Additive Manufacturing of Bioactive Poly(trimethylene carbonate)/ß-Tricalcium Phosphate Composites for Bone Regeneration.

Implants of bioresorbable materials combined with osteoconductive calcium phosphate ceramics show promising results to replace and repair damaged bone tissue. Here we present additive manufacturing of patient-specific porous scaffolds of poly(trimethylene carbonate) (PTMC) including high amounts of ß-tricalcium phosphate (ß-TCP). Tensile testing of composite networks showed that addition of ß-tricalcium phosphate reinforces the composites significantly. Three-dimensional structures containing up to 60 wt % ß-TCP could be built by stereolithography. By lowering the content to 51 wt %, manufacturing of a large-sized patient-specific prototype was possible at high resolution. Closer examination revealed that the created scaffolds contained more ß-TCP on the surface of the builds. Stereolithography therefore provides a manufacturing technique where the bioactive agent is directly available for creating an enhanced microenvironment for cell growth. The biocompatibility and bioresorption of PTMC coupled with the osteoconductivity of ß-TCP are an important candidate to consider in additive manufacturing of bone regeneration implants.

Patient-Specific Bioimplants and Reconstruction Plates for Mandibular Defects: Production Workflow and In Vivo Large Animal Model Study.

A major challenge with extensive craniomaxillofacial bone reconstruction is the limited donor-site availability to reconstruct defects predictably and accurately according to the anatomical shape of the patient. Here, patient-specific composite bioimplants, consisting of cross-linked poly(trimethylene carbonate) (PTMC) networks and ß-tricalcium phosphate (ß-TCP), are tested in vivo in twelve Göttingen minipigs in a large mandibular continuity defect model. The 25 mm defects are supported by patient-specific titanium reconstruction plates and receive either osteoconductive composite bioimplants (PTMC+TCP), neat polymer network bioimplants (PTMC), autologous bone segments (positive control), or are left empty (negative control). Postoperatively, defects treated with bioimplants show evident ossification at 24 weeks. Histopathologic evaluation reveals that neat PTMC bioimplant surfaces are largely covered with fibrous tissue, while in the PTMC+TCP bioimplants, bone attached directly to the implant surface shows good osteoconduction and histological signs of osteoinductivity. However, PTMC+TCP bioimplants are associated with high incidence of necrosis and infection, possibly due to rapid resorption and/or particle size of the used ß-TCP. The study highlights the importance of testing bone regeneration implants in a clinically relevant large animal model and at the in situ reconstruction site, since results on small animal models and studies in nonloadbearing areas do not translate directly.

Improved Bone Regeneration in Rabbit Bone Defects Using 3D Printed Composite Scaffolds Functionalized with Osteoinductive Factors.

Large critical size bone defects are complicated to treat, and in many cases, autografts become a challenge due to size and availability. In such situations, a synthetic bone implant that can be patient-specifically designed and fabricated with control over parameters such as porosity, rigidity, and osteogenic cues can act as a potential synthetic bone substitute. In this study, we produced photocuring composite resins with poly(trimethylene carbonate) containing high ratios of bioactive ceramics and printed porous 3D composite scaffolds to be used as bone grafts. To enhance the overall surface area available for cell infiltration, the scaffolds were also filled with a macroporous cryogel. Furthermore, the scaffolds were functionalized with osteoactive factors: bone morphogenetic protein and zoledronic acid. The scaffolds were evaluated in vitro for biocompatibility and for functionality in vivo in critical bone defects (∼8 mm) in two clinically relevant rabbit models. These studies included a smaller study in rabbit tibia and a larger study in the rabbit cranium. It was observed that the bioactive molecule-functionalized 3D printed porous composite scaffolds provide an excellent conductive surface inducing higher bone formation and improved defect healing in both critical size long bones and cranial defects. Our findings provide strong evidence in favor of these composites as next generation synthetic bone substitutes.

Local treatment of a pleural mesothelioma tumor with ONCOS-102 induces a systemic antitumor CD8+ T-cell response, prominent infiltration of CD8+ lymphocytes and Th1 type polarization.

Late stage cancer is often associated with reduced immune recognition and a highly immunosuppressive tumor microenvironment. The presence of tumor infiltrating lymphocytes (TILs) and specific gene-signatures prior to treatment are linked to good prognosis, while the opposite is true for extensive immunosuppression. The use of adenoviruses as cancer vaccines is a form of active immunotherapy to initialise a tumor-specific immune response that targets the patient's unique tumor antigen repertoire. We report a case of a 68-year-old male with asbestos-related malignant pleural mesothelioma who was treated in a Phase I study with a granulocyte-macrophage colony­stimulating factor (GM-CSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in prominent infiltration of CD8+ lymphocytes to tumor, marked induction of systemic antitumor CD8+ T-cells and induction of Th1-type polarization in the tumor. These results indicate that ONCOS-102 treatment sensitizes tumors to other immunotherapies by inducing a T-cell positive phenotype to an initially T-cell negative tumor.