Glucose-Triggered Gelation of Supramolecular Peptide Nanocoils with Glucose-Binding Motifs.

Peptide self-assembly is a powerful tool to prepare functional materials at the nanoscale. Often, the resulting materials have high aspect-ratio, with intermolecular ß-sheet formation underlying 1D fibrillar structures. Inspired by dynamic structures in nature, peptide self-assembly is increasingly moving toward stimuli-responsive designs wherein assembled structures are formed, altered, or dissipated in response to a specific cue. Here, a peptide bearing a prosthetic glucose-binding phenylboronic acid (PBA) is demonstrated to self-assemble into an uncommon nanocoil morphology. These nanocoils arise from antiparallel ß-sheets, with molecules aligned parallel to the long axis of the coil. The binding of glucose to the PBA motif stabilizes and elongates the nanocoil, driving entanglement and gelation at physiological glucose levels. The glucose-dependent gelation of these materials is then explored for the encapsulation and release of a therapeutic agent, glucagon, that corrects low blood glucose levels. Accordingly, the release of glucagon from the nanocoil hydrogels is inversely related to glucose level. When evaluated in a mouse model of severe acute hypoglycemia, glucagon delivered from glucose-stabilized nanocoil hydrogels demonstrates increased protection compared to delivery of the agent alone or within a control nanocoil hydrogel that is not stabilized by glucose.

Diboronate crosslinking: Introducing glucose specificity in glucose-responsive dynamic-covalent networks.

Dynamic-covalent motifs are increasingly used for hydrogel crosslinking, leveraging equilibrium-governed reversible bonds to prepare viscoelastic materials with dynamic properties and self-healing character. The bonding between aryl boronates and diols is one dynamic-covalent chemistry of interest. The extent of network crosslinking using this motif may be subject to competition from ambient diols such as glucose; this approach has long been explored for glucose-directed release of insulin to control diabetes. However, the majority of such work has used phenylboronic acids (PBAs) that suffer from low-affinity glucose binding, limiting material responsiveness. Moreover, many PBA chemistries also bind with higher affinity to certain non-glucose analytes like fructose and lactate than they do to glucose, limiting their specificity of sensing and therapeutic deployment. Here, dynamic-covalent hydrogels are prepared that, for the first time, use a new diboronate motif with enhanced glucose binding-and importantly improved glucose specificity-leveraging the ability of rigid diboronates to simultaneously bind two sites on a single glucose molecule. Compared to long-used PBA-based approaches, diboronate hydrogels offer more glucose-responsive insulin release that is minimally impacted by non-glucose analytes. Improved responsiveness translates to more rapid blood glucose correction in a rodent diabetes model. Accordingly, this new dynamic-covalent crosslinking chemistry is useful in realizing more sensitive and specific glucose-responsive materials.

Glucose-Fueled Peptide Assembly: Glucagon Delivery via Enzymatic Actuation.

Nature achieves remarkable function from the formation of transient, nonequilibrium materials realized through continuous energy input. The role of enzymes in catalyzing chemical transformations to drive such processes, often as part of stimuli-directed signaling, governs both material formation and lifetime. Inspired by the intricate nonequilibrium nanostructures of the living world, this work seeks to create transient materials in the presence of a consumable glucose stimulus under enzymatic control of glucose oxidase. Compared to traditional glucose-responsive materials, which typically engineer degradation to release insulin under high-glucose conditions, the transient nanofibrillar hydrogel materials here are stabilized in the presence of glucose but destabilized under conditions of limited glucose to release encapsulated glucagon. In the context of blood glucose control, glucagon offers a key antagonist to insulin in responding to hypoglycemia by signaling the release of glucose stored in tissues so as to restore normal blood glucose levels. Accordingly, these materials are evaluated in a prophylactic capacity in diabetic mice to release glucagon in response to a sudden drop in blood glucose brought on by an insulin overdose. Delivery of glucagon using glucose-fueled nanofibrillar hydrogels succeeds in limiting the onset and severity of hypoglycemia in mice. This general strategy points to a new paradigm in glucose-responsive materials, leveraging glucose as a stabilizing cue for responsive glucagon delivery in combating hypoglycemia. Moreover, compared to most fundamental reports achieving nonequilibrium and/or fueled classes of materials, the present work offers a rare functional example using a disease-relevant fuel to drive deployment of a therapeutic.

Temperature-Responsive Supramolecular Hydrogels by Ternary Complex Formation with Subsequent Photo-Cross-linking to Alter Network Dynamics.

Supramolecular hydrogels prepared from host-guest physical cross-linking of polymers have versatile utility in a number of applications. Routes to integrate stimuli-responsive features in these materials are intended to add another dimension to enhance their functionality. Herein, a guest which forms a homoternary complex with the cucurbit[8]uril macrocycle was appended to the ends of Pluronic F-127 polymers. This polymer undergoes temperature-responsive micelle formation, upon which CB[8] promotes their physical cross-linking via its host-guest interactions with the appended guests yielding a percolated hydrogel network. The particular guests used to form the homoternary complex can further be photo-dimerized to replace the physical host-guest interaction with a covalently bonded interaction. This change results in a reduction in hydrogel dynamics of roughly 2 orders of magnitude, yet temperature-responsive gelation and overall network architecture remain apparently unchanged. Hydrogels composed of micelles cross-linked by both supramolecular and photo-dimerized interactions support the injection and encapsulation of cells and enable inclusion and release of macromolecular payloads in vitro and in vivo. Thus, this approach points to a strategy to integrate external stimuli into supramolecular hydrogels through a combination of responsive polymers and light-directed supramolecular motifs.

Recent progress of glycopolymer synthesis for biomedical applications.

Glycopolymers are an important class of biomaterials which include carbohydrate moieties in their polymer structure. In addition to biological research on the interactions of glycopolymers with lectin-carbonate, glycopolymers have recently been used as a new synthetic biomaterial for direct therapeutic methods, medical adhesives, and biosensors. Thus, a comprehensive understanding of new advances in glycopolymer research is essential for the next level of biomaterial studies. This review article highlights commonly used glycopolymer synthesis methods and biomedical applications thereof. Glycopolymers can be synthesized by modern polymerization methods that can control the molecular weight, molecular weight distribution, chemical functionality, and polymer architecture. The polymerizations include free radical polymerization, atom transfer radical polymerization, reversible addition-fragmentation chain-transfer polymerization, and nitroxide-mediated polymerization. Because the carbohydrate-lectin interactions with glycopolymers are involved in many biological processes, carbohydrates containing glycopolymers are used in (1) fundamental studies to understand the specificity and strength of biological binding, (2) controllable interactions to prevent microorganism adhesion to human cells, (3) large scale bulk adhesives for medical applications, (4) biocompatible therapeutic nanoparticles, (5) direct drug delivery vehicles, and (6) precise quantitative measurement of biosensor materials that can detect physiological signals.

Single-Phase Photo-Cross-Linkable Bioinspired Adhesive for Precise Control of Adhesion Strength.

A bioinspired, modular terpolymer adhesive, poly(N-methacryloyl-3,4-dihydroxyl-l-phenylalanine-co-9-(acryloyloxy)butyl anthracene-9-carboxylate-co-acrylic acid), has been synthesized containing three different functionalities: a photo-cross-linking segment, a wet interfacial adhesion segment, and a water-soluble segment. The synthesized adhesive polymer is the first example of a single-phase, photo-cross-linkable adhesive which does not require additional photoinitiator or other cross-linking agents. The terpolymer demonstrates strong adhesion when it swells in water and/or ethanol. The terpolymer is composed of three repeating units: N-methacryloyl-3,4-dihydroxyl-l-phenylalanine (MDOPA), which has been known to generate strong adhesion under wet conditions, poly(acrylic acid), which has been known to increase water solubility of polymers, and a photo-cross-linking segment consisting of an anthracene-based monomer used for enhancement of cohesion properties via UV irradiation (352 nm). A photomediated [4 + 4] cycloaddition reaction of anthracene results in the cross-linking of individual polymer chains after interfacial adhesion between substrates and adhesive polymers. Chemically, the covalent photo-cross-linking was confirmed by UV-vis, 1H NMR, and gel permeation chromatography (GPC). The cross-linking-fortified cohesion of the adhesive polymer network yields strengthened cohesion properties of the bulk material. The photoreaction was conveniently controlled via the duration of UV-irradiation. The adhesion properties of new adhesives were characterized by lap shear strength on transparent Mylar film and glasses after the adhesive was swollen in biologically friendly solvents including water and ethanol. The adhesion strength (J/m2) was enhanced by 850% under 352 nm UV-irradiation. Multiple application variables were tested to determine the optimal conditions, such as solvent, concentration, polymer composition, and substrate. The best adhesion properties were obtained from a 1:1 weight ratio of polymer:solvent in water on a Mylar film surface. As a single-phase system, the synthesized terpolymer is very convenient to use, and its adhesion strength can be easily modified by UV light. Additionally, the terpolymer's high water compatibility makes it ideally suited for application in the biomedical field.

POSS-Containing Bioinspired Adhesives with Enhanced Mechanical and Optical Properties for Biomedical Applications.

A new terpolymer adhesive, poly(2-methoxyethyl acrylate-co-N-methacryloyl 3,4-dihydroxyl-l-phenylalanine-co-heptaisobutyl substituted polyhedral oligomeric silsesquioxane propyl methacrylate) (poly(MEA-co-MDOPA-co-MPOSS) was synthesized by thermally initiated radical polymerization. In this study, we investigated the effect of the POSS component on adhesion, mechanical, and optical properties of the catechol-group containing bioinspired adhesives. The terpolymer contains the catechol group which is known to improve the adhesion properties of polymers. Only a very small amount of the POSS-containing monomer, MPOSS, was included, 0.5 mol %. In the presence of POSS, the synthesized poly(MEA-co-MDOPA-co-MPOSS) demonstrated strong adhesion properties, 23.2 ± 6.2 J/m2 with 0.05 N preloading and 300 s holding time, compared to many previously prepared catechol-containing adhesives. The mechanical properties (Young's modulus and stress at 10% strain) of the POSS-containing terpolymer showed significant increases (6-fold higher) over the control polymer, which does not contain POSS. Optical transmittance of the synthesized terpolymer was also improved significantly in the visible light range, 450-750 nm. Cell testing with human embryonic kidney cells (HEK293A) indicates that the new terpolymer is a promising candidate in biomedical adhesives without acute cytotoxicity. The synthesized poly(MEA-co-MDOPA-co-MPOSS) is the first example of POSS-containing pressure sensitive bioinspired adhesive for biomedical applications. The study of poly(MEA-co-MDOPA-co-MPOSS) demonstrated a convenient method to enhance two important properties, mechanical and optical properties, by the addition of a very small amount of POSS. Based on this study, it was found that POSS can be used to strengthen mechanical properties of bioinspired adhesive without the need for a covalent cross-linking step.