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• The lack of clinical research on PRP
  Lars Engebretsen
  Published on: 11 October 2022
• PRP within the wider context of regenerative medicine
  Leon Creaney
  Published on: 11 October 2022

• Published on: 11 October 2022

  The lack of clinical research on PRP

  • Lars Engebretsen , Surgeon

  I fully agree with the comment from Dr Creaney regarding PRP. Unfortunately, there is little sound clinical science supporting the use at the moment. The design of studies published so far has been far from perfect. The studies with poor design have tended to produce good results, whereas the RCTs with proper design have shown less of an effect. Another challenge is the multitude of unknown clinical variables such as amou...

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  I fully agree with the comment from Dr Creaney regarding PRP. Unfortunately, there is little sound clinical science supporting the use at the moment. The design of studies published so far has been far from perfect. The studies with poor design have tended to produce good results, whereas the RCTs with proper design have shown less of an effect. Another challenge is the multitude of unknown clinical variables such as amount of PRP, number of injections, when to inject, where to inject etc. In our paper, we citically evaluate current use of PRP and call for proper, well executed clinical research.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 11 October 2022

  PRP within the wider context of regenerative medicine

  • Leon Creaney, SEM Physician

  Dear Sir,

  I congratulate the IOC Consensus panel on having produced as clear a summary of the current understanding of the basic and clinical science relating to PRP as the body of published literature allows. While there was initially great hope in Sport Medicine circles that PRP would become the magic bullet for injuries, recent trials such as de Vos [1], have failed to provide that conclusive evidence so de...

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  Dear Sir,

  I congratulate the IOC Consensus panel on having produced as clear a summary of the current understanding of the basic and clinical science relating to PRP as the body of published literature allows. While there was initially great hope in Sport Medicine circles that PRP would become the magic bullet for injuries, recent trials such as de Vos [1], have failed to provide that conclusive evidence so desired.

  This is not surprising. The more we learn about tissue regeneration, the more apparent it becomes how complex a process it is. Tissue regeneration is not a passive phenomenon, instead it is a highly co- ordinated interplay of multiple cell lines at different stages of maturation. Different cellular and humoral components play their different roles. The process can be likened to the repair of a collapsed building. Consider muscle injury. The initial cells on scene, due to bleeding, are platelets, but they appear to be relatively passively involved - alarm bells which sequester and awaken the major players. Platelets release chemotactic factors which attract neutrophils to clear the debris [2,3]. However within 24 hours macrophages [4] arrive, akin to the foreman, and it is these cells that appear to regulate the process from this point onwards. If there is any 'brains' or 'thinking' to tissue repair, it would seem to be the macrophages doing it. Next come the actual builders. Fibroblasts are activated to produce a collagen infrastructure, and satellite cells, to form myocytes and finally myotubes, merging to become a single strand of muscle fibre [5].

  So where do 'growth factors' come into it? These proteins are simply the communications being sent between the foreman and his workers. The messages are very simple - move or stay put, divide or don't divide, live or die, make collagen etc. In biology we use the terms chemotaxis; mitosis; quiescence; apoptosis and protein biosynthesis. The point is this - growth factors are just the messenger molecules used by one cell to send an instruction to another, they are not the person giving the orders.

  Unfortunately the 'language' of growth factors is very different to English. We are used, pretty much, to one word having roughly one meaning. However growth factor 'words' are more like a tonal language, Mandarin. In these languages the same word can have multiple different meanings depending on how you pronounce it. In the same manner, growth factors can produce varying effects depending on their concentration, time of release, point in cell cycle and recipient cell. Thus trying to pin any one growth factor down to one particular action can be pointless - TGF-?[1] is commonly associated with fibrosis [3,6,7], but it can stimulate regeneration or fibrosis, chemoattraction or stasis, depending on its concentration [8], target cell, and sequence within the tissue regeneration process.

  Moving back to the analogy, it requires a great deal of intelligence to rebuild a collapsed building. The foreman has to send and receive accurate messages, at the right time, and to the right people, otherwise the building will end up with structural flaws, and will probably fall down again. Imagine if he simply threw the blueprints in the air, and allowed the workers to pick up a piece each and act on what it said - complete chaos! In the same way macrophages co-ordinate a complex interplay between themselves and fibroblasts/satellite cells.

  This is where PRP has the potential to fall down. PRP has variable and inconsistent content and concentration. [9] There is no consensus on timing of injection. What does a random bolus injection into an injury achieve? Are we sending these effector cells a clear and co-ordinated set of instructions with PRP? Or are they being sent a completely confusing message? It would seem hopelessly optimistic and na?ve to presume that we are accurately reproducing biological complexity.

  PRP has shown promise in promoting accelerated scar tissue formation in dental grafts [10] and wound healing [11], where regeneration of complex tissue is not a goal. In Sports Medicine however, we require restoration of functional tissue - contractile muscle or tendon of high tensile strength - tissue of much greater complexity. The successes in maxillo- facial applications are perhaps not analogous to these situations.

  Whether or not PRP is eventually proven or disproven in Sports Injuries, it is nevertheless a good start. The Sports Medicine world has woken to the possibilities of regenerative medicine, and is trying to be scientific in the development of novel therapies. In the future we will have improved understanding of how the complex and overlapping processes of tissue regeneration [12] are controlled by co-ordinating cells, stem cells, effector cells and the messenger molecules that they employ, and more importantly, how to manipulate these processes for a beneficial effect.

  References

  1. de Vos RA, Weir A, van Schie HTM et al. Platelet-Rich Plasma injection for Chronic Achilles Tendinopathy JAMA 2010;303(2):144-149

  2. Anitua E, Andia I, Ardanza B, et al. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost 2004;91:4-15.

  3. Toumi H, F'guyer S, Best T. The role of neutrophils in injury and repair following muscle stretch. J Anat 2006;208:459-470

  4. Chazaud B, Brigitte M, Yacoub-Youssef H et al. Dual and beneficial roles of macrophages during skeletal muscle regeneration. Exerc Sport Sci Rev 2009;37(1):18-22

  5. Jarvinen TAH, Jarvinen TLN, Kaariainen M. Muscle injuries: Biology and Treatment. AJSM 2005;33:745-764

  6. Li Y, Foster W, Deasy BM. Transforming growth factor-?1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle. Am J Path 2004;164(3):1007-1019

  7. Shen W, Li Y, Tang Y. NS-398, a Cyclooxygenase-2-specific inhibitor, delays skeletal muscle healing by decreasing regeneration and promoting fibrosis. Am J Path 2005;167(4):1105-1117

  8. Bischoff R. Chemotaxis of Skeletal muscle satellite cells. Dev Dyn 1997;208:505-515

  9. Creaney L, Hamilton B. Growth factor delivery methods in the management of sports injuries: the state of play. BJSM 2008;42:314-320

  10. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg 2004;62(8):1047-8

  11. Lacci KM, Dardik A. Platelet-rich plasma:support for its use in wound healing. Yale J Biol Med 2010;83(1):1-9

  12. Gates CB, Karthikeyan T, Fu F, Huard J. Regenerative Medicine for the musculoskeletal system based on muscle-derived stem cell. J Am Acad Orthop Surg 2008;16:68-76

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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