Bioinspired, ingestible electroceutical capsules for hunger-regulating hormone modulation.

The gut-brain axis, which is mediated via enteric and central neurohormonal signaling, is known to regulate a broad set of physiological functions from feeding to emotional behavior. Various pharmaceuticals and surgical interventions, such as motility agents and bariatric surgery, are used to modulate this axis. Such approaches, however, are associated with off-target effects or post-procedure recovery time and expose patients to substantial risks. Electrical stimulation has also been used to attempt to modulate the gut-brain axis with greater spatial and temporal resolution. Electrical stimulation of the gastrointestinal (GI) tract, however, has generally required invasive intervention for electrode placement on serosal tissue. Stimulating mucosal tissue remains challenging because of the presence of gastric and intestinal fluid, which can influence the effectiveness of local luminal stimulation. Here, we report the development of a bioinspired ingestible fluid-wicking capsule for active stimulation and hormone modulation (FLASH) capable of rapidly wicking fluid and locally stimulating mucosal tissue, resulting in systemic modulation of an orexigenic GI hormone. Drawing inspiration from Moloch horridus, the "thorny devil" lizard with water-wicking skin, we developed a capsule surface capable of displacing fluid. We characterized the stimulation parameters for modulation of various GI hormones in a porcine model and applied these parameters to an ingestible capsule system. FLASH can be orally administered to modulate GI hormones and is safely excreted with no adverse effects in porcine models. We anticipate that this device could be used to treat metabolic, GI, and neuropsychiatric disorders noninvasively with minimal off-target effects.

Interplay of Genotype and Substrate Stiffness in Driving the Hypertrophic Cardiomyopathy Phenotype in iPSC-Micro-Heart Muscle Arrays.

INTRODUCTION: In clinical and animal studies, Hypertrophic Cardiomyopathy (HCM) shares many similarities with non-inherited cardiac hypertrophy induced by pressure overload (hypertension). This suggests a potential role for mechanical stress in priming tissues with mutation-induced changes in the sarcomere to develop phenotypes associated with HCM, including hypercontractility and aberrant calcium handling. Here, we tested the hypothesis that heterozygous loss of function of Myosin Binding Protein C (MYBCP3 +/- , mutations in which account for almost 50% of inherited HCM) combines with environmental stiffness to drive HCM phenotypes. METHODS: We differentiated isogenic control (WTC) and MYBPC3 +/- iPSC into cardiomyocytes using small molecule manipulation of Wnt signaling, and then purified them using lactate media. The purified cardiomyocytes were seeded into "dog bone" shaped stencil molds to form micro-heart muscle arrays (µHM). To mimic changes in myocardial stiffness stemming from pressure overload, we varied the rigidity of the substrates µHM contract against. Stiffness levels ranged from those corresponding to fetal (5 kPa), healthy (15 kPa), pre-fibrotic (30 kPa) to fibrotic (65 kPa) myocardium. Substrates were embedded with a thin layer of fluorescent beads to track contractile force, and parent iPSC were engineered to express the genetic calcium indicator, GCaMP6f. High speed video microscopy and image analysis were used to quantify calcium handling and contractility of µHM. RESULTS: Substrate rigidity triggered physiological adaptation for both genotypes. However, MYBPC3 +/- µHM showed a lower tolerance to substrate stiffness with the peak traction on 15 kPa, while WTC µHM had peak traction on 30 kPa. MYBPC3 +/- µHM exhibited hypercontractility, which was exaggerated by substrate rigidity. MYBPC3 +/- µHM hypercontractility was associated with longer rise times for calcium uptake and force development, along with higher overall Ca2+ intake. CONCLUSION: We found MYBPC3 +/- mutations cause iPSC-µHM to exhibit hypercontractility, and also a lower tolerance for mechanical stiffness. Understanding how genetics work in combination with mechanical stiffness to trigger and/or exacerbate pathophysiology may lead to more effective therapies for HCM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s12195-021-00684-x).

Elastomer-Grafted iPSC-Derived Micro Heart Muscles to Investigate Effects of Mechanical Loading on Physiology.

Mechanical loading plays a critical role in cardiac pathophysiology. Engineered heart tissues derived from human induced pluripotent stem cells (iPSCs) allow rigorous investigations of the molecular and pathophysiological consequences of mechanical cues. However, many engineered heart muscle models have complex fabrication processes and require large cell numbers, making it difficult to use them together with iPSC-derived cardiomyocytes to study the influence of mechanical loading on pharmacology and genotype-phenotype relationships. To address this challenge, simple and scalable iPSC-derived micro-heart-muscle arrays (µHM) have been developed. "Dog-bone-shaped" molds define the boundary conditions for tissue formation. Here, we extend the µHM model by forming these tissues on elastomeric substrates with stiffnesses spanning from 5 to 30 kPa. Tissue assembly was achieved by covalently grafting fibronectin to the substrate. Compared to µHM formed on plastic, elastomer-grafted µHM exhibited a similar gross morphology, sarcomere assembly, and tissue alignment. When these tissues were formed on substrates with different elasticity, we observed marked shifts in contractility. Increased contractility was correlated with increases in calcium flux and a slight increase in cell size. This afterload-enhanced µHM system enables mechanical control of µHM and real-time tissue traction force microscopy for cardiac physiology measurements, providing a dynamic tool for studying pathophysiology and pharmacology.

Effect of the Management of LGBTT+ Identity on Psychological Wellbeing.

The current study, guided by the Minority Stress Model (Meyer, 2003), seeks to examine the effect of sexual orientation or gender identity management (disclosure or concealment) in the relationship between internalized negative ideals (internalized homonegativity and internalized transnegativity) and psychological wellbeing in LGBTT+ people in Puerto Rico. Four instruments were translated from English to Spanish, two of them relating to the management of the minority identity, and two regarding the internalized negative ideals. Additionally, reliability measures were calculated for each instrument. The sample consisted of 203 participants, 165 identified as cisgendered, and 38 identified themselves as trans or another gender. Results suggested that internalized negative ideals predicted the minority identity management in LGBTT+ people. However, the relationship between the internalized negative ideals and psychological wellbeing was only confirmed in terms of sexual orientation and not of gender identity, which suggests that other factors may better explain wellbeing in trans people. A discussion is presented on these results' implications and the study's challenges and limitations due to the Covid-19 pandemic, and suggestions for further studies.

La presente investigación, guiada por el Modelo de Estrés de Minorías (Meyer, 2003), busca examinar el efecto del manejo de la orientación sexual o identidad de género, entiéndase divulgación u ocultación, en la relación de homonegatividad internalizada/transfobia internalizada con el bienestar psicológico en personas LGBTT+ en Puerto Rico. Se tradujeron cuatro instrumentos, dos relacionados al manejo de la identidad minoritaria (ocultación o divulgación), y dos sobre los ideales negativos internalizados, y se calculó su confiabilidad. La muestra consistió de 203 participantes, donde 165 se identificaron como cisgénero, y 38 como trans u otro género. Los hallazgos mostraron que los ideales negativos internalizados predijeron el manejo de la identidad minoritaria para las personas LGBTT+. No obstante, la relación entre los ideales negativos internalizados y el bienestar psicológico solo se confirmó para los ideales de la orientación sexual, y no de la identidad de género, lo cual sugiere que otros factores pueden explicar de forma más significativa el bienestar en las personas transgénero. Se presenta una discusión de las implicaciones de estos resultados. A su vez, se describen los retos y las limitaciones del estudio debido al COVID-19, así como recomendaciones para futuros estudios.