光交联功能化水凝胶促进骨修复研究进展

doi:10.3877/cma.j.issn.2096-0263.2026.04.007

传统骨修复材料存在生长因子稳定性差、释药过程难以精确控制及病理微环境适应不足等问题。功能化光交联水凝胶可通过组分与交联网络设计改善局部递送，并调节免疫、代谢、氧化还原及血管生成微环境。本文综述功能化水凝胶促进骨再生的研究进展，重点分析微环境重编程、刺激响应释放、仿生设计及多层级协同修复机制。现有研究表明，物理、化学及多重刺激响应体系可提高活性物质释放的时空可控性，材料组成、结构和界面特性则可影响巨噬细胞极化、干细胞成骨分化及血管-骨耦合。当前证据仍以细胞和动物研究为主，临床转化尚需解决规模化制备的一致性、长期生物安全性、监管分类及临床有效性验证等问题。功能化水凝胶有望由被动递送载体发展为可调控的骨缺损修复平台。

关键词: 功能化水凝胶, 骨再生, 微环境重编程, 智能响应系统, 协同修复网络

Traditional bone-repair materials are limited by poor growth-factor stability, imprecise release kinetics, and insufficient adaptation to pathological microenvironments. Functionalized photocrosslinkable hydrogels provide a tunable platform for local delivery and for regulating immune, metabolic, redox, and angiogenic responses. This review summarizes recent advances in these hydrogels for bone regeneration, with emphasis on microenvironment reprogramming, stimulus-responsive release, biomimetic design, and coordinated repair mechanisms. Current studies show that physical, chemical, and multistimulus-responsive systems can improve the spatial and temporal control of bioactive cargo, while material composition, structure, and interfacial properties influence macrophage polarization, stem-cell osteogenesis, and vascular-bone coupling. Most evidence, however, remains preclinical. Reproducible manufacturing, long-term biosafety, regulatory classification, and validation in clinically relevant models remain major barriers to translation. Addressing these issues may support the development of functionalized hydrogels from passive carriers into adaptive platforms for bone-defect repair.

Key words: Functionalized hydrogels, Bone regeneration, Microenvironment reprogramming, Intelligent response systems, Synergistic repair networks

图1 光交联功能化水凝胶调控骨缺损微环境的策略示意图。图中从左至右概括：（1）传统递送体系存在生长因子突释、局部滞留不足、稳定性欠佳和功能单一等局限；（2）功能化水凝胶可从免疫、代谢、氧化还原及血管生成四个维度调节局部微环境；（3）物理刺激、化学微环境及多重响应网络可用于调控材料状态和载荷释放；（4）信号通路、细胞间通讯和生物因子序贯释放共同参与免疫-血管-成骨耦合；（5）3D生物打印和个体化结构设计为临床转化提供制造路径。图中的数字孪生和微传感器监测属于前瞻性概念，尚需实验和临床验证注：骨髓间充质干细胞（bone marrow mesenchymal stem cells，BMSCs）与人脐静脉内皮细胞（human umbilical vein endothelial cells，HUVECs）的空间组织可促进血管-骨耦合。骨形态发生蛋白-2（bone morphogenetic protein-2，BMP-2）与神经生长因子（nerve growth factor，NGF）的序贯释放可通过降钙素基因相关肽（calcitonin gene-related peptide，CGRP）相关信号协调神经重建和成骨；CGRP还参与H型血管与成骨祖细胞的耦合。D-甘露糖可调节核苷酸结合寡聚化结构域样受体蛋白3（NOD-like receptor family pyrin domain-containing 3，NLRP3）炎症小体及三羧酸循环（tricarboxylic acid cycle，TCA cycle），ROS响应体系则通过清除活性氧（reactive oxygen species，ROS）改善氧化应激。PI3K-AKT、Wnt/β-catenin和NF-κB等通路的变化应结合具体材料与细胞模型解释

表1 功能化水凝胶重构骨缺损多维微环境的策略与效能

微环境维度	核心材料体系与响应单元	针对传统载体局限性剖析	核心靶向机制与重编程效能	参考文献
免疫重塑	镁掺杂介孔生物玻璃凝胶	改善炎症微环境下的免疫失衡	促进巨噬细胞向M2表型极化，增强成骨	^[20]
代谢维稳	D-甘露糖复合GelMA凝胶	缓解炎症相关代谢紊乱	下调NLRP3炎症小体并缓解TCA循环紊乱	^[5]
氧化平抑	动态硼酸酯键/纳米酶级联系统	应对糖尿病病灶中的高糖和高ROS	消耗葡萄糖、清除ROS并抑制过度破骨	^[6]
血管耦合	双环GelMA-MCP支架/M2外泌体复合3D支架	改善细胞空间组织和血管化不足	分别通过HUVECs/BMSCs空间封装或M2外泌体递送促进血管生成与成骨	^[27][31]

表1 功能化水凝胶重构骨缺损多维微环境的策略与效能

微环境维度	核心材料体系与响应单元	针对传统载体局限性剖析	核心靶向机制与重编程效能	参考文献
免疫重塑	镁掺杂介孔生物玻璃凝胶	改善炎症微环境下的免疫失衡	促进巨噬细胞向M2表型极化，增强成骨	^[20]
代谢维稳	D-甘露糖复合GelMA凝胶	缓解炎症相关代谢紊乱	下调NLRP3炎症小体并缓解TCA循环紊乱	^[5]
氧化平抑	动态硼酸酯键/纳米酶级联系统	应对糖尿病病灶中的高糖和高ROS	消耗葡萄糖、清除ROS并抑制过度破骨	^[6]
血管耦合	双环GelMA-MCP支架/M2外泌体复合3D支架	改善细胞空间组织和血管化不足	分别通过HUVECs/BMSCs空间封装或M2外泌体递送促进血管生成与成骨	^[27][31]

表2 智能响应型水凝胶的触发机制与时空动态调控评估

刺激源类型	响应触发信号/设计范式	代表性水凝胶体系设计	时空动态调控优势与机制	临床转化潜力评估	参考文献
电场辅助构建	制备阶段外加电场	电场驱动丝素蛋白水凝胶	同步形成力学与生长因子梯度，模拟骨软骨界面	中（依赖外部电场及专用制备设备）	^[42]
化学响应	局部微环境酸碱度（pH）及ROS	天然芥子酸双交联系统	感知牙周炎局部pH值和ROS变化，实现天然芥子酸持续释放	中（响应阈值和体内稳定性仍需验证）	^[8]
时序递送	感染修复不同阶段的治疗需求	硫量子点/钙磷复合GelMA	依次实现早期抗菌、中期ROS清除和后期促骨作用	中（多组分体系需评价工艺一致性与长期安全性）	^[16]

表2 智能响应型水凝胶的触发机制与时空动态调控评估

刺激源类型	响应触发信号/设计范式	代表性水凝胶体系设计	时空动态调控优势与机制	临床转化潜力评估	参考文献
电场辅助构建	制备阶段外加电场	电场驱动丝素蛋白水凝胶	同步形成力学与生长因子梯度，模拟骨软骨界面	中（依赖外部电场及专用制备设备）	^[42]
化学响应	局部微环境酸碱度（pH）及ROS	天然芥子酸双交联系统	感知牙周炎局部pH值和ROS变化，实现天然芥子酸持续释放	中（响应阈值和体内稳定性仍需验证）	^[8]
时序递送	感染修复不同阶段的治疗需求	硫量子点/钙磷复合GelMA	依次实现早期抗菌、中期ROS清除和后期促骨作用	中（多组分体系需评价工艺一致性与长期安全性）	^[16]

表3 骨再生多维协同网络图谱及未来演进方向

协同网络层级	构建策略与仿生材料特性	核心信号通路枢纽与细胞交互行为	科学价值与未来精准医疗演进方向	参考文献
多通路交叉	Sr/Zn-GelMA/外泌体GelMA/柚皮苷铜碳点凝胶	激活PI3K-AKT或PI3K/Akt，并调节ROS和巨噬细胞极化	从材料信号、免疫调节和成骨反应层面解释协同机制	^[19][43][44]
旁分泌通讯	HAMA/GelMA共培养支架/circAars-ADSCs GelMA	促进成纤维细胞-成骨细胞通讯及ADSCs-内皮细胞旁分泌作用	建立多细胞协同的空间模型并增强成骨与血管生成	^[46][55]
时序递送	3D打印微球-凝胶多级递送体	快速释放NGF模拟肽并持续释放BMP-2模拟肽，激活CGRP依赖通路	匹配神经募集和成骨分化的时间顺序	^[47]
结构与力学线索	木材/微晶纤维素/大孔蛋白/多尺度丝素支架	通过各向异性、比表面积、刚性力学线索和层级孔隙调节细胞行为	材料结构可改善细胞黏附、浸润和成骨分化	^{[50][51][52][53]}
细胞工程递送	工程化ADSCs/工程化细胞外囊泡GelMA	促进成骨、M2极化和血管生成，或募集老龄BMSCs并减轻其衰老	拓展细胞和囊泡的局部递送，但需验证生产与长期安全性	^[55][56]

表3 骨再生多维协同网络图谱及未来演进方向

协同网络层级	构建策略与仿生材料特性	核心信号通路枢纽与细胞交互行为	科学价值与未来精准医疗演进方向	参考文献
多通路交叉	Sr/Zn-GelMA/外泌体GelMA/柚皮苷铜碳点凝胶	激活PI3K-AKT或PI3K/Akt，并调节ROS和巨噬细胞极化	从材料信号、免疫调节和成骨反应层面解释协同机制	^[19][43][44]
旁分泌通讯	HAMA/GelMA共培养支架/circAars-ADSCs GelMA	促进成纤维细胞-成骨细胞通讯及ADSCs-内皮细胞旁分泌作用	建立多细胞协同的空间模型并增强成骨与血管生成	^[46][55]
时序递送	3D打印微球-凝胶多级递送体	快速释放NGF模拟肽并持续释放BMP-2模拟肽，激活CGRP依赖通路	匹配神经募集和成骨分化的时间顺序	^[47]
结构与力学线索	木材/微晶纤维素/大孔蛋白/多尺度丝素支架	通过各向异性、比表面积、刚性力学线索和层级孔隙调节细胞行为	材料结构可改善细胞黏附、浸润和成骨分化	^{[50][51][52][53]}
细胞工程递送	工程化ADSCs/工程化细胞外囊泡GelMA	促进成骨、M2极化和血管生成，或募集老龄BMSCs并减轻其衰老	拓展细胞和囊泡的局部递送，但需验证生产与长期安全性	^[55][56]

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Research progress on photocrosslinkable functionalized hydrogels for promoting bone repair

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Research progress on photocrosslinkable functionalized hydrogels for promoting bone repair