Engineering of a NIR-activable hydrogel-coated mesoporous bioactive glass scaffold with dual-mode parathyroid hormone derivative release property for angiogenesis and bone regeneration

Osteogenesis,osteoclastogenesis,and angiogenesis play crucial roles in bone regeneration.Parathyroid hormone(PTH),an FDA-approved drug with pro-osteogenic,pro-osteoclastogenic and proangiogenic capabilities,has been employed for clinical osteoporosis treatment through systemic intermittent administration.However,the successful application of PTH for local bone defect repair generally requires the incorporation and delivery by appropriate carriers.Though several scaffolds have been developed to deliver PTH,they suffer from the weaknesses such as uncontrollable PTH release,insufficient porous structure and low mechanical strength.Herein,a novel kind of NIR-activable scaffold(CBP/MBGS/PTHrP-2)with dual-mode PTHrP-2(a PTH derivative)release capability is developed to synergistically promote osteogenesis and angiogenesis for high-efficacy bone regeneration,which is fabricated by integrating the PTHrP-2-loaded hierarchically mesoporous bioactive glass(MBG)into the N-hydroxymethylacrylamide-modified,photothermal agent-doped,poly(N-isopropylacrylamide)-based thermosensitive hydrogels through assembly process.Upon on/off NIR irradiation,the thermoresponsive hydrogel gating undergoes a reversible phase transition to allow the precise control of on-demand pulsatile and long-term slow release of PTHrP-2 from MBG mesopores.Such NIR-activated dual-mode delivery of PTHrP-2 by this scaffold enables a well-maintained PTHrP-2 concentration at the bone defect sites to continually stimulate vascularization and promote osteoblasts to facilitate and accelerate bone remodeling.In vivo experiments confirm the significant improvement of bone reparative effect on critical-size femoral defects of rats.This work paves an avenue for the development of novel dual-mode delivery systems for effective bone regeneration.

Development of a novel RNAi therapy:Engineered miR-31 exosomes promoted the healing of diabetic wounds

Rationale:Chronic wounds associated with diabetes exact a heavy burden on individuals and society and do not have a specific treatment.Exosome therapy is an extension of stem cell therapy,and RNA interference(RNAi)-based therapy is a type of advanced precision therapy.Based on the discovery of chronic wound-related genes in diabetes,we combined exosome therapy and RNAi therapy through an engineering approach for the treatment of diabetic chronic wounds.Methods:We combined exosome therapy and RNAi therapy to establish a precision therapy for diabetes-associated wounds via an engineered exosome approach.Results:First,chronic diabetic wounds express low levels of miR-31-5p compared with nondiabetic wounds,and an miR-31-5p mimic was shown to be effective in promoting the proliferation and migration of three wound-related cell types in vitro.Second,bioinformatics analysis,luciferase reporter assays and western blotting suggested that miR-31-5p promoted angiogenesis,fibrogenesis and reepithelization by inhibiting factor-inhibiting HIF-1(HIF1AN,also named FIH)and epithelial membrane protein-1(EMP-1).Third,engineered miR-31 exosomes were generated as a miR-31-5p RNAi therapeutic agent.In vivo,the engineered miR-31 exosomes promoted diabetic wound healing by enhancing angiogenesis,fibrogenesis and reepithelization.Conclusion:Engineered miR-31 exosomes are an ideal disease pathophysiology-initiated RNAi therapeutic agent for diabetic wounds.