Hamiti Yimurang, Liu Kai, Yang Xin, Wang Sulong, Kadier Xiriaili, Yusufu Aihemaitijiang
Department of Trauma and Microreconstructive Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Xinjiang Key Laboratory of Trauma Repair and Reconstruction, Urumqi, Xinjiang, China.
Mater Today Bio. 2025 Aug 14;34:102181. doi: 10.1016/j.mtbio.2025.102181. eCollection 2025 Oct.
Large bone defects present significant clinical challenges, with distraction osteogenesis (DO) requiring prolonged treatment periods and yielding suboptimal outcomes. Calcitonin gene-related peptide (CGRP) demonstrates potent bone-forming activity but suffers from rapid degradation and a short half-life, limiting its therapeutic applications. This study engineered sustained-release CGRP microspheres using poly(D,L-lactide-co-glycolide)/nano-hydroxyapatite/graphene oxide (PLGA/nHA/GO) composite matrices via W/O/W double emulsion-solvent evaporation method to address these limitations. The fabricated microspheres exhibited uniform spherical morphology (51.15 ± 0.40 μm), high encapsulation efficiency (86.14 ± 2.5 %), and sustained CGRP release over 42 days. In vitro studies compared four groups: control (untreated), blank microspheres, free CGRP solution, and CGRP-loaded microspheres. CGRP microspheres significantly enhanced rat bone marrow mesenchymal stem cell proliferation, migration capacity, and osteogenic differentiation compared to all other treatment groups. Mechanistic investigations confirmed activation of the cAMP/PKA/CREB signaling pathway with upregulation of osteogenic transcription factors (Runx2, Osterix) and bone matrix proteins (osteopontin, osteocalcin). In a rat femoral distraction osteogenesis model, CGRP microspheres demonstrated superior bone regeneration compared to control, blank microspheres, and free CGRP groups: substantially increased bone mineral density, significantly improved biomechanical properties, and accelerated bone formation. Histological analysis confirmed enhanced bone maturation and integration This engineered sustained-release system represents a promising therapeutic platform for enhancing bone regeneration through targeted molecular pathway activation, offering significant potential for clinical translation in orthopedic applications.
大的骨缺损带来了重大的临床挑战，牵张成骨术（DO）需要较长的治疗周期且效果欠佳。降钙素基因相关肽（CGRP）具有强大的成骨活性，但存在快速降解和半衰期短的问题，限制了其治疗应用。本研究通过W/O/W双乳液-溶剂蒸发法，使用聚（D，L-丙交酯-共-乙交酯）/纳米羟基磷灰石/氧化石墨烯（PLGA/nHA/GO）复合基质制备了缓释CGRP微球，以解决这些局限性。制备的微球呈现出均匀的球形形态（51.15±0.40μm），具有较高的包封率（86.14±2.5%），并且CGRP能持续释放42天。体外研究比较了四组：对照组（未处理）、空白微球组、游离CGRP溶液组和载CGRP微球组。与所有其他治疗组相比，CGRP微球显著增强了大鼠骨髓间充质干细胞的增殖、迁移能力和成骨分化。机制研究证实了cAMP/PKA/CREB信号通路的激活，同时成骨转录因子（Runx2、Osterix）和骨基质蛋白（骨桥蛋白、骨钙素）上调。在大鼠股骨牵张成骨模型中，与对照组、空白微球组和游离CGRP组相比，CGRP微球显示出更好的骨再生效果：骨矿物质密度显著增加，生物力学性能显著改善，骨形成加速。组织学分析证实了骨成熟和整合的增强。这种工程化的缓释系统代表了一个有前景的治疗平台，可通过靶向分子途径激活来增强骨再生，在骨科应用中具有显著的临床转化潜力。
