Oxygen consumption dynamics in a hollow fiber, hepatocyte-loaded bioartificial liver are investigated both theoretically and experimentally. The theoretical model is based upon the Krogh cylinder, which approximates the bioreactor as a collection of cylindrical elements comprised of an inner fiber lumen for media perfusion, the fiber wall through which oxygen can diffuse, and an annular region of hepatocytes surrounding the fiber. The primary non-dimensional parameters that describe the system are: (i) the Peclet number, Pe, which is the ratio of convective oxygen transport through the lumen to diffusive oxygen transport to the fiber walls; (ii) the hepatocyte saturation parameter, theta, which is the ratio of the inlet oxygen partial pressure to the Michaelis-Menten half-rate oxygen partial pressure; (iii) the Thiele modulus, phi2, which is the ratio of oxygen consumption rate to oxygen diffusion rate in the hepatocyte annulus; (iv) the hepatocyte permeability ratio, beta31, which is the ratio of oxygen permeability in the hepatocyte cell mass to oxygen permeability in the perfusing lumen medium; and (v) the hepatocyte annular thickness, rho3, which is the ratio of the exterior hepatocyte annular radius to the fiber lumen radius. Only Pe and theta are easily manipulated operating variables. phi2, beta31, and rho3 are engineering design parameters that are set when a bioreactor is fabricated. The model results are expressed as the effective hepatocyte utilization ratio, Vratio, which is the ratio of the observed oxygen consumption rate to the intrinsic hepatocyte oxygen consumption rate. Large regions of Vratio > 0.9, which is deemed an acceptable effective hepatocyte utilization are found for parameter values consistent with standard hollow fiber cartridges used in bioartificial liver fabrication. The extent of the Vratio > 0.9 region increases to a plateau with increasing Pe, increases with increasing theta, decreases with increasing phi2, increases with increasing beta31, and decreases with increasing rho3. The theoretical results indicate that Vratio > 0.9 is found whenever the experimentally observed fractional oxygen consumption from the perfusing medium, is less than 0.25. Combination of the theoretical and experimental results indicate that intrinsic, per cell oxygen consumption in the hollow fiber system may decrease as hepatocyte cell density increases and that this decrease may be due to lower intrinsic oxygen requirements in denser suspensions and not due to diffusion limitations in oxygen transport in the hollow fiber system as might be expected from two-dimensional, monolayer culture oxygen consumption measurements.
Elevated intracranial pressure (ICP) leads to loss of cerebral perfusion, cerebral herniation, and irreversible brain damage in patients with acute liver failure (ALF). Conventional techniques for monitoring ICP can be complicated by hemorrhage and infection. Transcranial doppler ultrasonography (TCD) is a noninvasive device which can continuously measure cerebral blood flow velocity, producing a velocity-time waveform that indirectly monitors changes in cerebral hemodynamics, including ICP. The primary goal of this study was to determine whether TCD waveform features could be used to differentiate ALF patients with respect to ICP or, equally important, cerebral perfusion pressure (CPP) levels. A retrospective study of 16 ALF subjects with simultaneous TCD, ICP, and CPP measurements yielded a total of 209 coupled ICP-CPP-TCD observations. The TCD waveforms were digitally scanned and seven points corresponding to a simplified linear waveform were identified. TCD waveform features including velocity, pulsatility index, resistive index, fraction of the cycle in systole, slopes, and angles associated with changes in the slope in each region, were calculated from the simplified waveform data. Paired ICP-TCD observations were divided into three groups (ICP Ͻ 20 mmHg, n ϭ 102; 20 Յ ICP Ͻ 30 mmHg, n ϭ 74; and ICP Ն 30 mmHg, n ϭ 33). Paired CPP-TCD observations were also divided into three groups (CPP Ն 80 mmHg, n ϭ 42; 80 Ͼ CPP Ն 60 mmHg, n ϭ 111; and CPP Ͻ 60 mmHg, n ϭ 56). Stepwise linear discriminant analysis was used to identify TCD waveform features that discriminate between ICP groups and CPP groups. Four primary features were found to discriminate between ICP groups: the blood velocity at the start of the Windkessel effect, the slope of the Windkessel upstroke, the angle between the end systolic downstroke and start diastolic upstroke, and the fraction of time spent in systole. Likewise, 4 features were found to discriminate between the CPP groups: the slope of the Windkessel upstroke, the slope of the Windkessel downstroke, the slope of the diastolic downstroke, and the angle between the end systolic downstroke and start diastolic upstroke. The TCD waveform captures the cerebral hemodynamic state and can be used to predict dynamic changes in ICP or CPP in patients with ALF. The mean TCD waveforms for corresponding, correctly classified ICP and CPP groups are remarkably similar. However, this approach to predicting intracranial hypertension and CPP needs to be further refined and developed before clinical application is feasible. Liver Transpl 14: 1048-1057, 2008. © 2008 AASLD. Received November 21, 2007 accepted January 22, 2008. Abbreviations: ␣ ED , end diastole angle; ␣ PS , peak systole angle; ␣ PW , peak Windkessel angle; ␣ PS , peak systole angle; ␣ SD , start diastole angle; ␣ SW , start Windkessel angle; ALF, acute liver failure; CBFV, cerebral blood flow velocity; CPP, cerebral perfusion pressure; HR, heart rate; ICP, intracranial pressure; MAP, mean arterial pressure; PaCO 2 , CO 2 partial pressur...
A Phase I clinical safety evaluation of the Excorp Medical, Inc, Bioartificial Liver Support System (BLSS) is in progress. Inclusion criteria are patients with acute liver failure of any etiology, presenting with encephalopathy deteriorating beyond Parson's Grade 2. The BLSS consists of a blood pump, heat exchanger to control blood temperature, oxygenator to control oxygenation and pH, bioreactor, and associated pressure and flow alarm systems. Patient liver support is provided by 70-100 g of porcine liver cells housed in the hollow fiber bioreactor. A single support period evaluation consists of 12 hour extracorporeal perfusion with the BLSS sandwiched between 12 hours of pre (baseline) and 12 hours of post support monitoring. Blood chemistries and hematologies are obtained every 6 hours during monitoring periods and every 4 hours during perfusion. Physiologic parameters are monitored continuously. The patient may receive a second treatment at the discretion of the clinical physician. Preliminary evaluation of safety considerations after enrollment of the first four patients (F, 41, acetaminophen induced, two support periods; M, 50, Wilson's disease, one support period; F, 53, acute alcoholic hepatitis, two support periods; F, 24, chemotherapy induced, one support period) is presented. All patients tolerated the extracorporeal perfusion well. All patients presented with hypoglycemia at the start of perfusion, treatable by IV dextrose. Transient hypotension at the start of perfusion responded to an IV fluid bolus. Only the second patient required heparin anticoagulation. No serious or unexpected adverse events were noted. Moderate biochemical response to support was noted in all patients. Completion of the Phase I safety evaluation is required to fully characterize the safety of the BLSS.
The first clinical use of the Excorp Medical Bioartificial Liver Support System (BLSS) in support of a 41-year-old African-American female with fulminant hepatic failure is described. The BLSS is currently in a Phase I/II safety evaluation at the University of Pittsburgh/UPMC System. Inclusion criteria for the study are patients with acute liver failure, any etiology, presenting with encephalopathy deteriorating beyond Parson's Grade 2. The BLSS consists of a blood pump; a heat exchanger to control blood temperature; an oxygenator to control oxygenation and pH; a bioreactor; and associated pressure and flow alarm systems. Patient liver support is provided by 70-100 g of porcine liver cells housed in the hollow fiber bioreactor. The patient exhibited transient hypotension and thrombocytopenia at initiation of perfusion. The only unanticipated safety event was a lowering of patient glucose level at the onset of perfusion with the BLSS that was treatable with intravenous glucose administration. Moderate changes in blood biochemistries pre-and post perfusion are indicative of liver support being provided by the BLSS. While the initial experience with the BLSS is encouraging, completion of the Phase I/II study is required in order to more fully understand the safety aspects of the BLSS.
Although longer patient follow-up is required and mandated to unequivocally establish the biosafety of this device and related bioartificial organ systems, these analyses support the conclusion that when used under standard operational conditions, the BLSS is safe.
Acute liver disease is a life-threatening condition for which liver transplantation is the only recognized effective therapy. While etiology varies considerably, the clinical course of acute liver failure is common among the etiologies: encephalopathy progressing toward coma and multiple organ failure. Detoxification processes, such as molecular adsorbent recirculating system (MARS) and Prometheus, have had limited success in altering blood chemistries positively in clinical evaluations, but have not been shown to be clinically effective with regard to patient survival or other clinical outcomes in any Phase III prospective, randomized trial. Bioartificial liver systems, which use liver cells (hepatocytes) to provide metabolic support as well as detoxification, have shown promising results in early clinical evaluations, but again have not demonstrated clinical significance in any Phase III prospective, randomized trial. Cell transplantation therapy has had limited success but is not practicable for wide use owing to a lack of cells (whole-organ transplantation has priority). New approaches in regenerative medicine for treatment of liver disease need to be directed toward providing a functional cell source, expandable in large quantities, for use in various applications. To this end, a novel bioreactor design is described that closely mimics the native liver cell environment and is easily scaled from microscopic (<1 ml cells) to clinical ( approximately 600 ml cells) size, while maintaining the same local cell environment throughout the bioreactor. The bioreactor is used for study of primary liver cell isolates, liver-derived cell lines and stem/progenitor cells.
Toxins that bind to albumin in the bloodstream and are associated with progressing liver failure have proven refractory to removal by conventional hemodialysis. Such toxins can, however, be removed by adding a binder to the dialysate that serves to capture the toxin as it is dialyzed across the membrane. Several approaches based upon this concept are in various stages of clinical evaluation. The thermodynamic basis common to these approaches has been used to develop an engineering description of 'bound solute dialysis' which has further been used to define the clinical expectations and limitations of the approach. Three dimensionless, independently controllable, operating parameters emerged from this analysis (i): kappa, the dialyzer mass transfer/blood flow rate ratio (clinical range: 0.5-2.5); (ii) alpha, the dialysate/blood flow rate ratio (clinical range: 0.1-2.0); and (iii) beta, the dialysate/blood binder concentration ratio (clinical range: 0.02-5.0). In the absence of binder in the dialysate, bound toxin removal is sensitive to kappa and alpha, with greater removal associated with greater kappa and/or alpha. Bound toxin removal, however, is dependent primarily upon kappa and independent of alpha and beta once a small amount of binder, beta > 0.02, is added to the dialysate. The improvement in bound toxin removal over conventional hemodialysis is dependent upon how tightly the toxin binds albumin ranging from a 6-fold increase for a relatively tightly bound solute such as unconjugated bilirubin, to 1.5-fold increase for a less tightly bound drug such as warfarin at 24 h perfusion time. Clinically, bound solute dialysis can be practiced in single-pass mode with as little as 1-2 g albumin/L dialysate. Because of the constraints imposed by the thermodynamic nature of the process, intervention should be made as early in the disease progression as feasible.
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