The use of microneedles has facilitated the painless localized delivery of drugs across the skin. However, their efficacy has been limited by slow diffusion of molecules and often requires external triggers. Herein, an autonomous and degradable, active microneedle delivery platform is introduced, employing magnesium microparticles loaded within the microneedle patch, as the built-in engine for deeper and faster intradermal payload delivery. The magnesium particles react with the interstitial fluid, leading to an explosive-like rapid production of H2 bubbles, providing thenecessary force to breach dermal barriers and enhance payload delivery. The release kinetics of active microneedles is evaluated in vitro by measuring the amount of IgG antibody (as a model drug) that passed through phantom tissue and a pigskin barrier. In vivo experiments using a B16F10 mouse melanoma model demonstrate that the active delivery of anti-CTLA-4 (a checkpoint inhibitor drug) results in greatly enhanced immune response. and significantly longer survival. Moreover, spatially resolved zones of active and passive microneedles allow a combinatorial rapid burst response along with slow, sustained release, respectively. Such versatile and effective autonomous dynamic microneedle delivery technology offers considerable promise for a wide range of therapeutic applications, toward a greatly enhanced outcome, convenience, and cost.

Infrared thermographs (IRTs) implemented according to standardized best practices have shown strong potential for detecting elevated body temperatures (EBT), which may be useful in clinical settings and during infectious disease epidemics. However, optimal IRT calibration methods have not been established and the clinical performance of these devices relative to the more common non-contact infrared thermometers (NCITs) remains unclear. In addition to confirming the findings of our preliminary analysis of clinical study results, the primary intent of this study was to compare methods for IRT calibration and identify best practices for assessing the performance of IRTs intended to detect EBT. A key secondary aim was to compare IRT clinical accuracy to that of NCITs. We performed a clinical thermographic imaging study of more than 1000 subjects, acquiring temperature data from several facial locations that, along with reference oral temperatures, were used to calibrate two IRT systems based on seven different regression methods. Oral temperatures imputed from facial data were used to evaluate IRT clinical accuracy based on metrics such as clinical bias (Δcb), repeatability, root-mean-square difference, and sensitivity/specificity. We proposed several calibration approaches designed to account for the non-uniform data density across the temperature range and a constant offset approach tended to show better ability to detect EBT. As in our prior study, inner canthi or full-face maximum temperatures provided the highest clinical accuracy. With an optimal calibration approach, these methods achieved a Δcb between ±0.03 °C with standard deviation (σΔcb) less than 0.3 °C, and sensitivity/specificity between 84% and 94%. Results of forehead-center measurements with NCITs or IRTs indicated reduced performance. An analysis of the complete clinical data set confirms the essential findings of our preliminary evaluation, with minor differences. Our findings provide novel insights into methods and metrics for the clinical accuracy assessment of IRTs. Furthermore, our results indicate that calibration approaches providing the highest clinical accuracy in the 37–38.5 °C range may be most effective for measuring EBT. While device performance depends on many factors, IRTs can provide superior performance to NCITs.

Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy‐induced side‐effects, termed neutropenia, can lead to immunodeficiency‐associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)‐based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid‐lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post‐HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil‐responsive degradation to sustain the release of granulocyte colony stimulating factor (G‐CSF) from HA cryogels. Sustained release of G‐CSF from HA cryogels enhanced post‐HSCT neutrophil recovery, comparable to pegylated G‐CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (T reg ) and suppression of T reg destabilization. Sustained release poly-(lactic-co-glycolic) acid (PLGA)-based biodegradable microparticles encapsulating ATRA (PLGA-ATRA MP) are retained in arthritic mouse joints after intra-articular (IA) injection. IA PLGA-ATRA MP enhance migratory T reg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of T reg . PLGA-ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen-induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA-ATRA MP is not associated with generalized immune suppression. PLGA-ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.

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Rapamycin encapsulated in mono-(6-amino-6-deoxy)-beta cyclodextrin efficiently expands regulatory T cells for cell-based immunotherapy.

Harnessing an individual's immune cells to mediate antitumor and antiviral responses is a life-saving option for some patients with otherwise intractable forms of cancer and infectious disease. In particular, T-cell-based engineered immune cells are a powerful new class of therapeutics with remarkable efficacy. Clinical experience has helped to define some of the major challenges for reliable, safe, and effective deployment of T-cells against a broad range of diseases. While poised to revolutionize immunotherapy, scalable manufacturing, safety, specificity, and the development of resistance are potential roadblocks in their widespread usage. The development of molecular engineering tools to allow for the direct or indirect engineering of T-cells to enable one to troubleshoot delivery issues, amplify immunomodulatory effects, integrate the synergistic effects of different molecules, and home to the target cells in vivo. In this review, we will analyze thus-far developed cell-and material-based tools for enhancing T-cell therapies, including methods to improve safety and specificity, enhancing efficacy, and overcoming limitations in scalable manufacturing. We summarize the potential of T-cells as immune modulating therapies and the potential future directions for enabling their adoption for a broad range of diseases.

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