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Neurological heterotopic ossification (NHO) is the abnormal formation of bone in soft tissues as a consequence of spinal cord or traumatic brain injury. NHO causes pain, ankyloses, vascular and nerve compression and delays rehabilitation in this high-morbidity patient group. The pathological mechanisms leading to NHO remain unknown and consequently there are no therapeutic options to prevent or reduce NHO. Genetically modified mouse models of rare genetic forms of heterotopic ossification (HO) exist, but their relevance to NHO is questionable. Consequently, we developed the first model of spinal cord injury (SCI)-induced NHO in genetically unmodified mice. Formation of NHO, measured by micro-computed tomography, required the combination of both SCI and localized muscular inflammation. Our NHO model faithfully reproduced many clinical features of NHO in SCI patients and both human and mouse NHO tissues contained macrophages. Muscle-derived mesenchymal progenitors underwent osteoblast differentiation in vitro in response to serum from NHO mice without additional exogenous osteogenic stimuli. Substance P was identified as a candidate NHO systemic neuropeptide, as it was significantly elevated in the serum of NHO patients. However, antagonism of substance P receptor in our NHO model only modestly reduced the volume of NHO. In contrast, ablation of phagocytic macrophages with clodronate-loaded liposomes reduced the size of NHO by 90%, supporting the conclusion that NHO is highly dependent on inflammation and phagocytic macrophages in soft tissues. Overall, we have developed the first clinically relevant model of NHO and demonstrated that a combined insult of neurological injury and soft tissue inflammation drives NHO pathophysiology.

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Craniofacial tissues are organized with complex 3-dimensional (3D) architectures. Mimicking such 3D complexity and the multicellular interactions naturally occurring in craniofacial structures represents one of the greatest challenges in regenerative dentistry. Three-dimensional bioprinting of tissues and biological structures has been proposed as a promising alternative to address some of these key challenges. It enables precise manufacture of various biomaterials with complex 3D architectures, while being compatible with multiple cell sources and being customizable to patient-specific needs. This review describes different 3D bioprinting methods and summarizes how different classes of biomaterials (polymer hydrogels, ceramics, composites, and cell aggregates) may be used for 3D biomanufacturing of scaffolds, as well as craniofacial tissue analogs. While the fabrication of scaffolds upon which cells attach, migrate, and proliferate is already in use, printing of all the components that form a tissue (living cells and matrix materials together) to produce tissue constructs is still in its early stages. In summary, this review seeks to highlight some of the key advantages of 3D bioprinting technology for the regeneration of craniofacial structures. Additionally, it stimulates progress on the development of strategies that will promote the translation of craniofacial tissue engineering from the laboratory bench to the chair side.

Flexible tubular structures fabricated from solution electrospun fibers are finding increasing use in tissue engineering applications. However it is difficult to control the deposition of fibers due to the chaotic nature of the solution electrospinning jet. By using non-conductive polymer melts instead of polymer solutions the path and collection of the fiber becomes predictable. In this work we demonstrate the melt electrospinning of polycaprolactone in a direct writing mode onto a rotating cylinder. This allows the design and fabrication of tubes using 20 μm diameter fibers with controllable micropatterns and mechanical properties. A key design parameter is the fiber winding angle, where it allows control over scaffold pore morphology (e.g. size, shape, number and porosity). Furthermore, the establishment of a finite element model as a predictive design tool is validated against mechanical testing results of melt electrospun tubes to show that a lesser winding angle provides improved mechanical response to uniaxial tension and compression. In addition, we show that melt electrospun tubes support the growth of three different cell types in vitro and are therefore promising scaffolds for tissue engineering applications.Electronic supplementary materialThe online version of this article (doi:10.1007/s13758-011-0013-7) contains supplementary material, which is available to authorized users.