A Pressure-Sensitive, Repositionable Bioadhesive for Instant, Atraumatic Surgical Application on Internal Organs.

Pressure-sensitive adhesives are widely utilized due to their instant and reversible adhesion to various dry substrates. Though offering intuitive and robust attachment of medical devices on skin, currently available clinical pressure-sensitive adhesives do not attach to internal organs, mainly due to the presence of interfacial water on the tissue surface that acts as a barrier to adhesion. In this work, a pressure-sensitive, repositionable bioadhesive (PSB) that adheres to internal organs by synergistically combining the characteristic viscoelastic properties of pressure-sensitive adhesives and the interfacial behavior of hydrogel bioadhesives, is introduced. Composed of a viscoelastic copolymer, the PSB absorbs interfacial water to enable instant adhesion on wet internal organs, such as the heart and lungs, and removal after use without causing any tissue damage. The PSB's capabilities in diverse on-demand surgical and analytical scenarios including tissue stabilization of soft organs and the integration of bioelectronic devices in rat and porcine models, are demonstrated.

A bioadhesive pacing lead for atraumatic cardiac monitoring and stimulation in rodent and porcine models.

Current clinically used electronic implants, including cardiac pacing leads for epicardial monitoring and stimulation of the heart, rely on surgical suturing or direct insertion of electrodes to the heart tissue. These approaches can cause tissue trauma during the implantation and retrieval of the pacing leads, with the potential for bleeding, tissue damage, and device failure. Here, we report a bioadhesive pacing lead that can directly interface with cardiac tissue through physical and covalent interactions to support minimally invasive adhesive implantation and gentle on-demand removal of the device with a detachment solution. We developed 3D-printable bioadhesive materials for customized fabrication of the device by graft-polymerizing polyacrylic acid on hydrophilic polyurethane and mixing with poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) to obtain electrical conductivity. The bioadhesive construct exhibited mechanical properties similar to cardiac tissue and strong tissue adhesion, supporting stable electrical interfacing. Infusion of a detachment solution to cleave physical and covalent cross-links between the adhesive interface and the tissue allowed retrieval of the bioadhesive pacing leads in rat and porcine models without apparent tissue damage. Continuous and reliable cardiac monitoring and pacing of rodent and porcine hearts were demonstrated for 2 weeks with consistent capture threshold and sensing amplitude, in contrast to a commercially available alternative. Pacing and continuous telemetric monitoring were achieved in a porcine model. These findings may offer a promising platform for adhesive bioelectronic devices for cardiac monitoring and treatment.

Experiment-free exoskeleton assistance via learning in simulation.

Exoskeletons have enormous potential to improve human locomotive performance1-3. However, their development and broad dissemination are limited by the requirement for lengthy human tests and handcrafted control laws2. Here we show an experiment-free method to learn a versatile control policy in simulation. Our learning-in-simulation framework leverages dynamics-aware musculoskeletal and exoskeleton models and data-driven reinforcement learning to bridge the gap between simulation and reality without human experiments. The learned controller is deployed on a custom hip exoskeleton that automatically generates assistance across different activities with reduced metabolic rates by 24.3%, 13.1% and 15.4% for walking, running and stair climbing, respectively. Our framework may offer a generalizable and scalable strategy for the rapid development and widespread adoption of a variety of assistive robots for both able-bodied and mobility-impaired individuals.

Adhesive anti-fibrotic interfaces on diverse organs.

Implanted biomaterials and devices face compromised functionality and efficacy in the long term owing to foreign body reactions and subsequent formation of fibrous capsules at the implant-tissue interfaces1-4. Here we demonstrate that an adhesive implant-tissue interface can mitigate fibrous capsule formation in diverse animal models, including rats, mice, humanized mice and pigs, by reducing the level of infiltration of inflammatory cells into the adhesive implant-tissue interface compared to the non-adhesive implant-tissue interface. Histological analysis shows that the adhesive implant-tissue interface does not form observable fibrous capsules on diverse organs, including the abdominal wall, colon, stomach, lung and heart, over 12 weeks in vivo. In vitro protein adsorption, multiplex Luminex assays, quantitative PCR, immunofluorescence analysis and RNA sequencing are additionally carried out to validate the hypothesis. We further demonstrate long-term bidirectional electrical communication enabled by implantable electrodes with an adhesive interface over 12 weeks in a rat model in vivo. These findings may offer a promising strategy for long-term anti-fibrotic implant-tissue interfaces.

Bioadhesive interface for marine sensors on diverse soft fragile species.

Marine animals equipped with sensors provide vital information for understanding their ecophysiology and collect oceanographic data on climate change and for resource management. Existing methods for attaching sensors to marine animals mostly rely on invasive physical anchors, suction cups, and rigid glues. These methods can suffer from limitations, particularly for adhering to soft fragile marine species such as squid and jellyfish, including slow complex operations, unreliable fixation, tissue trauma, and behavior changes of the animals. However, soft fragile marine species constitute a significant portion of ocean biomass (>38.3 teragrams of carbon) and global commercial fisheries. Here we introduce a soft hydrogel-based bioadhesive interface for marine sensors that can provide rapid (time <22 s), robust (interfacial toughness >160 J m-2), and non-invasive adhesion on various marine animals. Reliable and rapid adhesion enables large-scale, multi-animal sensor deployments to study biomechanics, collective behaviors, interspecific interactions, and concurrent multi-species activity. These findings provide a promising method to expand a burgeoning research field of marine bio-sensing from large marine mammals and fishes to small, soft, and fragile marine animals.

A 3D printable tissue adhesive.

Tissue adhesives are promising alternatives to sutures and staples for joining tissues, sealing defects, and immobilizing devices. However, existing adhesives mostly take the forms of glues or hydrogels, which offer limited versatility. We report a direct-ink-write 3D printable tissue adhesive which can be used to fabricate bioadhesive patches and devices with programmable architectures, unlocking new potential for application-specific designs. The adhesive is conformable and stretchable, achieves robust adhesion with wet tissues within seconds, and exhibits favorable biocompatibility. In vivo rat trachea and colon defect models demonstrate the fluid-tight tissue sealing capability of the printed patches, which maintained adhesion over 4 weeks. Moreover, incorporation of a blood-repelling hydrophobic matrix enables the printed patches to seal actively bleeding tissues. Beyond wound closure, the 3D printable adhesive has broad applicability across various tissue-interfacing devices, highlighted through representative proof-of-concept designs. Together, this platform offers a promising strategy toward developing advanced tissue adhesive technologies.

A Tunable Soft Silicone Bioadhesive for Secure Anchoring of Diverse Medical Devices to Wet Biological Tissue.

Silicone is utilized widely in medical devices for its compatibility with tissues and bodily fluids, making it a versatile material for implants and wearables. To effectively bond silicone devices to biological tissues, a reliable adhesive is required to create a long-lasting interface. BioAdheSil, a silicone-based bioadhesive designed to provide robust adhesion on both sides of the interface is introduced here, facilitating bonding between dissimilar substrates, namely silicone devices and tissues. The adhesive's design focuses on two key aspects: wet tissue adhesion capability and tissue-infiltration-based long-term integration. BioAdheSil is formulated by mixing soft silicone oligomers with siloxane coupling agents and absorbents for bonding the hydrophobic silicone device to hydrophilic tissues. Incorporation of biodegradable absorbents eliminates surface water and controls porosity, while silane crosslinkers provide interfacial strength. Over time, BioAdheSil transitions from nonpermeable to permeable through enzyme degradation, creating a porous structure that facilitates cell migration and tissue integration, potentially enabling long-lasting adhesion. Experimental results demonstrate that BioAdheSil outperforms commercial adhesives and elicits no adverse response in rats. BioAdheSil offers practical utility for adhering silicone devices to wet tissues, including long-term implants and transcutaneous devices. Here, its functionality is demonstrated through applications such as tracheal stents and left ventricular assist device lines.

3D printable high-performance conducting polymer hydrogel for all-hydrogel bioelectronic interfaces.

Owing to the unique combination of electrical conductivity and tissue-like mechanical properties, conducting polymer hydrogels have emerged as a promising candidate for bioelectronic interfacing with biological systems. However, despite the recent advances, the development of hydrogels with both excellent electrical and mechanical properties in physiological environments is still challenging. Here we report a bi-continuous conducting polymer hydrogel that simultaneously achieves high electrical conductivity (over 11 S cm-1), stretchability (over 400%) and fracture toughness (over 3,300 J m-2) in physiological environments and is readily applicable to advanced fabrication methods including 3D printing. Enabled by these properties, we further demonstrate multi-material 3D printing of monolithic all-hydrogel bioelectronic interfaces for long-term electrophysiological recording and stimulation of various organs in rat models.

Microfluidic bioprinting of tough hydrogel-based vascular conduits for functional blood vessels.

Three-dimensional (3D) bioprinting of vascular tissues that are mechanically and functionally comparable to their native counterparts is an unmet challenge. Here, we developed a tough double-network hydrogel (bio)ink for microfluidic (bio)printing of mono- and dual-layered hollow conduits to recreate vein- and artery-like tissues, respectively. The tough hydrogel consisted of energy-dissipative ionically cross-linked alginate and elastic enzyme-cross-linked gelatin. The 3D bioprinted venous and arterial conduits exhibited key functionalities of respective vessels including relevant mechanical properties, perfusability, barrier performance, expressions of specific markers, and susceptibility to severe acute respiratory syndrome coronavirus 2 pseudo-viral infection. Notably, the arterial conduits revealed physiological vasoconstriction and vasodilatation responses. We further explored the feasibility of these conduits for vascular anastomosis. Together, our study presents biofabrication of mechanically and functionally relevant vascular conduits, showcasing their potentials as vascular models for disease studies in vitro and as grafts for vascular surgeries in vivo, possibly serving broad biomedical applications in the future.

A strain-programmed patch for the healing of diabetic wounds.

Diabetic foot ulcers and other chronic wounds with impaired healing can be treated with bioengineered skin or with growth factors. However, most patients do not benefit from these treatments. Here we report the development and preclinical therapeutic performance of a strain-programmed patch that rapidly and robustly adheres to diabetic wounds, and promotes wound closure and re-epithelialization. The patch consists of a dried adhesive layer of crosslinked polymer networks bound to a pre-stretched hydrophilic elastomer backing, and implements a hydration-based shape-memory mechanism to mechanically contract diabetic wounds in a programmable manner on the basis of analytical and finite-element modelling. In mouse and human skin, and in mini-pigs and humanized mice, the patch enhanced the healing of diabetic wounds by promoting faster re-epithelialization and angiogenesis, and the enrichment of fibroblast populations with a pro-regenerative phenotype. Strain-programmed patches might also be effective for the treatment of other forms of acute and chronic wounds.

An off-the-shelf bioadhesive patch for sutureless repair of gastrointestinal defects.

Surgical sealing and repair of injured and resected gastrointestinal (GI) organs are critical requirements for successful treatment and tissue healing. Despite being the standard of care, hand-sewn closure of GI defects using sutures faces limitations and challenges. In this work, we introduce an off-the-shelf bioadhesive GI patch capable of atraumatic, rapid, robust, and sutureless repair of GI defects. The GI patch integrates a nonadhesive top layer and a dry, bioadhesive bottom layer, resulting in a thin, flexible, transparent, and ready-to-use patch with tissue-matching mechanical properties. The rapid, robust, and sutureless sealing capability of the GI patch is systematically characterized using ex vivo porcine GI organ models. In vitro and in vivo rat models are used to evaluate the biocompatibility and degradability of the GI patch in comparison to commercially available tissue adhesives (Coseal and Histoacryl). To validate the GI patch's efficacy, we demonstrate successful sutureless in vivo sealing and healing of GI defects in rat colon, stomach, and small intestine as well as in porcine colon injury models. The proposed GI patch provides a promising alternative to suture for repair of GI defects and offers potential clinical opportunities for the repair of other organs.

Modular Integration of Hydrogel Neural Interfaces.

Thermal drawing has been recently leveraged to yield multifunctional, fiber-based neural probes at near kilometer length scales. Despite its promise, the widespread adoption of this approach has been impeded by (1) material compatibility requirements and (2) labor-intensive interfacing of functional features to external hardware. Furthermore, in multifunctional fibers, significant volume is occupied by passive polymer cladding that so far has only served structural or electrical insulation purposes. In this article, we report a rapid, robust, and modular approach to creating multifunctional fiber-based neural interfaces using a solvent evaporation or entrapment-driven (SEED) integration process. This process brings together electrical, optical, and microfluidic modalities all encased within a copolymer comprised of water-soluble poly(ethylene glycol) tethered to water-insoluble poly(urethane) (PU-PEG). We employ these devices for simultaneous optogenetics and electrophysiology and demonstrate that multifunctional neural probes can be used to deliver cellular cargo with high viability. Upon exposure to water, PU-PEG cladding spontaneously forms a hydrogel, which in addition to enabling integration of modalities, can harbor small molecules and nanomaterials that can be released into local tissue following implantation. We also synthesized a custom nanodroplet forming block polymer and demonstrated that embedding such materials within the hydrogel cladding of our probes enables delivery of hydrophobic small molecules in vitro and in vivo. Our approach widens the chemical toolbox and expands the capabilities of multifunctional neural interfaces.

Rapid and coagulation-independent haemostatic sealing by a paste inspired by barnacle glue.

Tissue adhesives do not normally perform well on tissues that are covered with blood or other bodily fluids. Here we report the design, adhesion mechanism and performance of a paste that haemostatically seals tissues in less than 15 s, independently of the blood-coagulation rate. With a design inspired by barnacle glue (which strongly adheres to wet and contaminated surfaces owing to adhesive proteins embedded in a lipid-rich matrix), the paste consists of a blood-repelling hydrophobic oil matrix containing embedded microparticles that covalently crosslink with tissue surfaces on the application of gentle pressure. It slowly resorbs over weeks, sustains large pressures (approximately 350 mm Hg of burst pressure in a sealed porcine aorta), makes tough (interfacial toughness of 150-300 J m-2) and strong (shear and tensile strengths of, respectively, 40-70 kPa and 30-50 kPa) interfaces with blood-covered tissues, and outperforms commercial haemostatic agents in the sealing of bleeding porcine aortas ex vivo and of bleeding heart and liver tissues in live rats and pigs. The paste may aid the treatment of severe bleeding, even in individuals with coagulopathies.

Adaptive and multifunctional hydrogel hybrid probes for long-term sensing and modulation of neural activity.

To understand the underlying mechanisms of progressive neurophysiological phenomena, neural interfaces should interact bi-directionally with brain circuits over extended periods of time. However, such interfaces remain limited by the foreign body response that stems from the chemo-mechanical mismatch between the probes and the neural tissues. To address this challenge, we developed a multifunctional sensing and actuation platform consisting of multimaterial fibers intimately integrated within a soft hydrogel matrix mimicking the brain tissue. These hybrid devices possess adaptive bending stiffness determined by the hydration states of the hydrogel matrix. This enables their direct insertion into the deep brain regions, while minimizing tissue damage associated with the brain micromotion after implantation. The hydrogel hybrid devices permit electrophysiological, optogenetic, and behavioral studies of neural circuits with minimal foreign body responses and tracking of stable isolated single neuron potentials in freely moving mice over 6 months following implantation.

Soft Materials by Design: Unconventional Polymer Networks Give Extreme Properties.

Hydrogels are polymer networks infiltrated with water. Many biological hydrogels in animal bodies such as muscles, heart valves, cartilages, and tendons possess extreme mechanical properties including being extremely tough, strong, resilient, adhesive, and fatigue-resistant. These mechanical properties are also critical for hydrogels' diverse applications ranging from drug delivery, tissue engineering, medical implants, wound dressings, and contact lenses to sensors, actuators, electronic devices, optical devices, batteries, water harvesters, and soft robots. Whereas numerous hydrogels have been developed over the last few decades, a set of general principles that can rationally guide the design of hydrogels using different materials and fabrication methods for various applications remain a central need in the field of soft materials. This review is aimed at synergistically reporting: (i) general design principles for hydrogels to achieve extreme mechanical and physical properties, (ii) implementation strategies for the design principles using unconventional polymer networks, and (iii) future directions for the orthogonal design of hydrogels to achieve multiple combined mechanical, physical, chemical, and biological properties. Because these design principles and implementation strategies are based on generic polymer networks, they are also applicable to other soft materials including elastomers and organogels. Overall, the review will not only provide comprehensive and systematic guidelines on the rational design of soft materials, but also provoke interdisciplinary discussions on a fundamental question: why does nature select soft materials with unconventional polymer networks to constitute the major parts of animal bodies?

Hydrogel-based biocontainment of bacteria for continuous sensing and computation.

Genetically modified microorganisms (GMMs) can enable a wide range of important applications including environmental sensing and responsive engineered living materials. However, containment of GMMs to prevent environmental escape and satisfy regulatory requirements is a bottleneck for real-world use. While current biochemical strategies restrict unwanted growth of GMMs in the environment, there is a need for deployable physical containment technologies to achieve redundant, multi-layered and robust containment. We developed a hydrogel-based encapsulation system that incorporates a biocompatible multilayer tough shell and an alginate-based core. This deployable physical containment strategy (DEPCOS) allows no detectable GMM escape, bacteria to be protected against environmental insults including antibiotics and low pH, controllable lifespan and easy retrieval of genomically recoded bacteria. To highlight the versatility of DEPCOS, we demonstrated that robustly encapsulated cells can execute useful functions, including performing cell-cell communication with other encapsulated bacteria and sensing heavy metals in water samples from the Charles River.

A Multifunctional Origami Patch for Minimally Invasive Tissue Sealing.

For decades, bioadhesive materials have garnered great attention due to their potential to replace sutures and staples for sealing tissues during minimally invasive surgical procedures. However, the complexities of delivering bioadhesives through narrow spaces and achieving strong adhesion in fluid-rich physiological environments continue to present substantial limitations to the surgical translation of existing sealants. In this work, a new strategy for minimally invasive tissue sealing based on a multilayer bioadhesive patch, which is designed to repel body fluids, to form fast, pressure-triggered adhesion with wet tissues, and to resist biofouling and inflammation is introduced. The multifunctional patch is realized by a synergistic combination of three distinct functional layers: i) a microtextured bioadhesive layer, ii) a dynamic, blood-repellent hydrophobic fluid layer, and iii) an antifouling zwitterionic nonadhesive layer. The patch is capable of forming robust adhesion to tissue surfaces in the presence of blood, and exhibits superior resistance to bacterial adhesion, fibrinogen adsorption, and in vivo fibrous capsule formation. By adopting origami-based fabrication strategies, it is demonstrated that the patch can be readily integrated with a variety of minimally invasive end effectors to provide facile tissue sealing in ex vivo porcine models, offering new opportunities for minimally invasive tissue sealing in diverse clinical scenarios.

Electrical bioadhesive interface for bioelectronics.

Reliable functions of bioelectronic devices require conformal, stable and conductive interfaces with biological tissues. Integrating bioelectronic devices with tissues usually relies on physical attachment or surgical suturing; however, these methods face challenges such as non-conformal contact, unstable fixation, tissue damage, and/or scar formation. Here, we report an electrical bioadhesive (e-bioadhesive) interface, based on a thin layer of a graphene nanocomposite, that can provide rapid (adhesion formation within 5 s), robust (interfacial toughness >400 J m-2) and on-demand detachable integration of bioelectronic devices on diverse wet dynamic tissues. The electrical conductivity (>2.6 S m-1) of the e-bioadhesive interface further allows bidirectional bioelectronic communications. We demonstrate biocompatibility, applicability, mechanical and electrical stability, and recording and stimulation functionalities of the e-bioadhesive interface based on ex vivo porcine and in vivo rat models. These findings offer a promising strategy to improve tissue-device integration and enhance the performance of biointegrated electronic devices.

An organosynthetic dynamic heart model with enhanced biomimicry guided by cardiac diffusion tensor imaging.

The complex motion of the beating heart is accomplished by the spatial arrangement of contracting cardiomyocytes with varying orientation across the transmural layers, which is difficult to imitate in organic or synthetic models. High-fidelity testing of intracardiac devices requires anthropomorphic, dynamic cardiac models that represent this complex motion while maintaining the intricate anatomical structures inside the heart. In this work, we introduce a biorobotic hybrid heart that preserves organic intracardiac structures and mimics cardiac motion by replicating the cardiac myofiber architecture of the left ventricle. The heart model is composed of organic endocardial tissue from a preserved explanted heart with intact intracardiac structures and an active synthetic myocardium that drives the motion of the heart. Inspired by the helical ventricular myocardial band theory, we used diffusion tensor magnetic resonance imaging and tractography of an unraveled organic myocardial band to guide the design of individual soft robotic actuators in a synthetic myocardial band. The active soft tissue mimic was adhered to the organic endocardial tissue in a helical fashion using a custom-designed adhesive to form a flexible, conformable, and watertight organosynthetic interface. The resulting biorobotic hybrid heart simulates the contractile motion of the native heart, compared with in vivo and in silico heart models. In summary, we demonstrate a unique approach fabricating a biomimetic heart model with faithful representation of cardiac motion and endocardial tissue anatomy. These innovations represent important advances toward the unmet need for a high-fidelity in vitro cardiac simulator for preclinical testing of intracardiac devices.

Instant tough bioadhesive with triggerable benign detachment.

Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have potential advantages over sutures and staples for wound closure, hemostasis, and integration of implantable devices onto wet tissues. However, existing bioadhesives display several limitations including slow adhesion formation, weak bonding, low biocompatibility, poor mechanical match with tissues, and/or lack of triggerable benign detachment. Here, we report a bioadhesive that can form instant tough adhesion on various wet dynamic tissues and can be benignly detached from the adhered tissues on demand with a biocompatible triggering solution. The adhesion of the bioadhesive relies on the removal of interfacial water from the tissue surface, followed by physical and covalent cross-linking with the tissue surface. The triggerable detachment of the bioadhesive results from the cleavage of bioadhesive's cross-links with the tissue surface by the triggering solution. After it is adhered to wet tissues, the bioadhesive becomes a tough hydrogel with mechanical compliance and stretchability comparable with those of soft tissues. We validate in vivo biocompatibility of the bioadhesive and the triggering solution in a rat model and demonstrate potential applications of the bioadhesive with triggerable benign detachment in ex vivo porcine models.