The effects of matrix inhomogeneities on the cellular mechanical environment in tissue-engineered cartilage: An in silico investigation

摘要

Mechanical stimulation during cartilage tissue-engineering enhances extracellular matrix (ECM) synthesis and thereby improves the mechanical properties of tissue engineered (TE) cartilage. Generally, these mechanical stimuli are of a fixed magnitude. However, as a result of ECM synthesis and spatial variations thereof at both the macroscopic and microscopic scales, the internal mechanical conditions in the constructs change with time. Consequently, the physical signals in the environment of the cells will vary spatially and temporally, even though macroscopically the same loading is applied to the construct. The purpose of the present study was to numerically quantify such effects and thereby reveal the importance of adjusting loading regimes during cartilage tissue-engineering. A validated nonlinear fiber-reinforced poroviscoelastic swelling cartilage model that can accommodate for effects of collagen reinforcement and swelling by proteoglycans was used. At the microscopic scale, ECM was gradually varied from localized in the pericellular area, toward equally distributed throughout the surrounding interterritorial matrix. At the macroscopic tissue scale, ECM was gradually varied from predominantly localized in the periphery of the TE construct toward homogeneously distributed. Both concentration of ECM in the pericellular area and concentration of ECM in the periphery of a construct alter the physical signals up to an order of magnitude compared to those at the onset of the culture. Of particular interest, is the effect of elevated osmotic swelling pressure in the pericellular area, which shields not only the cells from receiving external mechanical compression, but also directly induces tension on the cells. Based on the present computational simulations, it is therefore, proposed that cartilage TE studies should consider ECM distribution as an important factor when developing loading protocols for cartilage culturing process. For instance, the level of mechanical compression should gradually increase to sufficiently deform chondrocytes over time, in case there is matrix accumulation in the pericellular area.