Polymerization-Mediated Through-Space Charge Transfer: An Emerging Strategy for Light-Emitting Materials.

Through-space charge transfer (TSCT) has attracted increasing attention owing to its great potential in designing efficient light-emitting molecules and polymers. Complementary to through-bond charge transfer and Förster resonance energy transfer, TSCT offers an alternative approach for the manipulation of molecular fluorescence. Recently, the synergy between TSCT and polymer systems through polymerization-mediated charge transfer has fostered the advancements of innovative light-emitting functional materials featuring thermally activated delayed fluorescence and/or aggregation-induced emission. This perspective highlights the significant progress in tailoring emission properties through structural engineering of donor and acceptor groups within polymeric systems, leveraging the TSCT mechanism. This strategy has transcended the limitations of traditional charge transfer systems with its tolerance to extended donor-acceptor distance, paving the way for novel applications beyond organic light-emitting diodes. The discussion concludes with a forward-looking analysis of potential future research trajectories in the field of polymerization-mediated charge transfer for developing next-generation light-emitting materials.

Coumarin-Based Photodegradable Hydrogels Enable Two-Photon Subtractive Biofabrication at 300†mm s-1.

Spatiotemporally controlled two-photon photodegradation of hydrogels has gained increasing attention for high-precision subtractive tissue engineering. However, conventional photolabile hydrogels often have poor efficiency upon two-photon excitation in the near-infrared (NIR) region and thus require high laser dosage that may compromise cell activity. As a result, high-speed two-photon hydrogel erosion in the presence of cells remains challenging. Here we introduce the design and synthesis of efficient coumarin-based photodegradable hydrogels to overcome these limitations. A set of photolabile coumarin-functionalized polyethylene glycol linkers are synthesized through a Passerini multicomponent reaction. After mixing these linkers with thiolated hyaluronic acid, semi-synthetic photodegradable hydrogels are formed in situ via Michael addition crosslinking. The efficiency of photodegradation in these hydrogels is significantly higher than that in nitrobenzyl counterparts upon two-photon irradiation at 780 nm. A complex microfluidic network mimicking the bone microarchitecture is successfully fabricated in preformed coumarin hydrogels at high speeds of up to 300 mm s-1 and low laser dosage down to 10 mW. Further, we demonstrate fast two-photon printing of hollow microchannels inside a hydrogel to spatiotemporally direct cell migration in 3D. Collectively, these hydrogels may open new avenues for fast laser-guided tissue fabrication at high spatial resolution.

Recent Trends in Advanced Photoinitiators for Vat Photopolymerization 3D Printing.

3D printing has revolutionized the way of manufacturing with a huge impact on various fields, in particular biomedicine. Vat photopolymerization-based 3D printing techniques such as stereolithography (SLA) and digital light processing (DLP) attract considerable attention owing to their superior print resolution, relatively high speed, low cost, and flexibility in resin material design. As one key element of the SLA/DLP resin, photoinitiators or photoinitiating systems have experienced significant development in recent years, in parallel with the exploration of 3D printing (macro)monomers. The design of new photoinitiating systems cannot only offer faster 3D printing speed and enable low-energy visible light fabrication, but also can bring new functions to the 3D printed products and even generate new printing methods in combination with advanced optics. This review evaluates recent trends in the development and application of advanced photoinitiators and photoinitiating systems for vat photopolymerization 3D printing, with a wide range of small molecules, polymers, and nanoassemblies involved. Personal perspectives on the current limitations and future directions are eventually provided.

Controlling Molecular Aggregation-Induced Emission by Controlled Polymerization.

In last twenty years, the significant development of AIE materials has been witnessed. A number of small molecules, polymers and composites with AIE activity have been synthesized, with some of these exhibiting great potential in optoelectronics and biomedical applications. Compared to AIE small molecules, macromolecular systems-especially well-defined AIE polymers-have been studied relatively less. Controlled polymerization methods provide the efficient synthesis of well-defined AIE polymers with varied monomers, tunable chain lengths and narrow dispersity. In particular, the preparation of single-fluorophore polymers through AIE molecule-initiated polymerization enables the systematic investigation of the structure-property relationships of AIE polymeric systems. Here, the main polymerization techniques involved in these polymers are summarized and the key parameters that affect their photophysical properties are analyzed. The author endeavored to collect meaningful information from the descriptions of AIE polymer systems in the literature, to find connections by comparing different representative examples, and hopes eventually to provide a set of general guidelines for AIE polymer design, along with personal perspectives on the direction of future research.

Ammonia uptake by transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) polymersomes.

Transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes were investigated for their potential use in the detoxification of ammonia, a metabolite that is excessively present in patients suffering from urea cycle disorders and advanced liver diseases, and which causes neurotoxic effects (e.g., hepatic encephalopathy). Polymers varying in PI and PEG block length were synthesized via nitroxide-mediated polymerization and screened for their ability to self-assemble into polymersomes in aqueous media. Ammonia sequestration by the polymersomes was investigated in vitro. While most vesicular systems were able to capture ammonia in simulated intestinal fluids, uptake was lost in partially dehydrated medium mimicking conditions in the colon. Polymeric crosslinking of residual olefinic bonds in the PI block increased polymersome stability, partially preserving the ammonia capture capacity in the simulated colon environment. These more stable vesicular systems hold promise for the chronic oral treatment of hyperammonemia.

An Investigation of PS-b-PEO Polymersomes for the Oral Treatment and Diagnosis of Hyperammonemia.

Ammonia-scavenging transmembrane pH-gradient poly(styrene)-b-poly(ethylene oxide) polymersomes are investigated for the oral treatment and diagnosis of hyperammonemia, a condition associated with serious neurologic complications in patients with liver disease as well as in infants with urea cycle disorders. While these polymersomes are highly stable in simulated intestinal fluids at extreme bile salt and osmolality conditions, they unexpectedly do not reduce plasmatic ammonia levels in cirrhotic rats after oral dosing. Incubation in dietary fiber hydrogels mimicking the colonic environment suggests that the vesicles are probably destabilized during the dehydration of the intestinal chyme. The findings question the relevance of commonly used simulated intestinal fluids for studying vesicular stability. With the encapsulation of a pH-sensitive dye in the polymersome core, the local pH increase upon ammonia influx could be exploited to assess the ammonia concentration in the plasma of healthy and cirrhotic rats as well as in other fluids. Due to its high sensitivity and selectivity, this polymersome-based assay could prove useful in the monitoring of hyperammonemic patients and in other applications such as drug screening tests.

Surface-Associated Lipoproteins Link Enterococcus faecalis Virulence to Colitogenic Activity in IL-10-Deficient Mice Independent of Their Expression Levels.

The commensal Enterococcus faecalis is among the most common causes of nosocomial infections. Recent findings regarding increased abundance of enterococci in the intestinal microbiota of patients with inflammatory bowel diseases and induction of colitis in IL-10-deficient (IL-10-/-) mice put a new perspective on the contribution of E. faecalis to chronic intestinal inflammation. Based on the expression of virulence-related genes in the inflammatory milieu of IL-10-/- mice using RNA-sequencing analysis, we characterized the colitogenic role of two bacterial structures that substantially impact on E. faecalis virulence by different mechanisms: the enterococcal polysaccharide antigen and cell surface-associated lipoproteins. Germ-free wild type and IL-10-/- mice were monoassociated with E. faecalis wild type OG1RF or the respective isogenic mutants for 16 weeks. Intestinal tissue and mesenteric lymph nodes (MLN) were collected to characterize tissue pathology, loss of intestinal barrier function, bacterial adhesion to intestinal epithelium and immune cell activation. Bone marrow-derived dendritic cells (BMDC) were stimulated with bacterial lysates and E. faecalis virulence was additionally investigated in three invertebrate models. Colitogenic activity of wild type E. faecalis (OG1RF score: 7.2±1.2) in monoassociated IL-10-/- mice was partially impaired in E. faecalis lacking enterococcal polysaccharide antigen (ΔepaB score: 4.7±2.3; p<0.05) and was almost completely abrogated in E. faecalis deficient for lipoproteins (Δlgt score: 2.3±2.3; p<0.0001). Consistently both E. faecalis mutants showed significantly impaired virulence in Galleria mellonella and Caenorhabditis elegans. Loss of E-cadherin in the epithelium was shown for all bacterial strains in inflamed IL-10-/- but not wild type mice. Inactivation of epaB in E. faecalis reduced microcolony and biofilm formation in vitro, altered bacterial adhesion to intestinal epithelium of germ-free Manduca sexta larvae and impaired penetration into the colonic mucus layer of IL-10-/- mice. Lipoprotein-deficient E. faecalis exhibited an impaired TLR2-mediated activation of BMDCs in vitro despite their ability to fully reactivate MLN cells as well as MLN-derived colitogenic T cells ex vivo. E. faecalis virulence factors accounting for bacterial adhesion to mucosal surfaces as well as intestinal barrier disruption partially contribute to colitogenic activity of E. faecalis. Beyond their well-known role in infections, cell surface-associated lipoproteins are essential structures for colitogenic activity of E. faecalis by mediating innate immune cell activation.

Adhesive, Flexible, and Fast Degradable 3D-Printed Wound Dressings with a Simple Composition.

3D printing technology has revolutionized the field of wound dressings, offering tailored solutions with mechanical support to facilitate wound closure. In addition to personalization, the intricate nature of the wound healing process requires wound dressing materials with diverse properties, such as moisturization, flexibility, adhesion, anti-oxidation and degradability. Unfortunately, current materials used in digital light processing (DLP) 3D printing have been inadequate in meeting these crucial criteria. This study introduces a novel DLP resin that is biocompatible and consists of only three commonly employed non-toxic compounds in biomaterials, that is, dopamine, poly(ethylene glycol) diacrylate, and N-vinylpyrrolidone. Simple as it is, this material system fulfills all essential functions for effective wound healing. Unlike most DLP resins that are non-degradable and rigid, this material exhibits tunable and rapid degradation kinetics, allowing for complete hydrolysis within a few hours. Furthermore, the high flexibility enables conformal application of complex dressings in challenging areas such as finger joints. Using a difficult-to-heal wound model, the manifold positive effects on wound healing in vivo, including granulation tissue formation, inflammation regulation, and vascularization are substantiated. The simplicity and versatility of this material make it a promising option for personalized wound care, holding significant potential for future translation.

Effects of shape and structure of a new 3D-printed personalized bioresorbable tracheal stent on fit and biocompatibility in a rabbit model.

To date, several types of airway stents are available to treat central airway obstructions. However, the ideal stent that can overcome anatomical, mechanical and microbiological issues is still awaited. In addition, therapeutic effect and self-elimination of these stents are desirable properties, which pose an additional challenge for development and manufacturing. We aimed to create a prototype bioresorbable tracheal stent with acceptable clinical tolerance, fit and biocompatibility, that could be tested in a rabbit model and in the future be further optimized to enable drug-elution and ensure local therapeutic effect. Twenty-one New Zealand White Rabbits received five different types of bioresorbable tracheal stents, 3D-printed from poly(D,L-lactide-co-ε-caprolactone) metacrylates. Various configurations were tested for their functionality and improved until the best performing prototype could undergo detailed in vivo assessment, regarding clinical tolerance, migration and biocompatibility. Previously tested types of 3D printed stents in our preliminary study required improvement due to several problems, mainly related to breakage, unreliable stability and/or migration within the trachea. Abandoned or refined pre-prototypes were not analyzed in a comparative way. The final best performing prototype stent (GSP2 (Group Stent Prototype 2), n = 8) allowed a transoral application mode and showed good clinical tolerance, minimal migration and acceptable biocompatibility. The good performance of stent type GSP2 was attributed to the helix-shaped surface structure, which was therefore regarded as a key-feature. This prototype stent offers the possibility for further research in a large animal model to confirm the promising data and assess other properties such as bioresorption.

Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy.

Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

Redox balance via lactate dehydrogenase is important for multiple stress resistance and virulence in Enterococcus faecalis.

Enterococcus faecalis is a highly stress resistant opportunistic pathogen. The intrinsic ruggedness of this bacterium is supposed to be the basis of its capacity to colonize the hostile environments of hospitals and to cause several kinds of infections. We show in this work that general resistance to very different environmental stresses depends on the ability of E. faecalis to maintain redox balance via lactate dehydrogenase (LDH). Furthermore, LDH-deficient mutants are less successful than the wild type at colonizing host organs in a murine model of systemic infection. Taken together, our results, as well as those previously published for Staphylococcus aureus (A. R. Richardson, S. J. Libby, and F. C. Fang, Science 319:1672-1676, 2008), identify LDH as an attractive drug target. These drugs may have additional applications, as in the fight against glycopeptide antibiotic-resistant bacteria and even cancer.

3D printed elastomers with Sylgard-184-like mechanical properties and tuneable degradability.

The 3D printing of biodegradable elastomers with high mechanical strength is of great interest for personalized medicine, but rather challenging. In this study, we propose a dual-polymer resin formulation for digital light processing of biodegradable elastomers with tailorable mechanical properties comparable to those of Sylgard-184.

Digital Light 3D Printed Bioresorbable and NIR-Responsive Devices with Photothermal and Shape-Memory Functions.

Digital light processing (DLP) 3D printing is a promising technique for the rapid manufacturing of customized medical devices with high precision. To be successfully translated to a clinical setting, challenges in the development of suitable photopolymerizable materials have yet to be overcome. Besides biocompatibility, it is often desirable for the printed devices to be biodegradable, elastic, and with a therapeutic function. Here, a multifunctional DLP printed material system based on the composite of gold nanorods and polyester copolymer is reported. The material demonstrates robust near-infrared (NIR) responsiveness, allowing rapid and stable photothermal effect leading to the time-dependent cell death. NIR light-triggerable shape transformation is demonstrated, resulting in a facilitated insertion and expansion of DLP printed stent ex vivo. The proposed strategy opens a promising avenue for the design of multifunctional therapeutic devices based on nanoparticle-polymer composites.

Light-Based Printing of Leachable Salt Molds for Facile Shaping of Complex Structures.

3D printing is a powerful manufacturing technology for shaping materials into complex structures. While the palette of printable materials continues to expand, the rheological and chemical requisites for printing are not always easy to fulfill. Here, a universal manufacturing platform is reported for shaping materials into intricate geometries without the need for their printability, but instead using light-based printed salt structures as leachable molds. The salt structures are printed using photocurable resins loaded with NaCl particles. The printing, debinding, and sintering steps involved in the process are systematically investigated to identify ink formulations enabling the preparation of crack-free salt templates. The experiments reveal that the formation of a load-bearing network of salt particles is essential to prevent cracking of the mold during the process. By infiltrating the sintered salt molds and leaching the template in water, complex-shaped architectures are created from diverse compositions such as biomedical silicone, chocolate, light metals, degradable elastomers, and fiber composites, thus demonstrating the universal, cost-effective, and sustainable nature of this new manufacturing platform.

Deletion of the glycosyltransferase bgsB of Enterococcus faecalis leads to a complete loss of glycolipids from the cell membrane and to impaired biofilm formation.

BACKGROUND: Deletion of the glycosyltransferase bgsA in Enterococcus faecalis leads to loss of diglucosyldiacylglycerol from the cell membrane and accumulation of its precursor monoglucosyldiacylglycerol, associated with impaired biofilm formation and reduced virulence in vivo. Here we analyzed the function of a putative glucosyltransferase EF2890 designated biofilm-associated glycolipid synthesis B (bgsB) immediately downstream of bgsA. RESULTS: A deletion mutant was constructed by targeted mutagenesis in E. faecalis strain 12030. Analysis of cell membrane extracts revealed a complete loss of glycolipids from the cell membrane. Cell walls of 12030ΔbgsB contained approximately fourfold more LTA, and 1H-nuclear magnetic resonance (NMR) spectroscopy suggested that the higher content of cellular LTA was due to increased length of the glycerol-phosphate polymer of LTA. 12030ΔbgsB was not altered in growth, cell morphology, or autolysis. However, attachment to Caco-2 cells was reduced to 50% of wild-type levels, and biofilm formation on polystyrene was highly impaired. Despite normal resistance to cationic antimicrobial peptides, complement and antibody-mediated opsonophagocytic killing in vitro, 12030ΔbgsB was cleared more rapidly from the bloodstream of mice than wild-type bacteria. Overall, the phenotype resembles the respective deletion mutant in the bgsA gene. Our findings suggest that loss of diglucosyldiacylglycerol or the altered structure of LTA in both mutants account for phenotypic changes observed. CONCLUSIONS: In summary, BgsB is a glucosyltransferase that synthesizes monoglucosyldiacylglycerol. Its inactivation profoundly affects cell membrane composition and has secondary effects on LTA biosynthesis. Both cell-membrane amphiphiles are critical for biofilm formation and virulence of E. faecalis.

Coordination-induced polymerization of P═C bonds leads to regular (P─C) n polycarbophosphanes.

The replacement of carbon in (C─C) n chains of polyolefins by phosphorus leads to polycarbophosphanes (P─C) n , which may possess unique chemical and physical properties. However, macromolecules with a regular (P─C) n chain have never been unambiguously identified. Here, we demonstrate that addition polymerization, a general concept to polymerize olefins, can be extended to P═C double bonds. The polymerization of monomeric 2-phosphanaphthalenes is mediated by copper(I) halides and leads to polycarbophosphanes with an M n of 14 to 34 kDa. Each phosphorus is coordinated to Cu(I), which can be easily removed. Unlike long-term durable polyolefins, the metal-free polymers depolymerize rapidly back to monomers under sunlight or ultraviolet irradiation at λ = 365 nm. The monomers can be recycled for repolymerization, demonstrating a cradle-to-cradle life cycle for polycarbophosphanes.

Continuous color tuning of single-fluorophore emission via polymerization-mediated through-space charge transfer.

Tuning emission color of molecular fluorophores is of fundamental interest as it directly reflects the manipulation of excited states at the quantum mechanical level. Despite recent progress in molecular design and engineering on single fluorophores, a systematic methodology to obtain multicolor emission in aggregated or solid states, which gives rise to practical implications, remains scarce. In this study, we present a general strategy to continuously tune the emission color of a single-fluorophore aggregate by polymerization-mediated through-space charge transfer (TSCT). Using a library of well-defined styrenic donor (D) polymers grown from an acceptor (A) fluorophore by controlled radical polymerization, we found that the solid-state emission color can be fine-tuned by varying three molecular parameters: (i) the monomer substituent, (ii) the end groups of the polymer, and (iii) the polymer chain length. Experimental and theoretical investigations reveal that the color tunability originates from the structurally dependent TSCT process that regulates charge transfer energy.

Digital light 3D printing of customized bioresorbable airway stents with elastomeric properties.

Central airway obstruction is a life-threatening disorder causing a high physical and psychological burden to patients. Standard-of-care airway stents are silicone tubes, which provide immediate relief but are prone to migration. Thus, they require additional surgeries to be removed, which may cause tissue damage. Customized bioresorbable airway stents produced by 3D printing would be highly needed in the management of this disorder. However, biocompatible and biodegradable materials for 3D printing of elastic medical implants are still lacking. Here, we report dual-polymer photoinks for digital light 3D printing of customized and bioresorbable airway stents. These stents exhibit tunable elastomeric properties with suitable biodegradability. In vivo study in healthy rabbits confirmed biocompatibility and showed that the stents stayed in place for 7 weeks after which they became radiographically invisible. This work opens promising perspectives for the rapid manufacturing of the customized medical devices for which high precision, elasticity, and degradability are sought.

Engineered Polymersomes for the Treatment of Fish Odor Syndrome: A First Randomized Double Blind Olfactory Study.

Trimethylamine (TMA) is a metabolite overtly present in patients suffering from trimethylaminuria (TMAU), a rare genetic disorder characterized by a strong "fishy" body odor. To date, no approved pharmacological treatment to sequester excess TMA on the skin of patients exists. Here, transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes are investigated for the topical removal of TMA. PI-b-PEG amphiphiles of varying chain length are synthesized and evaluated for their ability to form vesicular structures in aqueous media. The optimization of the PI/PEG ratio of transmembrane pH gradient polymersomes allows for the rapid and efficient capture of TMA both in solution and after incorporation into a topical hydrogel matrix at the pH of the skin. A subsequent double blind olfactory study reveals a significant decrease in perceived odor intensity after application of the polymersome-based formulation on artificial skin substrates that has been incubated in TMA-containing medium. This simple and novel approach has the potential to ease the burden of people suffering from TMAU.