Moody Christopher T, Palvai Sandeep, Brudno Yevgeny
Joint Department of Biomedical Engineering, University of North Carolina - Chapel Hill and North Carolina State University - Raleigh, 1840 Entrepreneur Drive, Raleigh, NC 27695, USA.
Joint Department of Biomedical Engineering, University of North Carolina - Chapel Hill and North Carolina State University - Raleigh, 1840 Entrepreneur Drive, Raleigh, NC 27695, USA.
Acta Biomater. 2020 Aug;112:112-121. doi: 10.1016/j.actbio.2020.05.033. Epub 2020 Jun 1.
Injectable alginate hydrogels have demonstrated utility in tissue engineering and drug delivery applications due in part to their mild gelation conditions, low host responses and chemical versatility. Recently, the potential of these gels has expanded with the introduction of refillable hydrogel depots - alginate gels chemically decorated with click chemistry groups to efficiently capture prodrug refills from the blood. Unfortunately, high degrees of click group substitution on alginate lead to poor viscoelastic properties and loss of ionic cross-linking. In this work, we introduce tetrabicyclononyne (tBCN) agents that covalently cross-link azide-modified alginate hydrogels for tissue engineering and drug delivery application in vivo. Adjusting cross-linker concentration allowed tuning the hydrogel mechanical properties for tissue-specific mechanical strength. The bioorthogonal and specific click reaction creates stable hydrogels with improved in vivo properties, including improved retention at injected sites. Azide-alginate hydrogels cross-linked with tBCN elicited minimal inflammation and maintained structural integrity over several months and efficiently captured therapeutics drug surrogates from the circulation. Taken together, azide-alginate hydrogels cross-linked with tBCN convey the benefits of alginate hydrogels for use in tissue engineering and drug delivery applications of refillable drug delivery depots. STATEMENT OF SIGNIFICANCE: Ionically cross-linked, injectable alginate biomaterials hold promise in many different clinical settings. However, adding new chemical functionality to alginate can disrupt their ionic cross-linking, limiting their utility. We have developed a "click" cross-linking strategy to improve the mechanical properties and tissue function of modified alginate biomaterials and enable them to capture small molecule drugs from the blood. We show that click cross-linked materials remain in place better than ionically cross-linked materials and efficiently capture payloads from the blood. Development of click cross-linking for refillable depots represents a crucial step toward clinical application of this promising drug delivery platform.
可注射藻酸盐水凝胶已在组织工程和药物递送应用中展现出实用性，部分原因在于其温和的凝胶化条件、低宿主反应以及化学多功能性。最近，随着可再填充水凝胶贮库的引入，这些凝胶的潜力得到了扩展——藻酸盐水凝胶通过点击化学基团进行化学修饰，以有效从血液中捕获前药补充剂。不幸的是，藻酸盐上高度的点击基团取代会导致粘弹性性能不佳以及离子交联的丧失。在这项工作中，我们引入了四环壬炔（tBCN）试剂，其可共价交联叠氮化物修饰的藻酸盐水凝胶，用于体内组织工程和药物递送应用。调整交联剂浓度可调节水凝胶的机械性能，以实现组织特异性的机械强度。生物正交且特异的点击反应产生了具有改善的体内性能的稳定水凝胶，包括在注射部位的保留改善。与tBCN交联的叠氮化物 - 藻酸盐水凝胶引起的炎症最小，并在数月内保持结构完整性，且能有效从循环中捕获治疗药物替代物。综上所述，与tBCN交联的叠氮化物 - 藻酸盐水凝胶具有藻酸盐水凝胶的优点，可用于可再填充药物递送贮库的组织工程和药物递送应用。重要性声明：离子交联的可注射藻酸盐生物材料在许多不同的临床环境中都具有前景。然而，向藻酸盐添加新的化学功能可能会破坏其离子交联，限制其效用。我们开发了一种“点击”交联策略，以改善修饰的藻酸盐生物材料的机械性能和组织功能，并使其能够从血液中捕获小分子药物。我们表明，点击交联材料比离子交联材料在体内保留得更好，并能有效从血液中捕获有效载荷。用于可再填充贮库的点击交联的开发代表了这个有前景的药物递送平台迈向临床应用的关键一步。
