Showing papers in "Artificial Organs in 2001"

Development of regenerative cardiomyocytes from mesenchymal stem cells for cardiovascular tissue engineering.

Abstract: We have isolated a cardiomyogenic (CMG) cell line from murine bone marrow stroma. Stromal cells were immortalized, treated with 5-azacytidine, and spontaneous beating cells were repeatedly screened for. The cells showed a fibroblast-like morphology. However, this morphology changed after 5-azacytidine treatment in about 30% of the cells, which connected with adjoining cells after 1 week, formed myotube-like structures and began spontaneous beating after 2 weeks, and beat synchronously after 3 weeks. These cells expressed atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Electron microscopy revealed a cardiomyocyte-like ultrastructure including typical sarcomeres and atrial granules. They had sinus node-like or ventricular cell-like action potentials. Analysis of the isoform of contractile protein genes, such as myosin and alpha-actin, indicated that their phenotype was similar to fetal ventricular cardiomyocytes. These cells expressed Nkx2.5, GATA4, TEF-1, and MEF2-C mRNA before 5-azacytidine treatment, and expressed MEF2-A and MEF2-D after treatment. This new cell line provides a powerful model for the study of cardiomyocyte transplantation.

Extensive in vivo angiogenesis following controlled release of human vascular endothelial cell growth factor: implications for tissue engineering and wound healing.

Abstract: Vascular endothelial cell growth factor (VEGF) has strong stimulating effects on vascularization. Though very potent, VEGF is rapidly degraded due to its short half-life and when administrated by uncontrolled and nonspecific methods; however, its systemic administration in large doses can cause harmful side effects. Controlled release technology would allow delivering desired levels of bioactive VEGF within extended periods and permit examination of the in vivo effects of the compound in a broader way. The objective of this study was to determine the in vitro release behavior of VEGF from calcium alginate microspheres and the potency of this controlled release system in promoting localized neovascularization at the subcutaneous site of the rat model. In vitro release of human VEGF165 (2 and 4 microg/cm3 microsphere) was studied for 3 weeks under static conditions at 25 degrees C, and daily hormone release was measured using a competitive enzyme immunoassay. Following an uncontrolled release within the first 4 days, a quite constant zero-order VEGF release of 50 to 90 and 70 to 120 ng/day was achieved from 2 and 4 microg/cm3 polymer loaded microspheres respectively. In vivo angiogenesis was studied for a period of 8 weeks and evaluated using immunoperoidase staining and histopathological measurements. In vivo studies with rats (n = 24) showed a considerable level of capillary network formation at the epigastric groin fascia of VEGF microsphere-implanted rats starting from the first week. The most extensive neovascularization was observed in the group with 3 week postimplanted 4 microg VEGF containing microspheres; this level of vascularization was quite similar after 8 weeks. While the control group showed no evidence of angiogenesis, the difference in VEGF-induced neovascularization is statistically significant (p < 0.03). Immunostaining of the specimens showed a strong relationship between the release of human VEGF and neovascularization. The controlled VEGF release system described here promotes vigorous angiogenesis and has applicability for tissue engineering and wound healing studies.

Current concepts in tissue engineering technique for repair of cartilage defect.

Abstract: Hunter's observation in 1743 that cartilage "once destroyed, is not repaired," has not essentially changed for 250 years. At present, there is no well-established procedure for the repair of cartilage defect with articular cartilage, which has the same biochemical and biomechanical properties as the surrounding normal intact cartilage. In 1994, transplantation of human autologous chondrocytes in suspension, as reported by Brittberg et al., provided a potential procedure for articular cartilage repair. We have improved their procedure and developed a new technique which creates new cartilage-like tissue by cultivating autologous chondrocytes embedded in Atelocollagen gel for 3 weeks before transplantation. These improvements maintained the chondrocyte phenotype, evenly distributed chondrocytes throughout the osteochondral defects, and decreased the risk of leakage of grafted chondrocytes into the defects. Good clinical results suggest that this technique should be a promising procedure for repairing articular cartilage defect.

Assessment of Hemolysis Related Quantities in a Microaxial Blood Pump by Computational Fluid Dynamics

Abstract: A computational assessment or even quantification of shear induced hemolysis in the predesign phase of artificial organs (e.g., cardiac assist devices) would largely decrease efforts and costs of design and development. In this article, a general approach of hemolysis analysis by means of computational fluid dynamics (CFD) is discussed. A validated computational model of a microaxial blood pump is used for detailed analysis of shear stress distribution. Several methods are presented that allow for a qualitative assessment of shear stress distribution and related exposure times using a Lagrangian approach and mass distribution in combination with shear stress analysis. The results show that CFD offers a convenient tool for the general assessment of shear-induced hemolysis. The determination of critical regions and an estimation of the amount of blood subject to potential damage in relation to the total mass flow are shown to be feasible. However, awareness of limitations and potential flaws in CFD based hemolysis assessments is crucial.

Computational fluid dynamics as a development tool for rotary blood pumps

Abstract: Computational fluid dynamics (CFD) is beginning to significantly impact the development of biomedical devices, in particular rotary cardiac assist devices. The University of Pittsburgh's McGowan Center for Artificial Organ Development has extensively used CFD as the primary tool to analyze and design a novel axial flow blood pump having a magnetically suspended rotor. The blood-contacting surfaces of the pump were developed using a design strategy based on CFD that involved closely coupling a Navier-Stokes solver to a parameterized geometry modeler and advanced mesh movement techniques. CFD-based blood damage models for shear-induced hemolysis as well as surrogate functions describing thrombosis potential were employed to help guide design improvements. This CFD-based design approach resulted in the timely development of a pump subjected to multiple geometric refinements without building expensive physical prototypes for each design iteration. A physical prototype of the final improved pump was fabricated and experimentally analyzed using particle imaging flow visualization. The CFD predicted results correlated well with the experimental data including pressure-flow (H-Q) performance and specific flow field features. It is estimated that the present CFD-based design approach shortened the overall design time frame from an order of years to months.

Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis.

Abstract: The purpose of this study was to compare the efficacy of high-dose intravenous immunoglobulin (IVIG) treatment with plasma exchange in patients suffering from moderate to severe myasthenia gravis (MG) in a stable phase. There are no controlled studies comparing IVIG with plasma exchange in patients who despite immunosuppressive treatment have persistent incapacitating MG symptoms. This was a controlled crossover study. Twelve patients with generalized moderate to severe MG on immunosuppressive treatment for at least 12 months were included. The patients were evaluated clinically using a quantified MG clinical score (QMGS) before and at follow-up visits after each treatment. One week after the treatments, the patients who received plasma exchange treatment showed a significant improvement in QMGS compared to baseline but although some improvement was seen after IVIG this did not reach statistical significance. Four weeks after both plasma exchange and IVIG treatments, there was a significant improvement in QMGS compared to baseline. One week and 4 weeks after treatment, no significant difference between the 2 treatments was found. Both treatments have a clinically significant effect 4 weeks out in patients with chronic MG, but the improvement has a more rapid onset after plasma exchange than after IVIG.

A honeycomb collagen carrier for cell culture as a tissue engineering scaffold.

Abstract: As a three-dimensional carrier for cell culture, a honeycomb structure cell scaffold was created from atelopeptide collagen Types I, II, and III. The diameter of the honeycomb pores ranged from 100 to 1,000 microm. The depth of the pores was from 10 to 3,000 mm. The scaffold was elastic and hard. Creation of various shapes was easy, and these shapes were easily maintained. Human fibroblasts, CHO-K1, BHK-21, and bovine endothelial cells were cultured with the scaffold. The growth curves of these cells were satisfactory. These results suggest that this carrier is a suitable scaffold for cell culture and will be useful as a three-dimensional tissue engineering scaffold.

Hybrid Artificial Liver Using Hepatocyte Organoid Culture

Abstract: We developed 2 types of hybrid artificial liver modules using hepatocyte organoid culture. One was a polyurethane foam (PUF)/hepatocyte spheroid packed-bed module. Hepatocytes spontaneously formed spheroids in the PUF pores, and they maintained liver-specific functions well for at least 2 weeks in vitro. As a preclinical experiment, a hybrid artificial liver with 200 g porcine hepatocytes was applied to a pig (25 kg) with liver failure and showed that the hybrid artificial liver was effective in support of liver functions and stabilization of general conditions. We established a new technique of hepatocyte organoid formation using centrifugal force. A hepatocyte organoid formed by centrifugation in hollow fibers maintained functions for more than 4 months in vitro. We developed a new sinusoid-like structure module having hollow fibers arranged by spacers in a micro-regular arrangement. Inoculated hepatocytes in the extra-fiber space of the module formed the organoid by centrifugation, and they maintained the functions for at least 1 month in vitro. The results indicated that this module seems to be promising as a hybrid artificial liver.

Recombinant human bone morphogenetic protein-2 potentiates the in vivo osteogenic ability of marrow/hydroxyapatite composites.

Abstract: A composite of marrow mesenchymal stem cells (MSCs) and porous hydroxyapatite (HA) has bone-forming capability. To promote the capability, we added recombinant human bone morphogenetic protein-2 (BMP) to the composite. The bone formation was assessed by rat subcutaneous implantation of 4 different kinds of implants, i.e., HA alone, BMP/HA composites, MSCs/HA composites, and the composites containing BMP (MSCs/BMP/HA). Both HA and the BMP/HA composites did not show bone formation at any time after implantation. The MSCs/HA composites showed moderate bone formation at 4 weeks and extensive bone formation at 8 weeks. The MSCs/BMP/HA composites showed obvious bone formation together with active osteoblasts at 2 weeks and more bone formation at 4 and 8 weeks. The MSCs/BMP/HA composites demonstrated high alkaline phosphatase and osteocalcin expression at both the protein and gene levels. These results indicate that the combination of MSCs, porous HA, and BMP synergistically enhances osteogenic potential and provides a rational basis for their clinical application in bone reconstruction surgery.

Tissue-engineered product: allogeneic cultured dermal substitute composed of spongy collagen with fibroblasts.

Abstract: Recently, various types of allogeneic skin substitutes including cultured epidermal substitute (CES), cultured dermal substitute (CDS), and cultured skin substitute (CSS), which are composed of keratinocytes and/or fibroblasts as the cellular component(s), have been used as biological wound dressings. In our study, the allogeneic CDS was prepared by plating fibroblasts on a spongy collagen. The clinical evaluation was conducted using fresh or cryopreserved allogeneic CDS. In 145 of our clinical cases, 95% (138/145) of various wounds were evaluated as achieving good or excellent results, including 96% (22/23) of deep dermal burns (DDB) and dermal burns (DB), 100% (53/53) of partial-thickness donor wounds, 91% (21/23) of traumatic skin defects, 100% (5/5) of pressure ulcers, 82% (9/11) of chronic skin ulcers, 100% (6/6) of coverage for debrided DB, and 92% (22/24) of coverage for autologous meshed graft. The results obtained in our study suggest that the allogeneic CDS is able to provide an effective therapy for patients with partial and/or full-thickness skin defects.

The Heartmate III: design and in vivo studies of a maglev centrifugal left ventricular assist device.

Abstract: A compact implantable centrifugal left ventricular assist device (LVAD) (HeartMate III) featuring a magnetically levitated impeller is under development. The goal of our ongoing work is to demonstrate feasibility, low hemolysis, and low thrombogenicity of the titanium pump in chronic bovine in vivo studies. The LVAD is based on so-called bearingless motor technology and combines pump rotor, drive, and magnetic bearing functions in a single unit. The impeller is rotated (theta z) and levitated with both active (X, Y) and passive (Z, theta x, theta y) suspension. Six prototype systems have been built featuring an implantable titanium pump (69 mm diameter, 30 mm height) with textured blood contacting surfaces and extracorporeal electronics. The pumps were implanted in 9 calves (< or = 100 kg at implant) that were anticoagulated with Coumadin (2.5 < or = INR < or = 4.0) throughout the studies. Six studies were electively terminated (at 27-61 days), 1 study was terminated after the development of severe pneumonia and lung atelectasis (at 27 days) another study was terminated after cardiac arrest (at 2 days) while a final study is ongoing (at approximately 100 days). Mean pump flows ranged from 2 to 7 L/min, except for brief periods of exercise at 6 to 9 L/min. Plasma free hemoglobin ranged from 4 to 10 mg/dl. All measured biochemical indicators of end organ function remained within normal range. The pumps have met performance requirements in all 9 implants with acceptable hemolysis and no mechanical failures.

Oxygen transfer in a convection-enhanced hollow fiber bioartificial liver.

Abstract: A mathematical model was developed to predict oxygen transport in a hollow fiber bioartificial liver device. The model parameters were taken from the HepatAssist 2000 device, a plasma perfused hollow fiber cartridge with primary hepatocytes seeded in the extracapillary space. Cellular oxygen uptake was based on Michaelis-Menten kinetics. Oxygen transport due to the convective flow of plasma into the extracapillary space was considered. The effect of modulating several important parameters was investigated, namely, the Michaelis-Menten constant Vm (the maximum oxygen consumption per unit volume of the cell mass), the oxygen partial pressure, the flow rate of the plasma at device inlet, and the permeability of the cell mass contained in the extracapillary space. A computer implementation of the model was used to assess whether a given number of cells could be maintained within such a device. The results suggest that a substantial proportion of the hepatocytes are exposed to hypoxic conditions under which metabolism may be impaired.

The Heartmate II: design and development of a fully sealed axial flow left ventricular assist system.

Abstract: Our group is developing the control and power transmission components required to implement a permanent and fully sealed left ventricular assist system (LVAS). Starting with the percutaneously powered HeartMate II blood pump, our development efforts are focused in the following areas: a complete redesign of the transcutaneous energy transmission system (TETS) to include a rectification network and autonomous voltage regulation within the secondary coil, a hermetically sealed electronics package containing a miniaturized implementation of the existing redundant drive and control electronics with several power-input options, an implanted rechargeable lithium ion battery pack capable of providing up to 1 h of untethered operation, implantable electrical connectors that allow components to be connected after placement in the body or to be replaced if needed, and a radio telemetry subsystem to transmit diagnostic information and to permit remote adjustment of selected parameters.

Growth of endothelial cells on different concentrations of Gly-Arg-Gly-Asp photochemically grafted in polyethylene glycol modified polyurethane.

Abstract: To improve endothelial cell adhesion and growth on the surface of polyethylene glycol modified polyurethane (PU-PEG), cell adhesive peptide Gly-Arg-Gly-Asp (GRGD) was photochemically grafted to the surface. The surface grafted GRGD-N-Succinimidyl-6-[4′-azido-2′-nitrophenylamino]hexanoate (SANPAH) on a PU-PEG surface was performed by adsorption and subsequent ultraviolet irradiation. Fourier transform infrared spectra (FTIR) and electron spectroscopy for chemical analysis (ESCA) confirmed the GRGD grafted to form a PU-PEG-GRGD surface. The composition fraction of nitrogen calculated from ESCA analysis for the PU-PEG-GRGD surface was well correlated with the concentration of GRGD to be immobilized. Human umbilical vein endothelial cells (ECs) were well adhered and growing on the PU-PEG-GRGD surface. Moreover, the viability of ECs growing on PU-PEG-GRGD surfaces, analyzed by MTT test, was also well correlated with the GRGD concentrations immobilized on the surface. With photochemical techniques, we could manipulate different contents of GRGD to form multiple regions of PU-PEG-GRGD surface that could enhance the growth of ECs on the surface, and the enhancement efficiency was well correlated with GRGD contents.

Recent progress on transcutaneous energy transfer for total artificial heart systems.

Abstract: For many years, transcutaneous energy transfer (TET) systems have been developed for energizing total artificial heart systems. Although such a basic system can be developed without too much design effort, optimization toward high power transfer efficiency forces the introduction of novel system topologies and design strategies. In addition, for medical applications, the thermal impact of a TET system on the biological tissue should be taken into account, resulting in limitations on usable coil geometries. This article presents a TET system that has been developed for a power transfer of 25 W over a distance of 1 cm with minimal dimensions of 1 × 6 × 4 cm for the external driver and 5 × 3 × 1 cm for the internal electronics. The coil geometries have a thickness of 2 mm and a diameter of 6 cm. An overall system efficiency of 80% was achieved for an internal load of 25 W.

Replacing cardiopulmonary bypass with extracorporeal membrane oxygenation in lung transplantation operations.

Abstract: Cardiopulmonary bypass (CPB) is required in some lung transplantation (LTx) operations. However, it increases risks of bleeding and early graft dysfunction. We report our experiences of replacing CPB with heparin-bound extracorporeal membrane oxygenation (ECMO) in LTx operations. If extracorporeal circulation was anticipated for the LTx operations, ECMO support was set up through the femoral venoarterial route after induction of anesthesia; then, LTx was done as usual. Five thousand units of heparin was injected intravenously during the femoral vessels cannulation, but no more was used during the first 24 h of ECMO support. If necessary, as in patients undergoing single LTx for end-stage pulmonary hypertension, the ECMO support was directly extended into the postoperative period until reperfusion edema of the graft lung subsided. Twelve single LTxs and 3 bilateral sequential single LTxs were done under ECMO support. The advantages of using femoral ECMO rather than conventional CPB in LTx operations were the operative field was not disturbed by the bypass cannula, stable cardiopulmonary function and normothermia were maintained throughout the operations, there were less blood loss and transfusion requirements, and the left LTx was as easily performed as the right LTx. Red blood cell transfusion requirements during the operation and the first postoperative day were 4.4 +/- 2.8 and 2.4 +/- 2.0 U, respectively, in 10 adult patients undergoing uncomplicated single LTx with ECMO support, and 4.3 +/- 1.3 and 1.5 +/- 1.5 U in 8 adult patients undergoing single LTx without any extracorporeal circulatory support. The difference was not significant between the 2 groups (p = 0.53 and 0.32 by Mann-Whitney U test). The ECMO did not increase blood transfusion requirements. In comparison, 13 U of red blood cell transfusion was required in 2 patients receiving single LTx under CPB support. The ECMO support made the postoperative critical care easier in recipients with graft lung edema. Except for 2 cases of primary graft failure, the ECMO could be weaned off and removed at bedside within a short period (27.9 +/- 24.6 h, n = 13) with no major complications. In conclusion, the heparin-bound femoral ECMO rather than CPB should be used for LTx operations unless concomitant cardiac repair is planned.

Long-term expression of highly differentiated functions by isolated porcine hepatocytes perfused in a radial-flow bioreactor.

Abstract: To overcome the limitations of standard hollow-fiber module in ensuring efficient cell perfusion and long-term expression of highly differentiated hepatocyte functions, we developed a novel bioreactor in which a three-dimensional hepatocyte culture system was perfused in radial-flow geometry. Isolated porcine hepatocytes were cultured for 2 weeks in recirculating serum-free tissue culture medium, in which NH4Cl and lidocaine were repeatedly added, and ammonia removal, urea synthesis, monoethylglycinexylide (MEGX) production, albumin secretion, Po2, Pco2, O2 consumption, and pH were measured thereafter. During the whole duration of the study, ammonia removal was paralleled by urea production, while MEGX concentration was constantly increased. Our results indicated that hepatocytes remained differentiated and metabolically active throughout the duration of the study. The radial-flow bioreactor allowed physiological contact between recirculating fluid and cells by equalizing the concentration of the perfusing components, including O2, throughout the module, suggesting a potential use of this configuration for extracorporeal liver support.

An evaluation of a polyethersulfone hollow fiber plasma separator by animal experiment.

Abstract: Membrane plasma separators are being used routinely for therapy in various diseases. In this study, a newly developed plasma separator made of polyethersulfone (PES) hollow fibers was evaluated for its plasma filtration efficiency and blood compatibility by animal experiment. Hemolysis did not occur under the usual conditions of plasma separation. The sieving coefficients of total protein and albumin were over 95%, and the total cholesterol was over 90% throughout the perfusions. Decreases in white blood cells, platelets, fibrinogen, and coagulation factors were observed during the early stage of plasma separation, but appear to be within acceptable ranges for clinical use.

Initial stability of a cementless acetabular cup design: experimental investigation on the effect of adding fins to the rim of the cup.

Abstract: Different design solutions have been suggested for improvement of the initial stability of cementless acetabular cups, such as adding threads, spikes, or pegs to the hemispherical geometry, the pore structure of the surface; and screw fixation. This experimental study investigated the effect of fins on the initial stability of the acetabular cup. Three designs were studied, with none, 2, and 12 fins, respectively. The cups were press fit into cavities reamed in 2 different polyurethane foams, used to simulate 2 qualities of cancellous bone. Two millimeter press-fit and exact-fit conditions were investigated. The results show that the type of substrate and the interference value are important in determining the initial stability of the cup. The addition of fins on the cup rim enhances in vitro the initial stability, especially in cases of a poor press fit with a good substrate. This preclinical investigation suggests that the use of a cup design with fins may be beneficial in all cases in which press fit of the cup cannot be assured. However, further clinical studies are required to validate in vivo the efficacy of the fins as additional fixation devices.

A hybrid compliant vascular graft seeded with microvascular endothelial cells extracted from human omentum.

Abstract: We report the development of a hybrid vascular graft using an innovative compliant poly(carbonate-urea)urethane unlike any previous polyurethane MyoLink as a permanent scaffold. The engineered graft has a hierarchical arterial structure: a monolayer of oriented microvascular endothelial cells (MVECs) and 3-D matrix (human collagen Type 4/dermatan sulfate) bonded onto MyoLink. The grafts' clinical feasibility was evaluated by determining optimal MVEC seeding density, incubation time, viability, and adhesion of these cells when exposed to arterial shear stress. MVECs from human omentum were isolated by a new centrifugation protocol, radiolabeled and seeded onto hybrid graft 2 to 18 x 105 cells/cm(2) for 24 h at 37 degrees C and for 1 to 5 h at 6 x 105 cells/cm(2), washed 3 times, and gamma counted. Qualitative assessment of seeding density/incubation was also undertaken with scanning electron microscopy (SEM) and viability tested with a modified Alamar Blue assay. A pulsatile flow phantom was used to subject the hybrid graft (200 mm length, 5 mm internal diameter) seeded with radiolabeled MVECs (6 x 105 cells/cm(2) at 2 h) to arterial shear and dynamic scintigraphy images acquired in real time using a nuclear medicine gamma camera system during 14 h of perfusion (n = 6). The optimal seeding density was 6 x 105 cells/cm(2), and qualitative SEM confirmed this. Incubating cells for 2 h produced significantly greater cell attachment than was seen for 1 h incubation (p < 0.05), and there was no significant difference in adhesion between cells incubated over the 2 h. Exposure of grafts to acute shear stress resulted in significantly higher proportions of initial cells attached to hybrid grafts compared to native MyoLink grafts (67 +/- 3% versus 55 +/- 2%, p < 0.001). As shown here, tissue engineering of native Myolink grafts significantly reduces the seeding density and incubation time to produce a monolayer onto which cells adhere to better.

An Ultradurable and Compact Rotary Blood Pump with a Magnetically Suspended Impeller in the Radial Direction

Abstract: A magnetically suspended centrifugal blood pump has been developed with a self-bearing motor for long-term ventricular assist systems. The rotor of the self-bearing motor is not only actively suspended in the radial direction, but also is rotated by an electromagnetic field. The pump has a long lifetime because there are no mechanical parts such as seals and motor bearings. An outer rotor mechanism was adopted for the self-bearing motor. The stator was constructed in the central space of the motor. The rotor shaped thin ring was set at the circumferential space of the stator. Six vanes were extended from the upper surface of the rotor toward the center of the pump to construct an open-type impeller. The outer diameter and the height of the impeller are 63 mm and 34 mm, respectively. The magnetic bearing method and the servomotor mechanism were adopted to levitate and rotate the rotor. Radial movements of the rotor and rotation are controlled actively by using electromagnets in the stator. Axial movement and tilt of the rotor are restricted by passive stability to simplify the control. The radial gap between the rotor and the stator is 1 mm. A closed-loop circuit filled with water was used to examine basic performance of the pump. Maximum flow rate and pressure head were 8 L/min and 200 mm Hg, respectively. Maximum amplitude of radial displacement of the impeller was 0.15 mm. The impeller could be suspended completely without touching the casing wall during the entire pumping process. Power consumption of the pump was only 9.5 W to produce a flow rate of 5 L/min against a pressure head of 100 mm Hg. We conclude that the pump has sufficient performance for the implantable ventricular assist system.

Control Strategy for Rotary Blood Pumps

Abstract: The control strategy for ventricular support with a centrifugal blood pump was examined in this study. The control parameter was the pump rpm that determines pump flow. Optimum control of pump rpm that reflects the body's demand is important for long-term, effective, and safe circulatory support. Moreover, continuous, reliable monitoring of ventricular function will help successfully wean the patients from the ventricular assist device (VAD). The control strategy in this study includes determination of the target pump rpm that can provide the flow required by the body, fine-rpm-tuning to minimize deleterious effects such as suction in the ventricle, and assessment of ventricular function for successful weaning from VADs. To determine the target pump rpm, we proposed to use the relation between the native heart rate and cardiac output, and the relation between the pump rpm and centrifugal pump output. For fine-tuning of the pump rpm, the motor current waveform was used. We computed the power spectral density of the motor current waveform and calculated the ratio of the fundamental to the higher order components. When this ratio was larger than approximately 0.2, we assumed there would be a suction effect in the ventricle. As for assessment of ventricular function, we used the amplitude of the motor current waveform. The control system implemented using a DSP functioned properly in the mock circulatory loop as well as in acute animal experiments. The motor current also showed a good correlation with the ventricular pressure in acute animal experiments.

HeartMate left ventricular assist devices: a multigeneration of implanted blood pumps.

Abstract: The HeartMate family of implanted left ventricular assist devices (LVADs) developed by Thermo Cardiosystems, Inc. (TCI) span a time frame that goes back to the beginning of clinical use of mechanical circulatory support and will stretch well into the foreseeable future. Associated blood pump technology employed in the HeartMates range from an original pusher plate concept to the most advanced rotary pump devices. Starting initially with a pneumatic actuated pusher plate pump, clinical use of the HeartMate I began in 1986. In 1990, electric motor-actuated versions of the HeartMate I began to be used clinically. Presently, the HeartMate I has been implanted in some 2,300 patients worldwide, and this LVAD is a standard by which all others are currently measured. Following the HeartMate I is TCI's next-generation, the HeartMate II, a rotary-pump-based LVAD that uses an axial flow blood pump having blood immersed mechanical bearings. Clinical trials of the HeartMate II were initiated in 2000. The HeartMate III, representing TCI's next-generation LVAD, is structured around a centrifugal blood pump that uses a magnetically levitated rotating assembly. Compared to the HeartMate II, the HeartMate III has the potential for higher overall efficiency. The pump's operating life is not dependent on bearing wear. Given the significantly advanced LVAD technology represented by HeartMates II and III, coupled with the experience of HeartMate I, TCI is well-poised to keep its LVAD products as industry standards in the future.

From a lab type to a product: a retrospective view on Impella's assist technology.

Abstract: A lab type is best described by its value as a result of its handcrafted uniqueness in small numbers. Logically, there is not one lab type like another, and the fact that it has been realized does not mean that this special effort can be easily reproduced. Furthermore, most lab types have undergone stand alone test runs revealing fingerprints rather than universal results at a 20% effort to 80% effect ratio. A product development, on the other hand, is best described by an 80% effort to 20% effect ratio in terms of measurable results. Products are producible and cost effective goods which are well documented and have undergone numerous test runs and test procedures assuring safety and quality, a basic requirement for market approval and cost effective marking. Based on the intravascular pump technology, comprising a sensorized axial flow pump with an integrated micromotor, the iterative dependence of the product development on lab types is demonstrated showing in particular the importance of having highly developed lab types before initiating the product development. By example, we demonstrated that high product quality has a greater impact on the reduction of blood damage than numerous redesigns. Reengineering issues are addressed, which are part of the product development process. Furthermore, the previously mentioned technology serves as a platform leading directly from the perioperative biventricular system to a 7 day pump as well as a miniaturized 12 Fr version.

Development Status of Terumo Implantable Left Ventricular Assist System

Abstract: We have been developing an implantable left ventricular assist system (T-ILVAS) featuring a magnetically suspended centrifugal pump (MSCP) since 1995. In vitro and in vivo studies using a prototype MSCP composed of a polycarbonate housing and impeller (196 ml) have demonstrated long-term durability and excellent blood compatibility for up to 864 days, and excellent stability of the magnetic bearing of the MSCP. These preliminary results strongly suggested that the magnetic bearing of the MSCP is reliable and is a most feasible mechanism for a long-term circulatory assist device. We have recently devised a clinical version pump made of titanium (180 ml) with a new position sensor mechanism and a wearable controller with batteries. Cadaver fit study confirmed that the Type IV pump could be implanted in a small patient with a body surface area as small as 1.3. The in vitro performance tests of the Type IV pump demonstrated excellent hydrodynamic performances with an acceptable hemolysis rate. New position sensors for the titanium housing showed more uniform sensor outputs of a magnetic bearing than in the prototype polycarbonate pump. The Type IV pump then was evaluated in vivo in 6 sheep at the Oxford Heart Centre. Four sheep were electively sacrificed at 3 months and were allowed to survive for more than 6 months for long-term evaluation. In this particular series of experiments, no anticoagulant/antiplatelet regimen was utilized except for a bolus dose of heparin during surgery. There was a left ventricular mural thrombi around the inflow cannula in 1 sheep. Otherwise, there was no mechanical failure nor sign of thromboembolism throughout the study.

Tissue Engineering Research in Oral Implant Surgery

Abstract: In this article, we introduce some of the more extensively evaluated technologies using concepts of tissue engineering. We report on hard tissue engineering and soft tissue engineering and their utility for dental implant therapy. For hard tissue engineering, we evaluated human recombinant bone morphogenetic protein-2 and marrow mesenchymal stem cells using a model of sinus augmentation procedure in rabbit. We also describe distraction osteogenesis as another category for hard tissue engineering. In addition, we evaluate soft tissue management using cultured epithelial grafting for soft tissue engineering. The results of our tissue regeneration materials and methods in this study are positive. When the tissue engineering materials are used in clinics in the future, implant surgery could be the leading field.

First experiences with outpatient care of patients with implanted axial flow pumps.

Abstract: As known from patients with pulsatile ventricular assist devices (VADs), early mobilization, physical exercise, and return to normal life are essential for optimal recovery. Recently, implantable rotary pumps became available for extended left ventricular support as bridges to transplantation. Modified procedures are essential for patient training and hospital discharge. The MicroMed-DeBakey VAD was implanted in 10 patients with end-stage heart disease. After recovery, regular ergometer training was performed with loads adapted to the patient's condition. Procedures for patient observation under outdoor conditions and a blood pressure measuring device for low pulse pressure conditions were developed. Improvement of physical condition was achieved in 8 patients. In the first 2 patients, exercise capacity was limited due to flow obstruction. In the following patients, an increase of workload on the ergometer up to 120 W was observed. Correlated with training, lactate/load relationship and heart rate decreased. Three patients were discharged from the hospital during support. The DeBakey-VAD system can support patients for extended time periods and is suitable for recovery and exercise. Under optimal patient and environmental conditions, discharge from the hospital can be obtained.

Liver Stem Cells: A Potential Source of Hepatocytes for the Treatment of Human Liver Disease

Abstract: Severe liver injury often leads to the proliferation of oval cells, which differentiate along hepatocytic and biliary lineages. Because oval cells proliferate only when hepatocyte replication is impaired, they are considered to be the progeny of facultative liver stem cells (FLSCs). Identification and isolation of FLSCs has been hampered by the lack of markers that delineate these bipotential progenitors. We hypothesized that transition ductal cells are FLSCs because they are located in a unique anatomical niche sharing tight junctions with a neighboring hepatocyte and another terminal ductular cell. Alternatively, it has been proposed recently that bone marrow-derived stem cells are FLSCs since these cells differentiate along the hepatic lineage following colonization of the liver. The intent of this review is to provide insight into the nature and origin of liver stem cells and to explore the possibility that stem cell technology may lead to the development of clinical modalities for the treatment of human liver disease.

Development of the MEDOS/HIA DeltaStream extracorporeal rotary blood pump.

Abstract: The DeltaStream blood pump has been developed for extracorporeal circulation with one focus on potential integration into simplified bypass systems (SBS). Its small size and an embedded electric motor are the basic pump properties. A variation of the impeller design has been performed to optimize hydraulic and hematologic characteristics. A simple impeller design was developed which allows flow and pressure generation for cardiopulmonary bypass applications. The option of a pulsatile flow mode for ventricular assist device applications also was demonstrated in vitro. Impeller washout holes were implemented to improve nonthrombogenicity. The pump was investigated for potential thermal hazards for blood caused by the integrated electric motor. It could be demonstrated that there is no thermal risk associated with this design. Durability tests were performed to assess the lifetime of the pump especially with regard to the incorporated polymeric seal. Seal lifetimes of up to 28 days were achieved using different blood substitutes. In animal tests using either the pump as a single device or in an SBS setup, biocompatibility, low hemolysis, and nonthrombogenicity were demonstrated. In summary, the DeltaStream pump shows great potential for different extracorporeal perfusion applications. Besides heart-lung machine and SBS applications, ventricular assist and extracorporeal membrane oxygenation up to several days also appear promising as potential applications.

Low-flux versus high-flux synthetic dialysis membrane in acute renal failure: prospective randomized study.

Abstract: The influence of dialyzer membrane on the morbidity and mortality of patients with acute renal failure remains a matter of debate. The aim of the prospective randomized clinical study was to assess the influence of the flux of a synthetic dialyzer membrane on patients' survival rate, restitution of renal function, and duration of hemodialysis treatment of patients with acute renal failure as a part of multiorgan failure. Seventy-two patients treated in intensive care units of the University Medical Center Ljubljana were randomized according to the dialyzer used throughout the duration of hemodialysis treatment. There were 38 patients in the low-flux group (dialyzer F6, low-flux polysuphone, Fresenius, Bad Homburg, Germany) and 34 patients in the high-flux group (dialyzer Filtral 12, sulphonated high-flux polyacrylonitrile, Hospal, Industrie Meyzieu, France). Both groups were balanced in terms of sex, age, APACHE II score, oliguria before dialysis, cause of acute renal failure, inotropic support, mechanical ventilation, and the number of failing organs. The patients' survival rate was 18.7% in the low-flux group and 20.6% in the high-flux group. Ten patients (26.3%) recovered their renal function in the low-flux group and 8 (23.5%) in the high-flux group. Hemodialysis treatment lasted 11.2 days in the low-flux and 10.7 days in the high-flux group. An analysis of subgroups with a lower mortality rate (subgroup of patients without oliguria and subgroup of patients with less than 4 failed organ systems) did not show significant differences between the low-flux and high-flux groups in terms of survival rate, recovery of renal function, and duration of hemodialysis treatment. In conclusion, no significant differences were found in the results of low-flux versus high-flux synthetic membrane dialyzer treatment in patients with acute renal failure as a part of multiorgan failure in terms of survival rate, recovery of renal function, incidence of oliguria during hemodialysis, and duration of hemodialysis treatment. The number of failing organs seems to be the most important single factor determining the survival of patients with acute renal failure as a part of multiorgan failure.