Minimally invasive thermosensitive hydrogels to promote angiogenesis for bone regeneration and drug delivery

Abstract

OBJECTIVES The lack of sufficient blood supply to tissues due to the insufficient vascularity, the ultimate bone healing remains very challenging. Current clinical treatments often cause further blood loss due to multiple surgical interventions. Therefore, there is a significant need to develop minimally invasive injectable materials to promote bone angiogenesis. Stimuli responsive injectable hydrogels allow simple injection and in-situ gelation at targeted tissues, also offering therapeutic agents delivery e.g. drugs and cells. We aim to develop hybrid thermosensitive injectable hydrogels by incorporating biodegradable chitosan (CS), bioactive hydroxyapatite and heparin (Hep) to investigate its potential for angiogenesis due to its highly anionic nature that can anchorage physiological angiogenic growth factors. METHODS Injectable hydrogel solutions were produced via sol-gel technique after neutralization with sodium bicarbonate at 4°C, and hydrogels were formed upon incubation at 37°C. Sol injectability, rheological, gelation and chemical features and biological analyses involving cell cytotoxicity, angiogenesis via an ex-ovo Chick Chorioallantoic Membrane (CAM) assay, bioactivity and in-vitro degradation studies performed for characterisation of hydrogels. RESULTS AND CONCLUSIONS The thermosensitive liquid formulations allowing easy injection transferred to thermosetting gels instinctively at body temperature starting in 5-10 min. Hydrogels exhibited pro-angiogenic response in certain compositions achieved with minimal heparin concentrations. Bioactivity studies demonstrated needle-like carbonated apatite deposition on hydrogels. In-vitro degradation study of hydrogels showed substantial weight loss up to 60-70% at six-weeks. Bioactive and biodegradable CS/HA/Hep injectable hydrogels may be considered for clinical applications to stimulate bone angiogenesis in non-load bearing bone repair and regeneration.