EWOD Radiochemistry Chip
The current process for producing PET tracers relies on expensive infrastructure, equipment, and specially-trained personnel, resulting in a high overall production cost. A few companies have managed to reduce the cost of [F-18]FDG and [F-18]NaF by producing large batches of tracers and then dividing and distributing them to many patients in their local area. However, this model is not scalable to large numbers of different tracers and thus other tracers remain expensive and unavailable to most patients and researchers.
To address this challenge, a fundamental reduction in PET tracer production cost is needed. One of the most effective ways to reduce cost is through the development of new technologies. Several groups have been developing microfluidic platforms for PET tracer synthesis. The technologies can be broadly classified as "flow-through" and "batch".
Microfluidic technologies offer a number of advantages including:
- Small size (reduces the need for radiation shielding)
- Improved control of reaction conditions (faster synthesis, higher yield)
- Small volumes (consume less expensive precursor; improve specific activity)
- Low cost synthesizer (many complex fluidic functions can be integrated into a disposable chip)
- Reduced radiolysis of the tracer in microfluidic geometries
Our group has focused on "batch" format devices due to intrinsic advantages of using small volumes, including reduced production cost and improved specific activity. In a collaboration with Prof. C.J. Kim’s lab at UCLA, we successfully demonstrated successful radiosynthesis using a digital microfluidic device based on electrowetting-on-dielctric (EWOD) (see Figure 1). Control of droplets in these microchips is entirely electronic, which could improve reliability by eliminating the need for moving parts, and could improve miniaturization by eliminating the need for bulky valve actuators within the radiation shielding. These EWOD microchips are constructed from chemically-inert and thermally-stable materials, offering wide flexibility in terms of reagents and reaction conditions, and thus enabling a diverse array of PET tracers to be synthesized.
Figure 1: Diagram of the EWOD radiochemistry chip.
Microscale synthesis with high and reliable yield has been developed for [F-18]FDG, [F-18]FLT, [F-18]Fallypride, [F-18]FNB, and [F-18]SFB. Several batches have been subjected to clinical quality-control testing and passed all required tests.
Through optimization studies, general procedures and rules of thumb for translating known macroscale protocols to the microscale have been developed.
To enable safe operation of the chip, we have developed, in collaboration with Sofie Biosciences, Inc., two approaches for loading accurate volumes of reagents from sealed reagent sources to the chip. In one approach, reagents are dispensed via a syringe pump (see Figure 2). On-chip liquid detection using electrical impedance helps achieve high accuracy by providing feedback to compensate for any evaporation that has occurred from the dispensing needle. In a second approach, the delivery system is made from low-cost disposable components to eliminate the risk of cross-contamination and the need for cleaning.
In addition, in collaboration with CJ Kim's lab, we have developed some preliminary approaches for on-chip purification.
Figure 2: Automated dispensing of reagents to EWOD chip using a syringe pump. (A) Schematic of the fluid pathway and control system, including a photograph of the needle fixture and EWOD chip showing recently dispensed droplets. (B) Procedure for on-demand reagent delivery. After dispensing one droplet (step 1), undesired evaporation may occur at the tip of the dispensing needle (step 2). When the next droplet is needed, the control system advances the syringe pump until the liquid is detected electronically (step 3), and then dispenses the desired volume (step 4).
Current Status and Next Steps
The current focuses are on automation and the development of a prototype system (collaboration with Sofie Biosciences, Inc.), optimization of additional tracers, exploiting the small volume to produce high specific-activity tracers, and development of more robust chip fabrication (collaboration with Sofie Biosciences, Inc.).
- P. Y. Keng, S. Chen, H. Ding, S. Sadeghi, G. J. Shah, A. Dooraghi, M. E. Phelps, N. Satyamurthy, A. F. Chatziioannou, C.-J. Kim, and R. M. van Dam, “Micro-chemical synthesis of molecular probes on an electronic microfluidic device,” PNAS, vol. 109, no. 3, pp. 690–695, 2012.
- H. Ding, S. Sadeghi, G. J. Shah, S. Chen, P. Y. Keng, C. J. Kim, and M. van Dam, “Accurate dispensing of volatile reagents on demand for chemical reactions in EWOD chips,” Lab on a Chip, vol. 12, pp. 3331–3340, 2012.
- S. Sadeghi, H. Ding, G. J. Shah, S. Chen, P. Y. Keng, C.-J. “CJ” Kim, and R. M. van Dam, “On Chip Droplet Characterization: A Practical, High-Sensitivity Measurement of Droplet Impedance in Digital Microfluidics,” Anal. Chem., vol. 84, no. 4, pp. 1915–1923, Feb. 2012.
- S. Chen, J. Lei, R. M. van Dam, P.-Y. Keng, and C.-J. “CJ” Kim, “Planar alumina purification of 18F-labeled radiotracer synthesis on EWOD chip for positron emission tomography (PET),” in Proceedings of the 16th International Conference on Miniaturized Systems for Chemistry and Life Sciences, Okinawa, Japan, 2012, pp. 1771–1773.
- G. J. Shah, H. Ding, S. Sadeghi, S. Chen, C.-J. “CJ” Kim, and R. M. van Dam, “On-demand droplet loading for automated organic chemistry on digital microfluidics,” Lab Chip, vol. 13, pp. 2785–2795, May 2013.
- A. A. Dooraghi, P. Y. Keng, S. Chen, M. R. Javed, C.-J. “CJ” Kim, A. F. Chatziioannou, and R. M. van Dam, “Optimization of microfluidic PET tracer synthesis with Cerenkov imaging,” Analyst, vol. 138, no. 19, pp. 5654–5664, Aug. 2013.
- S. Chen, M. R. Javed, H.-K. Kim, J. Lei, M. Lazari, G. J. Shah, M. van Dam, P. Y. Keng, and C.-J. Kim, “Radiolabelling diverse positron emission tomography (PET) tracers using a single digital microfluidic reactor chip,” Lab Chip, Dec. 2013.
- S. Chen, A. Dooraghi, M. Lazari, R. M. van Dam, A. Chatziioannou, and C.-J. Kim, “On-chip product purification for complete microfluidic radiotracer synthesis,” in Proceedings of the 27th IEEE International Conference on Micro Electro Mechanical Systems (MEMS), San Francisco, CA, 2014, pp. 284–287.
- M. R. Javed, S. Chen, H.-K. Kim, L. Wei, J. Czernin, C.-J. “CJ” Kim, R. M. van Dam, and P. Y. Keng, “Efficient Radiosynthesis of 3′-Deoxy-3′-18F-Fluorothymidine Using Electrowetting-on-Dielectric Digital Microfluidic Chip,” J Nucl Med, vol. 55, no. 2, pp. 321–328, Feb. 2014.
- M. R. Javed, S. Chen, J. Lei, J. Collins, M. Sergeev, H.-K. Kim, C.-J. Kim, R. M. van Dam, and P. Y. Keng, “High yield and high specific activity synthesis of [18F]fallypride in a batch microfluidic reactor for micro-PET imaging,” Chem. Commun., vol. 50, no. 10, pp. 1192–1194, 2014.
- G. J. Shah, U. Tata, and R. M. van Dam, “Automation and interfaces for chemistry and biochemistry in digital microfluidics,” Technology, vol. 02, no. 02, pp. 83–100, May 2014.
- Jia Wang (graduate student)
- Philip Chao (graduate student)
- Alex Hsiao (collaborator from Sofie Biosciences, Inc.)
- Jeffrey Collins (staff radiochemist)
- Maxim Sergeev (postdoctoral scholar)
- Brandon Maraglia (collaborator from Sofie Biosciences, Inc.)
- Melissa Moore (collaborator from Sofie Biosciences, Inc.)
- Prof. Pei Yuin Keng (postdoctoral scholar; later collaborator)
- Hui-Jiang Ding (research staff)
- Supin Chen (collaborator in CJ Kim lab)
- Gaurav Shah (postdoctoral scholar; later collaborator from Sofie Biosciences, Inc.)
- Uday Tata (postdoctoral scholar)
- Sam Sadeghi (postdoctoral scholar)
- Wyatt Nelson (collaborator in CJ Kim lab)
- Xiaoxiao Ma (graduate student; later postdoctoral scholar)
- Jesus Vargas (undergraduate student)
- Steven Pan (research staff)
- Muhammad Rashed Javed (collaborator from Pei Yuin Keng lab)
- Hee-Kwon Kim (collaborator from Pei Yuin Keng lab)
- Jack Lei (collaborator from Pei Yuin Keng lab)
- Alex Dooraghi (collaborator from Arion Chatziioannou lab)
- Prof. Chang-Jin "CJ" Kim (collaborator)
- Prof. Arion Chatziioannou (collaborator)