Periodic Reporting for period 3 - PLS (Perinatal Life Support System: Integration of Enabling Technologies for Clinical Translation)
Okres sprawozdawczy: 2022-02-01 do 2023-05-31
Every year, 800.000 babies are born extremely preterm (EP; <28 weeks of age) worldwide. A large proportion of survivors from this group of smallest infants face lifelong disabilities, including breathing, cardiac, neurological, and metabolic problems. Current treatment requires the preterm initiation of body functions for which the respective organs are not prepared. This affects primarily the lungs which need to provide gas-exchange under air (i.e. oxygen-based mechanical ventilation), and the gut, which is needed for energy and nutrition. This approach causes major therapy-related morbidity such as bronchopulmonary dysplasia, necrotizing enterocolitis and germinal matrix bleeding. The Perinatal Life Support (PLS) consortium envisions a medical device that can support the safe development of EP infants outside the womb by preserving the innate fetal cardiorespiratory physiology ex vivo, with the following enabling technologies:
1. Computational models for fast and objective clinical decision support based on physiological data input;
2. A liquid-based environment with oxygen and nutrient exchange using an ´artificial placenta´;
3. A fetal manikin that can accurately simulate EP infants in an intensive care setting.
4. An extracorporeal system that serves as an artificial placenta
5. Continuous and non-invasive monitoring of fetal parameters such as heart rate and oxygenation;
1. Computational models for fast and objective clinical decision support based on physiological data input;
2. A liquid-based environment with oxygen and nutrient exchange using an ´artificial placenta´;
3. A fetal manikin that can accurately simulate EP infants in an intensive care setting.
4. An extracorporeal system that serves as an artificial placenta
5. Continuous and non-invasive monitoring of fetal parameters such as heart rate and oxygenation;
The PLS project's activities adhered to defined work packages. Introductory WP1's closure led to extensive requirement lists and initial knowledge, relevant for other packages. Key achievements in the reporting period with emphasis on recent third reporting period are:
1. Computational Models (WP1 and part of WP5):
WP1 defined technical and clinical PLS specifications. Computational model requirements set (D1.1 D1.2). Fetal physiology model verified. Recent milestones: PLS component implementation, regulation integration, and translation to fetal piglet physiology. WP1 ready for WP6 integration.
2. Liquid-Based Environment (WP2):
Liquid-filled lung (LFL) and chamber (LFC) concepts explored. Optimized LFC prototype and umbilical cord port design (D2.1 D2.2). LFL feasibility studies conducted. LFC and LFL systems optimized, ex-vivo liver circuit enhanced, umbilical cord harvesting protocols defined, and bioreactor design finalized for WP6 integration.
3. Fetal Manikins and Transfer Devices (WP3):
Developed actuators and sensors for accurate premature infant and maternal manikin simulation (D3.1 D3.3). Transfer procedures/devices analyzed (D3.4 D3.5). Enhanced fetal manikin features added, including mobility, sensors, and physiological components, all primed for clinical integration in WP6.
4. Extracorporeal Artificial Placenta (WP4):
Manufactured two-chamber oxygenator (minimal prime volume, low flow resistance), tested with whole blood (D4.1 D4.2 D4.3). Prototyped fetal dialyzer for liquid-filled chamber (D4.4). Recent activities: gas transfer and pressure measurements, design adjustments, comprehensive gas transfer and pressure loss tests.
5. Monitoring System (WP5):
Hybrid monitoring device (DCS, TD-NIRS) built, tested (D5.3 D5.4). Ongoing hybrid TD NIRS and DCS device optimization and validation in pre-clinical settings. Model of cerebral autoregulation developed. Potential fECG measurement through insulating layer explored.
6. Technical Validation of Integrated System (WP6):
Component integration discussed, evolving insights integrated into requirements. Final subsystem integration planned in Aachen (month 51). PLS prototype technical validation expected in Month 48. Progress on numerical simulations, oxygenation phantom testing, and hybrid DCS/TD NIRS device industrialization.
7. Dissemination:
Besides mentioned activities, results disseminated to stakeholders, plans created (D7.1 D7.2). Project managed for implementation, finances, monitoring, and reporting (D7.4 D7.5 D7.6). Active involvement of Advocate Advisory Board and Scientific Advisory Board.
Additional Eindhoven Engine-funded WP9 focuses on integrated PLS prototype development and clinical verification, including clinical protocol and training program. Spin-off plans halted due to subsystem readiness mismatch. Rest-funding used for decision support system exploration.
For a more extensive summary of achievements please refer to the PLS website: http://perinatallifesupport.eu/
1. Computational Models (WP1 and part of WP5):
WP1 defined technical and clinical PLS specifications. Computational model requirements set (D1.1 D1.2). Fetal physiology model verified. Recent milestones: PLS component implementation, regulation integration, and translation to fetal piglet physiology. WP1 ready for WP6 integration.
2. Liquid-Based Environment (WP2):
Liquid-filled lung (LFL) and chamber (LFC) concepts explored. Optimized LFC prototype and umbilical cord port design (D2.1 D2.2). LFL feasibility studies conducted. LFC and LFL systems optimized, ex-vivo liver circuit enhanced, umbilical cord harvesting protocols defined, and bioreactor design finalized for WP6 integration.
3. Fetal Manikins and Transfer Devices (WP3):
Developed actuators and sensors for accurate premature infant and maternal manikin simulation (D3.1 D3.3). Transfer procedures/devices analyzed (D3.4 D3.5). Enhanced fetal manikin features added, including mobility, sensors, and physiological components, all primed for clinical integration in WP6.
4. Extracorporeal Artificial Placenta (WP4):
Manufactured two-chamber oxygenator (minimal prime volume, low flow resistance), tested with whole blood (D4.1 D4.2 D4.3). Prototyped fetal dialyzer for liquid-filled chamber (D4.4). Recent activities: gas transfer and pressure measurements, design adjustments, comprehensive gas transfer and pressure loss tests.
5. Monitoring System (WP5):
Hybrid monitoring device (DCS, TD-NIRS) built, tested (D5.3 D5.4). Ongoing hybrid TD NIRS and DCS device optimization and validation in pre-clinical settings. Model of cerebral autoregulation developed. Potential fECG measurement through insulating layer explored.
6. Technical Validation of Integrated System (WP6):
Component integration discussed, evolving insights integrated into requirements. Final subsystem integration planned in Aachen (month 51). PLS prototype technical validation expected in Month 48. Progress on numerical simulations, oxygenation phantom testing, and hybrid DCS/TD NIRS device industrialization.
7. Dissemination:
Besides mentioned activities, results disseminated to stakeholders, plans created (D7.1 D7.2). Project managed for implementation, finances, monitoring, and reporting (D7.4 D7.5 D7.6). Active involvement of Advocate Advisory Board and Scientific Advisory Board.
Additional Eindhoven Engine-funded WP9 focuses on integrated PLS prototype development and clinical verification, including clinical protocol and training program. Spin-off plans halted due to subsystem readiness mismatch. Rest-funding used for decision support system exploration.
For a more extensive summary of achievements please refer to the PLS website: http://perinatallifesupport.eu/
The main future work in the project will be dedicated to further optimization of the different subsystems and integration into a technically validated PLS system prototype according to our original plan and are parts of activities in WP6.
1. The computational model of the fetal circulation and metabolic processes has been set-up. The models are extended regarding applicability to enable it to serve as optimization tool for the PLS system (Digital Twin principle) or as basis for the clinical decision support system regarding application of the PLS system in clinical practice. Integration and technical validation of the tools in the final PLS system prototype will be main activity.
2. Regarding the development of a liquid based environment, first laboratory prototypes for liquid the liquid filled lung concept as well as the liquid filled cavity concept (LFL and LFC) are available as well as first feasibility studies conducted for LFL system. The prototypes developed will be further evaluated and form the basis of the final prototype PLS system.
3. Regarding the fetal manikins and devices for the transfer procedure MRI scans and segmentation of both post-mortem 24-week fetus and in-utero fetus, placenta, UC, and uterus, were acquired successfully and led to the fabrication of the first prototype of the realistic 24-week premature manikin. In addition, a transfer device, procedure and transfer station has been developed and manufactured. In next steps functionality based on the computational models will be built in, such that clinical procedures and monitoring strategies can be integrated, evaluated and optimized in the prototype PLS system.
4. A completely new oxygenator principle was derived to allow for an increase in filling volume in the artificial placenta. The first laboratory prototype of the oxygenator is 3D-printed to evaluate design-feasibility in the first place. The first prototype has been evaluated regarding feasibility, thrombogenicity and hemocompatibility and a sealing concept will be derived. Simultaneously, the oxygenator design will be improved particularly with regard to its fluid mechanics using a simulation tool for computational fluid dynamics (CFD) and integrated and validated in the final PLS system prototype.
Regarding the monitoring system, the construction of a hybrid system (optical module) based on Diffuse Correlation Spectroscopy (DCS), for tissue perfusion measurement, and Time-Domain Near Infrared Spectroscopy (TD-NIRS), for tissue oxygenation measurement, was established. This module is part of the final workstation hosting all the sensors for fetal monitoring. The design of the optical module is completed. Also, a first version of of a computational model for fetal cardiovascular activity as a part of a clinical decision-support system has been developed such that integration with the computational models can be started.
1. The computational model of the fetal circulation and metabolic processes has been set-up. The models are extended regarding applicability to enable it to serve as optimization tool for the PLS system (Digital Twin principle) or as basis for the clinical decision support system regarding application of the PLS system in clinical practice. Integration and technical validation of the tools in the final PLS system prototype will be main activity.
2. Regarding the development of a liquid based environment, first laboratory prototypes for liquid the liquid filled lung concept as well as the liquid filled cavity concept (LFL and LFC) are available as well as first feasibility studies conducted for LFL system. The prototypes developed will be further evaluated and form the basis of the final prototype PLS system.
3. Regarding the fetal manikins and devices for the transfer procedure MRI scans and segmentation of both post-mortem 24-week fetus and in-utero fetus, placenta, UC, and uterus, were acquired successfully and led to the fabrication of the first prototype of the realistic 24-week premature manikin. In addition, a transfer device, procedure and transfer station has been developed and manufactured. In next steps functionality based on the computational models will be built in, such that clinical procedures and monitoring strategies can be integrated, evaluated and optimized in the prototype PLS system.
4. A completely new oxygenator principle was derived to allow for an increase in filling volume in the artificial placenta. The first laboratory prototype of the oxygenator is 3D-printed to evaluate design-feasibility in the first place. The first prototype has been evaluated regarding feasibility, thrombogenicity and hemocompatibility and a sealing concept will be derived. Simultaneously, the oxygenator design will be improved particularly with regard to its fluid mechanics using a simulation tool for computational fluid dynamics (CFD) and integrated and validated in the final PLS system prototype.
Regarding the monitoring system, the construction of a hybrid system (optical module) based on Diffuse Correlation Spectroscopy (DCS), for tissue perfusion measurement, and Time-Domain Near Infrared Spectroscopy (TD-NIRS), for tissue oxygenation measurement, was established. This module is part of the final workstation hosting all the sensors for fetal monitoring. The design of the optical module is completed. Also, a first version of of a computational model for fetal cardiovascular activity as a part of a clinical decision-support system has been developed such that integration with the computational models can be started.