Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, FDA, Silver Spring, Maryland 20993-002, USA.
J Biomed Mater Res A. 2010 Sep 1;94(3):893-904. doi: 10.1002/jbm.a.32760.
Hyaluronic acid (HA) is increasingly used for a number of medical device applications. Since the chemical structure of HA is identical no matter its bacterial or animal origin, it should be the ideal biomaterial. However, short term transient inflammatory reactions are common, while rare long-term adverse events may correlate with subclinical chronic inflammation. Concern has been raised that low molecular weight components or degradation fragments from implanted HA may directly stimulate inflammatory reactions. This study examined a panel of HA molecular weights from the unitary disaccharide up to 1.7 x 10(6) Dalton lengths, in which endotoxin was assayed at a very low level (less than 0.03 EU/mg). The murine cell line RAW 264.7, rat splenocytes, and rat adherent differentiated primary macrophages were assayed for nitric oxide production under a variety of inflammatory conditions plus or minus HA. Under the highest inflammatory states, nitric oxide production was mildly suppressed by HMW-HA while slightly augmented by LMW-HA at mg/mL concentrations. However, at micromolar concentrations fragments below 5000 Daltons, thought to have drug-like qualities, were without effect. These data support the hypothesis that if endotoxin is reduced to an extremely low level, LMW-HA may not directly provoke normal tissue macrophage-mediated inflammatory reactions.
透明质酸（HA）越来越多地用于许多医疗器械应用。由于 HA 的化学结构无论其来源于细菌还是动物都是相同的，因此它应该是理想的生物材料。然而，短期的短暂炎症反应很常见，而罕见的长期不良事件可能与亚临床慢性炎症有关。人们担心植入的 HA 的低分子量成分或降解片段可能直接刺激炎症反应。本研究检测了从单一二糖到 1.7 x 10(6) 道尔顿长度的一系列 HA 分子量，其中内毒素的检测水平非常低（小于 0.03 EU/mg）。在各种炎症条件下，用鼠源细胞系 RAW 264.7、大鼠脾细胞和大鼠贴壁分化原代巨噬细胞检测一氧化氮的产生，外加或不加 HA。在最高炎症状态下，高分子量 HA 轻度抑制一氧化氮的产生，而低分子量 HA 在 mg/mL 浓度下略有增加。然而，在微摩尔浓度下，低于 5000 道尔顿的片段，被认为具有类药性，没有效果。这些数据支持这样的假设，如果将内毒素降低到极低水平，低分子量 HA 可能不会直接引发正常组织巨噬细胞介导的炎症反应。
