A three-dimensional valve-on-chip microphysiological system implicates cell cycle progression, cholesterol metabolism and protein homeostasis in early calcific aortic valve disease progression.

BACKGROUND: Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. METHODS: In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed. RESULTS: Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment. CONCLUSIONS: In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. STATEMENT OF SIGNIFICANCE: Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment.

Serious Games Based on Cognitive Bias Modification and Learned Helplessness Paradigms for the Treatment of Depression: Design and Acceptability Study.

BACKGROUND: Depression is a debilitating mental health disorder, with a large treatment gap. Recent years have seen a surge in digital interventions to bridge this treatment gap. Most of these interventions are based on computerized cognitive behavioral therapy. Despite the efficacy of computerized cognitive behavioral therapy-based interventions, their uptake is low and dropout rates are high. Cognitive bias modification (CBM) paradigms provide a complementary approach to digital interventions for depression. However, interventions based on CBM paradigms have been reported to be repetitive and boring. OBJECTIVE: In this paper, we described the conceptualization, design, and acceptability of serious games based on CBM paradigms and the learned helplessness paradigm. METHODS: We searched the literature for CBM paradigms that were shown to be effective in reducing depressive symptoms. For each of the CBM paradigms, we ideated how to create a game so that the gameplay was engaging while the active therapeutic component remained unchanged. RESULTS: We developed 5 serious games based on the CBM paradigms and the learned helplessness paradigm. The games include various core elements of gamification, such as goals, challenges, feedback, rewards, progress, and fun. Overall, the games received positive acceptability ratings from 15 users. CONCLUSIONS: These games may help improve the effectiveness and engagement levels of computerized interventions for depression.