CN103520783A - 向组织提供流体流的系统 - Google Patents
向组织提供流体流的系统 Download PDFInfo
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- CN103520783A CN103520783A CN201310471166.7A CN201310471166A CN103520783A CN 103520783 A CN103520783 A CN 103520783A CN 201310471166 A CN201310471166 A CN 201310471166A CN 103520783 A CN103520783 A CN 103520783A
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Abstract
本发明提供了包括支架的装置,该支架具有设置在腔表面的至少一部分上的凝胶或液体组合物,该凝胶或液体组合物适合包括微气泡。还提供了包括减压的源、以上的支架、毗邻支架的歧管和用于提供歧管和减压的源之间的流体相通的导管的系统。另外提供了方法,该方法包括将以上的支架植入组织部位以及使微气泡中的大部分破裂以诱导流体流向支架。进一步提供的是包括支架的装置,该支架包括缓慢可降解的材料和快速可降解的材料。另外提供的是用于耦合神经组织和微芯片组件的系统。
Description
本申请是申请日为2009年12月29日,申请号为200980152941.4,发明名称为“向组织提供流体流的系统”的申请的分案申请。
相关申请的交叉引用
本申请要求2009年8月18日提交的美国临时申请第61/234,692号、2008年12月31日提交的美国临时申请第61/142,053号和2008年12月31日提交的美国临时申请第61/142,065号的权益,其全部通过引用并入本文。
发明领域
本申请一般涉及组织工程并且具体地涉及适合用于组织的治疗的系统和支架(scaffold)。
发明背景
临床研究和实践已经显示,在接近组织部位处提供减压加强和加速组织部位处的新的组织的生长。这种现象的应用有很多,但是减压的应用已经在治疗创伤中特别地成功。这种治疗(在医学界经常被称为“负压创伤疗法”、“减压疗法”或“真空疗法”)提供了很多益处,包括更快的愈合和增加肉芽组织的形成。典型地,减压已经被通过多孔垫或其他歧管工具施加于组织。多孔垫含有能够向组织分布减压并且引导从组织抽出的流体的孔。多孔垫经常被结合入具有其他帮助治疗的部件的敷料(dressing)。支架还可以被放置入缺陷中以支持组织向缺陷中的生长。支架通常是生物可吸收的,将新的组织留在其位置中。
用于减压治疗的支架在例如WO08/091521、WO07/092397、WO07/196590、WO07/106594中描述。目前用于减压治疗的支架的适合性可以根据创伤愈合的现有知识被评价。对身体组织的伤害导致随愈合的时序阶段做出创伤愈合响应(wound healing response),该愈合的时序阶段包括止血(几秒至几小时)、发炎(几小时至几天)、修复(几天至几周)以及重构(几周至几个月)。考虑到创伤愈合过程的早期阶段,在大多数组织类型中存在高度的同源性。然而,由于包含不同类型的生长因子、细胞因子和细胞,各种组织的愈合阶段随时间推移开始出现差异。由于响应的每个组成部分的时间模式的和响应的每个组成部分之间的相互关系的增强的复杂性,创伤愈合响应的后期阶段取决于前期阶段。
用于帮助受损组织的功能的正常修复、再生和复原的策略已经集中于用于支持和加强在该愈合响应中的特别步骤,特别是其后期的各方面的方法。为了这个目的,生长因子、细胞因子、细胞外基质(ECM)类似物、外生细胞以及各种支架技术已经被单独地或彼此结合地应用。虽然使用这种途径已经实现了某种程度的成功,但是仍然存在某些关键的挑战。一个主要的挑战是,在创伤愈合响应内的每个细胞因子和生长因子的时序与协调的影响使得在适当的时间且以正确的协调模式添加个体外生因子的能力变得复杂。由于外生细胞的潜在的免疫原性以及保持细胞活力方面的难度,外生细胞的引入还面临另外的复杂性。
合成的以及生物的支架已经被用于提供用于加强内源性细胞附接、迁移(migration)和定植(colonization)的立体框架。到目前为止,几乎所有的支架都根据它们可以被制造以根据原位生物学起作用的思想被设计。然而,传统的支架技术(scaffolding technology)依赖于内源性蛋白、细胞因子、生长因子和细胞的向多孔支架的间隙的被动流入。因此,内源性细胞向支架中的定植被距血管元件的距离限制,血管元件在支架的扩散限制内提供营养支持,而与组织类型无关。此外,支架还可以引起导致延长的修复过程以及在植入物周围形成纤维囊的免疫原性响应或异物响应。概括起来,这些复杂性全部可以导致在损伤部位处的减弱的功能性组织再生。
发明简述
因此,将是有利的是,提供额外的系统以进一步引导愈合组织生长。本发明提供了这样的系统。
本文描述的说明性实施方式的支架、系统和方法通过植入的支架提供组织再生的主动引导。在一种实施方式中,提供了用于提供减压治疗并促进在患者的组织部位处的组织生长的装置,该装置包括:适用于植入组织部位的支架,其中支架为组织的生长提供结构基质并具有腔表面;以及配置在腔表面的至少一部分上的凝胶或液体组合物,该凝胶或液体组合物适合包括微气泡(microbubble)。
在另一实施方式中,提供了用于提供减压治疗并促进在患者的组织部位处的组织生长的系统,该系统包括:用于供应减压的减压的源;可适用于植入组织部位的支架,其中支架为组织的生长提供结构基质并具有腔表面;设置在腔表面的至少一部分上的凝胶或液体组合物,其中凝胶或液体组合物适合包括微气泡;毗邻支架的歧管,其中歧管将减压分配到支架;以及用于提供歧管与减压的源之间的流体相通的导管。
在进一步的实施方式中,提供了提供减压治疗并促进在患者的组织部位处的组织生长的方法,该方法包括:在组织部位植入支架,其中支架提供用于组织生长的结构基质并包括在腔表面上的凝胶或液体组合物,其中凝胶或液体组合物适合包括微气泡;将减压应用到支架;并且使微气泡中的大部分破裂以向支架诱导流体流。
在另外的实施方式中,提供了用于提供减压治疗并促进在患者的组织部位处的组织生长的装置,装置包括:可适用于植入组织部位的支架,其中支架提供用于组织生长的结构基质并包括缓慢可降解的材料和快速可降解的材料,快速可降解的材料比缓慢可降解的材料降解更快以在支架中形成用于传输流体的通道;以及用于向支架提供减压的歧管,其中通道提供歧管与组织部位之间的流体相通。
在进一步的实施方式中,提供用于耦合神经组织和微芯片组件(microchip assembly)的系统,系统包括:减压的源;适用于毗邻于神经组织设置的生物相容的导管,其中导管流体地耦合到所述减压的源;和设置在导管内的微芯片组件,其中来自减压的源的减压促进神经组织的生长以操作性地连接到所述微芯片组件。
在该系统中,导管可以是生物可吸收的。
该系统还可包括:接口,其用于流体地耦合减压的源和导管。
在该系统中,微芯片组件可以被耦合到电子控制单元。
在该系统中,微芯片组件可以被耦合到假体或矫形器。
在该系统中,神经组织可以被设置在导管内。
本发明还提供了一种用于向组织部位的创伤提供减压并促进创伤内的组织生长的装置,该装置包括:支架,其用于植入创伤中,支架提供用于组织生长的结构并具有在支架中的与创伤流体相通的通道;化学物质,其覆盖通道的至少一部分且具有能适于包括微气泡的组合物;以及歧管,其用于向支架提供减压。
在该装置中,化学物质可以被预形成有微气泡。
在该装置中,化学物质可以是操作性的,以响应于诱导化学物质中的气相转变的刺激而形成微气泡。
在该装置中,支架在形状上可以是大体上管状的,具有形成通道的腔表面。
在该装置中,支架可以是基本上圆柱形的形状,具有与创伤流体相通的多个通道,通道的一部分至少部分地被化学物质覆盖。
在该装置中,化学物质可以包括全氟化碳。优选地,全氟化碳可以是全氟戊烷(C5F12)或全氟丁烷(C4F10)中的一种。
在该装置中,化学物质还可以包括两亲性物质。优选地,两亲性物质可以是嵌段共聚物。进一步地,嵌段共聚物可以是(聚(氧化乙烯)-嵌段-聚(L-丙交酯))(PEG-PLLA)、聚(氧化乙烯)-嵌段-聚(己内酯))或普卢兰尼克P-105。
在该装置中,化学物质还可以包括生物活性剂。优选地,生物活性剂可以是抗生素和生长因子中的至少一种。更优选地,生物活性剂可以是生长激素(GH)、骨形态发生蛋白(BMP)、转化生长因子-α(TGF-α)、TGF-β、成纤维细胞生长因子(FGF)、粒细胞集落刺激因子(G-CSF)、粒细胞/巨噬细胞-集落刺激因子(GM-CSF)、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、胰岛素样生长因子(IGF)、血管内皮生长因子(VEGF)、肝细胞生长因子/离散因子(HGF/SF)、白细胞介素、肿瘤坏死因子-α(TNF-α)或神经生长因子(NGF)。本发明还提供了一种用于向组织部位的创伤提供减压并促进创伤内的组织生长的系统,该系统包括:压力源,其用于提供减压;歧管,其与压力源流体相通,用于向组织部位提供减压;支架,其与歧管流体相通,用于将减压输送到创伤,支架具有支持创伤内组织生长的结构和结构内的与创伤流体相通的至少一个通道,通道具有腔表面;以及化学物质,其覆盖腔表面的至少一部分且包含微气泡,微气泡能适于促进来自创伤的流体流通过支架内的至少一个通道。
在该系统中,化学物质可以被预形成有微气泡。
在该系统中,化学物质可以是操作性的,以响应于诱导化学物质中的气相转变的刺激而形成微气泡。
在该系统中,支架可以是基本上管状的形状,具有与创伤流体相通的一个通道。
在该系统中,支架可以是基本上圆柱形的形状,具有与创伤流体相通的多个通道,具有腔表面的通道的一部分可以至少部分地被化学物质覆盖。
在该系统中,化学物质可以包括全氟化碳。优选地,化学物质可以是全氟戊烷(C5F12)或全氟丁烷(C4F10)中的一种。
在该系统中,化学物质还可以包括两亲性物质。优选地,两亲性物质可以是嵌段共聚物。更优选地,嵌段共聚物可以是(聚(氧化乙烯)-嵌段-聚(L-丙交酯))(PEG-PLLA)、聚(氧化乙烯)-嵌段-聚(己内酯))或普卢兰尼克P-105。
在该系统中,化学物质还可以包括生物活性剂。优选地,生物活性剂可以是抗生素和生长因子中的至少一种。更优选地,生物活性剂可以是生长激素(GH)、骨形态发生蛋白(BMP)、转化生长因子-α(TGF-α)、TGF-β、成纤维细胞生长因子(FGF)、粒细胞集落刺激因子(G-CSF)、粒细胞/巨噬细胞-集落刺激因子(GM-CSF)、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、胰岛素样生长因子(IGF)、血管内皮生长因子(VEGF)、肝细胞生长因子/离散因子(HGF/SF)、白细胞介素、肿瘤坏死因子-α(TNF-α)或神经生长因子(NGF)。
在该系统中,支架可以被预形成有低压力室。本发明还提供了一种向组织部位的创伤提供减压并促进创伤内的组织生长的方法,该方法包括:使用支架,支架具有在结构内的与创伤流体相通的至少一个通道,其中通道被包括微气泡的化学物质至少部分地覆盖;将支架植入创伤,用于提供用于组织生长的结构并向组织部位提供减压;将减压施加到支架和创伤;以及使微气泡中的大部分破裂,以诱导支架内的流体流,从而促进创伤内的组织生长。
在该方法中,使用支架可以包括使用化学物质,化学物质可以是操作性的,以响应于诱导化学物质中的气相转变的刺激而形成微气泡。
在该方法中,使用支架可以包括使用预形成有微气泡的化学物质。
该方法还可包括:在植入支架之后诱导化学物质中的气相转变以形成微气泡。进一步地,诱导化学物质中的气相转变可包括将化学物质暴露于患者的体温。
在该方法中,使微气泡中的大部分破裂可包括诱导减压中的梯度。
在该方法中,使微气泡中的大部分破裂可包括通过在支架的连续节段上连续地使微气泡破裂来诱导减压中的定向变化。
在该方法中,使微气泡中的大部分破裂可包括将化学物质暴露于超声能。
在该方法中,使微气泡中的大部分破裂可包括将化学物质暴露于光能。
在该方法中,使用支架可包括使用基本上为管状形状的具有形成通道的腔表面的支架。
在该方法中,使用支架可包括使用预形成的低压力室。
本发明还提供了一种该用于向组织部位的创伤提供减压并促进创伤内的组织生长的装置,装置包括:支架,其用于植入创伤中,以提供用于组织生长的结构,支架由第一材料形成且具有形成在支架中的通道,通道包括响应于减压而降解的第二材料;以及歧管,其用于向支架提供减压,由此第二材料降解以形成通路,以提高支架内的来自所述创伤的流体流动。
在该装置中,其中第一材料可以是可降解的且第二材料可以是以比第一材料快的速率可降解的。
在该装置中,第二材料可以包括水胶体。优选地,水胶体可以包括多糖。
在该装置中,支架可适合于植入在骨中的创伤处。
在该装置中,第二材料还可以包括生物活性剂。优选地,生物活性剂可以是生长因子和抗生素中的至少一种。更优选地,生物活性剂可以是生长激素(GH)、骨形态发生蛋白(BMP)、转化生长因子-α(TGF-α)、TGF-β、成纤维细胞生长因子(FGF)、粒细胞集落刺激因子(G-CSF)、粒细胞/巨噬细胞-集落刺激因子(GM-CSF)、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、胰岛素样生长因子(IGF)、血管内皮生长因子(VEGF)、肝细胞生长因子/离散因子(HGF/SF)、白细胞介素、肿瘤坏死因子-α(TNF-α)或神经生长因子(NGF)。
参考附图和以下详细的描述,说明性实施方式的其它目的、特征和优势将是明显的。
附图简述
图1是以部分横截面显示的用于将减压治疗应用到患者的组织部位的系统;
图1A是沿线1A-1A取的图1系统的横截面视图。
图2A-2C显示不同的时间点的图1系统中的支架;
图3是根据说明性实施方式的减压治疗装置的横截面视图。
图3A是沿线3A-3A得到的图3装置的横截面视图;以及
图4是用于连接神经组织与微芯片组件的系统的说明性实施方式。
优选实施方式的详细描述
在以下的对例证性的实施方案的详细描述中,参照了附图,附图形成例证性的实施方案的一部分。这些实施方案被足够详细地描述以使本领域的技术人员能够实践本发明,并且应当理解,可以利用其他的实施方案并且可以做出逻辑结构的、机械的、电的以及化学的变化而不偏离本发明的精神或范围。为了避免对于使本领域的技术人员能够实践本文描述的实施方案来说不必要的细节,描述可能省略了本领域的技术人员已知的某些信息。因此,以下的详细描述不应以限制的意义理解,并且例证性的实施方案的范围仅被所附的权利要求限定。
参考图1和2A-2C,用于将减压应用到患者103的组织部位102的减压治疗系统100包括提供减压的减压源106、经导管110流体地耦合到压力源106的歧管108,以及与歧管108流体相通的支架112。在这一实施例中,组织部位102是具有创伤105的骨104,创伤105是骨104的骨干中的裂隙。歧管108将减压传输到被植入到骨104的创伤105之内的支架112。支架112可具有取决于创伤类型的多种形状,并且在这一实施方式中具有管状形状以填充在骨104内的裂隙或创伤105。管状支架112具有单腔或流动通道124,单腔或流动通道124轴向地延伸通过支架112并且具有腔表面114。支架112也可以具有实质上圆柱状的形状,其具有用于在创伤105内生长新的组织所需的多个腔。最后,支架112由细胞和基质蛋白定植,细胞和基质蛋白响应于负压或其它刺激的应用而主要从骨104的髓内空间122流经流动通道124。
支架112的腔表面114涂敷有具有固体、胶状或液体形式的化学物质116,化学物质116包含微气泡118(未显示)。化学物质116可包括当被应用到流动通道124的腔表面114时在化学物质116中预形成的微气泡118。在其它实施方式中,化学物质116可包括在被应用到流动通道124的腔表面114之后形成微气泡118的组合物,作为化学物质116的部分响应于刺激或催化剂而转换成气相的结果,即,气相转变。在支架112被植入到创伤105内之后,作为治疗的一部分,微气泡118破裂以诱导来自髓内空间122的流体流通过流动通道124并进入支架112,如箭头126所指出的。
图2A至2C显示三个不同的时间点的支架112和化学物质116。图2A显示在微气泡118被形成之前且在气相转换的诱导之前的支架112和设置在腔表面114上的化学物质116。图2B显示包含微气泡118的化学物质116,当开始应用到腔表面114时微气泡118已经被形成,或在应用之后在气相转换的诱导时微气泡118被形成。微气泡118可通过多种刺激而形成,例如通过在化学物质116被设置在腔表面114上之前或之后使用对高频超声做出响应的化学物质116并且然后将化学物质116暴露于这些超声频率以产生微气泡。
微气泡118也可以通过其它刺激形成,包括,例如光能、机械刺激或化学刺激或由外部源或其自身提供的热。
当微气泡118在化学物质116中预形成时,植入和随后将支架112加热至体温可以增加预形成的微气泡118的大小,如WO2006/12753中所描述。当微气泡118不是预形成时,化学物质116的气相转换可以通过由于将支架112植入到处于较高体温的创伤105而导致的温度增加来诱导。在一些实施方式中,化学物质116具有在哺乳动物的体温(例如对于人37℃)诱导气相转换的组合物。在其它实施方式中,气相转换可以通过具有例如在约20kHz至约500kHz的范围内的相当低的频率的声波或超声波诱导。对于任何具体的化学物质116的最佳波长可以通过常规实验确定。无论使用什么诱导方法,气相转换可以在支架112的植入之前或之后被诱导。微气泡118可以由化学物质116的气体组分形成,例如,全氟戊烷(C5F12)或全氟丁烷(C4F10)。微气泡118是直径小于约100μm的泡。在一些实施方式中,微气泡118是在直径约1μm与直径约75μm之间。
任何生物相容的气体可以被用于微气泡118的形成,包括氮气、氧气、二氧化碳、氢气、惰性气体(例如,氦、氩、氙或氪)、氟化硫(例如,六氟化硫)、任选地卤代硅烷诸如甲基硅烷或二甲基硅烷、低分子量烃诸如烷烃、环烷烃、烯、醚、酮、酯、卤代的低分子量烃或前述的任何的混合物。在一些实施方式中,用于形成微气泡118的气体包括氟原子,例如溴氯二氟甲烷、氯二氟甲烷、二氯二氟甲烷、溴三氟甲烷、氯三氟甲烷、氯五氟乙烷、二氯四氟乙烷、氯三氟乙烯、氟乙烯、氟乙烷、六氟化硫、1,1-二氟乙烷和全氟化碳,例如,全氟丙烷、全氟丁烷和全氟戊烷。
微气泡118可通过将气体或在体温时是气体的化合物与两亲性化合物或表面活性剂混合而形成。参见,例如PCT专利公布WO2006/127853和美国专利申请公布US2005/0260189,两者通过引用并入。化学物质116中的用于形成微气泡118的表面活性剂可包括单个化合物或化合物的组合。有用的表面活性剂的实例包括类脂,包括甾醇、烃、脂肪酸和衍生物、胺、酯、鞘脂和硫醇-类脂;聚氧丙烯嵌段共聚物;聚氧乙烯;糖酯;脂肪醇、脂肪族氧化胺;透明质酸脂肪族酯及其盐、十二烷基聚-(乙二氧基)乙醇;壬基苯氧基聚(乙烯氧基)乙醇;羟乙基淀粉;羟乙基淀粉脂肪酸酯;葡聚糖;葡聚糖脂肪酸酯;山梨糖醇;脂肪酸山梨糖醇酯;明胶;血清白蛋白;含磷脂的表面活性剂(例如,卵磷脂[磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱或二硬脂酰卵磷脂等]、磷脂酸、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、心磷脂、鞘磷脂);非离子表面活性剂如聚氧乙烯-聚氧丙烯共聚物,例如,普卢兰尼克表面活性剂(Pluronic surfactant);聚氧乙烯脂肪酸包括聚氧乙烯硬脂酸酯、聚氧乙烯脂肪醇醚、聚氧乙烯化山梨糖醇脂肪酸酯、甘油聚乙二醇氧基硬脂酸酯、甘油聚乙二醇蓖麻油酸酯、乙氧基化大豆甾醇、乙氧基化蓖麻油及其氢化的衍生物;胆固醇;阴离子表面活性剂。在一些实施方式中,两亲性物质是嵌段共聚物,例如(聚(氧化乙烯)-嵌段-聚(L-丙交酯))(PEG-PLLA)、聚(氧化乙烯)-嵌段-聚(己内酯))或普卢兰尼克P-105(Pluronic P-105)。除了表面活性剂,其它的剂可以被并入化学物质116的水相。这些剂包括常规的粘度改进剂,缓冲剂如磷酸盐缓冲液或其它常规的生物相容的缓冲液或pH调节剂如酸或碱,渗透剂(以提供等渗性,高渗透压性(hyperosmolarity)或低渗透压性(hyposmolarity))。
在一些实施方式中,化学物质116可以进一步包括生物活性剂,其可以被包含在微气泡118之内,其中当微气泡118被破裂时生物活性剂被释放。微气泡118可以包入生物活性剂,生物活性剂可取决于其中微气泡118破裂的治疗而被释放,如下面更详细地描述。生物活性剂也可以存在于微气泡118外面的化学物质116之内,如在溶液中或被包入表面活性剂的微粒中,其中该剂是缓慢释放的(参见,例如,WO2006/127853)。在一些实施方式中,生物活性剂是抗生素或生长因子。用于各种应用的有用的生物活性的生长因子的非限制性实例是生长激素(GH)、骨形态发生蛋白(BMP)、转化生长因子-α(TGF-α))、TGF-β、成纤维细胞生长因子(FGF)、粒细胞集落刺激因子(G-CSF)、粒细胞/巨噬细胞-集落刺激因子(GM-CSF)、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、胰岛素样生长因子(IGF)、血管内皮生长因子(VEGF)、肝细胞生长因子/离散因子(HGF/SF)、白细胞介素、肿瘤坏死因子-α(TNF-α)或神经生长因子(NGF)。
图2C显示在经受使微气泡118破裂的刺激之后的支架112和化学物质116,以致他们破裂或坍塌以促进流体流,如箭头126所表示,通过流动通道124和化学物质116进入支架112,如上面所描述。微气泡118可被多种刺激弄破,例如通过将微气泡118暴露于具有约1MHz至约5MHz的范围内的频率的高频超声。微气泡118的破裂在化学物质116中产生开口,开口为流体占用提供了增加的区域且也可以形成用于促进或增强流体流的通道,如上面所描述,包括气态流体流和液态流体流如来自创伤105的流体流。在一些实施方式中,流体流的方向可以通过在化学物质116的不同的部分中集中微气泡118以将流指向支架112的预定部分来控制。在其它实施方式中,定向的流通过在支架112的连续节段上连续地使微气泡118破裂以产生流体流中定向的变化来增强。
如本文所用术语“支架”是指为细胞的生长和/或组织的形成提供结构性基质的物质。支架通常是三维多孔结构,其可以被注入有、涂敷有或包含细胞、生长因子、细胞外基质组分、营养素、整联蛋白或其它物质以促进细胞生长。支架可以通过引导流通过基质而采取歧管的性质。支架112可具有多种形状,包括,例如,基本上圆柱状形状如为产生神经纤维而制备的导管。这样的支架的实例描述在美国临时专利申请61/142,053和61/142,065中。支架112可以被用于可从定向的流中获益的任何组织工程应用。这些支架用于例如,鼓励长骨生长或用于神经再生,如美国临时专利申请61/142,053中所讨论。
适合的支架112材料的非限制性实例包括细胞外基质蛋白如纤维蛋白、胶原或纤连蛋白,以及合成的或天然产生的聚合物,包括生物可吸收的或非生物可吸收的聚合物,如聚乳酸(PLA)、聚乙醇酸(PGA)、聚丙交酯-共-乙交酯(PLGA)、聚乙烯吡咯烷酮、聚己内酯、聚碳酸酯、聚富马酸酯、己内酯、聚酰胺、多糖(包括藻酸盐[例如藻酸钙]和壳聚糖)、透明质酸、聚羟基丁酸酯、聚羟基戊酸酯、聚二氧六环酮、聚原酸酯(polyorthoesther)、聚乙二醇、泊洛沙姆、聚磷腈、聚酐、聚氨基酸、聚原酸酯(polyortho ester)、聚缩醛、聚氰基丙烯酸酯、聚氨基甲酸酯、聚丙烯酸酯、乙烯-醋酸乙烯酯聚合物和其它酰基取代的纤维素乙酸酯及其衍生物、聚苯乙烯、聚氯乙烯、聚氟乙烯、聚乙烯咪唑、氯磺化聚烯烃、聚氧化乙烯、聚乙烯醇、、水凝胶、明胶和尼龙。支架112也可以包括陶器,如羟基磷灰石、珊瑚磷灰石、磷酸钙、硫酸钙、碳酸钙或其它碳酸盐、生物玻璃、同种异体移植物、自体移植物、异种移植物、去细胞化组织(decellularized tissue)或上面的任何的混合物。在具体的实施方式中,支架112包括胶原、聚乳酸(PLA)、聚乙醇酸(PGA)、聚丙交酯-共-乙交酯(PLGA)、聚氨基甲酸酯、多糖、羟磷灰石或聚乙二醇(polytheryleneglycol)。另外,支架112可包含在支架112的分离的区域中的、或被非共价地结合或共价地结合的(例如共聚物,例如聚环氧乙烷-聚丙二醇嵌段共聚物或三元共聚物)、或以其的组合的方式的任何两种、三种或更多种材料的组合。合适的基质材料在例如Ma和Elisseeff,2005,和Saltzman,2004中讨论。
现在参考图3,减压治疗系统300的另一实施方式具有与减压治疗系统100类似的部件,如共同的数字参考所示。减压系统300包括与歧管108流体相通的支架312,支架312具有上面描述的支架112的所有特征,包括但不限于具有腔表面314的单腔或流动通道324。腔表面314也可以被涂敷有包含微气泡118的化学物质116(未显示),如上面所描述。支架312可以由生物可吸收的材料形成,其以不同的速率降解以进一步增强流体流通过支架312。例如,支架312可以主要由可以是可降解的第一材料或结构材料328和比第一材料更快速地降解的第二材料形成,第二材料即是可降解的材料例如在少于一天或两天中降解的水胶体。比结构材料328更快速地降解的第二材料可以被制成通道330的形式,其基本上径向从腔表面314延伸到歧管108。当通道330的材料在支架312被植入到创伤105内之后降解时,通路(channel passage)332被形成通过支架312以进一步促进来自髓内空间122的流体流通过流动通道324并且进入和通过支架312。
第二材料也可以被形成在支架312的结构材料328的各处分散的凹窝(pocket)334中。可降解材料的凹窝334可以在除了可降解材料的通道330之外使用或代替可降解材料的通道330而使用,且当与通道330结合使用时可以不同的速率降解。当可降解材料的凹窝334在支架312被植入到创伤105内之后降解时,孔(未显示)被形成在结构材料328中,其可以吸收更多的流体和/或提供通道以在除了通路332之外进一步促进流体流从髓内空间122到歧管108。
如上面所显示,当支架312被植入到创伤105内且通过歧管108应用减压时,减压梯度流经支架312,从骨104的髓内空间122通过流动通道324和通路332以促进用于递送包含在流体之内的细胞和有益蛋白(例如,生长因子和结构蛋白)的流体流动进入支架312。随着可降解材料的凹窝334分解时,支架312的结构材料328中的孔吸收来自髓内空间122的流体,加速支架312的细胞定植。应当理解结构材料328中的孔和通路332在降解之后可以是可渗透的材料基质,具有选择的渗透性以控制支架312吸收这些流体的速率。在其它实施方式中,结构材料328中的孔可以实质上是空的,且通路332也可以基本上是空的或狭窄的,以进一步提高流体流动通过支架312并进入歧管108。
当愈合或组织产生/重塑进行时,创伤愈合和组织工程可以从改变的流型式中获益。此外,如果不作出流的调整,那么支架312中的孔和通路332的堵塞可引起通过支架312的流随着时间减少。因此,用于治疗创伤105的治疗可以随着时间改变。例如,基于愈合的时序阶段,即,止血(数秒至数小时)、炎症(数小时至数天)、修复(数天至数周)和重塑(数周至数月),新的创伤(例如,手术后)将从促进止血的剂(例如,血小板活化因子,PAF)的提供获益,其条件是当愈合首先开始时剂被提供,且如果仅在制造创伤之后的数天提供将不是有益的。相反,如果在一天或两天之后被提供,修复或重塑中涉及的剂,例如TGF-β,将是最有益的。
支架312的结构材料328可以选自多种可降解的材料,只要它们比通道330的可降解材料降解更缓慢。在一种实施方式中,结构材料328持续六十天未完全地降解,同时通道330和/或凹窝334的可降解材料可以在少于六十天低至一天的时间期间完全地降解。结构材料328可以是基本上不降解的生物相容的材料,如金属或聚醚醚酮(PEEK)。在一些实施方式中,支架312由除了可降解材料的通道330和/或凹窝334外已经是多孔的结构材料328形成,以致多孔的结构材料328加速流体流进和通过支架312并为流体提供可选的通道,如果孔和通路332变得堵塞或阻滞。多孔结构材料328具有平均大小在约50微米与500微米之间的孔。在其它实施方式中,结构材料328不是多孔的,且通道330和凹窝334中可降解的材料的降解起到使流开始通过支架312的作用。支架312可由适合所选材料的多种方法制备,包括,例如,上面提到的那些方法且进一步包括盐过滤、冻干、相分离、织造纤维、结合非织造纤维,或起泡。
在一些实施方式中,通道330和凹窝334的可降解的材料包括水胶体,如包括天然产生的或化学修饰的多糖的那些。适合的化学修饰的多糖包括羧甲基纤维素凝胶、羟乙基纤维素凝胶、羟基-丙基甲基纤维素凝胶、壳聚糖、低-甲氧基果胶、交联葡聚糖和淀粉-丙烯腈接枝共聚物、聚丙烯酸钠接枝淀粉(starch sodium polyacrylate)及其混合物。适合的天然多糖包括褐藻酸及其盐、果胶、半乳甘露聚糖如黄原胶或瓜尔胶、豆角胶、刺梧桐胶、阿拉伯胶、透明质酸及其盐、淀粉,及其混合物。适合的合成的水胶体包括高分子量聚乙二醇和聚丙二醇,甲基乙烯醚和马来酸的聚合物以及衍生物;聚乙烯吡咯烷酮、聚乙二醇、聚丙二醇、聚丙烯酸的金属盐和/或铵盐和/或其共聚物,聚苯乙烯磺酸的金属盐或铵盐,及其混合物。
通道330和凹窝334的可降解的材料,以及到可降解程度的结构材料328,可进一步包括生物活性剂,如抗生素或生长因子,包括上面讨论的那些。在支架312的一些实施方式中,通道330和凹窝334,以及到可降解程度的结构材料328,可以包括多于一种类型的可降解的材料,例如,以两种不同的速率降解的材料,以控制用于为了向患者103施用治疗而以预定模式沉积细胞或释放生物活性剂的流体流的模式。例如,最接近于骨104的骨干的通道330可以由比支架312的中心的通道330降解更快的材料形成,以加速那些位置的流体流,由此加速创伤105的愈合。
如上面所示,当愈合或组织产生/重塑进行时,创伤愈合和组织工程可以从改变的流类型中获益。如果不作出流的调整,支架312中的孔和通路332的堵塞可引起通过支架312的流体流随着时间减少。因此,支架312也可以包括减压室340,当减压室340被刺破或破裂时其刺激流体和蛋白沿着期望的途径341向中央减压源如歧管108流动。这些减压室340可以是任何形状的,例如,球形的或椭圆形的,且包含低于支架312之内的环境压力的压力。当室340破裂和开放时,减压室340之内压力足够地低以致室340进一步诱导流体流从髓内空间122经过流动通道324,并进入和通过支架312。在治疗创伤105的治疗期间,随着流调整时,减压室340也用于使支架312中的孔和通路332畅通以促进流体流通过支架312。
创伤105可以是位于任何组织部位102之上或之内的伤害或缺陷,如骨折,组织部位102包括但不限于,骨组织、脂肪组织、肌肉组织、神经组织、皮组织、血管组织、结缔组织、软骨、腱或韧带。例如,创伤105可以包括烧伤、切开性创伤、切除性创伤、溃疡、创伤性伤口和慢性开放性伤。创伤105也可以是不一定是受伤的或有缺陷的任何组织,而是其中期望增加或促进另外的组织如骨组织的生长的区域。例如,减压组织治疗可以用于某些组织区域以生长可以被收获并移植到另一组织位置的另外的组织。组织部位102也可以包括用于在体外和体内维持内源性或外源性移植物的部位,和用于随后植入到患者103中的支持性支架。患者103可以是任何哺乳动物,如小鼠、大鼠、兔、猫、狗或灵长类,包括人类。
在本说明书的上下文中,术语“减压”一般指低于接受治疗的组织部位的环境压力的压力。在大多数情况中,该减压将低于患者位置的大气压力。虽然术语“真空”和“负压”可以用于描述应用到组织部位的压力,但是应用到组织部位的实际压力可以显著地大于通常与绝对真空相关的压力。与本命名法一致,减压或真空压力的增高指绝对压力的相对下降,而减压或真空压力的下降指绝对压力的相对增高。减压治疗典型地应用-5mm Hg至-500mm Hg,更通常地-5mm Hg至-300mm Hg,包括但不限于-50mm Hg、-125mm Hg或-175mm Hg的减压。
如本文所用术语“歧管”一般指这样的物质或结构,其被提供以帮助向组织部位102应用减压,递送流体至组织部位102,或从组织部位102除去流体。歧管108通常包括多个流动通道或路径,多个流动通道或路径分配提供到歧管108附近组织部位102的流体和从歧管108附近组织部位102除去的流体。在一种说明性实施方式中,流动通道或路径相互连接以提高提供的或从组织部位102除去的流体的分配。歧管108可以是生物相容的材料,其能够被放置成与组织部位102接触且将减压分配到组织部位102。歧管108的实例可以包括,例如,但不限于,具有被安排以形成流动通道的结构元件的器件,例如,多孔泡沫、开室泡沫、多孔组织结缔、液体、凝胶和包括或固化以包括流动通道的泡沫。歧管108可以是多孔的且可以由泡沫、纱布、毡制垫(felted mat),或适合具体的生物应用的任何其它材料制备。在一种实施方式中,歧管108是多孔泡沫且包括充当流动通道的多个相互连接的室或孔。多孔泡沫可以是聚氨基甲酸酯、开室、网状泡沫如由德克萨斯州的圣安东尼奥的Kinetic Concepts,Inc.制造的其它实施方式可包括“闭室”。歧管的这些闭室部分可以包含多个室,多个室中的大多数没有流体地连接到毗邻的室。闭室可以被选择性地设置在歧管108中以防止流体传递通过歧管108的周边表面(perimetersurface)。在一些情形中,歧管108也可以被用于将流体如药物、抗菌药、生长因子和各种溶液分配至创伤105。其它层可以被包括在歧管108中或歧管108上,如可吸收的材料、芯吸材料、水凝胶、疏水性材料和亲水性材料。
如上面所描述,减压治疗系统100将减压应用到创伤105,减压可以被均匀地分配通过支架112。在一些实施方式中,支架将减压间断地分配通过支架112和312,而不是以某种均匀的方式分配,因此产生减压梯度。例如,减压不是经单个点源,或经多个入口沿着线型的流动通道,或通过基本上均匀的分布歧管而均匀地递送。在一些实施方式中,减压梯度是空间上间断地,大小间断地或随着时间间断地。因此,减压梯度可以发生在创伤105的各处。
梯度是除了减压之外的任何可变的物理量的变化率,包括但不限于,生物梯度、热梯度、电梯度、磁梯度、化学梯度或正压梯度。歧管108和支架112与312可以被设计以分配这些其它物理特征的梯度。参照图1A和3A,例如,歧管108和支架112与312可以分配减压梯度和/或生物梯度,如分别由箭头126和326所示,如上面更详细地描述的和如进一步在通过引用并入本文的美国临时专利申请61/142,053和61/142,065中描述的。在对减压或其它刺激的应答中,环绕的支架112和312从骨104的髓内空间122径向地吸引流(未显示)通过它们各自的流动通道124和324,但是以间断的形式产生梯度以进一步促进组织生长和/或组织愈合。因此,本发明的方法和系统提供用于通过植入的支架112和312或在缺乏抵抗力的(compromised)部位如创伤105之内主动引导组织再生的方法,以使用这些物理梯度促进功能性恢复。因此,这些方法和系统提供主动机制,通过主动机制利用生物化学和物理线索来促进蛋白的内源性沉积和临时基质的组织,从而引导支架112和312或组织空间在创伤105内的细胞定居。
参考图4,显示用于将神经组织438耦合到微芯片组件440的系统436的说明性实施方式。这一实施方式的神经组织438可以是由于创伤而被损坏,以致仅留下一个分开的端部439。如本文所使用的,术语“耦合”包括通过另外的物体的间接耦合和直接耦合。术语“耦合”还包括两个或更多个部件,该两个或更多个部件由于部件中的每个从同一片材料形成而彼此连续。此外,术语“耦合”可以包括化学的、机械的、热的或电的耦合。流体耦合意指流体与指定的部分或位置之间连通。
微芯片组件440和神经组织438的分开的端部439被放置生物相容的神经导管442中,该生物相容的神经导管442在形状上是大体上管状的,用于在一端接收和密封神经组织438并在另一端由导管端壁443封闭以形成神经组织438的分开的端部439与导管端壁443之间的腔空间445。微芯片组件440具有毗邻分开的端部439放置的接触面441,且经延伸通过导管端壁443的连接物449被电耦合到电子控制单元(electronic controlunit)448。将电子控制单元448电耦合至微芯片组件440的连接物449可以是例如硬线连接或无线连接。电子控制单元448也可以包括用于经连接物449向微芯片组件440提供功率的电池450。应当理解电子控制单元448和电池450都可以在神经导管442内的腔空间445中与微芯片组件440结合。
神经导管442经导管459和歧管458流体地耦合到减压源456,歧管458将来自减压源456的减压分配到腔空间445。腔空间445中的减压向神经组织438的分开的端部439及其与微芯片组件440的接触面441的交接处提供流动类型,以促进神经组织438的生长和/或再生。更具体地,减压引起神经组织438中的纤维生长并操作性地连接到微芯片组件440的接触面441。歧管458可以是生物可吸收的以在神经组织438操作性地连接到微芯片组件440的接触面441之后便于导管459的除去。神经导管442本身也可以是在神经组织438的充分愈合之后生物可吸收的,以致其不需要被除去从而避免断裂神经组织438的分开的端部439与微芯片组件440的接触面441之间的操作性连接。
电子控制单元448控制假体的或矫形的器件(未显示)如假手。为了控制假体或矫形器件,电子控制单元448可以包括用于将无线电信号发射至假体或矫形器件的射频(RF)收发器。在其它实施方式中,电子控制单元448可以被包含在假体或矫形器件中用于直接控制活动。神经组织438的分开的端部439与微芯片组件440的接触面441之间的连接允许患者控制这些器件的活动,其借助于微芯片组件440使用思想控制的神经放电(firing)作为输入用于再生神经组织438。系统436可以被用作接口器件(interface device)以在神经创伤之后修复运动控制(motor control),或以建立矫正或假体器件的神经-引导的运动控制。
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所有在本说明书中引用的参考文献都在此以引用方式并入。本文对参考文献的讨论仅意在概括作者作出的结论,并且不作出任何参考文献构成现有技术的承认。申请人保留质疑所引用的参考文献的准确性和相关性的权利。
根据上文,将看到的是,本发明的优点被实现并且其他优点被获得。因为可以作出对上文的方法和内容的各种变化而不偏离本发明的范围,所以意图的是,在以上描述中包含的以及在附图中示出的所有内容应当被解释为是例证性的并且不作为限制性意义的。
Claims (14)
1.一种用于向组织部位的创伤提供减压并促进所述创伤内的组织生长的装置,所述装置包括:
支架,其用于植入所述创伤中,以提供用于所述组织生长的结构,所述支架由第一材料形成且具有形成在所述支架中的通道,所述通道包括响应于减压而降解的第二材料;以及
歧管,其用于向所述支架提供减压,由此所述第二材料降解以形成通路,以提高所述支架内的来自所述创伤的流体流动。
2.根据权利要求1所述的装置,其中所述第一材料是可降解的且所述第二材料是以比所述第一材料快的速率可降解的。
3.根据权利要求1所述的装置,其中所述第二材料包括水胶体。
4.根据权利要求3所述的装置,其中所述水胶体包括多糖。
5.根据权利要求1所述的装置,其中所述支架适合于植入在骨中的创伤处。
6.根据权利要求1所述的装置,其中所述第二材料还包括生物活性剂。
7.根据权利要求6所述的装置,其中所述生物活性剂是生长因子和抗生素中的至少一种。
8.根据权利要求6所述的装置,其中所述生物活性剂是生长激素(GH)、骨形态发生蛋白(BMP)、转化生长因子-α(TGF-α)、TGF-β、成纤维细胞生长因子(FGF)、粒细胞集落刺激因子(G-CSF)、粒细胞/巨噬细胞-集落刺激因子(GM-CSF)、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、胰岛素样生长因子(IGF)、血管内皮生长因子(VEGF)、肝细胞生长因子/离散因子(HGF/SF)、白细胞介素、肿瘤坏死因子-α(TNF-α)或神经生长因子(NGF)。
9.一种用于耦合神经组织和微芯片组件的系统,所述系统包括:
减压的源;
生物相容的导管,其适于布置成邻近神经组织,所述导管流体地耦合到所述减压的源;以及
微芯片组件,其设置在所述导管内,
其中来自所述减压的源的减压促进所述神经组织的生长从而操作性地连接到所述微芯片组件。
10.根据权利要求9所述的系统,其中所述导管是生物可吸收的。
11.根据权利要求9所述的系统,还包括:
接口,其用于流体地耦合所述减压的源和所述导管。
12.根据权利要求9所述的系统,其中所述微芯片组件被耦合到电子控制单元。
13.根据权利要求9所述的系统,其中所述微芯片组件被耦合到假体或矫形器。
14.根据权利要求9所述的系统,其中所述神经组织被设置在所述导管内。
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CN107007891B (zh) * | 2016-01-27 | 2023-09-19 | 上海交通大学医学院附属第九人民医院 | 一种密闭的带有组织再生室的组织器官的再生装置 |
CN113209383A (zh) * | 2021-05-17 | 2021-08-06 | 吉林大学 | 一种负载bmp-2基因缓释涂层的peek复合生物植入材料及其制备方法 |
CN113209383B (zh) * | 2021-05-17 | 2022-01-11 | 吉林大学 | 一种负载bmp-2基因缓释涂层的peek复合生物植入材料及其制备方法 |
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EP2370143B1 (en) | 2017-08-02 |
BRPI0918381A2 (pt) | 2019-09-24 |
BRPI0918185A2 (pt) | 2015-12-01 |
CN103520783B (zh) | 2016-02-24 |
RU2011122546A (ru) | 2013-02-10 |
TW201032849A (en) | 2010-09-16 |
CA2745867A1 (en) | 2010-07-08 |
SG172017A1 (en) | 2011-07-28 |
US20140276251A1 (en) | 2014-09-18 |
EP2370143A2 (en) | 2011-10-05 |
CN102264432A (zh) | 2011-11-30 |
US9918880B2 (en) | 2018-03-20 |
BRPI0918343A2 (pt) | 2019-09-24 |
JP2012513849A (ja) | 2012-06-21 |
WO2010078353A2 (en) | 2010-07-08 |
EP2370143A4 (en) | 2012-09-05 |
KR20110117129A (ko) | 2011-10-26 |
US20100168689A1 (en) | 2010-07-01 |
CN102264432B (zh) | 2013-10-23 |
WO2010078353A3 (en) | 2010-10-14 |
AU2009335032B2 (en) | 2015-08-27 |
US8734409B2 (en) | 2014-05-27 |
JP5643224B2 (ja) | 2014-12-17 |
AU2009335032A1 (en) | 2010-07-08 |
MX2011007052A (es) | 2011-07-20 |
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