Low back pain is the second most common cause of doctor visits and intervertebral disc (IVD) herniation is a direct cause of pain. Lumbar discectomy is the standard of care for herniation, yet this very common procedure has 5-25% complication rates including re-herniation and recurrent back pain at the same level. Discectomy complications cannot be further reduced by optimizing the amount of tissue removed during procedures, but instead discectomies require a reparative component to greatly reduce complications. This project develops, optimizes and validates biomaterials that seal the annulus fibrosus and restore nucleus pulposus swelling following discectomy procedures. The first funding period of this grant resulted in 34 papers that developed human and bovine organ culture models of IVD degeneration and determined that methods to repair large IVD defects are lacking and a critical scientific barrier that must be addressed to limit degeneration following IVD herniation and injury. We also developed novel hydrogels with promise to seal the annulus fibrosus, restore nucleus pulposus swelling, and return IVD biomechanical behaviors to the healthy state. Additional acellular biomaterial optimization, modification of biomaterials for use as cell carriers, and pre-clinical evaluations are required before clinical translation.
Aim 1 optimizes in situ performance of acellular biomaterials for IVD repair with biomaterial refinements and TGF?3 dose studies using bovine organ culture discectomy models.
Aim 2 optimizes in situ performance of biomaterials for mesenchymal stem cell delivery using these same models.
Aim 3 validates these IVD repair strategies in pre-clinical human organ culture and sheep in vivo studies. We apply a genipin- crosslinked fibrin hydrogel capable of sealing annulus fibrosus defects without risk of herniation under rigorous biomechanical loading. We also apply a novel carboxymethylcellulose/methylcellulose hydrogel formulation capable of restoring nucleus pulposus swelling and returning IVD biomechanical behaviors to intact conditions. The investigative team closely collaborates with extensive biomaterials, biomechanics, tissue engineering, and spine surgery expertise. All methods are well-established in the labs of this team. This project is highly significant because of the tremendous health burden of IVD herniation and injury, because discectomy procedures are among the most common spine surgery procedures, and because this project has a clear translational trajectory. This project is innovative because it uses novel biomaterial formulations and approaches for discectomy repair that are capable of transforming current surgical interventions and thinking since no IVD repair strategies exist. The approach is robust because it addresses fundamental questions for IVD repair in a systematic manner that allows iterative optimization with evaluation tests that increasingly challenge the repair strategies.

Public Health Relevance

Back pain is the second most common cause of doctor visits and intervertebral disc (IVD) herniation is a direct cause of pain. While discectomy procedures are an effective standard of care for herniation, complications including re-herniation and recurrent back pain at the same level are common. The proposed studies optimize and validate acellular and cell-based IVD repair techniques that advance discectomy procedures by including a reparative component that seals annulus fibrosus defects and restores nucleus pulposus swelling. The robust approach optimizes biomaterials and techniques using bovine organ culture models and validates them using pre-clinical human organ culture and sheep in vivo studies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Marquitz, Aron
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Cruz, Michelle A; Hom, Warren W; DiStefano, Tyler J et al. (2018) Cell-Seeded Adhesive Biomaterial for Repair of Annulus Fibrosus Defects in Intervertebral Discs. Tissue Eng Part A 24:187-198
Torre, Olivia M; Das, Rohit; Berenblum, Ramy E et al. (2018) Neonatal mouse intervertebral discs heal with restored function following herniation injury. FASEB J 32:4753-4762
Evashwick-Rogler, Thomas W; Lai, Alon; Watanabe, Hironobu et al. (2018) Inhibiting tumor necrosis factor-alpha at time of induced intervertebral disc injury limits long-term pain and degeneration in a rat model. JOR Spine 1:
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Nakazawa, Kenneth R; Walter, Benjamin A; Laudier, Damien M et al. (2018) Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration. Spine J 18:343-356
Long, Rose G; Zderic, Ivan; Gueorguiev, Boyko et al. (2018) Effects of Level, Loading Rate, Injury and Repair on Biomechanical Response of Ovine Cervical Intervertebral Discs. Ann Biomed Eng 46:1911-1920
Varma, D M; Lin, H A; Long, R G et al. (2018) Thermoresponsive, redox-polymerized cellulosic hydrogels undergo in situ gelation and restore intervertebral disc biomechanics post discectomy. Eur Cell Mater 35:300-317
Martin, John T; Gullbrand, Sarah E; Fields, Aaron J et al. (2018) Publication trends in spine research from 2007 to 2016: Comparison of the Orthopaedic Research Society Spine Section and the International Society for the Study of the Lumbar Spine. JOR Spine 1:e1006
Shi, Changgui; Qiu, Sujun; Riester, Scott M et al. (2018) Animal models for studying the etiology and treatment of low back pain. J Orthop Res 36:1305-1312
Long, Rose G; Rotman, Stijn G; Hom, Warren W et al. (2018) In vitro and biomechanical screening of polyethylene glycol and poly(trimethylene carbonate) block copolymers for annulus fibrosus repair. J Tissue Eng Regen Med 12:e727-e736

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