Implementation of gene editing technologies such as CRISPR/Cas9 in the manufacture of novel cell-based therapeutics has the potential to enable highly-targeted, stable, and persistent genome modifications without the use of viral vectors. Electroporation has emerged as a preferred method for delivering gene-editing machinery to target cells, but a major challenge remaining is that most commercial electroporation machines are built for research and process development rather than for large-scale, automated cellular therapy manufacturing. Here we present a microfluidic continuous-flow electrotransfection device designed for precise, consistent, and high-throughput genetic modification of target cells in cellular therapy manufacturing applications. We optimized our device for delivery of mRNA into primary human T cells and demonstrated up to 95% transfection efficiency with minimum impact on cell viability and expansion potential. We additionally demonstrated processing of samples comprising up to 500 million T cells at a rate of 20 million cells/min. We anticipate that our device will help to streamline the production of autologous therapies requiring on the order of 10$$^8$$ 8 –10$$^9$$ 9 cells, and that it is well-suited to scale for production of trillions of cells to support emerging allogeneic therapies.
Wireless neural stimulators are being developed to address problems associated with traditional lead-based implants. However, designing wireless stimulators on the sub-millimeter scale (<1 mm3) is challenging. As device size shrinks, it becomes difficult to deliver sufficient wireless power to operate the device. Here, we present a sub-millimeter, inductively powered neural stimulator consisting only of a coil to receive power, a capacitor to tune the resonant frequency of the receiver, and a diode to rectify the radio-frequency signal to produce neural excitation. By replacing any complex receiver circuitry with a simple rectifier, we have reduced the required voltage levels that are needed to operate the device from 0.5 to 1 V (e.g., for CMOS) to ~0.25–0.5 V. This reduced voltage allows the use of smaller receive antennas for power, resulting in a device volume of 0.3–0.5 mm3. The device was encapsulated in epoxy, and successfully passed accelerated lifetime tests in 80°C saline for 2 weeks. We demonstrate a basic proof-of-concept using stimulation with tens of microamps of current delivered to the sciatic nerve in rat to produce a motor response.
Next generation implantable medical devices will have the potential to provide more precise and effective therapies through adaptive closed-loop controllers that combine sensing and stimulation across larger numbers of electrode channels. A major challenge in the design of such devices is balancing increased functionality and channel counts with the miniaturization required for implantation within small anatomical spaces. Customized therapies will require adaptive systems capable of tuning which channels are sensed and stimulated to overcome variability in patient-specific needs, surgical placement of electrodes, and chronic physiological responses. In order to address these challenges, we have designed a miniaturized implantable fully-reconfigurable front-end system that is integrated into the distal end of an 8-wire lead, enabling up to 64 electrodes to be dynamically configured for sensing and stimulation. Full reconfigurability is enabled by two custom 32×2 cross-point switch (CPS) matrix ASICs which can route any electrode to either an amplifier with reprogrammable bandwidth and integrated ADC or to one of two independent stimulation channels that can be driven through the lead. The 8-wire circuit includes a digital interface for robust communication as well as a charge-balanced powering scheme for enhanced safety. The system is encased in a hermetic package designed to fit within a 14 mm bur-hole in the skull for neuromodulation of the brain, but could easily be adapted to enhance therapies across a broad spectrum of applications.
Complex suture prostheses that deliver sensory and position feedback require a more sophisticated integration with the human user. Here a micro-size active implantable system that provides many-degree-of-freedom neural feedback in both sensory stimulation and motor control is shown, as one potential human-use solution in DARPA's HAPTIX program. Various electrical and mechanical challenge and solutions in meeting both sensory /motor performance as well as ISO 14708 FDA-acceptable human use in an aspirin-size active implementation are discussed.
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