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1.
Proc Natl Acad Sci U S A ; 120(49): e2310088120, 2023 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-38015840

RESUMEN

A hallmark of concentrated suspensions is non-Newtonian behavior, whereby the viscosity increases dramatically once a characteristic shear rate or stress is exceeded. Such strong shear thickening is thought to originate from a network of frictional particle-particle contact forces, which forms under sufficiently large stress, evolves dynamically, and adapts to changing loads. While there is much evidence from simulations for the emergence of this network during shear thickening, experimental confirmation has been difficult. Here, we use suspensions of piezoelectric nanoparticles and exploit the strong local stress focusing within the network to activate charge generation. This charging can then be detected in the measured ac conductance and serve as a signature of frictional contact formation. The direct link between stress-activated frictional particle interactions and piezoelectric suspension response is further demonstrated by tracking the emergence of structural memory in the contact network under oscillatory shear and by showing how stress-activated friction can drive mechano-transduction of chemical reactions with nonlinear reaction kinetics. Taken together, this makes the ac conductance of piezoelectric suspensions a sensitive in-situ reporter of the micromechanics associated with frictional interactions.

2.
Nat Mater ; 20(6): 869-874, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33619367

RESUMEN

In nature, bone adapts to mechanical forces it experiences, strengthening itself to match the conditions placed upon it. Here we report a composite material that adapts to the mechanical environment it experiences-varying its modulus as a function of force, time and the frequency of mechanical agitation. Adaptation in the material is managed by mechanically responsive ZnO, which controls a crosslinking reaction between a thiol and an alkene within a polymer composite gel, resulting in a mechanically driven ×66 increase in modulus. As the amount of chemical energy is a function of the mechanical energy input, the material senses and adapts its modulus along the distribution of stress, resembling the bone remodelling behaviour that materials can adapt accordingly to the loading location. Such material design might find use in a wide range of applications, from adhesives to materials that interface with biological systems.


Asunto(s)
Materiales Biomiméticos/química , Fenómenos Mecánicos , Vibración , Ensayo de Materiales , Óxido de Zinc/química
3.
J Immunol ; 204(3): 611-621, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31871024

RESUMEN

Coxiella burnetii is an obligate intracellular bacterium and the causative agent of Q fever. C. burnetii is considered a potential bioterrorism agent because of its low infectious dose; resistance to heat, drying, and common disinfectants; and lack of prophylactic therapies. Q-Vax, a formalin-inactivated whole-bacteria vaccine, is currently the only prophylactic measure that is protective against C. burnetii infections but is not U.S. Food and Drug Administration approved. To overcome the safety concerns associated with the whole-bacteria vaccine, we sought to generate and evaluate recombinant protein subunit vaccines against C. burnetii To accomplish this, we formulated C. burnetii Ags with a novel TLR triagonist adjuvant platform, which used combinatorial chemistry to link three different TLR agonists together to form one adjuvanting complex. We evaluated the immunomodulatory activity of a panel of TLR triagonist adjuvants and found that they elicited unique Ag-specific immune responses both in vitro and in vivo. We evaluated our top candidates in a live C. burnetii aerosol challenge model in C56BL/6 mice and found that several of our novel vaccine formulations conferred varying levels of protection to the challenged animals compared with sham immunized mice, although none of our candidates were as protective as the commercial vaccine across all protection criteria that were analyzed. Our findings characterize a novel adjuvant platform and offer an alternative approach to generating protective and effective vaccines against C. burnetii.


Asunto(s)
Vacunas Bacterianas/inmunología , Coxiella burnetii/fisiología , Fiebre Q/inmunología , Receptores Toll-Like/agonistas , Adyuvantes Inmunológicos , Animales , Vacunas Bacterianas/síntesis química , Técnicas Químicas Combinatorias , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad , Inmunogenicidad Vacunal , Ratones , Ratones Endogámicos C57BL , Vacunas de Subunidad
4.
Small ; 17(42): e2102217, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34528371

RESUMEN

Frontal polymerization provides a rapid, economic, and environmentally friendly methodology to manufacture thermoset polymers and composites. Despite its efficiency and reduced environmental impact, the manufacturing method is underutilized due to the limited fundamental understanding of its dynamic control. This work reports the control and patterning of the front propagation in a dicyclopentadiene resin by immersion of phase-changing polycaprolactone particles. Predictive and designed patterning is enabled by multiphysical numerical analyses, which reveal that the interplay between endothermic phase transition, exothermic chemical reaction, and heat exchange govern the temperature, velocity, and propagation path of the front via two different interaction regimes. To pattern the front, one can vary the size and spacing between the particles and increase the number of propagating fronts, resulting in tunable physical patterns formed due to front separation and merging near the particles. Both single- and double-frontal polymerization experiments in an open mold are performed. The results confirm the front-particle interaction mechanisms and the shapes of the patterns explored numerically. The present study offers a fundamental understanding of frontal polymerization in the presence of heat-absorbing second-phase materials and proposes a potential one-step manufacturing method for precisely patterned polymeric and composite materials without masks, molds, or printers.


Asunto(s)
Polímeros , Transición de Fase , Polimerizacion , Temperatura
5.
Angew Chem Int Ed Engl ; 59(43): 18943-18947, 2020 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-33448568

RESUMEN

Efforts to synthesize degradable polymers from renewable resources are deterred by technical and economic challenges; especially, the conversion of natural building blocks into polymerizable monomers is inefficient, requiring multistep synthesis and chromatographic purification. Herein we report a chemoenzymatic process to address these challenges. An enzymatic reaction system was designed that allows for regioselective functional group transformation, efficiently converting glucose into a polymerizable monomer in quantitative yield, thus removing the need for chromatographic purification. With this key success, we further designed a continuous, three-step process, which enabled the synthesis of a sugar polymer, sugar poly(orthoester), directly from glucose in high yield (73 % from glucose). This work may provide a proof-of-concept in developing technically and economically viable approaches to address the many issues associated with current petroleum-based polymers.

6.
J Am Chem Soc ; 141(11): 4510-4514, 2019 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-30768257

RESUMEN

Polymeric nanoparticles (NPs) derived from self-assemblies of amphiphilic polymers have demonstrated great potential in clinical applications. However, there are challenges ahead. Notably, immunotoxicity remains a major roadblock that deters the NPs from further applications. Studies suggested that the hydrophobic component is a primary cause, yet biocompatible hydrophobic carbohydrate-based polymers may help mitigate this issue. Herein we design and synthesize novel NP systems having glucose poly(orthoesters) hydrophobic scaffold and polyethylene glycol (PEG) hydrophilic shell. The new NPs exhibited low immunotoxicity both in vitro and in vivo, as measured by the induced cytokine levels. In contrast, when other polymers, such as polylactide (PLA) or polycaprolactone (PCL), were used as the hydrophobic scaffold, the cytokine levels were orders of magnitude higher. Results from our multiple immunological studies indicate that carbohydrate-based polymers can largely mitigate the hydrophobicity-induced immunotoxicity, and thereby they may be good candidate polymers to engineer low immunotoxic biomaterials for various biomedical studies.


Asunto(s)
Glucosa/química , Interacciones Hidrofóbicas e Hidrofílicas , Inmunotoxinas/química , Poliésteres/química , Poliésteres/toxicidad , Animales , Línea Celular , Técnicas de Química Sintética , Diseño de Fármacos , Inmunotoxinas/toxicidad , Ratones , Poliésteres/síntesis química , Polimerizacion , Relación Estructura-Actividad
7.
Bioorg Med Chem ; 27(13): 2985-2990, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31128992

RESUMEN

We report a study that seeks to find a correlation between the overall sensitization potential quantified by the expression of IL-8 by stimulated monocytes and the chemical structure of a model contact allergen, 2,4-dinitrochlorobenzene (DNCB). We show that structure and reactivity of the chemical compounds play an important role in activation of the monocytes and subsequent inflammation in tissue. However, we observed a non-linear correlation between the rate of reaction and biological activity indicating a required balance of stability and reactivity.


Asunto(s)
Alérgenos/química , Dinitroclorobenceno/química , Estructura Molecular
8.
Nature ; 553(7689): 414-415, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32094788
9.
Nature ; 553(7689): 414-415, 2018 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-29368706
10.
Angew Chem Int Ed Engl ; 58(35): 12023-12026, 2019 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-31267620

RESUMEN

Mechanical initiation of polymerization offers the chance to generate polymers in new environments using an energy source with unique capabilities. Recently, a renewed interest in mechanically controlled polymerization has yielded many techniques for controlled radical polymerization by ultrasound. However, other types of polymerizations induced by mechanical activation are rare, especially for generating high-molecular-weight polymers. Herein is an example of using piezoelectric ZnO nanoparticles to generate free-radical species that initiate chain-growth polymerization and polymer crosslinking. The fast generation of high amounts of reactive radicals enable the formation of polymer/gel by ultrasound activation. This chemistry can be used to harness mechanical energy for constructive purposes in polymeric materials and for controlled polymerizations for bulk-scale reactions.

11.
Bioconjug Chem ; 29(3): 587-603, 2018 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-29378134

RESUMEN

Toll-like receptors (TLRs) are vital elements of the mammalian immune system that function by recognizing pathogen-associated molecular patterns (PAMPs), bridging innate and adaptive immunity. They have become a prominent therapeutic target for the treatment of infectious diseases, cancer, and allergies, with many TLR agonists currently in clinical trials or approved as immunostimulants. Numerous studies have shown that conjugation of TLR agonists to other molecules can beneficially influence their potency, toxicity, pharmacokinetics, or function. The functional properties of TLR agonist conjugates, however, are highly dependent on the ligation strategy employed. Here, we review the chemical structural requirements for effective functional TLR agonist conjugation. In addition, we provide similar analysis for those that have yet to be conjugated. Moreover, we discuss applications of covalent TLR agonist conjugation and their implications for clinical use.


Asunto(s)
Adyuvantes Inmunológicos/química , Receptores Toll-Like/agonistas , Vacunas Sintéticas/química , Inmunidad Adaptativa , Adyuvantes Inmunológicos/síntesis química , Adyuvantes Inmunológicos/farmacología , Animales , Técnicas de Química Sintética/métodos , Humanos , Inmunidad Innata , Modelos Moleculares , Receptores Toll-Like/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/farmacología
12.
Bioconjug Chem ; 29(3): 748-760, 2018 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-29172458

RESUMEN

The quest for new potent and safe adjuvants with which to skew and boost the immune response of vaccines against intracellular pathogens and cancer has led to the discovery of a series of small molecules that can activate Toll-like receptors (TLRs). Whereas many small molecule TLR agonists cope with a problematic safety profile, amphotericin B (AmpB), a Food and Drug Administration approved antifungal drug, has recently been discovered to possess TLR-triggering activity. However, its poor aqueous solubility and cytotoxicity at elevated concentrations currently hampers its development as a vaccine adjuvant. We present a new class of transiently thermoresponsive polymers that, in their native state, have a phase-transition temperature below room temperature but gradually transform into fully soluble polymers through acetal hydrolysis at endosomal pH values. RAFT polymerization afforded well-defined block copolymers that self-assemble into micellar nanoparticles and efficiently encapsulate AmpB. Importantly, nanoencapsulation strongly reduced the cytotoxic effect of AmpB but maintained its TLR-triggering capacity. Studies in mice showed that AmpB-loaded nanoparticles can adjuvant an RSV vaccine candidate with almost equal potency as a highly immunogenic oil-in-water benchmark adjuvant.


Asunto(s)
Acetales/química , Adyuvantes Inmunológicos/administración & dosificación , Anfotericina B/administración & dosificación , Preparaciones de Acción Retardada/química , Polímeros/química , Vacunas contra Virus Sincitial Respiratorio/administración & dosificación , Receptores Toll-Like/agonistas , Acetales/efectos adversos , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , Anfotericina B/efectos adversos , Anfotericina B/uso terapéutico , Animales , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Preparaciones de Acción Retardada/efectos adversos , Femenino , Ratones Endogámicos BALB C , Nanopartículas/efectos adversos , Nanopartículas/química , Polímeros/efectos adversos , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Vacunas contra Virus Sincitial Respiratorio/uso terapéutico , Temperatura , Receptores Toll-Like/inmunología , Temperatura de Transición
13.
Angew Chem Int Ed Engl ; 57(35): 11208-11212, 2018 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-29992680

RESUMEN

Mechano-activated chemistry is a powerful tool for remodeling of synthetic polymeric materials, however, few reactions are currently available. Here we show that using piezochemical reduction of a CuII -based pre-catalyst, a step-growth polymerization occurs via the copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction to form a linear polytriazole. Furthermore, we show that a linear polymer can be crosslinked mechanochemically using the same chemistry to form a solid organogel. We envision that this chemistry can be used to harness mechanical energy for constructive purposes in polymeric materials.

14.
Chembiochem ; 16(12): 1744-8, 2015 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-26097006

RESUMEN

The spatial and temporal aspects of immune cell signaling are key parameters in defining the magnitude of an immune response. Toll-like receptors (TLRs) on innate immune cells are important in the early detection of pathogens and initiation of an immune response. Controlling the spatial and temporal signaling of TLRs would enable further study of immune synergies and assist in the development of new vaccines. Here, we show a light-based method for the spatial control of TLR4 signaling. A TLR4 agonist, pyrimido[5,4-b]indole, was protected with a cage at a position critical for receptor binding. This afforded a photocontrollable agonist that was inactive while caged, yet effected NF-κB activity in cells following UV photocontrolled deprotection. We demonstrated spatial control of NF-κB activation within a population of cells by treating all cells with the caged TLR4 agonist and constraining light exposure and consequent activation to a region of interest.


Asunto(s)
Macrófagos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Toll-Like 4/agonistas , Animales , Células Cultivadas , Modelos Biológicos , Estructura Molecular , Proteínas Serina-Treonina Quinasas/efectos de la radiación , Rayos Ultravioleta , Quinasa de Factor Nuclear kappa B
15.
Angew Chem Int Ed Engl ; 54(20): 5962-5, 2015 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-25800006

RESUMEN

Inflammatory immune responses are mediated by signaling molecules that are both produced by and recognized across highly heterogeneous cell populations. As such, the study of inflammation using traditional immunostimulants is complicated by paracrine and autocrine signaling, which obscures the origin of a propagating response. To address this challenge, we developed a small-molecule probe that can photosensitize immune cells, thus allowing light-mediated inflammation. This probe was used to control the origin of inflammation using light. Following this motif, inflammation was initiated from fibroblasts or dendritic cells. The contributions of fibroblasts and dendritic cells in initiating inflammation in heterogeneous co-culture are reported, thus providing insights into the future development of vaccines and treatment of inflammation.


Asunto(s)
Inflamación/inmunología , Lipopéptidos/inmunología , Sondas Moleculares/inmunología , Técnicas de Cocultivo , Células Dendríticas/inmunología , Fibroblastos/inmunología , Humanos , Lipopéptidos/síntesis química , Lipopéptidos/química , Modelos Moleculares , Sondas Moleculares/síntesis química , Sondas Moleculares/química , Estructura Molecular , Procesos Fotoquímicos
16.
J Am Chem Soc ; 136(31): 10823-5, 2014 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-25029205

RESUMEN

The innate immune response is controlled, in part, by the synergistic interaction of multiple Toll-like receptors (TLRs). This multi-receptor cooperation is responsible for the potent activity of many vaccines, but few tools have been developed to understand the spatio-temporal elements of TLR synergies. In this Communication, we present photo-controlled agonists of TLR7/8. By strategically protecting the active agonist moiety based on an agonist-bound crystal structure, TLR activity is suppressed and then regained upon exposure to light. We confirmed NF-κB production upon light exposure in a model macrophage cell line. Primary cell activity was confirmed by examining cytokine and cell surface marker production in bone-marrow-derived dendritic cells. Finally, we used light to activate dendritic cell sub-populations within a larger population.


Asunto(s)
Células Dendríticas/inmunología , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/efectos de la radiación , Luz , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Aminoquinolinas/química , Aminoquinolinas/farmacología , Animales , Células de la Médula Ósea/citología , Línea Celular , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Células Dendríticas/efectos de la radiación , Imiquimod , Ratones , Modelos Moleculares , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/química , Receptor Toll-Like 8/metabolismo
17.
Angew Chem Int Ed Engl ; 53(1): 189-92, 2014 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-24259411

RESUMEN

We report increased stimulation of dendritic cells via heterodimers of immunostimulants formed at a discrete molecular distance. Many vaccines present spatially organized agonists to immune cell receptors. These receptors cluster suggesting that signaling is increased by spatial organization and receptor proximity, but this has not been directly tested for multiple, unique receptors. In this study we probe the spatial aspect of immune cell activation using heterodimers of two covalently attached immunostimulants.


Asunto(s)
Adyuvantes Inmunológicos/química , Polímeros/química , Fosforilación , Transducción de Señal
18.
Front Immunol ; 15: 1340384, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38322261

RESUMEN

The innate immune system initiates early response to infection by sensing molecular patterns of infection through pattern-recognition receptors (PRRs). Previous work on PRR stimulation of macrophages revealed significant heterogeneity in single cell responses, suggesting the importance of individual macrophage stimulation. Current methods either isolate individual macrophages or stimulate a whole culture and measure individual readouts. We probed single cell NF-κB responses to localized stimuli within a naïve culture with Fluidic Force Microscopy (FluidFM). Individual cells stimulated in naïve culture were more sensitive compared to individual cells in uniformly stimulated cultures. In cluster stimulation, NF-κB activation decreased with increased cell density or decreased stimulation time. Our results support the growing body of evidence for cell-to-cell communication in macrophage activation, and limit potential mechanisms. Such a mechanism might be manipulated to tune macrophage sensitivity, and the density-dependent modulation of sensitivity to PRR signals could have relevance to biological situations where macrophage density increases.


Asunto(s)
Inmunidad Innata , FN-kappa B , Microscopía de Fuerza Atómica , Macrófagos , Receptores de Reconocimiento de Patrones
19.
STAR Protoc ; 5(1): 102873, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38427566

RESUMEN

Here, we present a protocol to deliver nanoliter volumes of Toll-like receptor (TLR) agonist onto a culture of nuclear factor κB (NF-κB) reporter macrophages using fluidic force microscopy and a micron-scale probe. We describe steps for quantifying the dose of agonist by modeling their diffusion with experimental inputs. We then detail procedures for quantifying and categorizing macrophage responses to individual and varied doses and combining agonist concentration and macrophage response to analyze the NF-κB response to localized TLR stimulation. For complete details on the use and execution of this protocol, please refer to Mulder et al. (2024).1.


Asunto(s)
FN-kappa B , Receptores Toll-Like , FN-kappa B/fisiología , Microscopía de Fuerza Atómica , Receptor Toll-Like 4 , Macrófagos
20.
ACS Appl Mater Interfaces ; 16(14): 17973-17980, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38418392

RESUMEN

Frontal polymerization (FP) is an approach for thermosetting plastics at a lower energy cost than an autoclave. The potential to generate simultaneous propagation of multiple polymerization fronts has been discussed as an exciting possibility. However, FP initiated at more than two points simultaneously has not been demonstrated. Multipoint initiation could enable both large-scale material fabrication and unique pattern generation. Here, the authors present laser-patterned photothermal heating as a method for simultaneous initiation of FP at multiple locations in a 2-D sample. Carbon black particles are mixed into liquid resin (dicyclopentadiene) to enhance absorption of light from a Ti:sapphire laser (800 nm) focused on a sample. The laser is time-shared by rapid steering among initiation points, generating polymerization using up to seven simultaneous points of initiation. This process results in the formation of both symmetric and asymmetric seam patterns resulting from the collision of fronts. The authors also present and validate a theoretical framework for predicting the seam patterns formed by front collisions. This framework allows the design of novel patterns via an inverse solution for determining the initiation points required to form a desired pattern. Future applications of this approach could enable rapid, energy-efficient manufacturing of novel composite-like patterned materials.

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