Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul, Republic of Korea.
Institute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
Drug Deliv. 2022 Dec;29(1):489-498. doi: 10.1080/10717544.2022.2032873.
For the prolonged, controlled delivery of systemic drugs, we propose an implantable drug-delivery chip (DDC) embedded with pairs of a microchannel and drug-reservoir serving as a drug diffusion barrier and depot, respectively. We pursued a DDC for dual drugs: a main-purpose drug, diclofenac (DF), for systemic exposure, and an antifibrotic drug, tranilast (TR), for local delivery. Thus, the problematic fibrotic tissue formation around the implanted device could be diminished, thereby less hindrance in systemic exposure of DF released from the DDC. First, we separately prepared DDCs for DF or TR delivery, and sought to find a proper microchannel length for a rapid onset and sustained pattern of drug release, as well as the required drug dose. Then, two distinct DDCs for DF and TR delivery, respectively, were assembled to produce a Dual_DDC for the concurrent delivery of DF and TR. When the Dual_DDC was implanted in living rats, the DF concentration in blood plasma did not drop significantly in the later periods after implantation relative to that in the early periods before fibrotic tissue formation. When the Dual_DDC was implanted without TR, there was a significant decrease in the blood plasma DF concentration as the time elapsed after implantation. Biopsied tissues around the Dual_DDC exhibited a significant decrease in the fibrotic capsule thickness and collagen density relative to the Dual_DDC without TR, owing to the effect of the local, sustained release of the TR.
为了实现系统药物的长时间控制释放，我们提出了一种植入式药物输送芯片（DDC），其中嵌入了一对微通道和药物储库，分别作为药物扩散屏障和储库。我们设计了一种用于双药物输送的 DDC：一种主要药物双氯芬酸（DF）用于全身暴露，一种抗纤维化药物曲尼司特（TR）用于局部输送。因此，可以减少植入设备周围有问题的纤维组织形成，从而减少 DDC 释放的 DF 的全身暴露受到的阻碍。首先，我们分别制备了用于 DF 或 TR 输送的 DDC，并寻求找到合适的微通道长度，以实现快速起始和持续的药物释放模式以及所需的药物剂量。然后，将分别用于 DF 和 TR 输送的两个不同的 DDC 组装在一起，以产生用于 DF 和 TR 同时输送的 Dual_DDC。当 Dual_DDC 被植入活老鼠体内时，与纤维组织形成之前的早期相比，植入后后期的血浆中 DF 浓度没有明显下降。当 Dual_DDC 没有 TR 植入时，随着植入后时间的流逝，血浆中 DF 浓度显著下降。与没有 TR 的 Dual_DDC 相比，在 Dual_DDC 周围活检的组织中的纤维囊厚度和胶原密度显著降低，这是由于 TR 的局部持续释放的作用。
