Periodic Reporting for period 1 - SoftReach (Minimally-Invasive Soft-Robot-Assisted Deep-Brain Localized Therapeutics Delivery for Neurological Disorders)
Período documentado: 2023-02-01 hasta 2024-01-31
SoftReach aspires to radically improve the treatment of neurological disorders by providing innovative means of localised delivery of therapeutics to hard-to-reach regions of the Central Nervous System (CNS) that are currently not accessible by interventional approaches. We will develop and demonstrate for the first time a minimally-invasive robotic platform that will provide clinically innovative access to deep brain regions via the Ventricular System (VS). Specifically, a miniature soft steerable robot, driven by biomimetic apical extension methods, will safely navigate through the spinal subarachnoid space under MRI guidance and reach target locations in brain ventricles, where it will attach a tissue construct payload (TCP). Once attached on VS walls, the TCP will release its therapeutic content (pharmaceuticals, cells) into adjacent brain regions.
Our long-term vision is radical: localised delivery of therapeutics to specific deep brain regions can redefine the clinical practice across a broad range of neurological disorders, against which current treatments are inadequate or non-existing. By bypassing inefficiencies of current drug delivery practices, SoftReach will enable optimal compound dosing at specific brain regions and minimal side effects, while setting the stage for precise delivery of stem cells that are only effective when delivered locally.
Our long-term vision is radical: localised delivery of therapeutics to specific deep brain regions can redefine the clinical practice across a broad range of neurological disorders, against which current treatments are inadequate or non-existing. By bypassing inefficiencies of current drug delivery practices, SoftReach will enable optimal compound dosing at specific brain regions and minimal side effects, while setting the stage for precise delivery of stem cells that are only effective when delivered locally.
WP1 “System requirements & architecture, data collection and ethics”
Clinical requirements (anatomy of the subarachnoid space and brain ventricles) were consolidated in collaboration with our clinical teams. Technical requirements (system materials, communication protocols, MRI imaging) were consolidated by engineering and biology team members. See Deliverable D1_1.
A data collection and data sharing plan was developed. It details data types that will be acquired, image acquisition protocols, anonymisation procedure, and sharing protocol. A data sharing agreement has already been put in place between KCL and GRIT, another one is pending between KCL and UTH. See Deliverable D1_2.
Ethics have been put in place regarding in vivo evaluation of therapeutic agents and scaffolds, and data collection from healthy volunteers (KCL). See Deliverable D1_3.
WP2 “Design & development of robotic delivery system hardware”
1. we designed and characterised a prototype everting robot with with stiffening properties that achieves extension through pressurised low melting point alloy. Elongation and retraction of the system was successfully demonstrated. Catheter-based steering was presented. High force delivery capability was demonstrated.
2. Milli- and micro-scale Laser-based fabrication of LDPE everting sheaths was achieved using a commercial laser cutting/welding machine. Thorough system characterisation identified the best system parameters. A variety of everting sheaths were created.
3. We redeveloped our mechatronics system to enable for longer transmission systems, embedded sensing, and longer eversion robots.
WP3 “Sensor-based Robot Navigation and Control”
1. Collected publicly available MRI data and 3D annotated models for the sub-arachnoid space and tissue structures within the spine.
2. Developed a novel interpretable CNN architecture for the segmentation of the sub-arachnoid space in T2-Weighted MR Slices.
3. Developed a novel image-based 3D path-planning algorithm for path estimation of a soft-growing robot.
4. Evaluated developed methods in the context of the project, e.g. on MR examination. Developed software for fast interactive visualization of the multi-channel MRI data and therapy plan.
5. Developed a shared control architecture and a novel dynamic model for real-time control.
WP4 “Payload design and development”
1. We analyzed the key tasks of Tissue Construct Payloads (TCPs): state switching, stable attachment to robot, reliable detachment from the robot, delivery of therapeutics. Brainstormed ideas, run pilot experiments and identified risks.
2. We developed efficient 3D geometric models and finite element models of porous collagen based scaffolds (PCS). Utilized models to describe the macroscopic and microscopic mechanics of TCPs.
3. We designed and set-up a 4-axis laser microfabrication system for the fabrication of sub-μl PCS with user-defined shape and structure.
4. We developed an experimental setup for evaluating the strength of PCS attachment on a cell monolayer, which will be utilised to optimize TCP attachment on brain ventricle walls.
5. We developed and characterized means to deliver hydrophobic small-molecule compounds via PCS via the entrapment in electrospan polymeric microparticles.
WP5 “Demonstrate TCP therapeutic delivery in vivo”
• We designed a state-of-the-art stereotaxic surgery station and performed trial stereotaxic injections in the third ventricle and the hippocampus.
• We obtained and propagated 5xFAD mice.
• We tested the equipment for the behavioral evaluation of mice. We setup and tested behavioral tasks for evaluating memory performance in 5xFAD mice
• We characterised specific neurogenesis-related processes like neural stem cell (NSC) proliferation, differentiation and maturation.
• We developed primary cultures of mouse Neural Stem Cells (NSCs) and hiPSC-derived NSCs and optimised culture conditions inside porous collagen scaffolds.
WP6 “System integration & interventional procedure evaluation”
• We designed and fabricated three brain phantoms that contain hollow fluid-filled cavities, which will be utilized for soft robot development and evaluation: one that captures the full 3D geometry of brain ventricles and two that provide simplified geometries that ease experimental validation.
• We run pilot experiments of catheter elongation through phantom hollow cavities in 3D brain phantoms. We also run pilot experiments of TCP manipulation via fluid flow inside catheter lumen.
WP7 “Project Management, Dissemination and Exploitation”
• We completed an amendment due to the move of Dr. Tzeranis from partner UCY to partner FORTH.
• we setup a consortium website and linkedin page (Deliverable 7.1).
• We prepared the initial dissemination and communication plan (Deliverable 7.2) participated in the 2023 Marie Curie Researcher’s night event, showcased the project in public events, participated in EIC training courses, established communication channels with our TTOs, participated in several international conferences, organized a soft robotics workshop, published a paper in a peer-reviewed journal (1 more under review) and one in peer-reviewed conference proceedings (2 more accepted).
• We updated our risk assessment plan and submitted it as Deliverable 7.3.
• Members hold biweekly online meetings to monitor project progress and identify shortcomings, organized by Katarzyna Procyk (KCL). Tereza Karapathiotaki (FORTH) assists on administrative and financial management. FORTH has also dedicated personnel for monitoring the project.
Clinical requirements (anatomy of the subarachnoid space and brain ventricles) were consolidated in collaboration with our clinical teams. Technical requirements (system materials, communication protocols, MRI imaging) were consolidated by engineering and biology team members. See Deliverable D1_1.
A data collection and data sharing plan was developed. It details data types that will be acquired, image acquisition protocols, anonymisation procedure, and sharing protocol. A data sharing agreement has already been put in place between KCL and GRIT, another one is pending between KCL and UTH. See Deliverable D1_2.
Ethics have been put in place regarding in vivo evaluation of therapeutic agents and scaffolds, and data collection from healthy volunteers (KCL). See Deliverable D1_3.
WP2 “Design & development of robotic delivery system hardware”
1. we designed and characterised a prototype everting robot with with stiffening properties that achieves extension through pressurised low melting point alloy. Elongation and retraction of the system was successfully demonstrated. Catheter-based steering was presented. High force delivery capability was demonstrated.
2. Milli- and micro-scale Laser-based fabrication of LDPE everting sheaths was achieved using a commercial laser cutting/welding machine. Thorough system characterisation identified the best system parameters. A variety of everting sheaths were created.
3. We redeveloped our mechatronics system to enable for longer transmission systems, embedded sensing, and longer eversion robots.
WP3 “Sensor-based Robot Navigation and Control”
1. Collected publicly available MRI data and 3D annotated models for the sub-arachnoid space and tissue structures within the spine.
2. Developed a novel interpretable CNN architecture for the segmentation of the sub-arachnoid space in T2-Weighted MR Slices.
3. Developed a novel image-based 3D path-planning algorithm for path estimation of a soft-growing robot.
4. Evaluated developed methods in the context of the project, e.g. on MR examination. Developed software for fast interactive visualization of the multi-channel MRI data and therapy plan.
5. Developed a shared control architecture and a novel dynamic model for real-time control.
WP4 “Payload design and development”
1. We analyzed the key tasks of Tissue Construct Payloads (TCPs): state switching, stable attachment to robot, reliable detachment from the robot, delivery of therapeutics. Brainstormed ideas, run pilot experiments and identified risks.
2. We developed efficient 3D geometric models and finite element models of porous collagen based scaffolds (PCS). Utilized models to describe the macroscopic and microscopic mechanics of TCPs.
3. We designed and set-up a 4-axis laser microfabrication system for the fabrication of sub-μl PCS with user-defined shape and structure.
4. We developed an experimental setup for evaluating the strength of PCS attachment on a cell monolayer, which will be utilised to optimize TCP attachment on brain ventricle walls.
5. We developed and characterized means to deliver hydrophobic small-molecule compounds via PCS via the entrapment in electrospan polymeric microparticles.
WP5 “Demonstrate TCP therapeutic delivery in vivo”
• We designed a state-of-the-art stereotaxic surgery station and performed trial stereotaxic injections in the third ventricle and the hippocampus.
• We obtained and propagated 5xFAD mice.
• We tested the equipment for the behavioral evaluation of mice. We setup and tested behavioral tasks for evaluating memory performance in 5xFAD mice
• We characterised specific neurogenesis-related processes like neural stem cell (NSC) proliferation, differentiation and maturation.
• We developed primary cultures of mouse Neural Stem Cells (NSCs) and hiPSC-derived NSCs and optimised culture conditions inside porous collagen scaffolds.
WP6 “System integration & interventional procedure evaluation”
• We designed and fabricated three brain phantoms that contain hollow fluid-filled cavities, which will be utilized for soft robot development and evaluation: one that captures the full 3D geometry of brain ventricles and two that provide simplified geometries that ease experimental validation.
• We run pilot experiments of catheter elongation through phantom hollow cavities in 3D brain phantoms. We also run pilot experiments of TCP manipulation via fluid flow inside catheter lumen.
WP7 “Project Management, Dissemination and Exploitation”
• We completed an amendment due to the move of Dr. Tzeranis from partner UCY to partner FORTH.
• we setup a consortium website and linkedin page (Deliverable 7.1).
• We prepared the initial dissemination and communication plan (Deliverable 7.2) participated in the 2023 Marie Curie Researcher’s night event, showcased the project in public events, participated in EIC training courses, established communication channels with our TTOs, participated in several international conferences, organized a soft robotics workshop, published a paper in a peer-reviewed journal (1 more under review) and one in peer-reviewed conference proceedings (2 more accepted).
• We updated our risk assessment plan and submitted it as Deliverable 7.3.
• Members hold biweekly online meetings to monitor project progress and identify shortcomings, organized by Katarzyna Procyk (KCL). Tereza Karapathiotaki (FORTH) assists on administrative and financial management. FORTH has also dedicated personnel for monitoring the project.
The following research in the remit of SoftReach has been published:
Wu, Z., Sadati, S. M. H., Rhode, K. & Bergeles, C. Vision-based autonomous steering of a miniature eversion growing robot. IEEE Robotics and Automation Letters 8, 7841–7848 (2023).
An invention disclosure regarding eversion robots for therapeutic interventions in another clinical domain (to mitigate current length limitations) is being considered by King’s IP & Licensing office.
Wu, Z., Sadati, S. M. H., Rhode, K. & Bergeles, C. Vision-based autonomous steering of a miniature eversion growing robot. IEEE Robotics and Automation Letters 8, 7841–7848 (2023).
An invention disclosure regarding eversion robots for therapeutic interventions in another clinical domain (to mitigate current length limitations) is being considered by King’s IP & Licensing office.