1. Platelet Rich Plasma Musculoskeletal Clinical Indications and Evidence Dr Warren Leigh Orthopaedic Surgeon at Orthosports Millenium Institute of Sport

2. The Hype

3. What is PRP PRP is whole blood that is centrifuged to create an increased concentration of platelets with or without WBC’s This injected into damaged tissue This promotes healing of tissues Resulting in faster recovery and return to play

4. How does it work ? Platelets contain granules that store large numbers of “growth factors” Alpha granules released (activated) when platelets aggregate and adhere to a site of inflammation It is this activation of platelets and release of various growth factors that makes them special and is the key to enhancing tissue repair and healing Growth factors Interleukin-1, tumour necrosis factor, transforming growth factor and insulin growth factor

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6. How is PRP prepared

7. Is all PRP the same ? Every company has a different machine Creates PRP in a similar way but different concentrations of Platelets and can be white cell rich or poor

8. PRP Variations The study characterized the composition of single-donor PRP produced by 3 commercially available PRP separation systems Five healthy humans donated 100 mL of blood, which was processed to produce PRP using 3 PRP concentration systems (MTF Cascade, Arteriocyte Magellan, Biomet GPS III) The GPS III and Magellan concentrate leukocyte-rich PRP, which results in increased concentrations of WBCs, PDGF-αβ, PDGF-ββ, and VEGF as compared with the leukocyte-poor PRP from Cascade

9. Does it matter ? Increasing the platelet concentration within Leukocyte Reduced PRP preparations results in the delivery of more anabolic growth factors and less pro-inflammatory cytokines, but the biological effect on tendons is diminished metabolism as indicated by a decrease in the synthesis of both COL1A1 and COL3A1. This information suggests that minimizing leukocytes in PRP is more important than maximizing platelet numbers with respect to decreasing inflammation and enhancing matrix gene synthesis. This study suggests that reducing leukocytes to minimize catabolic signaling appears to be more important than increasing platelets A maximum biological threshold of benefit was demonstrated with regard to the number of platelets beyond which further increases in platelet concentration did not result in further anabolic up regulation.

10. PRP - Is the hype backed up by science ? Multiple lab studies showing good results Mixed results in studies usually with small numbers Comparing different PRP preparations Comparing different treatment regimes Increasing number of randomised controlled trials currently been published

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12. Lab Studies Majewski et al., accelerated healing of rat Achilles tendons has been reported in response to autologous condition serum. The autologous condition serum-treated tendons were thicker, produced more type I collagen, and had accelerated recovery of tendon stiffness Zhang et al. reported that PRP releasate in adult rabbits promoted the differentiation of tendon cells into active tenocytes that exhibited high proliferation rates and collagen production capabilities De Mos et al. Human tenocytes cultured in PRP showed increased cell proliferation and total collagen production Majewski M, Ochsner PE, Liu FJ, Fluckiger R, Evans CH. Accelerated Healing of the Rat Achilles Tendon in Response to Autologous Conditioned Serum. Am J Sports Med. 2009;37:2117–2125. doi: 10.1177/0363546509348047 de Mos M, van der Windt AE, Jahr H, van Schie HTM, Weinans H, Verhaar JAN, van Osch G. Can platelet- rich plasma enhance tendon repair? A cell culture study. Am J Sports Med. 2008;36:1171–1178. doi: 10.1177/0363546508314430 Zhang JY, Wang JHC. Platelet-Rich Plasma Releasate Promotes Differentiation of Tendon Stem Cells Into Active Tenocytes. Am J Sports Med. 2010;38:2477–2486. doi: 10.1177/0363546510376750

13. Roles of PRP in Musculoskeletal Medicine Chronic Tendinopathy Soft tissue injuries Cartilage Healing Early Arthritis Bone Healing Surgical Repair of Acute Soft-tissue Injuries Other e.g. Plantar fascititis

14. Chronic Tendonopathy Tendon healing proceeds through scar tissue formation, in a process that can take up to 1 to 2 years to mature. Infiltrating fibroblasts appear morphologically different than native tenocytes and the collagen is different than normal tendon This can result in pain and dysfunction PRP may rebalance the “healing” equation and move towards the formation of type I collagen rather than type III collagen that has inferior strength properties. Normally, type I collagen accounts for 65–80% of tendon collagen

15. Lateral Epicondylitis Dutch Randomized Controlled Trial with Level 1 evidence 100 patients – 51 PRP leukocyte enriched and 49 corticosteroid group Analyzed with VAS and DASH scores PRP significantly better at all time points (P<0.0001) Success was defined as 25% decrease on VAS or DASH without a reintervention At 2 year followup DASH and VAS of corticosteroid group had returned to normal level PRP group significantly improved and no complications

16. Lateral Epicondylitis Sixty five patients with lateral epicondylitis were included in the study and randomized into two groups Group A was treated with single injection of 1ml PRP with absolute platelet count of at least 1 million platelets/ mm(3). Group B was treated with single injection of 1ml (40mg) methyl-prednisolone All assessment parameters improved significantly in both the Groups at each follow up compared to baseline. At the end of three months group A showed significantly better improvement as compared to Group B PRP is a superior treatment option for longer duration efficacy

17. Systematic Review Ten of 374 identified studies were eligible This network meta-analysis provided additional information that PRP injection can improve pain and lower the risk of complications, whereas AB injection can improve pain, disabilities scores and pressure pain threshold but has a higher risk of complications.

18. Patella Tendinopathy Randomized controlled single-center trial, with 12 months of follow-up Inclusion criteria were chronic (≥6 months), unilateral, proximal patellar tendinopathy in a recreational or elite athlete confirmed by ultrasound (US); prior failed non-operative management that concluded ≥12 weeks prior to study entry; and ages 18 to 50 years Patients in the PRP group (n = 23) received 2 US-guided injections separated by 1 week and directed at the affected tendon portion Patients in the focused ESWT group (n = 23) received 3 treatments (2400 impulses at 0.17-0.25 mJ/mm per session) separated by 48 to 72 hours At 12 months a greater proportion of patients in the PRP group rated their response to treatment as good or excellent (PRP, 91.3% vs ESWT, 60.8%; P = 0.035), although at earlier follow-ups the groups did not differ

19. Patella Tendinopathy 43 patients with chronic patellar tendinopathy 2 injections of PRP 5 mls 2 weeks apart Follow up scores at 2, 6 and at least 36 months the VISA-P score increasing from 44.1 ± 15.6 at baseline to 61.4 ± 22.2 at two months, 76.6 ± 25.4 at six months, and 84.3 ± 21.6 at four years' follow-up. The same trend was confirmed by the other scores used 80 % of the patients were satisfied and returned to previous sports activities.

20. Patella Tendinopathy 36 patients treated with PRP injections 14 had been treated before with cortisone, ethoxysclerol, and/or surgical treatment (group 1), while the remaining patients had not been treated before (group 2) Followed up using VISA-P and VAS scores After PRP treatment, patients with patellar tendinopathy showed a statistically significant Patients who were not treated before with ethoxysclerol, cortisone, and/or surgical treatment showed the improvement

21. Achilles Tendinopathy A total of 83 tendons (73 patients, 59 males and 14 females; age 43±17.5 years) affected by non-insertional CRAT were treated with single PRP injection These were evaluated with the Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaire, Blazina score and satisfaction index at baseline at intervals of 3 weeks, 3 months, 6 months. Seventy-six tendons (91.6%) were rated as satisfactory and patients would repeat the treatment. Seven tendons (8.4%) were classified as unsatisfactory at the 6 months follow-up and underwent a second PRP injection. In addition to this, patients reported no Achilles tendon rupture.

22. Achilles Tendinopathy Thirty patients with chronic Achilles tendinosis who did not respond to a minimum of 6 months of traditional non-operative treatment modalities were treated with a single ultrasound guided injection of PRP The average AOFAS score increased from 34 (range, 20 to 60) to 92 (range, 87 to 100) by 3 months after PRP treatment and remained elevated at 88 (range, 76 to 100) at 24 months post-treatment. Pretreatment imaging abnormalities present in the Achilles tendon on MRI and ultrasound studies resolved in 27 of 29 patients at 6 months post-treatment. Clinical success was achieved in 28 of 30 patients

23. TA and PRP Tendon tissue biopsy samples were obtained from 20 patients with ruptured Achilles tendon by means of ultrasound-guided needle biopsies from the healing area of the Achilles tendon 6 weeks after treatment with PRP or placebo controls (10 patients each) Cellularity and glycosaminoglycans content were significantly higher in PRP- treated tendons than in controls Fiber structure of the tissue was significantly better in the PRP group than in the control tissue The findings reveal that locally applied PRP enhanced the maturity of the healing tendon tissues by promoting better collagen I deposition, decreased cellularity, less vascularity, and higher glycosaminoglycan content when compared with control samples

24. Hamstring Tendon Injuries PRP injection into acute hamstring injuries Randomized controlled trial – Level 2 evidence 28 patients Randomized to PRP and Rehabilitation or Rehabilitation alone. PRP group single injection Return to sport in PRP group was 26.7 +/- 7 days compared with 42.5 +/- 20.6 days in the standard rehabilitation group NO difference in pain interference score

25. Cartilage Healing PRP contains growth factors important in cartilage healing and repair IGF and PDGF is important in cartilage healing

26. Equine cartilage Intra-articular PRP was evaluated in seven horses with severe degenerative joint disease The animals were given three injections at 3-week intervals with a follow-up at 1 year. Clinical improvement was noted at 2 months and persisted at 8 months with no adverse clinical affects Carmona J, Arguelles D, Climent F, Prades M, Soler R, Vidal F, Orozco L. Autologous platelet-rich plasma injected intraarticularly diminished synovial effusion and degree of lameness in horses affected with severe joint disease. Lyon: Annual Scientific Meeting of the European College of Veterinary Surgeons; 2005.

27. How do you manage this ?

28. Early OA Knee Randomized controlled trial Level 1 Evidence 120 patients with gonarthrosis 60 given 4 intra-articular injections of PRP 60 given 4 intra-articular injections of HA (hyaluronic acid) Evaluated at 4, 12 and 24 weeks with WOMAC scores WOMAC significantly improved scores at all time points and at 24 weeks WOMAC of 65.1 HA and 36.5 PRP with P<.001 HA group did worse with grade 3 arthritis PRP group no difference with grade of arthritis PRP for Grade 3 arthritis 74.85 HA vs 41.2 in PPR group

29. Knee OA and PRP 65 patients suffering from OA PRP injection followed p for 1, 3, 6, 9 and 12 months VAS score decreased from 7.4 to 4.2 at 6 months IKDS score significantly improved during treatment Statistically significant negative correlation for patient age and PRP potential in the VAS and IKDC score Presence of PFJ had worse results Worse Kellgren-Lawree grade of OA was associated with less clinical effect and accelerated time for relapse of symptoms

30. Systematic Review 9 of 551 studies were eligible from Medline and Scopus In short-term outcomes (≤1 year), PRP injection has improved functional outcomes (WOMAC total scores, IKDC score and EQ-VAS) when compared to HA and placebo

31. Early Arthritis Arthroscopy Review – Systematic Review – 3 meta analyses met criteria PRP led to significant improvements in patient outcomes at 6 months after injection, and these improvements were seen starting at 2 months and were maintained for up to 12 months. It is unclear if the use of multiple PRP injections, the double-spinning technique, or activating agents leads to better outcomes. Patients with less radiographic evidence of arthritis benefit more from PRP treatment.

32. Hip OA and PRP Hip OA 40 patients meet inclusion criteria 9 patients obese, 17 overweight and 14 had normal weight Tonnis 3 grades in 70 % of hips WOMAC pain scores significantly reduced at 6-7 weeks and at 6 months VAS reduced at 6-7 weeks and 6 months Results showed BMI, gender and radiographic severity were not significantly related to pain relief.

33. Shoulder PRP

34. Adjuvant to Surgery - Shoulder A systematic review, meta-analysis, and meta-regression of all Level I and Level II studies comparing the clinical or structural outcomes, or both, after rotator cuff repair with and without platelet-rich product (PRP) supplementation Eleven studies were included in this review and a maximum of 8 studies were used for meta-analyses according to data availability no statistically significant differences in overall gain in outcome scores or retear rates between treatment groups. Gain in Constant scores was significantly increased when PRPs were applied at the tendon-bone interface when compared with application over the top of the repaired tendon Retear rates were significantly decreased when PRPs were used for the treatment of tears greater than 3 cm in anterior-posterior length using a double-row technique

35. Compared to another review Cochrane Library, PubMed, and EMBASE databases for randomized controlled trials comparing the outcomes of arthroscopic rotator cuff surgery with or without the use of platelet-rich plasma Eight randomized controlled trials were included, with the sample size ranging from 28 to 88 meta-analysis does not support the use of platelet-rich plasma in the arthroscopic repair of full-thickness rotator cuff tears over repairs without platelet-rich plasma because of similar re-tear rates and clinical outcomes

36. Bone Healing and PRP A monocortical long-bone defect in the radial diaphysis of 24 New Zealand white rabbits was filled either with autologous cancellous graft as a control group or with autologous cancellous graft combined with autologous PRP A significant improvement in bone healing was observed histomorphometrically in the PRP group in the central area of the defect zone (p <0.01) as well as the cortical defect zone (p <0.01). The radiological findings were in accordance with the histomorphometrical results The combination of PRP and autologous cancellous bone grafts improved bone healing significantly compared to the sole application of autologous bone

37. Adjuvant to Surgery - Knee Systemic Review from Arthroscopy May 2015 11 studies including 516 patients (266 ACL reconstructions using PRP and 250 ACLs without PRP) Six studies reported a statistically significant difference (4 studies) or tendency toward faster graft maturation in the platelet group (2 studies). One study found no differences. Regarding tunnel healing/widening, 1 study showed faster healing in the PRP group and 5 studies showed no differences between the 2 groups. Considering clinical outcomes, 1 study showed better clinical outcomes with PRP use and 5 studies showed no benefits with the use of PRP. ACL graft maturation, there is promising evidence that the addition of PRP could be a synergic factor in acquiring maturity more quickly than grafts with no PRP, with the clinical implication of this remaining unclear. Regarding tunnel healing, it appears that there is not an improvement with the addition of PRP

38. Knee Chondral Lesions and Microfracture 49 patients over 40 years of age with arthroscopic microfracture for cartilage lesions sized less than 4 cm 2 25 with arthroscopic microfracture 25 with arthroscopic microfracture and PRP VAS, IKDC pre op and post op at 1, 6, 12 and 24 months 10 patients had 2 nd look arthroscopy At 2 years both groups improved but PRP had significantly better results (p<0.012) VAS PRP Pre op 8.1 to post op 2.3 and Control Pre Op 8.5 to 3.4 post op

39. Plantar fasciitis Forty patients (23 females and 17 males) with unilateral chronic plantar fasciitis The cortisone group had a pretreatment average AOFAS score of 52, which initially improved to 81 at 3 months post treatment but decreased to 74 at 6 months, then dropped to near baseline levels of 58 at 12 months, and continued to decline to a final score of 56 at 24 months the PRP group started with an average pretreatment AOFAS score of 37, which increased to 95 at 3 months, remained elevated at 94 at 6 and 12 months, and had a final score of 92 at 24 months.

40. How far can PRP go ?

41. How many injections are needed ? Sixty-two patients received one (n = 36) or more (n = 26) PRP injections. The mean baseline to 6-month follow-up scores of the PREE and qDASH questionnaires improved significantly from 54.0 to 23.0 and 50.3 to 20.7, respectively The mean baseline visual analogue scale score improved from 62.5 to 82.9 by 6 months post-injection. These outcomes did not significantly differ between the patients who received varying numbers of injections

42. 3 Injections Patellar Tendinopathy – 28 athletes 17 professional 11 semi—professional 3 consecutive injections 1 week apart, with the same PRP preparation used Victorian Institute of Sport Assessment-Patella (VISA-P) score, visual analog scales (VAS) for pain, and Lysholm knee scale before surgery and after return to practice sports Tendon healing was assessed with MRI at 1 and 3 months after the procedure The average pre-procedure VISA-P, VAS, and Lysholm scores improved from 39 to 94 (P <.001), 7 to 0.8 (P <.0001), and 60 to 96 (P <.001), respectively, at the 2- year follow-up. Twenty- one of the 28 athletes returned to their presymptom sporting level at 3 months (range, 2-6 months) after the procedure Follow-up MRI assessment showed improved structural integrity of the tendon at 3 months after the procedure and complete return to normal structural integrity of the tendon in 16 patients (57%)

43. Future Need more randomized controlled trials Treatment regime – 1 injection vs 3 injections Timing of the injections What type of PRP – WCC rich/poor Activated or not activated Role in adjuvant to surgery

44. Conclusion PRP has good clinical results across a number of conditions Treatment of choice for chronic tendinopathy Soft tissue injuries have earlier return to play Good for early arthritis of the knee and potentially other joints Adjuvant to surgery is an evolving field

45. Thank you