Acid-based Hydrogel Research Articles

Preparation of a novel hyaluronic acid-based separable hydrogel microneedle with niacinamide to treat pigment deposition using solvent-free solid-state crosslinking method

With the increase in age and prolonged exposure to ultraviolet radiation, especially on the face, pigment deposition often has a negative impact on individuals physically and emotionally. In order to address this issue, a solvent-free solid-state crosslinked hyaluronic acid (HA)-based separable hydrogel microneedle (SHMN) was developed by combining the advantages of hydrogel microneedle and soluble microneedle. This microneedle could separate the needle tip from the backing within five minutes and had the advantage of slow drug release. Hydrogel microneedle tips were prepared by solid-state crosslinking method of HA and poly (methyl vinyl ether)-maleic acid (GAN) for the first time. This crosslinking method without the need for dialysis or the addition of organic solvents, making it a safer, more reliable, and significantly time-saving process compared to previous methods. The soluble material polyvinylpyrrolidone (PVP) was selected as the root and backing of the microneedle. When the microneedle penetrated the skin and contacted with interstitial fluid, the bottom of the microneedle dissolved, and the tip of hydrogel loaded with drugs was separated from the shaft. In addition, the microneedle patch has high drug loading and excellent mechanical properties, which can meet the effective treatment of skin pigmentation.

One Stone Three Birds: Silver Sulfadiazine Modulates the Stability and Dynamics of Hydrogels for Infected Wound Healing.

Dynamic covalent bond hydrogels have demonstrated significant application potential in biomedical fields for their dynamic reversibility. However, the contradiction between the stability and dynamics of the hydrogel restricts its application. Here, utilizing silver sulfadiazine (AgSD) as a catalyst, hyaluronic acid-based hydrogels are constructed through imine bond crosslinking and incorporated disulfide bonds within the same crosslinking chain. It is found that AgSD can accelerate the formation of imine crosslinking bonds to improve the stability of hydrogels, thereby shortening the gelation time by ≈36.9 times, enhancing compression strength and adhesion strength by ≈2.4 times and 1.7 times, respectively, while inhibiting swelling and degradation rates to ≈2.1 times and 3.7 times. Besides, AgSD can coordinate with disulfide bonds to enhance the dynamics of hydrogel, enhancing the hydrogel self-healing efficiency by ≈2.3 times while reducing the relaxation time by ≈25.1 times. Significantly, AgSD imparts remarkable antibacterial properties to the hydrogel, thereby effectively facilitating the healing of bacterial infected wounds. Consequently, introducing AgSD enables hydrogels to possess concurrent stability, dynamics, and antibacterial properties. This strategy of regulating hydrogels by introducing AgSD provides a valuable reference for the application of dynamic covalent bonds.

Hyaluronic acid hydrogels with excellent self-healing capacity and photo-enhanced mechanical properties for wound healing

A continuously stable moist healing environment is immensely beneficial for wound healing, which can be availably achieved by providing an in situ hydrogel with enough strength resembling skin tissue and self-healing ability. Herein, through a dual-crosslinking strategy, hyaluronic acid-based hydrogels with excellent self-healing capacity and enhanced mechanical properties are fabricated via the acylhydrazone linkages and subsequent photocrosslinking based on hydrazide-modified sodium hyaluronate and aldehyde-modified maleic sodium hyaluronate. The hydrogels demonstrate the fast gelation process (< 1 min), the controlled swelling behaviors, and the good biocompatibility. Notably, they possess enhanced mechanical strength similar to the human dermis (∼ 2.2 kPa). Also, they can self-heal rapidly with a self-healing efficiency of ∼90 % at 6 h. Based on this, the hyaluronic acid-based hydrogels, without any biological factors involved, can facilitate the full-thickness skin wound reconstruction process by accelerating the three phases of the wound repair, including reducing wound inflammation in the inflammatory phase, promoting angiogenesis in the proliferative phase, and promoting the deposition and reconstruction of collagen in the remodeling phase. The produced hyaluronic acid hydrogel can serve as an ideal candidate for wound healing.

Abstract 4268: Engineered hydrogel elucidates contributions of matrix mechanics to pathobiology of adenocarcinoma and identify matrix-activated therapeutic targets

Abstract Dysregulation of the extracellular matrix (ECM) properties disturbs tissue homeostasis and contributes to pathological conditions, such as cancer. Recent studies have demonstrated that ECM stiffening is associated with metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. This underscores a compelling need to develop a physiologically-relevant 3D culture model to enable the study of the independent contribution of matrix stiffness to the initiation and progression of esophageal adenocarcinoma (EAC). Such a model will then serve as a platform for pre-clinical drug screening in the context of matrix properties. In this context, we have engineered a hyaluronic acid-based 3D hydrogel platform that supports the growth and differentiation of patient-derived Barrett’s esophagus (BE) organoids, a precursor to EAC, as well as patient-derived EAC organoids. The engineered biomaterial 3D platform allows control over matrix stiffness to better recapitulate the mechanically dynamic esophageal cancer microenvironment and help identify therapeutic targets in EAC.Our data demonstrates that BE and EAC organoid density, growth and proliferation can be controlled by matrix stiffness. RNA sequencing data show that increased matrix stiffness promotes changes in the transcriptional profiles of BE and EAC organoids, revealing enrichment of pathways associated with tumorigenesis and disease progression. Furthermore, we demonstrate through molecular and functional assays that increased matrix stiffness endows stem-like properties to the EAC organoids via Yap-Sox9 mechano-activation. Finally, targeted therapy studies in our in vitro and in vivo engineered environments revealed that Yap inhibition regressed the effects of increased matrix stiffness in EAC organoids. In summary, our data suggest that matrix mechanics have a significant role in activation of EAC-associated signaling pathways in patient-derived BE and EAC organoids. We also demonstrate that the engineered hydrogel serves as a platform to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic matrix mechanics in EAC. Together, these studies establish an engineered patient-derived organoid culture platform that can be used to elucidate underlying matrix-mediated mechanisms of the metaplasia-dysplasia-adenocarcinoma sequence and inform the development of novel therapeutics that target ECM stiffness in EAC. FUNDING SOURCES: NCI P01CA098101, U54 CA163004 and NIDDK K01 DK133620. Citation Format: Ricardo Cruz-Acuna, Secunda W. Kariuki, Kensuke Sugiura, Spyros Karaiskos, Eleanor M. Plaster, Claudia Loebel, Gizem Efe, Tatiana Karakasheva, Joel T. Gabre, Jianhua Hu, Jason A. Burdick, Anil K. Rustgi. Engineered hydrogel elucidates contributions of matrix mechanics to pathobiology of adenocarcinoma and identify matrix-activated therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4268.

A nano-composite hyaluronic acid-based hydrogel efficiently antibacterial and scavenges ROS for promoting infected diabetic wound healing

Diabetic wound infection brings chronic pain to patients and the therapy remains a crucial challenge owing to the disruption of the internal microenvironment. Herein, we report a nano-composite hydrogel (ZnO@HN) based on ZnO nanoparticles and a photo-trigging hyaluronic acid which is modified by o-nitrobenzene (NB), to accelerate infected diabetic wound healing. The diameter of the prepared ZnO nanoparticle is about 50 nm. X-ray photoelectron spectroscopy (XPS) analysis reveals that the coordinate bond binds ZnO in the hydrogel, rather than simple physical restraint. ZnO@HN possesses efficient antioxidant capacity and it can scavenge DPPH about 40 % in 2 h and inhibit H2O2 >50 % in 8 h. The nano-composite hydrogel also exhibits satisfactory antibacterial capacity (58.35 % against E. coli and 64.03 % against S. aureus for 6 h). In vitro tests suggest that ZnO@HN is biocompatible and promotes cell proliferation. In vivo experiments reveal that the hydrogel can accelerate the formation of new blood vessels and hair follicles. Histological analysis exhibits decreased macrophages, increased myofibroblasts, downregulated TNF-α expression, and enhanced VEGFA expression during wound healing. In conclusion, ZnO@HN could be a promising candidate for treating intractable infected diabetic skin defection.

Physically and Chemically Crosslinked Hyaluronic Acid-Based Hydrogels Differentially Promote Axonal Outgrowth from Neural Tissue Cultures.

Our aim was to investigate axonal outgrowth from different tissue models on soft biomaterials based on hyaluronic acid (HA). We hypothesized that HA-based hydrogels differentially promote axonal outgrowth from different neural tissues. Spinal cord sliced cultures (SCSCs) and dorsal root ganglion cultures (DRGCs) were maintained on a collagen gel, a physically crosslinked HA-based hydrogel (Healon 5®) and a novel chemically crosslinked HA-based hydrogel, with or without the presence of neurotrophic factors (NF). Time-lapse microscopy was performed after two, five and eight days, where axonal outgrowth was assessed by automated image analysis. Neuroprotection was investigated by PCR. Outgrowth was observed in all groups; however, in the collagen group, it was scarce. At the middle timepoint, outgrowth from SCSCs was superior in both HA-based groups compared to collagen, regardless of the presence of NF. In DRGCs, the outgrowth in Healon 5® with NF was significantly higher compared to the rest of the groups. PCR revealed upregulation of NeuN gene expression in the HA-based groups compared to controls after excitotoxic injury. The differences in neurite outgrowth from the two different tissue models suggest that axons differentially respond to the two types of biomaterials.

Injectable, self-healing hyaluronic acid-based hydrogels for spinal cord injury repair

The cystic cavity that develops following spinal cord injury is a major obstacle for repairing spinal cord injury (SCI). The injectable self-healing biomaterials treatment is a promising strategy to enhance tissue repair after traumatic spinal cord injury. Herein, a natural extracellular matrix (ECM) biopolymer hyaluronic acid-based hydrogel was developed based on multiple dynamic covalent bonds. The hydrogels exhibited excellent injectable and self-healing properties, could be effectively injected into the injury site, and filled the lesion cavity to accelerate the tissue repair of traumatic SCI. Moreover, the hydrogels were compatible with cells and various tissues and possessed proper stiffness matched with nervous tissue. Additionally, when implanted into the injured spinal cord site, the hyaluronic acid-based hydrogel promoted axonal regeneration and functional recovery by accelerating remyelination, axon regeneration, and angiogenesis. Overall, the injectable self-healing hyaluronic acid-based hydrogels are ideal biomaterials for treating traumatic SCI.

Gallic Acid-Based Hydrogels for Phloretin Intestinal Release: A Promising Strategy to Reduce Oxidative Stress in Chronic Diabetes.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia caused by abnormalities in insulin secretion and/or action. In patients with diabetes, complications such as blindness, delayed wound healing, erectile dysfunction, renal failure, heart disease, etc., are generally related to an increase in ROS levels which, when activated, trigger hyperglycemia-induced lesions, inflammation and insulin resistance. In fact, extensive cell damage and death occurs mainly due to the effect that ROS exerts at the level of cellular constituents, causing the deterioration of DNA and peroxidation of proteins and lipids. Furthermore, elevated levels of reactive oxygen species (ROS) and an imbalance of redox levels in diabetic patients produce insulin resistance. These destructive effects can be controlled by the defense network of antioxidants of natural origin such as phloretin and gallic acid. For this reason, the objective of this work was to create a nanocarrier (hydrogel) based on gallic acid containing phloretin to increase the antioxidant effect of the two substances which function as fundamental for reducing the mechanisms linked to oxidative stress in patients suffering from chronic diabetes. Furthermore, since the bioavailability problems of phloretin at the intestinal level are known, this carrier could facilitate its release and absorption. The obtained hydrogel was characterized using Fourier transform infrared spectroscopy (FT-IR). Its degree of swelling (a%) and phloretin release were tested under pH conditions simulating the gastric and intestinal environment (1.2, 6.8 and 7.4). The antioxidant activity, inhibiting lipid peroxidation in rat liver microsomal membranes induced in vitro by a free radical source, was evaluated for four hours. All results showed that gallate hydrogel could be applied for releasing intestinal phloretin and reducing the ROS levels.

Bioadhesive Hyaluronic Acid-Based Hydrogels for Spinal Cord Injury.

Spinal cord injuries (SCI) have devastating physical, psychological, and psychosocial consequences for patients. One challenge of nerve tissue repair is the lack of a natural extracellular matrix (ECM) that guides the regenerating axons. Hyaluronic acid (HA) is a major ECM component and plays a fundamental role in facilitating lesion healing. Herein, we developed HA-based adhesive hydrogels by modification of HA with dopamine, a mussel-inspired compound with excellent adhesive properties in an aqueous environment. The hydrogels were loaded with the anti-inflammatory drug ibuprofen and the response of neuronal cells (SH-SY5Y) was evaluated in terms of viability, morphology, and adhesion. The obtained results suggested that the developed materials can bridge lesion gaps, guide axonal growth, and simultaneously act as a vehicle for the delivery of bioactive compounds.

Modulating the release of bioactive molecules of human mesenchymal stromal cell secretome: Heparinization of hyaluronic acid-based hydrogels

An amine derivative of hyaluronic acid (HA) was crosslinked to obtain a 3D dried sponge. The sponge was subsequently rehydrated using secretome from human mesenchymal stromal cells (MSCs), resulting in the formation of a hydrogel. The release kinetics analysis demonstrated that the hydrogel effectively sustained secretome release, with 70% of the initially loaded wound-healing-associated cytokines being released over a 12-day period. Tuning the hydrogel properties through heparin crosslinking resulted in a biomaterial with a distinct mechanism of action. Specifically, the presence of heparin enhanced water uptake capacity of the hydrogel and increased its sensitivity to enzymatic degradation. Notably, the heparin crosslinking also led to a significant retention of cytokines within the hydrogel matrix. Overall, the secretome-rehydrated HA hydrogel holds promise as a versatile device for regenerative medicine applications: the non-heparinized hydrogel may function as a biomaterial with low reabsorption rates, sustaining the release of bioactive molecules contained in MSC secretome. In contrast, the heparinized hydrogel may serve as a depot of bioactive molecules with faster reabsorption rates. Given its patch-like characteristic, the HA-based hydrogel appears suitable as topical treatment for external organs, such as the skin.

Effect of Amino Acid Types on the Mechanical and Antimicrobial Properties of Amino Acid-Based Polyionic Liquid Hydrogels.

Polyionic liquid hydrogels attract increasing attention due to their unique properties and potential applications. However, research on amino acid-based polyionic liquid hydrogels is still in its infancy stage. Moreover, the effect of amino acid types on the properties of hydrogels is rarely studied to date. In this work, amino acid-based polyionic liquid hydrogels (D/L-PCAA hydrogels) are synthesized by copolymerizing vinyl choline-amino acid ionic liquids and acrylic acids using Al3+ as a crosslinking agent and bacterial cellulose (BC) as a reinforcing agent. The effects of amino acid types on mechanical and antimicrobial properties are systematically investigated. D-arginine-based hydrogel (D-PCArg) shows the highest tensile strength (220.7 KPa), D-phenylalanine-based hydrogel (D-PCPhe) exhibits the highest elongation at break (1346%), and L-aspartic acid-based hydrogel (L-PCAsp) has the highest elastic modulus (206.9 KPa) and toughness (1.74MJ m-3). D/L-PCAsp hydrogels demonstrate stronger antibacterial capacity against Escherichia coli and Staphylococcus aureus, and D/L-PCPhe hydrogels possess higher antifungal activity against Cryptococcus neoformans. Moreover, the resultant hydrogels exhibit prominent hemocompatibility and low toxicity, as well as excellent self-healing capabilities (86%) and conductivity (2.8 S m-1). These results indicate that D/L-PCAA hydrogel provides a promise for applications in wound dressings.

An Intrinsic Self-Healable, Anti-Freezable and Ionically Conductive Hydrogel for Soft Ionotronics Induced by Imidazolyl Cross-Linker Molecules Anchored with Dynamic Disulfide Bonds.

Hydrogels are ideal materials for flexible electronic devices based on their smooth ion channels and considerable mechanical flexibility. A substantial volume of aqueous solution is required to enable the smooth flow of ions, resulting in the agony of low-temperature freezing; besides, long-term exposure to bending/tensile tress triggers fatigue issues. Therefore, it is a great challenge to prepare hydrogels with both freeze-resistance and long-term durability. Herein, a polyacrylic acid-based hydrogel with both hydrophobic interaction and dynamic reversible covalent bonding cross-linking networks is preparing (DC-hydrogel) by polymerizing a bi-functional imidazole-type ionic liquid monomer with integrated disulfide and alkene bonds (DS/DB-IL) and an octadecyl methacrylate, achieving self-healing. The DS/DB-IL anchored into the polymer backbone has a high affinity with water, reducing the freezing point of water, while the DS/DB-IL with free ions provides superior ionic conductivity to the DC-hydrogel. The polyacrylic acid with abundant carboxyl gives hydrogel good self-adhesiveness to different substrates. Ionotronics with resistance-type sensors with stable output performance are fabricated and explored its application to joint motion and health information. Moreover, hydrogel-based sensing arrays with high resolution and accuracy are fabricated to identify 2D distribution of stress. The hydrogels have great promise for various ionotronics in many fields.

Injectable conductive hydrogel electrodes for minimally invasive neural interfaces.

Soft bioelectronic neural interfaces have great potential as mechanically favourable alternatives to implantable metal electrodes. In this pursuit, conductive hydrogels (CHs) are particularly viable, combining tissue compliance with the required electrochemical characteristics. Physically-aggregated CHs offer an additional advantage by their facile synthesis into injectable systems, enabling minimally invasive implantation, though they can be impeded by a lack of control over their particle size and packing. Guided by these principles, an injectable PEDOT:PSS/acetic acid-based hydrogel is presented herein whose mechanical and electrochemical properties are independently tuneable by modifying the relative acetic acid composition. The fabrication process further benefits from employing batch emulsion to decrease particle sizes and facilitate tighter packing. The resulting material is stable and anatomically compact upon injection both in tissue phantom and ex vivo, while retaining favourable electrochemical properties in both contexts. Biphasic current stimulation yielding voltage transients well below the charge injection limit as well as the gel's non-cytotoxicity further underscore its potential for safe and effective neural interfacing applications.

A phenylboronic acid-based smart photonic crystal hydrogel sensor for colorimetric detection of glucose

A phenylboronic acid-based smart photonic crystal hydrogel (PNAPB) sensor with good recyclability was reported for the sensitive and colorimetric detection of glucose.

The effect of deoxycholic acid-based hydrogels on hepatic, muscle and pancreatic beta cells.

Aim: The aim of this study is to test the biocompatibility of hydrogels with polysaccharides and bile acids on three murine cell lines. Materials & methods: Novel hydrogels containing poloxamer 407, polysaccharides (starch, pectin, acacia, carboxymethyl and methyl 2-hydroxyethyl cellulose) and deoxycholic acid were prepared using cold method, sterilizedand used in biological assays to determine effects on hepatic, muscle, and pancreatic beta cells. Results and conclusion: Hydrogels with deoxycholic acid had tissue-depending effects on cellular survival and bioenergetics, resulting in the best cellular viability and bioenergetics within pancreatic beta cells. Further research is needed as proposed hydrogels may be beneficialfor cell delivery systems of pancreatic beta cells.

Engineering Single-Component Antibacterial Anti-inflammatory Polyitaconate-Based Hydrogel for Promoting Methicillin-Resistant Staphylococcus aureus-Infected Wound Healing and Skin Regeneration.

Hydrogel wound dressings play a crucial role in promoting the healing of drug-resistant bacterially infected wounds. However, their clinical application often faces challenges such as the use of numerous components, a complicated preparation process, and insufficient biological activity. Itaconic acid, known for its excellent biological and reaction activities, has not been extensively studied for the preparation of itaconic acid-based hydrogels and their application in infected wound healing. Therefore, there is a need to develop a multifunctional single-component itaconic acid-based hydrogel that is easy to synthesize and holds promising prospects for clinical use in promoting the healing of infected wounds. In this study, we present a single-component polyitaconate-based hydrogel (PICGI) with antibacterial, anti-inflammatory, and biological activity. The PICGI hydrogel demonstrates great potential in promoting healing of infected wounds and skin regeneration. It exhibits desirable thermosensitive, injectable, and adhesive properties, as well as broad-spectrum antibacterial activity and anti-inflammatory effects. Furthermore, the PICGI hydrogel is biocompatible and significantly enhances the migration and tube formation of endothelial cells. In the case of drug-resistant bacterially infected wounds, the PICGI hydrogel effectively inhibits bacterial infection and inflammation, promotes angiogenesis, and facilitates collagen deposition, thereby accelerating the healing and regeneration of the skin. This study highlights the promising application of the PICGI hydrogel as a single-component hydrogel in tissue repair associated with bacterial infection and inflammation. Moreover, the simplicity of its components, convenient preparation process, and sufficient biological activity make the PICGI hydrogel highly suitable for promotion and clinical application.

Human Minor Salivary Glands: A Readily Available Source of Salivary Stem/Progenitor Cells for Regenerative Applications.

Resident stem/progenitor cells within the secretory salivary glands offer a potential therapeutic resource for use in the regeneration of salivary glands needed to restore saliva production in patients with chronic xerostomia, or dry mouth. Methods were developed previously to isolate human stem/progenitor cells (hS/PCs) from major salivary glands (parotid/submandibular). Abundant minor salivary glands located in readily accessible locations in the oral cavity and lip could provide an additional valuable therapeutic resource. An advantage of this cell resource is that these minor glands about the size of grape seeds can be harvested from healthy donors using minimally invasive surgical procedures. The disadvantage of using minor glands is that they contain many fewer cells than do major glands, and thus harvested cells need to be expanded in the lab to create a therapeutic resource. While earlier work has described isolation of proliferative cell populations from minor salivary glands that could be used in regenerative medicine, most of these expanded cells possess properties of mesenchymal cells rather than the epithelial population that secretes salivary products.Here, we describe in detail our recently established methods to isolate and expand hS/PCs isolated from human labial minor salivary glands. Expanded hS/PC populations are epithelial assessed by their expression of epithelial progenitor markers K5 and K14. Like expandable cell populations previously isolated from the major salivary glands, these cells also express nuclear p63, consistent with their ability to be expanded after explant culture. When hS/PCs with these properties are encapsulated into a customized 3D biomimetic hyaluronic acid-based hydrogel, they will assemble into microstructures that retain some progenitor markers while also beginning to differentiate. The increased expression of secreted mucin MUC-7 was used to demonstrate differentiation and secretory potential in assembled hS/PC microstructures. Compared to hS/PCs from major glands, those from minor salivary glands tend to be more heterogeneous in early passage; thus, use of K5/K14/p63 as an early quality assessment tool is highly recommended. Additionally, hS/PCs from minor glands are sensitive to stress and if mishandled will demonstrate a stress response that leads to their transitioning to a flat, squamous cell-like appearance that is of limited utility in regenerative medicine applications. We conclude that properly handled hS/PCs from minor salivary glands represent a powerful new source of therapeutic cells for applications including treating patients with chronic xerostomia.

Combining protection with skin health: In vivo studies of an innovative gelatin/tannic acid-based hydrogel patch to prevent PPE-related skin lesions

The prolonged use of Personal Protective Equipment (PPE) can lead to skin problems due to persistent pressure, friction, and tension. This issue has prompted the exploration of solutions to protect the skin while maintaining the effectiveness of the PPE. This study aimed to evaluate the in vivo effectiveness of a gelatin/tannic acid-based hydrogel patch positioned beneath a mask to alleviate skin damage resulting from mask-wearing. To understand the pressure exerted by PPE, in vitro tests were conducted to measure the tensile strength of three types of facial masks. The FFP2 masks exhibited the highest tensile strength and were selected for subsequent in vivo biometric investigations. Biometric parameters were evaluated using the Flir E50bx® thermographic camera, Corneometer®, MoistureMap®, Sebumeter®, Tewameter®, and VISIA® systems. The results showed that when the hydrogel patch was used under the mask, there were no significant differences in facial skin temperature, sebum levels, or TEWL values (p > 0.05). However, a statistically significant increase in skin hydration and a decrease in frontal redness (p < 0.05) were observed. Consumer acceptance was assessed through sensory analysis questionnaires. In summary, the observed attenuation of physiological changes in the facial area and the positive consumer feedback suggest that this polymeric film-forming system is a simple yet effective solution to prevent PPE use-related skin issues.

Effect of Cell Density of a Methacrylic Acid-Based Hydrogel Implant on Embedded Islet Function and Viability.

Subcutaneous delivery of islets in a methacrylic acid-based hydrogel may offer a functional cure for type 1 diabetes. Here we show in mice that the hydrogel is able to provide sufficient vasculature to support islet function and viability, when islets are used at a low islet volume fraction (i.e., cell density). The Krogh cylinder model was used to mathematically estimate the effect of implant volume, for a fixed islet dose (600 islet equivalents [IEQ]), on the minimum vessel density required to maintain sufficient pO2 within the graft. Modeling suggested that 200 μL implants would have low enough islet densities and enough vessels to have islets remain viable, but that 50 μL implants would not; this was confirmed experimentally through measurement of glucose level in streptozotocin-induced diabetic severe combined immunodeficiency disease (SCID/bg) mice, comparing 200 and 50 μL implants, both with 600 IEQ. Vessel densities were ∼20-30 vessels/mm2 independent of implant volume and vessels were sufficient to increase subcutaneous oxygen tension, as measured with microcapsules containing oxygen sensitive material (a platinum [Pt] porphyrin); both these results were determined without cells. These results are useful in thinking about the scale-up of this system to humans: to maintain a low islet density (∼0.5%), many more islets will require attention to the subcutaneous implant configuration to satisfy the oxygen needs of the cells.

Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration

Retinitis pigmentosa (RP) is an outer retinal degenerative disease that can lead to photoreceptor cell death and profound vision loss. Although effective regulation of intraretinal inflammation can slow down the progression of the disease, an efficient anti-inflammatory treatment strategy is still lacking. This study reports the fabrication of a hyaluronic acid-based inflammation-responsive hydrogel (IRH) and its epigenetic regulation effects on retinal degeneration. The injectable IRH was designed to respond to cathepsin overexpression in an inflammatory environment. The epigenetic drug, the enhancer of zeste homolog 2 (EZH2) inhibitors, was loaded into the hydrogel to attenuate inflammatory factors. On-demand anti-inflammatory effects of microglia cells via the drug-loaded IRH were verified in vitro and in vivo retinal degeneration 10 (rd10) mice model. Therefore, our IRH not only reduced intraretinal inflammation but also protected photoreceptors morphologically and functionally. Our results suggest the IRH reported here can be used to considerably delay vision loss caused by RP.