Synthetic systems that provide structural support while activating endogenous cells to form functional bone tissues have been considered as an optimal therapeutic strategy for treating critical bone defects. Currently, autografts and allografs are the primary choice of implants, but both suffer from various drawbacks such as donor site morbidity, scarcity, immunorejection, or disease transmission. In contrast, synthetic bone grafts with intrinsic osteoinductivity and osteogenicity could provide an easy-to-manufacture, cost-effective, and widely available therapeutic strategy for treating bone defects/failures. In the proposed study, we will investigate the efficacy of a fully synthetic bone grafts being developed in our laboratory to form in vitro and in vivo bone tissues. The biomimetic bone graft described here is developed by using principles of biomineralization, which leads to formation of a synthetic bone-like extracellular matrix that recapitulates various static and dynamic physicochemical cues of the native tissue including the dynamic dissolution/formation of mineral phase. Using this graft, we will: (1) determine the role of various physicochemical cues from the matrix and the mineral environment on osteogenic differentiation of stem cells in vitro, (2) elucidate the mechanism by which the biomineralized grafts exhibits osteogenicity and osteoinductivity, and (3) in vivo bone formation ability of the grafts by using posterolateral fusin as a model system. The grafts are designed to provide the structural and mechanical integrity required for bone grafting, while activating endogenous cells to promote bone formation. Such an endogenous cell-driven strategy in regenerative medicine has the potential to circumvent the limitations of existing approaches associated with cost, space, and time. Such an approach involving synthetic grafts devoid of any growth factors will also confine the bone formation to the implant site and overcome major side effects associated with growth factor-containing grafts. Though the proposed study is focused on bone tissue formation and repair, the biomimetic approach can be applied to study other cells/systems, thus having a far-reaching impact.

Public Health Relevance

The proposal focuses on in vivo harnessing of osteoconductive and osteoinductive properties of a biomimetic synthetic bone grafts to direct osteogenic differentiation of progenitor cells and contribute to bone tissue repair. Successful completion of the proposed study will lead to development of an easy-to-manufacture, cost- effective bone repair strategy that could be a bona fide alternative to autografts. Additionally, this study will provide insights into the role of microenvironmental cues on pathological calcification enabling better drug developments for treating ectopic calcifications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR063184-01A1
Application #
8579775
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2013-08-01
Project End
2018-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$329,375
Indirect Cost
$116,875
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kang, Heemin; Wen, Cai; Hwang, Yongsung et al. (2014) Biomineralized matrix-assisted osteogenic differentiation of human embryonic stem cells. J Mater Chem B Mater Biol Med 2:5676-5688
Kang, Heemin; Shih, Yu-Ru V; Hwang, Yongsung et al. (2014) Mineralized gelatin methacrylate-based matrices induce osteogenic differentiation of human induced pluripotent stem cells. Acta Biomater 10:4961-70
Shih, Yu-Ru V; Hwang, YongSung; Phadke, Ameya et al. (2014) Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling. Proc Natl Acad Sci U S A 111:990-5