Development of an Integrated 3D Human Osteo-Mucosal Model

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SUMMARY: The integration and stability of the hard/soft tissue interface is a major challenge in regeneration and engineering of constructs composed of widely different tissue types. The current approach is employment of biocompatible natural adhesives, such as fibrin glue. However, using such adhesives, the adhesion strength is not strong enough in physiological condition and will loosen in time. Moreover, since they act as an additional layer/material between two tissues, the healthy cellular communication between tissues will be disturbed with adverse influence on interfacial tissue development. In this project, we propose a new method for adhesion of soft/hard tissues, which addresses both of the above drawbacks. We will optimize and apply our technique in oral mucosa/bone adhesion to develop an engineered osteo-mucosal complex as a key example of a construct containing widely dissimilar tissues. Our proposed approach relies on in situ incorporation of adhesive functional groups into a cell-laden soft scaffold based on a biocompatible method, which become readily adherent to a surface treated hard scaffold. More specifically, the photocurable gelatin-based matrix encapsulating cells will be enzymatically treated to have quinone functional groups which can form covalent bonds with the amine groups on the polycaprolactone bone scaffold. The interfacial adhesion will be based on Michael reaction. We claim that this new technique has three major advantages over current methods: 1) It directly integrates two compartments of soft/hard tissues without the need for employing a third material. 2) The adhesion is very strong and will not be diminished over time. 3) The formulation will lead to in depth penetration of cells and enhanced cell growth inside the scaffolds. To examine our hypotheses, the adhesion strength will be fully evaluated in vitro quantitatively and qualitatively over time after development of the osteo-mucosal complex, and the biological characteristics will be inspected in detail. A similar construct treated by fibrin glue as the adhesive agent will be produced in parallel to be used as the control sample. Moreover, the adhesion strength of our osteo-mucosal construct will be compared with the natural oral mucosa/bone interfacial tissue in a freshly slaughtered pig’s jaw. A successful outcome from the proposed adhesion method in the osteo-mucosal complex will suggest that the technique can potentially be applied (after relevant modifications) for engineering of interfacial tissues in periodontal complex, bone/cartilage, bone/ligament, bone/tendon, and dentin/pulp complexes. The applications of the developed osteo-mucosa complex include A) clinical transplantation such as alveolar reconstruction and intraoral grafting, B) production of a clinically relevant in vitro test system and an alternative to animal test models for 1) studying the interaction of biomaterials and oral tissue, and 2) oral disease screening and evaluation of drug delivery systems.