Advances in matrix engineering and matrix therapy driven by extracellular matrix mechanics
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摘要: 随着全球人口老龄化和慢性病的高发, 心血管疾病、肿瘤、糖尿病等重大难治性疾病已成为全球公共健康和社会经济发展的主要挑战. 其病理进程通常伴随着细胞外基质(ECM)的异常重塑与力学稳态失衡, 导致传统治疗方法难以有效逆转. 近期研究揭示, 结合材料学与工程学原理主动调控ECM的力化属性以精准介导细胞行为, 能够有效激活组织内源性修复从而显著促进组织再生. 该研究策略被称为力材料学, 即通过对材料进行主动设计, 利用力−结构−功能关系对生命系统的力学环境进行主动控制. 基于此概念, 本文提出从基质组学角度系统鉴定ECM的分子组成并解构其力学信息编码; 利用基质力生物学认识细胞-ECM互作机制并解析病理ECM“重编码”过程; 在深入认知和理解ECM力学微环境基础上结合基质力材料学的研究思路, 探索对异常ECM“去编码”与功能恢复的基质工程技术; 最终实现组织内源性修复的基质治疗目的. 具体而言, 本文在介绍ECM的组成与动态编码的基础上, 系统总结了异常ECM力学微环境的生理/病理变化, 着重提出并构建基于分子靶向与材料重建的基质工程与治疗新策略, 旨在为重大难治性疾病的干预和再生医学的发展提供新的理论依据和创新思路.Abstract: With the global aging population and high incidence of chronic diseases, major intractable conditions such as cardiovascular diseases, tumors, and diabetes have become primary challenges to public health and socioeconomic development worldwide. Their pathological processes are often accompanied by abnormal remodeling of the extracellular matrix (ECM) and disruption of mechanical homeostasis, rendering traditional treatments ineffective in reversing these conditions. Recent studies reveal that actively modulating the mechanical properties of the ECM through principles of materials science and engineering to precisely mediate cellular behavior can effectively activate endogenous tissue repair, significantly promoting tissue regeneration. This research strategy, termed force-materials science, involves actively designing materials to leverage force-structure-function relationships for proactive control of the mechanical environment within biological systems. Based on this concept, this paper proposes: systematically identifying the molecular composition of the ECM from a matrixomics perspective and deconstructing its mechanical information encoding; utilizing matrix biomechanics to understand cell-ECM interaction mechanisms and decipher pathological ECM “re-encoding” processes; and, grounded in deep understanding of the ECM's mechanical microenvironment, exploring matrix engineering technologies for “de-encoding” abnormal ECM and restoring function by integrating matrix biomechanics principles. ultimately achieving the goal of matrix therapy for endogenous tissue repair. Specifically, this paper introduces the composition and dynamic coding of the ECM, systematically summarizes the physiological/pathological changes in abnormal ECM mechanical microenvironments, and emphasizes the proposal and construction of novel matrix engineering and therapeutic strategies based on molecular targeting and material reconstruction. These efforts aim to provide new theoretical foundations and innovative approaches for the intervention of major intractable diseases and the advancement of regenerative medicine.
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Key words:
- Extracellular Matrix /
- Matrix Mechanics /
- Matrix Mechanobiology /
- Matrix Therapy /
- Matrix Engineering.
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图 1 基质组学和基质力生物学指导力材料学设计, 力材料学驱动基质工程与基质治疗的系统性研究思路. 基质组学: 系统性鉴定ECM分子组成并解码其力学信息编码的组学分支; 基质力生物学: 细胞感知ECM力化信号并重构其分子组成和结构, 从而调控细胞行为与组织功能; 基质工程: 结合材料学与工程学原理主动调控ECM的分子组成与微观架构以精准介导细胞行为; 基质治疗: 结合基质组学、基质力生物学、基质工程实现组织内源性修复的治疗新策略
图 3 生理病理下基质动态重塑与力学微环境变化. (a)动脉粥样硬化伴随基底膜损伤和增生. (b) ECM力学重塑促进肿瘤恶性表型与迁移. (c)纤维化疾病中的 ECM 过度沉积加剧病理过程. (d)衰老 ECM诱发慢性炎症及力学失衡
图 4 基质工程与基质治疗策略. (a)分子靶向与材料重建协同驱动ECM内源性再生. (b)分子靶向干预以调控ECM稳态. (c)刚度匹配水凝胶促进伤口愈合. (d)黏弹性水凝胶促进脑损伤修复. (e)力学自适应水凝胶促进心肌梗死治疗. (f) MMP-9响应型肠道栓塞剂促进IBD修复
图 5 基质工程与基质治疗潜在应用. (a) ECM跨尺度解构疾病发生: 利用高分辨率整体成像建立从微观分子交联到宏观组织力学特性的全景力学图谱(Shi et al. 2025). (b)动态调控细胞行为: 通过光控水凝胶等智能技术, 在时间和空间维度上模拟生理或病理的动态力学变化. (c)基质力学重塑与多靶点协同去编码: 通过智能响应平台将基质力学重塑与分子靶向治疗深度融合, 实现复杂组织的内源性修复与功能再生
表 1 专业术语及释义
术语 英文 中文解释 细胞外基质 Extracellular Matrix (ECM) 细胞外基质是细胞之间的一种结构网络, 提供支持、信号传导以及调控细胞行为的作用. 基质力学重塑 Matrix Mechanics Remodeling ECM的组成和结构在不同生理或病理状态下的动态变化过程. 透明质酸 Hyaluronan ECM中的重要糖胺聚糖之一, 参与细胞的迁移、增殖和修复
过程.层粘连蛋白 Laminin ECM中的重要糖蛋白, 参与基底膜的结构稳定和细胞粘附. 整合素 Integrins 一类细胞膜受体, 参与细胞与ECM的连接, 调节细胞的形态、迁移、增殖和存活. 胶原蛋白 Collagen ECM中最重要的蛋白之一, 提供结构支持, 影响组织的强度和弹性. 纤维连接蛋白 Fibronectin ECM中的重要糖蛋白, 参与细胞粘附、迁移及信号转导. 基质金属蛋白酶 Matrix Metalloproteinases (MMP) 基质金属蛋白酶, 降解ECM蛋白质, 参与组织重塑、伤口愈合及肿瘤转移等过程. 基质金属蛋白酶抑制因子 Tissue Inhibitors of Metalloproteinases (TIMP) 一类抑制基质金属蛋白酶的蛋白, 调节ECM的降解. 成纤维细胞 Fibroblasts 负责合成和分泌ECM成分的细胞, 尤其在组织修复和纤维化过程中发挥重要作用. 肌成纤维细胞 Myofibroblasts 成纤维细胞的一种类型, 具有类似平滑肌的功能, 在纤维化组织中发挥重要作用. 转化生长因子β Transforming Growth Factor-beta (TGF-β) 一类多功能细胞因子, 参与细胞的增殖、分化、迁移等过程, 在纤维化、肿瘤发展等中发挥重要作用. 晚期糖基化终产物 Advanced Glycation End Products (AGEs) 糖化反应过程中生成的产物, 与多种衰老和退行性疾病相关. JNK JNK (c-Jun N-terminal Kinase) 一类MAPK家族的激酶, 参与细胞应激反应、炎症及细胞凋亡. RAGE受体 RAGE (Receptor for AGEs) 一种细胞表面受体, 能识别晚期糖基化终产物, 参与慢性炎症反应及多种疾病的进展. YAP/TAZ
信号通路YAP/TAZ signaling 细胞机制中, Hippo信号通路的下游效应器, 调控细胞的增殖、形态和组织发育. 黏着斑激酶 Focal Adhesion Kinase (FAK) 参与细胞与ECM粘附的酶, 调节细胞迁移和信号传导. PI3K/Akt
信号通路PI3K/Akt Pathway 重要的信号转导通路, 参与细胞的增殖、存活和代谢调控. MAPK通路 MAPK Pathway 一类广泛存在的细胞内信号转导通路, 参与细胞增殖、分化和应激反应. FAK/Src通路 FAK/Src signaling 由黏着斑激酶(FAK)与Src家族激酶通过磷酸化级联反应形成的信号复合体 ERK ERK (Extracellular Signal-Regulated Kinase) MAPK信号通路的一部分, 调控细胞增殖、分化和存活. SMAD信号通路 SMAD Signaling 参与转化生长因子β(TGF-β)信号传导的关键通路, 调节细胞的增殖、分化和迁移. 热休克蛋白47 HSP47 (Heat Shock Protein 47) 一种分子伴侣蛋白, 主要与胶原蛋白的折叠和稳定化过程相关, 参与ECM的合成. 赖氨酸氧化酶 LOX (Lysyl Oxidase) 参与胶原蛋白和弹性蛋白交联的酶, 调节ECM的稳定性. 血小板源生长因子 PDGF (Platelet-Derived Growth Factor) 一种生长因子, 调节细胞增殖和组织修复, 尤其在伤口愈合中发挥作用. 白细胞介素6 IL-6 (Interleukin 6) 一种细胞因子, 参与炎症反应、免疫调节和肿瘤免疫逃逸. NF-kB NF-kB (Nuclear Factor kappa B) 重要的转录因子, 调节免疫反应、细胞存活和炎症过程. Hippo Hippo Pathway 一种重要的信号通路, 调节细胞增殖、形态保持和组织发育. 
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