CN110267667A - 制备含生长因子的血小板释放物的方法 - Google Patents
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Abstract
本发明涉及从流体哺乳动物血小板浓缩物制备含有生长因子的血小板释放物的方法,该方法包括以下连续步骤:使血小板浓缩物经历病原体减少步骤以破坏无包膜病毒;使血小板浓缩物经历活化步骤以使血小板释放生长因子;回收排除了纤维蛋白原的流体血小板释放物;使排除了纤维蛋白原的流体血小板释放物经历第二病原体浓度降低步骤以破坏包膜病毒;使血小板释放物经历无菌过滤并回收含有生长因子的滤液。用本发明方法获得的血小板释放物可用作治疗剂,以增强再生医学中多谱系细胞的增殖以及控制非愈合伤口和抗性溃疡。第二个适应症是作为细胞培养基中胎牛血清的替代品。
Description
本发明涉及根据第一项权利要求的前序部分所述的从哺乳动物血小板浓缩物中制备含有生长因子的血小板释放物的方法。
哺乳动物血小板含有大量具有重要生理功能的生物活性剂。其中,生长因子特别令人感兴趣,因为它们在增强不同细胞系增殖和组织再生中起作用,这两者在再生医学、损伤和溃疡愈合中都具有重要意义。
在20世纪90年代早期已经开发出在牙科、整形外科和再生医学中使用患者自己的富含血小板血浆(PRP)的概念。通过离心患者自身抗凝全血,或使用特殊装置如美敦力公司(Medtronic)的Magellan或哈伐斯特公司(Harvest)的SmartPrep获得血小板。然而,这种自体血小板的使用可能因为患者贫血或在需要大量使用或长时间使用的情况下受到限制。自体PRP最重要的限制之一是需要专用机器或实验室来制备血小板浓缩物。为了使它们适合使用,血小板即被激活以使它们释放其α颗粒的内容物。然而,从患者分离后必需在几小时内使用PRP,否则其中包含的生长因子有可能失去其大部分的生物活性。
已经描述了几种用于保存血小板的技术。添加DMSO和海藻糖是延长血小板保存的合适方法的两个实例,对于已经进行冻干(冷冻干燥)或不进行冷冻干燥的血小板都是如此。与冻干过程一起使用的冷冻保护剂组合物导致与保存相关的类似结果。仅在完整血小板上使用防腐剂和/或冻干的这些方法的缺点涉及蛋白质、受体等保留在血小板表面上或血小板内的事实。例如,一些血小板膜受体保持完整以与细胞外因子结合,响应血小板活化,例如导致血小板粘附,聚集等。
因此,配备一种更通用的方法是有益的,该方法可以将血小板转化为适合在各种应用中有效使用的制剂,包括伤口愈合,皮肤处理,身体组织(包括身体器官,例如肺组织)疾病的治疗,等等。因此,不希望的制剂与细胞外因子的相互作用的风险可能是最小的。
WO2013113024公开了制备适于治疗用途或用作培养基的组合物的方法,其中将血小板浓缩并进行裂解以破坏血小板膜。可以裂解至少30%的血小板。冻干的血小板溶胞产物在组合物中形成,该组合物还含有释放浓度的可用生长因子、细胞因子和趋化因子。WO2013113024还公开了处理哺乳动物组织的方法,其包括给予哺乳动物组织部位进行处理的步骤,上述组合物包括冻干的血小板溶胞产物。在一个实例中,从源血小板制备冻干的血小板溶胞产物,其中裂解至少30%的源血小板以形成冻干的血小板溶胞产物。然而,溶胞产物没有排除纤维蛋白原,并且WO2013113024没有认识到病毒或病原体感染的问题,并且没有解决该问题。
EP2389942公开了一种制备含有病毒灭活的生长因子的血小板溶胞产物的方法,所述血小板溶胞产物排除了血小板衍生的生长因子(PDGF)和血管内皮生长因子(VEGF),其适用于体外或离体细胞培养和促进干细胞向成骨细胞谱系和/或软骨细胞的增殖和/或分化。该方法包括在约6.0至约9.0的pH下,在2℃至50℃的温度下,使血小板浓缩物与0.2至5体积%的溶剂和/或洗涤剂接触和孵育5分钟至6小时的时间,通过油萃取除去溶剂和/或洗涤剂以获得蛋白质水相,并将蛋白质水相与木炭一起孵育以除去溶剂/洗涤剂。预备步骤可以包括通过血浆析离术(apheresis)或通过从全血中分离血沉棕黄层制备起始血小板浓缩物,其可以是新鲜的,过期的和储存的液体或过期并冷冻储存。在优选的实施方案中,血小板溶胞产物包含生长因子TGF-β,IGF,EGF和/或bFGF。然而,EP2389942中公开的方法存在若干缺点。尽管血小板溶胞产物可适用于体外或离体细胞培养,预期其在再生医学目的(包括骨折愈合)中的临床应用不十分有效,因为所有血小板衍生因子(特别是PDGF和VEGF)的完全混合物对于再生医学中临床使用血小板溶胞产物是必需的,例如在伤口愈合中。溶剂萃取产生的血小板产率低,相对于原始体积,常常仅为10-15体积%。EP2389942不包括纤维蛋白原排除步骤,不包括冷冻干燥步骤。溶剂/洗涤剂病毒灭活仅适用于包膜病毒,但不能灭活无包膜病毒,如Hepatits A病毒和Parovirus B19,溶剂/洗涤剂处理也不能去除其他潜在污染物,如细菌或其他微生物。
US8734854公开了一种用于在非破坏性介质中从患者的全血或血浆中释放生长因子的方法。从该方法获得的生长因子适合局部施用于表面伤口区域以促进伤口愈合,用于注射到软组织例如撕裂的肌腱中以促进组织生长和愈合。在另一种方法中,生长因子从全血源释放并通过常规冻干冷冻干燥。冷冻干燥的产品可以用生理盐水重建,用于治疗患者的伤口或用于外科手术。尽管US8734854公开了最终产品可以冻干,但单独冻干证明不足以提供可靠的病原体去除。此外,从US8734854的方法获得的生长因子没有排除纤维蛋白原。
其他已知的血小板释放的生长因子包括由新生层医学技术同种异体汇集的人血小板溶胞产物(Cambium Medical Technologies Allogeneic Pooled Human PlateletLysate)开发的那些。该产品尚未作为商业产品存在,虽然据说排除了纤维蛋白原,但没有迹象表明它已经过病原体/病毒减少处理。
许多文章讨论了血小板释放的生长因子作为胎牛血清替代物的作用。综述参见血小板溶胞产物作为间充质基质细胞培养物中胎牛血清的替代物(Platelet Lysate asReplacement for Fetal Bovine Serum in Mesenchymal Stromal Cell Cultures),Transfus Med Hemother 2013;40:326-335。
EP2757879公开了一种制备血小板溶胞产物的方法,其能够作为辅助佐剂用于干细胞、成纤维细胞或树突细胞的分离和/或生长和/或扩增。该方法包括以下步骤:(a)从得自至少两个对象的全血样品混合物中分离血沉棕黄层部分;(b)将分离的血沉棕黄层部分暴露于光化学试剂和UV照射以除去存在的任何污染物;(c)使血沉棕黄层部分经历至少一个冷冻/融化循环,以实现其中所含血小板的裂解;(d)离心所述部分并收集液相。由此获得的血小板溶胞产物可以用作辅助佐剂,用于干细胞(尤其是间充质细胞),以及源自脂肪组织、成纤维细胞和树突细胞的间充质干细胞的培养、生长和/或扩增。然而,用EP2757879中公开的方法获得的血小板溶胞产物没有排除纤维蛋白原,冷冻/解冻循环是否能够引起生长因子的有效释放以及生长因子的活性是否受到反复冷冻/解冻循环的影响是值得怀疑的,而且该方法仅使用一个单一的病原体去除步骤。
可获得商业血小板溶胞产物,例如来自马可制药公司(Macopharma)的那些。不幸的是,这些溶胞产物以大的冷冻体积形式提供,需要在解冻后缩小至较小尺寸的等分试样,具有潜在的微生物污染风险。密理博公司(Millipore)的人血小板溶胞产物PLTMax以及赞比欧公司(Zenbio)提供的那些也仅以大的冷冻体积提供;它们仅用于研究目的,不用于离体治疗用途。
根据T.Burnouf等人,Biomaterials 76(2016)371-387,存储在血小板颗粒中的生长因子和细胞因子可以通过添加氯化钙盐溶液,通过纤维蛋白形成和血小板脱粒,或使用凝血酶而直接激活。用于诱导血小板释放生长因子和其他生物分子的其他技术包括重复冷冻/解冻循环,单独超声处理或与冷冻/解冻循环组合,或溶剂/洗涤剂处理,其也使脂质包膜病毒失活。然而,认为血小板经历反复冻/融循环会影响生长因子。通过强制性测试每个捐赠而不使用确认的捐赠来管理传染性传播媒介的风险。建议进行强制性测试,以检测HIV-1/HIV-2、抗体、乙型肝炎表面抗原、丙型肝炎病毒抗体。
因此,仍然需要一种制备血小板衍生生长因子的方法,该方法提供生长因子的最佳产量,并且显示出病原体存在的最小风险,包括脂质包膜以及无包膜的病毒和菌。
因此,本发明的目的是提供一种从哺乳动物血小板浓缩物制备血小板衍生生长因子的方法,该方法允许获得生长因子的最佳产量,其显示出包膜以及无包膜的病毒、细菌、真菌和其他血液携带的微生物的存在的最小风险。
在一个优选的实施方案中,本发明的一个目的是提供一种制备血小板衍生的生长因子的方法,该方法不仅对最常见的病原体具有改进的病原体灭活作用,而且对于现有技术不能或几乎不能灭活的病原体也是如此。
本发明的另一个优选实施方案旨在提供一种适用于再生医学和伤口处理的血小板释放物。进一步优选的实施方案旨在提供可用作细胞培养基中胎牛血清的替代物的血小板释放物。
通过采用显示第一项权利要求的特征部分的技术特征的方法,本发明解决了从哺乳动物血小板浓缩物制备血小板衍生生长因子的方法存在的问题,其提供生长因子的最佳产量,其中血小板衍生生长因子显示出病原体存在的最小风险,包括脂质包膜以及无包膜的病毒、细菌和上面概述的其他血源性病原体。
因此,本发明所述制备含有生长因子的血小板溶胞产物的方法包括以下连续步骤:
a.使血小板浓缩物经历第一病原体浓度降低步骤,目的是破坏血小板浓缩物中存在的微生物的DNA和RNA,其中微生物包括包膜、无包膜的病毒、或细菌、真菌等;
b.通过使血小板浓缩物与活化剂接触使血小板浓缩物经历活化步骤,使血小板释放存在于其中的至少部分α颗粒和生长因子,从而提供流体血小板释放物;
c.使流体血小板释放物进行纤维蛋白原浓度降低步骤并回收排除了纤维蛋白原的流体血小板释放物;该步骤旨在降低流体血小板释放物中纤维蛋白原的浓度;
d.使排除了纤维蛋白原的流体血小板释放物进行第二确证病原体浓度降低步骤,目的是破坏包膜病毒;
e.使血小板释放物进行无菌过滤并回收含有生长因子的滤液。
本发明所述制备含有生长因子的血小板溶胞产物的方法包括以下连续步骤:
(a)使血小板浓缩物进行第一病原体浓度降低步骤。在优选的实施方案中,第一病原体浓度降低步骤包括将血小板浓缩物与光化学活性剂一起孵育并将血小板浓缩物暴露于UV照射的步骤。该步骤允许获得具有降低的病原体含量的血小板浓缩物,这是由于血小板浓缩物中存在的微生物的RNA和/或DNA的失活或破坏。特别是血小板浓缩物导致包膜和无包膜病毒的浓度降低。该第一步也可以使血小板浓缩物中含有的其他血源性微生物失活;
(b)通过使血小板浓缩物与活化剂接触以使上述处理的血小板浓缩物经受活化步骤,使得血小板释放至少部分内容物,特别是至少部分存在于血小板中的α颗粒以及包括生长因子的这些α颗粒的内容物,提供血小板释放物。血小板释放物通常采取流体组合物的形式,其包含活化的血小板的其余部分以及在活化步骤中释放的血小板的内容物。作为该活化步骤的结果,除了纤维蛋白原之外,超生理剂量的生长因子和细胞因子将从血小板释放到包含血小板浓缩物的组合物或溶液中。这很重要,因为α颗粒通常含有大部分生长因子。哺乳动物血小板及其浓缩物的活化可以通过使它们与能够诱导血小板破裂并使至少部分内容物释放的血小板活化剂接触来实现,包括超生理剂量的生长因子,细胞因子和趋化因子。合适的活化剂包括钙盐的水溶液,例如氯化钙,凝血酶,胶原,血栓素A2和二磷酸腺苷(ADP)。凝血酶的加入导致形成巨大的凝块,其实际上含有血小板浓缩物的全部内容物。在体温约37℃的温度下孵育足够长的时间,通常3小时或更长时间,使凝块收缩至可忽略的大小,所有生长因子在包埋的血小板内表达。因此,本发明可以实现释放悬浮在血浆中的一定体积的生长因子,其几乎与血小板浓缩物的初始体积相同。
(c)使流体血小板释放物进行纤维蛋白原减少步骤并回收排除了纤维蛋白原的流体释放物。该步骤实际上包含以下步骤:分离在血小板释放的纤维蛋白原与前一步骤中加入的活化剂相互作用后形成的纤维蛋白凝块,以引起血小板内容物的释放。建议尽可能地从释放物中除去血小板活化后释放的纤维蛋白原,因为它可能导致半固体凝胶的形成,当富含血小板的血浆(PRP)进一步用于例如肌肉骨骼系统损伤的病灶内注射,包括肌腱、韧带和关节,或面部年轻化或任何其他治疗时,可能会引起麻烦。然而,血小板的纤维蛋白原浓度低于血浆的纤维蛋白原浓度。本发明的方法可以进一步包括从血小板释放物中分离纤维蛋白原并恢复以进一步使用排除了纤维蛋白原的血小板的步骤。
(d)使排除了纤维蛋白原的血小板释放物进行第二病原体浓度降低步骤以破坏或灭活包膜病毒,并回收含有生长因子的蛋白质水相。该步骤的主要目的是进一步确定去除包膜病毒,例如脂质包膜的HBC,HCV和HIV包膜病毒。在本发明中使用两个正交病原体灭活步骤(步骤a和步骤d)是特别重要的,因为它允许实现无包膜和包膜病毒的灭活,以及更大的微生物如细菌和寄生虫如原生动物的灭活。因此,本发明的方法响应了生物制药工业的血液衍生产品的现代法规的基本要求。该步骤确保与细胞外因子的不希望的相互作用的风险最小化。
(e)将排除了纤维蛋白原的血小板释放物进行无菌过滤中,目的是除去任何残留的固体物质和细菌,并回收含有生长因子的液体或流体滤液。由于血小板源自哺乳动物血液,液体或流体滤液主要是水基的或者是包含蛋白质相的水溶液。
在上述方法中,步骤优选地以所描述的顺序连续进行。
除了允许灭活血小板浓缩物中存在的无包膜病毒的第一步骤a之外,本发明的方法还包括灭活包膜病毒的步骤,所述包膜病毒通常是脂质包膜病毒,其可以包含在血小板浓缩物中或包含在血小板中。实现这一目的的优选方法是将血小板释放物经历或接触溶剂和/或洗涤剂,目的是溶解释放物中所含的脂质膜并破坏其中所含的核酸,然后进行提取步骤(优选用油)以除去含有溶解的脂质膜的溶剂和/或洗涤剂,和过滤步骤以除去任何残留的固体。由于提取和过滤步骤的存在,脂质包膜病毒以及其他病原体如细菌和寄生虫如原生动物可以被灭活,并且可以除去初始血小板浓缩物中可能含有的血浆和血小板脂质。油提取和过滤的工艺步骤允许容易、快速和有效地制备病毒和细菌灭活的含有生长因子的血小板释放物,其中溶剂和洗涤剂浓度满足监管机构批准的用于肠胃外血液衍生的治疗产品的限制。
本发明提供了一种制备含有生长因子的血小板释放物的方法,其中传播由于不可估量的因子导致的残留的血源性疾病的风险最小化,特别是在血小板产品的情况下,所述血小板产品源自已经系统地进行去除白细胞的血液制品。去除白细胞的效果是血液的自我消毒能力在很大程度上丧失,并且经常完全丧失。这很重要,因为血浆构成了各种病原体存活或生长的最佳培养基。
此外,由于选择了病原体灭活处理的组合,可以确保用本发明获得的血小板衍生生长因子的绝对安全性。因此可以提供病毒灭活的血小板衍生的生长因子的混合物,其可以被有效地标准化以用于治疗性处理、细胞疗法或细胞培养。病毒/病原体灭活的双重步骤使通过本发明的方法获得的产品安全地用于临床研究和用于体内应用的间充质干细胞扩增。结果,消除了对患者使用自体血小板的需要,以及相关的限制。另外,本发明不是强制使用自体血小板,而是开启使用从哺乳动物血液制品池中获得的血小板释放物的可能性,所述血液制品源自多个对象,其传播血源性疾病的风险最小,所述疾病可能源自产生血小板浓缩物的一个或多个对象。
本发明的方法不仅适用于制备人血小板衍生的生长因子,而且还可以用最少的调整来从动物血小板产生马衍生的生长因子,例如来自具有类似医学应用的马血小板。重构的冻干血小板衍生的生长因子可以进一步用作细胞培养基和间充质干细胞扩增中的胎牛血清的替代物。
考虑到这样的事实,部分由于细菌污染的风险和止血功能活性的丧失,血小板通常具有有限的保质期5或7天,当临床静脉内使用用于校正大量或功能性血小板减少症时,每年通常丢弃超过5天或7天的大量血小板单位。在允许过期的血小板原料用于制备血小板衍生产品如本发明的血小板释放物时,本发明的方法显示出有希望的经济利益。
通过以上述顺序进行处理步骤,本发明还允许最大化所获得的释放物体积的量。诸如MirasolTM系统的现代技术允许通过血小板采集收集的大量血小板浓缩物经受病原体灭活,以最小的风险降低收集的血小板体积。通过仅在进行第一次病毒灭活后进行油提取步骤,可以将由病原体去除处理引起的释放物的损失或减少降低到最小。
由于可以避免使用冷冻/解冻循环,本发明提供了额外的优点,即由此获得的生长因子的主要蛋白质的内容物(例如白蛋白和免疫球蛋白)以及释放物中除了血小板衍生生长因子(PDGF)和血管内皮生长因子(VEGF)如TGF-β1、EGF和IGF之外的生长因子的浓度受到不利影响的风险最小。
在一个优选的实施方案中,可以在小体积小瓶中冻干含有通过本发明方法获得的含有生长因子的血小板释放物,所述小瓶可以根据实际需要通过添加水或盐水溶液在单个步骤中容易地重建。因此,优选选择体积使得其含有足以进行一次治疗的生长因子的量。根据初始血小板计数调整每个小瓶中分配的释放的生长因子的体积(即如上所述经历连续步骤(a)至(e)的血小板的量),可以标准化每个小瓶中生长因子的批内和批间浓度。在一个优选的实施方案中,将上述步骤(e)中获得的液体滤液分成单独的体积,其中每个单独的体积经调节使得其源自2x 105至2x 107血小板/cm3,优选约2x 106血小板/cm3。如果需要,根据预期的用途,血小板释放物可以富集某组生长因子。通过标准化每个小瓶中生长因子的数量,可以避免从较大的储存体积中制备较小的等分试样的需要,这种操作会导致潜在的污染风险和活性丧失,因为原料必需经历重复的解冻和冷冻循环以提取所需的小等分试样。
在上文中,术语“血小板浓缩物”是指任何含有血小板的生物或人工流体。此类流体的非限制性实例包括:衍生自哺乳动物来源(其可以是人或动物)的各种形式的全血,血浆,富血小板血浆,任何培养基中的浓缩血小板等。该流体通常是水基的。因此,该流体可以是自体的,或者它可以是源自几个不同对象的同种异体流体池,例如来自单采血小板或血沉棕黄层的血小板浓缩物,其具有一定的最小血小板含量,通常在血库中制备。通常,制造将标准化为同种异体的现成产品。血小板浓缩物通常使用血沉棕黄层法(该方法采用全血),PRP法或单采血小板制备,其源自储存的个体捐献的血液部分。后者的使用是优选的,特别是当另外进行存储前的白细胞消耗时。此外,由于它们已达到五至七天的储存极限而不能输注的血小板浓缩物可以冷冻,储存并用作生长培养基补充剂。
血小板浓缩物可以保持在血浆中或血浆和添加剂溶液的混合物中。为了延长保质期,血小板浓缩物可以由大量冷冻血小板浓缩物组成。
术语“浓缩物”或“浓缩”可以指血小板与大部分血浆、全血或存在的其他流体的分离,但它也可以指原始产品,例如全血或血浆。离心,光谱测定,过滤,倾析,重力沉降或从含血小板的流体浓缩血小板的其他方法可用于生产浓缩物。当浓缩血小板时,可能需要使用抗凝血剂(特别是用于离心或重力沉降)针对血小板源,以防止血小板与血液、血浆或其他流体的其他组分分离期间的凝结。术语“抗凝血剂”是指当浓缩或收集血小板以根据本公开的实施例使用时抑制凝结的组合物。抗凝血剂通常可用作凝血因子合成的抑制剂,凝血酶抑制剂或抗血小板药物。肝脏中抑制某些凝血因子产生的凝血因子合成抑制剂包括诸如华法林(Coumadin)的组合物。凝血酶的抑制剂通过阻断凝血酶的活性来干扰血液凝固,并且包括诸如肝素和来匹卢定(Refludan)的组合物。抗血小板药物本身与血小板相互作用,包括阿司匹林,噻氯匹定(Ticlid),氯吡格雷(Plavix),替罗非班(Aggrastat),依替巴肽(Integrilin)等药物。
在上文中,术语“血小板释放物”是指当血小板浓缩物经历活化步骤并且回收血小板释放的内容物时获得的组合物,如上所述,特别是如上所述的步骤b。
在上文中,“使血小板浓缩物经历活化步骤或活化处理”是指通过破坏它们的细胞膜来破坏血小板,以使血小板释放它们的颗粒内容物,特别是血小板中含有的α颗粒。活化的血小板可以释放其中包含的多种化合物,a.o.蛋白质,细胞微囊泡,例如质膜衍生的微粒,外来体,生长因子如VEGF,bFGF,PDGF,TGF-β和其他细胞因子。这可以通过化学,机械,流体均质化或超声处理或通过细胞溶解进行。但是根据本发明,优选通过使血小板浓缩物与活化剂接触来进行活化,因为这允许最大化血小板内容物释放到流体血小板释放中。合适的细胞溶解剂包括血栓形成蛋白,胶原蛋白,血栓素A2或ADP和钙盐溶液或其两种或多种的混合物。合适的钙盐的实例是氯化钙。然而,也可以使用技术人员认为合适的任何其他细胞溶解剂。
机械性细胞溶解可以例如使用冻融循环,通过冷冻血小板悬浮液然后将材料解冻至高于室温,例如30℃至45℃来进行。该方法使细胞在冰晶形成时溶胀和破裂,然后在解冻时收缩。周期性溶胀和收缩最终导致血小板破裂。根据冻融循环的次数,可通过血小板计数实现不同程度的血小板细胞溶解,例如,至少30%,至少50%,至少70%,至少90%或至多100%的细胞溶质。在本发明中,可以考虑机械性细胞溶解,但是因为疑似释放物的损失优选不采用机械性细胞溶解。
在本发明的范围内,“冻干的血小板释放物”包括“冻干的富含血小板的血浆释放物”或“LPRRL”作为特定类型的冻干血小板释放物,但不限于此。
在本发明的范围内,“抗凝血剂”是在浓缩或收集根据本发明使用的血小板时抑制凝结的组合物。抗凝血剂通常可以作为钙离子络合/螯合剂,凝血因子合成的抑制剂,凝血酶抑制剂或抗血小板药物获得。肝脏中抑制某些凝血因子产生的凝血因子合成抑制剂包括诸如华法林(Coumadin)的组合物。凝血酶的抑制剂包括诸如肝素和来匹卢定(Refludan)的组合物。抗血小板药物本身与血小板相互作用,包括阿司匹林,噻氯匹定(Ticlid),氯吡格雷(Plavix),替罗非班(Aggrastat),依替巴肽(Integrilin)等药物。
在本发明方法的步骤a中进行的UV照射优选包括将血小板释放剂暴露于UVA照射,优选暴露于能量密度为1至10 J/cm2,更优选约3 J/cm2的UVA照射。暴露于UV照射优选在血小板释放物与光化学试剂,特别是补骨脂素,特别是阿莫脂素(amotosalen)或核黄素孵育后进行。
在本发明方法的步骤d中,其中血小板释放物与溶剂和/或洗涤剂接触以溶解包膜病毒或其它病原体的膜,优选使用选自下组的溶剂孵育血小板浓缩物:磷酸二烷基酯或三烷基酯,优选磷酸三正丁基酯。适用于本发明方法步骤d的洗涤剂包括选自以下的洗涤剂:脂肪酸的聚氧乙烯衍生物,山梨糖醇酐的偏酯,非离子洗涤剂,脱氧胆酸钠和磺基甜菜碱的,优选Triton X-45,Triton X-100或吐温80。
在随后的用于除去溶剂和/或洗涤剂以及溶解在其中的组分的提取步骤中使用的油的量可以在很宽的范围内变化,但优选油的量在2至20重量%,优选5至15重量%,更优选5-10重量%,基于血小板浓缩物和溶剂和/或洗涤剂的混合物的总体积。因此,优选使用药用级油,例如蓖麻油。在提取过程中,通常将一定体积的油加入到血小板释放物中,并在血液混合器上振荡一段时间,通常为30、20或15分钟或更短时间。此后,进行提取的容器可以在倒置位置悬挂一段时间,例如10分钟或更短或更长时间,以获得上层油相和由于重力与上层的相分开的下层血小板释放物相。取决于提取效率,该步骤可以重复一次或两次或更多次。
本发明的方法可以包括在提取步骤e之后的至少一个离心步骤以将血小板与油和蛋白质水相分离。通常将血小板释放物在低温下进行离心,通常低于10℃,优选低于5℃,通常为约4℃,优选为倒置位置,以通过重力实现上层相中的任何油的残余物与下层相中的血小板释放物的分离。
本发明的方法可以包括在过滤步骤e之后的冷冻干燥步骤,以延长血小板释放的保质期。在进行冷冻干燥之前,将步骤e中获得的液体或流体滤液分成几个体积,调节所述体积使得每立方厘米的体积含有预定量的血小板的释放物,例如约2x 105至2x 107血小板的释放物/cm3,更优选约2×106血小板的释放物/cm3,但技术人员可以选择任何其他浓度的血小板。用本发明方法获得的产品结合了以合理体积的冻干(适合于立即使用而不需要进一步分成合适的样品)以及易于储存和重构并且排除了纤维蛋白原的特性。
在一个优选的实施方案中,为了实现生长因子的低温保护,在冷冻干燥之前,将人白蛋白提供给步骤e中获得的液体滤液。
在本发明的范围内,“冻干”是指通常用于保存血小板的冷冻干燥或脱水过程。然而,冻干也可以不仅用作防腐过程,而且还用作裂解血小板的处理,以在进行初始冻融或其他细胞溶解技术后进一步裂解血小板。换句话说,根据本公开的实施例,在如本文所述形成释放物后,冻干提供了保存生长因子、细胞因子、趋化因子和最初包封在血小板表面内或结合于血小板表面但是当血小板如本文所述裂解(例如冻融裂解)时释放的其他内容物的附加益处。该方法通常通过冷冻材料并降低周围压力以使材料中的冷冻水直接从固相升华至气相来进行。
如果需要,可以在使血小板经受活化步骤以使其内容物释放之前,对血小板浓缩物进行白细胞去除步骤。去除白细胞主要是为了降低与红细胞和血小板单位中存在的输血白细胞相关的不希望的并发症发生的风险。
本发明的方法用于从哺乳动物血小板浓缩物制备富含纤维蛋白原的血小板释放物,所述血小板浓缩物可以是人或动物血小板,例如马血小板。释放物可以是冻干的或不是冻干的。
用本发明的方法获得的血小板释放物可用于治疗伤口,溃疡或烧伤。血小板释放物可以在施用前以干燥形式或再水合形式施用,或作为凝胶施用。或者,即使皮肤没有伤口、溃疡或烧伤损坏,它也可用于修复由于衰老,光损伤,病理或退行性疾病等而发生的其他类型的损伤。用本发明方法得到的血小板释放物中血小板的浓度可以在很宽的范围内变化,但优选浓度尽可能高以达到最大效果。
在上文中,术语“伤口”是指对对象的任何组织的任何损伤,包括对皮肤的损伤以及对较深组织的损伤。因此,伤口可能是偶然或有意引起的,或者可能是由病理、疾病或退行性病症的正常过程引起的。例如,损伤可能是受伤或手术造成的。损伤的非限制性实例包括:溃疡,烧伤,骨折,穿刺,割伤和擦伤,撕裂伤,手术切口,炎症,感染等。
血小板释放物可以使用本领域技术人员已知的给药方法给予,包括使用流体,气溶胶,喷雾剂,雾剂,洗剂,乳膏,软膏,凝胶,树胶,雾化液滴或粉末,分配瓶,预浸织物,注射器,绷带,皮肤贴片或膏药等。在一个优选的实施方案中,用本发明方法获得的血小板释放物可以稳定的形式储存在试剂盒中,用于治疗伤口的紧急情况。可以重建血小板释放物以在需要时立即使用。另一方面,本发明涉及含有用本发明方法得到的包含生长因子的血小板释放物的气溶胶,治疗流体,喷雾剂,雾剂,洗剂,乳膏,软膏,凝胶,树胶,绷带,皮肤贴剂,膏药。
用本发明的方法获得的血小板释放物可以含有增加量的生长因子,细胞因子,趋化因子等。可以存在于释放物中的生长因子和其他物质的实例包括但不限于:PDGF、PDAF、VEGF、PDEGF、PF-4、TGF-B、FGF-A、FGF-B、TGF-A、IGF-1、IGF-2、BTG、TSP、vWF、PAI-1、IgG、IgM、IgA、KGF、EGF、FGF、TNF、IL-1、KGF-2、纤维肽A、纤维蛋白原、白蛋白、骨粘连蛋白、gro-α、玻连蛋白、纤维蛋白D-二聚体、因子V(favtor V)、抗凝血酶III、a2巨球蛋白、血管生成素、Fg-D和弹性蛋白酶。更详细地,可以存在的生长因子、细胞因子等包括但不限于:LIF、抗癌生长因子如IGFBP3、类二十烷酸如PG或白三烯、IL-1 TNFα、INFs、TNF-a、IL-6、IL-1(a/b)、前列腺素代谢物、补体成分、活性氧中间体、花生四烯酸代谢物、凝血因子、硝酸盐和趋化因子。人源性生长因子、趋化因子、细胞因子和激素可包括:α防御素、α突触核蛋白、β突触核蛋白、4-1 BBL、6Ckine、酸性FGF、激活素A(activin A)、激活素R1b(avtivin R1b)、血管生成素2、B-DNF、BAFF、BCA-1、BCA-1、BD-1、BMP-2、BMP-4、BMP-7、BMPRA1、BDNF、CNTF、CTGF、CTI_A-4Fc、CXCL1、CXCL2、心肌营养素-1、Cripto、胱抑素C、Dkk-1、EGF AOF、EGF、EMAP II、ENA-78、EPO、嗜伊红粒细胞趋化蛋白(Eotaxin)、FGF碱性AOF(FGF basic AOF)、FGF-10、FGF-16、FGF17、FGF18、FGF19、FGF4、FGF6、FGF7、FGF8、FGF8b、FGF9、Flt3、G-CSF、GDNF、GMCSF、HGF、HGH、IFNαA、IFNαA/D、IFNαD、IFNαa2b、IFN、β1A、IFN-γ、IGF1、IGFil、IGFBP-4、IGFBP6、ILIα、IL-1β、IL10、IL11、IL12、IL13、IL15、IL17、IL17A、IL17F、IL18、IL19、IL2、IL20、IL21、IL23、IL28A、IL28B、IL29、IL3、IL31、IL33、IL4、IL5、IL6、IL7、IL8、IL9、IL10、ITAC、KGF2、激肽释放酶11、激肽释放酶4、激肽释放酶7、LEFTY-A、LIF、瘦体素(Leptin)、MCSF AOF、MCSF、MCP-1、MCP2、MCP3、MCP4、MDC、MIG、MIP1α、MIP1β、MIP3α、MIP3β、MIP4、MIP5、中期因子(midkine)、NAP2、NT3、NT4、神经趋化因子(Neurotactin)、神经生长因子(neurturin)、制瘤素(Oncostatin)、骨保护素(osteoprotegrerin)、PDGF-AA、PDGF-AB、PDGF-BB、PTN、Rank配体、Rank受体、RANTES<SCF、SCFAOF、SDF-1α、SDF-1β、CD4、CD40L、TNF-RI、TNFRII、TARC、TECK、TGFα、TGF1βl、TGFβ2、TGFβ3、TNFβ/淋巴毒素、TNF-α、TPO、TRAIL、TWEAK和VEGF。
用本发明的方法获得的血小板释放物具有两个主要适应症,在这两个适应症中证明其具有重要价值,尽管它也可用于其它适应症。第一个适应症是用作治疗剂以增强再生医学中多谱系细胞的增殖以及控制非愈合伤口和抗性溃疡。在这些应用中,含有生长因子的血小板释放物由人或马血小板制备。用本发明方法获得的血小板释放物也可用于细胞培养基,特别是干细胞、成纤维细胞或树突细胞。第二个适应症是细胞培养基中胎牛血清的替代品。排除了纤维蛋白原的血小板释放物避免了凝胶形成的不良影响,并且使释放剂经受病原体/病毒减少的两个步骤确保了产品安全性。结果,自体血小板浓缩物不再是必须的,并且用于本发明方法的哺乳动物血小板浓缩物可包含源自不同哺乳动物对象的血小板库。
在下面的实施例中进一步说明了本发明。
实施例1
将人类与采集机(Haemonetics MCS+9000a)连接以获得富含血小板的浓缩物,其中血小板计数为初始血小板计数的3-5倍。富含血小板的浓缩物与核黄素一起孵育,并通过MIRASOLTM系统用紫外线照射,作为病原体减少的第一步。此后,以500单位/cmm的合适浓度加入无菌的凝血酶b,以活化所述浓缩物中的血小板。这导致随后从血小板颗粒中释放超生理剂量的生长因子和细胞因子。此外,活化的血小板释放出纤维蛋白原的α颗粒内容物,其被凝血酶活化形成不溶性凝块。当离心时,凝血酶处理的血小板浓缩物分离成上清液和不溶性纤维蛋白凝块的沉积物,所述上清液包含基本上由裂解的血小板组成的澄清的浅红色液体或流体,其内容物是从血小板颗粒释放的超生理剂量的生长因子。将上清液转移到新容器中以进行进一步的制备步骤。用溶剂和洗涤剂体系(0.3%TNBPc和1%Tween 20d)处理血小板释放物,在31℃下处理1小时。该步骤能够破坏包膜病毒(主要是HBC,HCV和HIV)。通过三个连续的植物油提取步骤除去溶剂和洗涤剂。将无菌蓖麻油(总体积的7.5%)加入到血小板释放物中,并将混合物在血液混合器上振荡15分钟,然后将容器以倒置位置悬置10分钟以获得上层油相和由于重力作用与上层的相分开的下层血小板相。将该步骤重复另外两次,然后将血小板释放物以倒置位置在4℃和1500g下离心20分钟,以通过重力实现上层相中的任何油的残余物与下层相中的血小板释放物的分离。
然后,对血小板释放物进行无菌过滤步骤以确保去除任何细菌污染物,然后在玻璃小瓶中以预定体积分配液体或流体滤液(根据浓缩物的初始血小板计数进行调整以确保相当于约100万血小板/平方厘米)并冻干这种主要由血小板衍生的生长因子组成的滤液。
实施例2
实施例1中获得的血小板释放物用于实现面部年轻化。将来自2x106血小板的一个小瓶注射到下巴,脸颊和鼻唇沟中的女性面部的每一侧。红肿、疼痛和肿胀可以显著减少。再生效果持续至少6个月。
对比实验
将含有2x106自体血小板的体积注射到患有与实施例2中相同的缺陷的女性面部的每一侧。红肿、疼痛和肿胀可仅在有限程度上减少。
实施例3
实施例1中获得的血小板释放物用于在腰痛控制中实现疼痛缓解。将两瓶源自2x106血小板的小瓶注射到腰部。疼痛可以大大减轻。一周后,通过注射一个小瓶重复治疗。再生效果持续数月。
实施例4
将实施例1中获得的血小板释放物掺入胶原海藻酸钠水凝胶伤口敷料中,并施用于超过6个月不能愈合的糖尿病溃疡。在几天内,可以实现显著的伤口愈合。
实施例5
根据实施例1的方法制备血小板释放物,这次使用马血。将两个小瓶分别注射到马的受伤肌肉中,每个小瓶源自2x106血小板。一周后重复治疗。肌肉愈合,没有留下创伤。
Claims (21)
1.一种从流体哺乳动物血小板浓缩物制备含有生长因子的血小板释放物的方法,其包括以下连续步骤:
a.使血小板浓缩物经历第一病原体浓度降低步骤,目的是破坏血小板浓缩物中存在的微生物的DNA和RNA;
b.通过使所述血小板浓缩物与活化剂接触使血小板浓缩物经历活化步骤,目的是使血小板释放至少部分α颗粒和存在于其中的生长因子,从而提供流体血小板释放物;
c.使所述流体血小板释放物经历纤维蛋白原浓度降低步骤并回收排除了纤维蛋白原的流体血小板释放物;
d.使所述排除了纤维蛋白原的流体血小板释放物经历第二病原体浓度降低步骤,目的是破坏包膜病毒;
e.使所述血小板释放物经历无菌过滤并从过滤步骤回收含有生长因子的滤液。
2.如权利要求1所述的方法,其中,对步骤e获得的包含生长因子的滤液进行冷冻干燥。
3.如权利要求1或2所述的方法,其中,所述活化剂是含有一种或多种选自钙盐,凝血酶,胶原,血栓素A2和二磷酸腺苷(ADP)的化合物的溶液,优选含有凝血酶的溶液。
4.根据前述权利要求中任一项所述的方法,其中,所述第一病原体浓度降低步骤包括将所述血小板浓缩物与光化学活性剂一起孵育并将所述血小板浓缩物暴露于UV照射。
5.如权利要求4所述的方法,其中,所述UV照射是UVA照射,优选能量密度为1至10J/cm2的UVA照射,更优选能量密度为3J/cm2的UVA照射。
6.如权利要求4或5所述的方法,其中,所述光化学活化剂是补骨脂素,特别是阿莫脂素或核黄素。
7.如前述权利要求中任一项所述的方法,其中,所述第二病原体浓度降低步骤包括将所述血小板释放物与溶剂和/或洗涤剂一起孵育,然后除去溶剂和/或洗涤剂并回收排除了溶剂和/或洗涤剂的血小板释放物。
8.如权利要求7所述的方法,其中,用于与血小板浓缩物一起孵育的溶剂选自磷酸二烷基酯或磷酸三烷基酯,优选磷酸三正丁酯。
9.如权利要求7或8所述的方法,其中,所述洗涤剂选自以下一种或多种:脂肪酸的聚氧乙烯衍生物,山梨糖醇酐的偏酯,非离子洗涤剂,脱氧胆酸钠和磺基甜菜碱,优选Triton X-45,Triton X-100或吐温80。
10.如权利要求7-9中任一项所述的方法,其中,通过油提取方式从血小板释放物除去所述溶剂和/或洗涤剂。
11.如权利要求10所述的方法,其中,所述油提取在一定量的油存在下进行,所述油的量为2至20重量%,优选5至15重量%,更优选5至10重量%,以血小板浓缩物和溶剂和/或洗涤剂的混合物的总重量计。
12.如前述权利要求中任一项所述的方法,还包括在第二病原体浓度降低步骤中除去溶剂和/或去污剂后离心血小板释放物的至少一个步骤。
13.如权利要求2-12中任一项所述的方法,其中,在冷冻干燥之前,将所述滤液分成单独的部分,调整所述单独的部分的体积,使得每个部分包含大致相同数量的血小板释放物。
14.如权利要求13所述的方法,其中,将滤液分成单独的部分,每个部分含有约2 x 105–2 x 107个血小板/cm3释放物,优选约2×106个血小板/cm3。
15.如权利要求2-14中任一项所述的方法,其中,在将步骤e中获得的滤液进行冷冻干燥之前,将人白蛋白提供给所述滤液。
16.如前述权利要求中任一项所述的方法,其中,在使血小板浓缩物经历活化步骤b之前,将血小板浓缩物进行白细胞灭活步骤。
17.如前述权利要求中任一项所述的方法,其中,所述哺乳动物血小板浓缩物富含来自人血小板或马血小板的生长因子。
18.如前述权利要求中任一项所述的方法,其中,所述哺乳动物血小板浓缩物包含源自不同对象的血小板浓缩物库。
19.一种通过权利要求1-18中任一项所述方法获得的含有生长因子的血小板释放物,用于再生医学,特别是用于选自增强多谱系细胞增殖和促进伤口愈合和溃疡愈合的一种或多种应用。
20.一种通过权利要求1-18中任一项所述方法获得的含有生长因子的血小板释放物,用于选自干细胞、成纤维细胞或树突细胞的一种或多种细胞培养基中。
21.一种制剂,其包含通过权利要求1-18中任一项所述方法获得的含有生长因子的血小板释放物,所述制剂选自:气溶胶、处理液、喷雾剂、雾剂、洗剂、乳膏、软膏、凝胶、树胶、绷带、皮肤贴片、膏药中的一种或多种。
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