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Supramolecular hydrogels formed through polymer-nanoparticle interactions are promising biocompatible materials for translational medicines. This class of hydrogels exhibits shear-thinning behavior and rapid recovery of mechanical properties, providing desirable attributes for formulating sprayable and injectable therapeutics. Characterization of hydrogel composition and loading of encapsulated drugs is critical to achieving the desired rheological behavior as well as tunable in vitro and in vivo payload release kinetics. However, quantitation of hydrogel composition is challenging due to material complexity, heterogeneity, high molecular weight, and the lack of chromophores. Here, we present a label-free approach to simultaneously determine hydrogel polymeric components and encapsulated payloads by coupling a reversed phase liquid chromatographic method with a charged aerosol detector (RPLC-CAD). The hydrogel studied consists of modified hydroxypropylmethylcellulose, self-assembled PEG-b-PLA nanoparticles, and a therapeutic compound, bimatoprost. The three components were resolved and quantitated using the RPLC-CAD method with a C4 stationary phase. The method demonstrated robust performance, applicability to alternative cargos (i.e., proteins) and was suitable for composition analysis as well as for evaluating in vitro release of cargos from the hydrogel. Moreover, this method can be used to monitor polymer degradation and material stability, which can be further elucidated by coupling the RPLC method with (1) a multi-angle light scattering detector (RPLC-MALS) or (2) high resolution mass spectrometry (RPLC-MS) and a Fourier-transform based deconvolution algorithm. We envision that this analytical strategy could be generalized to characterize critical quality attributes of other classes of supramolecular hydrogels, establish structure-property relationships, and provide rational design guidance in hydrogel drug product development.
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Hidrogeles , Nanopartículas , Hidrogeles/química , Cromatografía de Fase Inversa/métodos , Polietilenglicoles/química , AerosolesRESUMEN
Advances in hydrogel technology have unlocked unique and valuable capabilities that are being applied to a diverse set of translational applications. Hydrogels perform functions relevant to a range of biomedical purposes-they can deliver drugs or cells, regenerate hard and soft tissues, adhere to wet tissues, prevent bleeding, provide contrast during imaging, protect tissues or organs during radiotherapy, and improve the biocompatibility of medical implants. These capabilities make hydrogels useful for many distinct and pressing diseases and medical conditions and even for less conventional areas such as environmental engineering. In this review, we cover the major capabilities of hydrogels, with a focus on the novel benefits of injectable hydrogels, and how they relate to translational applications in medicine and the environment. We pay close attention to how the development of contemporary hydrogels requires extensive interdisciplinary collaboration to accomplish highly specific and complex biological tasks that range from cancer immunotherapy to tissue engineering to vaccination. We complement our discussion of preclinical and clinical development of hydrogels with mechanical design considerations needed for scaling injectable hydrogel technologies for clinical application. We anticipate that readers will gain a more complete picture of the expansive possibilities for hydrogels to make practical and impactful differences across numerous fields and biomedical applications.
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Hidrogeles , Ingeniería de Tejidos , Prótesis e ImplantesRESUMEN
Controlled radical polymerization of vinyl monomers with multivinyl cross-linkers leads to the synthesis of highly branched polymers with controlled spatial density of functional chain ends. The resulting polymers synthesized in this manner have large dispersities resulting from a mixture of unreacted primary chains, low molecular weight branched species, and high molecular weight highly branched species. Through the use of fractional precipitation, we present a synthetic route to high molecular weight highly branched polymers that are absent of low molecular weight species and that contain reactivity toward amines for controlled postpolymerization modification. The controlled spatial density of functional moieties on these high molecular weight macromolecular constructs enable new functional biomaterials with the potential for application in regenerative medicine, immunoengineering, imaging, and controlled drug delivery.
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Materiales Biocompatibles , Polímeros , Acrilamidas , Estructura Molecular , PolimerizacionRESUMEN
There are 150 million people with diabetes worldwide who require insulin replacement therapy, and the prevalence of diabetes is rising the fastest in middle- and low-income countries. The current formulations require costly refrigerated transport and storage to prevent loss of insulin integrity. This study shows the development of simple "drop-in" amphiphilic copolymer excipients to maintain formulation integrity, bioactivity, pharmacokinetics, and pharmacodynamics for over 6 months when subjected to severe stressed aging conditions that cause current commercial formulation to fail in under 2 weeks. Further, when these copolymers are added to Humulin R (Eli Lilly) in original commercial packaging, they prevent insulin aggregation for up to 4 days at 50 °C compared to less than 1 day for Humulin R alone. These copolymers demonstrate promise as simple formulation additives to increase the cold chain resilience of commercial insulin formulations, thereby expanding global access to these critical drugs for treatment of diabetes.
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Diabetes Mellitus , Insulina , Excipientes , Humanos , Insulina Regular Humana , RefrigeraciónRESUMEN
Monoclonal antibodies are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Moreover, existing excipients designed to stabilize these formulations are often limited by their toxicity and tendency to form particles such as micelles. Here, we demonstrate the ability of a simple "drop-in", amphiphilic copolymer excipient to enhance the stability of high concentration formulations of clinically-relevant monoclonal antibodies without altering their pharmacokinetics or injectability. Through interfacial rheology and surface tension measurements, we demonstrate that the copolymer excipient competitively adsorbs to formulation interfaces. Further, through determination of monomeric composition and retained bioactivity through stressed aging, we show that this excipient confers a significant stability benefit to high concentration antibody formulations. Finally, we demonstrate that the excipient behaves as an inactive ingredient, having no significant impact on the pharmacokinetic profile of a clinically relevant antibody in mice. This amphiphilic copolymer excipient demonstrates promise as a simple formulation additive to create stable, high concentration antibody formulations, thereby enabling improved treatment options such as a route-of-administration switch from low concentration intravenous (IV) to high concentration subcutaneous (SC) delivery while reducing dependence on the cold chain.
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Supramolecular hydrogels formed through polymer-nanoparticle interactions are promising biocompatible materials for translational medicines. This class of hydrogels exhibits shear-thinning behavior and rapid recovery of mechanical properties following applied stresses, providing desirable attributes for formulating sprayable and injectable therapeutics. Characterization of hydrogel composition and loading of encapsulated drugs is critical to achieving desired rheological behavior as well as tunable in vitro and in vivo payload release kinetics. However, quantitation of hydrogel compositions is challenging due to material complexity, heterogeneity, high molecular weight, and the lack of chromophores. Here, we present a label-free approach to simultaneously determine hydrogel polymeric components and encapsulated payloads by coupling a reversed phase liquid chromatographic method with a charged aerosol detector (RPLC-CAD). The hydrogel studied consists of modified hydroxypropylmethylcellulose, self-assembled PEG-b-PLA nanoparticles, and a therapeutic compound, Bimatoprost. The three components were resolved and quantitated using the RPLC-CAD method with a C4 stationary phase. The method demonstrated robust performance, applicability to alternative cargos (i.e. proteins), and was suitable for composition analysis as well as for evaluating in vitro release of cargos from the hydrogel. Moreover, this method can be used to monitor polymer degradation and material stability, which can be further elucidated by coupling the RPLC method with high resolution mass spectrometry and a Fourier-transform based deconvolution algorithm. To our knowledge, this is the first RPLC-CAD method for characterizing the critical quality attributes of supramolecular hydrogels. We envision this analytical strategy could be generalized to characterize other classes of supramolecular hydrogels, establish structure-property relationships, and provide rational design guidance in hydrogel drug product development.
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Directing biological functions is at the heart of next-generation biomedical initiatives in tissue and immuno-engineering. However, the ambitious goal of engineering complex biological networks requires the ability to precisely perturb specific signaling pathways at distinct times and places. Using lipid nanotechnology and the principles of supramolecular self-assembly, we developed an injectable liposomal nanocomposite hydrogel platform to precisely control the release of multiple protein drugs. By integrating modular lipid nanotechnology into a hydrogel, we introduced multiple mechanisms of release based on liposome surface chemistry. To validate the utility of this system for multi-protein delivery, we demonstrated synchronized, sustained, and localized release of IgG antibody and IL-12 cytokine in vivo, despite the significant size differences between these two proteins. Overall, liposomal hydrogels are a highly modular platform technology with the ability the mediate orthogonal modes of protein release and the potential to precisely coordinate biological cues both in vitro and in vivo.
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Designing yield stress fluids to exhibit desired functional properties is an integral challenge in many applications such as 3D printing, drilling, food formulation, fiber spinning, adhesives, and injectable biomaterials. Extensibility in particular has been found to be a highly beneficial characteristic for materials in these applications; however, few highly extensible, high water content materials have been reported to date. Herein we engineer a class of high water content nanocomposite hydrogel materials leveraging multivalent, noncovalent, polymer-nanoparticle (PNP) interactions between modified cellulose polymers and biodegradable nanoparticles. We show that modulation of the chemical composition of the PNP hydrogels controls the dynamic cross-linking interactions within the polymer network and directly impacts yielding and viscoelastic responses. These materials can be engineered to stretch up to 2000% strain and occupy an unprecedented property regime for extensible yield stress fluids. Moreover, a dimensional analysis of the relationships between extensibility and the relaxation and recovery time scales of these nanocomposite hydrogels uncovers generalizable design criteria that will be critical for future development of extensible materials.
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PURPOSE: To create an alkali injury symblephara mouse model to study conjunctival fibrosis pathophysiology and test polymer nanoparticle (PNP) hydrogel as a preventative therapeutic. METHODS: Mice were injured using NaOH-soaked filter paper to determine the optimal NaOH concentration to induce the formation of symblephara. Injured mice were observed for 7 days to detect the formation of symblephara. Forniceal shortening observed on hematoxylin and eosin (H&E)-stained tissue sections was used as a symblephara marker. Alpha-smooth muscle actin (α-SMA) expression, Masson's trichrome assay, and periodic acid-Schiff (PAS) staining were used to determine myofibroblast expression, collagen deposition, and goblet cell integrity. PNP hydrogel, with multivalent, noncovalent interactions between modified biopolymers and nanoparticles, was applied immediately after alkali injury to determine its ability to prevent the formation of symblephara. RESULTS: Forniceal shortening was observed in H&E images with 1N NaOH for 2 minutes after 7 days without globe destruction. PNP hydrogel prevented forniceal shortening after alkali injury as observed by H&E histology. α-SMA expression and collagen deposition in eye tissue sections were increased in the fornix after injury with 1N NaOH compared with uninjured controls. PNP hydrogel treatment immediately after injury reduced α-SMA expression and collagen deposition in the forniceal region. Mucin-secreting goblet cells stained with PAS were significantly lower in alkali-injured and PNP hydrogel-treated conjunctivas than in uninjured control conjunctivas. CONCLUSIONS: We observed that 1N NaOH for 2 minutes induced maximal forniceal shortening and symblephara in mice. PNP hydrogel prevented forniceal shortening and conjunctival fibrosis after injury. This first murine model for symblephara will be useful to study fibrosis pathophysiology after conjunctival injury and to determine therapeutic targets for cicatrizing diseases. TRANSLATIONAL RELEVANCE: This mouse model of symblephara can be useful for studying conjunctival scarring disease pathophysiology and preventative therapeutics. We tested PNP hydrogel, which prevented the formation of symblephara after injury.
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Enfermedades de la Conjuntiva , Lesiones Oculares , Nanopartículas , Álcalis , Animales , Colágeno , Modelos Animales de Enfermedad , Fibrosis , Hidrogeles , Ratones , Nanopartículas/uso terapéutico , Polímeros , Hidróxido de SodioRESUMEN
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.
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Incrustaciones Biológicas , Técnicas Biosensibles , Resinas Acrílicas , Incrustaciones Biológicas/prevención & control , Hidrogeles/química , Polímeros/química , Prótesis e Implantes , Propiedades de SuperficieRESUMEN
When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, this study explored the ability of a slow-releasing injectable hydrogel depot to reduce dose-limiting toxicities of immunostimulatory CD40 agonist (CD40a) while maintaining its potent anticancer efficacy. A previously described polymer-nanoparticle (PNP) hydrogel system is leveraged that exhibits shear-thinning and yield-stress properties that are hypothesized to improve locoregional delivery of CD40a immunotherapy. Using positron emission tomography, it is demonstrated that prolonged hydrogel-based delivery redistributes CD40a exposure to the tumor and the tumor draining lymph node (TdLN), thereby reducing weight loss, hepatotoxicity, and cytokine storm associated with standard treatment. Moreover, CD40a-loaded hydrogels mediate improved local cytokine induction in the TdLN and improve treatment efficacy in the B16F10 melanoma model. PNP hydrogels, therefore, represent a facile, drug-agnostic method to ameliorate immune-related adverse effects and explore locoregional delivery of immunostimulatory drugs.
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Melanoma , Nanopartículas , Anticuerpos , Antígenos CD40 , Citocinas , Humanos , Hidrogeles/química , Polímeros , Tomografía Computarizada por Rayos XRESUMEN
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.
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Neoplasias , Receptores Quiméricos de Antígenos , Citocinas , Humanos , Hidrogeles , Inmunoterapia Adoptiva/métodos , Neoplasias/patología , Neoplasias/terapia , Receptores Quiméricos de Antígenos/genética , Linfocitos T/patologíaRESUMEN
These methods describe how to formulate injectable, supramolecular polymer-nanoparticle (PNP) hydrogels for use as biomaterials. PNP hydrogels are composed of two components: hydrophobically modified cellulose as the network polymer and self-assembled core-shell nanoparticles that act as non-covalent cross linkers through dynamic, multivalent interactions. These methods describe both the formation of these self-assembled nanoparticles through nanoprecipitation as well as the formulation and mixing of the two components to form hydrogels with tunable mechanical properties. The use of dynamic light scattering (DLS) and rheology to characterize the quality of the synthesized materials is also detailed. Finally, the utility of these hydrogels for drug delivery, biopharmaceutical stabilization, and cell encapsulation and delivery is demonstrated through in vitro experiments to characterize drug release, thermal stability, and cell settling and viability. Due to its biocompatibility, injectability, and mild gel formation conditions, this hydrogel system is a readily tunable platform suitable for a range of biomedical applications.
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Sistemas de Liberación de Medicamentos , Hidrogeles/química , Inyecciones , Células Madre Mesenquimatosas/citología , Nanopartículas/química , Polímeros/química , Animales , Bovinos , Supervivencia Celular , Precipitación Química , Liberación de Fármacos , Humanos , Insulina/química , Cinética , Estabilidad Proteica , Reología , Albúmina Sérica Bovina/química , TemperaturaRESUMEN
Polymer-nanoparticle hydrogels are a unique class of self-assembled, shear-thinning, yield-stress fluids that have demonstrated potential utility in many impactful applications. Here, we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through comprehensive rheological and diffusion studies, we reveal insights into the structural dynamics of the polymer nanoparticle network that identify that stoichiometry plays a key role in gelation and yielding, ultimately enabling the development of hydrogel formulations with unique shear-thinning and yield-stress behaviors. Access to these materials opens new doors for interesting applications in a variety of fields including tissue engineering, drug delivery, and controlled solution viscosity.
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Biotherapeutics currently dominate the landscape of new drugs because of their exceptional potency and selectivity. Yet, the intricate molecular structures that give rise to these beneficial qualities also render them unstable in formulation. Hydrogels have shown potential as stabilizing excipients for biotherapeutic drugs, providing protection against harsh thermal conditions experienced during distribution and storage. In this work, we report the utilization of a cellulose-based supramolecular hydrogel formed from polymer-nanoparticle (PNP) interactions to encapsulate and stabilize insulin, an important biotherapeutic used widely to treat diabetes. Encapsulation of insulin in these hydrogels prevents insulin aggregation and maintains insulin bioactivity through stressed aging conditions of elevated temperature and continuous agitation for over 28 days. Further, insulin can be easily recovered by dilution of these hydrogels for administration at the point of care. This supramolecular hydrogel system shows promise as a stabilizing excipient to reduce the cold chain dependence of insulin and other biotherapeutics.
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Productos Biológicos , Nanopartículas , Hidrogeles , Insulina , PolímerosRESUMEN
Preclinical cancer research is heavily dependent on allograft and xenograft models, but current approaches to tumor inoculation yield inconsistent tumor formation and growth, ultimately wasting valuable resources (e.g., animals, time, and money) and limiting experimental progress. Here we demonstrate a method for tumor inoculation using self-assembled hydrogels to reliably generate tumors with low variance in growth. The observed reduction in model variance enables smaller animal cohorts, improved effect observation and higher powered studies.
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Carcinogénesis , Modelos Animales de Enfermedad , Hidrogeles , Animales , Xenoinjertos , RatonesRESUMEN
Vaccines are critical for combating infectious diseases across the globe. Influenza, for example, kills roughly 500,000 people annually worldwide, despite annual vaccination campaigns. Efficacious vaccines must elicit a robust and durable antibody response, and poor efficacy often arises 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 influenza vaccine platform. We utilized an injectable and self-healing polymer-nanoparticle (PNP) hydrogel platform to prolong the co-delivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique dynamic physical characteristics whereby physicochemically distinct influenza hemagglutinin antigen and a toll-like receptor 7/8 agonist adjuvant could be co-delivered over prolonged timeframes that were tunable through simple alteration of the gel formulation. We show a relationship between hydrogel physical properties and the resulting immune response to immunization. When administered in mice, hydrogel-based vaccines demonstrated enhancements in the magnitude and duration of humoral immune responses compared to alum, a widely used clinical adjuvant system. We found stiffer hydrogel formulations exhibited slower release and resulted in the greatest improvements to the antibody response while also enabling significant adjuvant dose sparing. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of influenza subunit vaccines.
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Adyuvantes Inmunológicos , Preparaciones de Acción Retardada , Hidrogeles , Inmunidad Humoral , Vacunas contra la Influenza , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Animales , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Vacunas contra la Influenza/química , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/farmacología , Ratones , Vacunas de Subunidad/química , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/farmacologíaRESUMEN
The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, clinically-relevant adjuvants Alum, AddaVax, and CpG/Alum are found unable to elicit neutralizing responses following a prime-boost immunization. Here, it has been shown that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer-nanoparticle (PNP) hydrogel elicited potent anti-RBD and anti-spike antibody titers, providing broader protection against SARS-CoV-2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically-relevant adjuvant systems. Notably, a SARS-CoV-2 spike-pseudotyped lentivirus neutralization assay revealed that hydrogel-based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.
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Anticuerpos Neutralizantes/inmunología , Hidrogeles/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas de Subunidad/inmunología , Adyuvantes Inmunológicos/química , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , COVID-19/virología , Islas de CpG/genética , Femenino , Humanos , Inmunidad Humoral , Ratones , Ratones Endogámicos C57BL , Nanopartículas/química , Polímeros/química , Dominios Proteicos/inmunología , SARS-CoV-2/química , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/aislamiento & purificación , Vacunas de Subunidad/química , Vacunas de Subunidad/metabolismoRESUMEN
The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, we found that clinically-relevant adjuvants Alum, AddaVax, and CpG/Alum were unable to elicit neutralizing responses following a prime-boost immunization. Here we show that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer-nanoparticle (PNP) hydrogel elicited potent anti-RBD and anti-spike antibody titers, providing broader protection against SARS-CoV-2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically-relevant adjuvant systems. Notably, a SARS-CoV-2 spike-pseudotyped lentivirus neutralization assay revealed that hydrogel-based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.
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Understanding how automated insulin delivery (AID) algorithm features impact glucose control under full closed loop delivery represents a critical step toward reducing patient burden by eliminating the need for carbohydrate entries at mealtimes. Here, we use a pig model of diabetes to compare AndroidAPS and Loop open-source AID systems without meal announcements. Overall time-in-range (70-180 mg/dl) for AndroidAPS was 58% ± 5%, while time-in-range for Loop was 35% ± 5%. The effect of the algorithms on time-in-range differed between meals and overnight. During the overnight monitoring period, pigs had an average time-in-range of 90% ± 7% when on AndroidAPS compared to 22% ± 8% on Loop. Time-in-hypoglycemia also differed significantly during the lunch meal, whereby pigs running AndroidAPS spent an average of 1.4% (+0.4/-0.8)% in hypoglycemia compared to 10% (+3/-6)% for those using Loop. As algorithm design for closed loop systems continues to develop, the strategies employed in the OpenAPS algorithm (known as oref1) as implemented in AndroidAPS for unannounced meals may result in a better overall control for full closed loop systems.