Autonomous Grippers in the Gastrointestinal Tract

胃肠道中的自主抓手

• 批准号: 10444385
• 负责人: David H Gracias
• 金额: $ 67.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444385
• 关键词: Affect; Allergic Reaction; Anaphylaxis; Autoimmune; Autoimmune Diseases; Award; Blood Circulation; Collaborations; Complication; Data; Deglutition; Development; Devices; Diabetes Mellitus; Drug Delivery Systems; Encapsulated; Engineering; Epithelial Cell Junction; Funding; Gastroenterologist; Gastrointestinal tract structure; Generations; Goals; Healthcare Systems; Hospitalization; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Infusion procedures; Injectable; Injections; Insulin; Insulin Antibodies; Insulin-Dependent Diabetes Mellitus; Insurance; Interdisciplinary Study; Intestinal Mucosa; Intestines; Intravenous; Intravenous infusion procedures; Measures; Medical; Monoclonal Antibodies; Mucous Membrane; National Institute of Biomedical Imaging and Bioengineering; Needles; Oral; Oral cavity; Outcome; Patient Noncompliance; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Peptide antibodies; Peptides; Performance; Persons; Pharmaceutical Preparations; Predisposition; Price; Reaction; Regimen; Research; Rheumatoid Arthritis; Robot; Route; Safety; Scientist; Sepsis; Sterilization; Subcutaneous Injections; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Tissues; Treatment Efficacy; Treatment-related toxicity; United States National Institutes of Health; absorption; adalimumab; capsule; compliance behavior; cost; design; gastrointestinal; grasp; improved; in vivo; infliximab; innovation; macromolecule; microrobot; millimeter; miniaturize; side effect; thrombotic complications

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.

项目摘要/摘要 多肽大分子是影响数亿人的疾病的主要治疗手段 全球各地的人们。例如，胰岛素是许多糖尿病患者的主要治疗手段。 糖尿病。此外，几种炎症性自身免疫性疾病(如炎症性肠病-IBD， 系统性红斑狼疮(SLE)、类风湿性关节炎(RA)等)通常用单抗治疗 抗体(单抗)，如英夫利昔单抗或阿达利单抗。胰岛素和这些单抗都是多肽大分子 因此，不能通过口服途径给药，而需要注射或输液。 静脉和注射给药途径已被证明有几个关键的缺点，当 与口头分娩相比。首先，患者对注射剂的依从性较低，导致随后 并发症、不断上升的成本和更糟糕的结果。此外，注射用药通常与 有并发症(如局部感染到脓毒症、局部组织损伤、血栓形成、过敏 反应范围从输液反应到过敏反应等)。此外，这些疗法中的一些 需要在医疗环境中进行灭菌、储存和管理，这在某些地方是不容易获得的 如果可行，将导致保险支付者的成本上升，并通过扩大医疗体系 和病人。净影响最终体现在更高的价格和更低的结果上。 多肽大分子不能口服，因为它们(1)被pH和体内的蛋白酶灭活 胃肠道；(2)肠道内紧密的上皮细胞连接，由于其体积较大，可忽略不计。 (5-150 kDa或更大)。在这里，我们建议开发一种由(A)胶囊组成的药物输送平台 它被吞噬了，它包含(B)多个毫米尺度的自主微型机器人(响尾蛇) 可携带活性多肽大分子药物，附着在胃肠道粘膜上，将其活性药物负荷注射到 体循环。作为其他努力的一部分，我们正在开发口服胶囊，并将在这里重点关注 开发多肽大分子经肠粘膜进入体循环的激活剂。 这项提议是建立在博士的实验室之间10多年来成功和富有成效的合作的基础上的。 约翰霍普金斯大学的塞拉鲁(胃肠病专家、科学家)和格雷西亚斯博士(工程师、科学家)。原版 概念，以及第一代振荡器的设计和制造是这一点的结果 协作。该项目通过R01(2014-2018)和续签得到了NIBIB的部分支持 R01(2018-2022)。目前的提案建立在先前成果的基础上，带来了令人信服的初步数据，以及 寻求更新R01以验证此处概述的创新假设。这项技术的成功开发 该项目将不仅影响患有胰岛素依赖型糖尿病和自身免疫性炎症的患者，而且 也可推广到其他非肠道治疗。