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Perinatal Life Support System: Integration of Enabling Technologies for Clinical Translation

Periodic Reporting for period 2 - PLS (Perinatal Life Support System: Integration of Enabling Technologies for Clinical Translation)

Reporting period: 2020-10-01 to 2022-01-31

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
In a first stage of the research an overview of the main requirements needed for the PLS system to be ready for clinical application are investigated. An outline of the impact on the work packages is given, and the refinements for which simulations are needed are discussed. The requirements enlisted are deemed to be necessary for successful execution of the project’s work packages and are either in need of further investigation, or ready to set specifications and conditions for features of the PLS system.

1. Computational models for fast and objective clinical decision support based on physiological data input.
In parallel, the purpose, main requirements, and structure of the computational models that will be developed in the PLS project for simulation of the PLS system have been defined (D1.2). The outcome of this activity will serve as a starting point and guideline for further development of the computational model that can be used to optimize the system on the one hand as and form the basis of the decision support system at the other hand.
2. A liquid-based environment with oxygen and nutrient exchange using an ´artificial placenta.
Regarding the development of a liquid based environment two concepts (liquid filled lungs and liquid filled cavity resp.) have been evaluated and several options for first prototypes have been investigated. In addition, the possibilities for cannulation of very small blood vessels with regard to an overview of existing methods and cannulas have been investigated.
3. A fetal manikin that can accurately simulate EP infants in an intensive care setting.
The possibility and feasibility of the design and prototyping technology of fetal manikins based on MRI information for use as a surrogate EP infant and validation tool for performance evaluation of the PLS system as well as the possibility to provide the system with an appropriate transfer device to deliver the fetus have been investigated.
4. An extracorporeal system that serves as an artificial placenta.
The design and development of a small volume, low resistance, membrane oxygenator that oxygenates the blood extracorporeally, and thus takes over the lung function of the placenta and might include a heat exchanger in order to keep the blood at body temperature has been investigated (D4.3). The need for a fetal dialyzer has been evaluated D4.4).
5. Continuous and non-invasive monitoring of fetal parameters such as heart rate and oxygenation.
The main activities in this period were dedicated to the development of sensory the mechanisms for unobtrusive monitoring and feedback of fetal parameters ready for integration into the PLS system with emphasis to brain oxygenation and perfusion. In addition, simulation studies (Monte Carlo) were performed in order to identify the best analysis algorithm for brain oxygenation assessment in fetus.
In addition to the substantial activities mentioned above, actions were taken for dissemination of results to stakeholders and promotion of further uptake of results, the creation of a development and exploitation plan and the project has been managed regarding implementation, financial aspects, monitoring, meetings, and reporting. In the first year of the project, we actively worked to begin forming connections to parents and advocates to form an Advocate Advisory Board (AAB) and to broaden our networks.
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 will 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 a 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 PLS system.
3. Regarding the feat 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 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 will be 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).
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 started. 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.
The current challenge and long-term vision of the Perinatal Life Support (PLS) project.