Bone loss is among the most disabling and costly conditions suffered by Americans, and can be caused by traumatic injury, inflammatory and infectious diseases, congenital defects or oncologic resection. Conventional treatment involves harvesting bone grafts from the patient or another tissue donor for repair of the defect. These approaches face limitations such as donor site morbidity, insufficient or poor quality donor tissue, and potential immunogenicity. Stem cell-based therapy offers a promising alternative approach for the repair of bone loss such as cranial and long bone defects, however, treating large bony defects remains one major challenge. A critical barrier to progress in the field is the lack of suitable cell carriers that can support stem cell survival, and guide vascularized and mineralized bone formation in situ. To address the above challenges, our proposed multidisciplinary approach aims to validate the efficacy of microribbon-based scaffolds as a novel type of cell carrier for enhancing stem cell survival and mineralized bone matrix deposition in vivo. The proposed work will be accomplished by an interdisciplinary research team comprised of basic and clinician scientists, with complementary expertise in biomaterials, stem cells, molecular imaging and animal models to validate the efficacy of novel tissue engineering strategies for bone repair. We have demonstrated the unique microribbon morphology confers markedly enhanced mechanical strength of the scaffolds, with interconnected macroporosity to support cell proliferation and extracellular matrix formation. We hypothesize that: (1) osteogenic differentiation of adipose-derived stem cells (ADSCs) in microribbon-based scaffolds can be enhanced by tuning the stiffness and biochemical cues of microribbons; and (2) the macroporosity of microribbon-based scaffolds would lead to enhanced cell survival, faster vascularization and enhanced bone tissue formation in vivo. To test these hypotheses, three specific aims will be pursued including (1) Develop and characterize poly(ethylene glycol) (PEG)-based microribbons for forming 3D macroporous cell niche with independently tunable biochemical and mechanical cues; (2) Determine the optimal biochemical ligands and stiffness of PEG-based microribbons that support osteogenic differentiation of human adipose-derived stromal cells in vitro; and (3) Assess the efficacy of microribbon-based scaffolds for repairing bony defects in vivo using a murine cranial defect model. We expect the findings from this proposal would improve the current treatment options for bone loss, a debilitating condition that afflicts individuals across all populations and ages, and correspondingly reduce the associated socio-economical burden on society.

Public Health Relevance

Bone loss is among the most disabling conditions affecting Americans, and conventional treatment rely mostly on bone grafts, which face limitations such as donor site morbidity, insufficient or poor quality donor tissue, and potential immunogenicity. This proposal will develop and validating the efficacy of novel biomaterials as three-dimensional niche to modulate stem cell differentiation towards bone pathway and enhance functional bone formation in vivo. We expect the findings from this proposal would lead to the development of new tissue engineering-based therapy for treating craniofacial and other large bony defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE024772-04
Application #
9415987
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lumelsky, Nadya L
Project Start
2015-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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