The Next Ankle Injury Trial Platelet Rich Plasma in Achilles Tendon Regeneration Joseph Alsousou AIM 2011
Outline 1) Introduction Tendon Rupture Platelet Biology PRP 2). Clinical Trial Trial design Methods Results Conclusion
Achilles tendon Mechanobiology
Acute TA rupture Prevalence: 18 per 100,000 per year Males >females Age: third and fourth decades Rupture location: 2 to 6 cm proximal to the tendon insertion Poor regenerative properties: Long rehabilitation periods are required many patients suffer from decreased performance and longstanding sequelae. Re-rupture rate 5-15% Need for cost effective regenerative therapy to Accelerate healing and return to normal function Reduce the re-rupture rate
Platelet granule release Alpha granules migrate to platelet periphery (a), where the plasma membrane blebs (b), and ruptures (c) Loss of electron density with rupture Polasek J. Lysosomal concept of platelet secretion - revisited. Eur J Haematol 1989. Suppl 50; Vol 43.
What is PRP? Platelet rich plasma is, by definition, a volume of the plasma fraction of autologous blood having a platelet concentration above baseline Marx, R.E., Carlson, E.R., Eichstaedt, R.M., Schimmele, S.R., Strauss, J.E., and Georgeff, K.R. Platelet rich plasma. Oral Surg Oral Med Oral Pathol. 1998; 85: 638.
Platelets & tendon: in vitro evidence II Human tendon cells in culture Platelet conditioned media stimulated proliferation, production of angiogenic factors Anitua et al 2005 Human tenocytes in culture Platelet conditioned media at two concentrations Stimulated cell proliferation, Collagen production Small increase in expression of matrix-degrading enzymes and endogenous growth factors de Mos et al 2008
Clinical Trial PATH = Platelet rich plasma in Accelerated Tendo- Achilles Healing a parallel double arm, Patient-blinded individually randomised controlled trial
Clinical Trial: Hypothesis PRP local application in the tendon rupture gap leads to accelerated healing and faster return to normal function than standard treatment alone.
Clinical Trial: Methods Dynamic USS selection tool, Kotnis et al 2007
Clinical Trial: conservative arm Dynamic USS is used to determine the gap size in equinus
Clinical Trial: Operative arm
Methods PRP Analysis Platelet Function Platelet count Functional outcome measures ATRS VISA-A FAOS Functional Ultrasound Elastography (FUSE) Statistical analysis with mixed linear regression model. Significance level 0.05. SPSS (PAWS 18.0)
PATH RCT: recruitment Operative arm Conservative arm Recruited 10 10 Age (mean±sd) 37.5 ± 8.8 41.7±7.1 Sex 5 males 5 females 6 males 4 females SAE 1 DVT (control) 1 partial-rerupture (control) Infection Nil Nil Average Rerupture gap 12.4mm 3.2mm Rupture location 4.8cm 4.1cm
PRP Function CD62p expression measured using flowcytometery n = 9 Before Thrombin Mean ± S.D. After Thrombin Mean ± S.D Activated Platelets % 7.43±6.5 68.42 ± 4.52 Resting Platelets % 92.57±4.1 31.58±3.82 100% 100%
PRP: Platelet count Mean ± S.D.; n = 9 Initial Blood (60 ml) PRP (8 ml) Yield PLT (x 1000/µL) 220.03 ± 48.58 1044.89 ± 302.00 4.74 ± 0.73 WBC (x 1000/µL) 5.49 ± 1.43 11.9 ± 7.01 2.16 ± 0.90 Hct (%) 32.87 ± 2.95 6.81 ± 1.59 N/A
Results: ATRS
Results: VISA-A
Results: FAOS FAOS: Pain, Symptoms, ADL, Sport and QOL categories
Results: FAOS - Pain Pain was significantly significant at week 3 onwards (p 0.009)
FAOS: Symptoms and ADL Symptoms ADL No statistical significance in Symptoms and ADL
FAOS: Sport and QOL Sport QOL
FUSE: Follow up Week 1 week4 Alsousou et al 2010
FUSE: displacement results Week 0 Week 6 Alsousou et al 2010
FUSE: Strain
Strain index Average Strain in A (Achilles tendon) Average Strain in B (Fat pad) Strain Index = A/B ratio compared to normal leg A 0.2 0.18 0.16 0.14 Patients index range Axial (1.2-5.3) Longtudinal (0.8-25) B 0.12 0.1 0.08 0.06 0.04 0.02 0 Alsousou et al 2010
FUSE: Results Strain index Strain index progression is significantly better in PRP group (p 0.031)
Summary Our preliminary findings show that PRP application in Achilles tendon rupture may lead to: faster regeneration Improve pain Faster return to function To achieve the desired statistical power in pragmatic settings, recruitment will continue in a multi-centre trial.
Acknowledgements Group members Dr. Paul Harrison, Prof. Alison Noble, Dr. Eugene McNally Mr. Robert Handley Prof. Keith Willett Funding Oxford Partnership BRC (NIHR) Joint Action (BOA) Commercial partner Arteriocyte Ltd