Biofouling on the surface of implanted medical devices and biosensors severely hinders device functionality and drastically shortens device lifetime. Poly(ethylene glycol) and zwitterionic polymers ...are currently considered “gold‐standard” device coatings to reduce biofouling. To discover novel anti‐biofouling materials, a combinatorial library of polyacrylamide‐based copolymer hydrogels is created, and their ability is screened to prevent fouling from serum and platelet‐rich plasma in a high‐throughput parallel assay. It is found that certain nonintuitive copolymer compositions exhibit superior anti‐biofouling properties over current gold‐standard materials, and machine learning is used to identify key molecular features underpinning their performance. For validation, the surfaces of electrochemical biosensors are coated with hydrogels and their anti‐biofouling performance in vitro and in vivo in rodent models is evaluated. The copolymer hydrogels preserve device function and enable continuous measurements of a small‐molecule drug in vivo better than gold‐standard coatings. The novel methodology described enables the discovery of anti‐biofouling materials that can extend the lifetime of real‐time in vivo sensing devices.
Hydrogel formulations that prevent protein and platelet adhesion in assays where “gold‐standard” polymers exhibit significant platelet adhesion are identified. By using machine‐learning techniques to analyze molecular features of the polyacrylamide‐based copolymers, features giving rise to this anti‐biofouling performance are identified. Coating electrochemical devices with these top‐performing polyacrylamide‐based hydrogels extend lifetime when implanted intravenously and enable in vivo real‐time monitoring of analytes.
Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant ...presentation to the immune system. In this work, we sought to exploit the immune system’s natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform. We utilized an injectable and self-healing polymer–nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.
While excipients are often overlooked as the “inactive” ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has ...identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by replacing zinc and the phenolic preservative metacresol with phenoxyethanol as an antimicrobial agent and an amphiphilic acrylamide copolymer excipient for stability. A greater understanding is needed of the interplay between excipients, insulin association state, and stability in order to optimize this formulation. Here, we formulated insulin with different preservatives and stabilizing excipient concentrations using both insulin lispro and regular human insulin and assessed the insulin association states using analytical ultracentrifugation as well as formulation stability. We determined that phenoxyethanol is required to eliminate hexamers and promote a high monomer content even in a zinc-free lispro formulation. There is also a concentration dependent relationship between the concentration of polyacrylamide-based copolymer excipient and insulin stability, where a concentration greater than 0.1 g/mL copolymer is required for a mostly monomeric zinc-free lispro formulation to achieve stability exceeding that of Humalog in a stressed aging assay. Further, we determined that under the formulation conditions tested zinc-free regular human insulin remains primarily hexameric and is not at this time a promising candidate for rapid-acting formulations.
The introduction of transcutaneous and subcutaneous implants and devices into the human body instigates fouling and foreign body responses (FBRs) that limit their functional lifetimes. Polymer ...coatings are a promising solution to improve the biocompatibility of such implants, with potential to enhance in vivo device performance and prolong device lifetime. Here we sought to develop novel materials for use as coatings on subcutaneously implanted devices to reduce the FBR and local tissue inflammation in comparison to gold standard materials such as poly(ethylene glycol) and polyzwitterions. We prepared a library of polyacrylamide‐based copolymer hydrogels, which were selected from materials previously shown to exhibit remarkable antifouling properties with blood and plasma, and implanted them into the subcutaneous space of mice to evaluate their biocompatibility over the course of 1 month. The top performing polyacrylamide‐based copolymer hydrogel material, comprising a 50:50 mixture of N‐(2‐hydroxyethyl)acrylamide (HEAm) and N‐(3‐methoxypropyl)acrylamide (MPAm), exhibited significantly better biocompatibility and lower tissue inflammation than gold standard materials. Moreover, when applied to polydimethylsiloxane disks or silicon catheters as a thin coating (45 ± 1 μm), this leading copolymer hydrogel coating significantly improved implant biocompatibility. Using a rat model of insulin‐deficient diabetes, we showed that insulin pumps fitted with HEAm‐co‐MPAm hydrogel‐coated insulin infusion catheters exhibited improved biocompatibility and extended functional lifetime over pumps fitted with industry standard catheters. These polyacrylamide‐based copolymer hydrogel coatings have the potential to improve device function and lifetime, thereby reducing the burden of disease management for people regularly using implanted devices.
With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an ...adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease.
Display omitted
•The secreted protein ISM1 increases adipocyte glucose uptake•ISM1 ablation impairs basal and insulin-induced glucose uptake by adipocytes•ISM1 suppresses hepatocyte lipid synthesis while increasing protein synthesis•Therapeutic administration of recombinant ISM1 improves diabetes and hepatic steatosis
Here, Jiang et al. describe the discovery of isthmin-1 (ISM1) as an adipose-secreted polypeptide hormone. ISM1 has dual roles in increasing adipocyte glucose uptake while suppressing hepatic lipid synthesis, thus improving hyperglycemia and reducing lipid accumulation in mouse models. ISM1, therefore, may offer a new therapeutic opportunity to simultaneously treat diabetes and fatty liver disease.
Cancer immunotherapy can be augmented with toll-like receptor agonist (TLRa) adjuvants, which interact with immune cells to elicit potent immune activation. Despite their potential, use of many TLRa ...compounds has been limited clinically due to their extreme potency and lack of pharmacokinetic control, causing systemic toxicity from unregulated systemic cytokine release. Herein, we overcome these shortcomings by generating poly(ethylene glycol)–poly(lactic acid) (PEG–PLA) nanoparticles (NPs) presenting potent TLR7/8a moieties on their surface. The NP platform allows precise control of TLR7/8a valency and resulting surface presentation through self-assembly using nanoprecipitation. We hypothesize that the pharmacokinetic profile of the NPs minimizes systemic toxicity, localizing TLR7/8a presentation to the tumor bed and tumor-draining lymph nodes. In conjunction with antiprogrammed death-ligand 1 (anti-PD-L1) checkpoint blockade, peritumoral injection of TLR7/8a NPs slows tumor growth, extends survival, and decreases systemic toxicity in comparison to the free TLR7/8a in a murine colon adenocarcinoma model. These NPs constitute a modular platform for controlling pharmacokinetics of immunostimulatory molecules, resulting in increased potency and decreased toxicity.
Thermoresponsive hydrogel materials show promise as biomaterials as their properties can be widely tuned to fit engineering requirements for an array of important applications. Here we show that the ...properties of thermogelling tri-block copolymers consisting of a central poly(ethylene glycol) block and pendant
N
-substituted polyacrylamides can be tuned by altering the random terpolymer compositions. The heterogeneity of the pendant terpolymer blocks is reflected in the concentration dependence of their critical solution behavior. The lower critical solution temperature (LCST) of the pendant blocks can be finely tuned, enabling controlled modulation of thermogel properties. Altering terpolymer composition to control LCST behaviour, therefore, provides a facile approach to design thermogel properties.
Thermogelling tri-block terpolymers were made from a bifunctional PEG RAFT agent. The critical solution behavior was tunable by alteration of the terpolymer composition, enabling modulation of gelation temperatures and hydrogel viscoelasticity.
Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel ...delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.
PDF
