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Carbene-based bioadhesives have favourable attributes for tissue adhesion, including non-specific bonding to wet and dry tissues, but suffer from relatively weak fracture strength after photocuring. Light irradiation of carbene-precursor (diazirine) also creates inert side products that are absent under thermal activation. Herein, a dual activation method combines light irradiation at elevated temperatures for the evaluation of diazirine depletion and effects on cohesive properties. A customized photo/thermal-rheometer evaluates viscoelastic properties, correlated to the kinetics of carbene:diazoalkane ratios via 19 F NMR). The latter exploits the sensitive -CF 3 functional group to determine joule-based light/temperature kinetics on trifluoroaryl diazirine consumption. The combination of heat and photoactivation produced bioadhesives that are 3× tougher compared to control. Dual thermal/light irradiation may be a strategy to improve viscoelastic dissipation and toughness of photo-activated adhesive resins., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

The development of new bioadhesives with integrated properties remains an unmet clinical need to replace staples or sutures. Current bioadhesives do not allow electronic activation, which would allow expansion into laparoscopic and robotic surgeries. To address this deficiency, voltage-activated adhesives have been developed on both carbene- and catechol-based chemical precursors. Herein, a third platform of voltage-activated adhesive is evaluated based on lipoic acid, a non-toxic dithiolane found in aerobic metabolism and capable of ring-opening polymerization. The electro-rheological and adhesive properties of lithium, sodium, and potassium salts of lipoic acid are applied for wet tissue adhesion. At ambient conditions, potassium lipoate displays higher storage modulus than lithium or sodium salt under similar conditions. Voltage stimulation significantly improves gelation kinetics to Na- and K-lipoates, while Li-lipoate is found to not require voltage stimulation for gelation. Lap shear adhesion strength on wetted collagen substrates reveals that the synthetic metal lipoates have comparable adhesion strength to fibrin sealants without viral or ethical risks.

The wet environment in the oral cavity is challenging for topical disease management approaches. The compromised material properties leading to weak adhesion and short retention (<8 h) in such environment result in frequent reapplication of the therapeutics. Composites of bacterial cellulose (BC) and carbene-based bioadhesives attempt to address these shortcomings. Previous designs comprised of aqueous formulations. The current design, for the first time, presents dry, shelf-stable cellulose patches for convenient ready-to-use application. The dry patches simultaneously remove tissue surface hydration while retaining carbene-based photocuring and offers on-demand adhesion. The dry patch prototypes are optimized by controlling BC/adhesive mole ratios and dehydration technique. The adhesion strength is higher than commercial denture adhesives on soft mucosal tissues. The structural integrity is maintained for a minimum of 7 days in aqueous environment. The patches act as selective nanoporous barrier against bacteria while allowing permeation of proteins. The results support the application of BC-based adhesive patches as a flexible platform for wound dressings, drug depots, or combination thereof., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Topical treatments for oral wounds and infections exhibit weak adhesion to wet surfaces which results in short retention duration (6-8 hours), frequent dosing requirement and patient incompatibility. To address these limitations, aqueous composites made of fibrillated bacterial cellulose and photoactive bioadhesives are designed for soft epithelial surfaces. The aqueous composites crosslink upon photocuring within a minute and exhibit a transition from viscous to elastic adhesive hydrogels. The light-cured composites have shear moduli mimicking oral mucosa and other soft tissues. The tunable adhesion strength ranges from 3 to 35 kPa on hydrated tissue-mimicking surfaces (collagen film). The results support the application of bacterial cellulose hydrogel systems for potential treatment of mucosal wounds.

Conductive hydrogels are rapidly rising as sensing materials for bioelectronics applications, but lack mechanical and adhesion strength due to their excess water content. We propose a diazirine-grafted polycaprolactone adhesive (CaproGlu)/carbon nanotubes (CNTs) composite that can provide wet adhesion and strong mechanical properties at the tissue-machine interface. The introduced CNTs not only reinforced the CaproGlu, but also formed electrically conducting pathways. The CaproGlu composites exhibited conductivity of 0.1 S m -1 and a charge storage capacity of 5 μC cm -2 . The resulting composites are biocompatible and can be used as strain sensors to detect mechanical deformations.

It is important to detect thrombin due to its physiological and pathological roles, where rapid and simple analytical approaches are needed. In this study, an aptasensor based on fluorescence attenuation kinetics for the detection of thrombin is presented, which incorporates the features of stilbene and aptamer. We designed and synthesized an aptasensor by one-step coupling of stilbene compound and aptamer, which employed the adaptive binding of the aptamer with thrombin to cause a change in stilbene fluorescence attenuation kinetics. The sensor realized detection of thrombin by monitoring the variation in apparent fluorescence attenuation rate constant ( k app ), which could be further used for probing of enzyme-aptamer binding. In comprehensive studies, the developed aptasensor presented satisfactory performance on repeatability, specificity, and regeneration capacity, which realized rapid sensing (10 s) with a limit of detection (LOD) of 0.205 μM. The strategy was successful across seven variants of thrombin aptasensors, with tunable k app depending on the SITS (4-Acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid disodium salt hydrate) grafting site. Analyte detection mode was demonstrated in diluted serum, requiring no separation or washing steps. The new sensing mode for thrombin detection paves a way for high-throughput kinetic-based sensors for exploiting aptamers targeted at clinically relevant proteins.

Topical approaches to oral diseases require frequent dosing due to limited retention time. A mucoadhesive drug delivery platform with extended soft tissue adhesion capability of up to 7 days is proposed for on-site management of oral wound. Bacterial cellulose (BC) and photoactivated carbene-based bioadhesives (PDz) are combined to yield flexible film platform for interfacing soft tissues in dynamic, wet environments. Structure-activity relationships evaluate UV dose and hydration state with respect to adhesive strength on soft tissue mimics. The bioadhesive composite has an adhesion strength ranging from 7 to 17 kPa and duration exceeding 48 h in wet conditions under sustained shear forces, while other mucoadhesives based on hydrophilic macromolecules exhibit adhesion strength of 0.5-5 kPa and last only a few hours. The work highlights the first evaluation of BC composites for mucoadhesive treatments in the buccal cavity., (Copyright © 2021. Published by Elsevier Ltd.)

Bone fractures are in need of rapid fixation methods, but the current strategies are limited to metal pins and screws, which necessitate secondary surgeries upon removal. New techniques are sought to avoid surgical revisions, while maintaining or improving the fixation speed. Herein, a method of bone fixation is proposed with transparent biopolymers anchored in place via light-activated biocomposites based on expanding CaproGlu bioadhesives. The transparent biopolymers serve as a UV light guide for the activation of CaproGlu biocomposites, which results in evolution of molecular nitrogen (from diazirine photolysis), simultaneously expanding the covalently cross-linked matrix. Osseointegration additives of hydroxyapatite or Bioglass 45S5 yield a biocomposite matrix with increased stiffness and pullout strength. The structure-property relationships of UV joules dose, pin diameter, and biocomposite additives are assessed with respect to the apparent viscosity, shear modulus, spatiotemporal pin curing, and lap-shear adhesion. Finally, a model system is proposed based on ex vivo investigation with bone tissue for the exploration and optimization of UV-active transparent biopolymer fixation.

Carbene-based macromolecules are an emerging new stimuli-sensitive class of biomaterials that avoid the impediments of free radical polymerization but maintain a rapid liquid-to-biorubber transition. Activation of diazirine-grafted polycaprolactone polyol (CaproGlu) is limited to UVA wavelengths that have tissue exposure constraints and limited light intensities. For the first time, UVA is circumvented with visible light-emitting diodes at 445 nm (blue) to rapidly activate diazirine-to-carbene covalent cross-linking. Iridium photocatalysts serve to initiate diazirine, despite having little to no absorption at 445 nm. CaproGlu's liquid organic matrix dissolves the photocatalyst with no solvents required, creating a light transparent matrix. Considerable differences in cross-linking chemistry are observed in UVA vs visible/photocatalyst formulations. Empirical analysis and theoretical calculations reveal a more efficient conversion of diazirine directly to carbene with no diazoalkane intermediate detected. Photorheometry results demonstrate a correlation between shear moduli, joules light dose, and the lower limits of photocatalyst concentration required for the liquid-to-biorubber transition. Adhesion strength on ex vivo hydrated tissues exceeds that of cyanoacrylates, with a fixation strength of up to 20 kg·f·cm 2 . Preliminary toxicity assessment on leachates and materials directly in contact with mammalian fibroblast cells displays no signs of fibroblast cytotoxicity.

Stimuli-sensitive biomaterials that are activated by light are in need of formulations that are stable under indoor lighting yet can be activated under direct sunlight. Carbene-based bioadhesives are a new generation of film-forming polymers that are stable under indoor lighting yet are rapidly activated with low-energy UVA light, but have never been evaluated under sunlight exposure. Previous investigations have evolved two flexible carbene-based platforms, where aryl-diazirine is grafted on to polyamidoamine dendrimers (PAMAM-NH 2 ; generation-5) or hydrophobic liquid polycaprolactone tetrol to yield G5-Dz x and CaproGlu, respectively. For the first time the activation of G5-Dz x and CaproGlu is investigated by natural sunlight with intensities up to 10 mW·cm -2 . Structure-property relationships of bioadhesion are investigated by: (1) joules dose of sunlight; (2) bioadhesive polymer structure; and (3) optical concentrators of magnifying glass and Fresnel lens. Using only natural sunlight, adhesion strength could be tuned from 20 to 150 kPa with crosslinking achieved in under 1 min. The results show that carbene-based polymers are a class of stimuli-sensitive biomaterials that are stable to indoor lighting, yet can be rapidly activated under direct sunlight, which may be useful for topical film forming polymers or as active ingredients in sunscreen formulations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Voltage-activated, one-pot adhesives are an emerging platform with many potential advantages, but require multicomponent grafting of electrochemical donors and acceptors for operation in organic environments. This formulation strategy reduces throughput efficiency, organic solubility, and requires additional purification of the grafted dendrimers. A more advanced strategy is proposed for setting up the donor-acceptor conductive network by exploiting a flexible blending design, providing faster throughput of structure-activity analyses with less synthetic investment. The blend method investigates the ampere-dependent storage modulus and gelation time as a function of both donor and acceptor concentration. This blend strategy allows a rapid evaluation of donor-acceptor parameters involved in voltage-activated adhesive formulations., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Driven by the clinical need for a strong tissue adhesive with elastomeric material properties, a departure from legacy crosslinking chemistries was sought as a multipurpose platform for tissue mending. A fresh approach to bonding wet substrates has yielded a synthetic biomaterial that overcomes the drawbacks of free-radical and nature-inspired bioadhesives. A food-grade liquid polycaprolactone grafted with carbene precursors yields CaproGlu. The first-of-its-kind low-viscosity prepolymer is VOC-free and requires no photoinitiators. Grafted diazirine end-groups form carbene diradicals upon low energy UVA (365 nm) activation that immediately crosslink tissue surfaces; no pre-heating or animal-derived components are required. The hydrophobic polymeric environment enables metastable functional groups not possible in formulations requiring solvents or water. Activated diazirine within CaproGlu is uniquely capable of crosslinking all amino acids, even on wet tissue substrates. CaproGlu undergoes rapid liquid-to-biorubber transition within seconds of UVA exposure-features not found in any other bioadhesive. The exceptional shelf stability of CaproGlu allows gamma sterilization with no change in material properties. CaproGlu wet adhesiveness is challenged against current unmet clinical needs: anastomosis of spliced blood vessels, anesthetic muscle patches, and human platelet-mediating coatings. The versatility of CaproGlu enables both organic and inorganic composites for future bioadhesive platforms., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Closure of wounds with tissue adhesives has many advantages over sutures, but existing synthetic adhesives are toxic and have poor workability. Blood-derived adhesives display complete resorption but have adhesion too weak for reliable wound dressings. We propose a semi-synthetic design that combines the positive attributes of synthetic and blood-derived tissue adhesives. PAMAM-g-diazirine (PDz) is a rapidly gelling bioadhesive miscible in both aqueous and organic solvents. PDz blended with platelet-rich plasma (PRP) forms PDz/PRP composite, a semi-synthetic formulation that combines PDz's wet tissue adhesion with PRP's potent wound healing properties. Light-activated PDz/PRP bioadhesive composite has similar elasticity to soft tissues and behaves as an induced hemostat-an unmet clinical need for rapid wound dressings. PDz/PRP composite applied to in-vivo full-thickness wounds observed a 25% reduction in inflammation, as assessed by the host-cell response., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TWJS has a patent pending concerning aspects of the carbene bioadhesive technology., (Copyright © 2020. Published by Elsevier Ltd.)

Photoactivation of aryl-diazirines is an emerging method of rapid, covalent crosslinking under ambient conditions. These attributes make those compounds candidates for grafting onto inert polymer backbones in order to produce stimuli-sensitive biomaterials. However, no risk assessments are available to gauge the toxicity of the leachable components after crosslinking activation. Herein, a stimuli-sensitive biomaterial is formulated from diazirine-grafted polycaprolactone tetrol. Also known as CaproGlu, this biomaterial undergoes UVA-activated crosslinking, with many positive attributes toward bioadhesive applications; hydrophobic, solvent-free, liquid at room temperature, and transitions into a foam biorubber after mild UVA illumination. As a model diazirine-grafted biomaterial, hydrolyzed CaproGlu leachates are evaluated for genotoxicity and skin sensitization, namely, Ames test, direct peptide reactivity, and ARE-Nrf2 luciferase assays. The degradation products of diazirine-mediated crosslinking observe little to no risk of in vitro genotoxicity or skin sensitization., (© 2020 Wiley-VCH GmbH.)

The Photochrome Aptamer Switch Assay (PHASA) relies on ligand binding by an aptamer to alter the local environment of a stilbene compound covalently attached to the 5' end of the aptamer. We used the PHASA with both structure switching and non-structure switching versions of the cocaine-binding aptamer. We show that the largest change in fluorescence intensity and the lowest concentration limit of detection (C L o o D ) is obtained using the structure-switching cocaine-binding aptamer. Fluorescence anisotropy measurements were used to quantify the affinity of the conjugated aptamer to cocaine. We also used thermal melt analysis and Nuclear Magnetic Resonance (NMR) spectroscopy to show that the addition of the stilbene to the aptamer increases the melt temperature of the cocaine-bound structure-switching aptamer by (6.4 ± 0.3) °C compared to the unconjugated aptamer while the free form of the structure-switching aptamer-stilbene conjugate remains unfolded., Competing Interests: Declaration of competing interest The authors have no competing interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Microneedles (MNs) offer a rapid method of transdermal drug delivery through penetration of the stratum corneum. However, commercial translation has been limited by fabrication techniques unique to each drug. Herein, a broadly applicable platform is explored by drug-loading via swelling effect of a hydrogel MN patch. A range of small molecule hydrophilic, hydrophobic, and biomacromolecule therapeutics demonstrate successful loading and burst release from hydrogel MNs fabricated from methacrylated hyaluronic acid (MeHA). The post-fabrication drug loading process allows MeHA MN patches with drug loadings of 10 μg cm -2 . Additional post-fabrication processes are explored with dendrimer bioadhesives that increase work of adhesion, ensuring stable fixation on skin, and allow for additional drug loading strategies., Competing Interests: 6The authors declare no conflict of interest., (© 2020 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals, Inc. on behalf of The American Institute of Chemical Engineers.)

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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Rapid adhesion between tissue and synthetic materials is relevant to accelerate wound healing and to facilitate the integration of implantable medical devices. Most frequently, tissue adhesives are applied as a gel or a liquid formulation. This manuscript presents an alternative approach to mediate adhesion between synthetic surfaces and tissue. The strategy presented here is based on the modification of the surface of interest with a thin polymer film that can be transformed on-demand, using UV-light as a trigger, from a nonadhesive into a reactive and tissue adhesive state. As a first proof-of-concept, the feasibility of two photoreactive, thin polymer film platforms has been explored. Both of these films, colloquially referred to as polymer brushes, have been prepared using surface-initiated atom transfer radical polymerization (SI-ATRP) of 2-hydroxyethyl methacrylate (HEMA). In the first part of this study, it is shown that direct UV-light irradiation of PHEMA brushes generates tissue-reactive aldehyde groups and facilitates adhesion to meniscus tissue. While this strategy is very straightforward from an experimental point of view, a main drawback is that the generation of the tissue reactive aldehyde groups uses the 250 nm wavelength region of the UV spectrum, which simultaneously leads to extensive photodegradation of the polymer brush. The second part of this report outlines the synthesis of PHEMA brushes that are modified with 4-[3-(trifluoromethyl)-3 H -diazirin-3-yl]benzoic acid (TFMDA) moieties. UV-irradiation of the TFMDA containing brushes transforms the diazirine moieties into reactive carbenes that can insert into C-H, N-H, and O-H bonds and mediate the formation of covalent bonds between the brush surface and meniscus tissue. The advantage of the TFMDA-modified polymer brushes is that these can be activated with 365 nm wavelength UV light, which does not cause photodegradation of the polymer films. While the work presented in this manuscript has used silicon wafers and fused silica substrates as a first proof-of-concept, the versatility of SI-ATRP should enable the application of this strategy to a broad range of biomedically relevant surfaces.

Lack of wet adhesion and biomechanical mismatch at tissue interfaces are the major challenges related to surgical adhesive formulations. Carbene-based bioadhesives seek to address those limitations, due to their ability to covalently bond to wet tissue surfaces. Herein, diazirine-grafted polyamidoamine (PAMAM) dendrimers (PDz) dissolved in various liquid polyethylene glycols (PEG) are reported. Non-aqueous liquid PEG 400 reinforced with high molecular weight PEGs (2 kDa, 6 kDA and 10 kDa) dissolved PDz to form tertiary blends for optimization of viscosity and shear storage modulus. Dynamic photorheometry correlated PEG molar mass and tertiary ratios to adhesion strength, swelling-in-water profile and potential weight loss in aqueous medium. Tertiary blended adhesives demonstrate an improvement in elongation and adhesion strength compared to the binary blends used as control., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Neurosurgery presents unique surgical challenges arising from delicate neural structures, limited accessibility, and the risk of CSF leakage that can lead to CNS infections. Sutures and staples may have limited applicability in the complex anatomical constraints of cranial and spinal surgeries, especially in trauma settings when time is of the essence. Surgical bioadhesives are emerging as attractive alternatives because they avoid traumatic application methods, provide a stress-distributed fixation, and provide good cosmesis and outcomes. This article presents the history of the development of surgical bioadhesives, and is also a review of current applications of commercial surgical bioadhesives within neurosurgical procedures and the unmet clinical needs that should be addressed in bioadhesives technologies., Methods: A PubMed literature search was performed using the terms "(glue OR bioadhesive OR fibrin OR tisseel OR evicel OR tachosil OR cyanoacrylate OR duraseal OR bioglue) AND (neurosurgery OR spine OR spinal OR dural OR microvascular decompression OR transsphenoidal OR endovascular)." Of 2433 records screened, 168 studies were identified that described the use of bioadhesives in neurosurgical procedures., Results: The greatest number of studies describing the use of bioadhesives in neurosurgery were identified for endovascular embolization, followed by dural closure and transsphenoidal surgeries. Other common areas of application were for microvascular decompression, skin closure, peripheral nerve repair, and other novel uses. Numerous case reports were also identified describing complications associated with bioadhesive use., Conclusions: Despite the paucity of approved indications, surgical bioadhesive use in neurosurgical procedures is prevalent. However, current bioadhesives still each have their own limitations and research is intense in the development of novel solutions.

Catechol adhesives are limited to two-part curing designs. For the first time, a one-pot catechol adhesive is demonstrated with multiple modes of external activation: self-curing, electrocuring, substrate, and two-part curing. Lap shear adhesion (50 kPa) and viscoelastic properties demonstrate that electrocuring is non-inferior to two-part curing methods.

Photochrome Aptamer Switch Assay (PHASA) is our unique and recently developed fluorescent biosensing platform that exploits the combination of aptamer adaptive binding and photoisomerisation kinetics of stilbenes. The PHASA is based on converting any suitable stilbene-ligand-aptamer complex into a reversible biosensor. Binding affinity, aptamer concentration, and stilbene molecular structure determine the PHASA performance criteria. Consequently, understanding of the structure-activity relationship of the stilbene-ligand conjugate is extremely important when predicting and optimising the biosensor sensitivity. In the present manuscript, new analytical methods relating to calculation of the limit of detection (LOD) of the PHASA are proposed and discussed. Using these methods, it is possible to optimise the independent or dependent physicochemical parameters of the stilbene-ligand conjugates and evaluate their general sensing performance. The proposed analytical methods are based on the inter-dependent relationships between the sensitivity and the range of analyte detection and provide starting conditions for known aptamer binding constants in various PHASA applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Laboratory investigations of polyester biomaterials overly rely on additives and solvent-casting manufacturing techniques that do not allow translation into industrial processing owing to the volatile organic compounds present. These impediments of bench to bedside translation are addressed with a "green chemistry" twin screw extrusion approach, where the extrusion parameters control the release profile. Advantages include elimination of volatile organic compounds, removal of plastic plasticizers/additives, and a low temperature production that is applicable to both academia and industry. Poly (d, l-lactide-co-glycolide) (PLGA), a labile polyester drug depot is loaded with fluorescein diacetate (FDAc), a pH/heat sensitive drug that degrades to fluorescein. Processing of FDAc suggests no degradation at elevated temperatures or high shears, indicating hydrophobic small molecules can be homogeneously dispersed with no detrimental effects. In vitro release of FDAc in physiological environments varies release profile through ratios of ester/acid-terminated PLGA without secondary additives. Postprocessing stability investigations of PLGA resin with size exclusion chromatography and differential scanning calorimetry validate no significant polymer degradation. Through judicious choice of parameters, release can be tuned from 15-250 microgram per sq. cm per day. Twin screw extrusion production of PLGA drug depots reveals a promising method of tailor-made drug delivering thin films for various pharmaceutical applications., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Surgical adhesives are an attractive alternative to traditional mechanical tissue fixation methods of sutures and staples. Ease of application, biocompatibility, enhanced functionality (drug delivery) are known advantages but weak adhesion strength in the wet environment and lack of tissue compliant behavior still pose a challenge. In order to address these issues, non-aqueous bioadhesive based on blends of polyamidoamine (PAMAM) dendrimer, conjugated with 4-[3-(trifluoromethyl)-3H-diazirin-3-yl] benzyl bromide (PAMAM-g-diazirine) and liquid polyethylene glycol (PEG 400) has been developed. PEG 400 biocompatible solvent reduces the viscosity of PAMAM-g-diazirine dendrimer without incorporating aqueous solvents or plasticizers, allowing application by syringe or spray. Upon UV activation, diazirine-generated reactive intermediates lead to intermolecular dendrimer crosslinking. The properties of the crosslinked matrix are tissue compliant, with anisotropic material properties dependent on the PEG 400 wt%, UV dose, pressure and uncured adhesive thickness. The hygroscopic PAMAM-g-diazirine/PEG 400 blend was hypothesized to absorb water at the tissue interface, leading to high interfacial adhesion, however porous matrices led to cohesive failure. The hydrophilic nature of the polyether backbone (PEG 400) shielded cationic PAMAM dendrimers with cured bioadhesive film displaying significantly less platelet activation than neat PAMAM-g-diazirine or PLGA thin films., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Two types of magnetic nanoparticles (MNPs), i.e. Ni ferrite nanoparticles (Fe 2 NiO 4 ) and Ni Zn ferrite nanoparticles (Fe 4 NiO 4 Zn) containing the trace metals Ni and Fe, were added to the anaerobic digestion of synthetic municipal wastewater at concentrations between 1 and 100 mg Ni L -1 in order to compare their effects on biogas (methane) production and sludge activity. Using the production of methane over time as a measure, the assays revealed that anaerobic digestion was stimulated by the addition of 100 mg Ni L -1 in Fe 2 NiO 4 NPs, while it was inhibited by the addition of 1-100 mg Ni L -1 in Fe 4 NiO 4 Zn NPs. Especially at 100 mg Ni L -1 , Fe 4 NiO 4 Zn NPs resulted in a total inhibition of anaerobic digestion. The metabolic activity of the anaerobic sludge was tested using the resazurin reduction assay, and the assay clearly revealed the negative effect of Fe 4 NiO 4 Zn NPs and the positive effect of Fe 2 NiO 4 NPs. Re-feeding fresh synthetic medium reactivated the NPs added to the anaerobic sludge, except for the experiment with 100 mg Ni L -1 addition of Fe 4 NiO 4 Zn NPs. The findings in this present study indicate a possible new strategy for NPs design to enhance anaerobic digestion., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Soft tissue fixation of implant and bioelectrodes relies on mechanical means (e.g., sutures, staples, and screws), with associated complications of tissue perforation, scarring, and interfacial stress concentrations. Adhesive bioelectrodes address these shortcomings with voltage cured carbene-based bioadhesives, locally energized through graphene interdigitated electrodes. Electrorheometry and adhesion structure activity relationships are explored with respect to voltage and electrolyte on bioelectrodes synthesized from graphene 3D-printed onto resorbable polyester substrates. Adhesive leachates effects on in vitro metabolism and human-derived platelet-rich plasma response serves to qualitatively assess biological response. The voltage activated bioadhesives are found to have gelation times of 60 s or less with maximum shear storage modulus (G') of 3 kPa. Shear modulus mimics reported values for human soft tissues (0.1-10 kPa). The maximum adhesion strength achieved for the ≈50 mg bioelectrode films is 170 g cm -2 (17 kPa), which exceeds the force required for tethering of electrodes on dynamic soft tissues. The method provides the groundwork for implantable bio/electrodes that may be permanently incorporated into soft tissues, vis-à-vis graphene backscattering wireless electronics since all components are bioresorbable., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bioadhesives are a current unmet clinical need for mending of blood contacting soft tissues without inducing thrombosis. Recent development of carbene precursor bioadhesives with the advantages of on-demand curing, tuneable modulus, and wet adhesion have been synthesized by grafting diazirine onto poly (amidoamine) (PAMAM-G5) dendrimers. Herein, the structure activity relationships of platelet adhesion and activation is evaluated for the first time on the cured PAMAM-g-diazirine bioadhesives. Three strategies were employed to prevent healthy human donor platelets from adhering and activating on light-cured bioadhesive surfaces: (1) Attenuation of cationic surface charge, (2) antifouling composites by incorporating heparin and alginate in uncured formulation, and (3) heparin wash of cured bioadhesive surface. Topographical imaging of cured and ethanol dehydrated bioadhesive surfaces was used to quantify the adhered and activated platelets with scanning electron microscopy, whose resolution allowed identification of round senescent, short dendritic, and long dendritic platelets. Cured surfaces of PAMAM-g-diazirine (15%) had 10300 ± 500 adhered platelets mm -2 with 99.7% activation into short/long dendritic cells. Reduction of primary amines by higher degree of diazirine grafting or capping of free amines by acetylation reduces platelet adherence (2400 ± 200 vs 3000 ± 300, respectively). Physical incorporation of heparin and alginate in the formulations reduced the activated platelet; 1300 ± 300 and 300 ± 50, activated platelets mm -2 , in comparison with additive free adhesive formulation. Similarly, heparin rinse of the surface of additive free bioadhesive reduced the activated platelet to platelets of heparin composites at 600 ± 100 platelets mm -2 . PAMAM-g-diazirine (15%) bioadhesive retained the photocured mechanical properties and lap shear adhesion despite the addition of heparin and alginate additives.

Tissue adhesives based on polyamidoamine (PAMAM) dendrimer, grafted with UV-sensitive aryldiazirine (PAMAM-g-diazirine) are promising new candidates for light active adhesion on soft tissues. Diazirine carbene precursors form interfacial and intermolecular covalent crosslinks with tissues after UV light activation that requires no premixing or inclusion of free radical initiators. However, primary amines on the PAMAM dendrimer surface present a potential risk due to their cytotoxic and immunological effects. PAMAM-g-diazirine formulations with cationic pendant amines converted into neutral amide groups were evaluated. In vitro toxicity is reduced by an order of magnitude upon amine capping while retaining bioadhesive properties. The in vivo immunological response to PAMAM-g-diazirine formulations was found to be optimal in comparison to standard poly(lactic- co -glycolic acid) (PLGA) thin films., Competing Interests: The authors declare no conflict of interest.

Gold nanoparticles (AuNPs) have attracted great attention in biomedical fields due to their unique properties. However, there are few reports on clinical trial of these nanoparticles. In vivo, AuNPs face complex biological fluids containing abundant proteins, which challenge the prediction of their fate that is known as "bio-identity". These proteins attach onto the AuNPs surface forming protein corona that makes the first step of nano-bio interface and dictates the subsequent AuNPs fate. Protein corona formation even stealth active targeting effect of AuNPs. Manipulating the protein corona identity based on the researcher goal is the way to employ corona to achieve maximum effect in therapy or other applications. In this review, we provide details on the biological identity of AuNPs under various environmental- and/or physiological conditions. We also highlight how the particular corona can direct the biodistribution of AuNPs. We further discuss the strategies available for controlling or reducing corona formation on AuNPs surface and achieving desired effects using AuNPs in vivo by engineering protein corona on their surface., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Resazurin is widely used as a metabolic indicator for living cells, however, there has been considerable debate in the literature with regards to the specific location in the cell where the non-fluorescent resazurin is reduced to the strongly fluorescent resorufin. This lack of clarity about the reduction site makes the use of resazurin reduction data in cytotoxicity studies difficult to interpret. In this study, E. faecalis, a Gram-positive and facultative anaerobic bacterial strain, and the most toxic chlorophenol, pentachlorophenol (PCP), were chosen as models for an anaerobe and toxicant, respectively. By studying the kinetics of resazurin reduction by E. faecalis after different treatments (cell disruption, bacterial filtration, and pre-exposure to toxicant), we confirmed that resazurin reduction to resorufin by live Gram-positive and facultative anaerobic bacterial cells can only happen intracellularly under anaerobic conditions, while resorufin reduction to dihydroresorufin can happen both intracellularly and extracellularly. Based on the understanding of these fundamental mechanisms, we suggest that resazurin reduction can be used as a quick bioassay for measuring cytotoxicity., (© 2017 Wiley Periodicals, Inc.)

N,N-dimethyl-N'-picryl-4,4'-stilbenediamine (DMPSDA) was prepared, purified and crystallised in a form of black lustrous crystals, and its absorption and fluorescence spectra were recorded in cyclohexane, acetonitrile and dimethyl sulfoxide. Non-emissive intramolecular charge transfer state (ICT) was clearly observed in this molecule in all three solvents. Theoretical calculations demonstrating a betaine electronic structure of the trinitrophenyl group in the ground state of the molecule and a charge transfer nature of the long wavelength transition S 0  → S 1 supported the experimental observations of the ICT formation in the molecule.

The growth of new blood vessels from the pre-existing vasculature known as angiogenesis has a vital role in various physiological and pathological processes. In the present study, we demonstrate the pro-angiogenic properties of functional nanoconjugates of organosilane functionalized cerium oxide (CeO 2 ) nanoparticles (nanoceria). Aqueous dispersible CeO 2 and trivalent metal (samarium) ion-doped CeO 2 (SmCeO 2 ) nanoparticles conjugated with hydrophilic biocompatible and antifouling (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane moieties were prepared. These functional nanoconjugates were prepared via an in situ synthesis and functionalization procedure using an ammonia-induced ethylene glycol-assisted precipitation method. The prepared nanoconjugates were thoroughly characterized using various physico-chemical techniques such as transmission electron microscopy (TEM), X-ray diffraction (XRD) analysis, dynamic light scattering (DLS), Fourier-transform infrared (FTIR) spectroscopy, 13 C high-resolution solid-state nuclear magnetic resonance (NMR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The pro-angiogenic properties of the prepared nanoconjugates were evaluated by employing various angiogenesis assays (in vitro and in vivo). The results of the present study illustrate that the functional nanoconjugates of SmCeO 2 triggered endothelial cell proliferation and induced the growth of blood vessels in a chick embryo. The enhanced expression of pro-angiogenic markers (p38 MAPK/HIF-1α) by these functional nanoconjugates might be a plausible signaling mechanism underlying their pro-angiogenic properties. Considering all the observations, we believe that (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane conjugated SmCeO 2 nanoparticles could be developed as potential candidates for the treatment of cardiovascular, ischemic and ocular diseases where angiogenesis is the principal phenomenon.

Near-infrared (NIR) triggered chemical delivery allows on-demand release with the advantage of external tissue stimulation. Bioresorbable polyester poly-l-lactic acid (PLLA) was compounded with photoadditives of neat zinc oxide (ZnO) nanoparticles and 980→365nm LiYF 4 :Tm 3+ , Yb 3+ upconverting nanoparticles (UCNP). Subsequently, neat ZnO and UCNP blended PLLA films of sub-50μm thickness were knife casted with a hydrophobic small molecule drug mimic, fluorescein diacetate. The PLLA films displayed a 500 times increase in fluorescein diacetate release from the 50mW NIR irradiated PLLA/photoadditive film compared to non-irradiated PLLA control films. Larger ratios of UCNP/neat ZnO increased photocatalysis efficiency at low NIR duty cycles. The synergistic increase results from the self-assembled photoadditives of neat zinc oxide and upconverting nanoparticles (UCNPs), as seen in transmission electron microscopy. Colloidal ZnO, which does not self-assemble with UCNPs, had less than half the release kinetics of the self-assembled PLLA films under similar conditions, advocating Förster resonance energy transfer as the mechanism responsible for the synergistic increase. Alternative to intensity modulation, pulse width modulation (duty cycles from 0.1 to 1) of the low intensity 50mW NIR laser diode allowed tailorable release rates from 0.01 to 1.4% per day. With the low intensity NIR activation, tailorable release rates, and favorable biocompatibility of the constituents, implanted PLLA photoadditive thin films could allow feedback mediated chemical delivery., Statement of Significance: Upconverting nanoparticles and zinc oxide nanorods were found to spontaneously self-assemble into submicron particles in organic solvents. Exposure of the submicron particles to near-infrared light allows stop and go chemical release from biocompatible polymers. Sample preparation of thin films is done with ease through physical mixing of the photoadditives followed by air-dried knife casting. A colloidal ZnO variant that does not self-assemble with upconverting nanoparticles had slower chemical release, suggesting that synergistic chemical release is brought upon by highly efficient energy transfer mechanisms when the nanoparticles are less than 10nm apart. Never before seen composite particles of UCNP/ZnO are displayed, which shows the close interaction of the photoadditives within the polymer matrix., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Microfluidic droplet reactors have many potential uses, from analytical to synthesis. Stable operation requires preferential wetting of the channel surface by the continuous phase which is often not fulfilled by materials commonly used for lab-on-chip devices. Here we show that a silica nanoparticle (SiNP) layer coated onto a Poly(methyl methacrylate) (PMMA) and other thermoplastics surface enhances its wetting properties by creating nanoroughness, and allows simple grafting of hydrocarbon chains through silane chemistry. Using the unusual stability of silica sols at their isoelectric point, a dense SiNP layer is adsorbed onto PMMA and renders the surface superhydrophilic. Subsequently, a self-assembled dodecyltrichlorosilane (DTS) monolayer yields a superhydrophobic surface that allows the repeatable generation of aqueous droplets in a hexadecane continuous phase without surfactant addition. A SiNP-DTS modified chip has been used to monitor bacterial viability with a resazurin assay. The whole process involving sequential reagents injection, and multiplexed droplet fluorescence intensity monitoring is carried out on chip. Metabolic inhibition of the anaerobe Enterococcus faecalis by 30 mg L -1 of NiCl 2 was detected in 5 min.

Aptamer-ligand binding has been utilized for biological applications due to its specific binding and synthetic nature. However, the applications will be limited if the binding or the ligand is unstable. Malachite green aptamer (MGA) and its labile ligand malachite green (MG) were found to have increasing apparent dissociation constants (Kd) as determined through the first order rate loss of emission intensity of the MGA-MG fluorescent complex. The fluorescent intensity loss was hypothesized to be from the hydrolysis of MG into malachite green carbinol base (MGOH). Random screening organic additives were found to reduce or retain the fluorescence emission and the calculated apparent Kd of MGA-MG binding. The protective effect became more apparent as the percentage of organic additives increased up to 10% v/v. The mechanism behind the organic additive protective effects was primarily from a ~5X increase in first order rate kinetics of MGOH→MG (kMGOH→MG), which significantly changed the equilibrium constant (Keq), favoring the generation of MG, versus MGOH without organic additives. A simple way has been developed to stabilize the apparent Kd of MGA-MG binding over 24h, which may be beneficial in stabilizing other triphenylmethane or carbocation ligand-aptamer interactions that are susceptible to SN1 hydrolysis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Stimulation of anaerobic digestion by essential trace metals is beneficial from a practical point of view to enhance the biodegradability and degradation rate of wastes. Hence, a quick method to determine which metal species, and at what concentration, can optimize anaerobic digestion is of great interest to both researchers and operators. In this present study, we investigated the effect of nickel(II), cobalt(II), and their mixture, on the anaerobic digestion of synthetic municipal wastewater. Using a volumetric method, that is, measuring methane production over time, revealed that anaerobic digestion was stimulated by the addition of 5 mg L -1 nickel(II), and cobalt(II), and their mixture in day(s). However, using a novel resazurin reduction assay, and based on its change in rate over time, we evaluated both inhibition at 250 mg L -1 nickel(II) and cobalt(II), and also the stimulatory effect of 5 mg L -1 nickel(II), and cobalt(II), and their mixture, in just 6 h. By investigating the dynamic distribution of these metals in the liquid phase of the anaerobic system and kinetics of resazurin reduction by nickel spiked anaerobic sludge, the concentration of nickel(II) on anaerobic digestion performance was profiled. Three critical concentrations were determined; stimulation starting (around 1 mg L -1 ), stimulation ending (around 100 mg L -1 ) and stimulation maximizing (around 10 mg L -1 ). Hence, we propose that the resazurin reduction assay is a novel and quick protocol for studying the stimulation of anaerobic bioprocesses by bioavailable essential trace metals.

Ganciclovir and valganciclor are antiviral agents used for the treatment of cytomegalovirus retinitis. The conventional method for administering ganciclovir in cytomegalovirus retinitis patients is repeated intravitreal injections. In order to obviate the possible detrimental effects of repeated intraocular injections, to improve compliance and to eliminate systemic side-effects, we investigated the tuning of the ganciclovir pro-drug valganciclovir and the release from thin films of poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), or mixtures of both, as a step towards prototyping periocular valganciclovir implants. To investigate the drug release, we established and evaluated a high throughput fluorescence-based quantification screening assay for the detection of valganciclovir. Our protocol allows quantifying as little as 20 ng of valganciclovir in 96-well polypropylene plates and a 50× faster analysis compared to traditional HPLC measurements. This improvement can hence be extrapolated to other polyester matrix thin film formulations using a high-throughput approach. The acidic microenvironment within the polyester matrix was found to protect valganciclovir from degradation with resultant increases in the half-life of the drug in the periocular implant to 100 days. Linear release profiles were obtained using the pure polyester polymers for 10 days and 60 days formulations; however, gross phase separations of PCL and acid-terminated PLGA prevented tuning within these timeframes due to the phase separation of the polymer, valganciclovir, or both.