CN100561200C - 用于检测存在的生物物质并使其成像的方法和设备 - Google Patents
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Abstract
本发明涉及用于检测非生命表面上的生物物质的方法和设备，其中使样品与能够激发各种内在荧光团接触且这些荧光团发射可以测定的荧光的特定能量的电磁射线。由于要求来自生物物质的内在荧光团和由内在荧光团产生的信号强度落入预计的范围，因此从荧光信号中除去背景、散射激发光和反射激发光的信号。
Description
本申请要求2002年1月22日提交的授权的美国专利申请10/054,419的优先权，将该文献的全部内容引入本文作为参考。
发明领域
本发明涉及用于检测、鉴别表面上存在的生物物质(血液、精液、尿、唾液、痰等)并使其成像的方法和设备。
背景技术
内在荧光团因其高灵敏度、实时反馈、无样品接触和快速扫描大面积的能力而充分适合于检测生物物质。此外，它不需要可以破坏、改变或污染样品的试剂。由于荧光发射强度(表示存在生物物质的检测信号)与激发强度成正比，所以可以通过使用高能照明观察弱信号。(同样通过激发光源的能量输出测定可以检验的面积)。由于存在下列显示出内在荧光的广泛和高浓度的生物成分，因此能够检测生物物质：NAD[P]H和其它还原吡啶核苷酸(RPN)、2，4-二氧四氢蝶啶类、蝶呤类、黄素蛋白和其它次生代谢物。核酸聚合物(DNA/RNA)、蛋白质和各种脂类显示出高能荧光，由此使这些标记能够用于检测指纹。在尿中发现了荧光代谢分解产物。血液的血红素成分(新鲜的和氧化的)以及干燥的精液也显示出独特的荧光类型。可以鉴别生物物质内在荧光发射差异。由于许多生物物质显示出类似或不可辨别的成分，所以用以荧光成分激发为特征的多能量同时激发样品且随后采集并检测发射、反射和散射的光能(分别与所述荧光团有关和无关)是用本文所述方法检测表面上的生物物质的基础。
因两个原因而可以通过上述方法更可靠地对实际许多样品表面上的生物物质进行检测。首先，由多激发能量同时激发生物物质(或用单一能量依次激发)，随即同时检测大量荧光信号，这减少了干扰的机会，这是因为使大量荧光团特征加倍的干扰源出现的可能性极小。其次，已经发现相应量内在代谢物和由此产生的荧光信号属于生物上可测定的范围。使用能够进行两种步骤的方法分析信号：(1)使来源于存在的任意生物物质中的检测到的荧光信号与干扰或背景信号和/或散射激发信号分离；和(2)要求来自不同荧光成分的信号强度落在预计范围内。因此，检测生物物质的基础由下列步骤组成：第一步，用以生物物质内在荧光团为特征的多激发能量同时或依次激发样品；第二步，随后采集大量各自的荧光信号(与这些激发荧光团的最大和最小发射有关)；最终用能够除去背景荧光(既不是来源于生物物质的荧光成分、反射激发光、也不是来源于散射的反射光的信号)、反射激发信号和散射激发信号并比较预计范围的相对荧光信号数量的方法分析采集的信号。
长期建立的用于从表面采集生物物质的技术和方法包括直接用拭子或胶带取样和/或在用试剂处理后显色。通常用于使潜在的生物物质显色的试剂可以破坏、改变或污染样品。由于本发明使用了来自生物物质的多个内在荧光团与分析因这些荧光团产生的信号的相对量相结合进行检测，所以不仅可以测定存在的生物物质，而且能够区分不同类型的生物物质。本文所公开的发明不使用试剂、不需要与样品进行物理性接触且提供‘实时’结果。
用于检测特定法医学生物物质的方法包括使用抗体(美国专利US6,605,705)、与酶和底物偶联的抗体(美国专利US 6,696,569)和应用荧光染料的带状试验中的抗体(美国专利US 6,686,167)。其它方法在添加染料后利用使DNA、蛋白质或其它生物物质显色的荧光(美国专利US 6,512,236)。将光源用于照明并通过使用具有高能激发光源(美国专利RE37,136)的荧光和成像方法(美国专利US 6,392,238和US 6,636,701)检测生物物质。
在授权的Powers和Lloyd的美国专利申请10/054,419(引入本文作为参考)中公开了用于检测非生命表面和样品上的微生物的方法和设备，其中使样品接触能够激发来自各种代谢物、辅因子以及细胞和孢子成分的荧光的许多特定能量的电磁射线。因此，其中含有的待取样的微生物细胞和孢子(更具体的说是激发的代谢物、辅因子和其它细胞、病毒和/或孢子成分)发射可以测定的荧光。用能够(1)除去任何背景或反射/散射激发信号和(2)将代谢物、辅因子和孢子成分的相对荧光信号与已知的生理范围值比较的方法分析采集的荧光信号(与发射自细胞/病毒/孢子成分的信号的最大值和/或最小值相关)。
尽管Powers和Lloyd的上述专利申请取决于同时激发多种微生物成分，但是本发明使用同时或依次激发与生物物质相关的多个荧光团与扣除因散射和/或反射激发能产生的检测信号的算法的结合方法。这种在设计和方法上的差异使得本发明能够比其它荧光法更好地检测和辨别非生命表面上的各种生物物质。本发明在检测生物物质方面占优势，这是因为检测多个内在荧光团减少了因背景干扰产生的假阳性结果的可能性。使用上述方法和设备检测生物物质将应用于犯罪现场的证据采集、灭菌的检验、清洁过程、食品生产和制剂安全性的验证以及以公共基础设施设备的检测、净化和保护为工作的紧急反应组。
执法机构和犯罪实验室在检测和鉴定犯罪现场和证据基体(表面类型)上的生物样品的能力方面受到严重限制。许多机构实际上依赖于目测或触摸来证实可疑生物证据的存在。这些局限的影响在下列危害因素中显现出来：有价值的证据样品没有得到注意；采集并分析无价值的样品；可使用的证据样品受到污染；强化技术破坏或改变了证据样品；有害样品被不适当地采集和包装；犯罪现场人员与生物有害物进行物理性接触；犯罪现场人员接触有害环境；搜索和检验程序耗时；和耗费机构和/或实验室资源。证据反应组和第一批响应者因频繁接触现场、受害人和可能含有生物液体的其它证据也首先处于危险中。这些警官通常在证据最少受到污染时到达犯罪现场时，然而他们(1)缺乏找出可疑生物液体的技术且(2)不能在实际条件下或原始位置上捕捉液体图像。
发明内容
本发明的目的是提供应用于检测、鉴定生物证据并使其成像的方法和设备。
本发明的另一个目的是提供应用于检测食品表面上生物污染物的方法和设备，其中通过电磁射线激发生物物质荧光成分的荧光以便区分多种生物物质种类，从而使食品表面上的污染物得到测定而不接触所述表面。
因此，本发明的还一个目的是提供可以用于检验清洁过程的方法和设备。作为本发明的具体目的，可以将该方法和设备用于低廉和快速地发现例如保健用具、旅馆房间和公共建筑中的生物物质污染。
本发明的目的在于生物物质的检测方法和设备，其中使样品接触能够从各种内在荧光团中激发荧光的许多特定能量的电磁射线。因此，其中含有待取样的生物物质(更具体的说是激发的荧光成分)发射可以测定的荧光。用能够(1)除去任何背景或反射的/散射的激发信号和(2)将代谢物、辅因子和孢子成分的相对荧光信号与预计的范围比较的方法分析采集的荧光信号(与发射自生物物质成分的信号的最小值和/或最大值相关)。
因此，本发明的方法和设备提供了低廉而快速的方式，其中扫描表面以检测存在的生物物质而不接触样品物质。能够在不接触的情况下评价表面上的生物物质，从而减少了引入样品污染和人员接触的危害。
按照本发明的这种形式，通常需要使用发射200nm以上电磁射线的光源。按照本发明的这种形式，由该光源发射的光对特别激发下列生物物质的能量的电磁射线而言是特定的或经过滤后通过这种能量的电磁射线：NAD[P]H和其它还原吡啶核苷酸(RPN)、2，4-二氧四氢蝶啶类、蝶呤类、黄素蛋白、核酸聚合物(DNA/RNA)、蛋白质、各种脂类、尿中的代谢分解产物、血液的血红素成分(新鲜的和氧化的)以及精液和其它生物液体中的荧光团。
按照本发明的另一个实施方案，能够且有时需要使紫外线能量(波长为200-300nm)的电磁射线定向于样品。紫外光激发芳香氨基酸、脂类成分和核酸，它们中某些的发射依次被300-500nm范围的其它荧光代谢物样品自我吸收，它们中某些的发射依次被激发500-800nm范围的其它荧光代谢物的样品自我吸收，其部分发射用于进一步激发其它成分。如上所述采集并分析样品的荧光发射。紫外光的应用使样品的取样穿透深度相对表浅。
按照本发明的另一个实施方案，能够且有时需要使能够激发特定荧光生物成分的能量和还不与生物荧光团、生物物质和/或样品发现于其上的底物物质发生相互作用的能量的电磁射线定向。因此，按照本发明的该实施方案，可以测定所得的发射自样品的荧光信号(来自生物成分和那些单纯反射和/或散射自表面的成分)且通过将来自微生物的发射信号与那些反射和/或散射自底物的信号的比例进行比较来确定具体生物物质的存在。
根据本发明实践，将传感器不仅用于检测由内在荧光团产生的荧光，而且还用于检测反射和/或散射的电磁射线。该设备用于校准信号并补偿可能因使用探针与扫描样品之间的可变距离和不同样品或表面之间的变化引起的信号改变。
还发现通过快速改变定向于样品的以不同于60赫兹的频率的电磁射线，基本上可以将环境光(且特别是荧光)的作用减小到最低限度。调节激发能量还使传感器发生运转以使电磁射线定向于样品的不同部分，但基本上对检测各种表面上生物物质的能力不会产生影响。
激光和可选的光源已经在犯罪现场找到可能的证据液体方面取得了适度的成功。在公开的综述中描述了单一波长的荧光在检测所选择底物上的某些生物物质中的应用，这些综述包括：Watkin，J.E.，Wilkinson，D.A.“法医学用光源、Polilight，Luma-Lite和Spectrum9000的比较”-Journal of Foresic Identification，Vol.44，No.6，1994，p.632；和Auldel，M.J.“激光和高强度石英弧光管在检测身体分泌物中的比较”-Journal of Forensic Identification，Vo.33，No.4，1988，pp.929-945。然而，这些技术存在局限。许多光源具有特定的功率和支持体要求且某些光源不能被输送至远程的犯罪现场。另外，实际上拥有便携式激光或可选光源技术的机构受到不能区分通常来自也具有该荧光的物质的证据样品的仪器波长的限制(因为许多生物物质的荧光难以与背景区分)。可以鉴定潜在证据的方法和设备可以帮助证据反应组和第一批响应者建立一种可使用的视野计、采集有用和未污染的证据并减少有害接触。该方法和设备不需要试剂、不与样品接触、以低廉的方式进行并提供“实时”结果。本发明的这些和其它目的、特征和优点在对下面所公开实施方案的详细描述和待批权利要求进行综述时变得显而易见。
附图简述
附图1表示精液(-)、皮肤油(-··-··)、血液(——)、唾液(-·-·)和尿(——)因其在260nm(A)、375nm(B)、400nm(C)、450nm(D)、530nm(E)、580nm(F)、660nm(G)和800nm(H)发射的不同内在荧光团而产生的发射光谱。
附图2表示可以用于本发明实施方案的发射滤波器的光学特性。箭头表示可以通过滤波器的光的波长范围。
可以用于实施本发明的设备由光源、激发滤波器(如果需要)、聚焦光学部件、成像光学部件(如果需要)、发射滤波器和检测器组成。使来自光源的电磁射线定向于样品，通过激发滤波器(如果需要)和聚焦光学部件(如果必要)以激发样品中的内在荧光团。采集散射和反射的激发射线与发射的荧光射线并使它们定向于检测器。发射滤波器确保仅测定有意义的能量范围。
本发明的各种实施方案、包括不同结构和可应用的不同部件是可行的。用于该生物物质检测方法的基本部件允许：激发多个内在生物荧光团、采集和检测发射和反射和/或散射的光能并用能够校正背景干扰和比较相对信号强度与预计参数的方法分析检测的信号。在使用该方法的任何设备中所用的结构和部件应与应用的要求和预计的干扰相匹配。
能够且有时需要应用可提供宽带照明的光源。所用光源的种类受其产生激发有意义的内在微生物成分所需波长的电磁射线的能力的影响。另外，有时需要应用脉冲光源以便测定关闭回路过程中的环境背景。可以使用的光源包括带有各种电灯泡的灯(例如汞、钨、氘、氙灯)、发光二极管(LEDs)和对所需激发能量特异的二极管激光器。所用的光源类型取决于所需激发射线的强度和所需的检测极限。
在本发明各种实施方案中所用的激发和发射滤波器包括干扰滤波器、折射(rugate)滤波器、浸渍玻璃、截止滤波器系列、凝胶滤波器、单色仪、光栅等。所用的发射滤波器的光截止特性取决于分析方法可接受多少散射和反射的激发射线信号或所需的检测极限。如果使用仅具有有意义能量的光源，则可以不必使用激发滤波器；如果校准光源(诸如激光)，则可以不必使用聚焦光学部件。(聚焦光学部件(如果需要)的目的是使激发射线定向于取样的面积或体积)。重要的是应注意如果使用多光子激发，则能够使用具有低于单光子激发有意义荧光团的激发能量的能量的光源。
采集光学部件的目的在于将发射自激发荧光团的光以及散射和反射自样品的光输送至检测器。如果需要使来自激发表面的发射成像，则优选使用与成像相匹配的透镜和/或滤波器。如果将干扰滤波器用于区分这些发射能量，那么需要校准采集的光以便使这些滤波器以最佳状态工作。纤维光缆也可以用于将激发射线输送至样品并采集发射的射线且使其定向于检测器。当许多光学成分在紫外线和可见光范围内显示出荧光时，能够且有时需要应用抛光的反光金属、蓝宝石、熔凝硅石、石英、MgF2和/或CaF2光学成分。
检测器用于将发射的电磁射线转化成可以测定的电信号。大量具有不同灵敏度的检测器可以用于本发明的实施方案：光电倍增管(PMTs)、雪崩光二极管(APDs)、针型二极管、CCDs等。如果需要对荧光信号成像，则可以使用CCD阵列检测并成像。所选择的检测器取决于所检测的射线的能量、发射信号的强度和设备所需的检测极限。
使用能够除去任何背景荧光和产生的散射激发的方法分析已经转化成放大的电信号的采集的发射能量。对用于具体实施方案的激发和发射能量的选择取决于靶生物物质。表I中列举了大量不同生物物质中发现的某些具有很丰富的内在荧光化合物的激发和发射范围。
表I
| 激发范围(nm) | 发射范围(nm) | 皮肤油 | 精液 | 血液 | 尿 | 唾液 |
| 250-300 | 320-360 | X | X | X | X | X |
| 250-300 | 380-460 | X | ||||
| 250-290 | 430-480 | X | ||||
| 360-390 | 420-510 | X | X | |||
| 390-410 | 430-540 | X | X | |||
| 430-470 | 480-570 | X | X | |||
| 520-540 | 630-700 | w | w | |||
| 570-590 | 630-700 | X | X | |||
| 640-680 | 760-840 | X | ||||
| 790-810 | 860-930 | X |
(在表I中，符号‘X’表示存在这种荧光标记；符号‘w’表示存在弱荧光标记。430-470nm激发的发射范围由多重叠发射组成)。
附图1表示精液、皮肤油、血液、唾液和尿因其在260nm(A)、375nm(B)、400nm(C)、450nm(D)、530nm(E)、580hm(F)、660nm(G)和800nm(H)处发射的不同内在荧光团而产生的发射光谱。该附图说明了不同生物物质之间荧光信号的差异(存在和相对信号强度的差异)。分析方法使用这些差异以便在这些样品之间进行区分。可以将检测和扣除背景的信号的数值用于对样品上的物质量进行粗略定量。
在本发明的一个实施方案中，在375nm、580hm、660nm和800nm左右激发光源的应用使得检测并区分精液、血液和尿成为可能。这些光源允许激发还原吡啶核苷酸、各种黄素、血红素辅因子和其它内在荧光团。对用于激发荧光团的发射检测的滤波器的选择可以包括那些420-540nm、630-700nm、760-840nm和860-930nm所涉及的滤波器。另外，可以优选使用用于测定反射/散射背景数量的其它发射滤波器。此外，405nm左右的激发光源提供了可以用于检测和区分这些生物物质的进一步信息。
在本发明的另一个实施方案中，使用具有以附图2为典型的特性的发射滤波器。在该实施方案中，使用能够使预计发射的特定区的发射的荧光通过、不允许反射的激发光通过且允许高能量的光通过以便照明底物的发射滤波器。作为实例，附图2中的滤波器可以用于通过用290nm处的光激发表面来检测精液；精液中内在荧光团的发射在430-480nm之间(蓝色)出现且通过的红光可以用于照明底物表面，由此易于找到蓝色荧光(由精液产生)。为了清楚地在发射的内在荧光与用较高波长的光成像的底物表面之间区分，最低能量内在荧光发射与最高能量底物成像波长之差应尽可能大。实际上，100nm左右的差值可以使工作良好进行，而这一差值应至少为50nm，以利于人眼观察。
可以同时、以相应的方式或依次(如果检测发生在快于仪器运转的时间刻度)使激发能量定向于样品。尽管表I表明可以通过本文所述多波长荧光法检测并区分生物证据，但是可以以一种类似的方式检测并鉴定其它生物物质(包括植物提取物、天然药物、营养物、生物矿物等)。
上述本发明的实施方案仅作为典型使用，本领域技术人员可以使用上述基本构思进行其它组合、变化和修改而不会脱离本发明的实质。该生物物质的检测方法和设备的范围包括应用同时激发多个内在生物荧光团或用单一激发波长依次激发多个内在生物荧光团、随后使用同时计算背景、散射和反射激发信号并需要所述计算的反射和散射信号强度和测定的来自落入预计范围的生物荧光信号的检测信号的背景信号强度的方法分析检测的发射。所有变化、修改和组合均属于如待批权利要求所定义的本发明范围。
Claims (7)
1.生物物质的检测和鉴别方法，包括下列步骤：
a.激发至少一种具有200nm以上特定激发范围的电磁射线波长的内在生物荧光团；由此激发生物物质中所述内在荧光团发射荧光；和
b.检测与内在荧光最小值和最大值相关的信号强度；和
c.在没有激发的情况下检测内在荧光最小值和最大值处的背景强度；和
d.根据扣除背景的最小值的强度计算荧光最大值处的反射和散射强度；和
e.从检测的生物荧光信号中扣除计算的反射和散射信号强度和测定的背景强度；由此通过已经扣除产生的背景、反射和散射的检测荧光的数量确定所述物质的量。
2.如权利要求1中所述方法，其中测定已经扣除了测定的背景和计算的反射和散射的多个荧光信号强度的比例；由此对生物物质之间的鉴别取决于对背景、散射和反射校正的荧光信号的比例属于特定范围和根据其比例属于所述预计范围的所述检测信号的数量测定的物质的量的要求。
3.如权利要求1中所述方法，其中所述生物内在荧光选自在320-360、380-460、430-480、420-510、430-540、480-570、630-700、760-840和860-930nm区内发荧光的组。
4.生物物质的检测和鉴别方法，包括下列步骤：
a.用具有200-300nm激发波长的紫外电磁射线激发多个内在生物荧光团；由此激发任何生物物质中存在的内在荧光团发射荧光；它们中的某些被自我吸收以便激发其它内在荧光团依次发射荧光；和
b.检测与内在荧光最小值和最大值相关的荧光信号强度；和
c.在没有激发的情况下检测内在荧光最小值和最大值处的背景强度；和
d.根据扣除背景的最小值的强度计算荧光最大值处的反射和散射强度；和
e.从检测的生物荧光信号中扣除计算的反射和散射信号强度和测定的背景信号强度；和
f.确定已经扣除产生的背景、反射和散射的检测的荧光信号的比例属于预计的范围，由此根据已经扣除背景、反射和散射的、比例属于预计范围的检测荧光信号的数量确定生物物质的量。
5.如权利要求4所述方法，其中所述生物内在荧光的内在生物荧光团选自在320-360、380-460、430-480、420-510、430-540、480-570、630-700、760-840和860-930nm区内发荧光的组。
6.如权利要求4所述方法，其中二次激发的内在荧光包括430-480、420-510、430-540、480-570、630-700、760-840和860-930nm区等。
7.生物物质的检测、鉴别和成像方法，包括下列步骤：
a.激发至少一种具有200nm以上特定激发范围的电磁射线波长的内在生物荧光团；由此激发生物物质中所述内在荧光团发射荧光；和
b.检测与预计的所述生物物质内在荧光最大发射范围相关的信号强度并使其成像；和
c.用环境光、反射的激发射线和散射的激发光在至少高于内在荧光的最高预计发射波长范围50nm的波长处使底物背景成像；和
d.将内在荧光发射范围与来自至少高于内在荧光团最高预计发射波长范围50nm的波长的环境光、反射激发射线和散射激发光的底物表面的输出图像合并；由此通过较高波长底物表面图像上存在的较低波长图像检测生物物质；和
e.根据检测的内在荧光发射比例属于预计范围的要求鉴别生物物质样品并根据检测荧光的数量测定所述物质的量。
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- 2004-05-26 EP EP04012456A patent/EP1582860A1/en not_active Withdrawn
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| US20040197771A1 (en) | 2004-10-07 |
| JP2005292112A (ja) | 2005-10-20 |
| SG144722A1 (en) | 2008-08-28 |
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| CA2466433A1 (en) | 2005-10-02 |
| CN1677088A (zh) | 2005-10-05 |
| US7186990B2 (en) | 2007-03-06 |
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