The articulating joint is a complex system that is regularly subjected to trauma, inflammatory and metabolic processes. More than 20 million individuals in the United States have symptomatic osteoarthritis and suffer from some debilitation of the joints and therefore developing interventive and regenerative medical cures is a national priority. Our projects are aimed at gaining a greater understanding of the development of bone/cartilage interfaces for the reconstruction of articular joints such as the temporomandibular joint (TMJ). The long-term objective of this proposal is to develop strategies to regenerate multi-tissue interfaces with a focus on the bone-cartilage interface. We propose a hypothesis and design-driven tissue engineering project based on rapid fabrication of bioengineered scaffolds, with custom-tailored surface chemistry, that control the spatial and temporal release of bioactive factors to regenerate the bone and cartilage interface. The controlled generation of this interface will be directed via an in vivo regenerative gene therapy approach. The central hypothesis is that delivery of bioactive signaling factors (BMP-2 and Sox9) to distinct regions of designed scaffolds can control the lineage commitment of responsive cells to develop a bone/cartilage interface. 1. To custom-tailor the surface chemistry of biomaterials with precisely designed biological signaling properties. Poly 5-caprolactone (PCL) surfaces will be modified by chemical vapor deposition (CVD) to establish surface coatings with a variety of polymer properties and conjugation chemistries. Three different immobilization models will be developed in this specific aim to gain maximal control of viral release through a dynamic equilibrium of biotin/avidin and biomaterial interactions. 2. To immobilize two different viruses on a single scaffold to control delivery of specific biological signaling factors and to understand how these signals control the development of a biological interface. Material surfaces will be modified to control the delivery of multiple adenoviruses. Two-way CVD will also be used to generate signaling gradients to mimic natural developmental signaling patterns at an interface. 3. To develop a bone-cartilage interface by directing the lineage progression of responsive cells to bone and cartilage using in vivo regenerative gene transfer strategies on designed biomaterial scaffolds. Tissue interfaces will be generated on biomaterial scaffolds in vivo. The precision of interface development will be studied by delivering BMP-2 on one region of a scaffold and antagonists such as noggin or dominant negative BMP receptors on the adjacent surfaces. The development of bone/cartilage interfaces will be studied in vivo by the controlled delivery of BMP-2 (bone) and Sox-9 (cartilage).

Public Health Relevance

When congenital anomalies, traumatic injuries or inflammatory and degenerative diseases involve an articulating joint such as the temporomandibular joint (TMJ), the effects are often physically, financially and emotionally debilitating. Unfortunately, despite decades of targeted clinical and basic science research, well established methods to repair or regenerate such joints remain elusive, resulting in a significant unmet clinical need. The long-term objective of this proposal is to develop strategies to regenerate the bone-cartilage interface to regenerate joins like the TMJ.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lumelsky, Nadya L
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University of Michigan Ann Arbor
Schools of Dentistry
Ann Arbor
United States
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Hu, Wei-Wen; Wang, Zhuo; Krebsbach, Paul H (2016) Virus immobilization on biomaterial scaffolds through biotin-avidin interaction for improving bone regeneration. J Tissue Eng Regen Med 10:E63-72
Sun, Hongli; Zhu, Feng; Hu, Qingang et al. (2014) Controlling stem cell-mediated bone regeneration through tailored mechanical properties of collagen scaffolds. Biomaterials 35:1176-84
King, William J; Krebsbach, Paul H (2013) Cyclic-RGD peptides increase the adenoviral transduction of human mesenchymal stem cells. Stem Cells Dev 22:679-86
King, William J; Krebsbach, Paul H (2012) Growth factor delivery: how surface interactions modulate release in vitro and in vivo. Adv Drug Deliv Rev 64:1239-56
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Zhang, Ying; Deng, Xiaopei; Scheller, Erica L et al. (2010) The effects of Runx2 immobilization on poly (epsilon-caprolactone) on osteoblast differentiation of bone marrow stromal cells in vitro. Biomaterials 31:3231-6
Hu, W-W; Ward, B B; Wang, Z et al. (2010) Bone regeneration in defects compromised by radiotherapy. J Dent Res 89:77-81
Hu, Wei-Wen; Elkasabi, Yaseen; Chen, Hsien-Yeh et al. (2009) The use of reactive polymer coatings to facilitate gene delivery from poly (epsilon-caprolactone) scaffolds. Biomaterials 30:5785-92
Scheller, E L; Krebsbach, P H (2009) Gene therapy: design and prospects for craniofacial regeneration. J Dent Res 88:585-96
Hu, Wei-Wen; Lang, Michael W; Krebsbach, Paul H (2009) Digoxigenin modification of adenovirus to spatially control gene delivery from chitosan surfaces. J Control Release 135:250-8

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