04/12/2016. Disclosures. Bluetail Medical Group. Balloons, Boing-Boings, and Bioreactors. A Story of Knee Osteoarthritis

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1 Balloons, Boing-Boings, and Bioreactors A Story of Knee Osteoarthritis David Crane MD Bluetail Medical Group St. Louis, MO; Columbia, MO; Naples, FL Consultant for Arthrex Disclosures Bluetail Medical Group Non-operative sports medicine Percutaneous use of biologics Collaborate closely with surgeons Intra-operative use Post-operative use Over 24,000 patients treated to date 1

2 Biocellular Graft Use Follow FDA guidelines Minimal manipulation Point of care Most common treated disease Knee Osteoarthritis A blind doctor walks into a bar. And finds way more than he bargained for! 2

3 What I ve learned since fellowship There is a balloon What I ve learned since fellowship There is a boing boing What I ve learned since fellowship There is a bioreactor 3

4 These 3 roughly correlate to; Mechantransduction of the joint capsule And neurohormonal signalling And myotendionous support These 3 roughly correlate to; Hoop stress of the meniscus AND mechanotransduction of cartilage These 3 roughly correlate to; Synovium with: Growth Factors Progenitor Cells HA Chemokines, Cytokines, Interleukins MMP s 4

5 The Capsule Mechantransduction of the joint capsule Capsular Anatomy Capsular Anatomy 5

6 Capsular Anatomy Transverse section of the medial joint capsule above the level of the joint line: Layers I and II are fused anteriorly Layers II and III are fused posteriorly 6

7 Capsular Anatomy Capsular Anatomy Capsular Anatomy 7

8 Capsular Anatomy Capsular Anatomy The Meniscus and Cartilage Interface Hoop stress of the meniscus AND mechanotransduction of cartilage 8

9 Meniscus Anatomy Load and forces are distributed across a much larger surface area because of the menisci, which: (1) decrease focal contact pressure by increasing the contact area (2) protect the underlying articular cartilage. Resection of 15-34% of a meniscus may increase contact pressure by more than 350%. Normal knees have 20% better shock-absorbing capacity than meniscectomized knees. Insall JN, Scott WN, eds. Surgery of the Knee. 3rd ed. Philadelphia, Pa: WB Saunders Co; Rodkey WG. Basic biology of the meniscus and response to injury. Instr Course Lect : Vaziri A, Nayeb-Hashemi H, Singh A, Tafti BA. Influence of meniscectomy and meniscus replacement on the stress distribution in human knee joint. Ann Biomed Eng May 22. epub ahead of print. Three layers of the medial capsule: I. Crural fascia II. Superficial portion of the MCL III. Deep portion of the MCL including the meniscofemoral and meniscotibial extensions of the deep MCL. The Synovium and Fat Pad Synovium with: Growth Factors Progenitor Cells HA Chemokines, Cytokines, Interleukins MMP s 9

10 Why mixed results with cellular treatments? Many variables exist in product & delivery ere are many variables in product and delivery Platelet Activation Activation releases > 1500 proteins Unactivated platelets Alpha granules contain > 300 growth factors PDGF, VEGF, TGF-β1, bfgf, EGF Dense granules contain serotonin, histamine, Ca, adenosine and dopamine Activated platelets Growth Factors Anti-inflammatory Anti-degradative Analgesic Antimicrobial Modulate healing 10

11 Rationale for PRP in OA PRP Chondrocyte proliferation Chondrogenic markers Col 2, PG Synthesis Cartilage repair- PDGF and TGF MSC proliferation Inhibition of pain pathway Synovial HA Production Rationale for PRP in OA ACP vs HA ACP MMP-13 ACP HAS-2 expression in synoviocytes ACP cartilage synthetic activity } Compared with HA ACP acts to stimulate endogenous HA production and decrease cartilage catabolism Mechanism of Action for OA:ACP Cartilage and synovium co-culture model Sundman et al,

12 Mechanism of Action for OA:ACP Cartilage and synovium co-culture model Sundman et al., 2014 Mechanism of Action for OA:ACP Controlled Laboratory Study Investigated proliferation of Superficial Zone Protein (SZP) and cell proliferation at articular cartilage after contact with ACP Sakata et al, 2015 Level 1 Evidence PRP vs HA for OA Plasma based PRP versus HA: WBC preparation RCT patients 3 weekly injections 38% of patients receiving PRGF had 50% decrease in WOMAC pain score in 24 weeks vs 24% of patients receiving HA (p value 0.044) Sanchez et al,

13 IKDC Score VAS Pain Score 04/12/2016 Level 1 Evidence PRP vs HA for OA PRGF (Plasma Rich in Growth Factors- WBC) vs HA: 96 patients: PRGF 3 injections vs 1 injection HA PRP Superior to HA for up to 12 months Vaquerizo et al, 2013 Level 1 Evidence ACP vs. HA for OA ACP Superior to HA for up to 6 months Cerza et. al, 2012 Double Blind Level 1 ACP vs HA IKDC* 7 VAS Pain* ACP HA 3 2 ACP HA Visit Visit ACP Clinically Superior to HA at 6 months Cole BJ, Fortier L, Karas V, Merkow D, Stuckey A, Butty D, Verma N, Preliminary Data,

14 Concentration Concentration 04/12/2016 Double Blind Level 1 ACP vs HA TNF-α 20 IL-6* ACP 10 HA 8 ACP HA Visit Visit ACP Biologically Superior to HA at 6 months Cole BJ, Fortier L, Karas V, Merkow D, Stuckey A, Butty D, Verma N, Preliminary Data, 2014 Level 1 Data Meta-Analysis PRP HA Chang et al, 2014 Meta-Analysis WBC Effect 2015 Compared WBC concentration (LR vs LP) on efficacy Six RCT level 1 and three level 2 LP-PRP results in improved functional outcome- WOMAC and IKDC scores compared with HA and placebo when used for treatment of knee OA Adverse reactions to PRP may not be directly related to leukocyte concentration Riboh,

15 Systematic Review PRP for OA Six Level 1 Studies- 739 patients (817 knees) PRP showed significant clinical improvements compared to HA/saline up to 12 months WOMAC significantly better for PRP than HA 3-6 months (p=0.0008); 6-12 months (p=0.0062) 5 of 5 LP-PRP studies showed improvement! Filardo (LR-PRP) showed no improvement Meheux, 2015 Meta-Analysis of PRP Meta-Analyses Level IV systematic review Concluded that intra-articular PRP is a viable treatment for knee OA Particularly with early degenerative changes Shown to be more effective than other strategiesincluding HA or placebo treatments Campbell, 2015 Putting it all together. 15

16 BMC Bluetail Evaluation of Samples Samples from 11 patients All BMC drawn PSIS Same operator Same technique Evaluated at outside labs for cell ct & culture Previously validated shipping method 46 Pt. 1 at 48 hrs. BMC BMA CFU Colonies are easy to spot and count CFU 47 Pt. 1 at 72 hrs. BMC BMA Colonies become more difficult to distinguish from one another 48 16

17 Pt. 1 at 96 hrs BMC BMA Colonies blend together 49 Angel BMC Bone Marrow Aspirate 50 We found what we expected Cellular Concentrations 2% BMC/PPP Statistical Difference? 15% BMC/PPP PLT (k/μl) 145 ± 193 Yes, p = ± 732 WBC (k/μl) 1.90 ± 3.54 Yes, p = ± NE (k/μl) 0.16 ± 0.23 Yes, p = ± LY (k/μl) 0.95 ± 2.06 Yes, p = ± 9.32 MO (k/μl) 0.35 ± 0.69 Yes, p = ± 3.87 RBC (M/μL) 0.04 ± 0.01 Yes, p = < ± 0.65 TNC (k/ul) 2.22 ± 4.10 Yes, p = ± HPC (k/μl) 2.00 ± 4.47x10-4 No, p = ± 5.09x

18 But found something unexpected! There is IL-ra in BMC! IL-1ra Average ± StDev (pg/ml) 2% BMC/PPP 1693 ± % BMC/PPP ± 3877 Statistical Difference? Yes, p = <0.001 IL-1beta Average ± StDev (pg/ml) 2% BMC/PPP 8.8 ± % BMC/PPP 24.6 ± 35.0 Statistical Difference? Yes, p = IL-ra1 and BMC A ratio of IL-ra/IL-1β of :1 is sufficient to effect blockade of the IL-1 receptors, thereby alleviating the degenerative effects of IL-1 Wehling et al 2007 IL-1ra/IL-1beta Ratio Average 2% BMC/PPP % BMC/PPP Statistical Difference? Yes, p = Clinical Outcome of Bone Marrow Concentrate in Knee Osteoarthritis. Oliver, Bayes, Crane; J of Prolo: 2015 Prospective Case Review using Arthrex SOS 70 pts with II-IV Knee OA BMC and MM Adipose VAS and KOOS at 3 and 6 months Stat. significant improvement Pain Function QOL ADL s 18

19 Same Case Review carried out to 1 year 312 pts with II-IV Knee OA BMC and MM Adipose % Compliance Pre-tx 98.7 (305) 3 mo 96.2 (205) 6 mo 98.8 (170) 1 yr 100 (87) VAS and KOOS at 3,6 and12 months Stat. significant improvement in all measures Pre-surgical months months year 2.89 (-2.09) Angel BMC Knee OA SOS Data - VAS Pre-surgical months months year 73.6 (+19.2) Angel BMC Knee OA SOS Data - KOOS Pain Scale 19

20 Pre-surgical months months year 70.7 (+17.5) Angel BMC Knee OA SOS Data KOOS Symptoms Scale Pre-surgical months months year 78.6 (+18) Angel BMC Knee OA SOS Data - KOOS ADL s Pre-surgical months months year 51.3 (+17.7) Angel BMC Knee OA SOS Data KOOS Sports/Rec 20

21 Pre-surgical months months year 52.6 (+23.5) Angel BMC Knee OA SOS Data KOOS QOL Summary Biocellular grafts are showing continued promise as a viable, safe, effective, and cost effective way to treat mild to moderate and possibly some cases of severe OA in some cases. Choose your patients wisely Go out and do good in the world Thank You! David Crane MD dcranemd@gmail.com Bluetail Medical Group St. Louis, MO; Columbia, MO; Naples, FL 21