This proposal seeks support to investigate the use of a biologic scaffold composed of extracellular matrix (ECM) as an inductive scaffold for the in vivo generation of a temporo- mandibular joint (TMJ) meniscus. Strong pilot studies indicate that this inductive template can stimulate the endogenous formation of a fibrocartilaginous disc that closely mimics the composition, structure, and mechanical properties of native disc material. Approximately 3% to 4% of the population seeks treatment for TMJ disorders;90% of which are women. Approximately 70% of patients with TMJ disorders suffer from disc displacement;a fact that identifies the TMJ disc as a critical component in the cascade of events that lead to TMJ pathology. Spontaneous TMJ disc regeneration in vivo does not occur, and subsequent articulate surface degeneration can lead to the need for total joint replacement with marked negative consequences upon the quality of life. Development of a replacement disc would protect articulate joint surfaces, mitigate morbidity, and obviate the need for subsequent joint replacement. The central hypothesis of the proposed work is that constructive remodeling of an ECM scaffold toward a functional TMJ disc occurs as a result of recruitment of multipotential cells to the site of remodeling, modulation of the innate immune response, and that enhancement of the remodeling process can occur with associated mechanical preconditioning. In a focused 4-year study involving two Specific Aims, we will test this hypothesis. The first Specific Aim will determine whether controlled in vitro mechanical loading and seeding with a population of multipotential perivascular stem cells can enhance the ECM remodeling process. The second Specific Aim will compare the in vivo remodeling process of five different xenogeneic ECM constructs: 1) a non-crosslinked ECM scaffold, 2) a chemically cross-linked ECM scaffold, 3) a non-crosslinked cell seeded ECM scaffold, 4) a non-crosslinked, mechanically conditioned ECM scaffold, and 5) a non-crosslinked, cell seeded and mechanically conditioned scaffold. The temporo-spatial time course of remodeling will be determined and the relevance and importance of critical events at 4 separate time points post implantation: 2 weeks, 1, 3 and 6 months post implantation in a pig model of bilateral TMJ meniscectomy will be identified. This work is highly interdisciplinary and will utilize the ECM scaffold expertise of th Badylak laboratory, the mechanobiology expertise of the Almarza laboratory, and the surgical expertise of an accomplished oromaxillofacial surgeon to accomplish the Specific Aims. We have a biostatistician and a veterinary comparative anatomy consultant to complement our team. A clear timeline has been established and the studies are based upon solid preliminary data.

Public Health Relevance

This proposal describes work in which a biologic scaffold composed of mammalian extracellular matrix will be used as an inductive scaffold for the in vivo generation of the temporo-mandibular joint meniscus. Pilot studies suggest that this inductive template can stimulate the endogenous formation of a fibrocartilaginous disc that closely mimics the structure, composition and function of native disc material. A pig model will be used in the proposed studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022055-03
Application #
8687974
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lumelsky, Nadya L
Project Start
2012-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Almarza, Alejandro J; Brown, Bryan N; Arzi, Boaz et al. (2018) Preclinical Animal Models for Temporomandibular Joint Tissue Engineering. Tissue Eng Part B Rev 24:171-178
Huleihel, Luai; Scarritt, Michelle E; Badylak, Stephen F (2017) The Influence of Extracellular RNA on Cell Behavior in Health, Disease and Regeneration. Curr Pathobiol Rep 5:13-22
Huleihel, Luai; Dziki, Jenna L; Bartolacci, Joseph G et al. (2017) Macrophage phenotype in response to ECM bioscaffolds. Semin Immunol 29:2-13
Lowe, Jesse; Almarza, Alejandro J (2017) A review of in-vitro fibrocartilage tissue engineered therapies with a focus on the temporomandibular joint. Arch Oral Biol 83:193-201
Dearth, Christopher L; Keane, Timothy J; Carruthers, Christopher A et al. (2016) The effect of terminal sterilization on the material properties and in vivo remodeling of a porcine dermal biologic scaffold. Acta Biomater 33:78-87
Swinehart, Ilea T; Badylak, Stephen F (2016) Extracellular matrix bioscaffolds in tissue remodeling and morphogenesis. Dev Dyn 245:351-60
Henderson, Sarah E; Tudares, Mauro A; Tashman, Scott et al. (2015) Decreased Temporomandibular Joint Range of Motion in a Model of Early Osteoarthritis in the Rabbit. J Oral Maxillofac Surg 73:1695-705