Work package 3

Lung & renal assist device (LRAD) development (hollow fiber & microfluidic)

Lead: Universiteit Twente, Prof. Dr.-Ing. Jutta Arens

Development of out-side in dialyser hollow fiber membranes of fluid-mechanically optimised combined lung & renal assist devices (both hollow fiber & microfluidic), and of intelligent monitoring and control unit

We will develop a LRAD with either a mixed fiber bundle or microfluidic techniques to meet individual needs. The LRAD will be demand-driven and controlled by non-blood contacting sensors and intelligent microprocessor-based medical control unit with feedback loop monitor. In the hollow-fiber LRAD, oxygenation fibers and dialysis fibers in alternate layers share one housing. Inside the fibers flows either oxygen or dialysate fluid while the baby's blood flows around the fibers. The continuous bloodstream through the housing prevents clot formation. The dialysate flow and thus the dialyser function can be switched on and off depending on the patient's demand. In the microfluidic LRAD design, each channel of the vascular network provides both oxygenation and dialysis. At the same time, nanoporous membranes separate the blood and the dialysate channels. These are arranged next to each other and allow the exchange between the neighbouring channels.

3.1 Dialyser membrane development for low-flow, outside-in application
For the device (WP 3.2), we will develop a dialysis membrane suitable for outside-in filtration (OIF). For this, we will develop and apply a dual-layer mixed matrix membrane (MMM) consisting of an inside polymeric layer with activated carbon particles (in contact with the dialysate) and an outside polymeric particle-free layer (in contact with blood flowing on the outside of the fiber). The MMM combines filtration and adsorption and can remove a broad range of uremic toxins. The membranes will be prepared using novel polymer blends of PES / SlipSkinTM (SS). The SS is a random copolymer of the hydrophilic N-vinylpyrrolidone (NVP) and hydrophobic N-butyl methacrylate (BMA) and can provide membranes with long-term blood compatibility with no additive leakage. For the microfluidic module, we will fabricate nanoporous membranes by micro fabrication and micro replication technologies.

3.2 Development & manufacturing of LRAD devices and iterative optimisations
Based on the specifications defined in WP 1.2 and the findings of the FMEA (WP 1.3), we will develop scalable integrative combined lung & renal assist devices (LRADs) in two versions, a hollow fiber and a microfluidic design. These two design approaches will be followed in parallel to minimise the project risk. Both will be designed for different body weights ranging from 400 to 4,000 g, for a blood flow of 20 – 40 ml/kg/min, and minimal priming volume (ideally ≤ 10 mL/kg) and resistance (pressure drop below 30 mmHg) to allow for pumpless operation and bloodless priming. Both design processes will be supported by numerical simulations (WP 3.3). Development iterations will be followed by manufacturing lab prototypes by micro replication technologies with elastomers making use of the novel membranes developed in WP 3.1 and thorough in-vitro (WP 3.4) and in-vivo testing (WP 5). Each optimisation step of the device design will be based on the in-vitro and in-silico test results. To ensure hemocompatibility, a coating of inner surfaces with covalent antithrombin-heparin and albumin-heparin layers, as well as polymers with less protein binding, will be used in combination with nitric oxide enriched oxygenator gas.

3.3 Numerical modelling of novel devices
The effect of fluid stresses and possible increased risk of hemolysis and thrombus formation will be assessed for all components through fully resolved fluid dynamical simulations. The fluid will be modelled by 1) a non-Newtonian viscosity model for whole blood coupled with a scalar field representing the local variation in hematocrit or by 2) modelling plasma as weakly non-Newtonian adding a transport/ diffusion equation model to account for non-uniform distribution of macromolecules. Remaining blood constituents will be handled by Lagrangian Particle Tracking. Recommendations for the design optimisations in WP 3.2 for both the hollow fiber and the microfluidic device will be provided.

3.4 In-vitro testing of LRADs and ArtPlac system
Initial in-vitro testing for the determination of necessary membrane surface area for both gas exchange and dialysis function will be performed in a small laboratory test device. After each development step in WPs 3.1 & 3.2 the necessary in-vitro function tests according to the relevant international standards (e.g., ISO 7199, ISO 18193 and ISO 8638) over the complete range of operating points to assure detailed understanding of mass transfer capabilities for iterative optimisation of membranes and devices (WPs 3.1 & 3.2) will be performed. The new membranes will be systematically evaluated concerning long term blood compatibility and removal of toxins from blood and compared with commercial HD membranes used currently in the clinic, applied in the inside-out and OIF mode. The final version of the LRADs incl. the flow control and monitoring sensors (WP3.5) and the cannulas (WP4) will be subject to the full necessary verification testing according to the applicable international standards to ensure safe and effective in-vivo testing (WP 5).

3.5 Demand-driven use and sensors
A flow control unit will be developed as a feedback loop system for the control of the vital parameters of the newborn. Sensors for blood parameters (e.g. oxygen, pH, electrolyte, creatinine) will be integrated into device walls or measure indirectly in the diffusate channels without contact to blood flow in the LRAD device developed in WP3.2. The flow control unit directly processes the sensor values to adjust the blood flow valve, which will lead to a system imitating characteristics of the natural placenta.

3.6 Intermittent LRAD/device optimisations based on short- and long-term in-vivo experiences
The complete development processes of WP3 will be documented according to regulatory demands (WP 1.4).

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ArtPlac is a preclinical research project dedicated to develop an innovative technology of medical treatments for neonatal intensive care.


Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them.