Modulation of diabetic wound healing using carbon monoxide gas-entrapping materials.

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.

Thiol Coordination Softens Liquid Metal Particles To Improve On-Demand Conductivity.

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.

Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics.

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.

Impact of formulation on solid oxygen-entrapping materials to overcome tumor hypoxia.

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 (O2-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 O2-GeMs have on the entrapment and delivery of oxygen. Using a Parr reactor, we fabricated solid O2-GeMs using carbohydrate-based formulations used in the confectionary industry. In evaluating solid O2-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 O2-GeMs, especially polycaprolactone, effectively prolonged the dissolution of the solid O2-GeMs. In vivo evaluation confirmed robust insertion and positioning of O2-GeMs in a malignant peripheral nerve sheath tumor, highlighting potential clinical applications.

Activated Metals to Generate Heat for Biomedical Applications.

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.

Low-Cost, High-Pressure-Synthesized Oxygen-Entrapping Materials to Improve Treatment of Solid Tumors.

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 (O2 )-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 O2 -GeMs is promising as an adjunctive strategy for the treatment of solid tumors.

Actively Triggerable Metals via Liquid Metal Embrittlement for Biomedical Applications.

Actively triggerable materials, which break down upon introduction of an exogenous stimulus, enable precise control over the lifetime of biomedical technologies, as well as adaptation to unforeseen circumstances, such as changes to an established treatment plan. Yet, most actively triggerable materials are low-strength polymers and hydrogels with limited long-term durability. By contrast, metals possess advantageous functional properties, including high mechanical strength and conductivity, that are desirable across several applications within biomedicine. To realize actively triggerable metals, a mechanism called liquid metal embrittlement is leveraged, in which certain liquid metals penetrate the grain boundaries of certain solid metals and cause them to dramatically weaken or disintegrate. In this work, it is demonstrated that eutectic gallium indium (EGaIn), a biocompatible alloy of gallium, can be formulated to reproducibly trigger the breakdown of aluminum within different physiologically relevant environments. The breakdown behavior of aluminum after triggering can further be readily controlled by manipulating its grain structure. Finally, three possible use cases of biomedical devices constructed from actively triggerable metals are demonstrated.

Mucosa-interfacing electronics.

The surface mucosa that lines many of our organs houses myriad biometric signals and, therefore, has great potential as a sensor-tissue interface for high-fidelity and long-term biosensing. However, progress is still nascent for mucosa-interfacing electronics owing to challenges with establishing robust sensor-tissue interfaces; device localization, retention and removal; and power and data transfer. This is in sharp contrast to the rapidly advancing field of skin-interfacing electronics, which are replacing traditional hospital visits with minimally invasive, real-time, continuous and untethered biosensing. This Review aims to bridge the gap between skin-interfacing electronics and mucosa-interfacing electronics systems through a comparison of the properties and functions of the skin and internal mucosal surfaces. The major physiological signals accessible through mucosa-lined organs are surveyed and design considerations for the next generation of mucosa-interfacing electronics are outlined based on state-of-the-art developments in bio-integrated electronics. With this Review, we aim to inspire hardware solutions that can serve as a foundation for developing personalized biosensing from the mucosa, a relatively uncharted field with great scientific and clinical potential.

Delivery of therapeutic carbon monoxide by gas-entrapping materials.

Carbon monoxide (CO) has long been considered a toxic gas but is now a recognized bioactive gasotransmitter with potent immunomodulatory effects. Although inhaled CO is currently under investigation for use in patients with lung disease, this mode of administration can present clinical challenges. The capacity to deliver CO directly and safely to the gastrointestinal (GI) tract could transform the management of diseases affecting the GI mucosa such as inflammatory bowel disease or radiation injury. To address this unmet need, inspired by molecular gastronomy techniques, we have developed a family of gas-entrapping materials (GEMs) for delivery of CO to the GI tract. We show highly tunable and potent delivery of CO, achieving clinically relevant CO concentrations in vivo in rodent and swine models. To support the potential range of applications of foam GEMs, we evaluated the system in three distinct disease models. We show that a GEM containing CO dose-dependently reduced acetaminophen-induced hepatocellular injury, dampened colitis-associated inflammation and oxidative tissue injury, and mitigated radiation-induced gut epithelial damage in rodents. Collectively, foam GEMs have potential paradigm-shifting implications for the safe therapeutic use of CO across a range of indications.

Low-cost gastrointestinal manometry via silicone-liquid-metal pressure transducers resembling a quipu.

The evaluation of the tone and contractile patterns of the gastrointestinal (GI) tract via manometry is essential for the diagnosis of GI motility disorders. However, manometry is expensive and relies on complex and bulky instrumentation. Here we report the development and performance of an inexpensive and easy-to-manufacture catheter-like device for capturing manometric data across the dynamic range observed in the human GI tract. The device, which we designed to resemble the quipu-knotted strings used by Andean civilizations for the capture and transmission of information-consists of knotted piezoresistive pressure sensors made by infusing a liquid metal (eutectic gallium-indium) through thin silicone tubing. By exploring a range of knotting configurations, we identified optimal design schemes that led to sensing performances comparable to those of commercial devices for GI manometry, as we show for the sensing of GI motility in multiple anatomic sites of the GI tract of anaesthetized pigs. Disposable and customizable piezoresistive catheters may broaden the use of GI manometry in low-resource settings.

Advancing models of neural development with biomaterials.

Human pluripotent stem cells have emerged as a promising in vitro model system for studying the brain. Two-dimensional and three-dimensional cell culture paradigms have provided valuable insights into the pathogenesis of neuropsychiatric disorders, but they remain limited in their capacity to model certain features of human neural development. Specifically, current models do not efficiently incorporate extracellular matrix-derived biochemical and biophysical cues, facilitate multicellular spatio-temporal patterning, or achieve advanced functional maturation. Engineered biomaterials have the capacity to create increasingly biomimetic neural microenvironments, yet further refinement is needed before these approaches are widely implemented. This Review therefore highlights how continued progression and increased integration of engineered biomaterials may be well poised to address intractable challenges in recapitulating human neural development.

Conducting polymer-based granular hydrogels for injectable 3D cell scaffolds.

Injectable 3D cell scaffolds possessing both electrical conductivity and native tissue-level softness would provide a platform to leverage electric fields to manipulate stem cell behavior. Granular hydrogels, which combine jamming-induced elasticity with repeatable injectability, are versatile materials to easily encapsulate cells to form injectable 3D niches. In this work, we demonstrate that electrically conductive granular hydrogels can be fabricated via a simple method involving fragmentation of a bulk hydrogel made from the conducting polymer PEDOT:PSS. These granular conductors exhibit excellent shear-thinning and self-healing behavior, as well as record-high electrical conductivity for an injectable 3D scaffold material (~10 S m-1). Their granular microstructure also enables them to easily encapsulate induced pluripotent stem cell (iPSC)-derived neural progenitor cells, which were viable for at least 5 days within the injectable gel matrices. Finally, we demonstrate gel biocompatibility with minimal observed inflammatory response when injected into a rodent brain.

Conjugated Polymer for Implantable Electronics toward Clinical Application.

Owing to their excellent mechanical flexibility, mixed-conducting electrical property, and extraordinary chemical turnability, conjugated polymers have been demonstrated to be an ideal bioelectronic interface to deliver therapeutic effect in many different chronic diseases. This review article summarizes the latest advances in implantable electronics using conjugated polymers as electroactive materials and identifies remaining challenges and opportunities for developing electronic medicine. Examples of conjugated polymer-based bioelectronic devices are selectively reviewed in human clinical studies or animal studies with the potential for clinical adoption. The unique properties of conjugated polymers are highlighted and exemplified as potential solutions to address the specific challenges in electronic medicine.

Stretchable and Fully Degradable Semiconductors for Transient Electronics.

The next materials challenge in organic stretchable electronics is the development of a fully degradable semiconductor that maintains stable electrical performance under strain. Herein, we decouple the design of stretchability and transience by harmonizing polymer physics principles and molecular design in order to demonstrate for the first time a material that simultaneously possesses three disparate attributes: semiconductivity, intrinsic stretchability, and full degradability. We show that we can design acid-labile semiconducting polymers to appropriately phase segregate within a biodegradable elastomer, yielding semiconducting nanofibers that concurrently enable controlled transience and strain-independent transistor mobilities. Along with the future development of suitable conductors and device integration advances, we anticipate that these materials could be used to build fully biodegradable diagnostic or therapeutic devices that reside inside the body temporarily, or environmental monitors that are placed in the field and break down when they are no longer needed. This fully degradable semiconductor represents a promising advance toward developing multifunctional materials for skin-inspired electronic devices that can address previously inaccessible challenges and in turn create new technologies.

An Electrochemical Gelation Method for Patterning Conductive PEDOT:PSS Hydrogels.

Due to their high water content and macroscopic connectivity, hydrogels made from the conducting polymer PEDOT:PSS are a promising platform from which to fabricate a wide range of porous conductive materials that are increasingly of interest in applications as varied as bioelectronics, regenerative medicine, and energy storage. Despite the promising properties of PEDOT:PSS-based porous materials, the ability to pattern PEDOT:PSS hydrogels is still required to enable their integration with multifunctional and multichannel electronic devices. In this work, a novel electrochemical gelation ("electrogelation") method is presented for rapidly patterning PEDOT:PSS hydrogels on any conductive template, including curved and 3D surfaces. High spatial resolution is achieved through use of a sacrificial metal layer to generate the hydrogel pattern, thereby enabling high-performance conducting hydrogels and aerogels with desirable material properties to be introduced into increasingly complex device architectures.

Multi-scale ordering in highly stretchable polymer semiconducting films.

Stretchable semiconducting polymers have been developed as a key component to enable skin-like wearable electronics, but their electrical performance must be improved to enable more advanced functionalities. Here, we report a solution processing approach that can achieve multi-scale ordering and alignment of conjugated polymers in stretchable semiconductors to substantially improve their charge carrier mobility. Using solution shearing with a patterned microtrench coating blade, macroscale alignment of conjugated-polymer nanostructures was achieved along the charge transport direction. In conjunction, the nanoscale spatial confinement aligns chain conformation and promotes short-range π-π ordering, substantially reducing the energetic barrier for charge carrier transport. As a result, the mobilities of stretchable conjugated-polymer films have been enhanced up to threefold and maintained under a strain up to 100%. This method may also serve as the basis for large-area manufacturing of stretchable semiconducting films, as demonstrated by the roll-to-roll coating of metre-scale films.

Author Correction: Mechanically tunable conductive interpenetrating network hydrogels that mimic the elastic moduli of biological tissue.

The original version of this Article contained an error in the second sentence of the 'Materials' section of the Methods, which incorrectly read 'PEDOT:PSS synthesized by Orgacon (739324 Aldrich, MDL MFCD07371079) was purchased as a surfactant-free aqueous dispersion with 1.1 wt% solid content.' The correct version replaces this sentence with 'PEDOT:PSS Orgacon ICP 1050 was provided by Agfa as a surfactant-free aqueous dispersion with 1.1 wt% solid content.' This has been corrected in both the PDF and HTML versions of the Article.

Mechanically tunable conductive interpenetrating network hydrogels that mimic the elastic moduli of biological tissue.

Conductive and stretchable materials that match the elastic moduli of biological tissue (0.5-500 kPa) are desired for enhanced interfacial and mechanical stability. Compared with inorganic and dry polymeric conductors, hydrogels made with conducting polymers are promising soft electrode materials due to their high water content. Nevertheless, most conducting polymer-based hydrogels sacrifice electronic performance to obtain useful mechanical properties. Here we report a method that overcomes this limitation using two interpenetrating hydrogel networks, one of which is formed by the gelation of the conducting polymer PEDOT:PSS. Due to the connectivity of the PEDOT:PSS network, conductivities up to 23 S m-1 are achieved, a record for stretchable PEDOT:PSS-based hydrogels. Meanwhile, the low concentration of PEDOT:PSS enables orthogonal control over the composite mechanical properties using a secondary polymer network. We demonstrate tunability of the elastic modulus over three biologically relevant orders of magnitude without compromising stretchability ( > 100%) or conductivity ( > 10 S m-1).

Biodegradable Polymeric Materials in Degradable Electronic Devices.

Biodegradable electronics have great potential to reduce the environmental footprint of devices and enable advanced health monitoring and therapeutic technologies. Complex biodegradable electronics require biodegradable substrates, insulators, conductors, and semiconductors, all of which comprise the fundamental building blocks of devices. This review will survey recent trends in the strategies used to fabricate biodegradable forms of each of these components. Polymers that can disintegrate without full chemical breakdown (type I), as well as those that can be recycled into monomeric and oligomeric building blocks (type II), will be discussed. Type I degradation is typically achieved with engineering and material science based strategies, whereas type II degradation often requires deliberate synthetic approaches. Notably, unconventional degradable linkages capable of maintaining long-range conjugation have been relatively unexplored, yet may enable fully biodegradable conductors and semiconductors with uncompromised electrical properties. While substantial progress has been made in developing degradable device components, the electrical and mechanical properties of these materials must be improved before fully degradable complex electronics can be realized.

Skin electronics from scalable fabrication of an intrinsically stretchable transistor array.

Skin-like electronics that can adhere seamlessly to human skin or within the body are highly desirable for applications such as health monitoring, medical treatment, medical implants and biological studies, and for technologies that include human-machine interfaces, soft robotics and augmented reality. Rendering such electronics soft and stretchable-like human skin-would make them more comfortable to wear, and, through increased contact area, would greatly enhance the fidelity of signals acquired from the skin. Structural engineering of rigid inorganic and organic devices has enabled circuit-level stretchability, but this requires sophisticated fabrication techniques and usually suffers from reduced densities of devices within an array. We reasoned that the desired parameters, such as higher mechanical deformability and robustness, improved skin compatibility and higher device density, could be provided by using intrinsically stretchable polymer materials instead. However, the production of intrinsically stretchable materials and devices is still largely in its infancy: such materials have been reported, but functional, intrinsically stretchable electronics have yet to be demonstrated owing to the lack of a scalable fabrication technology. Here we describe a fabrication process that enables high yield and uniformity from a variety of intrinsically stretchable electronic polymers. We demonstrate an intrinsically stretchable polymer transistor array with an unprecedented device density of 347 transistors per square centimetre. The transistors have an average charge-carrier mobility comparable to that of amorphous silicon, varying only slightly (within one order of magnitude) when subjected to 100 per cent strain for 1,000 cycles, without current-voltage hysteresis. Our transistor arrays thus constitute intrinsically stretchable skin electronics, and include an active matrix for sensory arrays, as well as analogue and digital circuit elements. Our process offers a general platform for incorporating other intrinsically stretchable polymer materials, enabling the fabrication of next-generation stretchable skin electronic devices.