Molecular weight of hyaluronic acid crosslinked into biomaterial scaffolds affects angiogenic potential.
Molecular weight of hyaluronic acid crosslinked into biomaterial scaffolds affects angiogenic potential.
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DOI：
10.1016/j.actbio.2023.08.001
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发表时间：
2023-08
影响因子：
9.7
通讯作者：
Joshua Karam;B. Singer;H. Miwa;Limin H Chen;Kajal Maran;Mahdi Hasani;Sarahi Garza;Bianca Onyekwere-B
中科院分区：
文献类型：
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作者：
Joshua Karam;B. Singer;H. Miwa;Limin H Chen;Kajal Maran;Mahdi Hasani;Sarahi Garza;Bianca Onyekwere-B
虽然基于透明质酸（HA）的水凝胶已经在临床上使用了几十年，但是HA发挥分子量依赖性生物活性的机制以及化学修饰和交联如何影响分子量依赖性生物活性仍然知之甚少。这种知识差距是设计具有可预测生物活性的HA水凝胶的重要障碍。由于HA已被广泛报道对内皮细胞（EC）具有分子量依赖性作用，我们研究了可溶性或交联形式的HA分子量如何影响血管生成，并询问了内皮细胞表面上的CD44簇集作为这些影响的候选机制。使用可溶性HA，我们的研究结果表明，高分子量（HMW）HA，而不是低分子量（LMW）HA，增加的人脑微血管内皮细胞（HCMVECs）的活力和管形成。HA的大小不影响增殖。当以HA为基础的微孔退火颗粒支架（HMAPS）的形式与不同分子量的交联HA一起培养HCMVECs时，细胞反应与用可溶性HA培养时相当。我们还表明，抗体介导的CD44聚类导致HCMVECs与增加的活力和管状结构形成的方式相比，暴露于高分子量HA，表明高分子量的行为通过CD44 clustering.Statement of significance生物材料的基础上透明质酸（HA），生物活性的细胞外基质多糖，已被用于临床产品几年。尽管HA分子量严重影响其生物活性，但在HA基生物材料的开发中，分子量在很大程度上被忽视。由于高分子量HA的高粘度通常存在于天然组织中，因此较低分子量的多糖最常用于生物材料制造。通过比较可注射的，微孔退火颗粒支架（MAPS）制造的大尺寸的HA，以促进血管生成的能力，这项研究表明，MAPS与高分子量HA更好地支持血管形成，可能是通过一个独特的能力，诱导聚集的CD44受体的内皮细胞。
While hyaluronic acid (HA)-based hydrogels have been used clinically for decades, the mechanisms by which HA exerts molecular weight-dependent bioactivity and how chemical modification and crosslinking may affect molecular weight-dependent bioactivity remain poorly understood. This knowledge gap presents a significant barrier to designing HA hydrogels with predictable bioactivities. As HA has been widely reported to have molecular weight-dependent effects on endothelial cells (ECs), we investigated how the molecular weight of HA in either soluble or crosslinked forms affects angiogenesis and interrogated CD44 clustering on the surface of endothelial cells as a candidate mechanism for these affects. Using soluble HA, our results show high molecular weight (HMW) HA, but not low molecular weight (LMW) HA, increased viability and tube formation in cultured human cerebral microvascular ECs (HCMVECs). No size of HA affected proliferation. When HCMVECs were cultured with crosslinked HA of varying molecular weights in the form of HA-based microporous annealed particle scaffold (HMAPS), the cell response was comparable to when cultured with soluble HA.Similarly, when implanted subcutaneously, HMAPS with HMW HA were more vascularized than those with LMW HA. We also show that antibody-mediated CD44 clustering resulted in HCMVECs with increased viability and tube-like structure formation in a manner comparable to exposure to HMW HA, suggesting that HMW acts through CD44 clustering.Statement of significanceBiomaterials based on hyaluronic acid (HA), a bioactive extracellular matrix polysaccharide, have been used in clinical products for several years. Despite the knowledge that HA molecular weight heavily influences its bioactivity, molecular weight has been largely ignored in the development of HA-based biomaterials. Given the high viscosity of high molecular weight HA typically found in native tissues, lower molecular weight polysaccharides have been used most commonly for biomaterial fabrication. By comparing the ability of injectable, microporous annealed particle scaffolds (MAPS) fabricated from variably sized HA to promote angiogenesis, this study demonstrates that MAPS with high molecular weight HA better support vascularization, likely through an unique ability to induce clustering of CD44 receptors on endothelial cells.