Periodic Reporting for period 1 - BioMeld (A Modular Framework for Designing and Producing Biohybrid Machines)
Periodo di rendicontazione: 2022-10-01 al 2024-03-31
In the last 15 years, the development of biohybrid machines (BHM) expanded greatly. They combine living cell actuators with artificial materials in order to achieve greater autonomy, flexibility, and energy efficiency compared to standard robots. However, the available literature shows that BHMs are developed in silos of individual research groups, making their development more of an art relying on personal knowledge, intuition, and skills than on standardized decision-making processes. To scale-up discrete manufacturing of BHM, many challenges should be standardized such as: choosing appropriate cells and materials for building devices, determining operating limitations (e.g. temperature, surrounding medium), expected life span of BHMs, verification & validation (V&V) procedures, control of selective and coordinated actuation, information processing within a device, etc.
To push the manufacturing of BHMs towards bio-intelligent paradigm and model-based engineering, we propose to develop a self-monitoring and self-controlling manufacturing pipeline of BHMs. To realize such a pipeline, we would need to (i) Develop a modeling and simulation framework that will streamline the processes of design and preliminary testing thus speeding-up and reducing cost of steps that would otherwise be done manually. Also, given that actuators in BHMs are living cells, which greatly expands the parameter space, we believe that the development of BHMs would greatly benefit from an AI-guided modeling process to optimize search for the most efficient design; (ii) To experimentally test, optimize, and verify the platform by developing a proof-of-principle reconfigurable modular catheter BHM; (iii) To group all necessary manufacturing equipment into an integrated bio-intelligent manufacturing cell (BIMC) and demonstrate its adaptable operation.
As a proof-of-principle, we will use the BHM catheter as an innovative medical device that would be able to arrive into hard-to-reach regions of the human body and release drugs there. The operating environment in which the catheter will be tested will have embedded sensors to provide real-time information over multiple actuation modes (such as bending and the force exerted on vessel walls) so that the behavior of synthesized BHMs will be monitored and compared with simulation predictions and used for the update of the modeling framework.
To push the manufacturing of BHMs towards bio-intelligent paradigm and model-based engineering, we propose to develop a self-monitoring and self-controlling manufacturing pipeline of BHMs. To realize such a pipeline, we would need to (i) Develop a modeling and simulation framework that will streamline the processes of design and preliminary testing thus speeding-up and reducing cost of steps that would otherwise be done manually. Also, given that actuators in BHMs are living cells, which greatly expands the parameter space, we believe that the development of BHMs would greatly benefit from an AI-guided modeling process to optimize search for the most efficient design; (ii) To experimentally test, optimize, and verify the platform by developing a proof-of-principle reconfigurable modular catheter BHM; (iii) To group all necessary manufacturing equipment into an integrated bio-intelligent manufacturing cell (BIMC) and demonstrate its adaptable operation.
As a proof-of-principle, we will use the BHM catheter as an innovative medical device that would be able to arrive into hard-to-reach regions of the human body and release drugs there. The operating environment in which the catheter will be tested will have embedded sensors to provide real-time information over multiple actuation modes (such as bending and the force exerted on vessel walls) so that the behavior of synthesized BHMs will be monitored and compared with simulation predictions and used for the update of the modeling framework.
The BioMeld project has made significant progress toward achieving its four main objectives. Here's a summary of the activities performed and the project's main achievements:
Objective 1: Developing a Modeling and Simulation Framework for the Digital Design of BioHybrid Machines (BHMs)
In the first 18 months of the project, the BioMeld team established specifications for a comprehensive simulation framework to streamline the design process for BHMs. This framework includes the BioMeld software pipeline architecture, and plans for framework validation and verification. The framework is accompanied by a Bill of Materials that lists the required materials and actuators along with their properties. A tool for estimating observable parameters was developed along with software tools for generating the initial morphology of the BHM and optimizing physical material parameters. These tools enhanced BHM simulation by 30%, bridging the gap between simulation and reality through additional physics-oriented simulations focusing on electric-stimulus response dynamics and bending dynamics. COMSOL Multiphysics was utilized to create and test realistic simulation scenarios.
Objective 2: Fabricating a Set of BHM-based Modules for a Reconfigurable Modular Catheter
The project aimed to create flexible catheter modules using biohybrid actuators derived from skeletal muscle cells through 3D bioprinting, with a bioreactor ensuring cell viability. This biohybrid catheter, designed for navigation within the vascular system, employs magnetic control, integrated electrodes, and flexible strain sensors. Preliminary designs and fabrication work by SSSA focused on creating the basic catheter structure using biocompatible and hemocompatible elastomers. Bioactuators derived from skeletal muscle cells were integrated with the catheter skeleton. Flexible electronic platforms and force sensors were developed to enable precise control and monitoring of the catheter.
Objective 3: Validating the Framework
The project focused on ensuring that simulation results align with the behavior of synthesized BHMs, including error propagation analysis from simulation outputs to observed behavior. Experimental performance tests showed successful assembly of the bioactuator into the catheter. Analysis of bending and stimulation results indicated optimal configurations for the biohybrid actuator. Uncertainty analysis revealed the robustness of the Voxelyze simulator and identified key COMSOL input parameters.
Objective 4: Constructing the Demonstration Bio-Intelligent Manufacturing Cell (BIMC)
SS developed a high-level production flowchart for BHM catheter manufacturing, specifying manufacturing steps, processes, devices, and assembly machines. A tailored questionnaire distributed to relevant partners informed the production cycle's development. The BIMC is designed to integrate BHM characterization and simulation data to iteratively improve the product, creating bidirectional communication between AI-powered design and BHM manufacturing. This approach allows for adaptable fabrication processes, facilitating knowledge sharing and validation among multiple manufacturing cycles.
Objective 1: Developing a Modeling and Simulation Framework for the Digital Design of BioHybrid Machines (BHMs)
In the first 18 months of the project, the BioMeld team established specifications for a comprehensive simulation framework to streamline the design process for BHMs. This framework includes the BioMeld software pipeline architecture, and plans for framework validation and verification. The framework is accompanied by a Bill of Materials that lists the required materials and actuators along with their properties. A tool for estimating observable parameters was developed along with software tools for generating the initial morphology of the BHM and optimizing physical material parameters. These tools enhanced BHM simulation by 30%, bridging the gap between simulation and reality through additional physics-oriented simulations focusing on electric-stimulus response dynamics and bending dynamics. COMSOL Multiphysics was utilized to create and test realistic simulation scenarios.
Objective 2: Fabricating a Set of BHM-based Modules for a Reconfigurable Modular Catheter
The project aimed to create flexible catheter modules using biohybrid actuators derived from skeletal muscle cells through 3D bioprinting, with a bioreactor ensuring cell viability. This biohybrid catheter, designed for navigation within the vascular system, employs magnetic control, integrated electrodes, and flexible strain sensors. Preliminary designs and fabrication work by SSSA focused on creating the basic catheter structure using biocompatible and hemocompatible elastomers. Bioactuators derived from skeletal muscle cells were integrated with the catheter skeleton. Flexible electronic platforms and force sensors were developed to enable precise control and monitoring of the catheter.
Objective 3: Validating the Framework
The project focused on ensuring that simulation results align with the behavior of synthesized BHMs, including error propagation analysis from simulation outputs to observed behavior. Experimental performance tests showed successful assembly of the bioactuator into the catheter. Analysis of bending and stimulation results indicated optimal configurations for the biohybrid actuator. Uncertainty analysis revealed the robustness of the Voxelyze simulator and identified key COMSOL input parameters.
Objective 4: Constructing the Demonstration Bio-Intelligent Manufacturing Cell (BIMC)
SS developed a high-level production flowchart for BHM catheter manufacturing, specifying manufacturing steps, processes, devices, and assembly machines. A tailored questionnaire distributed to relevant partners informed the production cycle's development. The BIMC is designed to integrate BHM characterization and simulation data to iteratively improve the product, creating bidirectional communication between AI-powered design and BHM manufacturing. This approach allows for adaptable fabrication processes, facilitating knowledge sharing and validation among multiple manufacturing cycles.
The BioMeld project has made significant progress toward its scientific and technical objectives, demonstrating the feasibility of its biohybrid machine (BHM) catheter concept. The project has outlined a clear path to the anticipated impacts, which include strengthening European leadership in bio-intelligent manufacturing, developing key enabling technologies, integrating biological with other technologies, and fostering extensive interdisciplinary collaborations. However, the journey to commercialization presents considerable challenges, particularly in terms of regulatory requirements and financial investment.
While the potential for innovation and leadership in the biohybrid sector is evident, our assessment of catheter commercialization indicates a lengthy and complex process, with a number of regulatory and financial hurdles to overcome. Given this, the BioMeld team is committed to exploring alternative commercialization strategies that may offer more immediate returns through incremental advances, thereby mitigating the risks associated with being the first to market.
By synthesizing both scientific and commercial research findings, we conclude that while the BHM catheter remains a promising and valid target, the timeline for market readiness is likely to be extended. To ensure continued success and uptake, we plan to engage in further research, investigate additional demonstration projects, and seek access to broader markets and financial support. This approach will also require continued focus on IPR support, internationalization strategies, and alignment with a supportive regulatory and standardization framework. Our strategy will be to pursue incremental innovation while maintaining a long-term vision for the broader impact of the BHM catheter in the healthcare industry.
While the potential for innovation and leadership in the biohybrid sector is evident, our assessment of catheter commercialization indicates a lengthy and complex process, with a number of regulatory and financial hurdles to overcome. Given this, the BioMeld team is committed to exploring alternative commercialization strategies that may offer more immediate returns through incremental advances, thereby mitigating the risks associated with being the first to market.
By synthesizing both scientific and commercial research findings, we conclude that while the BHM catheter remains a promising and valid target, the timeline for market readiness is likely to be extended. To ensure continued success and uptake, we plan to engage in further research, investigate additional demonstration projects, and seek access to broader markets and financial support. This approach will also require continued focus on IPR support, internationalization strategies, and alignment with a supportive regulatory and standardization framework. Our strategy will be to pursue incremental innovation while maintaining a long-term vision for the broader impact of the BHM catheter in the healthcare industry.