Background: Disrupted social connections may negatively affect youth mental health. In contrast, sustained quality social connections (QSCs) can improve mental health outcomes. However, few studies have examined how these quality connections affect depression and anxiety outcomes within digital interventions, and conceptualization is limited. Objective: The aim of this study is to conceptualize, appraise, and synthesize evidence on QSC within digital interventions (D-QSC) and the impact on depression and anxiety outcomes for young people aged 14-24 years. Methods: A systematic scoping review and meta-analysis was conducted using the Joanna Briggs Institute methodological frameworks and guided by experts with lived experience. Reporting was guided by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The MEDLINE, Embase, PsycINFO, and CINAHL databases were searched against a comprehensive combination of key concepts on June 24, 2020. The search concepts included young people, digital intervention, depression, anxiety, and social connection. Google was also searched. A reviewer independently screened abstracts and titles and full text, and 9.99% (388/3882) of these were screened by a second reviewer. A narrative synthesis was used to structure the findings on indicators of D-QSC and mechanisms that facilitate the connection. Indicators of D-QSC from the included studies were synthesized to produce a conceptual framework. Results: Of the 5715 publications identified, 42 (0.73%) were included. Among the included studies, there were 23,319 participants. Indicators that D-QSC was present varied and included relatedness, having a sense of belonging, and connecting to similar people. However, despite the variation, most of the indicators were associated with improved outcomes for depression and anxiety. Negative interactions, loneliness, and feeling ignored indicated that D-QSC was not present. In 24% (10/42) of the applicable studies, a meta-analysis showed a significant decrease in depression (–25.6%, 95% CI –0.352 to –0.160; P<.001) and anxiety (–15.1%, 95% CI –0.251 to –0.051; P=.003) after a D-QSC. Digital mechanisms that helped create a quality connection included anonymity, confidentiality, and peer support. In contrast, mechanisms that hindered the connection included disconnection from the real world and inability to see body language. Data synthesis also identified a 5-component conceptual framework of D-QSC that included rapport, identity and commonality, valued interpersonal dynamic, engagement, and responded to and accepted. Conclusions: D-QSC is an important and underconsidered component for youth depression and anxiety outcomes. Researchers and developers should consider targeting improved QSC between clinicians and young people within digital interventions for depression. Future research should build on our framework to further examine relationships among individual attributes of QSC, various digital interventions, and different populations.

Exogenous insulin is essential for diabetes management; however, subcutaneous administration is associated with discomfort, poor adherence and non-physiological peripheral hyperinsulinemia. Oral administration would better mimic the physiological insulin distribution route but is hampered by gastrointestinal barriers, resulting in low bioavailability. Enabling access to the market for oral insulin nanocarriers requires rigorous control of their physicochemical attributes (size, charge, and surface chemistry) to ensure biocompatibility and mitigate risks such as the long-term bioaccumulation of non-biodegradable materials and the loss of intended targeting due to protein corona formation. In pre-clinical studies, nanoparticle carriers have shown promising results by protecting insulin and enhancing its absorption, yet clinical translation remains limited, with most candidates stalling in early-phase trials. This translational gap stems from the inadequacy of conventional animal models and regulatory frameworks to address the complexity of nanomedicines. This review goes beyond a simple summary of nanocarrier types and discusses the non-clinical and regulatory challenges hampering progress. We highlight the limitations of current preclinical models and the challenge of evaluating the pharmacokinetic profiles of both the nanocarrier and its insulin payload. The development of more rigorous and predictive strategies based on most recent successes and failures, described in this review, could help to bridge the translational gap.

Osteoarthritis (OA) is a condition that affects the quality of life of millions of patients worldwide. Current clinical treatments, in most cases, lead to cartilage repair with deposition of fibrocartilage tissue, which is mechanically inferior and not as durable as hyaline cartilage tissue. We designed an mRNA delivery strategy to enhance the natural healing potential of autologous bone marrow aspirate concentrate (BMAC) for articular cartilage repair. We used mineral-coated microparticles to deliver TGF-β1 mRNA to autologous BMAC. mRNA-activated BMAC was suspended in peripheral blood to generate therapeutic BMAC clots, which were then implanted in rabbit osteochondral defects. Tracking studies revealed that the clots were reliably maintained in the defects for at least 2 weeks. TGF-β1 mRNA delivery significantly increased TGF-β1 production in BMAC clots and increased early expression of articular chondrocyte markers within osteochondral defects. At 9 weeks post-surgery, the mRNA-treated defects had a superior macroscopic cartilage appearance, decreased type I collagen deposition, increased stain intensity for type II collagen and increased glycosaminoglycan deposition area when compared to the controls. Despite the transient expression of therapeutic mRNA we have detected lasting effects, such as a decrease in fibrocartilage formation demonstrated by the decrease in type I collagen deposition and the improvement in macroscopic appearance in the treatment group.