Biomedical subjects

William H Fissell

Publications and source records attributed to William H Fissell.

9 recordsLinked to original sources

PubMed2006

Electrochemical detection and characterization of proteins.

On-line detection of serum proteins is of clinical relevance, in detecting leaks and biofouling in hemofiltration equipment, biofilm growth on prosthetic devices, or hemolysis within a prosthetic or therapeutic device. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were employed to detect and analyze micromolar concentrations of four globular proteins of clinical importance. CV testing showed that identification and quantification of each of these proteins was possible through analysis of current changes at specific potentials. Preliminary CV studies into the contamination of Bovine Serum Albumin with a microgram amount of one of the other three proteins illustrated that direct detection of the contaminant protein was possible. The analysis of the EIS data demonstrated that with increase in relative concentration of proteins, the amount of electroactive proteins adsorption at the interface increases, leading to increase in surface charge density and capacitance, especially for lower molecular weight proteins. The impedance data was used to determine the values of Gibbs adsorption energy, adsorption coefficients for the four proteins, and develop an equivalent circuit model for the protein-containing solutions.

Biosensing Techniques↗

PubMed2006

Developments towards an artificial kidney.

This article reviews the present state of renal failure and its treatment in the industrialized world. Novel and experimental therapies for the treatment of renal failure are covered, with special emphasis on a hybrid bioartificial kidney currently undergoing clinical trials in the USA. Preclinical data, results from human trials and work on miniaturization of the bioartificial kidney for implantation are presented. Research on microfluidics and nanotechnology applied to dialysis is ongoing in many academic centers, and several promising approaches are discussed. After 10 years of incremental improvements in end-stage renal disease care, several revolutionary technologies are on the horizon and approaching the marketplace.

Bioartificial Organs↗

PubMed2004

Renal cell therapy in the treatment of patients with acute and chronic renal failure.

Hemodialysis and hemofiltration have been important technologies in saving the lives of patients with acute (ARF) and chronic renal failure by clearing small solutes from plasma and thereby preventing death from acidemia, hyperkalemia, volume overload, and uremia. These therapeutic approaches, however, are still suboptimal, as patients with ARF have mortality rates exceeding 50%, and patients with end-stage renal disease (ESRD) have, on average, a life expectancy of 4-5 years. The preeminent cause of death in patients with ARF is the development of sepsis or the systemic inflammatory response syndrome with resulting systemic vasodilation, hypotension, ischemic injury to solid organs, multi-organ failure, and death. This vasodilation is due to persistent and excessive pro-inflammation. Similarly, the reduced survival times of patients with ESRD on chronic dialysis have been associated with a persistent and chronic systemic pro-inflammatory state. We have hypothesized that the loss of renal tubule cell mass acutely in acute tubule necrosis and chronically in ESRD results in an immunologically dysregulated state leading to excessive pro-inflammation. The replacement of renal tubule cell function may thus change the current dismal prognosis of patients with these disorders. In this regard, this report presents the first patient ever treated with a bioartificial kidney consisting of a synthetic hemofilter in series with a renal tubule assist device (RAD) containing approximately 10(9) human renal tubule cells. This treatment in a critically ill patient with multi-organ failure and ARF in the intensive care unit was associated temporally with improved cardiovascular parameters and enhanced native kidney function. Multiple systemic plasma cytokine levels and gene expression profiles of peripheral white blood cells were also temporally changed with cell therapy. Clinical trials in patients suffering from either ARF or ESRD are currently ongoing to evaluate the influence of the RAD on the inflammatory response in these groups of patients.

Acute Kidney Injury↗

PubMed2003

Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals.

The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 x 10(10) bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n = 6) or a RAD with cells (n = 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P < 0.05) and cardiac output (P < 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-alpha, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P < 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time.

Animals↗

PubMed2003

Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock.

OBJECTIVE: Gram-negative septic shock has a clinical mortality rate approaching 50%. The cause of death is secondary to a systemic inflammatory response syndrome with resulting cardiovascular collapse, ischemic damage to vital organs, and multiple-organ systems failure. Renal tubule cell injury occurs early in septic shock but is not clinically appreciated. Since renal tubule cells appear to play a critical role in the immunoregulation of stress states, renal cell therapy during septic shock may alter the detrimental multiple-organ consequences of systemic Gram-negative infection. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 109 renal proximal tubule cells may be a new therapeutic approach to this clinical disorder. DESIGN: Laboratory study. SETTING: University medical school. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the bioartificial kidney and the RAD in septic shock, pigs were administered 30 x 10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in a continuous venovenous hemofiltration extracorporeal circuit with either a sham RAD without cells or a RAD with cells. MEASUREMENTS AND MAIN RESULTS: In this animal model, septic shock resulted within hours in acute tubule necrosis in the kidneys of all animals. Renal cell therapy resulted in significantly higher cardiac outputs and renal blood flow rates in treated animals compared with sham controls. RAD treatment also was associated with significantly lower plasma circulating concentrations of interleukin-6 and interferon-gamma compared with sham-treated animals. IL-6 release rates from peripheral blood mononuclear cells isolated from RAD-treated animals were significantly higher after endotoxin stimulation than those isolated from control animals. These physiologic and molecular alterations were associated with nearly a doubling of the average survival time in the RAD-treated group compared with the sham control group. CONCLUSION: These results demonstrate that renal cell therapy ameliorates cardiac and vascular dysfunction, alters systemic cytokine abnormalities, and improves survival time in a large animal model of Gram-negative septic shock. A cell therapeutic approach with a tissue-engineered bioartificial kidney may be a new treatment modality for this current unmet medical need.

Acute Kidney Injury↗

PubMed2002

The bioartificial kidney in the treatment of acute renal failure.

The application of cell therapy to the successful substitution process of hemofiltration may improve the poor prognosis of patients with acute renal failure (ARF) in the intensive care unit. An extracorporeal bioartificial kidney consisting of a conventional hemofilter followed in series with a renal tubule assist device (RAD) has been developed. The RAD is a hemofiltration cartridge containing 109 human renal tubule cells grown as monolayers along the inner surface of the hollow fibers. The fibers provide a porous scaffold that is immunoprotective. The ultrafiltrate from the hemofilter is delivered to the luminal compartment of the RAD, and the postfiltered blood is delivered to the extracapillary space of the RAD. The RAD has been shown to possess multiple differentiated transport, metabolic, and endocrinologic activities of renal epithelium. These activities have been demonstrated to occur when the RAD is placed in the extracorporeal circuit of the bioartificial kidney in uremic animals. This approach may improve the current therapies used to treat patients with ARF because of the RAD's ability to restore lost metabolic renal function and cytokine balance in these desperately ill patients. In this regard, the RAD was able to ameliorate endotoxin and bacteremic shock in uremic animals by altering cytokine levels, improve mean arterial blood pressure, and maintain better cardiac output. With these supportive preclinical data, an FDA-approved phase I/II clinical trial has been initiated and early results are encouraging.

Acute Kidney Injury↗

PubMed2002

Metabolic replacement of kidney function in uremic animals with a bioartificial kidney containing human cells.

Current renal substitution therapy with hemodialysis or hemofiltration has been an important life-sustaining technology, but it still has suboptimal clinical outcomes in patients with end-stage renal disease or acute renal failure. This therapy replaces the small solute clearance function of the glomerulus but does not replace the metabolic and endocrinologic functions of the tubular cells. This article shows that the combination of a synthetic hemofiltration cartridge and a renal tubule cell assist device (RAD) containing human cells in an extracorporeal circuit replaces filtration, metabolic, and endocrinologic functions in acutely uremic dogs. The RAD maintained excellent performance and durability characteristics for 24 hours of continuous use in the uremic animals. The RAD increased ammonia excretion, glutathione metabolism, and 1,25-dihydroxyvitamin D3 production. Cardiovascular stability in the animals was documented in these studies during this extracorporeal treatment. With these results, clinical evaluation of this device in the treatment of severely ill patients with acute renal failure in an intensive care unit has been initiated.

Acute Kidney Injury↗

PubMed2002

Bioartificial kidney alters cytokine response and hemodynamics in endotoxin-challenged uremic animals.

The mortality from sepsis complicated by renal failure remains extremely high despite the application of modern renal replacement therapy. This study investigated whether treatment with a bioartificial kidney consisting of a hemofilter in a continuous venovenous hemofiltration circuit (CVVH) with a cartridge containing renal proximal tubule cells, also called the Renal Tubule Assist Device (RAD), would alter the course of sepsis in an animal model. The RAD has been previously characterized in vitro and ex vivo and provides transport, metabolic and endocrine activity. Mongrel dogs (n = 10) underwent surgical nephrectomy and 48 h later were treated with CVVH and either a RAD containing cells (n = 5) or an identically prepared sham cartridge (n = 5). After 4 h of therapy, intravenous endotoxin 2 mg/kg was infused over 1 h to simulate gram-negative septic shock. Data on blood pressure, cardiac output and systemic markers of inflammation were collected. Mean peak levels of an anti- inflammatory cytokine, IL-10, were significantly higher in cell-treated animals (15.25 vs. 6.29 ng/ml; p = 0.037), and mean arterial pressures were higher in cell-treated versus sham-treated animals (p < 0.04). We have demonstrated that treatment of an animal model of endotoxin shock and renal failure with a bioartificial kidney has measurable effects on circulating mediators of inflammation and on hemodynamic stability of the challenged animal.

Acute Kidney Injury↗

PubMedDate not supplied

Differentiated growth of human renal tubule cells on thin-film and nanostructured materials.

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.

Biocompatible Materials↗