Periodic Reporting for period 4 - PLS (Perinatal Life Support System: Integration of Enabling Technologies for Clinical Translation)
Reporting period: 2023-06-01 to 2024-09-30
Annually, 800,000 extremely preterm (EP) babies (<28 weeks) are born globally, many facing lifelong disabilities. Current treatments require premature organ activation, leading to complications like bronchopulmonary dysplasia and necrotizing enterocolitis. The Perinatal Life Support (PLS) project aims to develop a medical device that mimics fetal physiology outside the womb, supported by these technologies:
1. Computational models for clinical decision support.
2. A liquid-based environment with an artificial placenta for oxygen and nutrient exchange.
3. A fetal manikin for intensive care simulation.
4. An extracorporeal artificial placenta.
5. Non-invasive fetal monitoring systems.
Each of these technologies is a subsystem of the final PLS system. In the last phase of the project relevant one-to-one integration of the subsystems will be investigated and verified.
1. Computational models for clinical decision support.
2. A liquid-based environment with an artificial placenta for oxygen and nutrient exchange.
3. A fetal manikin for intensive care simulation.
4. An extracorporeal artificial placenta.
5. Non-invasive fetal monitoring systems.
Each of these technologies is a subsystem of the final PLS system. In the last phase of the project relevant one-to-one integration of the subsystems will be investigated and verified.
WP1
Technical and clinical specifications of the PLS system were defined, resulting in detailed requirement lists (D1.1). Computational models for fetal physiology, circulation, and growth were verified, with sensitivity analyses performed. A wireless connection to the manikin's sensor output was established, and modules were adapted to fetal piglet physiology to support artificial placenta development. Work from WP1 is now integrated into WP6, with results published in peer-reviewed journals and a PhD thesis.
WP2
Development focused on the liquid-filled chamber (LFC) and liquid-filled lungs (LFL), optimizing prototypes (D2.1) and umbilical cord ports (D2.2). Trachea tubes (D2.3) and protocols for harvesting and maintaining umbilical cords were finalized, with a bioreactor designed to replicate physiological pressures. Recent efforts included improving LFC adaptability, sealing, filtration, and analyzing neonatal blood hemolysis. These are now ready for WP6 integration.
WP3
Advanced fetal and maternal manikins were developed with moving limbs, ribcage, and embedded sensors (e.g. temperature, air bubbles, cyanosis). Transfer devices for safe handling were prototyped, including a crib for cannulation. These innovations support WP6 integration. Results were disseminated in publications, including a concept PhD thesis.
WP4
A two-chamber oxygenator with minimal volume and low flow resistance was developed and tested (D4.1–D4.3). Recent enhancements improved gas transfer performance and pressure resistance. Tests aligned with ISO 7199 standards yielded excellent results, with findings partially published and a related PhD thesis underway.
WP5
A hybrid monitoring device combining Diffuse Correlation Spectroscopy (DCS) and Time Domain Near Infrared Spectroscopy (TD-NIRS) was optimized and validated (D5.3 D5.4). Modelling work led to a cerebral autoregulation model. Investigations into fECG measurements through the LFC's insulating layer concluded feasibility limitations with current electrodes.
WP6
Subsystem integration was finalized (month 51), verifying compliance with WP1 requirements. The verification and validation cycle (D6.1) demonstrated that subsystems meet expectations, establishing readiness for transition to pre-clinical testing.
WP7
The project was effectively managed by TU/e, with regular online and biannual in-person meetings fostering excellent collaboration among partners.
WP8
Dissemination activities targeted stakeholders, including development and exploitation plans (D7.1 D7.2). Advisory boards (AAB and SAB) were engaged to promote the uptake of results.
Technical and clinical specifications of the PLS system were defined, resulting in detailed requirement lists (D1.1). Computational models for fetal physiology, circulation, and growth were verified, with sensitivity analyses performed. A wireless connection to the manikin's sensor output was established, and modules were adapted to fetal piglet physiology to support artificial placenta development. Work from WP1 is now integrated into WP6, with results published in peer-reviewed journals and a PhD thesis.
WP2
Development focused on the liquid-filled chamber (LFC) and liquid-filled lungs (LFL), optimizing prototypes (D2.1) and umbilical cord ports (D2.2). Trachea tubes (D2.3) and protocols for harvesting and maintaining umbilical cords were finalized, with a bioreactor designed to replicate physiological pressures. Recent efforts included improving LFC adaptability, sealing, filtration, and analyzing neonatal blood hemolysis. These are now ready for WP6 integration.
WP3
Advanced fetal and maternal manikins were developed with moving limbs, ribcage, and embedded sensors (e.g. temperature, air bubbles, cyanosis). Transfer devices for safe handling were prototyped, including a crib for cannulation. These innovations support WP6 integration. Results were disseminated in publications, including a concept PhD thesis.
WP4
A two-chamber oxygenator with minimal volume and low flow resistance was developed and tested (D4.1–D4.3). Recent enhancements improved gas transfer performance and pressure resistance. Tests aligned with ISO 7199 standards yielded excellent results, with findings partially published and a related PhD thesis underway.
WP5
A hybrid monitoring device combining Diffuse Correlation Spectroscopy (DCS) and Time Domain Near Infrared Spectroscopy (TD-NIRS) was optimized and validated (D5.3 D5.4). Modelling work led to a cerebral autoregulation model. Investigations into fECG measurements through the LFC's insulating layer concluded feasibility limitations with current electrodes.
WP6
Subsystem integration was finalized (month 51), verifying compliance with WP1 requirements. The verification and validation cycle (D6.1) demonstrated that subsystems meet expectations, establishing readiness for transition to pre-clinical testing.
WP7
The project was effectively managed by TU/e, with regular online and biannual in-person meetings fostering excellent collaboration among partners.
WP8
Dissemination activities targeted stakeholders, including development and exploitation plans (D7.1 D7.2). Advisory boards (AAB and SAB) were engaged to promote the uptake of results.
The requirements enlisted advanced our knowledge about the developments needed to obtain the envisioned PLS system and form the basis for further development and optimization of the system (M1). New insights that evolve during the execution of the project will be integrated in the list of requirements.
1. The computational model of the fetal circulation and metabolic processes has been set-up. The models can be extended regarding applicability to eventually 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.
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 can be further evaluated and form the basis of the final 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 even more functionality based on the computational models can be built in, such that clinical procedures and monitoring strategies can be evaluated and optimized.
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 has been derived. The oxygenator design may need to be improved particularly with regard to its blood compatibility.
5. 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 implemented. 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 a computational model for fetal cardiovascular activity as a part of a clinical decision-support system has been developed.
The technical validation and proof-of-principle test performed in WP6 of the project did not give rise to change the statements given above based on the work performed in WP1 to WP5.
1. The computational model of the fetal circulation and metabolic processes has been set-up. The models can be extended regarding applicability to eventually 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.
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 can be further evaluated and form the basis of the final 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 even more functionality based on the computational models can be built in, such that clinical procedures and monitoring strategies can be evaluated and optimized.
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 has been derived. The oxygenator design may need to be improved particularly with regard to its blood compatibility.
5. 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 implemented. 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 a computational model for fetal cardiovascular activity as a part of a clinical decision-support system has been developed.
The technical validation and proof-of-principle test performed in WP6 of the project did not give rise to change the statements given above based on the work performed in WP1 to WP5.