Umberto Maria Musazzi

CDigital therapeutics (DTx) are software-based medical devices that deliver evidence-based therapeutic interventions directly to patients. While the clinical use of DTx is expanding rapidly, regulatory fragmentation and the absence of harmonized legal definitions hinder their assessment and reimbursement policies, as well as their integration into healthcare systems. There is currently a lack of comprehensive overviews of DTx clinical development, which are essential for informing policy, research and regulatory priorities. This paper provides an updated overview of randomised clinical trials involving DTx. 254 eligible trials on DTx, (defined according to ISO/TR 11147:2023) registered through January 2025 were identified through a search on C linicalTrials.gov . Mobile applications represent the most prevalent technology (65%), followed by web-based tools and virtual reality (20%). Psychiatric disorders are the primary therapeutic target (52% of the studies) with insomnia, depression, and anxiety being the most addressed conditions. Trials were primarily conducted in North America (41%) and Europe (32%), where Germany, Spain, and Italy represent the most active countries. The analysis of clinical trials registrations on ClinicalTrials.gov reveals a heterogenous geographical distribution of DTx development but also a clear direction in the type of conditions for which they are mostly indicated, namely psychiatric and nervous system disorders. The fragmented policies on DTx reimbursement, even among EU countries, and the different capacity of governments to fund DTx research and development emerge as key factors, along with cultural and ethical issues, in determining the willingness of the industry to invest in these devices.

The European Union Regulation (EU) 2015/2283 on novel foods has created new opportunities for the valorization of marine by-products within the framework of the circular bioeconomy and sustainable blue economy. Refined shrimp peptide concentrate (RSPC), obtained through enzymatic hydrolysis of Pandalus borealis shells and heads, represents a relevant case study for examining the interaction between food innovation, regulatory assessment, sustainability, and value-chain development. This study analyzes the EFSA scientific opinion on RSPC and reviews available compositional, toxicological, allergenicity, and clinical evidence, contextualizing the ingredient within European policies on circular economy, resource efficiency, and sustainable food systems. The assessment indicates that RSPC consists mainly of 8 low-molecular-weight peptides with demonstrated angiotensin-converting enzyme (ACE) inhibitory activity and potential applications in blood pressure management. Beyond its functional properties, the valorization of shrimp processing by-products offers opportunities to reduce waste generation, increase resource efficiency, and create new economic value within the seafood sector. The case study highlights how the novel food regulatory framework can support the safe market introduction of innovative marine-derived ingredients while contributing to circular economy objectives. Although challenges related to allergenicity management, consumer acceptance, and industrial scalability remain, RSPC demonstrates the potential of marine by-product valorization to foster more sustainable, resilient, and economically viable food systems.

The European Union Regulation (EU) 2015/2283 on novel foods has created new opportunities for the valorization of marine by-products within the framework of the circular bioeconomy and sustainable blue economy. Refined shrimp peptide concentrate (RSPC), obtained through enzymatic hydrolysis of Pandalus borealis shells and heads, represents a relevant case study for examining the interaction between food innovation, regulatory assessment, sustainability, and value-chain development. This study analyzes the EFSA scientific opinion on RSPC and reviews available compositional, toxicological, allergenicity, and clinical evidence, contextualizing the ingredient within European policies on circular economy, resource efficiency, and sustainable food systems. The assessment indicates that RSPC consists mainly of low-molecular-weight peptides with demonstrated angiotensin-converting enzyme (ACE) inhibitory activity and potential applications in blood pressure management. Beyond its functional properties, the valorization of shrimp processing by-products offers opportunities to reduce waste generation, increase resource efficiency, and create new economic value within the seafood sector. The case study highlights how the novel food regulatory framework can support the safe market introduction of innovative marine-derived ingredients while contributing to circular economy objectives. Although challenges related to allergenicity management, consumer acceptance, and industrial scalability remain, RSPC demonstrates the potential of marine by-product valorization to foster more sustainable, resilient, and economically viable food systems.

Skin aging is influenced by both internal and external factors, resulting in wrinkles, decreased elasticity and irregular pigmentation. Hyaluronic acid (HA), a key component of the extracellular matrix, is essential for skin hydration and structural support. Peptides, short amino acid chains, have gained attention in cosmetics due to their multifunctional biological activities. This study explored the moisturizing and metal-chelating properties of Chrono Control Penta (S-Cannabis Sativa-pentapeptide-1), a novel plant-derived peptide whose sequence is WVSPL. In vitro, it chelated iron ions up to 17.86 ± 2.50% and copper ions up to 47.08 ± 1.49% at 10 mM and 3 mM, respectively. Western blot and Enzyme-Linked Immunosorbent Assay (ELISA) analysis showed that, under H₂O₂-induced stress, Chrono Control Penta increased hyaluronan synthase 2 (HAS2) production by 81.72% in BJ-5ta fibroblasts and enhanced HA secretion by 20.11% compared to simulated aging conditions alone, respectively. Furthermore, experiments carried out with the Franz diffusion cell and human full thickness skin demonstrated the peptide’s ability to penetrate the skin layers and even diffuse laterally with a quantified peptide skin biodistribution accounting for 0.095/0.06 nM/mg in 6 h. Advanced AI-based modeling (AlphaFold2, RosettaFold) and docking analysis revealed stable peptide-peptide transporter 2 (PEPT2) interactions, supporting carrier-mediated skin permeation and linking computational predictions with experimental diffusion data. Hence, this study extends previous evidence on the cosmetic efficacy of Chrono Control Penta by (i) adding mechanistic insights into metal chelation and HAS2/HA modulation, (ii) rigorously quantifying local skin penetration and lateral diffusion with HPLC-MS/MS, and (iii) providing a plausible mechanistic link between skin biodistribution and PEPT2-mediated transport based on deep learning structural models.