Free Standing, Large-Area Silicon Nitride Membranes for High Toxin Clearance in Blood Surrogate for Small-Format Hemodialysis.

Developing highly-efficient membranes for toxin clearance in small-format hemodialysis presents a fabrication challenge. The miniaturization of fluidics and controls has been the focus of current work on hemodialysis (HD) devices. This approach has not addressed the membrane efficiency needed for toxin clearance in small-format hemodialysis devices. Dr. Willem Kolff built the first dialyzer in 1943 and many changes have been made to HD technology since then. However, conventional HD still uses large instruments with bulky dialysis cartridges made of ~2 m2 of 10 micron thick, tortuous-path membrane material. Portable, wearable, and implantable HD systems may improve clinical outcomes for patients with end-stage renal disease by increasing the frequency of dialysis. The ability of ultrathin silicon-based sheet membranes to clear toxins is tested along with an analytical model predicting long-term multi-pass experiments from single-pass clearance experiments. Advanced fabrication methods are introduced that produce a new type of nanoporous silicon nitride sheet membrane that features the pore sizes needed for middle-weight toxin removal. Benchtop clearance results with sheet membranes (~3 cm2) match a theoretical model and indicate that sheet membranes can reduce (by orders of magnitude) the amount of membrane material required for hemodialysis. This provides the performance needed for small-format hemodialysis.

Second Generation Nanoporous Silicon Nitride Membranes for High Toxin Clearance and Small Format Hemodialysis.

Conventional hemodialysis (HD) uses floor-standing instruments and bulky dialysis cartridges containing ≈2 m2 of 10 micrometer thick, tortuous-path membranes. Portable and wearable HD systems can improve outcomes for patients with end-stage renal disease by facilitating more frequent, longer dialysis at home, providing more physiological toxin clearance. Developing devices with these benefits requires highly efficient membranes to clear clinically relevant toxins in small formats. Here, the ability of ultrathin (<100 nm) silicon-nitride-based membranes to reduce the membrane area required to clear toxins by orders of magnitude is shown. Advanced fabrication methods are introduced that produce nanoporous silicon nitride membranes (NPN-O) that are two times stronger than the original nanoporous nitride materials (NPN) and feature pore sizes appropriate for middle-weight serum toxin removal. Single-pass benchtop studies with NPN-O (1.4 mm2 ) demonstrate the extraordinary clearance potential of these membranes (105 mL min-1 m-2 ), and their intrinsic hemocompatibility. Results of benchtop studies with nanomembranes, and 4 h dialysis of uremic rats, indicate that NPN-O can reduce the membrane area required for hemodialysis by two orders of magnitude, suggesting the performance and robustness needed to enable small-format hemodialysis, a milestone in the development of small-format hemodialysis systems.

Protein Separation and Hemocompatibility of Nitride Membranes in Microfluidic Filtration Systems.

Improving the health outcomes for end-stage renal Disease (ESRD) patients on hemodialysis (HD) requires new technologies for wearable HD such as a highly efficient membrane that can achieve standard toxic clearance rates in small device footprints. Our group has developed nanoporous silicon nitride (NPN) membranes which are 100 to 1000 times thinner than conventional membranes and are orders-ofmagnitude more efficient for dialysis. Counter flow dialysis separation experiments were performed to measure urea clearance while microdialysis experiments were performed in a stirred beaker to measure the separation of cytochrome-c and albumin. Hemodialysis experiments testing for platelet activation as well as protein adhesion were performed. Devices for the counter flow experiments were constructed with polydimethylsiloxane (PDMS) and a NPN membrane chip. The counter flow devices reduced the urea by as much as 20%. The microdialysis experiments showed a diffusion of ~ 60% for the cytochrome-c while clearing ~ 20% of the Albumin. Initial hemocompatibility studies show that the NPN membrane surface is less prone to both protein adhesion and platelet activation when compared to positive control (glass).

Towards an Implantable, Low Flow Micropump That Uses No Power in the Blocked-Flow State.

Low flow rate micropumps play an increasingly important role in drug therapy research. Infusions to small biological structures and lab-on-a-chip applications require ultra-low flow rates and will benefit from the ability to expend no power in the blocked-flow state. Here we present a planar micropump based on gallium phase-change actuation that leverages expansion during solidification to occlude the flow channel in the off-power state. The presented four chamber peristaltic micropump was fabricated with a combination of Micro Electro Mechanical System (MEMS) techniques and additive manufacturing direct write technologies. The device is 7 mm × 13 mm × 1 mm (<100 mm³) with the flow channel and exterior coated with biocompatible Parylene-C, critical for implantable applications. Controllable pump rates from 18 to 104 nL/min were demonstrated, with 11.1 ± 0.35 nL pumped per actuation at an efficiency of 11 mJ/nL. The normally-closed state of the gallium actuator prevents flow and diffusion between the pump and the biological system or lab-on-a-chip, without consuming power. This is especially important for implanted applications with periodic drug delivery regimens.

Nanoporous membrane robustness / stability in small form factor microfluidic filtration system.

The development of wearable hemodialysis (HD) devices that replace center-based HD holds the promise to improve both outcomes and quality-of-life for patients with end-stage-renal disease (ERD). A prerequisite for these devices is the development of highly efficient membranes that can achieve high toxin clearance in small footprints. The ultrathin nanoporous membrane material developed by our group is orders of magnitude more permeable than conventional HD membranes. We report on our progress making a prototype wearable dialysis unit. First, we present data from benchtop studies confirming that clinical levels of urea clearance can be obtained in a small animal model with low blood flow rates. Second, we report on efforts to improve the mechanical robustness of high membrane area dialysis devices.

Ultrathin silicon membranes for wearable dialysis.

The development of wearable or implantable technologies that replace center-based hemodialysis (HD) hold promise to improve outcomes and quality of life for patients with ESRD. A prerequisite for these technologies is the development of highly efficient membranes that can achieve high toxin clearance in small-device formats. Here we examine the application of the porous nanocrystalline silicon (pnc-Si) to HD. pnc-Si is a molecularly thin nanoporous membrane material that is orders of magnitude more permeable than conventional HD membranes. Material developments have allowed us to dramatically increase the amount of active membrane available for dialysis on pnc-Si chips. By controlling pore sizes during manufacturing, pnc-Si membranes can be engineered to pass middle-molecular-weight protein toxins while retaining albumin, mimicking the healthy kidney. A microfluidic dialysis device developed with pnc-Si achieves urea clearance rates that confirm that the membrane offers no resistance to urea passage. Finally, surface modifications with thin hydrophilic coatings are shown to block cell and protein adhesion.

In-plane biocompatible microfluidic interconnects for implantable microsystems.

Small mammals, particularly mice, are very useful animal models for biomedical research. Extremely small anatomical dimensions, however, make design of implantable microsystems quite challenging. A method for coupling external fluidic systems to microfluidic channels via in-plane interconnects is presented. Capillary tubing is inserted into channels etched in the surface of a Si wafer with a seal created by Parylene-C deposition. Prediction of Parylene-C deposition into tapered channels based on Knudsen diffusion and deposition characterizations allows for design optimization. Low-volume interconnects using biocompatible, chemical resistant materials have been demonstrated and shown to withstand pressure as high as 827 kPa (120 psi) with an average pull test strength of 2.9 N. Each interconnect consumes less than 0.018 mm3 (18 nL) of volume. The low added volume makes this an ideal interconnect technology for medical applications where implant volume is critical.

Micro-molded cannulae for intracochlear infusions in small rodents.

The design, fabrication, and testing of micro-cannulae with integrated insertion stops is presented. The micro-cannulae were engineered through the use of a silicon micro-mold fabricated via bulk-silicon micro-machining techniques. The use of microelectronic fabrication techniques allows precise control of three critical parameters, insertion depth, interface contact area, and tubing out of round. Worst case variations were found to be 5microm for insertion depth, 502microm(2) for interface contact area, and 7% for tip out of round. Histological evaluation revealed the cannula to be located correctly within the basal portion of scala tympani.