In vivo response to dynamic hyaluronic acid hydrogels.

In vivo response to dynamic hyaluronic acid hydrogels.
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DOI:
10.1016/j.actbio.2013.03.019
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发表时间:
2013-07
期刊:
影响因子:
9.7
通讯作者:
Engler, Adam J.
Engler, Adam J.
中科院分区:
工程技术1区
文献类型:
--
作者:
Young, Jennifer L.;Tuler, Jeremy;Braden, Rebecca;Schuep-Magoffin, Pamela;Schaefer, Jacquelyn;Kretchmer, Kyle;Christman, Karen L.;Engler, Adam J.

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组织特异性弹性部分来自细胞外基质随时间的发育变化,例如鸡胚中约10倍的心肌僵硬。当在体外用硫代透明质酸(HA-SH)水凝胶模拟这种依赖时间的硬化时,可以观察到心肌细胞成熟的改善。然而,宿主相互作用、基质聚合和硬化动力学在体内仍然不确定,并且每一种都在使用HA-SH的治疗应用中发挥关键作用。皮下注射HA-SH水凝胶的血液学和组织学分析显示,系统免疫反应最低,宿主细胞浸润最少。最重要的是,皮下注射的HA-SH水凝胶表现出与体外聚合水凝胶相似的孔隙率和硬度随时间变化的速度。当注射到心肌内时,宿主细胞在注射后1周内开始主动降解HA-SH水凝胶,并继续这一过程,同时在注射后1个月内产生几乎取代水凝胶的基质。不同于HA-SH,注射后1个月可见肉芽肿和巨噬细胞浸润,这可能是由于反应性的硫醇基团所致,虽然非硫代HA注入心肌后不会降解,但它也不会引起免疫反应。总而言之,这些数据表明,HA-SH水凝胶在体外已被证明的血管化较少的壁龛和僵硬的壁龛中有适当的反应,但在血管较多的组织中,体内的适用性似乎有限。
Tissue-specific elasticity arises in part from developmental changes in extracellular matrix over time, e.g. ~ 10-fold myocardial stiffening in the chicken embryo. When this time-dependent stiffening is mimicked in vitro with thiolated hyaluronic acid (HA-SH) hydrogels, improved cardiomyocyte maturation has been observed. However, host interactions, matrix polymerization, and stiffening kinetics remain uncertain in vivo, and each plays a critical role in therapeutic applications using HA-SH. Hematological and histological analysis of subcutaneously injected HA-SH hydrogels showed minimal systemic immune response and host cell infiltration. Most importantly, subcutaneously injected HA-SH hydrogels exhibited time dependent porosity and stiffness changes at a rate similar to hydrogels polymerized in vitro. When injected intramyocardially, host cells begin to actively degrade HA-SH hydrogels within 1-week post-injection, continuing this process while producing matrix to nearly replace the hydrogel within 1 month post-injection. While non-thiolated HA did not degrade after injection into the myocardium, it also did not elicit an immune response, unlike HA-SH, where visible granulomas and macrophage infiltration were present at 1 month post-injection, likely due to reactive thiol groups. Altogether, these data suggest that the HA-SH hydrogel responds appropriately in a less vascularized niche and stiffens as had been demonstrated in vitro, but in more vascularized tissues, in vivo applicability appears limited.
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