CN104822342A - 用于治疗生物组织的方法和系统 - Google Patents
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Classifications
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
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Abstract
组织假体,所述组织假体包括具有至少一个表面的支撑结构,所述支撑结构包括基体材料,所述支撑结构还包括细胞外基质(ECM)组合物,所述细胞外基质(ECM)组合物具有来自哺乳动物组织来源的至少一种ECM材料。所述组织假体当邻近于受损的生物组织配置时,所述组织假体诱导调节愈合。
Description
技术领域
本发明涉及用于治疗生物组织的可植入生物假体。更具体地,本发明涉及非抗原性的、弹性的、生物相容性的组织假体或移植物,所述组织假体或移植物可被设计成各种形状并用于治疗、增强或替换受损或病变的生物组织。
背景技术
如本领域众所周知的,组织假体或移植物通常用于治疗或替换受损或病变的生物组织。然而,尽管医疗技术的日益成熟,利用移植物来治疗或替换受损的生物组织在医疗保健方面仍然是频繁和严重的问题。所述问题通常与用于构建移植物的材料相关联。
也正如本领域众所周知的,最佳的移植物材料应当是化学惰性的、不致癌、能够抵抗机械应力、能够被制成所需的形式,并且是灭菌的。此外,所述材料应该能够抵抗由组织液导致的物理改性,而不是激发炎症反应,诱发过敏或超敏的状态,或者在某些情况下,导致内脏粘连。参见例如,Jenkins等人,Surgery,vol.94(2),第392-398页(1983)。
从而各种材料和/或结构已被用来构建满足上述最佳特性的移植物,所述材料和/或结构包括钽纱布、不锈钢网、尼龙、编织的聚丙烯(例如,)、微孔膨胀的聚四氟乙烯(例如,)、Dacron增强的硅橡胶(例如,)、聚糖乳酸910(polyglactin910)(例如,)、聚酯(例如,)、聚乙醇酸(例如,)、经加工的羊真皮胶原蛋白、交联的牛心包(例如,)、以及所保存的人类硬脑膜(如)。
如下面所详细论述的那样,虽然一些被注意到的移植物材料满足一些上述最佳的特性,但是很少(如果有的话)能够满足所有的最佳特性。
金属网(例如不锈钢网)的主要优势是它们是惰性的、抗感染并能够刺激纤维组织形成。几个主要的劣势是破裂,破裂会出现,而且在很多情况下将在施用第一年之后出现,而且缺乏柔韧性。
合成网具有易于模塑的优势,并且除了尼龙之外在身体内或在身体上保持其拉伸强度。在号为91122196.8的欧洲专利中,公开了三层人工血管,其利用不可再吸收性合成网作为中心层。合成的纺织网层被用作中心框架,将胶原纤维层添加到所述中心框架上,产生三层的假体装置。
存在与不可再吸收性合成网相关联的几个缺点和劣势。主要的劣势是缺乏惰性,易于感染,并干扰伤口愈合。
相比于不可再吸收性的合成网,在配置部位可吸收性的合成网具有暂时的优势,但通常具有在足够的细胞和组织向内生长之前损失机械强度(作为被宿主溶解的结果)的劣势。
在疝气修复期间最广泛使用的用于腹壁替换和用于加固的移植物材料是即聚丙烯。与聚丙烯网移植物相关联的主要劣势是随着瘢痕挛缩,聚丙烯网移植物变得扭曲并从周围的正常组织分离。
即聚四氟乙烯,目前被认为是最为化学惰性的移植物材料。然而,与使用聚四氟乙烯相关联的一个主要问题是在受污染的伤口中其不允许任何大分子引流,这限制了感染的治疗。
胶原蛋白是另一种常用的移植物材料。胶原蛋白因为它是一种天然的可从各种动物来源充足供应的生物移植替代物而首先获得作为医用材料的实用性。
对于原始胶原蛋白移植物的设计目标与合成聚合物移植物的相同,即移植物应当持续并且从本质上用作惰性材料。考虑到这些目标,开发出了纯化和交联的方法,以便提高胶原蛋白的机械强度和降低其的降解速率。
最初使用的交联剂包括戊二醛、甲醛、聚环氧化物、二异氰酸酯和酰基叠氮化物。戊二醛也被用作灭菌剂。
然而交联的胶原蛋白的主要劣势是通过连接抗原性表位,使得它们无法实施吞噬作用或不能被免疫系统识别而降低了材料的抗原性。
因此,通常来说,交联的胶原蛋白将产生胶原材料,其在机械和生物方面都比天然的生物组织更类似于合成材料。
来源于哺乳动物组织即细胞外基质(ECM)的组织假体或移植物材料也经常用于构建组织假体或移植物。示例性的是在号为3562820和4902508的美国专利中所公开的移植物,在号为3562820的美国专利中公开了为管状、片材和带材的移植物,其通过使用诸如胶原蛋白纤维糊料的粘合剂糊料或通过使用酸性或碱性介质粘附到一起而由粘膜下层形成;而在号为4902508的美国专利中公开了为三层的组织移植物组合物,其衍生自小肠,包括粘膜下层、粘膜肌层和粘膜鞘膜(tunica submucosa)的致密层)。
虽然一些基于ECM的组织假体或移植物满足许多的上述最佳特性,但是仍继续努力来开发出改进的假体和/或移植物,所述改进的假体和/或移植物可成功地被采用来替换生物组织(诸如腹壁缺损和血管)或促进生物组织的修复,从而使宿主自身细胞在修复过程中可被最佳地利用。
因此,本发明的目的在于提供组织假体,其诱导调节愈合;具体地,诱导新血管形成、宿主组织增生、生物重塑、以及组织和具有位点特定的结构特性和功能特性的相关结构的再生。
发明内容
本发明涉及非抗原性的、弹性的、可生物重塑的、生物相容性的组织假体,其可设计成各种形状并用于修复、增强或替换哺乳动物的组织和器官。
在优选的实施方案中,所述组织假体包括支撑结构和细胞外基质(ECM)组合物。根据本发明,支撑结构可以包括各种常规的金属、以及合成的和天然的材料,其包括但不限于钽纱布、不锈钢网、 尼龙、编织的聚丙烯(例如,)、微孔膨胀的聚四氟乙烯(例如,)、增强的硅橡胶(例如,)、聚糖乳酸910(例如,)、聚酯(例如,)、聚乙醇酸(例如,)、经加工的羊真皮胶原蛋白、交联的牛心包(例如,)、以及所保存的人类硬脑膜(如)。
在本发明的一些实施方案中,支撑结构涂覆有ECM组合物。在一些实施方案中,所述支撑结构浸渍有ECM组合物。
在本发明的优选实施方案中,所述ECM组合物包括至少一种ECM材料。根据本发明,所述ECM材料可来源于各种哺乳动物组织来源和用于制备其的方法,所述哺乳动物组织来源包括小肠、大肠、胃、肺、肝、肾、胰、胎盘、心脏、膀胱、前列腺、间皮、生长牙釉质周围的组织、生长骨骼周围的组织、以及来自任何哺乳动物器官的任何胎儿组织。
在一些实施方案中,所述ECM组合物进一步包括一种或多种另外的生物活性成分,以促进受损组织的治疗和/或组织再生的过程。
在一些实施方案中,所述ECM组合物从而包括至少一种药理学试剂或组合物,其可以包括但不限于,抗生素或抗真菌剂、抗病毒剂、抗疼痛剂、麻醉剂、止痛剂、甾体抗炎药、非甾体抗炎药、抗肿瘤药物、抗痉挛药、细胞-细胞外基质相互作用的调节剂、蛋白质、激素、酶和酶抑制剂、抗凝血剂和/或抗血栓形成剂、DNA、RNA、修饰的DNA和RNA、NSAID、(DNA、RNA或蛋白质合成的抑制剂)、多肽、寡核苷酸、多核苷酸、核蛋白、调节细胞迁移的化合物、调节增殖和组织生长的化合物、以及血管扩张剂。
在本发明的一些实施方案中,所述药理学试剂具体包括抗炎剂或组合物。
在本发明的一些实施方案中,所述生物活性成分包括他汀类药物。根据本发明,合适的他汀类药物包括但不限于阿托伐他汀、西伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀、和辛伐他汀。
在本发明的一些实施方案中,所述生物活性成分包括几丁质、壳聚糖或其衍生物。
在本发明的一些实施方案中,所述生物活性成分包括细胞。
在本发明的一些实施方案中,所述生物活性成分包括蛋白质。
根据本发明,在配置本发明的组织假体时,完成具有位点特定的结构特性和功能特性的组织结构的调节愈合和再生。
附图说明
从以下及对本发明的如附图所示的优选实施方案的更具体的描述中,进一步的特征和优势将变得明显,并且其中在贯穿整个视图中类似的附图标记通常指代相同的部分或要素,并且其中:
根据本发明,图1是组织假体的一个实施方案的透视图;以及
根据本发明,图2是图1中所示的组织假体的侧视局部剖面图。
具体实施方式
在详细描述本发明之前,应当理解的是,本发明并不局限于特定的示例性的装置、系统、组合物或方法,因为上述当然可以变化。因此,尽管在本发明的实践中可以使用与本文所述那些类似或等同的许多系统、组合物和方法,但是本文描述了优选的系统、组合物和方法。
还应当理解的是,本文所用的术语仅仅是为了描述本发明具体实施方案的目的,而并非意旨是限制性的。
除非另有定义,本文使用的所有技术和科学术语都具有本发明所属领域的普通技术人员通常理解的相同含义。
此外,本文(无论是在上文还是在下文)引用的所有出版物、专利和专利申请都以其整体通过引用并入本文。
最后,如在该说明书和所附权利要求中所使用的那样,单数形式“一(a或an)”以及“该(the)”包括复数指代物,除非内容另有明确说明。如此,例如,对“抗炎剂”的参照包括两种或更多种这样的试剂和类似物。
定义
术语“组织假体”和“移植物”在本文中可互换使用,并且意味着并包括配置成放置于生物组织上或其上方,或放置于血管结构内的假体装置,例如支架,以便治疗或替换受损或病变的生物组织。
术语“受损组织”和“病变组织”在本文中可互换使用,并且意味着并包括由疾病、病症、损伤或损害所导致的异常生物组织的任何区域,包括对心外膜、心内膜和/或心肌的损害。心血管组织损伤原因的非限制性实例包括急性或慢性应激(系统性高血压、肺动脉高血压、瓣膜功能障碍等)、冠状动脉疾病、局部缺血或梗塞形成,炎症性疾病和心肌病。
术语“防止(prevent)”和“预防”(preventing)”在本文中可互换使用,并且意味着并包括减少疾病、病况或病症的频率或严重程度。该术语不要求绝对排除疾病、病况或病症。相反,该术语包括降低疾病发生的可能性。
术语“治疗(treat)”和“治疗(treatment)”在本文中可互换使用,并且意味着并包括对患者的医疗管理,其意旨治愈、改善、稳定、或预防疾病、病理状态或病症。该术语包括“积极治疗”,即治疗具体涉及改善疾病、病理状态或病症,而“病因治疗”,即治疗涉及去除相关疾病、病理状态或病症的病因。
术语“治疗(treat)”和“治疗(treatment)”进一步包括:“姑息治疗”,即治疗设计成缓解症状,而不是治愈疾病、病理状况或病症;“预防性治疗”,即治疗涉及减少、或部分地或完全地抑制相关疾病、病理状态或病症的发展;和“支持治疗”,即用于补足涉及改善相关疾病、病理状态或病症的另一具体疗法的治疗。
如本文所使用的术语“血管生成”意味着一项生理过程,其涉及新血管从先前存在血管的生长。
如本文所使用的术语“新血管生成”意味着并包括可由血液或血液成分所灌注的功能性血管网的生成。新血管生成包括血管生成、萌芽血管生成、套叠式血管生成、出芽式血管生成、治疗性血管生成和自发性的血管生成。
术语“细胞外基质”、“细胞外基质材料”和“ECM材料”在本文中可互换使用,并且意味着存在于动物组织中细胞之间并用作组织中结构元件的富含胶原蛋白的物质。其典型地包括由细胞分泌的多糖和蛋白质的复杂混合物。细胞外基质可以以各种方式被分离和处理。细胞外基质材料(ECM)能够从小肠黏膜下层、胃粘膜下层、膀胱粘膜下层、组织粘膜、硬脑膜、肝基底膜、心包或其它组织中分离出来。在分离和处理之后,其通常被称为细胞外基质或ECM材料。
术语“药理学试剂”、“药物试剂试剂”、“试剂”、“活性剂”、“药物”和“活性剂制剂(active agent formulation)”在本文中可互换使用,并且意味着并包括试剂、药物、化合物、物质的组合物或其混合物,包括其制剂,上述提供一些通常是有益的治疗效果。这包括在动物中产生局部或全身的一种效果或多种效果的任何生理学或药理学上的活性物质,所述动物包括温血哺乳动物、人类和灵长类动物;鸟类;家庭驯养动物或农场动物,诸如猫、狗、绵羊、山羊、牛、马和猪;实验室动物,诸如小鼠、大鼠和豚鼠;鱼;爬行动物;动物园和野生动物;和类似物。
因此术语“药理学试剂”、“药物试剂”、“试剂”、“活性剂”、“药物”和“活性剂制剂”意味着并包括但不限于抗生素、抗病毒剂、止痛剂、甾体抗炎药、非甾体抗炎药、抗肿瘤药物、抗痉挛药、细胞-细胞外基质相互作用的调节剂、蛋白质、激素、酶和酶抑制剂、抗凝血剂和/或抗血栓形成剂、DNA、RNA、修饰的DNA和RNA、NSAID、(DNA、RNA或蛋白质合成的抑制剂)、多肽、寡核苷酸、多核苷酸、核蛋白、调节细胞迁移的化合物、调节组织增殖和生长的化合物、以及血管扩张剂。
术语“抗炎药”和“抗炎剂”在本文中也可互换使用,并且意味着并包括“药理学试剂”和/或“活性试剂制剂”,当以治疗上有效的量施用于受试者时,其预防或治疗身体组织炎症,即对于组织损伤或破坏的保护性组织反应,其用于破坏、减少或屏蔽掉有害试剂和受损组织。因此抗炎剂包括但不限于阿氯芬酸(Alclofenac)、双丙酸阿氯米松(Alclometasone Dipropionate)、丙缩阿尔孕酮(Algestone Acetonide)、α-淀粉酶、安西法尔(amcinafal)、安西非特(Amcinafide)、氨芬酸钠(Amfenac Sodium)、盐酸氨普立糖(Amiprilose Hydrochloride)、阿那白滞素(Anakinra)、阿尼罗酸(Anirolac)、阿尼扎芬(Anitrazafen)、阿扎丙宗(Apazone)、巴柳氮二钠(Balsalazide Disodium)、苄达酸(Bendazac)、苯噁洛芬(Benoxaprofen)、盐酸苄达明(Benzydamine Hydrochloride)、菠萝蛋白酶(Bromelains)、溴哌莫(Broperamole)、布地奈德(Budesonide)、卡布洛芬(Carprofen)、环洛芬(Cicloprofen)、辛喷他宗(Cintazone)、克利洛芬(Cliprofen)、丙酸氯倍他索(Clobetasol Propionate)、丁氯倍他松(Clobetasone Butyrate)、氯吡酸(Clopirac)、氯硫卡松丙酸盐(Cloticasone Propionate)、醋酸三氟米松(CormethasoneAcetate)、可托多松(Cortodoxone)、癸酸盐、地夫可特(Deflazacort)、庚酸睾酮(Delatestryl)、能普-睾酮(Depo-Testosterone)、地奈德(Desonide)、去羟米松(Desoximetasone)、二丙酸地塞米松(Dexamethasone Dipropionate)、双氯芬酸钾(Diclofenac Potassium)、双氯芬酸钠(Diclofenac Sodium)、双醋二氟拉松(DiflorasoneDiacetate)、二氟米酮钠(Diflumidone Sodium)、二氟尼柳(diflunisal)、二氟泼尼酯(Difluprednate)、双酞嗪酮(Diftalone)、二甲基亚砜、羟西奈德(Drocinonide)、甲地松(Endrysone)、恩莫单抗(Enlimomab)、依诺利康钠(Enolicam Sodium)、依匹唑(Epirizole)、依托度酸(Etodolac)、依托芬那酯(Etofenamate)、联苯乙酸(Felbinac)、非那莫(Fenamole)、芬布芬(Fenbufen)、芬氯酸(Fenclofenac)、苯克洛酸(Fenclorac)、芬度柳(Fendosal)、苯吡噁二酮(Fenpipalone)、芬替酸(Fentiazac)、夫拉扎酮(Flazalone)、氟扎可特(Fluazacort)、氟芬那酸(Flufenamic Acid)、氟咪唑(Flumizole)、醋酸氟尼缩松(FlunisolideAcetate)、氟尼辛(Flunixin)、氟尼辛葡甲胺(Flunixin Meglumine)、氟考丁酯(Fluocortin Butyl)、氟米龙醋酸酯(Fluorometholone Acetate)、苯氟喹酮(Fluquazone)、氟比洛芬(Flurbiprofen)、氟瑞托芬(Fluretofen)、丙酸氟替卡松(Fluticasone Propionate)、呋喃洛芬(Furaprofen)、呋罗布芬(Furobufen)、哈西奈德(Halcinonide)、丙酸卤倍他索(Halobetasol Propionate)、醋酸卤泼尼松(Halopredone Acetate)、异丁芬酸(Ibufenac)、布洛芬(Ibuprofen)、布洛芬铝(Ibuprofen Aluminum)、皮考布洛芬(Ibuprofen Piconol)、伊洛达普(Ilonidap)、吲哚美辛(Indomethacin)、吲哚美辛钠(Indomethacin Sodium)、吲哚布洛芬(Indoprofen)、吲哚克索(Indoxole)、吲四唑(Intrazole)、醋异氟龙(Isoflupredone Acetate)、氧卓乙酸(Isoxepac)、伊索昔康(Isoxicam)、酮基布洛芬(Ketoprofen)、盐酸洛非咪唑(Lofemizole Hydrochloride)、氯诺昔康(Lomoxicam)、氯替泼诺碳酸乙酯(Loteprednol Etabonate)、甲氯灭酸钠(Meclofenamate Sodium)、甲氯芬那酸(Meclofenamic Acid)、甲氯松二丁酯(Meclorisone Dibutyrate)、甲芬那酸(Mefenamic Acid)、美沙拉嗪(Mesalamine)、美西拉宗(Meseclazone)、甲二氢睾酮(Mesterolone)、美雄酮(Methandrostenolone)、美替诺龙(Methenolone)、美替诺龙醋酸酯(Methenolone Acetate)、磺庚甲泼尼龙(Methylprednisolone Suleptanate)、吗尼氟酯(Momiflumate)、萘丁美酮(Nabumetone)、诺龙(Nandrolone)、萘普生(Naproxen)、萘普生钠(Naproxen Sodium)、甲氧萘丙醇(Naproxol)、尼马宗(Nimazone)、奥沙拉嗪钠(Olsalazine Sodium)、肝蛋白(Orgotein)、奥帕诺辛(Orpanoxin)、氧甲氢龙(Oxandrolane)、奥沙普秦(Oxaprozin)、羟基保泰松(Oxyphenbutazone)、羟甲烯龙(Oxymetholone)、盐酸瑞尼托林(ParanylineHydrochloride)、戊聚糖多硫酸钠(Pentosan Polysulfate Sodium)、甘油保泰松钠(Phenbutazone Sodium Glycerate)、吡非尼酮(Pirfenidone)、吡罗昔康(Piroxicam)、肉桂酸吡罗昔康(Piroxicam Cinnamate)、吡罗昔康乙醇胺(Piroxicam Olamine)、吡诺布洛芬(pirprofen)、泼那扎特(Prednazate)、普立非酮(Prifelone)、普罗度酸(Prodolic Acid)、普罗喹宗(Proquazone)、普罗沙唑(Proxazole)、枸橼酸普罗沙唑(ProxazoleCitrate)、利美索龙(Rimexolone)、氯马扎利(Romazarit)、水杨酸胆碱硫酸镁(Salcolex)、沙那西定(Salnacedin)、双水杨酯(Salsalate)、血根氯铵(Sanguinarium Chloride)、司克拉宗(Seclazone)、丝美辛(Sermetacin)、康力龙(Stanozolol)、舒多昔康(Sudoxicam)、舒林酸(Sulindac)、舒洛芬(Suprofen)、他美辛(Talmetacin)、氟烟酞酯(Talniflumate)、他洛柳酯(Talosalate)、特丁非隆(Tebufelone)、替尼达普(Tenidap)、替尼达普钠(Tenidap Sodium)、替诺昔康(Tenoxicam)、氧喹苯胺(Tesicam)、苄叉异喹酮(Tesimide)、睾酮、睾酮混合物(Testosterone Blends)、四氢甲吲胺(Tetrydamine)、硫平酸(Tiopinac)、替可的松匹伐酯(Tixocortol Pivalate)、托美丁(Tolmetin)、托美丁钠(Tolmetin Sodium)、三氯氟松(Triclonide)、三氟氨酯(Triflumidate)、齐多美辛(Zidometacin)和苯酰吡酸钠(Zomepirac Sodium)。
如本文所使用的术语“壳聚糖”意味着并且包括线性多糖的家族,所述线性多糖由不同量的N-乙酰-2-氨基-2-脱氧-D-葡萄糖和2-氨基-2-脱氧-D-葡萄糖残基的β(1→4)连接残基、以及它们所有的衍生物构成。
术语“活性剂制剂”,“药理学试剂制剂”和“试剂制剂”在本文中也可互换使用,并且意味着并包括活性剂(和壳聚糖),所述活性剂任意与一种或多种制药学上可接受的载体和/或另外的惰性成分相组合。根据本发明,制剂可处于载体中的溶液或悬浮液中。
如本文所用的术语“药理学组合物”意味着并包括下述组合物:“药理学试剂”和/或“细胞外基质材料”和/或“药理学试剂制剂”和/或本文认同的任何附加试剂或成分。
如本文所用的术语“治疗上有效的”意味着所施用的“药理学组合物”和/或“药理学试剂”和/或“活性剂制剂”的量是足以改善疾病或病症的一种或多种病因、症状或后遗症的量。这样的改善只需要疾病或病症的病因、症状或后遗症的减轻或改变,而并不一定消除。
术语“患者”和“受试者”在本文中可互换使用,并且意味着并包括温血哺乳动物,人类和灵长类动物;鸟类;家庭驯养动物或农场动物,诸如猫、狗、绵羊、山羊、牛、马和猪;实验室动物,诸如小鼠、大鼠和豚鼠;鱼;爬行动物;动物园和野生动物;和类似物。
术语“包括(comprise)”和该术语的变体,诸如“comprising”和“comprises”意味着“包括但不限于”,而并不意旨排除例如其它添加物、组分、整体或步骤。
提供下面的公开内容来以能够实现的方式进一步解释说明执行本发明一个或多个实施方案的最佳模式。进一步提供本公开内容,用于增强对发明性原理及其优势的理解和认识,而并非以任何方式限制本发明。本发明只由所附的权利要求限定,所述权利要求包括在本申请的未决期间进行的任何修改以及提交的那些权利要求的所有等同物。
如将由本领域内的普通技术人员所容易理解的那样,本发明实质上减少或消除了与治疗受损或病变的生物组织的现有技术方法相关联的劣势和缺点。
总体上而言,本公开涉及非抗原性的、弹性的、可生物重塑的、生物相容性的组织假体或移植物,其可设计成各种形状并用于修复、增强或替换哺乳动物的组织和器官。
在一个优选的实施方案中,所述组织假体包括支撑结构和细胞外基质(ECM)组合物。根据本发明,支撑结构可以包括各种常规的金属,以及合成的和天然的材料,其包括但不限于钽纱布、不锈钢网、 尼龙、编织的聚丙烯(例如,)、微孔膨胀的聚四氟乙烯(例如,)、Dacron增强的硅橡胶(例如,)、聚糖乳酸910(例如,)、聚酯(例如,)、聚乙醇酸经加工的羊真皮胶原蛋白、交联的牛心包(例如,)、以及所保存的人类硬脑膜(如)。
在本发明的一些实施方案中,支撑结构涂覆有本发明的(ECM)组合物。在一些实施方案中,所述支撑结构浸渍有本发明的ECM组合物。
根据本发明,在将本发明的组织假体施用到(或接近于)受损或病变的生物组织时,实现调节愈合,包括具有位点特定的结构特性和功能特性的组织结构的再生。
如本文所用的短语“调节愈合”和该表达方式的变体通常指代对一项过程的调节(例如,改变、延迟、阻滞、减轻等),所述过程涉及响应于局部组织损伤或损害的天然存在的组织的修复的不同级联或序列,实质上减轻其炎症作用。如本文所用的调节愈合包括许多不同的生物过程,包括上皮生长,纤维蛋白沉积,血小板活化和附着、抑制、增殖和/或分化,结缔纤维组织的产生与功能,血管生成,以及急性和/或慢性炎症的几个阶段,以及它们与彼此的相互作用。
例如,在一些实施方案中,本发明的ECM组合物专门配制(或设计)成改变、延迟、阻滞、减轻和/或防止与受损组织愈合相关联的一个或多个阶段,包括但不限于炎性阶段(例如,血小板或纤维蛋白沉积)和增殖阶段。
在一些实施方案中,“调节愈合”是指ECM组合物在组织愈合过程开始时改变实质性的炎症阶段(例如,血小板或纤维蛋白沉积)的能力。如本文所用的短语“改变实质性的炎症阶段”是指ECM组合物实质上减轻在损伤位点处的炎症反应的能力。
在这种情况下,少量炎症可响应于组织损伤而跟随发生,但当与在不存在本发明ECM组合物的情况下所发生的炎症相比,炎症反应(例如血小板和/或纤维蛋白沉积)水平显著降低。
例如,本文所论述的ECM组合物通过实验已被证明可延迟或改变与受损组织相关联的炎症反应,以及在组织损伤或损害之后的结缔纤维组织的过量形成。所述ECM组合物通过实验也已被证明在组织损伤之后可延迟或减少纤维蛋白沉积和血小板附着到的血液接触表面。
在本发明的一些实施方案中,“调节愈合”是指本发明的ECM组合物的以下能力:诱导宿主组织增生、生物重塑,包括新血管生成(例如自发性的血管生成、血管生成以及套叠式血管生成),以及具有位点特定的结构特性和功能特性的组织结构的再生。
在本发明的优选实施方案中,所述ECM组合物包括至少一种细胞外基质(以下称“ECM材料”)。根据本发明,该ECM材料可来源于各种哺乳动物组织来源和用于制备其的方法,诸如在美国专利号7,550,004、7,244,444、6,379,710、6,358,284、6,206,931、5,733,337和4,902,508和美国申请号12/707,427中所公开的那样;上述文献以其全文通过引用并入本文。所述哺乳动物组织来源包括但不限于小肠、大肠、胃、肺、肝脏、肾脏、胰脏、胎盘、心脏、膀胱、前列腺、生长牙釉质周围的组织、生长骨骼周围的组织、以及来自任何哺乳动物器官的任何胎儿组织。
如本领域中已知的那样,膀胱粘膜下层是细胞外基质,其具有黏膜(其包括过渡上皮层和固有膜)、黏膜下层、三层肌层,以及外膜(疏松结缔组织层)。该通常的配置对于小肠粘膜下层(SIS)和胃粘膜下层(SS)也同样如此。
其它组织(诸如肝脏和胰腺)具有称为基底膜的ECM材料。基底膜一般不表现出在黏膜下层中发现的那种拉伸强度。然而,可适当地采用来自这种组织的ECM材料的其它有用性能,所述组织诸如肝脏、胰脏、胎盘和肺组织;所有上述具有基底膜或间质膜(interstitial membrane)(和肺一样)。例如,胰腺细胞外膜支持β胰岛细胞,其对于胰腺功能是关键的。另外,例如,肝脏是已知本身能够再生的一种组织,因此特殊的性质可存在于有助于促进该过程的肝基底膜内。生长的牙釉质和生长的骨骼周围的ECM材料也具有优于其它基质的特定优势,因为它们支持骨和牙釉质的坚硬组织的生长和分化。
根据本发明,所述ECM材料可全部或部分地使用,因此例如,ECM材料可仅包括具有下面紧邻的固有膜的基底膜(或过渡性上皮层),粘膜下层,肌层和浆膜。该组合物的ECM材料成分可包含这些层中的任何一部分或全部,并因此可以想象地仅包括基底膜部分,而不包括粘膜下层。然而通常情况下,并且特别是因为认为粘膜下层包含并支持体内组织再生所需的活性生长因子和其它蛋白质,所以来自任何给定来源的ECM或基质组合物将包含支持细胞发育和分化以及组织再生的活性细胞外基质部分。
为了本发明的目的,来自任何哺乳动物组织的ECM材料由广泛地被称为ECM材料的若干基本上不可分离的层构成。例如,如果有可能,认为将基底膜从粘膜下层分离是非常困难的,因为这些层是薄的,不可能将它们从彼此剥离,来自该特定层的ECM材料可能会必然包含一些带有粘膜下层的基底膜。
根据本发明,本发明的ECM组合物还可包括来自两种或多种哺乳动物来源的ECM材料。因此例如,组合物可包括来自这些来源的ECM材料的组合,例如所述来源包括但不限于小肠粘膜下层、肝基底膜、胃粘膜下层、膀胱粘膜下层、胎盘基底膜、胰腺基底膜、大肠粘膜下层、肺间质膜、呼吸道粘膜下层、心脏ECM材料、真皮基质、和在一般情况下,来自任何哺乳动物的胎儿组织的ECM材料。所述ECM材料来源也可包括不同的哺乳动物或完全不同种类的哺乳动物。
所述ECM组合物因此可包括来自三种哺乳动物组织来源、四种哺乳动物组织来源、五种哺乳动物组织来源、六种哺乳动物组织来源以及可想得到的多达十种或更多种组织来源的ECM材料。所述组织来源可来自同一哺乳动物(例如同一头牛、同一头猪、同一啮齿动物、同一个人等),来自相同种类的哺乳动物(例如牛、猪、啮齿动物、人类)、或来自不同的但种类相同的哺乳动物(例如牛1和牛2,或猪1和猪2),或来自不同种类的哺乳动物(例如来自猪的肝脏基质、来自牛的小肠粘膜下层、和来自狗的膀胱粘膜下层,在组合物中所有都混合到一起)。
根据本发明,所述ECM材料可包括混合的固体颗粒。ECM材料也可形成为颗粒状并流体化,如在美国专利号5275826、6579538和6933326中所述的那样,以便形成混合的乳液、混合的凝胶或混合的糊料。
根据本发明,所述ECM组合物(即凝胶,乳液或糊料)的液体或半固体成分可包括各种浓度。优选地,ECM组合物的液体或半固体成分的浓度是在约0.001mg/ml至约200mg/ml的范围内。因而合适的浓度范围包括但不限于:约5mg/ml至约150mg/ml、约10mg/ml至约125mg/ml、约25mg/ml至约100mg/ml、约20mg/ml至约75mg/ml、约25mg/ml至约60mg/ml、约30mg/ml至约50mg/ml、以及约35mg/ml至约45mg/ml、以及约40mg/ml至约42mg/ml。
然而所提到的浓度范围仅仅是示例性的,而不意旨是详尽的或限制性的。应当理解的是,在任一所列出范围内的任何值被认为对于ECM组合物的液体或半固体成分的浓度而言是合理的和有用的值。
根据本发明,形成两种ECM材料的凝胶乳液或糊料的干燥颗粒或再造颗粒也可以各种比例混合到一起。例如,所述颗粒可包括与50%的胰腺基底膜的混合的50%的小肠粘膜下层。然后该混合物可类似地通过在合适的缓冲液(诸如生理盐水)中水合而流体化。
根据本发明,本发明的ECM组合物可进一步包括一种或多种附加的生物活性剂或成分,以便有助于受损组织的治疗和/或促进组织再生的过程。
在一些实施方案中,本发明的ECM组合物从而包括至少一种药理学试剂或组合物,其可以包括但不限于抗生素或抗真菌剂、抗病毒剂、抗疼痛剂、麻醉剂、止痛剂、甾体抗炎药、非甾体消炎药、抗肿瘤药物、抗痉挛药、细胞-细胞外基质相互作用的调节剂、蛋白质、激素、酶和酶抑制剂、抗凝血剂和/或抗血栓形成剂、DNA、RNA、修饰的DNA和RNA、NSAID、(DNA、RNA或蛋白质合成的抑制剂)、多肽、寡核苷酸、多核苷酸、核蛋白、调节细胞迁移的化合物、调节增殖和组织生长的化合物、以及血管扩张剂。
合适的药理学试剂和/或组合物从而包括但不限于阿托品,托品酰胺,地塞米松,磷酸地塞米松,倍他米松,磷酸倍他米松,泼尼松龙,曲安西龙,曲安奈德,氟新诺龙丙酮,醋酸阿奈可他,布地奈德,环孢霉素,FK-506,雷帕霉素,鲁伯斯塔,米哚妥林,氟比洛芬,舒洛芬,酮洛芬,双氯芬酸,酮咯酸,奈帕芬胺,利多卡因,新霉素,多粘菌素b、,杆菌肽,短杆菌肽,庆大霉素,土霉素,环丙沙星,氧氟沙星,妥布霉素,丁胺卡那霉素,万古霉素,头孢唑林,替卡西林,氯霉素,咪康唑,伊曲康唑,三氟胸苷,阿糖腺苷,更昔洛韦,阿昔洛韦,西多福韦,单磷阿糖腺苷,膦甲酸,碘苷,阿德福韦酯,甲氨蝶呤,卡铂,苯肾上腺素,肾上腺素,地匹福林,噻吗洛尔,6-羟基多巴胺,倍他洛尔,毛果芸香碱,卡巴胆碱,毒扁豆碱,地美溴铵,多佐胺,布林唑胺,拉坦前列素,透明质酸钠,胰岛素,维替泊芬,哌加他尼,雷珠单抗,及其它抗体,抗肿瘤药,抗VGEF,睫状神经营养因子,脑源性神经营养因子、bFGF,胱天蛋白酶-1抑制剂,胱天蛋白酶-3抑制剂,α-肾上腺素能受体激动剂,NMDA拮抗剂,胶质细胞源性神经营养因子(GDNF),色素上皮衍生因子(PEDF),和NT-3,NT-4,NGF,IGF-2。
根据本发明,添加到本发明的ECM组合物的药理学试剂的量当然会随着试剂不同而有所不同。例如,在其中所述药理学试剂包括双氯芬酸(dicloflenac)的实施方案中,包含在ECM组合物中的双氯芬酸的量优选在10μg-75mg的范围内。
在本发明的一些实施方案中,药理学试剂具体包括抗炎试剂。根据本发明,合适的抗炎试剂包括但不限于阿氯芬酸(Alclofenac)、双丙酸阿氯米松(Alclometasone Dipropionate)、丙缩阿尔孕酮(Algestone Acetonide)、α-淀粉酶、安西法尔、安西非特(Amcinafide)、氨芬酸钠(Amfenac Sodium)、盐酸氨普立糖(Amiprilose Hydrochloride)、阿那白滞素(Anakinra)、阿尼罗酸(Anirolac)、阿尼扎芬(Anitrazafen)、阿扎丙宗(Apazone)、巴柳氮二钠(Balsalazide Disodium)、苄达酸(Bendazac)、苯噁洛芬(Benoxaprofen)、盐酸苄达明(Benzydamine Hydrochloride)、菠萝蛋白酶(Bromelains)、溴哌莫(Broperamole)、布地奈德(Budesonide)、卡布洛芬(Carprofen)、环洛芬(Cicloprofen)、辛喷他宗(Cintazone)、克利洛芬(Cliprofen)、丙酸氯倍他索(Clobetasol Propionate)、丁氯倍他松(Clobetasone Butyrate)、氯吡酸(Clopirac)、氯硫卡松丙酸盐(Cloticasone Propionate)、醋酸三氟米松(CormethasoneAcetate)、可托多松(Cortodoxone)、癸酸盐、地夫可特(Deflazacort)、庚酸睾酮(Delatestryl)、能普-睾酮(Depo-Testosterone)、地奈德(Desonide)、去羟米松(Desoximetasone)、二丙酸地塞米松(Dexamethasone Dipropionate)、双氯芬酸钾(Diclofenac Potassium)、双氯芬酸钠(Diclofenac Sodium)、双醋二氟拉松(Diflorasone Diacetate)、二氟米酮钠(Diflumidone Sodium)、二氟尼柳(Difiunisal)、二氟泼尼酯(Difluprednate)、双酞嗪酮(Diftalone)、二甲基亚砜、羟西奈德(Drocinonide)、甲地松(Endrysone)、恩莫单抗(Enlimomab)、依诺利康钠(Enolicam Sodium)、依匹唑(Epirizole)、依托度酸(Etodolac)、依托芬那酯(Etofenamate)、联苯乙酸(Felbinac)、非那莫(Fenamole)、芬布芬(Fenbufen)、芬氯酸(Fenclofenac)、苯克洛酸(Fenclorac)、芬度柳(Fendosal)、苯吡噁二酮(Fenpipalone)、芬替酸(Fentiazac)、夫拉扎酮(Flazalone)、氟扎可特(Fluazacort)、氟芬那酸(Flufenamic Acid)、氟咪唑(Flumizole)、醋酸氟尼缩松(Flunisolide Acetate)、氟尼辛(Flunixin)、氟尼辛葡甲胺(FlunixinMeglumine)、氟考丁酯(Fluocortin Butyl)、氟米龙醋酸酯(Fluorometholone Acetate)、苯氟喹酮(Fluq uazone)、氟比洛芬(Flurbiprofen)、氟瑞托芬(Fluretofen)、丙酸氟替卡松(Fluticasone Propionate)、呋喃洛芬(Furaprofen)、呋罗布芬(Furobufen)、哈西奈德(Halcinonide)、丙酸卤倍他索(Halobetasol Propionate)、醋酸卤泼尼松(Halopredone Acetate)、异丁芬酸(Ibufenac)、布洛芬(Ibuprofen)、布洛芬铝(Ibuprofen Aluminum)、皮考布洛芬(Ibuprofen Piconol)、伊洛达普(Ilonidap)、吲哚美辛(Indomethacin)、吲哚美辛钠(Indomethacin Sodium)、吲哚布洛芬(Indoprofen)、吲哚克索(Indoxole)、吲四唑(Intrazole)、醋异氟龙(Isoflupredone Acetate)、氧卓乙酸(Isoxepac)、伊索昔康(Isoxicam)、酮基布洛芬(Ketoprofen)、盐酸洛非咪唑(LofemizoleHydrochloride)、氯诺昔康(Lomoxicam)、氯替泼诺碳酸乙酯(LoteprednolEtabonate)、甲氯灭酸钠(Meclofenamate Sodium)、甲氯芬那酸(MeclofenamicAcid)、甲氯松二丁酯(Meclorisone Dibutyrate)、甲芬那酸(Mefenamic Acid)、美沙拉嗪(Mesalamine)、美西拉宗(Meseclazone)、甲二氢睾酮(Mesterolone)、美雄酮(Methandrostenolone)、美替诺龙(Methenolone)、美替诺龙醋酸酯(Methenolone Acetate)、磺庚甲泼尼龙(Methylprednisolone Suleptanate)、吗尼氟酯、萘丁美酮(Nabumetone)、诺龙(Nandrolone)、萘普生(Naproxen)、萘普生钠(Naproxen Sodium)、甲氧萘丙醇(Naproxol)、尼马宗(Nimazone)、奥沙拉嗪钠(Olsalazine Sodium)、肝蛋白(Orgotein)、奥帕诺辛(Orpanoxin)、氧甲氢龙(Oxandrolane)、奥沙普秦(Oxaprozin)、羟基保泰松(Oxyphenbutazone)、羟甲烯龙(Oxymetholone)、盐酸瑞尼托林(Paranyline Hydrochloride)、戊聚硫钠(Pentosan Polysulfate Sodium)、甘油保泰松钠(Phenbutazone Sodium Glycerate)、吡非尼酮(Pirfenidone)、吡罗昔康(Piroxicam)、肉桂酸吡罗昔康(Piroxicam Cinnamate)、吡罗昔康乙醇胺(Piroxicam Olamine)、吡诺布洛芬(pirprofen)、泼娜扎特(Prednazate)、普立非酮(Prifelone)、普罗度酸(Prodolic Acid)、普罗喹宗(Proquazone)、普罗沙唑(Proxazole)、枸橼酸普罗沙唑(Proxazole Citrate)、利美索龙(Rimexolone)、氯马扎利(Romazarit)、水杨酸胆碱硫酸镁(Salcolex)、沙那西定(Salnacedin)、双水杨酯(Salsalate)、血根氯铵(Sanguinarium Chloride)、司克拉宗(Seclazone)、丝美辛(Sermetacin)、康力龙(Stanozolol)、舒多昔康(Sudoxicam)、舒林酸(Sulindac)、舒洛芬(Suprofen)、他美辛(Talmetacin)、氟烟酞酯(Talniflumate)、他洛柳酯(Talosalate)、特丁非隆(Tebufelone)、替尼达普(Tenidap)、替尼达普钠(Tenidap Sodium)、替诺昔康(Tenoxicam)、氧喹苯胺(Tesicam)、苄叉异喹酮(Tesimide)、睾酮、睾酮混合物(Testosterone Blends)、四氢甲吲胺(Tetrydamine)、硫平酸(Tiopinac)、替可的松匹伐酯(Tixocortol Pivalate)、托美丁(Tolmetin)、托美丁钠(Tolmetin Sodium)、三氯氟松(Triclonide)、三氟氨酯(Triflumidate)、齐多美辛(Zidometacin)和苯酰吡酸钠(Zomepirac Sodium)。
根据本发明,添加到本发明的ECM组合物的抗炎药的量可类似地随着抗炎药的不同而有所不同。例如,在其中所述药理学试剂包括布洛芬的本发明的一个实施方案中,包含在ECM组合物中的布洛芬的量优选在100μg-200mg的范围内。
在本发明的一些实施方案中,药理学试剂包括他汀类药物,即HMG-CoA还原酶抑制剂。根据本发明,合适的他汀类药物包括但不限于阿托伐他汀西伐他汀、氟伐他汀洛伐他汀 美伐他汀、匹伐他汀普伐他汀罗苏伐他汀和辛伐他汀包含他汀和其它试剂组合的的几种活性剂(诸如依泽替米贝/辛伐他汀)也是合适的。
申请人已经发现,所提及的他汀类药物表现出提供几种有益的生化作用或活性的许多有益特性。几个显著特性和由此产生的有益作用在下文详细论述。额外的特性和有益作用在共同待审的申请(申请号13/373,569)中阐述;该文献以其全文通过引用并入本文。
抗炎特性/作用
他汀类药物对血管壁细胞和心血管系统具有众多有利的效果。一个具体的实例是,他汀类药物促进G蛋白偶联受体(血栓烷A2(TXA2))的减少,这降低了血小板活化和聚集,以及粘附分子和趋化因子的增强。
通过阻断ras同源物(homilog)基因家族的成员A(RhoA)的活化,他汀类药物进一步影响血管壁细胞和心血管系统。阻断RhoA活化进一步影响许多系统,诸如巨噬细胞生长、组织纤溶酶原激活物(t-PA)、纤溶酶原激活物抑制剂1型(PAI-1)、平滑肌细胞(SMC)的增殖、一氧化氮(NO)的产生、内皮素、和血管紧张素受体。
通过阻断RhoA活化所减少的巨噬细胞的生长导致基质金属蛋白酶(MMP)和组织因子(TF)的减少。降低MMP也导致所存在的血栓减少,因为MMP附着到存在于血栓的ECM或在伤口部位的受损的ECM。
纤维蛋白溶解特性/作用
阻断RhoA的活化也影响组织纤溶酶原激活物(t-PA)和为纤维蛋白溶解的主要抑制剂的纤溶酶原激活物抑制剂1型(PAI-1)的存在。随着通过他汀类药物所诱导的阻断RhoA活化带来的所存在的t-PA增多以及PAI-1减少,由于降低了血纤维蛋白形成止血塞的聚合物网的可能性而实现降低血栓形成的影响。
NO调节特性/作用
阻断RhoA活化也影响一氧化氮(NO)在心血管系统中的存在。NO通过抑制血管平滑肌收缩和生长、血小板聚集、和白细胞粘附到内皮而有助于血管动态平衡。
RhoA活化阻断特性/作用
他汀类药物的施用还可增强内皮素和血管紧张素受体的存在。内皮素和血管紧张素受体也会受到与他汀类药物施用相关联的RhoA活化的随后阻断的影响。
存在内皮素的三种亚型;ET-1、ET-2和ET-3,其中ET-1是主要受到他汀类药物和RhoA活化阻断影响的亚型。从内皮分泌ET-1给出血管收缩的信号并影响局部细胞生长和存活。
血管紧张素受体是蛋白质偶联的受体,其负责主要效应激素血管紧张素II的血管收缩刺激的信号转导。血管紧张素受体II类型I(AT-1)是主要受到他汀类药物施用和RhoA活化阻断影响的血管紧张素受体。AT-1尤其介导血管收缩、心脏肥大、血管平滑肌细胞增生。
C-反应蛋白的减少特性/作用
C-反应蛋白(CRP)也通过他汀类药物减少。CRP在血液中发现;CRP水平响应于不同炎症水平而发生偏离。
粘附分子的减少特性/作用
他汀类药物还减少粘附分子在内皮上的存在。粘附分子是蛋白质,它们位于细胞表面上,并涉及在血管内皮细胞中的炎症和凝血酶的形成。
Rac-1的减少特性/作用
Rac-1的表达也通过他汀类药物而降低。Rac-1是在人类细胞中发现的蛋白质,它在内皮细胞的迁移、小管发生(tubulogenesis)、粘附性以及渗透性方面起到核心作用。所存在的Rac-1的减少也导致活性氧类(ROS)的减少。
根据本发明,ECM支撑构件(或材料)可包括10mg或更多的他汀类药物以达到他汀类药物在所需组织内的更高的浓度,或可包括10ug或更少的他汀类药物以达到他汀类药物在所需组织内的更低的浓度。
根据本发明,添加到本发明的药物组合物中的他汀类药物的量优选小于20mg,更优选小于约10mg。
在本发明的一些实施方案中,ECM材料包含100ug-5mg的他汀类药物。在本发明的一些实施方案中,ECM材料包含500ug-2mg的他汀类药物。
在本发明的一些实施方案中,ECM支撑构件(或材料)包括壳聚糖或其衍生物。也如在共同待审的申请(申请号13/573,569)中详细阐述的那样,壳聚糖也表现出提供若干有益的生化作用或活性的众多有益特性。
根据本发明,添加到本发明的药物组合物中的壳聚糖的量优选小于50ml,更优选小于约20ml。
在本发明的一些实施方案中,壳聚糖并入到聚合物网络内,如在美国公开号2008/0254104和2009/0062849中所公开的那样,上述文献以其全文并入本文。
在本发明的一些实施方案中,生物活性剂包括细胞。根据本发明,所述细胞可包括但不限于干细胞,诸如人体胚胎干细胞,胎儿细胞,胎儿心肌细胞,肌成纤维细胞,间充质干细胞,自体移植的扩大心肌细胞(autotransplantedexpanded cardiomyocyte),脂肪细胞,全能细胞,多能细胞,血干细胞,成肌细胞,成体干细胞,骨髓细胞,间充质细胞,胚胎干细胞,实质细胞,上皮细胞,内皮细胞,间皮细胞,成纤维细胞,肌成纤维细胞,成骨细胞,软骨细胞,外源性细胞,内源性细胞,干细胞,造血干细胞,多能干细胞,骨髓来源的祖细胞,祖细胞,心肌细胞,骨骼肌细胞,未分化细胞,多能祖细胞,单能祖细胞,单核细胞,心肌细胞,心肌母细胞,骨骼肌成肌细胞,巨噬细胞,毛细血管内皮细胞,异种细胞,和同种异体细胞。
在本发明的一些实施方案中,所述生物活性剂包括蛋白质。根据本发明,所述蛋白质可包括但不限于生长因子、胶原蛋白、蛋白聚糖、糖胺聚糖(GAG)链、糖蛋白、细胞因子、细胞表面相关蛋白、细胞粘附分子(CAM)、血管生成生长因子、内皮配体、马曲金肽(matrikine)、基质金属蛋白酶、钙粘素、免疫球蛋白、原纤维胶原蛋白、非成纤维胶原蛋白、基底膜胶原蛋白、多丛状蛋白(multiplexin)、小富含亮氨酸的蛋白多糖、核心蛋白聚糖、双糖链蛋白聚糖、纤调蛋白、角膜蛋白、基膜聚糖(lumican)、骺蛋白聚糖(epiphycan)、硫酸肝素蛋白多糖、基底膜蛋白多糖、集聚蛋白(agrin)、睾丸蛋白聚糖(testican)、多配体蛋白聚糖(syndecan)、磷脂酰肌醇蛋白聚糖(glypican)、丝甘蛋白聚糖、选择蛋白、凝集蛋白聚糖、聚集蛋白聚糖、多(功)能(蛋白)聚糖、神经蛋白聚糖、短蛋白聚糖(brevican)、胞浆区-44(CD-44)、巨噬细胞刺激因子、淀粉样前体蛋白、肝素、硫酸软骨素B(硫酸皮肤素)、硫酸软骨素A、硫酸肝素、透明质酸、纤连蛋白(Fn)、腱生蛋白、弹性蛋白、原纤维蛋白、层粘连蛋白、巢蛋白(nidogen/entactin)、纤蛋白Ⅰ、纤蛋白II、整合素、跨膜分子、血小板衍生的生长因子(PDGF)、表皮生长因子(EGF)、转化生长因子α(TGF-α)、转化生长因子β(TGF-β)、成纤维细胞生长因子-2(FGF-2)(也称为碱性成纤维细胞生长因子(bFGF))、血小板反应蛋白、骨桥蛋白、血管紧张素转换酶(ACE)和血管上皮生长因子(VEGF)。
在本发明的一些实施方案中,所述ECM组合物具体包括他汀类药物和壳聚糖。已经发现,当施用到受损或病变的生物组织时,通过他汀类药物和壳聚糖的组合所表现出的协同作用显著增强诱导新血管形成、宿主组织增生、生物重塑和新组织以及相关结构(具有位点特定的结构和功能特性)的再生。
根据本发明,上面提到的生物活性剂可包括任何形式。在本发明的一些实施方案中,生物活性的一种成分或多种成分(例如,辛伐他汀和/或壳聚糖)包括微胶囊,其提供包含于其中的试剂的延迟递送。
如以上所指出的那样,在本发明的一些实施方案中,将本发明的一种或多种ECM组合物涂覆到支撑结构上,以形成本发明的组织假体或移植物。在本发明的一些实施方案中,将本发明的一种或多种ECM组合物并入到支撑结构内,以形成本发明的组织假体。在本发明的一些实施方案中,将本发明的一种或多种ECM组合物涂覆到支撑结构上而且并入到支撑结构内,以形成组织假体。
现在参照图1和图2,它们示出本发明的组织假体10,其具有支撑结构12,其中ECM组合物涂层14设置于支撑结构12上。如上所指出的那样,该支撑结构可包括各种常规的金属,以及合成的和天然的材料,所述材料包括但不限于包括钽纱布、不锈钢网、尼龙、编织的聚丙烯(例如,)、微孔膨胀的聚四氟乙烯(例如,)、增强的硅橡胶(例如,)、聚糖乳酸910(例如,)、聚酯(例如,)、聚乙醇酸(例如,)、经加工的羊真皮胶原蛋白、交联的牛心包(例如,)、以及所保存的人类硬脑膜(如)。支撑结构12还可包括基于ECM的材料。
根据本发明,可采用各种常规方法以形成组织假体10,包括喷涂、浸渍等。
为了增强本发明组织假体接合到生物组织,在一些设想的实施方案中,支撑结构12还可包括微针支撑结构,诸如在美国申请(申请号13/686,131)中所公开的那样,该文献以其全文明确地并入本文。
如由本领域内的普通技术人员将容易理解的那样,本发明提供相比于用于治疗受损心脏组织的现有技术的方法和系统的许多优势。其中的优势如下:
·提供组织假体,当组织假体被递送到受损或病变的生物组织时,所述组体假体诱导调节愈合,包括具有位点特定的结构特性和功能特性的组织结构的再生。
·提供细胞外基质(ECM)组合物,当细胞外基质(ECM)组合物与基体假体支撑结构一起被采用时,所述细胞外基质(ECM)组合物诱导宿主组织增生、生物重塑和具有位点特定的结构特性和功能特性的组织结构的再生。
·提供用于施用药理学组合物的改进的方法和设备;具体而言,将ECM组合物直接施用到受损或病变的生物组织上。
在不脱离本发明的精神和范围的情况下,普通技术人员可对本发明进行各种改变和修改,以使其适应各种用途和状况。因此,这些改变和修改是适当地、公正地,且意旨处于等同于随后所附权利要求的整个范围内。
Claims (16)
1.组织假体,其包括:
具有至少一个表面的支撑结构,所述支撑结构包括基体材料;
所述支撑结构进一步包括细胞外基质(ECM)组合物,所述ECM组合物包括来自哺乳动物组织来源的至少一种ECM材料;
其中,当所述组织假体邻近于受损的生物组织配置时,所述假体诱导所述受损组织的调节愈合。
2.根据权利要求1所述的组织假体,其中所述支撑结构包括选自于由下述所构成的组的合成材料:尼龙、编织的聚丙烯、微孔膨胀的聚四氟乙烯、增强的硅橡胶、和聚酯。
3.根据权利要求1所述的组织假体,其中所述支撑结构包括选自于由下述所构成的组的天然材料:经加工的羊真皮胶原蛋白、交联的牛心包、以及所保存的人类硬脑膜。
4.根据权利要求1所述的组织假体,其中所述支撑结构包括选自于由钽纱布和不锈钢网所构成的组的金属结构。
5.根据权利要求1所述的组织假体,其中所述ECM材料选自于由下述所构成的组:小肠黏膜下层(SIS)、膀胱粘膜下层(UBS)、泌尿系基底膜(UBM)、肝基底膜(LBM)、胃粘膜下层(SS)、间皮组织、皮下细胞外基质、大肠细胞外基质、胎盘细胞外基质、装饰用(ornamentum)细胞外基质、心脏细胞外基质和肺细胞外基质。
6.根据权利要求1所述的组织假体,其中所述ECM材料包括脱细胞的ECM材料。
7.根据权利要求1所述的组织假体,其中所述ECM材料包括至少一种补充的生物活性剂。
8.根据权利要求7所述的组织假体,其中所述生物活性剂包括生长因子,所述生长因子选自于由下述所构成的组:血小板衍生的生长因子(PDGF)、表皮生长因子(EGF)、转化生长因子-α(TGF-α)、转化生长因子-β(TGF-β)、成纤维细胞生长因子-2(FGF-2)、碱性成纤维细胞生长因子(bFGF)、血管上皮生长因子(VEGF)、肝细胞生长因子(HGF)、胰岛素样生长因子(IGF)、神经生长因子(NGF)、血小板衍生的生长因子(PDGF)、肿瘤坏死因子-α(TNA-α)、和胎盘生长因子(PLGF)。
9.根据权利要求7所述的组织假体,其中所述生物活性剂包括细胞,所述细胞选自于由下述所构成的组:人体胚胎干细胞、胎儿心肌细胞、肌成纤维细胞、间充质干细胞、自体移植的扩大心肌细胞、脂肪细胞、全能细胞、多能细胞、血干细胞、成肌细胞、成体干细胞、骨髓细胞、间充质细胞、胚胎干细胞、实质细胞、上皮细胞、内皮细胞、间皮细胞、成纤维细胞、成骨细胞、软骨细胞、外源性细胞、内源性细胞、造血干细胞、骨髓来源的祖细胞、心肌细胞、骨骼肌细胞、胎儿细胞、未分化细胞、多能祖细胞、单能祖细胞、单核细胞、心肌母细胞、骨骼肌成肌细胞、巨噬细胞、毛细血管内皮细胞、异种细胞、同种异体细胞和产后干细胞。
10.根据权利要求7所述的组织假体,其中所述生物活性剂包括活性剂,其选自于由下述所构成的组:胶原蛋白(I-V型)、蛋白聚糖、糖胺聚糖(GAG)、糖蛋白、细胞因子、细胞表面相关蛋白、细胞粘附分子(CAM)、内皮配体、马曲金肽、钙粘素、免疫球蛋白、原纤维胶原蛋白、非成纤维胶原蛋白、基底膜胶原蛋白、多丛状蛋白、小富含亮氨酸的蛋白多糖、核心蛋白聚糖、双糖链蛋白聚糖、纤调蛋白聚糖、角膜蛋白、基膜聚糖、骺蛋白聚糖、硫酸肝素蛋白多糖、基底膜蛋白多糖、集聚蛋白、睾丸蛋白聚糖、多配体蛋白聚糖、磷脂酰肌醇蛋白聚糖、丝甘蛋白聚糖、选择素、凝集蛋白聚糖、聚集蛋白聚糖、多功能蛋白聚糖、神经蛋白聚糖、短蛋白聚糖、胞浆区-44(CD-44)、巨噬细胞刺激因子、淀粉样前体蛋白、肝素、硫酸软骨素B(硫酸皮肤素)、硫酸软骨素A、硫酸肝素、透明质酸、纤连蛋白、腱生蛋白、弹性蛋白、原纤维蛋白、层粘连蛋白、巢蛋白、纤蛋白Ⅰ、纤蛋白II、整合素、跨膜分子、血小板反应蛋白、骨桥蛋白以及血管紧张素转换酶(ACE)。
11.根据权利要求7所述的组织假体,其中所述生物活性剂包括药理学试剂。
12.根据权利要求11所述的组织假体,其中所述药理学试剂其选自于由下述所构成的组:抗生素、抗真菌剂、抗病毒剂、抗疼痛剂、麻醉剂、镇痛药、甾体抗炎药、非甾体抗炎药、抗肿瘤药物、抗痉挛药、细胞-细胞外基质相互作用的调节剂、蛋白质、激素、酶和酶抑制剂、抗凝血剂、抗血栓形成剂、DNA、RNA、修饰的DNA和RNA、NSAID、DNA的抑制剂、多肽、寡核苷酸、多核苷酸、核蛋白以及血管扩张剂。
13.根据权利要求11所述的组织假体,其中所述药理学试剂包括HMG-CoA还原酶抑制剂。
14.根据权利要求13所述的组织假体,其中所述HMG-CoA还原酶抑制剂选自于由下述所构成的组:阿托伐他汀、西伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀和辛伐他汀。
15.根据权利要求1所述的组织假体,其中所述ECM组合物沉积到所述支撑结构表面上。
16.根据权利要求1所述的组织假体,其中所述ECM组合物浸渍到所述支撑结构基体材料内。
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- 2013-09-19 CN CN201380062893.6A patent/CN104822342A/zh active Pending
- 2013-09-19 CA CA 2887350 patent/CA2887350A1/en not_active Abandoned
- 2013-09-19 EP EP13844668.7A patent/EP2903560A4/en not_active Withdrawn
- 2013-09-19 KR KR1020157011719A patent/KR20150068427A/ko not_active Application Discontinuation
- 2013-09-19 AU AU2013330361A patent/AU2013330361A1/en not_active Abandoned
- 2013-09-19 BR BR112015007861A patent/BR112015007861A2/pt not_active Application Discontinuation
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CN105176924A (zh) * | 2015-10-15 | 2015-12-23 | 绵阳未来细胞生物科技有限公司 | 一种软骨再生干细胞制剂及其应用 |
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WO2017148255A1 (zh) * | 2016-03-01 | 2017-09-08 | 上海卓阮医疗科技有限公司 | 一种修复区稳固的复合软组织修复材料 |
CN106139249A (zh) * | 2016-07-18 | 2016-11-23 | 青岛三帝生物科技有限公司 | 一种多元聚合物人工角膜的制备方法 |
CN106139249B (zh) * | 2016-07-18 | 2019-06-04 | 青岛三帝生物科技有限公司 | 一种多元聚合物人工角膜的制备方法 |
CN107441556A (zh) * | 2017-07-05 | 2017-12-08 | 北京大清生物技术股份有限公司 | 一种聚氨基酸封端的组织修补材料及其制备方法 |
CN107441556B (zh) * | 2017-07-05 | 2020-07-17 | 北京大清生物技术股份有限公司 | 一种聚氨基酸封端的组织修补材料及其制备方法 |
CN108309503A (zh) * | 2018-01-29 | 2018-07-24 | 张士丰 | 一种硅橡胶疝修复补片 |
CN111166748A (zh) * | 2019-12-14 | 2020-05-19 | 深圳先进技术研究院 | 吡非尼酮在制备促血管生成药物中的应用 |
CN114984323A (zh) * | 2022-06-15 | 2022-09-02 | 上海交通大学医学院附属第九人民医院 | 一种腹壁缺损修复材料及制备方法 |
CN115006592A (zh) * | 2022-06-15 | 2022-09-06 | 上海交通大学医学院附属第九人民医院 | 一种脱细胞真皮复合材料、制备方法及用途 |
CN114984323B (zh) * | 2022-06-15 | 2023-09-12 | 上海交通大学医学院附属第九人民医院 | 一种腹壁缺损修复材料及制备方法 |
CN115006592B (zh) * | 2022-06-15 | 2024-01-30 | 上海交通大学医学院附属第九人民医院 | 一种脱细胞真皮复合材料、制备方法及用途 |
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US20140099330A1 (en) | 2014-04-10 |
EP2903560A4 (en) | 2016-05-25 |
SG11201502714TA (en) | 2015-05-28 |
HK1207557A1 (zh) | 2016-02-05 |
CA2887350A1 (en) | 2014-04-17 |
WO2014058587A1 (en) | 2014-04-17 |
BR112015007861A2 (pt) | 2018-04-24 |
IL238066A0 (en) | 2015-05-31 |
JP2016500526A (ja) | 2016-01-14 |
KR20150068427A (ko) | 2015-06-19 |
EP2903560A1 (en) | 2015-08-12 |
AU2013330361A1 (en) | 2015-04-23 |
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