Doctoral School in Integrative Biology, Faculty of Biology and Geology, "Babeș-Bolyai" University, 400015 Cluj-Napoca, Romania; Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, University of Medicine and Pharmacy Iuliu Hațieganu, 400010 Cluj-Napoca, Romania.
Macromolecular Chemistry Laboratory, Department of Chemistry-Ångstrom, Uppsala University, Uppsala 751 21, Sweden.
Carbohydr Polym. 2024 Sep 1;339:122251. doi: 10.1016/j.carbpol.2024.122251. Epub 2024 May 11.
In this study, the disulfide-linked hyaluronic acid (HA) hydrogels were optimised for potential application as a scaffold in tissue engineering through the Quality by Design (QbD) approach. For this purpose, HA was first modified by incorporating the cysteine moiety into the HA backbone, which promoted the formation of disulfide cross-linked HA hydrogel at physiological pH. Utilising a Design of Experiments (DoE) methodology, the critical factors to achieve stable biomaterials, i.e. the degree of HA substitution, HA molecular weight, and coupling agent ratio, were explored. To establish a design space, the DoE was performed with 65 kDa, 138 kDa and 200 kDa HA and variable concentrations of coupling agent to optimise conditions to obtain HA hydrogel with improved rheological properties. Thus, HA hydrogel with a 12 % degree of modification, storage modulus of ≈2321 Pa and loss modulus of ≈15 Pa, was achieved with the optimum ratio of coupling agent. Furthermore, biocompatibility assessments in C28/I2 chondrocyte cells demonstrated the non-toxic nature of the hydrogel, underscoring its potential for tissue regeneration. Our findings highlight the efficacy of the QbD approach in designing HA hydrogels with tailored properties for biomedical applications.
在这项研究中，通过质量源于设计（QbD）方法，对双硫键连接的透明质酸（HA）水凝胶进行了优化，以潜在应用于组织工程支架。为此，首先通过将半胱氨酸部分引入 HA 主链，使 HA 水凝胶在生理 pH 下形成二硫键交联。利用实验设计（DoE）方法，探索了实现稳定生物材料的关键因素，即 HA 取代度、HA 分子量和偶联剂比例。为了建立设计空间，使用 65 kDa、138 kDa 和 200 kDa 的 HA 和不同浓度的偶联剂进行了 DoE，以优化条件，获得具有改善流变性能的 HA 水凝胶。因此，用最佳偶联剂比例获得了 12%的改性度、约 2321 Pa 的储能模量和约 15 Pa 的损耗模量的 HA 水凝胶。此外，C28/I2 软骨细胞中的细胞相容性评估证明了水凝胶的无毒特性，突出了其在组织再生方面的潜力。我们的研究结果强调了 QbD 方法在设计具有定制性能的 HA 水凝胶用于生物医学应用方面的有效性。
