Autonomous Grippers in the Gastrointestinal Tract

项目总结/摘要 肽类大分子是治疗数亿人疾病的主要药物 of people across横过the地球仪.例如，胰岛素是许多糖尿病患者的主要治疗药物 糖尿病。此外，几种炎性自身免疫性疾病（如炎性肠病- IBD， 系统性红斑狼疮- SLE、类风湿性关节炎- RA和其他）通常用单克隆抗体治疗， 抗体（mAb），如英夫利昔单抗或阿达木单抗。胰岛素和这些单克隆抗体都是肽类大分子 因此不能通过口服途径给予，而是需要注射或输注。 静脉内和注射递送途径已被证明具有几个关键的缺点， 与口服相比。首先，患者对注射剂的依从性较低，导致随后的 并发症、不断上升的成本和更糟糕的结果。此外，注射药物通常与 并发症（如局部感染至败血症、局部组织损伤、血栓形成、过敏性 从输液反应到过敏反应等）。此外，其中一些方案 需要在医疗环境中进行消毒、储存和给药，这在某些地方是不容易获得的 如果可用的话，会导致保险支付者的成本不断上升，并通过扩大医疗保健系统 和病人。净效应最终以更高的价格和更低的结果来衡量。 肽大分子不能口服给药，因为它们（1）被pH和蛋白酶灭活， 胃肠道，和（2）可忽略的运输通过紧密的上皮细胞连接在肠道，由于他们的大尺寸 （5-150 kDa或更大）。在这里，我们提出开发一种药物递送平台，该平台由以下组成：（A）胶囊， 它被吞下，它包含（B）多毫米尺度的自主微型机器人（theragrippers）， 可携带活性肽类大分子药物，附着于胃肠道粘膜，将其活性载药量注入胃肠道， 体循环我们正在开发口服胶囊作为其他努力的一部分，并将重点放在这里 开发用于将肽大分子经肠粘膜递送至体循环的治疗裂解剂。 该提案是建立在博士的实验室之间10多年的成功和富有成效的合作。 约翰霍普金斯大学的Selaru（胃肠病学家，科学家）和Gracias博士（工程师，科学家）。原始 概念，以及第一代的设计和制造的theragrippers是这一结果 协作该项目通过R 01（2014-2018）和更新得到了NIBIB的部分支持 R01（2018 - 2022）。目前的提案建立在先前的结果基础上，带来了令人信服的初步数据， 寻求更新R 01以验证此处概述的创新假设。这一成功的发展 该项目不仅会影响胰岛素依赖型糖尿病和自身免疫性炎症患者， 也可以推广到其他肠胃外治疗。

PROJECT SUMMARY/ ABSTRACT Peptide macromolecules represent the mainstay of treatment for conditions affecting hundreds of millions of people across the globe. For example, insulin is the mainstay of treatment for many patients with diabetes mellitus. In addition, several inflammatory autoimmune disorders (such as Inflammatory Bowel Disease – IBD, systemic lupus erythematosus – SLE, rheumatoid arthritis – RA, and others) are often treated with monoclonal antibodies (mAbs), such as infliximab or adalimumab. Both insulin and these mAbs are peptide macromolecules and, as such, cannot be given by an oral route, instead requiring injection or infusion. Intravenous and injectable delivery routes have been shown to have several critical downsides when compared to oral delivery. First, patients have shown less compliance towards injectables, leading to subsequent complications, escalating costs and worse outcomes. In addition, injectable medications are often associated with complications (such as infection ranging from localized to sepsis, local tissue damage, thrombosis, allergic reactions ranging from infusion reactions to anaphylaxis, and others). Furthermore, some of these regimens require sterilization, storage, and administration in a medical setting, which is not readily available in some parts of the world and if available, result in escalating cost to insurance payers and by extesion the healthcare system and patients. The net effect is ultimately measured in higher price, and lower outcomes. Peptide macromolecules cannot be given orally because their (1) inactivation by pH and proteases in the GI tract, and (2) negligible transport across the tight epithelial cell junctions in the intestine due to their large size (5-150 kDa or more). Here we propose to develop a platform of drug delivery that is composed of (A) a capsule that is swallowed, and that contains (B) multiple millimeter scale, autonomous microrobots (theragrippers) that can carry the active peptide macromolecule drug, latch onto the GI mucosa and inject their active drug load into the systemic circulation. We are developing the oral capsule as part of other efforts and will focus here on developing theragrippers for peptide macromolecule delivery trans-intestinal mucosa to the systemic circulation. The proposal is built on 10+ years of successful and productive collaboration between the labs of Dr. Selaru (gastroenterologist, scientist) and Dr. Gracias (engineer, scientist) at Johns Hopkins. The original concept, as well as first-generation design and manufacturing of the theragrippers are a result of this collaboration. The project has been supported in part by the NIBIB through an R01 (2014-2018) and a renewal R01 (2018 - 2022). The current proposal builds on the prior results, brings compelling preliminary data, and seeks a renewal R01 to validate the innovative hypothesis outlined here. The successful development of this project will affect not only patients with insulin-dependent diabetes and autoimmune inflammatory conditions but may be generalizable to other parenteral treatments as well.