CN110302430A - 生物3d打印植入凝胶及其在软组织缺损修复中的应用 - Google Patents

生物3d打印植入凝胶及其在软组织缺损修复中的应用 Download PDF

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CN110302430A
CN110302430A CN201910607789.XA CN201910607789A CN110302430A CN 110302430 A CN110302430 A CN 110302430A CN 201910607789 A CN201910607789 A CN 201910607789A CN 110302430 A CN110302430 A CN 110302430A
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polyethylene glycol
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CN110302430B (zh
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贺超
郝永强
王磊
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Ninth Peoples Hospital Shanghai Jiaotong University School of Medicine
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Abstract

一种组合物，包括聚乙二醇、去细胞细胞外基质和透明质酸的溶液。其中，聚乙二醇浓度1.5w/v％～3.5％w/v，去细胞细胞外基质浓度10w/v％～30w/v％和透明质酸浓度10g/L～20g/L。本发明的组合物具有良好生物相容性，具有温敏特性，随着温度升高，逐渐固化，运用3D打印技术制成模拟细胞外基质形态的凝胶，有利于软组织切除手术后形成的空腔内的新生肉芽组织的粘附生长和再生修复，促进创伤愈合。

Description

生物3D打印植入凝胶及其在软组织缺损修复中的应用
技术领域
本发明涉及一种组合物，尤其涉及一种用于植入的组合物，以其制成凝胶用于软组织的修复。
背景技术
恶性肿瘤是一类致死性极高的疾病，手术是治疗恶性肿瘤的有效方式，而肿瘤手术往往需要扩大切除肿瘤及其周围组织，这就意味着手术后会导致巨大的软组织缺损。手术后，由于软组织切除而形成的空腔极易形成死腔，腔内形成积液，增加了术后感染等并发症的风险，不利于伤口的再生愈合。
中国发明专利申请201811170902.4公开了一种用于软骨修复的温敏性水凝胶，包括琼脂糖水溶液、明胶水溶液、透明质酸钠水溶液及DBM-RGD颗粒，其中：琼脂糖水溶液的质量体积比浓度为0.002g/ml～0.02g/ml；明胶水溶液的质量体积比浓度为0.05g/ml～0.1g/ml；透明质酸钠水溶液的质量体积比浓度为在0.0002g/ml～0.01g/ml；DBM-RGD颗粒的添加量以琼脂糖水溶液、明胶水溶液、透明质酸钠水溶液形成的混合溶液的体积计，其加入量为0.01g/ml～0.05g/ml；琼脂糖水溶液、明胶水溶液与透明质酸钠水溶液的体积比为5∶5∶2。
中国发明专利申请201810185988.1公开了一种注射用多功能复合型水凝胶，由胶原(Col)、透明质酸(HA)、聚乙烯吡咯烷酮(PVP)以及聚乳酸-羟基乙酸共聚物(PLGA)包裹的硫酸乙酰肝素(HS)和转化生长因子-β(TGF-β)复合而成的Col-HA-PVP-Nanoparticles四元复合型水凝胶，它高度仿生细胞外基质(ECM)的组成和结构，具有较好的稳定性，保水率及力学性能；同时，可促进骨组织的再生和修复。
对于缺损软组织的修复，现在临床上尚缺乏有效手段，比如：能够实现软组织空腔填充的材料，使得手术后形成的软组织空洞得以填补，进而促进创伤部位的软组织愈合。因此新型的空腔填充物的开发就显得尤为重要，将解决临床外科的普遍问题。
发明内容
本发明的一个目的在于提供一种组合物，具有温敏的特性，便于组合物植入对缺损的软组织实施修复。
本发明的另一个目的在于提供一种组合物，以生物3D打印方式形成，用于缺损的软组织实施修复。
本发明的再一个目的在于提供一种组合物，生物3D打印制成凝胶在修复缺损的肌肉组织中的应用。
本发明提供一种组合物，包括聚乙二醇(PEG)、去细胞细胞外基质和透明质酸的溶液，其中，聚乙二醇(PEG)浓度1.5w/v％～3.5％w/v，去细胞细胞外基质浓度10w/v％～30w/v％和透明质酸浓度10g/L～20g/L。
本发明提供另一种组合物，包括聚乙二醇(PEG)、去细胞细胞外基质和透明质酸的溶液，其中，PEG浓度2.5w/v％、去细胞细胞外基质浓度20w/v％和透明质酸浓度15g/L。
PEG的分子量为1,000Da～20,000Da，优先选择3,000Da。
本发明提供一种组合物，其在4℃时候为流体，便于注射使用，随着温度升高，逐渐固化，在37℃时候会转变为凝胶化状态。
根据CAD辅助建模，将本发明组合物形成的流体水凝胶3D打印成为模拟肌肉组织的梭形形态。
运用3D打印技术将凝胶打印成模拟细胞外基质的形态，有利于手术后形成的组织空腔内新生肉芽组织的粘附生长和再生修复。
在运用3D打印技术模拟肌肉组织的过程中，还同时或单独向本发明的组合物中加入止血因子抑肽酶、纤维细胞生长因子FGF2和肌肉卫星细胞。
本发明技术方案取得的技术效果如下：
本发明的组合物包括PEG、去细胞细胞外基质和透明质酸，具有良好生物相容性，具有温敏特性，制成凝胶填充物实现对软组织切除后形成空腔的填充。
本发明的组合物制成凝胶后，具有溶胀性能，溶胀后既可以填充空腔还可以起到压迫止血的作用，从而避免了积液的形成，降低感染风险，促进伤口愈合。
本发明的组合物适用于运用3D打印技术制成模拟细胞外基质形态的凝胶，有利于软组织切除手术后形成的空腔内的新生肉芽组织的粘附生长和再生修复，促进创伤愈合。
本发明的组合物还可根据需要添加其它物质，比如：止血因子、促生长因子和肌肉卫星细胞，在止血的同时促进软组织切除手术后形成的空腔内的组织再生。
附图说明
图1为本发明的凝胶交联示意图；
图2为本发明3D打印的凝胶植入缺损软组织实施修复一实施例的示意图；
图3为各种组分3D打印的凝胶植入软组织1个月后肌肉冻伤缺损处愈合情况统计图；
图4为各种组分3D打印的凝胶植入软组织1个月后肌肉冻伤缺损处愈合情况统计图。
具体实施方式
以下结合附图详细描述本发明的技术方案。本发明实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围中。
实施例1
分别将2.5w/v％PEG、20w/v％去细胞细胞外基质、15g/L透明质酸、2.5w/v％PEG+20w/v％去细胞细胞外基质、2.5w/v％PEG+15g/L透明质酸、20w/v％去细胞细胞外基质+15g/L透明质酸、2.5w/v％PEG+5w/v％去细胞细胞外基质+15g/L透明质酸、2.5w/v％PEG+10w/v％去细胞细胞外基质+15g/L透明质酸、2.5w/v％PEG+20w/v％去细胞细胞外基质+15g/L透明质酸，以及空白对照组等10组分别进行凝胶化处理后，植入1 0组大鼠(每组5只)股四头肌冻伤缺损部位，1个月后观察大鼠骨骼肌横截面面积作为判断肌肉缺损的愈合优劣的依据，并相应进行统计分析，详见图3。如图3所示，2.5w/v％PEG+20w/v％去细胞细胞外基质+15g/L透明质酸凝胶植入组的大鼠的愈合情况最好。
实施例2
将2.5w/v％PEG、20w/v％去细胞细胞外基质和15g/L透明质酸溶液混合，混合后搅拌24小时，制备PEG/去细胞细胞外基质/透明质酸水凝胶，其4摄氏度保存。4℃时候为流体，适合于注射使用，37℃时候会变为凝胶化状态。
凝胶制备中还加入止血因子抑肽酶和纤维细胞生长因子FGF2，或加入止血因子抑肽酶、纤维细胞生长因子FGF2和肌肉卫星细胞，与空白对照组等4组大鼠(每组5只)进行分组试验。
根据CAD辅助建模，将以上4组流体水凝胶3D打印成为模拟肌肉的梭形形态，植入大鼠股四头肌冻伤缺损部位，1个月后观察大鼠骨骼肌横截面面积作为判断肌肉缺损的愈合优劣的依据，并相应进行统计分析，详见图4。
如图4所示，从肌肉愈合情况，加入止血因子抑肽酶、纤维细胞生长因子FGF2和肌肉卫星细胞组优于加入止血因子抑肽酶和纤维细胞生长因子FGF2组，加入止血因子抑肽酶和纤维细胞生长因子FGF2组优于水凝胶组，水凝胶组优于空白对照组。

Claims (10)

1.一种组合物，其特征在于包括聚乙二醇、去细胞细胞外基质和透明质酸的溶液，其中，聚乙二醇浓度1.5w/v％～3.5％w/v，去细胞细胞外基质浓度10w/v％～30w/v％和透明质酸浓度10g/L～20g/L。
2.根据权利要求1所述的组合物，其特征在于还包括止血因子抑肽酶、纤维细胞生长因子FGF2和肌肉卫星细胞之一种或几种。
3.根据权利要求1所述的组合物，其特征在于所述聚乙二醇的浓度为2.5w/v％。
4.根据权利要求1所述的组合物，其特征在于所述去细胞细胞外基质浓度为20w/v％。
5.根据权利要求1所述的组合物，其特征在于所述透明质酸浓度为15g/L。
6.根据权利要求1所述的组合物，其特征在于所述聚乙二醇的分子量为1,000Da～20,000Da。
7.根据权利要求1所述的组合物，其特征在于所述聚乙二醇的分子量为3,000Da。
8.根据权利要求1所述的组合物，其特征在于4℃时候为流体，便于注射使用，随着温度升高，组件固化，在37℃时候会转变为凝胶化状态。
9.一种生物3D打印凝胶，其特征在于包括权利要求1～8之一所述的组合物。
10.根据权利要求9所述的生物3D打印凝胶在修复缺损的肌肉组织中的应用，根据CAD辅助建模，将所述的组合物形成的流体水凝胶3D打印成为模拟肌肉组织的梭形形态，以及打印成模拟细胞外基质的形态。
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