Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.
Hydrogel based scaffolds for neural tissue engineering can provide appropriate physico-chemical and mechanical properties to support neurite extension and facilitate transplantation of cells by acting as ‘cell delivery vehicles’. Specifically, in situ gelling systems such as photocrosslinkable hydrogels can potentially conformally fill irregular neural tissue defects and serve as stem cell delivery systems. Here, we report the development of a novel chitosan based photocrosslinkable hydrogel system with tunable mechanical properties and degradation rates. A two-step synthesis of amino-ethyl methacrylate derivitized, degradable, photocrosslinkable chitosan hydrogels is described. When human mesenchymal stem cells were cultured in photocrosslinkable chitosan hydrogels, negligible cytotoxicity was observed. Photocrosslinkable chitosan hydrogels facilitated enhanced neurite differentiation from primary cortical neurons and enhanced neurite extension from dorsal root ganglia (DRG) as compared to agarose based hydrogels with similar storage moduli. Neural stem cells (NSCs) cultured within photocrosslinkable chitosan hydrogels facilitated differentiation into tubulin positive neurons and astrocytes. These data demonstrate the potential of photocrosslinked chitosan hydrogels, and contribute to an increasing repertoire of hydrogels designed for neural tissue engineering.
Tissue engineering approaches for peripheral nerve regeneration employ biodegradable scaffolds coupled with growth factors for improved performance in regeneration of large nerve injuries. Electrospun nanofibers provide a versatile platform for fabrication of scaffolds with extracellular matrix like architecture and increased surface area. Incorporation of growth factors in nanofibers have been previously demonstrated using oil in water emulsion techniques but are associated with burst release and loss of valuable growth factor. Here, we show a novel blend of polycaprolactone and bovine serum albumin (BSA) to form nanofibers containing nerve growth factors. The BSA helps in overcoming the most common drawbacks associated with hydrophobic polymers such as reduced loading efficiency, long degradation periods, and burst release. The controlled release of nerve growth factor (NGF) from the nanofibers was evaluated using enzyme linked immune sorbent assay (ELISA) and PC12 based bioassay over a 28 day time period. A sustained release of NGF was obtained for at least 28 days. PC12 bioassays confirmed the bioactivity of the NGF, and showed that the released NGF was sufficient to induce neurite outgrowth from PC12 cells throughout the period of release, therefore, demonstrating the successful incorporation and controlled release potential of PCL BSA scaffolds.
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