Abstract
Biomaterials that promote angiogenesis are required for repair and regeneration of bone. In-situ formed injectable hydrogels functionalised with bioactive agents, facilitating angiogenesis have high demand for bone regeneration. In this study, pH and thermosensitive hydrogels based on chitosan (CS) and hydroxyapatite (HA) composite materials loaded with heparin (Hep) were investigated for their pro-angiogenic potential. Hydrogel formulations with varying Hep concentrations were prepared by sol–gel technique for these homogeneous solutions were neutralised with sodium bicarbonate (NaHCO3) at 4 °C. Solutions (CS/HA/Hep) constituted hydrogels setting at 37 °C which was initiated from surface in 5–10 minutes. Hydrogels were characterised by performing injectability, gelation, rheology, morphology, chemical and biological analyses. Hydrogel solutions facilitated manual dropwise injection from 21 Gauge which is highly used for orthopaedic and dental administrations, and the maximum injection force measured through 19 G needle (17.191 ± 2.296N) was convenient for manual injections. Angiogenesis tests were performed by an ex-ovo chick chorioallantoic membrane (CAM) assay by applying injectable solutions on CAM, which produced in situ hydrogels. Hydrogels induced microvascularity in CAM assay this was confirmed by histology analyses. Hydrogels with lower concentration of Hep showed more efficiency in pro-angiogenic response. Thereof, novel injectable hydrogels inducing angiogenesis (CS/HA/Hep) are potential candidates for bone regeneration and drug delivery applications.
Highlights
The conventional cell-scaffolds techniques in tissue engineering require direct surgical operations leading causality of bones, devastation of vicinal tissues and traumas as well as difficulties in their production and cell seeding into their inner cavities
The results have shown that the composite hydrogels with (CS/HA/Hep) and without heparin (CS/HA) have indicated pro-angiogenic response in Chorioallantoic Membrane (CAM)
Homogeneous chitosan and composite solutions were obtained at pH between 6.2–6.3 upon neutralisation with NaHCO3 while higher pH led to precipitation problems
Summary
The conventional cell-scaffolds techniques in tissue engineering require direct surgical operations leading causality of bones, devastation of vicinal tissues and traumas as well as difficulties in their production and cell seeding into their inner cavities. In situ form-injectable hydrogels have drawn attentions since they offer minimal invasive straightforward injection and subsequent crosslinked gel formation by moulding complex tissue defects in the body stimulated by an external or internal stimulus [1,2]. Hydrogels as extra cellular matrix (ECM) mimetic materials due to their highly hydrated, permeable and porous structures enable guided tissue regeneration facilitating cell activities, nutrition and waste transfer through their crosslinked networks [3]. Swelling and degradation ability of polymer matrix hydrogels make them suitable vehicles to encapsulate and deliver numerous therapeutic agents, such as cells, growth factors, drugs, and genes at tissue defects [4]. In-situ forming thermosensitive hydrogel found as liquid in room temperature and form gel via an internal stimuli of natural body temperature. Thermally responsive hydrogels are soluble below a certain temperature, which is known as lower critical solution temperature (LCST) whereas they form insoluble gels above this temperature in body [6]
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