CN112955193A - 糖尿病足病患者定制型皮肤再生片的制造方法及利用其制造的糖尿病足病患者定制型皮肤再生片 - Google Patents
糖尿病足病患者定制型皮肤再生片的制造方法及利用其制造的糖尿病足病患者定制型皮肤再生片 Download PDFInfo
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- CN112955193A CN112955193A CN201980003589.1A CN201980003589A CN112955193A CN 112955193 A CN112955193 A CN 112955193A CN 201980003589 A CN201980003589 A CN 201980003589A CN 112955193 A CN112955193 A CN 112955193A
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- diabetic foot
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Abstract
本说明书涉及一种糖尿病足病患者定制型皮肤再生片的制造方法及利用其制造的糖尿病足病患者定制型皮肤再生片，所述制造方法包括以下步骤：A)提取自体脂肪组织；B)利用具有2mm至3mm孔(pore)径的第一过滤器，去除自体脂肪组织中的纤维质；C)使所述去除纤维质的自体脂肪组织，依次穿过具有450μm至550μm孔(pore)径的第二过滤器及具有150μm至250μm孔(pore)径的第三过滤器，以粉碎自体脂肪组织；D)提取由具有25μm至75μm孔(pore)径的第四过滤器捕集的所述经粉碎的自体脂肪组织，获取脂肪组织提取物；E)利用三维扫描仪，获取患者的皮肤缺损区域的三维数据后，以此为基础，利用三维打印机，制造与皮肤缺损区域对应的三维模具；F)将包含所述脂肪组织提取物和纤维蛋白原的第一液涂覆于所述三维模具内，以形成原型层(proto‑layer)；G)将包含凝血酶的第二液涂覆于所述原型层上，以固化成皮肤再生层；以及H)去除所述三维模具。
Description
技术领域
本发明涉及糖尿病足病患者定制型皮肤再生片的制造方法及利用其制造的糖尿病足病患者定制型皮肤再生片。
背景技术
所谓糖尿病足病，尤其是指糖尿病病患足部皮肤创伤引起皮肤组织溃烂而产生的足部溃疡。此为糖尿病引起的神经病变或周围血管病变在糖尿病患者足部引发溃疡或是伤口感染恶化而出现的现象。患有糖尿病的患者中约有20％必患一次以上糖尿病足病，其中有1～3％左右的患者接受腿部部分截肢手术。
另外，除外伤导致之外，据所知，导致腿部部分截肢的原因有一半以上是糖尿病足病。如上所述，作为降低糖尿病患者生活质量的很重要原因，对于糖尿病足病需要有一种治疗手段。尤其，实情是，需要有一项研究，以恢复糖尿病足病坏死区域皮肤组织，使正常生活成为可能。
发明内容
技术问题
本说明书旨在提供一种能够使糖尿病足病患者坏死部位皮肤恢复为正常皮肤的糖尿病足病患者定制型皮肤再生片的制造方法及利用其制造的糖尿病足病患者定制型皮肤再生片。
问题解决方案
本发明的一种实施方式提供一种糖尿病足病患者定制型皮肤再生片的制造方法，包括：A)提取自体脂肪组织；B)利用具有2mm至3mm孔(pore)径的第一过滤器，去除自体脂肪组织中的纤维质；C)使所述去除纤维质的自体脂肪组织，依次穿过具有450μm至550μm孔(pore)径的第二过滤器及具有150μm至250μm孔(pore)径的第三过滤器，以粉碎自体脂肪组织；D)提取由具有25μm至75μm孔(pore)径的第四过滤器捕集的所述经粉碎的自体脂肪组织，获取脂肪组织提取物；E)利用三维扫描仪，获取患者的皮肤缺损区域的三维数据后，以此为基础，利用三维打印机，制造与皮肤缺损区域对应的三维模具；F)将包含所述脂肪组织提取物和纤维蛋白原的第一液涂覆于所述三维模具内，以形成原型层(proto-layer)；G)将包含凝血酶的第二液涂覆于所述原型层上，以固化成皮肤再生层；以及H)去除所述三维模具。
本发明的又一实施方式提供一种利用所述制造方法制造的糖尿病足病患者定制型皮肤再生片。
发明效果
根据本发明的糖尿病足病患者定制型皮肤再生片的制造方法，能够迅速制造适合糖尿病足病患者的皮肤再生片，具有可预期的高细胞活性及细胞生长因子的皮肤再生促进效果，能够有效实现患部的恢复。
根据本发明的糖尿病足病患者定制型皮肤再生片的制造方法制造与糖尿病足病患者的患部一致形状(即，形状及深度一致的形状)的皮肤再生片，患部能够更有效恢复。
通过以下对发明的详细描述、权利要求书及附图，本发明的其他目的及优点能够理解得更加明确。
附图简要说明
图1分步骤示出了根据实施例的脂肪组织提取物的获取过程。
图2示出了实施例的患者定制三维模具的制造过程。
图3示出了将根据实施例的患者定制型皮肤再生片应用于糖尿病足病患者的过程及其结果。
具体实施方式
在本说明书中，当涉及某种部件位于其它部件“上”时，这不仅包括：某种部件接触于其它部件，还包括：两个部件之间存在另外的部件。
在本说明书中，当涉及某部分“包括”某组件时，其所指的是，只要没有尤其相反的记载，并不排除其它组件，并且还可以包括其它组件。
下面对本发明进行详细说明。
本发明的一个实施方式提供一种糖尿病足病患者定制型皮肤再生片的制造方法，包括：
A)提取自体脂肪组织；
B)利用具有2mm至3mm孔(pore)径的第一过滤器，去除自体脂肪组织中的纤维质；
C)使所述去除纤维质的自体脂肪组织，依次穿过具有450μm至550μm孔(pore)径的第二过滤器及具有150μm至250μm孔(pore)径的第三过滤器，以粉碎自体脂肪组织；
D)提取由具有25μm至75μm孔(pore)径的第四过滤器捕集的所述经粉碎的自体脂肪组织，获取脂肪组织提取物；
E)利用三维扫描仪，获取患者的皮肤缺损区域的三维数据后，以此为基础，利用三维打印机，制造与皮肤缺损区域对应的三维模具；
F)将包含所述脂肪组织提取物和纤维蛋白原的第一液涂覆于所述三维模具内，以形成原型层(proto-layer)；
G)将包含凝血酶的第二液涂覆于所述原型层上，以固化成皮肤再生层；以及
H)去除所述三维模具。
下面对所述糖尿病足病患者定制型皮肤再生片的制造方法的各步骤进行详细说明。
步骤A)：提取自体脂肪组织。
所述步骤A)可以是，利用普通的吸脂术，提取糖尿病足病患者的自体脂肪组织。具体而言，所述步骤A)的自体脂肪组织可以是在吸脂术提取物去除吸脂术所使用的盐水以及混于其中一同流出的血液而得的。
根据本发明的一种实施方式，所述步骤A)可以是，从利用吸脂术获取的提取物中去除血液及生理盐水，以提取自体脂肪组织。具体而言，所述步骤A)可以是，将利用吸脂术获取的提取物放置预定时间，以滤除与脂肪层分离的血液及生理盐水层，提取自体脂肪组织。以此方式去除血液及生理盐水，能够更有效地提取下述脂肪组织提取物，进而，所提取的脂肪组织提取物能够更有效地包含适合治疗的生长因子及活性细胞。
步骤B)：去除自体脂肪组织中的纤维质。
所述步骤B)可以利用孔径相对较大的第一过滤器，去除所提取的自体脂肪组织中的纤维质。具体而言，所述步骤B)中的所述第一过滤器可以为不锈钢材质的针头式过滤器。具体而言，所述第一过滤器具有高强度的不锈钢材质的过滤器部，可以从所述自体脂肪组织有效分离纤维质。更具体而言，所述步骤B)可以是在所述第一过滤器的两端加装注射器后，利用注射器的活塞运动，使提取的自体脂肪组织穿过所述第一过滤器2次以上，具体而言为2至3次。在所述步骤B)的情况下，使得可以第一次滤除自体脂肪组织中的纤维质，更有效地在短时间内实现自体脂肪组织的粉碎。
步骤C)：粉碎自体脂肪组织。
所述步骤C)可以包括：使所述去除纤维质的自体脂肪组织穿过所述第二过滤器，以粉碎自体脂肪组织，使其过滤物穿过所述第三过滤器，以进一步粉碎自体脂肪组织。
根据本发明的一种实施方式，所述步骤C)可以是，向过滤袋(filter bag)注入所述去除纤维质的自体脂肪组织后，施加外部压力以使其穿过过滤器，从而粉碎所述去除纤维质的自体脂肪组织。具体而言，所述步骤C)可以是，向过滤袋(filter bag)注入所述去除纤维质的自体脂肪组织后，在外部利用诸如硅胶铲等的工具，使所述去除纤维质的自体脂肪组织依次穿过第二及第三过滤器，以粉碎自体脂肪组织。
在本说明书中，过滤袋(filter bag)作为一种柔软塑料材质的密闭袋状的过滤器试剂盒，可以是一侧具有注入口、另一侧具有排出口、内部空间由过滤器分隔的形态。
所述步骤C)中的第二过滤器及第三过滤器的一个示例，可以变形使用Tiss'You公司的Lipocell试剂盒的过滤袋。不过，并非限于此，可以利用符合本发明目的的过滤器。
如所述步骤C)，逐步利用孔径渐小的过滤器粉碎自体脂肪组织，可极大缩短细微粉碎自体脂肪组织所需的时间，脂肪组织提取物中的细胞能够保持高细胞活性。具体而言，在利用所述步骤C)时，即使是以物理方法细微粉碎脂肪组织，仍然具有能够有效确保大量对治疗有效的脂肪组织、活性细胞及活性蛋白质的优点。进而，当利用所述步骤C)时，能够以最佳活性状态收集细胞外间质及生长因子，还可以使其具有能够执行(3D)生物打印的物性。
D)获取脂肪组织提取物。
所述步骤D)可以是，利用所述第四过滤器对经所述步骤C)粉碎的自体脂肪组织进行过滤之后，丢弃滤出的物质，获得由过滤器捕集的物质。具体而言，所述步骤D)可以是，将经步骤C)粉碎的自体脂肪组织与生理盐水混合后，利用所述第四过滤器进行过滤，分离去除所滤出的物质之后，将由所述第四过滤器捕集的物质用作脂肪组织提取物。所述滤出并被去除的物质可以包含过度细微粉碎而细胞活性下降的脂肪组织、血液、生理盐水等，这些会妨碍本发明所意图的最终皮肤再生片的活性，因而应去除。
所述步骤D)可以是，向过滤袋(filter bag)注入所述去除纤维质的自体脂肪组织及生理盐水后，去除由所述第四过滤器滤出的物质。具体而言，所述步骤D)可以是，在向过滤袋(filterbag)注入所述去除纤维质的自体脂肪组织及生理盐水后，施加适当压力，使所述经粉碎的自体脂肪组织被所述第四过滤器过滤。
所述步骤D)中的第四过滤器的一个示例，可以变形使用Tiss'You公司的Lipocell试剂盒的过滤袋。不过，并非限于此，可以利用符合本发明目的的过滤器。
根据本发明制造的所述脂肪组织提取物，尤其能够富含糖尿病足病患者皮肤恢复所需的生长因子(growth factor)、活性细胞及活性蛋白质等。进而，利用所述脂肪组织提取物的生物打印组合物(例如，第一液)在生物打印过程中不堵塞喷嘴，进而能够保持适当粘度而以稳定速度喷出，因而适合需要进行精密生物打印的皮肤再生片的制造。
另外，所提取的所述脂肪组织提取物可以在短时间内最大限度地包含生长因子、活性细胞及活性蛋白质等，因而能够使更有效的治疗成为可能。
步骤E)：制造与皮肤缺损区域对应的三维模具。
所述步骤E)可以利用本领域公知的三维扫描装备或三维打印装备。进而，所述三维模具能够在涂覆所述第一液及第二液时，保持患部的立体形态(即，形状、大小、深度等三维形态)，可以在制造皮肤再生片后去除。所述三维模具可以利用本行业一般使用的生物兼容性高分子来形成。具体而言，所述三维模具可以利用聚己内酯(PCL)制造。所述PCL具有低融点，并且具有高柔韧性，因而具有能够易于与所制造的皮肤再生片分离的优点。进而，用PCL能够制作符合患部立体形状的最佳模具，利用与患部立体形状相同的三维模具制造的皮肤再生片,可以有效贴合于患部，以帮助恢复。
步骤F)：形成原型层(proto-layer)。
步骤G)：固化成皮肤再生层。
在本说明书中，所谓原型层(proto-layer)，可以指，固化之前的涂覆了生物组合物的层。具体而言，可以指，涂覆于三维模具内，由包含凝血酶的组合物固化之前的层。
所述步骤F)及步骤G)分别可以利用喷墨生物打印或三维生物打印执行。具体而言，所述步骤F)及步骤G)可以利用本领域公知的具有2个以上喷嘴的生物打印装置，各个喷嘴分别喷吐所述第一液及第二液，可以形成立体形状。进而，在形成所述原型层时，利用三维生物打印机或喷墨生物打印机，使得细胞及细胞外间质均质分布，进而可以防止固化后皮肤再生层中的细胞结团现象等。
根据本发明的一种实施方式，所述步骤G)可以在30秒至5分钟以内，具体而言，可以在10秒至1分钟以内完成固化。
根据本发明的一种实施方式，所述步骤B)至步骤G)可以在30分钟以内完成。具体而言，所述步骤B)至步骤G)可以在提取脂肪组织后，在1分钟至15分钟，或在1分钟至5分钟以内完成。
在利用所述制造方法的情况下，在提取自体脂肪组织后，可以非常迅速地制造患者定制型皮肤再生片，因此具有可以使患者定制型皮肤再生片中的细胞及细胞外间质等的活性最大化的优点。
步骤H)：去除三维模具。
所述步骤H)可以是，使包括皮肤再生层的糖尿病足病患者定制型皮肤再生片(选择性地包括后述的表皮再生层)从三维模具分离。从所述三维模具去除的糖尿病足病患者定制型皮肤再生片，可以贴于糖尿病足病患者的皮肤缺损部位，使患部的皮肤再生效果最大化。
第一液及第二液
所述第一液可以包含脂肪组织提取物和纤维蛋白原。所述脂肪组织提取物可以包含脂肪组织源性基质血管组分及脂肪组织源性细胞外间质。所述脂肪组织源性基质血管组分可以包含脂肪组织源性干细胞(adipose-derived stem cells)。所述脂肪组织源性基质血管组分可以在糖尿病足病患者的患部分化成皮肤组织，与所述脂肪组织源性细胞外间质一同帮助患部的恢复。所述脂肪组织源性细胞外间质可以在糖尿病足病患者患部提供可供分化成皮肤组织的细胞固定的环境。
根据本发明的一种实施方式，所述第一液可以包含选自胰岛素、***(insulin-like growth factor)、粒细胞(granulocytes)、淋巴细胞(lymphocytes)、内皮细胞(endothelialcells)、单核细胞(monocytes)、巨噬细胞(macrophages)、脂肪源干细胞(adipose-derivedstemcells)、脂肪细胞因子(adipocytokines)、脂连蛋白(adiponectin)、瘦蛋白(leptin)、白介素6(IL-6)、白介素1β(IL-1β)、单核细胞趋化蛋白1(MCP-1)及人纤溶酶原激活物抑制因子1(PAI-1)所组成的群组的至少一种。具体而言，所述第一液可以包含含量高于糖尿病足病患者患部胰岛素浓度的胰岛素，或包含***，由此，可以弥补糖尿病足病患者患部毛细血管坏死导致的胰岛素供应不足，有效实现患部恢复。
所述第一液中的纤维蛋白原可以与所述第二液中的凝血酶反应，形成纤维蛋白网络，这可以起到充分固定所述皮肤再生层中活性细胞的作用。
根据本发明的一种实施方式，所述第一液中的纤维蛋白原可以是40％至60％稀释的60IU纤维蛋白原。
另外，根据本发明的一种实施方式，所述第二液中的凝血酶可以是是40％至60％稀释的500IU凝血酶。
如果所述纤维蛋白原及凝血酶的浓度超过所述范围，则所述皮肤再生层中的纤维蛋白胶含量过高，向皮肤细胞的分化不够有效，会产生细胞存活率降低的问题，进而，所述皮肤再生层硬度过高，可能会使患部适合性降低。进而，当所述纤维蛋白原及凝血酶的浓度不及所述范围时，所述皮肤再生层的硬度过低而难以操控，且所制造的皮肤再生片流动性过高，故在应用于患部时，会产生不够有效的问题。即，所述纤维蛋白原及凝血酶的浓度在所述范围以内时，可以使细胞存活率最大化，所制造的皮肤再生片硬度及流动性适宜，故应用于患部时，能够体现最大效果，进而，使皮肤再生片中的蛋白质及活性细胞的分布保持均匀，使有效治疗成为可能。
根据本发明的一种实施方式，所述第一液还可以包含抑肽酶。所述抑肽酶(aprotinin)是胰脏分泌的蛋白质分解酶的抑制剂，是由共58个氨基酸组成的多肽。据所知，主要从牛肺中提取，在血液中阻止纤维蛋白的分解，从而发挥止血作用。
根据本发明的一种实施方式，1ml的第一液可以包含900KIU至1,100KIU(kininogen Inactivator Unit)的所述抑肽酶，具体可以包含1000KIU。
根据本发明的一种实施方式，所述第二液可以为氯化钙溶液分散凝血酶。具体而言，所述第二液可以包含5mg至6.5mg的氯化钙。
所述第一液及第二液的溶剂可以为水，具体而言，可以为生理盐水。另外，所述第一液中的纤维蛋白原与所述第二液中的凝血酶可以通过常用的纤维蛋白胶试剂盒获得。
本发明将纤维蛋白原及凝血酶所组成的纤维蛋白胶用作粘合剂，这可以确保比透明质酸粘合剂或胶原蛋白粘合剂更高的粘性，因而所述皮肤再生层可以具有与患部的优秀粘合力，进而，可以保持适当的强度。
根据本发明的一种实施方式，所述第一液中的脂肪组织提取物与纤维蛋白原的体积比可以为3：1至5：1。所述第一液中的脂肪组织提取物与纤维蛋白原的体积比在所述范围内时，所制造的皮肤再生片的强度及细胞分化能力能够最有效地体现。
皮肤再生层
根据本发明的一种实施方式，所述皮肤再生层可以是在在内部具备细微粉碎的脂肪组织源性细胞及活性因子的纤维蛋白矩阵。具体而言，所述皮肤再生层除了脂肪组织源性细胞外间质、脂肪组织源性基质血管组分之外，可以包含各式各样的细胞及/或活性因子。
表皮再生层
根据本发明的一种实施方式，可以还包括：将包含脂肪组织提取物、纤维蛋白原及角化细胞(keratinocyte)的附加的第一液涂覆于所述皮肤再生层上，形成附加的原型层后，将包含凝血酶的附加的第二液涂覆于所述附加的原型层上，以固化成表皮再生层。所述附加的第一液及附加的第二液可以利用与前述第一液及第二液的涂覆方法相同的方法，涂覆于所述三维模具内。
根据本发明的一种实施方式，所述附加的第一液包含脂肪组织提取物、纤维蛋白原及角化细胞(keratinocyte)，可以为前述第一液再包含角化细胞(keratinocyte)。进而，所述附加的第二液可以与前述第二液相同。
所述附加的第一液可以涂覆于固化的所述皮肤再生层上，形成附加的原型层，附加的第二液涂覆于所述附加的原型层上，固化成皮肤再生层。
即，所述表皮再生层如前述皮肤再生层，在纤维蛋白矩阵内具备细微粉碎的脂肪组织源性细胞及活性因子，在此基础上，还可以具备角化细胞(keratinocyte)。
所述表皮再生层可以作为一部分包含于所述糖尿病足病患者定制型皮肤再生片，特别是位于患部最外侧，能够更有效地帮助患部表皮再生。具体而言，所述皮肤再生层能够有效地帮助患部真皮层恢复，所述表皮再生层位于患部最外侧，能够帮助所述患部表皮层恢复，因而具有能够快速恢复的优点。
糖尿病足病患者定制型皮肤再生片
根据本发明的又一实施方式，提供一种利用所述制造方法制造的糖尿病足病患者定制型皮肤再生片。所述糖尿病足病患者定制型皮肤再生片既可以仅由前述皮肤再生层构成，还可以包括前述皮肤再生层和表皮再生层全部。
根据本发明的一种实施方式，所述糖尿病足病患者定制型皮肤再生片的厚度可以至少为1mm。具体而言，当所述糖尿病足病患者定制型皮肤再生片的厚度不足1mm时，真皮层中的皮肤细胞无法再生，故患部恢复缓慢或恢复的皮肤表面会不均匀。更具体而言，所述糖尿病足病患者定制型皮肤再生片的厚度可以为1mm至10mm，或者是1mm至5mm。
下面为了具体说明本发明，将举实施例进行详细说明。但是，根据本发明的实施例可以变形为各种不同形态，本发明范围不解释为限定于以下所叙述的实施例。本说明书中实施例的提供，旨在向本领域普通技术人员更完整地说明本发明。
[实施例]
(1)脂肪组织提取物的获取
对糖尿病足病患者进行麻醉后，利用吸脂术，在糖尿病足病患者的腹部提取70ml至150ml的吸入物，放置约5分钟，使混于脂肪组织一同流出的盐水和血液沉淀而除去沉淀物，获取自体脂肪组织。
然后，将盛装患者脂肪的注射器和新注射器加装于包含2.4mm孔径不锈钢针头式过滤器(Adnizer,SKT-AN-2400,BSL)的连接器的双向注入口，通过活塞运动使脂肪穿过过滤器2～3次，从而去除自体脂肪组织中的纤维质。
然后，将去除纤维质的脂肪注入具备孔径为500μm的聚乙烯(PET)过滤器的滤袋(filter bag)(脂肪组织处理装置，Tiss'You)，利用硅胶铲进行过滤。然后，利用具备孔径200μm的PET过滤器的滤袋(脂肪组织处理装置，Tiss'You)，以相同方法过滤已穿过500μm过滤器的脂肪。进而，将穿过200μm过滤器的脂肪与等量的生理盐水一同注入具备孔径为50μm的PET过滤器的滤袋(脂肪组织处理装置，Tiss'You)，滤除生理盐水和其他杂质，获取脂肪组织提取物。
图1按步骤示出了实施例的脂肪组织提取物的获取过程。具体而言，图1的A示出了利用针头式过滤器去除自体脂肪组织中的纤维质的过程。图1的B至C示出了将去除纤维质的自体脂肪组织注入滤袋后，利用硅胶铲使自体脂肪组织穿过过滤器的情形。图1的D示出了最终获取的脂肪组织提取物。
(2)第一液及第二液的制造
将Beriplast试剂盒(Beriplast P Combi-Set，美国杰特贝林生物制品有限公司(CSL Behring L.L.C.))的纤维蛋白原(60IU)溶液和凝血酶(500IU)溶液分别用生理盐水稀释为50％。
将为50％稀释的纤维蛋白原溶液和所述脂肪组织提取物按1：4的体积比混合，制造第一液。然后，将所述稀释为50％的凝血酶溶液用作第二液。
(3)患者定制型三维模具的制造
在经蒸气灭菌消毒的、贴有10cm×10cm乳胶的玻璃板中央标记原点。然后，按照比患者患部大1mm至2mm的大小，将1张透析膜(dialysis membrane)裁剪成四边形形状后，浸于生理盐水，并贴在贴有乳胶的玻璃板中点。将玻璃板的原点对准三维生物打印机(INVIVO,ROKIT HELTHCARE)打印平台(bed)原点，进行玻璃板打印平台调平(bedleveling)。进而，为了制作与患部形状和大小相符的PCL三维模具，拍摄患部形状照片，并转换成三维建模文件。然后，将三维建模文件输入三维生物打印机(INVIVO,ROKITHELTHCARE)，将医疗级PCL(RESOMER C 209，赢创(EVONIK)，MW 45,000)1g至2g放入三维生物打印机(INVIVO,ROKITHELTHCARE)的空气分配器(air dispenser)后，以80℃至100℃的温度及600kPa至800kPa的压力条件，输出三维模具。
图2示出了实施例的患者定制型三维模具的制造过程。具体而言，图2的A示出了在贴上透析膜的贴有乳胶的玻璃板。图2的B示出了糖尿病足病患者的患部，图2的C是对患者患部进行三维建模的结果。进而，图2的D示出了最终制造的患者定制型三维模具。
(4)患者定制型皮肤再生片的制造
将根据三维生物打印机(INVIVO，ROKIT HELTHCARE)打印平台原点输出的三维模具加装于三维生物打印机(INVIVO，ROKIT HELTHCARE)。并且，
在设置为喷嘴尺寸0.5mm、打印速度10mm/s、挤出量300％、填充50％、外壁厚度0.5mm的分配器1中加装所述第一液，在设置为喷嘴尺寸0.5mm、打印速度10mm/s、挤出量500％及填充70％的分配器2中加装所述第二液，然后向所述三维模具内输出所述第一液，随即输出所述第二液并固化。进而，去除所述三维模具，获取患者定制型皮肤再生片。
(5)应用于糖尿病足病患者
清洁糖尿病足病患者患部后，利用加装于注射器的喷雾器，在患部粘合面充分喷洒凝血酶。然后，将所述制造的患者定制型皮肤再生片贴于患部，进行湿性敷料处理后，在患部周边利用海绵泡沫保护患部及周围。然后，每过一周更换患部的敷料并观察经过。
图3示出了将实施例的患者定制型皮肤再生片应用于糖尿病足病患者的过程及其结果。具体而言，图3的A示出了糖尿病足病患者的患部，图3的B示出了将制造的皮肤再生片贴于患部。进而，图3的C示出了手术后第二周的患部。根据图3可以确认，当将根据本发明的患者定制型皮肤再生片应用于糖尿病足病患者的患部时，损失的区域在短时间内恢复。具体而言，如果参考图3的C，可以确认手术后仅仅第二周的治疗期间，缺损部位100％恢复，被皮肤组织填满。
以上详细叙述了本发明内容的特定的部分，本领域普通技术人员应该明白，这种具体叙述只是优选的实施形式，而非用于限制本发明的范围。因此，本发明的实质性范围由所附权利要求项以及其等同物所定义。
Claims (11)
1.一种糖尿病足病患者定制型皮肤再生片的制造方法，包括以下步骤：
A)提取自体脂肪组织；
B)利用具有2mm至3mm孔径的第一过滤器，去除自体脂肪组织中的纤维质；
C)使去除纤维质的所述自体脂肪组织，依次穿过具有450μm至550μm孔径的第二过滤器及具有150μm至250μm孔径的第三过滤器，以粉碎自体脂肪组织；
D)提取由具有25μm至75μm孔径的第四过滤器捕集的经粉碎的所述自体脂肪组织，获取脂肪组织提取物；
E)利用三维扫描仪，获取患者的皮肤缺损区域的三维数据后，以此为基础，利用三维打印机，制造与皮肤缺损区域对应的三维模具；
F)将包含所述脂肪组织提取物和纤维蛋白原的第一液涂覆于所述三维模具内，以形成原型层；
G)将包含凝血酶的第二液涂覆于所述原型层上，以固化成皮肤再生层；以及
H)去除所述三维模具。
2.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述步骤B)至步骤G)在30分钟以内完成。
3.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述第一过滤器为不锈钢材质的针头式过滤器。
4.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
在所述步骤C)中，将去除纤维质的所述自体脂肪组织注入到过滤袋后，施加外部压力以使所述自体脂肪组织穿过过滤器，从而粉碎去除纤维质的所述自体脂肪组织。
5.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述第一液中的纤维蛋白原是将60IU纤维蛋白原稀释到40％至60％。
6.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述第二液中的凝血酶是将500IU凝血酶稀释到40％至60％。
7.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述第一液中的脂肪组织提取物与纤维蛋白原的体积比为3：1至5：1。
8.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述第一液包含选自胰岛素、***、粒细胞、淋巴细胞、内皮细胞、单核细胞、巨噬细胞、脂肪源干细胞、脂肪细胞因子、脂连蛋白、瘦蛋白、白介素6、白介素1β、单核细胞趋化蛋白1及人纤溶酶原激活物抑制因子1所组成的群组的至少一种。
9.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述制造方法还包括：将包含脂肪组织提取物、纤维蛋白原及角化细胞的附加的第一液涂覆于所述皮肤再生层上，形成附加的原型层后，将包含凝血酶的附加的第二液涂覆于所述附加的原型层上，以固化成表皮再生层。
10.根据权利要求1所述的糖尿病足病患者定制型皮肤再生片的制造方法，其特征在于，
所述糖尿病足病患者定制型皮肤再生片的厚度至少为1mm。
11.一种糖尿病足病患者定制型皮肤再生片，其特征在于，
所述糖尿病足病患者定制型皮肤再生片利用权利要求1所述的制造方法制造。
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