Blood compatible microfluidic system for pharmacokinetic studies in small animals

Abstract

New radiotracer developments for nuclear medicine imaging require the analysis of blood as a function of time in small animal models. A microfluidic device was developed to monitor the radioactivity concentration in the blood of rats and mice in real time. The microfluidic technology enables a large capture solid angle and a reduction in the separation distance between the sample and detector, thus increasing the detection efficiency. This in turn allows a reduction of the required detection volume without compromising sensitivity, an important advantage with rodent models having a small total blood volume (a few ml). A robust fabrication process was developed to manufacture the microchannels on top of unpackaged p-i-n photodiodes without altering detector performance. The microchannels were fabricated with KMPR, an epoxy-based photoresist similar to SU-8 but with improved resistance to stress-induced fissuring. Surface passivation of the KMPR enables non-diluted whole blood to flow through the channel for up to 20 min at low speed without clotting. The microfluidic device was embedded in a portable blood counter with dedicated electronics, pumping unit and computer control software for utilisation next to a small animal nuclear imaging scanner. Experimental measurements confirmed model predictions and showed a 4- to 19-fold improvement in detection efficiency over existing catheter-based devices, enabling a commensurate reduction in sampled blood volume. A linear dose-response relationship was demonstrated for radioactivity concentrations typical of experiments with rodents. The system was successfully used to measure the blood input function of rats in real time after radiotracer injection.

Real-Time Microfluidic Blood-Counting System for PET and SPECT Preclinical Pharmacokinetic Studies

“…The proposed microfluidic blood-counting system was successfully used with rats (27) and mice in this work after injection of PET and SPECT tracers. The counter-derived AIF was successfully compared with manual samples in a phantom experiment.…”

“…The detailed fabrication process was reported elsewhere (27) and is briefly summarized in the supplemental materials. The resulting microfluidic chips had a 37 · 1125 mm 2 cross section and 16-mm length for a detection volume of 0.66 mL.…”

“…2A). Furthermore, the microfluidic chips were designed to leave only a few micrometers between the sample and the detector, drastically decreasing particle energy loss (27) before reaching the detection region (;2 keV) compared with a conventional design built with a catheter (e.g., polyethylene tubing, Intramedic PE50 or PE10 [Becton Dickinson]) (;200 keV).…”

“…We also proposed a method to improve the blood compatibility of the microchannel polymer building material (26). The microfluidic geometry was optimized, the fabrication process detailed, and a preliminary characterization of the microfluidic chip was performed (27). In the present work, we describe a prototype blood-counting system comprising the microfluidic chip together with dedicated electronics, software, and pumping unit.…”

Plastic Scintillator‐Based Microfluidic Devices for Miniaturized Detection of Positron Emission Tomography Radiopharmaceuticals

“…If significantly low limits of detection could be achieved, the platform may also have the potentialf or quantification of radiotracer metabolism in the blood of small animalsd uring new tracer development. [10,25]…”