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Regenerative Medicine

Original Editor - Malisha van der Berg

Top Contributors - Malisha van der Berg  

This article or area is currently under construction and may only be partially complete. Please come back soon to see the finished work! (10/11/2026)

Introduction

The body has an intrinsic capacity to repair and remodel tissue in response to injury. Whether caused by acute trauma, repetitive overload, degeneration, or systemic factors such as ischaemia, infection and immune dysfunction.[1][2] This capacity ranges from regeneration of skeletal muscle by resident muscle stem cells (satellite cells), to scar formation in ligaments and tendons.[2][3][4] However, it is limited by factors such as poor vascularisation, ageing and systemic disease.[5][6]

Regenerative medicine aims to enhance these intrinsic processes by repairing, replacing or regenerating damaged cells and tissues. With the goal to restore both the original structure of the tissue and its mechanical function.[7][8] This contrasts with conventional pharmacological treatments, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid injections, which relieve symptoms but do not halt underlying degeneration.[9][10][11] The field covers a wide range of treatments. The main groups relevant to musculoskeletal practice are listed below:

  • Orthobiologics: biological substances, often taken from the patient’s own blood, bone marrow or fat, that are injected or placed at an injury site to support healing.[9][12] They are either cell-based (bone marrow aspirate concentrate (BMAC), Mesenchymal stem cells (MSC) and adipose-derived cells) or acellular (platelet-rich plasma (PRP), hyaluronic acid (HA) and extracellular vesicles (EV's)).[6][13][14]
  • Prolotherapy: injection of an irritant solution, typically dextrose, to initiate an inflammatory healing response in injured joints and connective tissues.[15]
  • Peptides: short chains of amino acids. Some are licensed medicines, such as glucagon-like peptide-1 (GLP-1) receptor agonists. Others, such as Body Protection Compound-157 (BPC-157), are sold without approval and have little human evidence.[16][17]

These treatments are relevant to physiotherapists for three reasons:

  1. Patients increasingly encounter these treatments through clinics, social media and online vendors, and may seek guidance on them.[17]
  2. Many patients attend physiotherapy before or after these treatments, so rehabilitation must account for factors such as the timing of medicines and the loading of healing tissue.[2][18]
  3. Outcomes depend on what happens after treatment, as loading, exercise and education remain central to recovery.[2][19]

This page outlines the body’s natural healing process, describes the main regenerative treatments and their proposed mechanisms, summarises the current evidence, and discusses the implications for physiotherapy management.

Historical Development

Attempts to enhance tissue repair have a long history, but regenerative medicine emerged as a recognised discipline only in the late twentieth century. The term “regenerative medicine” was first used in 1992 and came into wider use around 2000.[7] [20] The field drew together several lines of work that had developed largely independently, as shown in the table below:

Period Development
1930s to 1950s Hyaluronic acid is isolated from vitreous humour.[21]

Sclerosant injections are used to stabilise hypermobile joints.[22]

Hackett introduces the term “prolotherapy”.[23]

1960s to 1970s Friedenstein identifies osteogenic, colony-forming cells in bone marrow, later termed bone marrow stromal cells.[24][25]
1970s to 1990s PRP moves from haematology into cardiac and maxillofacial surgery.[26][27][28]

Intra-articular hyaluronic acid (IAHA) is developed as viscosupplementation.[29]

1980s to 1990s EV's (exosomes) are described and named.[30][31]

Cell-penetrating peptides are characterised.[32][33]

1991 to 1993 Caplan popularises the term “mesenchymal stem cell”.[34]

Tissue engineering is defined as the combination of cells, scaffolds and signals.[35]

BPC-157 is first described.[36]

2000s PRP is adopted widely in sports medicine.[37]

Autologous conditioned serum (ACS) is developed.[38]

Extracellular matrix is investigated as a scaffold.[39]

Exenatide, the first GLP-1 receptor agonist, is approved for type 2 diabetes in 2005.[40]

Induced pluripotent stem cells are generated.[41][42]

2010s to present GLP-1 receptor agonists are approved for weight management.[43]

Mesenchymal stem cells are reconceptualised as “medicinal signalling cells”.[34]

Reporting standards for EV's (exosome) research are published.[44]

Many of these interventions were therefore developed for surgery, transfusion medicine or endocrinology before being applied to musculoskeletal conditions. This partly explains why the musculoskeletal evidence base is often less mature than the history of the treatments might suggest.

The Body’s Natural Healing Process

To understand how regenerative medicine works, it is first important to understand how the body responds to injury. Regenerative treatments do not replace this response. Instead, they aim to enhance specific stages of it, or to overcome the factors that limit it.[45]

This section therefore describes each stage of healing in detail, from the initial cellular response to the remodelling of repair tissue, and highlights where regenerative treatments may intervene. Further information on soft tissue healing is available on the Soft Tissue Healing page.

Each stage prepares the ground for the next: fibrin clot stabilises the site, inflammation clears damaged tissue, proliferation lays down a temporary scaffold, and remodelling converts that scaffold into organised tissue.[1]

Cellular Response to Injury

Healing begins with the response of individual cells. Cells can be injured by many intrinsic and extrinsic causes, summarised in the table below.[1]

Cause of injury Examples relevant to musculoskeletal practice
Hypoxia and ischaemia Reduced blood supply after trauma, compartment syndrome or vascular disease
Physical agents Crushing, tearing or repetitive mechanical overload, and extremes of temperature
Chemical agents and drugs Toxins and some medicines
Infectious agents Bacterial infection, for example after an injection or surgery
Immune dysfunction Inflammatory and autoimmune joint disease
Genetic factors Inherited abnormalities of collagen or other structural proteins
Nutritional imbalance Deficiencies that leave cells more vulnerable to injury
Ageing Cellular senescence where cells can no longer withstand injury.

Mechanical trauma can damage cells directly, by crushing or tearing, or indirectly, by disrupting their blood supply.[1] The 10minute video below gives an animated explanation on the mechanism of cell injury and the diverse causes behind cellular damage.

[46]

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Summary

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References

  1. ↑ 1.0 1.1 1.2 1.3 Miller MA, Zachary JF. Mechanisms and Morphology of Cellular Injury, Adaptation, and Death. In: Pathologic Basis of Veterinary Disease. Elsevier; 2017:2-43.e19.
  2. ↑ 2.0 2.1 2.2 2.3 Darrieutort-Laffite C, Blanchard F, Soslowsky LJ, Le Goff B. Biology and physiology of tendon healing. Joint Bone Spine. 2024;91(5):105696.
  3. ↑ Yin H, Price F, Rudnicki MA. Satellite Cells and the Muscle Stem Cell Niche. Physiol Rev. 2013;93(1):23-67.
  4. ↑ Hildebrand KA, Frank CB. Scar formation and ligament healing. Canadian Journal of Surgery. 1998;41(6):425-429.
  5. ↑ Kwan KYC, Ng KWK, Rao Y, et al. Effect of Aging on Tendon Biology, Biomechanics and Implications for Treatment Approaches. Int J Mol Sci. 2023;24(20):15183.
  6. ↑ 6.0 6.1 Del Toro Runzer C, Balmayor ER, van Griensven M. Biologics for bone regeneration: advances in cell, protein, gene, and mRNA therapies. Bone Res. 2026;14(1):5.
  7. ↑ 7.0 7.1 Mason, C., & Dunnill, P. (2008). A brief definition of regenerative medicine. Regenerative medicine, 3(1), 1-5.
  8. ↑ Regeneration: what does it mean and how does it work? | Eurostemcell. Accessed November 9, 2026. https://www.eurostemcell.org/regeneration-what-does-it-mean-and-how-does-it-work
  9. ↑ 9.0 9.1 Lee, W., Ruan, Q. Z., Hasoon, J. J., Kulich, R. J., Deer, T. R., Sayed, D., ... & Robinson, C. L. (2026). Current state of orthobiologics in treatment of knee osteoarthritis—Future directions. International Journal of Molecular Sciences, 27(11), 4738.
  10. ↑ Mobasheri A, Mahmoudian A, Kalvaityte U, et al. A White Paper on Collagen Hydrolyzates and Ultrahydrolyzates: Potential Supplements to Support Joint Health in Osteoarthritis? Curr Rheumatol Rep. 2021;23(11):78.
  11. ↑ Manchikanti L, Knezevic E, Knezevic NN, et al. Effectiveness of Intradiscal Regenerative Medicine Therapies for Long-Term Relief of Chronic Low Back Pain: A Systematic Review and Meta-Analysis. Pain Physician. 2024;27(10):E995-E1032.
  12. ↑ Wessely-Szponder J, Zdziennicka J, Junkuszew A, Latalski M, Świeca M, Szponder T. Prospects and Applications of Natural Blood-Derived Products in Regenerative Medicine. Int J Mol Sci. 2021;23(1):472.
  13. ↑ Pawlak M, Wałecka J, Bąkowski P, Tyczewska A, Grzywacz K. [Biological strategies supporting the orthopaedic treatment]. Postepy Biochem. 2024;69(4):310-318.
  14. ↑ Ivanov AA, Kuznetsova AV, Popova OP, Danilova TI, Yanushevich OO. Modern Approaches to Acellular Therapy in Bone and Dental Regeneration. Int J Mol Sci. 2021;22(24):13454.
  15. ↑ Wang F, Cheung CW, Wong SSC. Regenerative medicine for the treatment of chronic low back pain: a narrative review. J Int Med Res. 2023;51(2):3000605231155777.
  16. ↑ Yuan C, Demers A, Silva-Ortiz V, et al. From Regeneration to Analgesia: The Role of BPC-157 in Tissue Repair and Pain Management. Int J Mol Sci. 2026;27(6):2876.
  17. ↑ 17.0 17.1 Moiz A, O’Keefe EL, O’Keefe JH. Dangers of Injectable Peptides and Other Unregulated “Biohacking” Drugs. Mo Med. 2026;123(4):337-343.
  18. ↑ Mormone E, D’Esposito V, De Luca P, et al. Platelet-Rich Plasma from the Research to the Clinical Arena: A Journey Toward the Precision Regenerative Medicine. Int J Mol Sci. 2026;27(2):1058.
  19. ↑ Brumini C, Natour J, Adolph SMM, Furtado RNV, Jones A. Exercises plus intra-articular injection for knee osteoarthritis: a systematic review with meta-analysis. Adv Rheumatol. 2025;66(1):5.
  20. ↑ Sampogna G, Guraya SY, Forgione A. Regenerative medicine: Historical roots and potential strategies in modern medicine. Journal of Microscopy and Ultrastructure. 2015;3(3):101-107.
  21. ↑ Meyer, K., & Palmer, J. W. (1934). The polysaccharide of the vitreous humor. Journal of Biological Chemistry, 107(3), 629-634.
  22. ↑ Schultz, L. W. (1937). A treatment for subluxation of the temporomandibular joint. Journal of the American Medical Association, 109(13), 1032-1035.
  23. ↑ Hackett, G. S. (1958). Ligament and tendon relaxation treated by prolotherapy. The British Journal of Surgery
  24. ↑ Friedenstein, A. J., & Petrakova, K. Kurolesova AI, et a1. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation, 1(968), 6.
  25. ↑ Friedenstein, A. J., Chailakhjan, R. K., & Lalykina, K. (1970). The development of fibroblast colonies in monolayer cultures of guinea‐pig bone marrow and spleen cells. Cell Proliferation, 3(4), 393-403.
  26. ↑ Ferrari, M., Zia, S., Valbonesi, M., Henriquet, F., Venere, G., Spagnolo, S., ... & Panzani, I. (1987). A new technique for hemodilution, preparation of autologous platelet-rich plasma and intraoperative blood salvage in cardiac surgery. The International journal of artificial organs, 10(1), 47-50.
  27. ↑ Marx, D. R. E., Carlson, D. E. R., Eichstaedt, D. R. M., Schimmele, D. S. R., Strauss, D. J. E., & Georgeff, K. R. (1998). Platelet-rich plasma: Growth factor enhancement for bone grafts. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 85(6), 638-646.
  28. ↑ Alves, R., & Grimalt, R. (2018). A review of platelet-rich plasma: history, biology, mechanism of action, and classification. Skin appendage disorders, 4(1), 18-24.
  29. ↑ Balazs, E. A., & Denlinger, J. L. (1993). Viscosupplementation: a new concept in the treatment of osteoarthritis. The Journal of Rheumatology. Supplement, 39, 3-9.
  30. ↑ Pan, B. T., & Johnstone, R. M. (1983). Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell, 33(3), 967-978.
  31. ↑ Johnstone, R. M., Adam, M., Hammond, J. R., Orr, L., & Turbide, C. (1987). Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). Journal of Biological Chemistry, 262(19), 9412-9420.
  32. ↑ Frankel, A. D., & Pabo, C. O. (1988). Cellular uptake of the tat protein from human immunodeficiency virus. Cell, 55(6), 1189-1193.
  33. ↑ Derossi, D., Joliot, A. H., Chassaing, G., & Prochiantz, A. (1994). The third helix of the Antennapedia homeodomain translocates through biological membranes. Journal of Biological Chemistry, 269(14), 10444-10450.
  34. ↑ 34.0 34.1 Caplan, A. I. (2017). Mesenchymal stem cells: time to change the name!. Stem cells translational medicine, 6(6), 1445-1451.
  35. ↑ Vacanti, J. P., & Langer, R. (1999). Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation. The lancet, 354, S32-S34.
  36. ↑ Sikirić, P., Petek, M., Ručman, R., Seiwerth, S., Grabarević, Z., Rotkvić, I., ... & Karakas, I. (1993). A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. Journal of Physiology-Paris, 87(5), 313-327.
  37. ↑ Mishra, A., & Pavelko, T. (2006). Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. The American journal of sports medicine, 34(11), 1774-1778.
  38. ↑ Meijer, H., Reinecke, J., Becker, C., Tholen, G., & Wehling, P. (2003). The production of anti-inflammatory cytokines in whole blood by physico-chemical induction. Inflammation Research, 52(10), 404-407.
  39. ↑ Badylak, S. F. (2007). The extracellular matrix as a biologic scaffold material. Biomaterials, 28(25), 3587-3593.
  40. ↑ Müller, T. D., Finan, B., Bloom, S. R., D'Alessio, D., Drucker, D. J., Flatt, P. R., ... & Tschöp, M. H. (2019). Glucagon-like peptide 1 (GLP-1). Molecular metabolism, 30, 72-130.
  41. ↑ Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.
  42. ↑ Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. cell, 131(5), 861-872.
  43. ↑ Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., ... & Wilding, J. P. (2015). A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine, 373(1), 11-22.
  44. ↑ Welsh, J. A., Goberdhan, D. C., O'Driscoll, L., Buzas, E. I., Blenkiron, C., Bussolati, B., ... & Benedikter, B. J. (2024). Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Journal of extracellular vesicles, 13(2), e12404.
  45. ↑ Ganesan O, Kiwanuka H, Hamaguchi R, Orgill DP. A review of regenerative medicine and tissue engineering with a focus on wound healing and anti-aging. Front Surg. 2025;12:1504563.
  46. ↑ Medi study go.Cell Injury | Mechanisms | Animated Explanation. Available from: https://www.youtube.com/watch?v=fcV1ira3gl0 [last accessed 10/11/2026]
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