Bos Gert W, Hennink Wim E, Brouwer Linda A, den Otter Wim, Veldhuis Theo F J, van Nostrum Cornelus F, van Luyn Marja J A
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80 082, 3508 TB Utrecht, The Netherlands.
Biomaterials. 2005 Jun;26(18):3901-9. doi: 10.1016/j.biomaterials.2004.10.008.
In this study, the in vivo biocompatibility of physically crosslinked dextran hydrogels was investigated. These hydrogels were obtained by mixing aqueous solutions of dextran grafted with L-lactic acid oligomers and dextran grafted with D-lactic acid oligomers. Gelation occurs due to stereocomplex formation of the lactic acid oligomers of opposite chirality. Since gelation takes some time, in situ gel formation is possible with this system. A number of sterilization methods was evaluated for their effect on the chemical and physical properties of the hydrogel. It was shown that of the investigated options (filtration, gamma irradiation, dry-heat and autoclaving) dry-heat sterilization was the preferred method to prepare sterile gels suitable for in vivo evaluations. Two types of stereocomplex gels were prepared and implanted subcutaneously in rats. The tissue reaction was evaluated over a period of 30 days. A mild ongoing foreign body reaction was observed characterized by infiltration of macrophages. Giant cells were only scarcely formed and the low numbers of lymphocytes showed that priming of the immune system is hardly involved. Importantly, the gels fully degraded in vivo within 15 days, which is in good agreement with the in vitro degradation behaviour of these gels. In conclusion, stereocomplexed dextran-oligolactic gels showed good biocompatibility which makes them suitable candidates for the design of controlled release devices for pharmaceutically active proteins.
在本研究中，对物理交联葡聚糖水凝胶的体内生物相容性进行了研究。这些水凝胶是通过将接枝了L-乳酸低聚物的葡聚糖水溶液与接枝了D-乳酸低聚物的葡聚糖水溶液混合而获得的。由于具有相反手性的乳酸低聚物形成立体复合物，从而发生凝胶化。由于凝胶化需要一些时间，因此该系统可以实现原位凝胶形成。评估了多种灭菌方法对水凝胶化学和物理性质的影响。结果表明，在所研究的选项（过滤、γ射线辐照、干热和高压灭菌）中，干热灭菌是制备适合体内评估的无菌凝胶的首选方法。制备了两种类型的立体复合凝胶并皮下植入大鼠体内。在30天的时间内评估组织反应。观察到轻微的持续异物反应，其特征为巨噬细胞浸润。仅极少形成巨细胞，淋巴细胞数量少表明几乎未涉及免疫系统的启动。重要的是，凝胶在15天内在体内完全降解，这与这些凝胶的体外降解行为高度一致。总之，立体复合葡聚糖-低聚乳酸凝胶显示出良好的生物相容性，这使其成为设计用于药物活性蛋白控释装置的合适候选材料。
