Sticky Architecture: Encoding Pressure Sensitive Adhesion in Polymer Networks.

Pressure sensitive adhesives (PSAs) are ubiquitous materials within a spectrum that span from office supplies to biomedical devices. Currently, the ability of PSAs to meet the needs of these diverse applications relies on trial-and-error mixing of assorted chemicals and polymers, which inherently entails property imprecision and variance over time due to component migration and leaching. Herein, we develop a precise additive-free PSA design platform that predictably leverages polymer network architecture to empower comprehensive control over adhesive performance. Utilizing the chemical universality of brush-like elastomers, we encode work of adhesion ranging 5 orders of magnitude with a single polymer chemistry by coordinating brush architectural parameters-side chain length and grafting density. Lessons from this design-by-architecture approach are essential for future implementation of AI machinery in molecular engineering of both cured and thermoplastic PSAs incorporated into everyday use.

Co-prevalence and incidence of myocardial infarction and/or stroke in patients with depression and/or anxiety: A systematic review and meta-analysis.

OBJECTIVE: Co-prevalence and incidence of depression and/or anxiety with stroke and myocardial infarction are currently unclear. This paper explores the relationships, as these are important comorbidities affecting patient outcomes. METHODS: A systematic search across five databases (PubMed, Scopus, PsycINFO, Embase, Cochrane) was conducted for observational studies reporting co-prevalence of depression or anxiety with stroke or myocardial infarction. We used random-effects models in all meta-analyses and evaluated heterogeneity using I2. RESULTS: This analysis included 48 studies with a total of 57,342 patients. In patients with depression, the pooled prevalence of stroke was 5.9% (95% CI = 5.53-6.37). In patients with myocardial infarction, the pooled prevalence of anxiety and depression was 9.1% (95% CI = 7.07-11.40, I2 = 85.6%) and 25.9% (95% CI = 18.46-34.12, I2 = 99.1%), respectively, and the pooled cumulative incidence of depression at one year was 20.5% (95% CI = 18.36-22.79). The pooled prevalence of anxiety and depression in patients with stroke was 13.5% (95% CI = 7.67-22.66, I2 = 96.9%) and 23.0% (95% CI = 17.93-28.99, I2 = 96.7%), respectively. The pooled cumulative incidences of depression at two weeks, three months, six months, and one year, were 29.1% (95% CI = 26.60-31.81), 17.0% (95% CI = 10.74-25.92, I2 = 98.0%), 7.4% (95% CI = 6.52-8.49), and 9.1% (95% CI = 3.71-20.79, I2 = 99.8%), respectively. CONCLUSIONS: This meta-analysis outlines the co-morbid burden between depression/anxiety and stroke/myocardial infarction. Future research should be done to evaluate the effectiveness of screening anxiety/depression in myocardial infarction/stroke.

Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration.

BACKGROUND & AIMS: Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Herein, we aimed to reconcile these conflicting reports by repeating a key lineage-tracing study from pericentral hepatocytes and characterising this Axin2CreERT2 model in detail. METHODS: We performed detailed characterisation of the labelled population in the Axin2CreERT2 model. We lineage traced this cell population, quantifying the labelled population over 1 year and performed in-depth phenotypic comparisons, including transcriptomics, metabolomics and analysis of proteins through immunohistochemistry, of Axin2CreERT2 mice to WT counterparts. RESULTS: We found that after careful definition of a baseline population, there are marked differences in labelling between male and female mice. Upon induced lineage tracing there was no expansion of the labelled hepatocyte population in Axin2CreERT2 mice. We found substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/ß-catenin signalling and related metabolomic disturbance. CONCLUSIONS: We find no evidence of predominant expansion of the pericentral hepatocyte population during liver homeostatic regeneration. Our data highlight the importance of detailed preclinical model characterisation and the pitfalls which may occur when comparing across sexes and backgrounds of mice and the effects of genetic insertion into native loci. IMPACT AND IMPLICATIONS: Understanding the source of cells which regenerate the liver is crucial to harness their potential to regrow injured livers. Herein, we show that cells which were previously thought to repopulate the liver play only a limited role in physiological regeneration. Our data helps to reconcile differing conclusions drawn from results from a number of prior studies and highlights methodological challenges which are relevant to preclinical models more generally.

The Impact of Cognitive Impairment on Clinical Outcomes After Transcatheter Aortic Valve Implantation (from a Systematic Review and Meta-Analysis).

This study sought to investigate the impact of pre-existing cognitive impairment on outcomes after transcatheter aortic valve implantation (TAVI). TAVI has been increasingly used in seniors, and evidence suggests better outcomes than surgical aortic valve replacement. Although frailty has been shown to be associated with poorer outcomes after TAVI, the effect of pre-existing cognitive impairment on patient outcomes after TAVI remains unclear. We searched the Medline, Embase, Scopus and Cochrane databases until May 14, 2022. The risk of bias was assessed using the Newcastle-Ottawa scale. The primary outcome was short-term (6 months to 1 year) mortality, and secondary outcomes included long-term (1 year to 3 years) mortality, in-hospital mortality, and postoperative delirium. A total of 14 studies with 32,746 patients (5,098 patients with cognitive impairment at baseline, 27,648 without) were included in our meta-analysis. Among studies that reported the raw proportion of patients with mortality of postoperative delirium, cognitive impairment significantly increased mortality (risk ratio 2.10, 95% confidence intervals [CIs] 1.43 to 3.08, p = 0.0002) and postoperative delirium (risk ratio 2.27, 95% CI 1.76 to 2.93, p <0.0001). Studies which reported the hazards for mortality (pooled hazards ratio 1.97, 95% CI 1.50 to 2.60, p <0.0001) and odds of postoperative delirium (pooled odds ratio 2.40, 95% CI: 1.51 to 3.80, p = 0.0002) yielded results consistent with the primary meta-analysis. In conclusion, pre-existing cognitive impairment is a significant risk factor for poorer outcomes after TAVI and should be carefully considered in this group of patients. Guidelines and future studies should take cognitive impairment into consideration for preoperative risk stratification.

Super-soft, firm, and strong elastomers toward replication of tissue viscoelastic response.

Polymeric networks are commonly used for various biomedical applications, from reconstructive surgery to wearable electronics. Some materials may be soft, firm, strong, or damping however, implementing all four properties into a single material to replicate the mechanical properties of tissue has been inaccessible. Herein, we present the A-g-B brush-like graft copolymer platform as a framework for fabrication of materials with independently tunable softness and firmness, capable of reaching a strength of ∼10 MPa on par with stress-supporting tissues such as blood vessel, muscle, and skin. These properties are maintained by architectural control, therefore diverse mechanical phenotypes are attainable for a variety of different chemistries. Utilizing this attribute, we demonstrate the capability of the A-g-B platform to enhance specific characteristics such as tackiness, damping, and moldability.

Mechanically Diverse Gels with Equal Solvent Content.

Mechanically diverse polymer gels are commonly integrated into biomedical devices, soft robots, and tissue engineering scaffolds to perform distinct yet coordinated functions in wet environments. Such multigel systems are prone to volume fluctuations and shape distortions due to differential swelling driven by osmotic solvent redistribution. Living systems evade these issues by varying proximal tissue stiffness at nearly equal water concentration. However, this feature is challenging to replicate with synthetic gels: any alteration of cross-link density affects both the gel's swellability and mechanical properties. In contrast to the conventional coupling of physical properties, we report a strategy to tune the gel modulus independent of swelling ratio by regulating network strand flexibility with brushlike polymers. Chemically identical gels were constructed with a broad elastic modulus range at a constant solvent fraction by utilizing multidimensional network architectures. The general design-by-architecture framework is universally applicable to both organogels and hydrogels and can be further adapted to different practical applications.

Injectable bottlebrush hydrogels with tissue-mimetic mechanical properties.

Injectable hydrogels are desired in many biomedical applications due to their minimally invasive deployment to the body and their ability to introduce drugs. However, current injectables suffer from mechanical mismatch with tissue, fragility, water expulsion, and high viscosity. To address these issues, we design brush-like macromolecules that concurrently provide softness, firmness, strength, fluidity, and swellability. The synthesized linear-bottlebrush-linear (LBL) copolymers facilitate improved injectability as the compact conformation of bottlebrush blocks results in low solution viscosity, while the thermoresponsive linear blocks permit prompt gelation at 37°C. The resulting hydrogels mimic the deformation response of supersoft tissues such as adipose and brain while withstanding deformations of 700% and precluding water expulsion upon gelation. Given their low cytotoxicity and mild inflammation in vivo, the developed materials will have vital implications for reconstructive surgery, tissue engineering, and drug delivery applications.

Botulinum toxin in the masseter muscle: Lingering effects of denervation.

Botulinum neurotoxins (BoNTs) are paralytic agents used to treat a variety of conditions in jaw muscles. Although their effect is considered temporary, there are reports of persistent functional changes. Using rabbits that received BoNT injection in one masseter muscle, the recovery of neuromuscular connection was investigated using nerve stimulation to evoke an electromyographic (EMG) response, and the recovery of muscle fibers was investigated using histological morphometry and bromodeoxyuridine (BrdU) immunohistochemistry. One month after treatment, evoked EMG was greatly reduced in both amplitude and duration, indicating that little reinnervation had taken place. Muscle fibers were atrophied and collagenous tissue was increased. Three months after treatment, evoked EMG duration was normal, indicating that at least some neuromuscular junctions were functional. Histologically, some muscle fibers were hypertrophied, some were still atrophied, and some appeared to have died. Fibrosis was still apparent amid slight increases in dividing cells and regenerating fibers. The histological effects of BoNT were evident although attenuated at a distance of about 1 cm from the injection level, but no regional differences could be discerned for the evoked EMGs. In conclusion, there were persistent muscular deficits seen 3 months after BoNT treatment that may have been caused by the failure of some affected muscle fibers to become reinnervated.

Regulating Tissue-Mimetic Mechanical Properties of Bottlebrush Elastomers by Magnetic Field.

We report on a new class of magnetoactive elastomers (MAEs) based on bottlebrush polymer networks filled with carbonyl iron microparticles. By synergistically combining solvent-free, yet supersoft polymer matrices, with magnetic microparticles, we enable the design of composites that not only mimic the mechanical behavior of various biological tissues but also permit contactless regulation of this behavior by external magnetic fields. While the bottlebrush architecture allows to finely tune the matrix elastic modulus and strain-stiffening, the magnetically aligned microparticles generate a 3-order increase in shear modulus accompanied by a switch from a viscoelastic to elastic regime as evidenced by a ca. 10-fold drop of the damping factor. The developed method for MAE preparation through solvent-free coinjection of bottlebrush melts and magnetic particles provides additional advantages such as injection molding of various shapes and uniform particle distribution within MAE composites. The synergistic combination of bottlebrush network architecture and magnetically responsive microparticles empowers new opportunities in the design of actuators and active vibration insulation systems.

Coating small-diameter ePTFE vascular grafts with tunable poly(diol-co-citrate-co-ascorbate) elastomers to reduce neointimal hyperplasia.

Lack of long-term patency has hindered the clinical use of small-diameter prosthetic vascular grafts with the majority of these failures due to the development of neointimal hyperplasia. Previous studies by our laboratory revealed that small-diameter expanded polytetrafluoroethylene (ePTFE) grafts coated with antioxidant elastomers are a promising localized therapy to inhibit neointimal hyperplasia. This work is focused on the development of poly(diol-co-citrate-co-ascorbate) (POCA) elastomers with tunable properties for coating ePTFE vascular grafts. A bioactive POCA elastomer (@20 : 20 : 8, [citrate] : [diol] : [ascorbate]) coating was applied on a 1.5 mm diameter ePTFE vascular graft as the most promising therapeutic candidate for reducing neointimal hyperplasia. Surface ascorbate density on the POCA elastomer was increased to 67.5 ± 7.3 ng mg-1 cm-2. The mechanical, antioxidant, biodegradable, and biocompatible properties of POCA demonstrated desirable performance for in vivo use, inhibiting human aortic smooth muscle cell proliferation, while supporting human aortic endothelial cells. POCA elastomer coating number was adjusted by a modified spin-coating method to prepare small-diameter ePTFE vascular grafts similar to natural vessels. A significant reduction in neointimal hyperplasia was observed after implanting POCA-coated ePTFE vascular grafts in a guinea pig aortic interposition bypass graft model. POCA elastomer thus offers a new avenue that shows promise for use in vascular engineering to improve long-term patency rates by coating small-diameter ePTFE vascular grafts.

Injectable non-leaching tissue-mimetic bottlebrush elastomers as an advanced platform for reconstructive surgery.

Current materials used in biomedical devices do not match tissue's mechanical properties and leach various chemicals into the body. These deficiencies pose significant health risks that are further exacerbated by invasive implantation procedures. Herein, we leverage the brush-like polymer architecture to design and administer minimally invasive injectable elastomers that cure in vivo into leachable-free implants with mechanical properties matching the surrounding tissue. This strategy allows tuning curing time from minutes to hours, which empowers a broad range of biomedical applications from rapid wound sealing to time-intensive reconstructive surgery. These injectable elastomers support in vitro cell proliferation, while also demonstrating in vivo implant integrity with a mild inflammatory response and minimal fibrotic encapsulation.

To Mimic Mechanical Properties of the Skin by Inducing Oriented Nanofiber Microstructures in Bottlebrush Cellulose-graft-diblock Copolymer Elastomers.

Skin is a vital biological defense system that protects the body from physical harm with its unique mechanical properties attributed to the hierarchical organization of the protein scaffold. Developing a synthetic skinlike material has aroused great interest; however, replication of the skin's mechanical response, including anisotropic softness and strain-stiffening, is difficult to achieve. Here, to mimic the mechanical behaviors of skin, a reprocessable bottlebrush copolymer elastomer was designed with renewable and rigid cellulose as backbones; meanwhile, poly(n-butyl acrylate)-b-poly(methyl methacrylate) (PBA-b-PMMA) diblocks were designed as the grafted side chains. The so-made elastomers were subjected to a step-cyclic tensile deformation, by which the internal structures became oriented nanofibers and endowed stress-strain behaviors pretty much similar to those of the real skin. Overall, our research work currently undertaken would be of great importance in the development of a series of biomimetic skinlike polymer materials.

Bottlebrush Bridge between Soft Gels and Firm Tissues.

Softness and firmness are seemingly incompatible traits that synergize to create the unique soft-yet-firm tactility of living tissues pursued in soft robotics, wearable electronics, and plastic surgery. This dichotomy is particularly pronounced in tissues such as fat that are known to be both ultrasoft and ultrafirm. However, synthetically replicating this mechanical response remains elusive since ubiquitously employed soft gels are unable to concurrently reproduce tissue firmness. We have addressed the tissue challenge through the self-assembly of linear-bottlebrush-linear (LBL) block copolymers into thermoplastic elastomers. This hybrid molecular architecture delivers a hierarchical network organization with a cascade of deformation mechanisms responsible for initially low moduli followed by intense strain-stiffening. By bridging the firmness gap between gels and tissues, we have replicated the mechanics of fat, fetal membrane, spinal cord, and brain tissues. These solvent-free, nonleachable, and tissue-mimetic elastomers also show enhanced biocompatibility as demonstrated by cell proliferation studies, all of which are vital for the safety and longevity of future biomedical devices.

Strained Bottlebrushes in Super-Soft Physical Networks.

ABA triblock copolymers composed of a poly(dimethylsiloxane) (PDMS) bottlebrush central block and linear poly(methyl methacrylate) (PMMA) terminal blocks self-assemble into a physical network of PDMS bottlebrush strands connected by PMMA spherical domains. A combination of small- and ultrasmall-angle X-ray scattering techniques was used to concurrently examine dimensions of PMMA spherical domains and PDMS bottlebrush strands both in the bulk and at the PMMA-PDMS interface. In agreement with scaling model predictions, the degrees of polymerization of the bottlebrush backbone (nbb) and PMMA block (nA) correlate with the measured PMMA domain size and area per molecule at the PMMA-PDMS interface as DA ∝ (nbbnA)1/3 and S ∝ nA2/3nbb-1/3, respectively. In the bulk, bottlebrush strands are extended due to steric repulsion between the side chains and unfavorable interactions between the different blocks. At the PMMA-PDMS interface with large curvature, packing constraints require additional bottlebrush backbone extension and alignment of side chains along the backbone in the direction perpendicular to the interface.

Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer.

Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline- block-2-butyl-2-oxazoline- block-2-methyl-2-oxazoline) (P(MeOx- b-BuOx- b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

Chameleon-like elastomers with molecularly encoded strain-adaptive stiffening and coloration.

Active camouflage is widely recognized as a soft-tissue feature, and yet the ability to integrate adaptive coloration and tissuelike mechanical properties into synthetic materials remains elusive. We provide a solution to this problem by uniting these functions in moldable elastomers through the self-assembly of linear-bottlebrush-linear triblock copolymers. Microphase separation of the architecturally distinct blocks results in physically cross-linked networks that display vibrant color, extreme softness, and intense strain stiffening on par with that of skin tissue. Each of these functional properties is regulated by the structure of one macromolecule, without the need for chemical cross-linking or additives. These materials remain stable under conditions characteristic of internal bodily environments and under ambient conditions, neither swelling in bodily fluids nor drying when exposed to air.

Small-incision Descemet stripping automated endothelial keratoplasty: a comparison of small-incision tissue injector and forceps techniques.

PURPOSE: To describe a novel, small-incision, no-fold Descemet stripping automated endothelial keratoplasty (DSAEK) graft injector and to compare complications, visual acuity, and endothelial cell loss with a forceps technique. METHODS: An Institutional Review Board-approved, interventional, nonrandomized, consecutive case series analysis of 175 eyes undergoing DSAEK for Fuchs dystrophy and bullous keratopathy. The injector arm is prospective, and the forceps arm is retrospective. Seventy grafts were performed with a DSAEK graft injector, and 105 grafts were performed using a small-incision forceps technique. Preoperative and postoperative visual acuities at 3 and 6 months, 6-month endothelial cell counts, and complications, including graft dislocation, failure, and rejection, were recorded. Fifty-seven of 232 eyes met exclusion criteria for previous incisional corneal or glaucoma surgery. RESULTS: There were 4 eyes (5.7%) in the injector group and 29 eyes (27.6%) in the forceps group that required a re-bubble procedure because of graft detachment. One graft (1.4%) failed in the injector group and 7 grafts (6.5%) failed in the forceps group. Excluding eyes with other ocular comorbidities (43), in the injector group 74% were 20/40 or better at 6 months and 100% were 20/60 or better. In the forceps group, 72% were 20/40 or better at 6 months and 98% were 20/60 or better. Six-month postoperative endothelial cell counts were available for 84 (46 injector and 38 forceps) eyes, with an average cell loss of 28.3% in the injector group and 44.1% in the forceps group. CONCLUSIONS: DSAEK is an effective treatment of endothelial dysfunction. Surgical technique is important to limit endothelial cell loss and prevent complications, such as graft dislocation. The injector device has several advantages over the trifold forceps technique, including decreased endothelial cell loss, graft dislocation rate, and graft failure rate, and it reduces the DSAEK learning curve. DSAEK graft injectors likely will have a role in the future of endothelial keratoplasty.

Supraglottic stenosis in localized Wegener granulomatosis.

We present what we believe is the first reported case of a patient with supraglottic stenosis secondary to Wegener granulomatosis. The diagnosis was unclear initially because the biopsy results were nonspecific, but a finding of an elevated cytoplasmic-pattern antineutrophil cytoplasmic antibody (c-ANCA) level established the diagnosis of localized supraglottic Wegener granulomatosis. Wegener granulomatosis is characterized by necrotizing vasculitis that is localized predominantly to the kidneys and the upper and lower airways. In the airways, subglottic involvement is well documented, but to the best of our knowledge, supraglottic stenosis has not previously been described. Localized forms of Wegener granulomatosis are characterized by limited disease that involves only the upper airway. The diagnosis in localized forms is complex because histology is diagnostic in only 50% of cases, and only 60% of patients have a positive c-ANCA level. We discuss the diagnostic criteria and management strategies for these localized forms.

Thermodynamically balanced inside-out (TBIO) PCR-based gene synthesis: a novel method of primer design for high-fidelity assembly of longer gene sequences.

A novel thermodynamically-balanced inside-out (TBIO) method of primer design was developed and compared with a thermodynamically-balanced conventional (TBC) method of primer design for PCR-based gene synthesis of codon-optimized gene sequences for the human protein kinase B-2 (PKB2; 1494 bp), p70 ribosomal S6 subunit protein kinase-1 (S6K1; 1622 bp) and phosphoinositide-dependent protein kinase-1 (PDK1; 1712 bp). Each of the 60mer TBIO primers coded for identical nucleotide regions that the 60mer TBC primers covered, except that half of the TBIO primers were reverse complement sequences. In addition, the TBIO and TBC primers contained identical regions of temperature- optimized primer overlaps. The TBC method was optimized to generate sequential overlapping fragments (approximately 0.4-0.5 kb) for each of the gene sequences, and simultaneous and sequential combinations of overlapping fragments were tested for their ability to be assembled under an array of PCR conditions. However, no fully synthesized gene sequences could be obtained by this approach. In contrast, the TBIO method generated an initial central fragment (approximately 0.4-0.5 kb), which could be gel purified and used for further inside-out bidirectional elongation by additional increments of 0.4-0.5 kb. By using the newly developed TBIO method of PCR-based gene synthesis, error-free synthetic genes for the human protein kinases PKB2, S6K1 and PDK1 were obtained with little or no corrective mutagenesis.