Prevention of surface encrustation of urological implants by coating with inhibitors.

The encrustation of materials used for urological implants is as yet an unresolved problem. The crystallisation-inhibiting effect of the glycosaminoglycan heparin was used to reduce encrustation. Heparin was covalently bound to the surface of slotted-tube stents of tantalum and stainless steel using a spacer molecule. To verify the inhibition of crystallisation processes, reproducible in vitro tests and in vivo tests using the rat as animal model were carried out. The in vitro and in vivo experiments showed that the heparin coating has a significant influence on the encrustation of the surface. After 7 days in vitro and 120 days in vivo, heparin coated stents were free of encrustation, whereas the uncoated reference stents were extensively covered.

Paced epimyocardial electrograms for noninvasive rejection monitoring after heart transplantation.

BACKGROUND: Diagnosis of acute heart rejection after transplantation with the help of epimyocardial electrograms has been reported as a sensitive and practicable method. Long-term follow-up has been limited, however, by variations o signal, which can be avoided by using pacemaker-induced signals. METHODS: For stimulation and detection of the ventricular evoked response, a new type of electrode with fractal surface structure was used. Seventeen patients undergoing heart transplantation were included in the study. Amplitudes of the depolarization and repolarization parts of ventricular evoked response signals were analyzed and related to the degree of acute rejection according to histologic findings from endomyocardial biopsy. RESULTS: In cases of focal moderate rejection (grade 2, International Society for Heart and Lung Transplantation grading) and higher degrees of rejection, significant amplitude decreases were found. CONCLUSION: This sensitive noninvasive method for rejection monitoring with a high level of reliability provides the possibility of reducing the number of endomyocardial biopsies.

On the chemical modification of pacemaker electrodes and patterned surface functionalization of planar substrates.

We report on experiments towards the chemical modification of metal electrodes in order to enhance biocompatibility or improve cell adhesion properties. In the first example pacemaker electrodes were modified with a thin polysiloxane network which allowed for further derivatization with a poly(ethylene glycol) layer. The primary goal was to suppress inflammatory response of tissue after implantation of electrodes. FTIR, ESCA and a.c.-impedance spectroscopy show the integrity of the ultrathin membrane. No significant reduction of the electrode capacitance was observed, providing further proof for the deposition of a homogeneously thin membrane. The second example deals with the patterned chemical modification of planar surfaces. The goal was to eventually effect selective adhesion of electrosensitive cells above microelectrodes for stimulation and/or recording. First results demonstrate the compatibility of monolayer deposition techniques with common photolithography. It is thus possible to create surfaces with patterned chemical functionality. A gas-phase silylation process was developed in order to control more precisely surface hydration and reaction parameters than is possible with common solution-based silylation procedures.

Dynamic cardiomyoplasty: long-term clinical results in patients with dilated cardiomyopathy.

BACKGROUND: Dynamic cardiomyoplasty has been considered to be an effective method of surgical treatment of patients with end-stage heart failure, and is an alternative to heart transplantation. METHODS: We critically evaluated the long-term course of 52 patients with dilated cardiomyopathy who underwent dynamic cardiomyoplasty and were followed-up for up to 110 months. RESULTS: Dilated cardiomyopathy was due to undetermined cause in 42 patients (80.8%), Chagas disease in 8 (15.4%), viral infection in 1 (1.9%), and peripartum cardiomyopathy in 1 (1.9%). In the nonchagasic group the survival rates were 79.5% +/- 6.1%, 67.8% +/- 7.1%, 53.7% +/- 8.3%, 49.9% +/- 8.3%, 14.9% +/- 12.2%, and 14.9% +/- 12.2%, respectively, at 12, 24, 48, 60, 80 and 110 months of follow-up. In the chagasic patients the survival rates were 37.5% +/- 17.1%, 12.5% +/- 11.7%, 12.5% +/- 11.7% and 0%, respectively, at 12, 24, 48, and 60 months of follow-up, making chagasic cardiomyopathy a possible contraindication for dynamic cardiomyoplasty. CONCLUSIONS: There was no correlation between the clinical improvement and hemodynamic data. Ventricular fibrillation was a frequent cause of immediate and late death, suggesting the need for prophylactic use of antiarrhythmic drugs or implantable cardioverter/ defibrillators.

Prediction of the onset of atrial fibrillation after cardiac surgery using the monophasic action potential.

OBJECTIVE: To show that the monophasic action potential (MAP) recorded continuously from human epicardium may be used to predict the imminent onset of atrial fibrillation or flutter (AF) following surgery, thus allowing prophylactic treatment to be started. PATIENTS: 22 patients (14 male, 8 female; mean (SD) age 64 (12) years) undergoing aortic valve replacement. SETTING: Tertiary referral centre. METHODS: Over a mean observation period of 8 (2.7) days (range 4 to 14), nine episodes of AF were seen in six patients. Before AF, specific and significant alterations of the MAP morphology were observed. In seven of nine episodes the MAP shortened (25 (4)% 60 minutes before AF), developed a triangular shape, and the plateau amplitude decreased from 5.3 (1.2) to 2 (0.2) mV. In the two remaining episodes the beat to beat variability of cycle length and MAP duration at 90% repolarisation (MAPd90) increased significantly from 24 (7) ms and 12 (8) ms (24 hours before AF) to 137 (27) ms and 56 (11) ms (30 minutes before AF) respectively. AF was successfully treated by the administration of sotalol in three cases and by a combination of verapamil and digoxin in a further four. Previously observed changes of MAPd90 and MAP morphology regressed after conversion to sinus rhythm. CONCLUSIONS: The continuous and intermediate term recording of the MAP from atrial epicardium appears to be a valid tool for detecting imminent AF after cardiac surgery with a high sensitivity (99%) and specificity (88%). Optimised antiarrhythmic treatment may thus be given selectively for prophylaxis.

Ketamine blocks a conditioned taste aversion (CTA) in neonatal rats.

These experiments explored the effects of glutamate, N-methyl-D-aspartate (NMDA) receptor blockade on the formation, retention, and expression of conditioned taste aversion (CTA) in young rats. Previous data from our laboratory suggested that ketamine administration potentiates a CTA in E18 rat fetuses. The current studies investigated this phenomenon in neonates. High-pressure liquid chromatography (HPLC) methods were used to determine the amount of ketamine that must be injected intraperitoneally (i.p.) to achieve brain ketamine levels in neonates comparable to those found in the fetuses from our previous experiments. Then, on their day of birth, Sprague-Dawley rat pups received injections of either 0.1, 10, or 70 mg/kg of ketamine HCI, i.p. or a Sal control injection. One-half hour later, pups were injected orally with either Saccharin (Sac; 10 microL of 0.3%) or water followed by an injection of either lithium chloride (LiCl; 81 mg/kg) or Sal (i.p.). The CTA was evaluated in two different tests. Two weeks after conditioning, the dam was anesthetized and the frequency with which pups attached to Sac-painted nipples versus nipples painted with water was measured (i.e., the nipple taste test, NTT). Controls for state-dependent learning were run in which 10 mg/kg of ketamine or saline (Sal) was administered before both taste aversion conditioning and the NTT. After weaning, the CTA was also evaluated by measuring the amount of Sac (0.3%) or water consumed during a two-bottle test. Neonates that received Sal control injections before the Sac + LiCl pairing acquired CTAs and avoided Sac-painted nipples. However, the pups injected with ketamine on the conditioning day only (P0) did not avoid Sac-painted nipples (as compared to controls). Pups that had ketamine both at the time of CTA training and testing, or just before the NTT, also failed to avoid Sac-painted nipples. Ketamine's acute effects apparently influenced the outcome of the NTT of state-dependent control subjects. Rat pups that received the highest doses of ketamine (10 or 70 mg/kg) and tasted Sac on P0 later failed to show a neophobia for Sac-painted nipples. Whereas, rat pups that received the high dose of ketamine and water on P0, later exhibited a neophobic response. These data suggest that ketamine did not impair the animal's ability to taste Sac. These data reflecting a ketamine-induced blockade of neonatal CTAs may be contrasted with our previous findings in which ketamine potentiated fetal CTAs. However, they are in consonance with data from adult rats suggesting that ketamine can cause an amnesia for CTAs. NMDA receptor blockade may shape memory formation in a manner that is dependent on the stage of brain development.

Rate-responsive pacing based on sympathetic activity.

Modern pacemaker technology makes the adaptation of pacing rate to haemodynamic requirements possible. The most ambitious approach aims at restoration of the physiological closed-loop system by utilising the information that is supplied by the autonomic nervous system (ANS) and extracted from myocardial contractile performance. Measurement is accomplished by the impedance method, with the stimulation electrode as measuring electrode. The ventricular inotropic parameter (VIP) has been identified as an ANS-dependent parameter. A special detection algorithm RQ (regional effective slope quantity) with high ANS sensitivity has been developed. Rate adaptation has been achieved by using an individually adjustable inotropic index (II). The concept has been evaluated in a multicentre study employing a standardised exercise protocol. The results in patients with AV block demonstrate the excellent agreement between the spontaneous sinus rhythm and the ANS-controlled stimulation rate during different forms of exercise. Measurement of mean arterial blood pressure (MABP) supports the physiological approach to adapting the pacing rate to different kinds of haemodynamic challenge.

Haemocompatibility optimisation of implants by hybrid structuring.

State of the art in biomaterial research and implant design is a compromise between functionality and biocompatibility. Consequently, results often have disadvantages with respect to both aspects. With regard to biocompatibility, the activation of the clotting system by alloplastic materials is of great significance, because it necessitates anticoagulant therapy. Further improvements in implant technology require an understanding of the interactions between blood and implants. Therefore a microscopic model of thrombogenesis at alloplastic surfaces is briefly presented, relating thrombogenicity of a material to the electronic structure of its surface. The electronic requirements for high haemocompatibility, which result from this model (especially a low band-gap density of states and a high surface conductivity) are fulfilled by an amorphous alloy of silicon and carbon (a-SiC:H). The advantage of amorphous materials is that they do not obey stoichiometric rules. Thus they allow a continuous adjustment of the electronic parameters without fundamental changes in their mechanical and chemical properties. The theoretical results were checked in vitro by total internal reflection intrinsic fluorescence (TIRIF) spectroscopy as well as thrombelastography experiments (TEG). In comparison with conventional materials such as titanium or LTI carbon, the TEG-clotting time of a-SiC:H-coatings was prolonged by in excess of 200 per cent. As a consequence, a-SiC:H is well suited as a haemocompatible coating material for hybrid structuring of cardiovascular implants.

Non-invasive temperature imaging of muscles with magnetic resonance imaging using spin-echo sequences.

The application of spin-echo magnetic resonance imaging sequences on non-invasive temperature imaging for temperature mapping of human limbs is investigated. In an in vitro experiment performed on a meat sample, the equilibrium magnetisation P and the spin-lattice relaxation time T1 are calculated from the values for the repetition time TR and the signal intensities obtained by a spin-echo sequence at different tissue temperatures as measured by a fibre-optic probe. T1 is linearly correlated to the tissue temperature, and P is linearly correlated to the reciprocal value of the absolute temperature. Both effects, taken together, lead to a non-linear dependency of the signal intensity on temperature. Therefore a TR leading to maximum temperature dependency of the signal intensity is calculated and used in the further experiments. In the in vivo experiments, the lower legs of two volunteers are cooled from outside. Images are acquired with a spin-echo sequence (1.5 T, TR = 1200 ms, TE = 10 ms). A rise in signal intensity in the muscle with falling skin temperature is observed, particularly in more peripheral muscle layers. This study shows that spin-echo sequences can be used to monitor temperature changes and temperature differences in living muscle tissue.

Coating of cardiovascular stents with a semiconductor to improve their hemocompatibility.

Thrombogenesis on artificial surfaces can be described as an electron transfer reaction. To inhibit this oxidation process and thereby achieve high hemocompatibility, a surface requires semiconducting properties. However, because all known solid semiconductors are extremely brittle, the requirements for high hemocompatibility and mechanical stability cannot be met by any single material. Therefore, a hybrid design is introduced as a new approach to improve the hemocompatibility of cardiovascular stents.

[Pre-ejection period controlled cardiac pacemaker]. / PEP-gesteuerter Herzschrittmacher.

Numerous investigations have been performed in search for suitable parameters for physiologic adaptation of the pacing rate. In case of chronotropic incompetence corporeal as well as cardiac control parameters permit open or closed loop control of the pacing rate. Criteria to be considered are the patient's condition, the response time of the system, the proportionality to the oxygen uptake and the susceptibility to interference. A high specificity of the rate response is particularly important for the patient with a low cardiac reserve. The use of a parameter relating to the central hemodynamics, such as the systolic time intervals, particularly the pre-ejection period (PEP), as input signal for rate control is, therefore, of special interest. The concept presented of a PEP-controlled rate adaptive pacemaker is based on the linear proportionality between PEP and the cardiac cycle length. Changing with the sympathetic tone, the PEP permits adaptation of the pacing rate in response to physical as well as emotional stress. The right ventricular PEP parallels the left ventricular one and is measured between the electrode tip and the pacemaker housing. Clinical results obtained confirm the high sensitivity and specificity of this control parameter with respect to the metabolic demand. Technical details of an implantable multiprogrammable device are dealt with.

[Physical mechanisms of solid-protein interactions in the interface between amorphous silicon carbide and fibrinogen]. / Physikalische Mechanismen der Festkörper-Protein-Wechselwirkung an der Phasengrenze a-SiC:H-Fibrinogen.

State of the art in biomaterial research and implant design is a compromise between functionality and biocompatibility. Consequently the results often have disadvantages with respect to both aspects. In regard to biocompatibility the activation of the clotting system by alloplastic materials is of great significance, because it necessitates anticoagulant therapy. Further improvements of implant technology require an understanding of the interactions between blood and implants. Therefore a microscopic model of thrombogenesis at alloplastic surfaces will shortly be presented, which relates thrombogenicity of a material to the electronic structure of its surface. The requirements for high hemocompatibility, which result from this model--especially in regard to the density of states and the conductivity at the surface--are fulfilled by an amorphous alloy of silicon and carbon (a-SiC:H). The advantage of amorphous materials is that they do not obey stoichiometric rules. Thus they allow a continuous adjustment of the electronic parameters without fundamental changes of their mechanical and chemical properties. The theoretical results where checked by total internal reflection intrinsic fluorescence spectroscopy (TIRIF) as well as thrombelastography experiments (TEG). In comparison to conventional materials like titanium or LTI carbon the TEG-clotting time of a-SiC:H-coatings is prolonged in excess of 200%. As a consequence a-SiC:H is well suited as a hemocompatible coating material for hybrid structuring of cardiovascular implants.

[Mechanical aspects of the development of artificial heart valves]. / Mechanische Aspekte bei der Entwicklung künstlicher Herzklappen.

The development of an antithrombogenic coating permits a hybrid design for artificial heart valves. A substrate material optimized for its application is coated to meet the electrochemical requirements of improved hemocompatibility. But future progress in artificial heart valves requires an improvement in design as well as of the material. The basis of both aspects is the determination of such fundamental mechanical properties as the elasticity and plasticity of the valve ring and the deformation and fraction behaviour of the occluder. Analytical and numerical calculations of various different models result in different requirements for the substrate of ring and occluder. A combination of high elastic temper and low resistance to flow requires a ring material with a Young's modulus of 40 GPa or more, and a 0.2% proof stress to (Young's modulus)2/3 ratio of 0.3 MPa1/3. The best occluder materials should have a Young's modulus of more than 50 GPa and a flexural strength of at least 800 MPa. On the basis of these criteria, a heart valve consisting of a TiA15Fe2,5 ring and occluders made partially stabilized zirconia is introduced.

[Model based study of myocardial stimulation mechanisms]. / Modellbasierte Untersuchung myokardialer Stimulationsmechanismen.

The present study investigated the mechanisms of electrical stimulation of a myocardial fibre with the aim of developing improved minimally invasive stimulation methods. Using a dynamic myocyte model, the ionic currents crossing the voltage-dependent channels of the membrane are computed. To trigger an action potential, the membrane must first be depolarized to the threshold potential, when further depolarization continues spontaneously through the avalanche-like opening of the sodium channels. For the development of an action potential, not merely the amount of charge injected into the cell during the stimulus is of importance, but an above-threshold magnitude of the stimulation current is also required. The smallest energy required is achieved when the stimulus duration is chosen to be equal to the chronaxie. A second aspect of the study concerned the far-field stimulation of a muscle fibre, achieved by generating a potential gradient along the fibre. First, using a continuous fibre model, the fibre activating function is computed. In a more detailed study, the discrete segmental structure of the fibre determined by the gap junctions is taken into account, and the impact of these junctions on the activating function analysed. By optimizing the electrode configuration, an appropriate activating function results which guarantees successful stimulation when its maximum is above than threshold potential. The most important finding is that the myocardium can be stimulated by floating electrodes, thus opening up new possibilities for a less invasive electro-stimulation of the heart.

[Titanium nitride cardiac pacemaker electrodes]. / Titannitrid-Herzschrittmacher-Elektroden.

The sensing and pacing performance of pacemaker electrodes is characterized by the electrochemical properties of the electrodes/tissue layer; the usually smooth metallic electrode surface results in a high pass filter characteristic. Consequently, the detected intracardiac signals, which control the implantable systems, are not optimally matched to the spectral contents of the depolarisation signal. To avoid interference caused by noise (EMI, muscle potentials, etc.) a shift of the frequency of the band pass towards the lower frequency spectrum is required. As previously reported, the electrochemical properties of sintered and surface-treated electrodes prove the predicted improvement of sensing performance if titanium-nitride coated electrodes are used. Our results demonstrate their superiority above all the other electrodes presently known. The advantages can be referred to the micro-crystalline surface structure achieved by sputter-deposited electrode coatings and the kinetics of the ionic exchange. Furthermore, the acute thresholds achieved with the TiN-systems were significantly better than those of the smooth metallic surface. These results were also confirmed for chronic implants and are attributable to the known biocompatibility of titanium and its alloys.

[Motion energy as a control variable for adapting stimulation frequency]. / Bewegungsenergie als Steuergrösse für die Anpassung der Stimulationsfrequenz.

An activity sensing rate-responsive pacing system is presented which adaptively controls heart rate to adjust cardiac output in response to increased metabolic demand, and more optimally restore homeostasis of the intact cardiovascular system. The current use of ventricular demand and DDD universal pacing systems, although rate and multi-parameter and multi-function programmable, are fixed at these programmed settings. These devices are adequate for patients at rest or during moderate exertion, but are suboptimal for physically active patients whose physiology requires increased oxygen supply to meet an increased cardiac demand. In the past, these patients may have experienced fatigue or dyspnea out of proportion to their cardiovascular disease. The Ergos rate-adaptive single- and dual-chamber pacing system is a second generation pulse generator which is rate responsive to a patient's increased physiologic demand by sensing a motion signal which reflects increased work load and the need for a compensating increase in heart rate. Ergos offers increased assistance to patients with sinus bradycardia who may require the rate-responsiveness with the additional advantage of AV synchrony. Clinical results show the effectiveness of the presented sensor control by motion energy for rate adaptive pacing therapy.

[Simulation of myocardial action potentials of various cell types in relation to neural parameters]. / Simulation myokardialer Aktionspotentiale verschiedener Zelltypen in Abhängigkeit von nervalen Einflussfaktoren.

Action potentials of various myocardial cell types were simulated in a computer model based on current knowledge of the electrical properties of ionic channels and pumps in the ventricular cell membrane and the sarcoplasmic reticulum. The transport mechanisms of sodium, potassium, calcium and chlorine ions through the cell membrane are described mathematically, as is the exchange of calcium between the myoplasm and sarcoplasmic reticulum. Ten ionic channels and three pumps of the cell membrane are taken into account, while three channels and one pump of the sarcoplasmic reticulum are considered in the computations. For the first time, the transient outward potassium current IK,to was simulated, the effect of which on the early repolarisation phase of the action potential was reproducible in the model. Calcium buffers in the myoplasm and the sarcoplasmic reticulum are also considered. From the resulting ionic currents through the channels and pumps, the membrane potential is computed using an equivalent circuit diagram of the cell membrane. In particular the influence of neural activity on channel conductance and the probability of channel patency were taken into account. By means of this model, different shapes of ventricular action potentials were simulated. The action potentials of epicardial cells, M-cells, endocardial cells and Purkinje fibres were accurately simulated. In addition, the effects of sympathetic drive and various drugs were demonstrated in the model as well as the shortening of the action potential duration with increasing stimulation frequency.

[Measurement and analysis of monophasic action potentials using fractally coated electrodes--I]. / Messung und Analyse monophasischer Aktionspotentiale mit Hilfe fraktal beschichteter Elektroden--Teil I.

The monophasic action potential (MAP) contains a wealth of information about the stat of the myocardium, which makes it very useful for numerous diagnostic and therapeutic applications in patients with heart disease. The silver-silver chloride electrodes which are currently used for the measurement of MAP have poor long-term stability in contact with biological tissue. This study was therefore undertaken with the aim of investigating the electrochemical behaviour of fractally coated leads in terms of their signal-detection performance. Experience gained with these leads in cardiac pacemakers has already demonstrated the long-term stability and biocompatibility of the fractally coated leads. Present results show that, due to their large electrochemically active surface area, fractally coated leads have a very low impedance over a wide frequency range. The negligible polarization artifact of these leads permits the measurement of cardiac potentials immediately after a stimulus. Fractally coated leads are thus highly suitable for the measurement of MAP, and have clear advantages over Ag/AgCl electrodes. The second part of this study reports on the results of MAP measurements using fractally coated leads.

[Measuring intracardiac impedance for determining sympathetic nerve activity in frequency-adjustment electrostimulation--1: Biomedical technical principles]. / Intrakardiale Impedanzmessung zur Bestimmung der Sympathikusaktivität bei frequenzadaptiver Elektrostimulation--Teil 1: Biomedizintechnische Grundlagen.

Modern Pacemaker technology makes it possible to adapt the pacing rate to hemodynamic requirements. The most ambitious approach aims at restoring the physiological closed-loop system by utilizing the information supplied by the Autonomic Nervous System and extracted from myocardial contractile performance. Measurement is accomplished by the impedance method using the stimulating electrode as the measuring electrode. The Ventricular Inotropic Parameter (VIP) has been identified as an ANS-dependent parameter. A special detection algorithm, the Regional Effective Slope Quantity (RQ), with a high ANS sensitivity has been developed specially for the purpose. Rate adaptation is achieved by using an individually-adjustable Inotropic Index (II). The concept has been evaluated in a multicenter study employing a standardized exercise protocol. The clinical results will be presented in Part 2 of this paper.

[Technology and algorithms for implantable dual chamber defibrillators]. / Technologie und Algorithmen für implantierbare Zweikammer-Defibrillatoren.

The next generation of implantable cardioverter/defibrillators (ICDs) will have the capability for sensing and defibrillating in both chambers of the heart. These devices, which are presently being developed, will thus be able to differentiate between ventricular and supraventricular tachycardias, and to respond accordingly. The burden of stress on the patient will therefore also be further reduced by avoiding unnecessary shock treatment of supraventricular tachycardias. In addition, the new generation of ICDs can also be used for the treatment of chronic atrial tachyarrhythmias. With the dual-chamber IEGM-recording capability, these ICDs will also provide the physician with an important diagnostic tool. The present article describes such an ICD.