Periodic Reporting for period 2 - SYNMAT FOR ORGANOIDS (High-throughput and reproducible development of intestinal organoids by microfluidics encapsulation in synthetic niches for intestinal bowel disease research)
Reporting period: 2024-07-01 to 2025-06-30
Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, represents a major and growing global health challenge. Current treatments primarily target inflammation and symptom management but rarely address the underlying tissue damage or support long-term mucosal healing. Consequently, many patients experience recurrent disease flares, progressive tissue degeneration, and serious complications, leading to a diminished quality of life. Moreover, conventional therapies often cause systemic side effects and may lose efficacy over time. The absence of effective regenerative strategies highlights a crucial gap in IBD management. There is an urgent need for innovative therapeutic approaches that not only control inflammation but also actively promote intestinal tissue repair and regeneration. Given the chronic nature of IBD and its increasing prevalence worldwide, developing regenerative solutions would significantly alleviate patient suffering, enhance long-term disease remission, and reduce the economic burden. This project aims to develop an innovative regenerative medicine approach for IBD through the encapsulation of intestinal mesenchymal cells (IMCs) derived from human intestinal organoids within fully synthetic degradable microgels. These engineered systems will provide a cell-instructive environment that supports IMC viability and regenerative function, offering a clinically translatable alternative to animal-derived matrices such as Matrigel.
Specific Objectives
1. Engineering of Degradable Synthetic Microgels.
2. Encapsulation and Functional Support of Intestinal Mesenchymal Cells.
3. Evaluation of Regenerative Capacity Using Human Intestinal Organoids.
Conclusions: This project will establish a novel regenerative therapy that goes beyond conventional anti-inflammatory treatments by addressing the root cause of intestinal damage in IBD. Through the integration of synthetic biomaterials and patient-derived cells, the proposed system aims to restore intestinal structure and function by combining material engineering, stem cell biology, and organoid technology. This research will provide a versatile and clinically relevant platform for personalized regenerative medicine in IBD. Ultimately, the outcomes are expected to pave the way for next-generation injectable therapies that promote durable mucosal healing and improve the long-term quality of life of patients suffering from chronic intestinal inflammation.
Specific Objectives
1. Engineering of Degradable Synthetic Microgels.
2. Encapsulation and Functional Support of Intestinal Mesenchymal Cells.
3. Evaluation of Regenerative Capacity Using Human Intestinal Organoids.
Conclusions: This project will establish a novel regenerative therapy that goes beyond conventional anti-inflammatory treatments by addressing the root cause of intestinal damage in IBD. Through the integration of synthetic biomaterials and patient-derived cells, the proposed system aims to restore intestinal structure and function by combining material engineering, stem cell biology, and organoid technology. This research will provide a versatile and clinically relevant platform for personalized regenerative medicine in IBD. Ultimately, the outcomes are expected to pave the way for next-generation injectable therapies that promote durable mucosal healing and improve the long-term quality of life of patients suffering from chronic intestinal inflammation.
In the first stage of the project, I successfully developed an ultrafast and facile microfluidic technique to fabricate degradable synthetic microgels for cell encapsulation. The use of microfluidic technology enabled precise control over the size, uniformity, and architecture of the microgels, ensuring high reproducibility and scalability. By employing ultraviolet (UV)-induced photopolymerization, I achieved controlled crosslinking of the polymeric matrix, generating microgels with tunable mechanical stiffness and degradation kinetics. This degradation was modulated through the incorporation of protease-sensitive crosslinkers, allowing the microgels to degrade selectively in response to specific enzymatic cues that mimic physiological remodeling processes. As a proof of concept, human mesenchymal stem cells (hMSCs) were encapsulated within these synthetic microgels. The cells displayed excellent viability, structural integrity, and metabolic activity over extended culture periods, demonstrating that the engineered microenvironment effectively supports cell survival and function. These results validate the potential of the developed microgels as a fully synthetic, Matrigel-free platform for diverse regenerative medicine applications, including cell delivery, tissue repair, and organoid culture. These results were published in Advanced Healthcare Materials in 2023.
During the second phase of the project, I focused on optimizing the encapsulation of intestinal mesenchymal stem cells (IMCs) derived from human intestinal organoids within the degradable synthetic microgels. The encapsulated IMCs exhibited distinct secretory profiles depending on the mechanical properties of the microgels, revealing the ability of the synthetic platform to dynamically modulate cell behavior under both naïve and inflammatory conditions. Specifically, altering the macromer concentration in the polymeric network effectively tuned the cellular secretome, demonstrating the capacity of the matrix to guide regenerative and immunomodulatory responses. Finally, the regenerative capacity of the encapsulated IMCs was evaluated using advanced in vitro intestinal models, including human intestinal organoids. The cellular and molecular responses were analyzed through bulk RNA sequencing, which provided comprehensive insights into the transcriptional programs associated with tissue repair, extracellular matrix remodeling, and cytokine signaling. These findings collectively highlight the promise of synthetic degradable microgels as adaptive biomimetic matrices capable of supporting cell-driven regeneration in inflammatory environments. This project thus lays the foundation for the development of a novel cell-based regenerative therapy for IBD. By combining synthetic biomaterial engineering, stem cell biology, and organoid technology, the platform offers a clinically translatable strategy to restore intestinal integrity, enhance mucosal healing, and overcome the limitations of current anti-inflammatory treatments. In the long term, this work opens the door to the personalization of regenerative therapies, where patient-derived cells could be encapsulated within tailored synthetic microenvironments to promote durable tissue regeneration and improve patient outcomes in chronic intestinal disorders.
The results of this Action have been disseminated in 9 scientific conferences, several departamental seminars, one Open Access scientific publication, with other manuscript in preparation.
During the second phase of the project, I focused on optimizing the encapsulation of intestinal mesenchymal stem cells (IMCs) derived from human intestinal organoids within the degradable synthetic microgels. The encapsulated IMCs exhibited distinct secretory profiles depending on the mechanical properties of the microgels, revealing the ability of the synthetic platform to dynamically modulate cell behavior under both naïve and inflammatory conditions. Specifically, altering the macromer concentration in the polymeric network effectively tuned the cellular secretome, demonstrating the capacity of the matrix to guide regenerative and immunomodulatory responses. Finally, the regenerative capacity of the encapsulated IMCs was evaluated using advanced in vitro intestinal models, including human intestinal organoids. The cellular and molecular responses were analyzed through bulk RNA sequencing, which provided comprehensive insights into the transcriptional programs associated with tissue repair, extracellular matrix remodeling, and cytokine signaling. These findings collectively highlight the promise of synthetic degradable microgels as adaptive biomimetic matrices capable of supporting cell-driven regeneration in inflammatory environments. This project thus lays the foundation for the development of a novel cell-based regenerative therapy for IBD. By combining synthetic biomaterial engineering, stem cell biology, and organoid technology, the platform offers a clinically translatable strategy to restore intestinal integrity, enhance mucosal healing, and overcome the limitations of current anti-inflammatory treatments. In the long term, this work opens the door to the personalization of regenerative therapies, where patient-derived cells could be encapsulated within tailored synthetic microenvironments to promote durable tissue regeneration and improve patient outcomes in chronic intestinal disorders.
The results of this Action have been disseminated in 9 scientific conferences, several departamental seminars, one Open Access scientific publication, with other manuscript in preparation.
This project has advanced the field of regenerative medicine by developing degradable synthetic microgels specifically designed for the encapsulation of intestinal mesenchymal cells. Current therapies for IBD focus primarily on managing inflammation but do not restore damaged intestinal tissue. Existing biomaterials, such as Matrigel or other natural polymers, suffer from batch variability, limited tunability, and potential immunogenicity, which limit their reproducibility, clinical translation, and scalability. The synthetic microgel platform developed in this project overcomes these limitations, offering a fully defined, tunable, and biodegradable matrix that can be precisely adjusted for mechanical properties, degradation kinetics, and bioactivity. The use of IMCs for intestinal regeneration represents a novel therapeutic approach, moving beyond symptomatic treatment to strategies that actively promote tissue repair and restoration of intestinal function. The societal impact of this work is significant. By enabling regenerative therapies for IBD, the platform has the potential to reduce dependence on chronic medication, lower healthcare costs, and improve patient quality of life. Beyond IBD, the versatile and reproducible nature of the synthetic microgels could be applied to other chronic diseases, fostering innovation in personalized regenerative medicine while promoting ethical, animal-free research practices.