Diarthrodial joint resurfacing: Multi-scale biofabrication of mechanically stable implants. Osteochondral tissue regeneration in the knee joint

Abstract

In the quest for new treatments for (osteo)chondral defects and to eliminate or postpone total knee replacement surgery, the potential of 3D bioprinting of (osteo)chondral implants as a surgical procedure has been explored. The overarching aim of this thesis was to fabricate a functional (osteo)chondral implant, inspired by native tissue architecture, by combining advanced 3D (bio)fabrication technologies. Part I demonstrated how melt electrowriting (MEW) was used to improve the mechanical properties of (osteo)chondral implants. Here, it was shown that microfibres, deposited in an out-of-plane fashion, improve the shear-properties of hydrogel scaffolds while using only a limited volume-fraction of biodegradable polymer fibres (Chapter 2). Additionally, microfibre meshes were used to improve the interconnection between the cartilage-to-bone interface by interlocking them within a printed calcium phosphate-based (pCaP) bone cement structure (Chapter 3). To further address the zonal structure and composition of the native cartilage tissue through the layered deposition of cells and matrix components, the incorporation of the MEW-based production of microfibres within the bioprinting process was explored in Part II. First, the state-of-the-art concept of combining different manufacturing processes into a single biofabrication platform was reviewed and future perspectives of such approaches were discussed (Chapter 4). Further, it demonstrated, for the first time, the successful convergence of MEW and extrusion-based bioprinting into a single printing platform enabling control over the fibrous and non-fibrous components of chondral grafts (Chapter 5). Moreover, the potential of this converged approach for resurfacing anatomically relevant structures and clinically relevant materials was demonstrated. The importance of ensuring a constant electrical field strength and directing the electrical force normal to the collecting structure for accurate microfibre patterning on non-planar surfaces was shown (Chapter 6). Part III subsequently addressed the pre-clinical application of the developed multi-scale (bio)fabrication approaches. First, it was shown that bone morphogenic protein 9 (BMP-9) can be used to stimulate articular cartilage resident chondroprogenitor cells (ACPCs) to produce large quantities of reinforced cartilage-like matrix in a time-efficient manner which holds promise for the clinical translation of large biofabricated implants (Chapter 7). Next, long-term in vivo evaluation showed that pre-cultured osteochondral plugs with hierarchy in both cell density and microfibre organization were stable enough to withstand the mechanically challenging environment of the stifle joint in an equine model. This study highlights the importance of structural reinforcement and suggests that the use of transplanted cells is, in fact, secondary to the presence of the mechanical structure (Chapter 8). Upscaling from relatively small osteochondral plugs to larger patient-specific implants demonstrated that the size of the implants significantly affected load distribution and that the design of the implant should take into account the position of implantation to effectively restore mechanical functioning of the joint. Additionally, this study introduced a new computer aided design (CAD) to computer aided manufacturing (CAM) software tool to more easily generate the MEW printing trajectory for the resurfacing of patient-specific geometries (Chapter 9).