Abstract

To conveniently modulate the degree of local analgesia in response to changes in patients’ needs and level of activity, a NIR-activated drug delivery system based on jammed microgels was introduced in the present study to realize on-demand local anesthesia. Chemically cross-linked gelatin microgels (5–15 μm) containing N-isopropylacrylamide (NIPAM), methylallyl polyethylene glycol (APEG) and graphene oxide (GOs) were fabricated through emulsion. After the in situ free radical polymerization, the physical network was formed, producing microgels with double networks (DN microgels). The DN microgels exhibited thermosensitive properties. The copolymerization of APEG resulted in the increase of lower critical solution temperature (LCST) of microgels. The maximum volume shrinkage ratio of DN microgels (NIPAM40 + APEG60) increased with the increase of the content of physical cross-linking network. The DN microgels also exhibited NIR-responsive ability. Under the NIR irradiance of 272 mW/cm², the temperature of DN microgels with 3 mg/mL GOs reached 40 °C within 60 s, resulting in the volume shrinkage of 14%. Ropivacaine release from DN microgels could be effectively triggered by NIR irradiation in vitro. After centrifugation, a jammed microgels system was produced where microgels packed densely, displaying shear-thinning behavior for achieving injection. The jammed DN microgels carrying ropivacaine were injected subcutaneously into rat footpad. NIR irradiation produced on-demand and repeated infiltration anesthesia in the rat footpad. The jammed DN microgels system thus was beneficial in the management of pain.

摘要

为了方便地调节局部镇痛程度以响应患者需求和活动水平的变化，本研究引入了一种基于堵塞微凝胶的近红外激活给药系统，以实现按需局部麻醉。通过乳液制备含有 N-异丙基丙烯酰胺 (NIPAM)、甲基烯丙基聚乙二醇 (APEG) 和氧化石墨烯 (GO) 的化学交联明胶微凝胶 (5–15 μm)。原位自由基聚合后，形成物理网络，产生具有双网络的微凝胶（DN microgels）。DN 微凝胶表现出热敏特性。APEG的共聚导致微凝胶的下临界溶解温度（LCST）增加。DN微凝胶(NIPAM40+APEG60)的最大体积收缩率随着物理交联网络含量的增加而增加。DN 微凝胶也表现出 NIR 响应能力。在 272 mW/cm 的 NIR 辐照度下^如图2所示，具有3 mg/mL GOs的DN微凝胶在60 s内温度达到40°C，导致体积收缩14%。体外近红外辐射可有效触发 DN 微凝胶中罗哌卡因的释放。离心后，产生了一个堵塞的微凝胶系统，其中微凝胶密集堆积，显示出剪切稀化行为以实现注射。将载有罗哌卡因的堵塞的 DN 微凝胶皮下注射到大鼠足垫中。NIR 照射在大鼠足垫中产生按需和重复的浸润麻醉。因此，堵塞的 DN 微凝胶系统有利于疼痛的管理。