Organization for Research and Development of Innovative Science and Technology (ORDIST), Kansai University, 3-3-35 Yamate, Suita 564-8680, Osaka, Japan.
Faculty of Chemistry, Materials, Bioengineering, Kansai University, 3-3-35 Yamate, Suita 564-8680, Osaka, Japan.
ACS Appl Bio Mater. 2021 Apr 19;4(4):3079-3088. doi: 10.1021/acsabm.0c01467. Epub 2021 Feb 24.
Postoperative adhesion remains a problem in surgery and causes postoperative complications. Laparoscopic surgery is now common, making it increasingly important to develop injectable formulations of adhesion barriers that can be applied during such surgeries. Temperature-responsive injectable polymer (IP) systems exhibiting a sol-to-gel transition in response to temperature are promising candidates as effective adhesion barriers that can be applied conveniently during laparoscopic surgery. We previously developed IP systems exhibiting temperature-responsive irreversible gelation based on a triblock copolymer of poly(ε-caprolactone--glycolic acid) (PCGA) and poly(ethylene glycol) (PEG) (PCGA--PEG--PCGA: tri-PCG) and a tri-PCG derivative with acrylate groups at the termini (tri-PCG-acryl). A mixture of tri-PCG-acryl micelle solution and tri-PCG micelle solution containing polythiol exhibited an irreversible sol-to-gel transition in response to a temperature increase. The gel contains partial covalent cross-linking, and the degradation and physical properties of these IP hydrogels can easily be controlled by changing the mixing ratio of tri-PCG-acryl in the formulation. In this study, we investigated the effect of physical properties of the IP hydrogel on the efficacy of adhesion prevention using our IP system containing various amounts of tri-PCG-acryl. Our results show that an IP system with lower physical strength and rapid degradation reduces adhesion more effectively. Chymase plays a crucial role in exacerbating adhesion formation, and a peptide derivative-type chymase inhibitor (CI), Suc-Val-Pro-Phe(OPh), was previously reported to prevent adhesion. We thus investigated the concomitant use of this CI with our IP system using two methods: separate administration of the CI and IP and entrapping the CI in the IP hydrogel. IP systems with separately administrated CI provided better results than the administration of an IP system entrapping the CI or sole IP systems. These findings suggest that the pharmacological effect of the CI and a physical barrier generated by our IP system effectively prevents adhesion.
术后粘连仍然是外科手术中的一个问题，并导致术后并发症。腹腔镜手术现在很常见，因此开发可在手术过程中应用的可注射粘连屏障制剂变得越来越重要。对温度响应的可注射聚合物 (IP) 系统在响应温度时表现出溶胶-凝胶转变，是作为有效的粘连屏障的有前途的候选物，可在腹腔镜手术中方便地应用。我们之前开发了基于聚（ε-己内酯- 乙交酯）（PCGA）和聚乙二醇（PEG）的嵌段共聚物（PCGA-PEG-PCGA：三-PCG）和末端带有丙烯酸酯基团的三-PCG 衍生物（三-PCG-丙烯酰基）的 IP 系统，该系统表现出温度响应的不可逆胶凝。三-PCG-丙烯酰基胶束溶液和含有多硫醇的三-PCG 胶束溶液的混合物在温度升高时表现出不可逆的溶胶-凝胶转变。凝胶包含部分共价交联，并且通过改变制剂中三-PCG-丙烯酰基的混合比，可以轻松控制这些 IP 水凝胶的降解和物理性质。在这项研究中，我们研究了 IP 水凝胶的物理性质对我们的 IP 系统中包含的各种量的三-PCG-丙烯酰基预防粘连效果的影响。我们的结果表明，具有较低物理强度和快速降解的 IP 系统更有效地减少粘连。糜酶在加剧粘连形成中起着至关重要的作用，先前报道的糜酶肽衍生物型抑制剂 (CI) Suc-Val-Pro-Phe(OPh) 可预防粘连。因此，我们使用两种方法研究了这种 CI 与我们的 IP 系统的同时使用：CI 的单独给药和 IP 的单独给药以及将 CI 包埋在 IP 水凝胶中。与单独给药 CI 的 IP 系统相比，给药包埋 CI 的 IP 系统或单独的 IP 系统提供了更好的结果。这些发现表明，CI 的药理学作用和我们的 IP 系统产生的物理屏障有效地防止了粘连。
