Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA.
Department of Biomedical Engineering, The University of Texas at San Antonio, San Antonio, TX, USA.
Acta Biomater. 2020 Mar 15;105:159-169. doi: 10.1016/j.actbio.2020.01.021. Epub 2020 Jan 20.
Injectable hydrogels represent a valuable tool for the delivery of therapeutic molecules aimed to restore the functionality of damaged tissues. In this study, we report the design of a nanocomposite DNA-based hydrogel crosslinked with oxidized alginate (OA) via the formation of reversible imine linkages. The formulated hydrogel functioned as an injectable carrier for the sustained delivery of a small molecule drug, simvastatin. The degree of oxidation of alginate and the concentration of silicate-based nanoparticles (nSi) were varied to modulate the rheological properties of the hydrogels. Specifically, the formulations consisting of OA with higher degree of oxidation displayed the highest value of storage moduli, yield stress, yield strain, and rapid recovery after removal of cyclic stress. The hydrogel formulations exhibited self-healing and shear-thinning properties due to the reversible nature of the covalent imine bonds formed between the aldehyde groups of OA and the amine groups present in the DNA nucleotides. Moreover, the incorporation of charged nSi further enhanced the shear strength of the formulated hydrogels by establishing electrostatic interactions with the phosphate groups of the DNA network. The optimized hydrogel was able to promote the sustained release of simvastatin for more than a week. The bioactivity of the released drug was confirmed by testing its ability to induce osteogenic differentiation and migration of human adipose-derived stem cells in vitro. Overall, the results obtained from this study demonstrate that DNA could be used as a natural biopolymer to fabricate self-healing injectable hydrogels with sustained release properties for minimally invasive therapeutic approaches. STATEMENT OF SIGNIFICANCE: Dynamic covalent chemistry, especially Schiff base reactions have emerged as a promising route for the formation of injectable hydrogels. Our study demonstrated the development of a DNA-based self-healing hydrogel formed via Schiff base reaction occurring at physiological conditions. The hydrogels functioned as sustained delivery vehicles for the hydrophobic drug simvastatin, which requires a polymeric carrier for controlled delivery of therapeutic concentrations of the drug without exhibiting cytotoxic effects. Presently available hydrogel-based drug delivery systems encounter major challenges for the delivery of hydrophobic drugs due to the hydrophilic nature of the base matrix. Our strategy presents a platform technology for the design of minimally invasive approaches for the sustained delivery of hydrophobic drugs similar to simvastatin.
可注射水凝胶是一种有价值的工具，可用于递送治疗分子，旨在恢复受损组织的功能。在这项研究中，我们报告了一种纳米复合 DNA 水凝胶的设计，该水凝胶通过形成可逆亚胺键与氧化海藻酸盐 (OA) 交联。所制备的水凝胶可作为小分子药物辛伐他汀的持续递送的可注射载体。通过改变海藻酸盐的氧化程度和基于硅酸盐的纳米粒子 (nSi) 的浓度来调节水凝胶的流变性质。具体而言，具有较高氧化程度的 OA 组成的配方显示出最高的储能模量、屈服应力、屈服应变以及在去除循环应力后快速恢复的值。由于 OA 中的醛基和 DNA 核苷酸中的胺基之间形成的共价亚胺键的可逆性质，水凝胶配方表现出自修复和剪切变稀特性。此外，带电荷的 nSi 的掺入通过与 DNA 网络中的磷酸基团建立静电相互作用进一步增强了配方水凝胶的剪切强度。优化的水凝胶能够促进辛伐他汀的持续释放超过一周。通过测试其在体外诱导人脂肪源性干细胞成骨分化和迁移的能力，证实了释放药物的生物活性。总体而言，这项研究的结果表明，DNA 可用作天然生物聚合物来制造具有自修复和持续释放特性的可注射水凝胶，用于微创治疗方法。
动态共价化学，特别是席夫碱反应已成为形成可注射水凝胶的有前途的途径。我们的研究表明，在生理条件下通过席夫碱反应形成了一种基于 DNA 的自修复水凝胶。水凝胶作为疏水性药物辛伐他汀的持续递送载体，该药物需要聚合物载体来以治疗浓度控制递送药物，而不会表现出细胞毒性作用。目前可用的水凝胶药物递送系统在递送疏水性药物（如辛伐他汀）方面遇到重大挑战，因为基础基质具有亲水性。我们的策略为设计微创方法提供了平台技术，用于以治疗浓度持续递送疏水性药物，类似于辛伐他汀。
