Microfabricated reciprocating micropump for intracochlear drug delivery with integrated drug/fluid storage and electronically controlled dosing.
Microfabricated reciprocating micropump for intracochlear drug delivery with integrated drug/fluid storage and electronically controlled dosing.
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DOI：
10.1039/c5lc01396h
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发表时间：
2016-03-07
期刊：
影响因子：
6.1
通讯作者：
Borenstein JT
中科院分区：
文献类型：
--
作者：
Tandon V;Kang WS;Robbins TA;Spencer AJ;Kim ES;McKenna MJ;Kujawa SG;Fiering J;Pararas EE;Mescher MJ;Sewell WF;Borenstein JT
内耳的解剖学和药理学上的不可接近性是听觉障碍的药物治疗中的主要挑战。这也使得具有全身递送的新药的药代动力学表征具有挑战性，因为功效与药物到达其靶点的效率相关联。将药物直接递送到耳蜗液绕过了药代动力学障碍，并有助于最大限度地减少全身毒性，但解剖学障碍使得在没有自动递送系统的情况下难以进行多剂量给药。毛细胞再生治疗可能需要这样的系统，这可能需要定时输送几种药物。为了应对这些挑战，我们开发了一种用于受控，自动化内耳药物输送的微型泵，其最终目标是生产长期可植入/可穿戴的输送系统。电流泵设计为在临床前药物表征实验中与豚鼠头部支架一起使用。在这个系统中，我们已经解决了几个微流体挑战，包括在安全、低流速下保持受控输送，以及在不增加耳蜗中液体体积的情况下输送药物。通过将药物储存器和所有流体组件集成到泵的微流体结构中，与之前使用单独的管道连接组件的系统相比，我们使药物输送系统变得更加强大。在这项研究中，我们在实验室和豚鼠动物模型中表征了泵独特的输注-回输和按需给药能力。对于动物实验，我们使用谷氨酸受体拮抗剂DNQX作为药物递送的生理指示剂。DNQX抑制复合动作电位（CAP），因此我们能够通过测量CAP对几个特征频率刺激的反应变化来推断DNQX随时间的分布和扩散。
The anatomical and pharmacological inaccessibility of the inner ear is a major challenge in drug-based treatment of auditory disorders. This also makes pharmacokinetic characterization of new drugs with systemic delivery challenging, because efficacy is coupled with how efficiently a drug can reach its target. Direct delivery of drugs to cochlear fluids bypasses pharmacokinetic barriers and helps to minimize systemic toxicity, but anatomical barriers make administration of multiple doses difficult without an automated delivery system. Such a system may be required for hair-cell regeneration treatments, which will likely require timed delivery of several drugs. To address these challenges, we have developed a micropump for controlled, automated inner-ear drug delivery with the ultimate goal of producing a long-term implantable/wearable delivery system. The current pump is designed to be used with a head mount for guinea pigs in preclinical drug characterization experiments. In this system, we have addressed several microfluidic challenges, including maintaining controlled delivery at safe, low flow rates and delivering drug without increasing the volume of fluid in the cochlea. By integrating a drug reservoir and all fluidic components into the microfluidic structure of the pump, we have made the drug delivery system robust compared to previous systems that utilized separate, tubing-connected components. In this study, we characterized the pump’s unique infuse-withdraw and on-demand dosing capabilities on the bench and in guinea pig animal models. For the animal experiments, we used DNQX, a glutamate receptor antagonist, as a physiological indicator of drug delivery. DNQX suppresses compound action potentials (CAPs), so we were able to infer the distribution and spreading of the DNQX over time by measuring the changes in CAPs in response to stimuli at several characteristic frequencies.