(D-134) Masked Stereolithography Fabrication Process to Improve Microfluidic PET Radiotracer Synthesis Platform Design

Introduction:: Radiopharmaceuticals are a critical tool for diagnostic imaging, have great potential as therapeutics, and may even serve as “theranostics” (two similar compounds capable of both diagnosing and treating a disease). However, advancements towards this are limited by the high cost of resources required to synthesize these compounds. To overcome this barrier to employing radiopharmaceuticals for personalized medicine, we have developed a novel and inexpensive microfluidic platform that can quickly and easily synthesize single doses of a wide array of radiopharmaceuticals [1], [2]. The work described herein has advanced this technology by transitioning the fabrication process to employing 3D printed templates and introducing improved flow paths to reduce overall fluidic resistance and thus lower production times (a critical metric when dealing with decaying radioisotopes).

Materials and Methods:: Devices were fabricated by printing molds with a Phrozen Sonic Mini 8K high-resolution SLA printer. The CAD files were designed in Fusion 360, sliced with Chitubox and edited further using UVTools to enable control over single layer parameters. The molds were then coated with ~2 µm of parylene using a LabCoter Parylene Deposition System. PDMS microfluidic devices were patterned from the parylene-coated templates. To test fluidic resistance, a New Era syringe pump was used to vary the flowrate of water through a Honeywell 26PC in-line pressure sensor at the inlet of various column designs. At each flowrate, the system was allowed to stabilize for a period of 5 mins prior to measurement.

Results, Conclusions, and Discussions:: Results: The 3D printing-based technique yields templates with features of various heights on the same print, an architecture that is extremely difficult using standard photolithography techniques. This enabled us to shift the approach for retaining ion exchange beads within the columns from an X-Y grid-based design that only allowed fluid through narrow channels (~40 µm wide) to a design that lowers the height of the channel ceiling such that it is too shallow for beads to pass through (~20 µm deep). This is an increase from 44µm² to 96µm² of cross section through which fluid may flow at the point of bead retention, and dramatically reduces resistance (Figure 1).

Conclusions: We demonstrated a high-resolution 3D printing approach that avoids the need for more traditional photolithography-based approaches. This greatly reduces both fabrication cost and time when optimizing new fluidic architectures. Additionally, exchange bead retention methods have been modified to dramatically reduce baseline fluidic resistance.
Discussion: Reducing the baseline fluidic resistance is a critical first step towards reducing overall resistance in the column when packed; ongoing experiments studying capture and release of model compounds (e.g. fluorescent dyes) will allow us to optimize the architecture such that large quantities of desired material can be rapidly concentrated and purified. Additionally, with this high throughput design and fabrication process, we can quickly study and optimize on-chip column design for our purposes. More generally, next steps are focused on proving the robustness of the platform in its ability to make more complicated radiotracers that may require more than a single microfluidic chip.


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References (Optional): : [1] X. Zhang, F. Liu, K.-A. Knapp, M. L. Nickels, H. C. Manning, and L. M. Bellan, “A simple microfluidic platform for rapid and efficient production of the radiotracer [18F]fallypride,” Lab. Chip, vol. 18, no. 9, pp. 1369–1377, May 2018, doi: 10.1039/C8LC00167G.

[2] X. Zhang, F. Liu, A. C. Payne, M. L. Nickels, L. M. Bellan, and H. C. Manning, “High-Yielding Radiosynthesis of [68Ga]Ga-PSMA-11 Using a Low-Cost Microfluidic Device,” Mol. Imaging Biol., vol. 22, no. 5, pp. 1370–1379, Oct. 2020, doi: 10.1007/s11307-020-01515-7.