Giovanni Traverso

Postoperative ileus (POI) is the leading cause of prolonged hospital stay after abdominal surgery and is characterized by a functional paralysis of the digestive tract, leading to symptoms such as constipation, vomiting, and functional obstruction. Current treatments are mainly supportive and inefficacious and yield acute side effects. Although electrical stimulation studies have demonstrated encouraging pacing and entraining of the intestinal slow waves, no devices exist today to enable targeted intestinal reanimation. Here, we developed an ingestible self-propelling device for intestinal reanimation (INSPIRE) capable of restoring peristalsis through luminal electrical stimulation. Optimizing mechanical, material, and electrical design parameters, we validated optimal deployment, intestinal electrical luminal contact, self-propelling capability, safety, and degradation of the device in ex vivo and in vivo swine models. We …

A method for the systemic delivery of a polypeptide within a subject is provided by creating genetically modified skin cells via topical introduction of a genetically engineered virus which delivers a nucleic acid encoding a therapeutic polypeptide for expression by the skin cells, wherein the expressed therapeutic polypeptide is secreted by the skin cells and is introduced into the circulatory system of the subject.

Ingestible electronics have the capacity to transform our ability to effectively diagnose and potentially treat a broad set of conditions. Current applications could be significantly enhanced by addressing poor electrode-tissue contact, lack of navigation, short dwell time, and limited battery life. Here we report the development of an ingestible, battery-free, and tissue-adhering robotic interface (IngRI) for non-invasive and chronic electrostimulation of the gut, which addresses challenges associated with contact, navigation, retention, and powering (C-N-R-P) faced by existing ingestibles. We show that near-field inductive coupling operating near 13.56 MHz was sufficient to power and modulate the IngRI to deliver therapeutically relevant electrostimulation, which can be further enhanced by a bio-inspired, hydrogel-enabled adhesive interface. In swine models, we demonstrated the electrical interaction of IngRI with the gastric mucosa by recording conductive signaling from the subcutaneous space. We further observed changes in plasma ghrelin levels, the "hunger hormone," while IngRI was activated in vivo, demonstrating its clinical potential in regulating appetite and treating other endocrine conditions. The results of this study suggest that concepts inspired by soft and wireless skin-interfacing electronic devices can be applied to ingestible electronics with potential clinical applications for evaluating and treating gastrointestinal conditions.

Pills are a cornerstone of medicine but can be challenging to swallow. While liquid formulations are easier to ingest, they lack the capacity to localize therapeutics with excipients nor act as controlled release devices. Here we describe drug formulations based on liquid in situ-forming tough (LIFT) hydrogels that bridge the advantages of solid and liquid dosage forms. LIFT hydrogels form directly in the stomach through sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by a drug-containing polymer solution of alginate and four-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels robustly form in the stomachs of live rats and pigs, and are mechanically tough, biocompatible and safely cleared after 24 h. LIFT hydrogels deliver a total drug dose comparable to unencapsulated drug in a controlled manner, and protect encapsulated therapeutic enzymes and bacteria …

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune-modulating effects. To facilitate delivery of CO, we have designed hyaluronic-acid-based CO gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N2-GEMs and untreated controls.

In vitro systems that accurately model in vivo conditions in the gastrointestinal tract may aid the development of oral drugs with greater bioavailability. Here we show that the interaction profiles between drugs and intestinal drug transporters can be obtained by modulating transporter expression in intact porcine tissue explants via the ultrasound-mediated delivery of small interfering RNAs and that the interaction profiles can be classified via a random forest model trained on the drug–transporter relationships. For 24 drugs with well-characterized drug–transporter interactions, the model achieved 100% concordance. For 28 clinical drugs and 22 investigational drugs, the model identified 58 unknown drug–transporter interactions, 7 of which (out of 8 tested) corresponded to drug-pharmacokinetic measurements in mice. We also validated the model’s predictions for interactions between doxycycline and four drugs …

BackgroundDosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients.MethodsWe designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK).FindingsWe demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that …

Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas‐entrapping material containing CO in a pre‐clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly …

2023-08-31 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LANGER, ROBERT S., KHANG, Minsoo, BENSEL, Taylor, ABRAMSON, Alex G., ROXHED, Niclas, SALVADOR, Ester Caffarel2023-08-31 Assigned to THE BRIGHAM AND WOMEN'S HOSPITAL, INC., MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment THE BRIGHAM AND WOMEN'S HOSPITAL, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TRAVERSO, Carlo Giovanni

Nanoparticles exhibit anisotropy when distinct features can be identified along different axes. Such disruption in shape and/or composition symmetry can change how nanoparticles behave and interact with the surrounding environment compared with their isotropic counterparts. Anisotropic combinations can be limitless and show potential for tackling biological barriers and developing programmable, targeted, and combined delivery of bioactive molecules, mainly when featuring autonomous motion. In this Review, we summarize the main methods for the generation of anisotropic particles at the nanoscale. We further discuss how geometric cues or the incorporation of propulsive agents (chemically or physically driven) improve transport across biological fluids, promote cellular adhesion and internalization, and/or increase tissue penetration. We finally highlight considerations for the design of anisotropic …

Percutaneous cryoablation is a common clinical therapy for metastatic and primary cancer. There are rare clinical reports of cryoablation inducing regression of distant metastases, known as the “abscopal” effect. Intratumoral immunoadjuvants may be able to augment the abscopal rate of cryoablation, but existing intratumoral therapies suffer from the need for frequent injections and inability to confirm target delivery, leading to poor clinical trial outcomes. To address these shortcomings, an injectable thermoresponsive gel‐based controlled release formulation is developed for the FDA‐approved Toll‐like‐receptor 7 (TLR7) agonist imiquimod (“Imigel”) that forms a tumor‐resident depot upon injection and contains a contrast agent for visualization under computed tomography (CT). The poly‐lactic‐co‐glycolic acid‐polyethylene glycol‐poly‐lactic‐co‐glycolic acid (PLGA‐PEG‐PLGA)‐based amphiphilic copolymer gel …

A drug delivery device may be configured to delivery an active pharmaceutical ingredient (API) to a subject via the subject's oral-gastrointestinal (GI) tract. The drug delivery device may be configured to deliver a payload of an API while within the GI tract of the subject. The drug delivery device may include a reservoir, a potential energy source, a plurality of outlets, and a plurality of valves, wherein each outlet has a corresponding valve. The drug delivery device may further include a sensor configured to sense the direction of gravity, and the valves may be selectively opened based on a sensed direction of gravity. Thus, the drug delivery device may dispense a dose of API within the GI tracts of the subject based at least in part on the sensed direction of gravity.

Triggerable coatings, such as pH-responsive polymethacrylate copolymers, can be used to protect the active pharmaceutical ingredients contained within oral solid dosage forms from the acidic gastric environment and to facilitate drug delivery directly to the intestine. However, gastrointestinal pH can be highly variable, which can reduce delivery efficiency when using pH-responsive drug delivery technologies. We hypothesized that biomaterials susceptible to proteolysis could be used in combination with other triggerable polymers to develop novel enteric coatings. Bioinformatic analysis suggested that silk fibroin is selectively degradable by enzymes in the small intestine, including chymotrypsin, but resilient to gastric pepsin. Based on the analysis, we developed a silk fibroin-polymethacrylate copolymer coating for oral dosage forms. In vitro and in vivo studies demonstrated that capsules coated with this novel silk …

Page 2 kinetics with no potential for burst release for weeks to months. In some embodiments, the residence articles described herein comprise biocompatible materials and/or are safe for gastric retention. In certain embodiments, the residence article includes dimensions configured for transesophageal retrieval. In some cases, the residence articles described herein may comprise relatively large doses of drug (eg, greater than or equal to l gram).

Point‐of‐care (POC) has the capacity to support low‐cost, accurate and real‐time actionable diagnostic data. Microneedle sensors have received considerable attention as an emerging technique to evolve blood‐based diagnostics owing to their direct and painless access to a rich source of biomarkers from interstitial fluid. This review systematically summarizes the recent innovations in microneedle sensors with a particular focus on their utility in POC diagnostics and personalized medicine. The integration of various sensing techniques, mostly electrochemical and optical sensing, has been established in diverse architectures of “lab‐on‐a‐microneedle” platforms. Microneedle sensors with tailored geometries, mechanical flexibility, and biocompatibility are constructed with a variety of materials and fabrication methods. Microneedles categorized into four types: metals, inorganics, polymers, and hydrogels, have …

Delivering heat in vivo could enhance a wide range of biomedical therapeutic and diagnostic technologies, including long-term drug delivery devices and cancer treatments. To date, providing thermal energy is highly power-intensive, rendering it oftentimes inaccessible outside of clinical settings. We developed an in vivo heating method based on the exothermic reaction between liquid-metal-activated aluminum and water. After establishing a method for consistent activation, we characterized the heat generation capabilities with thermal imaging and heat flux measurements. We then demonstrated one application of this reaction: to thermally actuate a gastric resident device made from a shape-memory alloy called Nitinol. Finally, we highlight the advantages and future directions for leveraging this novel in situ heat generation method beyond the showcased example.

PURPOSE: While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration after injury to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal.METHODS: Here, we describe the design and validation of a new platform for nerve regeneration and interfacing: Absorbable, Conductive, Electrotherapeutic Scaffolds (ACES). ACES are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open and minimally invasive percutaneous approaches.RESULTS: In a rodent model of sciatic nerve repair, ACES significantly improved motor and sensory recovery (p< 0.05), increased muscle mass (p< 0.05), and increased axonogenesis (p< 0.05). Triggered dissolution of ACES enabled atraumatic …

An ingestible capsule includes a housing forming a cavity and having a textured outer surface. The textured outer surface forms a helical depression and a plurality of protruding studs disposed in the helical depression. The capsule further includes a therapeutic agent disposed in or on the housing. The capsule also includes a biodegradable coating on the textured outer surface of the housing, the biodegradable coating configured to dissolve in a fluid having a pH of 1.5 to 9.

The present disclosure provides compositions, methods, and kits that enable the in situ growth of polymers on or within a subject. In some aspects, the tissue-active monomers, including monomers comprising macromolecules, provide abroad set of material choices for synthetic tissue barriers. In additional aspects, the compositions, methods, and kits are useful for treating or preventing a disease or disorder.

Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal (GI) theranostics. Here, we report the development of e-GLUE, an electroadhesive hydrogel interface for robust and prolonged mucosal retention following electrical activation. Notably, this novel mucosal adhesion mechanism can increase the adhesion energy of hydrogels on the mucosa by up to 30-fold and enable in vivo GI retention of e-GLUE devices for up to 30 days. Strong mucosal adhesion occurs within one minute of electrical activation, despite the presence of luminal fluid, mucus exposure, and organ motility, thereby ensuring compatibility with complex in vivo environments. In swine studies, we demonstrate the utility of e-GLUE for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the GI tract. This system can enable improved treatments for various health conditions, including gastrointestinal bleeding, inflammatory bowel disease, and diagnostic applications in the GI tract and beyond.