Immunotherapy for type 1 diabetes mellitus by adjuvant-free Schistosoma japonicum-egg tip-loaded asymmetric microneedle patch (STAMP).

BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disease mediated by autoreactive T cells and dominated by Th1 response polarization. Insulin replacement therapy faces great challenges to this autoimmune disease, requiring highly frequent daily administration. Intriguingly, the progression of T1DM has proven to be prevented or attenuated by helminth infection or worm antigens for a relatively long term. However, the inevitable problems of low safety and poor compliance arise from infection with live worms or direct injection of antigens. Microneedles would be a promising candidate for local delivery of intact antigens, thus providing an opportunity for the clinical immunotherapy of parasitic products. METHODS: We developed a Schistosoma japonicum-egg tip-loaded asymmetric microneedle patch (STAMP) system, which serves as a new strategy to combat TIDM. In order to improve retention time and reduce contamination risk, a specific imperfection was introduced on the STAMP (asymmetric structure), which allows the tip to quickly separate from the base layer, improving reaction time and patient's comfort. After loading Schistosoma japonicum-egg as the immune regulator, the effects of STAMP on blood glucose control and pancreatic pathological progression improvement were evaluated in vivo. Meanwhile, the immunoregulatory mechanism and biosafety of STAMP were confirmed by histopathology, qRT-PCR, ELISA and Flow cytometric analysis. RESULTS: Here, the newly developed STAMP was able to significantly reduce blood glucose and attenuate the pancreatic injury in T1DM mice independent of the adjuvants. The isolated Schistosoma japonicum-eggs micron slowly degraded in the skin and continuously released egg antigen for at least 2 weeks, ensuring localization and safety of antigen stimulation. This phenomenon should be attributed to the shift of Th2 immune response to reduce Th1 polarization. CONCLUSION: Our results exhibited that STAMP could significantly regulate the blood glucose level and attenuate pancreatic pathological injury in T1DM mice by balancing the Th1/Th2 immune responses, which is independent of adjuvants. This technology opens a new window for the application of parasite products in clinical immunotherapy.

Advanced Temporally-Spatially Precise Technologies for On-Demand Neurological Disorder Intervention.

Temporal-spatial precision has attracted increasing attention for the clinical intervention of neurological disorders (NDs) to mitigate adverse effects of traditional treatments and achieve point-of-care medicine. Inspiring steps forward in this field have been witnessed in recent years, giving the credit to multi-discipline efforts from neurobiology, bioengineering, chemical materials, artificial intelligence, and so on, exhibiting valuable clinical translation potential. In this review, the latest progress in advanced temporally-spatially precise clinical intervention is highlighted, including localized parenchyma drug delivery, precise neuromodulation, as well as biological signal detection to trigger closed-loop control. Their clinical potential in both central and peripheral nervous systems is illustrated meticulously related to typical diseases. The challenges relative to biosafety and scaled production as well as their future perspectives are also discussed in detail. Notably, these intelligent temporally-spatially precision intervention systems could lead the frontier in the near future, demonstrating significant clinical value to support billions of patients plagued with NDs.

Intestinal Villi-Inspired Mathematically Base-Layer Engineered Microneedles (IMBEMs) for Effective Molecular Exchange during Biomarker Enrichment and Drug Deposition in Diversified Mucosa.

The mucosa-interfacing systems based on bioinspired engineering design for sampling/drug delivery have manifested crucial potential for the monitoring of infectious diseases and the treatment of mucosa-related diseases. However, their efficiency and validity are severely restricted by limited contact area for molecular transfer and dissatisfactory capture/detachment capability. Herein, inspired by the multilayer villus structure of the small intestine that enables high nutrient absorption, a trigonometric function-based periodic pattern was fabricated and integrated on the base layer of the microneedle patch, exhibiting a desirable synergistic effect with needle tips for deep sample enrichment and promising molecular transfer, significantly improving the device-mucosa bidirectional interaction. Moreover, mathematical modeling and finite element analysis were adopted to visualize and quantify the microcosmic molecular transmission process, guiding parameter optimization in actual situation. Encouragingly, these intestinal villi-inspired mathematically base-layer engineered microneedles (IMBEMs) have demonstrated distinguished applicability among mucosa tissue with varying surface curvatures, tissue toughness, and local environments, and simultaneously, have gained favorable support from healthy volunteers receiving preliminary test of IMBEMs patches. Overall, validated by numerous in vitro and in vivo tests, the IMBEMs were confirmed to act as a promising candidate to facilitate mucosa-based sampling and topical drug delivery, indicating highly clinical translation potential.

Smart hydrothermally responsive microneedle for topical tumor treatment.

Locoregional therapy has attracted increasing attention for subcutaneous tumors owing to its merits of minimally invasive operation and negligible systematic toxicity. However, to accelerate clinical translation, further promotions in deep-seated penetration, temporal-spatial controllability, personalized adaptability, as well as easy operation are still urgently needed. This work proposed a self-heating-cooking-package-inspired hydrothermally responsive multi-round acturable microneedle (HRMAM) system, which loaded docetaxel (DTX) in the polycaprolactone (PCL), to serve as deeply penetrable, hydrothermal-chemotherapy synergetic, on-demand and self-service anti-tumor treatment. The optimized hydrothermally responsive formulation served as base components for water-based self-heating responsive drug release with synergistic anti-tumor thermal therapy, and simultaneously in combination with well-designed grooved-structure needle tips for directional deep delivery and enhanced transfer efficiency. To satisfy spatial precision and flexible controllability, this engineering-based detachable HRMAM system was divided into three relatively independent segments, which were fitted perfectly with an original-designed applicator for ensuring easy operation in a smart self-service manner. Impressively, the HRMAM system achieved encouraging tumor growth inhibition of 75.11% and 72.29% in animal model of melanomas and breast carcinoma, respectively, much higher than those of other groups receiving traditional treatment, without obvious side effects. It was anticipated that the HRMAM system would manifest great promise to combat unreachable and deep-seated subcutaneous tumors, bellowing clinical values upon locoregional therapy products with high efficiency, low toxicity, flexible controllability, temporal-spatial precision, easy operation, as well as patient's painless, comfort and compliance.

Microneedle arrays integrated with living organisms for smart biomedical applications.

Various living organisms have proven to influence human health significantly, either in a commensal or pathogenic manner. Harnessing the creatures may remarkably improve human healthcare and cure the intractable illness that is challenged using traditional drugs or surgical approaches. However, issues including limited biocompatibility, poor biosafety, inconvenience for personal handling, and low patient compliance greatly hinder the biomedical and clinical applications of living organisms when adopting them for disease treatment. Microneedle arrays (MNAs), emerging as a promising candidate of biomedical devices with the functional diversity and minimal invasion, have exhibited great potential in the treatment of a broad spectrum of diseases, which is expected to improve organism-based therapies. In this review, we systemically summarize the technologies employed for the integration of MNAs with specific living organisms including diverse viruses, bacteria, mammal cells and so on. Moreover, their applications such as vaccination, anti-infection, tumor therapy and tissue repairing are well illustrated. Challenges faced by current strategies, and the perspectives of integrating more living organisms, adopting smarter materials, and developing more advanced technologies in MNAs for future personalized and point-of-care medicine, are also discussed. It is believed that the combination of living organisms with functional MNAs would hold great promise in the near future due to the advantages of both biological and artificial species.

Anti-HSV-1 effect of dihydromyricetin from Ampelopsis grossedentata via the TLR9-dependent anti-inflammatory pathway.

OBJECTIVES: Herpes simplex virus 1 (HSV-1) is one of the most prevalent viruses in humans worldwide. Owing to limited therapeutic options mainly with acyclovir (ACV) and analogues and the emergence of ACV-resistant strains, new drugs with different modes of action and low toxicity are required. The aim of this study was to determine the anti-HSV-1 effect and mechanism of action of the flavonoid compound dihydromyricetin (DHM) from Ampelopsis grossedentata. METHODS: The HSV-1 inhibitory effect of DHM was evaluated by measuring plaque formation and generation of progeny virus as well as expression of HSV-1-related genes in Vero cells. The molecular mechanism of the antiviral activity of DHM against HSV-1 was explored by real-time quantitative PCR and ELISA. RESULTS: DHM presented a significant inhibitory effect on HSV-1 plaque formation and generation of progeny virus, with an EC50 (50% effective concentration) of 12.56 µM in Vero cells. Furthermore, expression of HSV-1 immediate-early genes (ICP4 and ICP22), early genes (ICP8 and UL42) and late genes (gB, VP1/2) was decreased by DHM at concentrations of 16 µM and 32 µM. DHM specifically suppressed mRNA levels of Toll-like receptor 9 (TLR9), leading to inhibition of the inflammatory transcriptional factor NFκB and a decrease in TNFα. CONCLUSION: These findings indicate that the effective inhibitory activity of DHM was achieved by suppressing TNFα production in a TLR9-dependent manner. Although further studies are needed to better characterise the activity of DHM in vivo, the results suggest this extract as a promising new anti-HSV-1 agent.

Preparation of a nanoscale dihydromyricetin-phospholipid complex to improve the bioavailability: in vitro and in vivo evaluations.

Dihydromyricetin (DMY), a flavanonol compound found as the most abundant and bioactive constituent in Ampelopsis grossedentata (Hand-Mazz) W.T. Wang, possesses numerous pharmacological activities, such as antioxidant, anti-inflammation, anticancer, anti-microbial, hypoglycemic and hypolipidemic effects, and so on. Recently, DMY shows a promising potential to develop as an agent for the prevention and treatment of Type 2 diabetes mellitus (T2DM). However, the low oral bioavailability of DMY was one of the special concerns to be resolved for its clinical applications. In this study, DMY phospholipid complex (DMY-HSPC COM) was prepared by the solvent evaporation technique and optimized with DMY combination ratio. Scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrophotometry (FT-IR) were carried to characterize the formation of DMY-HSPC COM. The particle size, zeta potential, drug loading and solubility of DMY-HSPC COM were further investigated. The phospholipid complex technology could significantly improve the solubility of DMY. Pharmacokinetic study results of DMY-HSPC COM in healthy SD rats and T2DM rats demonstrated that the oral bioavailability was significantly increased when compared with pure DMY as well, which could be attributed to the improvement of the aqueous solubility of the complex, absorption promotion and a probable decrease in intestinal and hepatic metabolism. In addition, when compared with healthy SD rats, pharmacokinetic parameters of pure DMY and DMY-HSPC COM showed significant difference in T2DM rats. Thus, phospholipid complex technology holds a promising potential for increasing the oral bioavailability of DMY.