Optimal Design of Biocompatible Materials for Cartilage Repair
Articular cartilage is the hydrated biological soft tissue that lines surfaces of bones in joints such as the knee, shoulder and hip. Cartilage contains no blood vessels or nerve endings but is populated with cells (chondrocytes) that maintain the extracellular matrix by regulating their metabolic activity in response to the local extracellular environment. Osteoarthritis is a condition in which cartilage loses its structural integrity and, ultimately, can result in complete tissue degradation with painful bone-on-bone contact necessitating joint replacement. Osteoarthritic cartilage can exhibit “holes” called osteochondral defects that, in theory, could be “filled” with biocompatible materials that facilitate restoration of the tissue’s structural integrity.
Elastin-like polypeptides (ELPs) are injectable in situ polymerizing biomaterials that can be genetically engineered to exhibit a fluid-to-gel phase transition at physiological temperature (approximately 37 degrees centigrade) and, thus, show promise in filling osteochondral defects see Figure 1. Since the ELP genetic sequence is native to cartilaginous tissue, it is believed to promote tissue repair. At present, relationships between ELP material characteristics and successful repair outcomes are not well understood. Outcomes of using such an engineered biomaterial to repair the tissue depend on many diverse factors including ELP hydrogel mechanical properties, biocompatibility between the hydrogel and cells, as well as nutrient diffusion, cell proliferation and cell metabolic response in the repaired gel-tissue construct.
Figure 1. Osteoarthritic cartilage: osteochondral defect (left) and hydrogel repair (right).
Studies in the laboratory of Dr. Lori Setton at Duke University Medical Center indicate that, among ELP genetic design parameters, ELP concentration has the strongest influence on macroscopic stiffness of the resulting ELP hydrogel. Furthermore, in a study in which ELP hydrogels were seeded with chondrocytes and cultured up to 6 weeks, the resulting gel-tissue constructs exhibited a high stiffness modulus in the case of high ELP concentration and long culture time. Interestingly, an even higher stiffness modulus was achieved for a sub-group of samples with low ELP concentration and shorter culture times. These findings suggest that ELP hydrogel concentration, alone, is not the best predictor of repaired tissue stiffness, possibly due to enhanced nutrient diffusion to the cells at lower extracellular ELP concentrations.
The aim of this project is to formulate mathematical models for biosynthesis in the local environment of a chondrocyte seeded in an ELP hydrogel. The primary modeling goal is to predict extracellular matrix stiffness as a function of initial ELP hydrogel concentration and cell culture time. The project is expected to involve coupling between time-varying models for cell synthesis of extracellular matrix proteins, protein accumulation in the ELP hydrogel, and nutrient diffusion to the cell in the evolving gel-tissue construct.
For background reading on the application of hydrogel scaffolds in cartlage repair see:
1. McHale MK, Setton LA and Chilkoti A, Synthesis and in vitro evaluation of enzymatically cross-linked elastin-like polypeptide gels for cartilaginous tissue repair, Tissue Engineering, 11(11-12), 1768-1779, Nov 2005.
2. Nettles DL, Vail TP, Morgan MT, Grinstaff MW and Setton LA, Photocrosslinkable hyaluronan as a scaffold for articular cartilage repair, Annals of Biomedical Engineering, 32(3): 391-397, Mar 2005.