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.

pH-labile and photochemically cross-linkable polymer vesicles from coumarin based random copolymer for cancer therapy.

The stability of a drug payload inside a nanocarrier at physiological environment and the release of the said drug at specific tumor cells in a sustainable manner are the two most important factors that determine the efficiency of a smart targeted drug-delivery system. In this work, 2-hydroxyethyl methacrylate and a coumarin-based methacrylate monomer containing ß-thiopropionate moiety were copolymerized via reversible addition-fragmentation chain transfer (RAFT) process, followed by characterization using NMR and GPC. The said copolymer self-assembled at physiological pH to form vesicular nano-aggregates which was confirmed using DLS, TEM and by fluorescence measurements. These vesicles were further stabilized by photochemical crosslinking via coumarin (2π + 2π) cycloaddition reaction. These cross-linked vesicles (CVs) exhibited a 38% reduction in premature drug leakage as compared to the uncross-linked vesicles (UCVs) at physiological pH. Additionally, a slow hydrolysis of the ß-thiopropionate moieties under mildly acidic conditions prevalent in tumor cells resulted in disassembly of the vesicles, thereby releasing the loaded drug in a sustainable manner. Studies related to in vitro toxicity, efficiency of cellular uptake and pH-responsive antineoplastic activity of doxorubicin (DOX) loaded in the cross-linked vesicles (CVs) toward cancer cell lines were undertaken. A significant reduction in IC50 was noticed for DOX-loaded CVs in comparison to free DOX toward MG63 cancer cell lines, making these vesicles as potent nanocarrier systems for cancer therapy.

Simultaneous hydrothermal bioactivation with nano-topographic modulation of porous titanium alloys towards enhanced osteogenic and antimicrobial responses.

Post-implantation failure associated with insufficient host tissue integration at the bone-implant interface and aseptic loosening is a major concern in orthopaedics as well as in dentistry. To overcome the failure in early stages of implantation, prosthetic design combining the mechanisms of porosity guided bone ingrowth along with topographic manipulation of osteogenic cells over bacterial colonization would be an ideal choice, although achieving such a goal is highly challenging. In this study, facile rapid hydrothermal synthesis of nanostructures with simultaneous deposition of hydroxyapatite on the titanium alloy surface was demonstrated by using an aqueous sodium tripolyphosphate and calcium hydroxide mixture. Nanostructures with wire-like morphology exhibited significantly higher osteogenic related gene expression (COL I, OPN, and OCN) through differentiation of adipose derived mesenchymal stem cells as well as the bactericidal response against S. aureus and E. coli as compared to other nanotopographic features. The same also exhibited elongated cell morphology with the highest expression of paxillin towards cell boundaries as compared to the polished surface with flattened cell morphology and localized expression of paxillin around the nucleus. Implantation of treated porous Ti6Al4V samples representing a multiscalar hierarchy with wire-like nanostructures accelerated osteochondral healing in rabbits without any major signs of infection. Also, significantly higher bone formation was observed within the defects implanted with treated porous Ti6Al4V (44.0%) as compared to that of untreated porous samples (36.9%) as well as empty defects (19.6%).

Influence of Porosity and Pore-Size Distribution in Ti6Al4 V Foam on Physicomechanical Properties, Osteogenesis, and Quantitative Validation of Bone Ingrowth by Micro-Computed Tomography.

Cementless fixation for orthopedic implants aims to obviate challenges associated with bone cement, providing long-term stability of bone prostheses after implantation. The application of porous titanium and its alloy-based implants is emerging for load-bearing applications due to their high specific strength, low stiffness, corrosion resistance, and superior osteoconductivity. In this study, coagulant-assisted foaming was utilized for the fabrication of porous Ti6Al4 V using egg-white foam. Samples with three different porosities of 68.3%, 75.4%, and 83.1% and average pore sizes of 92, 178, and 297 µm, respectively, were prepared and subsequently characterized for mechanical properties, osteogenesis, and tissue ingrowth. A microstructure-mechanical properties relationship study revealed that an increase of porosity from 68.3 to 83.1% increased the average pore size from 92 to 297 µm with the subsequent reduction of compresive strength by 85% and modulus by 90%. Samples with 75.4% porosity and a 178 µm average pore size produced signifcant osteogenic effects on human mesenchymal stem cells, which was further supported by immunocytochemistry and real-time polymerase chain reaction data. Quantitative assessment of bone ingrowth by micro-computed tomography revealed that there was an approximately 52% higher bone formation and more than 90% higher bone penetration at the center of femoral defects in rabbit when implanted with Ti6Al4 V foam (75.4% porosity) compared to the empty defects after 12 weeks. Hematoxylin and eosin (H&E) and Masson trichrome (MT) staining along with energy-dispersive X-ray mapping on the sections obtained from the retrieved bone samples support bone ingrowth into the implanted region.