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 crosslinks 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.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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.
A multifunctional patch presents new opportunities for sealing tissues in minimally invasive surgeries. Integration of a dynamic hydrophobic fluid layer, a microtextured bioadhesive layer, and a zwitterionic‐interpenetrated elastomer layer enables the patch to withstand fluid‐rich environments, maintain a robust seal, and minimize biofouling and inflammation. By employing various origami‐based designs, the patch can be adapted for different clinical applications.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Slippery and hydrophilic surfaces find critical applications in areas as diverse as biomedical devices, microfluidics, antifouling, and underwater robots. Existing methods to achieve such surfaces ...rely mostly on grafting hydrophilic polymer brushes or coating hydrogel layers, but these methods suffer from several limitations. Grafted polymer brushes are prone to damage and do not provide sufficient mechanical compliance due to their nanometer‐scale thickness. Hydrogel coatings are applicable only for relatively simple geometries, precluding their use for the surfaces with complex geometries and features. Here, a new method is proposed to interpenetrate hydrophilic polymers into the surface of diverse polymers with arbitrary shapes to form naturally integrated “hydrogel skins.” The hydrogel skins exhibit tissue‐like softness (Young's modulus ≈ 30 kPa), have uniform and tunable thickness in the range of 5–25 µm, and can withstand prolonged shearing forces with no measurable damage. The hydrogel skins also provide superior low‐friction, antifouling, and ionically conductive surfaces to the polymer substrates without compromising their original mechanical properties and geometry. Applications of the hydrogel skins on inner and outer surfaces of various practical polymer devices including medical tubing, Foley catheters, cardiac pacemaker leads, and soft robots on massive scales are further demonstrated.
Multifunctional hydrogel skins by interpenetrating hydrophilic polymers into the surfaces of diverse polymers with arbitrary shapes, which provide soft, low‐friction, hydrophilic, antifouling, and ionically conductive surfaces, are reported. This new strategy not only addresses challenges for existing methods but also enables unprecedented applications including hydrogel‐coated complex medical devices and soft robots on massive scales.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
Abstract Wound healing is a physiological reparative response to injury and a well-orchestrated process that involves hemostasis, cellular migration, proliferation, angiogenesis, extracellular matrix ...deposition, and wound contraction and re-epithelialization. However, patients with type 2 diabetes mellitus (T2D) are frequently afflicted with impaired wound healing that progresses into chronic wounds or diabetic ulcers, and may lead to complications including limb amputation. Herein, we investigate the potential role of microRNA-26a (miR-26a) in a diabetic model of wound healing. Expression of miR-26a is rapidly induced in response to high glucose in endothelial cells (ECs). Punch skin biopsy wounding of db/db mice revealed increased expression of miR-26a (~ 3.5-fold) four days post-wounding compared to that of WT mice. Local administration of a miR-26a inhibitor, LNA-anti-miR-26a, induced angiogenesis (up to ~ 80%), increased granulation tissue thickness (by 2.5-fold) and accelerated wound closure (53% after nine days) compared to scrambled anti-miR controls in db/db mice. These effects were independent of altered M1/M2 macrophage ratios. Mechanistically, inhibition of miR-26a increased its target gene SMAD1 in ECs nine days post-wounding of diabetic mice. In addition, high glucose reduced activity of the SMAD1-3′-UTR. Diabetic dermal wounds treated with LNA-anti-miR-26a had increased expression of ID1, a downstream modulator or SMAD1, and decreased expression of the cell cycle inhibitor p27. These findings establish miR-26a as an important regulator on the progression of skin wounds of diabetic mice by specifically regulating the angiogenic response after injury, and demonstrate that neutralization of miR-26a may serve as a novel approach for therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cardiovascular disease remains a major health care challenge. The knowledge about the underlying mechanisms of the respective vascular disease etiologies has greatly expanded over the last decades. ...This includes the contribution of microRNAs, endogenous non-coding RNA molecules, known to vastly influence gene expression. In addition, short interference RNA has been established as a mechanism to temporarily affect gene expression. This review discusses challenges relating to the design of a RNA interference therapy strategy for the modulation of vascular disease. Despite advances in medical and surgical therapies, atherosclerosis (ATH), aortic aneurysms (AA) are still associated with high morbidity and mortality. In addition, intimal hyperplasia (IH) remains a leading cause of late vein and prosthetic bypass graft failure. Pathomechanisms of all three entities include activation of endothelial cells (EC) and dedifferentiation of vascular smooth muscle cells (VSMC). RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH, AA or IH. Successful RNAi delivery to the vessel wall faces multiple obstacles. These include the challenge of cell specific, targeted delivery of RNAi, anatomical barriers such as basal membrane, elastic laminae in arterial walls, multiple layers of VSMC, as well as adventitial tissues. Another major decision point is the route of delivery and potential methods of transfection. A plethora of transfection reagents and adjuncts have been described with varying efficacies and side effects. Timing and duration of RNAi therapy as well as target gene choice are further relevant aspects that need to be addressed in a temporo-spatial fashion.
While multiple preclinical studies reported encouraging results of RNAi delivery to the vascular wall, it remains to be seen if a single target can be sufficient to the achieve clinically desirable changes in the injured vascular wall in humans. It might be necessary to achieve simultaneous and/or sequential silencing of multiple, synergistically acting target genes. Some advances in cell specific RNAi delivery have been made, but a reliable vascular cell specific transfection strategy is still missing. Also, off-target effects of RNAi and unwanted effects of transfection agents on gene expression are challenges to be addressed. Close collaborative efforts between clinicians, geneticists, biologists, and chemical and medical engineers will be needed to provide tailored therapeutics for the various types of vascular diseases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract An excessive tissue response to prosthetic arterial graft material leads to intimal hyperplasia (IH), the leading cause of late graft failure. Seroma and abnormal capsule formation may also ...occur after prosthetic material implantation. The matricellular protein Thrombospondin-2 (TSP-2) has shown to be upregulated in response to biomaterial implantation. This study evaluates the uptake and release of small interfering RNA (siRNA) from unmodified and surface functionalized electrospun PET graft materials. ePET graft materials were synthesized using electrospinning technology. Subsets of the ePET materials were then chemically modified to create surface functional groups. Unmodified and surface-modified ePET grafts were dip-coated in siRNAs alone or siRNAs complexed with transfection reagents polyethyleneimine (PEI) or Lipofectamine RNAiMax. Further, control and TSP-2 siRNA–PEI complex treated ePET samples were placed onto a confluent layer of human aortic smooth muscle cells (AoSMCs). Complexation of all siRNAs with PEI led to a significant increase in adsorption to unmodified ePET. TSP-2 siRNA-PEI released from unmodified-ePET silenced TSP-2 in AoSMC. Regardless of the siRNA–PEI complex evaluated, AoSMC migrated into the ePET. siRNA–PEI complexes delivered to AoSMC from dip-coated ePET can result in gene knockdown. This methodology for siRNA delivery may improve the tissue response to vascular and other prosthetics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Obesity is often considered a contraindication to extracorporeal membrane oxygenation (ECMO) candidacy due to technical challenges with vascular access, higher cardiac output requirements, and known ...associations between obesity and overall increased morbidity and mortality due to chronic health conditions. However, a growing body of literature suggests that ECMO may be as safe and efficacious in both obese and nonobese patients. This scoping review provides a synthesis of the available literature on the outcomes of obese patients supported with (1) venovenous (VV)-ECMO in acute respiratory distress syndrome (ARDS) not due to coronavirus disease 2019 (COVID-19), (2) VV-ECMO in ARDS due to COVID-19, (3) venoarterial (VA)-ECMO for all indications, and (4) studies combining data of patients supported with VA- and VV-ECMO. A librarian-assisted search was performed using 4 primary electronic medical databases (PubMed, Web of Science, Excerpta Medica database Embase, and Cochrane Library) from January 2003 to March 2023. Articles that reported outcomes of obese patients requiring ECMO support were included. Two reviewers independently screened titles, abstracts, and full text of articles to determine eligibility. Data extraction was performed using customized fields established a priori within a systematic review software system. A total of 354 publications were imported for screening on titles and abstracts, and 30 studies were selected for full-text review. A total of 26 publications met the inclusion criteria: 7 on VV-ECMO support in non–COVID-19 ARDS patients, 6 on ECMO in COVID-19 ARDS patients, 8 in patients supported with VA-ECMO, and 5 combining both VA- and VV-ECMO data. Although the included studies are limited to retrospective analyses and display a heterogeneity in definitions of obesity and comparison groups, the currently available literature suggests that outcomes and complications of ECMO therapy are equivalent in obese patients as compared to nonobese patients. Hence, obesity as measured by body mass index alone should not be considered an exclusion criterion in the decision to initiate ECMO.
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