CN113303948A - 一种神经血管化骨膜 - Google Patents

一种神经血管化骨膜 Download PDF

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CN113303948A
CN113303948A CN202110380789.8A CN202110380789A CN113303948A CN 113303948 A CN113303948 A CN 113303948A CN 202110380789 A CN202110380789 A CN 202110380789A CN 113303948 A CN113303948 A CN 113303948A
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nerve
blood vessel
periosteum
pcl
dnm
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郭晓东
杨亮
苏延林
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Tongji Medical College of Huazhong University of Science and Technology
Union Hospital Tongji Medical College Huazhong University of Science and Technology
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Union Hospital Tongji Medical College Huazhong University of Science and Technology
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Abstract

本发明公开了医疗领域的一种神经血管化骨膜，神经血管化骨膜通过神经再生活性的神经脱细胞基质和血管再生活性的小肠粘膜下层脱细胞基质为基材，利用同轴静电纺技术构建定向有序微纳纤维结构，负载具有多重生物学效应的神经生长因子和血管内皮生长因子，以募集背根神经节神经纤维和血管内皮祖细胞，获得能原位诱导内源性神经/血管细胞靶向募集、定向迁移、定向分化的神经血管化仿生骨膜。本发明以DNM作为仿生骨膜中的神经诱导膜基材，引入血管诱导膜，神经、血管二者相互伴行、交互对话，形成神经‑血管网络微环境，诱导内源性干细胞成骨分化，能够为原位诱导骨再生提供理想微环境，有利于人们的使用。

Description

一种神经血管化骨膜
技术领域
本发明涉及医疗领域，具体是一种神经血管化骨膜。
背景技术
我国每年由于创伤、肿瘤骨转移等引起的骨缺损患者有300多万人，亟需大量骨修复材料来提高患者的康复质量，尤为重要的是，在骨缺损患者中有大量的难治性骨缺损，其特点表现为血运差、成骨能力弱及缺损范围过大，这一直是骨科医生的巨大挑战，目前，在市场上，同种异体骨及各种人工骨材料成骨能力弱，单独使用效果不好，这一巨大挑战的很重要的一个原因是，由于目前大家对骨缺损的研究主要集中在成骨、成血管角度，对神经在骨中的重要作用没有深入的认识，国际同行及本团队研究发现，天然骨膜中强大的故再生能力主要是感觉神经及交感血管的复杂交互作用，而感觉神经在骨缺损修复中有着关键先行者的重要作用，因此，如何在骨缺损部位原位诱导神经再生、形成神经血管化网络，为原位诱导骨缺损修复提供良好的再生微环境，是大段及难治性骨缺损修复目前急需解决的问题。
近年来，对天然骨膜的研究逐渐发现，其内含有的大量感觉神经对启动及调控骨再生具有非常重要的作用，2016年秦岭教授发现，含镁离子的髓内针能通过促进感觉神经元（DRG）细胞分泌神经递质CGRP促进骨形成，因此，强化骨移植材料的神经再生诱导能力对于诱导骨再生至关重要，天然骨膜有丰富的相互伴行的神经、血管，共同构成神经-血管网络，对诱导内源性骨膜干细胞、骨髓间充质细胞等的成骨分化，具有重要作用，哈佛大学Jang团队于2018年在生物材料权威期刊MaterialsToday提出了构建神经血管化骨植入材料加速骨再生的初步设想，但是，目前这一新概念材料尚处于初始阶段，只是在血管化方面取得一些进展，在神经化方面依然局限于通过创伤性手术进行自体神经束移植，目前国内外对在骨缺损局部如何实现神经再生、如何重建神经-血管网络，尚无有效策略。因此，本领域技术人员提供了一种神经血管化骨膜，以解决上述背景技术中提出的问题。
发明内容
本发明的目的在于提供一种神经血管化骨膜，以解决上述背景技术中提出的问题。
为实现上述目的，本发明提供如下技术方案：
一种神经血管化骨膜，所述神经血管化骨膜通过神经再生活性的神经脱细胞基质和血管再生活性的小肠粘膜下层脱细胞基质为基材，利用同轴静电纺技术构建定向有序微纳纤维结构，负载具有多重生物学效应的神经生长因子和血管内皮生长因子，以募集背根神经节神经纤维和血管内皮祖细胞，获得能原位诱导内源性神经/血管细胞靶向募集、定向迁移、定向分化的神经血管化仿生骨膜。
作为本发明进一步的方案：所述神经再生活性的神经脱细胞基质采用猪坐骨神经制备出DNM，且DNM作为仿生骨膜中的神经诱导膜基材。
作为本发明再进一步的方案：所述小肠粘膜下层脱细胞基质采用猪小肠粘膜下层脱细胞基质SIS，且SIS作为原位诱导骨再生的组织诱导膜材料。
作为本发明再进一步的方案：所述同轴静电纺技术能够制备出以DNM为壳、聚己内酯（PCL）为核的有序微纳纤维结构的神经诱导膜DNM/PCL。
作为本发明再进一步的方案：所述同轴静电纺技术能够制备出以SIS为壳、聚己内酯（PCL）为核的有序微纳纤维结构的血管诱导膜SIS/PCL。
作为本发明再进一步的方案：所述神经血管化仿生骨膜通过血管诱导膜与神经诱导膜的多层交互叠加而获得。
作为本发明再进一步的方案：所述神经血管化骨膜用于促进难治性骨缺损的修复。
一种神经血管化骨膜的制造方法，包括以下步骤：
S1：取新鲜屠宰的肉猪猪坐骨,对猪骨进行漂洗、沥干，应用0.1％胰蛋白酶和0.01％EDTA于37℃震荡条件下脱除神经细胞成分，得到猪坐骨神经细胞基质；
S2：取新鲜屠宰的肉猪猪小肠，对猪小肠进行漂洗、沥干，应用0.1％胰蛋白酶和0.01％EDTA于37℃震荡条件下脱除血管细胞成分，得到小肠粘膜下层脱细胞基质；
S3：将S1中得到的猪坐骨神经细胞基质通过静电纺丝技术制备出以DNM 为壳、聚己内酯（PCL）为核的有序微纳纤维结构的神经诱导膜DNM/PCL，将S2中得到的小肠粘膜下层脱细胞基质通过静电纺丝技术制备出有序微纳纤维结构的血管诱导膜SIS/PCL；
S4：将得到的血管诱导膜SIS/PCL与得到的神经诱导膜DNM/PCL多层交互叠加，得到神经血管化骨膜成品。
与现有技术相比，本发明的有益效果是：
1、本发明以DNM作为仿生骨膜中的神经诱导膜基材，引入血管诱导膜，神经、血管二者相互伴行、交互对话，形成神经-血管网络微环境，诱导内源性干细胞成骨分化，能够为原位诱导骨再生提供理想微环境，有利于人们的使用。
2、本发明通过静电纺丝技术，在保留DNM生物活性的同时，获得定向有序的微纳纤维结构和更好的力学强度，可更好地诱导感觉神经纤维定向迁移延伸。
附图说明
图1为本发明流程图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
请参阅图1，本发明实施例中，一种神经血管化骨膜，神经血管化骨膜通过神经再生活性的神经脱细胞基质和血管再生活性的小肠粘膜下层脱细胞基质为基材，神经再生活性的神经脱细胞基质采用猪坐骨神经制备出DNM，且DNM作为仿生骨膜中的神经诱导膜基材，小肠粘膜下层脱细胞基质采用猪小肠粘膜下层脱细胞基质SIS，且SIS作为原位诱导骨再生的组织诱导膜材料，利用同轴静电纺技术构建定向有序微纳纤维结构，同轴静电纺技术能够制备出以DNM为壳、聚己内酯（PCL）为核的有序微纳纤维结构的神经诱导膜DNM/PCL，同轴静电纺技术能够制备出以SIS为壳、聚己内酯（PCL）为核的有序微纳纤维结构的血管诱导膜SIS/PC，负载具有多重生物学效应的神经生长因子和血管内皮生长因子，以募集背根神经节神经纤维和血管内皮祖细胞，获得能原位诱导内源性神经/血管细胞靶向募集、定向迁移、定向分化的神经血管化仿生骨膜，神经血管化仿生骨膜通过血管诱导膜与神经诱导膜的多层交互叠加而获得，神经血管化骨膜用于促进难治性骨缺损的修复。
一种神经血管化骨膜的制造方法，包括以下步骤：S1：取新鲜屠宰的肉猪猪坐骨,对取新骨进行漂洗、沥干，应用0.1％胰蛋白酶和0.01％EDTA于37℃震荡条件下脱除神经细胞成分，得到猪坐骨神经细胞基质；S2：取新鲜屠宰的肉猪猪小肠，对猪小肠进行漂洗、沥干，应用0.1％胰蛋白酶和0.01％EDTA于37℃震荡条件下脱除血管细胞成分，得到小肠粘膜下层脱细胞基质；S3：将S1中得到的猪坐骨神经细胞基质通过静电纺丝技术制备出以DNM为壳、聚己内酯（PCL）为核的有序微纳纤维结构的神经诱导膜DNM/PCL，将S2中得到的小肠粘膜下层脱细胞基质通过静电纺丝技术制备出有序微纳纤维结构的血管诱导膜SIS/PCL；S4：将得到的血管诱导膜SIS/PCL与得到的神经诱导膜DNM/PCL多层交互叠加，得到神经血管化骨膜成品。
蛋白组学检测发现，DNM保留有天然神经细胞外基质中的多种粘附分子和生物活性因子，主要活性成分为纤维连接蛋白、糖胺多糖、I/IV 型胶原等，而且生物相容性好，免疫原性低，工作证实，DNM 能够诱导背根神经节（DRG）的轴突延伸及施旺细胞增殖分化，目前利用DNM 诱导骨膜感觉神经再生尚未见报道，因此，以DNM 作为仿生骨膜中的神经诱导膜基材，诱导内源性感觉神经DRG 的轴突再生，具有创新性。
定向有序微纳纤维结构的仿生骨膜能够诱导感觉神经定向迁移延伸，研究证实，通过静电纺丝可制备有序取向的纤维结构，促进种子细胞的定向迁移，本发明利用壳核同轴电纺技术，制备出以DNM 为壳、聚己内酯（PCL）为核的有序微纳纤维结构的神经诱导膜DNM/PCL，在保留DNM生物活性的同时，获得定向有序的微纳纤维结构和更好的力学强度，可更好地诱导感觉神经纤维定向迁移延伸，尽管骨再生过程中感觉神经长入要早于血管形成，神经细胞可分泌成血管神经肽促进血管形成，但随后再生的血管亦可为神经提供营养、可分泌NGF等因子能促进神经再生。
募集内皮祖细胞，从而构建出能原位诱导内源性EPCs募集、迁移、分化的血管诱导膜，然后与神经诱导膜多层交互叠加，获得神经血管化仿生骨膜，本发明的设计思路具有创新性，不仅可能在骨缺损局部，原位诱导神经再生、重建神经-血管网络，为原位诱导骨再生提供理想微环境，在一定程度上解决难治性骨缺损瓶颈背后的核心问题。
神经血管化仿生骨膜，不仅可以直接覆盖于植骨材料表面，促进难治性骨缺损的修复，还可与脱钙骨基质等材料复合，通过3D生物打印等技术，构建具有微纳梯度分级结构的大块神经血管化仿生骨材料，更好地修复难治性骨缺损。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。

Claims (8)

1.一种神经血管化骨膜，其特征在于：所述神经血管化骨膜通过神经再生活性的神经脱细胞基质和血管再生活性的小肠粘膜下层脱细胞基质为基材，利用同轴静电纺技术构建定向有序微纳纤维结构，负载具有多重生物学效应的神经生长因子和血管内皮生长因子，以募集背根神经节神经纤维和血管内皮祖细胞，获得能原位诱导内源性神经/血管细胞靶向募集、定向迁移、定向分化的神经血管化仿生骨膜。
2.根据权利要求1所述的一种神经血管化骨膜，其特征在于：所述神经再生活性的神经脱细胞基质采用猪坐骨神经制备出DNM，且DNM作为仿生骨膜中的神经诱导膜基材。
3.根据权利要求1所述的一种神经血管化骨膜，其特征在于：所述小肠粘膜下层脱细胞基质采用猪小肠粘膜下层脱细胞基质SIS，且SIS作为原位诱导骨再生的组织诱导膜材料。
4.根据权利要求2所述的一种神经血管化骨膜，其特征在于：所述同轴静电纺技术能够制备出以DNM为壳、聚己内酯（PCL）为核的有序微纳纤维结构的神经诱导膜DNM/PCL。
5.根据权利要求3所述的一种神经血管化骨膜，其特征在于：所述同轴静电纺技术能够制备出以SIS为壳、聚己内酯（PCL）为核的有序微纳纤维结构的血管诱导膜SIS/PCL。
6.根据权利要求5所述的一种神经血管化骨膜，其特征在于：所述神经血管化仿生骨膜通过血管诱导膜与神经诱导膜的多层交互叠加而获得。
7.根据权利要求1所述的一种神经血管化骨膜，其特征在于：所述神经血管化骨膜用于促进难治性骨缺损的修复。
8.一种神经血管化骨膜的制造方法，其特征在于：包括以下步骤：
S1：取新鲜屠宰的肉猪猪坐骨,对猪骨进行漂洗、沥干，应用0.1％胰蛋白酶和0.01％EDTA于37℃震荡条件下脱除神经细胞成分，得到猪坐骨神经细胞基质；
S2：取新鲜屠宰的肉猪猪小肠，对猪小肠进行漂洗、沥干，应用0.1％胰蛋白酶和0.01％EDTA于37℃震荡条件下脱除血管细胞成分，得到小肠粘膜下层脱细胞基质；
S3：将S1中得到的猪坐骨神经细胞基质通过静电纺丝技术制备出以DNM 为壳、聚己内酯（PCL）为核的有序微纳纤维结构的神经诱导膜DNM/PCL，将S2中得到的小肠粘膜下层脱细胞基质通过静电纺丝技术制备出有序微纳纤维结构的血管诱导膜SIS/PCL；
S4：将得到的血管诱导膜SIS/PCL与得到的神经诱导膜DNM/PCL多层交互叠加，得到神经血管化骨膜成品。
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