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.
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.
|Swärd, Per; Wang, Yang; Hansson, Maria et al. (2017) Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity. Arthritis Res Ther 19:157|
|Grodzinsky, Alan J; Wang, Yang; Kakar, Sanjeev et al. (2017) Intra-articular dexamethasone to inhibit the development of post-traumatic osteoarthritis. J Orthop Res 35:406-411|
|Bajpayee, A G; De la Vega, R E; Scheu, M et al. (2017) Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis. Eur Cell Mater 34:341-364|
|Connizzo, Brianne K; Grodzinsky, Alan J (2017) Tendon exhibits complex poroelastic behavior at the nanoscale as revealed by high-frequency AFM-based rheology. J Biomech 54:11-18|
|Kar, Saptarshi; Smith, David W; Gardiner, Bruce S et al. (2016) Modeling IL-1 induced degradation of articular cartilage. Arch Biochem Biophys 594:37-53|
|Kar, Saptarshi; Smith, David W; Gardiner, Bruce S et al. (2016) Systems Based Study of the Therapeutic Potential of Small Charged Molecules for the Inhibition of IL-1 Mediated Cartilage Degradation. PLoS One 11:e0168047|
|Felka, T; Rothdiener, M; Bast, S et al. (2016) Loss of spatial organization and destruction of the pericellular matrix in early osteoarthritis in vivo and in a novel in vitro methodology. Osteoarthritis Cartilage 24:1200-9|
|Wang, Yang; Li, Yang; Khabut, Areej et al. (2016) Quantitative proteomics analysis of cartilage response to mechanical injury and cytokine treatment. Matrix Biol :|
|Smith, David W; Gardiner, Bruce S; Davidson, John B et al. (2016) Computational model for the analysis of cartilage and cartilage tissue constructs. J Tissue Eng Regen Med 10:334-47|
|Varady, N H; Grodzinsky, A J (2016) Osteoarthritis year in review 2015: mechanics. Osteoarthritis Cartilage 24:27-35|
Showing the most recent 10 out of 31 publications