Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics
Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics
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DOI：
10.1073/pnas.0737381100
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发表时间：
2003-04-29
影响因子：
11.1
通讯作者：
Hubbell, JA
中科院分区：
文献类型：
--
作者：
Lutolf, MP;Lauer-Fields, JL;Hubbell, JA
合成水凝胶经过分子工程设计，以模拟天然临时细胞外基质的侵入特性：需要整合素结合位点和基质金属蛋白酶（MMP）的底物相结合，才能使网络可被细胞通过细胞分泌的MMPs降解和侵入。凝胶的降解是从对合成的可溶形式的MMP底物以及交联成三维水凝胶网络后的降解动力学（$k_{cat}$和$K_m$）进行表征开始设计的。已证明原代人成纤维细胞能够蛋白水解性地侵入这些网络，这一过程取决于MMP底物活性、黏附配体浓度和网络交联密度。用于将重组人骨形态发生蛋白 - 2递送至大鼠颅骨关键缺损部位的凝胶被细胞完全浸润，并在每个缺损5微克的剂量下于4周内重塑为骨组织。骨再生也被证明取决于基质的蛋白水解敏感性。这些水凝胶在组织工程和细胞生物学中可用作天然存在的细胞外基质衍生材料（如纤维蛋白或胶原蛋白）的替代品。
Synthetic hydrogels have been molecularly engineered to mimic the invasive characteristics of native provisional extracellular matrices: a combination of integrin-binding sites and substrates for matrix metalloproteinases (MMP) was required to render the networks degradable and invasive by cells via cell-secreted MMPs. Degradation of gels was engineered starting from a characterization of the degradation kinetics (k(cat) and K-m) of synthetic MMP substrates in the soluble form and after crosslinking into a 3D hydrogel network. Primary human fibroblasts were demonstrated to proteolytically invade these networks, a process that depended on MMP substrate activity, adhesion ligand concentration, and network crosslinking density. Gels used to deliver recombinant human bone morphogenetic protein-2 to the site of critical defects in rat cranium were completely infiltrated by cells and remodeled into bony tissue within 4 wk at a dose of 5 mug per defect. Bone regeneration was also shown to depend on the proteolytic sensitivity of the matrices. These hydrogels may be useful in tissue engineering and cell biology as alternatives for naturally occurring extracellular matrix-derived materials such as fibrin or collagen.