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Non‐spherical stimuli‐responsive polymeric particles have shown critical importance in therapeutic delivery. Herein, pH‐responsive poly(methacrylic acid) (PMAA) cubic hydrogel microparticles are synthesized by crosslinking PMAA layers within PMAA/poly(N‐vinylpyrrolidone) hydrogen‐bonded multilayers templated on porous inorganic microparticles. This study investigates the effects of template porosity and surface morphology on the PMAA multilayer hydrogel microcube properties. It is found that the hydrogel structure depends on the template's calcination time and temperature. The pH‐triggered PMAA hydrogel cube swelling depends on the hydrogel's internal architecture, either hollow capsule‐like or non‐hollow continuous hydrogels. The loading efficiency of the doxorubicin (DOX) drug inside the microcubes is analyzed by high‐performance liquid chromatography (HPLC), and shows the dependenceof the drug uptake on the network structure and morphology controlled by the template porosity. Varying the template calcination from low (300 °C) to high (1000 °C) temperature results in a 2.5‐fold greater DOX encapsulation by the hydrogel cubes. The effects of hydrogel surface charge on the DOX loading and release are also studied using zeta‐potential measurements. This work provides insight into the effect of structural composition, network morphology, and pH‐induced swelling of the cubical hydrogels and may advance the development of stimuli‐responsive vehicles for targeted anticancer drug delivery. Cubic porous hydrogel microparticles are obtained through polymer multilayer templated assembly using porous inorganic microcubes. The effects of template morphology on the architecture of the poly(methacrylic acid) multilayer hydrogel microcubes , hydrogel swelling, and the doxorubicin drug encapsulation and release are demonstrated. This work may advance the development of stimuli‐responsive vehicles for targeted drug delivery.

Pain is a key symptom associated with rheumatoid arthritis (RA) and can persist even in the context of overall disease control by standard‐of‐care disease modifying anti‐rheumatic drugs (DMARDs). Analgesic agents and corticosteroids are often used to supplement DMARDs for pain relief but lack disease modifying properties, and their sustained use carries adverse risks. In this work, we characterized the progression of pain sensitivity in the SKG mouse model of RA and evaluated the potential therapeutic interventions. Male and female SKG mice, after systemic mannan injection, developed a mechanical pain phenotype and joint swelling, with a strong inverse correlation between clinical arthritis scores and pain thresholds. To test potential interventions for pain alleviation, we evaluated all‐trans retinoic acid (ATRA)‐loaded poly(lactic‐co‐glycolic acid) microparticles (ATRA‐PLGA MP) administered via intra‐articular injection, which we have previously demonstrated to be disease‐modifying. The pain and inflammation patterns assessed by the von Frey test and clinical scoring showed ATRA‐PLGA MP monotherapy reduced inflammation and alleviated mechanical allodynia in arthritic SKG mice, an effect that was amplified by combination treatments with standard‐of‐care agents. In early‐stage arthritis, co‐administration with cytotoxic T‐lymphocyte‐associated protein (CTLA)‐4‐Ig, clinically known as abatacept, delayed disease progression and sustained the reduction of mechanical allodynia. In established arthritis, sequential treatment with the corticosteroid dexamethasone (Dex) reduced cumulative disease burden and reduced mechanical allodynia. These findings highlight the potential of combining ATRA‐PLGA MP with standard‐of‐care treatments as a potential strategy to enhance the efficacy and durability of disease modification and pain alleviation for arthritis management.

A significant portion of adolescents suffer from mental illnesses and persistent pain due to repeated stress. The components of the nervous system that link stress and pain in early life remain unclear. Prior studies in adult mice implicated the innate immune system, specifically Toll-like receptors (TLRs), as critical for inducing long-term anxiety and pain-like behaviors in social defeat stress (SDS) models. In this work, we investigated the pain and anxiety behavioral phenotypes of wild-type and TLR4-deficient juvenile mice subjected to repeated SDS and evaluated the engagement of TLR4 by measuring dimerization in the spinal cord, dorsal root ganglia, and prefrontal cortex. Male juvenile (4-week-old) mice (C57BL/6J or Tlr4-/-) underwent six social defeat sessions with adult aggressor (CD1) mice. In WT mice, SDS promotes chronic mechanical allodynia and thermal hyperalgesia assessed via von Frey testing and the Hargreaves test, respectively. In parallel, the stressed WT mice exhibited transient anxiety-like behavior and long-lasting locomotor activity reduction in the open-field test. Tlr4-/--stressed animals were resistant to the induction of pain-like behavior but had a remnant of anxious behavior, spending less time in the center of the arena. In WT SDS, there were concordant robust increases in TLR4 dimerization in dorsal root ganglia macrophages and spinal cord microglia, indicating TLR4 activation. These results suggest that the chronic pain phenotype and locomotor impairment induced by SDS in juvenile mice depends on TLR4 engagement evidenced by dimerization in immune cells of the dorsal root ganglia and spinal cord.

Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.

Polymer thin films possess unique properties, cost-effectiveness, and flexibility, making them vital for enhancing surface functionality. Layer-by-layer (LbL) assembly allows for synthesis of ultrathin polymeric films with precise control over film thickness, material selection, surface chemistry, and responsiveness. Current advancements in LbL assembly focus on understanding film formation and deposition conditions on film’s structure and properties. Covalent cross-linking of physically bonded LbL networks forms multilayer hydrogel networks capable of absorbing large amounts of water. The use of stimuli-responsive polymers has facilitated the advancement of \"smart\" materials capable of responding to external stimuli. Stimuli-responsive hydrogels exhibit reversible volume changes, making them valuable in biosensing and controlled therapeutic delivery. Thus, this dissertation explores pH-sensitive ultrathin hydrogen-bonded coatings and hydrogel films, investigating the influence of network structure on film properties.Chapter 1 of the dissertation provides an introductory overview of stimuli-responsive polymers and hydrogels, emphasizing the significance of the relationship between structure and the properties of hydrogels. Chapter 2 focuses on the growth of hydrogen-bonded poly(methacrylic acid)/poly(N-vinylpyrrolidone) (PMAA/PVPON) multilayers using atomic force microscopy and examines the impact of shaking during film assembly on chain diffusion, polymer adsorption, and film properties. Chapter 2 examines the impact of molecular chain rearrangements on the roughness and thickness of planar membranes or multilayer capsule shells following the removal of the substrate.In Chapter 3, the synthesis of free-standing ultrathin hydrogen-bonded (PMAA/PVPON) films and (PMAA) hydrogels is discussed. The effects of the release method on film properties are investigated, and the influence of Zr(IV) ionic species on the mechanical properties and swelling of hydrogels is explored. The chapter highlights the control of thin film properties through pH-triggered hydration and the incorporation of ionic species.Chapter 4 presents a two-module research project utilizing an alginate gel platform to study hydrogel structure-property relationships. Students investigate the impact of synthesis conditions on gel bead size and analyze the effects of gel size and solution environment on dye encapsulation and release. The experiment provides a comprehensive learning experience, integrating concepts from general chemistry, polymer science, and material science.Chapter 5 concludes by discussing the potential applications of pH-responsive LbL hydrogel coatings in sensing and drug delivery, highlighting their significance, versatility, and future research directions.Overall, this dissertation contributes to our understanding of polymer thin hydrogen-bonded films and hydrogels, offering insights into their synthesis, properties, and applications across various fields of research.