Osteoarthritis is a painful, degenerative joint disease that leads to significant disability and reduced quality of life, especially in the aging populatio. This affected population numbers 53 million in the United States according to newly-released data from the CDC, 23 million of whom suffer during activities of daily living. Treatment options remain limited; after implementation of lifestyle modifications, patients are given the option of joint replacement surgeries, but wear of implanted metal and polymer-based prosthetics yields an efficacy period of only 10-15 years. We intend to engineer a living tissue-based replacement that will avoid immune rejection, maintain the mechanical properties of normal cartilage tissue, be as durable as the host's original joints, and integrate into an osteochondral defect. To do so, we have created a three-dimensional scaffold woven with the biocompatible, FDA-approved, and slowly-degrading polymer poly(e-caprolactone) (PCL), with mechanical strength equivalent to native cartilage. With this scaffold, we have also demonstrated scaffold- mediated lentiviral transduction of chondrogenesis-inducing transforming growth factor 3 (TGF-3), and separately with osteogenesis-inducing bone morphogenic protein 2 (BMP-2), both yielding sustained transgene expression in mesenchymal stem cells (MSCs). Induced pluripotent stem cells (iPSCs) are genetically matched to the donor somatic cells from which they are derived and represent a plentiful source of cells with potential to form all tissues. Our lab has shown tha iPSCs from mouse tail fibroblasts can be re-engineered to be chondrogenic, suggesting the possibility of turning patient-specific adult cells into chondrocytes and osteoblasts for osteochondral tissue engineering. However, to stimulate osteogenesis, additional small molecules are necessary usually as media supplements. In order to deliver these small molecules only to the osteogenic part of the construct, we will use a biosynthetic polymer, Elastin-Like Polypeptide (ELP), which has been engineered to have a reverse transition temperature at 35C (just below the temperature of the body), lending itself to being injected as a liquid at lower room temperatures, with solidification occurring above this temperature. This biocompatible hydrogel has been shown to induce chondrogenesis of adult stem cells and shown to be an excellent drug delivery vehicle; it may prove the key to creating an osteochondral tissue construct. The goals of this study are to develop functionalized scaffolds for chondrogenic and osteogenic differentiation of iPSCs, and to deliver local osteogenic factors using ELP as a carrier.
The repair or regeneration of articular cartilage remains an important and unsolved problem. The goal of this study is to use spatially-controlled delivery of chondrogenic and osteogenic factors, via scaffold-mediated lentiviral transduction and via small molecule encapsulation in elastin-like polypeptide hydrogels, to develop a functional osteochondral tissue implant in vitro, ultimately for the treatment of cartilage defects leading to osteoarthritis.
