公开(公告)号：US07043287B1

公开(公告)日：2006-05-09

申请号：US09419461

申请日：1999-10-15

申请人： Omar S. Khalil ,  Shu-Jen Yeh ,  Xiaomao Wu ,  Stanislaw Kantor ,  Charles F. Hanna ,  Tzyy-Wen Jeng

发明人： Omar S. Khalil ,  Shu-Jen Yeh ,  Xiaomao Wu ,  Stanislaw Kantor ,  Charles F. Hanna ,  Tzyy-Wen Jeng

IPC分类号： A61B5/00

CPC分类号： A61B5/14532 ,  A61B5/0059 ,  A61B5/1455 ,  A61B5/1495 ,  A61B2562/0242

摘要： Devices and methods for non-invasively measuring at least one parameter of a sample, such as the presence of a disease condition, progression of a disease state, presence of an analyte, or concentration of an analyte, in a biological sample, such as, for example, a body part. In these devices and methods, temperature is controlled and is varied between preset boundaries. The methods and devices measure light that is reflected, scattered, absorbed, or emitted by the sample from an average sampling depth, dav, that is confined within a region in the sample wherein temperature is controlled. According to the method of this invention, the sampling depth dav, in human tissue is modified by changing the temperature of the tissue. The sampling depth increases as the temperature is lowered below the body core temperature and decreases when the temperature is raised within or above the body core temperature. Changing the temperature at the measurement site changes the light penetration depth in tissue and hence dav. Change in light penetration in tissue as a function of temperature can be used to estimate the presence of a disease condition, progression of a disease state, presence of an analyte, or concentration of an analyte in a biological sample. According to the method of this invention, an optical measurement is performed on a biological sample at a first temperature. Then, when the optical measurement is repeated at a second temperature, light will penetrate into the biological sample to a depth that is different from the depth to which light penetrates at the first temperature by from about 5% to about 20%.

摘要翻译： 用于非侵入性地测量样品的至少一个参数的装置和方法，例如疾病状况的存在，疾病状态的进展，分析物的存在或分析物的浓度， 例如，身体部位。 在这些装置和方法中，控制温度并在预设的边界之间变化。 方法和装置测量由样品中的平均采样深度d> av is is is is is is is measure measure measure measure measure measure measure measure measure measure measure measure measure measure measure or or wherein wherein wherein wherein wherein wherein。。。。。。。。 根据本发明的方法，通过改变组织的温度来改变人体组织中的采样深度d>。。 当温度降低到体芯温度以下时，采样深度增加，当温度升高到体芯内温度以上时，采样深度降低。 改变测量部位的温度会改变组织中的光穿透深度，从而改变组织的光穿透深度。 可以使用作为温度的函数的组织中的光穿透的变化来估计生物样品中疾病状况，疾病状态的进展，分析物的存在或分析物的浓度的存在。 根据本发明的方法，在第一温度下对生物样品进行光学测量。 然后，当在第二温度下重复光学测量时，光将穿透生物样品至与第一温度下的光渗透约5％至约20％的深度不同的深度。

公开(公告)号：US06353226B1

公开(公告)日：2002-03-05

申请号：US09198094

申请日：1998-11-23

申请人： Omar S. Khalil ,  Xiaomao Wu ,  Johannes Sake Kanger ,  Rene′ Alexander Bolt ,  Shu-Jen Yeh ,  Charles F. Hanna ,  Frits Frans Maria de Mul

发明人： Omar S. Khalil ,  Xiaomao Wu ,  Johannes Sake Kanger ,  Rene′ Alexander Bolt ,  Shu-Jen Yeh ,  Charles F. Hanna ,  Frits Frans Maria de Mul

IPC分类号： A61B500

CPC分类号： A61B5/1455 ,  A61B5/14532 ,  A61B2562/0233 ,  A61B2562/0242 ,  A61B2562/043 ,  G01N21/49

摘要： Apparatus and method for non-invasively measuring at least one optical parameter of a sample, particularly a sample of tissue that comprises a plurality of layers. The at least one parameter can be used to determine the presence or concentration of an analyte of interest in the sample of tissue. The apparatus and method of the present invention (1) measure light that is substantially reflected, scattered, absorbed, or emitted from a shallower layer of the sample of tissue, (2) measure light that is substantially reflected, scattered, absorbed, or emitted from a deeper layer of the sample of tissue, (3) determine at least one optical parameter for each of these layers, and (4) account for the effect of the shallower layer on the at least one optical parameter of the deeper layer. Specifying the sampling depth allows determinations of the optical properties of a specific layer of the sample of the tissue, e.g., dermis, and decreases interference from other layers, e. g., stratum corneum and epidermis, in these determinations.

摘要翻译： 用于非侵入性地测量样品，特别是包括多个层的组织样品的至少一个光学参数的装置和方法。 可以使用至少一个参数来确定组织样品中感兴趣的分析物的存在或浓度。 本发明的装置和方法（1）测量从组织样本的较浅层基本反射，散射，吸收或发射的光，（2）测量基本上被反射，散射，吸收或发射的光 从组织样本的较深层，（3）确定这些层中的每一层的至少一个光学参数，以及（4）考虑较浅层对较深层的至少一个光学参数的影响。 指定采样深度允许确定组织样品（例如真皮）的特定层的光学性质，并减少来自其它层的干扰，例如， 在这些决定中，例如角质层和表皮。

公开(公告)号：US5441894A

公开(公告)日：1995-08-15

申请号：US056219

申请日：1993-04-30

申请人： Carole L. Coleman ,  Kevin R. Genger ,  Hugh W. Graham ,  Charles F. Hanna ,  Omar S. Khalil ,  David C. Wender

发明人： Carole L. Coleman ,  Kevin R. Genger ,  Hugh W. Graham ,  Charles F. Hanna ,  Omar S. Khalil ,  David C. Wender

IPC分类号： G01N21/64 ,  B01L3/00 ,  G01N21/77 ,  G01N33/543

CPC分类号： G01N33/54366 ,  B01L3/5023 ,  B01L3/50255 ,  B01L2300/0681 ,  B01L2300/069 ,  B01L2300/0829 ,  B01L2400/0406 ,  Y10S435/81 ,  Y10S436/805 ,  Y10S436/809 ,  Y10S436/81

摘要： An improved device is used for performing solid-phase chemiluminescent immunoassays. The device comprises a container having a fibrous matrix and a porous absorbent material. An improvement in the device is the use of light absorbing material as the absorbent material or as a light barrier between the fibrous matrix and the absorbent material. A second improvement comprises a fibrous matrix of binderless fiber matrix, such as glass fiber. The invention improves the direct measurement of the chemiluminescent signal from a solid surface by reducing background signal. The device is disposable and is suitable for manual use or for use with an apparatus having programmed instructions. The device is designed to be employed in a variety of solid-phase diagnostic assays such as sandwich or competitive binding assays. The device is also designed for use with microparticle capture or ion capture methods of separating the immunochemical reaction products.

摘要翻译： 改进的装置用于进行固相化学发光免疫测定。 该装置包括具有纤维基质和多孔吸收材料的容器。 该装置的改进是使用光吸收材料作为吸收材料或作为纤维基质和吸收材料之间的光阻挡层。 第二改进包括无粘合剂纤维基质如玻璃纤维的纤维基质。 本发明通过降低背景信号来改善来自固体表面的化学发光信号的直接测量。 该装置是一次性的并且适用于手动使用或用于具有编程指令的装置。 该设备设计用于各种固相诊断测定，例如三明治或竞争性结合测定。 该装置还设计用于分离免疫化学反应产物的微粒捕获或离子捕获方法。

公开(公告)号：US06662031B1

公开(公告)日：2003-12-09

申请号：US09566415

申请日：2000-05-08

申请人： Omar S. Khalil ,  Xiaomao Wu ,  Shu-jen Yeh ,  Charles F. Hanna ,  Stanislaw Kantor ,  Tzyy-Wen Jeng

发明人： Omar S. Khalil ,  Xiaomao Wu ,  Shu-jen Yeh ,  Charles F. Hanna ,  Stanislaw Kantor ,  Tzyy-Wen Jeng

IPC分类号： A61B500

CPC分类号： G01N21/4795 ,  A61B5/0059 ,  A61B5/14535 ,  A61B5/14546 ,  A61B5/1455 ,  A61B5/1491 ,  A61B5/6824 ,  A61B2562/0233 ,  A61B2562/0242 ,  A61B2562/043

摘要： A method for the determination of hemoglobin and hematocrit by means of an apparatus that is capable of controlling the temperature of a defined subcutaneous volume of human skin. The method involves a calculation of hemoglobin concentration and hematocrit value that takes into consideration the values of optical parameters of the sample at various pre-set temperatures. The apparatus and method employ steady state optical measurements of samples, such as, for example, human tissue, by means of a reflectance tissue photometer and localized control of the temperature of the sample. According to the method of this invention, an optical signal from a defined subcutaneous volume of human skin is measured as the temperature of this volume is controlled. The method and apparatus of this invention allow determination of hemoglobin concentration and hematocrit value non-invasively in a population of subjects having different skin colors by means of steady state reflectance measurements. The method of this invention for determination of hemoglobin concentration and hematocrit value is useful for monitoring patients, testing at the point of care, and screening for anemia. In contrast to other attempts in the prior art that rely on signals of cardiac pulses, the method of this invention has the advantage for the determination of analytes in weak cardiac pulse situations, such as, for example, in elderly patients.

摘要翻译： 用于通过能够控制人皮肤的规定的皮下体积的温度的装置来测定血红蛋白和血细胞比容的方法。 该方法涉及在各种预设温度下考虑样品的光学参数的值的血红蛋白浓度和血细胞比容值的计算。 该装置和方法利用反射组织光度计对样品（例如人体组织）进行稳态光学测量并且对样品的温度进行局部控制。 根据本发明的方法，当控制该体积的温度时，测量来自人体皮肤的确定的皮下体积的光学信号。 本发明的方法和装置允许通过稳态反射测量在具有不同皮肤颜色的受试者群体中非侵入性地测定血红蛋白浓度和血细胞比容值。 用于测定血红蛋白浓度和血细胞比容值的本发明的方法对于监测患者，在护理点进行测试和筛查贫血是有用的。 与依靠心脏脉冲信号的现有技术的其他尝试相反，本发明的方法具有测定弱心脏脉搏情况下的分析物的优点，例如老年患者。

公开(公告)号：US06654620B2

公开(公告)日：2003-11-25

申请号：US09835705

申请日：2001-04-16

申请人： Xiaomao Wu ,  Omar S. Khalil ,  Tzyy-Wen Jeng ,  Shu-Jen Yeh ,  Charles F. Hanna

发明人： Xiaomao Wu ,  Omar S. Khalil ,  Tzyy-Wen Jeng ,  Shu-Jen Yeh ,  Charles F. Hanna

IPC分类号： A61B550

CPC分类号： G01N21/4795 ,  A61B5/14532 ,  A61B5/14546 ,  A61B5/1455 ,  A61B5/1491 ,  A61B5/6824 ,  A61B2562/0233 ,  A61B2562/0242 ,  A61B2562/043

摘要： A method for determining the concentration of an analyte in a biological sample comprising the steps of: (1) providing an optical measuring instrument comprising a thermally controllable optical measuring element that comes into contact with the surface of the biological sample; (2) applying a coupling agent to the optical measuring element or to the surface of the biological sample or to both so that the coupling agent will be disposed at the interface of the surface of the biological sample and the optical measuring element; (3) measuring optical properties of the biological sample by means of the optical measuring instrument; and (4) correlating the optical properties of the biological sample with the concentration of the analyte in the biological sample. The coupling agent can be selected from the group consisting of silicone oil, mineral oil, polyethylene glycols, and oils from natural resources.

摘要翻译： 一种用于确定生物样品中分析物浓度的方法，包括以下步骤：（1）提供光学测量仪器，其包括与生物样品表面接触的热可控光学测量元件;（2） 偶联剂到光学测量元件或生物样品的表面或两者以使得偶联剂将被布置在生物样品的表面与光学测量元件的界面处;（3）测量光学特性 通过光学测量仪器生物样品; 和（4）将生物样品的光学性质与生物样品中分析物的浓度相关联。偶联剂可以选自硅油，矿物油，聚乙二醇和来自天然资源的油。

公开(公告)号：US07167734B2

公开(公告)日：2007-01-23

申请号：US09834440

申请日：2001-04-13

申请人： Omar S. Khalil ,  Shu-jen Yeh ,  Stanislaw Kantor ,  Charles F. Hanna ,  Eric B. Shain

发明人： Omar S. Khalil ,  Shu-jen Yeh ,  Stanislaw Kantor ,  Charles F. Hanna ,  Eric B. Shain

IPC分类号： A61B5/00

CPC分类号： A61B5/1495 ,  A61B5/14532 ,  A61B5/1455 ,  A61B5/7264

摘要： A method for collecting optical data at two morphologically similar, substantially non-overlapping, and preferably adjacent, areas on the surface of a tissue, while the temperature in each area is being maintained or modulated according to a temperature program. The optical data obtained are inserted into a mathematical relationship, e.g., an algorithm, that can be used to predict a disease state (such as the diabetes mellitus disease state) or the concentration of an analyte for indicating a physical condition (such as blood glucose level). This invention can be used to differentiate between disease status, such as, for example, diabetic and non-diabetic. The method involves the generation of a calibration (or training) set that utilizes the relationship between optical signals emanating from the skin under different thermal stimuli and disease status, e.g., diabetic status, established clinically. This calibration set can be used to predict the disease state of other subjects. Structural changes, as well as circulatory changes, due to a disease state are determined at two morphologically similar, but substantially non-overlapping areas on the surface of human tissue, e.g., the skin of a forearm, with each area being subjected to different temperature modulation programs. In addition to determination of a disease state, this invention can also be used to determine the concentration of an analyte in the tissues. This invention also provides an apparatus for the determination of a disease state, such as diabetes, or concentration of an analyte, such as blood glucose level, by the method of this invention.

摘要翻译： 一种用于在组织表面上的两个形态上类似的，基本上不重叠的，优选相邻的区域收集光学数据的方法，同时根据温度程序维持或调节每个区域中的温度。 所获得的光学数据被插入到数学关系中，例如算法，其可用于预测疾病状态（例如糖尿病状态）或用于指示身体状况的分析物的浓度（例如血糖 水平）。 本发明可用于区分疾病状况，例如糖尿病和非糖尿病。 该方法包括产生校准（或训练）组，其利用在不同热刺激下发生的光学信号与疾病状态（例如临床确立的糖尿病状态）之间的关系。 该校准集可用于预测其他受试者的疾病状态。 由于疾病状态引起的结构变化以及循环变化在人组织表面上的两个形态相似但基本上非重叠的区域确定，例如前臂的皮肤，每个区域经受不同的温度 调制程序。 除了确定疾病状态之外，本发明还可以用于确定组织中分析物的浓度。 本发明还提供了一种用于通过本发明的方法测定疾病状态的装置，例如糖尿病或分析物的浓度，例如血糖水平。

公开(公告)号：USD332834S

公开(公告)日：1993-01-26

申请号：US570565

申请日：1990-08-21

申请人： Charles F. Hanna ,  Thomas F. Zurek ,  Omar S. Khalil

设计人： Charles F. Hanna ,  Thomas F. Zurek ,  Omar S. Khalil

公开(公告)号：US5006309A

公开(公告)日：1991-04-09

申请号：US184726

申请日：1988-04-22

申请人： Omar S. Khalil ,  Charles F. Hanna ,  Thomas F. Zurek ,  Denise A. Grigalauski

发明人： Omar S. Khalil ,  Charles F. Hanna ,  Thomas F. Zurek ,  Denise A. Grigalauski

IPC分类号： B01L3/00 ,  G01N33/543

CPC分类号： G01N33/54366 ,  B01L3/5023 ,  B01L2200/027 ,  B01L2300/0809 ,  B01L2400/0406 ,  B01L2400/049 ,  Y10T436/255 ,  Y10T436/2575

摘要： A disposable device suitable for performing automated solid-state diagnostic assays which employs microparticles to complex an analyte and where the microparticle complex becomes retained and immobilized on a fibrous matrix such that the presence of analyte on the microparticles can be detected by an optical device. A device is disclosed having a shallow sample well for receiving a sample and reagents for forming a reaction mixture, a read well having (a) an entrance port and wash receiving structure for receiving a quantity of sample and assay reagents, (b) a fibrous matrix for retaining and immobilizing microparticle/analyte complexes for detection, the fibrous matrix positioned below the wash receiving structure, and having an average spatial separation of fibers greater than the average diameter of the microparticles and (c) a structure below the fibrous matrix for assisting the flow of sample and assay reagents through the fibrous matrix, such as an absorbent material or vacuum below the fibrous matrix and a passage means communicating between the shallow sample well and the read well where the sample and reaction mixtures can be transferred and washed from the shallow sample well into the read well without being contacted by any apparatus.

摘要翻译： 一种适用于执行自动化固态诊断测定的一次性装置，其使用微粒来复合分析物，并且其中微粒复合物保留并固定在纤维基质上，使得微粒上的分析物的存在可以通过光学装置检测。 公开了一种装置，其具有用于接收样品的浅样品阱和用于形成反应混合物的试剂，读数井具有（a）用于接收一定量的样品和测定试剂的入口和洗涤接收结构，（b）纤维 用于保持和固定用于检测的微粒/分析物复合物的基质，所述纤维基质位于洗涤接收结构下方，并且具有大于微粒平均直径的纤维的平均空间分离，和（c）纤维基质下面的结构用于辅助 通过纤维基质（例如吸收材料或纤维基质下方的真空）的样品和测定试剂的流动以及在浅样品阱和读数井之间连通的通道装置，其中样品和反应混合物可以从 浅样品很好地进入读取井，而不被任何装置接触。

公开(公告)号：US06615061B1

公开(公告)日：2003-09-02

申请号：US09366084

申请日：1999-08-03

申请人： Omar S. Khalil ,  Xiaomao Wu ,  Shu-jen Yeh ,  Charles F. Hanna ,  Stanislaw Kantor ,  Tzyy-Wen Jeng

发明人： Omar S. Khalil ,  Xiaomao Wu ,  Shu-jen Yeh ,  Charles F. Hanna ,  Stanislaw Kantor ,  Tzyy-Wen Jeng

IPC分类号： A61B500

CPC分类号： A61B5/1455 ,  A61B5/14532 ,  A61B2562/0233 ,  A61B2562/0242 ,  A61B2562/043 ,  G01N21/49

摘要： A method and apparatus for the measurement of trans-cutaneous diffuse reflectance at a single sampling distance for determining the concentration of an analyte in a biological sample, such as, for example, human tissue. The determination of the concentration of the analyte has been found to depend on the sampling distance and reaches an optimal result at a defined sampling distance for a given analyte and a given sample. The method involves measuring the light re-emitted from the sample at a distance from a light introduction site and correlating the intensity of the re-emitted light to the concentration of an analyte. For a given sample, the distance between the light collection site and a light introduction site (i.e., the sampling distance) corresponds to the depth from the surface into the sample at which scattering and absorption events significantly affect the intensity of re-emitted light (i.e., the sampling depth). Prior knowledge about the sample determines the optimal sampling depth for performing a measurement for a specific analyte and the corresponding sampling distance needed to reach that optimal sampling depth. Optimization of the sampling distance, as well as the correlation relationship, can be established in a calibration procedure.

摘要翻译： 一种用于在单个采样距离处测量透皮漫反射率以确定生物样品（例如人体组织）中的分析物的浓度的方法和装置。 已经发现分析物浓度的确定取决于采样距离，并且在给定分析物和给定样品的定义的采样距离处达到最佳结果。 该方法包括测量从光引入位置一段距离处从样品再发射的光并将再发射的光的强度与分析物的浓度相关联。 对于给定的样品，光采集位置和光引入位点之间的距离（即采样距离）对应于从表面到样品的深度，其中散射和吸收事件显着影响再发射光的强度（ 即采样深度）。 关于样品的现有知识决定了对特定分析物进行测量的最佳采样深度以及达到该最佳采样深度所需的相应采样距离。 可以在校准过程中建立采样距离的优化以及相关关系。

公开(公告)号：US06526298B1

公开(公告)日：2003-02-25

申请号：US09693122

申请日：2000-10-20

申请人： Omar S. Khalil ,  Shu-jen Yeh ,  Charles F. Hanna ,  Stanislaw Kantor

发明人： Omar S. Khalil ,  Shu-jen Yeh ,  Charles F. Hanna ,  Stanislaw Kantor

IPC分类号： A61B500

CPC分类号： A61B5/1495 ,  A61B5/0059 ,  A61B5/14532 ,  A61B5/14546 ,  A61B5/1455 ,  A61B5/1491 ,  A61B5/6824 ,  A61B2562/0233 ,  A61B2562/0242 ,  A61B2562/043 ,  G01N21/4795

摘要： A method for the determination of concentrations of analytes, e.g., glucose, and other metabolites in human tissue, wherein the temperature of a defined cutaneous volume of tissue, e.g., human skin, is controlled. The method involves calculating the concentration of an analyte in the tissue by taking into consideration the values of optical parameters of a sample of tissue measured in the defined cutaneous volume of the tissue at various temperatures. The selection of the defined volume is a function of the sampling distance along the surface of the tissue, the wavelength of light used to illuminate the tissue, and the temperature in the defined volume of tissue, which is a function of the temperature at the surface of the tissue. In one embodiment of the method of this invention, an optical signal re-emitted from a defined cutaneous volume of the tissue is measured, as the temperature of this volume is maintained at a constant value. In another embodiment of the method of this invention, the temperature of the defined cutaneous volume of the tissue is varied within a defined physiological range to change the depth of penetration of light into the tissue, thereby achieving a depth profile for the optical signal. The method of this invention is useful for monitoring the concentrations of analytes in tissues, testing at the point of care, and screening for diseases, such as, for example, diabetes. The method of this invention utilizes changes in temperature and selection of wavelengths to define cutaneous volumes below the surface of the tissue, in which volumes the concentration of an analyte can be determined.

摘要翻译： 用于测定人组织中分析物（例如葡萄糖）和其它代谢物的浓度的方法，其中控制例如人皮肤的组织的定义的皮肤体积的温度。 该方法包括通过考虑在各种温度下在组织的定义的皮肤体积中测量的组织样品的光学参数的值来计算组织中分析物的浓度。 定义体积的选择是沿着组织表面的采样距离，用于照亮组织的光的波长和组织的限定体积中的温度的函数，其是表面温度的函数 的组织。 在本发明的方法的一个实施例中，当该体积的温度保持在恒定值时，测量从组织的规定皮肤体积重新发射的光学信号。 在本发明方法的另一实施例中，组织的限定皮肤体积的温度在规定的生理范围内变化，以改变光进入组织的深度，从而实现光信号的深度分布。 本发明的方法可用于监测组织中分析物的浓度，在护理点进行测试和筛选疾病，例如糖尿病。 本发明的方法利用温度的变化和波长的选择来限定组织表面以下的皮肤体积，其中可以确定分析物的浓度。