2/6/2019. Can We Do Better? Tissue Engineering. Tissue Engineering. Tissue Engineering. Mechanism. Why did repair of the ACL fail?

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1 DISCLOSURES Bridge-Enhanced Repair: From Concept to Clinical Trials Martha M. Murray, MD Professor of Orthopaedic Surgery Boston Children s Hospital Harvard Medical School I, Martha Murray, have relevant financial relationships to be discussed, directly or indirectly, referred to or illustrated with or without recognition within the presentation as follows: Founder, MIACH Orthopaedics, Inc Inventor on Patents owned by BCH about the BEAR technology Research Funds Received from: Translational Research Program at Boston Children s Hospital NIH/NIAMS Children s Orthopaedic Surgery Foundation Children s Sports Medicine Foundation National Football League Players Association Surgical Treatment for Injury Surgical Treatment for Injury - 50 to 90% Failure Rate - 2 RCTs: Results no better than non-op treatment. Procedure abandoned. Torn Repair: Sutures used to reapproximate torn ligament ends: Torn Repair: Sutures used to reapproximate torn ligament ends: Abandoned. Surgical Treatment for Injury Outcomes of Reconstruction Good but not perfect Torn Repair: Sutures used to reapproximate torn ligament ends: Abandoned. Reconstruction: Old is removed and replaced with a tendon graft. Pain and loss of strength from taking the graft 1 Patients report persistent pain and stiffness of the knee 2 Return to preinjury level of activity only 63% 3 70% risk of arthritis 15 years later 7 50% increase in MI later in life 8 2. Wasserstein et al, OAC, 2015, 3. Ardern, Webster et al, BJSM, March 2011, 4.Kaeding et al, AJSM 2016, 5. Webster et al, AJSM 2016, 6. Hanypsiak et al, Von Porat et al, 2004, 8. Meehan et al, Amer J Cardiol,

2 Can We Do Better? Tissue Engineering Sponge or scaffold Tear Reconstruction: Removal and Replacement Innovation? Tear Reconstruction: Removal and Replacement Tissue Engineering Tissue Engineering Growth Factors Scaffold Growth Factors Cells Tear Reconstruction: Removal and Replacement Tear Reconstruction: Removal and Replacement Repair + biologic boost? Mechanism Mechanism Why did repair of the fail? Why did repair of the fail? Other tissues heal on their own or with suture repair, skin, Achilles tendon, etc. Other tissues heal on their own or with suture repair, skin, Achilles tendon, etc. 2

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4 Mechanism: vs Injury Response Mechanism: vs Injury Response Cell/Vessel Yes 1 Yes 3 Proliferation Cell Migration Yes 1 Yes 2,3 Cell/Vessel Yes 1 Yes 3 Proliferation Cell Migration Yes 1 Yes 2,3 Collagen Production Bridge forms in wound site Yes 1 Yes 4 1. Frank et al, JOR Murray et al, JOR Murray et al, JOR 2001, Spindler et al, JOR Murray et al, JBJS 2000 Collagen Production Bridge forms in wound site 1. Frank et al, JOR Murray et al, JOR Murray et al, JOR 2001, Spindler et al, JOR Murray et al, JBJS 2000 Mechanism: vs Injury Response Mechanism: vs Injury Response Cell/Vessel Yes 1 Yes 3 Proliferation Cell Migration Yes 1 Yes 2,3 Cell/Vessel Yes 1 Yes 3 Proliferation Cell Migration Yes 1 Yes 2,3 Collagen Production Bridge forms in wound site Yes 1 Yes 4 1. Frank et al, JOR Murray et al, JOR Murray et al, JOR 2001, Spindler et al, JOR Murray et al, JBJS 2000 Collagen Production Bridge forms in wound site Yes 1 Yes 4 Yes 1 NO 5 1. Frank et al, JOR Murray et al, JOR Murray et al, JOR 2001, Spindler et al, JOR Murray et al, JBJS

5 FGF-2 Expression: One week Mechanism Why no filling of the wound site for the??? Fibrin in Normal Wound Healing Inside the joint Intra-articular Plasminogen Thrombin Plasmin Fibrinogen Fibrin Degradation Products Thrombin Plasmin Fibrinogen Fibrin Degradation Products Inside the joint after injury Inside the joint after injury Intra-articular Plasminogen upa Intra-articular Plasminogen upa Thrombin Plasmin Fibrinogen Fibrin Degradation Products Fibrinogen Thrombin Fibrin Plasmin Degradation Products Harrold, 1961, Brommer et al, 1992, Rosc et al

6 Mechanism: Premature Loss of Provisional Scaffold Design to Address Mechanism Mechanism: Bridging of wound site is required for healing. Implant a stable bridge Maintains the ability to stimulate cell ingrowth and proliferation Resistant to synovial fluid degradation Combine with mechanical suture repair for a Bridge-Enhanced Repair Murray et al, JBJS, Design: Carrier Hypothesis testing: Fit-for-purpose model Designed to absorb 5X its weight in blood Stimulates blood to clot/solidify Activates platelets Made of same proteins found in normal Resorbs 8 weeks after implantation Bridge-Enhanced Repair (BEAR) scaffold Large animal study Bilateral transection One side: suture + scaffold +platelets Contralateral: suture alone Outcomes: Gross anatomy MRI Biomechanics Histology Murray et al, JOR, 2006; Joshi et al, AJSM 2009 Preclinical Testing In Vivo: 3 months Bridge-Enhanced Repair vs Reconstruction Porcine model, 15 weeks 0.4 B io -Enhanced AC L R epair AC L R econstruction AC L Transection Intact Suture Only Suture + platelets + carrier Joshi et al, Amer J Sports Med, 2009 % of Intact * * * Y ield Load M ax Load Linear stiffness Vavken, Fleming et al, Arthroscopy,

7 Mechanical Properties: One Year Later Cartilage changes 1 % of Intact Transection Reconstruction Bridge-Enhanced Repair 0 Yield Load Stiffness Murray and Fleming, AJSM 2013 Transection Reconstruction Bridge-Enhanced Repair Moving to Patients FDA permission for safety study (IDE) Issued Oct 2014 BEAR I Trial started Feb 2015 First-in-Human Study: BEAR I Surgeon: Lyle Micheli, MD Cohort Study 10 patients Bridge-Enhanced Repair (BEAR) 10 patients reconstruction 18 to 35 YO BEAR I Trial: Safety Outcomes Infections/Rejection: None No difference in effusion or pain No significant ROM deficit in either group First Bridge-Enhanced Repair patient Pre-Op 3 months 6 months 12 months 24 months Murray, Flutie, Kalish, Fleming, Ecklund, Proffen and Micheli, OJSM, Nov KT within 1 mm of contralateral normal side 7

8 BEAR I: Primary Outcomes at 2 Years BEAR I: Primary Outcomes at 2 Years IKDC Subjective scores BEAR was 7 points higher than reconstruction Similar to age matched norms 2 or contemporary uninjured cohort 3 KT-1000 Testing (AP Knee Laxity) SSD similar in both groups Similar to other trials for R Range 1 to 3 mm SSD 1,2 3.3 KT-1000 at 2 yrs Post-Op R BEAR Uninjured Refs: 1. Cox et al, AJSM Anderson et al, AJSM, Fleming et al, AJSM Gifstad et al, Holmm et al, Liden et al, Ahlden et al, Sajovic et al, Webster et al, Zaffagniniet al, 2. Akelman AJSM BEAR I Trial: Hamstring Strength Hamstring strength recovery faster in the Bridge-Enhanced Repair (BEAR) group. BEAR I Results No infection, rejection, failure 2 Year Results: BEAR subjects had Good patient reported outcomes Good knee stability Better hamstring strength BEAR patient hiking at 6 months post-op BEAR I Results No infection, rejection, failure 2 Year Results: BEAR subjects had Good patient reported outcomes Good knee stability Better hamstring strength But what about our adolescent patients? High risk for graft failure High risk for PTOA Can we help them? BEAR patient at three years after surgery. No swelling or pain at the end of a 70.3 mi Ironman. BEAR patient hiking at 6 months post-op Age (Years) 8

9 BEAR II Trial PI: Dr Yi-Meng Yen Single Center (BCH) Randomized Control Trial Three surgeons: Yen, Micheli, Dennis Kramer BEAR vs reconstruction with autograft 100 patients 65 BEAR and 35 R 14 to 35 YO, Surgery within 6 weeks of injury FDA IDE issued, IRB approval granted Opened May 2016 Fully enrolled May 2017 One year follow-up completed June 2018 (97% followup) BEAR II Outcome Measures Primary Outcomes Patient Reported Outcome (IKDC Subjective Score) KT-1000 testing (AP laxity of the knee) Secondary Outcomes Hamstring strength Safety measures (Infection, loss of ROM, DVT, Failure, etc) Osteoarthritis (6 and 10 years) Future: Next Steps: Upscaling of Manufacturing One possibility: Trials have problems, go back to the lab and figure it out. But what if the trials show it works? We are struggling to make enough scaffolds for the trials. 200,000 s/yr? MIACH Orthopaedics, Inc Series A Funding closed Sept 2018 Goal: Upscale manufacturing of the BEAR scaffold Scale-Up ManufacturingTeam at DSM Biomedical BEAR: Where are we now? Acknowledgments: Financial Support Safety profile acceptable Efficacy reasonable Work to be done: How can we improve outcomes? Surgical technique Rehabilitation Perhaps someday, we will be able to repair and regenerate the torn instead of replacing it. Mechanism/Design/Preclinical Testing: NIH/NIAMS Program Officer: Fei Wang Early Clinical Trials National Football League Player s Association Translational Research Program at BCH Department of Orthopaedic Surgery Multicenter RCT: NIH/NIAMS Program Officer: Chuck Washabaugh 9