Title: Tissue Engineered Total Disc Replacement in a Large Animal Model The objective of this project is to develop a tissue-engineered construct including an engineered nucleus pulposus and annulus fibrosus to treat degenerative changes of the intervertebral disc (IVD).
In Specific Aim 1, we will build on our preliminary small animal studies to construct cell- seeded DAPS whose geometric dimensions are comparable to human and goat IVDs. A novel compression-torsion bioreactor and simulated ex vivo disc-like microenvironment will be utilized to promote growth; we will also establish an endplate region to promote boney integration.
In Specific Aim 2, we will investigate the impact of physiological loading on DAPS in vivo maturation and integration in a large animal (goat) cervical spine disc replacement model. Pre- matured DAPS constructs will be implanted into the goat cervical spine following a single-level cervical discectomy. Constructs will be implanted either with or without an integrated PCL foam endplate. Immediately after implantation, a cohort of animals will have their implanted motion segment stabilized using an anterior cervical plate. An additional cohort will undergo implantation without instrumentation. In vivo DAPS maturation will be assessed via MRI, based on our prior in vivo DAPS work. Motion of the goat cervical spine and head will be monitored using a custom large animal motion-tracking device that our group has developed. Terminal assays will assess motion segment mechanics and DAPS biochemical content and ECM distribution at 12 weeks post-implantation.
In Specific Aim 3, we will investigate remobilization of the tissue-engineered motion segment and analysis of longer-term viability/segmental stability. The DAPS construct with best biomechanical performance in Aim 2 will be implanted after discectomy; at 12 weeks post-implantation, instrumentation will be removed, restoring unconstrained motion. Animals will continue free-range activity for 12 additional weeks, with regular acquisition of cervical motion and fluoroscopy data. At 24 weeks post-implantation, animals will be sacrificed and DAPS-implanted motion segments will be assessed via MRI analysis, biomechanical testing, histological analysis of matrix content and distribution, and biochemical analysis. The goal of this project is to develop tissue-engineered constructs and to assess their therapeutic potential in the treatment of degenerative disc disease. It is anticipated that the proposed study will offer an increased understanding of degenerative disc disease and demonstrate the potential of a novel therapeutic treatment.

Public Health Relevance

The objective of this Merit proposal is to develop novel treatment strategies for degenerative disc disease. This strategy will entail the development of tissue-engineered constructs to replace the entire disc using mesenchymal stem cells, and their in vivo evaluation in a large animal (goat) model, with outcomes assessed using advanced mechanical and imaging techniques. If successful, this work will advance the state of the art in disc replacement with engineered, living implants, and will set the stage for future translation to humans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Translational Rehab (Basic) (RRD0)
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Philadelphia VA Medical Center
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Gullbrand, Sarah E; Ashinsky, Beth G; Bonnevie, Edward D et al. (2018) Long-term mechanical function and integration of an implanted tissue-engineered intervertebral disc. Sci Transl Med 10:
Gullbrand, Sarah E; Kim, Dong Hwa; Bonnevie, Edward et al. (2018) Towards the scale up of tissue engineered intervertebral discs for clinical application. Acta Biomater 70:154-164