Periodic Reporting for period 1 - PROTOMAT (Integrating non-living and living matter via protocellular materials (PCMs) design and synthetic construction)
Reporting period: 2023-03-01 to 2025-08-31
The construction of synthetic cells, or protocells, from non-living molecules represents one of the grand challenges in modern science, bridging the gap between inanimate matter and living systems. While significant progress has been made in enhancing the biochemical complexity of individual protocells, the controlled assembly of these building blocks into functional tissue-like materials—termed prototissues or protocellular materials (PCMs)—remains largely unexplored. PROTOMAT seeks to pioneer advancements in this emerging frontier by integrating synthetic chemistry, materials science, microfluidics, and tissue engineering to design adaptive prototissues capable of mimicking living tissues and interacting with biological cells.
PROTOMAT aims to develop PCMs with three key functionalities:(1) mechanical properties resembling soft living tissues, (2) adaptive and self-regulating behaviours, and (3) the ability to integrate with living cells. These goals address critical gaps in bottom-up synthetic biology, where current research has focused primarily on individual protocells rather than their organized integration into materials with collective behaviour.
The project builds on the Principal Investigator's foundational work, including adhesive proteinosome-based prototissues capable of muscle-like contractions (Nature Materials, 2018) and centimetre-scale PCMs with complex 3D architectures (Advanced Materials, 2021). PROTOMAT extends these findings through three interlinked Research Themes:
1. RT1: Advancing Mechanical Properties – Engineering prototissues with tuneable elastic moduli (1 kPa–1 MPa) to match soft tissues like brain, muscle, and epithelial cells using protocells with synthetic polymeric cytoskeletons assembled via microfluidics.
2. RT2: Higher-Order Behaviours – Pioneering light-responsive prototissues capable of converting luminous stimuli into mechanical motions and biochemical feedback, such as regulating enzymatic activity through photo-induced structural changes.
3. RT3: Integration with Living Cells – Creating hybrid systems where prototissues deliver mechanical and chemical cues to living cells, functionalizing PCM surfaces with cell-adhesion peptides, studying mechanochemical signalling, and developing symbiotic systems where PCMs feed cells and/or protect them from toxins.
The expected impact of PROTOMAT is profound. By bridging non-living and living matter, the project generates foundational knowledge for synthetic biology, enabling the design of "active materials" with applications in regenerative medicine, soft robotics, and biosensing. The high-risk/high-gain nature of the research is mitigated by the PI's expertise, preliminary results, and interdisciplinary approach.
In summary, PROTOMAT aims to transform our understanding of life-like materials, offering innovative solutions to unmet needs in healthcare and biotechnology while pushing the boundaries of synthetic biology. The project's interdisciplinary framework ensures its outcomes will resonate across scientific disciplines, fostering collaborations at the life/non-life interface.
PROTOMAT aims to develop PCMs with three key functionalities:(1) mechanical properties resembling soft living tissues, (2) adaptive and self-regulating behaviours, and (3) the ability to integrate with living cells. These goals address critical gaps in bottom-up synthetic biology, where current research has focused primarily on individual protocells rather than their organized integration into materials with collective behaviour.
The project builds on the Principal Investigator's foundational work, including adhesive proteinosome-based prototissues capable of muscle-like contractions (Nature Materials, 2018) and centimetre-scale PCMs with complex 3D architectures (Advanced Materials, 2021). PROTOMAT extends these findings through three interlinked Research Themes:
1. RT1: Advancing Mechanical Properties – Engineering prototissues with tuneable elastic moduli (1 kPa–1 MPa) to match soft tissues like brain, muscle, and epithelial cells using protocells with synthetic polymeric cytoskeletons assembled via microfluidics.
2. RT2: Higher-Order Behaviours – Pioneering light-responsive prototissues capable of converting luminous stimuli into mechanical motions and biochemical feedback, such as regulating enzymatic activity through photo-induced structural changes.
3. RT3: Integration with Living Cells – Creating hybrid systems where prototissues deliver mechanical and chemical cues to living cells, functionalizing PCM surfaces with cell-adhesion peptides, studying mechanochemical signalling, and developing symbiotic systems where PCMs feed cells and/or protect them from toxins.
The expected impact of PROTOMAT is profound. By bridging non-living and living matter, the project generates foundational knowledge for synthetic biology, enabling the design of "active materials" with applications in regenerative medicine, soft robotics, and biosensing. The high-risk/high-gain nature of the research is mitigated by the PI's expertise, preliminary results, and interdisciplinary approach.
In summary, PROTOMAT aims to transform our understanding of life-like materials, offering innovative solutions to unmet needs in healthcare and biotechnology while pushing the boundaries of synthetic biology. The project's interdisciplinary framework ensures its outcomes will resonate across scientific disciplines, fostering collaborations at the life/non-life interface.
To date, the PROTOMAT project has achieved significant breakthroughs in the design and construction of prototissues that integrate non-living and living matter. Our research has produced transformative advancements in three (3) key areas:
1) We developed an innovative photochemical methodology for dynamic patterning of mechanical properties in hydrogels. We coupled this methodology with micro-indentation techniques and custom analytical software to quantitatively characterize the engineered mechanical patterns. This breakthrough enables precise control over material mechanical properties for tissue engineering and digital information storage applications (published in Advanced Functional Materials 2025).
2) In collaboration with Keio University, we pioneered freestanding prototissue fibres with magnetotaxis capabilities and enzymatic cascades assembled via interfacial salt bridges, establishing new possibilities for 3D bioprinting and biohybrid robotics (published in Advanced Science 2025).
3) Through partnership with University of Trieste and CIC BiomaGUNE, we optimized photocatalytic carbon dots for synthetic biology applications (published in ACS Nano 2025).
These achievements have established new frontiers in programmable biomaterials, nanomaterial synthesis, and synthetic biology, creating platforms that merge materials science with biological principles for applications in micro-bioreactors, adaptive microsystems, and programmable synthetic tissues.
1) We developed an innovative photochemical methodology for dynamic patterning of mechanical properties in hydrogels. We coupled this methodology with micro-indentation techniques and custom analytical software to quantitatively characterize the engineered mechanical patterns. This breakthrough enables precise control over material mechanical properties for tissue engineering and digital information storage applications (published in Advanced Functional Materials 2025).
2) In collaboration with Keio University, we pioneered freestanding prototissue fibres with magnetotaxis capabilities and enzymatic cascades assembled via interfacial salt bridges, establishing new possibilities for 3D bioprinting and biohybrid robotics (published in Advanced Science 2025).
3) Through partnership with University of Trieste and CIC BiomaGUNE, we optimized photocatalytic carbon dots for synthetic biology applications (published in ACS Nano 2025).
These achievements have established new frontiers in programmable biomaterials, nanomaterial synthesis, and synthetic biology, creating platforms that merge materials science with biological principles for applications in micro-bioreactors, adaptive microsystems, and programmable synthetic tissues.
To date, PROTOMAT has achieved several paradigm-shifting advances that redefine boundaries between synthetic biology and programmable materials. Our freestanding, modular prototissue fibres with programmable functionalities introduce unprecedented hierarchical control over synthetic biological structures, enabling precise dimension control and composition programming for applications in adaptive biohybrid systems.
We developed the first methodology for spatiotemporal patterning of mechanical properties in soft materials, addressing a longstanding challenge in tissue engineering. Our approach enables direct quantification of intensive mechanical properties rather than relying on indirect metrics, crucial for replicating the heterogeneous mechanical environments of biological tissues.
Further advancement of these technologies requires:
1. Additional research on biohybrid interfaces to improve the integration between prototissues and living cells, focusing on ECM compatibility and two-way communication.
2. Scaled demonstration projects to validate performance in practical tissue engineering applications.
3. Standardization of characterization methodologies for mechanical and biochemical properties of protocellular materials.
4. Regulatory framework development addressing the unique considerations of semi-living materials.
5. Industry partnerships to translate these foundational platforms into commercial applications for bioprinting, drug delivery, and soft robotics.
These breakthroughs lay groundwork for next-generation adaptive biomaterials with transformative potential in regenerative medicine, biohybrid robotics, and programmable tissue engineering.
We developed the first methodology for spatiotemporal patterning of mechanical properties in soft materials, addressing a longstanding challenge in tissue engineering. Our approach enables direct quantification of intensive mechanical properties rather than relying on indirect metrics, crucial for replicating the heterogeneous mechanical environments of biological tissues.
Further advancement of these technologies requires:
1. Additional research on biohybrid interfaces to improve the integration between prototissues and living cells, focusing on ECM compatibility and two-way communication.
2. Scaled demonstration projects to validate performance in practical tissue engineering applications.
3. Standardization of characterization methodologies for mechanical and biochemical properties of protocellular materials.
4. Regulatory framework development addressing the unique considerations of semi-living materials.
5. Industry partnerships to translate these foundational platforms into commercial applications for bioprinting, drug delivery, and soft robotics.
These breakthroughs lay groundwork for next-generation adaptive biomaterials with transformative potential in regenerative medicine, biohybrid robotics, and programmable tissue engineering.