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Regenerative medicine

Topic: Medicine

 From HandWiki - Reading time: 15 min
Short description: Field of medicine involved in regenerating tissues
A colony of human embryonic stem cells

Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function".[1] This field holds the promise of engineering damaged tissues and organs by stimulating the body's own repair mechanisms to functionally heal previously irreparable tissues or organs.[2]

Regenerative medicine also includes the possibility of growing tissues and organs in the laboratory and implanting them when the body cannot heal itself. When the cell source for a regenerated organ is derived from the patient's own tissue or cells,[3] the challenge of organ transplant rejection via immunological mismatch is circumvented.[4][5][6] This approach could alleviate the problem of the shortage of organs available for donation.

Some of the biomedical approaches within the field of regenerative medicine may involve the use of stem cells.[7] Examples include the injection of stem cells or progenitor cells obtained through directed differentiation (cell therapies); the induction of regeneration by biologically active molecules administered alone or as a secretion by infused cells (immunomodulation therapy); and transplantation of in vitro grown organs and tissues (tissue engineering).[8][9]

History

The ancient Greeks postulated whether parts of the body could be regenerated in the 700s BC.[10] Skin grafting, invented in the late 19th century, can be thought of as the earliest major attempt to recreate bodily tissue to restore structure and function.[11] Advances in transplanting body parts in the 20th century further pushed the theory that body parts could regenerate and grow new cells. These advances led to tissue engineering, and from this field, the study of regenerative medicine expanded and began to take hold.[10] This began with cellular therapy, which led to the stem cell research that is widely being conducted today.[12]

The first cell therapies were intended to slow the aging process. This began in the 1930s with Paul Niehans, a Swiss doctor who was known to have treated famous historical figures such as Pope Pius XII, Charlie Chaplin, and king Ibn Saud of Saudi Arabia. Niehans would inject cells of young animals (usually lambs or calves) into his patients in an attempt to rejuvenate them.[13][14] In 1956, a more sophisticated process was created to treat leukemia by inserting bone marrow from a healthy person into a patient with leukemia. This process worked mostly due to both the donor and receiver in this case being identical twins. Nowadays, bone marrow can be taken from people who are similar enough to the patient who needs the cells to prevent rejection.[15]

The term "regenerative medicine" was first used in a 1992 article on hospital administration by Leland Kaiser. Kaiser's paper closes with a series of short paragraphs on future technologies that will impact hospitals. One paragraph had "Regenerative Medicine" as a bold print title and stated, "A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems."[16][17]

The term was brought into the popular culture in 1999 by William A. Haseltine when he coined the term during a conference on Lake Como, to describe interventions that restore to normal function that which is damaged by disease, injured by trauma, or worn by time.[18] Haseltine was briefed on the project to isolate human embryonic stem cells and embryonic germ cells at Geron Corporation in collaboration with researchers at the University of Wisconsin–Madison and Johns Hopkins School of Medicine. He recognized that these cells' unique ability to differentiate into all the cell types of the human body (pluripotency) had the potential to develop into a new kind of regenerative therapy.[19][20] Explaining the new class of therapies that such cells could enable, he used the term "regenerative medicine" in the way that it is used today: "an approach to therapy that ... employs human genes, proteins and cells to re-grow, restore or provide mechanical replacements for tissues that have been injured by trauma, damaged by disease or worn by time" and "offers the prospect of curing diseases that cannot be treated effectively today, including those related to aging".[21][22]

Later, Haseltine would go on to explain that regenerative medicine acknowledges the reality that most people, regardless of which illness they have or which treatment they require, simply want to be restored to normal health. Designed to be applied broadly, the original definition includes cell and stem cell therapies, gene therapy, tissue engineering, genomic medicine, personalized medicine, biomechanical prosthetics, recombinant proteins, and antibody treatments. It also includes more familiar chemical pharmacopeia—in short, any intervention that restores a person to normal health. In addition to functioning as shorthand for a wide range of technologies and treatments, the term “regenerative medicine” is also patient friendly. It solves the problem that confusing or intimidating language discourages patients.

The term regenerative medicine is increasingly conflated with research on stem cell therapies. Some academic programs and departments retain the original broader definition while others use it to describe work on stem cell research.[23]

From 1995 to 1998 Michael D. West, PhD, organized and managed the research between Geron Corporation and its academic collaborators James Thomson at the University of Wisconsin–Madison and John Gearhart of Johns Hopkins University that led to the first isolation of human embryonic stem and human embryonic germ cells, respectively.[24]

In March 2000, Haseltine, Antony Atala, M.D., Michael D. West, Ph.D., and other leading researchers founded E-Biomed: The Journal of Regenerative Medicine.[25] The peer-reviewed journal facilitated discourse around regenerative medicine by publishing innovative research on stem cell therapies, gene therapies, tissue engineering, and biomechanical prosthetics. The Society for Regenerative Medicine, later renamed the Regenerative Medicine and Stem Cell Biology Society, served a similar purpose, creating a community of like-minded experts from around the world.[26]

In June 2008, at the Hospital Clínic de Barcelona, Professor Paolo Macchiarini and his team, of the University of Barcelona, performed the first tissue engineered trachea (wind pipe) transplantation. Adult stem cells were extracted from the patient's bone marrow, grown into a large population, and matured into cartilage cells, or chondrocytes, using an adaptive method originally devised for treating osteoarthritis. The team then seeded the newly grown chondrocytes, as well as epithelial cells, into a decellularised (free of donor cells) tracheal segment that was donated from a 51-year-old transplant donor who had died of cerebral hemorrhage. After four days of seeding, the graft was used to replace the patient's left main bronchus. After one month, a biopsy elicited local bleeding, indicating that the blood vessels had already grown back successfully.[27][28]

In 2009, the SENS Foundation was launched, with its stated aim as "the application of regenerative medicine – defined to include the repair of living cells and extracellular material in situ – to the diseases and disabilities of ageing".[29] In 2012, Professor Paolo Macchiarini and his team improved upon the 2008 implant by transplanting a laboratory-made trachea seeded with the patient's own cells.[30]

On September 12, 2014, surgeons at the Institute of Biomedical Research and Innovation Hospital in Kobe, Japan, transplanted a 1.3 by 3.0 millimeter sheet of retinal pigment epithelium cells, which were differentiated from iPS cells through directed differentiation, into an eye of an elderly woman, who suffers from age-related macular degeneration.[31]

In 2016, Paolo Macchiarini was fired from Karolinska University in Sweden due to falsified test results and lies.[32] The TV-show Experimenten aired on Swedish Television and detailed all the lies and falsified results.[33]

Research

Widespread interest and funding for research on regenerative medicine has prompted institutions in the United States and around the world to establish departments and research institutes that specialize in regenerative medicine including: The Department of Rehabilitation and Regenerative Medicine at Columbia University, the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, the Center for Regenerative and Nanomedicine at Northwestern University, the Wake Forest Institute for Regenerative Medicine, and the British Heart Foundation Centers of Regenerative Medicine at the University of Oxford.[34][35][36][37] In China, institutes dedicated to regenerative medicine are run by the Chinese Academy of Sciences, Tsinghua University, and the Chinese University of Hong Kong, among others.[38][39][40]

In dentistry

A diagram of a human tooth. Stem cells are located in the pulp in the center.[41]

Regenerative medicine has been studied by dentists to find ways that damaged teeth can be repaired and restored to obtain natural structure and function.[42] Dental tissues are often damaged due to tooth decay, and are often deemed to be irreplaceable except by synthetic or metal dental fillings or crowns, which requires further damage to be done to the teeth by drilling into them to prevent the loss of an entire tooth.

Researchers from King's College London have created a drug called Tideglusib that claims to have the ability to regrow dentin, the second layer of the tooth beneath the enamel which encases and protects the pulp (often referred to as the nerve).[43]

Animal studies conducted on mice in Japan in 2007 show great possibilities in regenerating an entire tooth. Some mice had a tooth extracted and the cells from bioengineered tooth germs were implanted into them and allowed to grow. The result were perfectly functioning and healthy teeth, complete with all three layers, as well as roots. These teeth also had the necessary ligaments to stay rooted in its socket and allow for natural shifting. They contrast with traditional dental implants, which are restricted to one spot as they are drilled into the jawbone.[44][45]

A person's baby teeth are known to contain stem cells that can be used for regeneration of the dental pulp after a root canal treatment or injury. These cells can also be used to repair damage from periodontitis, an advanced form of gum disease that causes bone loss and severe gum recession. Research is still being done to see if these stem cells are viable enough to grow into completely new teeth. Some parents even opt to keep their children's baby teeth in special storage with the thought that, when older, the children could use the stem cells within them to treat a condition.[46][47]

Extracellular matrix

Extracellular matrix materials are commercially available and are used in reconstructive surgery, treatment of chronic wounds, and some orthopedic surgeries; as of January 2017 clinical studies were under way to use them in heart surgery to try to repair damaged heart tissue.[48][49]

The use of fish skin with its natural constituent of omega 3, has been developed by an Icelandic company Kereceis.[50] Omega 3 is a natural anti-inflammatory, and the fish skin material acts as a scaffold for cell regeneration.[51][52] In 2016 their product Omega3 Wound was approved by the FDA for the treatment of chronic wounds and burns.[51] In 2021 the FDA gave approval for Omega3 Surgibind to be used in surgical applications including plastic surgery.[53]

Cord blood

Though uses of cord blood beyond blood and immunological disorders is speculative, some research has been done in other areas.[54] Any such potential beyond blood and immunological uses is limited by the fact that cord cells are hematopoietic stem cells (which can differentiate only into blood cells), and not pluripotent stem cells (such as embryonic stem cells, which can differentiate into any type of tissue). Cord blood has been studied as a treatment for diabetes.[55] However, apart from blood disorders, the use of cord blood for other diseases is not a routine clinical modality and remains a major challenge for the stem cell community.[54][55]

Along with cord blood, Wharton's jelly and the cord lining have been explored as sources for mesenchymal stem cells (MSC),[56] and as of 2015 had been studied in vitro, in animal models, and in early stage clinical trials for cardiovascular diseases,[57] as well as neurological deficits, liver diseases, immune system diseases, diabetes, lung injury, kidney injury, and leukemia.[58]

See also

References

  1. ↑ Mason, Chris; Dunnill, Peter (2008). "A brief definition of regenerative medicine" (in en). Regenerative Medicine 3 (1): 1–5. doi:10.2217/17460751.3.1.1. ISSN 1746-0751. PMID 18154457. 
  2. ↑ "UM Leads in the Field of Regenerative Medicine: Moving from Treatments to Cures - Healthcanal.com". 8 May 2014. http://www.healthcanal.com/public-health-safety/50621-um-leads-in-the-field-of-regenerative-medicine-moving-from-treatments-to-cures.html. 
  3. ↑ "Stem cells application in regenerative medicine and disease threpeutics". International Journal of Cell Biology 2016 (7): 1–24. 2016. doi:10.1155/2016/6940283. PMID 27516776. 
  4. ↑ "Regenerative Medicine. NIH Fact sheet". September 2006. https://report.nih.gov/nihfactsheets/Pdfs/RegenerativeMedicine(NIBIB).pdf. 
  5. ↑ Mason C; Dunnill P (January 2008). "A brief definition of regenerative medicine". Regenerative Medicine 3 (1): 1–5. doi:10.2217/17460751.3.1.1. PMID 18154457. 
  6. ↑ "Regenerative medicine glossary". Regenerative Medicine 4 (4 Suppl): S1–88. July 2009. doi:10.2217/rme.09.s1. PMID 19604041. 
  7. ↑ Riazi AM; Kwon SY; Stanford WL (2009). Stem cell sources for regenerative medicine. Methods in Molecular Biology. 482. pp. 55–90. doi:10.1007/978-1-59745-060-7_5. ISBN 978-1-58829-797-6. 
  8. ↑ Stoick-Cooper CL; Moon RT; Weidinger G (June 2007). "Advances in signaling in vertebrate regeneration as a prelude to regenerative medicine". Genes & Development 21 (11): 1292–315. doi:10.1101/gad.1540507. PMID 17545465. 
  9. ↑ Muneoka K; Allan CH; Yang X; Lee J; Han M (December 2008). "Mammalian regeneration and regenerative medicine". Birth Defects Research. Part C, Embryo Today 84 (4): 265–80. doi:10.1002/bdrc.20137. PMID 19067422. 
  10. ↑ 10.0 10.1 "What is Regenerative Medicine?". University of Nebraska. https://www.unmc.edu/regenerativemed/about/whatis/index.html. 
  11. ↑ Rahlf, Sidsel Hald (2009). "The Use of Skin Grafting for the Treatment of Burn Wounds in Denmark 1870-1960". Dansk Medicinhistorisk Arbog 37: 99–116. PMID 20509454. https://pubmed.ncbi.nlm.nih.gov/20509454/#:~:text=Following%20the%20revolutionary%20work%20by,was%20abandoned%20for%20ointment%20treatments.. Retrieved June 27, 2020. 
  12. ↑ Sampogna, Gianluca; Guraya, Salman Yousuf; Forgione, Atonello (September 2015). "Regenerative medicine: Historical roots and potential strategies in modern medicine". Journal of Microscopy and Ultrastructure 3 (3): 101–107. doi:10.1016/j.jmau.2015.05.002. PMID 30023189. 
  13. ↑ "Dr. Paul Niehans, Swiss Surgeon, 89". The New York Times. September 4, 1971. https://www.nytimes.com/1971/09/04/archives/dr-paul-niehans-swiss-surgeon-89-expert-in-cellular-therapy-against.html. "Dr. Paul Niehans was a former physician of Pope Paul XII, among others. A surgeon who performed more than 50,000 operations in 40 years, he developed his own rejuvenation treatment by injecting humans with the foetus of unborn lambs and other animals." 
  14. ↑ Milton, Joyce (1998). Tramp: The Life of Charlie Chaplin. HarperCollins. ISBN 0060170522. 
  15. ↑ "1956: The First Successful Bone Marrow Transplantation". Home.cancerresearch. 7 December 2014. https://home.cancerresearch/1956-the-first-successful-bone-marrow-transplantation/. 
  16. ↑ Kaiser LR (1992). "The future of multihospital systems". Topics in Health Care Financing 18 (4): 32–45. PMID 1631884. 
  17. ↑ Lysaght MJ; Crager J (July 2009). "Origins". Tissue Engineering. Part A 15 (7): 1449–50. doi:10.1089/ten.tea.2007.0412. PMID 19327019. 
  18. ↑ https://www.nsf.gov/pubs/2004/nsf0450/ Viola, J., Lal, B., and Grad, O. The Emergence of Tissue Engineering as a Research Field. Arlington, VA: National Science Foundation, 2003.
  19. ↑ Bailey, Ron (2005). Liberation Biology: The Scientific and Moral Case for the Biotech Revolution. Prometheus Books. 
  20. ↑ Alexander, Brian (January 2000). "Don't Die, Stay Pretty: The exploding science of superlongevity". Wired 8 (1). https://www.wired.com/2000/01/forever/. 
  21. ↑ Haseltine, WA (6 July 2004). "The Emergence of Regenerative Medicine: A New Field and a New Society". E-biomed: The Journal of Regenerative Medicine 2 (4): 17–23. doi:10.1089/152489001753309652. 
  22. ↑ Mao AS, Mooney DJ (Nov 2015). "Regenerative medicine: Current therapies and future directions". Proc Natl Acad Sci U S A 112 (47): 14452–9. doi:10.1073/pnas.1508520112. PMID 26598661. Bibcode: 2015PNAS..11214452M. 
  23. ↑ Sampogna, Gianluca; Guraya, Salman Yousuf; Forgione, Antonello (2015-09-01). "Regenerative medicine: Historical roots and potential strategies in modern medicine" (in en). Journal of Microscopy and Ultrastructure 3 (3): 101–107. doi:10.1016/j.jmau.2015.05.002. ISSN 2213-879X. PMID 30023189. 
  24. ↑ "Bloomberg Longevity Economy Conference 2013 Panelist Bio". http://www.bloomberglink.com/people/michael-d-west-ph-d/. 
  25. ↑ "E-Biomed: The Journal of Regenerative Medicine". E-Biomed. ISSN 1524-8909. http://journalseek.net/cgi-bin/journalseek/journalsearch.cgi?field=issn&query=1524-8909. Retrieved 2020-02-25. 
  26. ↑ Haseltine, William A (2011-07-01). "Interview: Commercial translation of cell-based therapies and regenerative medicine: learning by experience". Regenerative Medicine 6 (4): 431–435. doi:10.2217/rme.11.40. ISSN 1746-0751. PMID 21749201. 
  27. ↑ "Tissue-Engineered Trachea Transplant Is Adult Stem Cell Breakthrough". Science 2.0. 2008-11-19. http://www.scientificblogging.com/news_releases/tissueengineered_trachea_transplant_adult_stem_cell_breakthrough. 
  28. ↑ "Regenerative Medicine Success Story: A Tissue-Engineered Trachea". Mirm.pitt.edu. http://www.mirm.pitt.edu/news/article.asp?qEmpID=395. 
  29. ↑ "Sens Foundation". sens.org. 2009-01-03. http://www.sens.org?ref=health. 
  30. ↑ Fountain, Henry (2012-01-12). "Surgeons Implant Synthetic Trachea In Baltimore Man". The New York Times. https://www.nytimes.com/2012/01/13/health/research/surgeons-transplant-synthetic-trachea-in-baltimore-man.html. 
  31. ↑ Cyranoski, David (12 September 2014). "Japanese woman is first recipient of next-generation stem cells". Nature. doi:10.1038/nature.2014.15915. ISSN 0028-0836. 
  32. ↑ Oltermann, Philip (2016-03-24). "'Superstar doctor' fired from Swedish institute over research 'lies'" (in en-GB). The Guardian. ISSN 0261-3077. https://www.theguardian.com/science/2016/mar/23/superstar-doctor-fired-from-swedish-institute-over-research-lies-allegations-windpipe-surgery. 
  33. ↑ Sweden, Sveriges Television AB, Stockholm. "Experimenten" (in sv). https://www.svt.se/dokument-inifran-experimenten/. 
  34. ↑ "Research" (in en). http://med.stanford.edu/stemcell/research.html. 
  35. ↑ "CRN Origins and Mission | Center for Regenerative Nanomedicine, Northwestern University". http://crn.northwestern.edu/about-crn. 
  36. ↑ "Wake Forest Institute for Regenerative Medicine (WFIRM)". https://school.wakehealth.edu/Research/Institutes-and-Centers/Wake-Forest-Institute-for-Regenerative-Medicine. 
  37. ↑ "Centres of Regenerative Medicine" (in en). https://www.bhf.org.uk/what-we-do/our-research/mending-broken-hearts/research/centres-of-regenerative-medicine. 
  38. ↑ "Guangzhou Institute of Biomedicine and Health,Chinese Academy of Sciences". http://english.gibh.cas.cn/sci/overview/. 
  39. ↑ "Institute for Stem Cell Biology and Regenerative Medicine - School of Pharmaceutical Sciences Tsinghua University". http://www.sps.tsinghua.edu.cn/en/study/ganxibao.html. 
  40. ↑ administrator. "Home" (in en-US). https://www.iterm.cuhk.edu.hk/. 
  41. ↑ Lan, Xiaoyan; Sun, Zhengwu; Chu, Chengyan; Boltze, Johannes; Li, Shen (2 August 2019). "Dental Pulp Stem Cells: An Attractive Alternative for Cell Therapy in Ischemic Stroke". Frontiers in Neurology 10: 824. doi:10.3389/fneur.2019.00824. PMID 31428038. 
  42. ↑ Steindorff, Marina M.; Lehl, Helena; Winkel, Andreas; Stiesch, Meike (February 2014). "Innovative approaches to regenerate teeth by tissue engineering". Archives of Oral Biology 59 (2): 158–66. doi:10.1016/j.archoralbio.2013.11.005. PMID 24370187. https://www.sciencedirect.com/science/article/abs/pii/S0003996913003427. Retrieved 27 June 2020. 
  43. ↑ King's College London (March 10, 2020). "Teeth That Repair Themselves – Study Finds Success With Natural Tooth Repair Method". https://scitechdaily.com/teeth-that-repair-themselves-study-finds-success-with-natural-tooth-repair-method/. 
  44. ↑ "Japanese scientists grow teeth from single cells". Reuters. February 20, 2007. https://www.reuters.com/article/us-teeth-mice/japanese-scientists-grow-teeth-from-single-cells-idUSN1834654020070220#:~:text=WASHINGTON%20(Reuters)%20%2D%20Japanese%20researchers,and%20transplanted%20them%20into%20mice.. 
  45. ↑ Normile, Dennis (August 3, 2009). "Researchers Grow New Teeth in Mice". Science. https://www.science.org/content/article/researchers-grow-new-teeth-mice. 
  46. ↑ Childs, Dan (April 13, 2009). "Could Baby Teeth Stem Cells Save Your Child?". ABC News. https://abcnews.go.com/Health/Dental/story?id=4942116&page=1. 
  47. ↑ Ratan-NM, M. Pharm (April 30, 2020). "Repairing Teeth using Stem Cells". https://www.news-medical.net/health/Repairing-Teeth-using-Stem-Cells.aspx. 
  48. ↑ Saldin, LT; Cramer, MC; Velankar, SS; White, LJ; Badylak, SF (February 2017). "Extracellular matrix hydrogels from decellularized tissues: Structure and function.". Acta Biomaterialia 49: 1–15. doi:10.1016/j.actbio.2016.11.068. PMID 27915024. 
  49. ↑ Swinehart, IT; Badylak, SF (March 2016). "Extracellular matrix bioscaffolds in tissue remodeling and morphogenesis.". Developmental Dynamics 245 (3): 351–60. doi:10.1002/dvdy.24379. PMID 26699796. 
  50. ↑ Hannan, Daniel (October 25, 2020). "Taking back control of fishing could be an enormous growth opportunity for Britain". https://www.telegraph.co.uk/news/2020/10/25/taking-back-control-fishing-could-enormous-growth-opportunity/. 
  51. ↑ 51.0 51.1 "Fish Skin for Human Wounds: Iceland's Pioneering Treatment". https://www.bloomberg.com/news/features/2017-06-27/fish-skin-may-be-the-answer-to-chronic-wounds. 
  52. ↑ "Alaska's seafood industry by the numbers, plus fish skin's medical applications and antibiotics in Chilean salmon". https://www.adn.com/business-economy/2019/04/30/alaskas-seafood-industry-by-the-numbers-plus-fish-skins-medical-applications-and-antibiotics-in-chilean-salmon/. 
  53. ↑ "FDA Approves Kerecis' Implantable Fish-Skin Product". https://icelandmonitor.mbl.is/news/news/2021/10/22/fda_approves_kerecis_implantable_fish_skin_product/. 
  54. ↑ 54.0 54.1 Walther, Mary Margaret (2009). "Chapter 39. Cord Blood Hematopoietic Cell Transplantation". in Appelbaum, Frederick R.; Forman, Stephen J.; Negrin, Robert S. et al.. Thomas' hematopoietic cell transplantation stem cell transplantation (4th ed.). Oxford: Wiley-Blackwell. ISBN 9781444303537. 
  55. ↑ 55.0 55.1 Haller M J (2008). "Autologous umbilical cord blood infusion for type 1 diabetes". Exp. Hematol. 36 (6): 710–15. doi:10.1016/j.exphem.2008.01.009. PMID 18358588. 
  56. ↑ Caseiro, AR; Pereira, T; Ivanova, G; Luís, AL; Maurício, AC (2016). "Neuromuscular Regeneration: Perspective on the Application of Mesenchymal Stem Cells and Their Secretion Products.". Stem Cells International 2016: 9756973. doi:10.1155/2016/9756973. PMID 26880998. 
  57. ↑ "Impact of umbilical cord blood-derived mesenchymal stem cells on cardiovascular research". BioMed Research International 2015: 975302. 2015. doi:10.1155/2015/975302. PMID 25861654. 
  58. ↑ Li, T; Xia, M; Gao, Y; Chen, Y; Xu, Y (2015). "Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy.". Expert Opinion on Biological Therapy 15 (9): 1293–306. doi:10.1517/14712598.2015.1051528. PMID 26067213. 
  59. ↑ Hsueh, Ming-Feng; Önnerfjord, Patrik; Bolognesi, Michael P.; Easley, Mark E.; Kraus, Virginia B. (October 2019). "Analysis of "old" proteins unmasks dynamic gradient of cartilage turnover in human limbs". Science Advances 5 (10): eaax3203. doi:10.1126/sciadv.aax3203. ISSN 2375-2548. PMID 31633025. Bibcode: 2019SciA....5R3203H. 
  60. ↑ "Humans Have Salamander-Like Ability to Regrow Cartilage in Joints". Duke Health. October 8, 2019. https://corporate.dukehealth.org/news-listing/humans-have-salamander-ability-regrow-cartilage-joints. 

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