CN1200174A - 基于荧光寿命的人体组织及其它无规则介质成象技术和光谱技术 - Google Patents
基于荧光寿命的人体组织及其它无规则介质成象技术和光谱技术 Download PDFInfo
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Abstract
本申请公开了利用低亮度光进行无损生物医学光学成象和光谱分析的一种***和方法。该技术包括一个调制光源(120),其作用于需用激发光照射的病人的人体组织。用探测器(148)探测响应激发光发出的荧光。将激发光和所探测荧光的AC强度和相位传送到与探测器(148)相连的一个处理器(160)。处理器(160)应用所测得的激发光和荧光的再辐射动力学特性“映射”组织(100)的一种或多种荧光特性的空间变化。荧光特性可以由外来造影剂、内生荧光团、或者两者结合而产生。通过作为递归估算算法的一部分对应于组织中一组指定点求解频率域漫射方程确定所说空间变化。处理器(160)根据荧光特性的空间变化产生图象信号,传输给一个输出装置(164)。输出装置(164)显示对应于组织(100)中荧光特性空间变化的图象,以帮助检测和诊断疾病。
Description
发明背景
本发明涉及一种异质光散射介质的光谱成象技术,更具体地说,但不是唯一地,本发明涉及在活的有机体内通过探测在从一个时变光源中发出的激发光作用下而辐射出的光来测定其组织的荧光特性从而对生物组织成象的技术。
疾病的早期诊断保证了治疗发挥更大的效力。近年来,无损检测技术得到了发展,这种技术通过检测病人身体组织内的生化变化提高了对于各种疾病的确诊和早期诊断能力。例如,磁共振成象(MRI)技术已经成功地通过监测顺磁原子核自旋状态的弛豫获得人体组织的生物医学图象和生化光谱。但是,磁共振诊断技术的复杂性及其昂贵的费用限制了它的可利用性,特别是作为一种常规疾病监测装置。
在生物科学领域中应用日益广泛的另一种有力的分析技术是荧光光谱技术。这些应用包括生物医学诊断、遗传排列、和流动血细胞计数。迄今为止,已有许多工业和研究机构开发用于观察有关的代谢物和环境状态的荧光和磷光化合物,诸如Ca++、pH、葡萄糖、pO2、和pCO2。随着染料和能够激发和再辐射近红外红光波长范围光的光动力荧光剂的开发,由于红色激发光和再辐射光可以在组织-空气界面中穿透很深的距离并从中发射出来,所以对于隐藏在组织深处的病灶组织也能够进行无损检测(参见Wilson等人所写“时间相关的光谱及生物医学应用成象”一文,此文刊登于80 Proceedings IEEE pp.918-30(1992))。
如在授予Richards-Kortum等人的美国专利US-5421337和授予Wu等人的美国专利US-5452723中所例举的,一些研究者已经提出各种根据外部无损测量的荧光发射或损伤最小的内窥镜测量技术区分有病组织和正常组织的方法。但是,这些方法一般都不是可行的空间成象方法。基于荧光的成象方法难于实现的一个原因是很难获得对从一种无规则的、多重散射介质,例如人体组织中发出的荧光特性的有意义的相关测量结果。例如,作为荧光化合物(或荧光团)浓度或“摄入量”函数的荧光强度是用于成象的一个可能的选择量;但是,当这种特性用于一种光致密介质,例如颗粒(细胞)悬浮液、粉末、或组织时,其局部散射和吸收性质使得测量的荧光强度混淆不清。
除了强度,所选择荧光的其它特性如荧光量子效率和寿命对于局部生化环境也是敏感的。如在本申请中所使用的含义,“荧光量子效率”指的是每一个被吸收的激发光子再辐射荧光光子的分数或者导致发射荧光光子的湮灭事件的分数。“荧光寿命”,如在本申请中所使用的含义,定义为被激发的荧光团的平均残存时间或者吸收一个激发光子与再辐射一个荧光光子之间的平均时间。与强度一样,这些荧光特性的测量通常局限于实验室中严格限定的活体应用或者在诸如散射、吸收、和变化的荧光团浓度一类的问题容易得到控制或者易于测量的流动血细胞计数方面。此外,这些限制常常妨碍对于无法利用视觉检查发现的隐藏组织异质、例如肿瘤或者其它有病组织区域进行有意义的荧光成象。
因此,仍然需要有一种技术能够基于一种或多种荧光特性对具有多重散射性质的组织进行无损成象,这种技术不需要有关组织固有光学性质的大量信息,并且利用由荧光产额和寿命特性形成的对比性能来帮助识别组织异质性。本发明满足这种需求。
发明概要
本发明涉及异质光散射物质的光谱成象技术。本发明的各个方面都是新颖的、非显而易见的、和具有许多优点的。虽然在本申请中提出的发明的实际特征仅仅由所附的权利要求书确定,但是在下文中对本发明的某些特征予以简要描述。
本发明的一个特点是涉及异质光散射物质成象技术。这种方法包括利用一个光源发射的光照射一种物质的表面,并检测激发辐射。利用一个处理器确定这种物质的作为辐射函数的荧光特性的空间变化。这种空间变化可以利用表示作为位置函数的荧光特性的一组参数值来表现其特征。根据对应于这种物质的异质成分的空间变化生成一幅图象。这种技术可以应用于活的有机体内的生物组织,即利用外置设备或内窥镜检测指示疾病的异质性。这种技术可以包括将一种荧光造影剂引入这种物质中。所检测的荧光特性可以是荧光寿命、荧光量子效率,荧光团吸收系数、荧光产额(荧光量子效率和荧光团吸收的函数)、或者本领域技术人员熟知的其它荧光特性。
根据本发明的另一个特点,具有异质成分的光散射物质的空间变化是通过以下步骤确定的,即,建立光学性质或荧光特性变化的一个估算模型,计算出这种物质作为该估算模型的函数的辐射,将计算出的辐射与检测到的辐射比较以确定相应的误差。改进这种变化估算模型,利用这个改进的估算模型重新确定计算辐射,反复进行比较,直到所说误差达到所需的最小值。然后按照对应于所说异质成分的这种改进估算模型生成该物质的一幅图象。
所以,本发明的一个目的是测定一种光散射物质的随该物质中异质成分变化的荧光特性以生成相应的图象。
本发明的另一个目的是提供无损监测活的有机体内隐藏组织荧光特性和监测活的有机体内一种器官的选定代谢物的一种光谱技术。
本发明的再一个目的是提供一种荧光成象***和利用内生或外生荧光团作为造影剂识别有病组织的方法。这种造影可以由正常组织与有病组织之间的荧光浓度、寿命、或量子效率差别来实现。
本发明的又一个目的是提供基于与局部荧光团浓度无关的一种光学性质的对比度而成象的一种技术和算法。
通过附图和本说明书的描述,可以了解本发明的其它目的、特征、方面、和优点。
附图简介
图1为根据本发明的一个实施例构成的***的示意图。
图2为利用图1所示***的一种方法的流程图。
图3为用于表示本发明各个方面的一种组织模型的示意图。
图4-7为表示用于本发明的各个方程的选择特性的曲线图。
图8和9为利用本发明的一个实施例分别模拟测量荧光产额和荧光寿命空间变化的收敛曲线图。
图10-14为在本发明的实验例1-3中所得的图象。
图15为根据本发明另一个实施例构成的***的示意图。
优选实施例的描述
为了促进对本发明原理的理解,现在参照附图中所示实施例并利用专业术语对这些实施例予以描述。但是无论如何应当理解这些描述并不是对本发明范围的限制。就象本发明所述技术领域中技术人员能够做到的那样,对于本申请所述装置所作的任何改变和进一步的改进,以及对于本发明原理的进一步应用都是可以预见的。
图1表示本发明用于对组织100进行荧光成象的***110。组织100具有表面101和用表面101之下的区域102、103表示的异质成分。异质成分102、103一般无法通过对表面101的视觉检查检测出来。
***110包括调制光源120,其通过光纤123向组织100发射具有预定频率和波长、强度经过调制的激发光。可取的是,光源120是调制输出在1-500兆赫兹频率范围、单色光输出在100-1000纳米波长范围的常规设计的一个激光二极管。选择特定的波长激发组织100中指定荧光团。可以用分光器126将一小部分激发光信号引导至基准探测器128以备处理时使用。
***100还包括探测子***140,它包括从许多相应的探测位置探测从组织100辐射出的光子的光纤143。子***140包括一个或多个辐射探测传感器148。探测子***140还包括一个干涉滤波器以获得相应于组织100中指定荧光团辐射的选定辐射波长。在一个实施例中,子***140包括一个探测器148,从光纤143输出的信号经过倍增。可取的是,探测器128、148为光电倍增管(PMTs)或光电二极管,但是其它类型的探测器,例如图象增强器和电荷耦合器件也是可以采用的。
探测器128、148和光源120均与外差式子***130连接。子***130利用常规激光器外差技术获得有关由探测器128探测的光相对于由探测器148探测的光的相位、AC、和DC强度。在一个实施例中,外差式子***130包括与用作光源120的激光器脉冲重复频率相位同步的一个信号合成器。在这个实施例中,子***130包括与具有激光器脉冲重复频率的谐波频率(当使用脉冲激光器时)或者具有所说调制频率加一个偏差(当使用一个调制激光二极管时)的增益调制探测器128、148相连的一个放大器,以产生所需外差。在该实施例的一个变形中,将80兆赫兹脉冲激光器脉冲重复频率分频为10兆赫兹,输入到所说合成器中,并将100千赫兹的外差输入到探测器128、148的放大器中。
探测器128、148与处理器160连接。处理器160包括输入/控制装置162、输出装置164、和存储器166。处理器160可以是由一个或多个元件构成的电子电路。同样,处理器160可以由数字电路、模拟电路、或者两者结合构成。处理器160还可以是可编程的,集成状态机,或者是前述各种结构混合构成。可取的是,输入装置162是一个键盘或者常规类型的输入控制装置,输出装置166为一个用于视频显示的阴极射线管(CRT)、打印机、或者本领域技术人员熟知的其它图象显示***。存储器166最好是容易与电子控制器或处理器结合使用的电子(例如固态)、磁性、或光学一类存储器。此外,存储器166可以包括光盘存储器(CD)、电磁硬盘或软盘、或者上述存储器的组合。
图2表示***110的一种工作模式的程序210。程序210包括利用处理器160测定荧光产额和寿命的空间变化,和根据测定结果产生图象信号。输出装置164响应图象信号显示出一幅图象。程序210开始时在步骤212向组织100中注入一种荧光造影剂。这种造影剂构成了由子***240探测的荧光辐射源。调制光源120、外差式子***130、和探测子***140的结构设计成与选定荧光造影剂的激发和辐射特性相适配。在另一个实施例中,还可以更换或附加使用内生荧光团,并相应调整***110。
在步骤214,利用相应于选定荧光团构成的光源120激发组织100。在步骤216,以外差(或偏差)频率确定在各个探测位置“i”探测的辐射相对于光源120的激发光的相位θobs、和AC强度的对数Mobs。对于数目为“Di”的探测位置,所探测或观测的相位和AC强度分别利用指标“i”标识为(θobs)i和(Mobs)i。处理器160将这些相对相位和AC强度信息存储在存储器166中。
在步骤218,为选定成象的组织100的一个区域建立一个两维网格坐标,建立一个网格点阵列,并用“j”标识。在每个网格点j指定一致的原始值,即荧光产额yj=(ημax→m)j和荧光寿命(τ)j。这些值都是对荧光产额值和荧光寿命值的初始均匀估计值,这些值在以后的步骤中会发生改变。项“η”为荧光量子效率,其随着荧光团周围环境的不同而变化。项“μax→m”为荧光团的吸收系数,它是荧光团衰减系数的自然对数值与荧光团浓度的乘积。因此,荧光产额y=ημax→m受到周围代谢物和荧光团摄入量的影响。某些已知荧光团的摄入量根据主组织的类型和状态的不同而不同,从而提供了有益于检测疾病的又一种荧光特性。由这些特性产生的对比度与荧光团浓度基本无关。对于荧光产额和寿命的初始估计值由处理器160存储在存储器166中以备其后使用。
在建立荧光产额ημax→m和寿命τ特性初始估计值之后,在步骤230进入处理循环220中。可取的是,由处理器160利用预先编程的软件、专用硬件、或者两者的适当结合执行处理循环步骤220。为了帮助理解程序210和循环220中的各种数学运算,以下列出所选定的变量表:
c 光速;
D(r) 光散射系数;
Di 探测位置编号;
f 调制频率;
I 单位矩阵;
i 探测位置标号;
J 表示各个网格点j的灵敏度与各个探测位置的响应之
间相关性的雅各比矩阵;
j 网格点标号;
Jj,i 雅各比矩阵J中的各个矩阵元;
k 源标号;
M 调制荧光在某一位置的AC强度的对数;
m 调制频率倍频率
n 平均折射率;
r 位置(两维或三维);
Sk 调制光源的数目
S(r,ω) 调制光在位置r和频率ω的源项;
希腊字母
χ2 表示最小平方差的品质函数;
Фx(r,ω) 表示在频率域中位置r和频率ω的光子通量的复数;
η 荧光示踪物或染料的量子效率;
μa 平均吸收系数;
μam 非荧光发色团和荧光团对荧光的吸收系数;
μax 非荧光发色团和荧光团对激发光的吸收系数;
μax→c 由于非荧光发色团产生的吸收系数;
μax→m 荧光团对激发光的吸收系数;
μ’s 有效散射系数;
θ 一种调制光波相对于另一种的相移;
τ 被激发的示踪物或染料在位置r处的寿命;
ω 角调制频率,给定单位2πf;
下标
obs 观测或实验数据
x 激发光;
m 荧光或辐射光。
在步骤230,作为每个网格点j处荧光产额和寿命的初始估计值的函数计算出在每个探测位置“i”处的相位和相对AC强度。计算出的各个探测点i的相位和强度分别表示为(θm)i和(Mm)i。这些(θm)i和(Mm)i值是利用辐射传输方程的漫散射方程近似求出的。这种漫散射方程近似描述了光在组织中或在多散射介质中的空间和时间传输特性。可以用一对频率域漫散射方程,即方程(1)和(2)来分别预测在组织100的选定网格中任意位置r处的激发和辐射能量流量Фx(r,ω)和Фm(r,ω): 表示激发光的源项Sx(r,ω)是由于具有角频率ω=2ωf的正弦调制光形成的,其中f一般在兆赫兹的频率范围。在漫散射方程(1)和(2)中的第一项表示光的漫散射或“无规则移动”传输,其中Dx,m为如下述方程(3)所示的光漫散射系数: 其中μa和μ’s分别为组织100和检测介质的吸收系数和各向同性系数。这些光学性质与光波长相关,因此对于从光源120发出的激发光(下标为x)和利用子***140探测到的荧光辐射(下标为m)是不同的。对于激发波长的光的总吸收系数μax是由于非荧光发色团以及荧光团对应于激发波长的贡献形成的。总吸收系数由非荧光发色团的吸收系数μax→c与荧光团吸收系数μax→m相加得出。一般可以假定对于荧光波长的光的吸收主要是由于非荧光发色团产生的。在组织中的光速为cn=c/n,其中n为平均折射率。荧光辐射的源项与激发光能量流量Фx(r,ω)相关,由下列方程(4)给出: 这一项来自对在时间域继激发光入射脉冲之后的荧光衰减项的时间域富里叶变换,其中τ为荧光团寿命,η为量子效率,吸收系数μax→m为处于基态的荧光团的衰减系数的自然对数与浓度的乘积。如上所述,组合乘积ημax→m为荧光产额y,其正比于所产生的荧光能量流量。将方程(4)代入方程(2)便于求出各个网格点“j”的Фm。漫散射方程(1)和(2)在由网格点“j”限定的两维区域中的解很容易扩展到三维空间中,估算出一种或多种荧光特性在对应于三维空间中位置“r”的选定区域中的空间变化。
漫散射方程(1)和(2)都是线性复数椭圆方程,可以将其作为复数量Фx(r,ω)和Фm(r,ω)的边界值问题求解。这种求解利用有限差值方法建立相应的有限差值方程。利用这些差值方程得到在各个网格点j的近似解。这种求解方法记载在Fulton等人的其它文章中,椭圆问题的多网格方法A Review,114 American Meteorological Society pp.934-59(5月,1986);和B.W.Pogue等人的文章中频域漫散射光学层析摄影用的简单***的初始评估,40 Physics in Medicine and Biology pp.1709-1729(1995)。一种优选的求解方法是利用在Adams,J.C.的文章MUDPACK:为线性椭圆偏微分方程提供有效解的多网格便携Fortran软件34 App.Math Comp.p.133(1989)中所述的MUDPACK程序进行的。为了求解这个漫散射方程,假设在组织100的表面101上Фm(r,ω)=0,这个假设称为零能量流量边界条件。应当认识到还可以选择其它的边界条件,因而求解方法也不同。
从漫散射方程(1)和(2)可以求解出各个网格点j的复数解Фm。表面的探测信号正比于光子能量流量梯度的正态分量。为了逼近位于组织100表面101上探测器位置“i”所得信号,根据光子能量流量梯度的正态分量正比于刚好在表面内侧101的Фm的关系,选择最接近该位置的内网格点处的Фm值。从复数Фm的虚部和实部计算出探测位置“Di”处相对于光源120的相位和AC强度的相位延迟θm和AC强度对数Mm。
漫散射方程(1)和(2)使人深入了解到组织100的荧光光学特性对于在探测器位置i测得的θm和Mm的灵敏度。通过固定漫散射方程(1)和(2)中的各种参数并进行一系列计算可以获得这些结果。这些计算假设了圆形组织模拟体300,其中在模拟体背景303中隐藏有嵌入的异质物302,如图3所示。为模拟体300建立一个两维网格,该网格可以很容易地扩展为三维。在这些模拟条件下,赋予模拟组织体外部的所有点对激发光和荧光具有较大的吸收系数值。图3所示的四个源S1-S4(Sk=4)通过赋予在最接近各个源的表面附近的一个网格点一个任意复数来模拟。图3所示的20个探测位置D1-D20(Di=20)利用从最接近探测位置的网格点“j”处的Фm求出的计算值来模拟。对于方程(1)和(2)的模拟解是对于一个65×65的两维网格求出的,所说网格覆盖一个100毫米直径的圆形组织模拟体300,在组织模拟体中包含一个直径30毫米、位于组织模拟体300中心(这个位置稍微不同于图3所示异质物的位置)的圆形嵌入异质物。对于20个等间距环绕设置的探测位置D1-D20,求出荧光相移和AC强度的模拟测量结果。调制频率f设定为150兆赫兹。异质物和背景的光学性质表示在下列表1中:
表1
为了估算出ημax→m的影响,当异质物中的ημax→m从10-4mm-1增大到10-1mm-1而背景303中的ημax→m值保持恒定时计算各个探测点D1-D20处的θm和Mm。对于由于ημax→m的不同而产生对比度的目标物和背景,荧光寿命τ都设定为1毫微秒。相对于一个有效源Sl的θm和Mm曲线图分别表示在图4和图5中。当异质物102的ημax→m值增加到较大值时,AC强度趋近于一个上限,与在稀释非漫射解中所预计的相似。图5表示当荧光团吸收系数μax→m减少背景物质吸收系数的10至100倍时,荧光相移θm如何减少。根据这些模拟结果,可知Mm似乎与模拟的组织异质物102的ημax→m的变化直接相关,其中θ直接依赖于由于光子迁移变化产生的ημax→m。
为了估算τ的影响,当异质物中的τ值在10-1毫微秒到103毫微秒之间变化而背景中的τ值保持在1毫微秒时计算各个探测点D1-D20处的θm和Mm。背景ημax→m设定为10-5mm-1,而异质物的ημax→m设定为10-3mm-1。如图6所示,当τ值减小时探测的AC强度增大。图7表示当异质物中的荧光寿命在0.1毫微秒至1000毫微秒之间变化时在各个探测点测得的荧光相移值。在给定调制频率下(在此计算中为150赫兹),θm首先增大,达到一个最大值,然后当τ从0.1毫微秒增大到1000毫微秒时又连续减小。所以,可以认为各个探测点D1-D20处的θm和Mm与异质物中荧光寿命值直接相关。
再参照图2,在步骤240,将计算出的辐射相位和强度(θm)i和(Mm)i与在各个探测点“i”测量的辐射相位和强度(θobs)i和(Mobs)i比较以确定测量值与计算值之间的差值或“误差”。由于(ημax→m)j影响(Mm)i,所以这种比较是以如下所示方程(5)的品质函数χμ 2的形式进行的: 其中σM为Mm中典型的噪声偏差,取为0.01;Sk=激发源点数目,下标为k;Di=探测点数目,下标为i。这种算法的目的是通过适当更新(ημax→m)j而使χμ 2达到最小值。在初次更新(ημax→m)j之后,关于(τ)j的另一个品质函数参与步骤240的比较。这个品质函数χτ 2表示为如下所示的方程(6) 其中σ0为(θm)i中典型的噪声偏差,取为1度;Sk=激发源点数目,下标为k;Di=探测点数目,下标为i。因为寿命对于(θm)i和(Mm)i都有影响,在方程(6)中使用了相位和AC强度值。
在通过计算出品质函数χμ 2、χτ 2而进行了步骤240中的比较之后,控制程序进入条件判断步骤250,判断测量值(θobs)i和(Mobs)i与计算值(θm)i和(Mm)i之间借助于品质函数所得的比较结果是否满足选定的收敛判据。这个判据相当于确定荧光产额和寿命值时的允差度。在一个实施例中,当下列三个量值(i)χ2,(ii)在连续的迭代循环220中χ2的变化,(ii)在连续的迭代循环220中χ2的相对变化中任何一个小于一个1.0×10-2的阈值时达到收敛标准。在其它实施例中,如本领域技术人员所知的,可以采用不同的比较计算方法和条件判断标准。如果条件判断250得到满足,控制程序进入步骤270,退出循环220;但是,如果不满足该判据,继续在步骤260执行循环220。
在步骤260中,更新各个网格点j的荧光产额(y)j=(ημax→m)j和寿命(τ)j,从而使这些值可以达到相应于比较步骤240和条件判断步骤250的最小偏差。为了更新这些值,可以使用雅各比矩阵,这种矩阵表示在各个探测点i的响应对于各个网格点j的荧光产额(y)j=(ημax→m)j和寿命(τ)j的变化的灵敏度。采用三个雅各比矩阵:
和
。这些雅各比矩阵的矩阵元Ji,j分别由[Mi/((ημax→m)j];Ji,j=[Mi/τj];以及Ji,j=[Q/τj]给出。通过对每个网格点j求解漫散射方程(1)和(2)四次,利用(τ)j和(τ+δτ)j,以及(ημax→m)j和(ημax→m+δημax→m)j计算出Mm,i和θm,i,可以求得这些矩阵元。按照最小平方求最小值方法,计算出荧光产额和寿命的更新值。在一个优选实施例中,这种更新算法选自用于重构利用电阻抗层析摄影所获得的图象的一种算法,如Yorkey等人在“电阻抗层析摄影用重构算法的比较”(34 Transactions in Biomedical Engineering pp.843-52(1987))中提出的算法。这些雅各比矩阵用于求解更新矢量[
Δημax→m]和[
Δτ],以分别估算产额矢量[
ημax→m]和寿命矢量[
τ]。这些矢量的维数对应于网格点的数目。在每次迭代循环220中,求解下列的雅各比矩阵(7)和(8)以确定产额和寿命矢量估算值的更新值: Mmobs和
Mm分别为在各个探测点i处的AC强度对数的测量矢量值和计算矢量值。
θmobs和
θm分别为在各个探测点i处的相位滞后的测量矢量值和计算矢量值。由于雅各比矩阵的病态特性,增加了λ1I或λ2I项作为马夸特最小化概型的一部分,其中I为单位矩阵。参数λ1或λ2利用在Press等人所写“数值方法:科学计算手段”(Cambridge UniversityPress,1992)一文中公开的那种Maquardt-Levenberg型算法进行调整。从雅各比矩阵方程(7)和(8)同时生成的各个线性代数方程采用常规的数值方法求解。在每次迭代循环220中重新计算雅各比矩阵。已经发现方程(7)和(8)提供了一种选择产额和寿命估算值的适合变化值的方式;但是,本领域技术人员熟知的通过递归迭代获得令人满意的估算值的其它数值方法也是可以考虑的。更新程序一旦完成,则控制程序返回到步骤230。
如果在条件判断步骤250中收敛判据得到满足,则说明各个网格点的荧光产额和寿命估算值达到令人满意的最小值,控制程序返回步骤270。在步骤270处理器160根据产额和/或寿命荧光特性的空间变化产生图象信号。这个图象信号被传送到输出装置164,其响应该信号显示出一幅图象。由于产额和寿命这些荧光特性一般随荧光团周围生物环境的不同而变化,因此这种图象通常指示出组织异变,能够由此检测出异质体102、103。例如,激光二极管能够发出近红外光(NIR),这种近红外光可以穿透人体组织几厘米之深,可以使用对近红外光灵敏的荧光造影剂构成一个实用的成象***。在一个实施例中,这种***应用了一个内窥镜。
除了产额和寿命以外,还可以利用漫散射方程(1)和(2)变换其它有助于识别有病组织的荧光特性的空间变化。这类其它的荧光特性包括,但是不局限于,作为不依赖于荧光产额的独立特性的量子效率η和/或荧光吸收系数μax→m。
在本发明的另一个实施例中,利用光子能量流量方程和雅各比估算方法确定指定荧光团摄入浓度的变换关系。在这个实施例中,在不使用指定荧光团的情况下通过估算各个网格点j的非荧光发色团吸附系数μax→c和散射系数μ’s,而不是产额和寿命来确定散射系数μ’s和发色团吸附系数μax→c和的第一变换关系。可以将关于Фx(r,ω)的漫射方程(1)与改进的雅各比方程(7)和(8)结合使用建立这种第一变换关系。这种改进使用发色团吸附系数和散射系数代替荧光产额,调整之后,这些新的特性满足下列方程: 和 所用四个雅各比矩阵的矩阵元
和
分别由
和
给出。更新这些吸收系数和散射系数变换关系以使品质函数χ2最小化: 其中ns=Sk,nd=Di。
在产生第一变换关系之后,施加指定的荧光造影剂,并代替μax→c将μax代入方程(9)-(11)确定总吸附系数μax,以获得总吸附系数的第二变换关系。应指出μax=μax→m+μax→x,荧光造影剂的摄入量正比于μax→m,摄入浓度可以通过确定第一和第二变换关系中吸附系数变化量之间的差值换算出来。然后可以利用这种“差值换算”生成对应于摄入量浓度的一幅图象。
另一个实施例测量响应各个光源调制频率f的辐射。所使用的不同频率的总数规定为Mf。为了获得这个附加数据,对于下标为m的每个频率f执行迭代循环220。光源数目Sk和探测点Di分别用k和i作下标。这种附加数据可以用于改善利用***110获得的图象效果,或者可以减少在估算中使用的探测点数目或激发光源数目。相应于这个附加数据的一个特征品质函数由下列方程(12)给出:χτ2= 除了荧光产额和寿命方法之外,还可以使用多频方法变换其它感兴趣的光学特性。除了正弦调制光源以外,本发明在其它实施例中还可以应用脉冲或其它时变激发光源。
图15表示在本发明的另一个实施例中采用的一个光学***410。这个***包括调制光源420,该光源包括与激光二极管424相连的激光器驱动器422和基准频率发生器426。光源420用于将调制光传输到组织体400,然后通过50毫米透镜432将从组织体再辐射出的光聚焦到一个增益调制图象增强器430中。增强器430包括一个将光子转换为电子的光阴极面,一个多信道板(MCP),其通过雪崩倍增效应使电子信号倍增,和一个磷光屏,其将电子转换为光学图象。可取的是,增强器430为Litton Electronics公司生产的一个快速增强器,它能够通过在光阴极和多信道板之间施加一个直流偏压和来自放大器428的一个RF信号进行调制。在这个实例中,对于来自增强器430的图象的调制是利用从合成器426输出的一个10兆赫兹信号与激光二极管424相位同步的。通过按照相同的频率对激光二极管424和图象增强器430进行调制,可以在磷光屏上生成稳态图象。授予Gratton等人的美国专利US-5213105中提供了与这项技术有关的一些背景内容。在磷光屏生成的图象经过一个150毫米微距透镜436并通过干涉滤光器433聚焦到一个电子耦合器件(CCD)摄像机434中。摄像机434具有一个512×512的CCD探测器阵列,以形成相应的象素化图象。摄像机434与具有上述处理器160相似结构的处理器460相连。
在每次获取图象之后,通过在处理器460的控制下利用频率合成器452使图象增强器430的相位在0至360度之间步进,在图象增强器430与激光二极管424之间产生相位延迟。由于图象增强器430和激光二极管424的增益调制是按照相同频率进行的,零差化使得在依赖于相位的增强器430上产生一幅稳态磷光图象。可取的是,利用常规的GPIB接口实现合成器452与处理器460之间的控制。然后将图象增强器430的磷光屏上的图象以各个相位延迟叠加在一起。然后利用增加的相位延迟图象产生激发光与组织体400再辐射光之间相移和强度调制比的变换关系。通过施加干涉或适合的滤光器,可以有选择地将辐射光与激发光分离并进行测量。摄像机434的输出可以由处理器460利用程序210进行处理。
下面参照具体实例1-3进一步描述本发明。可以理解这些实例只是说明性的,而不是限制性的。实例1-3包括对程序210的计算机模拟。这种模拟,包括人体组织的模拟,对于本领域技术人员来说,是演示荧光光谱图象特性的一种有效方式。这些实例利用在下列表2所示条件下求解关于θm和Mm的漫射方程(1)和(2)所获得的模拟值:
表2
这些实例模拟图3所示具有100毫米直径的组织体300。计算出在图3所示各个探测点D1-D20相应于位于其周围的四个调制光源S1-S4的θm和Mm值。激发光调制频率f模拟为150兆赫兹。求解漫射方程(1)和(2)获得相应于探测点和光源位置的各种组合(Sk*Di=4×20=80)的80组θm和Mm模拟值。在漫射方程解中θm上叠加0.1度(或放宽到1度),Mm上叠加1%的标准偏差高斯噪声。在一个SunSpare10计算机上利用适应的MUDPACK程序求解漫射方程(1)和(2)。利用所获得的数据组作为实例1-3中程序210的模拟输入值。结果表示在下列的表3和表4中:
表3
表4
实施例 | 面积,目标1(mm2) | 位置,目标1(x,y),(mm,mm) | 面积,目标2(mm2) | 位置,目标2(x,y),(mm,mm) |
5.1 | 706.0(期望值)742.2(测量值) | (60,60)(期望值)(60.8,58.5)(测量值) | 未用 | 未用 |
5.2 | 706.0(期望值)703.1(测量值) | (60,60)(期望值)(59.4,58.3)(测量值) | 未用 | 未用 |
5.3 | 314.1(期望值)381.0(测量值) | (32.3,67.7)(期望值)(34.0,67.7)(测量值) | 314.1(期望值)342.0(测量值) | (67.7,32.3)(期望值)(65.0,35.0)(测量值) |
实施例 | ημax→m(目标)(mm-1) | τ(目标)(ns) |
5.1 | 1.0×10-3(期望值)0.93×10-3(测量值) | 1.0(期望值)1.03(测量值) |
5.2 | 1.0×10-3(期望值)0.8×10-3(测量值) | 1.0(期望值)0.7(测量值) |
5.3 | (上部左侧目标)1.0×10-3(期望值)2×10-3(测量值)(下部右侧目标)2.0×10-3(期望值)1.8×10-3(测量值) | (上部左侧目标)1.0(期望值)4.1(测量值)(下部右侧目标)2.0(期望值)3.5(测量值) |
实例1
实例1在没有非荧光发色团产生的吸收情况下重构荧光产额和寿命。在这个实例中为了模拟实验数据,相应于背景和异质成分302的荧光产额(ημax→m)j分别选定为1×10-5mm-1和1×10-3mm-1,相应于背景和异质成分302的荧光寿命(τ)j分别选定为10毫微秒和1毫微秒。在执行循环220过程中,不预先假定异质成分302的位置以及背景荧光特性,而是分别给出一致的假定值,即荧光产额(ημax→m)j为1×10-5mm-1,寿命(τ)j为10毫微秒。对于一个两维17×17网格,少于50次迭代循环220即实现收敛结果(在SunSparc10计算机上的计算时间为2小时)。图8和图9分别表示在模拟目标所在网格点的ημax→m和τ的平均值在50次迭代内收敛到ημax→m=0.93×10-3mm-1和τ=1.03毫微秒。图10和图11分别表示根据ημax→m和τ的变换值重构的图象,并且表示所期望图象。在实例1-3中通过内插法去掉具有不合理高值,但是却被处于合理范围的值包围的假点而使图象平滑。这些假点值用在模拟循环220中获得的荧光产额和寿命的平均本底值代替。
模拟背景上的网格点的ημax→m平均值在50次迭代内收敛到9×10-5mm-1。背景的τ值收敛到5.4毫微秒。最终所得图象对于初始假定值的相关性通过分别对(ημax→m)j和(τ)j给出1×10-4mm-1和10毫微秒的初始相同假定值来检验。其结果是获得与图10和图11所示相似的图象。
由所有ημax→m值大于ημax→→m峰值的35%(任意选定)的网格点构成的部分被识别为异质成分302所在位置(图10所示)。所有被识别为目标的网格点的坐标中点在位置(60.8,58.5),这个点接近用于模拟实验数据的位置点(60,60)。如表3所列,按照我们任意定义的识别标准,异质成分的面积为72平方毫米,接近用于产生我们的模拟实验数据的数值。
实例2
实例2在利用模拟发色团吸收模拟人体组织的情况下重构荧光产额和寿命。除了假定具有均匀的背景发色团吸收系数ημax→=1×10-3mm-1以外,采用与在实例1中所述相同的隐藏异质成分以及光学参数和模拟设备产生模拟实验数据。虽然激发光并不用于图象重构,但是我们假定已知这种光学特性以估算出在生理条件下反向重构图象的最佳可能特性。图12和图13分别表示荧光产额(ημax→m)j和(τ)j的两维重构空间变换。如表3所示,根据我们基于ημax→m的判据,目标位置的平均值为(59.4,58.3),与用于模拟实验数据的条件一致。按照我们任意定义的识别标准(所有ημax→m值大于最大值的35%的网格点),异质成分的面积为703平方毫米,这个值接近用于产生我们的模拟实验数据的数值。模拟目标区域的网格点的ημax→m和τ平均值在50次迭代内收敛到ημax→m=0.8×10-3mm-1和τ=0.7毫微秒,它们与用于产生模拟实验数据的值一致(见表3)。模拟背景区域的网格点的ημax→m和τ的平均值在50次迭代内收敛到与实例1中报告值相近的值。
实例3
实例3模拟在组织体内有两个隐藏异质成分的情况(在图3中未示出)。在这种情况下,除了将对应于目标1和目标2的荧光产额ημax→m分别选定为1×10-3mm-1和2×10-3mm-1,将对应于目标1和目标2的荧光寿命τ分别选定为1毫微秒和2毫微秒之外,其它所用参数与实例1中所述相同。用一个33×33网格代替了17×17的网格。在图14中表示了与荧光产额变换相应的一幅图象。
所有在本说明书中引用的出版物和专利申请都以参照的方式结合在本申请中,就象对于每一份出版物或专利申请都单独而且具体地指出以参照方式结合在本申请中一样。尽管在附图中和上面的描述中详细地解释了本发明,但是这些内容只是说明性,而不是限制性的,应当理解为它只是表示和描述了优选实施例,在本发明构思范围内的所有变化和改进都是需要保护的。
Claims (26)
1、一种成象方法,它包括以下步骤:
(a)用一个光源发出的激发光照射一种光散射物质的表面,所说物质的表面之下包含一种异质成分;
(b)探测所说物质响应步骤(a)而发出的荧光辐射;
(c)给出这种物质的荧光特性的空间变化估算值;
(d)确定作为所说估算值函数的计算辐射;
(e)将在步骤(b)探测的辐射与计算辐射比较以确定误差;
(f)给出所说荧光特性空间变化的改善估算值,并重复步骤(d)至(f),直到所说误差达到所需的最小值;和
(g)根据改善的估算值产生一幅图象,该图象对应于所说物质中的异质成分。
2、如权利要求1所述方法,它还包括在所说物质中施加荧光造影剂的步骤。
3、如权利要求1所述方法,其特征在于步骤(f)包括应用雅各比矩阵。
4、如权利要求1所述方法,其特征在于所期望的辐射是作为一个漫射方程的函数求出的。
5、如权利要求1所述方法,其特征在于步骤(e)包括将计算辐射的强度和相位与在步骤(b)探测的辐射的强度和相位比较的步骤。
6、如权利要求1所述方法,其特征在于所说物质中包含一种荧光造影剂,所说荧光特性是荧光量子效率、荧光寿命、和荧光造影剂浓度中至少一种的函数。
7、如权利要求6所述方法,其特征在于所说荧光特性是荧光量子效率的函数,所说光源是以预定频率进行强度调制的光源,步骤(e)包括将计算辐射的AC强度和相位与在步骤(b)探测的辐射的强度和相位比较的步骤,步骤(f)包括应用雅各比算子的步骤,所期望的辐射是作为组织中光子能量流量的函数求出的。
8、一种成象方法,它包括以下步骤:
(a)用一个光源发出的激发光照射活体生物组织;
(b)探测所说组织响应所说照射发出的荧光辐射;
(c)用一个处理器确定所说组织中作为所说辐射函数的荧光特性的空间变化;和
(d)根据所说空间变化生成所说组织的一幅图象。
9、如权利要求8所述方法,其特征在于它还包括在所说组织中施加一种荧光团的步骤。
10、如权利要求8所述方法,其特征在于所说荧光特性是荧光寿命、荧光量子效率、或荧光吸收中至少一种的函数。
11、如权利要求9所述方法,其特征在于所说照射步骤包括将所说光源定位于所说组织表面附近的步骤,所说探测步骤包括探测在所说表面辐射的光的步骤。
12、如权利要求8所述方法,其特征在于所说照射步骤包括将邻近所说组织表面的一组调制光源定位的步骤,所说探测步骤包括探测在所说表面上一组位置处辐射的光的步骤。
13、如权利要求8所述方法,其特征在于所说确定步骤包括以下步骤:(i)给出所说荧光特性的空间变化的估算值,(ii)作为所说估算值的函数确定计算辐射值,(iii)将计算的辐射值与在所说探测步骤获得的荧光辐射值进行比较以确定误差,(iv)给出所说荧光特性的空间变化的改善估算值,和(v)对改善的估算值重复进行所说的确定步骤和所说的比较步骤,直到所说误差达到所需的最小值。
14、一种成象方法,它包括以下步骤:
(a)在含有异质成分的光散射生物组织中加入一种荧光造影剂;
(b)用一个光源发出的光照射所说组织表面,以激发所说造影剂;
(c)探测所说组织响应所说照射发出的辐射光;
(d)确定表示作为位置和辐射函数的荧光特性的一组值;和
(e)根据这些值产生一幅图象,该图象对应于所说组织中的异质成分。
15、如权利要求14所述方法,其特征在于所说荧光特性是荧光量子效率的函数。
16、如权利要求14所述方法,其特征在于所说荧光特性对应于荧光寿命。
17、如权利要求14所述方法,其特征在于所说探测步骤包括在所说表面上一组位置探测响应所说照射步骤而发出的荧光。
18、如权利要求14所述方法,其特征在于所说照射步骤包括从沿表面分开放置的一组光源中发光的步骤。
19、如权利要求14所述方法,其特征在于所说照射步骤包括用具有一组不同频率的调制光激发在所说组织中的荧光造影剂,并确定作为不同频率的函数的辐射值。
20、如权利要求14所述方法,其特征在于所说确定步骤包括以下步骤:(i)给出估算值,(ii)确定作为所说估算值函数的计算辐射值,(iii)将计算辐射与所述探测的辐射进行比较以确定误差,(iv)给出改善的估算值,和(v)对于改善的估算值重复所说确定步骤和所说比较步骤,直到所说误差达到所需最小值。
21、用于对包含一种异质成分和一种荧光团的光散射组织成象的一种***,它包括:
(a)适用于激发所说荧光团的一个光源;
(b)一个探测器,其用于产生相当于所说组织响应从所说光源发出的光而发出的荧光辐射的探测光信号;
(c)一个处理器,其与所说探测器操作性相连,并响应所说的探测光信号产生表示所说组织中作为位置函数的荧光特性的一组值,所说荧光特性相当于荧光寿命、荧光量子效率、和荧光吸收中至少一种,所说处理器用于产生作为所说值的函数的图象信号;和
(d)一个输出装置,其响应所说的图象信号产生相应于所说组织中异质成分的一幅图象。
22、如权利要求21所述***,它还包括一组调制光源。
23、如权利要求21所述***,其特征在于所说荧光特性相当于荧光产额。
24、如权利要求21所述***,其特征在于所说探测器用于在所说组织表面上一组位置探测所说辐射。
25、如权利要求21所述***,其特征在于所说处理器用于根据将计算辐射与从所说探测光信号得到的测量辐射的比较结果确定所说值,所说计算辐射是作为所说荧光特性的空间变化估算值的函数确定的,更新所说估算变化值,并重复所说比较,直到所说计算辐射与所说测量辐射之间的差值达到所需的最小值。
26、如权利要求21所述***,其特征在于所说光源包括一个激光二极管,所说探测器包括一个CCD摄像机。
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JP3819032B2 (ja) | 2006-09-06 |
AU1130797A (en) | 1997-03-19 |
CA2230228C (en) | 2006-11-14 |
EP0846262A1 (en) | 1998-06-10 |
JP2000500228A (ja) | 2000-01-11 |
CA2230228A1 (en) | 1997-03-06 |
EP0846262A4 (en) | 1999-11-03 |
NO980750L (no) | 1998-04-23 |
NO980750D0 (no) | 1998-02-23 |
US5865754A (en) | 1999-02-02 |
WO1997008538A1 (en) | 1997-03-06 |
MX9801351A (es) | 1998-07-31 |
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