Regenerative Medicine in Sports Medicine – Panacea or Pandora’s Box?
Jonathan Finnoff, DO Professor, Department of PM&R, Mayo Clinic College of Medicine, Rochester, MN Medical Director, Mayo Clinic Sports Medicine Center, Minneapolis Team Physician: US Ski Team, Timberwolves, Lynx ©2014 MFMER | 3375858-1
DISCLOSURE I receive royalties from Demo’s Publishing for a book I edited. The book and it’s contents are not relevant to this presentation.
©2014 MFMER | 3375858-2
Case 1 • 32 y/o professional free skier with significant PMHx/PSHx of right ACL sprain x 2, ACL reconstruction x 2, medial meniscal tear x 2, medial meniscal debridement x 2
• Moderately severe tricompartmental osteoarthritis on the right knee • Pain 0-5/10, aching or sharp • Increased with impact activities
• Decreased with rest • Tried multiple non-operative treatments including physical therapy, bracing, nutritional supplements, NSAIDs, corticosteroid injections, viscosupplementation injections • Interested in additional non-surgical treatment options ©2014 MFMER | 3375858-3
Case 1 • Treatment?? • One potential treatment is regenerative medicine
©2014 MFMER | 3375858-4
NIH Definition of Regenerative Medicine • Rapidly growing multidisciplinary field involving the life, physical and engineering sciences that seeks to develop functional cell, tissue, and organ substitutes to repair, replace or enhance biological function that has been lost due to congenital abnormalities, injury, disease, or aging.
©2014 MFMER | 3375858-5
NIH Definition of Regenerative Medicine • Can include research in • Biomaterials/scaffolds • Identifying optimal cell sources (autologous, allogeneic, syngeneic, and xenogeneic cells, stem and progenitor cells, and genetically engineered cells) • Biomolecules (growth factors, differentiation factors, angiogenic factors)
©2014 MFMER | 3375858-6
Non-Operative Applications of Regenerative Medicine Sports Medicine • Two primary regenerative medicine (RM) products • Platelet Rich Plasma (PRP) • Autologous Stem Cells
©2014 MFMER | 3375858-7
Non-Operative Applications of Regenerative Medicine Sports Medicine • PRP is an autologous concentrate of platelets made from whole blood • Platelet concentration? • Other constituents? • WBC • RBC • Other
©2014 MFMER | 3375858-8
Non-Operative Applications of Regenerative Medicine Sports Medicine • Over time, has had many different names • Platelet rich concentrate • Platelet gel • Platelet releasate • Platelet rich fibrin • Platelet rich fibrin network • PRP-gel • PRP-clot • Plasma rich in growth factors • Autologous conditioned plasma • Etc.
©2014 MFMER | 3375858-9
Non-Operative Applications of Regenerative Medicine Sports Medicine • How is PRP made? • First centrifugation • 3 layers • Acellular plasma – platelet poor plasma (PPP). (Top layer) • Buffy coat – platelet concentrate, leukocytes, and serum. (Intermediate layer) • RBC’s (Bottom layer) • Second centrifugation • Only involves PPP and buffy coat (partial or complete) • Increases platelet concentration, +/- elimination of leukocytes and/or RBC’s (Dohan et al 2009) (http://wfisher11.files.wordpress.com/2010/03/fig2.jpg)
©2014 MFMER | 3375858-10
Non-Operative Applications of Regenerative Medicine Sports Medicine
©2014 MFMER | 3375858-11
Non-Operative Applications of Regenerative Medicine Sports Medicine • PRP is used to treat many musculoskeletal conditions • Chronic tendinopathy • Osteoarthritis (OA) • Muscle injuries • Ligament injuries
©2014 MFMER | 3375858-12
Non-Operative Applications of Regenerative Medicine Sports Medicine • Scientific rationale for treating tendinopathy with PRP • Why tendinopathy and not tendonitis? • Normal healing response following tendon injury: • Inflammatory phase (0-7 days) • Proliferative phase (1-6 weeks) • Maturation/Remodeling phase (6 weeks-1 year)
(Sharma 2005)
©2014 MFMER | 3375858-13
Non-Operative Applications of Regenerative Medicine Sports Medicine • During proliferative phase • Type III collagen synthesis peaks • Glycosaminoglycan synthesis increases • Increased water content • Hypercellular
(Sharma 2005) ©2014 MFMER | 3375858-14
Non-Operative Applications of Regenerative Medicine Sports Medicine • What are the histologic findings of chronic tendon injuries? • High type III collagen, glycosaminoglycan, and water content • Hypercellular • The same as the proliferative phase of healing • Histopathologic finding called angiofibroblastic hyperplasia
(Sharma 2005, Kraushaar 1999, Chang 2009) ©2014 MFMER | 3375858-15
Non-Operative Applications of Regenerative Medicine Sports Medicine
Angiofibroblastic Hyperplasia
Normal Tendon (Kraushaar 1999) ©2014 MFMER | 3375858-16
Non-Operative Applications of Regenerative Medicine Sports Medicine • Chronic tendon injury appears to be a failed healing response, stalled in the proliferative phase of healing
• Degenerative rather than inflammatory condition • Not an “-itis” (inflammatory), but rather an “-osis” (degenerative) • Since we don’t perform histologic analyses on most patients, use term “tendinopathy”, which is generic term for pathologic tendon • Since this is a degenerative condition, most appropriate treatment is to stimulate regeneration
©2014 MFMER | 3375858-17
Non-Operative Applications of Regenerative Medicine Sports Medicine • Scientific rationale for treating tendinopathy with PRP • Platelets = delivery vehicle of growth factors • Forms matrix for cell migration/tissue formation • Chemotactic for fibroblasts, monocytes, neutrophils, and mesenchymal stem cells • Mitogenic for fibroblasts and vascular smooth muscle cells • Stimulates collagen production • Initiates and regulates all 3 phases of tissue healing • Decreases blood loss and infection (Dennison 1994, Kawase 2003, Smith 2009)
©2014 MFMER | 3375858-18
Non-Operative Applications of Regenerative Medicine Sports Medicine • Basic science • Promotes tenocyte proliferation, and production of collagen, VEGF and HGF in culture • Increases strength of tendon repair in equine (FDS) and rat (Achilles) model (particularly when combined with bone marrow derived stem cells) • Mobilizes and attracts circulating stem cells • Promotes differentiation of tendon stem cells into active tenocytes
(de Mos 2010, Anitua 2005, Bosch 2010, Aspenberg 2004, Kajikawa 2008, Zang 2010, Morizaki 2010) ©2014 MFMER | 3375858-19
Non-Operative Applications of Regenerative Medicine Sports Medicine • Clinical Studies • 11 case series17,48,49,52,88,90,92,93,98,99,100 • 11/11 PRP = beneficial • 2 case-control studies44,89 • 2/2 PRP equivalent to rehabilitation • 10 prospective randomized trials16,45,46,47,50,51,91,94,95,96 • 3/10 PRP > needling • 2/10 PRP = needling • 2/10 PRP = ABI • 2/10 PRP > steroid
• 1/10 PRP = steroid
©2014 MFMER | 3375858-20
Non-Operative Applications of Regenerative Medicine Sports Medicine • Is PRP effective for chronic tendinopathy? • Yes, but… • Doesn’t seem to be better than other treatments such as dry needling or autologous blood injections • Outstanding questions • What is the optimal platelet concentration? • WBC/RBC good or bad?
©2014 MFMER | 3375858-21
Non-Operative Applications of Regenerative Medicine Sports Medicine • Scientific rationale for treating OA • OA micro-environment favors catabolism rather than anabolism • Increased concentrations of inflammatory mediators (TNFα, IL-6, IL1β, and various MMP) • Breakdown of cartilage extracellular matrix (e.g., type II collagen, aggrecan, decreased molecular mass of hyaluronic acid, etc) • Can adding growth factors to joints with OA via a platelet vehicle stimulate anabolism? • Are there anti-inflammatory properties to PRP that could reduce the inflammation associated with OA?
©2014 MFMER | 3375858-22
Non-Operative Applications of Regenerative Medicine Sports Medicine • Basic Science for OA • Synoviocyte/chondrocyte cultures mixed with PRP • Reduces TNFα and IL-6 concentrations • Increased IL-4 and IL-10 concentrations • Increased proteoglycan and type II collagen production • Decreased MMP-13 • Increased HAS-2 (hyaluronan)
(Braun 2014, Smyth 2013, van Buul 2011) ©2014 MFMER | 3375858-23
Non-Operative Applications of Regenerative Medicine Sports Medicine • Basic Science for OA • Compared to leukocyte rich PRP, leukocyte poor PRP • Less cell death • Less increase in inflammatory mediators (first 96 hours) • Larger increase in anti-inflammatory mediators • Red blood cells (RBC’s) also appear to be deleterious to synovium (Braun 2014, Smyth 2013, van Buul 2011) ©2014 MFMER | 3375858-24
Non-Operative Applications of Regenerative Medicine Sports Medicine • Clinical Studies • Case Series • 8/8 = good results • PRP vs HA • 7/7 = PRP better than hyaluronic acid • PRP vs Saline • 1/1 = PRP better than saline (Sah 2013, Sampson 2010, Halpern 2012, Cerza 2012, Wang-Saegusa 2010, Sanchez 2008, Kon 2010, Jang 2013, Kon 2011, Filardo 2012, Filardo 2010, Battaglia 2011, Gobbi 2013, Kon 2012, Torrero 2012, Spakova 2012, Patel 2013, Sanchez 2011)
©2014 MFMER | 3375858-25
Non-Operative Applications of Regenerative Medicine Sports Medicine • Is PRP effective for OA? • Yes • Typically lasts 12 months
©2014 MFMER | 3375858-26
Non-Operative Applications of Regenerative Medicine Sports Medicine • Mesenchymal stem cells (MSC) • Pluripotent stromal cells that can differentiate into a variety of cell types including myocytes, chondrocytes, fibroblasts, osteoblasts
©2014 MFMER | 3375858-27
(Sampson 2010)
Non-Operative Applications of Regenerative Medicine Sports Medicine • How do mesenchymal stem cells work? • Differentiate into appropriate cell type, replace degenerated or injured tissue • Paracrine effects = secrete cytokines and chemokines • Immunomodulation (Sampson 2010, Steinert 2012, Gupta 2012, Caplan 2007, Wynn 2004, Bashir 2014) ©2014 MFMER | 3375858-28
Non-Operative Applications of Regenerative Medicine Sports Medicine • Two primary locations to acquire MSC’s • Bone marrow • Fat
(Sampson 2010, Steinert 2012, Gupta 2012, Caplan 2007, Wynn 2004) ©2014 MFMER | 3375858-29
Non-Operative Applications of Regenerative Medicine Sports Medicine • How do we get bone marrow derived MSC’s? • Anesthetize the skin and subcutaneous tissue over posterior-superior iliac spine with lidocaine • Small scalpel incision • 11 gauge Jamshidi needle into the bone marrow • Aspirate 10 cc, then reposition needle • Aspirate from 6 different sites (60 cc total aspirate) ©2014 MFMER | 3375858-30
(Sampson 2010)
Non-Operative Applications of Regenerative Medicine Sports Medicine
(Sampson 2010)
©2014 MFMER | 3375858-31
Non-Operative Applications of Regenerative Medicine Sports Medicine
(Sampson 2010) ©2014 MFMER | 3375858-32
Non-Operative Applications of Regenerative Medicine Sports Medicine • Basic science • Circulating MSC migrate to area of tissue injury and form new tissue • Local inflammation stimulates upregulation of CXCR4 receptors on the cell surface • Stimulate angiogenesis through release of growth factors (SCF, GM-CSF, M-CSF) • Release chemokines to attract other MSC to the area • Release bioactive factors that stimulate local precursor cells to replicate and differentiate (Filardo et al. Am J Sports Med 2015, Cerza et al. Am J Sports Med 2012, Kon et al. Arthroscopy 2011)
©2014 MFMER | 3375858-33
Non-Operative Applications of Regenerative Medicine Sports Medicine • Basic science • Inhibit monocyte differentiation into dendritic cells that present antigens to T-cells (ie: decrease inflammation) • Inhibit T-cell proliferation and change their secretory profile such that they are anti- rather than pro-inflammatory • Suppress harmful effects of MMPs on vascular matrix and endothelial cells via TIMP-1
(Filardo et al. Am J Sports Med 2015, Cerza et al. Am J Sports Med 2012, Kon et al. Arthroscopy 2011)
©2014 MFMER | 3375858-34
Non-Operative Applications of Regenerative Medicine Sports Medicine • Basic science • Intra-articular injection of MSC & HA in rabbit knees with OA = less cartilage degeneration, subchondral bone formation, osteophyte formation, stimulated partial articular cartilage repair, increased type II collagen, and suppressed pro-inflammatory mediators • Intra-articular MSC injections in rat knees with OA = less pain, slowed progression of OA • Intra-articular MSC injections in sheep knees with OA = significant hyaline cartilage regeneration, improved peri-articular muscle contraction, slowed knee degeneration, NO ADVERSE EVENTS (Filardo et al. Am J Sports Med 2015, Cerza et al. Am J Sports Med 2012, Kon et al. Arthroscopy 2011)
©2014 MFMER | 3375858-35
Non-Operative Applications of Regenerative Medicine Sports Medicine • Basic science • The closer the origin is of the stem cell to the target tissue, the better the differentiation • Bone marrow derived stem cells have more chondrogenic potential than adipose derived stem cells • Stem cells from the synovial tissue of the knee have better chondrogenesis than bone marrow derived stem cells (Centeno 2014, Vidal 2008, Niemeyer 2010, Yoshimura 2007, Frisbie 2009, Bashir 2014)
©2014 MFMER | 3375858-36
Non-Operative Applications of Regenerative Medicine Sports Medicine • Clinical trials for OA • MSC surgery used successfully to treat knee OA for years in form of microfracture • Majority of current studies combine MSC injections with surgery • Injection studies either used expanded cultures (considered a drug in the US) or non-bone marrow derived MSC • Centeno et al: 2 bone marrow derived MSC expansion studies = improved symptoms, improved cartilage volume • Hauser et al. injected unconcentrated BMA into the hip, knee or ankle of 7 patients with OA, between 2-7 injections, all patients reported improved function, pain, and QOL (Centeno 2008, Centeno 2008, Connell 2009, Clarke 2011, Hauser 2013, )
©2014 MFMER | 3375858-37
Non-Operative Applications of Regenerative Medicine Sports Medicine • Clinical trials for OA • Hauser et al. injected unconcentrated BMA into the hip, knee or ankle of 7 patients with OA, between 2-7 injections, all patients reported improved function, pain, and QOL • Emadedin et al. – cultured expanded BMAC injections into 6 patients with knee OA = decreased subchondral bone marrow edema & increased cartilage thickness • Emadedin et al. – cultured expanded BMAC injections into patients with knee, ankle, or hip OA = reduce pain, improved function x 30 month follow-up • Davatchi et al. cultured expanded BMAC injections into 4 patients with knee OA = 6 month f/u 3 of 4 had significant improvement, 1 no improvement. 5 year follow-up, 3 still better than pre-injection, but not as good as at 6 months. (Emadedin 2012, Emadedin 2015, Davatchi 2011, Davatchi 2015)
©2014 MFMER | 3375858-38
Non-Operative Applications of Regenerative Medicine Sports Medicine • Are bone marrow derived MSC injections an effective treatment for OA? • Unknown, but… • Basic science and limited clinical research suggests MSC can improve pain and function associated with knee OA through a variety of mechanisms • Safe • No increased risk of cancer (1873 patients over 12.5 years, & 339 patients over 5 years) • No reported significant adverse events • 22/844 patients who received BMAC procedures for knee OA reported some localized pain and swelling and bone marrow aspiration site • 19,259 bone marrow aspirates in Great Brittain = 16 adverse events (0.08%)
(Centeno 2010, Hendrich 2009, Peeters 2013, Hatzistergos 2011, Bain 2005)
©2014 MFMER | 3375858-39
Case 1 Conclusion • Patient opted for PRP • Pre-procedure • No NSAIDS x 7 days (3 half lives) • Post-procedure • Rest x 2 days • Gradually resume normal activities as tolerated • Avoid NSAIDS x 2 weeks • Noted significant pain reduction by 4 weeks • Pain reduction still present at 1 year • Opted to repeat injections as needed in the future
©2014 MFMER | 3375858-40
Summary • Regenerative medicine harnesses the bodies ability to heal itself by delivering growth factors or stem cells to areas of degenerative or injured tissues. • The 2 most common types of regenerative therapies for non-operative sports medicine are PRP and MSC injections • The evidence suggests: • PRP is effective for OA • PRP is effective for tendinopathy, but may not be better than similar less expensive and less invasive treatments • Bone marrow derived stem cells are an exciting new frontier, and while the basic science research is promising, the clinical evidence is limited at this time.
©2014 MFMER | 3375858-41
Thank You
©2014 MFMER | 3375858-42
