The PLS approach
The aim of WP1 is to define the technical and clinical specifications of the PLS system. This was the critical first step in the first six months of the project (Oct 2019-March 2020). The consortium defined the requirements and specifications for the PLS system, including all technological components such as fetal manikin, life support systems, clinical procedures, parent-infant bonding strategies.
The needs and constraints in combining a liquid-based environment (see WP2), fetal manikin (see WP3) with vitals supply through an artificial placenta (see WP4), and non-invasive monitoring with model-based clinical decision support (see WP5) were evaluated. These requirements are part of the overall project management (see WP7) and are discussed in regular project meetings and progress reports.
In addition, computational modeling for hemodynamics and gas exchange will support the definition of requirements of several critical components of the PLS system.
The aim of WP2 is to develop a prototype of a liquid-based environment to maintain liquid-filled lungs (LFL) in EP infants. Based on the analysis performed in WP1, a fluid-based prototype of the PLS system will be developed based on: 1) an (artificial) amniotic fluid-filled incubator housing the infant (manikin), or 2) a non-submerged alternative where the manikin’s lungs only remain fluid-filled. These fluid-based prototypes will be used to develop ex vivo organ models to evaluate prototype suitability in ensuring prolonged viability of individual organs (standard pediatric oxygenators and dialyzers are used initially for this purpose, while fetal-compatible devices are developed in WP4). This work package will also investigate how to maintain fetal blood and nutrients supply in the PLS system. Finally, the completed system prototype will be technically verified, in order to deliver a system compatible with clinical procedures.
The aim of WP3 is to design and optimize fetal manikins for use as a surrogate EP infant and validation tool for performance evaluation of the PLS system. First, a fetal manikan will be developed. The manikin will include tissue- and organ-mimicking materials which are 3D-printed according to high-resolution MRI images of fetuses of 24 weeks GA. The manikin will mimic fetal cardiorespiratory physiology. A prototype will be developed to mimic the heart and vasculature of the fetus to drive ´blood flow´, and will inform the design of the artificial placenta (see WP4) next to that of the manikin. These parameters can also be modulated through mathematical modelling, with actual data. Next, In order to prevent the transition from fetal to neonatal cardiorespiratory physiology, a safe transfer procedure after birth will be established. This will involve the use of maternal manikins and safe and antiseptic transfer to PLS. Lastly, The performance of the manikin in accurately simulating fetal physiology will be validated with data from scientific literature and laboratory measurements. The transfer procedure will be tested and validated using the fetal manikin by maintenance and monitoring of fetal cardiorespiratory indicators such as clinically safe cut-offs for transfer time, water-tight, and aseptic birth and transition.
The aim of WP4 is to develop an artificial placenta for extracorporeal life support (ECLS) for the fetus in PLS.
First, A membrane oxygenator is needed to oxygenate the blood, taking over the lung function of the placenta. This system will be developed corresponding to fetoplacental cardiorespiratory function and capacity as well as in close agreement with the liquid system (WP2) and fetal manikin (WP3) to ensure compatibility in design and function. The oxygenator might include a heat exchanger in order to keep the blood at body temperature if needed.
After the amniotic fluid-filled incubator is developed, a fetal dialyzer will be developed to remove waste products in umbilical cord blood, to take over the continuous dialyzation function of the placenta. Parallel activities in WP5 will enable autonomous regulation of nutrient/blood levels by incorporating model-predictive control algorithms.
Finally, verification of the artificial placenta will be performed using both the manikin and in vitro test set-ups for measurement of hemodynamics, gas exchange, and waste products removal. Results will be benchmarked against clinical measurements and data from scientific literature as reference.
The aim of WP5 is To develop and integrate into the PLS system: 1) computational models that can accurately simulate pathophysiological processes and predict therapeutic outcomes, and 2) sensory mechanisms for unobtrusive monitoring and feedback of fetal parameters.
First, sensory mechanisms for fetal monitoring will be developed. These include electrodes and transducers that monitor fetal core temperatures. They also include near infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) to simultaneously measure oxygenation and flow in various tissues (e.g. brain, muscle). All methods will be assessed based on PLS requirements and quantitation analyses. Other signals such as motion and skin color will be measured using digital cameras. Sensory systems will be developed next to fetal manikins (WP3).
Concurrently, a clinical decision-support system will be established. Computational models developed in WP1 will be optimized based on multimodal monitoring achieved in WP5 and requirements analysis derived from WP1. These models will be adapted to predict the outcome of simulated medical interventions for the individual fetal manikin. Subsequently, machine learning techniques will be used to refine this system and for future autonomous functioning.
Finally, sensory and feedback mechanisms will be validated by measuring established clinical parameters such as fetal heart rate, blood pressure, and oxygen saturation, which will be fed into the models using theoretical as well as experimental data.
The aim of WP6 is to validate the PLS system following the integration of all components and provide Proof-of-Principle in a full clinical simulation.
Prototypes developed in WP 2-5 will be integrated according to requirements outlined in WP1. These include: the liquid system, development and connection of artificial placenta, fetal manikin, monitoring systems, and software packages for simulation and clinical decision-support.
Then technical validation of the integrated PLS system will comprise the implementation of an optimized transfer procedure, whereby the fetal manikin is transferred to PLS with an umbilical connection established to an artificial placenta. Sensors embedded within the manikin and liquid environment will be calibrated according to known vital parameters. Running software will monitor the health status of the manikin from the transfer to PLS, reporting data in real-time from all sensors and providing decision-support based on these data.
Following technical validation, the PLS prototype will be set-up in the neonatology department of TU/e and evaluated against defined operational needs in a clinical environment simulating extreme preterm delivery and perinatal intensive care. Clinicians will assess the accuracy of vital parameters, perform routine assessments on the fetal manikin and ensure the quality of decision-support systems as well as of parent-infant bonding systems Data and decision-support output from this study will be verified against real datasets of fetal physiological parameters and interventions generated by collaborators.
The aim of WP7 is to successfully implement the project, perform financial management, assess and monitor project progress and reporting to the EU.
At the beginning of the project, a data management plan was put in place. In addition, the planning and monitoring of the work plan by measuring progress against project deliverables and milestones is performed by a designated project manager. Progress of each WP is discussed in regular project meetings The consortium project kicked off with an in-person meeting. Continual progress meetings have taken place monthly, and when the pandemic situation changes we will meet again in-person.
The aim of WP8 is to provide efficient and effective dissemination of results to stakeholders and promotion of further uptake of results and develop and exploitation plan. The project and results will be promoted via a series of communication activities, specifically aimed at relevant target audiences during the project. A plan for dissemination and exploitation has been created and will be maintained over the course of the project. An Advocate Advisory Board is being established to bring a parent/family perspective to the project. For the latest project updates, follow us on LinkedIn and Twitter.
Experiences from previous research projects have taught us that there can be a gap between all knowlegde, solutions and insights gained, and the market needs.
The main goal of the PLS project is to ultimately help as many extremely premature born infants as best as current technology can facilitate, and to support medical staff in doing so. As it is a highly complex challenge that we are solving, we have decided to found Juno Perinatal Healthcare, to ensure the perspectives of all stakeholders: market (hospitals, end users, insurances, investors and competition) as well as scientists, doctors, parents and of course premature born infants, are all involved, their opinions respected and potential blockers evaded.
The timelines to succesfully develop a complex device like ours, with different expertises involved, are long. Therefore we would like to gain all relevant information, have short feedback loops and execute tests as often and as soon as possible Additionally, essential IP is divided between the different consortium partners. To tackle these aspects of the project, an early stage start-up company is founded aimed at securing IP and investigating market needs, to ensure the product developed in the end will reach the market.