Periodic Reporting for period 2 - SKINDEV (SKIN MICROBIAL DEVICES)
Okres sprawozdawczy: 2024-02-01 do 2025-07-31
The utilization of genetic engineering technology applied to Cutibacterium acnes (C. acnes), a common inhabitant of the skin microbiome, represents a significant advancement in the field. By engineering C. acnes to produce specific therapeutics against AD and integrating innovative sensor technologies, the SSMDs have the capability to detect relevant skin signals and deliver therapeutic treatments in real-time.
The objectives outlined by SKINDEV - identifying key biomarkers for skin diseases, developing genetic tools for live detection of these biomarkers, implementing bacterial-produced therapeutics, and validating and improving the technology using Human Skin 3D models - demonstrate a comprehensive and systematic approach towards achieving their goal.
Overall, the vision of SKINDEV to revolutionize skin health management through personalized, effective, and convenient solutions reflects a significant step forward in the field of dermatological care and preventive medicine.
The objectives outlined by SKINDEV - identifying key biomarkers for skin diseases, developing genetic tools for live detection of these biomarkers, implementing bacterial-produced therapeutics, and validating and improving the technology using Human Skin 3D models - demonstrate a comprehensive and systematic approach towards achieving their goal.
Overall, the vision of SKINDEV to revolutionize skin health management through personalized, effective, and convenient solutions reflects a significant step forward in the field of dermatological care and preventive medicine.
The long-term vision of the SKINDEV consortium is to complement the human skin microbiome with Smart Skin Microbial Devices (SSMDs) in AD patients and other dermatological conditions as a new transformative healthcare system for treatment and monitoring of disease. We aim to make SSMDs applicable through innovative technologies like sensing applications in wearables to reach at-home on-demand skin health information and intervention. To reach this main goal we are focusing on:
Steppingstone 1: developing computational models of AD and the skin microbiome to guide how to engineer SSMDs.
Steppingstone 2: genetic engineering to create sensing and actuation circuits in C. acnes.
Steppingstone 3: tissue engineering to create a high-throughput skin organoid platform for AD.
During the second reporting period, significant progress was made across these pillars:
In silico modelling: We developed data-driven and mechanistic models describing Staphylococcus aureus–Cutibacterium acnes (SA–CA) interactions and host–microbiome dynamics. These models predict how engineered SSMDs can shift diseased AD states toward healthy equilibria, and provide dosing strategies to overcome competition with native CA strains.
Chassis engineering: A versatile genetic toolbox for C. acnes was established, including genome integration platforms, CRISPRi, recombinases, and surface display methods. Novel endogenous sensors and synthetic sensors were implemented. Actuation modules were validated.
Functional validation: Initial testing of SOD-secreting strains demonstrated secretion activity and partial protective effects against oxidative stress in keratinocyte assays. While plasmid-based systems showed instability, genome-integrated strains now enable more robust expression. Specific binders and bacteriocin prototypes are under active evaluation.
Skin model development: Human epidermal equivalents and 3D atopic dermatitis skin models were refined for microbial colonisation. A defined “minimal microbiome” community was established with selective culture strategies to track microbial dynamics. These platforms allow controlled testing of SSMD prototypes under AD-like conditions.
Steppingstone 1: developing computational models of AD and the skin microbiome to guide how to engineer SSMDs.
Steppingstone 2: genetic engineering to create sensing and actuation circuits in C. acnes.
Steppingstone 3: tissue engineering to create a high-throughput skin organoid platform for AD.
During the second reporting period, significant progress was made across these pillars:
In silico modelling: We developed data-driven and mechanistic models describing Staphylococcus aureus–Cutibacterium acnes (SA–CA) interactions and host–microbiome dynamics. These models predict how engineered SSMDs can shift diseased AD states toward healthy equilibria, and provide dosing strategies to overcome competition with native CA strains.
Chassis engineering: A versatile genetic toolbox for C. acnes was established, including genome integration platforms, CRISPRi, recombinases, and surface display methods. Novel endogenous sensors and synthetic sensors were implemented. Actuation modules were validated.
Functional validation: Initial testing of SOD-secreting strains demonstrated secretion activity and partial protective effects against oxidative stress in keratinocyte assays. While plasmid-based systems showed instability, genome-integrated strains now enable more robust expression. Specific binders and bacteriocin prototypes are under active evaluation.
Skin model development: Human epidermal equivalents and 3D atopic dermatitis skin models were refined for microbial colonisation. A defined “minimal microbiome” community was established with selective culture strategies to track microbial dynamics. These platforms allow controlled testing of SSMD prototypes under AD-like conditions.
- Identification of Key Chemokines and Markers: Integration of patient metagenomic and transcriptomic data has revealed microbial gene clusters and immune factors that strongly correlate with AD severity.
- In Silico Modelling: Computational models reproduce healthy versus disease states and predict how engineered SSMDs with antioxidant or antimicrobial functions may restore balance. Simulations also suggest that periodic dosing of SSMDs is likely required to overcome competition with native CA strains, providing key design rules for future application.
- Dynamic Interplay Between Skin and Microbial Species: New in silico and in vitro studies demonstrate how CA–SA interactions drive skin health or disease states, reinforcing the significance of developing SSMDs to aid in skin recovery and fulfil the project’s objective of innovative AD treatment.
- Genetic Toolkit for C. acnes: A versatile and stable engineering platform has been established, including genome integration (“landing pad”), CRISPRi, recombinases, and surface display systems. Novel endogenous sensors (e.g. for tryptophan, vitamin B12, oxidative stress) and synthetic regulators have been implemented, expanding the possibilities for precise sensing and therapeutic delivery.
- Enhanced Bacterial Strains: Prototype SSMD strains with therapeutic activity have been created and genome-integrated to ensure stability. These include antioxidant-secreting strains, immune-modulatory prototypes (IL-4R blocking), and bacteriocin-producing candidates targeting S. aureus.
- Bacterial Interactions: Using stratum corneum and epidermal equivalent models, the consortium is able to track competition, colonisation, and therapeutic effects under AD-like conditions.
- 3D Skin Models: Human epidermal equivalents (HEEs) and advanced AD skin models were refined to stably mimic lesional and non-lesional disease phenotypes. Minimal synthetic microbiomes composed of CA, SA, S. epidermidis, and C. striatum have been established, enabling reproducible investigations of microbial dynamics in disease-relevant environments.
- Bacterial Engraftment and RNA Analysis: Methodologies for engrafting live bacteria onto skin models have been validated, and new workflows for microbial RNA isolation and ciRNAseq are under development. These methods will allow simultaneous monitoring of host and microbial transcriptional responses, creating a powerful platform for understanding therapeutic action.
- Biocontainment Strategies: First-generation auxotrophic C. acnes strains have been successfully generated and tested in syntrophic combinations, showing potential as safety layers for future therapeutic application.
In regard to dissemination and communication, the plan implemented by the SKINDEV project ensures consistency and visibility across all published articles. Guidelines, including publication standards, are established to maintain uniformity and quality in disseminating research findings to the scientific community and the general public.
To further amplify the project’s visibility, UPF has taken the lead in producing promotional and outreach materials, while multiple partners have published peer-reviewed papers, delivered conference presentations, and engaged in public-facing activities. Together, these efforts strengthen SKINDEV’s impact and pave the way for translation, commercialisation, and regulatory uptake of its results.
- In Silico Modelling: Computational models reproduce healthy versus disease states and predict how engineered SSMDs with antioxidant or antimicrobial functions may restore balance. Simulations also suggest that periodic dosing of SSMDs is likely required to overcome competition with native CA strains, providing key design rules for future application.
- Dynamic Interplay Between Skin and Microbial Species: New in silico and in vitro studies demonstrate how CA–SA interactions drive skin health or disease states, reinforcing the significance of developing SSMDs to aid in skin recovery and fulfil the project’s objective of innovative AD treatment.
- Genetic Toolkit for C. acnes: A versatile and stable engineering platform has been established, including genome integration (“landing pad”), CRISPRi, recombinases, and surface display systems. Novel endogenous sensors (e.g. for tryptophan, vitamin B12, oxidative stress) and synthetic regulators have been implemented, expanding the possibilities for precise sensing and therapeutic delivery.
- Enhanced Bacterial Strains: Prototype SSMD strains with therapeutic activity have been created and genome-integrated to ensure stability. These include antioxidant-secreting strains, immune-modulatory prototypes (IL-4R blocking), and bacteriocin-producing candidates targeting S. aureus.
- Bacterial Interactions: Using stratum corneum and epidermal equivalent models, the consortium is able to track competition, colonisation, and therapeutic effects under AD-like conditions.
- 3D Skin Models: Human epidermal equivalents (HEEs) and advanced AD skin models were refined to stably mimic lesional and non-lesional disease phenotypes. Minimal synthetic microbiomes composed of CA, SA, S. epidermidis, and C. striatum have been established, enabling reproducible investigations of microbial dynamics in disease-relevant environments.
- Bacterial Engraftment and RNA Analysis: Methodologies for engrafting live bacteria onto skin models have been validated, and new workflows for microbial RNA isolation and ciRNAseq are under development. These methods will allow simultaneous monitoring of host and microbial transcriptional responses, creating a powerful platform for understanding therapeutic action.
- Biocontainment Strategies: First-generation auxotrophic C. acnes strains have been successfully generated and tested in syntrophic combinations, showing potential as safety layers for future therapeutic application.
In regard to dissemination and communication, the plan implemented by the SKINDEV project ensures consistency and visibility across all published articles. Guidelines, including publication standards, are established to maintain uniformity and quality in disseminating research findings to the scientific community and the general public.
To further amplify the project’s visibility, UPF has taken the lead in producing promotional and outreach materials, while multiple partners have published peer-reviewed papers, delivered conference presentations, and engaged in public-facing activities. Together, these efforts strengthen SKINDEV’s impact and pave the way for translation, commercialisation, and regulatory uptake of its results.