Glucose-responsive Hydrogel Research Articles

PH- and glucose-responsive antioxidant hydrogel promotes diabetic wound healing.

Excessive oxidative stress and persistent inflammation are key factors contributing to the formation of diabetic chronic wounds. Delivering antioxidants through a microenvironment-responsive hydrogel system can effectively enhance wound healing and tissue regeneration. In this study, we developed a novel pH- and glucose-responsive hydrogel using Schiff base reaction and phenyl borate group for intelligent antioxidant release. Hyaluronic acid (HA) modified with phenylboronic acid (PBA) (HA-PBA) was oxidized to form OHA-PBA, which was then crosslinked with carboxymethyl chitosan (CMCS) and incorporated Proanthocyanidins (PA) to create an OHA-PBA/CMCS/PA (OPCP) hydrogel. The reversible nature of imine and borate groups enabled the responsive release of PA from OPCP hydrogels under acidic and high glucose conditions. The OPCP hydrogel exhibited excellent biocompatibility, suitable mechanical properties, and biodegradability. Both in vitro and in vivo results demonstrated that the OPCP hydrogel effectively reduced reactive oxygen species (ROS), suppressed inflammation, promoted vascularization, accelerated collagen deposition, and facilitated diabetic wound healing. This strategy offers novel insights into microenvironment-responsive scaffolds, highlighting the potential application of this responsive antioxidant hydrogel scaffold for chronic diabetic wound treatment.

Multifaceted Catalytic Glucose Depletion and Reactive Oxygen Species-Scavenging Nanoenzyme Composite Hydrogel for Facilitating Diabetic Bone Regeneration.

Regeneration of diabetic bone defects remains a formidable challenge due to the chronic hyperglycemic state, which triggers the accumulation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). To address this issue, we have engineered a bimetallic metal-organic framework-derived Mn@Co3O4@Pt nanoenzyme loaded with alendronate and Mg2+ ions (termed MCPtA) to regulate the hyperglycemic microenvironment and recover the osteogenesis/osteoclast homeostasis. Notably, the Mn atom substitution in the Co3O4 nanocrystalline structure could modulate the electronic structure and significantly improve the SOD/CAT catalytic activity for ROS scavenging. By integration with GOx-like Pt nanoparticles, the MCPtA achieved effective multiple cascade catalytic performance that facilitated the clearance of glucose and ROS. Furthermore, the MCPtA was encapsulated within a glucose-responsive hydrogel cross-linked via a borate ester bond, termed PAM, to evaluate the potential of the composite hydrogel for cranial defect repair in diabetic rats. The in vitro/vivo experiments as well as the RNA sequencing analysis demonstrated that the nanoenzyme composite hydrogel could disrupt the glucose-ROS-induced inflammation and promoted osteogenesis and angiogenesis, in consequence, improving the therapeutic effects for diabetic bone regeneration. This study provided crucial insights into nanoenzyme-mediated microenvironmental regulation for diabetic bone regeneration.

Enhanced glucose-responsivity of PBA–diol hydrogel networks by reducing crosslink affinity

New diol chemistries are explored for insulin delivery from glucose-responsive hydrogels comprised of dynamic-covalent crosslinking interactions between phenylboronic acids and diols.

In-situ Forming Multipolymeric Glucose-Responsive Hydrogels.

Stimuli-responsive hydrogels (HGs) have shown promise for smart drug delivery applications. Specifically, glucose-responsive HGs having phenylboronic acid (PBA) functional groups are extensively pursued for insulin delivery in hyperglycemia. Current polymeric glucose-responsive HGs are cumbersome to fabricate and show a limited insulin release profile. Herein, we develop a straightforward fabrication of glucose-responsive multipolymer HGs (MPHGs) using a three-component in situ mixing. Molecular cargo, such as insulin, was loaded during the gelation. Heterobifunctional formylphenylboronic acid (FPBA) crosslinkers were used to interconnect polyvinyl alcohol (PVA) and branched polyethyleneimine (PEI) via boronate ester and imine bonds, respectively. Three positional isomers of FPBA (2FPBA, 3FPBA, and 4FPBA) resulted in HGs with distinct viscoelastic behaviors under the same conditions. HGs derived from 4FPBA exhibited more solid-like properties compared to 2FPBA and 3FPBA due to a higher crosslinking density. All the HGs exhibited glucose-responsive dissolution and release of embedded insulin cargo without disrupting the native structure. Insulin release profiles show a higher glucose-responsive release from 4FPBA-derived MPHGs. All the HGs were injectable, self-healing, and noncytotoxic below 10 μg/ml concentrations. The MPHGs developed in this study uncover new directions in creating glucose-responsive matrices for self-regulating drug delivery applications. In the future, detailed in vivo studies will be performed for clinical applications.

Intelligent microneedle patch based on functionalized alginate and chitosan for long-term self-regulated insulin delivery

Severely diabetic patients need insulin input to maintain the body's glycemic balance. However, traditional injection methods are often associated with poor adherence and an increased risk of hypoglycemia. Microneedle technology offers a promising solution by minimizing pain and trauma during insulin administration. Nonetheless, achieving prolonged glycemic control by microneedle with high insulin loading remains a significant challenge. Herein, we introduce an innovative microneedle patch that draws inspiration from the elegant light-induced blooming of water lily petals. The patch features a glucose-responsive hydrogel network crafted from two modified polysaccharide polymers, which enables the delivery of long-acting insulin without depending on glucose oxidase. By incorporating phenylboronic acid-modified sodium alginate, quaternary ammonium chitosan, and polyvinyl alcohol into a hydrogel matrix, we have created a microneedle system that harbors dynamic borate ester linkages and electrostatic attractions, resulting in heightened sensitivity to blood glucose levels. The electrostatic interaction acts as a relatively stable crosslinking point, balancing the dynamic reproducibility response based on the borate ester bond. This self-adaptive hydrogel can regulate insulin-controlled release by responding to changes in glucose concentration. Herein, we achieved massive insulin loading (20 IU) with long lasting glycaemic control (48 h) in a single treatment of diabetic SD rats.

Smart photonic crystal hydrogels for visual glucose monitoring in diabetic wound healing

Diabetes is a global chronic disease that seriously endangers human health and characterized by abnormally high blood glucose levels in the body. Diabetic wounds are common complications which associate with impaired healing process. Biomarkers monitoring of diabetic wounds is of great importance in the diabetes management. However, actual monitoring of biomarkers still largely relies on the complex process and additional sophisticated analytical instruments. In this work, we prepared hydrogels composed of different modules, which were designed to monitor different physiological indicators in diabetic wounds, including glucose levels, pH, and temperature. Glucose monitoring was achieved based on the combination of photonic crystal (PC) structure and glucose-responsive hydrogels. The obtained photonic crystal hydrogels (PCHs) allowed visual monitoring of glucose levels in physiological ranges by readout of intuitive structural color changes of PCHs during glucose-induced swelling and shrinkage. Interestingly, the glucose response of double network PCHs was completed in 15 min, which was twice as fast as single network PCHs, due to the higher volume fraction of glucose-responsive motifs. Moreover, pH sensing was achieved by incorporation of acid-base indicator dyes into hydrogels; and temperature monitoring was obtained by integration of thermochromic powders in hydrogels. These hydrogel modules effectively monitored the physiological levels and dynamic changes of three physiological biomarkers, both in vitro and in vivo during diabetic wound healing process. The multifunctional hydrogels with visual monitoring of biomarkers have great potential in wound-related monitoring and treatment.Graphical abstract

Smart glucose-responsive hydrogel with ROS scavenging and homeostasis regulating properties for diabetic bone regeneration

Diabetic patients often suffer from delayed tissue healing and bone metabolism disorder, presenting a significant clinical challenge in the regeneration of diabetic bone defects. Hyperglycemia weakens osteogenesis and angiogenesis and destroys the balance of homeostasis. To solve this problem, a smart glucose-sensitivity sustained-release Resveratrol-loaded hydrogel platform is proposed to restore the function of mesenchymal stem cells. In this study, phenylboronic acid (PBA), known for its unique glucose sensitivity, is grafted onto the methacrylated gelatin (GelMA) chain, enabling the immobilization of Resveratrol (Res) molecules within the hybrid hydrogel through dynamic borate bond formation. Both in vivo and in vitro findings demonstrate that this hydrogel platform effectively scavenges excessive reactive oxygen species, ameliorates inflammation, modulates macrophage polarization, and enhances osteogenesis by activating the PI3K/AKT/GSK-3β signaling pathway. Collectively, all results suggest that this novel glucose-responsive hydrogel platform may be a potential therapy for diabetic bone regeneration.

A Glucose-Responsive Hydrogel Inhibits Primary and Secondary BRB Injury for Retinal Microenvironment Remodeling in Diabetic Retinopathy.

Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.

A Glucose-Responsive Hydrogel Platform Based on Poly(vinyl alcohol) for Enhanced Diabetic Wound Healing

A Glucose-Responsive Hydrogel Platform Based on Poly(vinyl alcohol) for Enhanced Diabetic Wound Healing

Glucose-Responsive hydrogel optimizing Fenton reaction to eradicate multidrug-resistant bacteria for infected diabetic wound healing

The treatment of infected diabetic wounds faces severe challenges due to vascular deficiencies induced by a hyperglycemia microenvironment and the extensive proliferation of drug-resistant bacteria. In this work, we developed a glucose-responsive hydrogel dressing system (CGH) with dual properties that effectively treat methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds in rats and enhance wound healing. The hydrogel is synthesized using copper nanoclusters (CuNCs) cross-linked with oxidized hyaluronic acid (HA-ALD) in situ and decorated with glucose oxidase (GOx). GOx enzymatically degrades excess glucose at the wound site, generating gluconic acid and H2O2, and optimizes the limiting factors of the Fenton reaction. Decreasing pH weakens the interaction between CuNCs and HA-ALD, resulting in the release of CuNCs that catalyze the production of reactive oxygen species (ROS) by degradation of H2O2 through the Fenton reaction. This process can eradicate drug-resistant bacteria. In addition, CuNCs endowed hydrogels with excellent conductivity, thus enabling the promotion of blood vessel formation by electrical stimulation (ES), thereby facilitating tissue repair around the wound area. In conclusion, the developed novel multifunctional wound healing system can conform to irregular wound shapes, reduce glucose levels within the wound, establish a sustained sterile environment, and promote blood vessel formation through electrical stimulation, thus emerging as a highly promising and comprehensive option for effectively treating complex diabetic wounds.

PH and glucose dual-responsive phenylboronic acid hydrogels for smart insulin delivery.

Phenylboronic acid (PBA) is a widely exploited glucose-sensitive element for constructing glucose-responsive hydrogels to enable smart insulin delivery. However, its relatively high intrinsic pKa affects its binding with glucose under physiological conditions and thus limits its application. Herein, we developed a series of boronate-containing PLP-PBA polymers by conjugating glucose-sensitive 3-aminophenylboronic acid (3-PBA) onto the backbone of a metabolite-derived, pH-responsive poly-L-lysine isophthalamide (PLP) polymer with a pKa value of 4.4 at various substitution degrees. Dual-responsive LME-(PLP-PBA) hydrogels were further synthesized by crosslinking the PLP-PBA polymers with L-lysine methyl ester (LME). The rheological properties and swelling ratio of the hydrogel could be manipulated by the PBA grafting degree and crosslinking ratio. With the increase of pH and glucose concentration, the pore size of the hydrogel enhanced, thus promoting the release of loaded insulin. Under physiological conditions, the hydrogel with optimal formulation could establish acute pH-responsive and glucose-responsive insulin release. The development of this dual-responsive hydrogel suggests a strategy to overcome the high pKa problem associated with PBA and provide a promising delivery system for smart insulin delivery.

Glucose-Responsive Self-Regulated Injectable Silk Fibroin Hydrogel for Controlled Insulin Delivery.

Stimuli-responsive drug delivery systems are gaining importance in personalized medicine to deliver therapeutic doses in response to disease-specific stimulation. Pancreas-mimicking glucose-responsive insulin delivery systems offer improved therapeutic outcomes in the treatment of type 1 and advanced stage of type 2 diabetic conditions. Herein, we present a glucose-responsive smart hydrogel platform based on phenylboronic acid-functionalized natural silk fibroin protein for regulated insulin delivery. The modified protein was synergistically self-assembled and cross-linked through β-sheet and phenylboronate ester formation. The dynamic nature of the bonding confers smooth injectability through the needle. The cross-linked hydrogel structures firmly hold the glucose-sensing element and insulin in its pores and contribute to long-term sensing and drug storage. Under hyperglycemic conditions, the hydrogen peroxide generated from the sensing element induces hydrogel matrix degradation by oxidative cleavage, enabling insulin release. In vivo studies in a type 1 diabetic Wistar rat model revealed that the controlled insulin release from the hydrogel restored diabetic glucose level to physiological conditions for 36 h. This work establishes the functional modification of silk fibroin into a glucose-responsive hydrogel platform for regulated and functional insulin delivery application.

Preparation of phenylboronic acid‐based glucose-responsive hydrogels and microneedles for regulated delivery of insulin

Phenylboronic acid (PBA)-based glucose-responsive microneedles that can painlessly deliver insulin and self-regulate the release of insulin according to the blood glucose levels (BGLs) have been considered promising in the treatment of diabetes. However, the reported PBA-based glucose-responsive microneedles are still faced with the challenges of complicated insulin loading process or insulin denaturation. Herein, we report a novel kind of PBA‐based glucose-responsive microneedles derived from PBA‐based glucose-responsive hydrogels. 3-fluoro-4-carboxy-phenylboronic acid-grafted polylysine (PLL-PBA) were synthesized and combined with natural guar gum (GG) to produce PLL-PBA/GG hydrogels via the phenylboronate ester bonds formed between the FCPBA groups on PLL-PBA and the diols on GG. The resulting hydrogels could regulate the release amount of insulin according to the glucose concentrations based on the glucose-induced disintegration mechanism. The PLL-PBA/GG microneedles were prepared via micro-mold casting method using the hydrogels as the precursors. Due to the simple and mild preparation conditions of the microneedles, the bioactivity of insulin was greatly preserved. The microneedles had uniform morphology, moderate skin penetration ability as well as good glucose-responsive insulin release capability. In animal experiments, the PLL-PBA/GG microneedles demonstrated BGLs lowering and maintain performance via glucose-responsive transdermal insulin delivery.

A High-Linearity Glucose Sensor Based on Silver-Doped Con A Hydrogel and Laser Direct Writing

A continuous glucose monitoring (CGM) system is an ideal monitoring system for the blood glucose control of diabetic patients. The development of flexible glucose sensors with good glucose-responsive ability and high linearity within a large detection range is still challenging in the field of continuous glucose detection. A silver-doped Concanavalin A (Con A)-based hydrogel sensor is proposed to address the above issues. The proposed flexible enzyme-free glucose sensor was prepared by combining Con-A-based glucose-responsive hydrogels with green-synthetic silver particles on laser direct-writing graphene electrodes. The experimental results showed that in a glucose concentration range of 0-30 mM, the proposed sensor is capable of measuring the glucose level in a repeatable and reversible manner, showing a sensitivity of 150.12 Ω/mM with high linearity of R2 = 0.97. Due to its high performance and simple manufacturing process, the proposed glucose sensor is excellent among existing enzyme-free glucose sensors. It has good potential in the development of CGM devices.

Advances in the Design of Phenylboronic Acid-Based Glucose-Sensitive Hydrogels.

Diabetes, characterized by an uncontrolled blood glucose level, is the main cause of blindness, heart attack, stroke, and lower limb amputation. Glucose-sensitive hydrogels able to release hypoglycemic drugs (such as insulin) as a response to the increase of the glucose level are of interest for researchers, considering the large number of diabetes patients in the world (537 million in 2021, reported by the International Diabetes Federation). Considering the current growth, it is estimated that, up to 2045, the number of people with diabetes will increase to 783 million. The present work reviews the recent developments on the hydrogels based on phenylboronic acid and its derivatives, with sensitivity to glucose, which can be suitable candidates for the design of insulin delivery systems. After a brief presentation of the dynamic covalent bonds, the design of glucose-responsive hydrogels, the mechanism by which the hypoglycemic drug release is achieved, and their self-healing capacity are presented and discussed. Finally, the conclusions and the main aspects that should be addressed in future research are shown.

Glucose-Responsive Boronic Acid Hydrogel Thin Films Obtained via Initiated Chemical Vapor Deposition.

Glucose-responsive materials are of great importance in the field of monitoring the physiological glucose level or smart insulin management. This study presents the first vacuum-based deposition of a glucose-responsive hydrogel thin film. The successful vacuum-based synthesis of a glucose-responsive hydrogel may open the door to a vast variety of new applications, where, for example, the hydrogel thin film is applied on new possible substrates. In addition, vacuum-deposited films are free of leachables (e.g., plasticizers and residual solvents). Therefore, they are, in principle, safe for in-body applications. A hydrogel made of but-3-enylboronic acid units, a boronic acid compound, was synthesized via initiated chemical vapor deposition. The thin film was characterized in terms of chemical composition, surface morphology, and swelling response toward pH and sucrose, a glucose–fructose compound. The film was stable in aqueous solutions, consisting of polymerized boronic acid and the initiator unit, and had an undulating texture appearance (rms 2.1 nm). The hydrogel was in its shrunken state at pH 4–7 and swelled by increasing the pH to 9. The pKa was 8.2 ± 0.2. The response to glucose was observed at pH 10 and resulted in thickness shrinking.

A responsive hydrogel-based microneedle system for minimally invasive glucose monitoring

Blood glucose (BG) monitoring in patients with diabetes is critical for diabetes management. Minimally invasive BG monitoring is urgently required to increase the patient compliance. Herein, based on a responsive hydrogel system, we developed a smart microneedle patch system for minimally invasive glucose monitoring. The patch consisted of a transparent substrate of photocurable resin and microneedles made of a pH-responsive and glucose-responsive hydrogel. The responsive hydrogel was composed of a photocrosslinkable hydrogel of gelatin methacrylate (GelMA) together with a pH-responsive nanogel (nano(CMC-pHEA)) and glucose oxidase (GOx). The composite hydrogel showed fast response and high sensitivity to glucose levels in physiological range, mainly due to the ionization of CMC-pHEA component and proton balance. The microneedles showed sufficient mechanical strength to penetrate the skin of mice with minimal invasion, and achieved in situ extraction of glucose in interstitial fluid (ISF) and in situ glucose-responsive reaction. We demonstrated the rapid glucose monitoring by microneedle patch system in skin-mimicking gels in vitro and in diabetic mice in vivo. The microneedles quickly and sensitively responded to glucose concentrations, allowed quantitative readouts of glucose levels through the changes of microneedle heights and swelling ratios. Moreover, the readouts in mice in vivo were consistent with BG levels measured by glucometer. This smart microneedle system has potentials to replace blood sampling, and minimize patient discomfort during BG testing, therefore has potentials in minimally invasive, rapid and reliable BG monitoring.

Repurposing pinacol esters of boronic acids for tuning viscoelastic properties of glucose-responsive polymer hydrogels: effects on insulin release kinetics.

In the era of the diabetes pandemic, injectable hydrogels (HGs) capable of releasing the desired amount of insulin under hyperglycemic conditions will significantly advance smart insulin development. Several smart boronic acid-based polymer HGs release insulin under high-glucose conditions. However, the correlation of insulin release characteristics with rheological properties is not well understood yet. Herein, we report a generalized and facile fabrication strategy of a new class of glucose-responsive hydrogels by crosslinking a biocompatible polymer, poly(vinyl alcohol) with pinacol esters of bisboronic acids via transesterification reactions. We show the versatility of the method by fabricating four hydrogels with diverse rheological properties. The HGs embody more than 70% water amenable for hosting insulin in the matrix. HG with high storage modulus, derived from 1,4-benzenediboronic acid bis(pinacol) ester releases ∼3 fold less insulin compared to softer HGs derived from acetylene-1,2-diyl bis(boronic acid pinacol ester) and bis[(pinacolato)boryl]methane under hyperglycemic conditions. We find that HG derived from the bis[(pinacolato)boryl]methane crosslinker exhibits superior insulin release properties due to the softness of the hydrogel matrix. We further show that the newly formulated gel is injectable without any structural change in the released insulin molecules and does not cause cytotoxicity. We believe that glucose-responsive hydrogels with tunable viscoelastic properties will pave the way for developing a variety of hydrogels with programmable insulin release properties.

Wearable Bifocal Contact Lens for Continual Glucose Monitoring Integrated with Smartphone Readers.

Commercial implantable continuous glucose monitoring devices are invasive and discomfort. Here, a minimally-invasive glucose detection system is developed to provide quantitative glucose measurements continually based on bifocal contact lenses. A glucose-sensitive phenylboronic acid derivative is immobilized in a hydrogel matrix and the surface of the hydrogel is imprinted with a Fresnel lens. The glucose-responsive hydrogel is attached to a commercial soft contact lens to be transformed into a bifocal contact lens. The contact lens showed bifocal lengths; far-field focal length originated from the contact lens' curvature, and near-field focal length resulting from the Fresnel lens. When tear glucose increased, the refractive index and groove depth of the Fresnel lens changed, shifting the near-field focal length and the light focusing efficiency. The recorded optical signals are detected at an identical distance far from the contact lens change. The bifocal contact lens allowed for detecting the tear glucose concentration within the physiological range of healthy individuals and diabetics (0.0-3.3mm). The contact lens rapidly responded to glucose concentration changes and reached 90% of equilibrium within 40min. The bifocal contact lens is a wearable diagnostic platform for continual biomarker detection at point-of-care settings.

Cross-Linking-Density-Changeable Microneedle Patch Prepared from a Glucose-Responsive Hydrogel for Insulin Delivery.

To simplify the preparation process of a glucose-responsive microneedle patch, a cross-linking-density changeable microneedle patch was designed. The microneedle patch was made up of a hydrogel formed by phenylboronic acid-grafted polyallylamine and poly(vinyl alcohol) (PVA). The gel was cross-linked by boronate ester bonds between phenylboronic acid groups and PVA. It still had fluidity and could be filled into a mold to prepare microneedle patches. Moreover, insulin could be directly loaded into the microneedle patch by mixing with the gel. The boronate ester bond would be broken in the presence of glucose, resulting in a decrease in the cross-linking density. Therefore, the gel could achieve a greater swelling degree and insulin could be released faster. In addition, PVA chains were crystallized by repeatedly freezing and thawing to improve the mechanical strength of the microneedle patch. In terms of glucose-dependent insulin release, the gel showed good glucose-responsive insulin-release ability. Through additional ion cross-linking, the microneedle patch could also control the insulin release according to glucose concentration. In the hypoglycemic experiment of diabetic rats, the microneedle patch effectively pierced the skin and slowly released insulin.