Mechanoresponsive Drug Release from a Flexible, Tissue-Adherent, Hybrid Hydrogel Actuator.

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.

Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform.

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.

Longitudinal Study after Sputnik V Vaccination Shows Durable SARS-CoV-2 Neutralizing Antibodies and Reduced Viral Variant Escape to Neutralization over Time.

Recent studies have shown a temporal increase in the neutralizing antibody potency and breadth to SARS-CoV-2 variants in coronavirus disease 2019 (COVID-19) convalescent individuals. Here, we examined longitudinal antibody responses and viral neutralizing capacity to the B.1 lineage virus (Wuhan related), to variants of concern (VOC; Alpha, Beta, Gamma, and Delta), and to a local variant of interest (VOI; Lambda) in volunteers receiving the Sputnik V vaccine in Argentina. Longitudinal serum samples (N = 536) collected from 118 volunteers obtained between January and October 2021 were used. The analysis indicates that while anti-spike IgG levels significantly wane over time, the neutralizing capacity for the Wuhan-related lineages of SARS-CoV-2 and VOC is maintained within 6 months of vaccination. In addition, an improved antibody cross-neutralizing ability for circulating variants of concern (Beta and Gamma) was observed over time postvaccination. The viral variants that displayed higher escape to neutralizing antibodies with respect to the original virus (Beta and Gamma variants) were the ones showing the largest increase in susceptibility to neutralization over time after vaccination. Our observations indicate that serum neutralizing antibodies are maintained for at least 6 months and show a reduction of VOC escape to neutralizing antibodies over time after vaccination. IMPORTANCE Vaccines have been produced in record time for SARS-CoV-2, offering the possibility of halting the global pandemic. However, inequalities in vaccine accessibility in different regions of the world create a need to increase international cooperation. Sputnik V is a recombinant adenovirus-based vaccine that has been widely used in Argentina and other developing countries, but limited information is available about its elicited immune responses. Here, we examined longitudinal antibody levels and viral neutralizing capacity elicited by Sputnik V vaccination. Using a cohort of 118 volunteers, we found that while anti-spike antibodies wane over time, the neutralizing capacity to viral variants of concern and local variants of interest is maintained within 4 months of vaccination. In addition, we observed an increased cross-neutralization activity over time for the Beta and Gamma variants. This study provides valuable information about the immune response generated by a vaccine platform used in many parts of the world.

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.

Minimally invasive electroceutical catheter for endoluminal defect sealing.

Surgical repair of lumen defects is associated with periprocedural morbidity and mortality. Endovascular repair with tissue adhesives may reduce host tissue damage, but current bioadhesive designs do not support minimally invasive deployment. Voltage-activated tissue adhesives offer a new strategy for endoluminal repair. To facilitate the clinical translation of voltage-activated adhesives, an electroceutical patch (ePATCH) paired with a minimally invasive catheter with retractable electrodes (CATRE) is challenged against the repair of in vivo and ex vivo lumen defects. The ePATCH/CATRE platform demonstrates the sealing of lumen defects up to 2 millimeters in diameter on wet tissue substrates. Water-tight seals are flexible and resilient, withstanding over 20,000 physiological relevant stress/strain cycles. No disruption to electrical signals was observed when the ePATCH was electrically activated on the beating heart. The ePATCH/CATRE platform has diverse potential applications ranging from endovascular treatment of pseudo-aneurysms/fistulas to bioelectrodes toward electrophysiological mapping.

Adenoviral-induced rash and mucositis: Expanding the spectrum of reactive infectious mucocutaneous eruption.

Mucocutaneous eruptions associated with respiratory pathogens, specifically Mycoplasma pneumoniae (MP), has recently been described as a MIRM (MP-induced rash and mucositis). The term reactive infectious mucocutaneous eruption (RIME) has been proposed, since non-MP pathogens may also cause a similar rash and mucositis. We report two cases with clinical manifestations suggestive of MIRM/RIME, both with documented adenovirus infection.

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.

Dry double-sided tape for adhesion of wet tissues and devices.

Two dry surfaces can instantly adhere upon contact with each other through intermolecular forces such as hydrogen bonds, electrostatic interactions and van der Waals interactions1,2. 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 interactions3,4. Although tissue adhesives have potential advantages over suturing or stapling5,6, existing liquid or hydrogel tissue adhesives suffer from several limitations: weak bonding, low biological compatibility, poor mechanical match with tissues, and slow adhesion formation5-13. 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.

Multiscale Experimental and Computational Modeling Approaches to Characterize Therapy Delivery to the Heart from an Implantable Epicardial Biomaterial Reservoir.

Delivery of therapeutic-laden biomaterials to the epicardial surface of the heart presents a promising method of treating a variety of diseased conditions by offering targeted, localized release with limited systemic recirculation and enhanced myocardial tissue uptake. A vast range of biomaterials and therapeutic agents using this approach been investigated. However, the fundamental factors that govern transport of the drug molecules from the biomaterials to the tissue are not well understood. Here, the transport of a drug analog from a biomaterial reservoir to the epicardial surface is characterized using experimental techniques and microscale modeling. Using the experimentally determined parameters, a multiscale model of transport is developed. The model is then used to study the effect of important design parameters such as loading conditions, biomaterial geometry, and orientation relative to the cardiac fibers on drug delivery to the myocardium. The simulations highlight the significance of the cardiac fiber anisotropy as a crucial factor in governing drug distribution on the epicardial surface and limiting factor for penetration into the myocardium. The multiscale model can be useful for rapid iteration of different device concepts and for determination of designs for epicardial drug delivery that may be optimal and most promising for the ultimate therapeutic goal.

Optimizing Epicardial Restraint and Reinforcement Following Myocardial Infarction: Moving Towards Localized, Biomimetic, and Multitherapeutic Options.

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.

A comparison of two quasi-static computational models for assessment of intra-myocardial injection as a therapeutic strategy for heart failure.

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.

Optogenetic Peripheral Nerve Immunogenicity.

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.

Towards Alternative Approaches for Coupling of a Soft Robotic Sleeve to the Heart.

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.

Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir.

The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development and application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. The pre-clinical use of the therapeutic epicardial reservoir as a research model may enable insights into regenerative cardiac therapy, and assist the development of experimental therapies towards clinical use.

Browning effects of (-)-epicatechin on adipocytes and white adipose tissue.

In this study, we demonstrate that (-)-epicatechin (Epi), a cacao flavanol, induces the browning of fat by promoting mitochondrial biogenesis, enhancing indicators of mitochondrial structure and function, increasing fatty acid metabolism and upregulating the expression of brown adipose tissue-specific proteins in a high-fat diet mouse model of obesity and in cultured human adipocytes. Epi treatment significantly improved mitochondrial function, as measured by citrate synthase activity, and also reduced protein acetylation of total and specific regulators in both adipose tissue and human adipocytes. Browning of fat via Epi was evidenced by the increased expression of key thermogenic genes, phosphorylation of upstream regulators of fatty acid oxidation, and reduced triglyceride levels. Properly designed clinical trials are needed to explore the potential of Epi as an agent that promotes the browning of fat.

Effects of a natural extract of Aronia Melanocarpa berry on endothelial cell nitric oxide production.

The effects of acute and chronic treatment with Aronia extracts on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation in bovine coronary artery endothelial cells were investigated. Acute time-course and concentration-response experiments were performed to determine the time and concentration at which Aronia induced maximal NO synthesis and eNOS phosphorylation. The findings indicate that relatively low concentrations (0.1 µg/mL) of Aronia extract significantly induced NO synthesis and eNOS phosphorylation after 10 min of treatment. Increased sensitivity of eNOS and a significant increase in NO synthesis resulted from longer-term stimulation with Aronia (48 hr) and an acute re-treatment of the cells (10 min). PRACTICAL APPLICATIONS: These in vitro results may be translated into potential future clinical applications where Aronia extracts may be used for prevention and coadjuvant treatment of cardiovascular diseases via increases in endothelial NO synthesis and related improvements in vascular functions. Given the dose-response effect of Aronia extract in vitro and metabolism of polyphenols that occurs in humans, dose-response studies would be necessary to define the optimal daily amount to be consumed.

Resultados de la cirugía del tortícolis horizontal por nistagmus ocular congénito / Surgical results of horizontal ocular torticollis present in congenital nistagmus

Objetivo: Conocer los resultados de nuestra cirugía correctora del tortícolis (T) horizontal por nistagmus ocular congénito sin estrabismo. Material y Métodos: Estudio retrospectivo de 31 casos operados con diferentes procedimientos según las características del bloqueo y magnitud del T. Según esto último, los casos se clasificaron en 5 grupos. Resultados: La corrección del T fue exitosa (T residual del 12° o menos) en 80.7 por ciento del total de casos. En dos grupos obtuvimos curación del 100 por ciento de los casos, en otros 2,77 por ciento y 75 por ciento, respectivamente. En el 5° grupo la cirugía no fue uniforme y no es posible extraer normas de sus resultados. Como complicaciones tuvimos la aparición de un pequeño estrabismo en 3 casos y 4 pacientes debieron ser reintervenidos por tortícolis residual. Conclusiones: Las publicaciones con procedimientos comparables a los nuestros son escasas o con resultados vagos. Este estudio permite sacar guías quirúrgicas cuantitativas recomendables para 4 de los 5 grupos.

Purpose: To evaluate our surgical results in horizontal ocular torticollis present in congenital nystagmus without strabismus. Methods: A retrospective review was made in 31 consecutive patients, undergoing different surgical procedures considering the so called null zone and quantity of torticollis. Cases were classified in five groups. Results: In 80.7 percent of cases a successful result was obtained, defined as a residual torticollis not greater than 12°. Two groups obtained 100 percent correction. Two other groups obtained 77 and 75 percent correction respectively. The surgery indicated in group five was too heterogeneous and therefore non conclusive. After surgery a small strabismus presented in 3 cases. Four other patients were reoperated due to remaining torticollis. Conclusions: Papers with comparable procedures are few and don't show exact or detailed results. Our review allows us to obtain guide lines at least in 4 of the 5 groups.

Utilidad de la detección de anticuerpos anti-factor VIII por Elisa en hemofílicos / Usefulness of detection of afVIII antibodies by Elisa in haemophiliacs

Los hemofílicos pueden desarrollar en forma concomitante inhibidor lúpico (LA) e inhibidor neutralizante anti-factor VIII (a-fVIII). El diagnóstico diferencial es complejo ya que el LA interfiere en la identificación de los a-fVIII. A fin de detectar a-fVIII sin interferencia de LA, desarrollamos un ELISA utilizando fVIII recombinante libre de fosfolípidos como antígeno con la muestra y revelamos la IgG unidad mediante un anticuerpo anti-IgG humana-fosfatasa. El sistema permitió detectar un anticuerpo monoclonal a-fVIII al ser revelado con el antisuero anti-IgG ratón. Como control inespecífico se utlizaron anticuerpos monoclonales anti-GPIIIa y anti-factor von Willebrand. Para evaluar la utilidad del ELISA, se analizaron plasmas de pacientes hemofílicos con a-fVIII, con o sin LA y hemofílicos sin inhibidor. Como controles negativos se incluyeron plasmas con LA y normales. Los plasmas de hemofílicos con a-fVIII dieron valores de absorbancia >X Normalñ3DE; algunos plasmas hemofílicos sin inhibidor también mostraron absorbancias superiores al normal, aunque inferiores a las observadas para a-fVIII. Las lecturas de los controles no fueron significativas. No observamos interferencias por la presencia de LA. El ELISA a-fVIII sería un elemento diagnóstico complementario, al permitir evidenciar anticuerpos capaces de unirse al fVIII, aún en plasmas LA.

Utilidad de la detección de anticuerpos anti-factor VIII por Elisa en hemofílicos / Usefulness of detection of afVIII antibodies by Elisa in haemophiliacs

Los hemofílicos pueden desarrollar en forma concomitante inhibidor lúpico (LA) e inhibidor neutralizante anti-factor VIII (a-fVIII). El diagnóstico diferencial es complejo ya que el LA interfiere en la identificación de los a-fVIII. A fin de detectar a-fVIII sin interferencia de LA, desarrollamos un ELISA utilizando fVIII recombinante libre de fosfolípidos como antígeno con la muestra y revelamos la IgG unidad mediante un anticuerpo anti-IgG humana-fosfatasa. El sistema permitió detectar un anticuerpo monoclonal a-fVIII al ser revelado con el antisuero anti-IgG ratón. Como control inespecífico se utlizaron anticuerpos monoclonales anti-GPIIIa y anti-factor von Willebrand. Para evaluar la utilidad del ELISA, se analizaron plasmas de pacientes hemofílicos con a-fVIII, con o sin LA y hemofílicos sin inhibidor. Como controles negativos se incluyeron plasmas con LA y normales. Los plasmas de hemofílicos con a-fVIII dieron valores de absorbancia >X Normalñ3DE; algunos plasmas hemofílicos sin inhibidor también mostraron absorbancias superiores al normal, aunque inferiores a las observadas para a-fVIII. Las lecturas de los controles no fueron significativas. No observamos interferencias por la presencia de LA. El ELISA a-fVIII sería un elemento diagnóstico complementario, al permitir evidenciar anticuerpos capaces de unirse al fVIII, aún en plasmas LA. (AU)