phd in tissue engineering and regenerative medicine

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Tissue Engineering and Regenerative Medicine

Research in tissue engineering and regenerative medicine seeks to replace or regenerate diseased or damaged tissues, organs, and cells – a challenging endeavor, but one that has tremendous potential for the practice of medicine.

Technologies under investigation range from biomaterial/cell constructs for repairing various tissues and organs, to stem cell therapies, to immune therapies. Our work in this area is highly multidisciplinary, combining materials science, cell biology, clinical science, immunology, stem cell biology, genome science, and others.

Accordingly, researchers in this area within Duke BME are broadly interactive with departments throughout the university including Duke University Medical Center clinical departments, the Duke University School of Medicine departments of Cell Biology and Immunology, the Duke Department of Chemistry, and others. This community is also supported by centers and programs such as Regeneration Next and the Center for Biomolecular and Tissue Engineering (CBTE) .

Primary Faculty

Nenad Bursac

Professor of Biomedical Engineering

Research Interests: Embryonic and adult stem cell therapies for heart and muscle disease; cardiac and skeletal muscle tissue engineering; cardiac electrophysiology and arrhythmias; genetic modifications of stem and somatic cells; micropatterning of proteins and hydrogels.

Pranam D. Chatterjee

Assistant Professor of Biomedical Engineering

Research Interests: Integration of computational and experimental methodologies to design novel proteins for applications in genome editing, targeted protein modulation, and reproductive bioengineering

Joel Collier

Theodore Kennedy Professor of Biomedical Engineering

Research Interests: The design of biomaterials for a range of biomedical applications, with a focus on understanding and controlling adaptive immune responses. Most materials investigated are created from molecular assemblies- proteins, peptides or bioconjugates that self-organize into useful…

Sharon Gerecht

Paul M. Gross Distinguished Professor of Biomedical Engineering

Research Interests: stem cells, biomaterials, hypoxia, blood vessels, physics of cancer, regenerative medicine

Charles Gersbach

John W. Strohbehn Distinguished Professor of Biomedical Engineering

Research Interests: Gene therapy, genomics and epigenomics, biomolecular and cellular engineering, regenerative medicine, and synthetic biology.

John Wirthlin Hickey

Samira Musah

Assistant Professor in the Department of Biomedical Engineering

Research Interests: Induced pluripotent stem cells (iPS cells), disease mechanisms, regenerative medicine, molecular and cellular basis of human kidney development and disease, organ engineering, patient-specific disease models, biomarkers, therapeutic discovery, tissue and organ transplantation,…

Tatiana Segura

Research Interests: The design of biomaterials to promote endogenous repair and reducing inflammation through the design of the geometry of the material, and delivering genes, proteins and drugs.

George A. Truskey

R. Eugene and Susie E. Goodson Distinguished Professor of Biomedical Engineering

Research Interests: Cardiovascular tissue engineering, mechanisms of atherogenesis, cell adhesion, and cell biomechanics.

Shyni Varghese

Professor of Biomedical Engineering, Mechanical Engineering & Materials Science and Orthopaedics

Research Interests: Musculoskeletal tissue repair, disease biophysics and organ-on-a-chip technology

Secondary Faculty

Geoffrey Steven Ginsburg

Adjunct Professor in the Department of Medicine

Cynthia Ann Toth

Joseph A.C. Wadsworth Distinguished Professor of Ophthalmology

Stefan Zauscher

Professor in the Thomas Lord Department of Mechanical Engineering and Materials Science

Research Interests: Nano-mechanical and nano-tribological characterization (elasticity, friction, adhesion) of materials including organic thin films; self-assembled monolayers, polymeric gels, and cellulosics; Fabrication of polymeric nanostructures by scanning probe lithography; Colloidal probe…

Adjunct Faculty

Jennifer L West

Adjunct Professor of Biomedical Engineering

Research Interests: Biomaterials, nanotechnology and tissue engineering that involves the synthesis, development, and application of novel biofunctional materials, and the use of biomaterials and engineering approaches to study biological problems.

Faculty Emeritus

William M. Reichert

Professor Emeritus of Biomedical Engineering

Research Interests: Biosensors, protein mediated cell adhesion, and wound healing.

Updates on COVID-19 for Grad Students and Postdocs

Graduate program in stem cell biology & regenerative medicine, stanford is a world leader in stem cell research and regenerative medicine. central discoveries in stem cell biology – tissue stem cells and their use for regenerative therapies, transdifferentiation into mature cell-types, isolation of cancerous stem cells, and stem cell signaling pathways – were made by stanford faculty and students. our mission is to train the next generation of stem cell scientists..

About the SCBRM Graduate Program

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Stem Cell PhD Program

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Learn about the many ways to support the institute for Stem Cell Biology and Regenerative Medicine

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Regenerative Sciences

Regenerative sciences track.

faculty spanning multidisciplinary departments

education in discovery, clinical translation, and application of regenerative solutions

Guaranteed 5-year internal fellowship

includes full tuition, stipend and benefits

Seeking to spur development of innovative medical breakthroughs, Mayo Clinic Graduate School of Biomedical Sciences, in partnership with the Center for Regenerative Biotherapeutics , started one of the nation's first doctoral research training programs in regenerative sciences.

Regenerative medicine is transforming clinical practice with the development of new therapies, treatments and surgeries for patients with chronic conditions, debilitating injuries and degenerative diseases. Advances in developmental and cell biology, immunology, and other fields unlock new opportunities for innovative breakthroughs for the next generation of regenerative diagnostic and therapeutic medical solutions.

The Regenerative Sciences (REGS) Ph.D. track at Mayo Clinic is a transdisciplinary Ph.D. Program designed to prepare the next generation of scientists to accelerate the discovery, translation, and application of cutting-edge regenerative diagnostics and therapeutics. The REGS Ph.D. track builds on the existing Mayo Clinic Regenerative Sciences Training Program (RSTP) to now offer in-depth curriculum and advanced training opportunities. 

The Regenerative Sciences Track places a significant emphasis on laboratory-based research training. Laboratory research is complemented with both core and track-specific courses, as well as advanced courses on current topics in regenerative science and medicine.

The regenerative sciences curriculum encompasses the full spectrum of regenerative science topics, including molecular and cell biology, stem cell biology, developmental biology, tissue engineering, biomaterials and nanomedicine, genome editing and gene therapies, regulatory and translational science, product development, biomanufacturing, entrepreneurship and more.

Students in Regenerative Sciences join a close-knit community of learners, are provided unique hands-on- experiences and collaborate with some of the brightest minds in the field.

See the full Regenerative Sciences Track curriculum (PDF)

Graduates of the Regenerative Sciences Ph.D. track will be integral to forming the multidisciplinary workforce needed to drive the future of health care at Mayo Clinic and across the world.

Learn more:  What is Regenerative Medicine - Mayo Clinic Radio

Focus areas

• Molecular and epigenetic mechanisms of stem and progenitor cell proliferation and differentiation, as well as tissue degeneration and regeneration
• Immune responses to viral insult and tissue healing
• Gene editing for cell therapy applications and to alter disease progression
• Extracellular vesicles in disease progression and for tissue regeneration
• Tissue engineering and bioengineering of novel therapies, including 3-D printing, electrospinning, and advanced biomanufacturing 

Mayo Clinic is an incredible place for doctoral training in regenerative science. The interdisciplinary strategy here allows research and courses to be tailored according to each student’s interests and ability. Moreover, Mayo Clinic provides a wealth resource to develop collaborations within the institution, which will offer students more ways to communicate and promote students to achieve their personal goals.

Shan Gao Ph.D. student, Regenerative Sciences Track

Mayo Clinic provides unparalleled access to world-renowned clinicians and researchers all focused on clinically relevant research. Mayo Clinic’s Center for Regenerative Medicine permeates throughout the institution. Thus, the REGS program gives students the necessary experience and knowledge to drive future research in restoring form and function in any field of medicine.

Armin Garmany M.D.-Ph.D. student, Regenerative Sciences Track

The study of Regenerative Sciences (REGS) at Mayo Clinic is unparalleled. Students are funded to study cutting-edge biomedical science in their domain of interest with plentiful opportunities to translate benchside discoveries to the patient bedside and beyond. I chose Mayo Clinic's REGS program to join its community of researchers, practitioners, and entrepreneurs who everyday advance the science and practice of regenerative medicine and bring new regenerative solutions to the world.

Samuel Buchl Ph.D. student, Regenerative Sciences Track

The Regenerative Sciences Ph.D. track at Mayo Clinic thoroughly equips students to be leaders in biomedical research through an unmatched curriculum of multidisciplinary science and world-class research training. REGS is a collaborative and supportive program in a promising field of medicine that provides the foundational skills to pipeline research to patient care.

Delaney Liskey Ph.D. student, Regenerative Sciences Track

Thesis topics

Current students thesis topics.

• "Targeted Regenerative Therapies for Heart Failure Susceptibility," Armin Garmany (Mentor: Andre Terzic, M.D., Ph.D.)
• "Novel Look Into the Crude Stromal Vascular Fraction (SVF) from Human Adipose-Derived Tissue and Its Role in Regulating the Self-Renewing Capacity of Brain Tumor-Initiating Cells," Rawan Alkharboosh (Mentor: Alfredo Quinones-Hinojosa, M.D.)
• "Tissue Quality in Existing and Emerging Treatments for Osteoarthritis," Katherine Arnold (Mentor: Jennifer Westendorf, Ph.D.)
• "Harnessing the Mesenchymal Stem Cell Secretome to Target Alpha-Synuclein-Associated Dysfunction in Parkinson's Disease," Jeremy Burgess (Mentor: Pamela McLean, Ph.D.)
• "Retinal Neuroprotection Properties of an ATP-Sensitive Potassium Channel Opener," Catherine Knier (Mentor: Michael Fautsch, Ph.D.)
• "Towards a Subcutaneous Combination Biodevice for the Treatment of Type 1 Diabetes," Ethan Law (Mentor: Quinn Peterson, Ph.D.)
• "Modulation of CART Cell Activation to Enhance Antitumor Response via CRISPR-mediated Gene Editing and Combined Immunotherapy," Claudia Manriquez Roman (Mentor: Saad Kenderian, M.B., Ch.B.)
• "Systems Biology for Engineering Regenerative Immunotherapies in Precision Neuro-oncology," Dileep Monie (Mentors: Hu Li, Ph.D. and Richard Vile, Ph.D.
• "APOE2 Effects on Central and Peripheral Vasculature," Francis Shue (Mentor: Guojun Bu, Ph.D.)
• "Engineering of Antiviral Extracellular Vesicles," Amanda Terlap (Mentor: Atta Behfar, M.D., Ph.D.) 
• "Glycome of Breast Cancer-Derived Extracellular Vesicles in Metastasis," Sierra Walker (Mentor: Joy Wolfram, Ph.D.)
• "Bidirectional Interactions Between Stem Cell Populations of the Subventricular Zone and Glioblastoma," Emily Norton (Mentor: Hugo Guerrero Cazares, M.D., Ph.D.)
• "Measles Virus Vector for Gene Editing and Reprogramming of Human Fibroblasts," Ramya Rallabandi (Mentor: Patricia Devaux, Ph.D.)
• "Precise Genetic Engineering of Human Primary Cells for Cell Therapy-Based Applications," (Mentor: Stephen Ekker, Ph.D.)

Recent graduates thesis topics

• "Epigenetic Control of the Architectural and Trophic Functions of Mesenchymal Stem Cells in Musculoskeletal Tissue Regeneration Therapies," (Mentor: Andre van Wijnen, Ph.D.)
• "Metabolic Regulation of Muscle Stem Cells," (Mentor: Jason Doles, Ph.D.)
• "Purified Exosome Product Enhances Neovascularization in Peripheral Arterial Disease," (Mentors: Atta Behfar, M.D., Ph.D. and Andre Terzic, M.D., Ph.D.)
• "Antigen Presentation by CNS-Resident Microglia and Macrophages is Required for Antigen-Specific CD8 T Cell Responses in the Brain Following Viral Challenge," (Mentor: Aaron Johnson, Ph.D.)

Meet the director

Training opportunities extend from fundamental science principles through laboratory skills and hands-on experiences. Students will also have the opportunity to develop an understanding of national and international regulatory agencies, and business requirements and procedures needed to implement the discovery, translation, application pipeline for new regenerative technologies.

We are excited to provide a program of training that will serve as an incubator to develop the next generation of leaders in regenerative science and medicine.

Isobel Scarisbrick, Ph.D. Regenerative Sciences Track Director Professor of Physical Medicine & Rehabilitation Phone: 507-284-0124 Email: [email protected] See research interests

Browse a list of Regenerative Sciences Track faculty members

KEY APPLICATION AREA

Tissue Engineering & Regenerative Medicine

Research in tissue engineering and regenerative medicine encompasses all aspects of the research and development continuum from mechanistic studies to translational approaches. Collaborative efforts with colleagues at Rice and the Texas Medical Center address unmet clinical needs for a plethora of tissues ranging from bone to cartilage to heart valve to inner ear.

Specific areas of interest include structure and function relationships in living tissues, synthesis and fabrication of biomimetic materials and extracellular matrix constructs, combinations of biomaterials with cell populations for modulating cell function and guiding tissue growth, stem cell programming, drug and gene delivery systems for tissue induction and regeneration, 3D printing and bioprinting, and bioreactor designs for cell culture and disease modeling.

Rice BIOE researchers working in this key application area:

Caleb bashor, phd, faculty profile | laboratory website, jane grande-allen, phd, isaac hilton, phd, kevin mchugh, phd, antonios mikos, phd, jordan miller, phd, robert raphael, phd, omid veiseh, phd.

Institute for Stem Cell & Regenerative Medicine

Tissue engineering.

These are the faculty members that are specialized in tissue engineering.

Nancy Allbritton, MD, PhD (Bioengineering) Research in my laboratory focuses on the development of novel methods and technologies to answer fundamental questions in biology & medicine.  Much of biology & medicine is technology limited in that leaps in knowledge follow closely on the heels of new discoveries and inventions in the physical and engineering sciences; consequently, interdisciplinary groups which bridge these different disciplines are playing increasingly important roles in biomedical research.  Our lab has developed partnerships with other investigators in the areas of biology, medicine, chemistry, physics, and engineering to design, fabricate, test, and utilize new tools for biomedical and clinical research.  Collaborative projects include novel strategies to measure enzyme activity in single cells using microelectrophoresis innovations, to build organ-on-a-chips particularly intestine-on-chip, array-based methods for cell screening and sorting.  An additional focus area is the development of software and instrumentation to support these applications areas. The ultimate goal is to design and build novel technologies and then translate these technologies into the marketplace to insure their availability to the biomedical research and clinical communities to enable humans to lead healthier and more productive lives.

Cole A. DeForest, PhD  (Chemical Engineering) While the potential for biomaterial-based strategies to improve and extend the quality of human health through tissue regeneration and the treatment of disease continues to grow, the majority of current strategies rely on outdated technology initially developed and optimized for starkly different applications. Therefore, the DeForest Group seeks to integrate the governing principles of rational design with fundamental concepts from material science, synthetic chemistry, and stem cell biology to conceptualize, create, and exploit next-generation materials to address a variety of health-related problems. We are currently interested in the development of new classes of user-programmable hydrogels whose biochemical and biophysical properties can be tuned in time and space over a variety of scales. Our work relies heavily on the utilization of cytocompatible bioorthogonal chemistries, several of which can be initiated with light and thereby confined to specific sub-volumes of a sample. By recapitulating the dynamic nature of the native tissue through 4D control of the material properties, these synthetic environments are utilized to probe and better understand basic cell function as well as to engineer complex heterogeneous tissue.

David A. Dichek, MD (Medicine/Cardiology) Our work focuses on defining the molecular mechanisms that drive aortic aneurysm formation and that precipitate atherosclerotic plaque rupture (the proximal cause of most heart attacks). We are also developing a gene therapy—delivered to the blood vessel wall—that prevents and reverses atherosclerosis. Experiments are performed in a mouse model of heritable thoracic aortic aneurysms, a mouse model of atherosclerotic plaque rupture, and with advanced human plaque tissue. Our gene therapy research uses helper-dependent adenoviral vectors to test therapies in rabbit models of carotid artery and vein graft atherosclerosis.  We anticipate that insights from our work will lead to therapies that prevent or stabilize aortic aneurysms and that prevent and reverse atherosclerosis.

Benjamin Freedman, PhD  (Medicine/Nephrology) Our laboratory has developed techniques to efficiently differentiate hPSCs into kidney organoids in a reproducible, multi-well format – a prototype ‘kidney-in-a-dish’. In addition, we have generated hPSC lines carrying naturally occurring or engineered mutations relevant to human kidney diseases, such as polycystic kidney disease and nephrotic syndrome. The goal of our research is to use these new tools to model human kidney disease and identify therapeutic approaches, including kidney regeneration.

Cecilia Giachelli, PhD  (Bioengineering) My lab is interested in applying stem cell and regenerative medicine strategies to the areas of ectopic calcification, tissue engineering, biomaterials development and biocompatibility.

Ray Monnat, PhD  (Pathology and Genome Sciences) Our research focuses on human RecQ helicase deficiency syndromes such as Werner syndrome; high resolution analyses of DNA replication dynamics; and the engineering of homing endonucleases for targeted gene modification or repair in human and other animal cells.

Tracy E. Popowics, PhD (Oral Health Sciences) Our team focusses on regeneration of the periodontal ligament (PDL) that maintains tooth position and provides support during chewing. Our approach is to engineer three-dimensional (3D) periodontal constructs that mimic the native tissue structure and function. Our 3D PDL constructs include cells that are suspended in collagen matrix and recreate the living PDL tissue. Periodontal tissue loss not only includes loss of the ligament, but also the alveolar bone and cementum that anchor the periodontal ligament and hold the tooth in place. This tissue loss may occur to different degrees during an individual’s lifespan due to changes in oral care, periodontal disease, systemic disease or other health problems. This is particularly true for the aged population in which diminished oral care can contribute to persistent and recurring periodontal inflammation and tissue breakdown. Regenerating these three layers is essential to restore the structural and functional integrity of PDL and to prevent tooth loss.

Feini (Sylvia) Qu, VMD, PhD (Orthopaedics & Sports Medicine, Mechanical Engineering) The long-term goal of our research is to understand the cellular and molecular mechanisms of musculoskeletal tissue regeneration, especially with respect to the bones and connective tissues of limbs and joints, and then leverage this knowledge to regenerate lost or diseased structures using stem cells, gene editing, and biomaterials. Our lab uses the mouse digit tip, one of the few mammalian systems that exhibits true regeneration, to identify pathways that regulate tissue patterning and outgrowth after amputation. Armed with a better understanding of the cues that direct complex tissue formation in adulthood, we will develop therapeutic strategies that enhance the regeneration of limbs and joints after injury and degenerative disease in patients.

Buddy Ratner, PhD  (Bioengineering) Stem cells proliferate and differentiate in response to micromechanical cues, surface biological signals, orientational directives and chemical gradients. To control stem cell proliferation and differentiation, the Ratner lab brings 30 years experience in surface control of biology, polymer scaffold fabrication and controlled release of bioactive agents to address the challenges of directing stem cell differentiation and subsequent tissue formation.

Michael Regnier, PhD  (Bioengineering) The Regnier lab works in a highly collaborative environment to develop both cell replacement and gene therapies approaches to treat diseased and failing hearts and skeletal muscle. Cell replacement strategies include development and testing of tissue engineered constructs. Gene therapies are target and improve myofilament contractile protein function.

Jenny Robinson, PhD (Orthopaedics & Sports Medicine and Mechanical Engineering) Our primary goal is to understand what cues are needed to promote connective tissue (ligament, cartilage, fibrocartilage) regeneration after knee injuries and reduce the onset of osteoarthritis. We have a particular interest on how these cues may differ in male and female athletes. We engineer biomaterial-based environments that mimic native tissue biochemical and mechanical properties to pinpoint specific cues that are required for regeneration of the connective tissues in the knee. We aim to use this knowledge to inform the treatment options for patients with knee injuries to ensure they can get back to performance with reduced or minimal chance for the development of osteoarthritis.

Shelly Sakiyama-Elbert, PhD (Bioengineering) Our lab works on developing novel approaches to treat peripheral nerve and spinal cord injury.  We use stem cell derived neurons and glia for transplantation following injury to replace cells that are lost as well as model systems to test potential drugs to promote regeneration.  Our ultimate goal is to provide patients with new therapies that will improve functional outcomes after injury.

Mehmet Sarikaya, PhD  (Materials Science and Engineering) Our research focuses on Molecular Biomimetics in which we use combinatorial mutagenesis to select peptides with specific affinity to desired materials, use bioinformatics-based pathways to in-silico design peptides, tailor their structure and function using genetic engineering protocols, couple them with synthetic self-assembled molecular hybrids, and use them as molecular tools in practical medicine and materials technologies. Our focus at the biology/materials interface incorporates molecular biology and nanotechnology, computational biology and bioinformatics, molecular assemblers, bio-enabled nanophotonics (quantum-dot and surface-enhanced probes), and peptide-based matrices for neural, dental and soft tissue regeneration.

Drew L. Sellers, PhD  (Bioengineering) Despite possessing a resident pool of neural stem cells, the mammalian brain and spinal cord shows a limited ability to regenerate damaged tissue after traumatic injury.  Instead, injury initiates a cascade of events that direct reactive gliosis to wall off an injury with a glial scar to mitigate damage and preserve function. My current research interests explore approaches to re-engineer the stem cell niche, to utilize gene-therapy and genome editing approaches to reprogram and engineer stem cells directly, and to enhance drug delivery into the central nervous system (CNS) to drive regenerative strategies that augment functional recovery in the diseased or traumatically injured CNS.

Alec Smith, PhD (Physiology & Biophysics) My lab’s research is focused on understanding the mechanistic pathways that underpin muscle and nervous tissue development in health and disease. To achieve this, we are developing human stem cell-derived models of neuromuscular diseases, such as amyotrophic lateral sclerosis (ALS). By analyzing the behavior of these cells, we aim to better define how the causal mutation leads to the development and progression of neurodegenerative disease. Ultimately, identification of pathways critical to disease progression will provide new targets for therapeutic intervention, leading to the development of new treatments for patients suffering from these debilitating and life-threatening conditions.

Nathan Sniadecki, PhD   (Mechanical Engineering) Our mission is to understand how mechanics affects human biology and disease at the cellular level. If we can formulate how cells are guided by mechanics, then we can direct cellular response in order to engineer cells and tissue for medical applications. We specialize in the design and development of micro- and nano-tools, which allows us to probe the role of cell mechanics at a length scale appropriate to the size of cells and their proteins.

Kelly R. Stevens, PhD  (Bioengineering and Pathology) Our research is focused on developing new technologies to assemble synthetic human tissues from stem cells, and to remotely control these tissues after implantation in a patient. To do this, we use diverse tools from stem cell biology, tissue engineering, synthetic biology, microfabrication, and bioprinting. We seek to translate our work into new regenerative therapies for patients with heart and liver disease.

Thomas N. Wight, PhD  (Benaroya Research Institute) This investigator leads a research program focused on the role that the extracellular matrix molecules, proteoglycans and hyaluronan, play in regulating vascular cell type and the regulation of extracellular matrix assembly. These pathways are fundamental to understanding the growth of new blood vessels in different tissues of the body, and have potential for direct tissue regeneration applications through the use of proteoglycan genes to bioengineer vascular tissue.

Ying Zheng, PhD  (Bioengineering) Dr. Zheng’s research focuses on understanding and engineering the fundamental structure and functions in living tissue and organ systems from nanometer, micrometer to centimeter scale.

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Tissue Engineering and Regenerative Medicine

What are tissue engineering and regenerative medicine, how do tissue engineering and regenerative medicine work, how do tissue engineering and regenerative medicine fit in with current medical practices, what are nih-funded researchers developing in the areas of tissue engineering and regenerative medicine.

Tissue engineering evolved from the field of biomaterials development and refers to the practice of combining scaffolds, cells, and biologically active molecules into functional tissues. The goal of tissue engineering is to assemble functional constructs that restore, maintain, or improve damaged tissues or whole organs. Artificial skin and cartilage are examples of engineered tissues that have been approved by the FDA; however, currently they have limited use in human patients.  

Regenerative medicine is a broad field that includes tissue engineering but also incorporates research on self-healing – where the body uses its own systems, sometimes with help foreign biological material to recreate cells and rebuild tissues and organs.  The terms “tissue engineering” and “regenerative medicine” have become largely interchangeable, as the field hopes to focus on cures instead of treatments for complex, often chronic, diseases.

This field continues to evolve. In addition to medical applications, non-therapeutic applications include using tissues as biosensors to detect biological or chemical threat agents, and tissue chips that can be used to test the toxicity of an experimental medication.

Cells are the building blocks of tissue, and tissues are the basic unit of function in the body. Generally, groups of cells make and secrete their own support structures, called extra-cellular matrix. This matrix, or scaffold, does more than just support the cells; it also acts as a relay station for various signaling molecules. Thus, cells receive messages from many sources that become available from the local environment. Each signal can start a chain of responses that determine what happens to the cell. By understanding how individual cells respond to signals, interact with their environment, and organize into tissues and organisms, researchers have been able to manipulate these processes to mend damaged tissues or even create new ones.

The process often begins with building a scaffold from a wide set of possible sources, from proteins to plastics. Once scaffolds are created, cells with or without a “cocktail” of growth factors can be introduced. If the environment is right, a tissue develops.  In some cases, the cells, scaffolds, and growth factors are all mixed together at once, allowing the tissue to “self-assemble.”  

Another method to create new tissue uses an existing scaffold. The cells of a donor organ are stripped and the remaining collagen scaffold is used to grow new tissue. This process has been used to bioengineer heart, liver, lung, and kidney tissue. This approach holds great promise for using scaffolding from human tissue discarded during surgery and combining it with a patient’s own cells to make customized organs that would not be rejected by the immune system.

Currently, tissue engineering plays a relatively small role in patient treatment. Supplemental bladders, small arteries, skin grafts, cartilage, and even a full trachea have been implanted in patients, but the procedures are still experimental and very costly. While more complex organ tissues like heart, lung, and liver tissue have been successfully recreated in the lab, they are a long way from being fully reproducible and ready to implant into a patient. These tissues, however, can be quite useful in research, especially in drug development. Using functioning human tissue to help screen medication candidates could speed up development and provide key tools for facilitating personalized medicine while saving money and reducing the number of animals used for research.

Research supported by NIBIB includes development of new scaffold materials and new tools to fabricate, image, monitor, and preserve engineered tissues. Some examples of research in this area are described below.

• Controlling stem cells through their environment: For many years, scientists have searched for ways to control how stems cells develop into other cell types, in the hopes of creating new therapies. Two NIBIB researchers have grown pluripotent cells—stem cells that have the ability to turn into any kind of cell—in different types of defined spaces and found that this confinement triggered very specific gene networks that determined the ultimate fate for the cells. Most other medical research on pluripotent stem cells has focused on modifying the combination of growth solutions in which the cells are placed. The discovery that there is a biomechanical element to controlling how stem cells transform into other cell types is an important piece of the puzzle as scientists try to harness stems cells for medical uses.

• Implanting human livers in mice: NIBIB-funded researchers have engineered human liver tissue that can be implanted in a mouse. The mouse retains its own liver as well, and therefore its normal function-but the added piece of engineered human liver can metabolize drugs in the same way humans do. This allows researchers to test susceptibility to toxicity and to demonstrate species-specific responses that typically do not show up until clinical trials. Using engineered human tissue in this way could cut down on the time and cost of producing new drugs, as well as allow for critical examinations of drug-drug interactions within a human-like system.  
• Engineering mature bone stem cells : Researchers funded by NIBIB completed the first published study that has been able to take stem cells all the way from their pluripotent state to mature bone grafts that could potentially be transplanted into a patient. Previously, investigators could only differentiate the cells to a primitive version of the tissue which was not fully functional. Additionally, the study found that when the bone was implanted in immunodeficient mice there were no abnormal growths afterwards—a problem that often occurs after implanting stem cells or bone scaffolds alone.    
• Using lattices to help engineered tissue survive: Currently, engineered tissues that are larger than 200 microns (about twice the width of a human hair) in any dimension cannot survive because they do not have vascular networks (veins or arteries). Tissues need a good “plumbing system”—a way to bring nutrients to the cells and carry away the waste—and without a blood supply or similar mechanism, the cells quickly die. Ideally, scientists would like to be able to create engineered tissue with this plumbing system already built in.  One NIBIB funded researcher is working on a very simple and easily reproducible system to solve this problem: a modified ink-jet printer that lays down a lattice made of a sugar solution. This solution hardens and the engineered tissue (in a gel form) surrounds the lattice. Later, blood is added which easily dissolves the sugar lattice, leaving pre-formed channels to act as blood vessels.

• New hope for the bum knee: Until now, cartilage has been very difficult, if not impossible, to repair due to the fact that cartilage lacks a blood supply to promote regeneration. There has been a 50% long-term success rate using microfracture surgery in young adults suffering from sports injuries, and little to no success in patients with widespread cartilage degeneration such as osteoarthritis. An NIBIB-funded tissue engineer has developed a biological gel that can be injected into a cartilage defect following microfracture surgery to create an environment that facilitates regeneration. However, in order for this gel to stay in place within the knee, researchers also developed a new biological adhesive that is able to bond to both the gel as well as the damaged cartilage in the knee, keeping the newly regrown cartilage in place. The gel/adhesive combo was successful in regenerating cartilage tissue following surgery in a recent clinical trial of fifteen patients, all of whom reported decreased pain at six months post-surgery. In contrast, the majority of microfracture patients, after an initial decrease in pain, returned to their original pain level within six months. This researcher worked in collaboration with another NIBIB grantee to image the patients who had undergone surgery enabling scientists to combine new, non-invasive methods to see the evolving results in real-time.  
• Regenerating a new kidney:   The ability to regenerate a new kidney from a patient’s own cells would provide major relief for the hundreds of thousands of patients suffering from kidney disease. Experimenting on rat, pig and human kidney cells, NIDDK supported researchers broke new ground on this front by first stripping cells from a donor organ and using the remaining collagen scaffold to help guide the growth of new tissue. To regenerate viable kidney tissue, researchers seeded the kidney scaffolds with epithelial and endothelial cells. The resulting organ tissue was able to clear metabolites, reabsorb nutrients, and produce urine both in vitro and in vivo in rats. This process was previously used to bioengineer heart, liver, and lung tissue. The creation of transplantable tissue to permanently replace kidney function is a leap forward in overcoming the problems of donor organ shortages and the morbidity associated with immunosuppression in organ transplants.

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Heath Topics

• Heart Disease
• Kidney Disease
• Osteoarthritis

Research Topics

• Tissue engineering
• Tissue Regeneration

Scientific Program Areas

• Division of Applied Science & Technology (Bioimaging)
• Division of Discovery Science & Technology (Bioengineering)
• Division of Health Informatics Technologies (Informatics)
• Division of Interdisciplinary Training (DIDT)

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Rocky S. Tuan, PhD

Dr. Rocky Tuan is the Vice-Chancellor and President, and Distinguished Professor of Tissue Engineering and Regenerative Medicine, of The Chinese University of Hong Kong (CUHK).  Prior to this he was the Director, Center for Cellular and Molecular Engineering, Distinguished Professor and the Arthur J. Rooney, Sr. Professor and Executive Vice Chair, Department of Orthopaedic Surgery, the Associate Director, McGowan Institute for Regenerative Medicine, the Director, Center for Military Medicine Research, and a Professor in the Departments of Bioengineering and Mechanical Engineering & Materials Science, University of Pittsburgh, Pittsburgh, Pennsylvania.

Dr. Tuan received his PhD in 1977 from the Rockefeller University in New York, under the mentorship of Zanvil A. Cohn, MD. His postdoctoral research fellowship was at Harvard Medical School in Boston, first with Melvin J. Glimcher, MD, in the Department of Orthopaedic Surgery at the Children’s Hospital, and then from 1978 to 1980 with Jerome Gross, MD, in the Developmental Biology Laboratory at the Massachusetts General Hospital. In 1980, Dr. Tuan was appointed as Assistant Professor in the Department of Biology, University of Pennsylvania in Philadelphia, and was promoted to Associate Professor in 1986. In 1988, Dr. Tuan joined Thomas Jefferson University, Philadelphia, to be the Director of Orthopaedic Research and Professor and Vice Chairman in the Department of Orthopaedic Surgery with a joint appointment in the Department of Biochemistry and Molecular Biology. From 1992-1995, Dr. Tuan was the Academic Director of the MD/PhD program at Jefferson, and in 1997, he established the USA’s first Cell and Tissue Engineering PhD program at Jefferson, with the mission of training the next generation of “cross-cultural” biomedical scientists committed to regenerative medicine and the development of functional tissue substitutes.

In the fall of 2001, Dr. Tuan joined the Intramural Research Program of the National Institute of Arthritis, and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), as Chief of the newly created Cartilage Biology and Orthopaedics Branch.  In 2004, Dr. Tuan received the Marshall Urist Award for Excellence in Tissue Regeneration Research of the Orthopaedic Research Society.  In the fall of 2009, Dr. Tuan was recruited by the University of Pittsburgh School of Medicine to be the Founding Director of the Center for Cellular and Molecular Engineering, and as the Arthur J. Rooney, Sr. Chair Professor and Executive Vice Chairman of the Department of Orthopaedic Surgery, with a joint appointment as Professor in the Department of Bioengineering.

At Pitt, Dr. Tuan served previously as the Co-Director of the Armed Forces Institute of Regenerative Medicine, a U.S. Department of Defense-funded, national, multi-institutional consortium focused on developing regenerative therapies for battlefield injuries. He also served as the Associate Director of the McGowan Institute for Regenerative Medicine, and was the Founding Director of the Center for Military Medicine. Dr. Tuan has published over 550 research papers, has lectured extensively, and is the Founding Editor-in-Chief of Stem Cell Research and Therapy , and Associate Editor of Stem Cells Translational Medicine . He is an elected Fellow of the American Institute for Medical and Biological Engineering, National Academy of Inventors, Orthopaedic Research Society, American Association of Anatomy, and Tissue Engineering and Regenerative Medicine International Society, among others, and a recipient of the NIH Outstanding Mentor Award, Society for Biomaterials Clemson Award, Carnegie Science Award, and other awards.

At CUHK, Dr. Tuan founded the Institute for Tissue Engineering and Regenerative Medicine in 2016.  In addition to his university leadership role, Dr. Tuan directs a multidisciplinary research program at CUHK, focusing on the biological mechanisms regulating the development, growth, function, and health of musculoskeletal tissues, and the utilization of this knowledge to develop technologies that will regenerate and/or restore function to diseased and damaged skeletal tissues.  Ongoing research projects are directed towards multiple aspects of skeletal and related biology, including skeletal development, stem cells, growth factor signaling, bone-biomaterial interaction, extracellular matrix and cell-matrix interaction, nanotechnology, biomaterials, 3D printing, mechanobiology, regenerative medicine, and tissue engineering, utilizing an integrated experimental approach combining contemporary technologies of biochemistry, cell and molecular biology, embryology and development, cellular imaging, and engineering. Dr. Tuan is also actively involved in multiple global educational activities, including leadership roles in the United Nation’s Sustainable Development Solutions Network. Worldwide University Network, Association of Pacific Rim Universities, and others.

View a partial list of Dr. Tuan’s publications here .

Name: Dr. Rocky Tuan

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Research profile

Research excellence.

The Centre for Regenerative Medicine (CRM) is a world leading research centre based at the University of Edinburgh’s Institute for Regeneration and Repair.

Our scientists and clinicians study stem cells, disease and tissue repair to advance human health. By better understanding how stem cells are controlled and how diseases develop in a lab environment, we hope to find new ways to treat patients.

Our research is aimed at developing new treatments for major diseases including cancer, heart disease, diabetes, degenerative diseases such as multiple sclerosis and Parkinson's disease, and liver failure.

The Centre houses 25 research groups and has a staff of more than 270 scientists, graduate students, support and ancillary staff.

Research themes

Our work is currently organised into five themes. To promote collaboration within the Centre, we adopt a flexible approach to these themes, with each Principal Investigator (PI) having one or more secondary affiliations.

Two themes focus on fundamental research:

• pluripotency and iPS
• lineage and cell specification

The other three themes aim to translate fundamental research discoveries into clinical programmes relevant to brain, blood and liver diseases and to tissue repair.

The Centre has strong collaborative links to other centres within the University, such as the Euan MacDonald Centre for MND Research, the MS Centre and the Roslin Institute.

We also invest in technological development in all areas.

Training and support

Training within the Centre is provided through a structured series of seminars and literature reviews, in addition to the laboratory and scientific research skills training provided to you by your supervisors.

Many of our PhD students are involved in collaborative projects that provide cross-disciplinary experience and/or promote translation into the biotechnology or clinical fields.

How will I learn?

Our programme includes short courses taught by basic and clinical stem cell scientists, providing a state-of-the-art theoretical background in a variety of areas relating to regenerative medicine including:

• developmental biology
• pluripotent and tissue stem cell biology
• degeneration and regeneration of adult tissues
• genetic engineering
• bioinformatics

We provide specialist lectures and short practical modules covering key technologies, including:

• DNA analysis and genetic engineering
• flow cytometry

In Year 1, you will participate in a weekly Centre for Regenerative Medicine ( CRM ) Postgraduate Discussion Group led by CRM group leaders. These discussion groups aim to widen your knowledge of stem cell and regenerative medicine research and to enhance your ability to critically review the literature in this field.

In addition to the taught components and research project, you will participate in a number of activities, including:

• regular lab meetings of your research group
• an internal seminar series
• seminars by visiting national and international speakers
• Journal Club
• poster presentations
• Three Minute Thesis presentation session.

Generic and transferable skills training is provided through the University's Institute for Academic Development (IAD).

• Institute of Academic Development

Since 2011, the Centre has been housed in a new, specially designed building that provides high quality research facilities, including:

• state of the art centralised cell culture facility for isolation and culture of primary and established cell lines including embryonic and induced pluripotent stem cells
• clinical-grade GMP cell culture facility
• specific pathogen free animal facility
• transgenic service covering derivation and provision of mouse embryonic stem cells, blastocyst injection, morula aggregation and production of defined genetic alterations
• ultrasound micro-injection equipment
• flow cytometry service consisting of a suite of cell sorters and analysers operated by facility staff that can be operated by users following comprehensive training
• a recently established single cell genomic analysis service using a 10x Genomics Chromium Controller
• quantitative real-time polymerase chain reaction equipment
• Fluidigm Biomark and CellPrep for single cell transcriptomics

Imaging facilities

We also have imaging facilities, including:

• standard compound microscopy
• widefield, confocal, and lightsheet microscopes
• high-content and timelapse imaging

The facility has dedicated imaging managers and offers two high-end workstations for bio-image processing and analysis.

Take a virtual tour of our facilities at the Centre for Regenerative Medicine:

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Entry requirements

These entry requirements are for the 2024/25 academic year and requirements for future academic years may differ. Entry requirements for the 2025/26 academic year will be published on 1 Oct 2024.

A UK 2:1 honours degree or its international equivalent.

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Check whether your international qualifications meet our general entry requirements:

• Entry requirements by country
• English language requirements

Regardless of your nationality or country of residence, you must demonstrate a level of English language competency at a level that will enable you to succeed in your studies.

English language tests

We accept the following English language qualifications at the grades specified:

• IELTS Academic: total 6.5 with at least 6.0 in each component. We do not accept IELTS One Skill Retake to meet our English language requirements.
• TOEFL-iBT (including Home Edition): total 92 with at least 20 in each component. We do not accept TOEFL MyBest Score to meet our English language requirements.
• C1 Advanced ( CAE ) / C2 Proficiency ( CPE ): total 176 with at least 169 in each component.
• Trinity ISE : ISE II with distinctions in all four components.
• PTE Academic: total 62 with at least 59 in each component.

Your English language qualification must be no more than three and a half years old from the start date of the programme you are applying to study, unless you are using IELTS , TOEFL, Trinity ISE or PTE , in which case it must be no more than two years old.

Degrees taught and assessed in English

We also accept an undergraduate or postgraduate degree that has been taught and assessed in English in a majority English speaking country, as defined by UK Visas and Immigration:

• UKVI list of majority English speaking countries

We also accept a degree that has been taught and assessed in English from a university on our list of approved universities in non-majority English speaking countries (non-MESC).

• Approved universities in non-MESC

If you are not a national of a majority English speaking country, then your degree must be no more than five years old* at the beginning of your programme of study. (*Revised 05 March 2024 to extend degree validity to five years.)

Find out more about our language requirements:

Fees and costs

Additional programme costs.

Most laboratories require a bench fee of up to £5,000 per year. This cost can be covered in Research Council studentships.

Living costs

You will be responsible for covering living costs for the duration of your studies.

Tuition fees

Scholarships and funding, featured funding.

• College of Medicine & Veterinary Medicine funding opportunities

UK government postgraduate loans

If you live in the UK, you may be able to apply for a postgraduate loan from one of the UK’s governments.

The type and amount of financial support you are eligible for will depend on your programme, the duration of your studies, and your residency status.

Programmes studied on a part-time intermittent basis are not eligible.

• UK government and other external funding

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Further information

• Postgraduate Administrator, Kelly Douglas
• Phone: +44 (0)131 651 9500
• Contact: [email protected]
• Centre for Regenerative Medicine
• Institute for Regeneration and Repair
• The University of Edinburgh
• Little France
• Programme: Regenerative Medicine
• School: Edinburgh Medical School: Clinical Sciences
• College: Medicine & Veterinary Medicine

Select your programme and preferred start date to begin your application.

PhD Regenerative Medicine - 3 Years (Full-time)

Phd regenerative medicine - 6 years (part-time), application deadlines.

We encourage you to apply at least one month prior to entry so that we have enough time to process your application. If you are also applying for funding or will require a visa then we strongly recommend you apply as early as possible.

• How to apply

You must submit two references with your application.

Before making your application, you must make contact with a potential supervisor to discuss your research proposal. Further information on making a research degree application can be found on the College website:

• How to apply for a research degree

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• Review Article
• Published: 19 December 2023

Single-cell transcriptomics in tissue engineering and regenerative medicine

• Anna Ruta 1   na1 ,
• Kavita Krishnan   ORCID: orcid.org/0000-0003-1345-0249 1   na1 &
• Jennifer H. Elisseeff   ORCID: orcid.org/0000-0002-5066-1996 1  

Nature Reviews Bioengineering volume  2 ,  pages 101–119 ( 2024 ) Cite this article

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• Computational biology and bioinformatics
• Regenerative medicine
• Tissue engineering

Regenerative medicine and tissue engineering aim to promote functional rebuilding of damaged tissue. Comprehensively profiling cell identity, function and interaction in healthy tissues, as well as understanding how these change upon tissue disruption, such as that caused by injury, ageing or infection, is foundational to advancing tissue engineering and regenerative therapeutics. Tissue injury response is a highly dynamic process driven by complex interactions between immune and stromal cell populations, with dysregulation leading to deleterious fibrosis and chronic inflammation. Advances in single-cell RNA sequencing now allow in-depth mapping of the complex cellular response to injury and biomaterial implantation. In this Review, we first describe the fundamentals of sequencing and computational methods for the generation and analysis of high-dimensional single-cell RNA sequencing data sets. We then highlight how these methods can be applied to study tissue injury responses and guide the rational design of biomaterials and regenerative therapeutics.

Single-cell RNA sequencing (scRNA-seq) affords unprecedented resolution in profiling cellular transcriptomics by simultaneously detecting the expression of thousands of genes on an individual cell basis.

Tissue engineers can leverage scRNA-seq to comprehensively map healthy and perturbed (such as injured or diseased) tissue environments and explore cellular heterogeneity, gene expression shifts, differentiation trajectories and interaction networks.

Insights gained by scRNA-seq profiling of biological systems can be leveraged to guide the rational design of new biomaterials and regenerative therapeutics.

scRNA-seq can be used to characterize the host response to implanted engineered constructs or regenerative therapeutics and discern mechanisms of action (regenerative or fibrotic).

Sharing of data sets in public repositories, development of large-scale atlases and formation of dedicated consortiums promote low-cost accessibility, increase diversity and maximize exploration of generated scRNA-seq data sets.

Interdisciplinary teams of basic scientists, bioinformaticians, tissue engineers and clinicians should work together to connect computational approaches to outstanding biological questions, driving innovation of new regenerative therapeutics.

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Acknowledgements

This work was funded in part by the National Institutes of Health (NIH) Pioneer Award DP1AR076959 (to J.H.E.), Bloomberg~Kimmel Institute and Morton Goldberg Professorship (to J.H.E.). A.R. is funded through NSF GRFP DGE-1746891.

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Ruta, A., Krishnan, K. & Elisseeff, J.H. Single-cell transcriptomics in tissue engineering and regenerative medicine. Nat Rev Bioeng 2 , 101–119 (2024). https://doi.org/10.1038/s44222-023-00132-7

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Brush Up: Tissue Engineering and Regenerative Medicine

A new frontier in repairing organ damage.

Jen has a PhD in human genetics from the University of California, Los Angeles where she is currently a project scientist. She enjoys teaching and communicating complex scientific concepts to a wide audience.

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What Is Regenerative Medicine?   Regenerative medicine replaces tissue or organs that are damaged by trauma, disease, or congenital disorders. This is different from more traditional therapies that treat the symptoms of tissue damage. There are three main concentrations within the field of regenerative medicine: tissue engineering, cellular therapy, and artificial organs. The use of tissue engineering in regenerative medicine, known as TERM, is an active area of research that involves creating functional tissue through the combination of cells, scaffolds, and growth factors to restore normal biological function. 1  Clinicians treat millions of patients with tissue engineered regenerative devices. So far, the most successful tissue regeneration therapies occur in soft tissues such as skin, cartilage, and corneal tissues.

Using Tissue Engineering to Regenerate Damaged Tissue

How does tissue engineering work?

During healthy tissue development, cells build and surround themselves with an extracellular matrix. This matrix, or scaffold, contains structural proteins and acts as a reservoir for signaling molecules that cells use to communicate and organize themselves into functional complexes or tissues. 

The overall goal of tissue engineering in the context of regenerative medicine is to establish a 3D cell or biomaterial complex that functions similarly to the in vivo tissue extracellular matrix. In general, tissue engineering involves the design and implantation of a scaffold that is biologically compatible with the area to be regenerated. New cells are then either attracted to or grown directly onto the scaffold. 2 The FDA has approved engineered artificial cartilage and skin therapies, and researchers are developing many other therapies for different tissues and disorders (see table below).

Scaffolds in tissue engineering Scientists seed scaffolds with their desired cell type during or following implantation. Alternatively, they may add growth factors to the scaffold and wait until the structure is populated by the surrounding tissue.

Choosing a scaffold type and source for tissue engineering is imperative for regenerating functional tissue. Pore size and overall architecture are important variables to consider when designing a scaffold. Pores play a crucial role in tissue regeneration because they allow for the exchange of nutrition and oxygen with surrounding tissue as well as expulsion of waste products and vascularization. The overall architecture of the tissue is important for exposing surfaces for cell attachment as well as mechanical cell stimuli.

Scaffolds can be natural or synthetic. Natural scaffolds are derived from donor tissues where the cells are chemically removed, leaving only the extracellular matrix. Natural scaffolds can either come from a patient or a healthy donor, and they have the advantage of retaining the unique structural and functional architecture of complex tissues. Researchers can also create natural scaffolds in vitro, such as those made from collagen and Matrigel, which are comprised of basement membrane proteins. 3,4

Scientists can develop synthetic scaffolds from various polymers, including polyglycolic acid (PGA), polylactic acid (PLA), and poly(lactide-co-glycolide) acid (PLGA). Scaffolds made with these polymers are flexible and porous, making them ideal structures for cellular integration. Synthetic scaffolds are also biodegradable, with different polymers degrading at different times, allowing damaged tissue to regenerate without the use of permanent prosthetic implants. Synthetic scaffolds also have consistent structures between replicates as they are generated in a laboratory; however, they can cause inflammation in the recipient more readily than natural scaffolds. 5

3D printing in tissue engineering With recent progress in 3D printing methods, researchers create complex synthetic scaffold structures with more consistent architecture and pore sizes. Hydrogel materials, such as alginate hydrogel and gelatin, are typically used in 3D printing due to their effective crosslinking and biocompatible properties. 6

Stem cells in tissue engineering and regenerative therapy Mesenchymal, embryonic, and induced pluripotent stem cells effectively promote damaged tissue regeneration. However, in many tissues, transplanted stem cells have poor survival and differentiation capabilities. The development of stem cell technology in combination with tissue engineering techniques, such as scaffolds and the addition of growth factors, has allowed researchers to improve the viability and proliferation of stem cells in regenerative medicine. 7

2. F. Han et al., “Tissue engineering and regenerative medicine: Achievements, future, and sustainability in Asia,” Front Bioeng Biotechnol , 8:83, 2020.

3. S. Sundaram et al., “Tissue engineering and regenerative medicine” in   Rossi's Principles of Transfusion Medicine . Fifth edition. T.L. Simon, ed., New York, N.Y.: John Wiley & Sons Inc., 2016, pp. 488-504.

4. C. Motta et al., “Tissue engineering and regenerative medicine” in Rossi's Principles of Transfusion Medicine . Sixth edition. T.L. Simon, ed., New York, N.Y.: John Wiley & Sons Inc., 2022, pp. 648-660.

5. Y. Li et al., “The effect of mechanical loads on the degradation of aliphatic biodegradable polyesters,” Regen Biomater , 4:179-190, 2017.

6. Z. Yazdanpanah et al., “3D bioprinted scaffolds for bone tissue engineering: State-of-the-art and emerging technologies,” Front Bioeng Biotechnol , 10:824156, 2022.

7. S.G. Kwon et al., “Recent advances in stem cell therapeutics and tissue engineering strategies,” Biomater Res , 22:36, 2018.

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Regenerative Medicine and Tissue Engineering

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University of Malaga , Spain

Published 22 May 2013

Doi 10.5772/46192

ISBN 978-953-51-1108-5

eBook (PDF) ISBN 978-953-51-4248-5

Copyright year 2013

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Few events in science have captured the same level of sustained interest and imagination of the nonscientific community as Stem Cells, Tissue Engineering, and Regenerative Medicine. The fundamental concept of Tissue Engineering and Regenerative Medicine is appealing to scientists, physicians, and lay people alike: to heal tissue or organ defects that the current medical practice deems difficult or...

Few events in science have captured the same level of sustained interest and imagination of the nonscientific community as Stem Cells, Tissue Engineering, and Regenerative Medicine. The fundamental concept of Tissue Engineering and Regenerative Medicine is appealing to scientists, physicians, and lay people alike: to heal tissue or organ defects that the current medical practice deems difficult or impossible to cure. Tissue engineering combines cells, engineering, and materials methods with suitable biochemical and physiochemical factors to improve or replace biologic functions. Regenerative medicine is a new branch of medicine that attempts to change the course of chronic disease, in many instances regenerating failing organ systems lost due to age, disease, damage, or congenital defects. The area is rapidly becoming one of the most promising treatment options for patients suffering from tissue failure. This book of Regenerative Medicine and Tissue Engineering fairly reflects the state of the art of these two disciplines at this time as well as their therapeutic application. It covers numerous topics, such as stem cells, cell culture, polymer synthesis, novel biomaterials, drug delivery, therapeutics, and the creation of tissues and organs. The goal is to have this book serve as a reference for graduate students, post-docs, teachers, scientists and physicians, and as an explanatory analysis for executives in biotech and pharmaceutical companies.

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Christopher A. Moskaluk, MD, PhD, Awarded $3.2 Million to Fund Cooperative Human Tissue Network

April 16, 2024 by [email protected]

Christopher Moskaluk, MD, PhD

Christopher A. Moskaluk, MD, PhD, the Walter Reed Chair of Pathology, was awarded a $3.2 million UM1 grant from the National Cancer Institute to fund the Mid-Atlantic Division of the Cooperative Human Tissue Network (CHTN).

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UVA became a member of the CHTN through a competitive grant process in 2001, specifically for our expertise in creating tissue microarrays (TMAs). Typically only a single tissue specimen can be placed on a glass slide in a histologic preparation for scientists to perform analytic techniques. Tissue microarray technology allows up to several hundred small tissue samples to be placed on a single glass slide, greatly increasing the efficiency of population-based studies and greatly decreasing the analytic costs of the experiments.

Dr. Moskaluk has successfully re-competed through several grant funding cycles to remain in the CHTN. UVA continues to this day to be the major provider of TMAs to the CHTN, supporting research in the major types of cancer and providing surveys of normal tissue types.

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Clinical utility of mesenchymal stem/stromal cells in regenerative medicine and cellular therapy

• Vitali V. Maldonado 1 ,
• Neel H. Patel 1 ,
• Emma E. Smith 1 ,
• C. Lowry Barnes 2 ,
• Michael P. Gustafson 3 ,
• Raj R. Rao 1 , 4 &
• Rebekah M. Samsonraj 1 , 4 , 2  

Journal of Biological Engineering volume  17 , Article number:  44 ( 2023 ) Cite this article

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Mesenchymal stem/stromal cells (MSCs) have been carefully examined to have tremendous potential in regenerative medicine. With their immunomodulatory and regenerative properties, MSCs have numerous applications within the clinical sector. MSCs have the properties of multilineage differentiation, paracrine signaling, and can be isolated from various tissues, which makes them a key candidate for applications in numerous organ systems. To accentuate the importance of MSC therapy for a range of clinical indications, this review highlights MSC-specific studies on the musculoskeletal, nervous, cardiovascular, and immune systems where most trials are reported. Furthermore, an updated list of the different types of MSCs used in clinical trials, as well as the key characteristics of each type of MSCs are included. Many of the studies mentioned revolve around the properties of MSC, such as exosome usage and MSC co-cultures with other cell types. It is worth noting that MSC clinical usage is not limited to these four systems, and MSCs continue to be tested to repair, regenerate, or modulate other diseased or injured organ systems. This review provides an updated compilation of MSCs in clinical trials that paves the way for improvement in the field of MSC therapy.

Mesenchymal stem/stromal cells (MSCs) are somatic stem cells that have the capacity for self-renewal, multilineage differentiation, and immunomodulation. MSCs can be isolated from various sources, including bone marrow, adipose tissue, umbilical cord, cord blood, placenta, among other tissue sources. Originally MSCs were identified as stromal or support cells for the hematopoietic stem cells in the bone marrow. The ease of isolation and their accessibility make MSCs a desirable source for different clinical applications. Numerous studies showcase the immunomodulatory and homeostatic roles of MSCs in inflammation regulation, exhibiting this immunomodulatory regulation through cell–cell contact and paracrine signaling [ 1 , 2 ]. MSCs also exhibit growth factor secretion and can traffic towards injured areas [ 3 ]. These properties, combined with the ease of in vitro expansion, make MSCs suitable candidates for experimental research, pre-clinical studies and clinical trials. The current review briefly discusses the key characteristics of MSCs from various tissue sources, and summarizes key evidence of therapeutic potential for musculoskeletal, nervous, cardiovascular, and immune repair, highlighting the clinical utility of MSCs in treating some common disorders within each organ system considered.

Identity, characterization and tissue sources of MSCs

The International Society of Cellular Therapy (ISCT) put four minimum criteria for defining mesenchymal stem/stromal cells [ 4 ], which include fibroblast-like morphology, plastic adherence, multilineage and multipotential capacity for differentiation into osteoblasts, adipocytes, and chondrocytes, along with expression of cell surface proteins CD73, CD90 and CD105, and lacking expression of lineage-specific markers CD45, CD34, CD14, CD19, CD11b, and HLA-DR. In earlier investigations, MSCs were predominantly obtained from bone marrow; however, as research on MSCs expanded, other tissue sources were identified, which include adipose tissue, placenta, amniotic fluid, umbilical cord, dental pulp, to name a few. Furthermore, these different sources give rise to MSCs with unique characteristics.

MSCs derived from bone marrow (BM–MSCs) are considered the most widely used and exhibit all the typical characteristics of MSCs [ 5 , 6 ]. Cells from this source have been used in more clinical trials than MSCs derived from any other source based on data available from clinicaltrials.gov. However, they cannot be easily obtained since the donor must undergo a painful and invasive procedure of bone marrow aspiration usually from the iliac crest. This motivated researchers to search for alternative sources of MSCs that could be more easily obtained in larger quantities. Adipose tissue has emerged as one of the major alternative sources of allogeneic MSCs and are being extensively investigated owing to their ease of isolation and availability in large tissue quantities useful for procurement of sufficient primary cells. Adipose MSCs (Ad-MSCs) can differentiate into various types of cells like adipocytes, osteoblasts, myocytes, chondrocytes, neural cells, hepatocytes, epithelial cells, and endothelial cells [ 7 ]. Characterization of Ad-MSCs revealed identification of non-classical markers including CD36, CD200, and CD274 [ 8 ]. Ad-MSCs require greater doses of growth factors (TGF-β and IGF-1) to have a comparable chondrogenic differentiation to the one observed in BM-MSCs [ 9 ].

MSCs derived from the placenta are readily sourced and available in abundance. In addition to expressing the classic cell surface markers satisfying the ISCT minimal criteria, placental MSCs (P-MSCs) are positive for UEA-1 (which is negative in BM-MSCs), CD166, CD73, CD44, CD105, CD29, and HLA-ABC while being negative for CD31, CD34, CD14, CD45, and HLA-DR. In addition, these cells also express renin and flt-1, which are not expressed in BM-MSCs [ 10 ]. Placental MSCs can be differentiated into multiple cell types successfully. However, the proliferative capacities of MSCs derived from the same placenta are heterogenous, with some placental cells showing a proliferative capacity of more than twenty passages, while others only proliferate between ten and twenty passages [ 11 ]. Another suitable alternative source of MSCs is human amniotic fluid (AF-MSCs). Moreover, MSCs derived from this source are better at self-renewing and have a higher and faster proliferative capacity than BM-MSCs. Additionally, they have a higher capacity to differentiate into hepatic cells and express liver-specific markers. In addition, they have the same gene stability and immunophenotype as that of BM-MSCs [ 12 ].

Umbilical cord and cord blood is a convenient source of MSCs because it can be easily harvested, and there is no significant difference between umbilical cord blood-derived MSCs (UCB-MSCs) and BM-MSCs in terms of immunophenotype and morphology. However, UCB-MSCs have a lower expression of CD105 and CD90; and a lower colony frequency compared to BM-MSCs. Also, UCB-MSCs have no adipogenic differentiation capacity. Nevertheless, UCB-MSCs can be cultured for a longer time and have a higher capacity to proliferate compared to BM-MSCs [ 13 ]. A disadvantage of UCB-derived MSCs is that the isolation efficiency is low. On the contrary, umbilical cord-derived MSCs (UC-MSCs) are much more efficient at being isolated [ 14 ]. UC-MSCs are similar to BM-MSCs in gene expression: when comparing abundant transcripts between the two cell types, only 0.8% of tags found in UC-MSCs are not found in BM-MSCs. On the other hand, only 2.9% of tags found in BM-MSCs are not found in UC-MSCs [ 15 ].

Dental pulp can be effective source for stem cells since stem cells from deciduous teeth pulp have a higher proliferative capacity than BM-MSCs. Also, stem cells derived from dental pulp (DP-SCs) have a higher expression of the basic fibroblast growth factor, BMP-2, RUNX2, and ALP genes. In contrast, BM-MSCs have a higher osteogenic differentiation capacity and higher expression of alkaline phosphatase [ 16 ]. DP-SCs show more odontogenic differentiation capacity than bone marrow stromal stem cells and have greater mineralization rates. Moreover, DP-SCs express multiple stem cell crest-derived surface markers, like GFAP, HNK-1, nestin, P75, and S-100, suggesting that they are derived from cranial neural crest cells [ 17 ].

Therapeutic applications of mesenchymal stem cells

Recent research has provided evidence that MSCs exert therapeutic effects not only by engraftment and differentiation but also through the secretion of biologically active molecules that exert beneficial effects on other cells. MSC paracrine effects can be broadly classified into trophic, immunomodulatory, and chemoattraction. Specifically, secreted factors from MSCs are known to mediate angiogenic, mitogenic, anti-fibrotic, anti-apoptotic, anti-scarring, and neurogenic functions (Fig.  1 ). Researchers have been actively using MSCs in numerous studies, with more than 1476 clinical trials listed in clinicaltrials.gov (as of March 2023) of which a majority are targeted at treating disorders of the musculoskeletal, nervous, cardiovascular, and immune-related disorders (Fig.  2 ). The key molecular players involved in regeneration or repair of each of the disease systems are represented schematically (Fig.  3 ) In this review, we will discuss outcomes of preclinical and clinical studies utilizing MSCs for these four major disease categories. The sources of MSCs used for specific clinical applications are tabulated in Table 1 .

Functionality of MSCs: Schematic of key trophic functions of mesenchymal stem cells and participating bioactive factors in tissue repair and immunomodulation

MSC clinical trials by disease category: Schematic representation of recorded clinical trials utilizing mesenchymal stem cells across multiple organ systems and related disorders. Pie chart was plotted using MSC clinical trial numbers obtained from clinical trials.gov (as of March 2023) and computing percentage distribution of MSC trials across various disease categories

Key disease systems managed by MSCs in clinical applications: Schematic showing significant molecular players involved in repair and regeneration of tissues of the musculoskeletal, nervous, immune, and cardiovascular systems

Musculoskeletal applications

Multiple conditions affecting the musculoskeletal system can have life-long effects on the patients. To find a potential treatment for these conditions, researchers have explored and demonstrated the regenerative abilities of MSCs. Because of their efficacy in regenerating and repairing bone, tendons, joints, and skeletal muscles, several trials have been performed. Common disorders/injuries undergoing clinical trials with MSCs include muscular dystrophy, osteonecrosis, cranial defects, non-union bone fractures, and osteoarthritis.

Muscular dystrophy

Muscular dystrophy (MD) is a common neuromuscular disorder and is characterized by progressive degeneration of muscle resulting in muscular weakness [ 18 ]. For every 10,000 males between the ages of 5 and 24, 1.38 have Duchenne or Becker MD in the USA [ 19 ].

The transplantation of MSCs could be a possible treatment for MD since many clinical trials with these cells showed positive outcomes. The transplantation of human UC-MSCs in patients with Duchenne’s Muscular Dystrophy (DMD) resulted in stable muscle power in one-year follow-up, without any negative effects, like graft-versus-host disease [ 20 ]. In an animal study, IL-10 expressing AAV vector-transduced rat BM-MSCs (IL-10 MSCs) were shown to maintain long-term engraftment and help with tissue repair in mice. Furthermore, IL-10 MSCs protected muscles from damage-induced injury thereby improving muscle malfunction in DMD [ 21 ]. Likewise, combined IGF-1 and human UC-MSCs injection into a dystrophic mouse model promoted efficient repair of the muscles, thus, improving muscle strength. The combination also reduced fibrosis and inflammation of muscles [ 22 ]. The combination of MyoD (regulator of differentiation into the skeletal muscle) and human UC-MSCs showed myogenic differentiation of MSCs as early as five days after treatment with MyoD. Nevertheless, these cells were also able to combine with primary rat myoblasts and form heterokaryotic myotubules [ 110 ]. Similarly, P-MSCs and their exosomes lowered levels of creatine kinase, fibrosis, and expression of TGF-β on the cardiac muscles and diaphragm of an mdx mouse model of Duchenne MD. Also, the mice showed increased levels of utrophin and a reduction in inflammation [ 111 ]. Finally, treatment with dystrophin expressing chimeric (DEC) BM-MSCs myoblasts on an mdx mouse model of Duchenne MD increased the function and strength of the muscle and lowered immune response [ 112 ].

Osteonecrosis

Osteonecrosis, also known as aseptic necrosis, avascular necrosis, or ischemic bone necrosis, is one of the common bone degenerative diseases in the U.S., with about 10,000–20,000 new cases every year [ 23 ]. In osteonecrosis, the deficiency of blood flow to the bone is followed by cell death at the site, resulting in severe pain [ 24 ]. Although the most common type of osteonecrosis is the osteonecrosis of the femoral head, it can happen in other bones like the bones of the shoulders, ankle, and knee [ 25 ].

Surgical and non-surgical interventions are available for the treatment of osteonecrosis. However, researchers are searching for better alternatives, and MSCs have continued to remain as promising candidates for treatment of musculoskeletal disorders. Intravenous injection of induced pluripotent stem cells (iPSC)-derived MSCs showed a significant reduction of bone loss and an increase in microvessel density at the femoral head in a mouse model with steroid-induced osteonecrosis which was attributed to the induction of angiogenesis [ 26 ]. Likewise, BM-MSCs implantation on a femoral head with early-stage osteonecrosis reduced the total hip replacement arthroplasty conversion rate [ 27 ]. Similarly, exosomes isolated from BM-MSCs harvested from healthy rats when incubated with MSCs from rats with steroid-induced necrosis of the femoral head suppressed adipogenesis and upregulated SOX9 in the later rats. This might be because MSC’s exosomes induce osteogenesis in patients with osteonecrosis [ 113 ]. Next, a composite implant containing BM-MSCs, carboxymethyl chitosan, endothelial progenitor cells, and alginate facilitated the repair of the bone through angiogenesis and osteogenesis induction and reduced adipogenesis on steroid-induced osteonecrosis of the femoral head rabbit model [ 28 ]. Finally, intravenous administration of methylprednisolone stimulated rabbit-derived MSCs labeled with a green fluorescent protein showed the expression of the green fluorescent protein only on the femur, suggesting that MSCs can be utilized in preventing osteonecrosis [ 29 ].

Cranial defects

Cranial and craniofacial defects are conditions characterized by the inappropriate migration, formation, and differentiation of the neural crest-derived cells, causing malformed, small, or missing craniofacial bones. These conditions are common, with approximately one-third of all birth defects consisting of craniofacial abnormalities [ 30 ].

The effectiveness of MSC treatment for cranial defects is under investigation, with numerous successful outcomes in animal studies. The rats with cranial defects, when treated with BM-MSCs, had a greater bone mineral density, higher expression of osteocytes and osteoclasts, and accelerated cranial bone healing [ 31 ]. A comparative study on the osteogenic differentiation capacity between Ad-MSCs and human UC-MSCs in vitro and in vivo using rats with cranial defects showed that Ad-MSCs have higher osteogenic differentiation and a higher rate of bone formation in the cranial bone of the treated rats [ 32 ]. Likewise, the rats with cranial defects seeded with human UC-MSCs and human BM-MSCs had a greater expression of Runx2, collagen I, alkaline phosphate, and osteocalcin. They also had higher quantities of new bone and blood vessels than the control group [ 114 ]. More recent comparison studies, between dental pulp MSCs (DP-MSCs) and BM-MSCs, have shown that DP-MSCs implanted in rabbit calvarial defects model exhibit similar bone regeneration efficacy as BM-MSCs. Furthermore, DP-MSCs are easier to collect and more accessible than BM-MSCs. The results showed that in-vivo treatment of DP-MSCs had similar bone mineral density, new bone formation, and osteogenic protein expression [ 115 ]. Finally, the comparison of the therapeutic potential of ecto-MSCs (MSCs derived from human embryonic stem cells) and BM-MSCs in a calvarial defect rat model proved that the ecto-MSC treated group had higher cellularity and a higher number of proliferative cells. However, both cells (implanted on a scaffold) promoted regeneration of the bone [ 33 ].

Non-union bone fractures

The American Food and Drug Administration (FDA) defines a non-union bone fracture as any fracture that persists for at least nine months without signs of healing for three months. Non-union bone fractures comprise nearly 4.9% of all bone fractures [ 34 ]. Nevertheless, these fractures do not heal without medical intervention [ 35 ]. This highlights the need for a regenerative approach for non-union bone fracture treatment.

MSC therapy for non-union bone fractures have been trialed extensively with notable successes. Combination of Ad-MSCs, Chitosan hydrogen, and cancellous bone graft showed Vegf and Bmp2 gene expression, as well as osteogenic differentiation and vascularization in non-union fracture models in rats. This indicates that Ad-MSCs have positive effects on bone reconstruction and induction of bone cells at the injury site [ 36 ]. Similarly, the combination of UC-MSCs, BMP-2, and Hydroxyapatite in an infected non-union fracture of a 54-year-old patient showed faster and more optimal bone formation at the disease site with no side effects [ 37 ]. Also, transplantation of cell sheets of rat BM-MSCs into a non-union femur fracture rat model showed bone union in eight weeks [ 116 ]. Likewise, BM-MSCs, when combined with extracorporeal shock-wave therapy in a rabbit model of nonunion bone fracture, improved fracture stiffness, mechanical strength, and histological scores [ 117 ]. Finally, injection of exosomes derived from BM-MSCs into the site of the nonunion femoral bone fracture rat model once every week enhanced osteogenesis, bone healing processes, and angiogenesis [ 38 ].

Osteoarthritis

Osteoarthritis (OA), a bone degenerative disease, affects more than 32 million adults in the U.S [ 39 ]. The characteristics of this disease include articular cartilage degeneration, changes in subchondral and peri-articular bone, and limited intraarticular inflammation accompanied by synovitis [ 40 ].

Many studies have analyzed the effects of MSCs in the treatment of OA, and multiple clinical trials have shown positive outcomes. The intra-articular injection of hyaluronic acid combined with cultured BM-MSCs into the patients with osteoarthritic knee after surgery showed a better magnetic resonance observation of cartilage repair tissue (MOCART) scores in comparison to the patients receiving only hyaluronic acid [ 118 ]. Additionally, intra-articular injection of Ad-MSCs into patients with OA in the knee improved the pain and knee function of patients and had no negative effects. This improvement in pain and knee function can be attributed to a decrease in cartilage defects and an increase in the cartilage volume at the site [ 119 ]. Moreover, an injection dose of 10 8 MSCs was found to be the most effective in reducing OA symptoms [ 120 ].

Nervous system applications

Many of the diseases affecting nervous systems are neurodegenerative in nature. Neurodegenerative diseases occur due to the progressive loss of function and ultimate death of neurons. Though symptomatic cures for these diseases are available, no known cures are available to date. Thus, scientists are researching regenerative approaches to treat neurodegenerative disorders wherein MSCs have been trialed as suitable candidates owing to their ability to be differentiate into neurons in vitro. However, their in vivo effectiveness and potency for nerve repair are still being investigated in preclinical and clinical studies. Some clinical trials have shown that MSC treatment improves survival rates, reduces pathology, rescues the decline of cognitive functions, ameliorates disease symptoms, and reduces relapse occurrences [ 121 ]. Common neurodegenerative diseases undergoing clinical trials include Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Parkinson’s disease (PD), and spinal cord injury (SCI).

Alzheimer’s disease

Alzheimer’s disease causes dementia, which is characterized by a decline in language, memory, cognitive skills, and problem-solving abilities of the affected patient. This disrupts the person’s lifestyle and is fatal over time. The disorder is caused by the damage or destruction of nerve cells in specific parts of the brain [ 122 ]. In the U.S., around 121,000 deaths caused by Alzheimer’s disease were recorded in 2019 [ 123 ], and as many as 6.2 million may have Alzheimer’s disease according to a report from the Alzheimer’s Disease Association in 2022 [ 41 ].

Considering regenerative medicine approaches to treat Alzheimer’s disease, MSCs have been proposed as promising cellular therapy candidates owing to their observed ability to halt disease progression and regenerate damaged neural tissue [ 42 , 43 ]. There is evidence that UCB-MSCs prevented deposition of the β-amyloid peptide (Aβ) plaques and activated microglial cells. MSCs were also noted to induce endogenous neurogenesis, which can preserve or restore the cognitive functions of patients with Alzheimer’s disease [ 44 ]. Similarly, BM-MSC derived EV can ameliorate Alzheimer’s disease through targeting BACE1 through miR-29c-3p introduction to the neurons. This helps in activating the Wnt/β-catenin pathway [ 45 ]. Additional evidence that transplantation of MSC-derived exosomes relieved Aβ 1–42 induced cognitive impairment and promoted neurogenesis in a mouse model with Alzheimer’s disease supports the regenerative potential of MSC-derived products, like exosomes [ 124 ]. Additionally, intracerebroventricular injection of BM-MSCs into an Alzheimer’s mouse model ameliorated cognitive impairment by reducing synaptogenesis and astrocytic inflammation. The treated mice showed increased microRNA-146a expression in the hippocampus, which is most likely involved in the improvement of cognitive impairment [ 46 ]. Finally, transplantation of menstrual blood-derived MSCs (MB-MSCs) intracerebrally into a mouse model improved memory and spatial learning, reduced tau hyperphosphorylation, and improved amyloid plaques, while increasing Aβ degrading enzymes and reduced pro-inflammatory cytokines [ 47 ]. Together, these studies support the clinical potential and utility of MSCs in treating neurodegenerative disorders.

Parkinson’s disease

PD is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. In 2019, there were around 35,000 deaths attributed to PD in the U.S. alone [ 123 ]. Currently, there is no neuroprotective treatment or cure available for treating PD [ 48 ].

Reports on cellular therapy using MSCs for treating PD have yielded several promising outcomes. The use of UC-MSCs in PD rodent models ameliorated locomotor deficit as well as neuroinflammation. This allowed the mouse to preserve more dopaminergic neurons. Moreover, the administered MSCs allowed the mouse to preserve intestinal goblet cells which protected the host from pathogens [ 49 ]. Similarly, human BM-MSCs reduced neural loss and the expression of hydroxylase immunoreactive cells in vivo. This study suggested that human MSCs have a neuroprotective effect and prevent the loss of dopaminergic neurons [ 50 ]. Moreover, administration of Wharton’s Jelly-derived MSCs (WJ-MSCs) into PD rat models caused restoration of BDNF and NGF, as well as hippocampal long-term potentiation, passive avoidance, and memory [ 125 ]. In another rat model, delivery of human UC-MSC-derived exosomes resulted in successful biodistribution to the substantia nigra of the brain, resulting in the reduction of the loss of dopaminergic neurons and apoptosis. Additionally, increased dopamine levels in the striatum were observed accompanied by relieving apomorphine-induced asymmetric rotation [ 126 ]. Further developments in research document the post-treatment effects of administering rat BM-MSCs to the substantia nigra in a rat model wherein double immunofluorescence and immunohistochemical assessments revealed increases in the number of TH positive neuronal cells and fibers, as well as functionality, compared to non-treated controls [ 51 ].

Multiple system atrophy

MSA is a fatal neurodegenerative disease characterized by parkinsonian elements, autonomic malfunction, cerebellar features, and pyramidal features [ 52 ]. The prevalence of Multiple System Atrophy is around 4.4 per 100,000 people [ 53 ].

A myriad of studies on the effects of MSCs in treating MSA has shown positive results. Intra-arterial delivery of BM-MSCs to patients with cerebral type MSA. Different doses of MSCs were administered to the patients (low dose: 3 × 10 5 , medium dose: 6 × 10 5 , and high dose: 9 × 10 5 cells/kg body weight of the patient). The results show that the medium and high doses showed a slower increase in the Unified MSA Rating Scale score (lower score = improvement), showing that MSCs can protect the patients from neurodegeneration [ 54 ]. The long-term effect of UCB-MSCs was studied in MSA patients who received the cells through lateral atlanto-occipital space puncture. The Unified MSA rating scale was used to assess the patients for 3–5 years. UCB-MSCs seemed to ameliorate MSA with no adverse effects. However, the greatest effect of MSCs on MSA was observed 3–6 months after the first dose [ 55 ]. Another important study documented improvement in behavioral disorders and prevention of neurodegeneration in patients on a toxin-induced multiple system atrophy model which was attributed to the likely reduction of polyamine-induced and cholesterol-induced damage mediated by BM-MSCs trophic and reparative functions [ 127 ]. Clinical research involving intrathecal administration of 10 and 200 million autologous Ad-MSCs to 24 patients with multiple system atrophy resulted in lower rates of disease progression, as assessed by UMSARS score without any side effects [ 128 ]. Of particular significance in cellular therapy are studies that examine dosage safety and optimize administration route. Delivery of higher doses of BM-MSCs (2 × 10 9 ) through the internal carotid artery in an animal model of MSA was found to be lethal to the animal. Animals that received a comparatively lower dose, i.e., 8 × 10 7 MSCs, had a greater survival rate of nigrostriatal neurons without any side effects [ 56 ]. Research investigations to determine optimal dose and delivery must be carefully considered to ensure safety and efficacy of MSC therapies.

Amyotrophic lateral sclerosis

ALS is a disease that selectively affects motor neurons, weakening muscles and impacting physical functions, eventually leading to progressive paralysis of most voluntary muscles. It affects as many as 30,000 people in the United States, with 5,000 new cases diagnosed each year; being a degenerative disorder, ALS is most common in adults 60 years and older [ 57 , 58 ].

Studies on the effects of MSCs in ALS demonstrated safety and efficacy in the treatment strategies tested. Two injections in a month interval of an average of 0.42 × 10 6 WJ-MSCs to the cervical, lumbar, and thoracic regions of 43 ALS patients did not show any adverse effects confirming the safety of MSC administration [ 59 ]. Phase I clinical trials investigating effects of single-dose intramuscular or intrathecal administration of autologous BM-MSCs or Ad-MSCs secreting neurotrophic factors, followed by both intramuscular and intrathecal injection in Phase II of the study showed no negative secondary effects. Moreover, the rate of the ALS Functional Rating Scale-Revived score and the forced vital capacity lowered in patients administered with MSCs intrathecally (accounting for the combination of intrathecally and intramuscularly) [ 60 ]. In another study, survival time increased in 67 subjects administered with three intrathecal injections of 30 × 10 6 WJ-MSCs [ 129 ]. BM-MSCs in combination with Riluzole seem to reduce ALS disease progression of subjects after 4 and 6 months compared to the control group (Riluzole alone). The ALS Functional Rating Scale was reduced in the treatment group. The MSC-treated group also showed an increase in anti-inflammatory and a decrease in pro-inflammatory cytokines. There was no difference in treatment-related adverse effects between the 2 groups [ 61 ]. Another study administered BM-MSCs induced to secrete high levels of neurotrophic factors to patients with ALS. Results showed an improvement in neurodegeneration, neuroinflammation, and neurotrophic factors as shown in the cerebrospinal biomarker analysis [ 62 ], demonstrating their potential to be applied as suitable therapeutic candidates for treating ALS.

Spinal cord injury

SCI is the result of damage to the spinal cord, which results in a loss of function, feeling, and mobility. The spinal cord does not have to be severed for a loss of function. About 17,900 new cases of SCI are diagnosed every year, with 78% being male patients [ 63 ]. Currently, there is no cure for SCI; however, new advances in research continue to develop in research and translational laboratories.

MSC transplantation continues to be explored as noninvasive treatment options to regenerate injured spinal cords. Clinical trials data support their usefulness for treatment; specifically, intravenous injection of UC-MSCs (1 × 10 6 /kg) each month for four months in early-stage SCI patients improved neurological dysfunction and was found to be safe and effective in restoring quality of life as observed in 1-, 3-, 6-, and 12-months post-treatment follow-up. Motor and sensory functions notably improved, along with improvements in the overall mobility of the patients [ 64 ]. In a related study, administration of NeuroRegen scaffold with UC-MSCs, via a small incision in eight SCI patients under general anesthesia, improved the motor and sensory functions of the patients without any side effects, as seen in a 1-month follow-up [ 65 ]. Likewise, intrathecal injection of 9 × 10 7 Ad-MSCs through lumbar tapping in 14 patients showed improved motor and sensory skills 8 months post-treatment. However, further research is underway to verify the correct dosage needed [ 130 ]. Studies demonstrating the safety and feasibility of MSC therapy indicate that intrathecal administration of autologous BM-MSCs (2–3 total injections) in six patients did not produce any negative effects [ 131 ]. In a similar trial, researchers labeled UC-MSCs with aggregation induced emission-Tat nanoparticles to track how effective MSC treatment was for SCI. A rat model was used to track the MSC therapy effectiveness. The results showed no adverse effects as well as SCI recovery showed by histopathological and behavioral rehabilitation results. Moreover, the cells were able to conserve the cell viability in microenvironments with highly reactive oxygen species and produce nerve growth factors [ 132 ].

MSC utility and its therapeutic merits for neural repair and regeneration are supported by several preclinical and clinical trials, together offering more effective treatment approaches for neurodegenerative disorders.

Cardiovascular applications

Cardiovascular diseases are a major cause of death in the United States with 1 in every 4 deaths caused by heart disease [ 66 ]. Although there are numerous efforts in scientific community to find effective treatments, researchers are focusing on MSCs due to their coveted regenerative properties and ease of isolation and expansion. Currently, MSC application in-vitro and in-vivo cardiovascular disease treatments have shown ameliorating results indicating promising therapeutic potential. In this section, an overview of MSCs used in hypertension, myocardial infarction, stroke, heart failure, and chronic ischemic cardiomyopathy is presented.

Hypertension

Pulmonary arterial hypertension can lead to elevated arterial pressure and increased pulmonary vascular resistance. The World Health Organization estimates that about 1.28 billion adults within the age range 30–79 have hypertension worldwide [ 67 ]. Moreover, there is no cure for the disease to date.

Of the several treatment options being carefully considered for hypertension in recent years, MSCs have emerged as suitable therapies based on preclinical evidence in attenuating hemodynamic and histological progression of pulmonary arterial hypertension [ 68 ]. Human MSC-derived extracellular vesicles restored right ventricular systolic pressure to baseline levels; and reversed right ventricular hypertrophy and peripheral pulmonary artery muscularization on a rat Sugen/hypoxia model with pulmonary hypertension [ 69 ]. Injection of extracellular vesicles from iPSC-derived MSCs through the mice tail vein reduced arterial stiffness and hypertension; and promoted the expression of AMPKα, eNOS, and SIRT1 [ 70 ]. Similarly, BM-MSC transplantation on a chronic hypoxia-induced pulmonary hypertension rat model improved collagen deposition, decreased muscularization, thickening, and pulmonary arterial pressure of the disease carrier. MSCs also attenuated EndMT and factor-2α (hypoxia-induced factors) [ 133 ]. Additionally, treatment with skin-derived MSCs decreased vascular damage and systolic blood pressure; reduced Th17 cells in peripheral blood; and lowered the levels of protein, and IL-17 mRNA on the aorta and serum in an AngII-induced hypertensive mouse model. MSCs also switched macrophages to an anti-inflammatory profile (M1 to M2) and increased the rates of migration and proliferation of MSCs [ 71 ]. In another study, human UC-MSC-derived exosomes showed promising results both when injected into the monocrotaline-induced pulmonary hypertension rat model and hypoxia-induced cell model. MSC exosomes lessened hypertrophy in the right ventricle and caused pulmonary vascular remodeling. It was further noted that pulmonary arterial smooth muscle cell proliferation and pulmonary arterial endothelial cell apoptosis were inhibited, while increases in Wnt5a expression and suppression of endothelial to mesenchymal transition (EndMT) factor were observed [ 73 ].

Myocardial infarction

Myocardial infarction is the primary cause of disability and death in patients affected by this disorder which is normally treated as a medical emergency. It is characterized by cardiomyocyte death induced by cardiac ischemia [ 72 ]. Since no effective treatments are available, research is underway to explore regenerative approaches for tissue repair and regeneration.

Several clinical trials have tested MSCs for treating myocardial infarction, and the results have thus far been promising. Exosomes from Ad-MSCs suppressed cardiac dysfunction, fibrosis, and apoptosis on myocardial infarction-induced cardiac damage using H9c2cells, HAPI cells, and cardiac fibroblasts. Also, a decrease in the inflammatory response, an increase in macrophage M2 polarization, and activation of sphingosine 1 phosphate signaling, S1P/SK1/S1PR1, was observed [ 74 ]. Furthermore, intramyocardial injection of synthetic MSCs into a myocardial infarction mouse model showed improvement in angiogenesis and remodeling of the left ventricle. Synthetic MSCs are produced by inserting factors secreted by BM-MSCs into poly(lactic-co-glycolic acid) microparticles covered with the MSC’s membrane structure [ 72 ]. A related study documented that EVs secreted from SDF1 overexpressing MSCs promoted the microvascular restoration of endothelial cells and inhibited apoptosis of myocardial cells in a myocardial infarction mouse model. The secretion of these exosomes, as seen by coculture experiments, was interrupted by the neural sphingomyelinase inhibitor GW4969, whereas it was promoted by the SDF1 plasmid [ 134 ]. Similarly, anti-miR-155-5p BM-MSCs improved angiogenesis and cell survival in a myocardial infarction mouse model. It was noted that anti-miR-155-5p MSCs resulted in improvement in cardiac function in comparison to the MSCs alone [ 75 ]. Exosomes derived from human UC-MSCs that overexpressed TIMP2 enhanced cardiac function and promoted angiogenesis at the myocardial infarction site on a myocardial infarction rat model. In addition, MSCs alleviated oxidative stress produced by myocardial infarction and ECM restoration, with significant involvement of the Akt/Sfrp2 pathway in mediating cellular responses to MSC intervention [ 76 ].

Stroke is the resulting damage to the brain due to interruption of blood supply. It can be either ischemic (caused by the lack of blood flow) or hemorrhagic (caused by bleeding). Finding effective treatments for stroke is a clinical need as it continues to remain as one of the leading causes of death worldwide [ 77 ].

Multiple clinical trials involving MSCs and MSC-derived extracellular vesicles have suggested that MSC-based regenerative therapy could lead to effective stroke therapy [ 78 ]. Intravenous injection of exosomes from BM-MSCs enhanced recovery of neurological function, improved neurogenesis and angiogenesis, and reduced IL-1β expression in a mouse model of ischemic stroke [ 79 ]. Similarly, human UC-MSC-derived exosomes reduced inflammation in vitro in microglia-mediated neuroinflammation after experiencing ischemic stroke. Additionally, they decreased behavioral defects, lowered infarct volume, and enhanced activation of microglia. These neuroprotective effects of MSC-derived exosomes, however, were partially undone by miR-146a-5p [ 135 ]. In a related clinical work, administering MSCs from various sources as adjuvant therapy to the standard treatment for patients with severe infarction of the middle cerebral artery greatly improved motor functions in the lower extremities without any side-effects compared to groups that only received the standard treatment [ 80 ]. MicroRNA-184 and microRNA-210 present in rat BM-MSC-EVs were found to be the key factors in promoting angiogenesis and neurogenesis in a stroke model. Also, MSC-EVs were more efficient in the improvement of behavior than whole parental MSCs [ 81 ]. Exosomes derived from BM-MSCs improved neurological function, reduced weight loss after stroke, and enhanced neuroprotective effects in type 2 diabetic stroke rat model compared to control. These exosomes caused remodeling of white matter and anti-inflammatory responses. Additionally, it was found that the treatment decreased miR-9 expression, which increased the ABCA1 pathway [ 82 ].

Heart failure

Congestive heart failure is a chronic condition characterized by the inadequate pumping of blood. Though this disease lacks effective treatments, some symptomatic treatments that can increase survival are currently available [ 83 ].

Many studies have been conducted to elucidate the applications of MSCs in the treatment of heart failure, with hopes of developing effective treatments. Administration of allogeneic UC-MSCs into patients with congestive heart failure increased the expression of hepatocyte growth factor (associated with immunomodulation, myogenesis, and cell migration), and enhanced the ejection in the left ventricle [ 84 ]. Similarly, MSCs overexpressing adrenomedullin (ADM) enhanced heart function and increased cell survival in a rat model of heart failure. This was accompanied by decreased expression of matrix metalloproteinase-2 and the fibrotic area percentage; and significantly influenced ADM and hepatocytic growth factors as compared to the rat model treated with the normal MSCs [ 136 ]. We also note that superparamagnetic iron oxide nanoparticles-labeled human amniotic MSCs increased cell homing and enhanced myocardial hypertrophy and heart function in the presence of a magnetic field on a heart failure rat model. In addition, a reduction in fibrosis was also seen in comparison to the group tested in the absence of the magnetic field [ 85 ]. Interestingly, preclinical work showed methods to increase AD-MSC therapeutic efficiency in a mouse model of pressure overload heart failure. The study showed that enhancing the MSCs exosomes through treatment of adiponectin improved cardiac function and reduced inflammation and fibrosis in the mouse model [ 86 ]. Supporting studies on intravenous BM-MSCs injection into a rat heart failure model demonstrate the efficacy of MSCs in reducing myocardial infarction size and interstitial fibrosis and enhancing heart rate variability and baroreflex sensitivity [ 87 ].

Chronic ischemic cardiomyopathy

Chronic Ischemic Cardiomyopathy (CIC) is characterized by a significant reduction in the heart’s ability to pump blood either due to the main pumping chamber of the heart being enlarged or dilated due to a lack of blood supply to the heart. It is one of the most common cardiovascular disorders [ 88 ].

Clinical trials with MSCs have yielded positive outcomes suggesting that cellular therapies involving MSCs may prove useful to treat CIC. A study ( n  = 50) demonstrated that injection of UC-MSCs lowered the percentage of infarct size change [ 89 ]. Transplantation of either BM-MSCs or UC-MSCs with a Coronary Artery Bypass Grafting Surgery (CABG) showed a decline in NT-proBNP in 1, 3, 6, and 12 months follow-up as compared to the patients receiving CABG intervention alone. It was noted that the UC-MSC group had an increase in left ventricular ejection fraction (LVEF) in comparison to the control group [ 137 ]. Similarly, patients receiving BM-MSC infusion with revascularization showed improvement in left ventricle function in comparison to the group who only received the revascularization, as well as patients who received BM-MSC infusion via intracoronary administration. Together, these results demonstrate that MSC infusion significantly increases and improves cardiac function in CIC [ 138 ]. In a similar study, intramyocardial injection of either UC-MSCs or BM-MSCs along with coronary artery bypass grafting (CABG) surgery improved left ventricle function in patients as seen in 1, 3, 6, and 12 months follow-up. However, further tests and parameters must be considered before effectiveness of such treatment can be confirmed [ 139 ]. Another study documented the effects of transendocardial and intramyocardial injection of BM-MSCs in the left ventricle scar of the patients in significantly improving the regional function of the left ventricle in 3- and 6- months follow-up [ 140 ].

Overall, MSC treatment potential for cardiovascular diseases can be attributed to their immunoregulatory ability, anti-fibrotic and anti-scarring effects, angiogenic, and neovascularization functions.

Immune-related applications

The immunoregulatory properties of MSCs can influence both innate and adaptive immune responses. MSCs inhibit T-lymphocyte proliferation that is induced by mitogenic and by allogeneic peripheral blood lymphocyte (PBLs) and dendritic cells (DCs) [ 141 ]. This T cell inhibition is dose-dependent with the peak significant reduction in T-lymphocyte proliferation. MSCs have also been seen to influence the formation of regulatory T cells that help with the inhibition of allogenic lymphocyte proliferation. Even though the exact mechanism for MSC immunosuppressive effects remains to be fully explored, we note from established literature that soluble factors such as prostaglandin E2 (PGE2)], indoleamine2,3-dioxygenase (IDO), hepatocyte growth factor (HGF), and transforming growth factor (TGF)-b1 play a major role in the immunosuppressive effects of MSCs. MSCs are known to involve in the generation and development of DCs, which are antigen-presenting cells (APC) in the immune system. Furthermore, MSCs in coculture with DCs were found to reduce the expression of CCR7 by the DCs and inhibit the differentiation of monocytes to DCs [ 90 ]. MSCs are also able to promote M1-to-M2 phenotype transformation of macrophages. Macrophages are specialized immune cells involved in the detection, phagocytosis, and removal of pathogenic agents in the innate immune system. Macrophage differentiation from monocytes occurs in the tissue in response to microenvironmental signals resulting in acquisition of specific functional phenotypes [ 91 ]. MSCs mediate the regulation of macrophages, which is crucial for limited inflammation response and damaged tissue healing. BM-MSCs have been known to regulate the host’s inflammatory response to sepsis and significantly improve the host’s survival [ 90 ]. The roles of MSCs in regulating various immune cell types pose them as suitable therapeutic candidates for treatment of immune-related diseases. Common immune related disorders that are targeted for MSCs therapy include autoimmune type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, and graft vs. host disease, which will be discussed below.

Type 1 diabetes mellitus

The pancreatic islet houses a group of cells, such as beta (β) cells, to synthesize insulin [ 137 ]. The progressive autoimmune attack on pancreatic β-cells results in the loss of insulin secretion and production, ultimately affecting the blood sugar levels and metabolic functions resulting in a condition termed type 1 diabetes mellitus (T1D) [ 92 ]. As of 2020, about 34.2 million people of different ages were diagnosed with T1D [ 93 ].

Although insulin injections are effective in glycemic control, they fail to address the other side effects of T1D, such as nephropathy, high blood pressure, and foot diseases [ 138 ]. Thus, a permanent cure to T1D must address the autoimmune response, followed by an emphasis on islet regeneration and replacement. Therefore, MSC transplantation are thought to be possible treatments for this disorder owing to their engraftment with differentiation and trophic effects. A trial showed that intrapancreatic transplantation of BM-MSCs decreased blood glucose and increased C-peptide and insulin in a rat model. This suggests that MSCs can improve damaged pancreases function [ 94 ]. In another trial, the mechanism by which MSCs aid in T1D recovery has been studied in a diseased mice model. human UC-MSCs were used in this study. The results showed that TGFBI was crucial for MSC immunosuppressive capacity an suppression of activated T-cell proliferation [ 142 ]. BM-MSCs were shown to be a better treatment than platelet-rich plasma injection in T1D rat model. The results showed that the group treated with BM-MSCs had an increase in the diameter of Langerhans islets and the amount of zymogen granules compared to the untreated group and the group treated with platelet-rich plasma [ 95 ]. A study tested the immunomodulatory capacity and beta cell protection of Ad-MSCs in a diabetic mice model. This study showed that Ad-MSCs can maintain the secretion of insulin and the viability of pancreatic islets when reactive splentocytes are present. Moreover, Ad-MSCs decreased splentocyte proliferative response [ 96 ]. A similar studied the use of human UC-MSCs that were previously modified to express exenatide in a T1D mice model. The results showed that UC-MSCs aided in damaged islet tissue repair. These cells also decreased the renal tissue lesions as well as the blood glucose levels. Moreover, there was less pro-inflammatory and more anti-inflammatory intestinal bacteria [ 143 ].

Rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disorder where the immune system attacks the healthy cells, causing swelling and inflammation of joints. RA can also spread to other areas of the body and is mostly diagnosed in females [ 97 ]. The causes of RA are yet to be fully understood.

MSC administration, in RA patients, has shown positive outcomes in recent clinical trials. Administration of UC-MSCs (4 × 10 7 cells total dose) to 64 patients diagnosed with RA resulted in a significant decrease in blood globulin and blood platelet levels during 1-year and 3-year post-treatment follow-up. In addition, there was a significant decrease in the erythrocyte sedimentation rate (ESR), C-reactive protein levels, and rheumatoid factor (RF). This decrease in serological and immunological markers in patients with RA and high immune system activity highlights MSC therapeutic potential and immunomodulation. Long-term patient relief and joint function (measured by the DAS28 score) also showed a significant decrease in these levels post MSC treatment at 1-year and 3-years [ 98 ]. Similarly, a clinical trial investigated 105 patients showing little to no responses to traditional RA drugs, such as disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs), to study the effects of MSC transplantation. Patients were divided into control group and MSC transplantation group (MSCT). The MSCT group was intravenously infused with UC-MSCs (1 × 10 6 cells/kg in a 50 ml saline solution) and followed up at 1, 2, 3, 4, 12, 24, and 48 weeks. Of the 52 patients in the MSCT group, 28 patients were observed to have a response to the MSC treatment after 12 weeks and a significant decrease in the Disease Activity Score-28 (DAS28). Also, patients in the control group and those non-responsive to the MSC treatment did not show any significant changes in DAS28, together indicating that the MSC treatment improved overall clinical symptoms [ 99 ]. RA patients typically exhibit a low percentage of CD4 + CD25 + Foxp3 + Tregs and a high percentage of CD4 + IL-17A + Th17 cells. Thus, a low ratio between Tregs to Th17 cells indicates an imbalance in the immune homeostasis [ 144 ]. This study showed a significantly high Treg to Th17 ratio in the response group, as compared to the control and non-response groups, showcasing UC-MSC immunomodulatory effects on deregulating RA development. Additionally, there was a significant decrease in IL-6 and a significant increase in IL-10 levels at the 4-weeks checkup. Typically, RA patients are observed to have low IL-10 and high IL-6 levels [ 99 ]. A clinical trial in phase 1a tested MSC as a treatment for RA in humans. Human UCB-MSCs were infused into patients with RA. These patents received a single infusion of MSCs. Serum cytokines were measured to determine the effectiveness of the treatment after 24 h. The results showed a decrease in IL-8, IL-6, IL-1β, and TNF-α in the group that received the higher cell dose (1*10^8 cells). Moreover, No adverse or safety threats were observed short-term [ 100 ]. A study aimed to investigate the molecular mechanisms by which BM-MSCs ameliorate RA symptoms. This study showed that the cells effectively decreased microRNA-584e levels through reduction of NF-κB activity. Mice models were used for this study [ 101 ]. Finally, implantation of BM-MSCs (40 million BM-MSCs per joint) in RA patients with a knee injury showed greater improvements in their knee injury than the placebo group that received normal saline instead of MSCs [ 145 ]. Although BM-MSC transplantation treatment may be a beneficial for RA patients, research with more patients must be done.

Systemic lupus erythematosus

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder and the most common form of lupus. According to the Centers for Disease Control and Prevention (CDC), SLE is a disorder in which the immune system attacks healthy tissues, causing widespread inflammation and tissue damage in organs. It can affect the lungs, blood vessels, joints, brain, kidneys, and skin. More women are diagnosed with SLE compared to men: the ratio is at least 4 women to every 1 man [ 102 ].

While there is no cure for SLE, MSC transplantation, in recent clinical trials, shows promising results as a novel cell therapy. Intravenous injection of allogeneic UC-MSCs in 39 patients with active SLE twice in a 1-week interval showed a significant decrease in the SLE disease activity index (SLEDAI) score in 1, 3, 6, 9, and 12 months follow-up. Additionally, improvement in the levels of serum albumin was seen at the 1-month follow-up, which was maintained up to 12 months, after which it declined [ 103 ]. This indicates a possibility of disease relapse thus, repetitive UC-MSC infusions after 6-months should be considered. In another study, BM-MSCs of passages between 3 and 5were intravenously injected (1 × 10 6 cells BM-MSCs/kg body weight) in 15 patients (14 women and 1 man) of an average age of 28 years and a SLEDAI score greater or equal to 8. Then the measurement of regulatory T cells (Tregs), urinary protein excretion, glomerular filtration rate (GFR) assessments, and serological testing was done after 1-week, 1, 3, 6, 12, and 18 months followed by once every half a year post-transplantation. Overall improvement in SLE was observed: SLEDAI scores significantly improved on the 12-month follow-up, serological tests (ANA and anti-dsDNA antibodies) showed substantial improvement, anti-dsDNA antibody significantly decreased from the baseline at 1-month and 3-month follow-up, proteinuria significantly decreased at the 1-week,1-month, 3-months, 6-months, and 12-month examination, and GFR improved significantly in two patients with a low baseline GFR. Likewise, there was a significant increase in CD4 + Foxp3 + Treg cell percentage at the 1-week, 3-month, and 6-month examinations [ 104 ]. This increase in CD4 + Foxp3 + Treg cell percentage suggests a possible Treg expansion caused by the BM-MSCs, which helped maintain immune self-tolerance. CD4 + Foxp3 + cells are a subset of the CD4 T-cells that are involved in modulating immune-homeostasis and immune cell activation. Decreased regulatory T cells (Tregs) can be related to the progression of human autoimmune diseases [ 146 ] Measurements of the CD4 + Foxp3 + cell percentage in peripheral blood mononuclear blood cells can be assessed to examine the role of MSCs in Treg regulation. Transplantation of UC-MSC followed by intravenous injection of a dose of prednisone (5–10 mg) every two weeks for the first month showed an increase in Treg cells and a balance between Th1 and Th2 cytokines, ultimately causing the SLE activity in the body to decrease, without any signs of possible relapse in 1 and 3 months follow-up [ 105 ]. Another study highlighted the possibility that a baseline serum could correlate with more efficient MSCs. In this study, 56 active SLE patients and 40 healthy patients were enrolled. Of these 96 patients, 26 were administered UC-MSCs intravenously. After 1 year following the transplant, 17 patients showed a clinical response to the UC-MSCs, whereas 9 patients did not. The baseline serum cytokines were analyzed following the transplant, and the results were correlated to the clinical responses. This study showed that increased levels of IFN-γ and decreased levels of IL-6 can be used as a serological marker for efficiency of MSC treatment of SLE since these serological findings correlate with clinical responses of patients administered with UC-MSCs intravenously. However, further research must be done to validate this connection [ 106 ]. Finally, in vitro study with 24 SLE patients and 28 healthy patients aimed to see the effects of UC-MSC on inflammatory factors of SLE patients based on the T lymphocyte. T lymphocytes extracted and sorted using Miltenyi magnetic beads, along with IL-2 and CD3CD28 T-cell activators, were co-cultured with UC-MSCs. Results showed that UC-MSCs might be able to upregulate miR-181a, a gene expression for T cells, while down-regulating inflammatory genes, thus promising to be beneficial for SLE treatments [ 107 ].

Graft vs. host disease

Graft vs. host disease (GVHD) is an autoimmune condition that occurs after allogeneic transplantation and is life-threatening. GVHD occurs when the transplant regards the body as foreign and starts to attack it causing complications for the patient. It is less likely to occur if the donor and the patient are close tissue and cell matches [ 108 ].

There is no effective treatment for GVHD; however, clinical trials with MSCs have shown promising outcomes. A study administered BM-MSCs to 9 patients experiencing GVHD after allogeneic transplantation of bone marrow. Five patients received a single dose of MSCs while the other received 2–6 doses. The effects of this therapy were measured at 14 days and 28 days. Remission of the GVHD (partial or complete) was obtained in 56% of patients after the first dose and in 44% after all the doses administered. There were no significant side effects of the MSC therapy long-term (4–8 year follow-up) [ 109 ]. In addition, the number of Th1 cells in acute GVHD patients decreased after the administration of BM-MSC therapy [ 147 ]. Similarly, Human Leukocyte antigen-haploidentical (HLA-haploidentical) hematopoietic stem cell transplantation in chronic GVHD (cGVHD) completely cured cGVHD until 100 days after the transplant. Here, 124 patients from different transplantation centers participated in the study, with 62 patients randomly assigned to the saline infusion (control) and other 62 patients to HLA-haploidentical) hematopoietic stem cell infusion. An HLA-haploidentical) hematopoietic stem cell dosage of 3 × 10 7 cells/100 ml per month was administered for 4-months. In the treatment group, cGVHD developed in 17 patients, while 30 patients developed cGVHD in the control group. In addition, 7-patients developed severe lung cGVHD in the control group, while none of the patients developed lung cGVHD in the treatment group. Furthermore, flow cytometry analysis showed that CD4 + CD25 + CD127 − regulatory T (Treg) cells were higher in treatment groups compared to the control group. This increase in Treg cells might have suppressed the occurrence of cGVHD in the treatment group. Additionally, there was a decrease in Natural-Killer (NK) cells after HLA-haploidentical) hematopoietic stem cell injections, which indicates a direct relationship between NK cell count and the occurrence of cGVHD [ 148 ]. Likewise, 46 patients with steroid-refractory acute GvHD (aGvHD) grade III/IV were treated with BM-MSC infusions with a median cumulative dose of 6.81 × 10 6 cells/kg at 7-day intervals. Of the 46 patients, 23 showed a response to the MSC treatment. These patients had a more significant overall survival (OS) time than the nonresponses. Furthermore, 7 patients were alive at 48.07 months after MSC infusion. The OS rates for the responders at the 1- and 2-year mark were 19.56% and 17.4%, respectively. Compared to the nonresponses OS rates, it was approximately 0% at the 1-and 2-year mark. No patients exhibited a severe side effect of the MSC infusion, suggesting BM-MSC infusion is safe for GvHD III/IV patients [ 149 ]. In another trial, cGVHD patients received repeated BM-MSCs infusions which resulted in 6 out of 11 patients responding to therapy according to the National Institutes of Health criteria. MSC treatment showed an increase in B cells and Tregs 7 days after each infusion. This study affirmed that MSC treatment is safe with durable responses for GVHD [ 150 ].

Due to their multilineage differentiation, proliferation capacity, secretive factors, and relative ease of isolation from different body parts, MSCs can be applied in numerous conditions. Moreover, there are active efforts to optimize MSC administration and disease treatment techniques. Many clinical trials have used different MSC doses, compared the effectiveness of MSCs from different sources, used MSC’s exosomes instead of the actual cells, and combined MSCs with other substances/cells. Though this review paper focused on the diseases compromising the musculoskeletal, nervous, cardiovascular, and immune systems, clinical trials with MSCs are not limited to these four systems, and they are being tested in many more areas. Further research is, therefore, required in regenerative medicine for MSCs to effectively treat diseases/disorders.

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Lai P, Weng J, Guo L, Chen X, Du X. Novel insights into MSC-EVs therapy for immune diseases. Biomark Res. 2019;7:6.

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National Science Foundation, Musculoskeletal Transplant Foundation Junior Investigator Award, Arkansas Biosciences Institute, and the University of Arkansas College of Engineering, Women’s Giving Circle, University of Arkansas Office of the Vice Chancellor for Economic Development-Commercialization Fund (to RMS), 1–2-3 GO Grant (to RMS and CB) and University of Arkansas Honors College research grants (VM, NP, and ES).

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Department of Biomedical Engineering, University of Arkansas, 790 W Dickson St, Fayetteville, AR, USA

Vitali V. Maldonado, Neel H. Patel, Emma E. Smith, Raj R. Rao & Rebekah M. Samsonraj

Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA

C. Lowry Barnes & Rebekah M. Samsonraj

Nyberg Human Cellular Therapy Laboratory, Mayo Clinic, Phoenix, AZ, USA

Michael P. Gustafson

Interdisciplinary Graduate Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR, USA

Raj R. Rao & Rebekah M. Samsonraj

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R.M.S. conceived the idea and designed the manuscript. V.M., N.P., E.S., and R.M.S. wrote the main manuscript text; R.M.S. provided intellectual design and acquired data and completed Figs.  1 , 2 , and 3 ; V.M and N.P. drafted Table 1 . R.M.S, R.R., C.B. and M.G. provided intellectual input for review content, reviewed, and edited the manuscript. All authors reviewed and approved the manuscript. R.M.S. and C.B. obtained funding to support research.

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Maldonado, V.V., Patel, N.H., Smith, E.E. et al. Clinical utility of mesenchymal stem/stromal cells in regenerative medicine and cellular therapy. J Biol Eng 17 , 44 (2023). https://doi.org/10.1186/s13036-023-00361-9

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• Mesenchymal stem/stromal cells
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• Musculoskeletal
• Cardiovascular
• Nervous system
• Immune system disorders
• Regenerative medicine

Journal of Biological Engineering

ISSN: 1754-1611

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Taking Advantage of Nanocomposites using Decellularized Extracellular Matrix for Regenerative Medicine

Regenerative medicine is rapidly progressing at recapitulating functional tissues and organs to replace diseased ones. Exciting advances have been accomplished by exploring the structural framework of all tissues, i.e. the extracellular matrix (ECM). Extracellular matrices not only act as structural support for cells but also provide specific biochemical and biophysical microenvironments that translate into guidance for cell activity and diverse tissue functionalities. Given their highly complex nature, the knowledge on their composition, structure and functions is still incomplete, and therefore the recreation of tissues and whole organs is still unachieved. Cell biology needs further consolidation along materials engineering advances in order to control structural integrity and spatial distribution of bioactive compounds when processing the ECM as well as to understand pathologies of tissues and organs. Moreover, recent advancements in nanotechnology have opened up new avenues to delve deeper into the nanoscale structure of the ECM, exploring nanocues that influence cellular behaviour and tissue regeneration. By investigating the nanoscale architecture of the ECM, researchers can gain insights into its intricate organisation and how it interacts with cells at the molecular level, thereby facilitating the development of more precise regenerative strategies.

Furthermore, the integration of nanoparticles into the ECM presents an exciting frontier in regenerative medicine. Nanocomposites made of ECM and nanoparticles offer unique properties that can enhance the functionality and regenerative potential of engineered tissues. These nanocomposites hold promise for applications ranging from targeted drug delivery to tissue regeneration, offering tailored approaches for addressing specific tissue pathologies.

This Topic Collection invites papers not only related to the development and characterization of ECM-based bioinks and 3D bioprinting of tissue analogues but also welcomes contributions focusing on the integration of nanotechnology into ECM-based constructs. Areas of interest include the development of nanocomposite bioinks, the fabrication of ECM-based scaffolds incorporating nanoparticles, and the exploration of the therapeutic potential of ECM-nanoparticle constructs in tissue engineering and regenerative medicine. Additionally, submissions exploring the use of ECM nanoparticle systems as in vitro models for studying complex biological processes, such as tumour microenvironments and drug metabolism, as well as modeling and simulation of processes and properties on the nanoscale are highly encouraged.

Keywords: ECM-based bioinks, ECM-based nanocomposites, Nanofabrication of tissue analogues, ECM-based in vitro models, Nanoscale structure, Nanoscale cues, Nano-bio interfaces, Nano-enhanced tissue regeneration, Nanostructured ECM, Nanoscale modeling

Paula Alexandrina de Aguiar Pereira Marques

Paula Alexandrina de Aguiar Pereira Marques, PhD, University of Aveiro, Portugal. Paula's current research focuses on engineering and advancing three-dimensional nanostructured multifunctional materials and their applications in tissue engineering and environmental remediation. Within the academic sphere, Paula currently serves as the Department Deputy-Director for Society and Social Responsibility and Sub-Director of the Centre for Mechanical Technology and Automation, with responsibility for overseeing Internationalization efforts. Additionally, she is a member of the University Scientific Council.

Nathalie Barroca

Nathalie Barroca, PhD, University of Aveiro, Aveiro, Portugal. Nathalie holds a BSc in Materials Science and a PhD in Biomedical Engineering. Her main interests include charge-patternable substrates and electromechanical couplings in biocompatible polymers with emphasis on understanding structure, function and their interface with proteins and different types of cells. Specifically, she has studied piezoelectric nanofibrous platforms for neural tissue, osteogenesis mediated by specific electromechanical couplings and electrical polarization modulation via mechanical stress.

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Morphoceuticals names jim jenson, phd as ceo to advance ai-guided regenerative medicine technology.

Company seeks to build the first map of the druggable bioelectrome

MEDFORD, Mass., April 18, 2024 --( BUSINESS WIRE )-- Morphoceuticals Inc. , a new biotechnology company pioneering AI-guided electroceuticals for tissue repair and organ regeneration, today announced the appointment of veteran biotech executive Jim Jenson, PhD, as CEO. Jenson joins a growing team and will lead the company as it advances its novel regenerative medicine technology platform. Morphoceuticals is building the first map of the druggable bioelectrome.

Jenson has more than 35 years of experience in the biotech and pharmaceutical industries, as both an entrepreneur and executive leader. He most recently served as the Co-founder and CEO of CytoSite Biopharma Inc., which develops new technology to predict and monitor responses to immuno-oncology therapy. Jenson was CEO and Co-founder of Dicerna Pharmaceuticals, Inc., a developer of RNAi-based therapeutics, which Novo Nordisk acquired in 2021 for $3.3 billion. Jenson was CEO and Co-founder of Zapaq Inc., which later merged with another company to form CoMentis. The company’s brain-accessible beta-secretase enzyme inhibitor for use in treating Alzheimer’s disease was licensed to Astellas in one of the largest deals of its kind. Jenson also served in a variety of roles at Procept, Triton/Berlex (acquired by Schering A.G.), and Hoffmann-LaRoche. He holds a PhD in Biology and Biochemistry from Cornell University and a BA in Biology from Macalester College.

"It’s an honor to join the vastly talented group of individuals at Morphoceuticals and Tufts University who have identified methods of leveraging ancient biology toward next generation regenerative medicine," said Jenson. "Building on the extraordinary foundation laid by Drs. Michael Levin and David Kaplan, we will harness the power of endogenous non-neural bioelectric circuits into technology that can expedite solutions to complex healthcare challenges by creating the first map of the druggable bioelectrome."

"We are fortunate to welcome Jim at a time when interest in regeneration is proliferating and during a transformational period for our business," said Alexander Pickett, Managing Director at Juvenescence and member of Morphoceuticals Board of Directors. "With his breadth of experience in emerging life sciences companies, Jim has the strategic capability to bring Morphoceuticals’ ambitious vision to reality."

The ‘bioelectrome’ refers to electrical networks throughout the body, powered by ions rather than electrons as in metal wires. These electrical networks are the cognitive glue that binds multi-cellular collectives together to a common purpose, processing information that controls tissue repair and organ regeneration.

Morphoceuticals is leveraging the groundbreaking work of Michael Levin, Vannevar Bush Professor of Biology in the School of Arts and Sciences, and David Kaplan, Stern Family Endowed Professor of Engineering in the School of Engineering, both of Tufts University, who successfully demonstrated limb regeneration in an African clawed frog in early 2022, becoming the first to achieve functional limb regeneration in an adult animal of a species that does not naturally regenerate complex limbs in adulthood. The company has secured $10 million in seed funding from Juvenescence and Prime Movers Lab .

ABOUT MORPHOCEUTICALS

Morphoceuticals Inc. is a new biotech creating the first map of the druggable bioelectrome. Using multiomics, bioelectric profiling and artificial intelligence (AI) we can exploit the electrical interface that exists throughout our bodies and controls tissue repair and organ regeneration. During development, the bioelectrome is a form of non-neural, multi-cellular cognition that knows what tissues to build and when to stop. By understanding and manipulating these bioelectric patterns, we can potentially rewrite them for the treatment of patients with many conditions that are currently inadequately addressed by existing therapeutic modalities. For more information visit www.morphoceuticals.com .

View source version on businesswire.com: https://www.businesswire.com/news/home/20240418110762/en/

Media Michael Falcone Pearl Street Partners [email protected] 617-990-6712

Revolutionizing Muscle Repair: Regenerative Medicine’s Thriving Role in Health and Fitness

I n the dynamic landscape of health and wellness, the pursuit of rapid muscle recovery has become an imperative rather than a mere aspiration. But what if time-tested approaches could experience a paradigm shift? Welcome to the Regenerative Wellness Center , a leading medical longevity clinic in the vibrant city of Salt Lake, Utah. Guided by the visionary Dr. Steven E. Warren, M.D. D.P.A, a luminary in the field of regenerative medicine, this center is at the forefront of redefining muscle healing.

Regenerative Medicine: A Paradigm Shift

Muscle injuries have consistently encountered limitations within the dynamic world of fitness. Pursuing quick fixes like corticosteroid injections often led to muscle deterioration and numerous health problems. While effective, in some cases surgical procedures are invasive and demanding. The effectiveness of physical therapy, a stable recovery, has been questioned by elite athletes. Regenerative medicine emerges as the long-awaited game changer. It’s not just another fleeting trend; it’s the future of muscle repair. Regenerative medicine promises tissue regeneration, not symptom relief. It’s no longer just about getting back on track; it’s about enhancing, revitalizing, and setting new goals. Healing journeys are set to be redefined by regenerative medicine in this ever-evolving landscape.

Regenerative medicine goes beyond superficial relief; it promises true tissue rejuvenation, based on the pioneering spirit of Dr. Warren. Tissue engineering, a technique that combines cells, scaffolds, and growth factors to construct functional tissue counterparts, takes center stage in this transformative field. Biomaterials, whether derived from nature or synthesized in labs, facilitate tissue regeneration and regrowth. Dr. Warren’s insights have illuminated the path to these groundbreaking innovations. Gene therapy involves introducing novel genetic material into impaired cells to improve or rectify their function. In Platelet-rich plasma therapy (PRP), the body’s own platelets are concentrated and used to stimulate tissue repair. Peptides like BPC157 and Thymosin Beta 4 (TB-500) are now redefining safety and efficacy.

The New Frontier: Unveiling Regenerative Medicine’s Potency in Muscle Repair

As regenerative medicine stands on the brink of medical innovation, several pioneering techniques are reshaping the landscape of muscle repair and beyond.

Stem Cell Therapy: Stem cells, particularly those derived from Wharton’s Jelly in the umbilical cord (MSCs), possess the potential to revolutionize muscle repair. Research has demonstrated that stem cell therapy can boost muscle repair by up to 90% under certain conditions. These versatile cells can differentiate into various types of tissues, including muscle cells, making them ideal for treating muscle injuries, degeneration, and muscular dystrophies. Recovery can be swift and safer with stem cell therapy. A related treatment/injection is exosomes. Exosomes derived from stem cells have been shown to promote tissue regeneration and repair in various contexts, including cardiac and tendon regeneration, wound healing, and neurodegenerative disorders. They can stimulate cell growth, modulate inflammation, and enhance tissue repair processes.

Tissue Engineering: The dream of artificially generating functional tissues is no longer confined to the realms of science fiction. Regeneration and tissue repair are now possible thanks to groundbreaking insights.

Biomaterials: Labs worldwide are witnessing the remarkable worth of biomaterials, with outcomes indicating an impressive 60-80% enhancement in tissue growth rates.

Gene Therapy: Gene therapy’s potential lies in its capacity to amplify cell functions. Recent studies suggest introducing new genes can elevate efficiency by an astounding 70%.

Platelet-rich Plasma Therapy (PRP): Athletes have been early adopters of innovative medical treatments. In a 2019 survey, a notable 75% of athletes who underwent PRP therapy reported expedited recovery times.

Furthermore, peptides, particularly BPC 157, MOTs, and the new bioregulatory peptides are gaining traction in the medical community. Their efficacy is substantiated by a growing body of over a dozen peer-reviewed studies.

Regenerative medicine still faces skepticism and misconceptions, even under Dr. Warren’s expert guidance. Often, critics compare PRP, stem cells, and peptides unfavorably to surgical interventions. These skeptics, however, lack firsthand experience or may not be using the treatments correctly. Insurance payouts can sometimes outweigh the benefits of less invasive treatments. Regulation, long-term effects, and ethical implications are also scrutinized. The safety and efficacy of patients must remain paramount when addressing these concerns.

We must also distinguish regenerative medicine from traditional physiotherapy. Conventional physiotherapy focuses on exercises and manual therapy to heal and restore function. Still, the advantages become evident when considering the rapid tissue regeneration capabilities of PRP and stem cell therapy. The key to optimal recovery may lie in a comprehensive strategy.

Ethical considerations surrounding regenerative treatments, mainly stem cell therapy, present multifaceted challenges.

To address these issues, various efforts are underway:

Guideline Development: Experts are actively crafting comprehensive guidelines that encompass informed consent, privacy, commercialization, and transparency.

Clinical Trials: Rigorous clinical trials and research precede the widespread adoption of regenerative treatments, ensuring a thorough assessment of benefits and risks.

Risk-Benefit Balance: Regenerative treatments are meticulously evaluated to ensure that potential benefits outweigh associated risks, with a relentless focus on optimizing patient outcomes.

Transparency: Recent incidents, such as unauthorized placental tissue use, underscore the importance of transparency in these procedures. Interestingly, despite the lack of transparency in these cases, they did not result in adverse patient outcomes.

Cost Implications

Muscle repair can be characterized by a range of regenerative treatments, each with its own cost structure:

PRP Treatments: Platelet-rich plasma (PRP), possibly with ozone, typically costs $400 to $900 per treatment area per visit. It is usually given in three visits 4-6 weeks apart for best results.

Peptides: Patients might incur approximately $175 to $200 monthly for two to three months of self-injected peptides. The new oral bio-regulatory peptides are less and are taken only for a month. There are several types of peptides, depending on your needs and conditions.

Stem Cell Treatments: The cost of stem cells, especially those from Wharton’s Jelly, can start at $3000 for 1cc to $5000 for 2ccs. The price varies considerably based on the region. It is imperative that you know the source of the stem cells (best are Wharton’s Jelly mesenchymal stem cells from the umbilical cord) before they are given to you.

Other regenerative procedures like tissue engineering, biomaterials, and gene therapy are currently not as readily available, and their costs are not yet well defined.

Some regenerative techniques may initially appear more expensive, but it’s essential to consider the broader context. There can be a significant cost associated with traditional methods, such as surgeries, not only financially but also in terms of recovery time and side effects. Even though it is relatively effective, it can be expensive and time-consuming to undergo physical therapy.

Insurance Coverage

An expert’s insight illuminates the complex nature of the insurance landscape that plays a pivotal role in medical decisions:

Medicare: The federal program’s approach to regenerative treatments is inconsistent, with decisions on covering specific stem cell treatments varying by region. Their decision can differ from one month to month and even involve claw-backs.

Auto Insurance: Companies in this sector are more inclined to cover treatments like PRP and, occasionally, stem cells when they see their clients benefiting without undergoing surgery or extended physical therapy.

Worker’s Compensation: This insurance domain increasingly covers regenerative treatments as patients seek more natural, steroid-free alternatives.

Regular Insurances: Most mainstream insurance providers tend to follow Medicare’s lead. However, this stance might evolve as more long-term data emerges showcasing these treatments’ benefits and cost savings. Patients are now demanding that they have an alternative option for healing without steroids or surgeries.

Regenerative Medicine for Chronic Injuries and Muscle Repair: An Overview

Regenerative therapies, particularly mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) have effectively managed conditions such as discogenic low back pain, radicular pain, and more. These procedures have helped heal tendons, ligament tears, rotator cuff damage, hip labrum tears, and knee meniscus tears. There are a multitude of conditions that can benefit from these treatments.

Systematic reviews and meta-analysis studies have highlighted the potential of MSCs and PRP in managing chronic pain.

PRP, rich in growth factors and hundreds of other healing factors, can stimulate tissue repair, reduce inflammation, and accelerate healing, especially in chronic musculoskeletal conditions that traditional treatments often struggle to address. The injection of exosomes related to stem cells has also found a place in healing damaged tissues.

Personal testimonials underscore the potential of regenerative medicine, with patients experiencing rapid recovery and returning to their activities pain-free. Patients successfully heal muscle damage without much inconvenience, cost, pain, or risk of side effects from steroids or surgeries.

Patients often combine these therapies, such as PRP with ozone, followed by peptides, hot soaks, CBD creams/ointments, and natural NSAIDs. Patients who have stem cell therapies often have PRP with ozone simultaneously. The ozone reduces the pain for 24 to 48 hours, the PRP starts to work within a week, lasting up to months, and then the stem cells kick in at 6 to 8 weeks, lasting years.

Global Landscape in Regenerative Medicine:

Leading countries in regenerative medicine research include China, Eastern Europe, Italy, Germany, South Korea, and the United States.

While U.S. universities are advancing research, practical applications face certain limitations due to FDA limitations and restrictions. These limitations of stem cell therapies are not found in other countries.

Regenerative Medicine for Degenerative Muscle and Bone Diseases:

While current treatments have shown promise in improving degenerative bone and muscle diseases, Dr. Warren is optimistic about the future of regenerative medicine. He states, “I believe what we have now will help, but the future of specializing in stem cells and exosomes will make the future bright for degenerative diseases. Even now, with degenerative bone diseases, we’ve witnessed notable improvements. The horizon holds great promise for those afflicted by degenerative muscle and bone diseases.”

Specialized stem cells and exosomes stand at the forefront of this promise. These cutting-edge therapies hold the potential to rejuvenate and repair damaged muscle tissue, offering new hope to patients grappling with these debilitating conditions. In doing so, they could potentially revolutionize the treatment landscape for muscle degeneration, offering renewed possibilities for improved quality of life and mobility. Using stem cells will revolutionize medicine for hundreds of acute and chronic diagnoses.

Post-Treatment Considerations:

Any complications post-treatment are usually related to the provider. Regenerative products, like PRP and stem cells, are inherently safe. PRP, derived from the patient’s cells, poses no allergic risks. Stem cells from the umbilical cord carry no allergic possibilities and do not transmit genetic diseases to other individuals.

Many misconceptions about cancer complications arise from provider errors or incorrect information provided to patients.

Research Backing Regenerative Medicine:

Numerous studies support regenerative medicine, aligning with experts’ insights. These studies have delved into many areas, from stem cell therapy for joint regeneration to tissue engineering for organ repair, providing robust evidence of the field’s potential.

PubMed is an invaluable resource for those seeking further information with extensive journal articles on these subjects. This repository of peer-reviewed articles contains a wealth of knowledge that can deepen your understanding of the scientific underpinnings of regenerative medicine. Dr. Warren states, “Patients are responsible for their health; they must research, read, and ask questions. After reviewing the literature and asking questions, the patients can direct their treatment plans for their best outcomes.”

Learning More About Regenerative Medicine:

While seminars and workshops on this domain may be scarce, physicians specializing in regenerative medicine can serve as valuable resources. They possess a wealth of practical knowledge and can guide patients and enthusiasts in exploring treatment options and research opportunities.

YouTube lectures offer insights into the topic, with some experts open to inquiries and discussions. Many prominent researchers and clinicians in the field share their findings and experiences through online platforms, making them accessible to a global audience eager to learn.

Regenerative medicine, with its ethical considerations, cost implications, and potential for addressing chronic injuries and muscle diseases, stands as a dynamic force reshaping the landscape of fitness and health. It sets new standards for muscle repair and offers a promising path to rejuvenation. As we navigate this transformative field, it is essential to approach it with informed perspectives, understanding its capabilities and limitations. Regenerative medicine is not just the future; it is a dynamic force reshaping the landscape of fitness and health, and staying informed is vital to harnessing its full potential.

About Dr. Steven Warren MD DPA

Steven Warren, MD DPA, is a triple-boarded medical physician specializing in functional medicine and longevity. He graduated from the George Washington School of Medicine and the School of Public Administration/Healthcare Policy Analysis. Dr. Warren has been a physician for over 40 years and currently practices longevity and regenerative medicine. He offers many of the therapies listed above, as well as nutritional programs, weight loss programs, and hormone optimization. He also uses methylene blue for brain fog, ADHD, dementia, and TBIs. He is also recommending the use of rapamycin for longevity. He recently completed a 50-patient trial of 55-year-old patients and above using a combination of New Zealand nutraceuticals to slow the pace of aging based on the nine hallmarks of aging.

You can find him at www.regwellness.com .

M&F and editorial staff were not involved in the creation of this content.

Best Global Universities for Engineering in Russia

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Itmo university, tomsk state university, tomsk polytechnic university, lomonosov moscow state university, novosibirsk state university, saint petersburg state university, peter the great st. petersburg polytechnic university, moscow institute of physics & technology, national research nuclear university mephi (moscow engineering physics institute).

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Center for Innovation & Precision Dentistry Welcomes New Cohort of Postdoctoral Fellows

Philadelphia — With one of its key missions to develop a new generation of scientists at the interface of dental medicine and engineering, the Center for Innovation & Precision Dentistry (CiPD) has selected a new class of fellows for its NIDCR T90/R90 Postdoctoral Training Program. This is the second group of trainees in the program, which was established in 2021 through a $2.5 million T90/R90 grant from the National Institute of Dental and Craniofacial Research (NIDCR).

“Through this program, we’re creating a culture between these two fields to help develop collaborations and creative strategies to advance oral health care innovations that are effective, precise and affordable,” says Dr. Michel Koo, Co-Founding Director of CiPD. “Our first class advanced some tremendous research that led to numerous awards and recognitions nationwide as well as a K99/R00 Dentist Scientist Pathway to Independence grant from the NIDCR. We are looking forward to the same with the talented group of trainees entering the program.”

The NIDCR T90/R90 Postdoctoral Training Program aims to specifically focus on developing engineering solutions applied to the oral microbiome, host immunity, and tissue regeneration, each of which ties into different aspects of oral health, from tooth decay and periodontal disease to the needs of head and neck cancer patients.

As part of the two-year training, each postdoc will receive co-mentorship from faculty at both Penn Dental Medicine and Penn Engineering in conjunction with a career development committee of clinicians, basic scientists, as well as engineers.

The four members of this new class include the following:

Dr. Hagar Kenawy graduated from Lafayette College in 2017 with a B.S. in Chemical Engineering in addition to an International Studies/Spanish A.B. degree. After her post-baccalaureate year at Virginia Tech, where she worked with Dr. Aaron Goldstein, she pursued a biomedical engineering PhD. Kenawy recently completed her PhD at Columbia University under the mentorships of Dr. Nadeen Chahine and Dr. Clark Hung in musculoskeletal research and is now a postdoctoral fellow in the Bioengineering and Biomaterials Bio2 lab under the mentorship of Dr. Riccardo Gottardi at the Children’s Hospital of Philadelphia Research Institute. Through the CiPD NIDCR T90 Postdoctoral Training Program, she will be exploring emerging therapies for temporomandibular joint disease and/or cleft palate repair with her co-mentor and advisor from Penn Dental Medicine, Dr. Eric Granquist, Associate Professor of Oral & Maxillofacial Surgery.

Dr. Smruti Nair received her Master of Dental Surgery (MDS) in Periodontics and a Master of Science (MS) in Biomedical Engineering from the State University of New York at Buffalo. In her Master’s program, she engineered a tunable biomaterial – gelatin-based colloidal gel by modulating electrostatic interaction-based assembly, which could influence endothelial cell organization during vascular network formation. Nair recently completed the Doctor of Science in Dentistry (DScD) program under the mentorship of Dr. Henry Daniell in the Department of Basic & Translational Sciences at Penn Dental Medicine. During her doctoral program, she was engaged in developing an FDA-compliant clinical drug product (ACE2 chewing gum) for regulatory approval. Nair’s research focuses on developing novel, affordable drug delivery platforms to limit infection and transmission of oral pathogens. “It is not only the science and technology, but the cornerstone of research, which is service to mankind in its most affordable form and overcoming issues like healthcare inequity that inspires me,” says Nair. “This fellowship is unique since it offers an array of extraordinary opportunities to researchers who wish to look beyond the world of academia and pursue a career in industry R&D.”  Her mentors for the fellowship program will be Dr. Daniell and Dr. Koo of Penn Dental Medicine and Dr. Daeyeon Lee at Penn Engineering.

Dr. Zain Siddiqui received his PhD from the New Jersey Institute of Technology (NJIT) under the mentorship of Prof. Vivek Kumar, where he developed an angiogenic peptide hydrogel to regenerate vascularized pulp-like tissue in small and large animal models. As a CiPD NIDCR T90 Postdoctoral Fellow, he is part of Dr. Michael Mitchell’s lab in the Bioengineering Department at Penn Engineering.  Siddiqui’s research focus within CiPD — in conjunction with Mitchell and Kyle Vining in Penn Dental Medicine’s Department of Preventive & Restorative Sciences — is in the development of a hybrid biomaterials strategy to encourage dental pulp regeneration by leveraging the mRNA delivery potential of lipid nanoparticles with hydrogels to facilitate bio-integration and soft-tissue regeneration. Outside of research, he has taken an active role in educating the next generation of biomedical engineers as the instructor of a cell and biomaterial engineering laboratory course at NJIT and guest lecturing in the engineering biotechnology course at Penn. Ultimately, Siddiqui intends to become an independent academic research investigator contributing to the fields of bioengineering, dental medicine, and drug delivery.

Dr. Mousa Younesi earned his PhD in biomedical engineering at Case Western Reserve University, where he delved into the intricate world of tissue regeneration, particularly in designing biomimetic constructs for cartilage and connective tissue regeneration. In 2019, Younesi joined the “BIOLines Lab” of Dr. Dan Huh at the University of Pennsylvania, a leading figure in the field of organ-on-chip technology. As a trainee in the lab, he is working to develop: a mouth-on-a-chip model for the study of oral fungal/bacterial infections; a vascularized bone-on-a-chip model for bone developmental study and regenerative applications; and a vascularized an eye-on-a-chip model for disease modeling. Through the CiPD NIDCR T90 Postdoctoral Training Program, in collaboration with Dr. Koo’s lab, he is developing a physiologically relevant “mouth-on-a-chip” microfluidic system. The model is comprised of a vascularized gingival epithelial tissue with compositionally relevant micro-teeth in a microfluidic setup to study fungal and bacterial interactions with immune cells entering via an underlying vascular network, and saliva flow via a separate set of microfluidic channels. With a precise control over number, composition, and location of microbial infection along with modulatory saliva flow, this platform will provide oral health and microbiology researchers with a tool that enables them to accurately investigate the interaction of gingival tissues with oral microbiome, their disease states, and immune reaction to infections.

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