Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA.
The Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut, USA.
Tissue Eng Part A. 2021 Jul;27(13-14):867-880. doi: 10.1089/ten.TEA.2020.0124. Epub 2020 Oct 15.
Glycol chitosan (GC) is a hydrophilic chitosan derivative, known for its aqueous solubility. Previously, we have demonstrated the feasibility of preparing injectable, enzymatically crosslinked hydrogels from HPP [3-(4-Hydroxyphenyl)-propionic acid (98%)]-modified GC. However, HPP-GC gels showed very slow degradation, which presents challenges as an protein delivery vehicle. This study reports the potential of acetylated HPP-GC hydrogels as a biodegradable hydrogel platform for sustained protein delivery. Enzymatic crosslinking was used to prepare injectable, biodegradable hydrogels from HPP-GC with various degrees of acetylation (DA). The acetylated polymers were characterized using Fourier transform infrared and nuclear magnetic resonance spectroscopy. Rheological methods were used to characterize the mechanical behavior of the hydrogels. degradation and protein release were performed in the presence and absence of lysozyme. degradation was studied using a mouse subcutaneous implantation model. Finally, two hydrogel formulations with distinct / degradation and protein release were evaluated in 477-SKH1-Elite mice using live animal imaging to understand protein release profiles. The lysozyme-mediated degradation of the gels was demonstrated and the degradation rate was found to be dependent on the DA of the polymers. degradation study further confirmed that gels formed from polymers with higher DA degraded faster. protein release demonstrated the feasibility to achieve lysozyme-mediated protein release from the gels and that the rate of protein release can be modulated by varying the DA. protein release study further confirmed the feasibility to achieve differential protein release by varying the DA. The feasibility to develop degradable enzymatically crosslinked GC hydrogels is demonstrated. Gels with a wide spectrum of degradation time ranging from less than a week and more than 6 weeks can be developed using this approach. The study also showed the feasibility to fine tune protein release by modulating HPP-GC acetylation. The hydrogel platform therefore holds significant promise as a protein delivery vehicle for various biomedical and regenerative engineering applications. Impact statement The study describes the feasibility to develop a novel enzyme sensitive biodegradable and injectable hydrogel, where in the degradation rate and protein release profile can be modulated over a wide range. The described hydrogel platform has the potential to develop into a clinically relevant injectable and tunable protein delivery vehicle for a wide range of biomedical applications.
羟丙基壳聚糖（GC）是一种亲水性壳聚糖衍生物，以其水溶性而闻名。此前，我们已经证明了可以从 HPP[3-（4-羟基苯基）-丙酸（98%）]-改性 GC 制备可注射的酶交联水凝胶。然而，HPP-GC 凝胶的降解速度非常缓慢，这给作为蛋白质输送载体带来了挑战。本研究报告了乙酰化 HPP-GC 水凝胶作为可生物降解水凝胶平台用于持续蛋白质输送的潜力。通过酶交联，从具有不同乙酰化程度（DA）的 HPP-GC 制备可注射的、可生物降解的水凝胶。使用傅里叶变换红外和核磁共振光谱对乙酰化聚合物进行了表征。流变学方法用于表征水凝胶的力学行为。在有和没有溶菌酶的情况下进行降解和蛋白质释放。在小鼠皮下植入模型中研究降解。最后，使用活体动物成像在 477-SKH1-Elite 小鼠中评估两种具有不同降解和蛋白质释放特性的水凝胶配方，以了解蛋白质释放曲线。证明了凝胶的溶菌酶介导降解，并且降解速率发现取决于聚合物的 DA。降解研究进一步证实，DA 较高的聚合物形成的凝胶降解更快。蛋白质释放证明了从凝胶中实现溶菌酶介导的蛋白质释放的可行性，并且可以通过改变 DA 来调节蛋白质释放的速率。蛋白质释放研究进一步证实了通过改变 DA 实现差异蛋白质释放的可行性。证明了可开发可降解酶交联 GC 水凝胶的可行性。使用这种方法可以开发出降解时间范围从不到一周到超过六周的广泛降解时间的水凝胶。该研究还表明，通过调节 HPP-GC 乙酰化，可以精细调节蛋白质释放的可行性。因此，水凝胶平台作为各种生物医学和再生工程应用的蛋白质输送载体具有重要的应用前景。
