Conflicts of Interest  I have no conflicts of interest regarding this presentation

Ramon Ylanan MD CAQSM Team Physician University of Arkansas Advanced Orthopeadic Specialists

Goals  Background Healing Response  The Basic Science  Uses  Evidence Based  Summary

Goals  Background Healing Response  The Basic Science  Uses  Evidence Based  Summary

Background  What is PRP (Platelet Rich Plasma)? Biologic, “regenerative biomedicine” Concentrated platelets ○ Ideally 3-8X Processed from autologous, whole blood Provides “Supra-physiologic” concentrations of growth factors  No universal definition of what constitutes PRP vs PPP  Ideal concentration is opinion based

Background  How is it made? Centrifuged whole blood Coagulation inhibitors may be used ○ Previous issues with bovine inhibitors Platelet activators may be used Volume produced depends on which system used Applied in either ○ Injectable form ○ Solid, matrix form

Background SystemPlatelet Conc.ActivatorCentrifuge timeLeukocytesBlood Volume needed (ml) PRP volume Arthrex ACP2-3XNo (use within 30 minutes) 1, 5 min stepNo93 Biomet GPS III3-8xAutologous thrombin and calcium chloride 1, 15 minute stepYes Cascade1-1.5xCalcium chloride1, 6 minute for PRP 2, 15 minute for fibrin matrix No SmartPReP24-6xBovine thrombin or calcium 2, 14 minute stepYes PRGF2-3xCalcium chloride1, 8 minute stepNo Magellan3-7xCalcium chloride2, 4-6 minute stepsYes30-606

Goals  Background Healing Response  The Basic Science  Uses  Evidence Based  Summary

Background: The Healing Response  Inflammatory phase First week after injury ○ Hemostasis  recruitment of macrophages and fibroblasts  Proliferative phase Within first 2 days to 2 weeks ○ Formation of extra-cellular scaffold  Maturation/remodeling phase Up to first year ○ Type 1 collagen replacing scaffold

Background: The Healing Response  Growth factors IGF-1  early inflammatory phase ○ Enhances collagen and matrix synthesis TGF-B  pro-inflammatory ○ Enhances matrix and collagen synthesis, angiogenesis PDGF  facilitates proliferation of other growth factors ○ Attracts stem cells and contributes to remodeling

Background: The Healing Response  Growth factors VEGF  peaks after inflammatory phase ○ Promotes angiogenesis and neo- vascularization b-FGF  angiogenesis, cell migration, creates collagenase, production of granulation tissue

Background: The Healing Response  What does PRP bring to the healing table? Alpha granules ○ The storage packets of growth factors ○ Each platelet contains granules ○ The de-granulation releases the growth factors needed to augment healing

Background: The Healing Response  Alpha granules Theory that activators will increase de- granulation ○ Reason why some systems include external activators Some studies show injured collagen fibers will stimulate de-granulation as well

Goals  Background Healing Response  The Basic Science  Uses Limit to Muscle, Tendon, Ligament  Evidence Based  Summary

The Basic Science  Horse tendons Schnabel et al. Culture in PRP vs other blood products Higher anabolic gene expression in PRP  Human tenocytes de Mos et al. PRP vs. PPP ○ PRP increase in matrix degrading enzymes (faster recovery)

The Basic Science  Rabbit skeletal muscle stem cells Gates et al. Increased expression of myogenic activity  Mesenchymal stem cells Mishra et al. Buffered in PRP, increased proliferation

Goals  Background Healing Response  The Basic Science  Uses Limit to Muscle, Tendon, Ligament  Evidence Based  Summary

Uses: Muscle  Hammond et al (2009) Animal study (rats) Tibialis anterior strain ○ large strain vs small strain PRP shortened healing by days in small strain group Little change in large strain group

Uses: Tendon  Lots of studies Lateral epicondylitis Patellar tendinopathy Achilles tendinopathy Rotator Cuff tendinopathy

Uses: Lateral Epicondylitis

 Mishra and Pavelko (2006) One of the most cited articles Chronic, refractory lateral epicondylitis 15 patients, failed conservative measures Single PRP injection ○ control was bupivicaine

Uses: Lateral Epicondylitis  Mishra and Pavelko (2006) Measures VAS and Mayo elbow scores at 2, 6 and 25 months Outcomes ○ 2 months  60% vs 16% improvement (P=.001) ○ Final f/u  93% reduction in pain, no complications ○ 60% of control group withdrew for other treatment

Uses: Lateral Epicondylitis  Peerbooms et al (2010) RCT, Level 1 data ○ Only true RCT to date 100 patients (51 PRP:49 CSI) 1 yr f/u ○ 73% success in PRP group ○ 49% in CSI group

Uses: Patellar Tendinopathy

 Human Data is limited  Filardo et al (2010) Non-RCT, N=31 Serial PRP + PT (15) vs. PT alone (16) 3 PRP, 2 weeks apart with eccentric strengthening PRP group ○ Improved in all measures ○ Continued to improve at 6 months ○ Higher improvement in sports activity

Uses: Patellar Tendinopathy  Kon et al (2009) Prospective, pilot study (no control) 3 PRP injections, 15 days apart 6 month f/u ○ 70% stated complete or significant improvement ○ 80% satisfied with results

Uses: Achilles Tendinopathy

 de Vos et al (2010) Double blinded, placebo control, RCT N=54, chronic Achilles tendinopathy 2 months of symptoms Excluded if had previous eccentric strengthening program 27 PRP, 27 isotonic saline, US guidance used

Uses: Achilles Tendinopathy  de Vos et al (2010) Double blinded, placebo control, RCT N=54, chronic Achilles tendinopathy Both did 12 week supervised eccentric program f/u at 6, 12, 24 weeks -Both groups improved, No difference found -Used bupivicaine for anesthetic -? Inhibit effectiveness

Uses: Rotator Cuff  Mostly as surgical repair adjuncts  Studies have been +/- Only one major prospective, Level 1 randomized research Weber et al (2010) ○ No major difference in structural integrity compared with control Repair with PRP vs repair without PRP

Uses: MCL  No human studies  Letson and Dahners (1994) Rat MCL injury ○ Injected with PDGF  73% (+/- 55%) stronger than contralateral controls  Human results anecdotal 2-3 weeks earlier than anticipated

Goals  Background Healing Response  The Basic Science  Uses Limit to Muscle, Tendon, Ligament  Evidence Based  Summary

What does the evidence say?  Increasing number of basic science and animal studies  Paucity of human trials No standardization of treatment Anecdotally improves recovery by 2 weeks  1 vs. multiple injections 1 seems to be effective, fenestration may help The multiple injection “protocol” is without consistency

What does the evidence say?  When is best time to administer in acute setting? Chan et al  ○ Better results at day 7 than day 3 ○ At elite level, who waits 7 days?

What does the evidence say?  Exercise Early ROM can be helpful Early light aerobic activity can be helpful I begin eccentric strengthening program as early as tolerated Goal is RTP by 3 weeks

What does the evidence say?  NSAIDs Most hold for minimum of 10 days prior Not proven to inhibit, but possible ○ Don’t withhold ASA if cardio-protective  Ideal platelet concentration 600K-1mil per ml (no evidence for that)

What does the evidence say?  WBC in preparation Inhibit or help? ○ Help  anti-infective property ○ Inhibit  inhibitory effects on inflammatory mediators

What does the evidence say?  Local anesthetics and corticosteroids Carofino et al (2012) ○ Co-administration decreased PRP effectiveness  External platelet activators No consensus on if or when

What does the evidence say?  MSK US guidance improves results 0232T tracking CPT code ○ Includes imaging assisted guidance ○ I use it with every PRP

Where are we with PRP?

Summary  Limited human research  Tendon>Muscle>Ligament for now  Limit NSAID use around the injection  Don’t add local anesthetic  Still more to learn  Medicare tracking code now  IOC had banned it in 2010, removed in 2011

References  Nguyen RT, Borg-Stein J, McInnis, K. Applications of Platelet-Rish Plasma in Musculoskeletal and Sports Medicine: An Evidence-Based Approach. PM R 2011;3:  Schnabel LV, Mohammed HO, Miller BJ, et al. Platelet rich plasma (PRP) enhances anabolic gene expression patterns in flexor digitorum superficialis tendons. J Orthop Res 2007;25:  de Mos M, van der Windt AE, Jahr H, et al. Can platelet-rich plasma enhance tendon repair? A cell culture study. Am J Sports Med 2008; 36:  Mishra A, Tummala P, King A, et al. Buffered platelet-rich plasma enhances mesenchymal stem cell proliferation and chondrogenic differentiation. Tissue Eng Part C Methods 2009;15:  Gates CB, Karthikeyan T, Fu F, Huard J. Regenerative medicine for the musculoskeletal system based on muscle-derived stem cells. J Am Acad Orthop Surg 2008;16:  Hammon JW, Hinton RY, et al. Use of autologous platelet-rich plasma to treat muscle strain injuries. Am J Sports Med 2009;37:  Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med 2006;34:  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 cortico- steroid injection with a 1-year follow-up. Am J Sports Med 2010;38:  Filardo G, Kon E, Della Villa S, Vincentelli F, Fornasari PM, Marcacci M. Use of platelet-rich plasma for the treatment of refractory jumper’s knee. Int Orthop 2010;34:  Kon E, Filardo G et al. Platelet-rich plasma: New clinical application: A Pilot study for treatment of jumper’s knee. Injury 2009;40:  de Vos RJ, Weir A, van Schie HT, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: A randomized controlled trial. JAMA 2010;303:  WeberSC,PariseC,KatzSD,WeberSJ.Platelet-richfibrin-membrane in arthroscopic rotator cuff repair: A prospective, randomized study. Proc Am Acad Orthop Surg 2010;11:345.  Weber SC, Katz SD, Parise C, Weber SJ. Platelet-rich fibrin matrix in the management of arthroscopic repair of the rotator cuff: A prospec- tive, randomized study (SS-07). Arthroscopy 2010;26:e4.  Carofino B, Chowaniec Dm, et al. Corticosteroids and local anesthetics decrease positive effects of platelet-rich plasma: an in vitro study on human tendon cells. Arthroscopy May;28(5):711-9  Engebreatsen L, Steffen K et al. IOC consensus paper on the use of platelet-rich plasma in sports medicine. BJSM 2010;44: