Bioactive Patient-Specific Implants for Regeneration of Critical Size Bone Defects

Abstract

Bone possesses the ability to spontaneously heal itself. Traumatic injury or tumor resection can lead to a bone defect, a lack of bone where it should normally exist. If the deficit is larger than a diagnostic limit, the defect is said to be of critical size, therefore requiring clinical intervention. In such cases autologous bone, or a bioactive synthetic ceramic resembling the mineral component of bone, is used to fill the defect. Additive manufacturing (AM) of bone tissue engineering scaffolds presents an adaptable method for fabrication of patient-specific implants for the same clinical reconstruction. In this thesis polymer/tricalcium phosphate (TCP) composites for bone regeneration scaffolds were studied with the ultimate goal of manufacturing large implants for craniomaxillofacial reconstruction. Such a materials should possess physico-chemical properties optimal for inducing bone growth while being suitable for AM. Within the work two very different methods of AM and therefore also two unique polymer groups were investigated. Poly(trimethylene carbonate) (PTMC) was synthetized for preparing resins for vat photopolymerization. PTMC/TCP composite scaffolds with varying ceramic ratio were characterized to evaluate their performance. The encouraging results showed that large amounts of a TCP could be incorporated into the scaffolds, therefore reinforcing the biocompatible scaffold and turning it bioactive. The AM method allows full control over scaffold design for optimal bone regeneration enabling fine pore architectures and a bioactive surface of TCP with a microscale topographical surface roughness. The process was subsequently upscaled and augmented for consistent manufacturing of large patient-specific implants. Following successful initial screening the composite scaffolds were tested in vivo in two animal models including cranial and tibia defect in rabbits and proof-of-concept pre-clinical study in the mandible of minipigs. Results in the small animal model showed promising results showing that scaffolds provide a conductive surface that induces bone formation. The minipig study confirmed these findings, but PTMC/TCP scaffolds were associated with elevated incidence of infection likely due to high local concentrations of TCP. Therefore, the results point out an intricate balance between biocompatibility and bioactivity. As an alternative method, well-established and commercially readily available medical grade poly(L-lactide-co-D,L-lactide) and poly(L-lactide-co-glycolide) were evaluated in composites with TCP for fused filament fabrication. Comparable scaffolds could successfully be manufactured and the general properties were promising. However, based on further evaluation of existing clinical data and considering the specific clinical application, some challenges remain and potential risks need to be recognized.