William J Federspiel

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (128)297.61 Total impact

  • D T Arazawa · J D Kimmel · M C Finn · W J Federspiel
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    ABSTRACT: Unlabelled: The use of extracorporeal carbon dioxide removal (ECCO2R) is well established as a therapy for patients suffering from acute respiratory failure. Development of next generation low blood flow (<500mL/min) ECCO2R devices necessitates more efficient gas exchange devices. Since over 90% of blood CO2 is transported as bicarbonate (HCO3(-)), we previously reported development of a carbonic anhydrase (CA) immobilized bioactive hollow fiber membrane (HFM) which significantly accelerates CO2 removal from blood in model gas exchange devices by converting bicarbonate to CO2 directly at the HFM surface. This present study tested the hypothesis that dilute sulfur dioxide (SO2) in oxygen sweep gas could further increase CO2 removal by creating an acidic microenvironment within the diffusional boundary layer adjacent to the HFM surface, facilitating dehydration of bicarbonate to CO2. CA was covalently immobilized onto poly (methyl pentene) (PMP) HFMs through glutaraldehyde activated chitosan spacers, potted in model gas exchange devices (0.0151m(2)) and tested for CO2 removal rate with oxygen (O2) sweep gas and a 2.2% SO2 in oxygen sweep gas mixture. Using pure O2 sweep gas, CA-PMP increased CO2 removal by 31% (258mL/min/m(2)) compared to PMP (197mL/min/m(2)) (P<0.05). Using 2.2% SO2 acidic sweep gas increased PMP CO2 removal by 17% (230mL/min/m(2)) compared to pure oxygen sweep gas control (P<0.05); device outlet blood pH was 7.38 units. When employing both CA-PMP and 2.2% SO2 sweep gas, CO2 removal increased by 109% (411mL/min/m(2)) (P<0.05); device outlet blood pH was 7.35 units. Dilute acidic sweep gas increases CO2 removal, and when used in combination with bioactive CA-HFMs has a synergistic effect to more than double CO2 removal while maintaining physiologic pH. Through these technologies the next generation of intravascular and paracorporeal respiratory assist devices can remove more CO2 with smaller blood contacting surface areas. Statement of significance: A clinical need exists for more efficient respiratory assist devices which utilize low blood flow rates (<500mL/min) to regulate blood CO2 in patients suffering from acute lung failure. Literature has demonstrated approaches to chemically increase hollow fiber membrane (HFM) CO2 removal efficiency by shifting equilibrium from bicarbonate to gaseous CO2, through either a bioactive carbonic anhydrase enzyme coating or bulk blood acidification with lactic acid. In this study we demonstrate a novel approach to local blood acidification using an acidified sweep gas in combination with a bioactive coating to more than double CO2 removal efficiency of HFM devices. To our knowledge, this is the first report assessing an acidic sweep gas to increase CO2 removal from blood using HFM devices.
    Acta biomaterialia 07/2015; 25. DOI:10.1016/j.actbio.2015.07.007 · 6.03 Impact Factor
  • D T Arazawa · J D Kimmel · W J Federspiel
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    ABSTRACT: Artificial lung devices comprised of hollow fiber membranes (HFMs) coated with the enzyme carbonic anhydrase (CA), accelerate removal of carbon dioxide (CO2) from blood for the treatment of acute respiratory failure. While previous work demonstrated CA coatings increase HFM CO2 removal by 115 % in phosphate buffered saline (PBS), testing in blood revealed a 36 % increase compared to unmodified HFMs. In this work, we sought to characterize the CO2 mass transport processes within these biocatalytic devices which impede CA coating efficacy and develop approaches towards improving bioactive HFM efficiency. Aminated HFMs were sequentially reacted with glutaraldehyde (GA), chitosan, GA and afterwards incubated with a CA solution, covalently linking CA to the surface. Bioactive CA-HFMs were potted in model gas exchange devices (0.0119 m(2)) and tested for esterase activity and CO2 removal under various flow rates with PBS, whole blood, and solutions containing individual blood components (plasma albumin, red blood cells or free carbonic anhydrase). Results demonstrated that increasing the immobilized enzyme activity did not significantly impact CO2 removal rate, as the diffusional resistance from the liquid boundary layer is the primary impediment to CO2 transport by both unmodified and bioactive HFMs under clinically relevant conditions. Furthermore, endogenous CA within red blood cells competes with HFM immobilized CA to increase CO2 removal. Based on our findings, we propose a bicarbonate/CO2 disequilibrium hypothesis to describe performance of CA-modified devices in both buffer and blood. Improvement in CO2 removal rates using CA-modified devices in blood may be realized by maximizing bicarbonate/CO2 disequilibrium at the fiber surface via strategies such as blood acidification and active mixing within the device.
    Journal of Materials Science Materials in Medicine 06/2015; 26(6):5525. DOI:10.1007/s10856-015-5525-0 · 2.59 Impact Factor
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    Matthew E Cove · William J Federspiel
    Critical Care 04/2015; 19(1). DOI:10.1186/s13054-015-0769-0 · 4.48 Impact Factor
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    ABSTRACT: Hemoadsorption may improve outcomes for sepsis by removing circulating cytokines. We tested a new sorbent used for hemoadsorption. CTR sorbent beads were filled into columns of three sizes: CTR0.5 (0.5 ml), CTR1 (1.0 ml) and CTR2 (2.0 ml) and tested using IL-6 capture in vitro. Next, rats were subjected to cecal ligation and puncture and randomly assigned to hemoadsorption with CTR0.5, CTR1, CTR2 or sham treatment. Plasma biomarkers were measured. In vitro, IL-6 removal was accelerated with increasing bead mass. In vivo, TNF, IL-6, IL-10, high mobility group box1, and cystatin C were significantly lower 24 h after CTR2 treatment. Seven-day survival rate was 50, 64, 63, and 73% for the sham, CTR0.5, CTR1, CTR2, respectively. CTR appeared to have a favorable effect on kidney function despite no immediate effects on cytokine removal. However, CTR2 beads did result in a late decrease of cytokines. © 2015 S. Karger AG, Basel.
    Blood Purification 04/2015; 39(1-3):239-45. DOI:10.1159/000381006 · 1.28 Impact Factor
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    ABSTRACT: Respiratory assist devices seek optimized performance in terms of gas transfer efficiency and thromboresistance to minimize device size and reduce complications associated with inadequate blood biocompatibility. Gas exchange with blood occurs at the surface of the hollow fiber membranes (HFMs) used in these devices. In this study, three zwitterionic macromolecules were attached to HFM surfaces to putatively improve thromboresistance: 1) carboxyl-functionalized zwitterionic phosphorylcholine (PC) and 2)sulfobetaine (SB) macromolecules (mPC or mSB-COOH) prepared by a simple thiol-ene radical polymerization, and 3) a low molecular weight (LMW) sulfobetaine (SB)-co-methacrylic acid (MA) block copolymer (SBMAb-COOH) prepared by reversible addition fragmentation chain transfer (RAFT) polymerization. Each macromolecule type was covalently immobilized on an aminated commercial HFM (Celg-A) by a condensation reaction and HFM surface composition changes were analyzed by X-ray photoelectron spectroscopy. Thrombotic deposition on the HFMs was investigated after contact with ovine blood in vitro. CO2 removal by the HFMs also evaluated using a model respiratory assist device. The HFMs conjugated with zwitterionic macromolecules (Celg-mPC, Celg-mSB or Celg-SBMAb) showed expected increases in phosphorus or sulfur surface content. Celg-mPC and Celg-SBMAb experienced significantly lower platelet deposition than unmodified (Celg-A, >95% reduction) and heparin coated (>88% reduction) control HFMs. Lesser reductions were seen with Celg-mSB. The CO2 removal rate for Celg-SBMAb HFMs remained comparable to Celg-A. In contrast CO2 removal for heparin coated HFMs was significantly reduced. The results demonstrate a promising approach to modify HFMs using zwitterionic macromolecules for artificial lung devices with improved thromboresistance and without degradation of gas transfer.
    Langmuir 02/2015; 31(8). DOI:10.1021/la504907m · 4.46 Impact Factor
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    ABSTRACT: The objective of this work was to conduct pre-clinical feasibility studies to determine if a highly efficient, active-mixing, adult extracorporeal carbon dioxide removal (ECCO2R) system can safely be translated to the pediatric population. The Hemolung Respiratory Assist System (RAS) was tested in vitro and in vivo to evaluate its performance for pediatric veno-venous applications. The Hemolung RAS operates at blood flows of 350-550 ml/min and utilizes an integrated pump-gas exchange cartridge with a membrane surface area of 0.59 m2 as the only component of the extracorporeal circuit. Both acute and seven-day chronic in vivo tests were conducted in healthy juvenile sheep using a veno-venous cannulation strategy adapted to the in vivo model. The Hemolung RAS was found to have gas exchange and pumping capabilities relevant to patients weighing 3-25 kg. Seven-day animal studies in juvenile sheep demonstrated that veno-venous extracorporeal support could be used safely and effectively with no significant adverse reactions related to device operation.
    The International journal of artificial organs 01/2015; 37(12):888-899. DOI:10.5301/ijao.5000372 · 0.96 Impact Factor
  • 01/2015; DOI:10.15825/1995-1191-2014-4-125-134
  • Y.Mussin · D.Bulanin · G.Jeffries · Zh.Zhumadilov · F.Olzhayev · W. Federspiel
    Nazarbayev University Research Week Book of abstracts p. 53, Astana, 24-28 November, 2014, Astana, Kazakhstan; 11/2014
  • Y.Mussin · D.Bulanin · G.Jeffries · Zh.Zhumadilov · F.Olzhayev · W. Federspiel
    Nazarbayev University Research Week Book of abstracts p. 52, Astana, 24-28 November, 2014, Astana, Kazakhstan; 11/2014
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    ABSTRACT: Introduction Prior work suggests that leukocyte trafficking is determined by local chemokine gradients between the nidus of infection and the plasma. We recently demonstrated that therapeutic apheresis can alter immune mediator concentrations in the plasma, protect against organ injury, and improve survival. Here we aimed to determine whether the removal of chemokines from the plasma by apheresis in experimental peritonitis changes chemokine gradients and subsequently enhances leukocyte localization into the infected compartment, and away from healthy tissues. Methods In total, 76 male adult Sprague–Dawley rats weighing 400 g to 600 g were included in this study. Eighteen hours after inducing sepsis by cecal ligation and puncture, we randomized these rats to apheresis or sham treatment for 4 hours. Cytokines, chemokines, and leukocyte counts from blood, peritoneal cavity, and lung were measured. In a separate experiment, we labeled neutrophils from septic donor animals and injected them into either apheresis or sham-treated animals. All numeric data with normal distributions were compared with one-way analysis of variance, and numeric data not normally distributed were compared with the Mann–Whitney U test. Results Apheresis significantly removed plasma cytokines and chemokines, increased peritoneal fluid-to-blood chemokine (C-X-C motif ligand 1, ligand 2, and C-C motif ligand 2) ratios, and decreased bronchoalveolar lavage fluid-to-blood chemokine ratios, resulting in enhanced leukocyte recruitment into the peritoneal cavity and improved bacterial clearance, but decreased recruitment into the lung. Apheresis also reduced myeloperoxidase activity and histologic injury in the lung, liver, and kidney. These Labeled donor neutrophils exhibited decreased localization in the lung when infused into apheresis-treated animals. Conclusions Our results support the concept of chemokine gradient control of leukocyte trafficking and demonstrate the efficacy of apheresis to target this mechanism and reduce leukocyte infiltration into the lung.
    Critical care (London, England) 07/2014; 18(4):R141. DOI:10.1186/cc13969 · 4.48 Impact Factor
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    ABSTRACT: Providing partial respiratory assistance by removing carbon dioxide (CO2) can improve clinical outcomes in patients suffering from acute exacerbations of chronic obstructive pulmonary disease and acute respiratory distress syndrome. An intravenous respiratory assist device with a small (25 Fr) insertion diameter eliminates the complexity and potential complications associated with external blood circuitry and can be inserted by nonspecialized surgeons. The impeller percutaneous respiratory assist catheter (IPRAC) is a highly efficient CO2 removal device for percutaneous insertion to the vena cava via the right jugular or right femoral vein that utilizes an array of impellers rotating within a hollow-fiber membrane bundle to enhance gas exchange. The objective of this study was to evaluate the effects of new impeller designs and impeller spacing on gas exchange in the IPRAC using computational fluid dynamics (CFD) and in vitro deionized water gas exchange testing. A CFD gas exchange and flow model was developed to guide a progressive impeller design process. Six impeller blade geometries were designed and tested in vitro in an IPRAC device with 2- or 10-mm axial spacing and varying numbers of blades (2–5). The maximum CO2 removal efficiency (exchange per unit surface area) achieved was 573 ± 8 mL/min/m2 (40.1 mL/min absolute). The gas exchange rate was found to be largely independent of blade design and number of blades for the impellers tested but increased significantly (5–10%) with reduced axial spacing allowing for additional shaft impellers (23 vs. 14). CFD gas exchange predictions were within 2–13% of experimental values and accurately predicted the relative improvement with impellers at 2- versus 10-mm axial spacing. The ability of CFD simulation to accurately forecast the effects of influential design parameters suggests it can be used to identify impeller traits that profoundly affect facilitated gas exchange.
    Artificial Organs 05/2014; 38(12). DOI:10.1111/aor.12308 · 2.05 Impact Factor
  • Ayan Sen · John Kellum · William Federspiel
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    ABSTRACT: Introduction: Extracorporeal carbondioxide (CO2) removal (ECCOR) may enable lung protective ventilation (LPV) in Acute Respiratory Distress Syndrome (ARDS) by further reduction in minute ventilation and preventing hypercarbia. It can also avoid intubation and mechanical ventilation in primary hypercarbic respiratory failure as in acute COPD (chronic obstructive pulmonary disease)etc. ECCOR in the form of continuous hemodialysis offers an alternative, more available strategy compared to mechanical artificial lung technologies. However, previous attempts using continuous venovenous hemodialysis (CVVHD) have been limited by metabolic acidosis (MA). Methods: An in-vitro model was designed to develop and test a dialysate solution designed to remove bicarbonate. Freshly drawn bovine blood was used. CO2 was added to it using a Minimax plus hollow fiber oxygenator (Medtronic, Anaheim CA, USA) with a sweep gas composed of N2 and CO2 to simulate hypercarbic respiratory acidosis. The hypercarbic blood was pumped at blood flow rate (220 ml/min) and passed through an M10 dialysis filter (Gambro, Lyon France)with surface area of 0.04 m-sq. A zero bicarbonate dialysate solution was constituted using Stewart's physico-chemical approach designed to control the strong ion difference rather than replacing bicarbonate. Hemolysis was tested by measuring pre and post-LDH levels. Results: Our in vitro data shows successful removal of CO2 from hypercarbic bovine blood in vitro model using a zero bicarbonate dialysate without causing metabolic acidosis. CO2 removal was highly dependent on dialysate flows. Total CO2 removal was 70-120 ml/min (30-48% of production- similar to mechanical ECCOR devices) at IHD (Intermittent Hemodialysis) flow rate and 4-8 ml/min (1-3%) at standard CVVHD flows. Dose response saturation occurred at 240 ml/kg/hr of dialysate flow (IHD flow rate). LDH levels decreased by mean of 22.5% (5.8% standard deviation) in post-filter blood indicating no obvious hemolysis. Conclusions: Zero bicarbonate dialysis solutions can help in ECCOR without causing MA and enable application of LPV by limiting hypercarbia.
    43rd Annual Critical Care Congress; 12/2013
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    Laura W Lund · William J Federspiel
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    ABSTRACT: For patients experiencing acute respiratory failure due to a severe exacerbation of chronic obstructive pulmonary disease (COPD), noninvasive positive pressure ventilation has been shown to significantly reduce mortality and hospital length of stay compared to respiratory support with invasive mechanical ventilation. Despite continued improvements in the administration of noninvasive ventilation (NIV), refractory hypercapnia and hypercapnic acidosis continue to prevent its successful use in many patients. Recent advances in extracorporeal gas exchange technology have led to the development of systems designed to be safer and simpler by focusing on the clinical benefits of partial extracorporeal carbon dioxide removal (ECCO2R), as opposed to full cardiopulmonary support. While the use of ECCO2R has been studied in the treatment of acute respiratory distress syndrome (ARDS), its use for acute hypercapnic respiratory during COPD exacerbations has not been evaluated until recently. This review will focus on literature published over the last year on the use of ECCO2R for removing extra CO2 in patients experiencing an acute exacerbation of COPD.
    09/2013; 2(3):131-138. DOI:10.1007/s13665-013-0057-x
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    J D Kimmel · D T Arazawa · S-H Ye · V Shankarraman · W R Wagner · W J Federspiel
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    ABSTRACT: Extracorporeal CO2 removal from circulating blood is a promising therapeutic modality for the treatment of acute respiratory failure. The enzyme carbonic anhydrase accelerates CO2 removal within gas exchange devices by locally catalyzing HCO3 (-) into gaseous CO2 within the blood. In this work, we covalently immobilized carbonic anhydrase on the surface of polypropylene hollow fiber membranes using glutaraldehyde activated chitosan tethering to amplify the density of reactive amine functional groups for enzyme immobilization. XPS and a colorimetric amine assay confirmed higher amine densities on the chitosan coated fiber compared to control fiber. Chitosan/CA coated fibers exhibited accelerated CO2 removal in scaled-down gas exchange devices in buffer and blood (115 % enhancement vs. control, 37 % enhancement vs. control, respectively). Carbonic anhydrase immobilized directly on hollow fiber membranes without chitosan tethering resulted in no enhancement in CO2 removal. Additionally, fibers coated with chitosan/carbonic anhydrase demonstrated reduced platelet adhesion when exposed to blood compared to control and heparin coated fibers.
    Journal of Materials Science Materials in Medicine 07/2013; 24(11). DOI:10.1007/s10856-013-5006-2 · 2.59 Impact Factor
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    ABSTRACT: Introduction: Promising preclinical results have been obtained with blood purification therapies as adjuvant treatment for sepsis. However, the mechanisms by which these therapies exert beneficial effects remain unclear. Some investigators have suggested that removal of activated leukocytes from the circulation might help ameliorate remote organ injury. We designed an extracorporeal hemoadsorption device capable of capturing both cytokines and leukocytes in order to test the hypothesis that leukocyte capture would alter circulating cytokine profiles and influence immunological cell-cell interactions in whole blood taken from patients with sepsis. Methods: We performed a series of ex vivo studies in 21 patients with septic shock and 12 healthy volunteers. Blood circulated for four hours in closed loops with four specially designed miniaturized extracorporeal blood purification devices including two different hemoadsorption devices and a hemofilter in order to characterize leukocyte capture and to assess the effects of leukocyte removal on inflammation and immune function. Results: Hemoadsorption was selective for removal of activated neutrophils and monocytes. Capture of these cells led to local release of certain cytokines, especially IL-8, and resulted in complex cell-cell interactions involved in cell-mediated immunity. Inhibition of cell adherence reversed the cytokine release and the effects on lymphocyte function. Conclusions: Monocyte and neutrophil capture using a sorbent polymer results in upregulation of IL-8 and modulation of cell-mediated immunity. Further studies are needed to understand better these cellular interactions in order to help design better blood purification therapies.
    Critical care (London, England) 03/2013; 17(2):R59. DOI:10.1186/cc12587 · 4.48 Impact Factor
  • Azadeh Alikhani · William J Federspiel
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    ABSTRACT: Anti-A/B antibody removal from blood in the peritransplantation period facilitates ABO-incompatible transplantation and significantly increases the donor pool. We have been developing an anti-A/B immunoadsorption device (BSAF), compatible with whole blood perfusion. The BSAF is based on integrated microfiltration hollow fibers with antibody capturing beads uniformly distributed within the fiber interstitial space. In this study we fabricated BSAF prototypes, appropriately scaled down from a conceptual clinical scale device. We then, for the first time, measured the time course of anti-A capture from blood samples recirculating through the scaled down BSAF devices. We observed a significant reduction in IgM (96% ± 5%, n = 5, p < 0.001), and IgG (81% ± 18%, n = 5, p < 0.05) anti-A antibody titers within 2 h. We did not observe a significant change between the initial and final values of hematocrit, total plasma protein concentration, plasma free hemoglobin concentration, and anti-B antibody titer over five experiments. In conclusion we showed that the BSAF modules selectively removed anti-A antibodies from blood in a simple one step process, without requiring a separate plasmapheresis unit. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012.
    Journal of Biomedical Materials Research Part B Applied Biomaterials 11/2012; 100(8):2114-21. DOI:10.1002/jbm.b.32776 · 2.76 Impact Factor
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    Matthew E Cove · Graeme Maclaren · William J Federspiel · John A Kellum
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    ABSTRACT: Acute respiratory distress syndrome (ARDS) has a substantial mortality rate and annually affects more than 140,000 people in the USA alone. Standard management includes lung protective ventilation but this impairs carbon dioxide clearance and may lead to right heart dysfunction or increased intracranial pressure. Extracorporeal carbon dioxide removal has the potential to optimize lung protective ventilation by uncoupling oxygenation and carbon dioxide clearance. The aim of this article is to review the carbon dioxide removal strategies that are likely to be widely available in the near future. Relevant published literature was identified using PubMed and Medline searches. Queries were performed by using the search terms ECCOR, AVCO2R, VVCO2R, respiratory dialysis, and by combining carbon dioxide removal and ARDS. The only search limitation imposed was English language. Additional articles were identified from reference lists in the studies that were reviewed. Several novel strategies to achieve carbon dioxide removal were identified, some of which are already commercially available whereas others are in advanced stages of development.
    Critical care (London, England) 09/2012; 16(5):232. DOI:10.1186/cc11356 · 4.48 Impact Factor
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    ABSTRACT: The objective of this study was to demonstrate the safety and performance of a unique extracorporeal carbon dioxide removal system (Hemolung, ALung Technologies, Pittsburgh, PA) which incorporates active mixing to improve gas exchange efficiency, reduce exposure of blood to the circuit, and provide partial respiratory support at dialysis-like settings. An animal study was conducted using eight domestic crossbred sheep, 6-18 months of age and 49-115 kg in weight. The sheep were sedated and intubated, and a 15.5-Fr dual lumen catheter was inserted into the right jugular vein. The catheter was connected to the extracorporeal circuit primed with heparinized saline, and flow immediately initiated. The animals were then awakened and encouraged to stand. The animals were supported in a stanchion and monitored around the clock. Anticoagulation was maintained with heparin to achieve an aPTT of 46-70 s. Measurements included blood flow rate through the device, carbon dioxide exchange rate, pump speed and sweep gas flow rate. Safety and biocompatibility measurements included but were not limited to plasma-free hemoglobin, hematocrit, white blood cell count, platelet count and fibrinogen. The Hemolung removed clinically significant amounts of carbon dioxide, more than 50 ml/min, at low blood flows of 350-450 ml/min, with minimal adverse effects. The results of 8-day trials in awake and standing sheep supported by the Hemolung demonstrated that this device can consistently achieve clinically relevant levels of carbon dioxide removal without failure and without significant risk of adverse reactions.
    Intensive Care Medicine 08/2012; 38(10):1705-11. DOI:10.1007/s00134-012-2651-8 · 7.21 Impact Factor
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    ABSTRACT: Unlabelled: Improper compartmentalization of the inflammatory response leads to systemic inflammation in sepsis. Hemoadsorption (HA) is an emerging approach to modulate sepsis-induced inflammation. We sought to define the effects of HA on inflammatory compartmentalization in Escherichia coli-induced fibrin peritonitis in rats. Hypothesis: HA both reprograms and recompartmentalizes inflammation in sepsis. Sprague Dawley male rats were subjected to E. coli peritonitis and, after 24 h, were randomized to HA or sham treatment (sepsis alone). Venous blood samples collected at 0, 1, 3 and 6 h (that is, 24-30 h of total experimental sepsis), and peritoneal samples collected at 0 and 6 h, were assayed for 14 cytokines along with NO(2)(-/)NO(3)(-). Bacterial counts were assessed in the peritoneal fluid at 0 and 6 h. Plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, CXCL-1, and CCL2 were significantly reduced in HA versus sham. Principal component analysis (PCA) suggested that inflammation in sham was driven by IL-6 and TNF-α, whereas HA-associated inflammation was driven primarily by TNF-α, CXCL-1, IL-10 and CCL2. Whereas -peritoneal bacterial counts, plasma aspartate transaminase levels and peritoneal IL-5, IL-6, IL-18, interferon (IFN)-γ and NO(2)(-)/NO(3)(-) were significantly lower, both CXCL-1 and CCL2 as well as the peritoneal-to-plasma ratios of TNF-α, CXCL-1 and CCL2 were significantly higher in HA versus sham, suggesting that HA-induced inflammatory recompartmentalization leads to the different inflammatory drivers discerned in part by PCA. In conclusion, this study demonstrates the utility of combined in vivo/in silico methods and suggests that HA exerts differential effects on mediator gradients between local and systemic compartments that ultimately benefit the host.
    Molecular Medicine 06/2012; 18(10). DOI:10.2119/molmed.2012.00106 · 4.51 Impact Factor
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    ABSTRACT: Current artificial lungs and respiratory assist devices designed for carbon dioxide removal (CO(2)R) are limited in their efficiency due to the relatively small partial pressure difference across gas exchange membranes. To offset this underlying diffusional challenge, bioactive hollow fiber membranes (HFMs) increase the carbon dioxide diffusional gradient through the immobilized enzyme carbonic anhydrase (CA), which converts bicarbonate to CO(2) directly at the HFM surface. In this study, we tested the impact of CA-immobilization on HFM CO(2) removal efficiency and thromboresistance in blood. Fiber surface modification with radio frequency glow discharge (RFGD) introduced hydroxyl groups, which were activated by 1M CNBr while 1.5M TEA was added drop wise over the activation time course, then incubation with a CA solution covalently linked the enzyme to the surface. The bioactive HFMs were then potted in a model gas exchange device (0.0084 m(2)) and tested in a recirculation loop with a CO(2) inlet of 50mmHg under steady blood flow. Using an esterase activity assay, CNBr chemistry with TEA resulted in 0.99U of enzyme activity, a 3.3 fold increase in immobilized CA activity compared to our previous method. These bioactive HFMs demonstrated 108 ml/min/m(2) CO(2) removal rate, marking a 36% increase compared to unmodified HFMs (p < 0.001). Thromboresistance of CA-modified HFMs was assessed in terms of adherent platelets on surfaces by using lactate dehydrogenase (LDH) assay as well as scanning electron microscopy (SEM) analysis. Results indicated HFMs with CA modification had 95% less platelet deposition compared to unmodified HFM (p < 0.01). Overall these findings revealed increased CO(2) removal can be realized through bioactive HFMs, enabling a next generation of more efficient CO(2) removal intravascular and paracorporeal respiratory assist devices.
    Journal of Membrane Science 06/2012; 404-404:25-31. DOI:10.1016/j.memsci.2012.02.006 · 5.06 Impact Factor

Publication Stats

930 Citations
297.61 Total Impact Points


  • 1996–2015
    • University of Pittsburgh
      • • Department of Medicine
      • • Bioengineering
      • • Department of Surgery
      • • McGowan Institute for Regenerative Medicine
      • • Chemical and Petroleum Engineering
      Pittsburgh, Pennsylvania, United States
    • Jichi Medical University
      Totigi, Tochigi, Japan
  • 2006
    • University of Louisville
      • Department of Surgery
      Louisville, Kentucky, United States