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 #
5R01DE024772-03
Application #
9282581
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
2017-01-01
Budget End
2017-12-31
Support Year
3
Fiscal Year
2017
Total Cost
$361,177
Indirect Cost
$136,177
Name
Stanford University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Zhu, Danqing; Tong, Xinming; Trinh, Pavin et al. (2018) Mimicking Cartilage Tissue Zonal Organization by Engineering Tissue-Scale Gradient Hydrogels as 3D Cell Niche. Tissue Eng Part A 24:1-10
Conrad, Bogdan; Han, Li-Hsin; Yang, Fan (2018) Gelatin-Based Microribbon Hydrogels Accelerate Cartilage Formation by Mesenchymal Stem Cells in Three Dimensions. Tissue Eng Part A 24:1631-1640
Jiang, Xinyi; Wang, Christine; Fitch, Sergio et al. (2018) Targeting Tumor Hypoxia Using Nanoparticle-engineered CXCR4-overexpressing Adipose-derived Stem Cells. Theranostics 8:1350-1360
Tevlin, Ruth; Seo, Eun Young; Marecic, Owen et al. (2017) Pharmacological rescue of diabetic skeletal stem cell niches. Sci Transl Med 9:
Daldrup-Link, Heike E; Chan, Carmel; Lenkov, Olga et al. (2017) Detection of Stem Cell Transplant Rejection with Ferumoxytol MR Imaging: Correlation of MR Imaging Findings with Those at Intravital Microscopy. Radiology 284:495-507
Nabeshima, Akira; Pajarinen, Jukka; Lin, Tzu-Hua et al. (2017) Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model. Biomaterials 117:1-9
Wang, Tianyi; Yang, Fan (2017) A comparative study of chondroitin sulfate and heparan sulfate for directing three-dimensional chondrogenesis of mesenchymal stem cells. Stem Cell Res Ther 8:284
Serpooshan, Vahid; Chen, Pu; Wu, Haodi et al. (2017) Bioacoustic-enabled patterning of human iPSC-derived cardiomyocytes into 3D cardiac tissue. Biomaterials 131:47-57
Wang, Christine; Tong, Xinming; Jiang, Xinyi et al. (2017) Effect of matrix metalloproteinase-mediated matrix degradation on glioblastoma cell behavior in 3D PEG-based hydrogels. J Biomed Mater Res A 105:770-778
Zhu, Danqing; Wang, Huiyuan; Trinh, Pavin et al. (2017) Elastin-like protein-hyaluronic acid (ELP-HA) hydrogels with decoupled mechanical and biochemical cues for cartilage regeneration. Biomaterials 127:132-140

Showing the most recent 10 out of 23 publications