phd 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.

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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..

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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.

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Tissue Engineering & Regenerative Medicine Research Program

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Regenerative Medicine

18 Dec 2023 Turning the Tap Back On

07 Jan 2021 Stem Cell Treatment Corrects Skull Shape and Restores Brain Function in Mouse Model of Childhood Disorder

28 Jan 2021 Surgical Adhesive Inspired by Slug Slime

30 Sep 2019 How Does a Mouse’s Tooth Grow?

19 Nov 2018 The Quest to Understand Dental Stem Cells

15 Oct 2018 Human Skeletal Stem Cell Identified

Grantee News

26 Apr 2023 Do Spiny Mice Hold the Key to Regenerative Healing? UK Study Explores

17 Apr 2023 Healing the Unhealable: New Approach Helps Bones Mend Themselves

22 Mar 2023 Researchers Find Key to Healing Muscle Injuries in Elderly

09 Jan 2022 A Crowning Achievement in Understanding Head Development

18 Nov 2021 A Stunning 3D Map of Blood Vessels and Cells in a Mouse Skull Could Help Scientists Make New Bones

07 Sep 2021 Nerve Repair, With Help From Stem Cells

06 Oct 2021 Massage Doesn’t Just Make Muscles Feel Better, it Makes Them Heal Faster and Stronger

26 Apr 2021 Skin and Bones Repaired by Bioprinting during Surgery

14 May 2018 First Description of mEAK-7 Gene Could Suggest Path toward Therapies for Cancer, Other Diseases

12 Jul 2017 Diabetes Causes Shift in Oral Microbiome that Fosters Periodontitis, Penn Study Finds

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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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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.

Bioengineering

Tissue engineering & regenerative medicine.

The promise of regenerative medicine is truly remarkable. Over the last two decades, significant breakthroughs in understanding within the regenerative medicine and tissue engineering fields have yielded a more intimate understanding of the functioning of human tissue. In the future, new technologies may deliver islet cells for diabetes, neural regeneration for spinal cord injuries and more substantial heart repair. In addition, as biology, bioengineering and medicine continue to converge, the regenerative medicine field may succeed in building three-dimensional organs like hearts, kidneys or livers.

Traditionally, researchers in the BioE program focus was on replacement of tissues or growing cell-based substitutes outside the body for implantation into the body. However, as the field has evolved over the last decade, researchers have broadened their approach from a focus on tissue engineering to one that includes repair and regeneration.

Projects range from creating better techniques for wound repair to peripheral nerve regeneration. In addition, BioE researchers are using advanced bioengineering methods to develop technologies that will facilitate the transfer of research in musculoskeletal biology and regenerative medicine for treatment of wounded soldiers.

Julia Babensee

Associate professor.

Host responses to combination products, biomaterial interactions with dendritic cells, tissue engineering for rheumatoid arthritis, targeted DNA vaccine delivery, and biomaterial-applied immunology.

Stephen Balakirsky

Principal research scientist.

Collaborative robotics

Edward Botchwey

Tissue engineering and biomaterials, microvascular growth and remodeling, stem cell engineering The Botchwey Laboratory takes a multidisciplinary approach for improvement of tissue engineering therapies through study of microvascular remodeling, inflammation resolution and host stem cells. Our goal is development of effective new strategies to repair, replace, preserve or enhance tissue or organ function. 

Julie Champion

Developing therapeutic protein materials, where the protein is both the drug and the delivery system Engineering proteins to control and understand protein particle self-assembly Repurposing and engineering pathogenic proteins for human therapeutics Creating materials that mimic cell-cell interactions to modulate immunological functions for various applications, including inflammation, cancer, autoimmune disease, and vaccination

Ahmet Coskun

Assistant professor.

Bone Tissue Engineering, Computational Design and Fabrication of Resorbable Scaffolds, Composite Scaffolds, Direct Digital Manufacturing Technologies, Large-Area Micro- and Nanoscale Photopolymerization, Patterning, and Interference Lithography Technologies, Laser Materials Processing.

Prasad Dasi

Michael Davis

Our laboratory focuses on various aspects of cardiac regeneration and preservation using molecular-based and biomaterials-based approaches to restoring function after cardiac injury

Brandon Dixon

Bioengineering: lymphatics, lipid metabolism, biomechanics, biomedical optics, image processing, and tissue engineering.

Erik Dreaden

Assistant professor of biomedical engineering, assistant professor of pediatrics.

The Dreaden Lab uses molecular engineering to impart augmented, amplified, or non-natural function to tumor therapies and immunotherapies. The overall goal of our research is to engineer molecular and nanoscale tools that can (i) improve our understanding of fundamental tumor biology and (ii) simultaneously serve as cancer therapies that are more tissue-exclusive and patient-personalized. The lab is housed on the Emory SOM campus and currently focuses on three main application areas: optically-triggered immunotherapies, combination therapies for pediatric cancers, and nanoscale cancer vaccines. Our work aims to translate these technologies into the clinic and beyond.

Ross Ethier

My research area is biomechanics and mechanobiology with focus on: Glaucoma, including studies of aqueous humour drainage, optic nerve head biomechanics, and stem cell therapies in glaucoma; and Mechanobiology of osteoarthritis.

Andrés García

Executive director, parker h. petit institute for bioengineering and bioscience, regents' professor, george w. woodruff school of mechanical engineering.

Biomolecular, cellular, and tissue engineering strategies to direct cell function for biomaterial and regenerative medicine applications.

Rudy Gleason

Associate professor - joint appointment in the school of biomedical engineering.

Cardiovascular mechanics, soft tissue growth and remodeling, and tissue engineering.

Scott Hollister

Professor and patsy and alan dorris chair in pediatric technology.

My research interests focus on image-based computational design and 3D biomaterial printing for patient specific devices and regenerative medicine, with specific interests in pediatric applications. Clinical application interests include airway reconstruction and tissue engineering, structural heart defects, craniofacial and facial plastics, orthopaedics, and gastrointestinal reconstruction. We specifically utilize patient image data as a foundation to for multiscale design of devices, reconstructive implants and regenerative medicine porous scaffolds. We are also interested in multiscale computational simulation of how devices and implants mechanically interact with patient designs, combining these simulations with experimental measures of tissue mechanics. We then transfer these designs to both laser sintering and nozzle based platforms to build devices from a wide range of biomaterials.  Subsequently, we are interested in combining these 3D printed biomaterial platforms with biologics for patient specific regenerative medicine solutions to tissue reconstruction.

Stem cell, tissue engineering, mitochondrial engineering and bioenergetics, aging, muscular dystrophy, and neuromuscular disease.

Michelle LaPlaca

Traumatic brain and spinal cord injury, Neural tissue engineering, Injury biomechanics, Neural interfacing, and Cognitive impairment associated with brain injury and aging.

Joe Le Doux

I am a co-founder of STELAR: the Studio for Transforming Engineering Learning and Research. STELAR is a one-of-its-kind learning sciences research group embedded within the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. Our goal is to contribute to changing the engineering workforce so that it is diverse and inclusive and fully leverages all of our national talent to effectively address the complex problems of the 21st century. We aspire to graduate students who have agency as inclusive engineers who understand the need for a diverse and inclusive engineering workforce and have the knowledge, skills, and dispositions to create, and thrive within, inclusive study and work environments.

Shuming Nie

The wallace h. coulter distinguished faculty chair in biomedical engineering & professor.

Our research is in the areas of biomolecular engineering and nanotechnology, with a focus on bioconjugated nanoparticles for cancer molecular imaging, molecular profiling, pharmacogenomics, and targeted therapy.

John Oshinski

Dr. Oshinski is well known for his collaborative efforts between Emory and Georgia Tech's Department of Biomedical Engineering, along with his dedication to advancing the technologies of MR imaging. One area of concentration is the development of Cardiovascular MRI for clinical and basic science applications. Dr. Oshinski has worked on development of the contrast-enhanced MRA and phase-contrast MR for rapid assessment of the aorta and the peripheral runoff vessels. He also Implemented SSFP cine imaging for rapid breath-hold assessment of cardiac function, IR recovery sequences for myocardial perfusion imaging, and creating a protocol for using MR coronary angiography to diagnose the proximal course of the coronary arteries.

Muralidhar Padala

Associate professor of surgery & bme.

Sung-JIn Park

Felipe Quiroz

Philip Santangelo

RNA regulation, single molecule imaging, and RNA virus pathogenesis

Gregory Sawicki

Todd Streelman

Professor and director.

Evolution and development of functional systems.

Todd Sulchek

Bioengineering and Microelectromechanical Systems: Atomic force microscopy, pathogen adhesion and endocytosis, cell biomechanics, single molecule biophysics, drug delivery and targeting, cell membrane mimetics, and biosensors.

Shuichi Takayama

The MNM Biotech Lab uses engineering expertise to assist life scientists in the study, diagnosis, and treatment of human disease. By developing better models of the body, we help advance drug discovery, increase understanding of the mechanisms of disease, and develop clinical treatments.

Vascular biology with an emphasis on the role of vascular inflammation in the pathogenesis of hypertension, diabetes and atherosclerosis.

Johnna Temenoff

Carol ann and david d. flanagan professor.

Development of novel polymeric biomaterials, regeneration of tendon/ligament, and protein delivery for orthopaedic tissue engineering.

Randy Trumbower

Director of research & assistant professor.

Spinal cord injury, stroke, intermittent hypoxia, rehabilitation, motor control, and whole limb mechanics.

Our research focuses on applying systems analysis approaches and engineering tools to identify novel clinical therapeutic targets for complex diseases. It is challenging to develop new treatments for these diseases, such as Alzheimer's disease (AD) and Traumatic Brain Injury (TBI), because they do not have a single genetic cause and they simultaneously present broad physiologic changes. By combining novel engineered in vitro platforms, mouse models, and multivariate computational systems analysis, we will be able to 1) capture a holistic systems-level understanding of complex diseases, and 2) isolate specific mechanisms driving disease. The ultimate goal of our laboratory is to use these tools to identify new mechanisms driving disease onset and progression that will translate to effective therapeutic strategies.

Disruptive technologies enabled by nanoscale materials and devices will define our future in the same way that microtechnology has done over the past several decades. Our current research centers on the design and synthesis of novel nanomaterials for a broad range of applications, including nanomedicine, regenerative medicine, cancer theranostics, tissue engineering, controlled release, catalysis, and fuel cell technology. We are design and synthesize/fabricate novel nanomaterials that could serve as: 1) theranostic agents for cancer and other diseases; 2) multifucntional probes for cellular tracking; 3) smart capsules for site-specific, on-demand delivery; and 4) scaffolds for the repair or regeneration of tissues.

Shawn Hochman

Professor and interim chair,.

The spinal cord is the gateway for information transfer between body and brain but is not simply a conduit. Within its central gray matter lie millions of neurons that integrate and coordinate complex sensory, motor and autonomic events. Spinal cord injuries can permanently sever descending command pathways and produce paralysis. After some time the injured cord often become hyper-responsive and may result in spasticity (hyperreflexia), autonomic dysfunction and devastating chronic pain syndromes. Brain modulatory systems regulate spinal cord excitability and it may be disruption of their actions that are primarily responsible for the hyperactivity seen after cord injury or in diseases states. A major goal of our lab is to understand how the major brain monoamine modulatory transmitters (serotonin, dopamine, and nor-adrenaline) regulate cord function. These transmitters have been linked to activation of the spinal cord circuitry generating locomotion, control of autonomic NS function, as well as the potent inhibition of spinal cord pain systems. Dysfunction is spinal dopamine is also strongly implicated in the emergence of Restless Legs Syndrome (RLS). We are also very interested in additional mechanisms that limit body sensations.

Current research in the lab focuses on:
 1. Non-classical control of body sensations. 
2. Restless Legs Syndrome (RLS) and spinal cord dopamine.
 3. Plasticity of spinal cord function after injury.
 4. Regulation of spinal cord locomotor activity.
 5. Unusual modulatory mechanisms controlling spinal cord function.

Song Ih Ahn

Neuroengineering, Tissue Engineering, Organ-on-chips, Microfluidics, Drug Delivery, Cell Mechanics

Alexander Beach

Retinal research, tissue regeneration

Nicholas Beskid

Fredrick Bulondo

Ms. in bioengineering.

ImmunoEngineering, Biomaterials, Bioinstrumentation

Thomas Burkholder

Associate professor,.

Exploration of the coordination of skeletal muscle structure and function. This work has two thrusts: understanding the mechanism by which mechanical signals alter muscle structure and understanding the functional demands on muscle

Olivia Burnsed

Olivia is interested in the effects of both the structural and biochemical cues provided by the extracellular matrix on modulating cell phenotype and inflammation. She is currently working to create microcarriers to expand chondrocytes while maintaining their phenotype and direct the differentiation of stem cells. Olivia is also investigating the use of MSCs in combination with human amniotic membrane for osteoarthritis (OA) treatments in the context of modulating inflammation and OA progression.

Seleipiri Charles

Albert Cheng

Ricardo Cruz-Acuña

Biomaterials and Regenerative Medicine

Gilad Doron

Aaron Enten

Phd, mba, managing innovation and technology commercialization.

Medical Device Innovation / Clinically Translational Technology

Shaun Eshraghi

Jose Garcia

Biomaterials, Tissue Engineering, Therapies for Increased Vascularization, Stem Cell Therapies

Michael Griffin

Microfluidics, Arterial Thrombosis, Platelets, vWF

Robert Guldberg

Adjunct professor.

Guldberg’s research interests focus on musculoskeletal growth and development, functional regeneration following traumatic injury, and degenerative diseases, including skeletal fragility and osteoarthritis. His research is supported by the NIH, NSF, DoD, and several biotechnology companies and has resulted in over 150 book chapters and publications. Guldberg is a Fellow of the American Institute for Medical and Biological Engineering (AIMBE) and holds several national leadership positions.

Elijah Holland

Bioengineering.

Michael Hunckler

Kelly Hyland

Timothy Kassis

Lymphatic biology, lipid uptake and metabolism, obesity, lymphatic imaging, in situ imaging, image processing, vessel biomechanics, microfluidics, machine learning.

Myeongsoo Kim

Johnathon Long

Lina Maria Mancipe Castro

Drug delivery, Tissue Engineering & Regenerative Medicine, Biomaterials    

Karen Martin

Larry McIntire

Department chair emeritus.

Bioengineering aspects of vascular biology, thrombosis, inflammatory response, and infectious disease Cellular engineering

Alyssa Montalbine

Leandro Moretti

Adriana Mulero-Russe

My research is focused on the growth, expansion, and differentiation of human pluripotent stem cells (hPSC) into human intestinal organoids (HIOs) using an engineered synthetic polyethylene glycol (PEG) hydrogel platform.

Andre Norfleet

Systems Biology Computational Modeling, Personalized Medicine, Immunotherapeutics

Michelle Quizon

Mohammad Razavi

Rachel Ringquist

Immunology, organ-on-chip, immunotherapies

Stephen Robinson

In-vitro models of disease

Apoorva Salimath (Kalasuramath)

Angel Santiago-Lopez

Rebecca Schneider

Farbod Sedaghati

Cardiovascular Mechanics Soft tissue growth & remodeling Tissue engineering

Generation and regeneration of cells into hepatopancreatic lineages, Bone Morphogenetic Protein (BMP) 2b signaling, Zebrafish genetics, Morphogenesis and organogenesis

Sangeetha Srinivasan

Biomaterials, Immunology, Tissue Engineering, Polymers

Brennan Torstrick

Graduate student.

Vishwa Vasani

Microfluidics, Organoids, Microphysiological Systems

Hannah Viola

Muhammad Minhal Yusufali

Ph.d. student + r&d engineer.

Neural Engineering + Biomaterials

Nicholas Zhang

Daniel Zhang

Regenerative medicine, aging, longevity, stem cell engineering, tissue engineering, neuroengineering

Luiza DaMotta

Justin Damon

Laura Hansen

Assistant professor of medicine.

Anant Paravastu

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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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These authors contributed equally: Anna Ruta, Kavita Krishnan.

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Translational Tissue Engineering Center and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

Anna Ruta, Kavita Krishnan & Jennifer H. Elisseeff

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J.H.E. holds equity in Unity Biotechnology and Aegeria Soft Tissue, and is an advisor for Tessera Therapeutics, HapInScience and Font Bio. The remaining authors declare no competing interests.

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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.

Related cell biology Research Resources

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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.

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• 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:

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• pluripotent and tissue stem cell biology
• degeneration and regeneration of adult tissues
• genetic engineering
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Generic and transferable skills training is provided through the University's Institute for Academic Development (IAD).

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We also have imaging facilities, including:

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• widefield, confocal, and lightsheet microscopes
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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:

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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.

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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.

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

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

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

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Van Cleve Cardiac Regenerative Medicine Program

Unprecedented hope

Cardiovascular disease, the leading cause of premature death around the world, is on the rise. Traditional medical therapies are not able to fully address the burden of heart disease, and the shortage of organs available for transplantation remains a key barrier for offering solutions to millions of patients across the globe.

Through the visionary leadership and generous philanthropy of Russell and Kathy Van Cleve, unprecedented hope is beginning to translate into future healing options for those with heart disease.

By harnessing the body's natural ability to heal, regenerative medicine is addressing the unmet needs of patients with chronic or complex conditions who often have no other viable treatment options.

Broad impact

The goal of the Mayo Clinic Van Cleve Cardiac Regenerative Medicine Program is to advance stem cell therapies, cell-free regeneration and tissue engineering. To do this, the program accelerates the discovery, translation and application of innovative regenerative products for heart disease.

Importantly, results from this work will not only make an impact in cardiovascular health but also advance novel regenerative solutions across medical and surgical specialties to address vast unmet patient needs.

Strategic focus

Through a shared vision with Russell and Kathy Van Cleve, the Mayo Clinic Van Cleve Cardiac Regenerative Medicine Program has the goal of creating novel, affordable and accessible cardiac regenerative therapies to restore the health of people with heart disease.

After meeting the highest standards of quality control and best manufacturing practices, products undergo rigorous testing in clinical trials to ensure their safe translation to clinical practice. Finally, research findings are applied to patient care in areas such as surgery, radiology, laboratory medicine and more, fostering Mayo Clinic's regenerative care model of not only reversing chronic disease but also restoring health to individuals and their communities.

Research pillars

Research in the Mayo Clinic Van Cleve Cardiac Regenerative Medicine Program is based on three pillars of investigative focus:

• Cellular therapies
• Acellular therapies
• Tissue engineering

Contemporary regenerative medicine is underpinned by the recognition that full regeneration ultimately restores the person as a whole. Fostering the Mayo Clinic regenerative care model, the Mayo Clinic Van Cleve Cardiac Regenerative Medicine Program is advancing not only the restoration of organ health but also the rebuilding of individuals in their communities.

The mission of the Mayo Clinic Van Cleve Cardiac Regenerative Medicine Program is to position Mayo Clinic as the premier regenerative medicine destination: leading in the discovery of novel cell-therapy platforms that address cardiac pathologies, advancing off-the-shelf cell-free therapies from the bench toward clinical cardiovascular practice and establishing cardiac tissue engineering — thereby transforming the reach of modern regenerative care.

Investing in Humanity

The Mayo Clinic Van Cleve Cardiac Regenerative Medicine Program is funded with the generous support of Russ and Kathy Van Cleve.

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Home > Books > Tissue Engineering and Regenerative Medicine

Regenerative Medicine and Tissue Engineering

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Academic Editor

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

Number of pages 868

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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My lab focuses on identifying and translating regenerative materials and technologies to reestablish dental, oral, and craniofacial (DOC) tissue health. We use both in vitro and in vivo pre-clinical animal models to gain further insight into the potential clinical safety and efficacy of the developed biomaterials and overall regenerative strategies.

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Human Nasal Inferior Turbinate-Derived Neural Stem Cells Improve the Niche of Substantia Nigra Par Compacta in a Parkinson’s Disease Model by Modulating Hippo Signaling

• Original Article
• Open access
• Published: 10 April 2024

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• Junwon Choi 1 , 2 ,
• Sun Wha Park 1 , 2 ,
• Hyunji Lee 1 , 2 ,
• Do Hyun Kim 1 &
• Sung Won Kim   ORCID: orcid.org/0000-0002-8981-2536 1 , 2  

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Background:

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases, following Alzheimer’s disease. The onset of PD is characterized by the loss of dopaminergic neurons in the substantia nigra. Stem cell therapy has great potential for the treatment of neurodegenerative diseases, and human nasal turbinate-derived stem cells (hNTSCs) have been found to share some characteristics with mesenchymal stem cells. Although the Hippo signaling pathway was originally thought to regulate cell size in organs, recent studies have shown that it can also control inflammation in neural cells.

Dopaminergic neuron-like cells were differentiated from SH-SY5Y cells (DA-Like cells) and treated with 1-Methyl-4-phenylpyridinium iodide to stimulate Reactive oxidative species (ROS) production. A transwell assay was conducted to validate the effect of hNTSCs on the Hippo pathway. We generated an MPTP-induced PD mouse model and transplanted hNTSCs into the substantia nigra of PD mice via stereotaxic surgery. After five weeks of behavioral testing, the brain samples were validated by immunoblotting and immunostaining to confirm the niche control of hNTSCs.

In-vitro experiments showed that hNTSCs significantly increased cell survival and exerted anti-inflammatory effects by controlling ROS-mediated ER stress and hippocampal signaling pathway factors . Similarly, the in-vivo experiments demonstrated an increase in anti-inflammatory effects and cell survival rate. After transplantation of hNTSCs, the PD mouse model showed improved mobility and relief from PD symptoms.

Conclusion:

hNTSCs improved the survival rate of dopaminergic neurons by manipulating the hippocampal pathway through Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ) by reducing inflammatory cytokines. In this study, we found that controlling the niche of hNTSCs had a therapeutic effect on PD lesions.

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1 Introduction

Parkinson’s disease is the second most prevalent neurodegenerative disorder and affects motor function, causes resting tremors, and affects the autonomic nervous system [ 1 , 2 ]. The etiology of the disease is not clear, but alpha-synuclein (αSyn) deposition and the Lewy-body (LB) formation have been observed to affect the loss of dopaminergic neurons in the substantia nigra par compacta through the post mortem analyses [ 3 , 4 ]. Syn is a small abnormal protein that is found in various cell types, mostly in the presynaptic terminals of the central nervous system [ 5 ]. The domains of αSyn play a role membrane attachment and fibril aggregation. The N-terminal domain of αSyn is composed of an amphipathic α-helix structure which has high affinity to the mitochondrial membrane. The C-terminal domain contains numerous negatively charged amino acids including Ser129. This promotes αSyn aggregation by strengthening the interaction between metal ions and proteins [ 6 , 7 , 8 ]. In contrast, ROS are by-products of cellular metabolism in the mitochondria. ROS is necessary for maintaining mitochondrial homeostasis through the mitophagy quality control system [ 9 , 10 , 11 ]; however, aggregated αSyn bounds to the mitochondria membrane and disrupts electron transfer system (ETS) complex I, which leads to increase ROS levels in mitochondria [ 10 , 12 ]. Excessive ROS levels alter mitochondrial membrane permeability and lead to mitochondrial dysfunction and cell death [ 13 , 14 ]. Thus, αSyn deposition in the central nerve system produces ROS, which disrupts mitochondrial homeostasis [ 15 , 16 , 17 , 18 ].

The Hippo signaling pathway controls organ size, cancer development, and tissue regeneration [ 19 , 20 ]. Recent studies have shown that the Hippo-signaling pathway also plays a critical role in controlling neuroinflammation, neuronal cell differentiation, and neuronal cell death [ 21 , 22 ]. The canonical Hippo-signaling pathway is mainly composed of mammalian Ste20-like kinases 1/2 (MST 1/2), large tumor suppressor 1/2 (LATS 1/2), YAP/TAZ. MST 1/2 phosphorylates LAT 1/2, which leads to the phosphorylation of the downstream YAP/TAZ under oxidative stress. Phosphorylation of YAP/TAZ prevents their translocation into the nucleus and interaction with cytosolic protein 14-3-3, resulting in cell death [ 23 ]. In contrast, Unphosphorylated YAP/TAZ translocates to the nucleus and binds to the TEAD family of transcription factors, promoting the expression of genes related to cell proliferation, differentiation, and survival [ 24 , 25 ].

Mesenchymal stem cells (MSCs) are promising for cell therapy because of their immunomodulatory and therapeutic functions in lesions. A sufficient number of cells are needed for clinical trials. MSCs have various sources, such as bone marrow, umbilical cord blood, and adipocytes, and are relatively easy to obtain. Several studies have investigated the therapeutic effects of MSCs [ 26 , 27 ], and MSCs have been observed to secrete anti-inflammatory cytokines with immune suppression effects [ 28 , 29 ]. Human nasal turbinate-derived neural crest stem cells (hNTSCs) represent a new source of light for the treatment of neurodegenerative diseases. hNTSCs show characteristics similar to MSCs, are relatively functional, and differentiate into neurons and astrocytes. As hNTSCs are derived from the neural crest and have neural lineage features, hNTSCs have better compatibility than MSCs [ 30 , 31 , 32 ]. Restoring the nigrostriatal pathway through dopaminergic neuron regeneration is a promising method for the treatment of Parkinson’s [ 33 , 34 ]. Furthermore, improving the survival rate of the transplanted cells is important for successful therapeutic effects [ 35 , 36 ]. In this study, we generated a Parkinson’s disease model using SH-SY5Y cells that differentiated into dopaminergic neurons and treated them with 1-methyl-4-phenyl pyridinium (MPP + ) and utilized a MPTP-mediated mice model. The substantia nigra par compacta was relieved by niche control of hNTSCs in the lesion.

2 Materials and methods

2.1 hntscs generation and cell culture.

The study using hNTSCs followed the guidelines of the Institutional Review Board of Seoul St. Mary’s Hospital (KC08TISS0341), Catholic University of Korea, including informed consent regulations and the Declaration of Helsinki. Before surgery, the participants provided written informed consent to participate in the study. The tissue was donated by patient who conducted hypertrophied nasal inferior turbinate volume reduction surgery. hNTSCs were isolated from the discarded tissue following partial turbinectomy using previously described methods [ 30 ]. First, the tissues were washed with 0.9% saline and phosphate-buffered saline (Thermo Fisher Scientific). The specimens were cut into 1 mm pieces and placed in a culture dish. Finally, a sterilized glass cover slide was placed on top. The tissue was placed in a humidified incubator and maintained at a temperature of 37 °C with 5% CO 2 . The specimen was cultured in α-minimum essential medium (α-MEM; Thermo Fisher Scientific) which was supplemented with 1% penicillin/streptomycin (Invitrogen, CA, USA), and 10% fetal bovine serum (FBS; Thermo Fisher Scientific). The culture medium was changed every two days for three weeks. The cells were harvested from the tissue by removing the glass cover slide and using 0.25% trypsin and 1 mM EDTA solution. hNTSCs were cultured and expanded for use in experiments.

2.2 hBM-MSC generation and cell culture

Healthy donors provided human bone marrow aspirates from the iliac crest following approval from the Institutional Review Board of Seoul St. Mary’s Hospital (KC10CSSE0651). Bone marrow aspirates were sent to the good manufacturing practice-compliant facility of the Catholic Institute of Cell Therapy (Seoul, Korea, http://www.cic.re.kr ) for hBM-MSCs isolation, expansion, and quality control, with written consent from the participants [ 26 ]. The hBM-MSCs were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 1% penicillin/streptomycin (Invitrogen) and 20% FBS (Thermo Fisher Scientific). The cells were incubated at 37 °C in a humidified atmosphere containing 5% of CO 2 .

2.3 SH-SY5Y cell culture and differentiation

SH-SY5Y cells were purchased from the Korean Cell Line Bank (Seoul, Korea). The cells were cultured in the humidified incubator, which maintained 37 °C and contained 5% CO 2 , in α-MEM supplemented with 1% penicillin/streptomycin (Invitrogen), and 10% FBS (Thermo Fisher Scientific). SH-SY5Y cells were seeded at a density of 3 × 10 4 cells in a 6-well-plate, and the differentiation medium was changed according to a previously described protocol [ 37 ].

2.4 Trans-well assay

DA-like cells (1 × 10 6 cells of DA-like cells were cultured in the bottom chamber, treated with 500 mM MPP + in culture medium overnight, and the following day, the medium was replaced with fresh medium. One day later, 5 × 10 5 hNTSCs and hBC-MSCs were cultured in the upper chamber, after being placed at the chamber bottom, and incubated overnight.

2.5 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model generation

Seven-week-old C57BL/6N mice were obtained from Orient Bio (Gyeonggi-do, South Korea). Ten mice were randomly assigned to one of four groups: control, MPTP-saline, MPTP_hNTSCs, and MPTP_hBC-MSCs. MPTP was administered at a dose of 25 mg/kg for seven consecutive days. The motor dysfunction of the PD mouse model was validated using the rotarod and open field tests.

2.6 Stereotaxic surgery

hNTSCs and hBM-MSCs were incubated for 5 min with trypsin–EDTA (Thermo Fisher Scientific), centrifuged, and then, the supernatant was removed. Mice were anesthetized, and their heads were fixed in a stereotaxic apparatus. After cleaning the surface of the skull, according to the Allen Brain Atlas, the distance between the two points of the lambda and bregma was identified. The hNTSCs and hBM-MSCs [1 × 10 5 cells/10 µl N-Acetyl-L-cysteine(NAC)] were injected into the substantia nigra par compacta. The coordinates were as follows: AP = − 3.2, ML = 0.71 mm and DV = 4.6 mm.

2.7 Behavior test

One week after MPTP IP injection, the motor function of the mice was validated by rotarod and open field tests, using a rotarod machine with falling sensors (MED-Associates Inc., FL, USA). In the rotarod test, ten mice for each group were placed side by side in a rotarod machine. The mice were allowed to remain in the machine for 5 min. Each session was performed after habituation. The acceleration of the rotation and rotation speed were set to 0–15 m/min and 0–50 rpm, respectively. Each rail on the machine was turned off as soon as the mouse fell off the platform. The rotarod test was conducted consecutively for four days. The open field test was conducted using SMART software (version 3.0) and an open field box (Panlab, MA, USA). The open field box was a 42 × 42 × 42 cm polyvinyl chloride box, which was monitored and recorded using a camera connected to the SMART 3.0 software. The camera measured the movements of the mice in the peripheral and central zones. Trajectory tracing, total travel distance, and time spent in the zone were measured to analyze the motor function of the animal.

2.8 Flow cytometry

hNTSCs (1 × 10 5 cells) were collected in a round bottom tube and resuspended to 100 μL of 5% FBS (Thermo Fisher Scientific) diluted in Dulbecco’s phosphate-buffered saline (DPBS; Thermo Fisher Scientific). Cells were stained with human CD90-PE conjugated (BD Bioscience, NJ, USA) and CD34 (FITC) at RT for 2 h. The cells were then evaluated using a FACSAria III (BD Biosciences) machine.

2.9 Immunofluorescence staining

DA-Like cells were washed three times with DPBS (Thermo Fisher Scientific) and then fixed in cold methanol on ice for 15 min. After fixation, normal goat serum was used as a blocking buffer, for an hour at RT. Primary antibodies were diluted to 1:100 in blocking buffer and added to the cells. The cells were incubated overnight at 4 °C and then washed with DPBS three times. Secondary antibodies were diluted 1:500 in DPBS and incubated in the buffer for an hour. DAPI (Vector Laboratories) was diluted 1:5000 and incubated with the samples for 5 min at RT. The brain of MPTP-induced PD mouse model was fixed in 4% paraformaldehyde for 2 h and incubated in 30% of sucrose until it is crysectioned. The brain was sectioned 7 μm from the bregma to the end. The brain section slide was selected by referring to mouse brain atlas map and the slide was blocked with blocking buffer for an hour at RT. Primary antibody was diluted to 1:100 in blocking buffer and added to the slide. The slide was incubated overnight at 4 °C and washed with DPBS three times. Secondary antibody was diluted 1:500 in DPBS and incubated with the slide for an hour. DAPI was diluted 1:5000 and incubated for 5 min at RT. The fluorescence intensity of the cells and the slide were measured using a Zeiss LSM 800 Confocal Laser Scanning Microscope (Zeiss, Jena, Germany).

2.10 Protein isolation

Brain proteins were extracted using RIPA buffer (LPS Solution, Daejeon, Korea) with EDTA-free Complete Ultra tablets and an EASYpack Protease Inhibitor Cocktail (Roche, Basel, Switzerland). The tissues were homogenized using a tissue grinder with lysis buffer containing proteinase and phosphatase inhibitors. Lysates were then sonicated for 10 secs in an ice bath sonication machine, followed by centrifuging at 14,000 × g for 20 min at 4 °C. The protein concentrations were measured using a bicinchoninic acid protein assay kit (Thermo Fisher Scientific).

2.11 Immunoblotting

The proteins (15 μg) used for immunoblotting were mixed with 5 μL of NuPAGE™ LDS Sample Buffer (4x; Thermo Fisher Scientific), 2 μL of dithiothreitol (10x; Sigma-Aldrich, MO, USA), and distilled water, added to a final volume of 20 μL. The protein mixture was heated up to 75 °C for 10 min to denature the proteins. The protein mixture then underwent electrophoresis in a 10% SDS-PAGE gel for 40 min, in Invitrogen™ NuPAGE™ MOPS SDS Running Buffer (20x; Invitrogen). Proteins were separated by SDS-PAGE using the Trans-Blot Turbo Transfer System (Bio-Rad, Hercules, CA, USA). The PVDF membranes were blocked with 5% skim milk for 2 h at RT. The membranes were then washed three times with 0.1% tween-20 diluted in tris-buffered saline (0.1% T-TBS) for 5 min, three times, at RT. The transferred PVDF was then incubated with the primary antibody, either eukaryotic translation initiation factor 2 alpha subunit (EIF2α; Cell signaling technology, MA, USA), phosphorylated EIF2α activating transcription factor 4 (ATF4, Cell signaling technology), NEDD4L (Cell signaling), Yes-associated protein/transcription activator with PDZ binding motif (YAP/TAZ; Cell signaling), phosphorylated YAP/TAZ (Cell signaling), Large neutral amino acids transporter small subunit 1(LAT1; Cell signaling), or phosphorylated LAT1(Cell signaling). All the antibodies were diluted to 1:1000 with 0.1% sodium azide (Sigma-Aldrich) and incubated with the membranes at 4 °C overnight. The PVDF membranes were then washed with T-TBS for 10 min, three times, and then incubated with a goat anti-rabbit IgG antibody labeled with peroxidase (Vector Laboratory, Inc., CA, USA), diluted 1:5000, for 10 min at RT. The PVDF membranes were then analyzed using an LAS-3000 (FUJI PHOTO FILM CO., LTD, Tokyo, Japan).

2.12 RNA isolation and cDNA synthesis

Midbrain tissue was homogenized using a tissue grinder and 300 μL of TRIzol ® reagent (Invitrogen). Tissue lysates were added to 60 μL of chloroform (DAEJUNG CHEMICALS & METALS Co., Ltd, Gyeonggi-do, Korea) and vortexed for 3 secs, to mix. The lysates were then centrifuged at 12,000 × g for 15 min at 4 °C. Supernatants were transferred to new 1.7 mL tubes, incubated in 0.5 mL of isopropanol (Sigma-Aldrich), and centrifuged at 12,000 × g for 15 min at 4 °C. The resulting RNA pellet was washed with 70% cold ethanol and centrifuged at 12,000 × g for 10 min at 4 °C. The RNA pellet was then dissolved in 30–50 μL of diethyl pyrocarbonate-treated water, according to the size of the pellet. The RNA was then incubated for 10 min at 65 °C. cDNA was synthesized from 1 µg of total RNA using the iScript™ cDNA Synthesis Kit (Bio-RAD).

2.13 Poly-chain reaction (PCR) assay

The mRNA was isolated from the midbrain of each group using a manual protocol. cDNA was synthesized using the iScript™ cDNA Synthesis Kit (Bio-RAD). Then, 1 µg of cDNA was used for gene expression level analysis. CFX386 touch (Bio-RAD) was used to conduct qRT-PCR. The reaction efficiency and number of cycles were determined using innate software.

2.14 Statistics

The Kruskal–Wallis and Mann–Whitney U post-hoc tests were used to compare the results across groups. SPSS version 22 (IBM Corporation, NY, USA) was used to determine statistically significant differences between groups. The results are expressed as mean ± standard deviation (SD). Differences were considered significant at * p  < 0.05 versus Control; ** p  < 0.01 versus Control; *** p  < 0.001 versus control; # p  < 0.05 versus MPTP-saline and MPP + -saline; ## p  < 0.01 versus MPTP-saline and MPP + -saline; ### p  < 0.001 versus MPTP-saline and MPP + -saline.

3.1 hNTSCs generation and characteristics analysis

Nasal turbinate-derived normal tissues were obtained from each patient. The tissues were washed several times with DPBS (−/−) and reduced to a size of 1.5 cm. The tissue was chopped into a 1 mm size sample, placed in a cell culture dish under an autoclaved cover glass, and incubated in growth media for three weeks (Fig.  1 A). hNTSCs expressed neuronal stem cell bio markers TUJ1, Nestin, P75, and NGFR [ 31 ]. To confirm the characteristics that are similar to those of hBM-MSCs, CD34 and CD90 that are considered stem cell surface markers. Notably, the hNTSCs showed similar characteristics to hBM-MSCs in the flow cytometry analysis (Fig.  1 B, C).

hNTSCs generated from nasal turbinate tissue. Nasal turbinate normal tissue donated from patients was chopped into 1 mm size and placed in a culture dish under the autoclaved cover slide. The dishes were then filled with culture media, and hNTSCs were grown from the tissue ( A ). Images show CD 90 (PE), CD 34 (FITC), stem cell marker flow cytometry data of hBM-MSCs ( B ). Images show the CD 90 (PE), CD 34 (FITC), and stem cell marker flow cytometry data of hNTSCs ( C ). bar = 50 μm

3.2 hNTSCs foster an MPP + -induced dopaminergic neuron-like cell niche

The SH-SY5Y human neuroblastoma cell line relies on gradual serum deprivation and retinoic acid supplementation, which reduce the period of time for differentiation into DA-Like cells. SH-SY5Y cells were cultured to differentiate into DA-Like cells in the bottom chamber of a trans-well chamber for three weeks (Fig.  2 A). Three types of differentiation media composed of differentiation-related small molecules and chemicals were used (Table  1 ). The cells were completely differentiated by day 18 (Supplementary 1 , 2 ). The fully differentiated DA-like cells were treated with a solution of 500 mM of MPP + overnight. hNTSCs and hBM-MSCs were cultured in the upper chamber of a transwell culture dish. The relative TH/TUJ1 immunofluorescent staining intensity of DA-Like cells showed that cells treated with MPP + saline had a significantly decreased intensity compared to that of the control group, MPP + _hNTSCs, and MPP + _hBM_MSCs. MPP + hNTSCs and MPP + hBM_MSCs showed increased relative intensity compared to MPP + saline-treated cells. Notably, MPP + hNTSCs showed no significant differences from MPP + hBM_MSCs.

Differentiating SH-SY5Y cells to dopaminergic neuron-like cells. The diagram shows the morphological changes of SH-SY5Y cells during differentiation ( A ). The images show the TH and Tuj1 immunofluorescence staining of DA-Like cells after MPP + treatment ( B ). The graph indicates the intensity of TH/Tuj1 of DA-Like cells ( C ). The graph indicates the impact of a ROS concentration gradient on SH-SY5Y derived DA-Like cells ( D ). * p  < 0.05 versus control; *** p  < 0.001 versus control; ### p  < 0.001 versus MPP + -saline. bar = 50 μm

3.3 hNTSCs modulate hippo-pathway signaling factors of MPP + induced dopaminergic neuron-like cells

MPP + -induced PD DA-like cells are damaged by ROS-mediated ER stress in the cytoplasm, and the Hippo signaling pathway is involved in cell death. The protein expression levels of phosphorylated EIF2α and ATF4 of the MPP + saline group were significantly higher than those of control, MPP + _hNTSCs, and MPP + _hBM_MSCs cohorts. In contrast, the protein expression level of NEDD4.2, which inhibits the phosphorylation of LAT1, was lower than that of the control, MPP + _hNTSCs, and MPP + _hBM_MSCs groups (Fig.  3 A). Furthermore, the protein expression levels of phosphorylated LAT1 and YAP/TAZ in the MPP + _saline group were significantly higher than those in the control, MPP + _hNTSCs, and MPP + _hBM_MSCs groups (Fig.  3 B). The relative gene expression levels of inflammatory factors, TNF-α, IL-6, and INF-γ, were significantly decreased in MPP + _hNTSCs and MPP + _hBM-MSCs groups, compared to the MPP + _saline group (Fig.  3 C–E). The sequence is informed in Table  2 .

Images show the western blot results of ER-Stress factors, EIF2α, p-EIF2α, ATF4, NEDD4.2, and β-actin. The immunoblotting was performed on MPP + -treated DA-like cells ( A ). Images show the results for hippo-signaling pathway factors, p-MST1/2, LAT1/2, p-LAT1/2, YAP/TAZ, p-YAP/TAZ, upon immunoblotting of MPP + -treated DA-like cells ( B ). The graph indicates the relative gene expression levels of TNF-α, IL-6, and interferon-γ in DA-like cells ( C – E ). ** p  < 0.01 versus control; *** p  < 0.001 versus control; # p  < 0.05 versus MPP + -saline; ## p  < 0.01 versus MPP + -saline; ### p  < 0.001 versus MPP + -saline

3.4 MPTP-induced Parkinson’s disease mouse model generation and validation

Seven-week old male mice were used as a PD mimic animal model, and each group consisted of 10 mice. The mice were separated randomly and intraperitoneally injected with MPTP (25 mg/kg IP for a week, consecutively). The animals were validated by PD modeling using the rotarod and open field tests. Most mice injected with MPTP showed motor dysfunction, which was validated by the rotarod and open field tests. Latency, drop speed, and distance were significantly decreased in MPTP-injected mice (Fig.  4 B). Furthermore, in the open field test, the MPTP-injected mice showed a significant decrease in motor function (Fig.  4 C). The PD mouse model was then subjected to stereotaxic surgery two days after the behavioral test. The hNTSCs and hBM-MSCs were transplanted into the substantia nigra pars compacta via stereotaxic surgery (Fig.  4 A).

MPTP-mediated PD animal model generation and validation. The diagram indicates the MPTP-induced PD animal preparation schematic and a list of behavior tests ( A ). The graph shows the results of the first week of the Rotarod test in the MPTP-induced PD animal model ( B ). The graph shows the first week of the open field test of the MPTP-induced PD animal model ( C ). *** p  < 0.001 versus control

3.5 hNTSCs regulate hippo-pathway signaling factors of the MPTP-induced PD mouse model

The mice were sacrificed four weeks after cell transplantation. The midbrains were isolated and homogenized for immunoblotting and PCR analyses. eIF2α, p-eIF2α, ATF4, and NEDD4.2 primary antibodies were used to confirm the presence of ROS-mediated ER-stress. The protein expression level of p-eIF2α and ATF4 were downregulated in MPTP-hNTSCs and MPTP-hBM-MSCs, compared to those of the MPTP-saline group, and NEDD4.2 levels were upregulated (Fig.  5 A). The protein levels of p-MST 1/2, p-LAT 1/2, and p-YAP were downregulated in MPTP-hNTSCs and MPTP-hBM-MSCs, compared to the respective levels in the MPTP-saline group (Fig.  5 B). The inflammatory gene expression levels of TNF-α, IL-6, and INF-γ were significantly downregulated as well (Fig.  5 C–E and Table  3 ).

The images show the immunoblotting results for ER-Stress factors, EIF2α, p-EIF2α, ATF4, NEDD4.2, and β-actin from midbrain samples of MPTP-induced Parkinson’s model mice ( A ). Images indicate the immunoblotting results of hippo-signaling pathway factors, p-MST1/2, LAT1/2, p-LAT1/2, YAP/TAZ, p-YAP/TAZ, from mid-brain samples of MPTP-induced Parkinson’s model mice ( B ). The graphs indicate TNF-α, IL-6 and INF-γ gene expression levels ( C – E ). ** p  < 0.01 versus control; *** p  < 0.001 versus control; # p  < 0.05 versus MPTP-saline; ## p  < 0.01 versus MPTP-saline; ### p  < 0.001 versus MPTP-saline

3.6 hNTSCs restore the dopaminergic neuron of MPTP-induced PD mouse model

The brains of the MPTP-induced PD mouse model were cut 7 μm cryo-section and stained to TH antibody to validate the influence of hNTSCs on dopaminergic neuron survival (Fig.  5 A). The MPTP-hNTSCs and MPTP-hBM-MSCs group showed higher number of TH positive cells than those of MPTP-saline group statistically. However, MPTP-hNTSCs and MPTP-hBM-MSCs group showed less number of TH positive cells than those of control group. On the other hands, MPTP-hNTSCs group showed higher number of TH positive cells than those of MPTP-hBM-MSCs group statistically (Fig.  5 B).

3.7 The MPTP-induced PD mouse model presented recovered and improved motor function

The mice showed valid behavioral differences during the four weeks after cell transplantation. The rotarod test showed a gradual restoration of latency, drop speed, and travel distance of hNTSCs and hBM-MSCs, compared with those of the MPTP-saline group (Fig.  6 A). In the open field trajectory test, the trace data also showed increased mobility of MPTP-hNTSCs and MPTP-hBM-MSCs, compared to that of the MPTP-saline group (Fig.  6 B). In addition, the travel distance and time in the zone also reflected increased mobility (Figs. 6 C and 7 ).

Presenting images indicate tyrosine hydroxylase (TH) positive immunofluorescence staining, DAPI (Blue), TH (Green) ( A ). The graph indicates the number of TH cell/DAPI ( B ). *** p  < 0.001 versus control; ## p  < 0.01 versus MPTP-saline. Scale bar = 200 μm

MPTP-induced PD animal model validation after cell transplantation. The graph shows the results of the Rotarod test over four weeks ( A ). The graph shows the result of the Rotarod test on the fourth week The images indicate the trajectory tracking of animal models in the open field test on the fourth week ( B ). The graph indicates the travel distance, zone distance and time in zone data over four weeks ( C ) * p  < 0.05 versus control; ** p  < 0.01 versus control; *** p  < 0.001 versus control; # p  < 0.05 versus MPTP-Saline; ## p  < 0.01 versus MPTP-Saline; ### p  < 0.001 versus MPTP-Saline

4 Discussion

Stem cell therapy has been highlighted as a regenerative medicine for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Despite considerable efforts to elucidate the etiology of Parkinson’s disease, Parkinson’s disease modeling is still having difficulty implementing an accurate model. The human neuroblastoma SH-SY5Y cell line is an alternative source of human Parkinson’s disease modelling, and it is relatively easy to differentiate dopaminergic neuron-like cell phenotypes within three weeks upon lowering FBS to 1% and adding 10 μM retinoic acid. SH-SY5Y-derived dopaminergic neuron-like cells not only express DJ-1 protein and TH, which are extensively related to the early onset of PD, but also the dopamine transporter (DAT), which regulates dopamine homeostasis, incorporates MPP + , and can be utilized in MPP + -induced neurotoxicity [ 38 , 39 ]. MPP + induces ROS production, which disrupts the electron transportation system of the mitochondria and leads to DNA laddering. Also, alpha-synuclein (α-syn) protein aggregation commences the ROS stress in mitochondria and the α-syn overexpression and aggregation are affected by numeral genes such as apolipoprotein E (APOE). In Parkinson’s disease, APOE-ε4, one of the phenotypes of APOE, is well known to promote neurodegenerative disease. APOE-ε4 is highly expressed in PD patients and the overexpressed APOE-ε4 accelerates aggregating α-syn in the lesion, leading to ROS stress in the lesion [ 40 ]. In this study, we mimicked ros-mediated neurotoxicity by using the MPP + . In the transwell assay, MPP + -treated dopaminergic neuron-like cells showed shortened dendrites and neuronal cell death. In contrast, the Hippo signaling pathway is well known for its role in organ size, cancer development, and tissue regeneration. There are many hurdles to overcome in the perception of transplanting cells into lesions. First, it is important to improve the viability of the transplanted cells to regenerate their functions. The lesion of substantia nigra in Parkinson’s disease is upregulated and produced higher levels of inflammatory factors, TNF-α, Interleukin-6, and interferon gamma. The upregulation of these inflammatory factors and cytokines induces glial cell migration and exacerbates inflammation, which affects transplanted cell viability and leads to a lower engraftment rate. hNTSCs show characteristics similar to those of mesenchymal stem cells (MSCs), and the anti-inflammatory effects of MSCs are well known, though many studies before [ 27 , 28 , 29 ]. The trans-well in vitro assay showed that MPP + saline-treated dopaminergic neuron-like cells upregulated inflammatory genes, TNF-α, and IL-6. However, after the hNTSCs were placed in the upper chamber, the expression of the inflammatory genes was downregulated, while anti-inflammatory gene expression levels were upregulated. The MPTP-induced in vivo test showed results similar to those of the in vitro test. Inflammatory gene expression levels in the mid-brain were downregulated in MPTP-hNTSCs and MPTP-hBC-MSCs groups, whereas anti-inflammatory gene expression levels were upregulated. In the live/dead assay with brain slides, the substantia nigra showed better cell viability in the lesions. Moreover, because hNTSCs are derived from the neural crest, they express neural lineage markers such as nestin, neural growth factor receptor p75, and sox2, which are more compatible with the central nervous system when engrafted. Although the same number of cells was transplanted into the MPTP-induced PD model, hNTSCs showed better cell viability than hBC-MSCs. Both stem cell types exhibit anti-inflammatory effects and relieve niches.

Data availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (Grant Number 2021M3F7A1083232) and Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean Government (23C0121L1).

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Choi, J., Park, S.W., Lee, H. et al. Human Nasal Inferior Turbinate-Derived Neural Stem Cells Improve the Niche of Substantia Nigra Par Compacta in a Parkinson’s Disease Model by Modulating Hippo Signaling. Tissue Eng Regen Med (2024). https://doi.org/10.1007/s13770-024-00635-3

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Regenerative medicine and tissue engineering: Six companies leading the way

The field of tissue engineering blends principles from medtech and biotech. In the modern era, tissue engineering has seen rapid development, particularly with the advent of microfabrication and three-dimensional bioprinting technologies , with many companies being created in the field.

These advancements have enabled the creation of tissue constructs with greater precision and customization, improving outcomes in terms of biocompatibility, immune response reduction, and the integration and longevity of the engineered tissues. Big names in the biotech industry such as Abbvie have stakes in the market, and in this article, we take a closer look at six tissue engineering companies.

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Founded in 1997 under the name TissueTech, the Miami-based company rebranded as BioTissue in November 2022. This biotech is focused on the field of regenerative medicine and is particularly known for its use of human birth tissue in creating products for ocular surface disease, surgical, chronic wound, and musculoskeletal applications. The company utilizes its proprietary CryoTek cryopreservation technology to maintain the structural and functional integrity of tissues in its products like Prokera, AmnioGraft, AmnioGuard for ocular application, Neox, and Clarix for surgical applications.

The company’s technology relies on human birth tissues, specifically the heavy chain hyaluronic acid/pentraxin3 (HC-HA/PTX3) complex that plays a role in the healing process in the fetal environment. Their tissue processing technology, CryoTek allows the preservation of the structural integrity of the placental tissues and HC-HA/PTX3 in the graft. Through its “Sharing Miracles” program, BioTissue partners with organizations like Dakota Lions Sight & Health to promote birth tissue donation, promoting a circular model.

BioTissue has conducted studies demonstrating the effectiveness of its CryoTek-preserved amniotic membrane in surgeries for pterygium , cataracts , and conjunctivochalasis, leading to improved patient outcomes. It has also shown that its amniotic allografts are effective in treating complex foot ulcers and traumatic wounds. In another study , the use of Prokera has led to improvement in moderate to severe dry eye disease.

Cellular Logistics

Cellular Logistics, based in Madison, Wisconsin, has developed CFX (Cardiac Fibroblast matriX), a therapeutic biomaterial produced using induced pluripotent stem cell technology. CFX is designed for local administration to prevent the pathological changes that lead to heart failure following myocardial infarction (heart attack). Moreover, CFX can also be used in conjunction with therapeutic stem cells to help remuscularize and restore function in scarred myocardium, particularly in cases of chronic heart failure.

The CFX technology presents several advantages. It is a cell-free product that is immune-privileged, allowing it to be administered to patients without the need for immunosuppressive drugs. It can modulate immune cells to promote healing properties and allows for the production of injectable particulates or patches, with the ability to adjust sizes according to clinical needs. These formulations enhance the retention of injected stem cells, preventing their rapid dispersal in the heart.

Earlier this year, Cellular Logistics and Allele Biotechnology entered into a partnership to develop regenerative medicine products for treating ischemic heart disease. The partnership leverages Allele’s cell reprogramming technology and aims to advance Solus to clinical-grade production for treating heart disease.

Japan Tissue Engineering

Japan Tissue Engineering (J-TEC), a company based in Gamagori, Aichi, Japan, is a pioneer in the field of regenerative medicine. Established in 1999, J-TEC has focused on developing, manufacturing, and selling tissue-engineered medical products. 

J-TEC’s business is divided into three main segments: Regenerative medicine, custom development and manufacturing, and R&D support. Its flagship products include autologous cultured epidermis JACE, and autologous cultured cartilage JACK.

J-TEC has developed autologous cultured epidermis products for treating severe burns, congenital giant pigmented nevus and epidermolysis bullosa. It is also working on treatments for vitiligo and second-degree burns using cultured epidermis.

Its autologous cultured cartilage product, approved for traumatic cartilage defects or osteochondritis dissecans, is one of Japan’s first regenerative medical products. Ongoing clinical trials aim to expand its use to secondary knee osteoarthritis .

In the field of ophthalmology, J-TEC has introduced autologous cultured corneal and oral mucosal epithelium products for treating corneal epithelial stem cell deficiency.

Moreover, J-TEC’s involvement in the broader landscape of regenerative medicine in Japan is significant, where the regulatory environment, such as the Regenerative Medicine Promotion Act of 2014, has catalyzed the development and approval of cell therapies. Japan’s strategic focus on regenerative medicine, supported by institutions like the Agency for Medical Research and Development (AMED), positions J-TEC in a thriving ecosystem.

Lattice Medical

Lattice Medical, established in 2017, is a French company specializing in the development of innovative implants for reconstructive surgery using tissue engineering, biomaterials, and 3D printing technologies. The company’s flagship products include Mattisse, a 3D-printed resorbable breast implant, and rodin, designed for hypodermal reconstruction. 

Mattisse stands out for being a 3D-printed, bioresorbable tissue engineering chamber designed for women who have undergone mastectomy due to breast cancer. This implant is made from a medical-grade resorbable biomaterial that naturally degrades over a few months post-implantation and is currently tested in the TIDE clinical trial in France. The design of Mattisse includes a porous base for fixing the autologous tissue to be regenerated and a dome that helps achieve the desired volume and shape.

Tissue Regenix

Tissue Regenix is a medical technology company headquartered in Leeds, England, specializing in regenerative medicine. The tissue engineering company is focused on the development and commercialization of regenerative products utilizing its proprietary technologies, dCELL and BioRinse.

The dCELL technology is a decellularization process that removes DNA and cellular material from animal and human tissue, leaving an acellular scaffold that can be used for the repair of damaged body parts without being rejected by the patient’s body. This technology has applications in sports injuries, foot and ankle surgery, and wound care. 

BioRinse is a technology used to sterilize bone allografts, minimizing tissue damage and preserving the quality of the grafts used primarily in sports medicine for tendon and ligament reconstruction.

Tissue Regenix has shown notable business growth, with a reported turnover of $29.5 million in 2023, indicating a substantial increase from the previous year. Additionally, Tissue Regenix has successfully expanded its market reach with new distributor agreements in Turkey and Ireland.

Vericel Corporation

Vericel Corporation, based in Cambridge, Massachusetts, specializes in advanced therapies for the sports medicine and severe burn care markets. Founded in 1989 and initially known as Aastrom Biosciences, Vericel underwent significant transformation after acquiring Sanofi’s cell therapy and regenerative medicine business in 2014, which led to its name change.

Their key products include Maci, Epicel, and NexoBrid, each utilizing different biotechnological approaches.

Maci (autologous cultured chondrocytes on porcine collagen membrane) is a product used for knee cartilage repair. It involves cultivating a patient’s own cells, which are then expanded and placed onto a collagen membrane. This membrane is then implanted into the damaged cartilage area, where it integrates with the surrounding tissue to repair the defect. MACI is specifically tailored to the size and shape of the cartilage damage, ensuring complete coverage and optimal healing​​.

Epicel (cultured epidermal autografts) is a skin graft technology used for treating patients with severe burns. It involves growing skin grafts from a small sample of the patient’s own skin, which can then be expanded to cover extensive burn areas​.

NexoBrid is a topical treatment used for the removal of eschar in patients with deep partial-thickness or full-thickness thermal burns. It contains proteolytic enzymes derived from pineapples that selectively remove nonviable burn tissue without harming surrounding healthy tissue. This process is crucial for the subsequent healing and treatment of severe burn injuries​.

The tissue engineering company is currently exploring other applications for its products as FDA approval for arthroscopic delivery of MACI is expected later this year and is on track to initiate a clinical trial for the treatment of ankle cartilage defects next year. Vericel also expects a FDA decision on NexoBrid pediatric usage later this year. 

Tissue engineering: an evolving industry

The current state of the tissue engineering industry is marked by a growing enthusiasm, driven by increasing clinical studies in regenerative medicine and tissue engineering. The market faces challenges such as high development costs and ethical issues surrounding stem cell research . Orthopedics, musculoskeletal, and spine applications dominate the market due to the rising prevalence of related disorders. The industry is also experiencing significant advancements in cardiology and vascular segments, fueled by the development of stem cell therapies and regenerative treatments for heart tissue .

Regionally, North America leads the market, supported by strong investment in research and development. The Asia Pacific region is also emerging as a significant player, with countries like Japan at the forefront of technological advances in the field.

Partnering 2030: The Biotech Perspective 2023

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Trichologist, Dermatotrichologist, or Trichiatrist? A Global Perspective on a Strictly Medical Discipline

Ralph michel trüeb.

a Center for Dermatology and Hair Diseases Professor Trüeb and University of Zurich, Zurich, Switzerland

Sergio Vañó-Galván

b Ramon y Cajal Hospital, University of Alcala, Madrid, Spain

Daisy Kopera

c Center of Aesthetic Medicine, Department of Dermatology, Medical University Graz, Graz, Austria

Vicky M.L. Jolliffe

d The Royal London Hospital, London, United Kingdom

Demetrios Ioannides

e 1st Department of Dermatology-Venereology, Hospital of Skin and Venereal Diseases, Aristotle University Medical School, Thessaloniki, Greece

Maria Fernanda Reis Gavazzoni Dias

f Department of Dermatology, Centro de Ciências Médicas, Hospital Universitário Antonia Pedro, Universidade Federal Fluminense, Niterói, Brazil

Melanie Macpherson

g Department of Dermatology and Venereology, San Gabriel Clinic, Lima, Peru

Javier Ruíz Ávila

h Dermedica Clinic, Polanco, Mexico City, Mexico

Aida Gadzhigoroeva

i Moscow Scientific and Practical Center of Dermatology and Cosmetology, Moscow City Health Department, Moscow, Russian Federation

Julya Ovcharenko

j General and Clinical Immunology and Allergology Department, School of Medicine, V.N. Karazin Kharkiv National University, Kharkiv, Ukraine

Won-Soo Lee

k Department of Dermatology, Wonju College of Medicine, Yonsei University, Gangwon-do, Republic of Korea

Sundaram Murugusundram

l Chennai Skin Foundation and Yesudian Research Institute, Chennai, India

Sotaro Kurata

m Beppu Garden Hill Clinic and Kurata Clinic, Beppu, Japan

n Prince of Wales Hospital and the Chinese University of Hong Kong, Hong Kong, China

Chuchai Tanglertsampan

o Department of Dermatology, Bumrungrad International Hospital, Mae Fah Luang University Hospital, Bangkok, Thailand

Few dermatologic problems carry as much emotional overtones as the complaint of hair loss. The best way to alleviate the distress related to hair loss is to effectively treat it. In fact, one of the oldest medical professions is the Egyptian physician who specialized on diseases of the head. And yet, from ancient Egypt down to modern times, human hair has been the object of superstition and mystery. Remarkably and despite the genuine advances in effective medical treatments, hair cosmetics, and surgical procedures, phony hair loss solutions continue to be marketed with an amazing success. In 1860, a quasi-scientific interest in hair loss and hair care originated in a London barbershop and became known as trichology, with the Institute of Trichologists being founded. Other corporations successively followed internationally, but it was only in 2010 that the term dermatotrichologist was proposed for board-certified dermatologists dealing with the scientific study of the hair and scalp, in contrast to the trichologist who is rather associated with laity and cosmetics than with medical professionalism, or – worse – offers opportunities to possible imposters with a primary commercial interest. The new term “trichiatrist” is proposed, literally meaning the “medical treatment of the hair,” to designate the strictly medical professional dealing with the hair and scalp in health and disease. Trichiatrists differ from trichologists by virtue of being physicians. The quality and stringency of their graduate medical training is identical to that of other physicians.

The medical practice is divided among them (the Egyptians) as follows: each physician is for one kind of sickness, and no more, and all places are crowded with physicians: for there are physicians for the eyes, physicians for the head , physicians for the teeth, physicians for the stomach, and for internal disease.

Herodotus, Histories 2,84

Few dermatologic problems carry as much emotional overtones as the complaint of hair loss, and the best way of alleviating the distress related to hair loss is to treat it effectively. In fact, one of the oldest medical professions documented in Greek historian and traveler Herodotus' “Histories” is the Egyptian physician who specialized on diseases of the head. Herodotus (484–425 BC) was the first historian known to have broken from the Homeric tradition to treat historical subjects as a method of investigation by collecting his materials systematically and critically and arranging them into a historiographic narrative. Thereby, Herodotus provides us with much information about the nature of the world and the status of science during his lifetime [ 1 ].

The most remote representations of hair loss that can be traced back around 30′000 years to wall engravings in a prehistorical cave are somewhat reminiscent of today's categorization of pattern hair loss, and the story is still ongoing in our modern society [ 2 ]. The first written document on the importance of making a distinction between inflammatory alopecia (tzaraat, Hebrew תערצ, breaking out on the head) from common baldness dates back to the Old Testament. The term tzaraat describes disfigurative conditions of the skin, hair of the beard and head. All variations are mainly referred to in chapters 13–14 of Leviticus (written ca. 538–332 BC) [ 3 ].

And yet, from the 4′000-year-old medical papyri of the ancient Egyptians down to modern times, human hair growth and color have been the object of superstition and mystery, besides arousing cosmetic and medical interest [ 4 ]. For the prevention or treatment of hair loss, countless herbal solutions, oils, lotions, magic pills, and even spiritual invocations have been advocated. What is remarkable about the history of hair loss cures is that despite the more recent genuine advances in effective medical treatments, hair cosmetics, and surgical procedures, phony hair loss solutions continue to be marketed today with an amazing success. Despite their outrageous claims, most lack scientifically measurable efficacy in preventing hair loss or promoting hair growth. As much today as in biblical times, people are so desperately concerned about their hair loss that they want to believe some miracle cure or some charismatic healer will help them.

The first genuine scientific studies on hair probably began when the English natural philosopher and polymath Robert Hooke (1635–1703) studied the hair shaft under the microscope [ 5 ] and the Italian biologist and physician Marcello Malphighi (1628–1694) described the anatomy of the hair follicle in his treatise “De pilis observationes” [ 6 ]. However, the biology of hair growth was not understood at this time. In search of information before engaging in the development of a new hair growth-promoting agent, makers of cosmetics turned to the medical faculty and received only very vague indications. When questioned, doctors remained evasive, and the hair was thus abated to malpractices of all sorts. The charlatan chemists of this age were as ineffectual but significantly more risky than their physician colleagues. With certain lotions in which toxic ingredients playing a role, accidents must have occurred frequently, and the French chemist Antoine Laurent de Lavoisier (1743–1794) urged for regulatory control of ingredients, which was never realized. France held the monopoly for miraculous elixirs and exported to America its “Eau de Ninon de L'enclos,” named after a beautiful courtesan whom had preserved her hair to the age of 85 years [ 7 ]. The French physician Auguste Caron, who published an “Encyclopedia of Beauty” [ 8 ] in 1806, warned the women of fashion of his time against the potential toxicity of products of mysterious origin, as a wretched woman had been driven to madness after using a tonic called “Eau de Chine.” The products remained just as dubious, whilst acquiring sentimental names as befitting the Romantic period. With the advance of medical technologies, ultraviolet light-emitting lamps, electrical scalp stimulators, and vacuum-cap machines have joined the repertory of treatments alleged to help stimulating the follicles to grow hair.

Probably the first sound scientific attempt toward hair restoration was the demonstration that it was possible to transplant hair from a hair-bearing to a non-hair bearing area in 1822 by the German medical student Johann Dieffenbach (1792–1847) [ 9 ]. However, it was not until 1939 that the era of hair transplantation began in earnest with the efforts of the Japanese physician Shoji Okuda (1886–1962) and later the New York dermatologist Norman Orentreich. Today, we hardly know anything about the medical background of Shoji Okuda, and his seminal work on hair transplantation remained virtually unknown outside Japan because of the outbreak of World War II. Moreover, the papers were written using old kanji (Japanese pictographs) and are consequently unintelligible even to modern Japanese medical readers. It was only in 2004 that the “Okuda Papers” were translated into English by Yoshihiro Imagawa, a retired gynecologist trained in the USA [ 10 ]. Okuda developed a circular scalpel for the purpose of transplanting hair into areas of alopecia [ 11 ]. In 1959, Norman Orentreich established the pivotal theory of donor dominance of the hair transplant. The basis of the theory was that plugs of hair follicles taken from the occipital scalp would continue growing when moved to the balding frontal scalp because those hair follicles were genetically programmed to do so. The concept became the foundation for the entire ensuing field of hair restoration surgery, and for the following decades, dedicated surgeons all over the globe have worked on refining the method with today close to natural results [ 12 ].

In 1860, a quasi-scientific interest in hair loss and hair care originated in a London barbershop under a self-styled Professor Wheeler. By1902, this interest in hair disorders became known as trichology, and the first Institute of Trichologists was founded. The International Association of Trichologists (IAT) was established in California in 1974 and offers a course by home-study for the training of students internationally who desire more knowledge about hair. Registered members can use the letters IAT after their name. Other corporations that have evolved globally are the Australian Institute of Trichology, the US Trichology Institute, the Argentine Association of Trichology (AATRI), and the World Trichology Society. Trichologists themselves are not normally medically qualified, although members of the medical profession can undertake courses and/or careers within trichology. Trichologists are not medically qualified but are taught the practice of care and treatment of the human hair and scalp in health and disease within their restricted but specialized role [ 13 ]. Nevertheless, there has been criticism regarding the ability of the public to reliably differentiate nonmedical trichologists from unqualified charlatans who monopolize publicity and proliferate in the high street, and concerns have been voiced about how to educate the public in choosing appropriate practitioners [ 14 , 15 ].

The dawn of the modern age of pharmacological therapy of hair loss can be traced back to the original clinical studies performed with topical minoxidil in the 1980s [ 16 ] and with oral finasteride in the 1990s [ 17 ]. For the first time in 4′000 years of history, pharmacological agents have been scientifically proven to stop hair loss and to promote hair growth. It is the introduction of these drugs into the treatment of hair loss that has heralded the emancipation of the treatment of hair loss from its age-old tradition of quackery. With respect to the study design and criteria for efficacy and safety, the respective clinical studies have set the standards for any agent with the claim of promoting hair growth.

Although testing medical interventions for efficacy had existed since the time of Avicenna's (980–1037) “The Canon of Medicine” in the 11th century [ 18 ], it was only in the 20th century that this effort evolved to impact almost all fields of health care and policy. In 1967, the American physician and mathematician Alvan R. Feinstein (1925–2001) published his seminal work “Clinical Judgment” [ 19 ], which together with Archie Cochrane's (1909–1988) celebrated book “Effectiveness and Efficiency” [ 20 ] led to an increasing acceptance of clinical epidemiology and controlled studies during the 1970s and 1980s and prepared the way for the institutional development of evidence-based medicine (EBM) in the 1990s. Ultimately, EBM aims for the ideal that healthcare professionals should make conscientious, explicit, and judicious use of the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of the evidence of risks and benefits of diagnostic tests and treatments, using techniques from science, engineering, and statistics, such as the systematic review of medical literature, meta-analysis, risk-benefit analysis, and randomized controlled trials.

Nonetheless, the limited success rate of evidence based therapies points to a more important complexity of hair loss and its management. Ultimately, EBM guidelines do not remove the problem of extrapolation to different populations. Even if several top-quality studies are available, questions remain as to how far and to which populations their results may be generalized. Certain groups have been historically under-researched, such as special age groups, ethnic minorities, and people with comorbid conditions. EBM applies to groups of people, but this should not preclude clinicians from using their personal experience in deciding how to treat the individual patient at hand.

For centuries, physicians propagated the viability of a complex approach in the diagnosis and treatment of disease, while modern medicine, which boasts a wide range of diagnostic methods and variety of therapeutic procedures, stresses specification. This raises the question: How does one wholly evaluate the state of a patient who suffers from a number of diseases simultaneously, where to start from and which disease(s) require(s) primary and subsequent treatment? This crucial question remained unanswered until 1970 when Alvan R. Feinstein coined the term “comorbidity” [ 21 ], which has been defined as “presence of one or more additional diseases co-occurring with a primary disease; or the effect of such additional diseases, whereby the additional disorder may also be a behavioural or mental disorder.” The effect of comorbid pathologies on clinical implications, diagnosis, prognosis, and therapy of trichologic conditions is polyhedral and patient specific. Therefore, presence of comorbidity must be taken into account when selecting the algorithm of the diagnosis and treatment plan for any given condition, including trichologic disease [ 22 ].

Ultimately, the dermatologist participates with the other medical disciplines in the diagnosis and treatment of all types of hair problems as they may relate to systemic disease [ 23 ].

On the other hand, hair loss is an important cause of discomfort and disability. The general physician is not always aware of the significance of hair loss and therefore may fail to refer patients with hair disorders to the dermatologist for appropriate management. Too often a delay in correct diagnosis and the resultant delay in ini­tiation of appropriate therapy results in potentially irreversible loss of hair, prolonged discomfort, and possible disfigurement.

As with any medical problem, the patient complaining of hair loss requires a comprehensive medical and drug history, physical examination of the hair and scalp, and appropriate laboratory evaluation to identify the cause. Dermatologic conditions are satisfying to diagnose as most conditions are visibly present at the time of consultation. Just looking would seem to be the simplest of diagnostic skills, and yet its very simplicity can result in its being overlooked. To reach the level of true artistry, looking must be a skillful active undertaking. The skill comes in interpreting the visual signs and having made a diagnosis hunting for the cause. The diagnostic process may be one of instantaneous recognition. The informed look is the one most practiced by the knowledgeable dermatologist, and is a combination of understanding, experience, and visual memory. If a visual diagnosis is not possible, then diagnostic tests are needed in the forms of specific dermatological examination techniques such as dermoscopy and laboratory evaluation (trichogram, biochemical investigations, microbiological studies, or scalp biopsy) as needed.

A prerequisite for delivering appropriate patient care is an understanding of the underlying pathologic dynamics of hair loss and its potentially multitudinous causes. By approaching the hair loss patient in a methodical way, commencing with objects the simplest and easiest to recognize, and ascending step by step to understanding the more complex aspects, an individualized treatment plan can be designed. Once the diagnosis is established, appropriate treatment is likely to be successful.

Alongside progress in clinical diagnosis and care, advances in the understanding of hair growth biology and its pathologic conditions is being made at a high pace thanks to the impetus of a generation of both astute clinicians and basic scientists interested in the hair follicle, the sophistication of molecular biology, and new technologies. Across the globe, Hair Research Societies have evolved such as the Australasian Hair and Wool Research Society; the European Hair Research Society; the North American Hair Research Society; the Society of Hair Research, Japan; the Korean Hair Research Society; the Hair Research Society of India; the Association of Professional Society of Trichologists, Moscow, Russia; and the Ukrainian Hair Research Society. These communities of interest and of practice regularly meet to bring together enthusiastic hair biologists and dermatologists for the exchange and discussion of the advances in hair research and clinical practice in the fields of genetics, molecular biology, immunology, aging, neurobiology, psychosomatics, diagnostic techniques and technologies, pharmacology, hair transplantation surgery, stem cells, and tissue-engineering research [ 24 ].

It was with the backdrop that in 2010 Dr. Patrick Yesudian, dermatologist practicing in India and founder of the Hair Research Society of India, proposed the term “dermatotrichologist” for board-certified dermatologists dealing with the scientific study of the hair and scalp in health and disease to distinguish them from the trichologist, who is not medically qualified and more involved with the cosmetic aspects of hair, or – worse – could offer opportunities to imposters with a primary commercial interest [ 25 ]. At the 2012 meeting of the Hair Research Society of India in UNESCO world heritage site Mamallapuram, the theme of the meeting was “To Abolish Quackery in Trichology,” and the consensus was that good medical practice in clinical trichology aims at (from [ 26 ]):

• Understanding the hair patient on an emotional level and the medical problem on a technical level
• Delivering sound patient education and effective trichologic therapy
• Representing trichology as a discipline based on evidence from science, engineering, and statistics
• Setting standards of good medical practice in trichology
• Supporting progress in trichology through continuous medical education
• Abolishing quackery in trichology

The ultimate question that arises, however, is whether the term “trichiatrist” for board-certified health care professionals (MDs) dealing with hair may be the yet more appropriate designation than trichologist or dermatotrichologist, in analogy to the term psychiatrist versus psychologist.

The term psychiatrist was originally coined by the German physician Johann Christian Reil in 1808 [ 27 ] and literally means the “medical treatment of the soul” (psych – “soul,” and –iatry – “medical treatment” from ancient Greek). Psychiatrists differ from psychologists in that they are physicians and have postgraduate training called residency in psychiatry (usually 4–5 years). The quality and stringency of their graduate medical training is identical to that of all other medical disciplines. Psychiatrists can therefore counsel patients, prescribe medication, conduct physical examinations, and order laboratory tests.

Parallels may easily be drawn with the care of hair disorders, when the same concept applies to the trichiatrist versus the trichologist, literally meaning the “medical treatment of the hair” (trich – “hair” from ancient Greek) to designate the strictly medical professional dealing with the hair and scalp in health and disease, with the capacity to counsel patients, prescribe medication, conduct physical examinations, and order pertinent laboratory tests as needed.

Furthermore, psychiatrists, more than other physicians, specialize in the doctor–patient relationship and are trained in therapeutic communication techniques [ 28 , 29 ].

In very much the same manner, prerequisites for a successful management of hair loss are twofold: on the technical and on the psychological level. On the technical level, prerequisites are a specific diagnosis, a profound understanding of the underlying pathophysiology, and the best available evidence gained from the scientific method for clinical decision making. On the psychological level, one must be sure that the patient's key concerns have been directly and specifically solicited and addressed: acknowledge the patient's perspective on the hair loss problem, explore patient's expectations from treatment, and educate patients into the basics of the hair cycle, and why patience is required for effective cosmetic recovery. Physicians should recognize that alopecia goes well beyond the simple physical aspects of hair loss and acknowledge the psychological impact of hair loss.

Ultimately, successful communication is the main reason for patient satisfaction and treatment success, while failed communication is the main reason for patient dissatisfaction, irrespective of treatment success [ 30 ].

In summary, as a trichiatrist, communication skills and treatment success require a genuine interest in recognizing and treating hair loss with knowledgeability on the scientific level and a genuine interest in supporting the patient complaining of hair loss with compassion on the emotional and psychological level. Ideally, credentials should include:

• Medical degree and residency in a medical discipline relevant to the management of the hair and scalp in health and disease (usually dermatology)
• Certification of traineeship or fellowship in the scientific study of the hair and scalp in health and disease with a syllabus expressing accountability and commitment
• Membership in one of the Hair Research Societies or Societies of Hair Restoration Surgery with regular participation at respective scientific meetings
• Accredited CME in the respective professional activity

Let's welcome the trichiatrist to the list of tricky “trichs” in dermatology [ 31 ]!

Statement of Ethics

The authors have no ethical conflicts to disclose.

Disclosure Statement

The authors have no conflicts of interest to disclose.

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Hydrogels and Injectable Therapeutics: How “Jell-O” May Become a Tissue Engineering Marvel

Yes, I know what you are thinking: Jell-O? Why would Jell-O be used in a materials lab for growing cells? Well, it isn’t the taste of this childhood snack that makes it perfect for tissue engineering; it is its composition. The most abundant protein in our body is a compound called collagen, which makes up most of the extracellular matrix that cells live in. If you take collagen and break it up into smaller pieces, you get gelatin, the material that makes up Jell-O. Tissue engineers, who work to maintain, improve, and/or restore biological tissues in our bodies, can use gelatin to simulate an in vivo environment, meaning the natural environment of a living organism. This not only opens applications in tissue culture but also has innumerable applications for injectable therapeutics, which are injectable solutions that can regrow or enhance existing tissue. While the field of tissue engineering is in its infancy, promising therapeutics with tissue culture using scaffolds like gelatin are already being applied to synthetic skin and organs for injured patients.

Injuries and degenerative diseases, such as Alzheimer’s and multiple sclerosis, can lead to long recoveries and/or irreversible damage. To alleviate these effects, one could inject specific stem cells into the damaged area t o grow themselves, trigger new growth within your body, and limit inflammation. However, direct injection of cells into the body results in low viability and significant dispersion of the cells throughout the body, moving them away from where they are needed most. Here is where our “scientific Jell-O” comes in. Gelatin, which is a hydrated complex of polymers, can be used to surround encapsulated cells, thereby increasing viability and stabilizing cell location following their injection. My research in Dr. Kyung Jae Jeong’s lab at the University of New Hampshire, which was funded by the Research Experience and Apprenticeship Program (REAP) through the Hamel Center for Undergraduate Research, looked at ways to alter hydrogels made of gelatin to make them more efficient when used in injectable therapeutics.

Figure 1. A microscope image of Jeong lab's novel 10% gelatin microgels. 

Microporous Hydrogel Methodology and Characterization

Conventional hydrogels are a complex of polymer chains that hold large amounts of water in comparison to their mass. However, these hydrogels lack porosity, mitigating cell growth and penetration of host biology. To address this, my faculty mentor, Dr. Jeong, and my graduate mentor, Dr. Seth Edwards, use novel injectable microporous hydrogels made of gelatin to promote cell spreading and proliferation. It may be easier to think of conventional hydrogels as one solid block of Jell-O with cells stuck inside, while a microgel structure is composed of many small beads of Jell-O with cells growing in the space bet ween. My summer research focused on the alteration of microgel diameter. Controlling microgel diameter can influence hydrogel properties such as nutrient transfer and available surface area, and cellular responses such as cell morphology, spreading, and differentiation. These variables help characterize cell behavior for predictability and safety of therapeutics in vivo.  

Figure 2. A microscope image of 5% gelatin microgels with a TWEEN 20 emulsifier developed by the author. 

I formed the microgels by dissolving gelatin in water and dropping the solution into an oil bath, creating an emulsion. The gelatin solution breaks up into small droplets in the oil that can be collected and cured together. The small spheres of gelatin are connected by microbial transglutaminase (mTG), a bacterial enzyme that connects the glutamine and lysine substituents of gelatin. After curing, a bulk hydrogel is left with space for cells to grow in between the microspheres. (Figure 1)

I tried lower concentrations of gelatin during the emulsion process, varying the mixing speeds and microgel curing times. Each variable had its own effect, some greater than others. I also integrated an emulsifier (TWEEN 20) of varying concentrations to reduce polarity on the hydrated gelatin’s surface. By integrating an emulsifier into the hydrogel emulsion protocol and decreasing gelatin concentration to 5% (from the original 10%), the diameter of the microgels were reduced to an eighth of their original size (around 40 µm). (Figure 2)

With this new manipulation of microgels I further researched cytotoxicity (toxicity of the environment to the cells). To do this, I cultured 3T3 cells (a fast-growing cell line of mouse fibroblasts) and formed microgels with small diameters and the control diameters. After three days of culture, I compared the control of pure gelatin microgels with the TWEEN 20 with a lowered gelatin concentration.

Figure 3. A confocal microscopy stack image (left) and slice image (right) of living cells (green) and dead cells (red) growing within a microporous hydrogel structure.   

I measured viability by performing a live/dead assay with confocal imaging. This entails using a high-definition microscope and adding dye to stain living cells green and dead cells red. I detected no difference in cell viability between the two hydrogels. (Figure 3)

For further analysis I conducted a rheology test on the bulk hydrogel I had created with smaller microgels to measure and characterize its elasticity. This showed that the smaller hydrogels formed a stiffer bulk hydrogel than the one formed with larger control microgels at all points in the curing process. Rheology was performed only once, making the results less reliable. However, the stiffness is most likely caused by a larger surface area, which makes more interactions through mTG cross-links/bonds.

Results and Avenues for Application within Tissue Engineering

In the end I was able to decrease the diameter of the gelatin microgels, but I have yet to show their relation to cell growth. In theory, the differing concentrations of gelatin and emulsifier used in the microgels I created should induce different cell proliferation and differentiation. It has been shown through conventional nonporous hydrogels that stiffness does change cell differentiation trends. However, it is unclear if the cells are affected by the stiffness change in the porous environment. While the bulk hydrogel may have more mTG cross-linking, and thus be stiffer, there is still a large interior network that could limit the cells from experiencing overall stiffness. If that is the case, then a variation in hydrogel stiffness is important for different applications within the body. Depending on the biological environment this technology is applied to, less stiff hydrogel that degrades more quickly may be required, while others require the opposite. For example, neurons might like a less rigid structure with a smaller microgel for increased surface area, while bone cells may like a stiffer gel with larger microgels for better penetration of host biology.

Having control over all variables in the hydrogel leads to greater specificity and customization, depending on the intended use. As of now, conventional hydrogels are nonporous, and therefore restrict cell growth, penetration of host biology, nutrient transfer, and cell viability. The novel microporous hydrogels fix these problems but are not fully understood. Every cell location and cell type will need different conditions for efficient use in injectable therapies. These conditions can theoretically be accommodated with this technology, but these possibilities must be researched. If my research could be extrapolated, a full understanding of microgel cross-linking and diameter could lead to a new field of injectable therapeutics. Personally, I hope to continue my work in the Jeong lab by applying this technology to the culture of red blood cells. And to think, all of this possibility was sitting right in front of our faces in Jell-O’s composition.

I would like to acknowledge my faculty research mentor Dr. Kyung Jae Jeong for not only taking me on as a first-year researcher but accelerating my learning and cultivating an environment of opportunity. Further, I am grateful to Dr. Seth Edwards, my graduate mentor, for being alongside me every step of the way and for always being in my corner—truly the guiding voice in my process. None of this would be possible without the amazing staff and donors  (Mr. Dana Hamel, Dr. George Wildman, Mr. Nicholas Bencivenga)  at the Hamel Center for Undergraduate Research at UNH; without the Research, Experience, and Apprenticeship Program, I would not be writing today. I owe my future to the work and charity of these people, and I am forever grateful to the numerous efforts that have been made to benefit me.

Author and Mentor Bios

Originally from Concord, New Hampshire, Jack Fenway Reynolds will graduate in May 2026 with a bachelor of science degree in bioengineering. He conducted his research on microgels through a Research Experience and Apprenticeship Program (REAP) grant funded by the Hamel Center for Undergraduate Research. Jack was looking for a project involving neurons and therapeutics, specifically in neurodegenerative diseases due to his mother's diagnosis with multiple sclerosis. He is very interested in the limited regenerative capacity of neurons and methods of circumnavigating this limitation. In talking with Dr. Jeong about possible topics relating to Jack’s interests, Dr. Joeng proposed the microgels his lab had been working on. Jack was pleasantly surprised at how accessible research was. As a new researcher, Jack describes having a steep learning curve, but he was mostly independent and was involved in scientific conversation with Ph.D. students and professors within a few weeks. He decided to submit to Inquiry because he is passionate about the public understanding of science. While using gelatin in this project, he wanted to convey the simplicity of this technology to excite people about the future, highlight the possibilities, and maybe inspire someone else. Jack would like to pursue a Ph.D. in a related scientific field and work in pharmaceutical/therapeutic development. While the research was very enlightening for the content and methodology, writing for Inquiry has shown him where science meets the public. Jack now wants to be on the cutting edge of science and educate the public about scientific developments.  

Dr. Kyung Jae Jeong is an associate professor of chemical engineering and bioengineering at the University of New Hampshire, beginning in 2013. His research interests revolve around biomaterials, drug delivery systems, medical devices, and tissue engineering. He mentored author, Jack Reynolds, for a Research Experience Apprenticeship Program (REAP) during the summer of 2023. Dr. Jeong has been interested in creating functional injectable hydrogels for medicine. However, the injectable hydrogels were nonporous and not optimal for cell delivery. His lab worked to develop the approach of assembling gelatin microgels using an enzymatic reaction in 2018 and applied the approach to neural stem cell encapsulation last year. Dr. Jeong has mentored Inquiry author, Ryan Boudreau previously. He describes Jack as “pleasant to work with” as well as being “highly motivated to learn new things, intellectually bright, and hard-working.”

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Copyright 2024, Jack Reynolds

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Exosome-loaded decellularized tissue: Opening a new window for regenerative medicine

Affiliations.

• 1 Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
• 2 Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
• 3 Department of Tissue Engineering, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.
• 4 Faculty of Medicine, Graduate School 'Molecular Medicine, University of Ulm, 89081, Ulm, Germany.
• 5 Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran. Electronic address: [email protected].
• PMID: 38594147
• DOI: 10.1016/j.jtv.2024.04.005

Mesenchymal stem cell-derived exosomes (MSCs-EXO) have received a lot of interest recently as a potential therapeutic tool in regenerative medicine. Extracellular vesicles (EVs) known as exosomes (EXOs) are crucial for cell-cell communication throughout a variety of activities including stress response, aging, angiogenesis, and cell differentiation. Exploration of the potential use of EXOs as essential therapeutic effectors of MSCs to encourage tissue regeneration was motivated by success in the field of regenerative medicine. EXOs have been administered to target tissues using a variety of methods, including direct, intravenous, intraperitoneal injection, oral delivery, and hydrogel-based encapsulation, in various disease models. Despite the significant advances in EXO therapy, various methods are still being researched to optimize the therapeutic applications of these nanoparticles, and it is not completely clear which approach to EXO administration will have the greatest effects. Here, we will review emerging developments in the applications of EXOs loaded into decellularized tissues as therapeutic agents for use in regenerative medicine in various tissues.

Keywords: Decellularized tissue; Exosome; Regenerative medicine; Tissue engineering.

Copyright © 2024 Tissue Viability Society / Society of Tissue Viability. Published by Elsevier Ltd. All rights reserved.

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