Sequential gastrodin release PU/n-HA composite scaffolds reprogram macrophages for improved osteogenesis and angiogenesis

Wound healing is a highly orchestrated process involving a variety of cells,including immune cells.Developing immunomodulatory biomaterials for regenerative engineering applications,such as bone regeneration,is an appealing strategy.Herein,inspired by the immunomodulatory effects of gastrodin(a bioactive component in traditional Chinese herbal medicine),a series of new immunomodulatory gastrodin-comprising biodegradable polyurethane(gastrodin-PU)and nano-hydroxyapatite(n-HA)(gastrodin-PU/n-HA)composites were developed.RAW 264.7 macrophages,rat bone marrow mesenchymal stem cells(rBMSCs),and human umbilical vein endothelial cells(HUVECs)were cultured with gastrodin-PU/n-HA containing different concentrations of gastrodin(0.5%,1%,and 2%)to decipher their immunomodulatory effects on osteogenesis and angiogenesis in vitro.Results demonstrated that,compared with PU/n-HA,gastrodin-PU/n-HA induced macrophage polarization toward the M2 phenotype,as evidenced by the higher expression level of pro-regenerative cytokines(CD206,Arg-1)and the lower expression of pro-inflammatory cytokines(iNOS).The expression levels of osteogenesis-related factors(BMP-2 and ALP)in the rBMSCs and angiogenesis-related factors(VEGF and BFGF)in the HUVECs were significantly up-regulated in gastrodin-PU/n-HA/macrophage-conditioned medium.The immunomodulatory effects of gastrodin-PU/n-HA to reprogram macrophages from a pro-inflammatory(M1)phenotype to an anti-inflammatory and pro-healing(M2)phenotype were validated in a rat subcutaneous implantation model.And the 2%gastrodin-PU/n-HA significantly decreased fibrous capsule formation and enhanced angiogenesis.Additionally,2%gastrodin-PU/n-HA scaffolds implanted in the rat femoral condyle defect model showed accelerated osteogenesis and angiogenesis.Thus,the novel gastrodin-PU/n-HA scaffold may represent a new and promising immunomodulatory biomaterial for bone repair and regeneration.

Gastrodin modified polyurethane conduit promotes nerve repair via optimizing Schwann cells function

Peripheral nerve regeneration and functional recovery remain a major clinical challenge.Nerve guidance conduit(NGC)that can regulate biological behavior of Schwann cells(SCs)and facilitate axonal regeneration through microenvironmental remodeling is beneficial for nerve regeneration and functional recovery.Gastrodin,a main constituent of a Chinese traditional herbal medicine,has been known to display several biological and pharmacological properties,especially antioxidative,anti-inflammatory and nerve regeneration.Herein,polyurethane(PU)NGCs modified by different weight ratio of Gastrodin(0,1 and 5 wt%)were designed for sequential and sustainable drug release,that created a favorable microenvironment for nerve regeneration.The scaffold showed suitable pore structure and biocompatibility in vitro,and evidently promoted morphological and functional recovery of regenerated sciatic nerves in vivo.Compared to the PU and 1% Gastrodin/PU scaffolds,the 5% Gastrodin/PU significantly enhanced the proliferation,migration and myelination of SCs and up-regulated expression of neurotrophic factors,as well as induction of the differentiation of PC12 cells.Interestingly,the obvious anti-inflammatory response was observed in 5% Gastrodin/PU by reduced expression of TNF-α and iNOS,which also evidenced by the few fibrous capsule formation in the subcutaneous implantation.Such a construct presented a similarity to autograft in vivo repairing a 10 mm sciatic nerve defects.It was able to not only boost the regenerated area of nerve and microvascular network,but also facilitate functional axons growth and remyelination,leading to highly improved functional restoration.These findings demonstrate that the 5% Gastrodin/PU NGC efficiently promotes nerve regeneration,indicating their potential for use in peripheral nerve regeneration applications.