Vivian R. Feig

In situ -forming (ISF) medical devices are delivered as flowable precursors that assemble into macroscopic, tissue-conformal devices at the target site, enabling minimally invasive implantation. While historically limited to structural or passive roles, next-generation ISF systems must be engineered for multifunctional performance to enable expanded clinical utility. This review presents a design framework in which the device's structure and functionality are governed by precursor composition, phase-transformation mechanism, and transformation stimulus. We examine how this framework guides the development of functional devices across three key domains: drug delivery, tissue regeneration, and bioelectronics. For each, we define critical performance requirements and highlight recent advances addressing these challenges. We conclude with translational considerations and future priorities, including improved geometric control and integration of materials with advanced functionalities, to realize robust, multifunctional ISF systems. By linking materials design to application-specific device performance, this review outlines a path toward next-generation ISF medical technologies.

Ingestible hydrogels have long been used in food and therapeutic applications. Their polymeric composition endows these materials with programmable and dynamic properties to operate within the complex gastrointestinal tract. Recent advances have pushed the boundaries of hydrogel behavior and function; incorporating these features may enable new strategies to manage gastrointestinal and systemic diseases. In this perspective, we highlight some commercial ingestible hydrogel products to establish their current capabilities. We then discuss some recent advances of ingestible hydrogels that push these capabilities in the areas of tissue-specific activity, ultralong retention within the gastrointestinal tract, and incorporation into ingestible electronics and robots. Finally, we discuss some key considerations for translating ingestible macroscale hydrogels, which requires early consideration of in vivo models and regulation, safety, and manufacturing.

Abstract Injectable drug depots have transformed our capacity to enhance medication adherence through dose simplification. Central to patient adoption of injectables is the acceptability of needle injections, with needle gauge as a key factor informing patient discomfort. Maximizing drug loading in injectables supports longer drug release while reducing injection volume and discomfort. Here, to address these requirements, we developed self-aggregating long-acting injectable microcrystals (SLIM), an injectable formulation containing drug microcrystals that self-aggregate in the subcutaneous space to form a monolithic implant with a low ratio of polymer excipient to drug (0.0625:1 w/w). By minimizing polymer content, SLIM supports injection through low-profile needles (<25 G) with high drug loading (293 mg ml −1 ). We demonstrate in vitro and in vivo that self-aggregation is driven by solvent exchange at the injection site and that slower-exchanging solvents result in increased microcrystal compaction and reduced implant porosity. We further show that self-aggregation enhances long-term drug release in rodents. We anticipate that SLIM could enable low-cost interventions for contraceptives.

Injectable drug depots have transformed our capacity to enhance medication adherence through dose simplification. Central to patient adoption of injectables is the acceptability of needle injections, with needle gauge as a key factor informing patient discomfort. Maximizing drug loading in injectables supports longer drug release while reducing injection volume and discomfort. Here, to address these requirements, we developed self-aggregating long-acting injectable microcrystals (SLIM), an injectable formulation containing drug microcrystals that self-aggregate in the subcutaneous space to form a monolithic implant with a low ratio of polymer excipient to drug (0.0625:1 w/w). By minimizing polymer content, SLIM supports injection through low-profile needles (<25 G) with high drug loading (293 mg ml−1). We demonstrate in vitro and in vivo that self-aggregation is driven by solvent exchange at the injection site and that slower-exchanging solvents result in increased microcrystal compaction and reduced implant porosity. We further show that self-aggregation enhances long-term drug release in rodents. We anticipate that SLIM could enable low-cost interventions for contraceptives.

Conductive hydrogels combine the benefits of soft hydrogels with electrical conductivity and have gained significant attention over the past decade. These innovative materials, including poly(3,4-ethylenedioxythiophene) (PEDOTs)-based conductive hydrogels (P-CHs), are promising for flexible electronics and biological applications due to their tunable flexibility, biocompatibility, and hydrophilicity. Despite the recent advances, the intrinsic correlation between the design, fabrications, and applications of P-CHs has been mostly based on trial-and-error-based Edisonian approaches, significantly limiting their further development. This review comprehensively examines the design strategies, fabrication technologies, and diverse applications of P-CHs. By summarizing design strategies, such as molecular, network, phase, and structural engineering, and exploring both 2D and 3D fabrication techniques, this review offers a comprehensive overview of P-CHs applications in diverse fields including bioelectronics, soft actuators, energy devices, and solar evaporators. Establishing this critical internal connection between design, fabrication, and application aims to guide future research and stimulate innovation in the field of functional P-CHs, offering broad benefits to multidisciplinary researchers.

Biotherapeutics are among the therapeutics that have revolutionized standard inflammatory bowel disease (IBD) treatment, which was previously limited to mesalamine, 5-aminosalicylic acid, corticosteroids, and classical immunosuppressants. Self-administrable biotherapeutics for IBD would enable home-based treatment and reduce the burden on medical infrastructure. Self-administration is made possible through subcutaneous injectable, oral, and rectal dosage forms. Nevertheless, the full benefits of self-administration cannot be realized without first addressing the issue of medication adherence, which remains woefully inadequate for IBD biotherapies. Some of the major barriers to medication adherence in IBD are the route of administration, frequency of administration, and undesired side effects. In this review, we identify the main physiological and engineering constraints that underlie these three barriers to adherence. We then highlight key technological and behavioral innovations-spanning multiple scientific disciplines-that can be leveraged to design novel therapies and interventions that improve adherence to self-administered IBD biotherapies.

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.

Achieving tunable rupturing of eutectic gallium indium (EGaIn) particles holds great significance in flexible electronic applications, particularly pressure sensors. We tune the mechanosensitivity of EGaIn particles by preparing them in toluene with thiol surfactants and demonstrate an improvement over typical preparations in ethanol. We observe, across multiple length scales, that thiol surfactants and the nonpolar solvent synergistically reduce the applied stress requirements for electromechanical actuation. At the nanoscale, dodecanethiol and propanethiol in toluene suppress gallium oxide growth, as characterized by transmission electron microscopy and X-ray photoelectron spectroscopy. Quantitative AFM imaging produces force-indentation curves and height images, while conductive AFM measures current while probing individual EGaIn particles. As the applied force increases, thiolated particles demonstrate intensified softening, rupturing, and stress-induced electrical activation at forces 40% lower than those for bare particles in ethanol. To confirm that thiolation facilitates rupturing at the macroscale, a laser is used to ablate samples of EGaIn particles. Scanning electron microscopy and resistance measurements across macroscopic samples confirm that thiolated EGaIn particles coalesce to exhibit electrical activation at 0.1 W. Particles prepared in ethanol, however, require 3 times higher laser power to demonstrate a similar behavior. This unique collection of advanced techniques demonstrates that our particle synthesis conditions can facilitate on-demand functionality to benefit electronic applications.

Abstract 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.

Summary 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.

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 from gastric acid-mediated deactivation. Overall, LIFT hydrogels may expand access to advanced therapeutics for patients with difficulty swallowing.

Abstract Tumor hypoxia, resulting from rapid tumor growth and aberrant vascular proliferation, exacerbates tumor aggressiveness and resistance to treatments like radiation and chemotherapy. To increase tumor oxygenation, we developed solid oxygen gas‐entrapping materials (O 2 ‐GeMs), which were modeled after clinical brachytherapy implants, for direct tumor implantation. The objective of this study was to investigate the impact different formulations of solid O 2 ‐GeMs have on the entrapment and delivery of oxygen. Using a Parr reactor, we fabricated solid O 2 ‐GeMs using carbohydrate‐based formulations used in the confectionary industry. In evaluating solid O 2 ‐GeMs manufactured from different sugars, the sucrose‐containing formulation exhibited the highest oxygen concentration at 1 mg/g, as well as the fastest dissolution rate. The addition of a surface coating to the solid O 2 ‐GeMs, especially polycaprolactone, effectively prolonged the dissolution of the solid O 2 ‐GeMs. In vivo evaluation confirmed robust insertion and positioning of O 2 ‐GeMs in a malignant peripheral nerve sheath tumor, highlighting potential clinical applications.

High Resolution Image Download MS PowerPoint Slide 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.

Stem cells are a promising treatment option for various neurological diseases such as stroke, spinal cord injury, and other neurodegenerative disorders. However, the ideal environment to optimize the therapeutic potential of the cells remains poorly understood. Stem cells in the native environment are influenced by a combination of mechanical, chemical, and electrical cues for proliferation and differentiation. Because of their controllable properties, conductive hydrogels are promising biomaterials to interact with stem cells. Herein, this work develops an interpenetrating conducting polymer hydrogel with tunable mechanical properties. The hydrogel serves as a platform to provide mechanical and electrical cues for interactions with mesenchymal stem cells (MSCs). This work optimizes the formulation of the hydrogel for maximum viability of MSCs and relatively higher cytoskeletal protein expression. The viability of cells is not affected due to electrical stimulation (ES). Further, ES alters the trophic factor secretion of MSCs, with significant increase in VEGF pathway genes-VEGFA and HSPB1. In addition, substrate stiffness of the hydrogel enhances the VEGFB secretion compared to control. Hence, the conducting polymer hydrogel system creates a tunable physical and electrical niche to enhance the therapeutic potential of stem cells for neurological injuries.

Abstract Tumor hypoxia drives resistance to many cancer therapies, including radiotherapy and chemotherapy. Methods that increase tumor oxygen pressures, such as hyperbaric oxygen therapy and microbubble infusion, are utilized to improve the responses to current standard‐of‐care therapies. However, key obstacles remain, in particular delivery of oxygen at the appropriate dose and with optimal pharmacokinetics. Toward overcoming these hurdles, gas‐entrapping materials (GeMs) that are capable of tunable oxygen release are formulated. It is shown that injection or implantation of these materials into tumors can mitigate tumor hypoxia by delivering oxygen locally and that these GeMs enhance responsiveness to radiation and chemotherapy in multiple tumor types. This paper also demonstrates, by comparing an oxygen (O 2 )‐GeM to a sham GeM, that the former generates an antitumorigenic and immunogenic tumor microenvironment in malignant peripheral nerve sheath tumors. Collectively the results indicate that the use of O 2 ‐GeMs is promising as an adjunctive strategy for the treatment of solid tumors.