The present invention relates to a method of building instrument variation tolerance into calibration algorithms for spectroscopic devices for chemical composition analysis with spectroscopic methods. The method of the present invention is particularly suitable for blood glucose, cholesterol and other chemical components prediction based on near-infrared spectrophotometry measurements. A method includes developing a calibration algorithm on a first instrument; applying the calibration algorithm to a second instrument; calibrating the second instrument and adjusting the calibration algorithm to account for differences between the first instrument and the second instrument; and repeating the step of applying (above) in respect of (n) further instruments to provide a calibration algorithm which may then be used on other instruments. Methods are also provided that develop calibration algorithms by adding instrument variations, based on mathematical manipulation, of the spectral data collected on calibration instruments.

The present invention relates to the fields of spectroscopy, spectrophotometry, and chemometrics. In particular, the present invention relates to a method of building instrument variation tolerance into calibration algorithms for spectroscopic devices for chemical composition analysis with spectroscopic methods. The method of the present invention is particularly suitable for blood glucose, cholesterol and other chemical components prediction based on near-infrared spectrophotometry measurements.
Spectroscopy is a well established method, which has extremely wide applications for chemical analysis of plasma, gases, liquids and solids practically in all field of modern science and technology as well in everyday life including food production, food processing, healthcare and medicine. The role of spectroscopy is to identify and to perform quantitative analysis of chemical composition of various bodies and substances or to recognize and measure concentration one or more selected chemical components (analytes) in the bodies and substances. One of such applications is a non-invasive measurement of different substances like glucose, cholesterol water, fat, protein, hemoglobin, melanin and other in human body, therefore a non-invasive glucose concentration measurement has been selected here as an illustrative example only and cannot be considered as an exclusive area of patent application.
Biotechnological analysis and examination are often based on the measurement of various chemical analytes in the composition of a biological matrix such as blood, interstitial fluid, or living tissue. Such measurements may be used to evaluate a patient""s state of health and to determine what, if any, treatment is necessary. For example, the frequent monitoring of blood glucose levels in diabetic persons with glucometers is often necessary to allow such persons to manage the diabetes mellitus disease, by taking insulin injections or oral drugs to lower blood glucose when required. Intensive treatment based on frequent blood glucose measurements can significantly reduce the incidence of blindness, kidney loss, and other complications associated with diabetes.
Most home-based glucose measurement systems require the patient to invasively collect a blood sample, by pricking his or her finger, placing the sample on an appropriate test strip, and then testing the sample in an optical glucometer. For millions of diabetics around the world, the use of lancets or other sharp instruments to draw blood for monitoring their insulin levels is a painful process, and one that often builds up calluses on fingers, making the collection of blood even more difficult. This invasive procedure may be especially difficult to perform on children and therefore particularly trying on parents. Furthermore, the test strips required for each blood sample are generally not reusable, and when multiple measurements are taken each day, amount to significant costs from the patient""s point of view. Thus, despite the fact that a large number of diabetics should take several measurements throughout each day (for some individuals, physicians recommend testing glucose levels from 4 to 7 times daily), due to the pain, cost, and inconvenience involved, many diabetics do not monitor their glucose levels frequently enough. A non-invasive means of measuring blood glucose levels is needed to eliminate the pain and risk of infection associated with drawing blood and thus increase the likelihood that diabetics will perform the recommended number of measurements.
For example, spectroscopy of samples containing molecules of various chemical substances is based on the analysis of how incident radiation interacts with the vibrational and rotational states of molecules, which are of analytical interest. Spectroscopic measurement techniques have gained increased popularity because of the ability to provide fast and non-invasive measurements of concentrations of different chemicals or analytes. For the reasons indicated above, this is particularly desirable for home based glucometers. Spectrophotometry is a type of spectroscopy commonly used to quantitatively measure concentrations of analytes based on spectral energy distribution in the absorption spectrum of a sample solution or medium. In spectrophotometry, the spectral power (or energy) distribution is typically analyzed within a selected part of a range of the ultraviolet, visible, or infrared spectra.
For example, near-infrared radiation (NIR) is electromagnetic radiation having a wavelength of between about 0.75 and 2.5 micrometers (i.e. from 120 to 400 THz). Near-infrared spectrophotometry generally uses instruments, which spatially disperse radiation of different wavelengths within this range, and whose spectral power density (or integrated over certain time period spectral energy density) is measured with a suitable radiation detector. The NIR spectrophotometry is increasingly being used to measure in vivo analytes such as glucose, fructose, glycerol, and ethanol.
Non-invasive, spectrophotometric measurement of glucose in human beings is performed by illumination of the selected part of human body with radiation of a known spectral composition and detecting changes in the spectral composition of the radiation interacting with (affected by) the selected body part or sample, in general. Following the Beer""s law, most often these changes are expressed in the form of a function which presents a negative logarithm of the ratio of spectral power (or energy) densities of radiation flux affected by the sample to that of incident. Usually this function is referred to as absorbance. For non-absorbing samples, in absence of losses other than radiation absorption in the sample, this function is a constant equal to zero. If absorption of radiation in the sample is spectrally dependent, this function takes different values for different wavelengths (or frequencies) of the radiation and is usually called a spectral absorption (or absorbance) of the sample. Practically all known substances demonstrate absorption of electromagnetic radiation in certain spectral ranges, hence they modify spectral composition of light affected. The relative changes in spectral composition of radiation, caused by different molecules create different patterns spectral absorption pattern, specific for molecules. Therefore, recognition of this pattern can be used for identification of molecules creating the pattern. This is relatively easy when the pattern is created by a single or a very small number of sorts of molecules, with distinctively different absorption spectra. The problem becomes more complex when either the sample contains a large number of sorts of molecules or their spectra are very similar. In particular, the absorbance of the incident radiation by human body is due to presence of the various chemical components within that body as: water, fat, protein, hemoglobin, melanin, glucose and many other components. One difficulty with glucose measurement using spectral analysis, is the spectral overlap between glucose and other chemicals found in blood, often in much greater quantities than glucose. In addition, the thickness, color, and structure of the skin, bones, and blood through which the incident radiation passes affects the spectral changes in light interaction (transmitted, reflected or absorbed. Furthermore, the concentration of analytes can vary with changes in activity level, diet, hormone fluctuations, and other factors. Glucose concentration measurements are also particularly susceptible to variations in physical and chemical conditions including temperature, pressure, humidity, and skin hydration. As a result, to perform a reliable non-invasive glucose prediction, NIR spectral measurements should be performed through a vascular equilibrated region of the body, and a NIR glucose spectrophotometer must be carefully designed so that the quality of raw spectral information from an NIR glucometer is high. See generally Waynant and Chenault, xe2x80x9cOverview of Non-Invasive Optical Glucose Monitoring Techniquesxe2x80x9d, IEEE LEOS Newsletter, vol. 12, no. 2 (April 1998); and Burmeister and Arnold, xe2x80x9cSpectroscopic Considerations for Noninvasive Blood Glucose Measurements with Near Infrared Spectroscopyxe2x80x9d, IEEE LEOS Newsletter, vol. 12, no. 2 (April 1998).
Near-infrared glucose measurements are generally suitable for tissue depths ranging from about 1 mm to 10 cm, and are often performed through a patient""s fingertip, although other areas of the body (for example the web between two fingers, an ear lobe, or the upper lip) can also be used. Sample thickness is an important experimental parameter because a greater thickness increases the amount of absorption and thereby lowers the minimum limits for detection, whereas because less incident radiation successfully traverses through a thicker sample (i.e. without being absorbed) effectively increasing the spectral noise: see Burmeister and Arnold, supra.
Problems related to the non-invasive glucose measurement described above, give a good example of complexity of advanced spectrometric measurements. Application of spectroscopy for chemical analysis becomes particularly difficult when either there is big difference between signals produced by different chemical components, or when the spectra of these components are very similar. Sophisticated data processing and analysis methods, known under common name chemometrics, have been developed to deal with complex situations as described above.
In particular, multivariate correlation techniques such as Partial Least Squares (PLS) are commonly used to develop algorithms for extraction of required information from spectral measurements. In applying this process to non-invasive analyte measurements in humans, spectral measurements are made on the selected body part of volunteers. For each spectral measurement, a reference measurement of the target analyte is made from a drawn blood sample. PLS is used to correlate changes in the analyte value to changes in the spectral measurements. A calibration algorithm is developed from this correlation. It is the standard practice to perform all the above mentioned spectral measurements on a single instrument (often referred to as the master) to obtain the most consistent calibration algorithm.
The application of this solution imposes a few problems however. The first problem is related to variability of the spectra produced by sample. This can be caused either by change of the spectra of the substances existing in the sample due to variation of the sample chemical composition, temperature, humidity or pressure and so on, or as a result of the presence in the sample of chemical components that were not present during calibration measurement. The second problem is related to variation in instrument measurement characteristics. The third one arises when an algorithm developed on one instrument has to be translated to other instrument.
The first problem has been addressed by Haaland (David Haaland; Synthetic Multivariate Models to Accommodate Unmodeled Interfering Spectral Components during Quantitative Spectral Analysis; Applied Spectroscopy vol 54, 2000, no2 p 246), who describes incorporating a mathematically derived variation caused by xe2x80x9cUnmodeled Interfering Spectral Componentsxe2x80x9d into the calibration algorithm. This method involves identifying the spectrum of xe2x80x9cspectral interferentsxe2x80x9d (in an example given in the above publication this is the spectral change of water spectra caused by temperature variation). This spectrum is synthetically added to the original calibration spectra in a random or designated fashion over the range of variation that might be expected in future samples. An example of temperature variation is used in the samples to show that incorporating the interfering spectra from temperature variation improves the prediction of samples that have temperature variation. This document discloses the benefit of synthetic adding of specific spectral contributions from interfering chemical components, but does not address the issue of changes in spectrum caused by variation of technical characteristics of the instrument, which cannot be presented as an addition to the spectra. These include changes in spectral response of the instrument from measurement to measurement due to thermal and mechanical variations, and differences in wavelength calibration of different instruments where algorithm transfer between instruments is required. In a first order of approximation, in both cases, these changes can lead either to shift of whole spectrum, its contraction or expansion, or both effects together. None of these effects can be mathematically modeled by the addition of an interfering spectral component to the spectrum obtained with some instrument at some moment of time. A similar problem arises when the photometric response of the instrument changes over time. Some of these problems have been partially addressed within the art, but none offer a satisfactory solution of the problem when a large number of instruments, whose characteristics may vary over time and in response to environmental changes, has to be calibrated.
An algorithm (typically a calibration algorithm) developed on the master, as described above, is dependent upon the characteristics of the instrument that is used to develop it. Hence, if the characteristics of the instrument change, the algorithm may produce erroneous results. Transfer of the algorithm to other (slave) instruments that have differences in characteristics such as wavelength or spectral shape is often a difficult problem and the subject of much study. A number of techniques have been developed to translate the measurement results made on a slave instrument to match that of a master instrument. For example, a commonly use method is piecewise direct standardization (PDS; described in Y. Wang, D. J. Weltkamo and B. R. Kowalski; Analytical Chemistry vol. 63, 1991, p. 2750). This method is compared to a method based upon neural networks in Despagne et al. (Frederic Despagne, D. Luc Massart, Martin Jansen and Hansvan Daalen; Intersite Transfer of Industrial Calibration Models; Analytica Chimica Acta; vol 406, 2000, p233). A description and example of use of another approach, Shenk""s algorithm is described in Bouveresse et al. (E. Bouveresse, D. L. Massart and P Dardenne, Calibration transfer across near-infrared spectrometric instruments using Shenk""s algorithm: effect of different standardization samples; Analytica Chimica Acta; vol 297, 1994, p. 405). A characteristic, and limitation, of the above techniques is that they require measuring a set of standard samples, which are stable, on the master and each slave instrument. This is time consuming when a large number of slave.instruments are involved. It is also difficult to create a set of standard samples with the long-term stability required by a measurement as sensitive to instrument characteristics as glucose, for example. In addition, the translation algorithm developed is only valid as long as the characteristics of the both master and slave instruments remain as they were when the standardization samples were measured on it. Any subsequent change in instrument characteristics will cause errors in the analyte prediction.
For analytes that account for a minor part of the absorbance, such as glucose, minor changes in instrument characteristics result in large errors in the measurement of the analyte. Wavelength and photometric calibration must be used to make each instrument (slave) look like the master instrument. These calibrations must be extremely accurate for the slave instruments to match the master instrument to a sufficient degree so as to not cause unacceptable errors in analyte measurement. Even after these calibrations, small changes in instrument characteristics on a daily or even hourly basis can cause unacceptable error in analyte measurement. What is needed is a way to make the algorithm more tolerant of changes in instrument characteristics.
There has also been a report on the concept of adding more instrument variation into the algorithm as a way of building some tolerance into calibration algorithms (Durmis Ozdemir, Matt Mosley and Ron Williams; Hybrid calibration Models: An Altermative to Calibration Transfer; Applied Spectroscopy, vol 52, 1998, p. 599). Ozdemir et al. describes combining spectra measured on two instruments and show that the analytes predictions on the slave is better with an algorithm developed using spectra from both instruments than it is with an algorithm developed using only the spectra measured on the slave. This indicates that incorporating variation into the calibration algorithm could make it more tolerant of similar variations in the instruments when it is used for subsequent measurement. However, this method only includes variations between instruments that happen to occur in the two, or more, instruments that are being measured and only at the time of measurement.
As it follows from the above, there still exists a need for a method allowing incorporation of the instrument variability into calibration algorithm of spectral instrument.
The method as described herein consists in incorporation of wavelength variability of instrument calibration using either multiple instrument data collection for algorithm development or by incorporation of the synthetic instrument variability.
It is an object of the invention to overcome disadvantages of the prior art.
The above object is met by the combinations of features of the main claims, the sub-claims disclose further advantageous embodiments of the invention.
The present invention relates to a method of building instrument variation tolerance into calibration algorithms for spectroscopic devices for chemical composition analysis with spectroscopic methods. The method of the present invention is particularly suitable for blood glucose, cholesterol and other chemical components prediction based on near-infrared spectrophotometry measurements.
The present inventors have determined that partial least squares analysis (PLS) is able to identify patterns of change in a continuous measurement of spectra in a defined range.
Past experience has indicated how changes in spectra caused by scattering, temperature changes, and absorbance offsets due to differences in the interface to the subject are incorporated into an algorithm using the PLS technique. These changes have only a minor impact on the analyte value reported. While these features have been known, surprisingly, the present inventors have found that PLS can also accommodate changes in instrument characteristics, such as wavelength shift, if these changes follow a pattern and are incorporated into the algorithm.
Accordingly, in its broad aspect the present invention provides a method of taking into account the variability of spectral instruments through incorporation of variation expected from multiple instruments into an algorithm.
In an aspect of the present invention, the method comprises:
i) developing a calibration algorithm on a first instrument;
ii) applying the calibration algorithm to a second instrument;
iii) calibrating the second instrument and adjusting the calibration algorithm to account for differences between the first instrument and the second instrument; and
iv) repeating the step of applying (step ii)) in respect of (n) further instruments to provide an algorithm which may be used on all instruments. In developing such an algorithm, the instruments preferably have characteristics which span the ranges of those characteristics expected in all other instruments of the specified model.
According to another aspect of the present invention, the method comprise developing calibration algorithms on different instruments, combining the data collected from the calibrations and incorporating any variations mathematically into the algorithm.
According to yet another embodiment, the method comprises:
i) developing a calibration algorithm on a first instrument;
ii) applying the calibration algorithm to a second instrument;
iii) calibrating the second instrument and adjusting the calibration algorithm to account for differences between the first instrument and the second instrument;
iv) repeating the step of applying (step ii)) in respect of (n) further instruments to provide a first master algorithm;
v) developing one or more of the calibration algorithms on different instruments,
vi) combining the data collected from the one or more calibration algorithms and incorporating any variations mathematically into a second master algorithm; and
vii) combining the first and the second master algorithms to provide a final master algorithm, wherein in developing the final master algorithm, the instruments preferably have characteristics which span the ranges of those characteristics expected in all other instruments of a specified model.
Since the methods of the invention accommodate changes that follow a recognizable pattern, they can be used with instrument configurations that measure continuous spectra. These configurations often exhibit causes for instrument variance that result in patterned changes.
Stated differently these changes can be incorporated into an algorithm in at least 3 ways:
1. Develop the algorithm on multiple instruments either real or virtual, created by mathematical modification of readings obtained with real instruments to incorporate possible spectral and photometric variations of instrument response. The instrument characteristics must span the ranges of those characteristics expected in all other instruments of the specified model;
2. Incorporate the variations mathematically after calibration data has been collected. Again the variations incorporated must span the ranges of those characteristics expected in all instruments of the specified model; or
3. A combination of the above two approaches.
A clear benefit of including multiple instruments in the collection of calibration data is that the resulting algorithm could accommodate variations in characteristics beyond the targeted ones, such as those that affect the spectral shape of the absorbance curve in a specific pattern.
This summary of the invention does not necessarily describe all necessary features of the invention but that the invention may also reside in a sub-combination of the described features.
Other features and advantages of the present invention will become apparent from the following detailed description. It should he understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
The present invention relates to a method of building instrument variation tolerance into calibration algorithms for spectroscopic devices for chemical composition analysis with spectroscopic methods. The method of the present invention is particularly suitable for blood glucose, cholesterol and other chemical components prediction based on near-infrared spectrophotometry measurements.
The following description is of a preferred embodiment by way of example only and without limitation to the combination of features necessary for carrying the invention into effect.
The present inventors have determined that partial least squares analysis (PLS) is able to identify patterns of change in a continuous measurement of spectra in a defined range.
As used herein xe2x80x9cconcentrationxe2x80x9d or xe2x80x9cconcentration levelxe2x80x9d means the amount or quantity of a constituent in a solution whether the solution is in vitro or in vivo.
As used herein, xe2x80x9cconstituentxe2x80x9d means any substance, or any analyte found in any sample including but not limiting to a tissue and includes but not limited to carbohydrates such as for example glucose, bilirubin, a protein, for example albumin or hemoglobin.
As used herein xe2x80x9csamplexe2x80x9d means any substance in a form of plasma, gas, liquid or solid, consisting more than one chemical component, whose chemical composition is to be determined. Preferably the chemical composition is determined using spectroscopic methods in any spectral range where spectroscopic methods are applied.
As used herein, xe2x80x9ctissuexe2x80x9d means any tissue of the body of a subject including for example, blood, extracellular spaces, and can mean the entire composition of a body part such as a finger or ear lobe.
As used herein xe2x80x9csubjectxe2x80x9d means any member of the animal kingdom including, preferably, humans.
The present invention can be used with any spectrophotometer, including but not limiting to those working in NIR, the system having a light source which is projected through the item to be examined, a sample interface mechanism, a spectrometer to separate the light into its component wavelengths, a detector, amplification electronics and a computer. By measuring the loss (absorption), between the source and the detector and applying appropriate chemometric (mathematical) techniques, it is possible to non-invasively determine the chemicals being examined since different chemicals absorb different amounts of light.
Such a spectrophotometric device and method are described in detail in U.S. Pat. No. 5,361,758 (which is incorporated herein by reference). While the present description relates primarily to glucose measurement, one of the major fields of application for NIR measurement at present, it will be understood that the principles of the present invention equivalently apply to other analytes and chemical components measured invasively or non-invasively, using various spectroscopic techniques.
To utilize the NIR spectrum for glucose measurement, it is necessary to use a spectrometer which has wide dynamic range, a high signal to noise ratio, and exhibits low scattering losses. The output from the spectrometer is used to generate spectra with high precision both in absorbance and wavelength. Significant glucose absorption bands are centered about wavelengths of 1.67, 2.13, , 2.27, and 2.33 micrometers (as discussed in Small and Arnold, xe2x80x9cData handling Issues for Near-Infrared Glucose Measurementsxe2x80x9d, supra). To be able to use NIR to measure a particular compound/ analyte, chemometric mathematical analysis is applied to the measured spectrum. The mathematical analysis techniques are carried out by a computer equipped with advanced software capable of interpreting the resulting complex spectra.
To calibrate a spectrophotometer in the normal manner, the instrument response associated with the compound or analyte of interest must first be measured on a relatively large number of samples. These measurements are then compared to measurements made in a more accurate manner. From these comparisons an algorithm is developed that characterizes the compound or analyte to be measured. As was stated earlier, performance by an algorithm generated in this way will be degraded if a) new samples are measured on a slave instrument which measures at wavelengths slightly different from the master instrument, or b) the wavelengths of the master instrument shift between the measurement of calibration samples and measurement of prediction samples.
According to the present invention, to add tolerance to wavelength shifts, new calibration spectra of the samples are created. To create a new spectrum of the sample, the wavelengths of the spectrum of the sample are shifted by a fixed pattern and by a specified amount. The reference analyte (for example but not limited to glucose) value from the original sample is associated with the new sample. Additional new spectra of the samples are created in a like fashion by shifting the wavelengths of additional samples from the original calibration set by the same specified amount. Next the specified amount of the shift is changed to a new level, in a discrete step or by a random number, and additional spectra of the samples are created by shifting the wavelengths of some of the original calibration spectra by this new amount. This process is repeated until the amount of the shift covers the shift that is expected in future instruments.
The pattern of shift can be any pattern that would be expected to occur in the spectrometers. Typical kinds of shifts that occur in spectrometers would include a uniform shift, where the wavelengths for all measurement points shift by the same amount for all points, and a shift that is wavelength dependent. In this second (wavelength dependent) shift, the wavelengths of measurement points shift by a different amount dependent on position of the measurement point on wavelength axis. These and other kinds of shift can be incorporated using the method.
The above description is not intended to limit the claimed invention in any manner, furthermore, the discussed combination of features might not be absolutely necessary for the inventive solution.

Method for creating spectral instrument variation tolerance in calibration algorithms


The invention prevents dynamic airway compression during ventilatory support of a patient. The respiratory airflow is determined by measurement or calculation, and a measure of the degree of dynamic airway compression is derived from the determined airflow. This measure is servo-controlled to be zero by increasing expiratory pressure if the measure of the degree of dynamic airway compression is large or increasing, and by reducing expiratory pressure if the measure of the degree of dynamic airway compression is small or zero.

This invention pertains to the field of ventilatory support for respiratory failure, particularly due to lung disease, and in particular to automatically providing sufficient end expiratory pressure to unload intrinsic positive end expiratory pressure (PEEPi)
Subjects with chronic airflow limitation (CAL) due, for example, to emphysema and chronic bronchitis, may require ventilatory assistance, particularly during periods of acute exacerbation, or routinely at night.
Ventilatory support can reduce the work of breathing, reduce the sensation of breathlessness, and improve blood gases (oxygen and carbon dioxide levels). In subjects with CAL, most of the work of breathing is due to the high airway resistance. Approximately two thirds of this resistance is relatively fixed, and due to narrowing of the airways. However, of the order of one third of the resistance is due to dynamic airway compression during expiration. Dynamic airway compression occurs when the pleural pressure exceeds the pressure in the lumen of the airway during expiration, causing flow to become independent of effort.
In a normal subject, the alveolar pressure decays exponentially during expiration, so that the expiratory flow and alveolar pressure (relative to atmospheric) are both approximately zero at the end of expiration, and the lungs and chest wall have returned to their passive equilibrium volume VR. In patients with CAL, however, as a result of dynamic airway compression and fixed reduced expiratory flow rate, it is not possible for the lungs to return to VR in the time allowed before the start of the next inspiration. The chest is hyperinflated. The alveolar pressure remains positive, on the order of 5 to 15 cmH2O at the end of expiration. This raised alveolar pressure is termed intrinsic positive end expiratory pressure, or PEEPi. (Other names for the phenomenon are covert PEEP and occult PEEP.)
An important effect of the hyperinflation is that the patient must overcome the elastic recoil of the hyperinflated chest wall before inspiratory airflow can commence. The PEEPi is said to act as an inspiratory threshold load. A further undesirable effect of PEEPi is that during artificial mechanical ventilatory support, it interferes substantially with the triggering of the ventilator, causing patient-machine asynchrony.
It is now well understood that the addition of a counterbalancing external positive end expiratory pressure (called external PEEP, or just PEEP), approximately equal in magnitude to PEEPi, is of great benefit. First, it prevents dynamic airway compression, permitting greater expiratory airflow. Second, it balances the inspiratory threshold load. Third, it improves triggering of a ventilator by the patient.
Use of excessive PEEP, however, can be disadvantageous and even dangerous. Excessive PEEP above and beyond PEEPi will cause yet further hyperinflation. This will result in stiffening of the lung and chest wall, and an increase in the elastic work of breathing. It will also cause reduced cardiac output, and can lead to barotrauma. Further, the peak inspiratory airway pressure during ventilatory support cannot be arbitrarily increased without either exceeding the capacity of the ventilator, or reaching a pressure that is itself dangerous. Finally, excessive external PEEP will also reduce the possible airway pressure excursion or headroom available for lung inflation.
Therefore, it is advisable when applying external PEEP to set the external PEEP as close as possible to PEEPi. Since PEEPi varies from time to time, depending on a number of factors including, for example, the resistance of the small airways and the respiratory rate, both of which change with changing sleep stage, chest infection, or bronchospasm, it is desirable to be able to make multiple, or even continuous, measurements of PEEPi in order to optimize external PEEP.
A typical patient in an intensive care unit is heavily sedated and paralyzed during ventilatory support, and it is straightforward to measure the PEEPi. It is necessary only to occlude the airway during late expiration, and measure the airway pressure, which, after a few seconds of equilibration, will equal static PEEPi. Since the lung injury in CAL is usually markedly heterogeneous, different alveoli will have different end expiratory pressures, and static PEEPi is therefore a weighted average across all alveoli.
Another known method which is suitable for use in the paralyzed sedated patient is to measure the airway pressure at the start of machine inspiratory effort, and again at the start of actual inspiratory airflow. The difference between these two pressures is the dynamic PEEPi. Dynamic PEEPi reflects the end expiratory pressure in the least abnormal lung units, and substantially underestimates static PEEPi.
These simple methods do not work for patients who are not sedated and paralyzed, and who are making spontaneous breathing efforts, because they do not take into account the patients"" own respiratory muscle efforts.
One known method that is used with such patients requires a Muller manoeuvre (maximal inspiratory effort) during catheterization of the oesophagus and stomach, and is therefore completely unsatisfactory for repeated or continuous measurements in the ambulatory patient or the patient who is being treated at home long-term.
Methods for measuring the airway conductance in spontaneously breathing patients using oscillometry are taught by Peslin et al., Respiratory Mechanics Studied by Forced Oscillations During Mechanical Ventilation, Eur Respir J 1993; 6:772-784, and by Farre et al., Servo Controlled Generator to Measure Respiratory Impedance from0.25 to 26Hz in Ventilated Patients at Different PEEP Levels, Eur Respir J 1995; 8:1222-1227. These references contemplate separate measurements for inspiration and expiration. Oscillometry requires modulation of the airway pressure at a high frequency, such as 4 Hz, and measurement of the resultant modulation of the respiratory airflow at that frequency. However, these references fail to describe servo-controlling of ventilation to increase or decrease PEEP so that the inspiratory arid expiratory conductances are approximately equal.
Oscillometry has been used to control nasal CPAP (see U.S. Pat. No. 5,617,846) or bilevel CPAP for the treatment of obstructive sleep apnea (see U.S. Pat. No. 5,458,137). The problem there is essentially opposite to the problem under consideration here. In obstructive sleep apnea, there is increased resistance during inspiration, and the above two patents teach that increased resistance during inspiration can be treated by an increase in pressure. In patients with CAL and dynamic airway compression, there is increased resistance during expiration.
There is no known method or apparatus which can automatically or continuously control a ventilator or CPAP apparatus in conscious spontaneously breathing patients in order to prevent expiratory airflow limitation or to unload PEEPi in CAL.
Yet another known method for estimating PEEPi, taught, for example, by Rossi et al., The Role of PEEP in Patients with Chronic Obstructive Pulmonary Disease during Assisted Ventilation, Eur Respir J 1990; 3:818-822, is to examine the shape of the expiratory flow-volume curve, which has been observed to be exponential, if there is no dynamic airway compression. The reference further notes that in the absence of PEEPi, the flow-volume curve becomes a straight line.
The above known art only contemplates the application of an external pressure which is constant during any one expiratory cycle. However, the elastic recoil of the lung is higher at high lung volume, and lower at low lung volume. Therefore, it may be advantageous to find the minimum external pressure at each moment in time during an expiration that will prevent dynamic airway compression during that expiration.
It is an object of our invention to vary the ventilatory pressure during expiration as a function of the degree of the patient""s dynamic airway compression.
It is another object of our invention to vary the ventilatory pressure automatically based solely on continuous measurements that are already taken in conventional CPAP and ventilator apparatuses.
The present invention seeks to provide continuous and automatic adjustment of the expiratory pressure during ventilatory support, so as to substantially prevent dynamic airway compression and unload intrinsic PEEP with the smallest amount of external expiratory pressure.
The basic method of the invention prevents dynamic airway compression during ventilatory support using a conventional interface to a patient""s airway such as a face mask, nose mask, or endotracheal or tracheotomy tube, and providing the interface with an exhaust and a supply of breathable gas at a variable pressure as is known in the CPAP and ventilatory arts. The respiratory airflow is determined by measurement or calculation, and a measure of the degree of dynamic airway compression is derived. This measure is servo-controlled, preferably to be zero, by increasing expiratory pressure if the measure of the degree of dynamic airway compression is large or increasing, and by reducing expiratory pressure if the measure of the degree of dynamic airway compression is small or zero.
The measure of the degree of dynamic airway compression may be an instantaneous or pointwise measure within any given breath, and the step of servo-controlling the measure to be zero may similarly be performed pointwise within a given breath, so that the expiratory pressure is similarly varied pointwise within a breath. As an alternative to thus basing the airway compression determination and the servo control on multiple airflow determinations made within each individual respiratory cycle, the derivation of the measure of the degree of dynamic airway compression and the servo-controlling of the airway compression may be performed across a plurality of respiratory cycles.
During expiration, the expiratory pressure increase may be linear as a function of expired volume as will be described below.
The measure of the degree of dynamic airway compression is preferably derived by measuring the airway conductance separately during the inspiratory and expiratory portions of one or more respiratory cycles, and calculating the measure of the degree of dynamic airway conductance as a function of the inspiratory conductance minus the expiratory conductance, or alternatively as the ratio of the inspiratory conductance to the expiratory conductance. The two separate conductances during inspiration and expiration may be measured by superimposing a high-frequency oscillation on the patient interface pressure, at a known or measured amplitude, identifying the inspiratory and expiratory portions of each respiratory cycle, measuring the component of the respiratory airflow at the high frequency separately over the inspiratory and expiratory portions of one or more respiratory cycles, and from these measurements and the determined pressure amplitude calculating the inspiratory airway conductance and the expiratory airway conductance.
Alternatively, the measure of the degree of dynamic compression may be derived from the shape of the expiratory airflow versus time curve. The measure is zero when the expiratory flow decays exponentially from the moment of the peak expiratory flow to end expiration, but is large when the expiratory flow decreases suddenly from the peak expiratory flow and is then steady but non-zero for the remainder of expiration. The measure may be the ratio of the mean expiratory flow during approximately the last 25% of expiratory time to the peak expiratory flow.

Method and apparatus to counterbalance intrinsic positive end expiratory pressure


An automatically controlled expansion stent having an expansible stent body, actuation means for expanding the stent body, and control means for actively controlling the actuation means. The stent body is substantially tubular and includes material layers covering a plurality of radial expansion trusses. The stent employs MEMS motors under the control of a programmable logic device to expand the trusses and the stent body. Force from the motor is communicated to the expansion trusses through interconnects, which pivotally connect the trusses and provide channels for pull wires extending from the motors to the trusses. The trusses comprise a plurality of hinged links which produce symmetrical expansion of the stent body when actuated by the MEMS motor.

Coronary artery disease (CAD) is the leading cause of death among men and women in the United States, accounting for approximately one of every five deaths. Approximately 2.4 million adults have a history of myocardial infarction (MI), angina, or both, and it is estimated that millions of others have clinically silent coronary artery disease.
The traditional view has been that myocardial ischemia in CAD results from atherosclerotic plaques that narrow the vessel's lumen and decrease myocardial blood supply. However, research has shown that the reduction of blood flow results from the combination of fixed vessel narrowing and abnormal vascular tone, contributed to by atherosclerosis induced endothelial cell dysfunction.
Atherosclerotic coronary arteries can be treated by several methods. These treatment methods are divided into two major categories: non-invasive and invasive. Non-invasive treatments of coronary artery disease involve both medication and reduction of controllable risk factors of atherosclerosis. Non-invasive treatments cannot improve the coronary circulation when symptoms associated with coronary heart disease are severe. In such cases, invasive treatments are required to improve blood flow to the heart muscle. The most common invasive treatments for coronary heart disease include coronary artery bypass surgery (CABG), Percutaneous Transluminal Coronary Angioplasty (PTCA) and the use of percutaneously introduced prosthetic devices, namely, coronary stents. In CABG, a superfluous vein is removed from the patient's leg and sewn into the blood vessels that supply oxygenated blood to the heart. This transplanted vein, known as a graft, carries blood to the heart muscle, bypassing atherosclerotic areas in the coronary arteries. Alternatively, an internal mammary artery can be directly anastomosed distal to the stenotic site. CABG has become the most common major operation in the United States. It is usually a safe procedure with a ten-year patency rate of approximately 80–90 percent. Coronary bypass surgery effectively relieves chest pain (angina pectoris), increases exercise capacity, improves heart function in some patients, and prolongs life in certain patients. With current techniques, CABG requires a one-week hospitalization.
In PTCA, the lumen of an atherosclerotic coronary artery is increased by the inflation of an intravascular balloon catheter. Today, balloon angioplasty is used successfully to treat atherosclerosis in both systemic (peripheral, renal, cerebral) and coronary arteries in selected patients. The success rate of PTCA by an experienced staff ranges from 80 to 95 percent, and the average hospital stay after PTCA is roughly two days. Advantages of PTCA include decreased hospital stay, lower cost, decreased recuperation time, and no requirement of general anesthesia or chest incision. Although these advantages contributed to PTCA becoming a widely used alternative to coronary artery bypass surgery, the underlying mechanisms of balloon angioplasty continue to be elucidated. PTCA was originally thought to increase the lumen by compacting the atheromatous material within a relatively unyielding artery. Histological studies indicate, however, that the mechanisms of balloon angioplasty are much more complex and that the two primary mechanisms of this procedure are: (a) "over-stretching" of the vascular wall, which causes some mural injury, and (b) plaque fracture with partial separation from the vascular wall. This localized damage of the arterial wall is essential for a successful dilation via balloon angioplasty. Nevertheless, it is assumed that excessive damage likely contributes to complications such as restenosis, dissection, vasospasm, and rupture. Although this vascular wall damage results from mechanical forces, it is not known at which level of mechanical stress or strain it occurs.
The limitations of PTCA cited above resulted in the development of new technologies including atherectomy, laser angioplasty and coronary stenting.
The most significant change in interventional cardiology has been the growth of coronary stents, endovascular scaffolding devices that maintain the luminal integrity of diseased blood vessels. A typical stent implantation involves pre-dilatation of the target lesion via a PTCA procedure followed by implantation of the coronary stent in the same area of the coronary artery.
Clinical studies have shown that coronary stents improve the safety of PTCA by successfully treating abrupt and threatened closure, improve long-term clinical outcomes by reducing restenosis, and provide predictable angiographic results. Currently, coronary stents are available in several basic configurations: slotted tube, coil, mesh, ring, and multi-design. All are made of metal. Most stents are made of a plastically deformable material such as 316L stainless steel. Delivery of plastically deformable stents is commonly accomplished by the use of a balloon catheter. The balloon expandable stents are generally made of plastically deformable materials such as 316L stainless steel, elgiloy, nitinol, platinum-iridium and tantalum. They exhibit initial recoil due to elastic/plastic behavior of the plastically deformable stent material and initial vascular constriction. Once deployed, they provide fairly rigid scaffolding to the arterial lumen, thereby preventing abrupt closure and dissections. Self-expanding stents are generally secured on a delivery catheter under a constraining retractable sheath. Elgiloy and nitinol are the materials used for most self-expanding stent designs. Unlike the balloon expandable stents, which have some degree of recoil, self-expanding stents tend to continue expanding to their fixed diameters after deployment. Self-expanding stents do not expand beyond their pre-set nominal size. Therefore, pre-procedure proper sizing of the self-expanding stent is very important to prevent extensive vessel injury. It is not uncommon that both self-expanding and balloon expandable stents are post dilated to achieve optimum stent opposition. There are other stent designs such as bio-absorbable stents that are commonly manufactured using polymeric materials. They too are deployed using a balloon catheter. The primary advantages of such a stent over a metallic stent are: (a) there is a better match between stent stiffness and that of the vessel wall; and (b) they are designed to bio-absorb in the body after the diseased and injured vessel wall is healed. The disadvantages of such devices include low radial stiffness and visibility, and difficulty in identifying a biocompatible polymer for use in coronary arteries.
Clinically desirable stent characteristics include: minimal recoil; axial flexibility; low crossing profile; minimal surface area; adequate radial strength; good fluoroscopic visibility and good thrombo-resistance. Currently, none of the available stent designs incorporates all of these characteristics. Each stent design has its specific advantages and disadvantages. Acute clinical complications associated with coronary stenting include thrombosis (sub-acute), restenosis, bleeding due to required anticoagulation regimens, embolization, side-branch occlusion, coronary perforation and delivery balloon rupture.
Although several clinical studies have demonstrated that coronary stenting (when compared with PTCA alone) reduces restenosis rates in selected atherosclerotic lesions, restenosis within the stent (in-stent restenosis) remains a clinical problem. The incidence of in-stent restenosis has increased with recent advances in stent designs allowing stenting in difficult or less-than-ideal lesions, which leads to an intrinsically higher likelihood of restenosis following percutaneous intervention. It is estimated that of the 725,000 percutaneous coronary interventions completed in the United States, more than 80% will receive a new stent, and that 100,000 of these cases will develop symptoms due to in-stent restenosis.
The arteries, whose primary function is to carry blood from the heart to the capillaries, are generally subdivided into two categories. Those with large diameters and with many elastic constituents are called elastic arteries (e.g., aorta, carotids), whereas smaller diameter vessels are categorized as muscular arteries (e.g., coronaries, femorals). All arteries have similar wall organization and consist of three concentric layers.
The intima, or innermost layer of an artery, mainly consists of endothelial cells that line the vascular wall, the basement membrane, and a subendothelial layer. The subendothelial layer usually is present in large arteries with the exception of some special types of muscular arteries such as coronaries. The endothelial cells of the coronary arteries are elongated along the longitudinal axis of the vessel and constitute lineal folds. These endothelial folds of coronary arteries contribute to smooth peripheral blood flow and prevent the adherence of elements to the endothelial surface. The media, or middle layer of the artery, is composed of smooth muscle cells, a varied number of elastic sheets (laminae), bundles of collagen fibrils and a network of elastic fibrils all of which are embedded in a viscous gel matrix. The structure of the media is significantly different in elastic and muscular arteries. In elastic arteries, fenestrated elastic laminae, averaging 3 mm in thickness, are concentrically arranged and spaced equidistantly. Their numbers depend on the size of the elastic artery and vary between 20 and 60. A network of delicate elastic fibrils interconnects these elastic laminae. The smooth muscle cells are located within this framework. The majority of the smooth muscle cells are oriented obliquely, and run diagonally at small angles. The elastic components and the smooth muscle cells are held together by a network of collagen fibrils with two distinct and separate modes of fiber organization. The media of muscular arteries are distinguished by distinct internal elastic laminae separating the intima and the media, and less distinct external elastic laminae marking the outer border of the media. Compared to elastic arteries, muscular arteries do not have intermediate layers of concentric elastic laminae except in larger muscular vessels. Instead, muscular arteries consist of concentrically arranged populations of spindle-shaped smooth muscle cell layers. Concentrically arranged smooth muscle cells form helices that are invested within thin external lamina and narrow layers of delicate collagenous fibers. There is also a very fine network of elastin fibers throughout the media of the muscular arteries.
The adventitia, or the outermost layer of the arterial wall, consists primarily of longitudinally and circumferentially oriented collagen bundles, connective tissue cells, vasa vasorum, and a loose network of randomly oriented thin elastic fibers. Nerve cells and fibroblasts are also present in the adventitia. The thickness of the adventitia is not constant around the perimeter of the coronary arteries.
Arteries have been found to be thick-walled, nearly cylindrical, heterogeneous, anisotropic and nonlinearly viscoelastic composite materials. They undergo large deformations, relax when held at a constant strain, creep when subjected to a constant stress, and exhibit hysteresis when subjected to cyclic loading and unloading. Following preconditioning (i.e., sufficient number of loading cycles), their stress-strain relationship becomes unique, repeatable and predictable. In recent years in vivo studies performed on the coronary arteries to evaluate the role of coronary artery smooth muscle in the control of coronary circulation. These studies show not only a large potential contribution of coronary artery smooth muscle to arterial properties, but also the presence of a significant tone in coronary smooth muscle. The relative significance of this smooth muscle in the production of coronary spasm and in contributing to acute angina, however, remains unclear.
Biological tissues respond to mechanical stresses by growth and resorption when these stresses are applied over a long period of time. When the heart is overloaded its muscle cells increase in size. For example, the volume-overloaded heart increases its ventricular volume while a pressure-overloaded heart increases its wall thickness. When the oxygen supply to the lung is reduced suddenly, pulmonary blood pressure increases. As a result, the thickness of the adventitia and the smooth muscle layer in the pulmonary arteries increase, the lumens of small arteries decrease, and new muscle growth occurs on smaller and more peripheral arteries than normal. Pathological differences are observed (e.g., neointimal hyperplasia) in arteries stented via balloon-expandable versus self-expanding stents where slow growth of self-expanding stents yields greater late gains than those associated with the immediate large lumens achieved with balloon-expandable stents.
When shear stress due to blood flow artificially increases, histological and biochemical changes occur in the aortic endothelium. The transport of matter through cell membranes by active or passive mechanisms depends on strain in the cell membranes. Chemical reaction rate depends on pressure, stress, and strain. Therefore, it is reasonable to conclude that the remodeling of soft tissues involving growth and resorption of cells and extracellular materials is linked to the stress and strain in the tissue.
The determination of the failure characteristics of living tissues and organs is complex. There are many ways a material can fail in a biological sense. To study the failure characteristics of biological materials there must be correlative clinical observations and pathological examinations with stress and strain in the tissues. For example, soft tissues have very different stress-strain relationships than those of the typical engineering materials. Hysteresis, creep, and relaxation exist in soft tissues, and the strength of most soft tissues depends on the strain rate. In the physiological range, the stress in the soft tissue generally increases exponentially with increasing strain. At a certain strain higher than physiological, the tissue yields and breaks. Acute morphologic changes due to PTCA include endothelial denudation extrusion of fluid from the lesion, fracture of the plaque with partial separation from the underlying media, and "over-stretching" of the vascular wall. The majority of the damage occurs in the intima and the inner half of the media, medial damage consists primarily of smooth muscle cell layer disruption including torn cell-to-cell and cell-to-elastin connections, the intimal and medial damage increases with increasing dilation, and the adventitia remains largely undamaged. Any mechanical trauma, which alters a tissue morphologically, also produces physiologic changes. In the case of balloon angioplasty, long term effects include platelet and fibrin deposition on the damaged endothelium, formation of neointima, removal of damaged myocytes by macrophages, edema, and synthesis of new collagen by fibroblasts. Physiologic changes also include differences in sodium pump activity, prostacyclin release, and changes in the artery's nutrient supply and metabolism. In summary, the general characteristics of arterial damage due to PTCA can be summarized as follows: intimal and medial damage, increasing with dilation; intramural damage greater in the inner wall than in the outer wall; longitudinal intimal-medial dissection; medial damage consisting primarily of disrupted smooth muscle, including torn cell-to-cell and cell-to-elastin connections and torn elastic (some collagen) fibers.
These findings are consistent with known stress distributions in non-uniformly inflated cylinders. That is, in addition to higher stress concentrations in the inner walls, shearing stresses are produced in the walls of the cylinder in the tangential-axial (EZ) and radial-axial (RZ) planes. Data on uniformly hyper-distended vessels further suggest that the smooth muscles (and basal lamina) probably tear first. Muscle tears more easily than connective tissue and is probably why muscle is often surrounded by protective connective tissue sheaths. Elastin appears to tear before collagen and is consistent with mechanical data. The modulus of elastin is orders of magnitude less than that of collagen, and elastin is less undulated than collagen. Thus elastin becomes taut well before the collagen. Because of this, it is a common misconception that a balloon exerts only a radial pressure on the intimal surface. Since vessels usually experience only normal stresses (except near branch sites), they are not designed to resist this type of load and may therefore be susceptible to shear induced tearing.
The primary obstacle to the long-term success of PTCA and coronary stenting is restenosis. The restenosis occurs within three to six months in 25–50% of patients who have PTCA and/or stenting procedures. Costly additional interventional or surgical procedures are usually required to treat the restenosis. It is well accepted that vascular restenosis or renarrowing of the lumen of the coronary artery is a direct response of the vessel injury incurred during revascularization. In a recent paper, it was stated that the common denominator for all current revascularization techniques appears to be vessel wall injury, independent of revascularization method (i.e., removal of vascular endothelium and exposure to deep tissue components).
Utilizing an animal model, Robert Schwartz showed that restenosis and the related neointimal response have a direct correlation to the amount of coronary artery injury, regardless of the intervention type. This observation is consistent with the restenosis rates reported in the literature for small vessel interventions. Although the same sizing criterion (balloon to reference vessel diameter) is used, the circumferential stretch ratio in the wall of small vessel would be higher than that of the larger diameter vessel, and thus, the amount of vascular injury in the small diameter vessel would be much higher. Similarly, the treatment of a long, diffused lesion with PTCA would require inconsistent "over-stretching" between the normal and diseased segments of the target vessel and thus result in increased vascular damage. There are several mechanisms that lead to restenosis: thrombosis; inflammation; smooth muscle cell migration/proliferation; and extra-cellular matrix formation/degradation. These represent the fundamental sequence of response to injury. The final clinical consequence of these mechanisms is late lumen renarrowing due to neointimal hyperplasia.
Historically, restenosis has been treated with medical therapy, balloon angioplasty, or CABG surgery. Specifically, if the original invasive procedure was angioplasty without stenting, the next step, once restenosis occurs, is usually to repeat the angioplasty followed by stent implantation. If restenosis occurs within a stent, it is usually treated by repeat angioplasty. However, once restenosis has occurred, the chance of a second restenosis nearly doubles.
Over the past decade, several new devices and strategies have been developed to reduce restenosis. These include directional, rotational and extractional atherectomy devices, excimer laser angioplasty and cutting balloon, but no therapy has consistently achieved reduction in restenosis. The focus of the prevention of restenosis has also been on the use of pharmacological agents. Local drug delivery devices, including drug-eluding stents, and even more sophisticated cell-based vascular gene-delivered systems have been developed. The clinical application and efficacy of such therapies, however, remains to be demonstrated.
Finally, the United States Food and Drug Administration (FDA) recently approved a new therapy, two catheter-based radiation therapies for the treatment of in-stent restenosis. However, the long-term safety of this novel therapeutic approach has been argued. There are associated problems such as edge restenosis, late thrombotic occlusions and potential delayed restenosis. In addition, incorporating intracoronary radiation in daily clinical practice has practical problems.
The nature of both PTCA and/or stenting (with pre-dilatation) techniques is that they induce some degree of injury on the coronary artery wall via balloon dilatation. It is generally accepted that this so-called "controlled" wall injury is required to achieve the desired acute and long-term clinical outcomes. Inherent in response to this injury, restenosis remains to be a major clinical problem. Although, limiting the amount of injury during revascularization has been proposed as a means to limit the restenosis, there has been no attempt made to develop this idea further.
It would be desirable, therefore, to provide an interventional method that limits the amount of injury during revascularization and that comprises an alternative method to PTCA and current stenting practice. Such a revascularization technique would minimize vascular injury, and therefore, the restenosis rates associated with PTCA and stenting. The vascular wall would not be injured (or the injury would be minimal) when it is stretched at an actively controlled manner (or strain rate) where stresses in the vascular wall remain at or below the physiologic levels at all times. Under such loading conditions, the vascular tissue including the endothelial layer would not be exposed to a major mechanical trauma. Instead, the vascular tissue would adapt (condition) or positively remodel in response to this actively controlled stretching. The remodeling would be different than the remodeling associated with the restenosis process (i.e., vascular response to injury—neointimal hyperplasia following PTCA). This device would provide adequate initial scaffolding upon deployment and allow actively controlled expansion (gradual or step-wise) of the vascular wall. The novelty of this method is that adequate flow through the diseased segments of blood vessels (or conduits) would be achieved by an actively controlled stent-like implantable device. Preferably, the device would be motorized (e.g., by Micro-Electro-Mechanical Systems, MEMS) or otherwise mechanically actuated to provide controlled, gradual or step-wise expansion of blood vessels. The controlled, gradual or step-wise expansion would prevent trauma to the tissue, thus eliminating potential long-term complications (such as restenosis), and allow blood vessels (the living tissue) to remodel in a controlled manner. The utility of this method is that, with MEMS and/or nano technology, it is possible to design and build such a state of the art interventional device.

Flexible MEMS actuated controlled expansion stent


An improved process for producing a substantially pure gamma phase a quinacridone pigment or pigment derivative involving preparing an aqueous slurry of a crude quinacridone in the presence of caustic alkali and a non-polar, water immiscible solvent; and heating said slurry at a temperature above about 120xc2x0 C.

The present invention relates to a conditioning process for quinacridone pigment and quinacridone derivatives, useful as colorants for printing inks. More particularly, the invention relates to treatment of quinacridone and quinacridone derivatives at elevated temperatures with caustic alkali and non-polar water immiscible solvent to produce a substantially pure gamma phase quinacridone pigment of large particle size.
It is well known that opaque quinacridones of gamma phase with a high covering power can be prepared from two different approaches. One approach requires milling the large particle quinacridone crude with salt or conditioning the extremely fine quinacridone crude in solvent. For example, the cyclization of 2,5-dianilino-3,6-dihydro terephthalic acid or its methyl ester in Dowthern A (available from Dow Chemical Co., Midland, Mich.) will generate 6,13-dihydroquinacridone of large particle size. Oxidation of 6,13-dihydroquinacridone in aqueous methanol in the presence of sodium hydroxide yields a crude quinacridone which is subjected to salt-milling. Quinacridone of gamma modification is then produced by either treating the salt-milled material with various organic solvents or milling the crude with inorganic salt in the presence of an alcohol and a base.
In another approach, quinacridone crude can be prepared by cyclizing 2,5-dianilinoterephthalic acid in strong acid, e.g., polyphosphoric acid or its acid methyl ester. The resulting crude is extremely small and requires after-treatment to increase particle size for arbitrary application.
Crude quinacridones are normally conditioned with organic solvents to give dispersible pigments. For example, U.S. Pat. No. 4,895,948 discloses a one-step finishing process in which a crude quinacridone is ball milled in an alcohol containing a base. U.S. Pat. No. 5,084,573 also discloses a one-step finishing process in which 2,9-dichloroquinacridone is stirred in heated polar organic solvents containing, as essential ingredients, cedain long-chain thiol compounds and a base. U.S. Pat. No. 5,095,056 discloses a process for conditioning 2,9-dichloroquinacridone using large quantities of polar solvents, including esters such as methyl benzoate, at temperatures above 50xc2x0 C. Although bases and other such additional compounds are not required, the polar solvent is used in an amount that is about 3 to 20 times the weight of the pigment. Water can be tolerated but is not preferred. U.S. Pat. No. 3,256,285 similarly discloses a process for finishing aqueous pastes of quinacridones in large quantities of organic solvent (4 to 10 times the amount of pigment) at temperatures of 80xc2x0 to 150xc2x0 C. When using high-boiling or water-immiscible solvents (such as methyl benzoate and methyl salicylate) according to U.S. Pat. No. 3,256,285, the presscake must be washed with low boiling organic solvents, thus requiring the disposal of significant quantities of organic liquids which is more costly and time consuming.
U.S. Pat. No. 5,383,966 describes the preparation of quinacridone in methyl benzoate and aromatic esters (as the polar organic solvent) in relatively small quantities and without the need for special additives. However, the suitable quinacridone for this method is specified as 2,9-dimethylquinacridone, 2,9-dicholoquinacridone or solid solution of either chemical with unsubstituted quinacridone. Furthermore, it is important to note that caustic alkali is not used during the conditioning step in this method but rather is added after conditioning to hydrolyze methyl benzoate. The solvent used is methyl benzoate which is a polar solvent.
The present invention provides an improved and economic method for preparing gamma phase quinacridone of large particle size using caustic alkali and a non-polar water immiscible solvent.
The present is an improved process for conditioning a quinacridone pigment and quinacridone derivatives comprising: (a) preparing an aqueous slurry of a crude quinacridone in the presence of caustic alkali and a non-polar, water immiscible solvent; and (b) heating said slurry at a temperature above about 120xc2x0 C. thereby producing a substantially pure gamma phase quinacridone pigment.
It has been surprisingly found that substantially pure gamma crystal phase quinacridone pigment or derivative of large particle size can be prepared by treating a crude quinacridone preparation with water and caustic alkali in the presence of small amount of non-polar, water immiscible, solvent at a temperature above about 120xc2x0 C., and more preferably from about 120xc2x0 C. to about 170xc2x0 C., to give a soft and opaque pigment. The addition of caustic alkali and non-polar, water immiscible solvent is essential to the success of this invention. Elimination of caustic from process prevents the complete conversion of the alpha crude into the gamma modification and the removal of solvent retards crystal conversion totally.
The crude quinacridone can be prepared in a number of ways. Preferably, crude quinacridone is prepared by: (a) dissolving 2,5-dianilinoterephthalic acid in polyphosphoric acid (PPA), at a temperature of about 90 to 130xc2x0 C. to result in a magma; and (b) striking the resulting mixture (i.e. magma) into water to precipitate alpha phase crude quinacridone.
While dissolving 2,5-dianilinoterephthalic acid in PPA, the concentration and temperature of PPA are key elements affecting product opacity and cleanness. A high PPA concentration and low condensation temperature generally results in a crude which can be opacified easier. The PPA concentration can be increased through the addition of P2O5. It is preferable to maintain the PPA concentration between 117% to 119% and to control the condensation temperature at 90 to 120xc2x0 C. A lower PPA concentration or higher condensation temperature will result in a dark and poor dispersible pigment. After cyclization of 2,5-dianilinoterephthalic acid, the PPA mixture is then poured into water to precipitate quinacridone crude.
Preferably, the resulting crude quinacridone is washed to conductivity below 1000 mu, more preferably below 800 mu.
The purity of the 2,5-dianilinoterephthalic acid intermediate often affects product quality and therefore must be kept as high as possible. Major impurities such as 2-anilinoterephthalic acid and 2,5-dianilinobenzoic acid should be eliminated or substantially reduced during the preparation of intermediate. To maintain consistent quality of final pigment, the purity of 2,5-dianilinoterephthalic acid is preferably 98.0% or higher.
The crude quinacridone, which is in the form of alpha phase, may be washed thoroughly with water before reslurrying back into water. The filtercake must be broken down entirely to form a good dispersion. Any undispersible lump will lead to a dark, dirty and bluish material. The amount of water used should be enough to provide a fluidable mass and is preferable 10 to 15 times the pigment weight. Frequently, small amounts of surfactant can be added to the slurry to improve dispersion.
Both organic and inorganic alkali may be used in the conditioning process, but the caustic alkali such as sodium hydroxide, potassium hydroxide or lithium hydroxide is preferred due to their low cost. The alkali increases the ionic characteristics of quinacridone and speeds up particle size growth in water. The amount of caustic alkali is preferable at 0.3 to 0.8 times of pigment weight. Shortage of caustic would slow down the opacification process and result in a dark and dull pigment. Elimination of caustic from process prevents the complete conversion of alpha crystal into gamma modification, in certain case, such as at elevated temperature, part of alpha crystal can even transform into beta crystal.
Various types of non-polar, water immiscible solvent, such as xylene, alpha-olefin, textile spirits, mineral spirits and many aliphatic hydrocarbon solvents can be applied in this invention. Due to its water immiscible nature, it often encapsulates pigment and forms bead-like particles. The physical condition of the encapsulated pigment facilitates not only filtration speed but also provides soft texture after drying. The amount of non-polar solvent is preferable at about 0.1 to 2 part of pigment weight. Raising the amount of solvent will not affect the pigment quality but simply increasing the cost of production. However, the elimination of solvent from this process would be detrimental to the product in which the crude is unable to convert into gamma modification and results in a dark and dull material.
The pigment slurry after addition of solvent is heated slowly to a high temperature above 120xc2x0 C. The suitable temperature is around 130-160xc2x0 C. and is preferable at 140-150xc2x0 C. The length of heating is depended on the level of temperature and generally higher temperature requires less time to achieve similar particle size. The mixture is then cooled to 60xc2x0 C. before filtration and the presscake is washed to alkali free and dried to give an opaque, easy dispersible quinacridone with gamma modification.
Pigment made from this invention possesses a cherryish red with good covering power and its excellent light-fastness and heat stability are of considerable industrial importance for pigmenting finishes and paints and for coloring plastics.
Because of their light stability and migration properties, the quinacridone pigments prepared according to the present invention are suitable for many different pigment applications. For example, pigments prepared according to the invention can be used as the colorant (or as one of two or more colorants) for very light-fast pigmented systems. Examples include pigmented mixtures with other materials, pigment formulations, paints, printing ink, colored paper, or colored macromolecular materials. The term xe2x80x9cmixtures with other materialsxe2x80x9d is understood to include, for example, mixtures with inorganic white pigments, such as titanium dioxide (rutile) or cement, or other inorganic pigments. Examples of pigment formulations include flushed pastes with organic liquids or pastes and dispersions with water, dispersants, and, if appropriate, preservatives. Examples of paints in which pigments of this invention can be used include, for example, physically or oxidatively drying lacquers, stoving enamels, reactive paints, two-component paints, solvent- or water-based paints, emulsion paints for weatherproof coatings, and distempers. Printing inks include those known for use in paper, textile, and tinplate printing. Suitable macromolecular substances include those of a natural origin, such as rubber; those obtained by chemical modification, such as acetyl cellulose, cellulose butyrate, or viscose; or those produced synthetically, such as polymers, polyaddition products, and polycondensates. Examples of synthetically produced macromolecular substances include plastic materials, such as polyvinyl chloride, polyvinyl acetate, and polyvinyl propionate; polyolefins, such as polethylene and polypropylene; high molecular weight polyamides; polymers and copolymers of acrylates, methacrylates, acrylonitrile, acrylamide, butadiene, or styrene; polyurethanes; and polycarbonates. The materials pigmented with the quinacridone pigments of the present invention can have any desired shape or form.
The pigments prepared according to this invention are highly water-resistant, oil-resistant, acid-resistant, lime-resistant, alkali-resistant, solvent-resistant, fast to over-lacquering, fast to over-spraying, fast to sublimation, heat-resistant, and resistant to vulcanizing, yet give a very good tinctorial yield and are readily dispersible (for example, in plastic materials such as polyvinyl chloride and ABS).
The invention will be illustrated by the following specific examples, but it is to be understood that it is not limited to the details thereof and that changes may be made without departing from the scope of the invention.

Process for preparing a substantially pure gamma phase quinacridone pigment of large particle size