Exosomes derived from mesenchymal stem cells primed with disease-condition-serum improved therapeutic efficacy in a mouse rheumatoid arthritis model via enhanced TGF-ß1 production.

BACKGROUNDS: Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation-mediated progressive destruction of the cartilage and bone, resulting in reduced quality of life. We primed human telomerase reverse transcriptase-overexpressing immortalized human adipose tissue-derived mesenchymal stem cells (iMSCs) with serum derived from a non-human primate RA model and studied the immunomodulatory ability of exosomes obtained from primed iMSCs. METHODS: After immunophenotyping, nanoparticle tracking analysis, and in vitro functional tests, Dulbecco's phosphate-buffered saline (dPBS, Group C), exosomes derived from the supernatant of iMSCs (Exo-FBS, Group E), exosomes derived from the supernatant of iMSCs primed with RA serum (Exo-RA, Group F), and methotrexate (Group M) were administered in collagen-induced arthritis (CIA) model mice. dPBS was administered to the normal (N) group for comparison (n = 10/group). RESULTS: Exo-RA had a significantly higher number of exosomes compared to Exo-FBS when measured with nanoparticle tracking analysis or exosome marker CD81, and Transforming growth factor-ß1 amounts were significantly higher in Exo-RA than in Exo-FBS. When Exo-FBS or Exo-RA was administered to the collagen-induced arthritis model, serum interleukin (IL)-4 and the proportion of Th2 (CD4+CD25+GATA3+) and M2 (CD11c - CD206+ of CD45+CD64+) cells were significantly increased compared to the control group. Furthermore, Exo-RA could alleviate cartilage damage by significantly lowering the concentrations of proinflammatory cytokines such as tumor necrosis factor-α, keratinocyte chemoattractant, and IL-12p70. CONCLUSION: Exosomes derived from disease-condition-serum-primed iMSCs ameliorated cartilage damage in a RA model by enhancing TGF-ß1 production, inducing Th2 and M2 polarization and lowering proinflammatory cytokines, TNF-α, KC, and IL-12p70 in the host. Patient-derived serum can be used as an iMSC priming strategy in iMSC-derived exosome treatment of RA.

Individual Postprandial Glycemic Responses to Meal Types by Different Carbohydrate Levels and Their Associations with Glycemic Variability Using Continuous Glucose Monitoring.

This study aimed to investigate individual postprandial glycemic responses (PPGRs) to meal types with varying carbohydrate levels and examine their associations with 14-day glycemic variability using continuous glucose monitoring (CGM) in young adults. In a two-week intervention study with 34 participants connected to CGM, four meal types and glucose 75 g were tested. PPGRs were recorded for up to 2 h with a 15 min interval after meals. Data-driven cluster analysis was used to group individual PPGRs for each meal type, and correlation analysis was performed of 14-day glycemic variability and control with related factors. Participants had a mean age of 22.5 years, with 22.8% being male. Four meal types were chosen according to carbohydrate levels. The mean glucose excursion for all meal types, except the fruit bowl, exhibited a similar curve with attenuation. Individuals classified as high responders for each meal type exhibited sustained peak glucose levels for a longer duration compared to low responders, especially in meals with carbohydrate contents above 50%. A meal with 45% carbohydrate content showed no correlation with either 14-day glycemic variability or control. Understanding the glycemic response to carbohydrate-rich meals and adopting a meal-based approach when planning diets are crucial to improving glycemic variability and control.

Poisson-Nernst-Planck framework for modelling ionic strain and temperature sensors.

Ionically conductive hydrogels are gaining traction as sensing and structural materials for use bioelectronic devices. Hydrogels that feature large mechanical compliances and tractable ionic conductivities are compelling materials that can sense physiological states and potentially modulate the stimulation of excitable tissue because of the congruence in electro-mechanical properties across the tissue-material interface. However, interfacing ionic hydrogels with conventional DC voltage-based circuits poses several technical challenges including electrode delamination, electrochemical reaction, and drifting contact impedance. Utilizing alternating voltages to probe ion-relaxation dynamics has been shown to be a viable alternative for strain and temperature sensing. In this work, we present a Poisson-Nernst-Planck theoretical framework to model ion transport under alternating fields within conductors subject to varying strains and temperatures. Using simulated impedance spectra, we develop key insights about the relationship between frequency of the applied voltage perturbation and sensitivity. Lastly, we perform preliminary experimental characterization to demonstrate the applicability of the proposed theory. We believe this work provides a useful perspective that is applicable to the design of a variety of ionic hydrogel-based sensors for biomedical and soft robotic applications.

Hysteresis-free and high sensitivity strain sensing of ionically conductive hydrogels.

Hydrogels are promising materials for soft and implantable strain sensors owing to their large compliance (E<100 kPa) and significant extensibility (εmax >500%) compared to other polymer networks. Further, hydrogels can be functionalized to seamlessly integrate with many types of tissues. However, most current methods attempt to imbue additional electronic functionality to structural hydrogel materials by incorporating fillers with orthogonal properties such as electronic or mixed ionic conduction. Although composite strategies may improve performance or facilitate heterogeneous integration with downstream hardware, composites complicate the path for regulatory approval and may compromise the otherwise compelling properties of the underlying structural material. Here we report hydrogel strain sensors composed of genipin-crosslinked gelatin and dopamine-functionalized poly(ethylene glycol) for in vivo monitoring of cardiac function. By measuring their impedance only in their resistive regime (>10 kHz), hysteresis is reduced and the resulting gauge factor is increased by ~50x to 1.02±0.05 and 1.46±0.05 from approximately 0.03-0.05 for PEG-Dopa and genipin-crosslinked gelatin respectively. Adhesion and in vivo biocompatibility are studied to support implementation of strain sensors for monitoring cardiac output in porcine models. Impedance-based strain sensing in the kilohertz regime simplifies the piezoresistive behavior of these materials and expands the range of hydrogel-based strain sensors.

Recent Progress in Materials Chemistry to Advance Flexible Bioelectronics in Medicine.

Designing bioelectronic devices that seamlessly integrate with the human body is a technological pursuit of great importance. Bioelectronic medical devices that reliably and chronically interface with the body can advance neuroscience, health monitoring, diagnostics, and therapeutics. Recent major efforts focus on investigating strategies to fabricate flexible, stretchable, and soft electronic devices, and advances in materials chemistry have emerged as fundamental to the creation of the next generation of bioelectronics. This review summarizes contemporary advances and forthcoming technical challenges related to three principal components of bioelectronic devices: i) substrates and structural materials, ii) barrier and encapsulation materials, and iii) conductive materials. Through notable illustrations from the literature, integration and device fabrication strategies and associated challenges for each material class are highlighted.

Dual Ion Releasing Nanoparticles for Modulating Osteogenic Cellular Microenvironment of Human Mesenchymal Stem Cells.

In this study we developed a dual therapeutic metal ion-releasing nanoparticle for advanced osteogenic differentiation of stem cells. In order to enhance the osteogenic differentiation of human mesenchymal stem cells (hMSCs) and induce angiogenesis, zinc (Zn) and iron (Fe) were synthesized together into a nanoparticle with a pH-sensitive degradation property. Zn and Fe were loaded within the nanoparticles to promote early osteogenic gene expression and to induce angiogenic paracrine factor secretion for hMSCs. In vitro studies revealed that treating an optimized concentration of our zinc-based iron oxide nanoparticles to hMSCs delivered Zn and Fe ion in a controlled release manner and supported osteogenic gene expression (RUNX2 and alkaline phosphatase) with improved vascular endothelial growth factor secretion. Simultaneous intracellular release of Zn and Fe ions through the endocytosis of the nanoparticles further modulated the mild reactive oxygen species generation level in hMSCs without cytotoxicity and thus improved the osteogenic capacity of the stem cells. Current results suggest that our dual ion releasing nanoparticles might provide a promising platform for future biomedical applications.