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PubMed2004

[Chips instead of mice: cells on bioelectronic sensor-chips as an alternative to animal experiments].

An alternative assay for replacing animal experiments should serve the specific microphysiological needs of the cells and be endowed with multiparametric signal monitoring. These requirements are provided by a test system in which the key elements are biocompatible electronic sensor-chips. It is also connected to a medium perfusion set-up, which allows to control the supply of nutrients and test compounds, and the removal of culture medium. The chips are equipped with sensors that continuously monitor basic metabolic parameters and membrane-associated changes of living cells: pH-ISFETs for extracellular acidification, amperometric O2-sensors for oxygen consumption, and IDES for electrical impedance of the cell layer. Experiments with LS174T colon carcinoma cells in culture show the metabolic and electrical changes upon incubation with Zytochalasin B and chloroacetaldehyde. The signal patterns vary and indicate different mechanisms of action for these test compounds. With this test system it is possible to detect effects of unknown substances and mixtures, and to analyse the cellular probe for prolonged times.

Animal Testing Alternatives↗
PubMed1990

[Intestinal sensitivity disorders and irritable bowel syndrome].

Long neglected in the past, the study of visceral sensitivity (interoception) has progressed in recent years because of advances in neurobiological techniques. Dealing with the structure or the function of single neurons, these techniques have profoundly increased our knowledge about the sensitive mechanisms in the digestive tract. According to recent data, the visceral sensitivity organs are richer and more complex than imagined previously. Microphysiological techniques have shown that intestinal sensitive terminations are capable of transmitting information concerning visceral activity and physicochemical modifications of intestinal contents directly to the central nervous system. This means that visceral sensitivity intervenes under physiological as well as pathological conditions. This notion is new and of great interest. As progress was being made concerning the morphologic and electrophysiologic aspects and contemporaneous studies were establishing the richness of visceral, and particularly, intestinal, sensitive receptors, basic science research in humans and animals have emphasized the diversity of the implication of the extrinsic nervous system in pain, regulation of digestive motility, homeostasis and alimentary behaviour. Our present knowledge on the nervous and neurohumoral mechanisms has shed new light on the determinisms in digestive tract pathology. This is especially true in the irritable bowel syndrome which can be considered as an extrinsic nervous system derangement. Due to abnormal sensitivity by modification of the threshold values of sensitivity to distension, and/or to stimulation by substances such as cholecystokinin, for example, motor disorders occur. Other factors, such as stress, can be responsible for revelation or exacerbation of neurohumoral disorders.

Colonic Diseases, Functional↗
PubMedDate not supplied

Disorders of neuromuscular transmission other than myasthenia gravis.

Disorders of neuromuscular transmission in humans are caused by a wide variety of agents including systemic diseases, drugs, environmental toxins, animal envenomation, cations, and hormones. Some are genetically determined. Many are of known etiology. All such disorders interfere with one or more events in the sequence whereby a nerve impulse excites a muscle action potential. In many disorders of neuromuscular transmission, abnormal fatigue occurs, and some cases respond dramatically to treatment. Investigation of the microphysiology, microanatomy, and pharmacology of both normal and diseased neuromuscular junctions has increased our knowledge of these disorders.

Action Potentials↗
PubMed2004

Analysis of drug action on tumor cell metabolism using electronic sensor chips.

Chemotherapeutic drugs affect the metabolism of tumor cells regardless of the specific target of action. Basic parameters of cell metabolism are extrusion of acids into the microenvironment and oxygen consumption. To analyze these changes on living cells in real-time, a test system based on multiparametric chips with an array of sensors for monitoring pH and O(2) as well as electric impedance has been developed. Cells are cultivated on these chips and supplied with medium by a fluid perfusion set-up which mimics microphysiological conditions and allows for drug addition and removal. Human colon carcinoma cells LS174T were used as a model to test the effect of drugs. Cells growing on chips were monitored for 24 h and longer. Untreated cells showed a continuous increase in the rate of acidification, while the rate of respiration remained fairly constant. Addition of chloroacetaldehyde (50 microM) rapidly attenuated O(2) consumption with a gradual decrease in acidification following. In contrast, with cisplatin (16.7 microM) a delayed and gradual decrease in both the rates of acidification and respiration effect occurred over 2-3 days. These results provide insights to the mechanisms of action of these drugs, which are coherent with those already known. Thus, multiparametric sensor chips provide elementary information on drug action.

Antineoplastic Agents↗
PubMed1993

A contemporary view of salivary research.

The past 50 years of salivary research has been marked by a series of changing perceptions as new techniques and technologies have illuminated the complexities of the secretory mechanism, salivary composition, and function. The modern era began with the innovations of electrophoresis, chromatography, histochemistry, immunochemistry, electron microscopy, and microphysiology. The idea of saliva as primarily a digestive fluid composed of salts, amylase, and mucin was rapidly broadened to encompass a wide spectrum of protective proteins with the dual responsibility of protecting both hard and soft tissues. Characterization of the secretory IgA and nonimmunological antibacterial systems and the proteins responsible for the regulation of calcium and phosphate levels dominated the research in the 1960s and 1970s. An appreciation of the nature, formation, and role of the salivary pellicle and the interplay between bacterial adherence and agglutination provided a clinical thrust. Morphologists and physiologists redefined the secretory process on a molecular level. The 1980s saw the union of structure and function, both in terms of synthesis and release of the secretory products and their specific roles in the oral cavity in health and disease. The excitement of the 1990s is in the genetic control of processes and products, elucidating the mechanisms, and using the information to improve on nature: an era of great expectations and hubris. This article is essentially a personal guided tour through the past 50 years of salivary research.

Animals↗
PubMed2000

Non-invasive measurement of cell membrane associated proton gradients by ion-sensitive field effect transistor arrays for microphysiological and bioelectronical applications.

The pH in the cellular microenvironment (pH(M)) is an important regulator of cell-to-cell and cell-to-host interactions. Additionally the extracellular acidification rate of a cell culture is an important indicator of global cellular metabolism. In a new approach a biocompatible ion-sensitive field effect transistor (ISFET)-array was developed to measure the pH(M) close to a surface and the global extracellular acidification rate at the same time. This ISFET-array is part of a new multiparametric microsensor chip. The paper highlights some basic applications of this method for in-vitro measurements. Using a fluid perfusion system for cell culture media, it is possible to measure the pH(M) of few (five to ten) adherent tumor cells in a distance of 10-100 nm from the cell plasma membrane. Experiments showed a pH(M)-value of 6.68 +/- 0.06 pH. Further experiments suggest that both the low pH, and the extracellular acidification rate of the examined tumor cell line are mainly built up by glycolysis.

Biosensing Techniques↗
PubMed1987

A versatile chamber for microphysiologic studies with gas mixtures under high pressure.

A pressure chamber, designed for microelectrode recordings in isolated tissues or organs an capable of withstanding pressures up to 200 bar, is described. The versatility of the vessel allows a wide variety of experimental configurations and several types of studies. It features a complete access, easy visibility, interchangeable tissue bath and micromanipulator modules, as continuous perfusion and temperature control of the preparation under pressure. The ability to move micropipettes in 1-micron steps allows single unit recording on a variety of in vitro preparations at normal or elevated gas pressures. Successful physiologic tests, using the hippocampal slice preparation, are described. The results testify to the reliability of the system and to the usefulness of this in vitro model to study the gas pressure effects on isolated networks of mammalian CNS.

Air Pressure↗
PubMed1995

Geometry, kinetics and plasticity of release and clearance of ATP and noradrenaline as sympathetic cotransmitters: roles for the neurogenic contraction.

The paper compares the microphysiology of sympathetic neuromuscular transmission in three model preparations: the guinea-pig and mouse vas deferens and rat tail artery. The first section describes the quantal release of ATP and noradrenaline from individual sites. The data are proposed to support a string model in which: (i) most sites (> or = 99%) ignore the nerve impulse and a few (< or = 1%) release a single quantum of ATP and noradrenaline; (ii) the probability of monoquantal release is extremely non-uniform; (iii) high probability varicosities form 'active' strings; and (iv) an impulse train causes repeated quantal release from these sites. Analogy with molecular mechanisms regulating transmitter exocytosis in other systems is proposed to imply that coincidence of at least two factors at the active zone, Ca2+ and specific cytosolic protein(s), may be required to remove a 'fusion clamp', form a 'fusion complex' and trigger exocytosis of a sympathetic transmitter quantum, and that the availability of these proteins may regulate the release probability. The second section shows that clearance of noradrenaline in rat tail artery is basically > or = 30-fold slower than of co-released ATP, and that saturation of local reuptake and binding to local buffering sites maintain the noradrenaline concentration at the receptors, in spite of a profound decline in per pulse release during high frequency trains. The third section describes differences in the strategies by which mouse vas deferens and rat tail artery use ATP and noradrenaline to trigger and maintain the neurogenic contraction.

Adenosine Triphosphate↗
PubMed2007

Quantitative measurement and control of oxygen levels in microfluidic poly(dimethylsiloxane) bioreactors during cell culture.

Microfluidic bioreactors fabricated from highly gas-permeable poly(dimethylsiloxane) (PDMS) materials have been observed, somewhat unexpectedly, to give rise to heterogeneous long term responses along the length of a perfused mammalian cell culture channel, reminiscent of physiologic tissue zonation that arises at least in part due to oxygen gradients. To develop a more quantitative understanding and enable better control of the physical-chemical mechanisms underlying cell biological events in such PDMS reactors, dissolved oxygen concentrations in the channel system were quantified in real time using fluorescence intensity and lifetime imaging of an oxygen sensitive dye, ruthenium tris(2,2'-dipyridyl) dichloride hexahydrate (RTDP). The data indicate that despite oxygen diffusion through PDMS, uptake of oxygen by cells inside the perfused PDMS microchannels induces an axial oxygen concentration gradient, with lower levels recorded in downstream regions. The oxygen concentration gradient generated by a balance of cellular uptake, convective transport by media flow, and permeation through PDMS in our devices ranged from 0.0003 (mg/l)/mm to 0.7 (mg/l)/mm. The existence of such steep gradients induced by cellular uptake can have important biological consequences. Results are consistent with our mathematical model and give insight into the conditions under which flux of oxygen through PDMS into the microchannels will or will not contribute significantly to oxygen delivery to cells and also provide a design tool to manipulate and control oxygen for cell culture and device engineering. The combination of computerized microfluidics, in situ oxygen sensing, and mathematical models opens new windows for microphysiologic studies utilizing oxygen gradients and low oxygen tensions.

Animals↗
PubMed1999

Quantitation of microvascular plasma perfusion and neuronal microtubule-associated protein in ischemic mouse brain by laser-scanning confocal microscopy.

In an exposition of the technique of calculating distribution volumes from laser-scanning confocal microscopic (LSCM) data, three-dimensional images of the distribution of one or two fluorescent markers in mouse brain specimens were generated by LSCM and processed by a system developed for morphometric analysis of fixed and stained serial brain histologic samples. To determine the volume of perfused cerebral capillaries, one of two fluorescent plasma markers, either fluorescein isothiocyanate (FITC)-dextran or Evans blue, was intravenously administered to mice subjected to 1 hour of embolic middle cerebral artery (MCA) occlusion (n = 9) and to mice that were not operated on (n = 3); after 1 minute of circulation, brains were removed, immersion-fixed, and processed for LSCM. In some of these animals (n = 5), the volume of endogenous microtubule-associated protein-2 (MAP2) fluorescence was also determined using immunohistochemical staining. For mice that were not operated on, this methodology yielded highly localized volumes of (1) microvascular plasma, which agree with those determined for rodents by other techniques, and (2) MAP2 expression, which appears physiologically and morphologically reasonable. After 1 hour of MCA occlusion, the MAP2 volumes of distribution were less than 10% of normal in the ipsilateral hemisphere in which plasma perfusion essentially ceased. In conclusion, precise colocalization and quantitation of early ischemic neuronal damage and cerebral plasma perfusion deficit can be done with this three-dimensional, microphysiologic and microanatomic methodology.

Animals↗