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Biomedical subjects

D B Olsen

Publications and source records attributed to D B Olsen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Test controller design, implementation, and performance for a magnetic suspension continuous flow ventricular assist device.

A new continuous flow ventricular assist device using full magnetic suspension has been designed, constructed, and tested. The magnetic suspension centers the centrifugal pump impeller within the clearance passages in the pump, thus avoiding any form of contact. The noncontact operation is designed to give very high expected mechanical reliability, large clearances, low hemolysis, and a relatively small size compared to current pulsatile devices. A unique configuration of magnetic actuators on the inlet side and exit sides of the impeller provides full 5 axis control and suspension of the impeller. The bearing system is divided into segments which allow for 3 displacement axes and 2 angular control axes. The controller chosen for the first suspension tests consists of a decentralized set of 5 proportional integral derivative (PID) controllers. This document describes both the controller and an overview of some results pertaining to the magnetic bearing performance. The pump has been successfully operated in both water and blood under design conditions suitable for use as a ventricular assist device.

Equipment Design↗
PubMed1999

Characterization of a magnetic bearing system and fluid properties for a continuous flow ventricular assist device.

This article presents the performance test results of the CFVAD3 continuous flow blood pump in an artificial human circulation system. The CFVAD3 utilizes magnetic bearings that support a thin pancake impeller, the shape of which allows for a very compact pump whose total axial length is less than 5 cm with a radial length of about 10 cm. This gives a total volume of about 275 cc. The impeller itself has 4 vanes with a designed operating point of 6 L/min at 100 mm Hg of differential pressure and 2,000 rpm. The advantages of magnetic bearings, such as large clearance spaces and no mechanical wear, are elaborated upon. Furthermore, bearing model parameters such as load capacity and current gains are described. These parameters in conjunction with the operating conditions during testing are then used to estimate the fluid forces, stiffness, and damping properties while pumping. Knowledge of these parameters is desirable because of their effects on pump behavior. In addition, a better plant model will allow more robust control algorithms to be devised that can boost pump performance and reliability.

Equipment Design↗
PubMed1998

Rapid X-ray diffraction analysis of HIV-1 protease-inhibitor complexes: inhibitor exchange in single crystals of the bound enzyme.

The ability to replace an inhibitor bound to the HIV-1 protease in single crystals with other potent inhibitors offers the possibility of investigating a series of protease inhibitors rapidly and conveniently with the use of X-ray crystallography. This approach affords a fast turnaround of structural information for iterative rational drug designs and obviates the need for studying the complex structures by co-crystallization. The replacement approach has been successfully used with single crystals of the HIV-1 protease complexed with a weak inhibitor. The structures of the complexes obtained by the replacement method are similar to those determined by co-crystallization.

Binding Sites↗
PubMed1997

Development of a microcontroller-based automatic control system for the electrohydraulic total artificial heart.

An automatic physiological control system for the actively filled, alternately pumped ventricles of the volumetrically coupled, electrohydraulic total artificial heart (EHTAH) was developed for long-term use. The automatic control system must ensure that the device: 1) maintains a physiological response of cardiac output, 2) compensates for an nonphysiological condition, and 3) is stable, reliable, and operates at a high power efficiency. The developed automatic control system met these requirements both in vitro, in week-long continuous mock circulation tests, and in vivo, in acute open-chested animals (calves). Satisfactory results were also obtained in a series of chronic animal experiments, including 21 days of continuous operation of the fully automatic control mode, and 138 days of operation in a manual mode, in a 159-day calf implant.

Algorithms↗
PubMed1997

The importance of pulsatile and nonpulsatile flow in the design of blood pumps.

The traditional approach of total artificial heart (TAH) and ventricular assist device (VAD) development has been the mimicking of the native heart. Nonpulsatile flow using cardiopulmonary bypass has provided evidence of short-term physiologic tolerances. The design of nonpulsatile TAHs and VADs has eliminated the need for valves, flexing diaphragms, and large ventricular volumes. However, these devices require high efficiency power sources and reliable bearing seals or electromagnetic bearings while simultaneously attempting to avoid thromboemboli. The physiologic response to nonpulsatile flow is complex and variable. When compared to a pulsatile device, a nonpulsatile TAH or VAD needs to produce increased flow and higher mean intravascular pressures to maintain normal organ function. Despite its maintaining normal organ function, nonpulsatile flow does cause alterations in biochemical functions and organ specific blood flow. The combination of bioengineering superiority and the maintenance of physiologic homeostasis has directed future TAH and VAD research towards nonpulsatile systems.

Cardiopulmonary Bypass↗
PubMed1997

In vitro investigation of the St. Jude Medical Isoflow centrifugal pump: flow visualization and hemolysis studies.

Centrifugal blood pumps have become valuable therapeutic tools for cardiopulmonary bypass surgery. In addition, surgeons have used them as temporary ventricular assist devices, and this type of pump is also being developed for use as a permanent assist device and total artificial heart. However, centrifugal pumps create flow patterns that are significantly different from those the blood experiences physiologically. The St. Jude Medical Isoflow centrifugal pump has been used clinically during cardiopulmonary bypass surgery, yet no experimental results have been reported that describe the flow patterns within this pump or that quantify the hemolysis generated over a range of operating conditions. The purpose of this study was to investigate the flow patterns and hemolysis during 4 operating conditions. The experimental operating conditions included the design condition (6 L/min, 2,500 rpm, 350 mm Hg), a high flow condition (10 L/min, 2,500 rpm, 330 mm Hg), a low flow condition (2 L/min, 2,500 rpm, 370 mm Hg), and a near surge condition (2 L/min, 3,000 rpm, 550 mm Hg). The flow visualization results demonstrated that the flow within the impeller was well aligned with the impeller blades except near the inlet at the high flow condition. In contrast, the flow through the outlet was well aligned at the high flow condition while there was evidence of particle impact at the design condition, and the flow was disturbed at the low flow and near surge conditions. The indices of hemolysis (IH) for the 3 operating conditions at 2,500 rpm were 0.0082 +/- 0.0026 (mean +/- SD) for the design condition, 0.0035 +/- 0.0014 for the high flow condition, and 0.0326 +/- 0.0050 for the low flow condition. The indices for high and low flow were significantly different from that for the design condition (p < 0.05). The IH for the near surge condition (0.0748 +/- 0.0039) was significantly higher than that for all other conditions (p < 0.05). In addition to describing the flow patterns within the Isoflow, this study independently validated St. Jude Medical's reported IH at the design condition and showed how that IH significantly changed based on operating conditions.

Blood Flow Velocity↗
PubMed1997

Purge system for rotary blood pumps.

Purge liquid has been supplied successfully to lubricate the bearings and wash the seals of rotary blood pumps to minimize hemolysis and thrombosis, extending their operating endurance. Although encouraging results have been obtained and development is proceeding for pumps with blood lubricated bearings, their validation and clinical use will occur some time in the future. For rotary blood pumps with purged bearings, a miniature purge liquid pump weighing 80 g has been successfully developed to meet the design point of 1 ml/h at 1,000 mm Hg (required by an existing rotary blood pump) with a motor power of 4 mW. The novel device maintains the flow rate for a sufficient time to service or replace the pump without flow interruption. A preliminary design has been made for a wearable purge delivery unit comprising a purge liquid pump, an electronic control, a purge liquid reservoir, and a battery.

Biomechanical Phenomena↗
PubMed1996

Elucidation of basic mechanistic and kinetic properties of influenza endonuclease using chemically synthesized RNAs.

Influenza virus utilizes a unique mechanism for initiating the transcription of viral mRNA. The viral transcriptase ribonucleoprotein complex hydrolyzes host cell transcripts containing the cap 1 structure (m7GpppG(2'-OMe)-) to generate a capped primer for viral mRNA transcription. Basic aspects of this viral endonuclease reaction are elucidated in this study through the use of synthetic, radiolabeled RNA substrates and substrate analogs containing the cap 1 structure. Unlike most ribonucleases, this viral endonuclease is shown to catalyze the hydrolysis of the scissile phosphodiester, resulting in 5'-phosphate- and 3'-hydroxyl-containing fragments. Nevertheless, the 2'-OH adjacent to the released ribosyl 3'-OH is shown to be important for catalysis. In addition, while the endonuclease steady-state turnover rate is measured to be 2 h(-1), phosphodiester bond hydrolysis is not rate-limiting. The direct generation of a free 3'-OH and the subsequent slow release of this product are consistent with the viral need for efficient use of the capped primer in subsequent reactions of the influenza transcriptase complex.

Autoradiography↗
PubMed1996

Expression and purification of retroviral HIV-1 reverse transcriptase.

Modern molecular biology techniques have provided valuable tools which allow for the expression of large amounts of enzyme in E. coli. For potential therapeutic targets such as HIV-1 reverse transcriptase, it is desirable that the enzyme studied is pure and correlates to the active form of the enzyme found in vivo. This poses a particular challenge for those researchers studying HIV-RT since a significant degree of heterogeneity is introduced by nonspecific proteolytic cleavage of the p66 subunit by E. coli proteases. The advantage of the purification protocol presented here is that the association of monomers is facilitated by mixing an excess of p51 subunit, which is truncated at a site that is N-terminal to known bacterial cleavage sites, with p66 protein. This avoids enzymatic processing of the larger subunit since the formation of heterodimeric RT is rapid and the dimer is stable against proteolytic cleavage. Therefore, it is possible to isolate a pure homogeneous p66/p51 heterodimer. An enzyme prepared in this manner yields crystals that defract to a 3.2-A resolution. It has also been used to study both sensitivity of HIV-1 RT mutants to azidothymidine triphosphate and the kinetics of a potent nonnucleoside RT inhibitor (L-743,726). Finally, it is interesting to note the similarity of HIV-1 RT with reverse transcriptases from other lentiviruses (FIV and EIAV RT). Both of these enzymes consist of heterodimers of p66 and p51 subunits and share other biophysical characteristics. Purification of these reverse transcriptases can, in all likelihood, be optimized by using methods similar to those described in this chapter.

Chromatography, DEAE-Cellulose↗
PubMed1996

Prototype continuous flow ventricular assist device supported on magnetic bearings.

This article describes a prototype continuous flow pump (CFVAD2) fully supported in magnetic bearings. The pump performance was measured in a simulated adult human circulation system. The pump delivered 6 L/min of flow at 100 mm Hg of differential pressure head operating at 2,400 rpm in water. The pump is totally supported in 4 magnetic bearings: 2 radial and 2 thrust. Magnetic bearings offer the advantages of no required lubrication and large operating clearances. The geometry and other properties of the bearings are described. Bearing parameters such as load capacity and current gains are discussed. Bearing coil currents were measured during operation in air and water. The rotor was operated in various orientations to determine the actuator current gains. These values were then used to estimate the radial and thrust forces acting on the rotor in both air and water. Much lower levels of force were found than were expected, allowing for a very significant reduction in the size of the next prototype. Hemolysis levels were measured in the prototype pump and found not to indicate damage to the blood cells.

Animals↗
PubMed1996

Mechanical circulatory support as a bridge to transplantation: past, present and future.

OBJECTIVE: Historical and state-of-the-art review of clinical mechanical circulatory assist and replacement devices. Recent clinical experience at the University of Ottawa Heart Institute with various mechanical circulatory assist devices as a bridge to transplant, and experimental results with the development and testing of a new electrohydraulic ventricular assist device, are described in detail. DATA SOURCES: A Medline search of the English literature from 1980 to 1996 was done using the following words: artificial heart; ventricular assist device; and transplantation. STUDY SELECTION: Papers were selected to provide both a historical perspective and an overview of the current status and future prospects of mechanical circulatory assist devices and artificial hearts. DATA SYNTHESIS: Since the implantation in animals of the first devices in the 1960s and 70s, there have been astounding improvements in design, available materials and implementation of these devices. Increases in the understanding and management of thrombogensis and immunosuppressive drugs as well as developments in the fields of miniaturization, pumps and power sources will lead to concomitant improvements in these devices. CONCLUSIONS: The use of these devices has become an accepted treatment for end-stage heart disease. Additional development and testing is required to address persistent complications in most models if they are to become alternatives to cardiac transplantation. The basis of the future successes is dependent on both technological refinements in the developments of new devices and on continued research into the physiological effects of mechanical circulatory support. However, these devices are used both as a bridge to recovery and a bridge to cardiac transplant and it is expected that they will be used increasingly to provide permanent circulatory assistance or replacement.

Adult↗
PubMed1995

Assay for influenza virus endonuclease using DNA polymerase extension of a specific cleavage product.

The synthesis of influenza virus mRNA requires primers generated by cleavage of host cell transcripts 10-13 nucleotides from the 5' end by a virally encoded endonuclease. This novel enzyme is an attractive target for the development of antiviral agents. An assay for the influenza virus endonuclease has been developed that monitors the substrate cleavage reaction only at the correct position in the sequence, thereby discriminating against nonspecific RNA cleavage products. The influenza endonuclease assay is sensitive enough to detect 200 amol of product. The assay employs a DNA polymerase-catalyzed extension of the endonuclease cleavage product using radiolabeled dGTP and a DNA template containing a 3' region complementary to the product joined to a 5' region consisting of 10 dC residues. The influenza endonuclease assay does not involve gel electrophoretic separation and is amenable to high volume screening of potential inhibitors. The assay may also be employed to determine the site of influenza endonucleolytic cleavage in the substrate.

Base Sequence↗
PubMed1995

L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase.

The clinical benefit of the human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) is limited by the rapid selection of inhibitor-resistant viral variants. However, it may be possible to enhance the clinical utility of this inhibitor class by deriving compounds that express both high levels of antiviral activity and an augmented pharmacokinetic profile. Accordingly, we developed a new class of NNRTIs, the 1, 4-dihydro-2H-3, 1-benzoxazin-2-ones. L-743, 726 (DMP-266), a member of this class, was chosen for clinical evaluation because of its in vitro properties. The compound was a potent inhibitor of the wild-type HIV-1 RT (Ki = 2.93 nM) and exhibited a 95% inhibitory concentration of 1.5 nM for the inhibition of HIV-1 replicative spread in cell culture. In addition, L-7743, 7726 was found to be capable of inhibiting, with 95% inhibitory concentrations of < or = 1.5 microM, a panel of NNRTI-resistant mutant viruses, each of which expressed a single RT amino acid substitution. Derivation of virus with notably reduced susceptibility to the inhibitor required prolonged cell culture selection and was mediated by a combination of at least two RT amino acid substitutions. Studies of L-743, 726 in rats, monkeys, and a chimpanzee demonstrated the compound's potential for good oral bioavailability and pharmacokinetics in humans.

Alkynes↗
PubMed1994

Inhibition of HIV-1 reverse transcriptase by a quinazolinone and comparison with inhibition by pyridinones. Differences in the rates of inhibitor binding and in synergistic inhibition with nucleoside analogs.

6-Chloro-(4S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl)-ethynyl)quinazol in- 2(1H)-one (L-738,372) is representative of a novel structural class of nonnucleoside inhibitors of human immunodeficiency virus, strain 1 (HIV-1), reverse transcriptase (RT), the quinazolinones. L-738,372 is a reversible inhibitor of HIV-1 RT and is noncompetitive against dTTP with a Ki of 140 nM with poly(rA).oligo(dT) as primer-template. Mixed noncompetitive inhibition by L-738,372 was observed against poly(rC).oligo(dG) as primer-template. This quinazolinone binds to RT at a site that overlaps the binding site of other nonnucleoside inhibitors as evidenced by the ability of L-738,372 to displace bound radiolabeled L-696,229, a member of the pyridinone class of inhibitors of HIV-1 RT, from complexes of RT and primer-template. Inhibition by L-738,372 shows slow binding characteristics in reactions with all of the primer-templates employed. Synergistic inhibition of RT activity was evident in combinations of L-738,372 and any of the nucleoside analogs, azidothymidine triphosphate, dideoxyinosine triphosphate, or dideoxycytosine triphosphate. The azidothymidine-resistant form of RT (D67N, K70R, T215Y, K219Q) is inhibited by L-738,372 with 2-3-fold more potency than is the wild-type RT. Comparison of inhibition by L-738,372 with inhibition by pyridinone inhibitors reveals differences in synergistic inhibition with nucleoside analogs and in the rates of binding of the inhibitors.

Binding Sites↗
PubMed1994

Effect of template secondary structure on the inhibition of HIV-1 reverse transcriptase by a pyridinone non-nucleoside inhibitor.

The importance of RNA secondary structure on HIV-1 reverse transcriptase catalyzed polymerization and on the potency of the pyridin-2-one inhibitor 3-(4,7-dichlorobenzoxazol-2-ylmethylamino)-5-ethyl-6-meth ylpyridin-2(1H)-one, L-697,661, were investigated by employing heteromeric primer-template systems. Our data revealed that a stem-loop hairpin secondary structure in the RNA template could lead to strong hindrance of reverse transcription in the reaction catalyzed by HIV-1 reverse transcriptase resulting in the build up of intermediate-length (pause) polymerization products. The presence of L-697,661 greatly enhanced the accumulation of the pause products suggesting that the rate of enzyme translocation from the pause product might be more potently inhibited than polymerization up to the pause site. Model experiments using a synthetic RNA template containing a stem-loop hairpin revealed that the inhibitory potency of L-697, 661 increased 2-fold upon polymerization to within four bases of the secondary structure. Inhibitor potency was enhanced over 6-fold when primer-extension proceeded through the duplex region of the stem-loop.

Animals↗