WO2020014889A1 - 四肢主干神经的仿生修复体模型的建立方法 - Google Patents

四肢主干神经的仿生修复体模型的建立方法 Download PDF

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WO2020014889A1
WO2020014889A1 PCT/CN2018/096129 CN2018096129W WO2020014889A1 WO 2020014889 A1 WO2020014889 A1 WO 2020014889A1 CN 2018096129 W CN2018096129 W CN 2018096129W WO 2020014889 A1 WO2020014889 A1 WO 2020014889A1
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nerve
limb
nerves
model
dimensional
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PCT/CN2018/096129
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French (fr)
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戚剑
朱庆棠
闫立伟
姚执
刘小林
陆瑶
刘守亮
王涛
林焘
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中山大学附属第一医院
中山大学数据科学与计算机学院
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Priority to PCT/CN2018/096129 priority Critical patent/WO2020014889A1/zh
Priority to US16/246,544 priority patent/US10825179B2/en
Publication of WO2020014889A1 publication Critical patent/WO2020014889A1/zh

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    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T7/00—Image analysis
    • G06T7/0002—Inspection of images, e.g. flaw detection
    • G06T7/0012—Biomedical image inspection
    • G06T7/0014—Biomedical image inspection using an image reference approach
    • G06T7/0016—Biomedical image inspection using an image reference approach involving temporal comparison
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
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    • G06T2219/20—Indexing scheme for editing of 3D models
    • G06T2219/2021—Shape modification

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  • the invention relates to the technical field of clinical application of nerve defect repair, in particular to a method for establishing a biomimetic prosthesis model of limb nerves.
  • Peripheral nerve defect is a common clinical disease, especially the defect of the trunk nerves of the extremities will cause severe disability of the limb and bring a huge social burden.
  • the gold standard for clinical treatment of autologous nerve sources is limited, and there are defects such as impaired donor function.
  • Peripheral neurosurgery urgently needs to develop a neural restoration that can replace autologous nerve transplantation.
  • Existing applications for peripheral nerve defects mainly include two types: nerve conduits made from synthetic or natural materials, and acellular nerve grafts.
  • peripheral nerves The research on the internal structure of peripheral nerves has gone through decades, and the research level has been deepened from the gross anatomy of peripheral nerves to nerve bundles to the inner endometrial layer. With the continuous development of information technology, research methods have changed from traditional histological staining to modern imaging technology. Three-dimensional visualization and holographic imaging technology have also made neuroscience research more systematic and precise. In recent years, new developments in emerging medical imaging technologies Micro-CT and Micro-MRI have brought new ideas for technological breakthroughs in the study of neural structures. The nerves were pretreated with iodine combined with freeze-drying method, and Micro-CT was used to obtain high-precision two-dimensional images of the peripheral nerves.
  • Continuous scanning 2D images can be obtained by applying Micro-MRI T1 sequence to the peripheral nerve in the scan environment of tincture.
  • the complex and changeable shape of nerve bundles in 3D space is the focus and difficulty of designing and manufacturing nerve bundle grafts. At present, there is no bionic repair model that can meet the microstructural characteristics of nerve bundles for the variable injury types.
  • the present invention provides a method for establishing a bionic prosthetic model of the trunk nerves of the limbs, which makes full use of imaging technology and clinical data, and can build a bionic prosthesis that conforms to the characteristics of the nerve bundle microstructure according to the variable injury types
  • the model provides more accurate model information for the repair of limb nerve defects.
  • the invention provides a method for establishing a bionic prosthesis model of the trunk nerves of the extremities, which includes the following steps:
  • the step S1 includes the following steps:
  • the isolated nerve sample is taken from one or more of the following: upper limb nerves below the axillary plane, including the median nerve, radial nerve, ulnar nerve, and musculocutaneous nerve; and lower limb nerves below the groin plane, including femoral nerve , Sciatic nerve, tibial nerve and common peroneal nerve.
  • the two-dimensional image data includes a continuous scan image of a cross-section, a sagittal plane, and / or a coronal plane of the isolated nerve sample.
  • the step S2 includes the following steps:
  • the step S3 includes the following steps:
  • a section of the nerve bundle type structure matching the type, spatial position, length, and condition of the nerve branch of the defect nerve is located in the extremity main nerve bundle structure database. And extract its spatial structure data;
  • the parameter for evaluating the degree of matching is smaller than a preset value, repeat the steps of fitting, adjusting, modifying, and matching until the parameter for evaluating the degree of matching reaches or exceeds a preset value;
  • the matched three-dimensional model is used as a bionic restoration model of the nerve in the defect area.
  • FIG. 1 shows a three-dimensional model of a peripheral nerve bundle structure established in conjunction with imaging technology
  • FIG. 2 shows a main flowchart of an embodiment of a method for establishing a bionic restoration model of a trunk nerve of the extremity according to the present invention
  • FIG. 3 shows an embodiment of a Micro-MRI scan image of the trunk nerves of the extremities and a three-dimensional reconstruction of the nerve bundles thereof;
  • FIG. 4 shows an embodiment of constructing a bionic prosthesis model based on the three-dimensional information of the three-dimensional information of the trunk nerve bundle structure of the limbs to conform to the characteristics of the microstructure of the nerve bundle.
  • FIG. 2 shows a main flowchart of an embodiment of a method for establishing a bionic restoration model of a limb nerve in accordance with the present invention, which includes the following main steps:
  • S1 Establish a database of the trunk nerve bundle structure of the limbs with imaging technology
  • this embodiment includes the following specific steps:
  • Nerve nerves were obtained within 2 hours after the main vessels of the amputated specimen were ligated, including the nerves of the upper limbs below the axillary plane and the nerves of the lower limbs below the groin plane.
  • the nerves of the upper limb include the median nerve, the radial nerve, the ulnar nerve, and the musculocutaneous nerve;
  • the nerves of the lower limb include the femoral, sciatic, tibial, and common peroneal nerves.
  • 4% paraformaldehyde was used for fixation to prepare isolated nerve samples for scanning.
  • each segment of each type of nerve obtained at least 3 samples for scanning.
  • Imaging technology was used to obtain two-dimensional image data of each isolated nerve sample.
  • Imaging techniques include Micro-CT and / or Micro-MRI.
  • the scanning parameters of Micro-CT and / or Micro-MRI are set, and the isolated neural samples are scanned to obtain two-dimensional image data.
  • the two-dimensional image data includes continuous scan images of a cross-section, a sagittal plane, and / or a coronal plane of an isolated neural sample.
  • FIG. 3A and FIG. 3D exemplarily show two-dimensional continuous scanning cross-sectional images of isolated nerve samples of the tibial nerve and common peroneal nerve obtained by applying Micro-MRI.
  • the three-dimensional reconstruction of the nerve bundle structure was established, and a three-dimensional information database of the trunk nerve bundle structure of the limbs was established.
  • the three-dimensional reconstruction software is used to segment and extract the nerve bundles from the two-dimensional image data obtained in the above steps ( Figures 3B and 3E illustrate the nerve bundle segmentation in the two-dimensional image of the tibial nerve and the common peroneal nerve, respectively), and the visualization is presented Nerve bundle topological structure, three-dimensional reconstruction of each isolated nerve sample to obtain a three-dimensional mathematical model of each type of nerve bundle structure and save ( Figures 3C and 3F respectively show three-dimensional reconstructed tibial nerves by way of example And common peroneal nerve bundle structure), thereby establishing a three-dimensional information database of the trunk nerve bundle structure of the limbs.
  • a section of the neural bundle structure that matches the type, spatial location, length, and branching of the defect nerve is located in the limb neural bundle structure database of the limbs. And extract its spatial structure data;
  • the parameter for evaluating the degree of matching is smaller than a preset value, repeat the above-mentioned fitting, adjusting, modifying, and matching steps until the parameter for evaluating the degree of matching reaches or exceeds a predetermined value;
  • the matched three-dimensional model is used as a bionic restoration model of the nerve in the defect area.
  • FIG. 4 it schematically illustrates an embodiment of constructing a bionic restoration model conforming to the characteristics of the nerve bundle microstructure based on the three-dimensional database of three-dimensional information of the trunk nerve bundle structure of the limbs.
  • Figures 4A and 4B show the proximal and distal ends of the neural stem in the defect area, where the nerve bundle pattern structures in the proximal and distal ends and the differences between them can be clearly identified from Figure 4B.
  • FIG. 4C is a three-dimensional model of the neural stem of the defect region.
  • Figures 4D to 4F show the matching of the three-dimensional model of the neural stem in the defect area with the proximal and distal ends of the neural stem in the defect area.

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Abstract

一种四肢主干神经的仿生修复体模型的建立方法，包括以下步骤：结合影像学技术建立四肢主干神经束型结构数据库（S1）；获取待修复的缺损性四肢主干神经的信息（S2）；将待修复的缺损性四肢主干神经的信息与四肢主干神经束型结构数据库中的数据进行匹配和拟合，构建符合神经束微结构特点的四肢主干神经仿生修复体模型（S3）。该方法利用影像学技术和临床数据，能够针对多变的损伤类型建立符合神经束微结构特点的仿生修复体模型，为四肢主干神经缺损的修复提供更准确的模型信息。

Description

四肢主干神经的仿生修复体模型的建立方法 技术领域
本发明涉及一种神经缺损修复的临床应用技术领域，特别地涉及一种四肢主干神经的仿生修复体模型的建立方法。
背景技术
周围神经缺损是常见临床疾病，尤其是四肢主干神经的缺损会导致肢体严重残疾，带来巨大的社会负担。目前，临床上治疗的金标准自体神经来源有限，且存在供区功能损害等缺陷。周围神经外科亟需开发出能够替代自体神经移植的神经修复体。现存应用用于周围神经缺损的材料主要包括两种：以合成或天然材料制备的神经导管、去细胞神经移植物。然而在实际临床工作中，由于患者缺损性损伤的部位、神经的尺寸、远近段神经分支的情况千差万别，并没有良好的技术手段及技术储备针对多变的损伤类型有针对性地设计和制造神经束移植物。
应用生物制造的方式来构建出具有仿生结构的材料近几年备受关注，其主要优势在于仿生材料的结构是生物体进化实现其生物学功能的最佳结构分布。周围神经结构研究中发现仅通过改变自体神经移植物中神经束的匹配性就会对神经再生效果产生影响，证明神经束走形的物理引导起到重要作用。随着精准医疗理念的兴起及生物制造技术的快速发展，最新研究也尝试应用生物制造技术实现结构的仿生，然而并没有良好的神经移植物设计的体系，目前结构的匹配也仅仅停留在神经干层次，神经束层次的匹配大多仅依赖于想象。因此进一步深入研究周围神经束移植物的设计，首要解决的问题就是在大量数据的基础上充分认识神经束的交叉融合规律。
对于周围神经内部结构的研究经历了几十年，研究层次从周围神经大体解剖到神经束再到神经内膜层次不断深入。研究方法也随着信息技术的不断发展由传统的组织学染色切片到现代影像学技术，三维可视化与全息影像技术也使得神经科学研究更系统更确切。近年来，新兴医学影像技术Micro-CT、Micro-MRI的新进展为神经结构的研究带来了技术突破的新思路。应用碘剂联合冷冻干燥法预处理神经，采用Micro-CT可获得周围神经内部高精度二维图像。周围神经在钆剂的扫描环境下应用Micro-MRI T1序列亦可获得满足神经束分割重建的连续扫描二维图像。中山大学附属第一医院显微创伤手外科团队在多项课题基金的支持下开展对离体样本的多区域、多层次扫描，获得了周围神经束型结构的三维 重建模型，并从中能够观察出周围神经束在三维走形中空间位置、分布的变化。参见图1，分别截取三维重建模型的远、中、近段观察神经束分布情况，认识到神经束在较短距离即可存在较大的空间位置的变化。神经束在三维空间中复杂多变的走形是设计和制造神经束移植物的重点和难点，目前还没有能够针对多变的损伤类型建立符合神经束微结构特点的仿生修复体模型。
发明内容
为解决上述问题，本发明提供一种四肢主干神经的仿生修复体模型的建立方法，其充分利用影像学技术和临床数据，能够针对多变的损伤类型建立符合神经束微结构特点的仿生修复体模型，为四肢主干神经缺损的修复提供更准确的模型信息。
本发明提供一种四肢主干神经的仿生修复体模型的建立方法，包括以下步骤：
S1、结合影像学技术建立四肢主干神经束型结构数据库；
S2、获取待修复的缺损性四肢主干神经的信息；
S3、将所述待修复的缺损性四肢主干神经的信息与所述四肢主干神经束型结构数据库中的数据进行匹配和拟合，构建符合神经束微结构特点的四肢主干神经仿生修复体模型。
优选地，所述步骤S1包括以下步骤：
获取四肢主干神经的离体神经样本；
应用Micro-CT和/或Micro-MRI获得每个所述离体神经样本的二维图像数据；
应用所述二维图像数据获得每个所述离体神经样本的三维重建模型并保存，由此建立四肢主干神经束型结构三维信息数据库。
优选地，所述离体神经样本取自以下的一个或多个：腋窝平面以下的上肢神经，包括正中神经、桡神经、尺神经和肌皮神经；和腹股沟平面以下的下肢神经，包括股神经、坐骨神经、胫神经和腓总神经。
优选地，所述二维图像数据包括所述离体神经样本的横断面、矢状面和/或冠状面的连续扫描图像。
优选地，所述步骤S2包括以下步骤：
明确患者的损伤类型和损伤时间，初步定位目标损伤神经；
扫描患者健侧和患侧的神经干大体形态，获取患侧缺损区域以及与其相对应的健侧正常区域的扫描图像；
将所述患侧缺损区域的扫描图像与所述健侧正常区域的扫描图像进行对比与分析，以判定缺损区域神经干的类型、空间位置、长度和神经分支情况，并测量缺损区域神经干的 直径和长度。
优选地，所述步骤S3包括以下步骤：
根据所述待修复的缺损性四肢主干神经的信息，在所述四肢主干神经束型结构数据库中定位与所述缺损神经的类型、空间位置、长度和神经分支情况相匹配的一段神经束型结构并提取其空间结构数据；
将所述待修复的缺损性四肢主干神经的信息中的数据与四肢主干神经束型结构数据库中的数据进行拟合，并应用拟合的数据建立整体三维模型；
根据所述缺损性四肢主干神经的缺损区域神经干的近端和远端的神经大体形貌、神经分支和神经束三维空间位置分布，对所述建立的三维模型进行调整；
对所述调整的三维模型中神经干及神经束的形态、曲度、光滑度进行修饰；
将所述修饰的三维模型与所述缺损区域神经干的近端和远端进行神经大体形貌、神经分支和神经束三维空间位置分布的匹配；
若评估匹配程度的参数小于预先设定的值，则重复进行所述拟合、调整、修饰和匹配步骤，直到所述评估匹配程度的参数达到或超过预先设定的值；
若所述评估匹配程度的参数等于或大于预先设定的值，则将所述匹配的三维模型作为缺损区域神经的仿生修复体模型。
附图说明
图1示出了结合影像学技术建立的周围神经束型结构的三维模型；
图2示出了根据本发明的四肢主干神经的仿生修复体模型的建立方法的实施例的主要流程图；
图3示出了四肢主干神经的Micro-MRI扫描图像及其神经束的三维重建的实施例；
图4示出了基于四肢主干神经束型结构三维信息三维数据库进行构建符合神经束微结构特点的仿生修复体模型的实施例。
具体实施方式
为了使本发明要解决的技术问题、技术方案及有益效果更加清楚明白，以下结合附图和实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
首先，参见图2，其示出了根据本发明的四肢主干神经的仿生修复体模型的建立方法的实施例的主要流程图，包括以下主要步骤：
S1：结合影像学技术建立四肢主干神经束型结构数据库；
S2：获取待修复的缺损性四肢主干神经的信息；
S3：将待修复的缺损性四肢主干神经的信息与四肢主干神经束型结构数据库中的数据进行匹配和拟合，构建符合神经束微结构特点的四肢主干神经仿生修复体模型。
具体地，本实施例包括以下具体的步骤：
(1)结合影像学技术建立四肢主干神经束型结构数据库。
获取四肢主干神经的离体神经样本。选择截肢标本主干血管结扎后2小时内获取神经，包括腋窝平面以下的上肢神经和腹股沟平面以下的下肢神经。其中，上肢神经包括正中神经、桡神经、尺神经和肌皮神经；下肢神经包括股神经、坐骨神经、胫神经和腓总神经。获取神经后即刻应用4％多聚甲醛进行固定，制成用于扫描的离体神经样本。其中，每种类型的神经的每一段至少获取3个样本进行扫描。
应用影像学技术获得每个离体神经样本的二维图像数据。影像学技术在此包括Micro-CT和/或Micro-MRI。设置Micro-CT和/或Micro-MRI的扫描参数，对预处理之后的离体神经样本进行扫描，获得二维图像数据。优选地，二维图像数据包括离体神经样本的横断面、矢状面和/或冠状面的连续扫描图像。图3A和图3D分别示例性地示出了应用Micro-MRI获得的胫神经和腓总神经的离体神经样本的横断面连续扫描二维图像。
三维重建神经束型结构，建立四肢主干神经束型结构三维信息数据库。应用三维重建软件对上述步骤中获得的二维图像数据进行分割提取神经束(图3B和3E分别示例性地示出了胫神经和腓总神经的二维图像中神经束的分割)，可视化呈现神经束拓扑结构，对每个离体神经样本进行三维重建，获得每种类型的神经束型结构的三维走形数学模型并保存(图3C和3F分别示例性地示出了三维重建的胫神经和腓总神经的神经束型结构)，由此建立四肢主干神经束型结构三维信息数据库。
(2)获取待修复的缺损性四肢主干神经的信息。
明确患者的损伤类型和损伤时间，初步定位目标损伤神经；
扫描患者健侧和患侧的神经干大体形态，优选地应用高精度MRI进行扫描，获取患侧缺损区域以及与其相对应的健侧正常区域的MRI扫描图像；
将患侧缺损区域的MRI扫描图像与其对应的健侧正常区域的MRI扫描图像进行对比与分析，以判定缺损区域神经干的类型、空间位置、长度和神经分支情况，并测量缺损区域神经干的直径和长度。
(3)将待修复的缺损性四肢主干神经的信息与四肢主干神经束型结构数据库中的数据进行匹配和拟合，构建符合神经束微结构特点的四肢主干神经仿生修复体模型。
根据上述步骤所判定的缺损区域神经干的类型、空间位置和长度，在四肢主干神经束型结构数据库中定位与缺损神经的类型、空间位置、长度和神经分支情况相匹配的一段神经束型结构并提取其空间结构数据；
将上述步骤中获取的缺损区域的测量数据与四肢主干神经束型结构数据库中的数据进行拟合，并应用拟合的数据建立的整体三维模型；
根据缺损区域神经干的近端和远端的神经大体形貌、神经分支和神经束三维空间位置分布，对上述建立的三维模型进行调整；
应用三维模型软件对上述调整的三维模型中神经干及神经束的形态、曲度、光滑度等进行修饰；
将修饰的三维模型与缺损区域神经干的近端和远端进行神经大体形貌、神经分支和神经束三维空间位置分布的匹配；
若评估匹配程度的参数小于预先设定的值，则重复进行上述拟合、调整、修饰和匹配步骤，直到评估匹配程度的参数达到或超过预先设定的值；
若评估匹配程度的参数大于或等于预先设定的值，则将该匹配的三维模型作为缺损区域神经的仿生修复体模型。
参见图4，其示意性地示出了基于四肢主干神经束型结构三维信息三维数据库进行构建符合神经束微结构特点的仿生修复体模型的实施例。图4A和4B示出了缺损区域神经干的近端和远端，其中从图4B中可以清楚地辨识出近端和远端中神经束型结构及两者的差异。图4C为构建的缺损区域神经干的三维模型。图4D至4F为构建的缺损区域神经干的三维模型与缺损区域神经干的近端和远端的匹配。
以上所述仅为本发明较佳的具体实施方式，本发明的保护范围不限于以上列举的实施例，任何熟悉本技术领域的技术人员在本发明披露的技术范围内，可显而易见地得到的技术方案的简单变化或等效替换均落入本发明的保护范围内。

Claims (6)

  1. 一种四肢主干神经的仿生修复体模型的建立方法，包括以下步骤：
    S1、结合影像学技术建立四肢主干神经束型结构数据库；
    S2、获取待修复的缺损性四肢主干神经的信息；
    S3、将所述待修复的缺损性四肢主干神经的信息与所述四肢主干神经束型结构数据库中的数据进行匹配和拟合，构建符合神经束微结构特点的四肢主干神经仿生修复体模型。
  2. 根据权利要求1所述的四肢主干神经的仿生修复体模型的建立方法，其特征在于，所述步骤S1包括以下步骤：
    获取四肢主干神经的离体神经样本；
    应用Micro-CT和/或Micro-MRI获得每个所述离体神经样本的二维图像数据；
    应用所述二维图像数据获得每个所述离体神经样本的三维重建模型并保存，由此建立四肢主干神经束型结构三维信息数据库。
  3. 根据权利要求2所述的四肢主干神经的仿生修复体模型的建立方法，其特征在于，所述离体神经样本取自以下的一个或多个：腋窝平面以下的上肢神经，包括正中神经、桡神经、尺神经和肌皮神经；和腹股沟平面以下的下肢神经，包括股神经、坐骨神经、胫神经和腓总神经。
  4. 根据权利要求2所述的四肢主干神经的仿生修复体模型的建立方法，其特征在于，所述二维图像数据包括所述离体神经样本的横断面、矢状面和/或冠状面的连续扫描图像。
  5. 根据权利要求1所述的四肢主干神经的仿生修复体模型的建立方法，其特征在于，所述步骤S2包括以下步骤：
    明确患者的损伤类型和损伤时间，初步定位目标损伤神经；
    扫描患者健侧和患侧的神经干大体形态，获取患侧缺损区域以及与其相对应的健侧正常区域的扫描图像；
    将所述患侧缺损区域的扫描图像与所述健侧正常区域的扫描图像进行对比与分析，以判定缺损区域神经干的类型、空间位置、长度和神经分支情况，并测量缺损区域神经干的直径和长度。
  6. 根据权利要求5所述的四肢主干神经的仿生修复体模型的建立方法，其特征在于，所述步骤S3包括以下步骤：
    根据所述待修复的缺损性四肢主干神经的信息，在所述四肢主干神经束型结构数据库中定位与所述缺损区域神经干的类型、空间位置、长度和神经分支情况相匹配的一段神经 束型结构并提取其空间结构数据；
    将所述待修复的缺损性四肢主干神经的信息中的数据与四肢主干神经束型结构数据库中的数据进行拟合，并应用拟合的数据建立整体三维模型；
    根据所述缺损性四肢主干神经的缺损区域神经干的近端和远端的神经大体形貌、神经分支和神经束三维空间位置分布，对所述建立的三维模型进行调整；
    对所述调整的三维模型中神经干及神经束的形态、曲度、光滑度进行修饰；
    将所述修饰的三维模型与所述缺损区域神经干的近端和远端进行神经大体形貌、神经分支和神经束三维空间位置分布的匹配；
    若评估匹配程度的参数小于预先设定的值，则重复进行所述拟合、调整、修饰和匹配步骤，直到所述评估匹配程度的参数达到或超过预先设定的值；
    若所述评估匹配程度的参数等于或大于预先设定的值，则将所述匹配的三维模型作为缺损区域神经的仿生修复体模型。
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