Abstract:
The present invention relates to systems and methods using optical or electrical spectroscopy for accurate detection and monitoring of biological tissue properties in a noninvasive manner. To perform in vivo diagnose with more accurate and repeatable measurements, an air-tight micro suction cup is placed against biological tissue under test (such as skin of a patient), around which an electrical or optical sensing system comprising excitation and detection sensors is integrated. Applying a high power suction pump over the micro cup, a negative pressure is generated to reshape the skin covered by the cup to a contour suitable for better measurement results. Most important, as the suction power increases, certain amount of blood flow or body fluid is brought to skin layer, providing great potential of improving those diagnoses that require direct analysis over these biological components.

Description:
BACKGROUND 
       [0001]    Diabetes is a chronic disease which consists of various metabolic disorders. It is characterized by high levels of blood glucose and it is the result of a deficiency of insulin secretion or of resistance to the action of insulin or a combination of these [1]. Diabetes therapy must maintain near normal glycaemia values (60-120 mg/dl) in diabetic patients but this is so difficult that there is a need for a blood glucose monitoring system that can provide information throughout the day. Conventional blood sampling methods are painful and not able to monitor the glucose level continuously. In the last two decades, the non-invasive biological sensing has attracted extensive studies on techniques for evaluation of glycemia with an in vivo and noninvasive manner, i.e. techniques not requiring blood collection. The areas of studies vary in a wide range of different technologies, which can mainly be classified in two categories: optical sensing (Near/Mid infrared spectroscopy, and Raman/fluorescence spectroscopy[2][3][4][5]), or electrical sensing (bioelectrical impedance spectroscopy, dielectric analysis, and electromagnetic sensing [6][7][8][9]). In terms of accuracy and repeatability as compared to current existing blood-sample based method, however, noninvasive glucose monitoring have not yet reached to a mature stage for practical clinical application. The major difficulties stem from the fact that these technologies all have, because of the noninvasive nature, weaker access to the body issue that is directly correlated to the glycaemia content, such as blood. 
       SUMMARY OF INVENTION 
       [0002]    The present invention relates to systems and methods using optical or electrical spectroscopy for more accurate detection and monitoring of various biological tissue properties in a noninvasive or minimally invasive manner. The sensing system comprises an excitation source, and a single or a plurality of receiving sensors that collects the signal passing though the biological tissue under test, such as skin of human body. To perform in vivo diagnose with more accurate and repeatable measurements, an air-tight micro suction cup is placed facing against the skin of a patient, around which the sensing system is integrated. Applying a high power suction pump over the micro cup, a negative pressure is generated that reshapes the skin inside the cup to a contour suitable for better measurement results. More important, as the suction power increases, certain amount of blood flow or body fluid is brought to the skin layer, improving those diagnoses that require analysis over the blood or the body fluid. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0003]    The invention will be more fully understood by reference to the following drawings which are for illustrative purposes only: 
           [0004]      FIG. 1  illustrates the non-invasive sensing system using micro suction cup, deployed with a single optical sensor; 
           [0005]      FIGS. 2 and 3  describe detailed design of the suction cup system; 
           [0006]      FIG. 4  presents operation procedures of the suction cup sensing system; 
           [0007]      FIG. 5  illustrates the non-invasive sensing system using micro suction cup, deployed with a single electrical sensor; 
           [0008]      FIG. 6  illustrates the non-invasive sensing system using micro suction cup, deployed with an array of optical sensors; 
           [0009]      FIG. 7  is illustrates the non-invasive sensing system using micro suction cup, deployed with an array of electrical sensors; 
           [0010]      FIG. 8  illustrates the non-invasive sensing system using micro suction cup, deployed with a single optical sensor, wherein a feedback to the suction pumping is applied to control the suction power to right amount; 
           [0011]      FIG. 9  presents operation procedures of the suction cup sensing system with feedback to control the suction power; 
           [0012]      FIG. 10  gives an example of the use of the thermal sensor in a multiple optical sensor suction cup sensing system with feedback; 
           [0013]      FIG. 11  illustrates the non-invasive sensing system using micro suction cup, deployed with a single optical sensor, wherein a humility sensor is applied to improve the diagnoses accuracy; 
           [0014]      FIG. 12  illustrates the non-invasive sensing system using micro suction cup, deployed with a single optical sensor, wherein an calibration path is applied to cope with the fluctuation caused by an unstable input; 
           [0015]      FIG. 13  presents operation procedures of the suction cup sensing system when the calibration path and the humility sensor are deployed. 
       
    
    
     DETAILED DESCRIPTION 
       [0016]    Referring more specifically to the drawings, for illustrative purposes the present invention is embodied in the methods and apparatus a generally shown in  FIG. 1  through  FIG. 13 . It will be appreciated that the apparatus may vary as to configuration and as to details of the parts, and that the method may vary as to the specific steps and sequence, without departing from the basic concepts as disclosed herein. 
         [0017]    Referring now to  FIG. 1 , a first non-invasive biological sensing system  10  is schematically described in accordance with the present invention. The device  10  comprises an excitation or transmitting source  102  coupled to a first light guide  104 , such as a fiber optic unit, to direct and transport excitation light  106  to the biological tissue under measurement, such as skin  108  of a strategically selected area of the human body. The light signal  110  that is scattered from the tissue under test is collected and transported by a second light guide  112  to an receiving optical sensor (or light detector)  114 , wherein the light signal is converted to electric signal and sent to the computer analysis unit  116 . As means of improve measurement accuracy and repeatability, a micro suction cup  118 , is placed between the light entry and exit points, with opening facing to the surface of the skin. The suction cup is made air tight by the seal ring  120 . By connecting a high power air pump  122 , the air inside the micro cup is pumped out, generating suction pressure  124  that raises up the skin surface  126  to a desirable contour. With sufficiently high suction pressure, the blood flow (or body fluid)  128  is brought to the skin layer, improving those diagnoses that typically require analysis over the blood or body fluid. 
         [0018]    The suction pump  122  described in  FIG. 1  performs suction to get the air out of the sealed cup. It can be mechanical operating manually, or electrical powered by an electrical motor. 
         [0019]    The computer unit  116  described in  FIG. 1  performs the analysis over the data collected from the receiving sensor and delivers the diagnose result. The analysis may include near infrared spectral imaging, Raman or fluorescence spectroscopy, or other type of optical based spectral analysis methods. 
         [0020]    Referring to  FIG. 2 , the micro suction cup  118  in  FIG. 1  further comprises a cup-shaped capsule  202  with an opening  204 , which is placed against the sample under test. The capsule can be typically made of glass, plastic, steel or other solid materials. A seal ring  120 , which is typically made of rubber or silicon, or other type of sealing materials, is attached to the opening to keep air-tight between the skin and the capsule. There is also small opening  206  to connect to the air suction pump. Located at bottom of the cup, closing to the skin,  208  and  210 , are used to connect the excitation source and receiving sensor respectively. Wherever devices are connected to the capsule, air-tight seal needs to be maintained at each of the openings. A release valve  212  is placed somewhere on the cup to release the suction when the measurement is complete. The micro suction cup device can be shaped differently to meet custom needs. For example,  FIG. 3  shows a design of shadow cylinder shape to reduce the size, where the block  202 , 204 ,  206 , 208 , 210 , and  120  have the same functionality as in  FIG. 2 . 
         [0021]      FIG. 4  describes the procedure of operating the cup sensing system in an in vivo manner. In a first step  402  of the procedure, the micro cup is properly mounted at the selected skin area of interest. The cup opening with seal ring ( 120  in  FIG. 1 ) has to be placed against the skin with sufficient tightness so that air-tight sealing is ensured. In case of non-flat skin area at some locations, the opening shape can be specially made to follow the contour of human body. In a second step  404  of the procedure, the excitation source, receiving sensor, and computer unit ( 102 ,  114 ,  106  in  FIG. 1 ) are all turned on. When all these units reach steady state ready for operation, the computer unit starts to collect certain amount of data for calibration purpose. The computer may also optionally give an indication if the cup sensing system is appropriately mounted. In a third step  406  of the procedure, the suction pump is activated. When skin inside the cup is raised up to a desired level because of the suction, the suction pump is stopped. In a fourth step  408  of the procedure, the computer starts to collect data while the skin level inside the cup is maintained. In a fifth step  410  of the procedure, the release valve ( 212  in  FIG. 2 ) is pressed to release the suction when sufficient data is taken by the computer unit. In a sixth step  412  of the procedure, the computer unit performs analysis over the data collected in step  408 . The data captured during calibration step  404  may be optionally used to improve the diagnose outcome. 
         [0022]      FIG. 4  specifies the operation of the biological sensing system in more precise and detailed manner, it is understood, however, one or some steps may be optionally omitted and the order of the execution of the steps may vary in actual implementation. 
         [0023]    Referring now to  FIG. 5 , a second non-invasive biological sensing system  50 , which is using the electrical sensors, is schematically described in accordance with the present invention. The device  50  comprises an electrical excitation source  502  connected to, via an electrical wire  504 , to an excitation probe  506 . The excitation source  502  can typically generate electrical signals such as DC, AC, impulse, or other types of signal waveforms. The excitation probe  506  is passing through the small opening of the micro suction cup  118  (described in  FIG. 2 ) to be directly in touch with the skin area  126  under test. At the other opening of the micro suction cup  118 , a sensing probe  508  is installed, which is connected, via electrical wire  510 , to the computer analysis unit  512 . The computer unit  512  therefore can process the electrical signal received, such as providing impedance or dielectric analysis. The rest items in  FIG. 5 , including  118 , 120 , 124 , 126  and  128 , can be similarly described as in  FIG. 1  and  FIG. 2 , and the corresponding operation procedure also follows the steps given in  FIG. 4 . 
         [0024]    The micro cup sensing system can be extended to a design of using sensor arrays, where a plurality of receiving sensors deployed around the cup generate a plurality of signals sent to the computer unit in order to improve the diagnose accuracy.  FIG. 6  and  FIG. 7  show such designs using optical and electrical sensors respectively. 
         [0025]    Referring to  FIG. 8 , a third non-invasive biological sensing system  80 , which is using a feedback control over the air pressure inside the suction cup, is schematically described in accordance with the present invention. The system  80  comprises a first link  808  that connects the computer unit  806  to the suction pump  802 , and second link  810  that connects the computer unit  806  to the release valve  804 . Based on the measurement results, the computer unit dynamically controls (such as switch on and off) the suction pump and the release valve via the feedback links, in order to achieve optimal pressure inside the suction cup for best diagnose results. As an option, the release valve should be manually controlled to override suction process anytime during the feedback procedure. As another option, a pressure sensor can be installed inside the suction cup and connected to the computer unit, in order to accurately control the suction pressure to a desired level. Note that  FIG. 8  shows an example of the feedback suction cup system using optical sensors. It should be directly applicable to other variations of the designs described in this invention disclosure, such as the sensor systems using electrical sensors, or using sensor arrays. 
         [0026]    An operation procedure  90  of the suction feedback control is shown in  FIG. 9 . The procedure is essentially based on all the steps described in  FIG. 4 , except that additionally steps are added for the feedback control of the suction pressure. In a first additional step  902 , the receiving sensor collects measurement data received from the tissue under test after the air suction step. In a second additional step  904 , a real time analysis  904  over the measured data is performed by the computer unit  806  referred in  FIG. 8 . In a third additional step  906 , the computer unit decides whether suction pressure adjustment is need based on the analysis results. If decision is no, the procedure will proceed further steps including release the suction and post processing, using similar steps described in  FIG. 4 . Otherwise, the computer unit will further decide whether the suction pressure needs be increased or decreased in a fourth additional step  908 . For increasing the suction pressure, the computer unit, via the feedback link  808  in  FIG. 8 , switches on the suction pump in a fifth step  910  for a controlled time period, and for decreasing the suction pressure, the computer unit, via the feedback link  810 , partially opens the release valve in a sixth additional step  912  for another controlled time period. After these steps, the measurement is retaken in step  902  and the aforementioned step cycle repeats until decision is made by the computer unit that no further suction pressure adjustment is needed. As an option of the first additional step  902 , the measurement data is taken from an optional pressure sensor installed inside the suction cup and the third additional step  906  makes decision based on the measured pressure level, in order to precisely control the suction pressure to a desired value. 
         [0027]    Referring  FIG. 10 , a heating device  1002  is deployed inside the suction cup to raise the air temperature for different diagnose purposes. A thermal meter  1004  can also be installed inside the suction cup for controlling the temperature. Both  1002  and  1004  are controlled by the computer unit  1010  via the wire connections  1006  and  1008 . Clearly, a temperature adjustment by a feedback procedure can be designed to maintain the temperature to a desired value. 
         [0028]    Referring  FIG. 11 , a humility sensor  1101  is deployed inside the suction cup to measure the humility of the skin under test. The humility sensor  1101  is placed tightly against the surfaced of the tissue under test, such as skin of a human body, in order to provide analysis of its water contents. This humility sensor is connected to the computer unit  1103  via the wire  1102 . In  FIG. 11 , an interdigital-shaped humility sensor is applied as an example. Other types of humility sensor can also be utilized. 
         [0029]    Referring  FIG. 12 , an auxiliary sensor  1204 , which can be either optical or electrical, is deployed to the suction cup sensing system for the purpose of calibration. This sensor also receives the signal emitted by the excitation source  1202 , passing through an attenuator  1201  connected by links  1203  and  1204 . The attenuator  1201  is made of the material of known and constant optical or electrical property. For example, the attenuator has a known optical absorption coefficient for any of the optical sensing systems described in the disclosure. The auxiliary sensor  1204  further feeds the detected signal to the computer unit  1206  for processing. 
         [0030]      FIG. 13  describes the procedure  120  whereas the humidity sensor and the calibration auxiliary sensor are applied to any of the biological glucose sensing systems described in this embodiment. In a first step  1301  of the procedure, the main receiving sensor that is connected to skin under test in the suction cup, collects a spectrum of signals (which can be either optical or electrical) at different wavelengths or frequencies, and send it to the computer unit of the sensing system. In a second step  1302  of the procedure, the auxiliary sensor collects second spectrum of signals and sends it to the computer unit. Though described in two separate steps, the step  1301  and  1302  occurs concurrently when the excitation source described in any of the sensing systems in this embodiment emits at given frequencies or wavelengths. In a third step of the procedure  1303 , a compensation factor is calculated from the input of the auxiliary sensor and the attenuation coefficients stored in the computer at each frequency or wavelength point. As a simple example, assume Sa(f) is the input from the auxiliary detector and the R(f) as the constant attenuator coefficient at frequency f, the compensation factor C(f) is calculated by C(f)=|Sa(f)|/R(f), whereas |Sa(f)| represents the amplitude of signal from the auxiliary sensor. Other non-linear algorithm can also applied to calculated C(f). In a fourth step of the procedure, the signal from the main sensor is normalized by the compensation factor calculated by  1303 . In a fifth step  1305  of the procedure, the humility sensor senses the humility of the skin and sends the signal also to the computer unit. This step can occur before or after, or same time as, the step  1301 . In a sixth step of the procedure  1206 , the computer unit selects a set of reference signature from the database  1311  based on the sensed humility level. This set of signature consists of a series of reference spectrum calibrated beforehand in terms of various concentration level of the biological tissue property under measurement, such as glucose. In a seventh step of the procedure  1307 , the computer unit correlates the received spectrum with the selected reference signature set and calculates a plurality of decision metrics, corresponding to each member of the reference signature set. As an example, the correlation algorithm can be partial linear regression (PLR) or principle component regression (PCR). In a eighth step of the procedure  1308 , a single metric is selected among the calculated decision metrics according to a optimum criterion, such as a maximum rule or any other nonlinear algorithm. At last step  1206  of the procedure, this selected decision metric is uniquely mapped to the concentration level of the measured biological tissue property from a pre-calibrated table. 
         [0031]      FIG. 13  specifies the operation of the calibration and humility sensors in a general manner, it is understood, however, one or some steps may be optionally omitted and the order of the execution of the steps may vary in actual implementation. 
         [0032]    The apparatus and methods disclosed in the entire embodiment of this invention are mainly focusing on noninvasive blood glucose sensing and monitoring via a suction cup sensing system directly applied to skin of a human body. It will be more appreciated, however, that the same methods and techniques can be directly applied to sensing and monitoring other types of biological tissue properties that partially needs in-depth access to the body tissue, such as blood. Examples of the biological tissue properties may be some clinically important blood analytes such as albumin, cholesterol, or urea. 
       REFERENCES 
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