Background PET radiopharmaceutical development and the implementation of a production method on a synthesis module is a complex and time-intensive task since new synthesis methods must be adapted to the confines of the synthesis platform in use. Commonly utilized single fluid bus architectures put multiple constraints on synthesis planning and execution, while conventional microfluidic solutions are limited by compatibility at the macro-to-micro interface . In this work we introduce the ISAR synthesis platform and custom-tailored fluid paths leveraging up to 70 individually addressable valves on a chip-based consumable. The ISAR synthesis platform replaces traditional stopcock valve manifolds with a fluidic chip that integrates all fluid paths (tubing) and valves into one consumable and enables channel routing without the single fluid bus constraint. ISAR can scale between the macro- (10 mL), meso- (0.5 mL) and micro- (≤0.05 mL) domain seamlessly, addressing the macro-to-micro interface challenge and enabling custom tailored fluid circuits for a given application. In this paper we demonstrate proof-of-concept by validating a single chip design to address the challenge of synthesizing multiple batches of [ 13 N]NH 3 for clinical use throughout the workday. Results ISAR was installed at an academic PET Center and used to manufacture [ 13 N]NH 3 in > 96% radiochemical yield. Up to 9 batches were manufactured with a single consumable chip having parallel paths without the need to open the hot-cell. Quality control testing confirmed the ISAR-based [ 13 N]NH 3 met existing clinical release specifications, and utility was demonstrated by imaging a rodent with [ 13 N]NH 3 produced on ISAR. Conclusions ISAR represents a new paradigm in radiopharmaceutical production. Through a new system architecture, ISAR integrates the principles of microfluidics with the standard volumes and consumables established in PET Centers all over the world. Proof-of-concept has been demonstrated through validation of a chip design for the synthesis of [ 13 N]NH 3 suitable for clinical use.

[18F]FDG was prepared using a cartridge-based drying technique for [18F]fluoride. The application to a lab-on-chip platform demonstrates a proof of concept towards reduced hardware complexity.

nitrogen gas. COC foils were cut to size, the protective polyethylene terephtalate (PETg) layers removed, the foil rinsed with isopropyl alcohol and subsequently placed 5 minutes in a fume hood for drying. ____________________________________________________ 40 a GE Global Research, Freisinger Landstrasse 50, 85748 Garching bei Munich, Germany. Fax: +49-89-5528-3181; Tel: +49-89-5528-3613; Email: rensch@ge.com b University Hospital Munich, Department of Nuclear Medicine, Ludwig Maximilians-University, 81377 Munich, Germany. 45 c Department of Biomedical Sciences in Microand Nanotechnology, University of Applied Sciences Kaiserslautern Zweibrücken, Amerikastr. 1, 66482 Zweibrücken, Germany. d GE Healthcare, Schaimburgstraße 3, 48145 Münster, Germany. e Biomedical Chemistry, Department of Clinical Radiology and Nuclear 50

The application of microfluidics to the synthesis of Positron Emission Tomography (PET) tracers has been explored for more than a decade. Microfluidic benefits such as superior temperature control have been successfully applied to PET tracer synthesis. However, the design of a compact microfluidic platform capable of executing a complete PET tracer synthesis workflow while maintaining prospects for commercialization remains a significant challenge. This study uses an integral system design approach to tackle commercialization challenges such as the material to process compatibility with a path towards cost effective lab-on-chip mass manufacturing from the start. It integrates all functional elements required for a simple PET tracer synthesis into one compact radiochemistry platform. For the lab-on-chip this includes the integration of on-chip valves, on-chip solid phase extraction (SPE), on-chip reactors and a reversible fluid interface while maintaining compatibility with all process chemicals, temperatures and chip mass manufacturing techniques. For the radiochemistry device it includes an automated chip-machine interface enabling one-move connection of all valve actuators and fluid connectors. A vial-based reagent supply as well as methods to transfer reagents efficiently from the vials to the chip has been integrated. After validation of all those functional elements, the microfluidic platform was exemplarily employed for the automated synthesis of a Gastrin-releasing peptide receptor (GRP-R) binding the PEGylated Bombesin BN(7-14)-derivative ([(18)F]PESIN) based PET tracer.

Application of microfluidics to Positron Emission Tomography (PET) tracer synthesis has attracted increasing interest within the last decade. The technical advantages of microfluidics, in particular the high surface to volume ratio and resulting fast thermal heating and cooling rates of reagents can lead to reduced reaction times, increased synthesis yields and reduced by-products. In addition automated reaction optimization, reduced consumption of expensive reagents and a path towards a reduced system footprint have been successfully demonstrated. The processing of radioactivity levels required for routine production, use of microfluidic-produced PET tracer doses in preclinical and clinical imaging as well as feasibility studies on autoradiolytic decomposition have all given promising results. However, the number of microfluidic synthesizers utilized for commercial routine production of PET tracers is very limited. This study reviews the state of the art in microfluidic PET tracer synthesis, highlighting critical design aspects, strengths, weaknesses and presenting several characteristics of the diverse PET market space which are thought to have a significant impact on research, development and engineering of microfluidic devices in this field. Furthermore, the topics of batch- and single-dose production, cyclotron to quality control integration as well as centralized versus de-centralized market distribution models are addressed.

Autoradiolysis describes the degradation of radioactively labeled compounds due to the activity of the labeled compounds themselves. It scales with activity concentration and is of importance for high activity and microfluidic PET tracer synthesis. This study shows that microfluidic devices can be shaped to reduce autoradiolysis by geometric exclusion of positron interaction. A model is developed and confirmed by demonstrating in-capillary storage of non-stabilized [(18)F]FDG (2-[(18)F]Fluoro-2-deoxy-d-glucose) at max. 23 GBq/ml while maintaining >90% radiochemical purity over 14 h.

288 Objectives Microfluidic (MF) chip-based synthesizers promise radiotracer synthesis enhancements resulting from tight process control, high reagent concentrations, and integrated functionality in a small, disposable format. Key challenges include fluid connectors, on-chip flow control, and material selection for process compatibility. The objective of this work was to investigate a MF platform for FMISO labeling and deprotection, that showed the desired benefits while overcoming the challenges. Methods The MF platform consisted of 1) an MF chip, 2) a fixture with fluidic connectors, heaters, and valve actuators, and 3) a control box with electronics and 5 syringe pumps. The chip was 95mm x 60mm x 6mm, incorporated 2 reactors (200µl and 400µl), 16 fluid in-/outputs, 16 valves, and was produced in TOPAS COC 6015. Heat was applied to both sides of the chip by fixture heaters. Fluid interfaces, heating elements, and valve actuators were connected / disconnected to the chip in one automated motion. An externally dried mixture of 18F and K222/K2CO3 in DMSO was utilized for radiolabeling of Results NITTP was labeled with a yield of >80%, followed by near quantitative deprotection. All fluidic interfaces sealed without leaks in 12 consecutive runs. The on-chip valves directed fluids between waste and product, over >100 cycles and blocking gas at up to 6bar and liquids up to 3bar. The chip showed no evidence of material swelling. Conclusions The results demonstrate the synthesis of FMISO on a chip-based MF platform. The high labeling yield achieved in 60s-120s provides evidence that an MF platform results in performance improvements when compared to conventional scale devices. The overall system showed a path forward for MF synthesizers without the challenges described in the introduction. Research Support Work co-funded by Bavarian State & BMBF (Germany)

This paper reports on the comparison analysis of four main types of silicon-based microfilter for isolation of white blood cells (WBCs) from red blood cells (RBCs) in a given whole blood. The microfilter designs, namely, weir, pillar, crossflow, and membrane, all impose the same cut-off size of 3.5 mum to selectively trap WBCs. Using human whole blood, the microfilters have been characterized and compared for their blood handling capacity, WBCs trapping efficiency and RBCs passing efficiency. Based on the experimental results, the crossflow microfilter is superior and can be integrated with downstream components for on-chip genomic analysis.