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 beta-tricalcium phosphate (beta-TCP), are tested in vivo in twelve Gottingen 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 beta-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.Peer reviewe

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

Peer reviewe

Gene expression analysis of tumors demonstrates an induction of Th1 type immune response following intratumoral administration of ONCOS-102 in refractory solid tumor patients

2014-11-0

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

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

Multicenter, open-label, exploratory clinical trial with Rhodiola rosea extract in patients suffering from burnout symptoms

Siegfried Kasper,1 Angelika Dienel2 1Universitätsklinik für Psychiatrie und Psychotherapie, Medizinische Universität Wien, Wien, Austria; 2Dr Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany Purpose: This study is the first clinical trial aiming to explore the clinical outcomes in burnout patients treated with Rhodiola rosea. The reported capacity of R. rosea to strengthen the organism against stress and its good tolerability offer a promising approach in the treatment of stress-related burnout. The aim of the treatment was to increase stress resistance, thus addressing the source rather than the symptoms of the syndrome and preventing subsequent diseases associated with a history of burnout. The objective of the trial was to provide the exploratory data required for planning future randomized trials in burnout patients in order to investigate the clinical outcomes of treatment with R. rosea dry extract in this target group.Methods: The study was planned as an exploratory, open-label, multicenter, single-arm trial. A wide range of rating scales were assessed and evaluated in an exploratory data analysis to generate hypotheses regarding clinical courses and to provide a basis for the planning of subsequent studies. A total of 118 outpatients were enrolled. A daily dose of 400 mg R. rosea extract (WS® 1375, Rosalin) was administered over 12 weeks. Clinical outcomes were assessed by the German version of the Maslach Burnout Inventory, Burnout Screening Scales I and II, Sheehan Disability Scale, Perceived Stress Questionnaire, Number Connection Test, Multidimensional Mood State Questionnaire, Numerical Analogue Scales for different stress symptoms and impairment of sexual life, Patient Sexual Function Questionnaire, and the Clinical Global Impression Scales. Results: The majority of the outcome measures showed clear improvement over time. Several parameters had already improved after 1 week of treatment and continued to improve further up to the end of the study. The incidence of adverse events was low with 0.015 events per observation day.Discussion: The trial reported here was the first to investigate clinical outcomes in patients suffering from burnout symptoms when treated with R. rosea. During administration of the study drug over the course of 12 weeks, a wide range of outcome measures associated with the syndrome clearly improved.Conclusion: The results presented provide an encouraging basis for clinical trials further investigating the clinical outcomes of R. rosea extract in patients with the burnout syndrome. Keywords: burnout, clinical study, Rhodiola rose

Additive Manufacturing of Bioactive Poly(trimethylene carbonate)/β-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 β-tricalcium phosphate (β-TCP). Tensile testing of composite networks showed that addition of β-tricalcium phosphate reinforces the composites significantly. Three-dimensional structures containing up to 60 wt % β-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 β-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 β-TCP are an important candidate to consider in additive manufacturing of bone regeneration implants.Peer reviewe