Autonomous Grippers in the Gastrointestinal Tract

项目摘要/摘要

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.