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ntibiotic-loaded biomaterials (ALBs) have emerged as a potential useful adjunctive antimicrobial measure for the prevention of infection in open fracture care. A biodegradable thermo-responsive poly(N-isopropylacrylamide) grafted hyaluronic acid (HApN) hydrogel loaded with gentamicin has recently been shown to prevent implant-related infection in a rabbit osteosynthesis model. The primary aim of this study was to determine the influence of this HApN hydrogel on bone healing at an early stage (4 weeks). A rabbit humeral osteotomy model with plating osteosynthesis was used to compare fracture healing in rabbits receiving the hydrogel as compared with control animals. The secondary aim was to observe fracture healing in groups treated with and without antibiotic-loaded hydrogel in the presence of bacterial contamination. In all groups, outcome measures were mechanical stability and histological score, with additional quantitative bacteriology in the inoculated groups. Application of the HApN hydrogel in non-inoculated rabbits did not significantly influence humeral stiffness or histological scores for fracture healing in comparison to controls. In the inoculated groups, animals receiving the bacterial inoculum without hydrogel were culture-positive at euthanasia and found to display lower humeral stiffness values and higher histopathological scores for bacterial presence in comparison with equivalents receiving the gentamicin-loaded HApN hydrogel, which were also infection-free. In summary, our data showed that HApN was an effective antibiotic carrier that did not affect fracture healing. This data supported its suitability for application in fracture care. Addition of osteopromotive compounds could provide further support for accelerating fracture healing in addition to successful infection prophylaxis.

Mesenchymal stem cells (MSCs) are currently being investigated as candidate cells for regenerative medicine approaches for the repair of damaged articular cartilage. For these cells to be used clinically, it is important to understand how they will react to the complex loading environment of a joint in vivo. In addition to investigating alternative cell sources, it is also important for the structure of tissue‐engineered constructs and the organization of cells within them to be developed and, if possible, improved. A custom built bioreactor was used to expose human MSCs to a combination of shear and compression loading. The MSCs were either evenly distributed throughout fibrin‐poly(ester‐urethane) scaffolds or asymmetrically seeded with a small proportion seeded on the surface of the scaffold. The effect of cell distribution on the production and deposition of cartilage‐like matrix in response to mechanical load mimicking in vivo joint loading was then investigated. The results show that asymmetrically seeding the scaffold led to markedly improved tissue development based on histologically detectable matrix deposition. Consideration of cell location, therefore, is an important aspect in the development of regenerative medicine approaches for cartilage repair. This is particularly relevant when considering the natural biomechanical environment of the joint in vivo and patient rehabilitation protocols. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

INTRODUCTION: The recurrence rate of chronic osteomyelitis in adults is close to 30% [1]. Bacteria are known to migrate deeper into bone tissue through canaliculi and evade common systemic- and local-antibiotic therapies [2]. By fabricating antibiotic loaded poly(ϵ-caprolactone) (PCL) microspheres conjugated with the bone-chelator poly(aspartic acid) (PAA) we aim to prolong the microsphere residency near the site of infection, increasing bactericidal potential. METHODS: Hydrophobic Gentamicin-dioctyl sulfosuccinate (Gen-AOT) loaded PCL microspheres were made by oil/water emulsion methods. In vitro antimicrobial properties were tested by zone of inhibition (ZOI) in a serial plate transfer test with S. aureus. In vivo antimicrobial efficacy of 1 mg of microspheres was tested in a femoral defect in rats (n =5), infected with 2·106 colony forming units (CFU) of bioluminescent Xen-29 a week prior to treatment. In a 2nd study, the PCL microspheres underwent conjugation with PAA by carbodiimide chemistry. Interaction with bone mineral was assessed in the same model as above. IR780 iodide loaded PCL or PCL-PAA microspheres (1 mg) were injected in the bone defect and traced using an in vivo imaging system (IVIS Lumina III, Perkin Elmer). RESULTS & DISCUSSION: ZOI of Gen-AOT loaded PCL was measurable for 5 days, while a ZOI for bactericidal collagen-sheets was visible for 3 days. The Gen-AOT loaded PCL microspheres caused an 81% reduction in CFU compared to untreated control. In vivo, a brighter signal was measured for PCL-PAA compared to PCL microspheres, validating the hypothesis that PAA-grafted PCL resides longer in bone as control PCL. CONCLUSIONS: In the presented animal model, a monotreatment of 1 mg PCL microspheres caused an 81% CFU reduction. PCL-PAA microspheres enhance bone affinity by chelation of the PAA to bone mineral at the femoral defect. Further work is required to optimize the bone-targeted drug delivery system to bone.

Designing calcium phosphate-loaded polymeric porous scaffolds with controlled architecture using stereolithography (SLA) has great potential in the field of bone tissue engineering. However, the use of poly(ester)s with suboptimal degradation property has mainly been reported. In the present work, we introduced a poly(trimethylene carbonate) (PTMC) and nano-hydroxyapatite (HA) resin suitable for SLA manufacturing and created cytocompatible 3D porous structure. First, the resin formulation and HA content were optimized for photo-crosslink-based SLA fabrication process. Subsequently, we evaluated the influence of the resin composition on physico-chemical characteristics of fabricated films and scaffolds. Then, the influence of the biomaterial composition on human bone marrow mesenchymal stem cell viability, adhesion and proliferation was assessed. Films and macroporous scaffolds were successfully produced by photo-crosslinking with up to 40 wt% of HA (relative to PTMC). We demonstrated that addition of HA in PTMC matrices induced a direct effect on the surface properties, in terms of wettability and topography. Additionally, mechanical tests revealed a correlation between the amounts of HA loaded in PTMC and the stiffness of the SLA-fabricated scaffolds. Importantly, the different photo-crosslinked biomaterials exhibited in vitro cytocompatibility, similar to tissue culture polystyrene. Those data suggest the possibility to fabricate highly tunable HA-loaded PTMC 3D porous structures for bone tissue engineering application.

Complex bony defects such as those of the orbital floor are challenging to repair. Additive manufacturing techniques open up possibilities for the fabrication of implants with a designed macro-porosity for the reconstruction of such defects. Apart from a designed macro-porosity for tissue ingrowth, a micro-porosity in the implant struts will be beneficial for nutrient diffusion, protein adsorption and drug loading and release. In this work, we report on a low-temperature extrusion-based additive manufacturing method for the preparation of composite photo-crosslinked structures of poly(trimethylene carbonate) with bone-forming nano-hydroxyapatite and noricaritin (derived from bone growth stimulating icariin). In this method, we extrude a dispersion of nano-hydroxyapatite and noricaritin particles in a solution of photo-crosslinkable poly(trimethylene carbonate) in ethylene carbonate into defined three-dimensional structures. The ethylene carbonate is subsequently crystallized and extracted after photo-crosslinking. We show that this results in designed macro-porous structures with micro-pores in the struts. The dispersion used to fabricate these structures shows favorable properties for extrusion-based processing, such as a sharp crystallization response and shear thinning. The formed photo-crosslinked materials have a micro-porosity of up to 48%, and the E modulus, ultimate tensile strength and toughness are in excess of 24MPa, 2.0N/mm(2) and 113N/mm(2) respectively. A sustained release of noricaritin from these materials was also achieved. The results show that the technique described here is promising for the fabrication of micro-porous photo-crosslinked composite structures of poly(trimethylene carbonate) with nano-hydroxyapatite and that these may be applied in the reconstruction of orbital floor defects.

Repeated administration of gentamicin (Gen) is often necessary to have efficacious pharmacokinetics in both infection prophylaxis and treatment. In order to increase the half-time of Gen sulfate and minimize the dosage, the antibiotic can be grafted to polymers as a prodrug or encapsulated within polymers. Gen is positively charged and can interact with negatively charged macromolecules to form polyelectrolyte complexes (PECs). The complexation of Gen with hyaluronic acid (HA) was investigated here. Subsequently, several HA conjugates were prepared and screened for their thermo-responsive behavior and their ability to form PECs with Gen. PEC formation with HA poly(N-isopropylacrylamide) yields an injectable formulation, which precipitates out of solution to form microscopic or macroscopic gels, depending on its concentration, at temperatures higher than the lower critical solution temperature

Fractures of the orbital floor are common in traffic accidents and assaults, and inadequate treatment can result in serious complications. Accurate anatomical reconstruction of the orbit using implants is the preferred treatment. Implants require degradability, adequate mechanical properties to support the orbital contents, and osteoinductivity or osteoconductivity so that the implant is replaced by de novo bone over time. Here, we report on a semi-automatic process for the generation of virtual models of patient-specific implants for orbital floor reconstruction. These models were generated using clinical computed tomography images of five clinical cases of orbital fracture. To fabricate accurately shaped implants based on the models, we utilized stereolithography, a high-resolution additive manufacturing technique. We prepared resins from bioresorbable, photo-curable functionalized poly(trimethylene carbonate) oligomers and osteoinductive nano-hydroxyapatite to manufacture composite implants. Incorporation of 40 wt.% nano-hydroxyapatite into photo-crosslinked poly(trimethylene carbonate) leads to an increase of the E modulus, ultimate strength and toughness from 2.8 to 60 MPa, 2.4 to 7.1 N/mm2 and 330 to 1671 N/mm2, respectively. Additionally, water uptake increased from 0.8% to 7.3%, and water contact angle decreased from 80 degrees to 68 degrees. Patient-specific, homogeneous, and mechanically stable implants can readily be prepared using these composite resins. Copyright (C) 2015 John Wiley & Sons, Ltd.

Objectives: Implantation of genetically modified MSCs with polyurethane (PU) scaffolds is an attractive tool to treat articular cartilage defects. Here we evaluated whether rAAV sox9 gene transfer in hMSCs seeded onto PU scaffolds enhances the chondrogenic differentiation processes in dynamic culture[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)

Tissue engineering represents an alternative approach to the current invasive surgical procedures for the intervertebral disc (IVD) repair. The combination of injectable hydrogels and elastic biomaterials allow three-dimensional cell cultures and provide mechanical stability. In the present study a thermoreversible hyaluronan (HA) hydrogel as well as fibrin glue were mixed with polyurethane (PU) and their effect was investigated on the proliferation and differentiation of human IVD (hIVD cells) and mesenchymal stem cells (hMSCs) by in vitro and ex-vivo experiments.