Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University at Raleigh, NC United States of America; Comparative Medicine Institute, North Carolina State University, Raleigh, NC United States of America.
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University at Raleigh, NC United States of America.
Acta Biomater. 2022 Jan 15;138:208-217. doi: 10.1016/j.actbio.2021.10.046. Epub 2021 Oct 30.
Alginate hydrogels are gaining traction for use in drug delivery, regenerative medicine, and as tissue engineered scaffolds due to their physiological gelation conditions, high tissue biocompatibility, and wide chemical versatility. Traditionally, alginate is decorated at the carboxyl group to carry drug payloads, peptides, or proteins. While low degrees of substitution do not cause noticeable mechanical changes, high degrees of substitution can cause significant losses to alginate properties including complete loss of calcium cross-linking. While most modifications used to decorate alginate deplete the carboxyl groups, we propose that alginate modifications that replenish the carboxyl groups could overcome the loss in gel integrity and mechanics. In this report, we demonstrate that restoring carboxyl groups during functionalization maintains calcium cross-links as well as hydrogel shear-thinning and self-healing properties. In addition, we demonstrate that alginate hydrogels modified to a high degree with azide modifications that restore the carboxyl groups have improved tissue retention at intramuscular injection sites and capture blood-circulating cyclooctynes better than alginate hydrogels modified with azide modifications that deplete the carboxyl groups. Taken together, alginate modifications that restore carboxyl groups could significantly improve alginate hydrogel mechanics for clinical applications. STATEMENT OF SIGNIFICANCE: Chemical modification of hydrogels provides a powerful tool to regulate cellular adhesion, immune response, and biocompatibility with local tissues. Alginate, due to its biocompatibility and easy chemical modification, is being explored for tissue engineering and drug delivery. Unfortunately, modifying alginate to a high degree of substitution consumes carboxyl group, which are necessary for ionic gelation, leading to poor hydrogel crosslinking. We introduce alginate modifications that restore the alginate's carboxyl groups. We demonstrate that modifications that reintroduce carboxyl groups restore gelation and improve gel mechanics and tissue retention. In addition to contributing to a basic science understanding of hydrogel properties, we anticipate our approach will be useful to create tissue engineered scaffolds and drug delivery platforms.
海藻酸盐水凝胶由于其生理凝胶条件、高组织生物相容性和广泛的化学多功能性，在药物输送、再生医学和组织工程支架中得到了广泛的应用。传统上，海藻酸盐通过在羧基上进行修饰来携带药物有效负载、肽或蛋白质。虽然低取代度不会引起明显的机械变化，但高取代度会导致海藻酸盐性质的显著损失，包括完全丧失钙离子交联。虽然用于修饰海藻酸盐的大多数修饰方法都会耗尽羧基，但我们提出，补充羧基的海藻酸盐修饰方法可以克服凝胶完整性和力学性能的损失。在本报告中，我们证明了在功能化过程中恢复羧基可以保持钙离子交联以及水凝胶的剪切变稀和自修复特性。此外，我们证明了用恢复羧基的叠氮化物修饰改性的海藻酸盐水凝胶在肌肉内注射部位的组织保留能力以及捕获血液循环中环辛炔的能力优于用耗尽羧基的叠氮化物修饰改性的海藻酸盐水凝胶。总之，恢复羧基的海藻酸盐修饰方法可以显著改善海藻酸盐水凝胶的力学性能，从而满足临床应用的需求。
水凝胶的化学修饰为调节细胞黏附、免疫反应和与局部组织的生物相容性提供了一种强大的工具。由于其生物相容性和易于化学修饰，海藻酸盐被用于组织工程和药物输送。不幸的是，将海藻酸盐修饰到高取代度会消耗羧基，而羧基是离子凝胶所必需的，从而导致水凝胶交联不良。我们引入了恢复海藻酸盐羧基的海藻酸盐修饰方法。我们证明，重新引入羧基的修饰方法可以恢复凝胶化并改善凝胶力学性能和组织保留能力。除了对水凝胶性质的基础科学理解做出贡献外，我们预计我们的方法将有助于创建组织工程支架和药物输送平台。
