Acute injuries to cartilage are common and often result in defects that the body's innate healing response repairs with fibrocartilage. This repair tissue lacks the architecture and mechanical properties of native articular cartilage and most often degenerates over time. Tissue engineering strategies have faced the combined problems of encouraging cell migration, proliferation, chondrogenic differentiation and extracellular matrix (ECM) assembly such that neocartilage is formed and can integrate with the existing cartilage at the wound edges. We propose that engineering a biologically functional 3D-microenvironment for BMSCs within self- assembling peptide hydrogel scaffolds can stimulate chondrogenesis and cartilage neotissue integration in vivo. This peptide scaffold will be functionalized with ECM components and a novel heparin-binding form of IGF-1, which together will be optimized to stimulate chondrogenesis of infiltrating progenitor cells and to enhance integration at the cartilage-neotissue interface. Translation of these functionalized scaffolds developed in vitro to useful cartilage repair in vivo will be tested using both rabbit and equine models. These combined, integrated studies represent a collaboration between scientists and engineers at the Center for Biomedical Engineering, Massachusetts Institute of Technology, and clinical scientists at the Orthopaedic Research Center, Colorado State University.
Our Specific Aims are: (1) To develop second-generation KLD peptide nanofiber scaffolds by functionalizing with pro-chondrogenic molecules, including ECM constituents such as collagen types VI/I and heparan sulfate, and a pro-anabolic molecule, heparin binding IGF-1 (HB-IGF-1). We will then test the ability of these optimized acellular peptide scaffolds to promote the chondrogenesis of infiltrating progenitor cells, cartilage neotissue biosynthesis, and cartilage defect repair in a rabbit model in vivo. (2) To test the hypothesis that integration between construct and cartilage in vitro can be optimized through enzyme pre-treatments and peptide scaffold-incorporated HB-IGF-1 + collagen types VI/I;and then to test the hypothesis that integration between construct and cartilage in vivo can be optimized through enzyme pre- treatments and peptide scaffold-incorporated HB-IGF-1 + collagen types VI/I in a rabbit model;and (3) To test the ability of optimized acellular peptide scaffolds to attract progenitor cells and promote chondrogenesis, cartilage neotissue production, and integration with surrounding tissue in an equine model subjected to strenuous exercise.

Public Health Relevance

Acute injuries to cartilage are common and often result in defects that the body's innate healing response repairs with fibrocartilage. We propose that engineering a biologically functional 3D-microenvironment for bone marrow stromal cells within self-assembling peptide hydrogel scaffolds can stimulate chondrogenesis and cartilage neotissue integration in vivo. Translation of these functionalized scaffolds developed in vitro to useful cartilage repair in vivo will be tested using both rabbit and equine studies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AR060331-03
Application #
8721341
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
None
Type
Organized Research Units
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Li, Y; Wang, Y; Chubinskaya, S et al. (2015) Effects of insulin-like growth factor-1 and dexamethasone on cytokine-challenged cartilage: relevance to post-traumatic osteoarthritis. Osteoarthritis Cartilage 23:266-74
Rojas, Fredrick P; Batista, Michael A; Lindburg, C Alexander et al. (2014) Molecular adhesion between cartilage extracellular matrix macromolecules. Biomacromolecules 15:772-80
Batista, Michael A; Nia, Hadi T; Önnerfjord, Patrik et al. (2014) Nanomechanical phenotype of chondroadherin-null murine articular cartilage. Matrix Biol 38:84-90
Bajpayee, Ambika G; Wong, Cliff R; Bawendi, Moungi G et al. (2014) Avidin as a model for charge driven transport into cartilage and drug delivery for treating early stage post-traumatic osteoarthritis. Biomaterials 35:538-49
Ogawa, Hiroyasu; Kozhemyakina, Elena; Hung, Han-Hwa et al. (2014) Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways. Genes Dev 28:127-39
Kopesky, Paul W; Byun, Sangwon; Vanderploeg, Eric J et al. (2014) Sustained delivery of bioactive TGF-*1 from self-assembling peptide hydrogels induces chondrogenesis of encapsulated bone marrow stromal cells. J Biomed Mater Res A 102:1275-85
Byun, Sangwon; Sinskey, Yunna L; Lu, Yihong C S et al. (2013) Transport and binding of tumor necrosis factor-? in articular cartilage depend on its quaternary structure. Arch Biochem Biophys 540:1-8
Lee, Hsu-Yi; Han, Lin; Roughley, Peter J et al. (2013) Age-related nanostructural and nanomechanical changes of individual human cartilage aggrecan monomers and their glycosaminoglycan side chains. J Struct Biol 181:264-73
Nia, Hadi Tavakoli; Bozchalooi, Iman S; Li, Yang et al. (2013) High-bandwidth AFM-based rheology reveals that cartilage is most sensitive to high loading rates at early stages of impairment. Biophys J 104:1529-37
Lee, Christina M; Kisiday, John D; McIlwraith, C Wayne et al. (2013) Synoviocytes protect cartilage from the effects of injury in vitro. BMC Musculoskelet Disord 14:54

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