载大麻二酚海藻酸锶水凝胶促骨修复和增强骨弹性/塑性力学性能

由于意外或者疾病导致的骨缺损修复一直是骨科临床上的重点和难点。 骨缺损会引发神经性疼和炎症性疼痛。对疼痛的治疗也是骨修复材料研发 所需解决的问题之一。尽管非甾体镇痛药能抑制炎症疼痛，但其会损害骨缺 损的愈合。阿片类药物能抑制神经性疼痛，但其具有神经依赖性。大麻二酚 是一种兼具抗炎镇痛和神经镇痛的小分子，不具有神经依赖性，且能促进骨 损伤愈合。本研究通过对制备的新型载大麻二酚海藻酸锶水凝胶（cannabinol strontium alginate hydrogel, SA@Sr-CBD）进行材料学表征和性质的探索，明 确其交联方式。将该水凝胶用于修复大鼠骨缺损，研究其促骨生成、促血管 生成、抗炎、镇痛、以及骨力学性能恢复的功效。CBD 能通过酚羟基与 SA 分子形成氢键或者范德华作用力存在于水凝胶中，还能以无定形态填充到水 凝胶中。SA@Sr-CBD 水凝胶热力学性质稳定、能长效释放 CBD、具有一定 的机械力学性能。股骨缺损的大鼠对热刺激表现出更高的敏感性和更差的运 动步态。大麻二酚海藻酸锶水凝胶能使疼痛的敏感性和运动步态正常。本研 究发现该水凝胶在体内和体外能通过多种机制促进骨愈合。SA@Sr-CBD 水 凝胶在细胞实验中表现出促进 OCN、OPN、ALP、RUNX2 和 CoL1α 基因和 蛋白的表达，促进成骨分化。同时促进 VEFG 基因和蛋白的表达，抑制炎症 基因 IL-6、IL-1β、NFKB、INOS 的表达，以及促进成血管。此外还能抑制 TNFα、IL-23、PGE2、COX2 炎症基因和抑制 MCSF、CTR 破骨基因的表达。 进而在修复大鼠骨缺损中表现出显著的促进新骨生成、促进新血管生成、以 及抗炎和镇痛的功效。这些作用最终导致更高的骨体积分数、更高的骨矿物 质密度和新形成骨骼的弹性/塑性力学性能和运动功能的改善。总之，本研究 数据表明 SA@Sr-CBD 水凝胶具有镇痛的功能，恢复骨骼机械力学性能，以 及显著促进大鼠骨缺损愈合的作用。

Repair of bone defects caused by accidents or diseases has always been a focus and difficulty in clinical orthopedics. Bone defects can cause neuropathic and inflammatory pain. The treatment of pain is also one of the issues that needs to be solved in the development of bone repair materials. Although nonsteroidal analgesics suppress inflammatory pain, they can impair the healing of bone defects. Opioids can inhibit neuropathic pain, but they are nerve -dependent. Cannabidiol is a small molecule with both anti-inflammatory analgesia and neural analgesia. It is not nerve-dependent and can promote the healing of bone injuries. In this study, the materials characterization and properties of the prepared new cannabinol strontium alginate hydrogel (SA@Sr-CBD) were prepared to clarify its cross-linking method. The hydrogel was used to repair bone defects in rats, and its effects on promoting osteogenesis, promoting angiogenesis, anti-inflammation, analgesia, and restoring bone mechanical properties were studied. CBD can form hydrogen bonds or van der Waals forces with SA molecules through phenolic hydroxyl groups and exist in the hydrogel, and it can also be filled into the hydrogel in an amorphous form. SA@Sr-CBD hydrogel has stable thermodynamic properties, can release CBD for a long time, and has certain mechanical and mechanical properties. Rats with femoral defects showed higher sensitivity to thermal stimulation and worse locomotor gait. Cannabidiol strontium alginate hydrogel normalizes pain sensitivity and motor gait. This study found that the hydrogel can promote bone healing through multiple mechanisms in vivo and in vitro. SA@Sr-CBD hydrogel showed in cell experiments that it promoted the expression of OCN, OPN, ALP, RUNX2 and CoL1α genes and proteins, and promoted osteogenic differentiation. At the same time, it promotes the expression of VEFG genes and proteins, inhibits the expression of inflammatory genes IL-6, IL-1β, NFKB, and INOS, and promotes angiogenesis. In addition, it can inhibit the expression of TNFα, IL-23, PGE2, and COX2 inflammatory genes and inhibit the expression of MCSF and CTR Abstract III osteoclast genes. It then showed significant effects in promoting new bone formation, promoting new blood vessel formation, and anti-inflammatory and analgesic effects in repairing bone defects in rats. These effects ultimately lead to higher bone volume fraction, higher bone mineral density, and improved elastic/plastic mechanical properties of newly formed bone and motor function. In conclusion, the data of this study show that SA@Sr-CBD hydrogel has analgesic function, restores bone mechanical properties, and significantly promotes bone defect healing in rats. 

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