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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057397-07
Application #
9447124
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Fei
Project Start
2011-07-15
Project End
2022-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Orthopedics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Iatridis, James C; Kang, James; Kandel, Rita et al. (2017) New horizons in spine research: Intervertebral disc repair and regeneration. J Orthop Res 35:5-7
Cruz, Michelle A; McAnany, Steven; Gupta, Nikita et al. (2017) Structural and Chemical Modification to Improve Adhesive and Material Properties of Fibrin-Genipin for Repair of Annulus Fibrosus Defects in Intervertebral Disks. J Biomech Eng 139:
Nakazawa, Kenneth R; Walter, Benjamin A; Laudier, Damien M et al. (2017) Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration. Spine J :
Cruz, Michelle A; Hom, Warren W; Tyler, Distefano et al. (2017) Cell-Seeded Adhesive Biomaterial for Repair of Annulus Fibrosus Defects in Intervertebral Discs. Tissue Eng Part A :
Dowdell, James; Erwin, Mark; Choma, Theodoe et al. (2017) Intervertebral Disk Degeneration and Repair. Neurosurgery 80:S46-S54
Iatridis, James C; Kang, James; Kandel, Rita et al. (2016) New Horizons in Spine Research: Disc biology, spine biomechanics and pathomechanisms of back pain. J Orthop Res 34:1287-8
Long, Rose G; Torre, Olivia M; Hom, Warren W et al. (2016) Design Requirements for Annulus Fibrosus Repair: Review of Forces, Displacements, and Material Properties of the Intervertebral Disk and a Summary of Candidate Hydrogels for Repair. J Biomech Eng 138:021007
Lai, Alon; Moon, Andrew; Purmessur, Devina et al. (2016) Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo. Spine J 16:420-31
Walter, B A; Purmessur, D; Moon, A et al. (2016) Reduced tissue osmolarity increases TRPV4 expression and pro-inflammatory cytokines in intervertebral disc cells. Eur Cell Mater 32:123-36
Likhitpanichkul, Morakot; Torre, Olivia M; Gruen, Jadry et al. (2016) Do mechanical strain and TNF-? interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells? J Biomech 49:1214-1220

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