here, in order to categorize the questions, a strict definition of the term is adopted from the 2002 report of the President’s Council on Bioethics, with reproductive cloning, or “cloning-to-produce-children,” including all cloning technology designed to ultimately result in the birth of a child, no matter the stated reason or justification for such a procedure.) As table 18 outlines, in polls taken between 1993 and 2002, roughly 75 percent or more of respondents have consistently indicated—across a wide variety of stated purposes—that they disapprove of reproductive cloning. The few exceptions include screening for abnormalities in embryos (52 percent disapproved in 1993), cloning of embryos for infertility treatment (63 percent disapproved in 1998), and cloning to produce copies of humans for organs to save others (68 percent disapproved in 2001). Still, in all of these examples, a majority of Americans disapprove of the procedure.

Since the Dolly announcement of early 1997, more than 80 percent of Americans have consistently answered that reproductive cloning should not be allowed or should be illegal (tables 19a , 19b ), with one exception in a Beliefnet poll in August 2001, in which opposition to cloning was less.

Still, when the public was asked if they would favor or oppose either an “outright ban on the cloning of human beings” or “a law that would prohibit the cloning of human beings,” subtle differences appeared (tables 20a , 20b ). In this case, starting in early 1998 and into the spring of 2002, only a slight majority of Americans favored either an outright ban or a law that would prohibit cloning, suggesting that the public may be somewhat hesitant about backing legislation that completely closes the door on any and all cloning-related research. In fact, when Gallup asked in March 2003, “would you favor or oppose a law that would prohibit the cloning of human beings, or are you unsure ?” (emphasis added), a quarter of respondents answered that they were not entirely certain about the matter (table 20b ).

In contrast, however, a slight majority of Americans approve of cloning that is not designed specifically to result in the birth of a human, but is designed to aid in medical research into the treatment of diseases or for the purposes of cloning organs and adult cells (table 21 ). This slight majority support remains steady between late 2001 through September 2002. The public, however, appears to assert reservations when asked specifically about the cloning of embryos for medical research, with majorities voicing their disapproval in May and September 2002. Additionally, when asked specifically in early 2003 about legislation that would allow cloning for “laboratory research” but would ban reproductive cloning, a little more than a third of respondents indicated support for only a partial ban, whereas 40–60 percent of respondents indicated their support for a total ban (table 22 ).

The controversy over human embryonic stem cell research and therapeutic cloning remains unresolved, and the issue may mark a new era of divisive and deadlocked “biopolitics.” What the review of the polls makes clear is that public attention was captured by this emerging conflict during the summer of 2001 but has waned since, as media coverage has subsided, and many other competing issues have come to dominate the political and media agenda. Despite Americans’ elevated attention to the issue in 2001, however, it appears that the public remains in the dark about the science and the policy driving the controversy. Despite limited knowledge about the specifics of the issue, the public appears to have strong reservations about research that destroys embryos, preferring that if the research must move forward, scientists make use of either extra embryos left over from in vitro clinics, or adult cells. Additionally, evidence indicates that question wording in surveys can have strong effects on the public’s stated response to these volatile issues. On the matter of cloning, the public is strongly opposed to reproductive cloning, but resolve softens when it comes to medical applications, with about a third of Americans supporting this research, while a substantial proportion of Americans remain unsure about the matter. In all, the analysis points to an important role for the media in shaping future public judgments of stem cell research and human cloning. Evidence of strong question wording effects, combined with the findings relative to low levels of public knowledge, suggest that the public may be highly susceptible to influence by changes in media attention and media characterization of the issue.

Data Sources and Abbreviations

Many of the survey questions and results cited in this report were located using the public opinion online search engine (“Polls and Surveys”) of Lexis-Nexis and the Kaiser Health Poll Archive, both provided by the Roper Center for Public Opinion. Keywords such as “stem cell,” “cloning,” “clone,” or “conception,” or “life begin” were used for the search. Further polls were retrieved from the data archives of “pollingreport.com” or through a Web search. Most of the surveys cited are based on national adult samples with sample size of approximately one thousand or more, with exceptions noted. The questions cited were drawn from surveys conducted by the following survey organizations, news organizations, policy centers, or advocacy groups:

ABC: ABC News

ABC/Post: ABC News with Washington Post

Alliance for Aging Research: Survey conducted by Belden, Russonello, and Stewart.

Beliefnet: Beliefnet with ABC News

Center: The Genetics and Public Policy Center, Washington, DC. The center is part of the Phoebe R. Berman Bioethics Institute at Johns Hopkins University and is funded by the Pew Charitable Trusts. The survey was conducted by Princeton Data Source, LLC.

Gallup: Gallup Organization with CNN and USA Today

Harris: Louis Harris and Associates

HarrisIT: Harris Interactive

Ipsos: Ipsos-Reid

JDRF: Juvenile Diabetes Research Foundation. Survey conducted by Opinion Research Corporation International.

Kaiser: Henry J. Kaiser Foundation, Harvard School of Public Health. Survey conducted by Princeton Survey Research Associates.

LA Times: Los Angeles Times

NBC/WSJ: NBC News with Wall Street Journal . Survey conducted by Hart and Tecter Research Companies.

NCCB: National Council of Catholic Bishops. Survey conducted by International Communications Research.

Newsweek: Newsweek magazine. Survey conducted by Princeton Survey Research Associates.

PewPress: Pew Research Center for the People and the Press. Survey conducted by Princeton Survey Research Associates.

PewRel: Pew Research Center, Pew Forum on Religion and Public Life. Survey conducted by Princeton Survey Research Associates.

Roper: Roper Organization

VCU: Virgina Commonwealth University Life Sciences Survey. Survey conducted by VCU Center for Public Policy.

Yank.: Yankelovich Partners Poll Inc.

1. I’m going to read you a list of some stories covered by news organizations in the last month or so. As I read each one, tell me if you happened to follow this news story very closely, fairly closely, not too closely, or not at all closely. How closely did you follow this story? . . . Government decision about the use of federal funding for stem cell research.

N ote .—* = less than .5 percent; NA = not asked

As you may know, the federal government is considering whether to fund certain kinds of medical research known as “stem cell research.” . . . How closely have you followed the debate about government funding of stem cell research—very closely, somewhat closely, not too closely, or not closely at all?

How closely have you followed the issue of federal funding of stem cell research? Have you followed this issue extremely closely, somewhat closely, only a little, or not at all? If you have never heard of stem cell research, please just say so.

Now I’m going to read you a list of some stories covered by news organizations in the last month or so. As I read each one, tell me if you happened to follow this news story very closely, fairly closely, not too closely, or not at all closely. How closely did you follow this story? . . . The discussion of stem cell lines eligible for research with federal funding.

2. How much have you seen, read, or heard about medical research involving embryonic stem cells—a lot, a little, not much, or nothing at all?

As you may know, the federal government has debated whether to fund certain kinds of medical research known as “stem cell research.” How much have you heard about this? A lot, a little, or nothing at all?

3. As you may know, the federal government is considering whether to fund certain kinds of medical research known as “stem cell research.” . . . How important is the issue of stem cell research to you—very important, somewhat important, not too important, or not at all important?

4. As you may know, President (George W.) Bush gave a speech tonight (August 9, 2001) on stem cell research, and he announced that he would allow the government to fund research using stem cells that have been created in the past in a process that destroyed human embryos. The government will not fund stem cell research that would destroy additional embryos in the future . . . Did you happen to watch any of Bush’s speech on stem cell research tonight, or not?

As you may know, President [George W.] Bush gave a speech Thursday night [August 9, 2001] on stem cell research, and he announced that he would allow the government to fund research using stem cells that have been created in the past in a process that destroyed human embryos. The government will not fund stem cell research that would destroy additional embryos in the future . . . Did you happen to watch any of Bush’s speech on stem cell research Thursday night, or not?

5. I will read a list of some stories covered by news organizations in the past month. As I read each item, tell me if you happened to follow this news story very closely, fairly closely, not too closely, or not at all closely? . . . The cloning of a sheep by a Scottish biologist.

I will read a list of some stories covered by news organizations this past month. As I read each item, tell me if you happened to follow this news story very closely, fairly closely, not too closely, or not at all closely . . . Plans by a Chicago scientist [Richard Seed] to open a clinic for cloning people.

I will read a list of some stories covered by news organizations this past month. As I read each item, tell me if you happened to follow this news story very closely, fairly closely, not too closely, or not at all closely . . . The cloning of mice by scientists in Hawaii.

Now I will read a list of some stories covered by news organizations this past month. As I read each item, tell me if you happened to follow this news story very closely, fairly closely, not too closely, or not at all closely? . . . A religious group [Raëlians] claiming to have successfully cloned a human being.

6. I have a few more questions about some of the news stories that I just mentioned. If you’re not sure of an answer, that’s okay. Just tell me and I’ll go to the next question. . . . As you may know the government recently made a decision about the use of federal funds to do research on stem cells that come from very early human embryos. From what you’ve seen or heard in the news, did they decide to . . . allow scientists to use federal funds for this type of research or continue to ban the use of federal funds for this type of research?

7. Do you personally feel that you have a good basic understanding of the stem cell issue, or don’t you know that much about it?

8. Now, I have a few more questions about some of the news stories that I just mentioned. If you’re not sure of an answer, that’s okay. Just tell me and I’ll go to the next question. . . . You may have seen or heard news reports about the National Institutes of Health releasing a list of stem cell lines eligible for research with federal funding. As far as you know, under President [George W.] Bush’s current policy, will stem cell lines developed in the future be eligible for federal funding for research if they meet certain criteria, or will only those named recently be eligible for federal funding?

9. I have a few more questions about some of the news stories that I just mentioned. If you’re not sure of an answer, that’s okay. Just tell me and I’ll go to the next question. . . . You may have seen or heard news reports about the controversy involving federal funding of stem cell research. From what you may have seen or heard in the news, what is the major reason for this controversy? . . . Human embryos are destroyed in the research process; stem cell research is potentially dangerous to the adult subjects who participate in the research trials; there is not enough money in the federal budget to fund stem cell research.

10. There is a new branch of medicine that uses stem cell therapy to develop new treatments for disease. There are several different kinds of stem cells. What kind of stem cells come to your mind when you think about stem cell therapy?

N ote .—VCU coded open-ended responses into categories.

11. Some people feel that human life begins at the moment of conception. Others feel that human life does not begin until the baby is actually born. Do you, yourself, feel that human life begins at conception, at the time of birth, or at some point in between?

N ote .—NA = not asked.

There is a good deal of discussion these days on when human life begins and ends. Is it your view that life begins at conception or that life begins at birth? Those respondents indicating “somewhere in between” volunteered that specific response.

Do you believe that life begins at conception, or at birth, or somewhere in between, or haven’t you heard enough about that yet to say?

Nationwide sample of 2,406 adults, plus an oversample of 1,177 women. Men and women were weighted to their proper proportion in the population.

Do you believe that life begins at conception, or at birth, or somewhere in between?

12. In your opinion, when does human life begin . . . when a man’s sperm fertilizes a woman’s egg, when an embryo is implanted in a woman’s uterus, when a fetus is viable—that is, is able to survive outside the womb, or at birth?

13a. The kind of stem cell research the government is considering involves human embryos that have been created in medical clinics by fertilizing a woman’s egg outside the womb. An embryo may be implanted into a woman’s womb to develop into a baby. If an embryo is not implanted into a woman’s womb to develop into a baby, it may be destroyed, either by being discarded or by being used for medical research. Some scientists believe this type of medical research could lead to treatments for such diseases as Alzheimer’s, diabetes, heart disease, and spinal cord injuries. . . . Which comes closest to your view of this kind of stem cell research: it is morally wrong and is unnecessary, it is morally wrong but may be necessary, it is not morally wrong and may be necessary, or it is not morally wrong but is unnecessary?

I would like to ask about a specific type of research on stem cells developed from human embryos that have been created outside a woman’s womb. This kind of stem cell research destroys the embryos but may help find treatments for major diseases. As you may know, fertility clinics increase a woman’s chance to have a child by fertilizing several embryos, but only a few are implanted in her womb to enable her to have a baby. Some stem cells are developed from the remaining embryos that the fertility clinics usually discard. Which comes closest to your view of this kind of stem cell research—it is morally wrong and is unnecessary; it is morally wrong but may be necessary, it is not morally wrong and may be necessary, or it is not morally wrong but is unnecessary?

13b. Next, I’m going to read you a list of issues. Regardless of whether or not you think it should be legal, for each one, please tell me whether you personally believe that in general it is morally acceptable or morally wrong. How about . . . medical research using stem cells obtained from human embryos?

14a. Sometimes fertility clinics produce extra fertilized eggs, also called embryos, that are not implanted in a woman’s womb. These extra embryos either are discarded, or couples can donate them for use in medical research called stem cell research. Some people support stem cell research, saying it’s an important way to find treatments for many diseases. Other people oppose stem cell research, saying it’s wrong to use any human embryos for research purposes. What about you? Do you support or oppose stem cell research?

Sometimes fertility clinics produce extra fertilized eggs, also called embryos, that are not implanted in a woman’s womb. These extra embryos either are discarded, or couples can donate them for use in medical research called stem cell research. Some people support stem cell research, saying it’s an important way to find treatments for many diseases. Other people oppose stem cell research, saying it’s wrong to use any human embryos for research purposes. What about you? Do you support or oppose stem cell research?

As you may know, this kind of so-called stem cell research is being used by scientists trying to find cures for diseases such as Alzheimer’s disease, Parkinson’s disease, or diabetes. It involves using destroyed embryos discarded from fertility clinics that no longer need them. Do you favor or oppose using discarded embryos to conduct stem cell research to try to find cures for diseases such as those I mentioned?

14b. On the whole, how much do you favor or oppose medical research that uses stem cells from human embryos—do you strongly favor, somewhat favor, somewhat oppose, or strongly oppose this?

15a. Please tell me if you agree with each of the following statements strongly or somewhat? . . . Scientists should be able to use stem cells obtained from very early human embryos to find cures for serious diseases such as Alzheimer’s and Parkinson’s? Strongly agree, somewhat agree, somewhat disagree, strongly disagree, don’t know/refused.

15b. One of the issues involved in this type of research is whether or not the embryos used were developed specifically for stem cell research. Do you think the federal government should or should not allow scientists to fertilize human eggs specifically for the purpose of creating stem cells? Yes, should allow; no, should not allow; no opinion.

Stem cells come from embryos left over from in vitro fertilization, which are not used and are normally destroyed. Many medical researchers want to use them to develop treatments, or to prevent diseases, such as diabetes, Alzheimers’s, or Parkinson’s disease. On balance, do you think this research should or should not be allowed?

16. As you may already know, a stem cell is the basic cell in the body from which all other cells arise. Medical researchers have been able to isolate stem cells from excess human embryos developed through in vitro fertilization and fetal tissue that has been donated to research. The medical researchers believe that human stem cells can be developed as replacement cells to cure diseases such as diabetes, Parkinson’s, Alzheimer’s, cancer, heart disease, arthritis, burns, or spinal cord problems. Do you favor the funding of stem cell research by the National Institutes of Health?

Stem cells are the basic cells from which all of a person’s tissues and organs develop. Congress is considering whether to provide funding for experiments using stem cells from human embryos. The live embryos would be destroyed in their first week of development to obtain these cells. Do you support or oppose using your federal tax dollars for such experiments?

The federal government supports funding for a variety of medical research. Do you think federal funding for medical research should or should not provide funding for stem cell research?

As you may know, the federal government is considering whether to fund certain kinds of medical research known as “stem cell research.” . . . . . . Do you think the federal government should or should not fund this type of research, or don’t you know enough to say?

The kind of stem cell research the government is considering involves human embryos that have been created in medical clinics by fertilizing a woman’s egg outside the womb. An embryo may be implanted into a woman’s womb to develop into a baby. If an embryo is not implanted into a woman’s womb to develop into a baby, it may be destroyed, either by being discarded or by being used for medical research. Some scientists believe this type of medical research could lead to treatments for such diseases as Alzheimer’s, diabetes, heart disease and spinal cord injuries. . . . Giventhis information, do you think the federal government should or should not fund this type of research?

Based on what you have read or heard, do you think that the federal government should or should not fund stem cell research?

The federal government provides funding to support a variety of medical research. Do you think federal funding for medical research should or should not include funding for stem cell research?

As you may know, the federal government is considering whether to fund certain kinds of medical research known as “stem cell research.” . . . Do you think the federal government should or should not fund this type of research?

I would like to ask about a few specific types of research on stem cells developed from human embryos that have been created outside a woman’s womb. This kind of stem cell research destroys the embryos but may help find treatments for major diseases. . . . As you may know, fertility clinics increase a woman’s chance to have a child by fertilizing several embryos, but only a few are implanted in her womb to enable her to have a baby. Some stem cells are developed from the remaining embryos that the fertility clinics usually discard. Do you think the federal government should or should not fund research on stem cells from this kind of embryo?

Some stem cells may be developed from embryos produced by cloning cells from a living human being rather than by fertilizing a woman’s egg. Do you think the federal government should or should not fund research on stem cells from this kind of embryo?

I would like to ask about a few specific types of research on stem cells developed from human embryos that have been created outside a woman’s womb. This kind of stem cell research destroys the embryos but may help find treatments for major diseases. . . . Some stem cells are developed from embryos that are created in laboratories specifically for the purpose of conducting this research and not to help women have a child. Do you think the federal government should or should not fund research on stem cells from this kind of embryo?

There is another kind of research using stem cells that come just from adults and do not come from embryos at all. The research results in no injury to the person from whom the stem cells are taken. Do you think the federal government should or should not fund research on this kind of stem cells?

Do you think the federal government should or should not fund stem cell research?

17. As you may know, President [George W.] Bush gave a speech tonight [August 9, 2001] on stem cell research, and he announced that he would allow the government to fund research using stem cells that have been created in the past in a process that destroyed human embryos. The government will not fund stem cell research that would destroy additional embryos in the future. . . . Overall, do you approve or disapprove of Bush’s decision on stem cell research?

George W. Bush has said he will allow limited federal funding for research on stem cells taken from human embryos. Given what you know about the issue, do you approve or disapprove of Bush’s decision to allow limited federal funding for embryonic stem cell research?

As you may know, President [George W.] Bush gave a speech Thursday night [August 9, 2001] on stem cell research, and he announced that he would allow the government to fund research using stem cells that have been created in the past in a process that destroyed human embryos. The government will not fund stem cell research that would destroy additional embryos in the future. . . . Overall, do you approve or disapprove of Bush’s decision on stem cell research?

President [George W.] Bush announced that federal funding would be allowed only for research using embryos that have already been destroyed. Scientists can continue to grow and harvest stem cells from those experiments already under way. President Bush also announced that no more embryos could ever be destroyed for future research that uses federal funds. Do you approve or disapprove of President Bush’s decision to allow federal funding of stem cell research already under way using destroyed embryos, but banning any further destruction of embryos for future stem cell research?

18. Now here are a few questions about a different topic—a process called cloning. As you may have read or heard, medical researchers are on the verge of discovering a way to create new embryos, called clones, from a fertile egg. The original embryo and its clones can grow into babies that are identical copies of each other. A cloned embryo can be frozen and put into a mother’s womb for development at any time. Do you approve or disapprove of the use of cloning for each of the following purposes? . . . To make it possible for societies to clone and reproduce large numbers of individuals with genetically desirable traits?

. . . To establish embryo banks from which prospective parents could select a child with genetic characteristics they desire?

. . . To make it possible for parents to have a twin child at a later date, if they want to?

. . . To make it easier for scientists to screen embryos for inherited abnormalities?

. . . To produce babies whose vital organs can be used to save the life of others?

Do you approve or disapprove of the use of cloning for each of the following purposes?. . . To provide infertile couples using test-tube fertilization with more embryos to increase their chances of conceiving?

. . . To make it possible for parents to have a twin at a later date?

Do you think each of the following justifies creating a human clone or don’t you think so?. . . To allow parents who have lost a child to create a clone of the child they lost? Yes, no, not sure.

. . . To produce copies of humans whose vital organs can be used to save the lives of others?

. . . To allow gay couples to have children using on their own genes?

. . . To produce genetically superior human beings?

. . . To allow parents to have a twin child at a later date, if they wanted to?

. . . To help infertile couples to have children without having to adopt?

. . . To save the life of the person who is being cloned?

Do you approve or disapprove of cloning that is designed specifically to result in the birth of a human being?

Do you favor or oppose scientific experimentation on the cloning of human beings?

Do you favor or oppose each of the following? How about. . . cloning that is designed specifically to result in the birth of a human being?

19a. If it becomes possible, do you think the cloning of humans should or should not be allowed?

Do you think scientists should be allowed to clone human beings, or don’t you think so?

If it becomes possible, do you think the cloning of humans should or should not be allowed?

Do you think scientists should be allowed or should not be allowed to try to clone human beings?

19b. Scientists have cloned animals, using basic genetic material from one animal to produce an offspring with the exact genetic makeup. . . . Scientists say it’s also possible to clone humans, using basic genetic material from one person to produce a child with the exact same genetic makeup. Do you think it should be legal or illegal to clone humans in the United States?

Some scientists want to use human cloning for medical treatments only. They would produce a fertilized egg, or human embryo, that’s an exact genetic copy of a person, and then take cells from this embryo to provide medical treatments for that person. Supporters say this could lead to medical breakthroughs. Opponents say it could lead to the creation of a cloned person because someone could take an embryo that was cloned for medical treatments and use it to produce a child. Do you think human cloning for medical treatments should be legal or illegal in the United States?

Do you think that cloning that is designed specifically to result in the birth of a human being should be legal or illegal in the United States?

20a. Do you favor or oppose an outright ban on the cloning of human beings?

20b. Would you favor or oppose a law that would prohibit the cloning of human beings?

Would you favor or oppose a law that would prohibit the cloning of human beings, or are you unsure?

21. Do you approve or disapprove of cloning that is not designed specifically to result in the birth of a human being, but is designed to aid medical research that might find treatments for certain diseases?

Do you approve or disapprove of each of the following? . . . cloning of human organs or body parts that can then be used in medical transplants?

How about . . . cloning of human cells from adults for use in medical research?

How about . . . cloning of human embryos for use in medical research?

Do you favor or oppose using human cloning technology if it is used only to help medical research develop new treatments for disease-do you strongly favor (21 percent), somewhat favor (24 percent), somewhat oppose (13 percent), or strongly oppose (38 percent) this? In the table the response categories are collapsed.

22. As you may know, Congress is considering several proposals to ban human cloning. Which of the following positions do you most agree with—human cloning should not be banned; only human cloning that leads to the birth of a human should be banned, but cloning for purposes of laboratory research should be allowed; or all human cloning should be banned?

Which of these statements comes closest to your view on human cloning? I support a complete ban on all research into human cloning without exception. I support a ban on human cloning that would still allow research on cloned embryos to learn more about diseases. I oppose any law that restricts research into human cloning.

Two other polls during this time period included alternative measures of awareness. A July 1997 ABC News poll queried respondents with “I want to ask about some specific areas of science. For each, please tell me if you are very interested in news about that subject, somewhat interested, somewhat uninterested, or very uninterested. . . . Cloning.” In this case, 18 percent indicated they were very interested, 33 percent somewhat interested, 20 percent somewhat uninterested, and 28 percent very uninterested ( N = 505). A January 1998 CBS News poll asked respondents, “How much have you heard or read about the successful cloning last year by Scottish scientists of a sheep named Dolly? Have you heard or read a lot, some, not much, or nothing at all?” In response to this poll question, 24 percent indicated a lot, 46 percent some, 16 percent not too closely, and 14 percent not at all closely.

Cmiel , Kenneth . 2001 . “The President’s Textual Relations.” New York Times , Aug. 19, p. 14.

Dewar , Helen . 2002 . “Anti-Cloning Bills Stall in Senate; Vote Unlikely Soon.” Washington Post , June 14, p. A4.

Grady , Denise , and Robert Pear. 2002 . “Claim of Human Cloning Provokes Harsh Criticism.” New York Times , Dec. 29, p. 18.

Johnson , Judith A. 2001 . Stem Cell Research: CRS Report for Congress, August 10 . Washington, DC: Congressional Research Service.

Miller , John D. , and Linda Kimmel. 2001 . Biomedical Communications: Purposes, Audiences, and Strategies . New York: Academic Press.

National Bioethics Advisory Committee (NBAC). 1999 . Ethical Issues in Human Stem Cell Research . Vol. 1. Rockville, MD: NBAC.

Nerlich , Brigette , and David D. Clarke. 2003 . “Anatomy of a Media Event: How Arguments Clashed in the 2001 Human Cloning Debate.” New Genetics and Society 22 : 43 –59.

Nisbet , Matthew C. 2003 . “The Controversy over Stem Cell Research and Medical Cloning: Media, Policy, and Public Opinion” Ph.D. dissertation, Cornell University.

Nisbet , Matthew C. , Dominique Brossard, and Adrianne Kroepsch. 2003 . “Framing Science: The Stem Cell Controversy in an Age of Press/Politics.” Harvard International Journal of Press/Politics (8)2 : 36 –70.

President’s Council on Bioethics. 2002 . Human Cloning and Human Dignity . New York: Public Affairs.

Rowley , Janet D. , Elizabeth Blackburn, Michael S. Gazzaniga, and Daniel W. Foster. 2002 . “Harmful Moratorium on Stem Cell Research.” Science 297 : 1957 .

Shanahan , James , Dietram A. Scheufele, and Eungjung Lee. 2001 . “The Polls—Trends: Attitudes about Agricultural Biotechnology and Genetically Modified Organisms.” Public Opinion Quarterly 65 : 267 –81.

Singer , Eleanor , Amy Corning, and Mark Lamias. 1998 . “The Polls—Trends: Genetic Testing, Engineering, and Therapy.” Public Opinion Quarterly 62 : 633 –64.

Stolberg , Sheryl G. 2002 . “States Pursue Cloning Laws as Congress Debates.” New York Times , May 26, p. 1 .

Weiss , Rick . 2002 . “Hatch to Support Bill Allowing Stem Cell Study; Decision on Embryo Cloning Is a Setback for Conservatives.” Washington Post , May 1, p. A2 .

Weiss , Rick , and Juliet Elperin. 2001 . “House Votes Broad Ban on Cloning.” Washington Post , August 1, p. A1 .

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The Invisible Patient: Concerns about Donor Exploitation in Stem Cell Research

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• Published: 25 November 2022
• Volume 30 , pages 240–253, ( 2022 )

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• Pär Segerdahl   ORCID: orcid.org/0000-0003-3892-1537 1  

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As embryonic stem cell research is commercialized, the stem cell debate may shift focus from concerns about embryo destruction to concerns about exploitation of the women who donate eggs and embryos for research. Uncomfortable with the polarization of the embryo debate, this paper proposes a more “contemplative” approach than intellectual debate to concerns about exploitation. After examining pitfalls of rigid intellectual positions on exploitation, the paper investigates the possibility of a broader understanding of donation for research where patients are seen as the intended beneficiaries of the donation. Together with other actors, research is perceived as mediating altruistic gift relationships that extend from donors to patients. The paper explores how this broader perspective on “donation for research” can open up new possibilities of understanding donation and addressing risks of exploitation.

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Introduction

Debates about the ethical permissibility of embryonic stem cell research almost exclusively focus on the moral status of the embryo. However, the research also has another sensitive aspect. Since it relies on a supply of fresh ova and frozen embryos, and since commercial interests increasingly are interwoven with the research, worries about exploitation need to be seriously considered. But are they? In an article entitled, “The lady vanishes,” Donna L. Dickenson [ 1 ] called attention to a missing debate, addressing the role of women in the stem cell technologies:

In most public discussion of the ethical issues in stem cell research, only the status of the embryo seems to count. Yet because ova are crucial to stem cell research, there are also important regulatory issues concerning protection of women from whom ova are taken … In most cases and debates, the women from whom the ova are taken have virtually disappeared from view. [1: 43]

More recently, Søren Holm noticed how “arguments relating to the interests of embryo and gamete donors are curiously absent from the particular stem cell banking policy discourse” [ 2 : 265]. He also issued a warning to the field of embryonic stem cell work:

Although some in the stem cell field see themselves as outside of the sphere of reproduction and reproductive policy, it is not obvious that society sees it that way. A lack of proper attention to the rights and interests of embryo and gamete donors in relation to stem cell derivation may over time undermine policy support for the field. [ 2 : 275]

One could wonder why donor interests and risks of exploitation do not figure prominently in policy discussions on embryonic stem cell research. It may, I surmise, partly be due to a fear that concerns about donor exploitation could trigger an equally polarized debate as the concerns about embryo destruction did. With the debate about whether embryo destruction is murder in fresh memory, some in the stem cell field may fear a second polarized debate, this time about whether women are exploited in the stem cell industries. If Holm is right, however, sweeping such concerns under the rug may in the long run prove counterproductive. And unethical, one could add.

In this paper, I suggest that a second polarized stem cell debate is not improbable; that concerns about exploitation of donors need to be voiced rather than silenced; and finally, that bioethics needs to approach these concerns more cautiously and “contemplatively” than in debates for and against doctrines. A contemplative approach to an issue as serious as exploitation can itself seem provocative, of course, because the openness of such an approach could seem to imply openness to exploitation. However, that is why patience and caution are needed. We are considering sensitive normative notions like murder and exploitation, which can be contested in their application to embryonic stem cell research. We need to be aware of how these concepts provide quite worrying images of research practices, and that this property of the images risks preventing an open discussion about the applicability of the concepts. The discussion in this paper is therefore not based on any specific definition of exploitation and will not propose one, but focuses on this general difficulty in concepts that have both descriptive and evaluative aspects. Later in the paper, an attempt in the literature to define exploitation to fit egg donation for research will be examined from this point of view.

Intellectual Dangers of Thick Ethical Concepts

Bernard Williams [ 3 ] distinguished between thick ethical concepts such as “brave” and “brutal,” which have both descriptive and evaluative aspects, and thin ethical concepts such as “right” and “wrong,” which are purely evaluative and action-guiding. “Murder” and “exploitation” can be understood as thick ethical concepts. They have a descriptive aspect combined with a strong negative evaluative action-guiding aspect.

Although the two aspects cannot be separated, this duality of thick ethical concepts, their descriptive-normative Janus face, makes them useful for ideological purposes. If you oppose X, and can demonstrate that X, in fact , involves murder or exploitation (descriptive aspect), then you immediately seem to have demonstrated that X must be condemned (normative aspect). Thick ethical concepts have been used in conflicts to legitimize actions against people who were described as unreliable, greedy, exploitative and even murderous. Since the words are assumed to describe reality, the applicability of the concepts seems to justify us to both condemn and take action against these people.

In relation to the use of thick ethical concepts for ideological purposes, I want to mention three common intellectual dangers or temptations of such concepts.

Dogmatism: The first is that it can be difficult to raise questions about the applicability of such concepts, since it might seem as if you questioned their evaluative aspect. Let us say that you raise the question if embryo destruction is really murder. In the eyes of those who take this description for reality, you can appear like someone who does not take the negative evaluative aspect of the concept seriously. Just asking the question may seem suspicious. The very openness of the question already seems to speak against it and can evoke reactions such as: “Murder is not something to be open-minded about!”

Righteousness: A second troublesome feature is that thick ethical concepts easily produce a good self-image for any ideological movement. Any ideology is on the right side, regardless of which side it is on, since it strives for what its moral vocabulary unites with the good, and opposes what its vocabulary unites with the bad. Any ideology seems to have right and duty to act against what its thick moral vocabulary picks out as blameworthy features of reality.

Moral anxiety: A third problem is that thick ethical concepts can produce anxiety in the form of gnawing suspicions and fears. Most of us are not familiar with embryonic stem cell research, we do not know for sure what it is. Thick ethical concepts can then act as a substitute for what we do not know. They appear in the form of an inner voice that tells us what stem cell research is . This is not a purely descriptive “ is ,” but a double-edged one, for what the voice in the head says the research is could be a frightening, “It is murder.” Since we are ignorant of much, but not of our anxiety, we cannot shake off the thick ethical concepts that have begun to spin in our heads. They seem validated by the anxiety they produce, which is real, and we worry endlessly, caught in a whirlpool of thick descriptive-normative moral language and fear.

In pointing out these dangers of thick ethical concepts, I am not questioning their important functions in our language. It is difficult to imagine human life without these concepts. I am just pointing out how the dual nature of thick ethical concepts can sometimes lock our perspective on reality and make debates on important issues uncompromising. I think many of us have experienced getting caught up in such “thick” descriptions of reality.

Precisely because concerns about donor exploitation deserve careful attention, we need to be aware of the intellectual dangers of thick ethical concepts. The word “exploitation” easily puts us in a state of emergency and can trigger reactions as if we were facing an imminent threat. And that is our difficulty. The investigation is motivated by a concept that simultaneously threatens to short-circuit the investigation.

A Second stem cell war?

Although Dickenson [ 1 ] makes very important observations on a missing issue in the stem cell debate, she does not seem to particularly emphasize the problems surrounding its sometimes almost war-like nature. On the contrary, the metaphor is used to emphasize the importance of another front line:

What unites the two warring sides in “the stem cell wars” is that women are equally invisible in both: “the lady vanishes.” Yet the most legitimate property in the body is that which women possess in their reproductive tissue and the products of their reproductive labour. [1: 43]

I agree, of course, that concerns about women’s status as donors are at least as important as concerns about the status of the embryo and should be highlighted in the discussion about stem cell research. The question I want to raise in this paper is whether these concerns are best addressed by what could be described as a second stem cell war, where the spirit might sometimes be one of using “whatever weapons are available to us” [1: 53]?

Already the first debate, about the embryo, polarized debaters and exhibited tendencies towards dogmatism, righteousness, and moral anxiety [ 4 ]. My question is therefore whether the discussion of concerns about donor exploitation risks becoming a second stem cell war that reproduces similar problematic tendencies. Consider this way of initiating debate about exploitation in stem cell research, by Heather Widdows:

This article will argue that as practices qua practices, both trafficking for prostitution and egg donation for research are exploitive and thus should not be endorsed by feminists. Moreover, the failure to name such practices as exploitive serves to normalize and extend them, thus leading to the exploitation of more women. [ 5 : 6]

There are cases of “egg donation for research” that are alarmingly similar to trafficking for prostitution, as we shall soon see, and Widdows’ concerns are therefore important. Placing trafficking for prostitution next to egg donation for research, however, as if both were uniform practices that are exploitive “ qua practices,” mirrors a tendency in the embryo debate to place murder next to embryo destruction. When an obviously questionable practice is placed next to a practice that you want to debate, the obviously questionable practice easily becomes a model for what the debated practice inherently is like. Such a model can of course be illuminative, but it can also dominate the arguments that are meant to support the similarity between the compared practices. The difference between the practices must therefore also be noticed, as it is the reason why they are placed next to each other. The obviously questionable practice is needed to expose the not so obviously questionable practice. But the claimed similarity between the practices often remains unclear. The similarity then relies on a steady supply of philosophical arguments, which will be questioned, which will be defended, and the debate continues. Footnote 1

Widdows begins her article by discussing trafficking for prostitution, and then she turns to egg donation for research. Here, a second not entirely obvious comparison seems to be made, in that egg donation for research is exemplified by egg donation for research fraud. The story of how a Korean researcher, Hwang Woo-Suk, obtained large numbers of human eggs by coercing young female team members to “donate” eggs to him, and by illegally buying human eggs for his research, serves in the article as a paradigmatic example of “the practice of egg donation for research.”

These not entirely obvious connections between practices give rise to a question. How can trafficking for prostitution, and research fraud, be used as illuminating comparisons when we discuss the intrinsic nature of “the practice of egg donation for research”? What can make these comparisons seem plausible?

My proposal is that the thick ethical concept of exploitation is influencing the investigation into what egg donation for research is. Since the practice of egg donation for research is argued to be exploitive, it seems close at hand to illuminate what egg donation is by connecting it to trafficking for prostitution, and to illegal and coerced egg “donation” for research fraud. The latter practices seem to show more clearly what egg donation for research is , even if at first it did not seem obvious.

Debaters who argue philosophically what embryo destruction or egg donation are , sometimes emphasize what they see as these practices’ morally problematic aspects by using words like “intrinsically” and “inherently.” Combining essentialist vocabulary with thick ethical concepts can, paradoxically, make it sound as if a debatable case such as egg donation for research, by being “inherently exploitive,” or “exploitive qua practice,” was even more exploitive than the obvious cases. Essentialist words can make such a strong impression on us that we fail to see that it is the other way around. We do not say that the assassination of John F. Kennedy was inherently murder; it was murder. We do not say that slavery is intrinsically exploitive; slavery is exploitive. By emphasizing indisputability, the use of essentialist words often inadvertently reveals that the cases are debatable.

The legitimacy of the comparisons that Widdows makes between different practices depends on whether she can argue convincingly that egg donation for research is exploitive as a practice. Why? Because “exploitation” is the conceptual thread that allegedly runs through the different practices and makes it legitimate to place them next to each other. However, the search for a definition of exploitation that can work in the argument already seems to be guided by the need to describe the compared practices as exploitative. Unsatisfied with the fact that Marx’s notion of exploitation does not seem to work for this purpose, Widdows writes:

It is important to retain the elements of power, coercion, and subordination in any definition of exploitation, so that we rightfully can include cases such as Hwang’s junior female researchers. A definition of exploitation that focuses only on disparity of remuneration misses the example out. Particularly for feminists, this caveat is crucial. [ 5 : 20]

The aim with developing a thick ethical concept of exploitation, then, appears to be to enable us to identify exploitation when we see egg donation for research . A definition of exploitation is required that describes egg donation for research and justifies condemning it. The feature that in the end is deemed crucial seems to be gender subordination of women. Just as women’s choice in prostitution is exercised under systematic limitations, since men’s rights over their bodies are systematically privileged, “the need for women’s eggs in the stem cell technologies was simply taken for granted, as if medical research, too, enjoyed systematically privileged access to women’s bodies” [ 5 : 20]. This is proposed to explain also why exploitation of women in the stem cell technologies never was debated academically. I agree, of course, that such an important concern must be addressed. Here I only examine the possibilities of such a discussion and point out certain dangers of thick ethical concepts.

Does an account of exploitation in terms of gender subordination legitimize the connections drawn between trafficking for prostitution, Hwang’s research fraud, and the practice of egg donation for research? It seems to do so, if we view Hwang’s research fraud as a plausible example of egg donation for research. But his exploitation of female team members is a plausible example of “the practice of egg donation for research” only if we already view egg donation for research as inherently exploitive, or exploitive qua practice.

It seems to me that we are caught in a vicious circle of thick ethical concepts and essentialist vocabulary. Without an overview of what egg donation for research is or can become – it varies across legislations and is still in the making – the thick ethical account of exploitation seems to inform us that egg donation for research is exploitative qua practice and that condemning it is the right thing to do.

Concerns about exploitation of women who donate to stem cell research must be addressed. I hope the above considerations indicate the need for a more “contemplative” approach to these concerns, one that is open to differences between practices and to possibilities of change. Otherwise, we are easily exposed to the dangers of thick ethical concepts, which seem to be able to determine what we do not know for sure but need to discuss openly. I doubt that we can say what the practice of egg donation for research is, in definite singular form. The discussion probably needs to start in that uncertainty.

The Invisible Patient

Let me confess my own ignorance. When I hear of egg and embryo donation for research, I take for granted an IVF context and a strict regulation. I do not immediately think of research fraud. Neither do I think of an unregulated egg market in the US, or about poor women in different parts of the world who undergo hormonal treatment and surgery to offer their eggs at underprice, to get some much needed extra money. In other words, when I hear of egg donation for research, I admit that I tend to overlook some rather clear cases of exploitation, which are at the forefront of the articles just cited, and which, of course, need to be addressed.

Nevertheless, my ignorance of certain practices of donation is not completely out of touch with reality. It is in touch with some practices of donation, which are not as obviously exploitive as those of which I am more ignorant. And even if also regulated IVF practices could be exploitive, may we not be able to modify them to counteract the risks? By not talking about “ the practice of egg donation for research,” and by not construing it conceptually as inherently exploitive, we can become more open to the possibility that some present or future practices could be ethically better examples of egg donation for research than Hwang’s research fraud. But are such practices of donation, more worthy of imitation, possible at all? I now turn to this question.

I repeat, we assume an IVF context and strict regulation and control. The woman undergoes hormonal treatment for the purpose of producing eggs to be artificially fertilized and reinplanted in her body, hopefully resulting in one or more longed-for children. In connection with the IVF treatment, the woman is asked if she is willing to donate surplus eggs, or embryos, to some specified embryonic stem cell study. She is informed also that research results may, at some point, be commercialized.

Even after pregnancy, surplus eggs and embryos can continue to be of immense importance to the woman. Not only because she may need them in the future, but also because they are such intimately significant parts of her body. They can become her children. This presents us with a puzzling problem. Why would anyone be willing to donate such sensitive “reproductive tissue” to researchers who wish to develop new stem cell technologies? Especially if the researchers state that they plan to develop medical products from the tissue and offer these products on a market? It can almost sound as if donors voluntarily agreed to be exploited.

To understand the possibility of a willingness among some women undergoing IVF treatment to donate such sensitive parts of their bodies to a research institution, or to “the stem cell technologies,” I believe we need to bring in a figure that so far has been invisible: the patient.

In the critical accounts of egg donation considered above, there is no mention of the fact that the new “stem cell technologies” are meant to function as treatments for future patients. If patients are mentioned, in passing, as in Waldby and Cooper [ 6 : 5, 16], the potential benefits of regenerative medicine are described as “highly speculative” and as “fantasy,” as if patients were practically irrelevant to the field of stem cell research. Legally, the recipient of the donation is some research institution, of course, with its connections to industry and commercial activities. This conglomerate will potentially derive huge economic and other benefits from women’s donations, making the relationship between donor and recipient appear suspiciously unequal, even exploitive. Why would women want to give away reproductive tissue to support research institutions and entrepreneurs? Is it because, as women, they are expected to sacrifice their wellbeing for the wellbeing of others?

A plausible answer, I think, is that the more humanly intended beneficiary of the donation often is the hitherto invisible patient. Egg and embryo donation for research can make a puzzling impression if we leave the patient outside of our field of view. Of course, the donor may consider medical research important and worth supporting, even if it does not benefit any patient. However, we should not overlook the fact that medical research as a whole is related to the treatment of patients, and that even basic research and negative results are important in this broader context. That is why I want to broaden our field of vision, so that we can see the possibility that the legal recipient of the donation mediates gift relationships that extend further; a possibility which can make the donation look different than we first suspected – less asymmetric and puzzling. Of course, the “gift” is not always free for the patient, but it can at least become available to many patients, and even availability can be considered a gift (“gift” is not used here in opposition to “for a fee”; cf. how works of art can be considered as gifts to humanity even though museums charge and books have price tags). In other healthcare systems, the gift would be free, and that is enough for my purposes, which are about seeing possibilities when our way of thinking prevents us from seeing them.

The Intermediating Function of Research and Industry

One could suspect that I bring in the patient only to speak to common normative expectations that women should sacrifice themselves for the needs of others, and that I thereby support the exploitation of women as analyzed by Widdows in terms of gender subordination. My problem, however, is more about our way of looking at donation for research, our difficulty of understanding it, if we do not view medical research in a wider perspective. Altruistic blood donation is easy to understand from a human point of view because the recipient is a needy fellow being, a patient. But how can we understand altruistic donation to a research institution?

Donation for medical research can seem puzzling in the absence of the patient. That is why I bring in the patient who disappeared in the moral concerns that egg donation for research might be exploitive. So, once again, I am not arguing that women undergoing IVF have a care duty to support stem cell research because it will benefit patients in need, or that a donation would be appropriate to reciprocate the gift of IVF treatment. I am only considering the broader context in which a free will to give seems less puzzling or suspicious. What intermediates such a gift relationship from donor to patient, when the direct recipient of the donation is a research institution?

Perhaps a simile explains how we, often without being aware of it, rely on intermediaries who, in their turn, depend on us. It is common knowledge that our digestive tract contains roughly one kilogram of bacteria, without which many of the nutritive substances in the food we eat could not become available to us and our bodies. When we swallow the food, these bacteria are the first eaters, and we have to wait patiently until they have eaten. Even if we know this to be a fact, we do not consciously think that we swallow food to allow microorganisms in our bellies to eat first. We eat for various reasons, but usually unaware of the intermediating function of bacteria.

I suggest that we can look at research and industry as intermediators of gifts from donors to patients. I hope I do not appear condescending if I propose that researchers and entrepreneurs are the societal bacteria that are needed to make the donation available to the patient’s body. We may dislike the idea that our stomachs are full of bacteria, or we may dislike technocrats and capitalists. Still, we rely on bacteria, technocrats, and capitalists. Considered in this wider perspective, who is exploiting whom?

I am proposing a broader way of looking at donation for research that can make it look less puzzling. The proposal is that when someone freely supports medical research by donating tissue, it may be due to some level of awareness of the intermediating function of medical research. (This does not exclude other possibilities, e.g., in systems where the donation gives the woman better conditions for IVF treatment [ 7 ].) The contribution to research will, in the end, hopefully be a contribution to patients. Few, however, are clearly aware of the fact that virtually every successful medical treatment that research contributed to developing was finalized and made available to patients by the pharmaceutical industry. There are so many layers of interdependency at work, when we consider donation for medical research in a larger context. Even generally disliked layers are needed and play at least partially beneficiary roles within the system as a whole. Research alone cannot intermediate altruistic gift relationships from donors to patients. There has to be an industry too, and a healthcare system, and much else. Moreover, just as the proper functioning of bacteria in our digestive tract needs regulation in the form of a diet that supports the right balance of beneficial bacteria, the system of intermediation from donor to patient needs to be regulated and supervised, so that the interdependent actors function harmoniously together. We do not want a system where quacks are free to sell dangerous and ineffective substances to people who are ill, or where stem cell researchers obtain human eggs in any way they see fit. We are surveying a whole society that allows donors to give to patients, if they want, by donating “for research.”

Egg donation for research turns out to be more difficult to isolate as a separate practice than we first thought. Donation depends on a vast system of interdependencies, comparable to what needs to happen in concert in our bodies when we think that we are simply eating. Our concepts do not reflect all of these dependencies, on which they rely for their daily use. This is true not only of “eating,” but also of “donating for research,” and of most concepts. They are simpler than the interdependent realities and relationships that underpin their ordinary use. Having these easily neglected interdependencies in clear view, it becomes surprisingly difficult to isolate separate actors; to see who actually eats first and who eats last; to see who truly is superior and who is subordinate; to see who in fact is benefitting and who the real benefactor is.

The fact that our concepts are simpler than the interdependencies which their daily communicative use presuppose is not a shortcoming. It creates problems only when we expect that the concepts reflect all the relevant facts and relationships. Egg donation for research is a good example. Linguistically and legally such donation is, of course, “donation for research,” donation to some research institution. This is not denied. If this conceptually highlighted relationship is seen as the whole of the donation, however, donation for research can look puzzling and even suspicious “as a practice.” We fail to see the possibility that donating to a research institution can be like handing over a parcel to the post-office clerk. The immediate recipient, the research institution, although conceptually highlighted, can drop off as relatively uninteresting for the donor. We can see this possibility, although the concept represents the research institution (or “the stem cell industries”) as the only recipient.

Having seen that the concept of “donation for research” does not reflect what can make the donation meaningful for the donor – the patient – moral concerns about risks of exploitation in the stem cell technologies transform accordingly. The donation is no longer seen as a transaction between obviously unequal parties, since it is possible for the donor to merely use the direct recipient to give to someone else. Perhaps without being fully aware of it, the donor uses not only research, but a whole system of mutually dependent actors and institutions, such as industry, healthcare, regulation, and governmental supervision. This system can therefore, unexpectedly, be seen as subordinate to the needs of donors who wish to give to patients. Or, this subordination is at least an aspect of the relationship, like the subordination of bacteria with regard to human eating. We can always see the opposite aspect as well, if we want to, since we are considering interdependencies.

Let us sum up, before we move on. In the accounts of egg donation discussed above, the donating woman seems obviously subordinate to the recipient, the research institution, with its connections to “the stem cell technologies.” In that conceptual framework, where the patient is unseen, risks of exploitation appear almost a priori . Another way of looking at donation, however, is to see research, in conjunction with a whole system of interdependent actors, as intermediating gift relationships from donors to patients. The fact that this intermediation engages a multi-billion dollar conglomerate raises reasonable concerns, of course. If these concerns are discussed openly, and the practice is regulated and works within proper bounds, however, there is a possibility that the intermediating system can be made as irrelevant to donors as bacteria in our stomachs are to diners. This possibility does not rule out risks of exploitation, but the risks no longer appear a priori , as in the narrower conceptual framework mentioned above. My hope is that by broadening our view to include the patient, we will be able to discuss relevant risks of exploitation while dealing with the intellectual dangers of the thick ethical concept of exploitation.

Risks of Exploitation when the Humanly Intended Recipient is the Patient

As I mentioned in the introduction, instead of developing a conceptual analysis of exploitation, as in Zwolinski and Wertheimer [ 8 ], this paper describes general intellectual dangers that the word “exploitation” shares with many other thick ethical concepts, especially when the conceptual framework within which we think does not embrace all the relevant features of the practice that we are discussing. Having seen how concerns about exploitation can sometimes be a product of our conceptual framework, which emphasizes the direct recipient of the donation, I now want to exemplify some concerns that a broader view of donation for medical research may raise. Given the self-reflective nature of what I call a “contemplative” approach, I will only suggest four hypothetical cases, and only as an exercise in seeing possibilities that can emerge when we are no longer dominated by a limited conceptual framework.

One risk of exploitation could be well-intentioned attempts to counteract intellectually projected risks of exploitation by paying women for their “reproductive services” to the stem cell technologies, or by giving them a share of future profits. That could establish a tight relationship with the wrong other party, at least if we look at the matter from the broader perspective proposed here. I do not claim that paying for services inevitably means exploitation, but such frameworks invite concerns. Payment accentuates the donating woman’s relationship to a relatively powerful other party, “the stem cell technologies,” which can make exploitation a constant issue. Moreover, since the patient is hidden in such frameworks, such an attempt to counteract risks of exploitation makes practice of the limited conceptual framework that probably projects the concerns from the beginning. However, if the transaction is with the IVF clinic, some women may view donation rationally to be in their own interest, as in an empirical study by Haimes et al. [7: 1211]: “For the interviewees, exchanging eggs for more treatment and therefore for a greater chance of having a baby is a reasonable thing to do.” There are many possibilities.

Another risk of exploitation has to do with the gender differences that Dickenson and Widdows mention. To support an altruistic will to give, a patient perspective may be emphasized. Given normative expectations on women to devote themselves to the needs of others, such a perspective can be a delicate matter to handle. Caution is required to avoid exaggerating patient needs to such an extent that not donating appears unfeeling. Another related risk is presenting the donation as a gift in return for IVF treatment. If an individual freely donates in gratefulness for IVF treatment, this may be alright in the individual case. Framing egg or embryo donation in terms of reciprocation, however, can make the donation seem expected rather than free. Given the normative expectations mentioned above, both an overemphasized patient perspective and a perspective of reciprocation could coerce donation.

After these two possible concerns about exploitation – economization and “sentimentalization” of donation – I want to mention two concerns that donors themselves might have. The first has to do with the fact there are forms of egg donation worldwide that clearly do seem exploitive. Women who donate eggs or embryos in the course of undergoing IVF treatment may worry that their donation goes to institutions that exploit women in other circumstances, perhaps in other parts of the world. Could their free donation support exploitation of less fortunate women? However, these concerns, if addressed openly, could put pressure on research and industry to take a more global responsibility for what could one day, perhaps, deserve to be called, in definite singular form, “the practice of egg donation for research.”

Another possible concern that donors may have is the following. If women (or couples) donate with the patient in mind, they can worry that research and industry will fail to honor the altruistic spirit in which they gave to research. Some actors in the system that makes the donation available to patients may prioritize interests that interfere with the intermediating role that the donor more or less consciously expected. Stem cell treatments will in many cases not be made available to the most needing patients’ bodies, for example, because companies do not believe it is in their shareholders’ economic interest. Let me repeat here what I said earlier, that even accessibility can be considered a gift, that treatment in some healthcare systems is free, and that an open discussion of concerns can change practices. All I want to do here is help us see possibilities when a dominating conceptual framework prevents us from seeing them.

This brief exercise in seeing possible moral concerns can appear inconclusive for regulatory discussions about egg and embryo donation for stem cell research. My aims here, however, are preparatory. I want to counteract a second polarized stem cell debate and to demonstrate a more self-reflective and “contemplative” approach to concerns about exploitation, where we examine also possible intellectual dangers in our own concepts of donation and exploitation. Achieving these aims meant surveying relationships that are presupposed rather than expressed by the concept of “donation for research.” I would like to support regulatory discussions about donation for research that can navigate the conceptual dangers that so easily polarize debates. I would also like to suggest that such broader discussions could consider protecting gift relationships that extend beyond research, through commercialization, all the way to future patients and to future healthcare opportunities.

Protecting Human gift Relationships

This concluding section indicates human functions that altruistic donation for research can have, and which regulators could view as important to support. In a paper entitled, “Gifts of the Body and the Needs of Strangers,” Thomas H. Murray argues that “impersonal gifts acknowledge an entire realm of moral relationships and moral obligations wider than intimate, family ones, and wider still than legal, contractual ones” [ 9 : 35]. If Murray is right and impersonal gifts acknowledge larger dimensions of life, then regulatory discussions about donation for stem cell research could benefit from not putting all the emphasis on individual rights and interests. Individual rights and interests are very important if the sole intended receiver of the donation is the comparatively powerful direct recipient. If donation for research is made with future patients in mind, however, regulation could aim also towards maintaining some buffering distance between donors and direct recipients. Regulation could strive to ensure that intermediators function so harmoniously together that donors need not worry too much about them, but can confidently donate with the patient in mind. This could be an overall aim of regulation: to support a free will to give to unknown others by protecting gift relationships that extend from donors to future patients.

Murray’s paper focused on blood donation where it is relatively easy to see patients as the recipients of the donation. Egg and embryo donation for stem cell research is more complex, partly because the donation is literally “for research,” and partly because so many conjoined scientific, industrial, governmental, and other intermediating efforts are required to make the donation available to the bodies of future patients. If we do not consider the intermediating function of research and industry, and how the literal features of the concept of “donation for research” can obstruct seeing this function, we could be tempted to conclude that

…the claims of the gift relation are destabilized by the fact that donors to stem cell research give not to a fellow citizen [as in blood donation] but to an increasingly capitalized life science sector, which depends more and more transparently on the generally unremunerated labour of the donor. [ 6 : 13]

To avoid that this conceptually tempting view of “donation for research” becomes true, a possibility emerging from the broader outlook of this paper is that regulation could deliberately aim towards protecting donation for research that has patients in mind. Such regulation could enable the complexity of altruistic donation “for research” to illuminate, rather than obscure, how interdependent we are as donors, researchers, funders, industrialists, regulators, authority representatives, healthcare professionals, and patients. It could help us see what our concepts presuppose rather than express literally. I am not thinking of slogans such as, “Together we create better futures for diabetes patients,” which would overemphasize the patient perspective and could act as a form of coercion, as we saw above. I am thinking of well-regulated practices of donation as opportunities for people to cultivate large-mindedness and to acknowledge unselfishness as a human possibility. This implies that several parts of the regulation need to be considered together: not only those parts that deal specifically with donation for research, but also parts dealing with patentability, with biobanks in academic research and industry, with biomedical products, and much else.

In conclusion, it is noteworthy that “literal” views on egg donation “for research” tend to construe relationships in such a manner that donors appear to be the passive party while the recipients are the active ones. Instead of creating such passive donors vis-à-vis powerful recipients, regulation could support active donors to safely exercise altruistic donation with future patients in mind, through a well-regulated intermediary system. By seeing human gift relationships as streams moving through the intermediary system, transporting biotechnologically modified tissue from human to human, donation for research can “remind us that wealth is merely a means to an end, and that not all valuable things can be purchased”[ 9 : 35]. I am not suggesting, of course, that regulation should define patients rather than research institutions as the legal recipients of the donations. However, regulatory discussions can be sensitive to perspectives that are larger than the regulation itself, and this can leave imprints on the regulation. We are envisioning a whole society that allows donors to give to patients, if they want to, by “donating for research.”

Widdows’ use of the example of trafficking for prostitution is more complex, in that it is a rather obvious case of exploitation that nonetheless has been questioned by feminists who fear to appear paternalistic (another thick ethical concept). Widdows’ view is that these feminists fail to identify exploitation when they see it. What is compared, then, are two cases of (allegedly, equally clearly) failing to condemn exploitation of women.

Dickenson, D. L. (2006). The lady vanishes: what’s missing from the stem cell debate. Bioethical Inquiry , 3 , 43–54. https://doi.org/10.1007/s11673-006-9003-8 .

Article   Google Scholar  

Holm, S. (2015). Biobanking human embryonic stem cell lines: policy, ethics and efficiency. Monash Bioethical Review , 33 , 265–276. https://doi.org/10.1007/s40592-015-0050-y .

Williams, B. (1985). Ethics and the limits of philosophy . London: Fontana Press.

Google Scholar  

Segerdahl, P. (2022). Debating embryonic stem cell research: handling moral concerns more gently. In Ethical inquiries after Wittgenstein, eds. Ondrej Beran, Salla Aldrin Salskov and Nora Hämäläinen. Springer, pages 173-188. https://doi.org/10.1007/978-3-030-98084-9_11 .

Widdows, H. (2009). Border disputes across bodies: exploitation in trafficking for prostitution and egg sale for stem cell research. International Journal of Feminist Approaches to Bioethics , 2 (1), 5–24. https://www.jstor.org/stable/40339192 .

Waldby, C., & Cooper, M. (2010). From reproductive work to regenerative labour: the female body and the stem cell industries. Feminist Theory , 11 (1), 3–22. https://doi.org/10.1177/1464700109355210 .

Haimes, E., Taylor, K., & Turkmendag, I. (2012). Eggs, ethics and exploitation? Investigating women’s experiences of an egg sharing scheme. Sociology of Health & Illness , 34 (8), 1199–1214. https://doi.org/10.1111/j.1467-9566.2012.01467.x .

Zwolinski, M., & Wertheimer, A. (2017). Exploitation. In E. N. Zalta (Ed), The Stanford encyclopedia of philosophy (summer 2017 edition). Retrieved September 11, 2019, from https://plato.stanford.edu/archives/sum2017/entries/exploitation/

Murray, T. H. (1987). Gifts of the body and the needs of strangers. The Hastings Center Report , 17 (2), 30–38. https://doi.org/10.2307/3562041 .

Article   CAS   Google Scholar  

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Acknowledgements

I wish to thank seminar participants at the Centre for Research Ethics and Bioethics at Uppsala University for helpful comments on drafts of the paper. I would also like to thank the two reviewers, whose comments helped me improve the paper both in terms of content and style.

This study was funded by the Swedish Research Council (grant number 2016–02888).

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Segerdahl, P. The Invisible Patient: Concerns about Donor Exploitation in Stem Cell Research. Health Care Anal 30 , 240–253 (2022). https://doi.org/10.1007/s10728-022-00448-2

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Stem Cell Research Controversy: A Deep Dive (2023)

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Navigating the stem cell research controversy requires a deep dive into ethical considerations and conflicting viewpoints. This article aims to dissect the moral complexities and stakeholder perspectives shaping this ongoing debate.

Stem Cell Research Controversy

The controversy surrounding stem cell research primarily stems from ethical and political concerns. One of the main issues is the derivation of pluripotent stem cell lines from oocytes and embryos, which raises disputes about the onset of human personhood. The use of human embryonic stem cells (hESCs) is particularly contentious, as it involves the destruction of embryos, leading to debates over the moral status of human embryos.

Induced pluripotent stem cells (iPSCs), which are derived from reprogramming somatic cells, avoid some of the ethical problems specific to embryonic stem cell research. However, other dilemmas arise in stem cell research, such as sensitive downstream research, consent to donate materials for stem cell research, early clinical trials of stem cell therapies, and oversight of stem cell research.

There is a need to refocus the debate on stem cell research beyond the controversy over embryo destruction and address other ethical and policy issues to ensure that stem cell research is carried out in an ethically appropriate manner .

Arguments for Stem Cell Research

• Medical potential : Stem cells have the potential to revolutionize medicine by offering treatments for various diseases and conditions, such as Parkinson's disease, Alzheimer's disease, spinal cord injuries, and diabetes. They can differentiate into various cell types, which can help in tissue repair and regeneration.
• Scientific advancement : Stem cell research can contribute to a better understanding of human development and cellular processes, which can lead to new insights into disease mechanisms and potential therapies.
• Economic benefits : Investment in stem cell research can lead to the development of new therapies and medical technologies, which can create jobs, stimulate economic growth, and reduce healthcare costs in the long run.
• Utilization of unused embryos : In the case of embryonic stem cell research, many argue that using embryos leftover from in vitro fertilization (IVF) treatments, which would otherwise be discarded, is a better alternative than letting them go to waste.

Arguments Against Stem Cell Research

• Ethical concerns : The primary argument against stem cell research, particularly embryonic stem cell research, is the moral and ethical concerns surrounding the destruction of human embryos. Opponents argue that embryos have the potential for human life and should be protected.
• Alternative methods : Some argue that alternative methods, such as induced pluripotent stem cells (iPSCs) and adult stem cells, should be pursued instead of embryonic stem cells, as they do not involve the destruction of embryos and can avoid some of the ethical issues.
• Consent and exploitation : There are concerns about the informed consent process for obtaining embryos or other biological materials for stem cell research. Some worry that vulnerable populations may be exploited or coerced into donating materials.
• Safety and efficacy : Critics argue that the safety and efficacy of stem cell therapies are not yet well-established, and there is a risk of unintended consequences, such as tumor formation or immune rejection.

Different Types of Stem Cells Used in Research

There are several types of stem cells used in research, each with unique properties and potential applications. Some of the most commonly used stem cell types include:

• Embryonic Stem Cells (ESCs) : These pluripotent stem cells are derived from the inner cell mass of blastocysts during early embryonic development. They have the ability to differentiate into all cell types of the body and have been widely used in research for understanding human development and disease mechanisms
• Induced Pluripotent Stem Cells (iPSCs) : iPSCs are generated by reprogramming adult somatic cells, such as skin or blood cells, into a pluripotent state. They share many properties with ESCs, including the ability to differentiate into various cell types, but avoid some of the ethical concerns associated with embryonic stem cell research
• Adult Stem Cells : These are multipotent stem cells found in various tissues throughout the body, such as bone marrow, adipose tissue, and dental pulp. They have a more limited differentiation potential compared to pluripotent stem cells but are still widely used in research and clinical applications due to their accessibility and lower ethical concerns
• Mesenchymal Stem Cells (MSCs) : MSCs are a type of adult stem cell that can be isolated from various tissues, including bone marrow, adipose tissue, and umbilical cord. They have the ability to differentiate into various cell types, such as bone, cartilage, and fat cells, and have been widely used in regenerative medicine and tissue engineering
• Amniotic Epithelial Stem Cells (hAESCs) : These stem cells are derived from the amniotic membrane of the human placenta. They possess stem-cell-like plasticity, immune-privilege, and paracrine properties, making them a promising cell source for cellular therapy and clinical applications
• Organoids : Organoids are three-dimensional in vitro culturing models that originate from self-organizing stem cells and can mimic the in vivo structural and functional specificities of body organs. They have been established from multiple adult tissues as well as pluripotent stem cells and have recently become a powerful tool for studying development and diseases in vitro, drug screening, and host–microbe interaction

Each of these stem cell types has its own advantages and limitations, and researchers continue to explore their potential applications in various fields, including regenerative medicine, disease modeling, and drug discovery.

Understanding Stem Cells

Stem cells are undifferentiated cells with the potential to develop into specialized cell types, contribute to tissue repair and regeneration, and support normal growth and development. They have the remarkable ability to self-renew and differentiate into various cell lineages within the body. Stem cells play a crucial role in embryonic development and tissue homeostasis throughout an individual's life.

The Nature and Function of Stem Cells

Stem cells possess two unique characteristics: self-renewal and pluripotency. Self-renewal refers to the ability of stem cells to replicate themselves indefinitely, ensuring a constant supply of undifferentiated cells. Pluripotency, on the other hand, describes the potential of stem cells to differentiate into any cell type within the body, including those of the three germ layers: endoderm, mesoderm, and ectoderm.

The function of stem cells in the body depends on their type and location. Embryonic stem cells, derived from the inner cell mass of early-stage embryos, contribute to the development of an entire organism. Adult stem cells, also known as tissue-specific or somatic stem cells, are found in specific organs or tissues and play a role in tissue repair and regeneration.

Different Types of Stem Cells

Stem cells are broadly categorized into three main types: embryonic stem cells, adult stem cells, and induced pluripotent stem cells. Each type possesses distinct characteristics and potential applications in scientific research and medical treatments.

Embryonic stem cells (ESCs) are derived from embryos at the blastocyst stage, typically obtained from in vitro fertilization clinics. These ESCs are pluripotent and can differentiate into any cell type in the body. Their capacity to self-renew and differentiate makes them valuable tools for studying embryonic development and potential therapeutic applications.

Adult stem cells (ASCs) exist within various organs and tissues throughout the body. These cells are multipotent, meaning they have the ability to differentiate into a limited number of cell types within their tissue of origin. ASCs act as a repair system, replenishing damaged cells and helping to maintain tissue homeostasis.

Induced pluripotent stem cells (iPSCs) are generated by reprogramming adult cells, typically skin or blood cells, to a pluripotent state using specific genetic factors. iPSCs possess similar characteristics to embryonic stem cells and have the potential to differentiate into various cell types. They offer an ethical alternative to ESCs and hold promise for personalized medicine and disease modeling.

The Science and Potential of Stem Cell Research

Stem cell research has witnessed significant advances and has the potential to revolutionize medicine. The unique properties of stem cells make them valuable resources for studying cellular development, disease mechanisms, and potential therapeutic interventions. Stem cell-based therapies hold promise for treating a wide range of diseases and injuries, including neurodegenerative disorders, cardiovascular diseases, diabetes, and spinal cord injuries.

Stem cells can be manipulated and directed to differentiate into specific cell types, providing potential sources for cell replacement therapies. By replacing damaged or dysfunctional cells with healthy ones derived from stem cells, researchers aim to restore tissue function and improve patients' quality of life. Moreover, stem cells can serve as powerful tools for drug testing and disease modeling, accelerating the development of new therapies and the advancement of personalized medicine.

Despite the immense potential of stem cell research, it remains a topic of extensive debate and controversy.

Historical Background of Stem Cell Research

Early discoveries and research in stem cells.

Stem cell research has a storied history, with early discoveries dating back to the late 19th century. In 1868, German biologist Ernst Haeckel proposed the term "stem cell" to describe the ancestral cells giving rise to all other cell types. However, it wasn't until the mid-20th century that significant breakthroughs were made in understanding the nature and potential of stem cells.

In 1961, Canadian researchers Ernest McCulloch and James Till demonstrated the existence of stem cells in the bone marrow capable of reconstituting blood cells. This groundbreaking discovery laid the foundation for the study of adult stem cells and their therapeutic potential. Subsequent advancements in technology and techniques, such as flow cytometry and genetic engineering, led to further insights into stem cell biology.

Milestones and Achievements in Stem Cell Study

Over the years, numerous milestones have shaped the field of stem cell research. In 1998, James Thomson and his team at the University of Wisconsin-Madison successfully isolated and cultured human embryonic stem cells for the first time. This breakthrough opened new avenues for studying human development and regenerative medicine.

In 2006, Shinya Yamanaka and Kazutoshi Takahashi developed a groundbreaking technique to reprogram adult cells into induced pluripotent stem cells (iPSCs), earning them the Nobel Prize in Physiology or Medicine in 2012. iPSCs offered an ethical alternative to embryonic stem cells and contributed to advancements in disease modeling and personalized medicine.

Additionally, advancements in tissue engineering and organ transplantation have shown promising results. Scientists have successfully grown functional organs, such as heart tissue, kidney tissue, and liver tissue, from stem cells. These achievements provide hope for treating organ failure and revolutionizing transplantation therapies.

Shift in Public and Scientific Interest Towards Stem Cell Research

The field of stem cell research has gained considerable attention, both from the scientific community and the public. The potential therapeutic implications of stem cells have sparked excitement and hope for finding cures for currently incurable diseases. Governments and research institutions worldwide have recognized the significance of stem cell research, leading to increased funding and support for further studies in this field.

Public interest in stem cell research has been largely driven by the potential to address major health challenges, such as neurodegenerative diseases, heart disease, and spinal cord injuries. The media, along with prominent figures in the scientific and medical communities, have played a crucial role in highlighting the possibilities and successes of stem cell research. However, this increased visibility has also given rise to controversies and ethical dilemmas surrounding the use of stem cells.

The Promise of Stem Cell Research

Potential applications in medicine.

Stem cell research exhibits promising potential for addressing numerous medical conditions that currently lack effective treatments. By harnessing the regenerative capabilities of stem cells, researchers seek to develop therapies that can restore or replace damaged cells and tissues.

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, pose significant challenges to public health worldwide. Stem cells offer a potential avenue for developing treatments that can halt or reverse the degenerative processes occurring in the brain. By replacing lost or damaged neurons with new ones derived from stem cells, researchers aim to restore cognitive function and improve the quality of life for affected individuals.

Cardiovascular diseases, including heart failure and myocardial infarction, remain leading causes of death globally. Stem cell-based therapies have shown promise in regenerating damaged cardiac tissue and improving heart function. Transplantation of stem cell-derived cardiomyocytes or the stimulation of endogenous cardiac stem cells holds potential for restoring normal heart function and reducing the need for heart transplantation.

Stem cells also offer hope for treating spinal cord injuries, diabetes, and other debilitating conditions. Continued research and innovations in stem cell-based therapies have the potential to transform the future of medicine by providing novel approaches to previously untreatable diseases.

Stem Cells and Regenerative Therapy

Regenerative medicine represents a cutting-edge approach to treating and possibly curing diseases by replacing or regenerating damaged or dysfunctional tissues and organs. Stem cells, with their ability to differentiate into various cell types, are crucial components of regenerative therapies.

Tissue engineering, a field within regenerative medicine, combines stem cells, biomaterials, and growth factors to construct functional tissues and organs. By seeding stem cells onto biocompatible scaffolds and providing appropriate environmental cues, scientists aim to create artificial tissues that can be transplanted into patients in need.

For instance, researchers have made progress in creating laboratory-grown skin grafts for burn victims, thereby providing a potential alternative to currently limited donor supply. Similarly, the development of bioengineered organs, such as kidneys and livers, holds promise for addressing the critical shortage of organ donors and improving patient outcomes in transplantation.

Regenerative therapy, leveraging the potential of stem cells and tissue engineering, offers a novel and promising approach for overcoming the limitations of traditional treatments and addressing the unmet clinical needs of patients.

Stem Cells in Drug Testing and Disease Modeling

Stem cells have emerged as invaluable tools in drug discovery and disease modeling, enabling scientists to better understand the mechanisms of diseases and develop more effective treatments. Traditional drug discovery methods often rely on animal models or cell lines that may not accurately represent human physiology. Stem cells, particularly iPSCs, provide an alternative and more biologically relevant platform for testing potential therapeutics.

By differentiating iPSCs into disease-specific cell types, scientists can study the molecular and cellular mechanisms underlying various diseases in a controlled laboratory setting. This approach allows for personalized medicine, tailoring treatments to a patient's specific disease characteristics. Additionally, iPSC-based disease modeling enables the testing of potential therapeutics in a human context, potentially reducing the time and cost associated with traditional drug development.

Moreover, using iPSCs derived from patients with genetic diseases, scientists can investigate the disease progression, identify pathological mechanisms, and explore potential therapeutic interventions. This personalized approach has the potential to revolutionize the treatment of genetic disorders and improve patient outcomes.

Stem cell-based disease modeling and drug testing have the potential to accelerate the development of new treatments and provide safer and more effective therapies for various diseases.

Controversies Surrounding Stem Cell Research

Cultural and religious opposition to stem cell research.

Stem cell research has faced substantial opposition from various cultural and religious groups around the world. The controversies stem from differing beliefs regarding the beginnings of life, the moral status of the embryo, and the ethical implications of manipulating human cells.

Some religious groups, particularly those with pro-life perspectives, consider the destruction of embryos during the process of obtaining embryonic stem cells as morally wrong and akin to taking a human life. These groups argue that life begins at conception, and any research involving the destruction of embryos violates their deeply held values.

Additionally, cultural beliefs and traditions may contribute to the opposition. Stem cell research, particularly when it involves embryos, can challenge cultural norms and beliefs related to the sanctity of life and the role of science in manipulating natural processes. These cultural considerations must be taken into account when discussing the ethical implications of stem cell research.

Ethical Issues in Obtaining Stem Cells

One of the primary ethical concerns surrounding stem cell research lies in the process of obtaining stem cells, particularly embryonic stem cells. These cells are typically derived from surplus embryos donated by couples undergoing in vitro fertilization (IVF) procedures. The ethical dilemma arises from the destruction of these embryos to obtain the stem cells.

Critics argue that using embryos for research involves the destruction of potential human life, raising concerns about the sanctity and value of early human life. This issue becomes particularly contentious when considering the potential development of human clones for research purposes or creating embryos solely for the purpose of research.

Balancing the potential benefits of stem cell research with the ethical concerns regarding the status of the embryo remains a challenging and unresolved issue. Public discourse and policymaking play a crucial role in navigating the ethical landscape surrounding stem cell research.

Unproven and Hyped Stem Cell Treatments

The rapid advancement of stem cell research has led to the emergence of unproven and hyped stem cell treatments being offered to patients. These treatments promise miraculous cures for various diseases and conditions without rigorous scientific evidence to support their claims. Such clinics often operate outside of established regulatory frameworks and exploit the hopes and vulnerabilities of desperate patients.

The lack of scientific rigor and long-term safety and efficacy data surrounding these treatments raises significant ethical concerns. Patients seeking relief may unknowingly subject themselves to potential harm or financial exploitation by pursuing unproven stem cell therapies. Robust regulation and transparency are essential to ensuring patient safety and preserving the integrity of stem cell research.

The Ethical Dilemma

Destruction of human embryos for research.

A central ethical concern in stem cell research revolves around the destruction of human embryos to obtain embryonic stem cells. This practice raises questions about the moral status and rights of the embryo and whether it should be afforded the same protections as a fully formed human being.

Opponents argue that the early-stage embryo possesses intrinsic value and should be treated as a developing human life. They contend that destroying embryos for research purposes constitutes a violation of the fundamental sanctity of human life and should be strictly prohibited.

Proponents, on the other hand, emphasize the potential benefits of stem cell research in advancing medical knowledge and finding cures for debilitating diseases. They argue that the moral status of the embryo is not equivalent to that of a fully formed human being, and the potential benefits of stem cell research justify the destruction of embryos.

Resolving this ethical dilemma requires careful consideration of the scientific advancements and potential benefits of stem cell research, as well as engagement with diverse perspectives and ethical frameworks.

Potential for Human Cloning

The prospect of human cloning, although not directly related to stem cell research, raises significant ethical concerns within the broader stem cell discourse. The ability to derive embryonic stem cells from cloned human embryos, a technique known as somatic cell nuclear transfer (SCNT), raises profound questions about the nature of human identity and the manipulation of life.

Human cloning for reproductive purposes, often referred to as reproductive cloning, is widely recognized as ethically unacceptable due to the ethical and safety concerns it raises. However, the potential for therapeutic cloning to generate patient-specific embryonic stem cells for personalized medicine remains a subject of intense debate.

The ethical challenges raised by therapeutic cloning relate to concerns about the commodification of human life, the potential for reproductive cloning to be pursued clandestinely, and the potential for exploitation of vulnerable populations. Strict regulation and international consensus are necessary to navigate these ethical complexities and strike a balance between scientific progress and ethical boundaries.

Exploitation of Women for Egg Donation

Another ethical concern arises from the reliance on egg donation for certain types of stem cell research, such as SCNT. The process of extracting eggs from women carries potential risks, including physical discomfort and psychological implications. Moreover, the compensation and recruitment practices surrounding egg donation raise concerns about the exploitation of women, particularly those from disadvantaged backgrounds.

Egg donors may not always fully understand the long-term consequences and potential risks associated with the procedure. Additionally, the financial incentives offered to donors can create situations where women are driven by financial need to undergo potentially risky procedures.

Ensuring the protection and well-being of egg donors requires robust regulations, transparency, and informed consent processes. It is essential to strike a balance between advancing scientific knowledge and protecting the rights and well-being of women involved in stem cell research.

Legal and Regulatory Perspective

Laws and regulations governing stem cell research worldwide.

Countries vary in their legal and regulatory frameworks governing stem cell research. Some nations have embraced stem cell research and established comprehensive regulatory frameworks, while others have implemented stricter restrictions or outright bans on certain types of stem cell research.

In the United States, for example, the legal landscape surrounding stem cell research is complex and varies at the federal and state levels. The use of federal funds for research involving human embryonic stem cells is subject to stringent regulations, including limitations on the sources and approval process of embryonic stem cell lines.

In contrast, countries such as the United Kingdom and Sweden have adopted permissive regulatory environments that have facilitated significant advancements in stem cell research. These countries have established well-defined frameworks for obtaining and using embryonic stem cells, allowing for responsible research while addressing ethical concerns.

International collaboration and consensus-building are essential in formulating ethical guidelines and regulating stem cell research worldwide. The sharing of best practices and harmonization of regulations can foster responsible and ethical research practices while allowing scientific progress to thrive.

Controversial Court Rulings and Its Implications

The legality and regulation of stem cell research have been shaped by notable court rulings in various jurisdictions. These court decisions interpret and establish legal precedents that influence the ethical landscape surrounding stem cell research.

In 1996, the U.S. Congress passed the Dickey-Wicker Amendment, which prohibited the use of federal funds for research involving the creation, destruction, or purposeful injury to human embryos. This restriction was subsequently contested, leading to significant legal battles and court rulings.

In 2013, the U.S. Supreme Court declined to hear a case challenging the legality of federal funding for embryonic stem cell research, effectively allowing the National Institutes of Health (NIH) to continue funding such research. This decision provided clarity and allowed for the continuation of federally funded research in the United States.

While court rulings have helped shape the regulatory landscape, they also demonstrate the ongoing dynamic nature of the stem cell research controversy. The legal implications of these decisions impact not only researchers and institutions but also public perception and funding opportunities.

Role of Government and Policymakers in the Controversy

Government bodies and policymakers play a crucial role in shaping the ethical framework and guiding the direction of stem cell research. Their decisions and policies have the potential to significantly impact scientific progress, patient access to therapies, and the direction of funding.

Governments can support stem cell research by investing in research initiatives, establishing regulatory frameworks that balance scientific potential with ethical considerations, and encouraging collaboration between researchers, industry, and healthcare providers. They can also prioritize public education and engagement to foster a better understanding of the science and ethics of stem cell research.

Moreover, policymakers must navigate the differing ethical perspectives and cultural values surrounding stem cell research. Balancing the interests and concerns of various stakeholders while ensuring evidence-based decision-making is essential for promoting responsible and ethically sound research practices.

Alternative Approaches to Stem Cells

Adult stem cell research.

While embryonic stem cells have garnered significant attention, adult stem cells also play a vital role in regenerative medicine and scientific research. Adult stem cells are found in various tissues and organs throughout the body, supporting tissue homeostasis and repair.

Unlike embryonic stem cells, adult stem cells are multipotent, meaning they can differentiate into a limited number of cell types specific to their tissue of origin. However, recent research has challenged this long-held belief, suggesting that adult stem cells may possess broader differentiation potential than previously thought.

Harnessing the potential of adult stem cells offers several advantages, such as avoiding the ethical concerns associated with embryonic stem cells and ensuring a source of cells autologous to the patient. Adult stem cells can be obtained from patients' own tissues, eliminating the risk of rejection or graft-versus-host disease.

Advancements in techniques to isolate, expand, and manipulate adult stem cells have allowed for their potential use in regenerative therapies. This approach holds promise for treating conditions such as bone marrow transplantation, cartilage repair, and corneal regeneration, among others.

Induced Pluripotent Stem Cells

The development of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and Kazutoshi Takahashi in 2006 revolutionized stem cell research. iPSCs are generated by reprogramming adult cells, typically skin or blood cells, to a pluripotent state using specific genetic factors.

Induced pluripotent stem cells possess similar characteristics to embryonic stem cells, such as self-renewal and pluripotency. iPSCs offer an ethical alternative to embryonic stem cells, as they do not require the destruction of embryos.

iPSC technology has opened new avenues for disease modeling, personalized medicine, and drug testing. By obtaining iPSCs from patients with specific genetic diseases, researchers can study the underlying cellular and molecular mechanisms of these diseases and develop personalized therapeutic approaches. iPSCs also provide valuable platforms for drug discovery and toxicology testing, offering a more predictive model for human response than traditional approaches.

However, challenges remain in fully harnessing the potential of iPSCs, such as improving the efficiency and safety of the reprogramming process and resolving issues related to genetic stability and tumorigenicity.

Amniotic Stem Cells and Other Non-Embryonic Sources

In addition to embryonic and adult stem cells, various other sources of stem cells have been identified and explored for their potential therapeutic applications. One such source is amniotic fluid, which surrounds and protects the developing fetus during pregnancy.

Amniotic fluid contains a population of stem cells known as amniotic stem cells. These cells possess multipotency and can differentiate into various cell lineages, including muscle, bone, cartilage, and nerve cells. Amniotic stem cells hold promise for regenerative medicine applications and have demonstrated potential in tissue repair and regeneration.

Other non-embryonic sources of stem cells include umbilical cord blood, umbilical cord tissue, and dental pulp. Umbilical cord blood is a rich source of hematopoietic stem cells, which can be used in the treatment of blood disorders and as an alternative to bone marrow transplantation. Umbilical cord tissue is a valuable source of mesenchymal stem cells, which have the potential to differentiate into a variety of cell types. Dental pulp, found within teeth, also contains a population of mesenchymal stem cells with regenerative potential.

Further research is needed to fully understand the characteristics and therapeutic potential of these alternative sources of stem cells. Expanding the repertoire of available stem cell sources can broaden the scope of regenerative medicine and offer additional options for patients.

Public Opinion and Debate

Variations in public opinion across different demographics.

Public opinion on stem cell research varies significantly depending on demographic characteristics, cultural beliefs, and exposure to information. Opinion polls have highlighted variations in attitudes towards stem cell research across different countries and regions.

Several factors influence public opinion, including religious beliefs, education level, socioeconomic status, and personal experiences with diseases or conditions that could potentially benefit from stem cell-based therapies. Additionally, the framing of the stem cell debate by media, advocacy groups, and political entities can sway public opinion.

Religion plays a significant role in shaping public attitudes towards stem cell research. Conservative religious groups tend to oppose embryonic stem cell research due to their beliefs about the sanctity of human life and the moral status of embryos. In contrast, more liberal religious groups or those with less emphasis on pro-life perspectives may be more accepting of stem cell research.

Education and knowledge about stem cells and their potential applications can also influence public opinion. Individuals with a greater understanding of the science and the ethical nuances of stem cell research tend to have more informed and nuanced viewpoints.

Factors Influencing Public Perception

Media plays a crucial role in shaping public perception of stem cell research. Media coverage can both educate and influence public opinion. The accessibility and clarity of information presented by the media can significantly impact how the public understands and engages with the stem cell discourse.

The media has the power to highlight the scientific advancements and potential benefits of stem cell research, fostering public support and enthusiasm. However, sensationalist reporting or the amplification of unproven stem cell therapies can contribute to misunderstanding and skepticism.

Advocacy groups and political entities also play a role in shaping public perception. These groups may have vested interests in promoting or opposing certain aspects of stem cell research, framing the narrative to support their positions. Public engagement efforts should strive to provide balanced and evidence-based information, empowering individuals to form informed opinions.

The Role of Media in Shaping the Stem Cell Discourse

Media has a pivotal role in shaping public discourse and influencing policy decisions related to stem cell research. It serves as a bridge between the scientific community, policymakers, and the general public. The responsibility of the media lies in accurately and ethically reporting on scientific developments and their implications.

Effective science communication is crucial in ensuring accurate understanding and interpretation of stem cell research by the public. Journalists and science communicators must strive for clarity and balance in their reporting, avoiding sensationalism or oversimplification. Providing context, accurate information, and diverse perspectives can foster an informed public discourse that benefits society as a whole.

The media should also be proactive in dispelling misconceptions and addressing ethical concerns surrounding stem cell research. By accurately portraying the state of scientific knowledge and engaging in meaningful dialogue with experts, policymakers, and the public, the media can contribute to a more informed and nuanced understanding of the complex ethical issues surrounding stem cell research.

The Future of Stem Cell Research

Predicted advancements and breakthroughs.

The field of stem cell research holds immense potential for future advancements and breakthroughs. Ongoing research efforts and technological innovations are expected to broaden our understanding of stem cell biology and expand their therapeutic applications.

Advancements in stem cell biology, including the identification of novel stem cell populations and the elucidation of signaling pathways controlling stem cell self-renewal and differentiation, will contribute to refining existing protocols and developing new approaches in regenerative medicine. These advancements will enable researchers to enhance the efficiency and safety of stem cell-based therapies.

Moreover, the integration of stem cell research with other areas of science, such as gene editing and tissue engineering, will further propel the field forward. Advanced gene-editing techniques, such as CRISPR-Cas9, have the potential to precisely modify stem cells, enabling the correction of genetic abnormalities and enhancing their therapeutic potential.

Recent breakthroughs in organoid technology, which involves growing miniaturized versions of functional organs, have paved the way for more sophisticated disease modeling and drug testing. Combining organoid technology with stem cell research holds promise for improving our understanding of disease mechanisms and developing personalized treatment strategies.

Potential Challenges and Roadblocks

While the future of stem cell research is promising, several challenges and roadblocks must be addressed to realize its full potential. Some of the key challenges include:

• Safety and efficacy: Ensuring the safety and efficacy of stem cell-based therapies remains a significant challenge. Long-term studies and clinical trials are needed to establish the safety profile and therapeutic efficacy of stem cell treatments.
• Standardization and quality control: Developing standardized protocols and quality control measures is crucial for the translation of stem cell research into clinical applications. Consistency in cell culture techniques, characterization, and manufacturing processes are necessary to ensure reproducibility and reliability.
• Scalability and cost-effectiveness: Stem cell-based therapies must be scalable and cost-effective to be widely accessible. Techniques for large-scale expansion and differentiation of stem cells need to be refined, while reducing the cost and complexity of manufacturing processes.
• Ethical and regulatory considerations: The ethical dilemmas surrounding stem cell research require ongoing dialogue and the formulation of robust regulatory frameworks. Striking a balance between scientific progress and ethical concerns is essential to establish guidelines that maintain public trust and ensure responsible research practices.

Responsibility of the Scientific Community Moving Forward

The scientific community has a responsibility to navigate the complex ethical and societal issues surrounding stem cell research. Open and transparent communication, engagement with diverse stakeholders, and adherence to rigorous scientific standards are crucial in building public trust and advancing the field responsibly.

Scientists must continue to prioritize integrity, rigor, and reproducibility in their research practices. Collaboration and data sharing within the scientific community can expedite advancements, enhance scientific understanding, and facilitate responsible progress.

Additionally, scientists should actively engage in public dialogue and education, ensuring that accurate and evidence-based information about stem cells and their potential applications reaches the public. By addressing public concerns, clarifying misconceptions, and fostering understanding, scientists can bridge the gap between scientific research and public perception.

Ultimately, responsible stem cell research requires ongoing ethical reflection, continuous assessment of emerging technologies, and a commitment to ethical standards. By embracing these responsibilities, the scientific community can unlock the full potential of stem cells while navigating the ethical complexities that surround this field.

Balancing Science and Ethics

Finding a middle ground in the ethical controversy.

The ethical controversy surrounding stem cell research necessitates the search for a middle ground that balances scientific progress with moral considerations. Open dialogue and collaboration between scientists, policymakers, ethicists, and the public are vital to finding common ground and developing ethical guidelines.

The middle ground lies in recognizing and respecting diverse perspectives while prioritizing evidence-based decision-making. Ethical debates should be informed by scientific principles, societal values, and the potential benefits and risks associated with stem cell research.

Engaging in ethical deliberation, considering alternative viewpoints, and finding areas of consensus can lead to the development of responsible research practices. Respect for autonomy, informed consent, and safeguarding human dignity should serve as guiding principles in determining the boundaries and regulations of stem cell research.

The Role of Education and Awareness in Resolving Ethical Issues

Education and awareness play a crucial role in resolving the ethical issues surrounding stem cell research. Public outreach, science communication, and interdisciplinary collaboration are essential in ensuring an informed and engaged public.

Educational initiatives should strive to provide accurate, accessible, and unbiased information about stem cells, their potential applications, and the ethical dilemmas associated with their use. Incorporating stem cell research and its ethical implications into school curricula can foster an understanding and appreciation of this rapidly evolving field among students.

Furthermore, healthcare providers have a responsibility to inform patients about the state of stem cell research, available treatment options, and potential risks and benefits. Empowering patients to make informed decisions and fostering open and honest discussions about stem cell-based therapies can avoid exploitation and promote responsible usage.

Ways to Advance Stem Cell Research While Addressing Ethical Concerns

Advancing stem cell research while addressing ethical concerns requires a multidimensional approach. The following strategies can promote responsible research practices and facilitate the progress of stem cell research:

• International collaboration: Encouraging international collaboration and sharing best practices can enable the development of robust regulatory frameworks that harmonize ethical standards and facilitate responsible research.
• Ethical review boards: Establishing independent ethical review boards can provide guidance, oversight, and ensure compliance with ethical guidelines. These boards play a critical role in evaluating the ethical implications of proposed research studies involving stem cells and ensuring the protection of participants and human dignity.
• Public engagement and dialogue: Facilitating public engagement and dialogue can foster understanding, address misconceptions, and build trust. Researchers, policymakers, and ethicists should actively involve the public in the decision-making process, taking into account diverse perspectives and ethical considerations.
• Long-term monitoring and evaluation: Continuous monitoring and evaluation of stem cell-based therapies are essential to assess long-term safety and efficacy. Robust post-marketing surveillance and data collection can provide valuable insights and inform future research endeavors.
• Responsible media reporting: Media organizations should strive to report accurately and responsibly on stem cell research, providing balanced and evidence-based information. Promoting media literacy and encouraging critical evaluation of media coverage can empower individuals to navigate the stem cell discourse effectively.

By implementing these strategies and fostering a culture of responsible research and ethical reflection, it is possible to advance stem cell research while addressing ethical concerns. This delicate balance between scientific progress and ethical considerations ensures that the potential benefits of stem cell research are realized in an ethically responsible manner.

By: Louis A. Cona, MD

Medical Director | DVC Stem

Louis A. Cona, MD has been a pioneer in regenerative cell therapy, providing his first stem cell studies over a decade ago. He continues to research alternative therapies with IRB-certified clinical trials in Grand Cayman.

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Study documents safety, improvements from stem cell therapy after spinal cord injury

by Mayo Clinic

A Mayo Clinic study shows stem cells derived from patients' own fat are safe and may improve sensation and movement after traumatic spinal cord injuries. The findings from the Phase I clinical trial appear in Nature Communications . The results of this early research offer insights into the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited.

In the study of 10 adults, the research team noted seven participants demonstrated improvements based on the American Spinal Injury Association (ASIA) Impairment Scale. Improvements included increased sensation when tested with pinprick and light touch, increased strength in muscle motor groups, and recovery of voluntary anal contraction, which aids in bowel function.

The scale has five levels, ranging from complete loss of function to normal function. The seven participants who improved each moved up at least one level on the ASIA scale. Three patients in the study had no response, meaning they did not improve but did not get worse.

"This study documents the safety and potential benefit of stem cells and regenerative medicine," says Mohamad Bydon, M.D., a Mayo Clinic neurosurgeon and first author of the study.

"Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients."

No serious adverse events were reported after stem cell treatment. The most commonly reported side effects were headache and musculoskeletal pain that resolved with over-the-counter treatment.

In addition to evaluating safety, this Phase I clinical trial had a secondary outcome of assessing changes in motor and sensory function. The authors note that motor and sensory results are to be interpreted with caution given limits of Phase I trials. Additional research is underway among a larger group of participants to further assess risks and benefits.

The full data on the 10 patients follows a 2019 case report that highlighted the experience of the first study participant who demonstrated significant improvement in motor and sensory function.

Stem cells' mechanism of action not fully understood

In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

Participants' stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients' lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

Although it is understood that stem cells move toward areas of inflammation—in this case the location of the spinal cord injury—the cells' mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says.

As part of the study, researchers analyzed changes in participants' MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury.

One unexpected outcome of the trial was that two patients with cervical spine injuries of the neck received stem cells 22 months after their injuries and improved one level on the ASIA scale after treatment. Two of three patients with complete injuries of the thoracic spine—meaning they had no feeling or movement below their injury between the base of the neck and mid-back—moved up two ASIA levels after treatment.

Each regained some sensation and some control of movement below the level of injury. Based on researchers' understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

"In spinal cord injury, even a mild improvement can make a significant difference in that patient's quality of life," Dr. Bydon says.

Research continues into stem cells for spinal cord injuries

Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to the World Health Organization .

An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells .

"For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy," Dr. Bydon says.

"Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients."

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• Published: 01 January 2001

Human embryonic stem cell research: ethical and legal issues

• John A. Robertson 1 , 2  

Nature Reviews Genetics volume  2 ,  pages 74–78 ( 2001 ) Cite this article

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The use of human embryonic stem cells to replace damaged cells and tissues promises future hope for the treatment of many diseases. However, many countries now face complex ethical and legal questions as a result of the research needed to develop these cell-replacement therapies. The challenge that must be met is how to permit research on human embryonic tissue to occur while maintaining respect for human life generally.

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Thomson, J. A. et al . Embryonic stem cell lines derived from human blastocysts. Science 282 , 1145–1147 ( 1998).

Article   CAS   PubMed   Google Scholar  

Shamblott, M. J. et al . Derivation of pluripotent stem cells from cultured human primoridial germ cell. Proc. Natl Acad. Sci. USA 95 , 13726–13731 (1998).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Reubinoff, B. E., Pera, M. F., Fong, C. -Y., Trounson, A. & Bongso, A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro . Nature Biotechnol. 18 , 399–404 ( 2000).

Article   CAS   Google Scholar  

Andrews, L. State regulation of embryo research, (National Institutes of Health, Papers Commissioned for the Human Embryo Research Panel, Vol. II 1994).

Public Law No. 105–277, 112 Stat. 2681 ( 1998).

National Institutes of Health. National Institute of Health Guidelines for Research using Human Pluripotent Stem Cells. Federal Register 65 FR 51976–51981 (2000).

Department of Health. Stem Cell Research: Medical Progress with Responsibility A report from the chief medical officer's expert group reviewing the potential of developments in stem cell research and cell nuclear replacement to benefit human health (London, June, 2000).

France: Law No. 94-654 No. 175. 11060–11068 (Journal officiel de la République française, Lois et Decret, 30 July 1994).

Germany: Law of 13 December 1990 for the protection of embryos (the Embryo Protection Law), (Bundesgestetzblatt, Part I, 2746–2748, 19 December 1990).

The Infertility Treatment Act 1995 (Act No. 63/1995).

Szoke, H. in Controversies in Health Law (eds Freckelton, I. & Peterson, K.) 242–243 (Federation, Melbourne, 1999 ).

Google Scholar  

Michigan Public Acts 108 (Michigan Comp. Laws #333. 16274) (1998).

Clarke, D. L. et al . Generalized potential of adult neural stem cells. Science 288 , 1660–1663 ( 2000).

Dworkin, R. M. Life's Dominion: An Argument About Abortion, Euthanasia, and Individual Freedom (Knopf, New York, 1993).

Feinberg, J. Harm to Others: The Moral Limits of the Criminal Law (Oxford Univ. Press, New York, 1986).

Tooley, M. Abortion and infanticide. Phil. Pub. Affairs 2 , 1–31 (1972).

Grobstein, C. The early development of human embryos. J. Med. Phil. 10 , 213–220 (1985).

Robertson, J. A. Children of Choice: Freedom and the New Reproductive Technologies (Princton Univ. Press, Princeton, 1994).

American Fertility Society. Ethical considerations in the use of new reproductive technologies. Fertil. Steril. 46 , S5–S7 (1986).

Robertson, J. A. Symbolic issues in embryo research. Hastings Center Report 25 , 37–38 (1995).

Ad Hoc group of consultants to the advisory committee to the Director, NIH. Report of the Human Embryo Research Panel . (National Institutes of Health, Bethesda, Maryland, 1994).

National Bioethics Advisory Commission. The Ethical Use of Human Stem Cells in Research (National Bioethics Advisory Commission, Rockville, Maryland, 1999).

National Institutes of Health Revitalization Act of 1993, Pub. L. No. 10–43, Sect. 111, 107 Stat. 129 (codified at 42 U. S. C. Sec. 498A).

Solter, D. Mammalian cloning: advances and limitations. Nature Rev. Genet. 1 , 199–207 ( 2000).

Robertson, J. A. Embryo research. Western Ontario Law Rev. 24 , 15–37 (1986).

Annas, G. A., Caplan, A. & Elias, S. The politics of human-embryo research — avoiding ethical gridlock. N. Engl. J. Med. 334 , 1329–1332 (1996).

Lanza, R. P. et al . Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288 , 666–669 (2000).

Article   Google Scholar  

Cohen, C. B. (ed.) New Ways of Making Babies: The Case of Egg Donation (Indiana University, Bloomington, Indiana, 1996).

Wade, N. Ethics panel is guarded about hybrid of cow cells. New York Times A7 21 December 1998 ).

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Study documents safety, improvements from stem cell therapy after spinal cord injury

Susan Barber Lindquist

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ROCHESTER, Minn. — A Mayo Clinic study shows stem cells derived from patients' own fat are safe and may improve sensation and movement after traumatic spinal cord injuries . The findings from the phase 1 clinical trial appear in Nature Communications . The results of this early research offer insights on the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited.

In the study of 10 adults, the research team noted seven participants demonstrated improvements based on the American Spinal Injury Association (ASIA) Impairment Scale. Improvements included increased sensation when tested with pinprick and light touch, increased strength in muscle motor groups, and recovery of voluntary anal contraction, which aids in bowel function. The scale has five levels, ranging from complete loss of function to normal function. The seven participants who improved each moved up at least one level on the ASIA scale. Three patients in the study had no response, meaning they did not improve but did not get worse.

"This study documents the safety and potential benefit of stem cells and regenerative medicine," says Mohamad Bydon, M.D. , a Mayo Clinic neurosurgeon and first author of the study. "Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients."

No serious adverse events were reported after stem cell treatment. The most commonly reported side effects were headache and musculoskeletal pain that resolved with over-the-counter treatment.

In addition to evaluating safety, this phase 1 clinical trial had a secondary outcome of assessing changes in motor and sensory function. The authors note that motor and sensory results are to be interpreted with caution given limits of phase 1 trials. Additional research is underway among a larger group of participants to further assess risks and benefits.

The full data on the 10 patients follows a 2019 case report that highlighted the experience of the first study participant who demonstrated significant improvement in motor and sensory function.

Watch: Dr. Mohamad Bydon discusses improvements in research study

Journalists: Broadcast-quality sound bites are available in the downloads at the end of the post. Please courtesy: "Mayo Clinic News Network." Name super/CG: Mohamad Bydon, M.D./Neurosurgery/Mayo Clinic.

Stem cells' mechanism of action not fully understood

In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

Participants' stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients' lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

Although it is understood that stem cells move toward areas of inflammation — in this case the location of the spinal cord injury — the cells' mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says. As part of the study, researchers analyzed changes in participants' MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury. In the study, one patient with a cervical spine injury of the neck received stem cells 22 months after injury and improved one level on the ASIA scale after treatment.

Two of three patients with complete injuries of the thoracic spine — meaning they had no feeling or movement below their injury between the base of the neck and mid-back — moved up two ASIA levels after treatment. Each regained some sensation and some control of movement below the level of injury. Based on researchers' understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

"In spinal cord injury, even a mild improvement can make a significant difference in that patient's quality of life," Dr. Bydon says.

Research continues into stem cells for spinal cord injuries

Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to the  World Health Organization .

An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells.

"For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy," Dr. Bydon says. "Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients."

Dr. Bydon is the Charles B. and Ann L. Johnson Professor of Neurosurgery. This research was made possible with support from Leonard A. Lauder, C and A Johnson Family Foundation, The Park Foundation, Sanger Family Foundation, Eileen R.B. and Steve D. Scheel, Schultz Family Foundation, and other generous Mayo Clinic benefactors. The research is funded in part by a Mayo Clinic Transform the Practice grant.

Review the study for a complete list of authors and funding.

About Mayo Clinic Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the  Mayo Clinic News Network  for additional Mayo Clinic news.

Media contact:

• Susan Barber Lindquist, Mayo Clinic Communications, [email protected]
• Personal journey shapes unique perspective Mayo Clinic scientists pioneer immunotherapy technique for autoimmune diseases

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Stem Cell Research as Innovation: Expanding the Ethical and Policy Conversation

Rebecca dresser.

Daniel Noyes Kirby Professor of Law and Professor of Ethics in Medicine at Washington University in St. Louis.

In 1998, researchers established the first human embryonic stem cell line. Their scientific triumph triggered an ethics and policy argument that persists today. Bioethicists, religious leaders, government officials, patient advocates, and scientists continue to debate whether this research poses a promise, a threat, or a mixed ethical picture for society.

Scientists are understandably excited about the knowledge that could come from studying human embryonic stem cells. Most of them believe these cells offer a precious opportunity to learn more about why diseases develop and how they might be prevented or attacked. In their quest to gain support for stem cell research, scientists and others have claimed that the research could generate cures and treatment for everything from heart disease to cancer.

Although most people are now familiar with claims about the diverse medical benefits stem cell research might deliver, they are less familiar with the diverse ethical issues relevant to the research. Most of the ethics debate focuses on the morality of destroying human embryos for the benefit of others. This is an important issue, but stem cell research raises other important ethical issues — issues that have received relatively little attention in the public arena. After more than a decade of narrowly focused analysis, it is time to expand the discussion.

The debate over embryonic stem cell research should consider a diversity of ethical and policy issues. Many of the ethical and policy issues that stem cell research presents apply to biomedical research in general, such as questions about appropriate research priorities and allocation of limited resources for research and health care. In this sense, the debate over stem cell research offers an opportunity to examine a variety of ethical and policy issues raised by biomedical innovation.

In this article, I place stem cell research in a broader ethics and policy context by describing three considerations that merit more attention in the debate. These include the following: (1) truth-telling and scientific integrity; (2) priorities in resource allocation for research and health care; and (3) responsibilities in civic discourse about bioethical controversies.

Truth-Telling and Scientific Integrity

New breakthroughs in biomedical science are often hailed as potential cures for the diseases that plague modern society. In many cases, however, the breakthroughs fall short of initial expectations. Innovations such as the artificial heart, fetal tissue transplantation, and gene therapy proved disappointing when they were tested in humans.

A similar result could occur with stem cell research. The excitement over stem cell research is unprecedented, and this creates fertile ground for exaggeration. Researchers, patient advocates, and politicians promise stem cell remedies for nearly every major health problem in the United States. And the promises come from both supporters and opponents of embryonic stem cell research. Supporters stress the advances possible through embryonic stem cells, while opponents emphasize potential therapeutic benefits from adult stem cells and other alternative sources. 1

The predictions on both sides violate the ethical responsibility to be accurate in describing the state of scientific exploration. Although there are a few established therapies that employ adult stem cells, most of the claims about stem cell therapies lack a solid evidentiary foundation. Much of the existing data comes from laboratory and animal studies. The first human trial of an embryonic stem cell intervention did not begin until 2009. 2 It will be many years before researchers can gather the human data necessary to determine whether stem cells will live up to their promise.

Much remains to be learned about the therapeutic abilities of stem cells. The cells’ treatment potential lies in their capacity to develop into different types of specialized human cells. The hope is that they could replace cells damaged through illness or injury. For this to work, however, scientists must understand more about how transplanted cells behave in the human body. They must also develop the power to control how the cells develop. Without this power, the cells could cause cancer or other harm to the recipient.

Because the immune system rejects foreign tissue, immune rejection is another possible barrier to effective therapies. 3 In theory, the problem could be solved by using stem cells created from a cloned embryo made with an individual patient’s somatic cell, but this procedure appears to present significant scientific challenges. 4 Moreover, economic and practical difficulties could impede efforts to devise therapies using stem cells from cloned embryos. 5 More work is also needed to determine whether induced pluripotent cells, the latest potential substitute for embryonic stem cells, could be safe and effective sources of replacement tissue. Novel uses of other kinds of adult stem cells also need further investigation to determine their clinical utility. 6

These and other scientific uncertainties make unqualified or barely qualified claims about therapies and cures from stem cell research ethically suspect. Ordinary people, including patients and their families, may be misled by such claims. They may develop unfounded hope for relief in a matter of months or years, rather than a more realistic understanding. They will be sorely disappointed once they become aware of the “significant technical hurdles… that will only be overcome through years of intensive research.” 7

Inflated promises about stem cell benefits can harm vulnerable people and can harm the research endeavor, as well. When members of the public realize that much work remains before effective therapies can be devised, their support for stem cell studies may diminish. They may become less willing to urge government support for the research, and less willing to contribute to nonprofit organizations supporting stem cell research.

The hype about stem cell research threatens scientific integrity, too. The field was undermined when the world learned of the fraud committed by South Korean researchers who claimed they had created stem cell lines from cloned human embryos. Besides dismay at the research team’s failure to observe basic standards of scientific integrity, there was speculation that editors and peer reviewers at Science , the journal that published the research, were too eager to publish the cloning reports. Some wondered whether scientists’ enthusiasm for the stem cell field led them to be less demanding than they should have been in their scrutiny of the research claims. 8

Other threats to scientific integrity arise when stem cell research becomes the basis for exaggerated claims by interest group lobbyists. Scientific organizations have claimed that limits on government funding for embryonic stem cell research could damage U.S. scientific preeminence. In the funding controversy’s early years, critics predicted a huge “brain drain” as U.S. scientists migrated to other nations offering generous support for the research. 9 Yet few scientists actually left this country to engage in stem cell research. 10 Several states stepped in to offer substantial funding, and nonprofit and private-sector support became available, too. 11 Even before the Obama administration revised the federal funding policy, U.S. researchers had many opportunities to pursue embryonic stem cell research.

Stem cell research has become a hot-button political issue, and this development could tarnish the public’s respect for and trust in science. Traditionally, science has enjoyed bipartisan support in the U.S., and in many respects, it still does. The debate over government funding for embryonic stem cell research does not divide along party lines. At the same time, however, politicians and their supporters have used the stem cell cause to advance partisan objectives. As one observer reported in 2006, “Politicians from both major parties are trying to use such research as a ‘wedge issue’ to woo voters.” 12

During the past decade, stem cell research became enmeshed in partisan politics from the national to the local level. Senator John Kerry made his support for federal funding of embryonic stem cell research a major theme in his 2004 campaign for the presidency. 13 For his part, former president Bush used his opposition to embryo destruction for research as a means to advance his campaign. 14 In the 2008 presidential election, both candidates claimed to support expanded federal funding for embryonic stem cell research, but the issue became politicized when research advocates warned that Senator John McCain’s position might change if he were elected. 15 Stem cells have also taken center stage in some state elections. In my own state of Missouri, where an initiative about stem cell research was on the November 2006 ballot, U.S. Senate and even county council candidates made stem cell research central to their election efforts. 16 The topic was a major issue in the 2006 New York governor’s race as well. 17

Stem cell research has joined abortion as a controversial matter on which politicians are expected to take a stand. It has become impossible to insulate this type of research from political debate. If stem cell research becomes identified with a particular political party or with specific candidates, then its fate could be determined more by politics than by substantive results in the laboratory. 18

There is one positive development in the public discussion about stem cell research. Many stem cell research supporters have begun to convey more realistic messages about the prospects for stem cell therapies. 19 In an ironic twist, one of the cautionary voices is James Wilson, who led the gene transfer trial in which Jesse Gelsinger died. Recounting the problems that came from the hype and haste surrounding clinical trials of gene transfer interventions, Wilson wrote in 2009, “I am concerned that expectations for the timeline and scope of clinical utility of [human embryonic stem cells] have outpaced the field’s actual state of development and threaten to undermine its success.” 20 He called on stem cell researchers and professional organizations, like the International Society for Stem Cell Research, to “steadfastly discourage” the exaggeration characterizing many claims about medical benefits from stem cell research. 21

Like Wilson, more experts and journalists express caution about the potential for stem cell therapies and focus instead on the value of stem cells as basic science tools that could help researchers understand how and why diseases develop. 22 But it is still easy to find examples of hype about stem cell therapies, such as in the publicity surrounding the first human trial of an embryonic stem cell intervention. 23

Like the Human Genome Project, stem cell research is most likely a form of scientific inquiry whose benefits will emerge slowly and incrementally. (Indeed, the Human Genome Project is now criticized as a costly research effort that to date has produced few actual medical benefits. 24 ) Rather than presenting stem cell research as a short-term answer for today’s patients, supporters should portray it as a promising scientific development that might, after many years of investigation, contribute to new medical interventions. 25 Just as physicians should be honest in disclosing a poor prognosis to a patient, scientists and advocacy groups should be honest about the lack of certainty that stem cell research will produce cures and effective therapies.

Social Justice and Allocation of Limited Resources

Stem cell research raises general questions about the appropriate allocation of government and private resources in biomedicine. One set of allocation questions addresses priority setting in biomedical research. The other set of allocation questions concerns the relative priority of research versus health care in funding decisions. These are questions that apply to biomedical research in general, but stem cell research nicely illustrates the relationship between research funding choices and social justice considerations.

Stem cell research is just one form of promising research. The National Institutes of Health (NIH), the largest public funder of biomedical science, supports many kinds of research offering opportunities to advance knowledge. The research portfolios of industry and nonprofit organizations also reveal an array of promising research areas. But neither the public nor the private sector can support every promising research project. Every research funding source has limited resources. As a result, these entities face hard choices about where to invest their limited dollars. How should funding agencies, nonprofit organizations, and private companies decide where to channel their resources?

According to NIH officials, five considerations play a role in the agency’s spending choices: (1) public health needs; (2) scientific merit of specific study proposals; (3) potential for advances in a particular area; (4) distribution across diverse research areas (because it is impossible to predict exactly where advances will occur); and (5) national training and infrastructure needs. The first criterion, public health needs, is determined by the following factors: (1) number of people with a specific disease; (2) number of deaths a specific disease causes; (3) degree of disability a specific disease produces; (4) how much a specific disease shortens the average lifespan; (5) a specific disease’s financial and social costs; and (6) the threat posed to others by contagious disease. According to the NIH, all of these considerations play a role in allocating research resources; none is rated as more important than another. 26

In the private sector, industry tends to allocate funds to research on conditions and products offering the greatest potential for financial reward. Many nonprofit organizations represent a single disease or demographic group and use their limited funds to support research that could benefit their specific constituencies.

The choices these entities make about research funding allocation raise social justice issues. As a publicly funded agency, the NIH has a duty to distribute its resources in a just manner. People disagree about whether private organizations have justice-based obligations, but a growing literature on corporate responsibility contends that even for-profit entities have a duty to consider the public good in their decision making. 27

What qualifies as a just approach to allocation of resources for research? The NIH priority-setting criteria incorporate justice-based considerations, but they are quite general. Moreover, officials have been unwilling to rank the criteria in order of importance. This means that the agency takes no position on the relative importance of, for example, research aimed at conditions that shorten the average lifespan and research aimed at conditions affecting the most people. In reality, critics say, the priority-setting criteria are so loose that congressional politics often determines where NIH dollars are directed. 28

The NIH criteria also leave open a significant social justice question, which is whether the U.S. has obligations to support research primarily aimed at helping people in poor nations. Some would contend that research funded by the U.S. government should address only domestic health concerns, but for many years, NIH has funded some international health research. There has been little public discussion of whether this approach is appropriate, however, and if it is appropriate, what portion of the NIH budget should be devoted to the health problems of people in other countries. 29

Although the proper approach to research priority setting is contested, the NIH criteria offer a framework for evaluating stem cell research. Much stem cell research is aimed at understanding and treating chronic diseases of aging, such as heart disease and neurological diseases. Indeed, some advocates proclaim that stem cell research will pave the way to “regenerative medicine,” in which the tissues and organs that deteriorate with age will be replaced with new ones created from stem cells. According to this group, interventions developed through stem cell research will substantially extend the human life span. 30

Not only are these predictions inconsistent with the duty to acknowledge the uncertainties accompanying early-stage research, they also raise resource allocation questions. Should extending the average U.S. life span be a high priority in research funding decisions? Would it be more defensible to give conditions that cause premature death a higher priority? Should strategies targeting prevention rather than treatment have a higher priority? 31

Another factor is the costs of the treatments that might emerge though stem cell research. Although basic science studies involving stem cells might help researchers develop new drugs and other relatively affordable medical interventions, the stem cell therapies that regenerative medicine enthusiasts describe could be relatively costly. As one group considering justice issues raised by stem cell research observed, “It seems inevitable, and of serious moral concern, that there will be significant economic barriers to access to new therapies utilizing stem cells or other cell-based preparations.” 32 If stem cell research produces expensive treatments, how many people will be able to benefit from the research investment? 33

Even more dramatic social justice questions arise when one considers biomedical research in an international context. Research is concentrated in wealthy nations and much of it focuses on the health problems of people fortunate enough to live in those nations. 34 Stem cell research is a prime example of this phenomenon, since much of the research (although not all of it) targets conditions arising later in life. But does justice require that prosperous nations devote more of their research funds to conditions that cause premature death in poor countries? 35

Questioning the justice of research funding allocation decisions may seem sacrilegious, given how popular biomedical science is in this country. But bioethicist Daniel Callahan presents the following thought experiment:

[C]onsider — as an imaginative exercise — what we would get if there was no progress at all from this point forward, and medicine remained restricted to what is now available. The rich countries would remain rich. Most of their citizens would make it to old age in reasonably good health. There would continue to be incremental gains in mortality and morbidity, the fruits of improved social, economic, and educational conditions, and improvements in the evaluation and use of present therapies. No prosperous country would sink from the lack of medical advances. 36

Another startling take on research priorities comes from neuroscientist Floyd Bloom. In his 2003 presidential address to the American Association for the Advancement of Science, Bloom declared that the quest for improved health care should focus more on health outcomes research than on the genomics research so often portrayed as a vehicle to medical advances. 37 These points provide a basis for considering stem cell research in a broader research context. Although stem cell research might eventually deliver benefits to some patients, benefits could also be achieved by investing resources in other kinds of research.

The social justice inquiry is relevant to many areas of biomedical research, not just stem cell research. Indeed, such an inquiry might support research on some conditions that are the focus on stem cell research, such as juvenile diabetes and spinal cord injury, which affect many young people. Nevertheless, it is important to see stem cell research as simply one of many scientific opportunities that could deliver health benefits. Investments in stem cell research will reduce the funds available for other types of biomedical research. In stem cell research, as in other research areas, the relative value and likely cost of any potential therapeutic benefits should be part of the decision making about research priorities.

A second matter of social justice concerns the relative priority of research needs and health care needs. Is it more important to conduct research aimed at improving care for future patients, or to provide better health care to today’s patients? In the U.S., as Daniel Callahan observes, “[T]he research drive has received an awful lot of money and great attention, but we have done less well with the delivery of health care….” 38 Because millions of people lack health insurance coverage and millions more have inadequate coverage, many patients are unable to benefit from the clinical interventions developed through past research efforts. 39 Is it ethical to devote large sums of money to research while so many people lack access to medical care that could give them longer and better lives?

Supporters contend that stem cell research is needed to aid patients with conditions that cannot be treated with existing therapies. From this perspective, there is a social justice basis for channeling limited resources to stem cell research. But those defending a moral duty to conduct stem cell research should consider another social justice perspective. Expanding access to health care would assist a currently disadvantaged group of people. Most standard health care interventions have been studied and found to be reasonably effective. Many are also relatively affordable. For these reasons, directing limited resources to health care delivery might achieve social justice objectives more efficiently than directing resources to stem cell research. This argument has even more force in the international context. Lack of access to basic health care, clean water, and other public health services produces high death rates in poor countries. 40 In this situation, small amounts of money can make huge contributions to improving and extending human lives.

What justifies our nation’s substantial investment in biomedical innovation, when millions of people here and abroad are denied access to proven medical interventions? 41 Once again, the stem cell controversy opens a window to a larger moral problem. The social justice inquiry raises questions about the priority that stem cell and other basic science studies should have in the competition for limited resources. If government officials and health advocates want to help patients, meaningful help would also come from a system that supplied adequate health care to more people, both across the nation and worldwide.

Responsibilities in Civic Discourse

People have passionate views on stem cell research. Their passion has had two detrimental effects on the public debate. One is the exaggeration about therapeutic benefits I referred to earlier. The other is disrespect for people with opposing positions. Too often, people caught up in the debate portray those with different positions inaccurately and unfairly.

Opponents of embryonic stem cell research use the slippery slope to cast aspersions on the morality of research supporters. According to some opponents, research supporters will accept almost anything to advance science and human health. Thus, for example, those who would allow the creation and destruction of human embryos to advance knowledge will also accept a world in which human beings are “grown for spare body parts.” 42 And any move to allow early embryos to be destroyed in research “will provide the leverage to thrust the research door open for Franken-steinian experimentation on the most vulnerable of our species.” 43

On the other hand, people supporting embryonic stem cell research belittle those assigning a high moral status to early human embryos. Underlying this attitude is disdain for anyone who would let religious and other moral beliefs influence their positions on science policy. Some scientists and advocates recognize that scientific considerations alone cannot determine appropriate state policy on embryonic stem cell research. 44 Others, however, seem to assume that morality has no place in the debate, or alternatively, that no rational individual could assign a high moral status to the early human embryo. As a columnist who supports embryonic stem cell research put it, “Only Bush bitter-enders and the pope are in the perverse position of valuing the life of an ailing human being less than that of a tiny clump of cells no bigger than the period at the end of this sentence.” 45

Misleading terminology also characterizes the stem cell debate. For example, many embryonic stem cell research supporters deny that they endorse human cloning. 46 Implicit in this claim is a narrow definition of human cloning that covers only the creation of a child through cloning. But the initial process of creating the cloned embryo (which research supporters prefer to call somatic cell nuclear transfer) is the same in research cloning and cloning to have children. 47 People who believe that the early human embryo has a high moral status do not differentiate between the two activities. Yet speakers often fail to clarify which definition of cloning they adopt, which leads to confusion in the public debate.

Also misleading is the term “therapeutic cloning,” which suggests to the layperson that this is a procedure with proven clinical benefit, rather than one that remains theoretical at this point. And in yet another form of terminology manipulation, embryonic stem cell research supporters characterize their proposals for liberal federal funding policies as efforts “to promote all ethical forms of stem cell research.” 48 This characterization avoids what is at the heart of the policy controversy, which is the question of whether or not research requiring embryo destruction is ethical. Such language games fail to give due regard to the moral disagreements underlying the policy disputes over stem cell research.

Decisions about U.S. stem cell research — whether to prohibit, regulate, permit, or financially support it — occur in the democratic context. The ongoing debates over stem cell research ought to reflect a better deliberative process than we have seen so far. In their work on deliberative democracy, political scientists Amy Gutmann and Dennis Thompson offer guidance for improving the deliberations over stem cell research. Below I describe their general framework for deliberative democratic policymaking and then apply it to stem cell policy formation.

Gutmann and Thompson describe four deliberative democracy characteristics relevant to stem cell research policy. First, policy arguments and choices must be supported by reasons. The requirement for reason-giving rests on a moral principle that underlies democracy: the principle that citizens should be regarded as agents participating in their society’s decisions. To participate in a democracy, citizens must understand why certain choices are made. Learning the basis for official actions allows people to challenge decisions that rest on false or misleading reasons. The reason-giving requirement also demonstrates respect for all citizens, no matter what their economic or political power happens to be. All are entitled to an explanation for the policies their officials impose. 49

Gutmann and Thompson describe a second feature of deliberative democracy, which is that the reasons underlying a policy must be accessible to all affected by that policy. Accessible reasons are understandable not only to those agreeing with the policy, but also to those opposing it. To fulfill this requirement, decision makers must publicly articulate their reasons for a specific policy choice and those reasons must have an acceptable public content. This means that reasons should rest on facts, rather than false information. Members of the public should also be able to evaluate the beliefs supporting a policy choice: “It would not be acceptable, for example, to appeal only to the authority of revelation, whether divine or secular in nature.” 50 In a deliberative democracy, Thompson and Gutmann maintain, individuals can disagree with a policy and at the same time conclude that the policy has a legitimate basis.

Deliberative democracy’s third characteristic addresses the status of policies over time. Deliberations are aimed at a specific policy decisions, and at some point those decisions must be made. Policies then become binding on citizens. But deliberative democracy requires that policies remain open to revision. If new facts are discovered that undercut the initial policy choice, officials should reassess their original choice. If emerging discoveries or events provoke people to new value judgments affecting their policy views, officials should take these changes into account. People should be free to challenge existing policies, and officials should make revisions when they are justified. As Thompson and Gutmann observe, those disagreeing with a policy choice will be more likely to accept it if they know they can in the future work to alter that choice. 51

Thompson and Gutmann discuss a fourth dimension of deliberative democracy with special relevance to the stem cell research debate. Participants in deliberations should aim for what Thompson and Gutmann call “economy of moral disagreement.” 52 This concept comes from the deliberative directive to respect those with values and positions that differ from our own. The concept “does not ask us to compromise our moral understandings in the interest of agreement, but rather to search for significant points of convergence between our own understandings and those of citizens whose positions, taken in their more comprehensive forms, we must reject.” 53 Deliberative democracy asks parties in disagreement to seek common ground, sometimes forgoing their ideal policies for ones that elicit greater agreement. 54

Policy debates about stem cell research should incorporate these features. Proponents of different policies should offer accessible reasons for their positions. For example, research supporters should go beyond simplistic slogans linking stem cell research with lifesaving cures. They should supply clear and accurate information about potential clinical results, tempering the promises of effective therapies with realistic accounts of what must be achieved before therapies become available. In turn, people promoting alternatives to embryonic stem cell research should supply clear and accurate information about adult stem cells, induced pluripotent cells, and other alternative sources that avoid embryo destruction. They too should speak of therapies as possibilities that remain uncertain and probably many years away. Both groups should emphasize that most stem cell work remains in the laboratory and that no one can say whether or when medical applications will emerge from that work.

Both advocates and opponents of embryonic stem cell research should also do a better job of confronting the moral questions raised by their positions. Those whose views reflect religious beliefs about the moral status of early human embryos should offer reasons for their positions that can be accepted by people who fail to share those beliefs. Those who claim to see the human embryo as an entity owed special respect should explain why embryo destruction is consistent with this moral status position. People worried about risks to women providing eggs to create embryos for stem cell research should explain why the usual human subject protections are inadequate in this situation. And those who think the risks to women are justified should consider how they will respond if women experience harm from the egg production process.

Adversaries in the stem cell debate should aim for an economy of moral disagreement as well, seeking to develop policies that individuals with differing positions could accept. For example, if people on both sides agree that the goal of improved health care justifies government funding for stem cell research, federal officials could decide to pursue that goal in a manner that demonstrates respect for those opposed to embryo destruction. Officials could for a limited time period fund only stem cell research using cells from alternative sources. If suitable alternatives failed to emerge during that time, government support could be redirected to research involving stem cells from destroyed embryos. A similar policy approach could be taken to research cloning, with support initially directed to research aimed at developing patient-matched stem cells through methods that avoid the need for donated eggs.

Policies incorporating the reverse presumptions might also be devised. Such policies would authorize financial support for embryonic stem cell research from IVF and cloned embryos for a limited period, but would cease such support once alternative sources became available. 55 Policies like these would demonstrate respect for those holding different positions on the ethics of creating and destroying embryos for research. And these options are not the only possibilities. A deliberative commitment in policy development could yield a variety of options that accommodate to some degree the different moral positions on stem cell research.

How does the latest development in federal policy look through the lens of deliberative democracy? In the 2009 revision of the federal funding policy for stem cell research, some features of deliberate democracy were evident, but there were deliberative shortcomings as well. In announcing his plans to liberalize the policy, President Obama cautioned against exaggerating the possibility of medical benefits from the research. At the same time, he characterized the research as a step toward the “day when words like ‘terminal’ and ‘incurable’ are potentially retired from our vocabulary.” 56 He recognized the moral opposition of “thoughtful and decent people” to embryonic stem cell research and spoke of avoiding the “perils” the research presents through “proper guidelines and strict oversight.” 57 But he neither defined those perils nor explained how guidelines and oversight would avoid them. Thus, the president gave a nod to the moral dispute and the importance of supplying accessible reasons for the position he endorsed, but the deliberative effort was relatively superficial.

The final NIH Guidelines on Human Stem Cell Research 58 also exhibit deliberative strengths and weaknesses. The guidelines permit federal funding for research on stem cell lines created from embryos donated by couples who have completed their infertility treatment. But the guidelines rule out funding for research using lines created from embryos produced purely for research. In published commentary on the guidelines, NIH officials said there was “broad public support” for funding research using stem cells from donated embryos, but that “a similar consensus has not emerged” on the ethics of creating stem cells through procedures like cloning, in part because they require women to provide eggs at some risk to their health. 59 In this respect, we can see an effort to provide accessible reasons for the decision and, possibly, to economize moral disagreement by allowing only limited expansion of the funding rules.

But another aspect of the guidelines failed to conform to deliberative ideals. In a telephone press briefing on the final guidelines, Acting NIH Director Dr. Raynard Kington said the agency had received thousands of comments opposing government funding of any research using stem cell lines created through embryo destruction. The official commentary on the guidelines neither mentions those comments nor explains why they did not prevail. In the telephone briefing, Dr. Kington said that agency officials deemed the comments “nonresponsive” to their request for comments on the guidelines they had proposed earlier in the year. 60 A robust deliberative approach would have acknowledged the high number of opposing comments and devoted at least a few sentences to explaining why the agency’s position differed from that taken in the comments. 61

Stem cell research could generate knowledge that would allow certain individuals to live longer and better lives. It would be a happy event if in the future stem cell research produced relief for at least some individuals with illnesses or injuries not curable at present. Yet there are no guarantees that this happy future will materialize. Although we may support and admire the scientists devoted to developing a better understanding of human health and disease, we should also be aware that no one can ensure that effective treatments will emerge.

The therapeutic benefits of stem cell research are possible, but uncertain. And many other areas of biomedical science fit this description. Stem cell research is not the only field in which exciting discoveries are occurring and future patients may benefit from investments in these areas, too. This is not a reason to deny support to stem cell research, but it is a reason to consider it in a larger context. Advocates weaken their case when they portray stem cell research as if it were the only promising research around. 62 More government support for stem cell research could help patients in the future, but so could support for research in other biomedical fields.

Participants in the stem cell debate should also recognize deficiencies in the health system denying patients the benefits of past research. Advocacy for stem cell research should include advocacy for a better health system. Without improvements in this system, any therapeutic benefits developed through stem cell research will be unjustly limited to patients fortunate enough to have access to the best health care. 63

Moreover, the stem cell controversy should press us to reexamine existing research and health care priorities. Should officials devote more funds to research aimed at translating laboratory discoveries into actual clinical benefits? 64 Should they channel more funds to studies that could have a significant public health impact? And what level of investment should the U.S. make in programs aimed at developing and delivering affordable care to disadvantaged people in this nation and around the world? These are ethical questions with immense significance, but they are often overlooked amid the excitement over specific research discoveries like those involving stem cell research.

Last, ethical considerations sometimes justify setting limits on scientific innovation. For example, there is nearly universal agreement that people should not be forced to participate in research, even though a coercive research policy could generate extremely valuable knowledge. Some people believe there should also be severe limits on research involving early human embryos, while others disagree. These are not disputes that science can settle. They are instead value conflicts to be expected in a pluralistic society like ours. In struggling with these conflicts, we should maintain respect for those holding differing views, and we should look for policies that are consistent with as many of those views as possible.

Advocates often portray stem cell research as presenting a choice between ending human life and saving human life. 65 But the choices are much more complicated than that. Many ethical considerations are relevant to policy choices about stem cell research, but they often go unmentioned. Instead, the sound bite approach to stem cell research has produced a shrill and divisive policy climate. Fewer sound bites and an expanded ethical conversation could produce more defensible policy decisions about stem cell research.

Paralyzed man who can walk again shows potential benefit of stem cell therapy

A Mayo Clinic study used a patient's stem cells to help repair the spinal cord.

A man who was paralyzed from the neck down after a surfing accident seven years ago is now able to stand and walk on his own , thanks in part to a potentially groundbreaking stem cell treatment.

Chris Barr was the very first patient in a Mayo Clinic study that collected stem cells from his own stomach fat, expanded them in a laboratory to 100 million cells and then injected the cells into Barr's lumbar spine.

Over five years after undergoing the therapy, Barr said he is continuing to gain more independence and get faster at walking.

"I never dreamed I would have a recovery like this," Barr told ABC News' Will Reeve. "I can feed myself. I can walk around. I can do day-to-day independent activities."

Barr shared an update with Reeve on his own progress as Mayo Clinic published new data showing the success of the stem cell treatment in a clinical trial involving 10 patients, including Barr.

According to the trial's results, published Monday in the journal Nature Communications , seven of the 10 patients experienced increased strength in muscle motor groups and increased sensation to pinpricks and light touch.

MORE: Artificial intelligence used in medical procedure to help paralyzed man walk

Three patients in the study had no response to the stem cell therapy, meaning they did not get better or worse, according to the Mayo Clinic, based in Rochester, Minnesota.

"These findings give us hope for the future," Dr. Mohamad Bydon, a neurosurgeon and spinal cord researcher at the Mayo Clinic and the study's lead author, told Reeve, who is also the director of The Christopher Reeve Foundation, a nonprofit "dedicated to curing spinal cord injury," according to its website. The foundation, named in honor of Will Reeve's late father, was not involved in the funding of Bydon's research.

Bydon's research at the Mayo Clinic is a Phase 1 study that began in 2018.

The newly published results of the study show that of the seven patients who saw improvement after the stem cell therapy, each moved up at least one level on the American Spinal Injury Association -- or ASIA -- Impairment Scale, which has five levels documenting patients' function.

"This trial shows us that stem cells are safe and potentially beneficial in the treatment of spinal cord injury," Bydon said. "This can be a milestone in our field of neurosurgery, neuroscience and of treating patients with spinal cord injury."

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Bydon and other researchers are still trying to understand how and why the stem cells interact with the spinal cord to result in progress for some patients, and additional research is underway among a larger group of people to further assess risks and benefits.

In Barr's case, he told Reeve in 2019 he began to quickly see improvements, like getting feeling back in his legs, after undergoing the stem cell treatment.

Now five years later, he described making further long-term improvements, like being able to walk for consistent intervals without assistance.

"I'm just thrilled that there are people taking bold steps to try and do research to cure this," Barr said. "It's been a wild ride and it's not over yet."

Dr. Priscilla Koirala, a member of the ABC News Medical Unit, contributed to this report.

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• Open access
• Published: 29 March 2023

Engineering exosomes and biomaterial-assisted exosomes as therapeutic carriers for bone regeneration

• Ye Lu 1   na1 ,
• Zizhao Mai 1   na1 ,
• Li Cui 1 , 2 &
• Xinyuan Zhao 1  

Stem Cell Research & Therapy volume  14 , Article number:  55 ( 2023 ) Cite this article

4215 Accesses

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Mesenchymal stem cell-based therapy has become an effective therapeutic approach for bone regeneration. However, there are still limitations in successful clinical translation. Recently, the secretome of mesenchymal stem cells, especially exosome, plays a critical role in promoting bone repair and regeneration. Exosomes are nanosized, lipid bilayer-enclosed structures carrying proteins, lipids, RNAs, metabolites, growth factors, and cytokines and have attracted great attention for their potential application in bone regenerative medicine. In addition, preconditioning of parental cells and exosome engineering can enhance the regenerative potential of exosomes for treating bone defects. Moreover, with recent advancements in various biomaterials to enhance the therapeutic functions of exosomes, biomaterial-assisted exosomes have become a promising strategy for bone regeneration. This review discusses different insights regarding the roles of exosomes in bone regeneration and summarizes the applications of engineering exosomes and biomaterial-assisted exosomes as safe and versatile bone regeneration agent delivery platforms. The current hurdles of transitioning exosomes from bench to bedside are also discussed.

Introduction

Bone defects are often the consequence of high-energy trauma, infection, tumor excision or congenital defects. In addition, they are frequently accompanied by soft tissue damage, including injuries to muscles, tendons and joints. Bone healing might be initiated immediately following bone loss, which is a highly complex, well-orchestrated regenerative process of forming new bones and is involved in a series of fundamental cellular and molecular events [ 1 ]. Unfortunately, the intrinsic regenerative capacity of bone tissues fails to repair massive bone defects above a critical size [ 2 ]. Large bone defects require additional clinical intervention, and multiple options are currently available in clinical practice. The defective area is generally reconstructed and filled with grafts of an autogenous, allogeneic, or alloplastic nature to achieve satisfactory bone regeneration [ 3 , 4 ]. Despite the clinical success of bone grafting, it is limited by major drawbacks, such as invasive surgical procedures, pain, secondary complications and disease transmission [ 5 ]. In addition, an ideal bone graft substitute should possess the following characteristics: osteoconduction, osteoinduction, osteoincorporation, osteointegration and osteogenesis [ 3 ]. However, to date, no single material has all the necessary properties to efficiently promote bone regeneration. In recent decades, MSC-based tissue engineering has become an effective therapeutic approach in the field of regenerative medicine, which has opened a new path for bone repair and regeneration [ 6 , 7 ].

MSCs hold great promise for wide-ranging clinical applications and regenerative medicine, as they retain the potential to differentiate into multilineages under defined conditions and the ability to self-renew [ 8 , 9 ]. In addition, MSCs can be expanded rapidly and easily in vitro, and the supernatants, growth factors and cytokines derived from MSCs are also cell-free sources for tissue regeneration [ 10 ]. It has been well documented that MSCs are of great importance during the bone formation or healing process [ 11 , 12 ]. They have the capacity of migration and homing into or around the injured sites, which are the essential steps for achieving bone repair and regeneration. Then, MSCs are able to commit to osteogenic/chondrogenic progenitors and eventually differentiate into osteocytes/chondrocytes for bone tissue reconstruction after bone defects [ 13 ]. In addition, due to the immunomodulatory properties of MSCs, they escape immune recognition and protect against the cytotoxic effects of the host’s immune system [ 14 ]. Moreover, MSCs might promote bone regeneration by modulating the microenvironment. For instance, human adipose tissue-derived MSCs (hASCs) and their conditioned medium (CM) enhanced bone regeneration in a rabbit model of surgical bone lesions, suggesting that hASCs promoted bone regeneration mainly by releasing paracrine factors [ 15 ].

Considering the critical role of MSCs in bone regeneration, as expected, MSCs have been shown to be an efficacious treatment for bone defects [ 16 ]. For example, transplanted MSCs have been shown to not only survive and proliferate in injured sites but also differentiate into osteoblasts, leading to bone tissue reconstruction in a model of osteonecrosis of the femoral head [ 17 ]. Similarly, bone marrow MSC (BMSC) transplantation significantly accelerated bone regeneration in a rat mandibular osteodistraction model [ 18 ]. Percutaneous injection of MSCs isolated from bone marrow alone or with bioscaffolds such as biphasic hydroxyapatite/β-calcium-triphosphate granules has been shown to promote bone repair in patients with delayed healing of long bone fractures or avascular necrosis of the femoral head [ 19 , 20 ]. Despite the vast number of MSC-based clinical trials that have been completed, none of the approaches have been approved for the treatment of bone defects. There are several significant barriers to the clinical application of MSC-based bone regeneration [ 21 ]. First, standardized protocols need to be established to avoid unwanted MSC differentiation during ex vivo expansion [ 22 ]. Second, the beneficial effects of MSC osteogenic differentiation for bone repair and regeneration are significantly impaired due to the poor engraftment and survival of MSCs in the injury sites [ 23 ]. Third, the number of administered MSCs is not sufficient for treating large bone defects in the clinical setting, and long-term in vitro expansion might affect the biological functions of MSCs [ 24 ]. Other limitations in MSC-based bone regeneration concern ethical issues and the possible risk of tumorigenicity [ 25 ].

The key success factor of MSC-based bone regeneration is because MSCs are able to differentiate into bone-forming osteoblasts and cartilage-forming chondrocytes [ 26 ]. It is expected that the implanted or injected MSCs will commit to a particular lineage at the site of injury for tissue repair and regeneration. However, the survival status and the differentiation capacity of the implanted/injected MSCs are unfavorable, thereby casting doubt on its correct mechanism of action. Interestingly, growing evidence has demonstrated that MSCs might exert their therapeutic effects mainly through paracrine effects [ 19 , 27 , 28 ]. The MSC-derived secretome includes vesicles, growth factors, cytokines, chemokines, extracellular matrix (ECM) and metabolites and plays an indispensable role in modulating tissue repair and regeneration [ 29 ]. For example, after incorporating human umbilical cord MSC (hucMSC)-derived extracellular vesicles into tubular epithelial cells, the complex was injected into the injured kidneys, and surprisingly, kidney function and morphology were significantly improved [ 30 ]. MSC-derived immunomodulators and trophic factors, including vascular endothelial growth factor (VEGF), transforming growth factor-β, and hepatic growth factor, contribute to the positive effects of the BMSC secretome in the bone regenerative process [ 31 ]. The secretome in the CM from MSCs mimicked the native bone healing procedures to enhance bone regeneration [ 6 ].

As this review aims to summarize the recent progress on engineering exosomes and biomaterial-assisted exosomes as therapeutic carriers for bone regeneration, we mainly referred to the research articles published in recent 5 years. The databases we mainly used included PubMed, Google scholar, Scopus, Web of Science and ProQuest by using the following keywords: “exosomes”, “mesenchymal stem cells”, “preconditioning”, “exosome engineering”, “biomaterial scaffolds”, and “bone regeneration”. The articles were further screened to identify their relevance to this review.

Exosome concept, biogenesis, content and application

Exosomes are nanosized, lipid bilayer-enclosed structures carrying proteins, lipids, RNAs, metabolites, growth factors and cytokines and have attracted great attention for their critical role in mediating cell–cell communication locally and systemically [ 32 ]. Exosomes are derived from the endocytic pathway of most cells and released from multivesicular bodies (MVBs) into nearly all biological fluids, such as blood, saliva and urine [ 33 ]. The formation of exosomes can be classified into four processes: invagination, endosome formation, fusion and secretion. Initially, early endosomes are formed by invagination of the plasma membrane, which are subsequently transformed into late endosomes containing MVBs. Following the fusion of MVBs with the plasma membrane, the exosomes are consecutively released from the cells [ 34 ]. The abundance, composition and functional properties of exosomes depend on the origin of the cell/tissue, the physiological/pathological state and even the microenvironment in which the parental cells reside [ 35 ]. The main role of exosomes lies in their capability to deliver information to adjacent cells and even to those cells that are remote from the exosome cellular origin, thereby influencing their function [ 36 ]. The contents of circulating exosomes are different between patients and healthy individuals, which can reflect the real-time state. Therefore, exosomes are emerging as robust and promising noninvasive biomarkers for the diagnosis, prognosis and prediction of treatment efficacy in various diseases [ 37 ]. More importantly, exosomes have been developed as therapeutic carriers for treating diseases. The advantage of using exosomes as delivery vehicles is their capacity to load both hydrophobic and hydrophilic items either inside or in the lipid bilayer [ 38 ]. The cargos are shielded by the bilayer membranes, which effectively protects the cargos from enzymatic degradation [ 38 , 39 ]. In addition, the long circulation property of MSC exosomes prolongs their residence time in the blood and reduces the clearance rate of drugs they carry. MSC-produced exosomes can target specific cell types through their surface receptors [ 40 , 41 ]. Exosomes have also been proven to be able to cross biological barriers and travel into deep tissues [ 40 , 42 ]. Moreover, exosomes are efficacious for promoting regeneration, inducing stem cell differentiation and triggering particular immunological reactions [ 43 ]. Furthermore, they also exhibit great biocompatibility, biodegradability and stability, as well as low immunogenicity (Fig.  1 ) [ 43 ]. Small molecules, nucleic acid drugs or bioactive molecules can be functionally incorporated into exosome-based nanocarriers and then transported to targeted sites to achieve therapeutic outcomes [ 44 ]. Pascucci et al. [ 45 ] reported that MSC-derived exosomes loaded with chemotherapeutic drugs trafficked to tumor tissues and exerted antitumorigenic effects. In addition, MSC-derived exosomes also exhibit promising therapeutic potential for bone regeneration. As a critical mediator of intercellular communication, exosomes play a prominent role in a variety of biological processes including bone formation. MSC-derived exosomes exert prolific therapeutic efficacy in bone defects as they are capable of targeting bone tissues to induce osteogenic differentiation, thereby accelerating the process of bone regeneration [ 46 ]. For example, in a rat model of disuse osteoporosis, the diseased animals treated with hucMSC-derived exosomes formed new bone, and the bone structural parameters were significantly improved [ 47 ]. Exosomes secreted from human-induced pluripotent stem cells (hiPSC) enhanced bone regeneration in the osteoporotic rat model [ 48 ]. BMSC-derived exosomes stimulate osteoblast proliferation and osteogenic differentiation, thereby promoting osteogenesis in the rabbit model of osteonecrosis of the femoral head [ 49 ]. In addition, exosomes have a certain degree of natural targeting capacity. The targeting specificity of exosomes is mainly achieved by surface receptor–ligand binding to target specific cells, and then, exosomes can stimulate intracellular signaling in recipient cells or deliver their components to stimulate osteoblast proliferation and differentiation [ 50 ]. However, the therapeutic efficacy of natural exosomes for bone regeneration is limited [ 51 ]. MSC-derived exosomes can be captured by the reticuloendothelial system or cleared by the mononuclear phagocyte system, which might prevent their accumulation in the injured sites to exert desirable regenerative effects [ 52 , 53 ]. Additionally, the natural targeting property of MSC exosomes is not accurate enough for delivering the indicated cargos to the specific recipient cells or tissues. Engineering or manipulating exosomes can optimize their targeting capability, providing potential wide clinical applications for treating diseases, including bone defects [ 54 ]. Here, we summarize recent research progress on naturally derived exosomes and engineered exosomes in bone repair and regeneration. In addition, as biomaterial scaffolds are the basic material for bone tissue engineering, the effects of biomaterial-assisted exosomes on bone regeneration have also been reviewed. The practical challenges associated with exosome-based bone regeneration are also discussed.

Exosomes derived from MSCs as a delivery vehicle have the advantages of low immunogenicity, easily uptaken by cells, easily crossing biological barriers, cargo protection from degradation, easily loading therapeutics, high cargo release stability, high biocompatibility, long circulation, and having the ability of tissue targeting. Therefore, they have been developed as a novel strategy for treating various diseases

Mechanism of MSC-derived exosomes for bone regeneration

MSCs-derived exosomes promote bone regeneration by directly transferring their internal cargos and subsequently controlling downstream signaling pathways in the targeted cells [ 55 , 56 ]. Exosomes also regulate immune responses, inhibit osteoclast activities and induce osteogenesis and angiogenesis [ 57 ]. Various signaling cascades, including BMP/Smad, Wnt/β-catenin and PI3K/AKT, are activated by MSC exosomes, resulting in bone regeneration by promoting osteoblast proliferation and differentiation as well as the recruitment of endogenous MSCs to bone defect sites [ 57 , 58 , 59 ]. In addition, MSC exosomes repair bone defects by enhancing local angiogenesis and suppressing bone resorption, and activation of AKT/mTOR signaling pathway might be responsible for the osteogenesis-promoting effects [ 60 , 61 ]. Moreover, MSC exosomes are effective in improving overall wound healing by inhibiting inflammatory responses and preventing osteoclast activities [ 62 , 63 ]. The release of BMP-2 and other osteogenic growth factors from macrophages and non-stem cells were markedly elevated following the addition of MSC exosomes, which subsequently accelerated the healing of damaged tissues [ 46 , 62 ]. It has also been demonstrated that MSC exosomes promote angiogenesis in bone defect area, which play a crucial role in bone regeneration [ 60 , 61 ]. Vasculature serves as the main transport conduit for hormones and growth factors to supply the bone defect area with oxygen, nutrients and metabolites, which are essential for bone growth and regeneration [ 64 ]. A number of exosomal miRNAs such as miRNA-135b, miRNA-204 and miRNA-196a have been shown to play a critical role in regulating the bone regeneration process [ 65 , 66 , 67 ]. Interestingly, the immune microenvironment formed by immune cells and their metabolites is also indispensable for bone regeneration. The immune microenvironment not only controls the activities of osteoblasts and osteoclasts, but also the secretion of chemokines, growth factors and inflammatory factors, which in turn modulates the formation of new bone and the strength of existing bones [ 68 , 69 ]. MSC exosomes are crucial in modulating immune cell activities in the complicated internal environment [ 46 , 62 ]. For instance, by delivering the intracellular cargos, MSC exosomes induce the polarization of macrophages from the M1 to the M2 phenotype, contributing to the establishment of anti-inflammatory microenvironment during bone defect repair [ 70 ].

Modification of MSC-derived exosomes for bone regeneration

Due to the limitations of natural exosomes, such as lack of sufficient production, instability in circulation and poor targeting capacity, various strategies have been developed to modify MSC-derived exosomes and enhance their therapeutic potential [ 71 ]. The avenues for the modification of exosomes are mainly divided into two aspects: preconditioning of parental cells and exosome engineering (Fig.  2 ).

The avenues for the modification of exosomes are mainly divided into two aspects: preconditioning of parental cells and exosome engineering. Preconditioning of parental cells for bone regeneration mainly included hypoxic preconditioning, cytokine preconditioning and chemical preconditioning. Exosome engineering is mainly divided into two categories: cargo packaging into exosomes and surface modification of exosomes

Preconditioning of parental cells

Although exosomes derived from MSCs have been widely explored for cell-free therapy of various diseases, limitations, including low production of MSC exosomes, the demand for large amounts of exosomes, heterogeneity and low targetability impede the clinical trials of MSC-derived exosomes [ 51 ]. Growing evidence indicates that the preconditioning of parental cells is an adaptive strategy to enhance the therapeutic efficacy and yield of MSC exosomes [ 51 ]. Preconditioning of MSCs overcomes the limitations of natural exosomes by enhancing MSC paracrine activities to increase the production of MSC exosomes [ 72 , 73 ]. In addition, pretreatment can promote exosomes from MSCs to regulate both the innate and adaptive immune responses of recipient cells [ 72 , 73 ]. The approaches for preconditioning of MSCs mainly include hypoxic preconditioning, cytokine preconditioning and chemical preconditioning.

Hypoxic preconditioning

Hypoxia refers to the cell culture conditions under 0–10% oxygen tension. Oxygen tension plays an essential role in maintaining bone homeostasis [ 74 ]. The 1% oxygen tension in physiological cartilage and bone marrow is far lower than the 21% O 2 routinely used for MSC culture [ 75 ]. A hypoxic environment can lead to cell death; however, hypoxic preconditioning can reduce hypoxia-induced apoptosis by elevating the expression of pro-survival signaling [ 76 ]. Interestingly, recent studies showed that the therapeutic effects of MSC-derived exosomes after hypoxic preconditioning were significantly enhanced for treating a wide array of diseases, including bone fracture healing [ 77 , 78 ], acute kidney injury [ 79 ], spinal cord injury [ 80 ], diabetic wounds [ 81 ], myocardial infarction [ 82 , 83 , 84 ] and insufficient vessel growth [ 85 ].

Hypoxic preconditioning can enhance the cytoprotective and regenerative effects of MSCs to promote the secretion and therapeutic effects of their exosomes in injury sites such as bone defects and osteoarthritis [ 86 , 87 ]. Mechanistically, hypoxic preconditioning increases the levels of cytoprotective molecules and maintains the multipotent and proliferative capabilities of stem cells [ 88 , 89 , 90 ]. An increasing number of studies have demonstrated that hypoxic preconditioning may improve the osteogenic differentiation and proliferation of MSCs by elevating the expression of growth factors and stemness-related markers such as SOX2, OCT4, NANOG and KLF4 [ 91 , 92 ]. In addition, hypoxia preconditioning contributes to the activation of hypoxia-inducible factor (HIF-1α), which subsequently promotes the expression of angiogenic factors [ 93 ]. Similarly, hypoxic preconditioning can increase the relative expression levels of molecule contained in MSC exosomes in the same way.

MSC-derived exosomes from hypoxic conditioning have shown superior abilities in enhancing osteogenesis and angiogenesis, and the secretion of exosomes was found to be significantly improved after hypoxic preconditioning [ 77 , 78 ]. For example, the focal adhesion pathway, thyroid hormone synthesis and VEGF signaling pathway were significantly upregulated in exosomes from stem cells from human-exfoliated deciduous teeth (SHEDs) after hypoxic preconditioning [ 77 ]. Thus, exosomes derived from hypoxic-preconditioned SHEDs showed superior potential for cellular osteogenesis and angiogenesis in a rat calvarial defect model [ 77 ]. In addition, exosomes derived from hypoxia-preconditioned hucMSC healed bone fractures via the SPRED1/Ras/Erk signaling pathway [ 78 ]. In addition, hypoxic preconditioning activated HIF-1α to promote the secretion of exosomal miRNA-126 for bone fracture healing by enhancing proliferation, angiogenesis and migration to a greater extent [ 78 ]. Exosomes from BMSCs after hypoxic preconditioning promoted the proliferation and migration of chondrocytes and inhibited the apoptosis of chondrocytes via the miRNA-181c-5p/MAPK or miRNA-18-3p/JAK/STAT signaling pathways [ 86 ]. MicroRNAome analysis revealed that hsa-miRNA-18a-3p, hsa-miRNA-181c-5p, hsa-miRNA-337-5p and hsa-miRNA-376a-5p were differentially expressed between normoxia-preconditioned and hypoxia-preconditioned BMSC-derived exosomes [ 86 ]. In contrast, oxidative stress caused by H 2 O 2 inhibited the release of exosomes from human periodontal ligament cells (hPDLCs) through a large accumulation of MVB caused by reducing the expression of Rab11a and Rab27a [ 94 ]. In general, hypoxia preconditioning is a promising strategy for enhancing the effectiveness of MSC-exosome-based therapy in bone regeneration.

Cytokine preconditioning

Accumulating evidence has demonstrated that preconditioning MSCs with inflammatory cytokines promotes the secretion of immunoregulatory factors [ 95 ]. The immune responses regulated by exosomes from cytokine-preconditioned MSCs include transferring MSCs to a more anti-inflammatory phenotype and inducing the polarization of anti-inflammatory M2 macrophages [ 96 , 97 , 98 , 99 ]. MSC-chemokine preconditioning can concentrate numerous immunocytes for their migration and homing into or around the injured sites to combat inflammatory responses. This shows that MSC-chemokine preconditioning is a promising strategy for bone regeneration by decreasing inflammation in bone defects [ 98 , 99 , 100 , 101 ].

Tumor necrosis factor-alpha (TNF-α) is one of the most studied inflammatory cytokines. An increasing number of studies have shown that TNF-α preconditioning enhances the therapeutic effects of exosomes derived from MSCs in various diseases, including bone defects [ 100 ], periodontitis [ 98 ], retinal ganglion injury [ 102 ], acute liver failure [ 96 ] and urethral stricture [ 97 ]. TNF-α promoted the secretion of a greater number of anti-inflammatory MSC exosomes by upregulating inflammatory suppression-related miRNAs, including miRNA-146a and miRNA-299-3p [ 96 , 97 ]. These anti-inflammatory MSC exosomes contributed to the transfer of MSCs to a more anti-inflammatory phenotype [ 96 , 97 ]. Preconditioning MSCs with TNF-α not only promoted the anti-inflammatory ability of MSC exosomes but also enhanced the osteogenic differentiation potential of MSC exosomes. hASCs preconditioned with TNF-α regulated the proliferation and osteogenic differentiation of human primary osteoblastic cells through Wnt signaling [ 100 ]. Exosomes derived from gingival tissue-derived MSCs (GMSCs) preconditioned with TNF-α regulated inflammation and osteoclastogenesis in a ligature-induced periodontitis mouse model by promoting the secretion of exosomes, upregulation of the exosomal CD73 expression, and induction of the polarization of anti-inflammatory M2 macrophages [ 98 ]. In addition, preconditioning GMSCs with TNF-α promoted the therapeutic effects of GMSC exosomes, including decreasing the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and suppressing periodontal bone resorption [ 98 ].

Interleukin-1β (IL-1β) has been shown to promote the anti-inflammatory effects of MSC exosomes in osteoarthritis by increasing the expression of miRNA-147b [ 101 ]. In addition, exosomes derived from BMSCs preconditioned with IL-1β inhibited the inflammation of hippocampal astrocytes and status epilepticus mice through suppression of the NRF2 signaling pathway [ 103 ]. Exosomes derived from transforming growth factor-β1 (TGF-β1)-preconditioned BMSCs attenuated cartilage damage in osteoarthritis rat models by upregulating miRNA-135b, which promoted M2 polarization of synovial macrophages by targeting MAPK6 [ 99 ]. In summary, preconditioning of certain cytokines and growth factors promotes the osteogenic potential and anti-inflammatory function of MSC exosomes. It should be pointed out some potential cytokines and growth factors are promising candidates for MSC preconditioning. For example, preconditioning of MSCs with IFN-γ showed the potential of anti-inflammatory and angiogenic abilities [ 104 ]. In addition, growth factors such as FGF 2, IGF-1, IGF-2, TGF-β1 and PDGF are efficacious in promoting soft tissue healing, and the effects of MSC preconditioning with these growth factors on bone regeneration warrant further investigation [ 104 , 105 ].

Chemical preconditioning

Chemical signals can be rapidly detected by MSCs and may significantly alter their phenotypes [ 51 ]. In addition, the influence also changes the secretion and content of MSC exosomes, which show promising potential in immune regulation and tissue regeneration [ 106 ]. For example, exosomes derived from kartogenin-preconditioned hucMSCs induced chondrogenic differentiation by promoting the secretion of exosomal miRNA-381-3p through targeting TAOK1 [ 107 ]. Similarly, kartogenin-reconditioned mouse BMSC (mBMSC)-exosomes have a better ability to promote chondral matrix regeneration than exosomes derived from untreated mBMSCs [ 108 ]. In addition, exosomes derived from curcumin-preconditioned MSCs attenuated osteoarthritis by modulating the miRNA-124/NF-kB and miRNA-143/ROCK1/TLR9 signaling pathways [ 109 ].

• Exosome engineering

Exosome engineering has been explored to enhance the therapeutic potential of MSC exosomes [ 110 ]. Exosome engineering is mainly divided into two categories: cargo packaging into exosomes and surface modification of exosomes [ 51 ].

Cargo packaging into exosomes

Packaging cargo into exosomes can promote the therapeutic effects of MSC exosomes. The methods of packaging cargo into exosomes can be divided into two main categories: endogenous and exogenous cargo loading methods [ 51 ]. Endogenous cargo loading is the modification of parental cells with viral vectors and plasmids, while exogenous cargo loading is the direct loading of drugs into the extracted MSC exosomes [ 51 ]. Endogenous cargo methods are usually used to load endogenous proteins and nucleotides with therapeutic effects, while exogenous cargo loading methods are usually used to load small molecule drugs [ 111 ].

Endogenous cargo loading

Accumulating evidence shows that the functional biomolecules of MSC exosomes, such as nucleotides and proteins, play essential roles in osteogenesis, angiogenesis, immunomodulation and tissue regeneration in different kinds of disease models [ 112 ]. Genetic engineering tools, such as viral vectors and plasmids, can genetically manipulate the endogenous molecule expression levels in MSCs.

Growing evidence indicates that miRNA delivery plays a crucial role in improving the therapeutic potential of MSC exosomes in various disease models. Exosomes from miRNA-375-overexpressing hASCs embedded with hydrogel promoted the bone regeneration of BMSCs by inhibiting the expression of IGFBP3 [ 113 ]. Exosomes from miRNA-181b-overexpressing BMSCs enhanced osteogenesis in vitro and osteointegration in vivo by secreting VEGF and bone morphogenetic protein 2 (BMP2) to promote M2 polarization and inhibit inflammation by activating the PRKCD/AKT signaling pathway [ 114 ]. Exosomes from miRNA-140-5p-overexpressing synovial mesenchymal stem cells promoted the migration and proliferation of articular chondrocytes in an osteoarthritis rat model [ 115 ]. Exosomes from BMP2-overexpressing BMSCs enhanced osteogenic regeneration and osteoinduction in a rat calvarial defect model [ 116 , 117 ]. Exosomes derived from BMSCs modified with mutant HIF-1α (BMSC-Exos MU ) significantly promoted the osteogenic differentiation ability of BMSCs in vivo, while exosomes derived from BMSCs modified with wild-type HIF-1α (BMSC-Exos WT ) did not show osteogenic differentiation ability [ 118 ]. In addition, BMSC-Exos MU markedly increased angiogenesis and bone regeneration in the necrotic regions by increasing microvascular density and trabecular reconstruction [ 118 ].

Exogenous cargo loading

Physical methods are usually employed to encapsulate drugs into engineered exosomes, such as permeabilization with saponins, freeze‒thaw cycles, extrusion, or sonication, for treating various diseases [ 119 , 120 ]. For example, sonication was used to fractionate exosome membranes into small vesicles, and then, drugs were extruded into the vesicles [ 119 , 120 ]. Other methods for exogenous cargo loading usually included permeabilization with saponin, freeze‒thaw cycles and incubation at room temperature for treating various diseases [ 119 ]. BMP2 was directly loaded into engineered extracellular vesicles of BMSCs, which induced osteogenic regeneration in vitro and in vivo, while BMP2 was absent in the exosomes of untreated group [ 121 ]. Compared to naturally occurring extracellular vesicles, engineered BMP2-extracellular vesicles protected BMP2 from proteolysis [ 121 ]. ATDC5 was encapsulated with the VEGF gene into exosomes, which induced vascularized bone regeneration [ 122 ]. Mechanistically, exosomes loading VEGF gene promoted the osteogenic differentiation ability of MSCs by controllably releasing the vascularized gene VEGF to remodel the vascular system and combining the 3D-printed porous bone scaffolds with engineered exosome nanoparticles (NPs) [ 122 ]. In addition, the exosomes encapsulated with the VEGF gene showed the best bone regeneration ability and induced the formation of a large amount of new bone in a rat radial defect repair model [ 122 ].

Surface modification

Surface modification is used to enhance the targeting ability of MSC exosomes to promote their therapeutic effects by direct modification of exosome surface molecules [ 111 ]. Targeting ligands can be added onto the surface of exosomes to precisely deliver therapeutic drugs to the indicated lesions. For example, an aptamer was combined with exosomes derived from bone marrow stromal cells (STExos) to generate the STExo-aptamer complex [ 123 ]. The complex enhanced the bone mass in an ovariectomy-induced postmenopausal osteoporosis mouse model and promoted bone healing in a femur fracture mouse model after intravenous injection [ 123 ]. C-X-C motif chemokine receptor 4 (CXCR4) was added to the surface of exosomes derived from genetically engineered NIH-3T3 cells [ 124 ]. The complex was then combined with liposomes carrying antagomir-188 to generate hybrid NPs. The hybrid NPs recovered the loss of age-related trabecular bone and reduced cortical bone porosity in mice by specifically gathering in the bone marrow and controllably releasing antagomir-188 to inhibit adipogenesis and promote osteogenesis of BMSCs [ 124 ].

Collectively, the modification of exosomes enhances the osteogenic and angiogenic potential of MSC exosomes by increasing the secretion of MSC exosomes and regulating the expression levels of osteogenic and angiogenic genes, which are promising therapeutic strategies for bone regeneration. We summarized the methods of exosome modification in Table 1 .

Biomaterial-based MSC-derived exosomes for bone regeneration

Despite advancements in natural exosomes for bone regeneration applications, there are still certain limitations in complex composition properties, limited cargo loading efficiency and undesirable retention stability. However, exosomes can bind to biomaterial scaffolds to enhance bone regeneration mainly by inducing osteogenesis and angiogenesis (Fig.  3 ). A range of biomaterial scaffolds endows exosomes with desirable pharmaceutical acceptability by extending exosome storage time and altering the release properties, thereby overcoming the drawbacks of natural exosomes. The use of biomaterial-assisted exosomes has proven to be a novel strategy for regenerating bone tissues [ 125 ]. Biomaterials employed for scaffolds can be divided into metal materials, bioactive ceramics, hydrogels and synthetic polymers. We have summarized the biomaterial-based exosomes for bone regeneration applications in Table 2 .

Exosomes can bind to biomaterial scaffolds, including metal materials, bioactive ceramics, hydrogels and synthetic polymers, and then target injured sites to enhance bone regeneration mainly by inducing osteogenesis and angiogenesis

Metal materials

Biodegradable metal materials are widely used biomaterials in exosome engineering for repairing bone defects. Their excellent biocompatibility, easy production and processing, mild stretchability, and corrosion resistance make them suitable for use as exosome-loaded scaffolds to promote bone regeneration [ 126 ]. For example, MSC-derived exosomes incorporated into silver NPs hybrid scaffolds induced osteogenesis, thus serving as a promising cell-free therapeutic for bone regeneration [ 127 ]. In addition, titanium alloys are also scaffolds for bone defect treatment with desirable biocompatibility, excellent friction coefficient, high porosity and corrosion resistance. Exosomes derived from human MSCs (hMSCs) loaded into 3D-printed titanium alloy scaffolds can be used to achieve cell-free bone regeneration. The exosomes released by 3D-printed titanium alloy-decorated hMSCs induced osteogenic differentiation of hMSCs and regenerated bone tissues by upregulating osteogenic miRNAs, downregulating anti-osteogenic miRNAs and activating the PI3K/Akt and MAPK signaling pathways [ 128 ].

Bioactive ceramic

Bioactive ceramic biomaterials, including bioactive glass and tricalcium phosphate, are also desirable alternatives for repairing bone tissue that have good toughness and biocompatibility and different characteristics [ 129 ].

Mesoporous bioactive glass

Mesoporous bioactive glass (MBG) is a hierarchical structure scaffold that has been proven to be beneficial for bone repair with positive biological effects on osteogenesis [ 130 ]. For example, optimized osteogenic BMSC-derived exosomes were loaded into MBG scaffolds to realize bioactivity maintenance and sustained release of exosomes, thereby efficiently promoting bone-forming ability and enhancing rapid initiation of bone regeneration [ 131 ].

Tricalcium phosphate

β-Tricalcium phosphate (β-TCP), resembling the human autologous bone component, is one of the most commonly used bone tissue engineering biomaterials. β-TCP scaffolds with advanced osteotransductive ability and high osteoinductive potential are able to maintain the balance between material degradation and osteogenesis by releasing calcium ions and sulfates [ 132 ]. Therefore, β-TCP is an optimal scaffold for bone regeneration. Porous β-TCP scaffolds can be used as exosome carriers and implanted into the bone defect area, thereby promoting bone regeneration after being loaded into MSC-derived exosomes in a concentration-dependent manner. For instance, exosomes derived from MSCs in combination with β-TCP induced new bone formation. This MSC-exosome-β-TCP scaffold complex improved the osteoinductivity of β-TCP and possessed better osteogenesis activity than β-TCP alone. Moreover, gene expression profiling and bioinformatics analyses revealed that the MSC-exosome-β-TCP scaffold promoted bone regeneration mainly by activating the PI3K/AKT signaling pathway [ 133 ]. Exosomes released by hiPSC (hiPSC-Exos) combined with β-TCP scaffolds can potentially be used for bone repair. The β-TCP scaffolds incorporated into hiPSC-Exos were able to significantly promote bone regeneration in an osteoporotic rat skull defect model, and the therapeutic effect was increased with increasing concentrations of hiPSC-Exos. In addition to osteogenesis, the hiPSC-Exos + β-TCP scaffolds also markedly enhanced angiogenesis in the area of the calvarial defect, and the restoration of blood flow was capable of providing nutrients and renewable autologous cells to repair critical-sized bone defects [ 48 ]. BMSC-Exos-HIF1α loaded onto the β-TCP scaffolds implanted in the bone defect area repaired bone defects by promoting new bone regeneration in cranial critical-sized bone defect rats [ 134 ]. Additionally, β-TCP scaffolds are also employed to repair bone defects in alveolar regions for treating periodontitis. For example, exosomes secreted by SHED-derived exosomes combined with β-TCP scaffolds induced alveolar bone regeneration and neovascularization by promoting osteogenesis-related gene expression and phosphorylation of AMPK [ 135 ]. Exosomes released from human periodontal ligament stem cells (hPDLSCs) were loaded with β-TCP scaffolds and then applied to repair bone defects, leading to increased formation of alveolar bone in rat models of periodontitis [ 136 ].

Bioactive ceramic supplemented with bone substitute

However, the limited bioactivity of ceramics may influence their regenerative effects. Therefore, bioactive materials such as bone substitutes can be added to promote their performance. Using a calcium sulfate-nanohydroxyapatite nanocement (NC) bone filler as the MSC-exosome carrier provides a newly improved approach for bone regeneration. After implantation in rat tibia critical defect models, this complex enhanced bone regeneration by inducing bone mineralization [ 137 ].

Currently, hydrogels scaffolds have been extensively utilized in the field of bone regeneration, as they are compatible biomaterials acting as exosome carriers and exosome delivery reservoirs. For bone regeneration, hydrogels may be synthesized from various biodegradable polymers, such as hyaluronic acid (HA), chitosan (CS), silk fibroin (SF), alginate (ALG) and polyethylene glycol (PEG) [ 138 ].

Hydrogels are three-dimensional network structure polymer chains with superior mechanical strength and can mimic the natural ECM of bone tissue. Therefore, hydrogels provide nutrient environments suitable for endogenous cell proliferation, thus presenting a prospective ability of exosome encapsulation for bone regeneration [ 139 ]. Due to the 3D network structure and physiochemical properties of the hydrogels, the encapsulated bioactive molecules are confined in the meshes. In addition, exosomes formulated in hydrogel scaffolds may reduce the degradation rate and easily maintain the release of exosomes as needed, contributing to the high local concentrations of desired pharmacologically important molecules contained in exosomes to achieve desirable therapeutic effects. These properties make hydrogels a promising scaffold for cell-free therapy in targeting bone tissue sites and facilitate localized delivery of therapeutic agents, thereby promoting bone regeneration for treating bone defects [ 138 ].

Natural hydrogels

Hydrogels prepared by natural polysaccharides and proteins, including hyaluronic acid, hydrogel alginate, chitosan and gelatin, can be used as scaffolds for exosome carriers with desirable biodegradability and proper cell interactions in the treatment of bone defects.

HA is a nonimmunogenic natural polymer that is the major component of the ECM structure and critical to tissue regeneration [ 140 ]. Umbilical MSC-derived exosomes (uMSCEXOs) combined with HA hydrogels (HA-Gel) and then customized nanohydroxyapatite/poly-ε-caprolactone (nHP) scaffolds were shown to repair cranial defects in rats. The uMSCEXOs/HA-Gel/nHP complex markedly accelerated the bone regeneration process [ 141 ]. Yang et al. combined HA-ALG hydrogels and hydroxyapatite (HAP) with hucMSC-derived exosomes targeting bone defect sites in a calvarial defect rat model for bone regeneration. The composite hydrogel system durably retained exosomes at the targeting sites and significantly promoted the healing of damaged bone by enhancing osteogenic abilities [ 142 ]. CS is another polysaccharide with a linear structure composed of β-(1,4)-linked D-glucosamine and N-acetyl-D-glucosamine units with intrinsic bone healing properties. BMSC-derived exosomes were added to the CS/β-glycerophosphate hydrogel for bone regeneration in rats with calvarial defects. These exosome-release hydrogels were biocompatible and exhibited excellent therapeutic effects for repairing bone tissues [ 143 ]. Gelatin-based hydrogels have also attracted attention as potentially implantable materials in bone engineering applications due to their functionality. For example, hASC-derived exosomes combined with gelatin NPs hydrogel scaffolds accurately transported to the target sites and exerted a stronger bone repair capacity [ 70 ]. Natural hydrogel scaffolds have also shed light on the therapy of bone loss in periodontitis. For example, BMSC-derived exosomes were isolated and then loaded into a natural hydrogel for injection into rats with experimental periodontitis. The BMSC-Exo-hydrogel system promoted the migration, proliferation, and osteogenic differentiation of hPDLSCs for periodontal regeneration [ 62 ]. Exosomes derived from dental pulp stem cells (DPSCs) encapsulated into CS hydrogel effectively accelerated the regeneration of alveolar bone in a mouse model of periodontitis [ 144 ].

Moreover, the secretome of MSCs is able to provide specific peptides, and hydrogel-assisted exosomes combined with these peptides can improve the effects of bone regeneration. For example, small intestinal submucosa (SIS) hydrogels incorporated with 3-(3,4-dihydroxyphenyl) propionic acid (CA) modified by fusion peptides and exosomes derived from BMSCs were considered desirable for bone regeneration due to the positive effect of the exosomes in promoting the osteogenic differentiation of BMSCs. The combination of SIS hydrogels and CA significantly improved the mechanical properties of the hydrogels, and fusion peptides were designed to enhance the retention and stability of exosomes. Therefore, these scaffolds strengthen the therapeutic effect of MSC-derived exosomes on bone defects [ 145 ].

Synthetic hydrogels

Despite the advantages of using natural hydrogels in bone repair, the drawbacks of natural materials for hydrogel preparation are less stability, and undesirable mechanical characteristics. The incorporation of MSC-derived exosomes into synthetic hydrogels may be used to improve bone regeneration effects. Hydrogels can be synthesized from various polymeric biodegradable materials. Synthetic hydrogels present a longer shelf life, reliable mechanical properties and lower risk of immunogenicity, making them suitable for bone tissue regeneration. For instance, stem cells from apical papilla-derived exosomes (SCAP-Exos) loaded into a bioresponsive PEG/DNA hybrid hydrogel facilitated bone regeneration for diabetic bone defects by the controlled release of SCAP-Exos [ 146 ]. A coralline hydroxyapatite/SF/glycol CS/difunctionalized PEG self-healing hydrogel was synthesized, and hucMSC-derived exosomes were loaded into the hydrogel. This synthetic hydrogel containing exosomes effectively promoted bone regeneration [ 147 ].

Hydrogels combined with bone engineering materials

The use of hydrogels alone may cause problems, due to their poor mechanical and chemical properties. The emergence of composite bone engineering materials, such as metal–organic frameworks (MOFs) and β-TCP scaffolds, can promote the widespread use of hydrogel composite scaffolds in bone regeneration. MOFs are promising platforms for biomedical applications because of their structural diversity, high surface areas, adjustable porosity, simple surface functionalization and tunable biocompatibility. The application of MOF scaffolds as exosome carriers is a novel strategy for bone regeneration. For instance, hADSC-derived exosomes and Mg-gallic acid (GA) MOF were combined for bone regeneration applications, taking advantage of hADSC-Exos, Mg 2+ , GA and MOF scaffolds. As the scaffolds degraded, exosomes were released continuously and then internalized by hBMSCs to enhance their osteogenic effects by stabilizing the bone graft environment, promoting osteogenic differentiation and stimulating bone reconstruction. Furthermore, exosomes secreted from the composite scaffolds were also proven to induce new bone formation and osseointegration in the rat calvarial defect model [ 148 ]. β-TCP can also be combined with hydrogels to enhance bone regeneration. Zhang et al. extracted exosomes originating from rat BMSCs (rBMSCs) and then cocultured them with polyethylene glycol maleate citrate (PEGMC) hydrogels and β-TCP to promote bone regeneration. The PEGMC/β-TCP-MSC-Exos showed great potential in rapid osteogenesis [ 149 ].

Synthetic polymers

Synthetic polymers with tunable mechanical properties, such as poly-lactic-co-glycolic acid (PLGA) and polylactic acid (PLA), have also been used as scaffolds for the development of biocompatible and biodegradable polymeric structures to regenerate bone tissues.

PLGA with excellent mechanical strength and biodegradation properties is another widely used biocompatible scaffold for bone regeneration. For instance, hASC exosomes immobilized on polydopamine-coated PLGA scaffolds effectively promoted bone healing in mouse skull defect models, and polydopamine (pDA) was used to provide a more efficient coating on the PLGA substrate. hASC-derived exosomes combined with PLGA/pDA scaffolds were capable of consistently releasing exosomes, resulting in enhanced bone regeneration through their osteoinductive effects. In addition, this exosome-composite scaffold also promoted MSC migration and homing in newly formed bone tissues [ 150 ]. PLGA and PEG were engineered with human DPSC (hDPSC)-derived exosomes to improve the controlled release of exosomes for bone regeneration. These engineered scaffolds constantly released osteogenic hDPSC-derived exosomes that facilitated the osteogenic differentiation of BMSCs, leading to mineralization and accelerated bone healing [ 151 ]. PLA is a versatile and biodegradable scaffold widely used in repairing tissue defects. Exosomes were isolated from MSCs and coated with porous 3D PLA scaffolds to potentiate osteogenic differentiation. PLA-MSC-Exos significantly improved osteogenesis, which holds great potential for applications in bone tissue regeneration [ 152 ]. Polyetheretherketone (PEEK) is a noncytotoxic, highly biocompatible and chemically stable aromatic polymer material that can be used for bone regeneration. BMSC-derived exosomes packaged with tannic acid-modified sulfonated PEEK continually released exosomes and exerted osteoimmunomodulation effects to enhance osteogenesis by promoting macrophage M2 polarization [ 153 ].

Limitations and future perspectives

Despite the promising application of exosomes in bone regeneration, there are certain limitations with the use of MSC exosomes for bone regeneration [ 154 ]. The main bottleneck in clinical application is the lack of standardized isolation and purification strategies for exosomes. Exosomes, as carriers of elements of cellular communication and interaction, can be detected in nearly all biological fluids including blood, saliva, urine and cerebrospinal fluid [ 155 ]. Effective extraction and separation of exosomes from different sources for bone regeneration are challenging. Ultrafiltration is the most commonly used method to isolate exosomes, with the advantages of easy operation and screening based on size [ 156 ]. However, it still has problems with large-scale production. The production of both high-quality and high-quantity exosomes remains challenging for the translation of these nanosystems into the clinic [ 44 , 157 ].

Although the therapeutic benefits of modifications and exosome engineering have been demonstrated in various bone diseases, some challenges in preconditioning methods may limit their applications. MSC-exosome preconditioning can promote the anti-inflammatory and/or osteogenic potential of exosomes by regulating the secretion and content of MSC exosomes. However, the optimal time and intensity of different preconditioning still need to be further explored because of the heterogeneity of MSCs from different sources [ 51 ]. In addition, the long-term effects of preconditioning on the properties of MSCs and the evidence of consistently obtaining desirable exosomes from engineering methods still need to be evaluated in clinical [ 158 , 159 ]. Accordingly, addressing these problems may increase their possibility of regenerative applications.

The emergence of biomaterials provides various options for exosome-based therapy; encapsulating exosomes into biomaterial scaffolds can optimize their application in bone regeneration, but there are still some limitations. For instance, it is difficult to maintain exosome release by scaffolds. Although the slow release is achieved, strategies for the consistently stable release of exosomes are not available, and the most suitable release rate for bone regeneration has not yet been explored [ 160 ]. Additionally, there was insufficient evidence to support the scalable manufacturing of scaffolds and efficient delivery of exosomes, and thus, further studies need to be performed to address these issues [ 138 ]. The promising cell-free therapy will surely attract deeper investigations to improve the production efficiency and quality of exosomes, the preconditioning or engineering methods, and the release of exosomes from the matched scaffold at the most appropriate rate, thereby maximizing exosome function in bone regeneration.

It should be noted that there is still a long way before exosome-based therapy can be comprehensively applied for bone regeneration in clinical settings. Many hurdles should be overcome before the clinical translation of MSC-derived exosomes. Firstly, the loading efficiency for exosomes is relatively low as their naturally complex contents limit the space for the loading of exogenous therapeutics into exosomes [ 161 , 162 ]. More effective modification methodologies are required to develop to improve the drug loading efficiency. Secondly, the original sources, physiological states and cultural conditions of MSC may impact the targeting and biological properties of isolated exosomes [ 163 , 164 , 165 ]. Therefore, widely applicable standards for the isolation of MSC-derived exosomes should be established. Thirdly, several factors, such as the dosage of MSC exosomes and the use of scaffolds, may influence the potency of MSC exosomes for bone regeneration. A particular source and concentration of exosomes, a specific scaffold or delivery route and the frequency of treatment need to be identified for optimization in different treatments of specific bone defect/disease indications [ 16 ]. Exosomes provide a new direction for bone defect treatments. However, the regenerative efficacy of MSC exosomes for treating bone defects is still in infancy, as the current research is limited to small animal models. Efforts to progress to clinically related large animal models and ultimately to clinical trials would likely be helpful to advance the field of MSC exosomes for bone regeneration.

The process of natural bone healing lacks the capacity to repair massive bone defects beyond a critical size, which makes the treatment of bone defects an intractable clinical problem [ 166 ]. Currently, progress in the use of bone grafting for clinical applications has many challenges, such as invasive surgical procedures, pain, secondary complications and disease transmission. However, cell-free therapy has great potential for bone regeneration, with MSCs as the most commonly used cell-free source [ 167 ]. MSC-derived exosomes are able to promote bone regeneration, which is of great significance for the effective application of bone defect repair. Moreover, modifications of exosomes, exosomes engineering and combined with biomaterial scaffolds markedly enhance their therapeutic effects [ 57 ]. Although there are currently limitations in MSC-derived exosome-based cell-free therapy, this is a promising field in bone regeneration, which can attract further investigations to confirm the clinical effect of treating bone defects.

Availability of data and materials

Not applicable.

Abbreviations

Mesenchymal stem cell

Human adipose tissue-derived mesenchymal stem cells

Conditioned medium

Bone marrow mesenchymal stem cell

Human umbilical cord mesenchymal stem cell

Vascular endothelial growth factor

Multivesicular bodies

Human-induced pluripotent stem cells

Hypoxia-inducible factor

Stem cells from human exfoliated deciduous teeth

Human periodontal ligament cells

Tumor necrosis factor-alpha

Gingival tissue-derived mesenchymal stem cells

Tartrate-resistant acid phosphatase

Interleukin-1β

Transforming growth factor-β1

Mouse bone marrow mesenchymal stem cell

Bone morphogenetic protein 2

Nanoparticles

Exosomes derived from bone marrow stromal cells

C-X-C motif chemokine receptor 4

Human mesenchymal stem cells

β-Tricalcium phosphate

Exosomes released by human-induced pluripotent stem cells

Human periodontal ligament stem cells

Hyaluronic acid

Silk fibroin

Polyethylene glycol

Extracellular matrix

Umbilical mesenchymal stem cell-derived exosomes

Hyaluronic acid hydrogels

Nanohydroxyapatite/poly-ε-caprolactone

Dental pulp stem cells

Small intestinal submucosa

3-(3,4-Dihydroxyphenyl) propionic acid

Stem cells from apical papilla-derived exosomes

Metal–organic frameworks

Polyethylene glycol maleate citrate

Polylactic-co-glycolic acid

Polylactic acid

Polydopamine

Polyetheretherketone

Dimitriou R, Jones E, McGonagle D, Giannoudis PV. Bone regeneration: current concepts and future directions. BMC Med. 2011;9:66.

Article   PubMed   PubMed Central   Google Scholar  

Walmsley GG, Ransom RC, Zielins ER, Leavitt T, Flacco JS, Hu MS, Lee AS, Longaker MT, Wan DC. Stem cells in bone regeneration. Stem Cell Rev Rep. 2016;12(5):524–9.

Article   CAS   PubMed   Google Scholar  

Wang W, Yeung KWK. Bone grafts and biomaterials substitutes for bone defect repair: a review. Bioact Mater. 2017;2(4):224–47.

Fillingham Y, Jacobs J. Bone grafts and their substitutes. Bone Jt J. 2016;98(B(1 Suppl A)):6–9.

Article   Google Scholar  

Sanz-Sanchez I, Sanz-Martin I, Ortiz-Vigon A, Molina A, Sanz M. Complications in bone-grafting procedures: classification and management. Periodontol 2000. 2022;88(1):86–102.

Article   PubMed   Google Scholar  

Marolt Presen D, Traweger A, Gimona M, Redl H. Mesenchymal stromal cell-based bone regeneration therapies: from cell transplantation and tissue engineering to therapeutic secretomes and extracellular vesicles. Front Bioeng Biotechnol. 2019;7:352.

Kuo CK, Tuan RS. Tissue engineering with mesenchymal stem cells. IEEE Eng Med Biol Mag. 2003;22(5):51–6.

Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells. 2019;8(8):886.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther. 2020;11(1):492.

Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy. 2016;18(1):13–24.

Lin W, Xu L, Zwingenberger S, Gibon E, Goodman SB, Li G. Mesenchymal stem cells homing to improve bone healing. J Orthop Translat. 2017;9:19–27.

Qin Y, Guan J, Zhang C. Mesenchymal stem cells: mechanisms and role in bone regeneration. Postgrad Med J. 2014;90(1069):643–7.

Shang F, Yu Y, Liu S, Ming L, Zhang Y, Zhou Z, Zhao J, Jin Y. Advancing application of mesenchymal stem cell-based bone tissue regeneration. Bioact Mater. 2021;6(3):666–83.

Song N, Scholtemeijer M, Shah K. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Trends Pharmacol Sci. 2020;41(9):653–64.

Linero I, Chaparro O. Paracrine effect of mesenchymal stem cells derived from human adipose tissue in bone regeneration. PLoS ONE. 2014;9(9):e107001.

Tan SHS, Wong JRY, Sim SJY, Tjio CKE, Wong KL, Chew JRJ, Hui JHP, Toh WS. Mesenchymal stem cell exosomes in bone regenerative strategies-a systematic review of preclinical studies. Mater Today Bio. 2020;7:100067.

Yan Z, Hang D, Guo C, Chen Z. Fate of mesenchymal stem cells transplanted to osteonecrosis of femoral head. J Orthop Res. 2009;27(4):442–6.

Qi M, Hu J, Zou S, Zhou H, Han L. Mandibular distraction osteogenesis enhanced by bone marrow mesenchymal stem cells in rats. J Craniomaxillofac Surg. 2006;34(5):283–9.

Wu J, Guo H, Liu X, Li M, Cao Y, Qu X, Zhou H, Weng L. Percutaneous autologous bone marrow transplantation for the treatment of delayed union of limb bone in children. Ther Clin Risk Manag. 2018;14:219–24.

Rosset P, Deschaseaux F, Layrolle P. Cell therapy for bone repair. Orthop Traumatol Surg Res. 2014;100(1 Suppl):S107–12.

Zhou T, Yuan Z, Weng J, Pei D, Du X, He C, Lai P. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021;14(1):24.

Jung S, Panchalingam KM, Rosenberg L, Behie LA. Ex vivo expansion of human mesenchymal stem cells in defined serum-free media. Stem Cells Int. 2012;2012:123030.

Li M, Jiang Y, Hou Q, Zhao Y, Zhong L, Fu X. Potential pre-activation strategies for improving therapeutic efficacy of mesenchymal stem cells: current status and future prospects. Stem Cell Res Ther. 2022;13(1):146.

Bijonowski BM, Yuan X, Jeske R, Li Y, Grant SC. Cyclical aggregation extends in vitro expansion potential of human mesenchymal stem cells. Sci Rep. 2020;10(1):20448.

Neri S. Genetic stability of mesenchymal stromal cells for regenerative medicine applications: a fundamental biosafety aspect. Int J Mol Sci. 2019;20(10):2406.

Lin H, Sohn J, Shen H, Langhans MT, Tuan RS. Bone marrow mesenchymal stem cells: aging and tissue engineering applications to enhance bone healing. Biomaterials. 2019;203:96–110.

Ahn SY, Chang YS, Sung DK, Yoo HS, Sung SI, Choi SJ, Park WS. Cell type-dependent variation in paracrine potency determines therapeutic efficacy against neonatal hyperoxic lung injury. Cytotherapy. 2015;17(8):1025–35.

Park WS, Ahn SY, Sung SI, Ahn JY, Chang YS. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res. 2018;83(1–2):214–22.

Marote A, Teixeira FG, Mendes-Pinheiro B, Salgado AJ. MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential. Front Pharmacol. 2016;7:231.

Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, Zhang B, Wang M, Mao F, Yan Y, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther. 2013;4(2):34.

Katagiri W, Osugi M, Kawai T, Hibi H. First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. Head Face Med. 2016;12:5.

Batrakova EV, Kim MS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release. 2015;219:396–405.

Demirer GS, Zhang H, Matos JL, Goh NS, Cunningham FJ, Sung Y, Chang R, Aditham AJ, Chio L, Cho MJ, et al. High aspect ratio nanomaterials enable delivery of functional genetic material without DNA integration in mature plants. Nat Nanotechnol. 2019;14(5):456–64.

Elsharkasy OM, Nordin JZ, Hagey DW, de Jong OG, Schiffelers RM, Andaloussi SE, Vader P. Extracellular vesicles as drug delivery systems: why and how? Adv Drug Deliv Rev. 2020;159:332–43.

Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066.

Farooqi AA, Desai NN, Qureshi MZ, Librelotto DRN, Gasparri ML, Bishayee A, Nabavi SM, Curti V, Daglia M. Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds. Biotechnol Adv. 2018;36(1):328–34.

Samal S, Dash P, Dash M. Drug delivery to the bone microenvironment mediated by exosomes: an axiom or enigma. Int J Nanomed. 2021;16:3509–40.

Ren J, He W, Zheng L, Duan H. From structures to functions: insights into exosomes as promising drug delivery vehicles. Biomater Sci. 2016;4(6):910–21.

Barile L, Vassalli G. Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017;174:63–78.

Tang XJ, Sun XY, Huang KM, Zhang L, Yang ZS, Zou DD, Wang B, Warnock GL, Dai LJ, Luo J. Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy. Oncotarget. 2015;6(42):44179–90.

Tian X, Zhu M, Nie G. How can nanotechnology help membrane vesicle-based cancer immunotherapy development? Hum Vaccin Immunother. 2013;9(1):222–5.

Sterzenbach U, Putz U, Low LH, Silke J, Tan SS, Howitt J. Engineered exosomes as vehicles for biologically active proteins. Mol Ther. 2017;25(6):1269–78.

Zhu Q, Heon M, Zhao Z, He M. Microfluidic engineering of exosomes: editing cellular messages for precision therapeutics. Lab Chip. 2018;18(12):1690–703.

Luan X, Sansanaphongpricha K, Myers I, Chen H, Yuan H, Sun D. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol Sin. 2017;38(6):754–63.

Pascucci L, Cocce V, Bonomi A, Ami D, Ceccarelli P, Ciusani E, Vigano L, Locatelli A, Sisto F, Doglia SM, et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J Control Release. 2014;192:262–70.

Wang X, Thomsen P. Mesenchymal stem cell-derived small extracellular vesicles and bone regeneration. Basic Clin Pharmacol Toxicol. 2021;128(1):18–36.

Yang BC, Kuang MJ, Kang JY, Zhao J, Ma JX, Ma XL. Human umbilical cord mesenchymal stem cell-derived exosomes act via the miR-1263/Mob1/Hippo signaling pathway to prevent apoptosis in disuse osteoporosis. Biochem Biophys Res Commun. 2020;524(4):883–9.

Qi X, Zhang J, Yuan H, Xu Z, Li Q, Niu X, Hu B, Wang Y, Li X. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci. 2016;12(7):836–49.

Liao W, Ning Y, Xu HJ, Zou WZ, Hu J, Liu XZ, Yang Y, Li ZH. BMSC-derived exosomes carrying microRNA-122-5p promote proliferation of osteoblasts in osteonecrosis of the femoral head. Clin Sci (Lond). 2019;133(18):1955–75.

He J, Ren W, Wang W, Han W, Jiang L, Zhang D, Guo M. Exosomal targeting and its potential clinical application. Drug Deliv Transl Res. 2022;12(10):2385–402.

Chen S, Sun F, Qian H, Xu W, Jiang J. Preconditioning and engineering strategies for improving the efficacy of mesenchymal stem cell-derived exosomes in cell-free therapy. Stem Cells Int. 2022;2022:1779346.

Liu X, Yang Y, Li Y, Niu X, Zhao B, Wang Y, Bao C, Xie Z, Lin Q, Zhu L. Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration. Nanoscale. 2017;9(13):4430–8.

Imai T, Takahashi Y, Nishikawa M, Kato K, Morishita M, Yamashita T, Matsumoto A, Charoenviriyakul C, Takakura Y. Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice. J Extracell Vesicles. 2015;4:26238.

Al-Sowayan B, Alammari F, Alshareeda A. Preparing the bone tissue regeneration ground by exosomes: from diagnosis to therapy. Molecules. 2020;25(18):4205.

Xie Y, Chen Y, Zhang L, Ge W, Tang P. The roles of bone-derived exosomes and exosomal microRNAs in regulating bone remodelling. J Cell Mol Med. 2017;21(5):1033–41.

Gao M, Gao W, Papadimitriou JM, Zhang C, Gao J, Zheng M. Exosomes-the enigmatic regulators of bone homeostasis. Bone Res. 2018;6:36.

Wang D, Cao H, Hua W, Gao L, Yuan Y, Zhou X, Zeng Z. Mesenchymal stem cell-derived extracellular vesicles for bone defect repair. Membranes (Basel). 2022;12(7):716.

Yang H, Cong M, Huang W, Chen J, Zhang M, Gu X, Sun C, Yang H. The effect of human bone marrow mesenchymal stem cell-derived exosomes on cartilage repair in rabbits. Stem Cells Int. 2022;2022:5760107.

Yahao G, Xinjia W. The role and mechanism of exosomes from umbilical cord mesenchymal stem cells in inducing osteogenesis and preventing osteoporosis. Cell Transplant. 2021;30:9636897211057464.

Liang B, Liang JM, Ding JN, Xu J, Xu JG, Chai YM. Dimethyloxaloylglycine-stimulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/mTOR pathway. Stem Cell Res Ther. 2019;10(1):335.

Maity S, Das F, Ghosh-Choudhury N, Kasinath BS, Ghosh CG. High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis. FEBS Lett. 2019;593(16):2261–72.

Liu L, Guo S, Shi W, Liu Q, Huo F, Wu Y, Tian W. Bone marrow mesenchymal stem cell-derived small extracellular vesicles promote periodontal regeneration. Tissue Eng Part A. 2021;27(13–14):962–76.

Zhang Y, Xiong Y, Chen X, Chen C, Zhu Z, Li L. Therapeutic effect of bone marrow mesenchymal stem cells pretreated with acetylsalicylic acid on experimental periodontitis in rats. Int Immunopharmacol. 2018;54:320–8.

Filipowska J, Tomaszewski KA, Niedzwiedzki L, Walocha JA, Niedzwiedzki T. The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis. 2017;20(3):291–302.

Huang J, Zhao L, Xing L, Chen D. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells. 2010;28(2):357–64.

Xu S, Cecilia Santini G, De Veirman K, Vande Broek I, Leleu X, De Becker A, Van Camp B, Vanderkerken K, Van Riet I. Upregulation of miR-135b is involved in the impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients. PLoS ONE. 2013;8(11):e79752.

Kim YJ, Bae SW, Yu SS, Bae YC, Jung JS. miR-196a regulates proliferation and osteogenic differentiation in mesenchymal stem cells derived from human adipose tissue. J Bone Miner Res. 2009;24(5):816–25.

Loi F, Cordova LA, Pajarinen J, Lin TH, Yao Z, Goodman SB. Inflammation, fracture and bone repair. Bone. 2016;86:119–30.

Chen Z, Chen L, Liu R, Lin Y, Chen S, Lu S, Lin Z, Chen Z, Wu C, Xiao Y. The osteoimmunomodulatory property of a barrier collagen membrane and its manipulation via coating nanometer-sized bioactive glass to improve guided bone regeneration. Biomater Sci. 2018;6(5):1007–19.

Li R, Li D, Wang H, Chen K, Wang S, Xu J, Ji P. Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF. Stem Cell Res Ther. 2022;13(1):149.

Wu P, Zhang B, Ocansey DKW, Xu W, Qian H. Extracellular vesicles: a bright star of nanomedicine. Biomaterials. 2021;269:120467.

Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WC. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem Cells Int. 2016;2016:3924858.

Gorgun C, Ceresa D, Lesage R, Villa F, Reverberi D, Balbi C, Santamaria S, Cortese K, Malatesta P, Geris L, et al. Dissecting the effects of preconditioning with inflammatory cytokines and hypoxia on the angiogenic potential of mesenchymal stromal cell (MSC)-derived soluble proteins and extracellular vesicles (EVs). Biomaterials. 2021;269:120633.

Ejtehadifar M, Shamsasenjan K, Movassaghpour A, Akbarzadehlaleh P, Dehdilani N, Abbasi P, Molaeipour Z, Saleh M. The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull. 2015;5(2):141–9.

Das R, Jahr H, van Osch GJ, Farrell E. The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. Tissue Eng Part B Rev. 2010;16(2):159–68.

Yan F, Yao Y, Chen L, Li Y, Sheng Z, Ma G. Hypoxic preconditioning improves survival of cardiac progenitor cells: role of stromal cell derived factor-1alpha-CXCR4 axis. PLoS ONE. 2012;7(7):e37948.

Gao Y, Yuan Z, Yuan X, Wan Z, Yu Y, Zhan Q, Zhao Y, Han J, Huang J, Xiong C, et al. Bioinspired porous microspheres for sustained hypoxic exosomes release and vascularized bone regeneration. Bioact Mater. 2022;14:377–88.

Liu W, Li L, Rong Y, Qian D, Chen J, Zhou Z, Luo Y, Jiang D, Cheng L, Zhao S, et al. Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater. 2020;103:196–212.

Tang TT, Wang B, Wu M, Li ZL, Feng Y, Cao JY, Yin D, Liu H, Tang RN, Crowley SD, et al. Extracellular vesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI. Sci Adv. 2020;6(33):eaaz748.

Liu W, Rong Y, Wang J, Zhou Z, Ge X, Ji C, Jiang D, Gong F, Li L, Chen J, et al. Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization. J Neuroinflammation. 2020;17(1):47.

Wang J, Wu H, Peng Y, Zhao Y, Qin Y, Zhang Y, Xiao Z. Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of PI3K/Akt pathways. J Nanobiotechnol. 2021;19(1):202.

Article   CAS   Google Scholar  

Zhu LP, Tian T, Wang JY, He JN, Chen T, Pan M, Xu L, Zhang HX, Qiu XT, Li CC, et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics. 2018;8(22):6163–77.

Zhang CS, Shao K, Liu CW, Li CJ, Yu BT. Hypoxic preconditioning BMSCs-exosomes inhibit cardiomyocyte apoptosis after acute myocardial infarction by upregulating microRNA-24. Eur Rev Med Pharmacol Sci. 2019;23(15):6691–9.

PubMed   Google Scholar  

Cheng H, Chang S, Xu R, Chen L, Song X, Wu J, Qian J, Zou Y, Ma J. Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis. Stem Cell Res Ther. 2020;11(1):224.

Gonzalez-King H, Garcia NA, Ontoria-Oviedo I, Ciria M, Montero JA, Sepulveda P. Hypoxia inducible factor-1alpha potentiates jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells. 2017;35(7):1747–59.

Zhang B, Tian X, Qu Z, Hao J, Zhang W. Hypoxia-preconditioned extracellular vesicles from mesenchymal stem cells improve cartilage repair in osteoarthritis. Membranes (Basel). 2022;12(2):225.

Yuan N, Ge Z, Ji W, Li J. Exosomes secreted from hypoxia-preconditioned mesenchymal stem cells prevent steroid-induced osteonecrosis of the femoral head by promoting angiogenesis in rats. Biomed Res Int. 2021;2021:6655225.

Lan YW, Choo KB, Chen CM, Hung TH, Chen YB, Hsieh CH, Kuo HP, Chong KY. Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther. 2015;6:97.

Hawkins KE, Sharp TV, McKay TR. The role of hypoxia in stem cell potency and differentiation. Regen Med. 2013;8(6):771–82.

Berniakovich I, Giorgio M. Low oxygen tension maintains multipotency, whereas normoxia increases differentiation of mouse bone marrow stromal cells. Int J Mol Sci. 2013;14(1):2119–34.

Ahmed NE, Murakami M, Kaneko S, Nakashima M. The effects of hypoxia on the stemness properties of human dental pulp stem cells (DPSCs). Sci Rep. 2016;6:35476.

Hung SP, Ho JH, Shih YR, Lo T, Lee OK. Hypoxia promotes proliferation and osteogenic differentiation potentials of human mesenchymal stem cells. J Orthop Res. 2012;30(2):260–6.

Semenza GL. Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization. J Investig Med. 2016;64(2):361–3.

Chen Z, Lu M, Zhang Y, Wang H, Zhou J, Zhou M, Zhang T, Song J. Oxidative stress state inhibits exosome secretion of hPDLCs through a specific mechanism mediated by PRMT1. J Periodontal Res. 2022;57(6):1101–15.

Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Goncalves RM. Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning. Front Immunol. 2018;9:2837.

Zhang S, Jiang L, Hu H, Wang H, Wang X, Jiang J, Ma Y, Yang J, Hou Y, Xie D, et al. Pretreatment of exosomes derived from hUCMSCs with TNF-alpha ameliorates acute liver failure by inhibiting the activation of NLRP3 in macrophage. Life Sci. 2020;246:117401.

Liang YC, Wu YP, Li XD, Chen SH, Ye XJ, Xue XY, Xu N. TNF-alpha-induced exosomal miR-146a mediates mesenchymal stem cell-dependent suppression of urethral stricture. J Cell Physiol. 2019;234(12):23243–55.

Nakao Y, Fukuda T, Zhang Q, Sanui T, Shinjo T, Kou X, Chen C, Liu D, Watanabe Y, Hayashi C, et al. Exosomes from TNF-alpha-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss. Acta Biomater. 2021;122:306–24.

Wang R, Xu B. TGF-beta1-modified MSC-derived exosomal miR-135b attenuates cartilage injury via promoting M2 synovial macrophage polarization by targeting MAPK6. Cell Tissue Res. 2021;384(1):113–27.

Lu Z, Chen Y, Dunstan C, Roohani-Esfahani S, Zreiqat H. Priming adipose stem cells with tumor necrosis factor-alpha preconditioning potentiates their exosome efficacy for bone regeneration. Tissue Eng Part A. 2017;23(21–22):1212–20.

Kim M, Shin DI, Choi BH, Min BH. Exosomes from IL-1beta-primed mesenchymal stem cells inhibited IL-1beta- and TNF-alpha-mediated inflammatory responses in osteoarthritic SW982 cells. Tissue Eng Regen Med. 2021;18(4):525–36.

Mead B, Chamling X, Zack DJ, Ahmed Z, Tomarev S. TNFalpha-mediated priming of mesenchymal stem cells enhances their neuroprotective effect on retinal ganglion cells. Invest Ophthalmol Vis Sci. 2020;61(2):6.

Liu K, Cai GL, Zhuang Z, Pei SY, Xu SN, Wang YN, Wang H, Wang X, Cui C, Sun MC, et al. Interleukin-1beta-treated mesenchymal stem cells inhibit inflammation in hippocampal astrocytes through Exosome-activated Nrf-2 signaling. Int J Nanomed. 2021;16:1423–34.

Wang S, Umrath F, Cen W, Salgado AJ, Reinert S, Alexander D. Pre-conditioning with IFN-gamma and hypoxia enhances the angiogenic potential of iPSC-derived MSC secretome. Cells. 2022;11(6):988.

Cecerska-Heryc E, Goszka M, Serwin N, Roszak M, Grygorcewicz B, Heryc R, Dolegowska B. Applications of the regenerative capacity of platelets in modern medicine. Cytokine Growth Fact Rev. 2022;64:84–94.

Mirabel C, Puente-Massaguer E, Del Mazo-Barbara A, Reyes B, Morton P, Godia F, Vives J. Stability enhancement of clinical grade multipotent mesenchymal stromal cell-based products. J Transl Med. 2018;16(1):291.

Jing H, Zhang X, Luo K, Luo Q, Yin M, Wang W, Zhu Z, Zheng J, He X. miR-381-abundant small extracellular vesicles derived from kartogenin-preconditioned mesenchymal stem cells promote chondrogenesis of MSCs by targeting TAOK1. Biomaterials. 2020;231:119682.

Liu C, Li Y, Yang Z, Zhou Z, Lou Z, Zhang Q. Kartogenin enhances the therapeutic effect of bone marrow mesenchymal stem cells derived exosomes in cartilage repair. Nanomedicine (Lond). 2020;15(3):273–88.

Qiu B, Xu X, Yi P, Hao Y. Curcumin reinforces MSC-derived exosomes in attenuating osteoarthritis via modulating the miR-124/NF-kB and miR-143/ROCK1/TLR9 signalling pathways. J Cell Mol Med. 2020;24(18):10855–65.

Joo HS, Suh JH, Lee HJ, Bang ES, Lee JM. Current knowledge and future perspectives on mesenchymal stem cell-derived exosomes as a new therapeutic agent. Int J Mol Sci. 2020;21(3):727.

Cheng J, Sun Y, Ma Y, Ao Y, Hu X, Meng Q. Engineering of MSC-derived exosomes: a promising cell-free therapy for osteoarthritis. Membranes (Basel). 2022;12(8):739.

Hassanzadeh A, Rahman HS, Markov A, Endjun JJ, Zekiy AO, Chartrand MS, Beheshtkhoo N, Kouhbanani MAJ, Marofi F, Nikoo M, et al. Mesenchymal stem/stromal cell-derived exosomes in regenerative medicine and cancer; overview of development, challenges, and opportunities. Stem Cell Res Ther. 2021;12(1):297.

Chen S, Tang Y, Liu Y, Zhang P, Lv L, Zhang X, Jia L, Zhou Y. Exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration. Cell Prolif. 2019;52(5):e12669.

Liu W, Yu M, Chen F, Wang L, Ye C, Chen Q, Zhu Q, Xie D, Shao M, Yang L. A novel delivery nanobiotechnology: engineered miR-181b exosomes improved osteointegration by regulating macrophage polarization. J Nanobiotechnol. 2021;19(1):269.

Tao SC, Yuan T, Zhang YL, Yin WJ, Guo SC, Zhang CQ. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 2017;7(1):180–95.

Huang CC, Kang M, Lu Y, Shirazi S, Diaz JI, Cooper LF, Gajendrareddy P, Ravindran S. Functionally engineered extracellular vesicles improve bone regeneration. Acta Biomater. 2020;109:182–94.

Li F, Wu J, Li D, Hao L, Li Y, Yi D, Yeung KWK, Chen D, Lu WW, Pan H, et al. Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy. J Nanobiotechnol. 2022;20(1):135.

Li H, Liu D, Li C, Zhou S, Tian D, Xiao D, Zhang H, Gao F, Huang J. Exosomes secreted from mutant-HIF-1alpha-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit. Cell Biol Int. 2017;41(12):1379–90.

Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18–30.

Piffoux M, Volatron J, Cherukula K, Aubertin K, Wilhelm C, Silva AKA, Gazeau F. Engineering and loading therapeutic extracellular vesicles for clinical translation: a data reporting frame for comparability. Adv Drug Deliv Rev. 2021;178:113972.

Yerneni SS, Adamik J, Weiss LE, Campbell PG. Cell trafficking and regulation of osteoblastogenesis by extracellular vesicle associated bone morphogenetic protein 2. J Extracell Vesicles. 2021;10(12):e12155.

Zha Y, Li Y, Lin T, Chen J, Zhang S, Wang J. Progenitor cell-derived exosomes endowed with VEGF plasmids enhance osteogenic induction and vascular remodeling in large segmental bone defects. Theranostics. 2021;11(1):397–409.

Luo ZW, Li FX, Liu YW, Rao SS, Yin H, Huang J, Chen CY, Hu Y, Zhang Y, Tan YJ, et al. Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration. Nanoscale. 2019;11(43):20884–92.

Hu Y, Li X, Zhang Q, Gu Z, Luo Y, Guo J, Wang X, Jing Y, Chen X, Su J. Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss. Bioact Mater. 2021;6(9):2905–13.

Zhang M, Li Y, Feng T, Li R, Wang Z, Zhang L, Yin P, Tang P. Bone engineering scaffolds with exosomes: a promising strategy for bone defects repair. Front Bioeng Biotechnol. 2022;10:920378.

Glenske K, Donkiewicz P, Kowitsch A, Milosevic-Oljaca N, Rider P, Rofall S, Franke J, Jung O, Smeets R, Schnettler R, et al. Applications of metals for bone regeneration. Int J Mol Sci. 2018;19(3):826.

Lu H, Zhang Y, Xiong S, Zhou Y, Xiao L, Ma Y, Xiao Y, Wang X. Modulatory role of silver nanoparticles and mesenchymal stem cell-derived exosome-modified barrier membrane on macrophages and osteogenesis. Front Chem. 2021;9:699802.

Zhai M, Zhu Y, Yang M, Mao C. Human mesenchymal stem Cell derived exosomes enhance cell-free bone regeneration by altering their miRNAs profiles. Adv Sci (Weinh). 2020;7(19):2001334.

Fernandes JS, Gentile P, Pires RA, Reis RL, Hatton PV. Multifunctional bioactive glass and glass-ceramic biomaterials with antibacterial properties for repair and regeneration of bone tissue. Acta Biomater. 2017;59:2–11.

Baino F, Fiorilli S, Vitale-Brovarone C. Bioactive glass-based materials with hierarchical porosity for medical applications: review of recent advances. Acta Biomater. 2016;42:18–32.

Liu A, Lin D, Zhao H, Chen L, Cai B, Lin K, Shen SG. Optimized BMSC-derived osteoinductive exosomes immobilized in hierarchical scaffold via lyophilization for bone repair through Bmpr2/Acvr2b competitive receptor-activated Smad pathway. Biomaterials. 2021;272:120718.

Bohner M, Santoni BLG, Dobelin N. beta-tricalcium phosphate for bone substitution: synthesis and properties. Acta Biomater. 2020;113:23–41.

Zhang J, Liu X, Li H, Chen C, Hu B, Niu X, Li Q, Zhao B, Xie Z, Wang Y. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther. 2016;7(1):136.

Ying C, Wang R, Wang Z, Tao J, Yin W, Zhang J, Yi C, Qi X, Han D. BMSC-exosomes carry mutant HIF-1alpha for improving angiogenesis and osteogenesis in critical-sized calvarial defects. Front Bioeng Biotechnol. 2020;8:565561.

Wu J, Chen L, Wang R, Song Z, Shen Z, Zhao Y, Huang S, Lin Z. Exosomes secreted by stem cells from human exfoliated deciduous teeth promote alveolar bone defect repair through the regulation of angiogenesis and osteogenesis. ACS Biomater Sci Eng. 2019;5(7):3561–71.

Lei F, Li M, Lin T, Zhou H, Wang F, Su X. Treatment of inflammatory bone loss in periodontitis by stem cell-derived exosomes. Acta Biomater. 2022;141:333–43.

Teotia AK, Qayoom I, Singh P, Mishra A, Jaiman D, Seppala J, Lidgren L, Kumar A. Exosome-functionalized ceramic bone substitute promotes critical-sized bone defect repair in rats. ACS Appl Bio Mater. 2021;4(4):3716–26.

Pishavar E, Luo H, Naserifar M, Hashemi M, Toosi S, Atala A, Ramakrishna S, Behravan J. Advanced hydrogels as exosome delivery systems for osteogenic differentiation of MSCs: application in bone regeneration. Int J Mol Sci. 2021;22(12):6203.

Khayambashi P, Iyer J, Pillai S, Upadhyay A, Zhang Y, Tran SD. Hydrogel encapsulation of mesenchymal stem cells and their derived exosomes for tissue engineering. Int J Mol Sci. 2021;22(2):684.

Zhai P, Peng X, Li B, Liu Y, Sun H, Li X. The application of hyaluronic acid in bone regeneration. Int J Biol Macromol. 2020;151:1224–39.

Zhang Y, Xie Y, Hao Z, Zhou P, Wang P, Fang S, Li L, Xu S, Xia Y. Umbilical mesenchymal stem cell-derived exosome-encapsulated hydrogels accelerate bone repair by enhancing angiogenesis. ACS Appl Mater Interfaces. 2021;13(16):18472–87.

Yang S, Zhu B, Yin P, Zhao L, Wang Y, Fu Z, Dang R, Xu J, Zhang J, Wen N. Integration of human umbilical cord mesenchymal stem cells-derived exosomes with hydroxyapatite-embedded hyaluronic acid-alginate hydrogel for bone regeneration. ACS Biomater Sci Eng. 2020;6(3):1590–602.

Wu D, Qin H, Wang Z, Yu M, Liu Z, Peng H, Liang L, Zhang C, Wei X. Bone mesenchymal stem cell-derived sEV-encapsulated thermosensitive hydrogels accelerate osteogenesis and angiogenesis by release of exosomal miR-21. Front Bioeng Biotechnol. 2021;9:829136.

Shen Z, Kuang S, Zhang Y, Yang M, Qin W, Shi X, Lin Z. Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism. Bioact Mater. 2020;5(4):1113–26.

Ma S, Wu J, Hu H, Mu Y, Zhang L, Zhao Y, Bian X, Jing W, Wei P, Zhao B, et al. Novel fusion peptides deliver exosomes to modify injectable thermo-sensitive hydrogels for bone regeneration. Mater Today Bio. 2022;13:100195.

Jing X, Wang S, Tang H, Li D, Zhou F, Xin L, He Q, Hu S, Zhang T, Chen T, et al. Dynamically bioresponsive DNA hydrogel incorporated with dual-functional stem cells from apical papilla-derived exosomes promotes diabetic bone regeneration. ACS Appl Mater Interfaces. 2022;14(14):16082–99.

Wang L, Wang J, Zhou X, Sun J, Zhu B, Duan C, Chen P, Guo X, Zhang T, Guo H. A new self-healing hydrogel containing hucMSC-derived exosomes promotes bone regeneration. Front Bioeng Biotechnol. 2020;8:564731.

Kang Y, Xu C, Meng L, Dong X, Qi M, Jiang D. Exosome-functionalized magnesium-organic framework-based scaffolds with osteogenic, angiogenic and anti-inflammatory properties for accelerated bone regeneration. Bioact Mater. 2022;18:26–41.

Zhang B, Huang J, Liu J, Lin F, Ding Z, Xu J. Injectable composite hydrogel promotes osteogenesis and angiogenesis in spinal fusion by optimizing the bone marrow mesenchymal stem cell microenvironment and exosomes secretion. Mater Sci Eng C Mater Biol Appl. 2021;123:111782.

Li W, Liu Y, Zhang P, Tang Y, Zhou M, Jiang W, Zhang X, Wu G, Zhou Y. Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration. ACS Appl Mater Interfaces. 2018;10(6):5240–54.

Swanson WB, Zhang Z, Xiu K, Gong T, Eberle M, Wang Z, Ma PX. Scaffolds with controlled release of pro-mineralization exosomes to promote craniofacial bone healing without cell transplantation. Acta Biomater. 2020;118:215–32.

Zhang Y, Huo M, Wang Y, Xiao L, Wu J, Ma Y, Zhang D, Lang X, Wang X. A tailored bioactive 3D porous poly(lactic-acid)-exosome scaffold with osteo-immunomodulatory and osteogenic differentiation properties. J Biol Eng. 2022;16(1):22.

Fan L, Guan P, Xiao C, Wen H, Wang Q, Liu C, Luo Y, Ma L, Tan G, Yu P, et al. Exosome-functionalized polyetheretherketone-based implant with immunomodulatory property for enhancing osseointegration. Bioact Mater. 2021;6(9):2754–66.

Meng W, He C, Hao Y, Wang L, Li L, Zhu G. Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source. Drug Deliv. 2020;27(1):585–98.

Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19.

Momen-Heravi F, Balaj L, Alian S, Mantel PY, Halleck AE, Trachtenberg AJ, Soria CE, Oquin S, Bonebreak CM, Saracoglu E, et al. Current methods for the isolation of extracellular vesicles. Biol Chem. 2013;394(10):1253–62.

Li P, Kaslan M, Lee SH, Yao J, Gao Z. Progress in exosome isolation techniques. Theranostics. 2017;7(3):789–804.

Phan J, Kumar P, Hao D, Gao K, Farmer D, Wang A. Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy. J Extracell Vesicles. 2018;7(1):1522236.

Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol. 2021;16(7):748–59.

Wang W, Liang X, Zheng K, Ge G, Chen X, Xu Y, Bai J, Pan G, Geng D. Horizon of exosome-mediated bone tissue regeneration: The all-rounder role in biomaterial engineering. Mater Today Bio. 2022;16:100355.

Vader P, Mol EA, Pasterkamp G, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev. 2016;106(Pt A):148–56.

Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery - a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013;31(5):543–51.

Li X, Zheng Y, Hou L, Zhou Z, Huang Y, Zhang Y, Jia L, Li W. Exosomes derived from maxillary BMSCs enhanced the osteogenesis in iliac BMSCs. Oral Dis. 2020;26(1):131–44.

Xu T, Luo Y, Wang J, Zhang N, Gu C, Li L, Qian D, Cai W, Fan J, Yin G. Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5. J Nanobiotechnol. 2020;18(1):47.

Borger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, Giebel B. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci. 2017;18(7):1450.

Henkel J, Woodruff MA, Epari DR, Steck R, Glatt V, Dickinson IC, Choong PF, Schuetz MA, Hutmacher DW. Bone regeneration based on tissue engineering conceptions: a 21st century perspective. Bone Res. 2013;1(3):216–48.

Merimi M, El-Majzoub R, Lagneaux L, Moussa Agha D, Bouhtit F, Meuleman N, Fahmi H, Lewalle P, Fayyad-Kazan M, Najar M. The therapeutic potential of mesenchymal stromal cells for regenerative medicine: current knowledge and future understandings. Front Cell Dev Biol. 2021;9:661532.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81901006), Guangdong Basic and Applied Basic Research Foundation (2020A1515110051), Scientific Research Talent Cultivation Project of Stomatological Hospital, Southern Medical University (RC202005) and Science Research Cultivation Program of Stomatological Hospital, Southern Medical University (PY2020002).

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Ye Lu and Zizhao Mai contributed equally to this work

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Stomatological Hospital, School of Stomatology, Southern Medical University, 510280, Guangzhou, China

Ye Lu, Zizhao Mai, Li Cui & Xinyuan Zhao

School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA

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All authors contributed to the conception and the main idea of the work. XZ, LC, YL and ZM drafted the manuscript. YL and ZM designed the tables and figures. XZ and LC supervised and revised the work. All authors read and approved the final manuscript.

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Correspondence to Li Cui or Xinyuan Zhao .

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Lu, Y., Mai, Z., Cui, L. et al. Engineering exosomes and biomaterial-assisted exosomes as therapeutic carriers for bone regeneration. Stem Cell Res Ther 14 , 55 (2023). https://doi.org/10.1186/s13287-023-03275-x

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Received : 16 October 2022

Accepted : 08 March 2023

Published : 29 March 2023

DOI : https://doi.org/10.1186/s13287-023-03275-x

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