SuperGAGs with diverse capture agents.

Chemical modification of naturally derived glycosaminoglycans (GAGs) expands their potential utility for applications in soft tissue repair and regenerative medicine. Here we report the preparation of a novel crosslinked chondroitin sulfate (~200 to 2000 kilodaltons) that is both soluble in aqueous solution and microfilterable. We refer to these materials as “SuperGAGs.” One can further conjugate these materials with diverse capture agents to further modify polymer properties and add new capabilities. A representative material (GLX-100) demonstrated durable restoration of bladder impermeability in a gold standard animal model of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). Histologic examination of the animal bladders treated with a GLX-100 SuperGAG conjugated to biotin as a reporter demonstrated that the residence time of GLX-100 is superior to chondroitin sulfate (a product that is currently used for clinical treatment of patients with IC/BPS). As expected, this novel crosslinked GAG biopolymer was restricted to the luminal surface of the bladder wall. In this communication we describe a simple and versatile synthesis of a crosslinked glycosaminoglycan (GAG) biopolymer for soft tissue repair. Chondroitin sulfate (~12 kD) was crosslinked to form a water soluble and microfilterable polymer with approximately 200 to 2000 kD molecular weight. The synthesis presented here allows for control of molecular weight while avoiding formation of an extended block gel. Moreover, the procedure enables further chemical modification of the SuperGAG through the selection of a capture agent. A set of agents have been used, demonstrating the preparation of a family of SuperGAGs with diverse capabilities. We can optimize polymer properties, adjust adherence to various tissues, add reporters, and engage the biochemistry of surrounding tissues with peptides and other bioactives.天然来源的糖胺聚糖（glycosaminoglycans, GAGs）的化学修饰，可拓展其在软组织修复与再生医学领域的应用潜力。本研究报道了一种新型交联硫酸软骨素（分子量约200至2000千道尔顿）的制备方法，该材料可溶于水溶液且具备可微滤性，我们将此类材料命名为"SuperGAGs"。可进一步将此类材料与多种捕获试剂缀合，以修饰聚合物性能并赋予新功能。一款代表性材料（GLX-100）在间质性膀胱炎/膀胱疼痛综合征（Interstitial Cystitis/Bladder Pain Syndrome, IC/BPS）的金标准动物模型中，实现了膀胱屏障完整性的持久恢复。以生物素作为报告分子的GLX-100 SuperGAG缀合物处理的动物膀胱组织学检查结果显示，GLX-100的驻留时间优于目前临床用于IC/BPS患者治疗的硫酸软骨素产品。正如预期，这种新型交联糖胺聚糖生物聚合物仅局限于膀胱壁的腔面。本通讯报道了一种用于软组织修复的交联糖胺聚糖（GAG）生物聚合物的简便通用合成方法：将分子量约12千道尔顿的硫酸软骨素进行交联，可制得分子量约200至2000千道尔顿的水溶性、可微滤聚合物。本研究提出的合成方法可实现分子量调控，同时避免形成大块凝胶。此外，该工艺可通过选择捕获试剂，实现SuperGAG的进一步化学修饰。目前已使用一系列试剂，成功制备出具备多种功能的SuperGAG家族材料。该方法可优化聚合物性能、调控对多种组织的黏附性、添加报告分子，并通过肽类及其他生物活性物质调节周围组织的生物化学反应。