Prefabricated 3D-Printed Tissue-Engineered Bone for Mandibular Reconstruction: A Preclinical Translational Study in Primate.

The advent of three dimensionally (3D) printed customized bone grafts using different biomaterials has enabled repairs of complex bone defects in various in vivo models. However, studies related to their clinical translations are truly limited. Herein, 3D printed poly(lactic-co-glycolic acid)/ß-tricalcium phosphate (PLGA/TCP) and TCP scaffolds with or without recombinant bone morphogenetic protein -2 (rhBMP-2) coating were utilized to repair primate's large-volume mandibular defects and compared efficacy of prefabricated tissue-engineered bone (PTEB) over direct implantation (without prefabrication). 18F-FDG PET/CT was explored for real-time monitoring of bone regeneration and vascularization. After 3-month's prefabrication, the original 3D-architecture of the PLGA/TCP-BMP scaffold was found to be completely lost, while it was properly maintained in TCP-BMP scaffolds. Besides, there was a remarkable decrease in the PLGA/TCP-BMP scaffold density and increase in TCP-BMP scaffolds density during ectopic (within latissimus dorsi muscle) and orthotopic (within mandibular defect) implantation, indicating regular bone formation with TCP-BMP scaffolds. Notably, PTEB based on TCP-BMP scaffold was successfully fabricated with pronounced effects on bone regeneration and vascularization based on radiographic, 18F-FDG PET/CT, and histological evaluation, suggesting a promising approach toward clinical translation.

Bioinspired channeled, rhBMP-2-coated ß-TCP scaffolds with embedded autologous vascular bundles for increased vascularization and osteogenesis of prefabricated tissue-engineered bone.

To date, the recovery of large bone defects is a major clinical challenge despite the availability of numerous therapeutic procedures including tissue engineering. Although there is a pressing need for large tissue-engineered constructs, inadequate vascularization remains an insurmountable barrier for successful clinical translation. Considering that vascularization is a prerequisite for osteogenesis, we proposed an advanced design of large customized porous ß-tricalcium phosphate (TCP) scaffolds with biomimetic vascular hierarchy which upon embedding of femoral axial vascular bundles significantly improved overall vascularity of the scaffolds. Such scaffolds also promoted osteogenesis when they were coated with recombinant bone morphogenetic protein-2 (rhBMP-2). Compared to the conventional TCP scaffolds (S), the newly designed multi-channeled ß-TCP (CS) scaffolds led to adequate blood vessels and bone-like tissue formation throughout their porous hierarchy within 4 weeks of implantation. Especially, the scaffolds coated with rhBMP-2 and embedded with flow-through vascular bundle (FVB) were able to form more uniform vascularized bone within 2 weeks post-implantation. Based on the clinical, radiographic, angiographic and histological assessments, the newly designed multi-channeled scaffolds were found to be promising for successful recovery of large bone defects.

Understanding the role of dip-coating process parameters in the mechanical performance of polymer-coated bioglass robocast scaffolds.

The effect of different dip-coating variables-solvent, deposition temperature and polymer concentration-on the mechanical performance of polycaprolactone-coated 45S5 bioglass robocast scaffolds is systematically analyzed in this work. The reproducible geometry of the scaffolds produced by this additive manufacturing technique makes them an optimal model system and facilitates the analysis. The results suggest that the mechanical performance of the hybrid scaffolds is improved monotonically with polymer concentration, but this concentration cannot be increased indefinitely if the macroporosity interconnectivity, and thus the scaffold׳s capacity to promote tissue ingrowth, are to be preserved. An optimal concentration, and therefore viscosity (~1-4Pas in the present case), exists for any given set of process variables (scaffold geometry and material, polymer, solvent and process temperature) that yields coatings with optimal reinforcement and minimal reduction of scaffold functionality. Solvent and process temperature do not directly affect the strengthening provided by the polymeric coating. However they can determine the maximum concentration at the critical viscosity, and thereby the maximum achievable mechanical performance of the resulting hybrid scaffold.

Biological properties of solid free form designed ceramic scaffolds with BMP-2: in vitro and in vivo evaluation.

Porous ceramic scaffolds are widely studied in the tissue engineering field due to their potential in medical applications as bone substitutes or as bone-filling materials. Solid free form (SFF) fabrication methods allow fabrication of ceramic scaffolds with fully controlled pore architecture, which opens new perspectives in bone tissue regeneration materials. However, little experimentation has been performed about real biological properties and possible applications of SFF designed 3D ceramic scaffolds. Thus, here the biological properties of a specific SFF scaffold are evaluated first, both in vitro and in vivo, and later scaffolds are also implanted in pig maxillary defect, which is a model for a possible application in maxillofacial surgery. In vitro results show good biocompatibility of the scaffolds, promoting cell ingrowth. In vivo results indicate that material on its own conducts surrounding tissue and allow cell ingrowth, thanks to the designed pore size. Additional osteoinductive properties were obtained with BMP-2, which was loaded on scaffolds, and optimal bone formation was observed in pig implantation model. Collectively, data show that SFF scaffolds have real application possibilities for bone tissue engineering purposes, with the main advantage of being fully customizable 3D structures.