Diabetes has currently acquired the status of epidemic worldwide, and among its various pathological consequences like retinopathy and nephropathy, bone fragility fractures from diabetic osteopathy occurs in later stages and is equally destructive. Chronic hyperglycemia culminates into deteriorating microvasculature and quality of bone, making it prone to fractures. Among these, hip fractures are most common, especially in older diabetic patients apart from underlying neuropathy. Our study is an attempt to ameliorate hip fragility fracture and nerve trauma with electrical stimulation as an interface in a chronic diabetic rat model. We have fabricated reduced graphene oxide-substituted hydroxyapatite as an electroactive bone substitute and incorporated it into chitosan gelatin cryogels. The in situ reduction of graphene oxide during sintering of hydroxyapatite imparts higher potential to the fabricated composite in dealing with problem at question. The cryogels depicted optimum in vitro biocompatibility and enhanced mineralization after ectopic subcutaneous implantation in rats. The therapeutic potency of composite cryogels was evaluated in a hip fracture model with compression to the sciatic nerve in diabetic rats, mimicking the severe clinical trauma. The presence of cryogels in the femoral neck canal coupled with electrical stimulation and biochemical factors significantly improved bone regeneration in diabetic rats as depicted with microcomputed tomography analysis and histology images. The application of electrical stimulation also ameliorated the nerve trauma observed with 70% improvement in electrophysiological parameters such as the compound muscle action potential with combinatorial therapy. We therefore report the successful implication of a multitarget therapy in a chronic diabetic rat model unraveling the bone–nerve crosstalk with electroactive smart cryogels.

Nerve injuries leads to severe impairment of target tissue and standard treatment approaches from surgery to electrical stimulation are complex, yielding only brief relief. The current study addresses such limitations with reduced graphene oxide (rGO) functionalized “Electroband”. We attempt to conjugate electrical cues in the nerve wrap with in-situ electrical stimulation in a median nerve injury model in rats, underlining the significance of combinatorial therapy for nerve regeneration. “Electroband” targets three critical aspect of nerve regeneration: neuroprotection, neuroregeneration and neuroplasticity at single stroke. The nanofibrous extracellular matrix mimicking nature of “Electroband” assisted in reconciling the injured niche by preventing anoikis, exerting neuroprotective effect as depicted with aligned growth of compressed nerve fibers. The rGO functionalization coupled with intraoperative electrical stimulation of 3 V @ 20 Hz for 10 min aided in propelling the injured nerve to denervated target, prompting fascicular growth of nerve fibers, targeting neuroplasticity. The nerve growth factor incorporation enhanced the bioactivity of scaffold, augmenting regeneration leading to exuberant growth and myelination of nascent nerve tracts. These results led to significant improvement in electrophysiological recordings with 30–32 mV CMAP value (80% recovery) in combinatorial therapy group as compared to 10–11 mV in negative controls and 13–15 mV in animals with individual therapy. We therefore, report 80% regain in muscular strength within 8 weeks of implantation with combinatorial therapy as assessed with behavioural paw gripping and scratch tape assay. Thus, we successfully demonstrated the pre-clinical efficacy of “Electroband”, reducing the time and frequency of electrical stimulation currently in clinical practice.