ABSTRACT
Development of effective vaccines for infectious diseases has been one of the most successful global health interventions in history. Though, while ideal subunit vaccines strongly rely on antigen and adjuvant(s) selection, the mode and time scale of exposure to the immune system has often been overlooked. Unfortunately, poor control over the delivery of many adjuvants, which play a key role in enhancing the quality and potency of immune responses, can limit their efficacy and cause off-target toxicities. There is a critical need for improved adjuvant delivery technologies to enhance their efficacy and boost vaccine performance. Nanoparticles have been shown to be ideal carriers for improving antigen delivery due to their shape and size, which mimic viral structures but have been generally less explored for adjuvant delivery. Here, we describe the design of self-assembled poly(ethylene glycol)-b-poly(lactic acid) nanoparticles decorated with CpG, a potent TLR9 agonist, to increase adjuvanticity in COVID-19 vaccines. By controlling the surface density of CpG, we show that intermediate valency is a key factor for TLR9 activation of immune cells. When delivered with the SARS-CoV-2 spike protein, CpG nanoparticle (CpG-NP) adjuvant greatly improves the magnitude and duration of antibody responses when compared to soluble CpG, and results in overall greater breadth of immunity against variants of concern. Moreover, encapsulation of CpG-NP into injectable polymeric-nanoparticle (PNP) hydrogels enhances the spatiotemporal control over codelivery of CpG-NP adjuvant and spike protein antigen such that a single immunization of hydrogel-based vaccines generates humoral responses comparable to those of a typical prime-boost regimen of soluble vaccines. These delivery technologies can potentially reduce the costs and burden of clinical vaccination, both of which are key elements in fighting a pandemic.
Subject(s)
COVID-19 , Nanoparticles , Spike Glycoprotein, Coronavirus , Vaccines , Humans , COVID-19 Vaccines , Toll-Like Receptor 9/agonists , COVID-19/prevention & control , SARS-CoV-2 , Adjuvants, Immunologic , Antigens , Nanoparticles/chemistry , Antibodies, ViralABSTRACT
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.
ABSTRACT
After myocardial infarction (MI), adult mammals exhibit scar formation, adverse left ventricular (LV) remodeling, LV stiffening, and impaired contractility, ultimately resulting in heart failure. Neonatal mammals, however, are capable of natural heart regeneration after MI. We hypothesized that neonatal cardiac regeneration conserves native biaxial LV mechanics after MI. Wistar rat neonates (1 day old, n = 46) and adults (8-10 weeks old, n = 20) underwent sham surgery or permanent left anterior descending coronary artery ligation. At 6 weeks after neonatal MI, Masson's trichrome staining revealed negligible fibrosis. Echocardiography for the neonatal MI (n = 15) and sham rats (n = 14) revealed no differences in LV wall thickness or chamber diameter, and both groups had normal ejection fraction (72.7% vs 77.5%, respectively, p = 0.1946). Biaxial tensile testing revealed similar stress-strain curves along both the circumferential and longitudinal axes across a full range of physiologic stresses and strains. The circumferential modulus (267.9 kPa vs 274.2 kPa, p = 0.7847), longitudinal modulus (269.3 kPa vs 277.1 kPa, p = 0.7435), and maximum shear stress (3.30 kPa vs 3.95 kPa, p = 0.5418) did not differ significantly between the neonatal MI and sham groups, respectively. In contrast, transmural scars were observed at 4 weeks after adult MI. Adult MI hearts (n = 7) exhibited profound LV wall thinning (p < 0.0001), chamber dilation (p = 0.0246), and LV dysfunction (ejection fraction 45.4% vs 79.7%, p < 0.0001) compared to adult sham hearts (n = 7). Adult MI hearts were significantly stiffer than adult sham hearts in both the circumferential (321.5 kPa vs 180.0 kPa, p = 0.0111) and longitudinal axes (315.4 kPa vs 172.3 kPa, p = 0.0173), and also exhibited greater maximum shear stress (14.87 kPa vs 3.23 kPa, p = 0.0162). Our study is the first to show that native biaxial LV mechanics are conserved after neonatal heart regeneration following MI, thus adding biomechanical support for the therapeutic potential of cardiac regeneration in the treatment of ischemic heart disease.
Subject(s)
Myocardial Infarction , Animals , Animals, Newborn , Biomechanical Phenomena , Cicatrix/pathology , Disease Models, Animal , Myocardial Infarction/pathology , Myocardium/pathology , Rats , Rats, Wistar , Ventricular RemodelingABSTRACT
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.
Subject(s)
Hydrogels , Tissue Engineering , Prostheses and ImplantsABSTRACT
Physical networks typically employ enthalpy-dominated crosslinking interactions that become more dynamic at elevated temperatures, leading to network softening. Moreover, standard mathematical frameworks such as time-temperature superposition assume network softening and faster dynamics at elevated temperatures. Yet, deriving a mathematical framework connecting the crosslinking thermodynamics to the temperature-dependent viscoelasticity of physical networks suggests the possibility for entropy-driven crosslinking interactions to provide alternative temperature dependencies. This framework illustrates that temperature negligibly affects crosslink density in reported systems, but drastically influences crosslink dynamics. While the dissociation rate of enthalpy-driven crosslinks is accelerated at elevated temperatures, the dissociation rate of entropy-driven crosslinks is negligibly affected or even slowed under these conditions. Here we report an entropy-driven physical network based on polymer-nanoparticle interactions that exhibits mechanical properties that are invariant with temperature. These studies provide a foundation for designing and characterizing entropy-driven physical crosslinking motifs and demonstrate how these physical networks access thermal properties that are not observed in current physical networks.
ABSTRACT
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.
ABSTRACT
Physically associated hydrogels (PHs) capable of reversible transitions between solid and liquid-like states have enabled novel strategies for 3D printing, therapeutic drug and cell delivery, and regenerative medicine. Among the many design criteria (e.g., viscoelasticity, cargo diffusivity, biocompatibility) for these applications, engineering PHs for extrudability is a necessary and critical design criterion for the successful application of these materials. As the development of many distinct PH material systems continues, a strategy to determine the extrudability of PHs a priori will be exceedingly useful for reducing costly and time-consuming trial-and-error experimentation. Here, a strategy to determine the property-function relationships for PHs in injectable drug delivery applications at clinically relevant flow rates is presented. This strategy-validated with two chemically and physically distinct PHs-reveals material design spaces in the form of Ashby-style plots that highlight acceptable, application-specific material properties. It is shown that the flow behavior of PHs does not obey a single shear-thinning power law and the implications for injectable drug delivery are discussed. This approach for generating design criteria has potential for streamlining the screening of PHs and their utility in applications with varying geometrical (i.e., needle diameter) and process (i.e., flow rate) constraints.
Subject(s)
Hydrogels/chemistry , Biocompatible Materials/chemistry , Bioprinting , Drug Delivery Systems , Injections , Nanoparticles/chemistry , Polymers/chemistry , Pressure , Printing, Three-Dimensional , Rheology , Shear StrengthABSTRACT
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.
ABSTRACT
Polyphosphate fire retardants are a critical tactical resource for fighting fires in the wildland and in the wildland-urban interface. Yet, application of these retardants is limited to emergency suppression strategies because current formulations cannot retain fire retardants on target vegetation for extended periods of time through environmental exposure and weathering. New retardant formulations with persistent retention to target vegetation throughout the peak fire season would enable methodical, prophylactic treatment strategies of landscapes at high risk of wildfires through prolonged prevention of ignition and continual impediment to active flaming fronts. Here we develop a sprayable, environmentally benign viscoelastic fluid comprising biopolymers and colloidal silica to enhance adherence and retention of polyphosphate retardants on common wildfire-prone vegetation. These viscoelastic fluids exhibit appropriate wetting and rheological responses to enable robust retardant adherence to vegetation following spray application. Further, laboratory and pilot-scale burn studies establish that these materials drastically reduce ignition probability before and after simulated weathering events. Overall, these studies demonstrate how these materials actualize opportunities to shift the approach of retardant-based wildfire management from reactive suppression to proactive prevention at the source of ignitions.
Subject(s)
Conservation of Natural Resources/methods , Flame Retardants/analysis , Viscoelastic Substances/chemistry , Wildfires/prevention & control , Forests , Polyphosphates/chemistry , Seasons , Trees/chemistryABSTRACT
Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.
Subject(s)
Cardiac Surgical Procedures/methods , Hydrogels/chemistry , Pericardium/surgery , Polymers/chemistry , Tissue Adhesions , Animals , Cellulose, Oxidized , Hyaluronic Acid , Hydrogels/therapeutic use , Male , Models, Animal , Nanoparticles , Polymers/therapeutic use , Rats , SheepABSTRACT
Drug delivery and cell transplantation require minimally invasive deployment strategies such as injection through clinically relevant high-gauge needles. Supramolecular hydrogels comprising dodecyl-modified hydroxypropylmethylcellulose and poly(ethylene glycol)-block-poly(lactic acid) have been previously demonstrated for the delivery of drugs and proteins. Here, it is demonstrated that the rheological properties of these hydrogels allow for facile injectability, an increase of cell viability after injection when compared to cell viabilities of cells injected in phosphate-buffered saline, and homogeneous cell suspensions that do not settle. These hydrogels are injected at 1 mL min-1 with pressures less than 400 kPa, despite the solid-like properties of the gel when at rest. The cell viabilities immediately after injection are greater than 86% for adult human dermal fibroblasts, human umbilical vein cells, smooth muscle cells, and human mesenchymal stem cells. Cells are shown to remain suspended and proliferate in the hydrogel at the same rate as observed in cell media. The work expands on the versatility of these hydrogels and lays a foundation for the codelivery of drugs, proteins, and cells.
Subject(s)
Drug Delivery Systems , Hydrogels , Materials Testing , Mesenchymal Stem Cells/metabolism , Nanoparticles/chemistry , Cell Survival/drug effects , Humans , Hydrogels/chemistry , Hydrogels/pharmacology , Mesenchymal Stem Cells/cytology , Polyesters/chemistry , Polyesters/pharmacology , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacologyABSTRACT
Thermally triggerable polymer films that degrade at modest temperatures (≈85 °C) are created from a blend of cyclic polyphthalaldehyde (cPPA) and a polymeric thermoacid generator, poly(vinyl tert-butyl carbonate sulfone) (PVtBCS). PVtBCS depolymerizes when heated, generating acid which initiates the depolymerization of cPPA into volatile byproducts. The mass loss onset for 2 wt% PVtBCS/cPPA is 22 °C lower than the onset for neat cPPA alone in dynamic thermogravimetric analysis experiments. Increased concentrations of PVtBCS increase the rate of depolymerization of cPPA. Raman spectroscopy reveals that the monomer, o-phthalaldehyde, is the main depolymerization product of the acid-catalyzed depolymerization of cPPA. The PVtBCS/cPPA blend is a promising material for the design and manufacture of transient electronic packaging and polymers.
Subject(s)
Acids/chemistry , Polymers/chemistry , o-Phthalaldehyde/chemistry , Catalysis , Spectrum Analysis, Raman , Temperature , Thermogravimetry , Water/chemistryABSTRACT
Polymeric materials that depolymerize into volatiles on command may function as vanishing substrates or packaging for transient electronics. Poly(vinyl tert-butyl carbonate sulfone) is known to afford low-boiling byproducts upon heat-activated degradation; however, the polymer is rather unstable, even to the degree of being difficult to process and handle. Understanding the origin of this instability is important for the development of robust materials capable of programmed self-destruction. In this work, we show that poly(vinyl tert-butyl carbonate sulfone)s thermally decompose via carbonate elimination as the rate-determining step, indicating that its thermal instability stems from the lability of the tert-butyl carbonate group. We further examined the effect of isomeric butyl carbonate side chains on the thermal degradation of poly(vinyl butyl carbonate sulfone)s and found that the degradation onsets range from 91 to 213 °C, yielding as little as 2.77 ± 0.53 wt % residue. Results from our findings will aid in the development of vanishing polymers with tunable thermal degradation.