State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 10029, China; Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China.
State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 10029, China; Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR China.
Acta Biomater. 2022 Nov;153:308-319. doi: 10.1016/j.actbio.2022.08.061. Epub 2022 Aug 31.
By using the prominent merit of poly(N-isopropylacrylamide) (PNIPAm) that can reversibly switch from a linear state to a coiled state with the change in temperature, in this work, gelatin was grafted with carboxylic end-capped PNIPAm as the matrix material to fabricate a physical entanglement crosslinked hydrogel microneedles (MNs) patch that can control drug release after application on the skin. The crystallization of the drug during the fabrication process of MNs was decreased due to the thermo-reversible sol-gel transition of the matrix materials. In addition, to increase the mechanical strength of the MNs and to decrease the application time, the gelatin-g-PNIPAm (GP) MNs patch was mounted onto solid MNs to fabricate a rapidly separating MNs system (RS-GP-MNs). The combination of the rapidly separating technique and the thermosensitive hydrogel provides the combined ability to efficiently deliver drug-loaded MNs into the skin within few seconds and to control drug release within the skin. Through a series of tests, we found that RS-GP-MNs showed suitable lower critical solution temperature and adequate crosslinking speed for practical application. The hypoglycemic effect in diabetic mice was characteristically controlled by insulin release through RS-GP-MNs as compared to the MNs made from unmodified gelatin. The proposed RS-GP-MNs system is potentially applicable to various hydrophilic small molecular and peptide medicines that require frequent dosing, thus providing an effective, noninvasive, and painless administration method with minimal safety concerns. STATEMENT OF SIGNIFICANCE: 1. Hydrogel microneedles that can be reversibly triggered and controllably release drugs at body temperature were fabricated. 2. Hydrogel microneedles prepared from gelatin-g-PNIPAm can avoid the use of a molecular crosslinker that is toxic and difficult to be completely removed. 3. Gelatin-g-PNIPAm with thermosensitive property showed appropriate molecular interactions with the drug and slowed down the crystallization speed of the drug in the solution.
利用聚 N-异丙基丙烯酰胺（PNIPAm）的突出优点，它可以随温度变化可逆地从线性状态转变为卷曲状态，在这项工作中，将羧酸封端的 PNIPAm 接枝到明胶上作为基质材料，制备了一种物理缠结交联水凝胶微针（MNs）贴片，该贴片可以在贴在皮肤上后控制药物释放。由于基质材料的热可逆溶胶-凝胶转变，MNs 制造过程中的药物结晶减少。此外，为了提高 MNs 的机械强度并减少应用时间，将明胶接枝 PNIPAm（GP）MNs 贴片安装到固体 MNs 上，以制造快速分离 MNs 系统（RS-GP-MNs）。快速分离技术和温敏水凝胶的结合提供了将载药 MNs 高效递送至皮肤内几秒钟内并控制皮肤内药物释放的组合能力。通过一系列测试，我们发现 RS-GP-MNs 表现出适合的低临界溶液温度和足够的交联速度，适用于实际应用。与未修饰明胶制成的 MNs 相比，RS-GP-MNs 通过胰岛素释放可显著控制糖尿病小鼠的降血糖作用。所提出的 RS-GP-MNs 系统具有潜在的适用性，可以应用于各种需要频繁给药的亲水性小分子和肽类药物，从而提供一种有效、非侵入性、无痛的给药方法，最小化安全性问题。意义声明：1. 制造了可在体温下可逆触发和可控释放药物的水凝胶微针。2. 由明胶-g-PNIPAm 制备的水凝胶微针可以避免使用毒性大且难以完全去除的分子交联剂。3. 具有温敏性的明胶-g-PNIPAm 与药物表现出适当的分子相互作用，并减缓了药物在溶液中的结晶速度。
