Two dry surfaces can instantly adhere upon contact with each other through intermolecular forces such as hydrogen bonds, electrostatic interactions and van der Waals interactions
. However, such ...instant adhesion is challenging when wet surfaces such as body tissues are involved, because water separates the molecules of the two surfaces, preventing interactions
. Although tissue adhesives have potential advantages over suturing or stapling
, existing liquid or hydrogel tissue adhesives suffer from several limitations: weak bonding, low biological compatibility, poor mechanical match with tissues, and slow adhesion formation
. Here we propose an alternative tissue adhesive in the form of a dry double-sided tape (DST) made from a combination of a biopolymer (gelatin or chitosan) and crosslinked poly(acrylic acid) grafted with N-hydrosuccinimide ester. The adhesion mechanism of this DST relies on the removal of interfacial water from the tissue surface, resulting in fast temporary crosslinking to the surface. Subsequent covalent crosslinking with amine groups on the tissue surface further improves the adhesion stability and strength of the DST. In vitro mouse, in vivo rat and ex vivo porcine models show that the DST can achieve strong adhesion between diverse wet dynamic tissues and engineering solids within five seconds. The DST may be useful as a tissue adhesive and sealant, and in adhering wearable and implantable devices to wet tissues.
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
) and on-demand detachable integration of bioelectronic devices on diverse wet dynamic tissues. The electrical conductivity (>2.6 S m
) 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.
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
) 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.
Optogenetic technologies have been the subject of great excitement within the scientific community for their ability to demystify complex neurophysiological pathways in the central (CNS) and ...peripheral nervous systems (PNS). The excitement surrounding optogenetics has also extended to the clinic with a trial for ChR2 in the treatment of retinitis pigmentosa currently underway and additional trials anticipated for the near future. In this work, we identify the cause of loss-of-expression in response to transdermal illumination of an optogenetically active peroneal nerve following an anterior compartment (AC) injection of AAV6-hSyn-ChR2(H134R) with and without a fluorescent reporter. Using Sprague Dawley Rag2
rats and appropriate controls, we discover optogenetic loss-of-expression is chiefly elicited by ChR2-mediated immunogenicity in the spinal cord, resulting in both CNS motor neuron death and ipsilateral muscle atrophy in both low and high Adeno-Associated Virus (AAV) dosages. We further employ pharmacological immunosuppression using a slow-release tacrolimus pellet to demonstrate sustained transdermal optogenetic expression up to 12 weeks. These results suggest that all dosages of AAV-mediated optogenetic expression within the PNS may be unsafe. Clinical optogenetics for both PNS and CNS applications should take extreme caution when employing opsins to treat disease and may require concurrent immunosuppression. Future work in optogenetics should focus on designing opsins with lesser immunogenicity.
Abstract
Fibrous capsule (FC) formation, secondary to the foreign body response (FBR), impedes molecular transport and is detrimental to the long-term efficacy of implantable drug delivery devices, ...especially when tunable, temporal control is necessary. We report the development of an implantable mechanotherapeutic drug delivery platform to mitigate and overcome this host immune response using two distinct, yet synergistic soft robotic strategies. Firstly, daily intermittent actuation (cycling at 1 Hz for 5 minutes every 12 hours) preserves long-term, rapid delivery of a model drug (insulin) over 8 weeks of implantation, by mediating local immunomodulation of the cellular FBR and inducing multiphasic temporal FC changes. Secondly, actuation-mediated rapid release of therapy can enhance mass transport and therapeutic effect with tunable, temporal control. In a step towards clinical translation, we utilise a minimally invasive percutaneous approach to implant a scaled-up device in a human cadaveric model. Our soft actuatable platform has potential clinical utility for a variety of indications where transport is affected by fibrosis, such as the management of type 1 diabetes.
Soft robotic technologies for therapeutic biomedical applications require conformal and atraumatic tissue coupling that is amenable to dynamic loading for effective drug delivery or tissue ...stimulation. This intimate and sustained contact offers vast therapeutic opportunities for localized drug release. Herein, a new class of hybrid hydrogel actuator (HHA) that facilitates enhanced drug delivery is introduced. The multi-material soft actuator can elicit a tunable mechanoresponsive release of charged drug from its alginate/acrylamide hydrogel layer with temporal control. Dosing control parameters include actuation magnitude, frequency, and duration. The actuator can safely adhere to tissue via a flexible, drug-permeable adhesive bond that can withstand dynamic device actuation. Conformal adhesion of the hybrid hydrogel actuator to tissue leads to improved mechanoresponsive spatial delivery of the drug. Future integration of this hybrid hydrogel actuator with other soft robotic assistive technologies can enable a synergistic, multi-pronged treatment approach for the treatment of disease.
Efficient coupling of soft robotic cardiac assist devices to the external surface of the heart is crucial to augment cardiac function and represents a hurdle to translation of this technology. In ...this work, we compare various fixation strategies for local and global coupling of a direct cardiac compression sleeve to the heart. For basal fixation, we find that a sutured Velcro band adheres the strongest to the epicardium. Next, we demonstrate that a mesh-based sleeve coupled to the myocardium improves function in an acute porcine heart failure model. Then, we analyze the biological integration of global interface material candidates (medical mesh and silicone) in a healthy and infarcted murine model and show that a mesh interface yields superior mechanical coupling
via
pull-off force, histology, and microcomputed tomography. These results can inform the design of a therapeutic approach where a mesh-based soft robotic DCC is implanted, allowed to biologically integrate with the epicardium, and actuated for active assistance at a later timepoint. This strategy may result in more efficient coupling of extracardiac sleeves to heart tissue, and lead to increased augmentation of heart function in end-stage heart failure patients.
The southern and central Andes reflect significant along-strike differences of tectonic activity, including shortening, alternating flat-to-normal subduction styles and magmatism. In northern ...Patagonia, the subduction/supra-subduction system, fore arc, arc and back arc basins developed in an extensional setting during the Paleogene. This was accompanied by landward migration of calc-alkalic magmatism which changed to synextensional bimodal volcanism of rhyolitic ignimbrites and interbedded tholeiitic and alkalic basalts. These Paleogene events occurred during a time when the Farallon–Aluk active ridge reached the South American plate, and the Farallon plate subduction was interrupted. They represent a new tectonic regime, characterized by a transcurrent plate margin. The presence in the back arc of a rigid lithospheric block of 100,000
km
2 represented by the North Patagonian Massif focused the rotation of the coastal blocks. This resulted in the development of two Paleogene extensional regions to the north and south, respectively, of the Massif and replaced the former back arc. Plate rearrangement caused by the inauguration of the Nazca plate and its regime of orthogonal subduction at the beginning of the Miocene, re-established typical calc-alkaline arc magmatism at the former upper Cretaceous arc locus. Present seismic activity in the subducted plate and tomographic modeling of p-wave velocity anomalies in the upper mantle also suggest the presence of a subduction gap that lasted for most of the Paleogene in northern Patagonia.
► The Patagonian Andes shows a Farallon-SAM transform plate margin developed from the Farallon-Aluk-SAM triple junction. ► The Patagonian transform plate margin develops large extension in the former back arc due to rotation of the coastal blocks. ► In the former back arc, magmatic evolution show broad syn-extensional calc-alkaline ignimbrite flare up and alkali basalts. ► The Patagonian transition from transform back to subduciton is achieved when Farallon plate breaks up to develop Nazca plate. ► The Eocene-Oligocene Patagonian Andes syn-extensional magmatism in the former back arc resembles that of WUS Basin and Range.
Myocardial infarction, or heart attack, is the leading cause of mortality globally. Although the treatment of myocardial infarct has improved significantly, scar tissue that persists can often lead ...to increased stress and adverse remodeling of surrounding tissue and ultimately to heart failure. Intra‐myocardial injection of biomaterials represents a potential treatment to attenuate remodeling, mitigate degeneration, and reverse the disease process in the tissue. In vivo experiments on animal models have shown functional benefits of this therapeutic strategy. However, a poor understanding of the optimal injection pattern, volume, and material properties has acted as a barrier to its widespread clinical adoption. In this study, we developed two quasistatic finite element simulations of the left ventricle to investigate the mechanical effect of intra‐myocardial injection. The first model employed an idealized left ventricular geometry with rule‐based cardiomyocyte orientation. The second model employed a subject‐specific left ventricular geometry with cardiomyocyte orientation from diffusion tensor magnetic resonance imaging. Both models predicted cardiac parameters including ejection fraction, systolic wall thickening, and ventricular twist that matched experimentally reported values. All injection simulations showed cardiomyocyte stress attenuation, offering an explanation for the mechanical reinforcement benefit associated with injection. The study also enabled a comparison of injection location and the corresponding effect on cardiac performance at different stages of the cardiac cycle. While the idealized model has lower fidelity, it predicts cardiac function and differentiates the effects of injection location. Both models represent versatile in silico tools to guide optimal strategy in terms of injection number, volume, site, and material properties.
In preclinical models, intramyocardial injection of biomaterials has been shown to attenuate disease progression of cardiac tissue after a heart attack. Nonetheless, a poor understanding of the optimal injection pattern, volume, and material properties has posed a challenge to clinical adoption of this strategy. In this study, we developed two quasi‐static finite element simulations of the left ventricle to investigate the mechanical effect of intramyocardial injection.
The mechanical reinforcement of the ventricular wall after a myocardial infarction has been shown to modulate and attenuate negative remodeling that can lead to heart failure. Strategies include ...wraps, meshes, cardiac patches, or fluid-filled bladders. Here, we review the literature describing these strategies in the two broad categories of global restraint and local reinforcement. We further subdivide the global restraint category into biventricular and univentricular support. We discuss efforts to optimize devices in each of these categories, particularly in the last five years. These include adding functionality, biomimicry, and adjustability. We also discuss computational models of these strategies, and how they can be used to predict the reduction of stresses in the heart muscle wall. We discuss the range of timing of intervention that has been reported. Finally, we give a perspective on how novel fabrication technologies, imaging techniques, and computational models could potentially enhance these therapeutic strategies.
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