MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for X Polymers, Department of Polymer Science and Engineering, Zhejiang University, Haining, 314400, China.
Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
Biomaterials. 2023 May;296:122069. doi: 10.1016/j.biomaterials.2023.122069. Epub 2023 Feb 27.
The valid management of inflammation and precise inhibition of smooth muscle cells (SMCs) is regarded as a promising strategy for regulating vascular responses after stent implantation, yet posing huge challenges to current coating constructions. Herein, we proposed a spongy cardiovascular stent for the protective delivery of 4-octyl itaconate (OI) based on a "spongy skin" approach, and revealed the dual-regulation effects of OI for improving vascular remolding. We first constructed a "spongy skin" onto poly-l-lactic acid (PLLA) substrates, and realized the protective loading of OI with the highest dosage of 47.9 μg/cm. Then, we verified the remarkable inflammation mediation of OI, and surprisingly revealed that the OI incorporation specifically inhibited SMC proliferation and phenotype switching, which contributed to the competitive growth of endothelial cells (EC/SMC ratio ∼ 5.1). We further demonstrated that OI at a concentration of 25 μg/mL showed significant suppression of the TGF-β/Smad pathway of SMCs, leading to the promotion of contractile phenotype and reduction of extracellular matrix. In vivo evaluation indicated that the successful delivery of OI fulfilled the inflammation regulation and SMCs inhibition, therefore suppressing the in-stent restenosis. This "spongy skin" based OI eluting system may serve as a new strategy for improving vascular remolding, and provides a potential concept for the treatment of cardiovascular diseases.
有效的炎症管理和精确抑制平滑肌细胞（SMCs）被认为是调节支架植入后血管反应的有前途的策略，但对当前的涂层结构构成了巨大挑战。在此，我们提出了一种基于“海绵状皮肤”方法的用于保护递送 4-辛烯衣康酸（OI）的海绵状心血管支架，并揭示了 OI 改善血管重塑的双重调节作用。我们首先在聚 L-乳酸（PLLA）基质上构建了“海绵状皮肤”，并实现了 OI 的保护性负载，最高载药量为 47.9μg/cm。然后，我们验证了 OI 的显著炎症调节作用，并令人惊讶地发现，OI 的掺入特异性抑制了 SMC 的增殖和表型转换，这有助于内皮细胞（EC/SMC 比~5.1）的竞争生长。我们进一步证明，浓度为 25μg/mL 的 OI 对 SMC 的 TGF-β/Smad 通路具有显著的抑制作用，导致收缩表型的促进和细胞外基质的减少。体内评价表明，OI 的成功递送实现了炎症调节和 SMCs 抑制，从而抑制了支架内再狭窄。这种基于“海绵状皮肤”的 OI 洗脱系统可为改善血管重塑提供一种新策略，并为心血管疾病的治疗提供了一种潜在的概念。
