Leon Creaney, SEM Physician, BUPA

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 Vos1, 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 debris2,3. However within
24 hours macrophages4 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 fibre5.

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 concentration8,
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 grafts10 and wound healing11, 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 regeneration12 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