CN1729484A - 用于mri中的各向同性成像及使用各向同性或近似各向同性成像的定量图像分析中的多个成像平面的融合 - Google Patents
用于mri中的各向同性成像及使用各向同性或近似各向同性成像的定量图像分析中的多个成像平面的融合 Download PDFInfo
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Abstract
根据本发明，提供了一种用于从二维图像生成各向同性或近似各向同性三维图像的方法。根据本发明，所述方法包括如下步骤：获得身体局部在第一平面中的第一图像，其中所述第一图像生成第一图像数据量；获得所述身体局部在第二平面中的第二图像，其中所述第二图像生成第二图像数据量；且将所述第一图像数据量与所述第二图像数据量相组合，以形成所得图像数据量，其中所述所得的图像数据量为各向同性或近似各向同性。
Description
在联邦资助的研究与发展下所作出的关于发明权利的声明
下文所描述的本发明的某些方面是由美国政府在由美国国家标准与技术协会(NIST)所授予的先进技术计划70NANBOH3016的支持下所作出的。
优先权要求
该申请要求享受下列优先申请案的优先权利益：2002年12月4日提交美国初步专利申请案，其申请号为60/431,176。上述所有申请的全部一起构成本发明申请的一部分以作参考。
技术领域
本发明通常涉及一种医学成像，且更具体而言涉及一种有助于不止一维地分析的医学成像，例如磁共振成像(MRI)。更具体而言，本发明涉及用于医学成像的各向同性成像技术(诸如MRI)，以改进定量图像分析。
背景技术
磁共振成像(MRI)是一种非侵入性成像技术，其为临床医师及诊断医师提供了有关受检体内部相关区域的解剖结构和条件的信息。参看(例如)：于1997年9月30日颁予Lang等人的“Magnetic Resonance Imaging Technique for Tissue Characterization”的美国专利第5,671,741号；于2002年4月17日颁予Hargreaves等人的“Magnetic ResonanceImaging Using Driven Equilibrium Fourier Transform”的美国专利第6,219,571 B1号；于2002年11月12日颁予Hoogeveen等人的“Magnetic Resonance Imaging of SeveralVolumes”的美国专利第6,479,996号；于2002年7月4日公开的颁予Alexander等人的“Assessing the Condition of a Joint and Preventing Damage”的美国专利申请案第2002/0087274 A1号。通常，在MRI中，在一检查区域中设定一个大体上均匀的临时恒定的主磁场(B0)，其中放置有一个待成像或待检查的受检体。经由射频(RF)磁场(B1)激励及操作，受检体中否则与主磁场对准的所选磁偶极子被倾斜以激励磁共振。通常操作所述共振以诱导来自所述受检体的所选区域的可侦测磁共振回波。在成像过程中，所述回波经由主磁场中所建立的磁梯度而得以空间编码。来自MRI扫描仪的原始数据被收集到一通常被称为K空间的矩阵中。通过利用反向傅立叶变换、二维傅立叶变换、三维傅立叶变换或其它已知的变换，可从所述K空间数据重建所述受检体的图像表示。
常规MRI扫描产生一个数据量，其中所述数据量由具有三维特征的体素组成。所述体素维度由MRI机器的物理特征以及用户设定而确定。因而，每个体素的图像分辨率在至少一个维度上受到限制，其中在至少一个维度上分辨率的损失可能会导致三维成像问题。
存在许多其中深度或三维(“3D”)信息适用于诊断和陈述治疗策略的应用。例如，在对血管进行成像时，横截面仅展示出穿过血管的切片，从而难以诊断出狭窄或其它异常性。类似地，诸如针跟踪、尿导管跟踪及其类似方式之介入成像需要3D信息。同样，深度信息适用于所谓的交互式成像技术，其中图像得以实时或近似实时地显示，且响应于此，操作者可调整扫描参数，诸如视角、对比参数、视场、位置、翻转角、重复时间和分辨率。
三维成像通常涉及：采集多个二维或切片图像，其经组合可产生一体积图像；或者使用三维成像技术。对改进体积成像的效率所作的努力已集中于加速所述采集过程。例如，许多二维快速扫描程序已适用于三维成像。类似地，例如，已通过使用经改进的重建算法来努力改进重建速度和效率。尽管如此，三维成像仍然相对较慢。
然而，当前MRI采集技术并未在所有平面中提供高分辨率和使用各向同性或近似各向同性成像的定量图像分析。因而，本发明期待新的并经改进的磁共振成像技术。
当前3D MRI扫描技术并未解决的一个额外问题是部分体积效应的降低。在体素落在两个被扫描的物体之间的边界内时导致部分体积效应。例如，如果矢状扫描患者膝盖，那么可对体素进行定向以使得所述体素的一部分落在股骨内且一部分落在股骨外部的空间内。MR成像将在整个体素上求整体灰度值的平均值。扫描分辨率越低，那么部分体积效应就越大。在3D扫描中，其中在扫描的至少一个平面中存在低分辨率，部分体积效应的影响得以极大地增加。因而，需要用以形成部分体积效应的影响减小的3D MRI扫描的方法。
此外，常规3D MRI扫描程序的一额外缺陷为：归因于扫描分辨率和扫描定向而使得被扫描的物体的边界遗失。此在以下情形中发生：当被扫描的物体的边界处于扫描的切片厚度之间时，或物体的边界平行于成像平面时。因而，需要用于降低边界遗失的可能性的经改进方法。
发明内容
本发明解决了如下问题：使用当前3D图像采集技术，切片的平面内(x-y平面)分辨率通常比切片厚度(在z维上)高至少三倍。切片(通常在z方向上)之间的低分辨率导致产生关于3D图像分析和可视化的限制。无法在所有三个维度上以相同的精确度来描述3维物体的结构。部分体积效应对于z维上的解释和量测的影响比对于x-y平面中的解释和量测的影响程度更大。多平面再形成的分辨率和精确度因体积数据而取决于切割方向而定。
此外，本发明同样解决了图像(诸如MR图像)的组织分割和/或定量分析的精度不断增加的问题。例如，在获得了各向同性或近似各向同性三维MR图像之后(例如，使用本文所描述且所属领域已知的脉冲序列采集技术)，可以较高精度且此外定量地从图像中提取特定的组织。当前可用的主观目测技术无法实现定量且此外通常不精确。
因而，在一方面中，本发明提供了一种改进图像(诸如MR图像)分辨率的方法。在某些实施例中，所述方法包括(例如)：采集一身体局部的至少两个MR扫描(例如，垂直平面中的扫描)，并将所述扫描合并，进而增加分辨率。在本文所描述的任何方法中，所述扫描可在任何平面中，例如，矢状、冠状和/或轴成像平面。第二或随后扫描优选地含有足量切片以覆盖第一扫描的整个视场。此外，在本文所描述的任何方法中，从两个或两个以上的扫描中所获得的数据随后被合并以形成一个新的数据量，其为各向同性(或近似各向同性)且具有一个对应于面内分辨率S1和S2的分辨率。合并可包括(例如)：确定新的(经合并)数据量的每个体素(V)的灰度值。在某些实施例中，所述灰度值经由如下步骤获得：(a)确定3D空间中V的位置；(b)于此位置处进行融合之前，(例如，从原始扫描中)获得扫描的灰度值；(c)将来自S1和S2的灰度值内插(组合)入单一灰度值(G)中；和(d)将G分配给V。
在本文所描述的任何方法中，可对任何活组织进行成像，其中包括(但不限于)：关节、骨骼和/或器官(例如，脑、肝、肾、心、血管、肠胃道等)。
根据本发明，提供了一种MRI扫描方法，所述方法包含如下步骤：执行一身体局部在第一平面中的第一MRI扫描，其中所述第一MRI扫描生成第一图像数据量；执行所述身体局部在第二平面中的第二MRI扫描，其中所述第二MRI扫描生成第二图像数据量；且将所述第一与第二图像数据量相组合以形成所得图像数据量，其中所述所得图像数据量为各向同性。
根据本发明的另一实施例，提供了一种用于产生各向同性或近似各向同性图像数据的方法，所述方法包含如下步骤：从第一平面中的第一MRI扫描获得第一图像数据量；从第二平面中的第二MRI扫描采集第二图像数据量；从所述第一与第二图像数据量中的每一者中提取边界图像数据；将所述经提取的边界图像数据加以组合以形成所得图像数据量。
根据本发明，提供了一种用于生成三维数据量的方法，所述方法包含以下步骤：从在两个不同平面中执行的至少两个MRI扫描中采集至少两个数据量；将所述数据量加以组合以形成所得数据量；选择一个疗法以响应所述所得数据量；且获得植入物的形状。
系统包括一种图像分析方法。所述图像分析由以下步骤来执行：获得一身体局部在第一平面中的第一图像，其中所述第一图像生成第一图像数据量；获得所述身体局部在第二平面中的第二图像，其中所述第二图像生成第二图像数据量；且将所述第一与第二图像数据量加以组合以形成一个所得图像数据量，其中所述所得图像数据量为各向同性。此外，可在一或一个以上三维位置处从所述第一与第二图像数据量获得第一与第二灰度值。而后可将那数据内插以提供一个所得灰度值，而后，所述所得灰度值被分配给在所得数据量的三维位置中的体素。如所属领域的技术人员将了解，图像之间的角度可从约0°变化到约180°或从变化0°变化到约90°。一旦已获得了这些值，就可以选择一种疗法或治疗来补充所述数据量。所属领域技术人员将了解，一身体局部在不同于先前所使用的平面中的平面中所取得的至少一个额外图像可用于生成额外的图像量。从所述图像容积可生成数据量，从而接着将数据量与所述第一与第二图像数据量加以组合以形成所得数据量。诚然，如果需要，那么可从所述所得图像数据量中提取一边界图像数据量。
本发明同样描述了一种用于从图像中产生各向同性或近似各向同性图像数据的方法。此方法通常包含如下步骤：从第一平面中的第一图像获得第一图像数据量；从第二平面中的第二图像获得第二图像数据量；从所述第一与第二图像数据量中的每一者中提取边界图像数据；且将所提取的边界图像数据加以组合以形成所得图像数据量。诚然，也可能：从一个不同于所述第一平面与所述第二平面的平面中的至少一个额外图像中获得至少一个额外图像数据量；从所述额外图像数据量中提取额外边界图像数据；且将所述额外边界图像数据量与所述所得图像数据量相组合。此所得数据可为各向同性或近似各向同性。如所了解，所述第一平面可相对于所述第二平面呈一个角度；所述角度可为从约0°到180°或从约0°到90°。
本发明包括了一种用于生成三维数据量的方法。通常而言，所述方法包括如下步骤：从在两个不同平面中所执行的至少两个图像中采集至少两个数据量；将所述数据量加以组合以形成所得数据量；选择一疗法以响应所述所得数据量；选择一植入物；且获得植入物的形状。所述组合步骤可进一步包括如下步骤：在所述数据量的每一者中获得每个数据点的灰度值；将来自灰度值的所得灰度值内插；且将所述所得值分配给所述所得数据量的每个数据点。在将数据加以组合之前，可在每个平面中扫描并提取对应于任何表面的数据。
本发明同样揭示了一种用于生成三维数据的方法。所述方法包括如下步骤：从第一平面中采集第一图像，以产生具有默认分辨率的第一数据量；从第二平面中采集第二图像，以产生具有默认分辨率的第二数据量；将所述第一与第二数据量加以组合以产生所得数据量，其中所述所得数据量具有所得分辨率。如所了解，所述所得分辨率大于所述默认分辨率。
本发明揭示了一种图像分析方法，所述方法包括如下步骤：获得一身体局部在至少第一平面与第二平面中的至少一图像，其中所述第一平面生成第一图像数据量且所述第二平面生成第二图像数据量；且将所述第一与第二图像数据量加以组合以形成所得图像数据量，其中所述所得图像数据量为各向同性。
本发明又揭示了一种替代性图像分析方法，所述方法包括如下步骤：获得一身体局部在至少第一平面与第二平面中的至少一图像，其中所述第一平面生成第一图像数据量且所述第二平面生成第二图像数据量；且将所述第一与第二图像数据量加以组合以形成所得图像数据量，其中所述所得图像数据量为近似各向同性。
根据本发明，提供了一种用于生成三维MRI扫描数据的方法，所述方法包含如下步骤：在第一平面中执行第一MRI扫描，以产生具有默认分辨率的第一数据量；在第二平面中执行第二MRI扫描，以产生具有默认分辨率的第二数据量；将所述第一与第二数据量加以组合以产生所得数据量，所述所得数据量具有所得分辨率。
附图说明
图1说明了用于说明数据量S1和S2的两个MRI扫描；其中每个扫描均展示了在平行于初始扫描的平面中所取得的复数个图像幻灯片。
图2说明了由一图像扫描所产生的一组三个体素，以说明增加的z轴长度。
图3说明了由一图像扫描所产生的第一组三个体素，以说明z轴分量。
图4说明了由一图像扫描所产生的第二组三个体素，以说明z轴分量。
图5说明了由根据本发明的方法而生成的所得组九个像素。
图6说明了从两个图像扫描中所提取的经组合的边界图像数据。
图7说明了从至少两个图像扫描中所生成的三维植入物设计。
图8A-C说明了用于说明本发明的过程的流程图。
具体实施方式
呈现了以下描述以使得任何所属领域的技术人员能够制作并使用本发明。所属领域的技术人员将易了解对所描述实施例的各种修正，并且本文中所界定的一般原则可在不脱离如由前述权利要求书所界定的本发明的精神和范畴的前提下应用于其它实施例和应用。因而，本发明并非限定于所展示的实施例中，而是符合同本文所揭示的原则和特征相一致的最广泛的范畴。在有必要实现对所揭示的本发明完全了解的程度下，此申请案中所引用的所有已颁布的专利案、专利公开案和专利申请案的说明书和附图均以引用方式并入本文中。
如所属领域的技术人员将了解，本文所陈述的方法可以所陈述的事件在逻辑上可行的任何次序来实施，以及以所陈述的事件次序来实施。此外，当提供了一个范围内的值时，应理解，在所述范围的上限与下限之间的任何介入值及任何其它所阐述或在所述阐述范围内的介入值均涵盖于本发明内。同样，预期所描述的发明性变体的任何可选特征均可独立地或与本文所描述的任何一或多个特征相组合地陈述并主张。
本发明为一种可用于改进组织分割和/或定量图像分析的图像分析方法。具体而言，本发明将两个或两个以上图像相组合，以在三维方向上实现高分辨率。根据本发明的方法的原则和操作可参看随附描述而更好地被理解。
1.0概述
根据本发明，描述了一种用于改进取自一身体局部的图像的分辨率和/或组织分割的方法。此方法通常涉及在不同平面中采集至少两个图像，且将所述图像加以组合以在所有方向上实现相同程度(例如，高)的分辨率。所述图像可通过(例如)使用MRI而获得。然而，随着其它成像装置变得可用，所属领域的技术人员将了解，在不脱离本发明范畴的前提下，这些技术也可以提供给其它成像装置。
本文所描述的方法提供了各向同性或近似各向同性的分辨率，从而导致改进了组织分割。与当前所利用的具有高度主观性的目测不同，本文所描述的方法和组合物为定量的，且因而增加了诊断和治疗体系的设计的精确性。
1.1磁共振成像(MRI)
以普通术语描述MRI，活组织内的所有质子均具有固有磁矩且可随机旋转从而导致没有净磁化强度或方向。当将样品置于MR扫描仪的磁场中时，质子持续旋转但使其自身校直而平行于场(B0)方向或与场(B0)方向反平行，从而分别对应于低能状态和高能状态。在MR检查的过程中，从定向为垂直于B0的发射器线圈将射频(RF)脉冲(B1)施加到样品，且使质子临时倾斜而不校直；所诱导的净横向磁化在静态B0场的轴周围的进动在接收器线圈两端之间产生电压，其被侦测为MR信号。关于对基本MRI原则和技术的一般论述，参看MRI Basic Principles and Applications(第二版，Mark A.Brown和Richard C.Semelka，Wiley-Liss，Inc.(1999))；同样可参看Hargreaves等人的美国专利第6,219,571号。
1.1高分辨率3D MRI脉冲序列
MRI利用若干脉冲序列，所述脉冲序列允许接受成像的不同区域部分产生更好的对比度。不同脉冲序列可更好地适于不同解剖区域的可视化。可同时使用一个以上的脉冲序列。在2002年3月21日公开的Alexander等人的国际专利申请案第WO 02/22014号中提供了对不同类型的脉冲序列的简要论述。
可用于将组织(诸如，软骨)成像的惯常MRI脉冲序列包括：常规T1和T2加权自旋回波成像、梯度回波(GRE)成像、磁化传递对比(MTC)成像、快速自旋回波(FSE)成像、对比度增强成像、快速采集弛豫增强(RARE)成像、稳定状态下的梯度回波采集(GRASS)及驱动平衡傅立叶变换(DEFT)成像。由于这些成像技术已为所属领域的技术人员(例如，具有成像技术方面的高等学位的人员)所熟知，因而下文仅对每一者进行简要论述。
1.2 T1和T2弛豫的测量
由于随机热运动，致使样品内的质子自旋彼此间失去相干性。此相干性的损失导致信号衰减。MR信号返回到零所花费的时间视许多因素而定，其中一个因素为被激励的自旋相对于其直接环境而损失过多能量的速率。此现象称为自旋-晶格弛豫或T1弛豫，其主要影响平行于B0的磁化且引起来自自旋系统的能量的净损失。
所观察到的另一现象是：由于频率稍微不同而致使相邻质子的自旋倾向于漂移而使得彼此不校直。此引起相位相干性的损失，此被称为自旋-自旋弛豫或T2弛豫。T2弛豫影响磁化的横向分量但不会引起能量的净损失。
常规T1和T2加权MRI描绘了诸如关节软骨的活组织，并可论证缺陷和总的形态变化。所属领域的技术人员可不难取决于待成像的结构来选择T1或T2加权MRI。例如，T1加权图像展示出诸如透明软骨的某些组织的极好物质内解剖细节，而T2加权成像则提供了对关节渗出液及因而表面软骨变形的更好描绘。
1.3梯度回波(GRE)成像
梯度回波(GRE)成像具有3D能力及以相对短的扫描时间提供高分辨率图像的能力。对于检测透明软骨缺陷(诸如那些通常发生在膝盖部位的缺陷)而言，脂肪抑制3D扰相梯度回波(FS-3D-SPGR)成像已比标准MR成像展示出更高的敏感性。
1.4磁化传递对比成像
磁化传递成像可用于将关节软骨与相邻关节液以及发炎滑膜组织相分离。
1.5快速自旋回波(FSE)成像
快速自旋回波(FSE)成像是另一种有用的脉冲序列MRI技术。附带的磁化传递对比有助于快速自旋回波图像上的信号特征，且能增强组织之间的对比度。在关于关节镜相关性的研究中，据报道快速自旋回波成像的敏感性和特异性达87％和94％。
1.6回波平面成像(EPI)
回波平面成像(EPI)是一种成像技术，其中在单一射频(RF)脉冲之后快速诱导一系列回波。更具体而言，施加一RF脉冲和一切片选择梯度以在所选切片中激活共振且施加一相位编码梯度以对所述共振进行相位编码。以逐次方式施加一系列具有交替极性的频率编码或读取梯度。在每个读取梯度期间，读出一磁共振信号或回波。在每个读取梯度之间，施加沿相位编码梯度轴的短脉冲或反射脉冲，以通过所选切片中的一条线增加对共振的相位编码。每个回波的一维反向傅立叶变换提供了沿读取轴自旋分布的投影。沿经相位编码的回波的第二种反向傅立叶变换提供了空间编码的第二维度。通常，将相位编码梯度反射脉冲选择为具有恰当的量值，以使得在每个RF脉冲之后获得用于全视场的数据。总采样时间由每个读取梯度所采样的点的数目和相位编码梯度步骤的数目来决定。
回波量成像将回波平面成像技术扩展到多个平面。在执行了上述回波平面成像序列之后，施加沿次级相位编码轴的脉冲或反射脉冲。通常，所述次级相位编码反射脉冲将相位编码沿一垂直于初级相位编码和读取轴的轴而步进。而后，将相位编码梯度反射脉冲施加到每个读取梯度之间以在初级相位编码方向上逐行步进。由于第一k空间平面内的相位编码反射脉冲将相位编码移动到视场的一个最边缘，因而在次级相位编码方向上的第二k空间平面中的相位编码反射脉冲通常具有相反极性以使得相位编码在相反方向上步进返回。以此方式，多个平面得以校直，但在z方向上的步进存在偏移。上述回波平面成像与回波量成像技术的一个缺陷在于：穿过k空间的轨道被及时反向以改变相位编码行或视域。此导致相位不连续性，进而可致使产生重影。
螺旋状回波平面成像技术同样是已知的，其中所施加的x和y梯度脉冲(即沿传统读取轴和相位编码轴)正弦地变化且线性地增长。以此方式，数据采样从视场的中央开始且螺旋状地向外，从而沿螺旋状k空间轨道覆盖视场。然而，螺旋状回波平面成像的其中一个缺陷在于它是单一切片技术。为获得多个切片，可将螺旋状回波平面成像技术重复多次。为每一切片而施加在正弦地变化且线性地增长的x和y梯度之后的RF激励脉冲和切片选择梯度以实现相关量的覆盖范围。
1.7对比度增强成像
已经以若干不同的形式应用了钆在成像中的用途。例如，直接磁共振(MR)关节造影术，其中含有钆的稀释溶液被直接注射到组织(例如，关节)中，改进了软骨与关节液之间的对比度。也可以应用具有较小侵入性静脉内注射的直接MR关节造影术。钆增强成像具有监控葡糖胺聚糖含量的潜能，其可具有对受伤软组织(诸如软骨)的径向估测的推断。
1.8驱动平衡傅立叶变换
已开发出的另一种3D成像方法是基于驱动平衡傅立叶变换(DEFT)脉冲序列(于1997年9月30日颁布的Lang等人的美国专利第5,671,741号)且可特定用于软组织(例如，软骨)成像。DEFT提供了T2/T1加权与自旋密度对比度之间的有效折衷，以勾勒出相关结构。某些组织/结构中的对比噪声在使用DEFT情形下比在使用扰相梯度回波(SPGR)情形下更大。DEFT是SPGR的替代方法。DEFT对比度非常适用于成像关节软骨。滑液在信号强度方面很高，而关节软骨在信号强度方面居中。骨骼呈暗色，且脂质通过使用脂肪饱和脉冲而被抑制。
1.9 MR成像的代表性实例
MR成像可通过使用在1.5T场强下运作的整体磁体而执行(例如，配备有GE SR-120高速梯度[在184μsec上升时间中达2.2 Gauss/cm]的GE Signa)。在MR成像之前，可将填充有掺杂了水的Gd-DTPA(Magnevist.RTM.，Berlex Inc.，Wayne，N.J.)(T1弛豫时间约为1.0秒)的外部标记物涂覆到皮肤上。外部标记物可被包括于所有成像研究的视场中。患者可位于扫描仪中的仰卧位置处且使得恰当的区域被成像。在轴探测序列之后，可通过使用体线圈来采集冠状和矢状T1加权图像(自旋回波，TR＝500msec、TE＝15msec、1激励(NEX)、矩阵256×128元素、视场(FOV)48cm、切片厚度7mm、切片间间隔1mm)。而后，可移动扫描仪表以通过使用相同序列参数而获得冠状和矢状图像。这些T1加权扫描可用于识别出稍后可用于界定组织几何形状的轴。可通过使用梯度回波序列而在轴平面中采集快速探测扫描(GRASS，2D傅立叶变换(2DFT)、TR＝50msec、TE＝10msec、翻转角40°、1个激励(NEX)、矩阵256×128元素、视场(FOV)24cm、切片厚度7mm、切片间间隔3mm)。此探测扫描可用于确定位于所述身体局部的中心的所有随后高分辨率成像序列。此外，通过使用具有扫描仪软件的图解、基于图像的序列规定模式，探测扫描可有助于确保所有外部标记物均被包括在高分辨率MR序列的视场中。
为采集得良好的图像需要考虑若干问题。一个问题是在所成像的区域中不同组织之间的良好对比度，以有助于对数据组的勾勒与分割。此外，如果存在外部标记物，那么必须对其进行可视化。解决这些问题的一种方法是使用矢状平面中的三维扰相梯度回波序列，其具有如下参数(SPGR，3DFT、脂肪饱和、TR＝60msec、TE＝5msec、翻转角40°、1个激励(NEX)、矩阵256×160元素、矩形FOV 16×12cm、切片厚度1.3mm、128个切片、采集时间约为15分钟)。使用这些参数，可获得跨过身体区域和外部标记物在内外侧和前后方向上的完整覆盖范围，同时可实现良好的空间分辨率和对比噪声比。脂肪饱和3D SPGR序列可用于以三个维度再现许多组织，例如软骨。而后，可在矢状平面中，通过使用先前采集过程(使用脂肪饱和)期间所使用的相同参数和切片坐标来重复(不使用脂肪饱和)所述3D SPGR序列。所得非脂肪饱和3D SPGR图像论述了低信号强度皮层骨与高信号强度骨髓之间良好的对比度，进而有助于对股骨与胫骨轮廓进行3D再现。应理解，此途径仅代表性地用于关节而决不应被视为具有限制性。
1.10磁共振成像-垂直开放式磁体
也可通过使用0.5 T垂直开放式MR单元(GE Signa SP，General Electric，Milwaukee，Wis.)和MR跟踪系统来执行MR成像。在MR成像之前，可将填充有掺杂了水的Gd-DTPA(Magnevist.RTM.，Berlex Inc.，Wayne，N.J.)(T1弛豫时间约为1.0秒)的外部标记物涂覆到皮肤。受检体可位于所述磁体内部的直立位置中。身体局部可垂直于主磁场。可在一矢状平面中采集2DFT快速自旋回波脉冲序列(FSE、TR＝4000msec、TE＝25msec、带宽7.8kHz、回波链长度8、3个激励、切片厚度为4mm、切片间间隔0.5mm、矩阵256×192元素、视场24cm)。对于使用扫描平面跟踪的快速扫描采集而言，可在一矢状平面或在一轴平面中采集快速单一切片梯度-回波脉冲序列(GRASS、TR＝14msec、TE＝5msec、翻转角为40度、带宽32kHz、1个激励、切片厚度为4mm、矩阵256×128元素、视场20cm、临时分辨率为2秒/图像)。可选择20cm的视场，以在超内部实现足够的解剖覆盖范围。
2.0融合图像
尽管存在这些成像技术，但是在一个以上平面中的分辨率仍然十分困难。根据本发明，提供了用以克服分辨率困难的方法，其中将来自两个分离图像(诸如，MRI扫描)的至少两个数据量加以组合，以形成一个具有各向同性或近似各向同性分辨率的单一数据量。
现参看图1，展示了由至少两个分离图像所生成的至少两个示范性数据量S1 100和S2 200。如本文中所说明，每个数据量100、200均具有如由若干图像切片的堆叠所展示的复数个数据量100(1-n)、200(1-n)。S1为在冠状平面中所取得的膝盖关节图像，而S2为在矢状平面中所取得的膝盖关节图像。在此实例中，S1和S2取自彼此垂直的平面中。然而，如所属领域的技术人员所了解，在不脱离本发明范畴的前提下，可使用其它定向和平面关系。
每个数据量在两个维度(例如x和y轴)中可具有相同的成像尺寸，而在第三维度中(例如z轴上)所述成像尺寸则大于前两个维度(在此情形中为x轴和y轴)中的尺寸。在一优选实施例中，可以一在约0°与180°之间且更优选为在约0°与90°之间的角度来进行第二扫描。
尽管本发明是通过使用至少两个扫描而得以描述，但是所属领域的技术人员应了解，在不脱离本发明范畴的前提下可使用更多扫描。因而，也可采集并分析在相同或其它平面或方向中的额外扫描。例如，如果在矢状方向上采集第一扫描，那么而后可采集冠状或轴成像平面中的第二平面。
第二扫描与第一扫描在面内分辨率方面可能相同。而后，第二扫描可含有足量的切片以覆盖第一扫描的整个视场，进而致使两个数据量具有来自相同3D空间的信息。
如上文所描述，从每个图像中生成的数据量包括x轴、y轴和z轴坐标数据，其中如图1中所示，x轴和y轴数据为各向同性，而z轴数据为非各向同性。此现象在图2中得以更好地展示，其中展示了根据本发明如由MRI扫描所产生的一组示范性三个体素200。图2中所示的体素200被展示为定向于z轴中，其中箭头210指示图像的切片厚度，在此情形中为MRI扫描。体素200进一步包括待成像的实体物件220。如图2所示，可看出归因于切片厚度210，与待成像的实体物件220有关的信息导致精确度降低。
除了潜在遗失的数据之外，较大切片厚度所产生的另一问题是部分体积效应增加。当一体素仅覆盖待成像物体的一部分时，发生部分体积效应，因而所述体素的灰度值被平均而非为真正的灰度值。如图2所示，当一像素或体素被部分地置于待成像物体220上方时，发生部分体积效应。由于体素200被部分地置于待成像物体上方，因而体素的灰度值将被平均。为减小部分体积效应的发生，本发明减小了扫描的切片厚度，进而减小了每个体素被部分地置于待成像物体上的可能性。
现参看图3-5，展示了根据本发明产生一各向同性或近似各向同性体素的示范性实施例。如图3所示，展示了由图像扫描所产生的一组三个体素300，其中将所述体素展示为具有比x轴315和y轴320长度更长的z轴310。
现参看图4，展示了由第二图像扫描所产生的第二组三个体素330，其中所述第二扫描以相对于第一扫描呈角度θ而取得。如上文所论述，θ可从(例如)约0°变化到约180°。如图4所示，第二组体素具有大于其x轴345和y轴350的z轴尺寸340，其中第二组体素的z轴340可被定向于一与第一组体素的z轴310所定向的平面不同的平面中。
现参看图5，展示了由九个体素组成的第三组体素360，其中所述第三组体素360已通过将第一组体素与第二组体素加以组合而形成，其中第一组的z轴数据已与来自第二组体素的x轴或y轴数据组合以形成第三组体素360的新的z轴370，其中，第三体素的z轴370的长度等于或近似等于x轴375和y轴380的长度，因而产生了具有各向同性或近似各向同性维度的体素。
在执行了至少两个扫描而产生两组数据量(如图1所示)之后，将所述两个数据量随后合并成一个第三数据量，如图3-5所示。此所得数据量为各向同性或近似各向同性，且其具有对应于S1和S2的面内分辨率的分辨率。将所述第三数据量中的每个体素的灰度值优选地计算如下：(a)确定每个体素在3D空间内的位置；(b)确定(例如，查找)在此位置处S1和S2中的灰度值；(c)使用一恰当的内插方案，以将两个灰度值组合成单一灰度值；和(d)将每一所确定的灰度值分配给所得数据量中的每个体素。
可为更多扫描而重复这些操作。此外，为弥补(例如)归因于运动而在定位于接受扫描的受检体的S1与S2之间的差异，可应用诸如主轴或基于量的匹配的配准技术。
3.0组织分割
根据本发明的一替代性实施例，提供了一种用于从至少两个图像扫描中产生各向同性或近似各向同性MRI扫描数据的方法。
如上文所详细描述，两个独立数据量从两个分离图像扫描获得，其中所述扫描中的每一者均以相对于彼此呈角度θ而取得。在一优选实施例中，第二扫描或图像优选地以在约0°与180°之间且更优选地在约0°与90°之间的角度θ而取得。其中所述图像扫描中的每一者均产生具有x、y和z分量的独立数据量，其中x和y分量为各向同性或近似各向同性，且z轴大小由(例如)MRI机器的切片厚度(或步幅)确定。
可应用组织分割构件以从一或多个图像中提取一或多个组织。此可通过将电子解剖图像(例如，x射线、CT、螺旋状CT、MRI)的像素或体素分类成不同组而实现，其中每个组代表一个组织或解剖结构或组织或解剖结构的组合或图像背景。例如，如上文所描述，将第一数据量和第二数据量的每个数据点加以组合以形成所得数据量。而后，可对整个数据量或所述数据量的子部分执行分割。尽管可有效地产生各向同性或近似各向同性的所得数据量，但数据处理的量很大。因此，上述方法要求相当大量的计算机处理能力以及用以完成所要求的数学计算的时间。
现参看图6，展示了根据本发明的组织分割方法所产生的三维MRI扫描的示范性实施例，其中在将所提取的数据加以组合以产生图6的三维扫描之前，已将与待成像的目标有关的数据首先从所述数据量中的每一者中提取出来。如图6所示，展示了内侧股骨髁的软骨表面，其中获得了面内分辨率为0.27mm×0.27mm的分辨率、切片厚度为3mm且间隔为0.5mm的矢状扫描400和冠状扫描450两者。如图6所示，在冠状扫描中得以很好地概述出内侧边缘，而髁的后部边缘则可在矢状扫描中得以最好地看出。
根据替代性实施例，与相关表面或区域有关的数据被首先从由两个或两个以上的图像扫描中所产生的每个数据量中提取出来。在提取了相关的数据量之后，随后通过将所述数据量中的每个像素或体素变换成一个共同的坐标系而将所述像素或体素合并成一个新的数据量。此可通过明确地计算一或多个数据组的变换矩阵来实现，所述计算过程是通过使用解剖或其它用户所界定的界标或通过图像定位和定向的先验知识，诸如由DICOM成像标准所提供的信息来实现。为界定3D空间中的变换，需要识别原始数据量中四个点的坐标和其在新数据量中的对应位置。这些坐标对可用于建立具有如下形式的线性系统：
AxT＝B，
其中A为具有原始坐标的矩阵，T为变换矩阵且B为具有新坐标的矩阵。上述系统的解决方法可由下式给出：
T＝BxA-1
或者，变换矩阵可通过在数据组之间执行表面配准而得以含蓄地计算得出。表面配准算法通过最小化成本函数，诸如欧基理德距离变换且因此将量数据相组合来将两个数据量加以合并。图6展示出所得数据量的实例。此所得数据量为各向同性或近似各向同性，其具有对应于S1和S2的面内分辨率的分辨率。
在本发明的另一实施例中，可通过使用任何适合的技术来获得3D MRI图像，例如，通过使用可提供具有各向同性或近似各向同性分辨率的3D而非2D傅立叶变换采集的脉冲序列采集参数，或通过使用两个或两个以上2D采集的融合。如本文中所使用，各向同性分辨率是关于其中切片厚度等于面内分辨率的MRI图像。类似地，术语“近似各向同性分辨率”是关于其中切片厚度不超过面内分辨率的2倍的图像，更优选地不超过面内分辨率的1.5倍且甚至更优选地为不超过面内分辨率的1.25倍。各向同性或近似各向同性3DFT成像脉冲序列具有关于部分体积平均化的优势。部分体积平均化在切片方向上(z方向)通常不会大于在成像平面中(x和y方向)。
适用于获得近似各向同性或各向同性图像的脉冲序列的非受限实例包括：3D FSE、3D MFAST/3D SS-SPGR、3D FIESTA/3D SSFP、3D FEMR、3D DESS、3D VIBE和3DSSFP。3DFT各向同性或近似各向同性成像序列的优选面内分辨率小于0.5mm，且优选的切片厚度小于0.8mm，优选地小于0.5mm。
而后，这些各向同性或近似各向同性分辨率的图像用于增加分割或组织提取和任何随后的可视化和/或身体局部的定量测量(例如，软骨厚度或软骨缺陷大小的测量)的精确度。
因而，本文中所描述的本发明尤其允许提高分辨率和组织分割或组织提取的效率。在本文所述的操作(例如，将多个图像合并、各向同性或近似各向同性分辨率成像)之后，可使用可购得的分割软件，例如包括在标准个人计算机上运行的籽生长算法和主动轮廓算法的软件。
例如，可分析3D MR图像中所展示的关节软骨。在高信号强度骨髓与低信号强度皮层骨之间存在明显的分界面，进而有助于籽生长。
一种示范性(但不具有限制性)方法使用基于已被扩展到3D的2D边缘检测器(Wang-Binford)的3D表面检测技术。此表面检测技术可生成表面点和其对应的表面法线。为使轮廓平滑，程序采样25％表面点并使得所述样品点适于三次样条。所述程序可计算沿样品样条点的曲率并找出两个具有最大曲率且被轮廓上约一半数目的体素分离开的样品点。这些点将所述样条分割成两个子轮廓。对于每个子轮廓而言，所述程序可计算块体的点与中心之间的平均距离。
程序可允许用户通过使用鼠标和/或键盘而具有从任意角度观察景象的能力、开始并停止从3D数据中所获得的动画的能力。此外，用户可通过使用鼠标选择若干点而获得关于景象的定量信息。
软件程序可以C++计算机语言来编写，且可经编译以在(例如)Silicon Graphics工作站或在Window/Intel个人计算机上运行。
4.0三维图像
如上文所述，在通过使用3D采集或通过将两个或两个以上2D扫描相融合而获得3D MR图像之后，且在已通过使用分割技术提取了一或多个解剖物体之后，例如，所述物体信息可通过使用计算机程序而被变换成表面表示。所述程序可在(例如)AVS Express(Advanced Visual Systems，Inc.，Waltham，Mass.)中开发。如果每个体素不在相关物体内则其具有零值，或取决于如由1.5 T MR所记录的信号强度而具有从1变化到4095的的值。而后可计算出对应于相关量的边界元素的等值面。计算此等值面的镶嵌格局连同所述镶嵌格局的每个多面体的朝外指向的法线。这些多面体可写成呈标准图形格式的文件(例如，Virtual Reality Modeling Language Version 1.0：VRML输出语言)且在计算机屏幕上进行可视化。
也可用可视化程序，例如，用户可控3D视觉分析工具。这些程序可在景象中读取，所述景象由各种3D几何表示或“表演者”组成。所述程序允许用户通过使用鼠标和/或键盘而具有从任意角度观察景象的能力、开始并停止从3D数据中所获得的动画的能力。此外，用户可通过使用鼠标选择若干点而获得关于景象的定量信息。
所述软件程序可以C++计算机语言来编写，且可经编译以在(例如)Silicon Graphics工作站或在Window/Intel个人计算机上运行。生物化学组份(例如，软骨)同样可被可视化，(例如)如Alexander的WO 02/22014中所描述。
本发明同样描述了一种用于从图像中产生各向同性或近似各向同性的图像数据的方法。此方法展示于图8A中。第一步是获得图像800。如由可选重复步骤801所示，可重复此步骤以获得多个图像。合适的图像包括(例如)MRI。一旦获得了(多个)图像，便可获得810图像数据量。如由可选重复步骤811所指示，可一次或多次地获得图像数据量。而后，将所生成的图像数据加以组合，以形成一各向同性图像量820或近似各向同性图像量822。如所属领域的技术人员所了解，如由可选重复步骤821、823所示，形成一或多个各向同性或近似各向同性图像量的过程可重复一或多次。
本发明同样描述了一种用于从图像中生成各向同性或近似各向同性的图像量的方法。此方法展示于图8B中。第一步骤为获得图像数据量830。如由可选重复步骤831所展示，可重复此步骤以获得多个图像数据量。一旦获得了一或多个图像数据量，便可提取840边界图像数据。可按需要重复所述提取过程841。将所述被提取的数据量加以组合以形成各向同性图像量842或近似各向同性图像量844。如所属领域的技术人员所了解，可基于所提取的边界图像数据843、845而生成一个以上的量(如果需要的话)。
提供了另一种方法，其展示于图8C中。此方法包括从图像中获得数据量的步骤850，其为视情况可重复的过程851(如果需要的话)。一旦获得了数据量，便将所述数据量加以组合以形成至少一个所得数据量860。可获得861一个以上的所得数据量(如果需要的话)。在获得了所述所得数据量860之后，可基于所述数据量而选择870一种疗法或可选择或获得872一植入物的形状。这些步骤中的任一者或两者都可重复871、873(如果需要的话)。
现参看图7，展示了由根据本发明的方法所生成的植入物设计500，其中已根据本发明的方法生成了三维表面。而后，此三维表面可用于制作一植入物或选择一种包括一植入物的疗法。此类植入物和植入技术的实例可参见于2003年11月25日由Aaron Berez等人申请的“Patient Selectable Joint Arthroplasty Devices and Surgical Tools FacilitatingIncreased Accuracy，Speed and Simplicity in Performing Total and Partial Joint Arthroplasty”的同在申请中的美国专利申请案第——号，其全文以引用方式并入本文中。
或者，可在已生成了三维表面(诸如图7所示的三维表面)之后确定此类植入物并无必要或不能利用。因而，可选择一疗法作为此类植入物之替代例，或除此类植入物之外选择一疗法。疗法的实例包括：药物疗法，诸如止痛药、软骨保护剂、软骨再生剂、骨骼保护剂、骨骼再生剂、骨骼合成代谢剂、骨骼破骨细胞抑制剂；将透明质酸或硫酸软骨素或其它药物或生物活性物质注射到关节中；截骨术；软骨或骨软骨自体移植或同种异体移植；或其它类型的植入。其它类型的植入可包括(例如)完全或单侧退化性关节造形术装置。
本文所呈现的方法可在不同的时间点利用，例如时间点T1与稍后或之前的时间点T2。这些时间点可发生在(例如)单天的一个成像时间或可发生在多天的多个成像时间。时间间隔另外可为小时、天、周、月和年。而后可通过使用所得数据量V1和V2的定量测量而将组织特征化且组织组成或相对或绝对量方面的改变可得以评估。
本文中已在被认为是最实际且为优选实施例的内容中展示并描述了本发明。然而，应认识到，可从本发明作出在本发明范畴内的若干偏离，且所属领域的技术人员—阅读本揭示内容便可了解明显的修正。
Claims (41)
1.一种图像分析方法，其包含：
获得一身体局部在一第一平面中的一第一图像，其中所述第一图像生成一第一图像数据量；
获得所述身体局部在一第二平面中的一第二图像，其中所述第二图像生成一第二图像数据量；和
将所述第一图像数据量与所述第二图像数据量相组合，以形成一所得图像数据量，其中所述所得图像数据量为各向同性。
2.根据权利要求1所述的方法，其中所述组合步骤包含：
在一个三维位置处从所述第一图像数据量和所述第二图像数据量中获得第一和第二灰度值；
将一来自所述第一灰度值和所述第二灰度值的所得灰度值内插；和
将所述所得值分配给一位于所述所得数据量的所述三维位置处的体素。
3.根据权利要求1所述的方法，其中所述第二图像以一在约0度与约180度之间的角度从所述第一图像取得。
4.根据权利要求1所述的方法，其中所述第一图像以一第一角度而取得且所述第二图像以一第二角度而取得，且此外其中所述第一角度不等于所述第二角度。
5.根据权利要求1所述的方法，其中所述第一图像在一第一时间取得且所述第二图像在一第二时间取得。
6.根据权利要求3所述的方法，其中所述第二图像以一在约0度与约90度之间的角度从所述第一图像取得。
7.根据权利要求1所述的方法，其进一步包括：
选择一疗法以响应所述所得图像数据量。
8.根据权利要求1所述的方法，其进一步包括：
选择一治疗以响应所述所得图像数据量。
9.根据权利要求1所述的方法，其进一步包括：
获得一身体局部在一不同于其它平面的平面中的至少一额外图像，其中所述额外图像生成一额外图像数据量，其中所述额外数据量与所述第一图像数据量与所述第二图像数据量相组合以形成一所得数据量。
10.根据权利要求1所述的方法，其进一步包括：
从所述所得图像数据量中提取一边界图像数据量。
11.一种用于产生各向同性或近似各向同性图像数据的方法，其包括：
从一第一平面中的一第一图像获得一第一图像数据量；
从一第二平面中的一第二图像获得一第二图像数据量；
从所述第一图像数据量与所述第二图像数据量的每一者中提取边界图像数据；和
将所述被提取的边界图像数据加以组合以形成一所得图像数据量。
12.根据权利要求11所述的方法，其进一步包括：
从一不同于所述第一平面与所述第二平面的平面中的至少一额外图像中获得至少一额外图像数据量；
从所述额外图像数据量中提取一额外边界图像数据；和
将所述额外边界图像数据量与所述所得图像数据量相组合。
13.根据权利要求11所述的方法，其中所述所得图像数据量为近似各向同性。
14.根据权利要求11所述的方法，其中所述所得图像数据量为各向同性。
15.根据权利要求11所述的方法，其中所述第一平面相对于所述第二平面呈一角度。
16.根据权利要求15所述的方法，其中所述角度在约0度与约180度之间。
17.根据权利要求16所述的方法，其中所述角度在约0度与约90度之间。
18.一种用于生成一个三维数据量的方法，其包含：
从在两个不同平面中所执行的至少两个图像中采集至少两个数据量；
将所述数据量加以组合以形成一所得数据量；
使用所述所得数据量选择一疗法。
19.根据权利要求18所述的方法，其中所述组合步骤包含：
在所述数据量的每一者中获得每个数据点的灰度值；
将一来自灰度值的所得灰度值内插；和
将所述所得值分配给所述所得数据量的每个数据点。
20.根据权利要求19所述的方法，其进一步包括：
在将对应于所述平面中的每一者中一待扫描的表面的数据加以组合之前，提取所述数据。
21.根据权利要求18所述的方法，其中所述两个扫描以相对于彼此呈90度而执行。
22.一种用于生成三维数据的方法，其包含：
获得一第一平面中的一第一图像，以产生一具有一默认分辨率的第一数据量；
获得一第二平面中的一第二图像，以产生一具有所述默认分辨率的第二数据量；
将所述第一数据量与所述第二数据量加以组合以产生一所得数据量，其中所述所得数据量具有一所得分辨率。
23.根据权利要求22所述的方法，其中所述所得分辨率比所述默认分辨率大。
24.一种图像分析方法，其包含：
获得一身体局部在至少一第一平面与一第二平面中的至少一图像，其中所述第一平面生成一第一图像数据量且所述第二平面生成一第二图像数据量；和
将所述第一图像数据量与所述第二图像数据量加以组合以形成一个所得图像数据量，其中所述所得图像数据量为各向同性。
25.一种图像分析方法，其包含：
获得一身体局部在至少一第一平面与一第二平面中的至少一图像，其中所述第一平面生成一第一图像数据量且所述第二平面生成一第二图像数据量；和
将所述第一图像数据量与所述第二图像数据量加以组合以形成一个所得图像数据量，其中所述所得图像数据量为近似各向同性。
26.一种用于生成一个三维数据量的方法，其包含：
从至少一第一图像和一第二图像中采集至少一第一数据量和一第二数据量，其中所述第一图像在一第一平面中获得且所述第二图像在一第二平面中获得，且此外其中所述第一平面不等于所述第二平面；
将所述第一数据量与所述第二数据量相组合以形成一所得数据量；
利用所述所得数据量监控一疗法。
27.根据权利要求26所述的方法，其中所述组合步骤包含：
在所述数据量的每一者中获得每个数据点的灰度值；
将一来自灰度值的所得灰度值内插；和
将所述所得值分配给所述所得数据量的每个数据点。
28.根据权利要求27所述的方法，其进一步包括：
在将对应于所述平面中的每一者中一待扫描的表面的数据加以组合之前，提取所述数据。
29.根据权利要求26所述的方法，其中所述两个扫描以相对于彼此呈90度而执行。
30.根据权利要求26所述的方法，其中所述治疗包括一药物。
31.根据权利要求26所述的方法，其中所述治疗包括一生物活性剂。
32.根据权利要求26所述的方法，其中所述治疗包括外科手术。
33.根据权利要求26所述的方法，其中所述第一数据量在一第一时间点T1获得，且所述第二数据量在一第二时间点T2获得。
34.一种用于生成一个三维数据量的方法，其包括：
从在两个不同平面中所执行的至少两个图像中采集至少两个数据量；
将所述数据量加以组合以形成一所得数据量；
利用所述所得数据量选择一植入物。
35.根据权利要求34所述的方法，其中所述组合步骤包含：
在所述数据量的每一者中获得每个数据点的灰度值；
将一来自灰度值的所得灰度值内插；和
将所述所得值分配给所述所得数据量的每个数据点。
36.根据权利要求35所述的方法，其进一步包括：
在将对应于所述平面中的每一者中一待扫描的表面的数据加以组合之前，提取所述数据。
37.根据权利要求34所述的方法，其中所述两个扫描以相对于彼此呈90度而执行。
38.一种用于生成一个三维数据量的方法，其包含：
从在两个不同平面中所执行的至少两个图像中采集至少两个数据量；
将所述数据量加以组合以形成一所得数据量；
利用所述所得数据量获得一植入物形状。
39.根据权利要求38所述的方法，其中所述组合步骤包含：
在所述数据量的每一者中获得每个数据点的灰度值；
将一来自灰度值的所得灰度值内插；和
将所述所得值分配给所述所得数据量的每个数据点。
40.根据权利要求39所述的方法，其进一步包括：
在将对应于所述平面中的每一者中一待扫描的表面的数据加以组合之前，提取所述数据。
41.根据权利要求38所述的方法，其中所述两个扫描以相对于彼此呈90度而执行。
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1567985A2 (en) | 2005-08-31 |
| JP2006508746A (ja) | 2006-03-16 |
| US8638998B2 (en) | 2014-01-28 |
| US8094900B2 (en) | 2012-01-10 |
| KR20050072500A (ko) | 2005-07-11 |
| WO2004051301A3 (en) | 2004-12-02 |
| US7634119B2 (en) | 2009-12-15 |
| US20120201440A1 (en) | 2012-08-09 |
| US20040204644A1 (en) | 2004-10-14 |
| US20140115872A1 (en) | 2014-05-01 |
| WO2004051301A2 (en) | 2004-06-17 |
| AU2003298919A1 (en) | 2004-06-23 |
| CA2506849A1 (en) | 2004-06-17 |
| US20100054572A1 (en) | 2010-03-04 |
| US9687945B2 (en) | 2017-06-27 |
| EP1567985B1 (en) | 2019-04-24 |
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