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Toxins
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 external...
ASAIO journal (American Society for Artificial Internal Organs : 1992), 2015
Silicon nanopore membranes (SNM) 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 theSNM'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 (200ml/min) and pressures (1,448mmHg). Diffusive clearance was performed in an albumin solution and whole blood with blood and dialysate flow rates of 25ml/min. Hemocompatibility was evaluated using scanning electron microscopy and immunohistochemistry after 4-hours in an extra-corporeal porcine model. The pressure drop across the flow cell was 4.6mmHg at 200ml/min. Mechanical testing showed that SNM could withstand up to 775.7mmHg without fracture. Urea clearance did not show an appreciable decline in blood versus albumin solution. Extra-...
PloS one, 2016
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 transpo...
ASAIO Journal, 2016
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 ...
Membranes, 2020
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 metho...
Blood Purification, 2006
Nanotechnology, defined as the science of material features between 10–9 and 10–7 of a meter, has received extensive attention in the popular press as proof-of-concept experiments in the laboratory are published. The inevitable delay between feature articles and clinical endpoints has led to unwarranted skepticism about the applicability of the technology to current medical therapy. The theoretic advantages of micro- and nanometer scale engineering to renal replacement include the manufacture of high-hydraulic permeability membranes with implanted sensing and control structures. Recent data in membrane design and testing is presented, with a review of the challenges remaining in implementation of this technology.
Kidney International, 2002
The need to improve outcomes in dialysis therapies is ture; the case of the FX-class of hemodialyzers. Very few innodirecting clinical research toward epidemiologic studies, vations have characterized the different components of the randomized trials, and evidence-based analyses to adhemodialyzers in the past 20 years. Most improvements have dress critical issues. In parallel, there is a continuous concerned membrane biocompatibility. In this article, we focus demand for the development of new tools designed to our attention on the most recent advances in hemodialyzer improve dialysis quality and treatment efficiency. Dialcomponents from the macro design of the unit to the nanostructure of the membrane. For this purpose, we took as an example ysis machines and treatment techniques and modalities the FX class of hemodialyzers (FMC, Bad Homburg, Gerhave undergone significant changes in recent years. Howmany). The studied devices were chosen as an example repreever, the structure and design of hemodialyzers have senting some of the most recent hemodialyzers and are well seen few changes, being very similar to the state-of-thesuited to describe technical innovations occurring in the field art of twenty years ago; only minor modifications have of dialyzer technology. In vitro and in vivo studies were performed to characterize hemodynamic parameters of three modbeen introduced in the last decade [1-6]. In view of this els (1.4-1, 8, and 2.2 m 2 ) and to determine membrane permeconservative approach toward the perception and use of ability, sieving coefficients, and solute clearances. The units the hemodialyzer, higher blood and dialysate flows have were characterized by a relatively high resistance of the blood predominantly been employed to improve treatment and dialysate compartments, leading to an increased internal performance [7-13], and a need for newer, more efficient filtration if compared with similar hemodialyzers of other sedialyzers has clearly emerged recently. Other issues have ries. Nevertheless, the flow distribution in both compartments was homogeneous and well balanced. This effect was obtained spurred renewed interest in the design of both the hemoby the improved blood and dialysate ports design, the increased dialyzer and the hollow fiber membrane; for example, packing density of the fibers and a reduction of the inner we can mention the increased knowledge of internal diameter of the fibers from 200 to 180 m. At the same time, filtration mechanisms and the increasing usage of onthe sieving coefficients for middle-large solutes such as 2 line HDF. microglobulin and insulin were higher than those observed in standard high flux dialysers. The same effect was noted for the Most recently, new manufacturing procedures and reclearance values of these solutes. This was observed in the fined microanalytical methods have entailed a reevaluaabsence of significant albumin leakage. Theis results were obtion of the hemodialyzer from the macrodesign of its tained thanks to a new nano-controlled spinning technology individual components to the detailed nanostructure of applied to the fiber. The innermost layer of the membrane is in the membrane. In particular, the blood and dialysate fact characterized by a homogeneous porosity, with increased ports have been critically reevaluated and their design number of pores of large dimension but a sharp cutoff of the membrane excluding albumin losses. In conclusion, new has been optimized. The packing density of hollow fibers technologies and new diagnostic tools today allow for improve-
J Vasc Access, 2016
We present our experience with AVflo™, a nanofiber, electrospun, self-sealing, early-access graft for hemodialysis (HD). Objective: Evaluating the safety and efficacy of the AVflo™ graft in terms of patency and complications (early and late) over 2 years. Materials and methods: Twelve end-stage renal disease (ESRD) patients (age: mean 68.5 ± 10 years) were followed up for a mean period of 946 ± 570 days after receiving an implantation of the graft for HD. The grafts were implanted at the lower arm (loop configuration), upper arm (straight configuration) and the thigh (loop configuration). First dialysis was performed at day 7 (3-21) following implantation. results and discussion: After a mean follow up of 24 months, the primary patency was 56% and the secondary patency was 82%. In this group, AVflo™ shows similar if not superior efficacy and safety to that of available grafts in terms of safety, complications, and long-term patency.
The Lancet, 2016
Background-For patients with end-stage renal disease who are not candidates for fistula, dialysis access grafts are the best option for chronic haemodialysis. However, polytetrafluoroethylene arteriovenous grafts are prone to thrombosis, infection, and intimal hyperplasia at the venous anastomosis. We developed and tested a bioengineered human acellular vessel as a potential solution to these limitations in dialysis access. Methods-We did two single-arm phase 2 trials at six centres in the USA and Poland. We enrolled adults with end-stage renal disease. A novel bioengineered human acellular vessel was implanted into the arms of patients for haemodialysis access. Primary endpoints were safety (freedom from immune response or infection, aneurysm, or mechanical failure, and incidence of adverse events), and efficacy as assessed by primary, primary assisted, and secondary patencies at 6 months. All patients were followed up for at least 1 year, or had a censoring event. These trials are registered with ClinicalTrials.gov, NCT01744418 and NCT01840956.
Membranes, 2015
Hemodialysis involves large, periodic treatment doses using large-area membranes. If the permeability of dialysis membranes could be increased, it would reduce the necessary dialyzer size and could enable a wearable device that administers a continuous, low dose treatment of chronic kidney disease. This paper explores the application of ultrathin silicon membranes to this purpose, by way of analytical and finite element models of diffusive and convective transport of plasma solutes during hemodialysis, which we show to be predictive of experimental results. A proof-of-concept miniature nanomembrane dialyzer design is then proposed and analytically predicted to clear uremic toxins at near-ideal levels, as measured by several markers of dialysis adequacy. This work suggests the feasibility of miniature nanomembrane-based dialyzers that achieve therapeutic levels of uremic toxin clearance for patients with kidney failure.
Journal of Clinical Medicine
Tunneled central venous catheters (CVC) are mainly considered as a rescue vascular access option in dialysis but are still used on approximately one quarter of prevalent patients worldwide even though they are associated with poor performances and higher risks. Study design: in this retrospective single-center study, we aimed to report on the clinical performances achieved with high-flow tunneled CVCs (DualCath or DCath) and compared them with arteriovenous accesses (AVAs, e.g., AV fistula, AV graft, and Thomas Shunt) in a hospital-based dialysis unit. Methods: Sixty-eight stage 5 chronic kidney disease dialysis-dependent patients (CKD5D) receiving high volume hemodiafiltration were followed-up with for 30 months. The study consisted of two phases: baseline cross-sectional and longitudinal follow-ups of key performance indicators. Clinical performances consisting of effective blood flow and blood volume, recirculation, urea and ionic Kt/V, total Kt, ultrafiltration volume, and perce...
Advances in chronic kidney disease, 2013
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 resistanc...
ASME 2016 14th International Conference on Nanochannels, Microchannels, and Minichannels, 2016
Extracorporeal blood therapies such as hemodialysis and extracorporeal membrane oxygenation supplement or replace organ function by the exchange of molecules between blood and another fluid across a semi-permeable membrane. Traditionally, these membranes are made of polymers with large surface areas and thicknesses on the scale of microns. Therapeutic gas exchange or toxin clearance in these devices occurs predominantly by diffusion, a process that is described by an inverse square law relating a distance to the average time a diffusing particle requires to travel that distance. As such, small changes in membrane thickness or other device dimensions can have significant effects on device performance — and large changes can cause dramatic paradigm shifts. In this work, we discuss the application of ultrathin nanoporous silicon membranes (nanomembranes) with thicknesses on the scale of tens of nanometers to diffusion-mediated medical devices. We discuss the theoretical consequences of...
Journal of Membrane Science, 2009
Silicon micromachining provides the precise control of nanoscale features that can be fundamentally enabling for miniaturized, implantable medical devices. Concerns have been raised regarding blood biocompatibility of silicon-based materials and their application to hemodialysis and hemofiltration. A high-performance ultrathin hemofiltration membrane with monodisperse slit-shaped pores was fabricated using a sacrificial oxide technique and then surface-modified with poly(ethylene glycol) (PEG). Fluid and macromolecular transport matched model predictions well. Protein adsorption, fouling, and thrombosis were significantly inhibited by the PEG. The membrane retained hydraulic permeability and molecular selectivity during a 90 hour hemofiltration experiment with anticoagulated bovine whole blood. This is the first report of successful prolonged hemofiltration with a silicon nanopore membrane. The results demonstrate feasibility of renal replacement devices based on these membranes and materials.
Advanced Healthcare Materials, 2020
Clinical Journal of the American Society of Nephrology, 2019
The number of patients dialyzed for ESKD exceeds 500,000 in the United States and more than 2.6 million people worldwide, with the expectation that the worldwide number will double by 2030. The human cost of health and societal financial cost of ESKD is substantial. Dialytic therapy is associated with an unacceptably high morbidity and mortality rate and poor quality of life. Although innovation in many areas of science has been transformative, there has been little innovation in dialysis or alternatives for kidney replacement therapy (KRT) since its introduction approximately 70 years ago. Advances in kidney biology, stem cells and kidney cell differentiation protocols, biomaterials, sensors, nano/microtechnology, sorbents and engineering, and interdisciplinary approaches and collaborations can lead to disruptive innovation. The Kidney Health Initiative, a public–private partnership between the American Society of Nephrology and the US Food and Drug Administration, has convened a m...
American Journal of Kidney Diseases, 1997
• Difficulties in creating vascular access in patients on hemodialysis are encountered in most dialysis centers. This is usually due to a lack of suitable peripheral vessels due to previous access surgery in patients on longterm hemodialysis, but also may be seen in some patients de novo, particularly diabetics and patients with peripheral vascular disease. Surgical techniques used to overcome this problem vary depending on patient characteristics and, to a certain extent, on local expertise/preference. We report our experience of using silicon duallumen hemodialysis catheters over a 3-year period; during this time, 54 catheters were inserted into 32 hemodialysis patients. The indication for this procedure in 52 catheters (31 patients) was either exhausted vascular access or obvious difficulty identifying a suitable peripheral blood vessel. Of the catheters inserted, 20 were placed into subclavian veins by primary insertion (ie, patients did not have existing subclavian catheter); 34 were replaced over a guidewire (a procedure used to allow technique salvage). The catheter survival rate was 72.7% at 90 days and 48.7% at 1 year. Corresponding rates at 90 days and 1 year for technique survival were 93.3% and 81.8%, respectively. The mean catheter and technique survival was 387 (95% confidence intervals [CIs], 273, 502) and 844 (95% CIs, 684, 1,005) days, respectively. Poor flow accounted for 70.4% of catheter failures and, despite 18 episodes of catheter-related sepsis, no catheters were lost due to infection. Factors identified as leading to reduced catheter survival were left-sided placement and catheter tip placement in the superior vena cava (as opposed to right atrial placement). We did not observe poorer survival or increased sepsis in catheters replaced over a guidewire, and would advocate this technique as a means of salvage in this group of patients.
Canadian Urological Association Journal, 2013
case report E505 Cite as: Can Urol Assoc J 2013;7(7-8):e505-7. http://dx.
Annals of Biomedical Engineering, 2011
Silicon membranes with highly uniform nanopore sizes fabricated using microelectromechanical systems (MEMS) technology allow for the development of miniaturized implants such as those needed for renal replacement therapies. However, the blood compatibility of silicon has thus far been an unresolved issue in the use of these substrates in implantable biomedical devices. We report the results of hemocompatibility studies using bare silicon, polysilicon, and modified silicon substrates. The surface modifications tested have been shown to reduce protein and/ or platelet adhesion, thus potentially improving biocompatibility of silicon. Hemocompatibility was evaluated under four categories-coagulation (thrombin-antithrombin complex, TAT generation), complement activation (complement protein, C3a production), platelet activation (P-selectin, CD62P expression), and platelet adhesion. Our tests revealed that all silicon substrates display low coagulation and complement activation, comparable to that of Teflon and stainless steel, two materials commonly used in medical implants, and significantly lower than that of diethylaminoethyl (DEAE) cellulose, a polymer used in dialysis membranes. Unmodified silicon and polysilicon showed significant platelet attachment; however, the surface modifications on silicon reduced platelet adhesion and activation to levels comparable to that on Teflon. These results suggest that surface-modified silicon substrates are viable for the development of miniaturized renal replacement systems.
Nefrología : publicación oficial de la Sociedad Española Nefrologia, 2011
New directions in dialysis research include cheaper treatments, home based therapies and simpler methods of blood purification. These objectives may be probably obtained with innovations in the field of artificial kidney through the utilization of new disciplines such as miniaturization, microfluidics, nanotechnology. This research may lead to a new era of dialysis in which the new challenges are transportability, wearability and why not the possibility to develop implantable devices. Although we are not there yet, a new series of papers have recently been published disclosing interesting and promising results on the application of wearable ultrafiltration systems (WUF) and wearable artificial kidneys (WAK). Some of them use extracorporeal blood cleansing as a method of blood purification while others use peritoneal dialysis as a treatment modality (ViWAK and AWAK.) A special mention deserves the wearable/portable ultrafiltration system for the therapy of overhydration and congestiv...
Artificial Kidneys & Miniaturized Dialysis, 2021
Large number of patients who need renal replacement therapy are struggling to cope with daily life restrictions and complications because of dialysis therapy. They have to spend 3 half days a week for hemodialysis therapy which accounts for 95% of all renal replacement therapies. Moreover, they also have to be afraid of many complications associated with dialysis. Although these complications mostly arise from the shortage of dialysis quantity, we have been unable to improve the hemodialysis therapy system using extracorporeal circulation. Recently, we clinically investigated long-term dialysis therapiesone was a home-dialysis system and the other a portable dialysis system. We have also developed a very small dialysis device using nanotechnology, considering an implantable artificial kidney instead of transplantation in the near future.
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