Nanoporous Silicon Membrane Research Articles

The Future for End-Stage Kidney Disease Treatment: Implantable Bioartificial Kidney Challenge

Despite limited organ availability and post-transplant complications, kidney transplantation remains the optimal treatment for End-Stage Kidney Disease (ESKD). However, innovative dialysis technologies such as portable, wearable, and implantable bioartificial kidney systems are being developed with the aim of addressing these issues and improving patient care. An ideal implantable device could combine bioreactors and blood ultrafiltration to replicate key native cell functions for solute reabsorption, secretion, and endocrinologic activities. Today, the feasibility of an implantable bioreactor for renal cell therapy opens the challenge of developing a fully implantable bioartificial kidney based on silicon nanopore membranes to ensure immunological isolation, cell viability, and the possibility of maintaining a blood substrate for metabolic activities. Current technology is not sufficient to obtain an efficient artificial bioreactor to reach physiological blood purification, which requires a more complex system to produce an ultrafiltrate from the blood that can be processed by cells and eliminated as urine. The number of cells in the bioreactor, endocrine activity, immunological cell isolation, solute and fluid secretion/reabsorption, cell viability, blood and ultrafiltration flow control, and thrombogenicity are fundamental issues that require a new technology that today appears to be a challenge for the design of an implantable artificial kidney. This review aims to analyze the state of the art in this particular field of kidney replacement therapy to highlight the current limitations and possible future technology developments to create implanted and wearable organs capable of treating ESKD with artificial organs that can replicate all native kidneys functions.

Renal Embolization-Induced Uremic Swine Model for Assessment of Next-Generation Implantable Hemodialyzers.

Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans. While models exist for the induction of renal failure, none are optimized for the implantation of devices to the retroperitoneal vasculature. We successfully piloted an embolization-to-implantation protocol enabling the first implant of a silicon nanopore membrane hemodialyzer (SNMHD) in a swine renal failure model. Renal arterial embolization is a non-invasive approach to near-total nephrectomy that preserves retroperitoneal anatomy for device implants. Silicon nanopore membranes (SNM) are efficient blood-compatible membranes that enable novel approaches to RRT. Yucatan minipigs underwent staged bilateral renal arterial embolization to induce renal failure, managed by intermittent hemodialysis. A small-scale arteriovenous SNMHD prototype was implanted into the retroperitoneum. Dialysate catheters were tunneled externally for connection to a dialysate recirculation pump. SNMHD clearance was determined by intermittent sampling of recirculating dialysate. Creatinine and urea clearance through the SNMHD were 76-105 mL/min/m2 and 140-165 mL/min/m2, respectively, without albumin leakage. Normalized creatinine and urea clearance measured in the SNMHD may translate to a fully implantable clinical-scale device. This pilot study establishes a path toward therapeutic testing of the clinical-scale SNMHD and other implantable RRT devices.

Feasibility of an implantable bioreactor for renal cell therapy using silicon nanopore membranes

The definitive treatment for end-stage renal disease is kidney transplantation, which remains limited by organ availability and post-transplant complications. Alternatively, an implantable bioartificial kidney could address both problems while enhancing the quality and length of patient life. An implantable bioartificial kidney requires a bioreactor containing renal cells to replicate key native cell functions, such as water and solute reabsorption, and metabolic and endocrinologic functions. Here, we report a proof-of-concept implantable bioreactor containing silicon nanopore membranes to offer a level of immunoprotection to human renal epithelial cells. After implantation into pigs without systemic anticoagulation or immunosuppression therapy for 7 days, we show that cells maintain >90% viability and functionality, with normal or elevated transporter gene expression and vitamin D activation. Despite implantation into a xenograft model, we find that cells exhibit minimal damage, and recipient cytokine levels are not suggestive of hyperacute rejection. These initial data confirm the potential feasibility of an implantable bioreactor for renal cell therapy utilizing silicon nanopore membranes.

Nanoporous Silicon Membrane Embedded With Dielectrophoresis (DEP) Electrodes for Ultrafiltration Improvement for Artificial Kidney

Ultrafiltration is a vital process for toxin removal in an artificial kidney. However, blood clotting, which usually occurs on the surface of ultrafiltration membrane will cause a decrease in filtration efficacy; hence, reducing the efficiency of the haemofiltration process. In this study, a nanoporous silicon membrane with embedded dielectrophoresis (DEP) electrodes was introduced to reduce red blood cells (RBCs) clotting on the surface of membrane. The RBCs were deviated from the surface of membrane via DEP, to reduce clotting. The size of the nanopores were ranged between 50 nm and 80 nm. The efficiency of DEP embedded ultrafiltration membrane was tested by using polystyrene beads and RBCs. The particles responded to specific frequencies applied; ranging between 100 kHz and 15 MHz. To determine the efficacy of the ultrafiltration process, particle size analysis (PSA) was utilised. The results indicated that particles larger than 80 nm were unable to pass through the nanoporous membranes, whereas smaller particles were free to pass through. Finally, the concentration of the passed through particles between embedded DEP and non-embedded DEP was compared to gauge the separation efficacy of DEP electrodes by using a microplate reader. The concentration values showed that the percentage of albumin, ADH and blood plasma that had passed through were 65.80%, 92.60% and 71.40%, respectively, as compared to 44.38%, 47.04% and 34.08% of those without embedded DEP electrodes. This showed that the performance of ultrafiltration membrane had increased by the implementation of DEP mechanism, which reduced RBCs coagulation on the membrane surface. [2022-0097]

Characterization of human islet function in a convection-driven intravascular bioartificial pancreas.

Clinical islet transplantation for treatment of type 1 diabetes (T1D) is limited by the shortage of pancreas donors and need for lifelong immunosuppressive therapy. A convection-driven intravascular bioartificial pancreas (iBAP) based on highly permeable, yet immunologically protective, silicon nanopore membranes (SNM) holds promise to sustain islet function without the need for immunosuppressants. Here, we investigate short-term functionality of encapsulated human islets in an iBAP prototype. Using the finite element method (FEM), we calculated predicted oxygen profiles within islet scaffolds at normalized perifusion rates of 14-200 nl/min/IEQ. The modeling showed the need for minimum in vitro and in vivo islet perifusion rates of 28 and 100 nl/min/IEQ, respectively to support metabolic insulin production requirements in the iBAP. In vitro glucose-stimulated insulin secretion (GSIS) profiles revealed a first-phase response time of <15 min and comparable insulin production rates to standard perifusion systems (~10pg/min/IEQ) for perifusion rates of 100-200 nl/min/IEQ. An intravenous glucose tolerance test (IVGTT), performed at a perifusion rate of 100-170 nl/min/IEQ in a non-diabetic pig, demonstrated a clinically relevant C-peptide production rate (1.0-2.8pg/min/IEQ) with a response time of <5min.

Microfluidic devices for photo-and spectroelectrochemical applications

The review presents recent developments in electrochemical devices for photo- and spectroelectrochemical investigations, with the emphasis on miniaturization (i.e., nanointerdigitated complementary metal-oxide-semiconductor devices, micro- and nano-porous silicon membranes or microoptoelectromechanical systems), silica glass/microreactors (i.e., plasmonic, Raman spectroscopy or optical microcavities) or polymer-based devices (i.e., 3D-printed, laser-engraved channels). Furthermore, we have evaluated inter alia the efficiency of various fabrication approaches for bioelectrochemical systems, biocatalysis, photochemical synthesis, or single nanoparticle spectroelectrochemistry. We envisioned the miniaturization of applied techniques such as cathodoluminescence, surface plasmon resonance, surface-enhanced Raman spectroscopy, voltametric and amperometric methods in the spectroelectrochemical microdevices. The research challenges and development perspectives of microfluidic, and spectroelectrochemical devices were also elaborated on.

Artificial Kidney Engineering: The Development of Dialysis Membranes for Blood Purification.

The artificial kidney, one of the greatest medical inventions in the 20th century, has saved innumerable lives with end stage renal disease. Designs of artificial kidney evolved dramatically in decades of development. A hollow-fibered membrane with well controlled blood and dialysate flow became the major design of the modern artificial kidney. Although they have been well established to prolong patients’ lives, the modern blood purification system is still imperfect. Patient’s quality of life, complications, and lack of metabolic functions are shortcomings of current blood purification treatment. The direction of future artificial kidneys is toward miniaturization, better biocompatibility, and providing metabolic functions. Studies and trials of silicon nanopore membranes, tissue engineering for renal cell bioreactors, and dialysate regeneration are all under development to overcome the shortcomings of current artificial kidneys. With all these advancements, wearable or implantable artificial kidneys will be achievable.

Thermal conduction and rectification phenomena in nanoporous silicon membranes.

Non-equilibrium molecular dynamics simulations have been applied to study thermal transport properties, such as thermal conductivity and rectification, in nanoporous Si membranes. Cylindrical pores have been generated in crystalline Si membranes with different configurations, including step-like, ordered and random pore distributions. The effect of interface and overall porosity on thermal transport properties has been investigated as well as the impact of the porosity profile on the direction of the heat current. The lowest thermal conductivity and highest thermal rectification for equal porosity have been found for a step-like pore distribution. Increasing interface porosity resulted in an increase of thermal rectification, which has been found to be systematically higher for random pore distribution with respect to an ordered one. Furthermore, a maximum in rectification of 5.5% has been found for a specific overall porosity (Φtot = 0.02) in samples with constant interface porosity and ordered pore distribution. This has been attributed to an increased effect of asymmetric interface boundary resistance resulting from increased fluctuations of the latter with altering temperature. The average value of the interface boundary resistance has been found to decrease with increasing porosity for samples with ordered pore distribution leading to a decrease in thermal rectification.

Superporous agarose scaffolds for encapsulation of adult human islets and human stem-cell-derived β cells for intravascular bioartificial pancreas applications.

Type 1 diabetic patients with severe hypoglycemia unawareness have benefitted from cellular therapies, such as pancreas or islet transplantation; however, donor shortage and the need for immunosuppression limits widespread clinical application. We previously developed an intravascular bioartificial pancreas (iBAP) using silicon nanopore membranes (SNM) for immunoprotection. To ensure ample nutrient delivery, the iBAP will need a cell scaffold with high hydraulic permeability to provide mechanical support and maintain islet viability and function. Here, we examine the feasibility of superporous agarose (SPA) as a potential cell scaffold in the iBAP. SPA exhibits 66-fold greater hydraulic permeability than the SNM along with a short (<10μm) diffusion distance to the nearest islet. SPA also supports short-term functionality of both encapsulated human islets and stem-cell-derived enriched β-clusters in a convection-based system, demonstrated by high viability (>95%) and biphasic insulin responses to dynamic glucose stimulus. These findings suggest that the SPA scaffold will not limit nutrient delivery in a convection-based bioartificial pancreas and merits continued investigation.

Effective clearance of uremic toxins using functionalised silicon Nanoporous membranes.

In-house fabricated silicon nanoporous membranes (SNMs), functionalized for efficient clearance of uremic toxins, can lead to compact and portable dialysis systems. Efficacy of 15nm thick SNMs, with average pore diameter of 8nm, was tested for dialysis of two uremic toxins - urea and creatinine using custom made teflon apparatus of 2, 10 and 30ml. The apparatus consisted of two reservoirs, with the cis containing the uremic fluid, and the trans containing the dialysate. Peristalsis was found to enhance the clearance rate by a factor of four as compared to unstirred condition. Functionalisation of the SNMs reduced protein binding, and surface binding of urea from 23% to negligible values. A lateral array of nine SNMs and a new design for the dialysis apparatus, increased the clearance rate by a factor of twelve from that of the single SNM. The arrays cleared about 42% of urea and 48% of creatinine from 30ml of diluted serum samples, in 15min. Periodic replacement of the trans fluid cleared about 81% of high concentration uremic toxins from the cis reservoir in 45 mins. The SNM arrays are stable, reproducible, and with the superior clearance rates for urea and creatinine, they have the potential to be used as membranes for portable hemodialysers.

Thermal transport in nanoporous holey silicon membranes investigated with optically induced transient thermal gratings

In this study, we use transient thermal gratings—a non-contact, laser-based thermal metrology technique with intrinsically high accuracy—to investigate room-temperature phonon-mediated thermal transport in two nanoporous holey silicon membranes with limiting dimensions of 120 nm and 250 nm, respectively. We compare the experimental results with ab initio calculations of phonon-mediated thermal transport according to the phonon Boltzmann transport equation (BTE) using two different computational techniques. We find that the calculations conducted within the Casimir framework, i.e., based on the BTE with the bulk phonon dispersion and diffuse scattering from surfaces, are in quantitative agreement with the experimental data and thus conclude that this framework is adequate for describing phonon-mediated thermal transport in silicon nanostructures with feature sizes of the order of 100 nm.

A Scalable, Hierarchical Rib Design for Larger-Area, Higher-Porosity Nanoporous Membranes for the Implantable Bio-Artificial Kidney

Silicon nanoporous membranes provide the fundamental underlying technology for the development of an implantable bio-artificial kidney. These membranes, which are comprised of micromachined slit-pores that are nominally 10 nm wide, allow for high-efficiency blood filtration as well as immunoprotection for encapsulated cells. Our approach takes advantage of well-established semiconductor fabrication technology to give us precise dimensional control over pore widths, thereby enabling a highly selective filtration function and a clear path towards further miniaturization. This work builds on our prior results on “ribbed nanoporous membranes” by adding a second-level hierarchy of significantly taller “mega-ribs” to further strengthen the membranes. Relying on a two-step Deep Reactive Ion Etch (DRIE) process, we etch $4~\mu \text{m}$ -deep as well as $40~\mu \text{m}$ -deep trenches into a silicon substrate, grow a thermal oxide liner, and deposit a layer of polysilicon into this “mold” to form membranes which, when released after a backside DRIE etch, feature a network of reinforcing ribs on the underside. We have fabricated and tested freestanding membrane spans that are up to 14 times wider than before, with approximately double the measured permeability per unit area. The new architecture can also improve cross-membrane mass-transfer rates and reduce chip-fabrication costs. [2020-0170]

Sensor for Continuous and Real-Time Monitoring of Biomolecule Permeation Through Ultrathin Silicon Nanoporous Membranes

The increase in demand for continuous and real-time monitoring of permeation of biomolecules is addressed by using highly selective ultrathin silicon nanoporous membranes (SNMs) combined with detection using ultraviolet absorption. The membranes, with an average pore size of 8.8 nm, are fabricated using semiconductor batch processes including chemical vapor deposition and rapid thermal annealing. Bovine serum albumin (BSA) of a concentration of $250~\mu \text{g}$ /ml is used as the test molecule. The concentration of BSA diffused through the membrane is measured using optical transduction based in-house developed sensor. The photocurrent obtained from the sensor is measured every 15 min and compared with the standard Bradford assay at the same time-stamp. The concentration estimated by the sensor is found to agree with the Bradford assay with a standard deviation of 1.4%. The throughput of the membrane is increased by fabricating an array of SNMs, which showed an increase in diffusion rate by 3.8 times with respect to the single SNM. The clogging of pores by the biomolecules is analyzed using ionic conductivity experiments. The structural integrity of BSA diffused through the SNM is also analyzed.

In vitro and in vivo hemocompatibility assessment of ultrathin sulfobetaine polymer coatings for silicon-based implants.

Highly uniform silicon nanopore membranes were developed for applications in implantable bioartificial organs. A robust, readily scalable, non-fouling surface coating is required to enhance silicon nanopore membrane hemocompatibility. However, the coating must be ultrathin to keep the nanopores from occluding. Recently, zwitterionic brush polymers have demonstrated significantly lower fouling under biological conditions. In this study, we explore ultrathin zwitterionic poly(sulfobetaine methacrylate) (pSBMA) surface coating at sub-5 nm thickness. Membrane hydraulic permeability was measured before and after surface modification of silicon nanopore membranes, and pores were found to be patent and in agreement with coating thickness measurements. Coating stability was analyzed under biological shear as well as under blood flow in vitro and in vivo. Following exposure to shear over 24 h, coatings were characterized via X-ray photoelectron spectroscopy, goniometry, and ellipsometry, and found to survive biological shear. In vitro blood experiments with fresh human blood as well as in vivo 7-day and 26-day implants in a porcine model demonstrate minimal platelet adhesion and activation with pSBMA surface modification compared to unmodified silicon exposed to fresh human blood in vitro. These results demonstrate that ultrathin pSBMA surface modification is a viable choice for application in blood contacting implants with critical nanoscale features.

Evaluation of silicon membranes for extracorporeal membrane oxygenation (ECMO).

While extracorporeal membrane oxygenation (ECMO) is a valuable therapy for patients with lung or heart failure, clinical use of ECMO remains limited due to hemocompatibility concerns with pro-coagulatory hollow fiber membrane geometries. Previously, we demonstrated the feasibility of silicon nanopore (SNM) and micropore (SμM) membranes for transport between two liquid-phase compartments in blood-contacting devices. Herein, we investigate various pore sizes of SNM and SμM membranes - alone or with a polydimethylsiloxane (PDMS) protective coating - for parameters that determine suitability for gas exchange. We characterized the bubble or rupture point of these membranes to determine sweep gas pressures at which gas emboli would form. The smallest pore size SNM and the SμM with PDMS coating could be pressurized in excess of 260 cmHg without rupture, which is comparable to hollow fiber sweep gas pressures. Oxygen flux for the SμM with and without PDMS was insignificantly different at 0.0306 ± 0.0028 and 0.0297 ± 0.0012mL/min, respectively, while SNM flux was significantly lower at 0.0149 ± 0.0040mL/min. However, the area-normalized mass transfer coefficient of the SNM was 338 ± 54mL O2 m-2min-1 cmHg-1 - an order of magnitude higher than that of the SμM with and without PDMS (57.3 ± 5.5 and 55.6 ± 2.2mL O2 m-2min-1 cmHg-1). Ultimately, we conclude that SμM-PDMS may make effective membranes for ECMO, since they are both mechanically robust and capable of high oxygen flux.

Nanoporous membrane device for ultra high heat flux thermal management

High power density electronics are severely limited by current thermal management solutions which are unable to dissipate the necessary heat flux while maintaining safe junction temperatures for reliable operation. We designed, fabricated, and experimentally characterized a microfluidic device for ultra-high heat flux dissipation using evaporation from a nanoporous silicon membrane. With ~100 nm diameter pores, the membrane can generate high capillary pressure even with low surface tension fluids such as pentane and R245fa. The suspended ultra-thin membrane structure facilitates efficient liquid transport with minimal viscous pressure losses. We fabricated the membrane in silicon using interference lithography and reactive ion etching and then bonded it to a high permeability silicon microchannel array to create a biporous wick which achieves high capillary pressure with enhanced permeability. The back side consisted of a thin film platinum heater and resistive temperature sensors to emulate the heat dissipation in transistors and measure the temperature, respectively. We experimentally characterized the devices in pure vapor-ambient conditions in an environmental chamber. Accordingly, we demonstrated heat fluxes of 665 ± 74 W/cm2 using pentane over an area of 0.172 mm × 10 mm with a temperature rise of 28.5 ± 1.8 K from the heated substrate to ambient vapor. This heat flux, which is normalized by the evaporation area, is the highest reported to date in the pure evaporation regime, that is, without nucleate boiling. The experimental results are in good agreement with a high fidelity model which captures heat conduction in the suspended membrane structure as well as non-equilibrium and sub-continuum effects at the liquid–vapor interface. This work suggests that evaporative membrane-based approaches can be promising towards realizing an efficient, high flux thermal management strategy over large areas for high-performance electronics.

Slit pores preferred over cylindrical pores for high selectivity in biomolecular filtration

Microelectromechanical systems (MEMS) have enabled the fabrication of silicon nanopore membranes (SNM) with uniform non-overlapping “slit shaped” pores. The application of SNM has been suggested for high selectivity of biomolecules in a variety of medical filtration applications. The aim of this study was to rigorously quantify the differences in sieving between slit pore SNM and more commonly modeled cylindrical pore membranes, including effects of the extended Derjaguin, Landau, Verwey, and Overbeek (XDLVO) interactions. Applying equations derived for SNM in previous work, we compare the partition coefficient of slit and cylindrical pore membranes while accounting for both steric and XDLVO interactions. Simple, steric approximations demonstrate that slit pore membranes exhibit significantly lower partition coefficients than cylindrical pore models. Incorporating XDLVO interactions results in an even more marked difference between slit pore and cylindrical pore membranes. These partition coefficients were used to evaluate changes in beta-2-microglobulin (B2M) selectivity. The data demonstrate that XDLVO interactions increase the selectivity advantage that slit pores possess over cylindrical pores, particularly for larger values of the acid-base decay constant. Finally, the bovine serum albumin (BSA) to B2M selectivity ratio was investigated. The selectivity ratio appears larger in slit pores than cylindrical pores for all cases, indicating that slit pores are particularly well suited for hemofiltration applications. The results of this study have significant implications for the application of SNM in membrane processes where highly selective separation of biomolecules is desirable.

Electrochemically etched nanoporous silicon membrane for separation of biological molecules in mixture

This paper presents a technique for separating biological molecules in mixture using nanoporous silicon membrane. Nanopores were formed using electrochemical etching process (ECE) by etching a prefabricated silicon membrane in hydrofluoric acid (HF) and ethanol, and then directly bonding it with PDMS to form a complete filtration system for separating biological molecules. Tygon S3™ tubings were used as fluid interconnection between PDMS molds and silicon membrane during testing. Electrochemical etching parameters were manipulated to control pore structure and size. In this work, nanopores with sizes of less than 50 nm, embedded on top of columnar structures have been fabricated using high current densities and variable HF concentrations. Zinc oxide was diluted with deionized (DI) water and mixed with biological molecules and non-biological particles, namely protein standard, serum albumin and sodium chloride. Zinc oxide particles were trapped on the nanoporous silicon surface, while biological molecules of sizes up to 12 nm penetrated the nanoporous silicon membrane. The filtered particles were inspected using a Zetasizer Nano SP for particle size measurement and count. The Zetasizer Nano SP results revealed that more than 95% of the biological molecules in the mixture were filtered out by the nanoporous silicon membrane. The nanoporous silicon membrane fabricated in this work is integratable into bio-MEMS and Lab-on-Chip components to separate two or more types of biomolecules at once. The membrane is especially useful for the development of artificial kidney.

Silicon nanoporous membranes as a rigorous platform for validation of biomolecular transport models

Microelectromechanical systems (MEMS), a technology that resulted from significant innovation in semiconductor fabrication, have recently been applied to the development of silicon nanopore membranes (SNM). In contrast to membranes fabricated from polymeric materials, SNM exhibit slit-shaped pores, monodisperse pore size, constant surface porosity, zero pore overlap, and sub-micron thickness. This development in membrane fabrication is applied herein for the validation of the XDLVO (extended Derjaguin, Landau, Verwey, and Overbeek) theory of membrane transport within the context of hemofiltration. In this work, the XDLVO model has been derived for the unique slit pore structure of SNM. Beta-2-microglobulin (B2M), a clinically relevant “middle molecular weight” solute in kidney disease, is highlighted in this study as the solute of interest. In order to determine interaction parameters within the XDLVO model for B2M and SNM, goniometric measurements were conducted, yielding a Hamaker constant of 4.61×10–21J and an acid-base Gibbs free energy at contact of 41mJ/m2. The XDLVO model was combined with existing models for membrane sieving, with predictions of the refined model in good agreement with experimental data. Furthermore, the results show a significant difference between the XDLVO model and the simpler steric predictions typically applied in membrane transport. The refined model can be used as a tool to tailor membrane chemistry and maximize sieving or rejection of different biomolecules.

Correction: An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport.

Correction for 'An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport' by Shang Song et al., Lab Chip, 2017, 17, 1778-1792.