A New Multilayered Composite Hollow Fiber Membrane for Artificial Lung

The gas transfer performances in a gas/membrane/liquid system were investigated in detail with various membranes. It was found that the oxygen flux in the gas/membrane/liquid system was saturated when the oxygen flux (Fg-g) in the gas/membrane/gas system became more than 1.0 x 10(-5) cm3 (STP) cm-2s-1cm Hg-1 (Fcg-g). This was explained as follows: The resistance of a boundary layer at liquid phase is dominant, i.e., the membrane resistance is negligible in the region of Fg-g which is greater than Fcg-g. Consequently, Fg-g of the membrane should be designed to be greater than Fcg-g, in order to satisfy the gas transfer performance required for blood oxygenation. On the basis of the results above, we have developed a new three-layered composite hollow fiber membrane (MHF) consisting of an ultrathin polyurethane layer supported between two microporous polyethylene layers to prevent serum leakage. It was shown through the evaluation in vitro that MHF had good gas transfer performances for long-term perfusion, and no serum leakage was observed. These characteristics suggest that MHF is quite suitable for long-term usage such as extracorporeal membrane oxygenation (ECMO).     

Phenotypic Characteristics of Bone in Carbonic Anhydrase II-Deficient Mice

Carbonic anhydrase II (CAII)-deficient mice were created to study the syndrome of CAII deficiency in humans including osteopetrosis, renal tubular acidosis, and cerebral calcification. Although CAII mice have renal tubular acidosis, studies that analyzed only cortical bones found no changes characteristic of osteopetrosis. Consistent with previous studies, the tibiae of CAII-deficient mice were significantly smaller than those of wild-type (WT) mice (28.7 ± 0.9 vs. 43.6 ± 3.7 mg; p < 0.005), and the normalized cortical bone volume of CAII-deficient mice (79.3 ± 2.2%) was within 5% of that of WT mice (82.7 ± 2.3%; p < 0.05), however, metaphyseal widening of the tibial plateau was noted in CAII-deficient mice, consistent with osteopetrosis. In contrast to cortical bone, trabecular bone volume demonstrated a nearly 50% increase in CAII-deficient mice (22.9 ± 3.5% in CAII, compared to 15.3 ± 1.6% in WT; p < 0.001). In addition, histomorphometry demonstrated that bone formation rate was decreased by 68% in cortical bone (4.77 ± 1.65 μm³/μm²/day in WT vs. 2.07 ± 1.71 μm³/μm²/day in CAII mice; p < 0.05) and 55% in trabecular bone (0.617 ± 0.230 μm³/μm²/day in WT vs. 0.272 ± 0.114 μm³/μm²/day in CAII mice; p < 0.05) in CAII-deficient mice. The number of osteoclasts was significantly increased (67%) in CAII-deficient mice, while osteoblast number was not different from that in WT mice. The metaphyseal widening and changes in the trabecular bone are consistent with osteopetrosis, making the CAII-deficient mouse a valuable model of human disease.     

Development of an Intravenous Membrane Oxygenator: Enhanced Intravenous Gas Exchange Through Convective Mixing of Blood around Hollow Fiber Membranes

Abstract: In vitro testing of a new prototype intravenous membrane oxygenator (IMO) is reported. The new IMO design consists of matted hollow fiber membranes arranged around a centrally positioned tripartite balloon. Short gas flow paths and consistent, reproducible fiber geometry after insertion of the device result in an augmented oxygen flux of up to 800% with balloon activation compared with the static mode (balloon off). Operation of the new IMO device with the balloon on versus the balloon off results in a 400% increase in carbon dioxide flux. Gas flow rates of up to 9. 5 L/min through the 14–cm–long hollow fibers have been achieved with vacuum pressures of 250 mm Hg. Gas exchange efficiency for intravenous membrane oxygenators can be increased by emphasizing the following design features: short gas flow paths, consistent and reproducible fiber geometry, and most importantly, an active means of enhancing convective mixing of blood around the hollow fiber membranes     

Development of a New Hollow Fiber Silicone Membrane Oxygenator: In Vitro Study

An experimental silicone hollow fiber membrane oxygenator for long-term extracorporeal membrane oxygenation (ECMO) was developed in our laboratory using an ultrathin silicone hollow fiber. However, the marginal gas transfer performances and a high-pressure drop in some cases were demonstrated in the initial models. In order to improve performance the following features were incorporated in the most recent oxygenator model: increasing the fiber length and total surface area, decreasing the packing density, and modifying the flow distributor. The aim of this study was to evaluate the gas transfer performances and biocompatibility of this newly improved model with in vitro experiments. According to the established method in our laboratory, in vitro studies were performed using fresh bovine blood. Gas transfer performance tests were performed at a blood flow rate of 0.5 to 6 L/min and a V/Q ratio (V = gas flow rate, Q = blood flow rate) of 2 and 3. Hemolysis tests were performed at a blood flow rate of 1 and 5 L/min. Blood pressure drop was also measured. At a blood flow rate of 1 L/min and V/Q = 3, the O2 and CO2 gas transfer rates were 72.45 +/- 1.24 and 39.87 +/- 2.92 ml/min, respectively. At a blood flow rate of 2 L/min and V/Q = 3, the O2 and CO2 gas transfer rates were 128.83 +/- 1.09 and 47.49 +/- 5.11 ml/min. Clearly, these data were superior to those obtained with previous models. As for the pressure drop and hemolytic performance, remarkable improvements were also demonstrated. These data indicate that this newly improved oxygenator is superior to the previous model and may be clinically acceptable for long-term ECMO application.     

Score Model for the Evaluation of Dialysis Membrane Hemocompatibility

The interaction of blood with artificial surfaces is of particular interest during hemodialysis treatments with extracorporeal blood circuits. Components of the extracorporeal blood circuit are known to have only a moderate, sometimes even an unfavorable hemocompatibility, and thus may provoke adverse biochemical or clinical sequelae. This article describes a newly established hemocompatibility assessment score. This score is based on on a standardized series of in vitro tests and is applied to commercially available hemodialysis membranes. It relates to a variety of membrane polymers, such as regenerated cellulose, diethylaminoethyl‐modified cellulose, polyethersulfone/polyarylate blends and polysulfone. In order to compare different polymers used in the manufacturing of dialysis membranes, a set of the following hemocompatibility parameters was assessed and assembled to an overall score: generation of complement factor 5a, thrombin‐antithrombin III‐complex, release of platelet factor 4, generation and release of elastase from polymorphonuclear granulocytes, and platelet count. With respect to these parameters, the results reveal major differences between the selected dialysis membranes. This new score model proves to be an efficient tool to derive objective results, and it may, thus, be used in the future to facilitate the selection of membrane polymers with an appropriate hemocompatibility pattern for dialysis therapy.     

Carbonic Anhydrase IX in Renal Cell Carcinoma: Implications for Prognosis,Diagnosis, and Therapy

Context

The clinical management of patients with renal cell carcinoma (RCC) remains difficult, and the development of new diagnostic, prognostic, and therapeutic tools is still required.

Objective

To review the current knowledge on the RCC-associated antigen carbonic anhydrase IX (CAIX) and provide evidence for how this antigen may aid in the clinical management of RCC.

Evidence acquisition

Clinical papers describing diagnostic, prognostic, and/or therapeutic applications of CAIX in RCC were selected from the Pubmed database. The search was manually augmented by reviewing the reference lists of articles.

Evidence synthesis

Expression of CAIX is regulated by the Von Hippel Lindau (VHL) protein (pVHL). Because of the invariable VHL mutational loss in clear-cell RCC (ccRCC) patients, CAIX expression is ubiquitous in ccRCC. Determination of CAIX expression in nephrectomy specimens of RCC patients improves prognostic accuracy; high CAIX expression appears to correlate with a favourable prognosis and a greater likelihood of response to systemic treatment for metastatic disease. Therefore, CAIX expression might be used to stratify metastatic ccRCC (mRCC) patients for systemic treatment. When incorporated into the RCC nomogram, CAIX expression seems to improve diagnostic accuracy for primary RCC as well as mRCC patients, but further evidence is required. Clinical studies with the CAIX-specific monoclonal antibody (mAb) cG250 have provided unequivocal evidence that ccRCC lesions can be imaged with radiolabeled cG250. Results are awaited of a large, randomised trial that aims to establish the value of cG250 imaging for primary RCC. The outcome of another large, placebo-controlled study is awaited to establish the usefulness of CAIX-targeted therapy in the adjuvant setting. Therapeutic trials with high-dose radiolabeled cG250 and CAIX-loaded dendritic cells in mRCC patients are still in phase 1 or 2.

Conclusions

CAIX improves diagnostic accuracy and is an attractive target for imaging of and therapy for ccRCC.     

Simple Evaluation Method of Biocompatibility of Artificial Oxygenator Hollow Fiber

Abstract: We made miniature modules filled with artificial oxygenator hollow fibers and conducted a simple experiment to study the effect of different membrane structures on the blood. Three types of modules were made: one filled with polyolefin, one filled with polypropylene, and a blank module. The 3 modules were connected through 3 fine tubings to one needle so that the same blood that passed through the 3 modules could be analyzed simultaneously. Nonheparinized blood was continuously withdrawn from 6 healthy volunteers using a small pump and passed through the circuit by a single pass (10 ml/min, for 10 min). Platelet count, thrombin-anti-thrombin complex, and complement-3 were measured in the blood collected at 10 min from the outlet of each module. The results showed significantly better biocompatibility of polyolefin than polypropylene, which is attributable to the dense layer of the blood contact surface of polyolefin fibers. This method is useful in assessing biocompatibility of various hollow fibers in a simple and safe manner.     

Gas Transfer Performance of a Hollow Fiber Silicone Membrane Oxygenator: Ex Vivo Study

Based on the results of in vitro studies of many experimental models, a silicone hollow fiber membrane oxygenator for pediatric cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) was developed using an ultrathin silicone hollow fiber with a 300 microm outer diameter and a wall thickness of 50 microm. In this study, we evaluated the gas transfer performance of this oxygenator simulating pediatric CPB and ECMO conditions. Two ex vivo studies in a pediatric CPB condition for 6 h and 5 ex vivo studies in an ECMO condition for 1 week were performed with venoarterial bypass using healthy calves. At a blood flow rate of 2 L/min and V/Q = 4 (V = gas flow rate, Q = blood flow rate) (pediatric CPB condition), the O2 and CO2 gas transfer rates were maintained at 97.44 +/- 8.88 (mean +/- SD) and 43.59 +/- 15.75 ml/min/m2, respectively. At a blood flow rate of 1 L/min and V/Q = 4 (ECMO condition), the O2 and CO2 gas transfer rates were maintained at 56.15 +/- 8.49 and 42.47 +/- 9.22 ml/min/m2, respectively. These data suggest that this preclinical silicone membrane hollow fiber oxygenator may be acceptable for both pediatric CPB and long-term ECMO use.     

Experimental Approach to Visualize Flow in a Stacked Hollow Fiber Bundle of an Artificial Lung With Particle Image Velocimetry

Flow distribution is key in artificial lungs, as it directly influences gas exchange performance as well as clot forming and blood damaging potential. The current state of computational fluid dynamics (CFD) in artificial lungs can only give insight on a macroscopic level due to model simplification applied to the fiber bundle. Based on our recent work on wound fiber bundles, we applied particle image velocimetry (PIV) to the model of an artificial lung prototype intended for neonatal use to visualize flow distribution in a stacked fiber bundle configuration to (i) evaluate the feasibility of PIV for artificial lungs, (ii) validate CFD in the fiber bundle of artificial lungs, and (iii) give a suggestion how to incorporate microscopic aspects into mainly macroscopic CFD studies. To this end, we built a fully transparent model of an artificial lung prototype. To increase spatial resolution, we scaled up the model by a factor of 5.8 compared with the original size. Similitude theory was applied to ensure comparability of the flow distribution between the device of original size and the scaled‐up model. We focused our flow investigation on an area (20 × 70 × 43 mm) in a corner of the model with a Stereo‐PIV setup. PIV data was compared to CFD data of the original sized artificial lung. From experimental PIV data, we were able to show local flow acceleration and declaration in the fiber bundle and meandering flow around individual fibers, which is not possible using state‐of‐the‐art macroscopic CFD simulations. Our findings are applicable to clinically used artificial lungs with a similar stacked fiber arrangement (e.g., Novalung iLa and Maquet QUADROX‐I). With respect to some limitations, we found PIV to be a feasible experimental flow visualization technique to investigate blood‐sided flow in the stacked fiber arrangement of artificial lungs.     

Evidence for the Involvement of Carbonic Anhydrase and Urease in Calcium Carbonate Formation in the Gravity-Sensing Organ of Aplysia californica

To better understand the mechanisms that could modulate the formation of otoconia, calcium carbonate granules in the inner ear of vertebrate species, we examined statoconia formation in the gravity-sensing organ, the statocyst, of the gastropod mollusk Aplysia californica using an in vitro organ culture model. We determined the type of calcium carbonate present in the statoconia and investigated the role of carbonic anhydrase (CA) and urease in regulating statocyst pH as well as the role of protein synthesis and urease in statoconia production and homeostasis in vitro. The type of mineral present in statoconia was found to be aragonitic calcium carbonate. When the CA inhibitor, acetazolamide (AZ), was added to cultures of statocysts, the pH initially (30 min) increased and then decreased. The urease inhibitor, acetohydroxamic acid (AHA), decreased statocyst pH. Simultaneous addition of AZ and AHA caused a decrease in pH. Inhibition of urease activity also reduced total statoconia number, but had no effect on statoconia volume. Inhibition of protein synthesis reduced statoconia production and increased statoconia volume. In a previous study, inhibition of CA was shown to decrease statoconia production. Taken together, these data show that urease and CA play a role in regulating statocyst pH and the formation and maintenance of statoconia. CA produces carbonate ion for calcium carbonate formation and urease neutralizes the acid formed due to CA action, by production of ammonia. Received: 29 September 1996 / Accepted: 5 March 1997     

Evaluation of Capiox RX25 and Quadrox‐i Adult Hollow Fiber Membrane Oxygenators in a Simulated Cardiopulmonary Bypass Circuit

The Capiox RX25 and Quadrox‐i Adult oxygenators are commonly used in clinical adult cardiopulmonary bypass circuits. This study was designed to test the effectiveness of two adult oxygenators in order to evaluate gaseous microemboli (GME) trapping capability and hemodynamic performance. A simulated adult CPB circuit was used and primed with Ringer's lactate and packed red blood cells (hematocrit 25%). All trials were conducted at flow rates of 2–5 L/min (1 L/min increments) with a closed and open arterial filter purge line at 35°C. The postcannula pressure was maintained at 100 mm Hg. After a 5 cc of bolus air was introduced into the venous line, an Emboli Detection and Classification system was used to detect and classify GME at the preoxygenator, postoxygenator, and precannula sites. At the same time, real‐time pressure and flow data were recorded, and hemodynamic energy was calculated using a custom‐made data acquisition system and Labview software. Our results showed that the oxygenator pressure drops of Quadrox‐i Adult oxygenator were lower than Capiox RX25 at all flow rates. The Quadrox‐i Adult oxygenator retained more hemodynamic energy across the oxygenator. Both oxygenators could trap the majority of GME, but Capiox RX25 did better than the Quadrox‐i Adult oxygenator. No GME was delivered to the pseudo patient at all flow rates in the Capiox group. The Capiox RX25 venous reservoir could capture more GME at lower flow rates, while the Quadrox‐i Adult venous reservoir performed better at higher flow rates. An open arterial filter purge line reduced GME slightly in the Capiox group, but GME increased in the Quadrox group. The Quadrox‐i Adult oxygenator is a low‐resistance, high‐compliance oxygenator. The GME handling ability of Capiox RX25 performed well under our clinical setting. Further optimized design for the venous/cardiotomy reservoir is needed.     

Semipermeable Hollow Fiber Membranes in Hepatocyte Bioreactors: A Prerequisite for a Successful Bioartificial Liver?

Abstract: Recent studies have shown that liver support systems based on viable hepatocytes can prolong life in animal models of acute liver failure. Now the time has come to elucidate the design characteristics that are essential to construct an efficient bioreactor. The gold standard remains the intact liver. Despite the very high cell density in this organ, individual cell perfusion is guaranteed resulting in low diffusional gradients which are essential for optimal mass transfer. These conditions are not met in bioreactors based on hollow fiber membranes. Moreover, the semipermeable membranes can foul and act as a diffusional barrier between the hepatocytes and the blood or plasma of the recipient. We devised a novel bioreactor for use as a bioartificial liver that does not include hollow fiber membranes for blood or plasma perfusion. The device is based on an integral oxygenator and a nonwoven polyester matrix material for hepatocyte culture as small aggregates. The efficacy of this original design was tested in rats with liver ischemia. Preliminary results show statistically significantly improved survival; life was prolonged 100% compared to the control experiments.     

Optimal Dimensions of Capillary Membranes for Plasma Separation

The work presented in this article examines the relationship between the efficacy of the design (membrane consumption) and the design parameters for plasma separation modules. A computer simulation program for the design of hollow fiber modules was developed. It is based on a formula for filtrate flux prediction by Jaffrin. The limiting conditions set by red and white blood cell lysis are also taken into account. The results show that membrane area consumption is strictly related to the internal hollow fiber diameter. Low-efficiency devices (low infiltrate flux) can be designed nearly optimally, using 330-micron fibers. On the other hand, for high-efficiency devices, our model predicts lowest membrane consumption and, therefore, lowest costs using 220-micron fiber diameter. Furthermore, the results demonstrate that shear rates in commercially available plasma filters are too low.     

Three‐Dimensional Simulation of Mass Transfer in Artificial Kidneys

In this work, the three‐dimensional velocity and concentration fields on both the blood and dialysate sides in an artificial kidney were simulated, taking into account the effects of the flow profiles induced by the inlet and outlet geometrical structures and the interaction between the flows of blood and dialysate. First, magnetic resonance imaging experiments were performed to validate the mathematical model. Second, the effects of the flow profiles induced by the blood and dialysate inlet and outlet geometrical structures on mass transfer were theoretically investigated. Third, the clearance of toxins was compared with the clearance value calculated by a simple model that is based on the ideal flow profiles on both the blood and dialysate sides. Our results show that as the blood flow rate increases, the flow field on the blood side becomes less uniform; however, as the dialysate flow rate increases, the flow field on the dialysate side becomes more uniform. The effect of the inlet and outlet geometrical structures of the dialysate side on the velocity and concentration fields is more significant than that of the blood side. Due to the effects of the flow profiles induced by the inlet and outlet geometrical structures, the true clearance of toxins is lower than the ideal clearance, especially when the dialysate flow rate is low or the blood flow rate is high. The results from this work are significant for the structural optimization of artificial kidneys and the accurate prediction of toxin clearance.     

Surface Modification of Silicone Rubber Membrane by Plasma Induced Graft Copolymerization as Artificial Cornea

Abstract: In this study a highly biocompatible polymer membrane was prepared by surface modification. An artificial cornea was also developed for clinical applications. Silicone rubber (SR) membrane was grafted with hydrophilic monomers such as 2-hydroxyethyl methacry-late (HEMA) and acrylic acid by plasma induced grafted polymerization. Surface properties of the SR were characterized using secondary ions mass spectra, Fourier transform infrared/attenuated total reflection, and element spectra for chemical analysis. The corneal epithelial (CE) cell was cultured in vitro, and penetrating keratoplasty of albino rabbit cornea (in vivo) was performed to evaluate biological properties of modified SR membranes. The ability of the CE cell to attach onto various SR membranes was observed by inverted microscopy. The proliferation of CE cell was conducted in approximately 96 h. Experimental results indicated that the attachment and growth of CE onto SR-g-pHEMA (75 μg/ cm²) is enhanced. The morphologies of an attached CE cell are similar to those of a primary CE cell. In the in vivo study, the depth of anterior chamber was maintained 2 weeks after penetrating keratoplasty was performed with a SR grafted with pHEMA (210 μg/cm²). This phenomenon displayed a high biocompatibility of modified SR membrane with the CE cell. Furthermore, results in this study provide a valuable reference for application of the modified SR for an artificial cornea.     

Design of Hollow Fiber Modules for Uniform Shear Elution Affinity Cell Separation

Abstract: Large-scale monoclonal antibody based systems for the selection of cell subsets will play a prominent role in the development of hematotherapy and graft engineering. Hollow fiber systems for affinity cell separation rely on the generation of uniform fluid shear stress at the lumenal attachment interface. Potential mechanisms for nonuniformity of lumenal wall shear stress are fiber wall permeation fluxes driven by the pressure gradient along individual fibers and the influence of inlet header dynamic pressure on the radial distribution of axial flow within the fiber module. Dimensional analysis and numerical solution of the flow field within the lumen of a hollow fiber module illustrate the main physical criteria for design of hollow fiber modules. There will be a nearly uniform distribution of flow within the fiber bundle provided that the dynamic inlet pressure is small in comparison with the pressure drop along fibers. Fiber wall permeation fluxes will have a negligible effect on axial flow rate for nonporous membranes such as Cuprophan.     

Uniformity of the fluid flow velocities within hollow fiber membranes of blood oxygenation devices

A finite volume-based computational model was developed to investigate the uniformity of the fluid flow across the hollow fiber membranes in blood oxygenation devices. A two-dimensional annular cross section of a blood oxygenation device including about 3,300 hollow fiber membranes was used in the computation model. The equations governing the steady incompressible laminar flow in the blood oxygenation device were solved numerically and the results were compared with those obtained from the equivalent porous medium approximation. For the porous medium approximation, the Ergun equation was used for evaluating the permeability. The simulation results showed that the fluid molecules spend about six times longer in the fiber bundle region than that in its equivalent porous medium approximation model. The computational model also provides a more detailed fluid flow pattern in the membrane compartment of the blood oxygenator.     

Description of a flow optimized oxygenator with integrated pulsatile pump

Extracorporeal membrane oxygenation (ECMO) is a well-established therapy for several lung and heart diseases in the field of neonatal and pediatric medicine (e.g., acute respiratory distress syndrome, congenital heart failure, cardiomyopathy). Current ECMO systems are typically composed of an oxygenator and a separate nonpulsatile blood pump. An oxygenator with an integrated pulsatile blood pump for small infant ECMO was developed, and this novel concept was tested regarding functionality and gas exchange rate. Pulsating silicone tubes (STs) were driven by air pressure and placed inside the cylindrical fiber bundle of an oxygenator to be used as a pump module. The findings of this study confirm that pumping blood with STs is a viable option for the future. The maximum gas exchange rate for oxygen is 48mL/min/L(blood) at a medium blood flow rate of about 300mL/min. Future design steps were identified to optimize the flow field through the fiber bundle to achieve a higher gas exchange rate. First, the packing density of the hollow-fiber bundle was lower than commercial oxygenators due to the manual manufacturing. By increasing this packing density, the gas exchange rate would increase accordingly. Second, distribution plates for a more uniform blood flow can be placed at the inlet and outlet of the oxygenator. Third, the hollow-fiber membranes can be individually placed to ensure equal distances between the surrounding hollow fibers.     

Comparison of Perfusion Quality in Hollow‐Fiber Membrane Oxygenators for Neonatal Extracorporeal Life Support

Perfusion quality is an important issue in extracorporeal life support (ECLS); without adequate perfusion of the brain and other vital organs, multiorgan dysfunction and other deficits can result. The authors tested three different pediatric oxygenators (Medos Hilite 800 LT, Medtronic Minimax Plus, and Capiox Baby RX) to determine which gives the highest quality of perfusion at flow rates of 400, 600, and 800 mL/min using human blood (36°C, 40% hematocrit) under both nonpulsatile and pulsatile flow conditions. Clinically identical equipment and a pseudo‐patient were used to mimic operating conditions during neonatal ECLS. Traditionally, the postoxygenator surplus hemodynamic energy value (SHE_post, extra energy obtained through pulsatile flow) is the one relied upon to give a qualitative determination of the amount of perfusion in the patient; the authors also examined SHE retention through the membrane, as well as the contribution of SHE_post to the postoxygenator total hemodynamic energy (THE_post). At each experimental condition, pulsatile flow outperformed nonpulsatile flow for all factors contributing to perfusion quality: the SHE_post values for pulsatile flow were 4.6–7.6 times greater than for nonpulsatile flow, while the THE_post remained nearly constant for pulsatile versus nonpulsatile flow. For both pulsatile and nonpulsatile flow, the Capiox Baby RX oxygenator was found to deliver the highest quality of perfusion, while the Minimax Plus oxygenator delivered the least perfusion. It is the authors' recommendation that the Baby RX oxygenator running under pulsatile flow conditions be used for pediatric ECLS, but further studies need to be done in order to establish its effectiveness beyond the FDA‐approved time span.