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Novel biomaterials for medical device applications must be stable throughout all stages of preparation for surgery, including sterilization. There is a paucity of information on the effects of sterilization on sub-10 nm-thick polymeric surface coatings suitable for silicon-based bioartificial organs. This study explores the effect of five standard sterilization methods on three surface coatings applied to silicon: polyethylene glycol (PEG), poly(sulfobetaine methacrylate) (pSBMA), and poly (2-methacryloyloxyethyl phosphorylcholine) (pMPC). Autoclave, dry heat, hydrogen peroxide (H 2 O 2 ) plasma, ethylene oxide gas (EtO), and electron beam (E-beam) treated coatings were analyzed to determine possible polymer degradation with sterilization. Poststerilization, there were significant alterations in contact angle, maximum change resulting from H 2 O 2 (Δ - 14°), autoclave (Δ + 15°), and dry heat (Δ + 23°) treatments for PEG, pSBMA, and pMPC, respectively. Less than 5% coating thickness change was found with autoclave and EtO on PEG-silicon, E-beam on pSBMA-silicon and EtO treatment on pMPC-silicon. H 2 O 2 treatment resulted in at least 30% decrease in thickness for all coatings. Enzyme-linked immunosorbent assays showed significant protein adsorption increase for pMPC-silicon following all sterilization methods. E-beam on PEG-silicon and dry-heat treatment on pSBMA-silicon exhibited maximum protein adsorption in each coating subset. Overall, the data suggest autoclave and EtO treatments are well-suited for PEG-silicon, while E-beam is best suited for pSBMA-silicon. pMPC-silicon was least impacted by EtO treatment. H 2 O 2 treatment had a negative effect on all three coatings. These results can be used to determine which surface modifications and sterilization processes to utilize for devices in vivo. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2327-2336, 2018., (© 2017 Wiley Periodicals, Inc.)

Hemodialysis using hollow-fiber membranes provides life-sustaining treatment for nearly 2 million patients worldwide with end stage renal disease (ESRD). However, patients on hemodialysis have worse long-term outcomes compared to kidney transplant or other chronic illnesses. Additionally, the underlying membrane technology of polymer hollow-fiber membranes has not fundamentally changed in over four decades. Therefore, we have proposed a fundamentally different approach using microelectromechanical systems (MEMS) fabrication techniques to create thin-flat sheets of silicon-based membranes for implantable or portable hemodialysis applications. The silicon nanopore membranes (SNM) have biomimetic slit-pore geometry and uniform pores size distribution that allow for exceptional permeability and selectivity. A quantitative diffusion model identified structural limits to diffusive solute transport and motivated a new microfabrication technique to create SNM with enhanced diffusive transport. We performed in vitro testing and extracorporeal testing in pigs on prototype membranes with an effective surface area of 2.52 cm2 and 2.02 cm2, respectively. The diffusive clearance was a two-fold improvement in with the new microfabrication technique and was consistent with our mathematical model. These results establish the feasibility of using SNM for hemodialysis applications with additional scale-up.

An implantable hemofilter for the treatment of kidney failure depends critically on the transport characteristics of the membrane and the biocompatibility of the membrane, cartridge, and blood conduits. A novel membrane with slit-shaped pores optimizes the trade-off between permeability and selectivity, enabling implanted therapy. Sustained (3-8) day function of an implanted parallel-plate hemofilter with minimal anticoagulation was achieved by considering biocompatibility at the subnanometer scale of chemical interactions and the millimeter scale of blood fluid dynamics. A total of 400 nm-thick polysilicon flat sheet membranes with 5-8 nm × 2 micron slit-shaped pores were surface-modified with polyethylene glycol. Hemofilter cartridge geometries were refined based on computational fluid dynamics models of blood flow. In an uncontrolled pilot study, silicon filters were implanted in six class A dogs. Cartridges were connected to the cardiovascular system by anastamoses to the aorta and inferior vena cava and filtrate was drained to collection pouches positioned in the peritoneum. Pain medicine and acetylsalicylic acid were administered twice daily until the hemofilters were harvested on postoperative days 3 (n = 2), 4 (n = 2), 5 (n = 1), and 8 (n = 1). No hemofilters were thrombosed. Animals treated for 5 and 8 days had microscopic fractures in the silicon nanopore membranes and 20-50 ml of transudative (albumin sieving coefficient θalb ~ 0.5 - 0.7) fluid in the collection pouches at the time of explant. Shorter experimental durations (3-4 days) resulted in filtration volumes similar to predictions based on mean arterial pressures and membrane hydraulic permeability and (θalb ~ 0.2 - 0.3), similar to preimplantation measurements. In conclusion, a detailed mechanistic and materials science attention to blood-material interactions allows implanted hemofilters to resist thrombosis. Additional testing is needed to determine optimal membrane characteristics and identify limiting factors in long-term implantation.

Silicon nanopore membranes (SNMs) with compact geometry and uniform pore size distribution have demonstrated a remarkable capacity for hemofiltration. These advantages could potentially be used for hemodialysis. Here, we present an initial evaluation of the SNM's mechanical robustness, diffusive clearance, and hemocompatibility in a parallel plate configuration. Mechanical robustness of the SNM was demonstrated by exposing membranes to high flows (200 ml/min) and pressures (1,448 mm Hg). Diffusive clearance was performed in an albumin solution and whole blood with blood and dialysate flow rates of 25 ml/min. Hemocompatibility was evaluated using scanning electron microscopy and immunohistochemistry after 4 hours in an extracorporeal porcine model. The pressure drop across the flow cell was 4.6 mm Hg at 200 ml/min. Mechanical testing showed that SNM could withstand up to 775.7 mm Hg without fracture. Urea clearance did not show an appreciable decline in blood versus albumin solution. Extracorporeal studies showed blood was successfully driven via the arterial-venous pressure differential without thrombus formation. Bare silicon showed increased cell adhesion with a 4.1-fold increase and 1.8-fold increase over polyethylene glycol (PEG)-coated surfaces for tissue plasminogen factor (t-PA) and platelet adhesion (CD41), respectively. These initial results warrant further design and development of a fully scaled SNM-based parallel plate dialyzer for renal replacement therapy.

Silicon nanopore membranes (SNM) with monodisperse pore size distributions have potential applications in bioartificial kidneys. A protein resistant thin film coating on the SNM is required to minimize biofouling and, hence, enhance the performance efficiency of SNM. In this work, a zwitterionic polymer, poly(sulfobetaine methacrylate) (polySBMA), was used to coat silicon and SNM substrates via a surface initiated atom transfer radical polymerization method. The polySBMA-coated surfaces were characterized using contact angle goniometry, X-ray photoelectron spectroscopy (XPS), ellipsometry and scanning electron microscopy (SEM). Resistance of the coatings to protein fouling was examined by measurement of fibrinogen adsorption from fibrinogen solution and human plasma on coated silicon surfaces. Results showed that the polySBMA coating suppresses non-specific adsorption of fibrinogen. The protein-repellent property of polySBMA thin film coating is comparable to that of PEG-based coatings. Analysis of the surfaces by XPS indicated that the films remained stable when stored under physiologic conditions over a 4-week period.

The inference of the surface charge of polyethylene glycol (PEG)-coated and uncoated silicon membranes with nanoscale pore sizes from streaming potential measurements in the presence of finite electric double layer (EDL) effects is studied theoretically and experimentally. The developed theoretical model for inferring the pore wall surface charge density from streaming potential measurements is applicable to arbitrary pore cross-sectional shapes and accounts for the effect of finite salt concentration on the ionic mobilities and the thickness of the deposited layer of PEG. Theoretical interpretation of the streaming potential data collected from silicon membranes having nanoscale pore sizes, with/without pore wall surface modification with PEG, indicates that finite electric double layer (EDL) effects in the pore-confined electrolyte significantly affect the interpretation of the membrane charge and that surface modification with PEG leads to a reduction in the pore wall surface charge density. The theoretical model is also used to study the relative significance of the following uniquely nanoscale factors affecting the interpretation of streaming potential in moderate to strongly charged pores: altered net charge convection by applied pressure differentials, surface-charge effects on ionic conduction, and electroosmotic convection of charges., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Over 300,000 Americans are dependent on hemodialysis as treatment for renal failure, and kidney transplantation is limited by scarcity of donor organs. This shortage has prompted research into tissue engineering of renal replacement therapy. Existing bioartificial kidneys are large and their use labor intensive, but they have shown improved survival compared to conventional therapy in preclinical studies and an US Food and Drug Administration-approved phase 2 clinical trial. This hybrid technology will require miniaturization of hemofilters, cell culture substrates, sensors, and integration of control electronics. Using the same harvesting and isolation techniques used in preparing bioartificial kidneys for clinical use, we characterized human renal tubule cell growth on a variety of silicon and related thin-film material substrates commonly used in the construction of microelectromechanical systems (MEMS), as well as novel silicon nanopore membranes (SNMs). Human cortical tubular epithelial cells (HCTC) were seeded onto samples of single-crystal silicon, polycrystalline silicon, silicon dioxide, silicon nitride, SU-8 photoresist, SNMs, and polyester tissue culture inserts, and grown to confluence. The cells formed confluent monolayers with tight junctions and central cilia. Transepithelial resistances were similar between SNMs and polyester membranes. The differentiated growth of human tubular epithelial cells on MEMS materials strongly suggests that miniaturization of the existing bioartificial kidney will be feasible, paving the way for widespread application of this novel technology.