ENGINEERING CELLULAR MICROENVIRONMENT FOR CARTILAGE REGENERATION

Abstract

Articular cartilage defects, resulting from trauma or pathological change, affect a large population worldwide from adolescents to adults. The limited self-renewal ability of cartilage due to lack of blood vessels and cellular crosstalk makes it one of the most difficult tissues to regenerate. Common treatments to prevent the progression of critical cartilage defects involve surgical intervention such as microfracture and autologous chondrocyte implantation. Besides the time and cost involved in these clinical treatments, the quality of the regenerated tissue is not comparable to native tissue in regard to biological function; the cartilage synthesized at the defect region becomes fibrous and prone to failure over time, possibly due to the absence of required cellular microenvironment. To overcome the difficulties in cell expansion associated with chondrocytes, human mesenchymal stem cell (hMSC) has been explored as an alternative cell source for its abundance and ability to differentiate into chondrocytes. The work presented here is aimed at recapitulating the complex microenvironment of cartilage tissue by guiding stem cell alignment and differentiation on a 3D patterned scaffold to improve the repair outcome. The first aim of this work examined cellular responses to the addition of mechanical preconditioning in an environment which incorporated signaling molecules and supporting matrices. Our developed compression-perfusion bioreactor provided a solution to enhance chondrogenic differentiation of hMSCs by providing mechanical stimulation that recapitulates the native environment. The second aim of the thesis extended the development of cellular environment to the use of 3D printed scaffold with controlled micro-patterns. During extrusion 3D printing, sheered polymer generated an organized micro-environment of aligned polymer molecules that had an impact on cell alignment and differentiation. The scaffold was then functionalized with aggrecan and applied to an in vivo model combined the standard approach of microfracture to evaluate the regenerative potential. The results demonstrated improved quality of the newly formed cartilage tissue. In this dissertation, we have investigated the cellular microenvironment that provides both mechanical and biological cues for cartilage regeneration. The acellular patterned scaffold that provides controlled cell behavior in combination with current surgical procedures will provide a cost-effective way to restore better cartilage function