Regeneration of tissue interfaces: Biomaterial controlled morphogen gradients for tissue patterning in regeneration

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The healing of ostechondral defects in the joint still remains a challenge for orthopaedic surgeons and none of the current techniques achieve full reconstruction and functionality of the bone and cartilage phases. A reason for the limited clinical success of treatments is the tight interplay of bone and cartilage tissues at the osteochondral junction, a classical distinct tissue pattern. With the proposed project we want to validate a new concept for distinct tissue patterning in regenerative medicine using osteochondral defects as an example system. We base our concept on a fundamental principle of developmental biology, which includes locally activators and inhibitors acting tightly together to form distinct tissue patterns. For that purpose a multi-layered construct (microsphere-based PLG scaffold) that allows for the controlled release of both stimulatory agents and their antagonists from distinct layers ws developed in cooperation. We plan to employ our biomechanically well controlled osteochondral defect model in sheep to validate the concept in vivo and compare to endogenous factor release. Specifically, the layered scaffold is composed of a cartilage zone containing TGFbeta and anti-BMP4, a middle buffer zone containing anti-BMP and anti-TGFbeta antibodies and an osteogenic inductive layer composed of BMP4 and anti-TGFbeta It is our hypothesis that spatially controlled release of both stimulatory and opposing factors from the PLG scaffold can steer tissue patterning (cartilage like tissue-tidemark-subchondral bone) in an osteochondral defect model in sheep. Basis to our analyses will be the evaluation of the endogenous response to an osteochondral defect by means of the early hematoma formation. Towards that aim, we will investigate the inflammatory response cascade initiated within the first hours after implantation of a scaffold containing either no growth factors or TGFbeta3 or BMP4 alone. We will primarily investigate the cytokine pattern and inflammatory cell response in the hematoma that develops in the freshly created osteochondral defect. In the next step, the suggestibility of this phase by TGFbeta and BMP-4 will be analyzed by implanting the scaffold loaded either with TGFbeta or BMP-4. In summary, the proposed analyses will allow judging on the feasibility of a biomaterial-based strategy to control locally tissue formation at distinct tissue junctions such as in osteochondral repair. Further, it will allow gaining understanding if such approach is helpful to overcome the current clinical shortcomings in osteochondral repair by the growth factors TGFbeta and BMP4. Once validated, this concept of distinct tissue formation may be applied to multiple other even more complex organ structures.