Department of Orthopaedics Surgery, New York University Grossman School of Medicine, New York, NY, 10003, USA; Department of Orthopaedics & Rehabilitation, Yale University School of Medicine, New Haven, CT, 06510, USA.
Biomaterials Division - Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, 10010, USA; Department of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, NY, 11201, USA.
Biomaterials. 2023 Oct;301:122289. doi: 10.1016/j.biomaterials.2023.122289. Epub 2023 Aug 25.
Hydrogels with long-term storage stability, controllable sustained-release properties, and biocompatibility have been garnering attention as carriers for drug/growth factor delivery in tissue engineering applications. Chitosan (CS)/Graphene Oxide (GO)/Hydroxyethyl cellulose (HEC)/β-glycerol phosphate (β-GP) hydrogel is capable of forming a 3D gel network at physiological temperature (37 °C), rendering it an excellent candidate for use as an injectable biomaterial. This work focused on an injectable thermo-responsive CS/GO/HEC/β-GP hydrogel, which was designed to deliver Atsttrin, an engineered derivative of a known chondrogenic and anti-inflammatory growth factor-like molecule progranulin. The combination of the CS/GO/HEC/β-GP hydrogel and Atsttrin provides a unique biochemical and biomechanical environment to enhance fracture healing. CS/GO/HEC/β-GP hydrogels with increased amounts of GO exhibited rapid sol-gel transition, higher viscosity, and sustained release of Atsttrin. In addition, these hydrogels exhibited a porous interconnected structure. The combination of Atsttrin and hydrogel successfully promoted chondrogenesis and osteogenesis of bone marrow mesenchymal stem cells (bmMSCs) in vitro. Furthermore, the work also presented in vivo evidence that injection of Atsttrin-loaded CS/GO/HEC/β-GP hydrogel stimulated diabetic fracture healing by simultaneously inhibiting inflammatory and stimulating cartilage regeneration and endochondral bone formation signaling pathways. Collectively, the developed injectable thermo-responsive CS/GO/HEC/βG-P hydrogel yielded to be minimally invasive, as well as capable of prolonged and sustained delivery of Atsttrin, for therapeutic application in impaired fracture healing, particularly diabetic fracture healing.
具有长期储存稳定性、可控持续释放性能和生物相容性的水凝胶作为药物/生长因子传递载体在组织工程应用中受到关注。壳聚糖 (CS)/氧化石墨烯 (GO)/羟乙基纤维素 (HEC)/β-甘油磷酸酯 (β-GP) 水凝胶能够在生理温度 (37°C) 下形成 3D 凝胶网络，使其成为一种出色的可注射生物材料候选物。本工作专注于一种可注射的温敏 CS/GO/HEC/β-GP 水凝胶，旨在递送 Atsttrin，一种已知的软骨生成和抗炎生长因子样分子颗粒蛋白前体的工程衍生物。CS/GO/HEC/β-GP 水凝胶与 Atsttrin 的结合提供了独特的生化和生物力学环境，以增强骨折愈合。GO 含量增加的 CS/GO/HEC/β-GP 水凝胶表现出快速溶胶-凝胶转变、更高的粘度和 Atsttrin 的持续释放。此外，这些水凝胶表现出多孔相互连接的结构。Atsttrin 和水凝胶的组合成功地促进了骨髓间充质干细胞 (bmMSCs) 的体外软骨生成和成骨。此外，该工作还提供了体内证据，表明注射载有 Atsttrin 的 CS/GO/HEC/β-GP 水凝胶通过同时抑制炎症和刺激软骨再生和软骨内成骨信号通路来刺激糖尿病性骨折愈合。总之，所开发的可注射温敏 CS/GO/HEC/β-G-P 水凝胶具有微创性，并且能够延长和持续递送 Atsttrin，可用于治疗受损的骨折愈合，特别是糖尿病性骨折愈合。
