- Email: [email protected]
Platelet plasma rich products in musculoskeletal medicine: Any evidence?
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 1 4 8 e1 5 0
available at www.sciencedirect.com
The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Matter for Debate
Platelet plasma rich products in musculoskeletal medicine: Any evidence? Nicola Maffulli a,*, Angelo Del Buono b a
Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital, 275 Bancroft Road, London E1 4DG, UK b Department of Orthopaedic and Trauma Surgery, Campus Biomedico University of Rome, Via Alvaro del Portillo, Rome, Italy
article info
abstract
Article history:
Platelet Reach Plasma (PRP) is considered to accelerate muscle and tendon healing and
Received 8 March 2011
allow early return to elite competition, and it is often recommend as best practice for
Accepted 9 March 2011
management of musculoskeletal injuries. Even though several growth factors abundant in
Available online 31 May 2011
PRPs have been extensively studied in tissue regeneration, the key factors are yet unknown. Given our rudimentary knowledge of the mechanism of action of the PRPs, it is
Keywords:
challenging to use this technology to promote early healing, and produce improved and
Platelet Reach Plasma
accelerated functional recovery. We prompt researchers to undertake appropriately pow-
Level of evidence
ered level I studies with adequate and relevant outcome measures and clinically appro-
Muscle healing
priate follow up.
Tendon healing
ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
The vulnerability of the musculoskeletal systems to injuries is often dramatic for athletes, and their effects could be devastating for them and their clubs. Given the demands of training and competitions, the introduction of treatment strategies accelerating recovery from such injuries, without adversely affecting recurrence rate, is increasingly advocated, and often forced.1,2 Even though available evidencebased treatments are lacking, injection therapies, including Platelet Reach Plasma (PRP), are being increasingly used in the field of sport injuries.3 PRP is an autologous concentrate of human platelets in a small volume of plasma, containing biologically active factors, responsible for haemostasis, synthesis of new connective tissue, and revascularization.4 The rationale for PRP therapy lies in reversing the blood ratio by decreasing red blood cell (RBC) amount, which are
less useful in the healing process, to approximately 5%, and increasing the platelet amount to 94% to stimulate recovery.5,6 Growth factors, and the induction of further release of growth factors, supposedly improve the healing process in chronic injuries, and accelerate repair in acute lesions. At present, PRP is increasingly considered to accelerate muscle and tendon healing and allow early return to elite competition, and it is often recommend as best practice for management of musculoskeletal injuries. Firstly used in the 1980s to promote physiological wound healing of cutaneous ulcers,7 PRP has potential regenerative and healing effects in oral implantology.4 Successively, the use of PRP has spread to other clinical areas, including ophthalmology, orthopaedics, sports medicine, cardiology, dermatology, plastic surgery, and neurology.8
* Corresponding author. Tel.: þ44 20 8223 8839; fax: þ44 20 8223 8930. E-mail address: [email protected] (N. Maffulli). 1479-666X/$ e see front matter ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2011.03.004
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 1 4 8 e1 5 0
Concerning musculoskeletal disorders, PRP has been used to enhance the healing of meniscus defects and muscle injuries’, stimulate chondrocytes to engineer cartilaginous tissue, reduce pain and produce better and more balanced synovial fluid in arthritic knees, improve outcomes after total knee arthroplasty and subacromial decompression, accelerate bone formation, stimulate the healing of anterior cruciate ligament injury central defects, its primary repair or its reconstruction’, improve the outcome of operated ruptured Achilles tendons, reduce pain in chronic tendinopathies, and prevent and reverse inter-vertebral disc degeneration.9 Although the management of sports injuries with PRP injections has been advocated since 2003,10 this strategy has been mostly supported by scarce level IIIeIV studies. Although some trials report a great positive effect,11 more recent well executed and scientifically stricter ones report at best no effect,12,13 and possibly detrimental effects of PRP.14 There are still many unanswered questions about the best volume and frequency of the injections, the ideal period between multiple injections, mechanism of platelet activation and degranulation.15,16 Laboratory data indicate that such treatments can enhance myogenesis,17 but it is undefined when and how PRP therapies can be usefully employed in muscle injuries.18 Although the results of laboratory studies are encouraging,19 they always investigate healthy tendons or surgically induced muscle or tendon lesions, given the lack of good experimental models for tendinopathy.20 Therefore, it is unclear whether these results can be extended to tendinopathic tendons, and future research in the field of basic science should investigate this.21,22 There may be differences in natural healing response between loadbearing tendons, such as the patellar and Achilles tendon, and non-load-bearing tendons, such as the wrist and elbow extensors and flexors.11,13,14 For example, wrist extensor tendinopathy is usually self-limiting, with 80e90% recovery within 1 year,23 whereas patients with tendinopathy of the main body of the Achilles tendon did not improve in a trial with a four month wait and see arm.24 In some studies, the subjects included had a variety of mid-portion and insertional tendinopathies, and it is unclear whether these tendinopathies at different locations in the same tendon can be compared, given their different biomechanical and metabolic properties and responses to treatment. PRP therapies have been tested in few well conducted level I clinical trials on musculoskeletal injuries, and their best formulation of application is unclear. Despite no PRP formulation has yet provided solid evidence for the stimulation of healing and recovery after sports muscle injuries, two different liquid formulations are gathered under the same PRP terminology.25 L-PRP contains fivefold to eightfold more platelets and more leukocytes than peripheral blood; P-PRP, in which leukocytes are absent, has a moderate increase in platelet count (1.5e2.5-fold above baseline). A positive or negative effect of leukocytes cannot be generalized to all tissues and clinical conditions, and further investigations are needed. In addition, since it is unclear whether L-PRP or P-PRP progress in different ways in muscle and tendon injuries, both formulations need to be compared, preferably using large animal models and adequate outcome measurements.26 Even though several growth factors abundant in PRPs have been extensively studied in tissue regeneration, the key factors are yet unknown.27
149
Therefore, a major challenge is to disentangle the relative effects of the various components of PRP, and to understand how they influence cell activities. At present, the failure to understand the mechanism of action of PRPs frustrates the efforts to develop best formulations regarding the optimal platelet concentration and methods of preparation.20 Costs vary tremendously: a commercial kit yields a PRP concentrate at the cost of several hundred pound, but in house non-automatised techniques can produce a PRP concentrate for approximately US$10.20 Each method to concentrate platelets leads to a different product with different biology and potential uses, with a high variation (3e27 fold) in growth factor concentration and in the kinetics of release.5,25 These differences might be relevant for clinical management, although they have not been systematically studied.25 The best PRP formulation for musculoskeletal injuries can be reached after the relations between PRP components, healing mechanisms, and functional outcome will be clarified. To standardize PRP formulations and procedures for application, differences between pure plateletrich plasma and leukocyte-platelet concentrates, regarding tissue damage exacerbation, need to be established,28 as well as the optimal balance between plasma myogenic factors (IGFs and HGF), and platelet-secreted angiogenic or chemotactic factors.29 As the best timing for application is not clear, the implications of physicochemical temporal conditions of the tissue (i.e., pH, NO and oxygen levels) should be evaluated.30 Concerning the treatment effects, it is also mandatory to report and monitor complications.31 To date, there is not compelling evidence of systemic effect of local PRP injection. However, it is important to monitor for infections, further injuries and possible systemic effects when using autologous growth factors. Furthermore, there are no scientific reports suggesting potential cause-effect relationships between growth factors present in PRP and carcinogenesis.32 Some potential arguments for these considerations include the limited need of PRP injections in clinics (as PRP is not chronically administered), and the short in vivo half-lives and local bioavailability of growth factors produced by PRP.32 In 2010, PRP was specifically mentioned in the prohibited list for the first time. Intramuscular PRP injections were prohibited, while all other routes of administration, such as intraarticular, intra or peritendinous were permitted, requiring only a declaration of use. However, the different PRP formulations and treatment methodologies have not been found to increase muscle growth beyond return to a normal physiological state, and the use of PRP injections for therapeutic purposes only does not violate the spirit of sport. Although the prohibition for intramuscular injections of PRP has been removed in the 2011 Prohibited List, WADA will continue to review PRP use as new medical and scientific information becomes available.32 Given our rudimentary knowledge of the mechanism of action of the PRPs, it is challenging to use this technology to promote early healing, and produce improved and accelerated functional recovery. We prompt researchers to undertake appropriately powered level I studies with adequate and relevant outcome measures and clinically appropriate follow up. There is great potential for improvement by taking research findings and translating them into clinical investigation.33 Because of the relatively safety of these products, basic science, clinical discovery and patient-
150
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 1 4 8 e1 5 0
oriented research should be interdependent rather than successive steps. The substantial challenges of incorporating such research into clinical care must be pursued if the potential of PRPs is to be realized.
15.
16.
references 17. 1. Maffulli N, Longo UG, Loppini M, Spiezia F, Denaro V. New options in the management of tendinopathy. Open Access J Sports Med 2010;1:29e37. 2. Maffulli N, Longo UG, Denaro V. Novel approaches for the management of tendinopathy. J Bone Joint Surg Am 2010;92: 2604e13. 3. Orchard JW, Best TM, Mueller-Wohlfahrt HW, Hunter G, Hamilton BH, Webborn N, et al. The early management of muscle strains in the elite athlete: best practice in a world with a limited evidence basis. Br J Sports Med; 2008. 4. Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent 2001;10:225e8. 5. Sanchez M, Anitua E, Orive G, Mujika I, Andia I. Platelet-rich therapies in the treatment of orthopaedic sport injuries. Sports Med 2009;39:345e54. 6. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg 2004;62:489e96. 7. Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care 2001;24:483e8. 8. Anitua E, Sanchez M, Orive G, Andia I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials 2007;28:4551e60. 9. Leahy AL. Shortages of general and specialist surgeons. Surgeon 2010;8:61e2. 10. Sanchez M, Azofra J, Anitua E, Andia I, Padilla S, Santisteban J, et al. Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc 2003;35: 1648e52. 11. Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year followup. Am J Sports Med 2010;38:255e62. 12. Castricini R, Longo UG, De Benedetto M, Panfoli N, Pirani P, Zini R, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med 2011;39:258e65. 13. de Vos RJ, Weir A, van Schie HT, Bierma-Zeinstra SM, Verhaar JA, Weinans H, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA 2010;303:144e9. 14. Schepull T, Kvist J, Norrman H, Trinks M, Berlin G, Aspenberg P. Autologous platelets have no effect on the
18.
19. 20. 21. 22.
23.
24.
25.
26. 27. 28.
29. 30. 31.
32.
33.
healing of human achilles tendon ruptures: a randomized single-blind study. Am J Sports Med 2011;39:38e47. Anitua E, Sanchez M, Nurden AT, Nurden P, Orive G, Andia I. New insights into and novel applications for platelet-rich fibrin therapies. Trends Biotechnol 2006;24:227e34. Fufa D, Shealy B, Jacobson M, Kevy S, Murray MM. Activation of platelet-rich plasma using soluble type I collagen. J Oral Maxillofac Surg 2008;66:684e90. Sharma P, Maffulli N. Basic biology of tendon injury and healing. Surgeon 2005;3:309e16. Wilson T, Sahu A, Johnson DS, Turner PG. The effect of trainee involvement on procedure and list times: a statistical analysis with discussion of current issues affecting orthopaedic training in UK. Surgeon 2010;8:15e9. O’Connor T, Papanikolaou V, Keogh I. Safe surgery, the human factors approach. Surgeon 2010;8:93e5. Mei-Dan O, Mann G, Maffulli N. Platelet-rich plasma: any substance into it? Br J Sports Med 2010;44:618e9. Dreyer JS. Assessing professionalism in surgeons. Surgeon 2010;8:20e7. Taylor B, Slater A, Reznick R. The surgical safety checklist effects are sustained, and team culture is strengthened. Surgeon 2010;8:1e4. Rineer CA, Ruch DS. Elbow tendinopathy and tendon ruptures: epicondylitis, biceps and triceps ruptures. J Hand Surg Am 2009;34:566e76. Rompe JD, Nafe B, Furia JP, Maffulli N. Eccentric loading, shock-wave treatment, or a wait-and-see policy for tendinopathy of the main body of tendo Achillis: a randomized controlled trial. Am J Sports Med 2007;35:374e83. Dohan Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol 2009;27:158e67. Hutchins GG, Grabsch HI. Molecular pathologyethe future? Surgeon 2009;7:366e77. Anitua E, Sanchez M, Orive G, Andia I. Delivering growth factors for therapeutics. Trends Pharmacol Sci 2008;29:37e41. Tidball JG. Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 2005;288: R345e53. Toomey DP, Murphy JF, Conlon KC. COX-2, VEGF and tumour angiogenesis. Surgeon 2009;7:174e80. Andia I, Sanchez M, Maffulli N. Tendon healing and plateletrich plasma therapies. Expert Opin Biol Ther 2010;10:1415e26. Creaney L, Hamilton B. Growth factor delivery methods in the management of sports injuries: the state of play. Br J Sports Med 2008;42:314e20. Engebretsen L, Steffen K, Alsousou J, Anitua E, Bachl N, Devilee R, et al. IOC consensus paper on the use of plateletrich plasma in sports medicine. Br J Sports Med 2010;44: 1072e81. Hing CB, Back DL. A review of intellectual property rights in biotechnology. Surgeon 2009;7:228e31.
available at www.sciencedirect.com
The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Matter for Debate
Platelet plasma rich products in musculoskeletal medicine: Any evidence? Nicola Maffulli a,*, Angelo Del Buono b a
Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital, 275 Bancroft Road, London E1 4DG, UK b Department of Orthopaedic and Trauma Surgery, Campus Biomedico University of Rome, Via Alvaro del Portillo, Rome, Italy
article info
abstract
Article history:
Platelet Reach Plasma (PRP) is considered to accelerate muscle and tendon healing and
Received 8 March 2011
allow early return to elite competition, and it is often recommend as best practice for
Accepted 9 March 2011
management of musculoskeletal injuries. Even though several growth factors abundant in
Available online 31 May 2011
PRPs have been extensively studied in tissue regeneration, the key factors are yet unknown. Given our rudimentary knowledge of the mechanism of action of the PRPs, it is
Keywords:
challenging to use this technology to promote early healing, and produce improved and
Platelet Reach Plasma
accelerated functional recovery. We prompt researchers to undertake appropriately pow-
Level of evidence
ered level I studies with adequate and relevant outcome measures and clinically appro-
Muscle healing
priate follow up.
Tendon healing
ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
The vulnerability of the musculoskeletal systems to injuries is often dramatic for athletes, and their effects could be devastating for them and their clubs. Given the demands of training and competitions, the introduction of treatment strategies accelerating recovery from such injuries, without adversely affecting recurrence rate, is increasingly advocated, and often forced.1,2 Even though available evidencebased treatments are lacking, injection therapies, including Platelet Reach Plasma (PRP), are being increasingly used in the field of sport injuries.3 PRP is an autologous concentrate of human platelets in a small volume of plasma, containing biologically active factors, responsible for haemostasis, synthesis of new connective tissue, and revascularization.4 The rationale for PRP therapy lies in reversing the blood ratio by decreasing red blood cell (RBC) amount, which are
less useful in the healing process, to approximately 5%, and increasing the platelet amount to 94% to stimulate recovery.5,6 Growth factors, and the induction of further release of growth factors, supposedly improve the healing process in chronic injuries, and accelerate repair in acute lesions. At present, PRP is increasingly considered to accelerate muscle and tendon healing and allow early return to elite competition, and it is often recommend as best practice for management of musculoskeletal injuries. Firstly used in the 1980s to promote physiological wound healing of cutaneous ulcers,7 PRP has potential regenerative and healing effects in oral implantology.4 Successively, the use of PRP has spread to other clinical areas, including ophthalmology, orthopaedics, sports medicine, cardiology, dermatology, plastic surgery, and neurology.8
* Corresponding author. Tel.: þ44 20 8223 8839; fax: þ44 20 8223 8930. E-mail address: [email protected] (N. Maffulli). 1479-666X/$ e see front matter ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2011.03.004
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 1 4 8 e1 5 0
Concerning musculoskeletal disorders, PRP has been used to enhance the healing of meniscus defects and muscle injuries’, stimulate chondrocytes to engineer cartilaginous tissue, reduce pain and produce better and more balanced synovial fluid in arthritic knees, improve outcomes after total knee arthroplasty and subacromial decompression, accelerate bone formation, stimulate the healing of anterior cruciate ligament injury central defects, its primary repair or its reconstruction’, improve the outcome of operated ruptured Achilles tendons, reduce pain in chronic tendinopathies, and prevent and reverse inter-vertebral disc degeneration.9 Although the management of sports injuries with PRP injections has been advocated since 2003,10 this strategy has been mostly supported by scarce level IIIeIV studies. Although some trials report a great positive effect,11 more recent well executed and scientifically stricter ones report at best no effect,12,13 and possibly detrimental effects of PRP.14 There are still many unanswered questions about the best volume and frequency of the injections, the ideal period between multiple injections, mechanism of platelet activation and degranulation.15,16 Laboratory data indicate that such treatments can enhance myogenesis,17 but it is undefined when and how PRP therapies can be usefully employed in muscle injuries.18 Although the results of laboratory studies are encouraging,19 they always investigate healthy tendons or surgically induced muscle or tendon lesions, given the lack of good experimental models for tendinopathy.20 Therefore, it is unclear whether these results can be extended to tendinopathic tendons, and future research in the field of basic science should investigate this.21,22 There may be differences in natural healing response between loadbearing tendons, such as the patellar and Achilles tendon, and non-load-bearing tendons, such as the wrist and elbow extensors and flexors.11,13,14 For example, wrist extensor tendinopathy is usually self-limiting, with 80e90% recovery within 1 year,23 whereas patients with tendinopathy of the main body of the Achilles tendon did not improve in a trial with a four month wait and see arm.24 In some studies, the subjects included had a variety of mid-portion and insertional tendinopathies, and it is unclear whether these tendinopathies at different locations in the same tendon can be compared, given their different biomechanical and metabolic properties and responses to treatment. PRP therapies have been tested in few well conducted level I clinical trials on musculoskeletal injuries, and their best formulation of application is unclear. Despite no PRP formulation has yet provided solid evidence for the stimulation of healing and recovery after sports muscle injuries, two different liquid formulations are gathered under the same PRP terminology.25 L-PRP contains fivefold to eightfold more platelets and more leukocytes than peripheral blood; P-PRP, in which leukocytes are absent, has a moderate increase in platelet count (1.5e2.5-fold above baseline). A positive or negative effect of leukocytes cannot be generalized to all tissues and clinical conditions, and further investigations are needed. In addition, since it is unclear whether L-PRP or P-PRP progress in different ways in muscle and tendon injuries, both formulations need to be compared, preferably using large animal models and adequate outcome measurements.26 Even though several growth factors abundant in PRPs have been extensively studied in tissue regeneration, the key factors are yet unknown.27
149
Therefore, a major challenge is to disentangle the relative effects of the various components of PRP, and to understand how they influence cell activities. At present, the failure to understand the mechanism of action of PRPs frustrates the efforts to develop best formulations regarding the optimal platelet concentration and methods of preparation.20 Costs vary tremendously: a commercial kit yields a PRP concentrate at the cost of several hundred pound, but in house non-automatised techniques can produce a PRP concentrate for approximately US$10.20 Each method to concentrate platelets leads to a different product with different biology and potential uses, with a high variation (3e27 fold) in growth factor concentration and in the kinetics of release.5,25 These differences might be relevant for clinical management, although they have not been systematically studied.25 The best PRP formulation for musculoskeletal injuries can be reached after the relations between PRP components, healing mechanisms, and functional outcome will be clarified. To standardize PRP formulations and procedures for application, differences between pure plateletrich plasma and leukocyte-platelet concentrates, regarding tissue damage exacerbation, need to be established,28 as well as the optimal balance between plasma myogenic factors (IGFs and HGF), and platelet-secreted angiogenic or chemotactic factors.29 As the best timing for application is not clear, the implications of physicochemical temporal conditions of the tissue (i.e., pH, NO and oxygen levels) should be evaluated.30 Concerning the treatment effects, it is also mandatory to report and monitor complications.31 To date, there is not compelling evidence of systemic effect of local PRP injection. However, it is important to monitor for infections, further injuries and possible systemic effects when using autologous growth factors. Furthermore, there are no scientific reports suggesting potential cause-effect relationships between growth factors present in PRP and carcinogenesis.32 Some potential arguments for these considerations include the limited need of PRP injections in clinics (as PRP is not chronically administered), and the short in vivo half-lives and local bioavailability of growth factors produced by PRP.32 In 2010, PRP was specifically mentioned in the prohibited list for the first time. Intramuscular PRP injections were prohibited, while all other routes of administration, such as intraarticular, intra or peritendinous were permitted, requiring only a declaration of use. However, the different PRP formulations and treatment methodologies have not been found to increase muscle growth beyond return to a normal physiological state, and the use of PRP injections for therapeutic purposes only does not violate the spirit of sport. Although the prohibition for intramuscular injections of PRP has been removed in the 2011 Prohibited List, WADA will continue to review PRP use as new medical and scientific information becomes available.32 Given our rudimentary knowledge of the mechanism of action of the PRPs, it is challenging to use this technology to promote early healing, and produce improved and accelerated functional recovery. We prompt researchers to undertake appropriately powered level I studies with adequate and relevant outcome measures and clinically appropriate follow up. There is great potential for improvement by taking research findings and translating them into clinical investigation.33 Because of the relatively safety of these products, basic science, clinical discovery and patient-
150
t h e s u r g e o n 1 0 ( 2 0 1 2 ) 1 4 8 e1 5 0
oriented research should be interdependent rather than successive steps. The substantial challenges of incorporating such research into clinical care must be pursued if the potential of PRPs is to be realized.
15.
16.
references 17. 1. Maffulli N, Longo UG, Loppini M, Spiezia F, Denaro V. New options in the management of tendinopathy. Open Access J Sports Med 2010;1:29e37. 2. Maffulli N, Longo UG, Denaro V. Novel approaches for the management of tendinopathy. J Bone Joint Surg Am 2010;92: 2604e13. 3. Orchard JW, Best TM, Mueller-Wohlfahrt HW, Hunter G, Hamilton BH, Webborn N, et al. The early management of muscle strains in the elite athlete: best practice in a world with a limited evidence basis. Br J Sports Med; 2008. 4. Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent 2001;10:225e8. 5. Sanchez M, Anitua E, Orive G, Mujika I, Andia I. Platelet-rich therapies in the treatment of orthopaedic sport injuries. Sports Med 2009;39:345e54. 6. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg 2004;62:489e96. 7. Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care 2001;24:483e8. 8. Anitua E, Sanchez M, Orive G, Andia I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials 2007;28:4551e60. 9. Leahy AL. Shortages of general and specialist surgeons. Surgeon 2010;8:61e2. 10. Sanchez M, Azofra J, Anitua E, Andia I, Padilla S, Santisteban J, et al. Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc 2003;35: 1648e52. 11. Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year followup. Am J Sports Med 2010;38:255e62. 12. Castricini R, Longo UG, De Benedetto M, Panfoli N, Pirani P, Zini R, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med 2011;39:258e65. 13. de Vos RJ, Weir A, van Schie HT, Bierma-Zeinstra SM, Verhaar JA, Weinans H, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA 2010;303:144e9. 14. Schepull T, Kvist J, Norrman H, Trinks M, Berlin G, Aspenberg P. Autologous platelets have no effect on the
18.
19. 20. 21. 22.
23.
24.
25.
26. 27. 28.
29. 30. 31.
32.
33.
healing of human achilles tendon ruptures: a randomized single-blind study. Am J Sports Med 2011;39:38e47. Anitua E, Sanchez M, Nurden AT, Nurden P, Orive G, Andia I. New insights into and novel applications for platelet-rich fibrin therapies. Trends Biotechnol 2006;24:227e34. Fufa D, Shealy B, Jacobson M, Kevy S, Murray MM. Activation of platelet-rich plasma using soluble type I collagen. J Oral Maxillofac Surg 2008;66:684e90. Sharma P, Maffulli N. Basic biology of tendon injury and healing. Surgeon 2005;3:309e16. Wilson T, Sahu A, Johnson DS, Turner PG. The effect of trainee involvement on procedure and list times: a statistical analysis with discussion of current issues affecting orthopaedic training in UK. Surgeon 2010;8:15e9. O’Connor T, Papanikolaou V, Keogh I. Safe surgery, the human factors approach. Surgeon 2010;8:93e5. Mei-Dan O, Mann G, Maffulli N. Platelet-rich plasma: any substance into it? Br J Sports Med 2010;44:618e9. Dreyer JS. Assessing professionalism in surgeons. Surgeon 2010;8:20e7. Taylor B, Slater A, Reznick R. The surgical safety checklist effects are sustained, and team culture is strengthened. Surgeon 2010;8:1e4. Rineer CA, Ruch DS. Elbow tendinopathy and tendon ruptures: epicondylitis, biceps and triceps ruptures. J Hand Surg Am 2009;34:566e76. Rompe JD, Nafe B, Furia JP, Maffulli N. Eccentric loading, shock-wave treatment, or a wait-and-see policy for tendinopathy of the main body of tendo Achillis: a randomized controlled trial. Am J Sports Med 2007;35:374e83. Dohan Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol 2009;27:158e67. Hutchins GG, Grabsch HI. Molecular pathologyethe future? Surgeon 2009;7:366e77. Anitua E, Sanchez M, Orive G, Andia I. Delivering growth factors for therapeutics. Trends Pharmacol Sci 2008;29:37e41. Tidball JG. Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 2005;288: R345e53. Toomey DP, Murphy JF, Conlon KC. COX-2, VEGF and tumour angiogenesis. Surgeon 2009;7:174e80. Andia I, Sanchez M, Maffulli N. Tendon healing and plateletrich plasma therapies. Expert Opin Biol Ther 2010;10:1415e26. Creaney L, Hamilton B. Growth factor delivery methods in the management of sports injuries: the state of play. Br J Sports Med 2008;42:314e20. Engebretsen L, Steffen K, Alsousou J, Anitua E, Bachl N, Devilee R, et al. IOC consensus paper on the use of plateletrich plasma in sports medicine. Br J Sports Med 2010;44: 1072e81. Hing CB, Back DL. A review of intellectual property rights in biotechnology. Surgeon 2009;7:228e31.