WO2018220597A1

WO2018220597A1 - Machine for non-invasive and simultaneous analysis of perfusion and water content in biological tissues

Info

Publication number: WO2018220597A1
Application number: PCT/IB2018/053948
Authority: WO
Inventors: Roberto Alberto DE BLASI
Original assignee: Universita' Degli Studi Di Roma "La Sapienza"
Priority date: 2017-06-01
Filing date: 2018-06-01
Publication date: 2018-12-06
Also published as: IT201700060473A1

Abstract

An analysis machine (1) for the non-invasive analysis of a biological tissue, both human and animal, comprising a first spectroscopy unit (2) for the measurement of oxygenation and comprising at least three optical modules (M1, M2, M3), each of which is adapted to generate a light radiation with a constant intensity and a wave length comprised in the spectrum of near-infrared; an emitter (2b); a receiver (2c), a receiving unit (2d); a second spectroscopy unit (3) for measurement of the water and comprising at least three further optical modules (M1, M2, M3) each of which generates a light radiation at constant intensity with wave length comprised in the spectrum of near-infrared; a further emitter (3b); a further receiver (3c); and a further receiving unit (3d).

Description

"MACHINE FOR NON-INVASIVE AND SIMULTANEOUS ANALYSIS OF PERFUSION AND WATER CONTENT IN BIOLOGICAL TISSUES"

PRIORITY CLAIM

This application claims priority from Italian Patent Application No. 102017000060473 filed on June 1, 2017, the disclosure of which is incorporated by reference.

TECHNICAL FIELD

The present invention is relative to a machine for non- invasive simultaneous bedside analysis of perfusion and rheology of microcirculation and water content in biological tissues .

BACKGROUND ART

Near-infrared spectroscopy (NIRS) is a technology that has been widely used, from the late 70s, to evaluate the oxygenation of biological tissues, exploiting their relative transparency to light in the spectral region from 650nm to llOOnm. In the lower portion of the spectrum of interest ( 650nm-950nm) , haemoglobin represents the main absorber whereas water is the main absorber in the upper portion ( 950nm-1300nm) . Measurement of the concentration of tissue haemoglobin has led to evaluation of the microcirculation in terms of oxygenation, perfusion and compartmentalization of the volume of blood in the venules, representing approximately 70% of the total haematic volume. The interest of researchers and clinicians has so far focused on absorption of the light in a wavelength interval in which chromophores like haemoglobin and, to a much lesser extent, "cytochrome c", can vary their state of oxygenation in a short time.

The patent EP 2211692B1 describes a non-invasive instrument for the quantitative measurement of tissue haemoglobin exploiting absorption of the water at 980 nm as a reference (Matcher SJ et al . "Use of the absorption spectrum to quantify tissue chromophore concentration changes in near-infrared spectroscopy" Phys . Med Biol. 38: 177-196, 1993) . In the clinical field the need to be able to measure not only the quantity of haemoglobin but also the quantity of water present in the biological tissue is increasingly felt. In fact, water assumes a pre-eminent role in the diffusion of oxygen from the capillaries to the cells and in maintaining an adequate perfusion of the microcirculation, in particular in the encapsulated organs exposed to inflammation. In fact, in the presence of an inflammation, movements of water occur, also rapidly, from the blood vessels to the interstice with important consequences for functionality of the organs. For this reason, it is important for these water movements to be closely monitored and treated by the clinician to avoid or reduce the progression of tissue or organ damage.

The low penetration power of the light into the tissues at high wavelengths, according to the NIRS technology currently in use, is considered the main obstacle to evaluation of the water content. Furthermore, the relatively slow variation of this molecule outside conditions in which acute inflammation is present has not helped to stimulate implementation of the NIRS technology for measuring water in tissues.

An important aid for the clinician would be the availability of an instrument providing, again in a non-invasive manner, measurement of the pressures within the microcirculation that would give rise to outflow of liquid into the interstice, so as to be able to modulate the pharmacological and infusional therapy in order not to obstruct the diffusion of oxygen within the tissues and, therefore, maintain their functionality intact. To date, measurements of the volumes and pressures in the microcirculation, obtained by means of the variations in haemoglobin concentration following progressive vein occlusion, can be performed only off-line, with extreme difficulty, using complex and bulky vascular compression equipment, and only for the purpose of research. The need was therefore felt for an instrument for non-invasive measurement of the haemoglobin and water in the tissues, compact and easy to transport, able to provide easy to use and understand numerical indications concerning the need to infuse fluids, the effectiveness of vasoactive drugs, the degree of tissue distress, the endovascular pressures that can reduce the risk of bleeding, and the effectiveness of extracorporeal purification therapies.

DISCLOSURE OF INVENTION

The subject of the present invention is a machine for non^¬ invasive analysis of a biological tissue, both human and animal, comprising a first spectroscopy unit for measuring the oxygenation, comprising at least three optical modules, each of which is adapted to generate a continuous light radiation at constant wavelength intensity comprised in the near- infrared spectrum, an emitter adapted to convey the radiations generated by the three optical modules on a same part of biological tissue, a receiver adapted to gather the radiations coming out of the tissue, and a reception unit adapted to convert and amplify the optical signals received from said receiver into respective electric signals; a command/control unit adapted to process the electric signals received from said first spectroscopy unit and to set said optical modules; and a display device connected to said command/control unit and adapted to permit display of the processed electric signals; an optical module generating a radiation at a wavelength equal to 980 nm and the other optical modules generating radiations at a wavelength smaller than 980 nm; said analysis machine being characterized in that it comprises a second spectroscopy unit for measurement of the water, comprising at least three further optical modules, each of which is adapted to generate a continuous light radiation at constant intensity with wavelength comprised in the near- infrared spectrum, a further emitter adapted to convey the radiations generated by the three further optical modules on a same part of biological tissue, a further receiver adapted to gather the radiations coming out of the tissue, and a further reception unit adapted to convert and amplify the optical signals received from said further receiver into respective electric signals and send said electric signals to said command and control unit; a first of the further optical modules generating a radiation at a wavelength equal to 1300 nm and a second of the further optical modules generating a radiation at a wavelength equal to 980 nm; said emitter being positioned at a fixed distance from said receiver and said further emitter being positioned at a fixed distance from said further receiver. The choice of the wavelengths of the second spectroscopy unit derives from the fact that at wavelengths larger than 900 nm the water constitutes the main absorber, with an absorption peak around 1300 nm, and that in the near-infrared region (650 nm to 1300 nm) the tissues are relatively transparent to the light. The use of wavelengths that range from 980 to 1300 nm allow elective valuation of the concentration of the water discerning said molecule from the haemoglobin (oxygenated and deoxygenated) . The simultaneous evaluation of wavelengths smaller and larger than 900 nm allows the identification of regions belonging to specific absorption spectra of the haemoglobin (smaller range) and of the water (larger range) respectively and the formulation of algorithms for quantization of the molecules in question. The use of several wavelengths allows a balance to be reached between power and safety, making quantitative measurement of the molecules in the tissues possible. In fact, the problem of performing absorption measurements at wavelengths higher than 980 nm lies in the difficulty of obtaining optoelectronic components that are sufficiently powerful to penetrate the tissues in depth but, at the same time, do not damage the tissue to which they are applied.

Preferably, the analysis machine comprises one single probe in which said emitter, said further emitter, said receiver and said further receiver are integrated; said emitter, said further emitter, said receiver and said further receiver facing a surface of the probe which, in use, is positioned on the skin close to the tissue to be analysed. Preferably, a third one of the further optical modules generates a radiation at a wavelength smaller than 980 nm.

Preferably, said analysis machine comprises compression means comprising at least one compressor and an inflatable cuff adapted to produce gradual and graduated sequential vein occlusions .

BRIEF DESCRIPTION OF THE DRAWINGS

An embodiment example is given below purely by way of non- limiting example with the aid of the accompanying figures, in which :

- figure 1 illustrates in an extremely schematic manner the analysis machine according to the present invention with parts removed;

- figure 2 illustrates in an extremely schematic manner an optical source of the analysis machine according to the present invention; and

- figures 3 - 5 illustrate as many graphs shown in the display device of the analysis machine according to the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Figure 1 shows overall by the number 1 the analysis machine according to the present invention. The analysis machine 1 comprises a first spectroscopy unit 2 for detecting the quantity of haemoglobin in the tissue to be analysed and a second spectroscopy unit 3 for detecting the quantity of water in the tissue to be analysed. Both the first 2 and the second 3 spectroscopy unit comprise a respective optical source 2a and 3a, which generates the radiation in the near-infrared at constant intensity necessary for the measurement, a respective emitter 2b and 3b in which the radiation generated by the optical source is conveyed to a same part of the tissue to be analysed, a respective receiver 2c and 3c for gathering the attenuated signal coming out of the tissue, and a respective reception unit 2d and 3d which converts the optical signal coming out of the tissue into an electric signal and appropriately amplifies it.

The machine 1 comprises one single probe S in which the emitters 2b and 3b and the receivers 2c and 3c are integrated. The emitters 2b and 3b and the receivers 2c and 3c face a surface of the probe S which, in use, is positioned on the skin close to the tissue to be analysed. The machine 1 comprises a command/control unit 4 adapted to set in terms of time, intensity and wavelength the optical sources 2a and 3a and to process the electric signals received by the respective reception units 2d and 3d, and a display device 5 connected to said command/control unit and adapted to allow the display of the processed electric signals.

Lastly, the machine 1 comprises a compression device also illustrated schematically and indicated by the number 6 and connected to the command/control unit which sets the operation thereof. The compression device 6 comprises a compressor 7 and an inflatable cuff 8 adapted to be housed by the patient close to the tissue to be analysed which, when it inflates, causes gradual and sequential vein occlusions. The compressor 7 is managed by a regulation and control system and, inflates /deflates the inflatable cuff 8 with pressures which can be programmed in terms of intensity and duration. The development of moderate pressures externally to the tissue to be analysed allows variations to be obtained in the haematic volume and endovascular pressures upstream of the occlusion. These measurements provide calculation of the distribution of volumes in the venular system and the pressures inside them, providing an on-line measurement of the endovascular pressure value beyond which water will spill over into the tissue interstice.

As illustrated in figure 2, each of the two optical sources 2a and 3a comprises three optical modules indicated as Ml, M2 and M3, and an optic fibre 9 into which the radiations emitted by the three optical modules Ml, M2 and M3 are conveyed. Each of the optical modules Ml, M2 and M3 comprises a respective laser diode Ldl, Ld2 and Ld3 and a respective optical coupler CI, C2 and C3 adapted to introduce the optical signal generated into the optic fibre 9. In particular, in the optical source 2a relative to the first spectroscopy unit 2, an optical module emits at the wavelength of 980 nm corresponding to a water absorption peak, while the other two optical modules emit at lower wavelengths of 685 nm and 850 nm respectively.

In the optical source 3a relative to the second spectroscopy unit 3, an optical module emits at the wavelength 980 nm corresponding to a water absorption peak, another optical module emits at the wavelength of 1300 nm corresponding to another and more intense water absorption peak, while the other optical module emits at a wavelength lower than 980 nm, namely at 904 nm.

In order to obtain measurements of light absorption at wavelengths greater than 980nm, photodiodes were used, such as InGaAs, which at a wavelength higher than lOOOnm have a greater sensitivity than the traditional photodiodes. Unlike what is reported by way of non-limiting description, each optical source can also comprise more than three optical modules, provided that the conditions reported in the claims are respected in terms of wavelengths emitted.

The use of 3 or more wavelengths is of fundamental importance for discriminating the optical absorption due to the haemoglobin from that due to the water. In this way it will be possible both to quantify the concentration of the haemoglobin and of the water and to discern the volume of the vascular bed (linked to the haemoglobin) from the volume of the extravascular space (linked to the outflow of water from the vessels) .

In fact, the absorption of the light by chromophores occurs in an extended wavelength range, so as to configure an absorption spectrum that characterizes the single molecule. When more molecules are present in a medium (e.g. the oxygenated haemoglobin, the deoxygenated haemoglobin and the water inside a biological tissue) the absorption spectra of the molecules overlap in much of the wavelength range investigated. The power to discern the various molecules, in addition to being functional to their identification, becomes fundamental for the measurement of their concentration. Said identification, in addition to being decisive for quantization of the haemoglobin and water concentrations (useful clinically) , allows discernment of the volume of the vascular bed (derived from the haemoglobin concentration) from the volume of the extravascular space (linked to the presence of the water alone) .

The use of at least 6 wavelengths split into two ranges therefore becomes crucial as it allows to obtain identification of the molecules and their concentration in short acquisition times and using relatively inexpensive emitters .

Furthermore, as reported above, the use of several wavelengths guarantees the quantitative measurement of the molecules in the tissues without having to use optoelectronic components, the power of which can be damaging to the tissue.

The optical modules of the machine subject of the present invention emit a continuous light radiation with a constant intensity. The constant intensity emission with respect to a light of the pulsed type entails simpler processing of the light signal, use of less costly components which can be used in a higher number without greatly affecting the cost of the end product, and a simpler and more reliable calibration.

The calculation of the quantity of haemoglobin is carried out exactly as described in the patent EP2211692B1 included here for reference, in which a machine for the non-invasive measurement of oxygenation of the haemoglobin in biological tissues is described and claimed.

The calculation of the water is obtained by means of algorithms, inserted in the Lambert Beer equation. The concentrations c(Hb02), c (Hb) and c (H20) are determined by using the equation below.

Where λι is 904nm; λ2 is 980nm; λ3 is 1300nm Coefficients of absorption of the water and the haemoglobin at 904nm, 980nm and 1300nm acquired at the valve surface of the brachioradialis muscle of the forearm of a patient are given below . a Hbo2 (904 nm) c (Hb02) 4.82 *10-³ [mm-¹]

a Hb (904 nm) c (Hb02) 1.5 * 10-³ [mm-¹]

a H2o (904 nm) C (#20) 1.06 * 10-3 [mm-¹] a Hb02 (975 nm) * c (Hb0₂) * 2.26 * 10^~3 [mm-¹]

a Hi (975 nm) * c (fi Os) ¾ 1.44 * 10^~3 [mm-¹]

a H2o (975 nm) * c (H₂0) * 36.2 * 10^~3 [mm-¹] a Hb02 (1300 nm) * c (fib0₂) ¾ 1*10^~4 [mm-¹]

a Hi (1300 nm) * c (fib0₂) ¾ 1*10^~4 [mm-¹]

a H2o (1300 nm) * c (H2O) * 140*10-³ [mm-¹]

From the above, it is evident that at 1300nm absorption of the light by the water is significantly prevalent. Assuming that the coefficient of absorption at this wavelength is equal to the coefficient of absorption of the water, an error of approximately 9.26% was introduced into the value p_a(980nm) . Figures 3 - 5 show the graphs relative to the quantity of haemoglobin and water obtained by positioning the probe S at the valve surface of the forearm of a patient, at the brachioradialis muscle. The graphs were obtained by causing a gradual vein occlusion, by means of the inflatable cuff 8, at inflation pressures of 5, 10, 15, 20, 30, 40, 50 mmHg respectively and then 30 mmHg twice.

In particular, figure 3 shows the graphs relative to the quantity of haemoglobin and water obtained in a representative heart surgery patient after induction of general anaesthesia, prior to surgery; figure 4 shows the graphs relative to the quantity of haemoglobin and water obtained in the patient 20 minutes after the latter has undergone cardiopulmonary bypass; figure 5 shows the graphs relative to the quantity of haemoglobin and water obtained in the patient 24 hours after the latter has undergone cardiopulmonary bypass. From the graphs of figures 3 - 5 a person skilled in the art can clearly see that the variations in optical absorption (and therefore concentration) of the water in the muscle tissue are much higher (in the order of thousands of times) following application of the cardiopulmonary bypass and the administration of fluids involved in this method.

As will be evident from the above description, the present invention allows the production of an apparatus for on-line bedside measurement of concentrations of haemoglobin and water in tissues such as skeletal muscles, brain and kidney (in children) , which provide numerical indicators of the volumes and pressures in the microvascular bed, which have a high automation and can be easily used and interpreted even by non^¬ expert healthcare professionals. Furthermore, the presence of the compression means makes it possible to measure the pressures that would give rise to outflow of liquid into the interstice, so as to modulate the pharmacological and infusional therapy in order not to create damage in the transport of oxygen to the tissues and, therefore, maintain their functionality intact.

In particular, the apparatus of the present invention, based on the "quantitative" NIRS technology, provides a novel measurement of the water content in human tissues in relation to the pressures and volumes of the microvascular bed of the tissues . Lastly, as may be evident to a person skilled in the art, the apparatus subject of the present invention constitutes an important instrument for clinicians specialising in fields in which monitoring of organ perfusion and evaluation of the effects of treatments entailing contribution and removal of fluids become important for the purposes of diagnosis and treatment (cardiology, intensive care, heart surgery, nephrology, paediatrics, obstetrics]

Claims

1. An analysis machine (1) for the non-invasive analysis of a biological tissue, both human and animal, comprising a first spectroscopy unit (2) for the measurement of oxygenation and comprising at least three optical modules (Ml, M2, M3), each of which is adapted to generate a light radiation with a constant intensity and a wave length comprised in the spectrum of near-infrared, an emitter (2b) , which is adapted to convey the radiations generated by the three optical modules (Ml, M2, M3) onto a same part of biological tissue, a receiver (2c), which is adapted to gather the radiations coming out of the tissue, and a receiving unit (2d) , which is adapted to convert and amplify the optical signals received from said receiver (2c) into respective electric signals; a command/control unit (4), which is adapted to process the electric signals received from said first spectroscopy unit (2) and to set said optical modules (Ml, M2 , M3) ; and a displaying device (5) , which is connected to said command/control unit and is adapted to allow the display of the processed electric signals; an optical module generating a radiation with a wave length equal to 980 nm and the other optical modules generating radiations with a wave length smaller than 980 nm; said analysis machine being characterized in that it comprises a second spectroscopy unit (3) for the measurement of water and comprising at least three further optical modules (Ml, M2 , M3), each of which is adapted to generate a light radiation with a constant intensity and with a wave length comprised in the spectrum of near-infrared, a further emitter (3b), which is adapted to convey the radiations generated by the three further optical modules onto a same part of biological tissue, a further receiver (3c), which is adapted to gather the radiations coming out of the tissue, and a further receiving unit (3d), which is adapted to convert and amplify the optical signals received from said further receiver (3c) into respective electric signals and to send said electric signals to said command and control unit (4) ; a first one of the further optical modules generating a radiation with a wave length equal to 1300 nm and a second one of the further optical modules generating a radiation with a wave length equal to 980 nm; said emitter (2b) being placed at a fixed distance from said receiver (2c) and said further emitter (3b) being placed at a fixed distance from said further receiver (3c) .

2. The analysis machine (1) according to claim 1, characterized in that it comprises one single probe (S) in which said emitter (2b), said further emitter (3b), said receiver (2c) and said further receiver (3c) are integrated; said emitter (2b), said further emitter (3b), said receiver (2c) and said further receiver (3c) facing a surface of the probe (S) which, in use, is placed on the skin close to the tissue to be analysed.

3. The analysis machine according to claim 1 or 2, characterized in that a third one of the further optical modules generates a radiation with a wave length smaller than 980 nm.

4. The analysis machine according to any of the previous claims, characterized in that it comprises compression means (6) comprising at least one compressor (7) and an inflatable cuff (8) , which is adapted to be housed close to the tissue to be analysed to produce a vein occlusion.