KR101097399B1 - Apparatus for diagnosis of diseases by estimation advanced glycation end products using skin autofluorescence - Google Patents

Abstract

PURPOSE: A device for diagnosing a disease with the amount of final glycated substances using auto skin fluorescence is provided to diagnose self-fluorescence of a skin, thereby easily diagnosing a diabetic disease. CONSTITUTION: A first light source(11b) emits light whose wavelength is between 350 and 400nm. A second light source(11a) emits white light for measuring a reflective spectrum in a visible ray wavelength area. A probe unit includes an optical fiber channel for a light source(21) connected to the light sources and an optical fiber detection channel(22).

Description

Apparatus for diagnosis of diseases by estimation advanced glycation end products using skin autofluorescence}

The present invention relates to an apparatus for diagnosing a disease by evaluating the amount of the final glycation product using skin autofluorescence, and more particularly, to evaluating the amount of the final glycation product by measuring the amount of the final glycation product of the skin. A disease diagnosis apparatus capable of performing a diagnosis.

Advanced Glycation End products (AGEs) are formed in the oxidation of proteins in body organs as a result of the Maillard reaction. This reaction impairs the function of many proteins. Healthy people continue to accumulate these products as they age.

Figure 10 shows the accumulation of the final glycation product (AGE) over a lifetime. As shown in FIG. 10, oxidative stress may be caused by smoking, eating meals containing high fatty acids, or exposure to heart risk factors such as hypercholesterolemia, as well as acute diseases such as sepsis. As the stress increases rapidly, the final glycation product (AGE) occurs. This final saccharification product (AGE) slowly degrades and accumulates over time. Increases in end glycation products (AGEs) are associated with the development of chronic diseases such as atherosclerosis. The final glycation product (AGE) tends to increase as it accumulates in the body as the person ages.

If hyperglycemia persists, a continuous reaction of non-enzymatic protein glycation and glycation occurs, resulting in the formation of an advanced glycation end product (AGE), a complex of irreversible sugars and proteins.

Accumulation of end glycation products (AGEs) proceeds fairly rapidly in people with diseases of the vascular system such as diabetes, renal failure, and cardiovascular diseases. The final glycation product (AGE) product accumulates in various tissues, including the skin. The final glycation product (AGE) has the property of emitting self fluorescence (AF) in the blue spectral region (maximum near 440 nm) by excitation light irradiation in the ultraviolet region (maximum near 370 nm).

As is known, the final glycosylation product (AGE) can serve as a biomarker for a series of diseases, and by measuring the autofluorescence of the skin by non-invasive methods, Damage can be assessed.

Therefore, final glycation end products (AGEs) predict long-term complications in age-related diseases. Specifically, the amount of skin autofluorescence increases in patients with diabetes and renal failure and is associated with the progression of vascular complications and coronary heart disease (CHD).

Accumulation of these final glycation products (AGEs) is manifested by skin autofluorescence and can be measured non-invasively, and as a non-invasive clinical tool for assessing the risk of long-term vascular complications in conditions related to diabetes and the accumulation of final glycation products (AGEs). useful.

Attached FIG. 11 measures skin autofluorescence for diabetic patients of various ages and non-diabetic controls. It can be seen from the measurement results of skin autofluorescence in FIG. 11 that there is a significant correlation between age and autofluorescence size (control group 0.32, diabetic group 0.64). In addition, diabetes patients (solid line) can be seen that the average 25% higher than the control (dotted line).

In this regard, the proposed method and equipment for the evaluation of the final glycation product (AGE) by the measurement of skin autofluorescence (AF), US Patent Publication No. 2004-186363 to measure the skin fluorescence of the lower part of the patient to determine the final glycation product Suggest a technique for evaluating (AGE).

In the above literature the excitation light source is a black glass luminescent lamp which emits in the ultraviolet region in the 300-420 nm wavelength range. Collecting and recording light is performed by an optical fiber spectrometer. To increase the measuring area, the end face of the optical fiber was placed at a distance (d: 5-9 mm) from the transparent window of the instrument. The optical fiber was placed at an angle of 45 degrees to the surface of the window to reduce the influence of reflected light reflected from the skin. The direction was set.

In order to reduce the effects of pigmentation of the skin, a complex coefficient of equal proportion of autofluorescence (AF) of 420-600 nm to reflected excitation light of 285-420 nm was introduced. With the device manufactured according to the above proposal, "AGE-reader" of <DiagnOptics> is shown in Figure 12 (<DiagnOptics>. Groningen. The Netherlands. Http://www.diagnoptics.com/). The AGE-reader, mounted on a desk, is connected to a personal computer via a USB cable, and measurements are made on a 0.4 square foot skin area.

In particular, in connection with the measurement area of the skin surface in US Patent Publication No. 2004-186363, the skin surface in the transparent window is at least three to twenty times larger than the measurement window in order to provide a larger irradiation and measurement area in a compact installation. To be set. The measurement area of the set skin surface should be at least 0.1 cm 2, with 1 to 4 cm 2 being especially preferred.

Because skin pigments can affect autofluorescence, we investigated the relationship of relative skin reflection (R%) to skin autofluorescence (AF) for subjects according to Skin Photo Type (SPT). . The light intensity of the total amount of autofluorescence measured in the range of 420-600 nm was normalized by dividing by the light intensity of the total amount of reflected excitation light measured in the range of 285-420 nm.

The main disadvantages of the equipment proposed from the prior US Patent Publication No. 2004-186363 are as follows.

First, although the devices proposed from the above literature have to measure the final glycation product (AGE) by calculating the average value of the collected optical signals, there is a problem that the accuracy of the data sample is small due to the small area of the inspection target area, which is not accurate. .

In addition, the measurement is made for a specific body part (habak), because the measurement site has a limited structure, it is difficult to measure the other body parts, there is a disadvantage that the selective diagnosis of the body part to be measured is impossible.

Specifically, in US 2004-186363, in order to increase the light collecting area, the end face of the optical fiber for collecting light is disposed at a distance from the target site, and in this case, the measured target area is about 0.4 cm 2. to be. However, in this case, there is a problem that the fluorescence signal collected is greatly reduced as the measurement distance d is increased in order to increase the area to be measured.

Therefore, in the case of US Patent Publication No. 2004-186363, there is a problem that the reliability of data detection is deteriorated due to the size limitation of the measurable skin area. In particular, this accuracy problem is prevalent in areas of skin irregularities such as spots on the skin, blood vessels seen, wounds and the like.

On the other hand, if it is impossible to select and measure points for several skin areas, it is not possible to obtain a measurement with optimal accuracy depending on the disease. For example, diabetic foot requires measurement at the foot area unlike the previously proposed method in order to increase the accuracy of the measurement.

Diabetes often involves a disease of the diabetic foot, in which case the diabetic foot ulcer develops as the disease progresses and eventually requires amputation of the lower extremities. Diabetes foot develops in 15% of all diabetic patients, and 40-60% of all lower extremity amputations are diabetic. More than 80% of lower extremity amputations are caused by foot ulcers, and most of the lower extremity amputations have not been observed by a specialist. About 90% or more patients with diabetic feet can be cured without cutting the lower extremities, if appropriate measures are taken initially.

Autofluorescence assays can be used for early diagnosis of diabetic feet. In the early stages of diabetes, the disease develops in one of the lower legs before the other. Therefore, early diagnosis of diabetic foot by fluorescence can be seen by comparing and evaluating the degree of fluorescence of the skin at the symmetrical part of the foot.

Therefore, in order to diagnose a disease such as diabetic foot as well as general diabetes diagnosis, a diagnosis apparatus capable of selective diagnosis of a body part to be measured is required.

The present invention has been made to solve the above problems, in the present invention, in measuring the final glycation product (AGE) fluorescence from the skin, the skin configured to increase the accuracy of the measurement and to expand the inspection site of the skin fluorescence spectrum An apparatus for diagnosing a disease by evaluating the final glycation product amount using autofluorescence is provided.

Particularly, in the present invention, to realize this object, the probe part including the optical fiber can be diagnosed by scanning the skin surface, and at the same time, the miniaturization and the efficiency / accuracy of light detection can be simultaneously performed to enable the scanning method. It is intended to provide a diagnostic apparatus that can be implemented.

Therefore, the present invention improves the diagnosis possibility for various diseases related to diabetes by accurately evaluating the final glycation product (AGE) by the autofluorescence measurement of the skin.

Specifically, the present invention provides a number of diagnostic functions, such as A) diagnostic function to identify potential diabetic patients through rapid examination of the general majority, B) risk progress assessment of diabetic vascular complications, and C) initial examination of diabetic foot syndrome. To provide a device for diagnosing a disease by evaluating the amount of the final glycation product using the skin autofluorescence that can be carried out in combination.

In order to achieve the above object, the present invention includes a light source unit including a light source for exciting the self-fluorescence on the skin; A detection unit for measuring secondary emission light from the skin; And a probe unit including a light source optical fiber channel connected to the light source unit and a detection optical fiber channel connected to the detection unit, wherein the optical fibers in the probe unit include a plurality of light source optical fibers disposed around the single detection optical fiber. Provided is a disease diagnosis apparatus by evaluating the final glycation product amount using skin autofluorescence.

In this case, the light source provides a disease diagnosis apparatus by evaluating the amount of the final glycation product using the skin autofluorescence, characterized in that the first light source of the light emitting diode that emits ultraviolet light having a wavelength of 370nm as excitation light do.

In addition, the light source unit provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that it further comprises a short-wave pass filter for blocking light of 400nm or more.

The present invention also provides an apparatus for diagnosing a disease by evaluating a final glycation product amount using skin autofluorescence further comprising an optical lens for transmitting light from the first light source to the light source optical fiber channel.

The light source unit may further include a second light source of a light emitting diode emitting white light for measuring a reflection spectrum in a visible wavelength range. to provide.

In addition, the second light source is a plurality of light emitting diodes arranged around the first light source, the final glycation product using the skin autofluorescence, characterized in that located between the short-pass filter and the light source optical fiber channel. Provide a device for diagnosing diseases by quantitative evaluation.

In addition, the first light source provides a disease diagnosis apparatus by evaluating the amount of the final glycation product using the skin autofluorescence characterized in that the surface is disposed in close proximity to the light source optical fiber channel to transmit light directly to the light source optical fiber channel. do.

In addition, the detection unit provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that consisting of a spectrophotometer comprising an array camera having a multicoloring device and a linear array sensor.

In addition, the detection unit further includes a long wavelength pass filter for passing autofluorescence and attenuating diffused reflected light to the level of the autofluorescence intensity, thereby diagnosing a disease by evaluating the final glycation product amount using skin autofluorescence. Provide a device.

In addition, the detection unit provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that configured to recognize the barcode containing the subject's information from the detection optical fiber channel.

In addition, the long-wave pass filter provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that the detection unit is configured to be removed on the path of the detection optical fiber channel while the barcode is recognized.

In addition, the present invention provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that it further comprises a switch for controlling the switching between the first light source and the second light source.

In addition, the probe unit provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that a plurality of optical fibers are accommodated in a cylindrical case for easy gripping.

In addition, the cylindrical case provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that the remote control / instrument module is formed.

In addition, the present invention provides a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that it further comprises a signal processing unit for signal processing from the detection unit.

In addition, the signal processing unit calculates the diabetic parameters (F / R) _d , complication parameters (F / R) _c or diabetes foot parameters (F / R) _s from the detected fluorescence parameters (F / R) The present invention provides a disease diagnosis apparatus by evaluating the final glycation product amount using skin autofluorescence characterized by diagnosing diabetic disease by comparing it with a predetermined threshold.

As described above, the disease diagnosis apparatus by evaluating the amount of the final glycation product using the skin autofluorescence according to the present invention and the diabetic disease diagnosis method using the same have the following effects.

In the present invention, it is possible to easily diagnose diabetic diseases by evaluating the autofluorescence of the skin, enabling mass screening to identify potential diabetic patients, predicting the risk of cardiovascular and related complications, Early diagnosis of foot symptoms is possible.

Measurements are made by skin contact and scanning by the probe, enabling real-time measurements by non-invasive methods.

-As it consists of a small probe that is easy to grasp, it is possible to arbitrarily select and measure the optimal place for performing accurate diagnosis of the disease.

-By measuring by scanning method, the area of the measurement target area can be enlarged to a certain level or more, thereby improving the reliability of the signal and improving the accuracy of diagnosis.

-By performing signal statistical processing on the measured signal, it is possible to improve the reliability of the measured value by eliminating error factors that occur locally in the skin.

By using parameters that do not depend on biological age to compare measurement data from different subjects, a diagnosis can be made for all ages without additional corrections.

-The remote control / instrument module which performs switch and meter functions for start and end of measurement on the gripping probe is equipped with the effect that the inspector can easily perform diagnosis while gripping the probe.

-The optical fiber of the probe can be easily inputted by checking the barcode worn by the examinee in order to quickly input the examinee's information into the signal processing unit (computer).

-Easy to use the equipment, no special training is required for the inspector, and preparation for the examinee is easy.

-The measurement time of the examinee using the equipment is within several seconds, and the equipment is small and light, which is convenient to move.

1 is a graph of secondary emission spectra from the skin in the present invention.
2 is a graph showing a relationship between reflected excitation light (R) and autofluorescence (F) scattered from the skin.
3 is a conceptual diagram illustrating an example of a method of scanning the skin surface using the diagnostic device according to the present invention.
4 is a dispersion graph of self-fluorescence of skin according to age of diabetic patients and control group.
5 is a flow chart illustrating an embodiment of a method for diagnosing diabetic disease through the evaluation of the final glycation product amount in accordance with the present invention.
Figure 6 is a block diagram of a diagnostic device made in a preferred embodiment of the present invention.
Fig. 7A is a cross sectional view of the probe section showing the optical fiber arrangement at the probe tip end;
Fig. 7B is a sectional view showing the optical fiber channel and the light trajectory at the probe end;
8 is a block diagram of a light source and a light source optical fiber channel implemented to transfer light from the light source directly to the light source optical fiber channel.
Figure 9 is a photograph of the appearance of the actual diagnostic device produced in a preferred embodiment of the present invention.
10 is a graph showing the final glycation product (AGE) accumulated in the human body over a lifetime.
FIG. 11 is a graph of variance of skin autofluorescence with age in diabetics and controls.
12 is a photograph of the appearance of a conventionally manufactured diabetes diagnosis device.

The present invention relates to a disease diagnosis apparatus capable of accurate diagnosis of various diseases related to diabetes by accurately evaluating a final glycation product (AGE) at a desired body part using autofluorescence measurement of the skin. The present invention relates to a diagnostic apparatus capable of performing a combination of the diagnosis of diabetic vascular complications and the initial examination of diabetic foot syndrome.

In addition, in the present invention, the accuracy of diagnosis is corrected by correcting the influence of various factors in the measurement and diagnosis process so that the measurement of the final glycation product amount using skin autofluorescence and accurate diagnosis of a disease related to diabetes can be made from this measurement value. It provides specific measurement methods that can be improved.

To this end, the present invention uses an optical fiber-optic spectrophotometer to improve the accuracy of fluorescence measurements and to measure in skin areas associated with disease.

Unlike the existing equipment, the proposed device of the present invention can measure any part of the body as well as the skin of the lower chest, and the measurement area is sufficiently measured according to the movement of the probe while the inspector grips the probe. Is increased.

In addition, large skin irregularities in the skin of the measurement site, such as spots of the skin, visible blood vessels, wounds, etc., which reduce the accuracy of the final glycation product (AGE) fluorescence value, are excluded from the migration path to the measurement site. You can. Other inhomogeneities that are invisible or inevitable at the measurement site, such as changes in skin thickness, melanin concentration in the epidermis, blood vessels, hair, pores, wrinkles, etc. We propose a method for obtaining accurate measurements through statistical processing.

Therefore, the following manners were used in the present invention.

a) As the measurement method adopts the method of scanning by hand, unlike the fixed method of the existing equipment, and proposes a diagnostic device that can implement this, it is possible to measure the area of a considerably larger area than the existing equipment.

b) Choose a more uniform place in the body compared to Habakkuk. In addition to diabetic foot disease, this place is the upper arm. In the examination of diabetic feet, measurements are performed at symmetrical sites of both feet.

c) A calculation by comparison function of the parameters to obtain a unique autofluorescence value that does not depend on reflectance is necessary, taking into account the relationship between the reflection intensity of excitation light reflected from the skin and the intensity of autofluorescence. On the other hand, the integral region of the fluorescence spectrum to obtain the autofluorescence intensity is limited to the region near the final glycation product (AGE) emission maximum spectrum.

d) Statistical treatment of the measurement results was carried out with the exclusion of sites of considerable local inhomogeneity.

The risk assessment of vascular complications in patients with diabetes and related diseases associated with abnormal accumulation of final glycation product (AGE) by the above method is as follows.

The selected skin area was irradiated with a probe of a fiber-optic spectrometer, and the measurement was scanned over an area of 10 cm 2 or more for 2-4 seconds. The spectrum of the light emitted secondary to the excitation light was measured at least 20 times. The integrated excitation (R) and autofluorescence (F) signals constituting the respective spectra were integrated in the corresponding wavelength ranges, and the ratio of the integrated reflection to the value of autofluorescence (F / R) or diabetes For the foot, the values measured at the symmetrical skin area of the two feet were calculated. Integration of the autofluorescence spectrum was performed in the maximum region (440 ± 20 nm) of the final glycation product (AGE) emission spectrum. Inconsistencies in the scanning test were eliminated, and their average value was calculated more accurately through statistical processing on the obtained series of signals. In order to ensure that the amount of final glycation product (AGE) that increases with age does not make it difficult to compare data between patients and healthy people, we introduce a parameter that removes the dependence of fluorescence values with age, and is not dependent on age, but only for disease. Only information by degree should be provided.

Equipment for embodying the present invention was constructed. Here, a light emitting diode that emits light in an ultraviolet wavelength region having a maximum value near 370 nm is adopted as a light source. The transmission and collection of light used fiber-optic probes. The probe part held by the inspector performs measurement while being held by the inspector, and a remote control module is installed to allow the inspector to control the equipment according to a predetermined condition. As an additional feature of the equipment, it is configured to recognize a barcode containing the patient's information by means of a fiber-optic probe to quickly enter the patient's information into a computer.

As the detection unit, an optical fiber optical spectrophotometer having a photodetector of a linear array sensor was used. The long-wave pass filter installed in the spectrophotometer weakens the intensity of spectral components caused by the reflected excitation light to the level of the autofluorescence signal. The spectrophotometer is connected to a computer via a USB cable, which processes, analyzes and stores the collected signals and also controls the entire instrument.

Hereinafter, with reference to the accompanying drawings, prior to explaining the diagnostic device according to an embodiment of the present invention, by explaining the specific steps performed by the diagnostic device, by using the self-fluorescence measurement of the skin (AGE) ) To detect the amount and explain in more detail how to diagnose diabetes-related diseases more accurately.

In the present invention, the spectral component due to the reflected excitation light is measured simultaneously with the autofluorescence spectrum in the skin autofluorescence measurement using an optical fiber-optical spectrophotometer. For this purpose, a long-wave pass filter is installed on the spectrophotometer to partially transmit the reflected excitation light. This composite spectrum is called the fluorescence-reflection spectrum, and the corresponding sum total radiation is called the secondary emission (fluorescence-reflectance spectrum of secondary radiation).

The shape of this spectrum is shown in FIG. Areas smaller than 400 nm in this spectrum are due to diffuse scattered radiation in which excitation light is reflected from the skin tissue, and areas greater than 400 nm are due to the fluorescence of the phosphors in the skin tissue. The integrated signal in the corresponding spectral region is represented by a reflected excitation light signal R and a self-fluorescence signal F. The measurement results shown below were obtained by integrating in the 365-395 nm spectral region for reflected excitation light (R) and at 430-450 nm for self fluorescence (F). The first area was selected corresponding to the emission spectrum of the 365nm LED, and the short wavelength side was limited by installing a short-wave pass filter in the light source. On the other hand, a second region was selected corresponding to the position of the maximum value of the final glycosylated product (AGE) autofluorescence emission (near 440 nm).

Typically, the F and R signals are measured simultaneously to calculate the F / R ratio. This minimizes the effect of light absorption and light scattering characteristics of skin tissue and minimizes the influence of fluctuations in brightness of the light source. In an embodiment of the present invention, the autofluorescence (F) measurement value is selected in the 420-600 nm wavelength region and the total intensity of autofluorescence in the selected designated region is the reflected excitation light (R) measurement value is the 280-420 nm wavelength. Selected in the area, the total intensity in the specified area. The fluorescence measurement is normalized by dividing the fluorescence measurement by the reflected excitation light measurement.

Measuring Area Area (㎠)

Relative standard deviation (% RSD)

brachium

forearm
F

F / R
F
F / R
Point
24.7%

11.3%
29.0%
9.5%
0.5
8.7%

5.6%
9.3%
7.7%
over 10
4.5%

2.5%
5.1%
3.5%

Table 1 and FIG. 2 below show relative standard deviations (RSDs), indicating the convergence and reproducibility of F and F / R measurement signal values measured from the implemented equipment. For evaluation, the same person was measured for several body parts (upper, lower, and foot) and various measurement area areas at the same time.

FIG. 2 is a scatter graph showing a relationship between reflected excitation light R scattered from the skin and local autofluorescence F. FIG. The measurement area is the same as that of the skin type III subjects according to the degree of burning the skin within the size of 0.5 cm 2 (divided into 1 state based on the degree to which the skin was not burned at 1 and 4). Measured at various points in the upper arm.

Scatter plot of the F and R signals of the points measured according to the degree of burning the skin in the same upper arm of the subject (skin type III) from Figure 2, the effect of the color of the skin according to the degree of burning the skin You can see the decrease in the parameter of / R. Therefore, as shown in Table 1 and Figure 2 it can be seen that the fluorescence signal F / R normalized by the reflected excitation light is much more reliable than the results evaluated by only F in the lower and upper lean.

Moreover, according to the data of Table 1, the relationship with the accuracy of the measurement according to the measurement inspection area size can be confirmed. That is, the worst results are found in the case of the smallest point measurement, and the average value of the measured area (up to 0.5 cm 2) of similar products manufactured according to the prior art is twice as large as that of the point measurement. Is improved over.

In contrast, an average of 10 cm 2 When using the scan method (Skin-Scan-Reader) proposed in the present invention carried out in the above area, the measurement accuracy is approximately double compared to the conventional measurement method (up to 0.5 cm 2) of similar products.

On the other hand, another point that can be found in the data of Table 1 is that the measurement accuracy of the F and F / R measurement signal values depends on the position where the measurement is made. According to the data shown in Table 1, the convergence of the measurement results performed at the same time is higher at upper than lower than at night. These results are also confirmed by long-term experimental data (Table 2) for the same subject.

Measurement place

Relative standard deviation
forearm

6.9%
brachium

2.3%

As shown in Table 2, the relative standard deviation is 2.3% for upper arm and 6.9% for lower arm in the 22-day measurement. This suggests that measuring from upper arm rather than lower arm can improve accuracy in solving problems related to disruption of the body system (to identify diabetics and cardiovascular damage).

Therefore, in a preferred embodiment of the present invention, the final glycation product amount is measured by using skin autofluorescence in the upper arm of the subject to diagnose diabetic disease with improved accuracy.

In the case of diabetic foot examination, direct measurements should be made at the point of symmetry between the right foot and the left foot in areas of high probability of injury.

On the other hand, in order to increase the accuracy of the measurement at each site, it is necessary to set a large measurement area of the skin, for this purpose, the present invention proposes a scanning method of scanning.

The method proposed by the present invention is shown in FIG. 3. The biceps muscle was selected as the measurement site, and the tip of the optical fiber was lightly contacted with the skin along the skin surface of the area of at least 10 cm 2 selected from the biceps position and measured while moving the probe. The test is conducted for 2-4 seconds, in which case more than 20 spectra are recorded. These spectra are obtained from F and R through information processing. The probe is configured to measure through a predetermined movement path so as to have a sufficient measurement area. Preferably, the probe is measured while moving the probe in a zigzag-shaped movement path as shown in FIG. 3.

In addition, in the processing of information in the diagnostic apparatus according to the embodiment of the present invention, it is possible to exclude in advance any points causing severe non-uniformity locally on the skin surface so as not to affect the statistical processing of the measurement result. To this end, it is possible to avoid heterogeneous areas of skin (spots, blood vessels, wounds, etc.) located on the movement path of the probe, and by using a trimmed mean method in statistically processing the measured values, By averaging the remaining values, except for the lowest points, and removing non-ideal values that deviate from the mean, more accurate results can be obtained through statistical processing of the measurement results. Table 3 below shows the statistically processed data using this truncation average method.

Sample
medium

Standard
Deviation
opponent
error
Measures

8

8.5
8.2
4.3
8.2
8.4
8.3
8.1
8.4
8.2
7.86
1.26
16.0%
real

8

8.5
8.2
8
8.2
8.4
8.3
8.1
8.4
8.2
8.23
0.17
2.1%
Cut off
8

-
8.2
-
8.2
8.4
8.3
8.1
8.4
8.2
8.23
0.139
1.7%

Data relating to Table 3 was obtained by scanning a given area of selected skin corresponding to 10 sample measurements. Detected measurements were 8.0, 8.5, 8.2, 4.3, 8.1, 8.4, 8.3, 8.1, 8.4, 8.2, and the unusually low value of 4.3 means that some error sources (e.g. It seems to have entered. In this case, the arithmetic mean 7.86 is reduced by 4.5% compared to the actual mean value of 8.23, and the standard deviation 1.26 is increased by 7.4 times compared with the absence of error factor (0.17).

On the other hand, if eight values are selected as follows except for the largest and smallest values, 8.0, 8.2, 8.1, 8.4, 8.3, 8.1, 8.4, 8.2. The average value is 8.23, which is equal to the actual average value. In this way, the accuracy of the measurement of the mean value can be increased by using the trimming averaging method.

Final glycation product (AGE) values measured from the body are observed to be dependent on age as well as diabetes related diseases. Fluorescence signals (F / R) according to age were measured in each of the control group (normal) and diabetic patients who did not suffer from diabetes using the test method proposed in the present application, and are shown in FIG. 4.

As shown in FIG. 4, in the case of the control group, the value of the parameter (F / R) is closely related to age (correlation coefficient: r = 0.936, linear trend: y = 0.064x + 2.48) . Therefore, the age of the subject to be examined should be considered, as well as the indicated parameters (F / R) in tests to identify potential diabetics.

For this the fluorescence parameter (F / R) Instead, use parameters that take into account age dependence.

(F / R) _d = (F / R) / f (Age)

In the above equation, f (Age) corresponds to a parameter representing statistical dependence on age in a given population.

By applying the correction parameter (F / R) _t in consideration of the age relationship to the fluorescence parameter (F / R) as described above, as shown in FIG. 4, the dependency of age on the graph disappears and the fluorescence signal is irrelevant to age. Can be compared.

 Looking at a specific embodiment of each step performed for the test according to the diagnostic method proposed in the present invention, it is shown in the flowchart shown in FIG.

First, the age information of the examinee is input into the computer before the measurement is made from the diagnostic apparatus. The input method is manually inputted to a computer or automatically inputted through a bar code containing information of an examinee. The device is then calibrated using standard specimens embedded in the diagnostic device and similar in optical properties to human skin.

In addition, the measurement site of the examinee is selected according to the purpose of examination.

In order to identify potential diabetic patients and to evaluate the progression of the disease in diabetic complications, the measurement site was selected at the upper arm of the subject. This case is performed along the right branch line of the flowchart of FIG.

On the other hand, measurements are performed on the skin of two symmetrical sites in order to assess the risk of developing diabetic foot symptoms. In this case, it is performed along the left branch line of the flowchart of FIG. 5.

Once the selection for the measurement site is made, the end of the probe is lightly contacted with the selected skin site and the measurement is initiated. Measurement at the selected site is performed by the inspector for a test time of 2 to 4 seconds set by a timer according to the subject's skin characteristics and examination purpose. That is, after the timer is operated, the inspector continuously scans a selected area having an area of 10 cm 2 or more along the surface of the skin along a constant moving path with a probe.

The movement path to be scanned can be appropriately set according to the position of the measurement site and the area to be measured. Preferably, the movement path of the zigzag shape is to enable uniform and continuous measurement for a certain area having an area of 10 cm 2 or more. Scan to have

On the other hand, to measure the fluorescent signal, the excitation light having a center wavelength of 370 nm is irradiated to the skin area and n spectra of the wavelength region of 350-600 nm are measured. Spectra in the 350-400 nm region were used for the evaluation of the integrated reflected excitation light signal R, and spectra in the region of 400-600 nm were used for the evaluation of the integrated autofluorescence signal F. The first wavelength region in front may be, for example, 360-390 nm and the second may be 430-450 nm.

The relative fluorescence parameter (F / R) is obtained from the measured n spectral values. These fluorescence parameters (F / R) have less effect on the structural characteristics of the skin compared to F and in addition to the instantaneous fluctuations in brightness of the light source.

From the n fluorescence parameters (F / R) obtained, m error factors with significant nonuniformity locally on the skin should be excluded and statistically processed. For this purpose, the truncation average method can be used, and this method provides a statistically more reliable average value than the simple arithmetic average calculation including accidental error factors. For example, in the calculation of trimmed averaging, the maximum m / 2 and the minimum m / 2 can be selected and removed, and the remaining selected number (n-m) can be calculated. In addition, the average value of the reliable fluorescence parameter (F / R) can be obtained by various methods.

With the fluorescence parameter (F / R) obtained from the n spectral values according to the measurement, a diagnosis according to each selected measurement site is performed.

Each diagnostic procedure is classified according to whether the selected measurement site is an upper arm or a foot, and when upper arm is selected, diagnosing the possibility of diabetes and the progression of diabetes from the fluorescence parameter, and when the foot is selected, diabetic foot symptoms from the fluorescence parameter Diagnose

In the step where the upper arm was selected to diagnose the possibility of diabetes, the calculation of the diabetes parameter (F / R) _d was performed to identify potential diabetes patients from the subjects.

Where the fluorescence parameter (F / R) is the value measured from the above steps, which refers to the average value of the relative intensity of autofluorescence (AF) of the subject's upper arm skin, and f (Age) Corresponds to a parameter representing statistical dependence.

The diabetic parameter (F / R) _d value is compared with a given constant D and provides a criterion for diabetic suspicion for inequality (F / R) _d ≧ D.

In addition, in diagnosing the progression of diabetes, complication parameters are calculated to evaluate the change in health status of the diabetic patient and to predict the risk of developing diabetes complications, and the formula for calculating the complication parameters is as follows.

Here, (F / R) ^N is the fluorescence parameter value of the current state, and (F / R) ⁰ corresponds to the initial value of the fluorescence parameter.

The calculated (F / R) _c values were compared with the constant C, and the comparison results of (F / R) _c ≥ C provide a criterion of the extent of disease development in patients with cardio-vascular complications.

On the other hand, in the selection of the measurement site, when the foot is selected, the diagnosis about the symptoms of the diabetic foot is performed, and the calculation of the diabetic foot parameter (F / R) _s is performed to predict the progression of the symptoms of the diabetic foot, The calculation formula is as follows.

Where (F / R) ^l and (F / R) ^r are the mean values of the fluorescence parameters (F / R) at the symmetrical points of the left and right feet of each subject, and the diabetic foot parameters (F / R) _s of the value is compared with the constant s, │ (F / R) s │ left foot [(F / R) _s positive] according to the comparison result of ≥ s or right foot [(F / R) _s up sound proceeding diabetic foot possible in Provide criteria for judgment.

As can be seen from the above series of steps, in the present invention, each diagnostic parameter (diabetes parameter, complications) for diagnosing the possibility of diabetes, the progression of diabetes or the symptoms of diabetic foot from the measured fluorescence parameter (F / R) Parameter, diabetic foot parameter), and the diagnosis result is output from the result of comparing each calculated diagnosis parameter with a preset threshold value, thereby providing a diagnosis result for the diabetic disease of the examinee. do.

A specific embodiment of a diagnostic apparatus for diagnosing diabetic disease by the above specific diagnostic method will be described in detail below with reference to FIG. 6.

The device according to one embodiment of the present invention is a disease diagnosis apparatus for diagnosing diabetic disease by evaluating the amount of the final glycation product at the measurement site by using skin autofluorescence, while measuring at a desired body part, It is a disease diagnosis device implemented to enable a scanning method of diagnosis so as to secure a measurement area of a predetermined level or more.

Specifically, in the embodiment of the present invention, the light source unit 10, the Y-shaped fiber optic sensor (Y-shaped fiber optic sensor 20), the detection unit 30 consisting of a spectrophotometer unit (spectrophotometer unit), the signal processing unit 40 And a power supply unit 50. As the excitation light source in the light source unit 10, a first light source having a maximum value at a wavelength of 370 nm and composed of a light-emitting diode (LED) emitting ultraviolet light in the 350-400 nm wavelength range is used. In order to observe the portion in the visible light wavelength range, second light sources 11b corresponding to light emitting diodes emitting white light are respectively provided. In addition to the light emitting diodes (LEDs) corresponding to the first and second light sources 11a and 11b, the light source unit 10 includes an optical filter 13 and a lens of coupling optics 12a and 12b.

The optical fiber sensor 20 is functionally composed of three channels corresponding to the light source optical fiber channel 21, the detection optical fiber channel 22, and the probe optical fiber channel 23. The light source optical fiber channel 21 performs a function of transmitting light from the light source unit 10 to the skin region, and the detection optical fiber channel 22 collects secondary light emitted from the skin and transmits the light to the spectrophotometer 30. It plays a role. These two channels join in the probe fiber optic channel 23 and extend to the probe end 24 in contact with the surface of the skin of the subject 60.

The light source optical fiber channel is configured to integrally receive and transmit light irradiated from the first and second light sources, while being configured to switch to the first or second light source by a switch 14. And selectively transmit light from the first light source or the second light source to the light source optical fiber channel.

7A and 7B show cross-sectional and longitudinal cross-sectional views, respectively, for a probe fiber channel in an embodiment according to the present invention.

As shown in FIG. 7A, in the embodiment of the present invention, the detection optical fiber channel is configured to be disposed at the center of the cross section of the probe, while the plurality of optical fibers constituting the light source optical fiber channel include the detection optical fiber channel at the center of the cross section. When configured to be arranged in a surrounding form, and preferably composed of six detection optical fiber channels, as shown in Figure 7a, six optical fibers can be configured to surround the detection optical fiber channel at the same distance.

The optical fibers of the two channels arranged to perform the function of the light source and the detection in the probe optical fiber channel of the above configuration are configured such that the light source optical fibers surround the detection fiber around the detection fiber, unlike the general manner in which the light source fiber is centered. In addition, since a greater number of light sources are supplied, more light can be supplied to the skin of the examinee, and an efficient light signal can be detected in the photodetection channel.

7B is a cross-sectional view of the tip of the probe, and shows a light trajectory through which the reflected excitation light and the autofluorescence generated by the skin by the irradiation of the excitation light pass between the light source optical fiber channel and the detection optical fiber channel. As can be seen, these light trajectories have a banana shape.

Each light transmission depth Z and the distance d between the light source fiber channel and the detection fiber channel have the following relationship, and the distance d between the two channels in this embodiment is substantially equal to the diameter of the fiber channel. Do.

Therefore, as can be seen in FIGS. 7A and 7B, the light source optical fiber channel is disposed due to the cross-sectional structure in which the detection optical fiber channel is disposed in the center and the detection optical fiber channel in the center is surrounded by a plurality of light source optical fiber channels. By selectively receiving excitation light and white light from the first light source and the second light source and irradiating it to the surface of the skin, the size of the optical fiber channel can be reduced and the light irradiation efficiency can be improved. It is possible to detect a larger amount of light signals generated from the more efficiently.

In addition, the cross-sectional area of the end of the probe can be reduced, so that the diagnosis can be made by a scanning method through the miniaturization of the probe, and the structure of the optical fiber is simple and easy to manufacture.

On the other hand, in the present embodiment, without forming a separate measurement window at the end of the probe, it is configured so that the end of the probe directly contacts the skin to scan the skin surface of the measurement site. This configuration excludes bright spots of light from skin light reflections entering the detection fiber channel.

One end of the light source and the detection optical fiber channel is connected to the light source unit 10 and the connectors 26a and 26b corresponding to the spectrophotometer 30 corresponding to the detection unit, respectively. The other ends of the two channels are respectively included in the probe optical fiber channel 23, and the probe optical fiber channel is housed in a casing formed along the extending direction of the plurality of channels to form a cylindrical probe. It can be easily moved by hand so that the inspector can easily scan along the desired path of travel. In addition, the case constituting the cylindrical probe portion is attached to the remote control / instrument module 25 and performs the instrument function together with the measurement start and end switch control.

The light that is secondary radiation from the skin enters the spectrophotometer 30 through the detection fiber channel and enters the focal plane of the array camera 32 with a linear array sensor. The array camera 32 having a polychromator and a linear array sensor includes an electronic board microprocessor, an analog-to-digital converter and an interface (USB / RS232 interface) for optical signal detection and signal processing. Digital conversion, primary signal processing, and signal transmission to a computer. The long wavelength pass filter 31 is installed inside the spectrophotometer 30, and as shown in FIG. 1, the magnitude of the intensity of the signal R by the reflected excitation light is the magnitude of the signal F by the emitted fluorescence. Weak until

The signal processor 40 is configured as a computer that performs secondary signal processing and collectively controls all devices in the diagnostic apparatus according to the present embodiment. The power supply unit 50 supplies power to the light source, the array camera, and the remote control / instrument module. Reflective and fluorescent standard samples 70 are provided for the reliability of the measurements within the diagnostic device and for comparing the results obtained from the respective diagnostic devices. This, together with the standard sample function in the form of a lid that can cover the probe end 24, performs a protective function to prevent contamination and breakage of the probe end of the optical fiber.

The second light source 11b of the white light installed in the light source unit 10 is located between the short pass filter 13 and the optical lens 12b and illuminates the skin so that the state of the skin can be seen in color. Standard sample 70 is used for calibration. Switching of the first light source 11b of the white light and the second light source 11a of the ultraviolet light is performed through the switch 14.

On the other hand, the light source unit 10 can be configured not to include the optical lenses 12a and 12b. In this case, the light emitting surface of the light emitting diode, which is a light source, and the optical fiber of the light source optical fiber channel are configured to transmit light directly.

This embodiment is illustrated in detail with reference to FIG. 8, and referring to this, the light emitting surface of the light emitting diode (LED) is close to the optical fiber of the light source optical fiber channel with the short pass filter 13 interposed therebetween, thereby emitting the light. It can be configured to directly transmit the light emitted from the diode.

In addition, as a preferred embodiment, when the subject is wearing a barcode containing the subject's information, including age, it can be configured to automatically enter the subject's information through the probe. In this case, in order to read and input barcode information, the pen-type probe tip contacts the subject's barcode and moves along the barcode. The intensity of the light reflected from the barcode is read and the information of the site under test is input into the computer through a special program built into the computer.

9 shows the appearance of a diagnostic device manufactured according to an embodiment of the present invention. The high-power UVA LED model YL-UVP-370 (Yes International Co., Hong Kong) was used as the light source included in the diagnostic device.The spectrophotometer is an AvaSpec 2048 Spectrometer System (Avantes BV, The Netherlands). It consisted of

While the invention has been described with reference to the preferred embodiments, those skilled in the art will appreciate that modifications and variations of the elements of the invention may be made without departing from the scope of the invention. In addition, many modifications may be made to particular circumstances or materials without departing from the essential scope of the invention. Therefore, the invention is not limited to the details of the preferred embodiments of the invention, but will include all embodiments within the scope of the appended claims.

10: light source 11a: first light source
11b: second light source 12a, b: optical lens
13: Short pass filter 14: Switch
20: optical fiber sensor 21: light source optical fiber channel
22: detection optical fiber channel 23: probe optical fiber channel
24: probe end 25a, b: connector
26: remote control / meter module 30: spectrophotometer (detector)
31: long pass filter 32: array camera
40: computer (signal processing section) 50: power supply section
60: Testee 70: Standard Sample

Claims (16)

A first light source that emits light in the wavelength range of 350 to 400 nm to excite self-fluorescence to the skin, a second light source that emits white light for reflection spectrum measurement in the visible wavelength range, and a short wavelength that blocks light of 400 nm or more A light source unit including a pass filter;
A detection unit for measuring secondary emission light from the skin;
And a probe unit including a light source optical fiber channel connected to the light source unit and a detection optical fiber channel connected to the detection unit.
The optical fiber in the probe unit is a disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence, characterized in that a plurality of light source optical fibers are arranged around the detection optical fiber.
The apparatus of claim 1, wherein the first light source comprises a light emitting diode that emits ultraviolet light having a central wavelength of 370 nm. 5.
delete The disease diagnosis apparatus of claim 1, further comprising an optical lens configured to transmit light from the first light source to the light source optical fiber channel.
delete The method according to claim 1, wherein the second light source is a plurality of light emitting diodes arranged around the first light source, and is located between the short-wave pass filter and the light source optical fiber channel using skin autofluorescence Device for diagnosing diseases by evaluation of the amount of final glycation products.
3. The disease diagnosis according to claim 2, wherein the first light source has a surface disposed in close proximity to the light source optical fiber channel to transmit light directly to the light source optical fiber channel. Device.
The apparatus of claim 1, wherein the detection unit comprises a spectrophotometer including a multicolorization device and an array camera having a linear array sensor.
The method according to claim 1 or 8, wherein the detection unit further comprises a long-wave pass filter for passing the self-fluorescence while attenuating the diffuse reflected light to the level of the self-fluorescence intensity, the final glycation product amount using the skin autofluorescence Disease diagnosis device by evaluation of the.
The apparatus of claim 9, wherein the detection unit is configured to recognize a barcode containing information of the examinee from the detection optical fiber channel. 11.
The apparatus of claim 10, wherein the long-pass filter is configured to be removed on a path of a detection fiber channel while the detection unit recognizes a barcode.
The method of claim 1, wherein the first light source and the second light source share a light source optical fiber channel, and selectively from the first light source or the second light source from a switch that controls switching between the first light source and the second light source. A device for diagnosing diseases by evaluating the amount of the final glycation product using skin autofluorescence, characterized in that light irradiation is performed.
The apparatus of claim 1, wherein the probe unit is configured to accommodate a plurality of optical fibers in a cylindrical case so as to easily hold the probe.
The apparatus for diagnosing diseases according to claim 13, wherein the cylindrical case is provided with a remote control / instrument module.
The apparatus for diagnosing diseases according to claim 1, further comprising a signal processing unit for processing a signal from the detection unit.
The method according to claim 15, wherein the signal processing unit from the detected fluorescence parameters (F / R) diabetic parameters (F / R) _d , complication parameters (F / R) _c or diabetic foot parameters (F / R) _s And diagnosing diabetic disease by comparing it with a predetermined threshold, wherein the disease diagnosis apparatus by evaluating the final glycation product amount using the skin autofluorescence.

Images