Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration
Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration
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DOI：
10.1021/bm0604956
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发表时间：
2006-12-11
影响因子：
6.2
通讯作者：
Langer, Robert
中科院分区：
文献类型：
--
作者：
Jia, Xinqiao;Yeo, Yoon;Langer, Robert
声带疤痕会破坏固有层的粘弹性，而固有层对于正常发声至关重要。临床需要开发先进的生物材料，其机械性能接近固有层的机械性能，用于体内声带再生。我们开发了基于透明质酸 (HA) 的微凝胶和交联微凝胶网络，具有可调节的降解和机械性能。 HA 微凝胶是通过在反相乳液液滴内交联带有酰肼 (HAADH) 和醛 (HAALD) 官能团的 HA 衍生物来制备的。或者，使用聚乙二醇二醛 (PEGDiALD) 代替 HAALD。基于 HAADH/HAALD 的微凝胶比由 HAADH/PEGDiALD 生成的微凝胶更能抵抗酶促降解。使用声带成纤维细胞的体外细胞毒性研究表明，由HAADH/HAALD合成的微凝胶基本上是无毒的，而由HAADH/PEGDiALD衍生的微凝胶在高浓度(>=2 mg/mL)下对培养细胞表现出一定的不利影响。这些微凝胶表现出残留的官能团，可用作治疗分子共价缀合的反应手柄。残留官能团的存在还允许微凝胶与其他反应性聚合物随后交联，产生具有可调粘弹性的双交联网络（DXN）。使用扭转波装置进行的机械测量表明，基于 HA 的 DXN 在接近人类发声范围的频率下表现出与声带固有层相似的弹性模量。这些基于透明质酸的微凝胶系统是治疗声带疤痕的有希望的候选者，不仅作为生物相容性填充材料，而且作为可以修复局部缺陷、平滑声带边缘并可能软化和溶解疤痕组织的智能实体。
Vocal fold scarring disrupts the viscoelastic properties of the lamina propria that are critical for normal phonation. There is a clinical need for the development of advanced biomaterials that approximate the mechanical properties of the lamina propria for in vivo vocal fold regeneration. We have developed hyaluronic acid (HA)-based microgels and cross-linked microgel networks with tunable degradation and mechanical properties. HA microgels were prepared by cross-linking HA derivatives carrying hydrazide (HAADH) and aldehyde (HAALD) functionalities within the inverse emulsion droplets. Alternatively, poly(ethylene glycol) dialdehyde ( PEGDiALD) was employed in place of HAALD. Microgels based on HAADH/HAALD are more resistant to enzymatic degradation than those generated from HAADH/PEGDiALD. In vitro cytotoxicity studies using vocal fold fibroblasts indicate that microgels synthesized from HAADH/HAALD are essentially nontoxic, whereas microgels derived from HAADH/PEGDiALD exhibit certain adverse effects on the cultured cells at high concentration (>= 2 mg/mL). These microgels exhibit residual functional groups that can be used as reactive handles for covalent conjugation of therapeutic molecules. The presence of residual functional groups also allows for subsequent cross-linking of the microgels with other reactive polymers, giving rise to doubly cross-linked networks (DXNs) with tunable viscoelasticity. Mechanical measurements using a torsional wave apparatus indicate that HA-based DXNs exhibit elastic moduli that are similar to those of vocal fold lamina propria at frequencies close to the range of human phonation. These HA-based microgel systems are promising candidates for the treatment of vocal fold scarring, not just as biocompatible filler materials, but as smart entities that can repair focal defects, smooth the vocal fold margin, and potentially soften and dissolve scar tissue.