CN1440256A - 通过刺激蝶腭神经节改善bbb和脑部血流性质的方法及装置 - Google Patents
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Abstract
本发明涉及一种用于修正病人大脑性能的装置,其包括一个或多个电极(7),该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)(6)和传入或传出SPG的神经束;以及一个控制单元(8),该控制单元适用于驱动所述一个或多个电极,将电流施加到可以诱导(a)患者BBB通透性增加,(b)患者脑血流的变化,和/或(c)SPG副交感神经活动抑制。
Description
技术领域
概括地说,本发明涉及医疗方法和电子装置。更具体而言,本发明涉及将电子装置植入头部,如植入鼻腔内的应用。本发明也涉及给药的方法和装置,用于治疗中风和偏头痛以及改善脑部血流。
背景技术
血脑屏障(BBB)是一种中枢神经系统(CNS)特有的,将脑部和血液体循环隔离的屏障。为维持CNS的动态平衡,BBB起到了防止多种在血液中循环的物质进入脑部的作用。
BBB是一种由内皮细胞、星形胶质细胞、外膜细胞、血管周巨噬细胞和基膜所构成的复杂细胞系统。与其它组织相比,脑内皮质具有最为致密的细胞—细胞联系:内皮细胞相互紧密粘结,构成CNS所特有的,被称为“紧密接头”或小带咬合的结构。它们由两个相对的质膜组成,通过各自侧面的细胞质结合而融合成为一层膜。这些紧密接头防止了内皮细胞间的细胞迁移和细胞运动。在大脑毛细血管周围环绕一层连续、均匀的基膜。这种基膜包夹着称为外膜细胞的可收缩性细胞,这些细胞构成了一个间歇层,当BBB被突破时,这些间歇层在噬菌和防卫作用方面可能起到一定作用。覆盖大脑毛细血管的星形胶质细胞末梢构成一个连续的套管,并通过合成和分泌内皮细胞分化具有BBB特征所必须的可溶性生长因子(如γ-谷氨酰基转肽基酶),维持BBB的整体性。
由于BBB的存在,使得一些基于通过血流向体内引入化合物的一些非手术治疗方法无效或效果不好。例如,化学疗法对于系统癌(如乳腺癌、小细胞肺癌、淋巴瘤和生殖细胞肿瘤)的CNS转移病灶疗效不好,尽管这些肿瘤在非CNS的身体部位取得临床改善甚至完全消失。决定药物通过血液转运进入CNS的主要因素包括脂溶性、分子量和电性。药物的脂溶性由正辛醇/水分配系数表示,它与药物透过或渗过BBB的能力间存在好的相关性。当药物分子量小于600Da(道尔顿)时这种相关性尤为明显。正常BBB阻止分子量大于180 Da的离子化水溶性药物的通过。而大多数现有的有效化疗药物分子量在200至1200Da之间。因此,由于脂溶性和分子量的限制,很多药物的通过被BBB所阻止。
除亲脂性药物穿过细胞扩散外,将某些分子跨过脑内皮细胞转运还有几种特殊的机制。一些特殊的转运蛋白可以转运所需分子,如糖和氨基酸。此外,对于阳离子血浆蛋白存在吸收性胞吞和胞转作用。某些蛋白如铁传递蛋白和胰岛素的特异性受体调节跨过细胞的胞吞和胞转。
非手术治疗神经系统疾病通常局限在系统摄入化合物如神经学药物以及其它可以治疗或改善神经学相关行为或疾病的神经学活性药物。但是这种治疗方法仅局限在少数可以通过BBB的已知化合物之中。而这些可以通过BBB的化合物往往会对身体其它部位或脑内非目标区域造成副作用。
为跨过BBB现已开展了多种研究,特别是如何克服药物进入脑部的限制。这些研究包括例如化学修饰、开发亲脂性更高的类似物或将化学化合物连接到特殊的载体之上。颈动脉内灌注甘露醇的高渗溶液或缓激肽类似物可以使人体BBB暂时性开放。同时,已经发现P-糖蛋白的调控作用有助于药物向大脑的转运,这种糖蛋白的底物可以被主动地从脑细胞泵出而进入毛细血管内腔。但由于上述方法所固有的局限性,仍需要寻找更通用、更有效和更可预测的跨过BBB的方法。
为调节脑部血流开发可控的方法是需要的。异常血流会明显影响或加剧很多病理情况,如中风、偏头痛和阿尔茨海默氏病。
以下参考文献可能是有帮助的,此处引用作为参考:
Delepine L.Aubineau P,“通过刺激副交感蝶腭神经节在大鼠硬膜中诱导血浆蛋白外渗(Plasma protein extravasation induced in rat dura materby stimulation of the parasympathetic sphenopalatine ganglion),”Experimental Neurology,147,389-400(1997)
Hara H,Zhang QJ,Kuroyanagi T,Kobayashi S,“副交感脑血管神经支配:由大鼠中蝶腭神经节的顺行跟踪(Parasympathetic cerebrovascularinnervation:An anterograde tracing from the sphenopalatine ganglion in therat),”Neurosurgery,32,822-827(1993)
Jolliet-Riant P,Tillement JP,“药物跨血脑屏障的转移以及脑转运的提高(Drug transfer across the blood-brain barrier and improvement of braindelivery),”Fundam.Clin.Pharmacol.,13,16-25(1999)
Kroll RA,Neuwelt EA,“为治疗目的战胜血脑屏障:渗透开口及其他方法(Outwitting the blood brain barrier for therapeutic purposes:Osmoticopening and other means),”Neurosurgery,42,1083-1100(1998)
Sanders M,Zuurmond WW,“在66患有群发性头痛的位患者中蝶腭神经节阻断的效力:12-70个月随访评估(Efficacy of sphenopalatineganglion blockade in 66 patients suffering from cluster headache:A 12-70month follow-up evaluation),”Journal of Neurosurgery,87,876-880(1997)
Syelaz J,Hara H,Pinard E,Mraovitch S,MacKenzie ET,Edvinsson L,“蝶腭神经节对大鼠中颈总动脉血流的刺激作用(Effects ofstimulation ofthe sphenopalatine ganglion on cortical blood flow in the rat),”Journal ofCerebral Blood Flow and Metabolism,8,875-878(1988)
Van de Waterbeemd H,Camenisch G,Folkers G,Chretien JR,RaevskyOA,“用分子量和形状以及h结合descriptor评测药物跨过血脑屏障(Estimation of blood brain barrier crossing of drugs using molecular size andshape and h bonding descriptors),”Journal of Drug Targeting,6,151-165,(1998)
Suzuki N,Hardebo JE,Kahrstrom J,Owman C,“选择性电刺激由蝶腭神经节发出的节后脑血管副交感神经纤维增强大鼠中的颈总动脉血流(Selective electrical stimulation of postganglionic cerebrovascularparasympathetic nerve fibers originating from the sphenopalatine ganglionenhances cortical blood flow in the rat),”Journal of Cerebral Blood Flow andMetabolism,10,383-391(1990)
Suzuki N,Hardebo JE,Kahrstrom J,Owman C,“在大鼠中电刺激三联脑血管神经纤维对颈总动脉血流的影响(Effect on cortical blood flow ofelectrical stimulation of trigeminal cerebrovascular nerve fibers in the rat),”Acta Physiol.Scand.,138,307-315(1990)
发明内容
就某些方面而言,本发明的一个目的是提供用于向脑部、特别是透过BBB传递化合物之经改善的方法和装置。
就某些方面而言,本发明的一个目的是提供上述方法和装置,利用侵入性最小的方法,这些方法和装置可以用于透过BBB传递上述化合物。
就某些方面而言,本发明的另一个目的是提供上述方法和装置,这些方法和装置可以易化大分子量化合物透过BBB的传递。
就某些方面而言,本发明的另一个目的是提供费效比高的方法和装置,这些方法和装置用于透过血脑屏障传递化合物。
就某些方面而言,本发明的另一个目的是提供改善的方法和装置,这些方法和装置通过透过血脑屏障传递化合物来治疗或改善神经系统性能和疾病。
就某些方面而言,本发明的另一个目的是调节脑部血流。
就某些方面而言,本发明的另一个目的是提供用于治疗中风的改善方法和装置。
就某些方面而言,本发明的另一个目的是提供用于治疗偏头痛的改善方法和装置。
就某些方面而言,本发明的另一个目的是提供改善的方法和装置,用于治疗神经系统疾病(如阿尔茨海默氏病),这些疾病症状的预后和发展会受到脑部血流的影响。
就某些方面而言,本发明的一个目的提供植入性装置,这种装置并未真正植入脑部但可以影响大脑性能。具体而言,这种装置可以被植入鼻腔中。
通过对下列优选实施方案的描述,可以更为明了地理解本发明的这些以及其它目的。
在本发明的优选实施方案中,一个电刺激器驱动电流至蝶腭神经节(SPG)或来自或者到达SPG的神经束中。典型地,电刺激器驱动电流达到控制和/或改变SPG相关行为的目的,例如,诱导脑部血流改变和/或调节血脑屏障(BBB)的通透性。这些实施方案可以用于多种医疗应用中,例如但不限于(a)治疗脑血管疾病,如中风,(b)治疗偏头痛,或(c)易化药物透过BBB转运。
可以这样理解,尽管本发明的优选实施方案是按照驱动电流至SPG或与其直接相关的神经结构中这种模式进行描述的,但本发明的范围包括驱动电流至至脑部其它部位,对其进行刺激而达到调节脑部血流或BBB通透性的目的,只要对指定用途适合即可。
同样也可以这样理解,电“刺激”,如本发明优选实施方案所提出的那样,基本上包括作用于指定组织的任何形式的电流,甚至包括设计用于阻断或抑制神经活性的电流。
同样也可以这样理解,此处所描述的植入和刺激部位、植入方法以及刺激参数仅起示例而非定界作用,本发明的范围包括其它可能性,这些可能性对于已阅读过本发明申请的本领域普通技术人员来说是显而易见的。
同样也可以这样理解,尽管本发明的优选实施方案是按照能量的电传递和组织的电刺激这种模式进行概括描述的,但其它方式的能量传递也是可以采用的。这些能量包括但不限于直接或诱导的电磁能、射频传输、超声传输、光能、以及低能量激光能(例如,通过光纤传递)。
同样也可以这样理解,尽管本发明的优选实施方案是按照对组织进行电刺激这种模式进行描述的,但根据本发明申请上下文以及权利要求可以将其理解成基本与施加电场相等价,例如通过两个电极制造一个电压降。
SPG是一个处于鼻后位于脑中的神经元中心。它由分布于脑中和脑前室、面部皮肤血管和泪腺的副交感神经元组成。这个神经节的激活被认为是造成这些血管舒张的原因。这种刺激的第二个作用是使血管壁上的开孔开放,造成血浆蛋白外渗(PPE)。这种效应促进了分子从这些血管向周围组织的转运。
脑中动脉和脑前动脉为大脑半球提供主要的血液供应,包括全部额叶和顶叶、岛和边缘系统、以及以下结构的大部分:颞叶、内囊、基底神经节和丘脑。这些结构与多数大脑神经和精神疾病有关,本发明的优选实施方案的目的是改善这些结构的血液供应和药物传递。
对于在脑后动脉和基底动脉中存在SPG源副交感神经神经分布的论断也有一些动物学证据。与人体也存在这种情况的推测相一致,如下所述,本发明优选实施方案所提出的处理方法可以作用于人大脑的多个区域。
当前,SPG是临床医学的一个作用靶位,大多数被用于治疗剧烈头痛,如群发性头痛。采用利多卡因暂时性地或利用无线电频率探头永久性阻断该神经节。两种情况中作用途径都是通过鼻孔。在本发明的一些优选实施方案中,为实现电刺激或电阻断SPG的作用,也采用类似的作用途径。
在本发明的一个优选实施方案中提供了一种方法和装置,其中通过刺激SPG和/或传出副交感神经束和/或其它副交感中心促进了治疗分子透过BBB的传递。典型地,该装置刺激SPG的副交感神经纤维,从而诱导脑中和脑前动脉舒张,并且造成这些动脉壁对大分子的通透性增加。按照这种方式,大的治疗分子从血管内转移至大脑组织的量明显增加。因此,该方法优选可以作为神经系统药物传递的易化器,而不需采用现有技术中降低分子量的方法。概况地说,可以认为基本上所有为达到治疗神经或精神疾病的目的而作用于大脑细胞的药物疗法均适用于本发明的这些实施方案。具体而言,这些实施方案可以适用于治疗脑肿瘤、癫痫、帕金森氏病、阿尔茨海默氏病、多发性硬化症、精神分裂症、抑郁、紧张、焦虑、以及其它的CNS疾病,这些疾病会直接或间接地受到大脑血流变化或BBB通透性变化的影响。
有利的情况是(甚至在未出现BBB通透性改变的情况下),一般来说,刺激SPG继发的血管舒张,以及由此导致的神经元和其它组织氧供应增加的情况,对于患有这些或其它疾病的患者都有好处。对于某些情况,治疗采取长期的模式,例如长时间治疗阿尔茨海默氏病。而对于其它的情况,治疗采取短期的模式,例如使急性中风所造成的损伤最小化,启动神经元及其功能的复原。
在本发明的一些优选实施方案中通过阻断SPG和相关神经束的方法达到治疗和防止偏头痛的目的。
因此,本发明的一个优选实施方案提供了用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以诱导患者血脑屏障(BBB)通透性增加的作用部位。
本发明的一个优选实施方案还提供了用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以诱导患者大脑血流增加的作用部位。
本发明的一个优选实施方案还提供了用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以诱导患者大脑血流降低的作用部位。
本发明的一个优选实施方案还提供了用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以抑制SPG副交感活动的作用部位。
优选地,该一个或多个电极适用于在患者体内的植入期大于约一个月的情况。
在一个优选实施方案中,上述装置包括一个导线,适用于连接控制单元和一个或多个电极,其中控制单元适用于在患者体外驱动所述一个或多个电极。
任选或附加地,控制单元适用于通过无线通讯的方式在患者体外驱动所述一个或多个电极。在一个优选实施方案中,装置包含一个电磁耦合器,适用于耦合所述控制单元以及一个或多个电极。任选或附加地,控制单元适用于通过光电通讯的方式在患者体外驱动所述一个或多个电极。同样任选或附加地,控制单元适用于通过声光通讯的方式在患者体外驱动所述一个或多个电极。同样任选或附加地,控制单元适用于植入患者的鼻腔。
优选地,该一个或多个电极适用于植入患者的鼻腔。对于某些应用,所述一个或多个电极中至少有一个电极包含柔性电极,这种柔性电极适用于插入患者鼻孔并延伸至作用部位。
优选地,本发明的装置至少包括一个生物传感器,适用于测量患者的生理学参数并产生响应信号。因此,控制单元优选适用于根据信号修正施加电流的参数。如果适合,生物传感器可以包括以下一种或多种传感器:
·血流传感器
·温度传感器
·化学传感器
·超声传感器
·跨颅多普勒(TCD)仪
·激光—多普勒仪
·系统血压传感器
·颅内血压传感器
·一种检测单元,适用于固定在大脑血管上,而且控制单元适
用于分析信号以决定是否有指示血管堵塞的血压变化的症
状。
·一种动力学传感器(在这种情况下,控制单元典型地适用于
分析信号以决定是否有患者身体配置改变的症状)
·脑电图(EEG)传感器
·血管堵塞传感器
在一个优选实施方案中,控制单元适用于调节电流,使得BBB通透性增加时易化药物透过BBB的吸收。
任选或附加地,控制单元适用于调节电流,使得血管直径增加,致使血管位于某一部位的栓塞从该部位移走。
同样任选或附加地,控制单元适用于驱动一个或多个电极施加对抗中风症状的电流。
同样任选或附加地,控制单元适用于驱动一个或多个电极施加对抗偏头痛病人症状的电流。
本发明的一个优选实施方案还提供了用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以诱导患者BBB通透性增加的作用部位。
本发明的一个优选实施方案也提供了用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以诱导患者大脑血流增加的作用部位。
本发明的一个优选实施方案还提供了用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以诱导患者大脑血流降低的作用部位。
本发明的一个优选实施方案还提供了用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以抑制SPG副交感活动的作用部位。
对于某些应用,该一个或多个电极适用于在患者体内的植入期不小于一周的情况。
本发明的一个优选实施方案还提供了一种血管装置,其包括:
一个检测单元,适用于固定于患者血管上并生成相应于血管能量的信号;以及
一个控制单元,适用于分析上述信号以决定血管中是否存在栓塞的症状。
优选地,检测单元中包含一个能量发射器和一个能量接收器。例如,能量发射器可能包括一个超声发射器或一个电磁能发射器。
本发明的一个优选实施方案还提供了一种检测方法,其包括:
将一个检测单元固定于患者血管上;
生成相应于血管能量的信号;然后
分析信号以决定血管中是否存在栓塞的症状。
与附图一起,通过以下优选实施方案的描述可以更全面地理解本发明。
附图说明
图1为一种依据本发明的优选实施方案用于刺激SPG的、全部可植入的刺激器的示意图;
图2为另一种依据本发明的优选实施方案用于刺激SPG的刺激器的示意图;
图3为依据本发明的优选实施方案如图1所示的刺激器所采用的电路的框图;
图4为依据本发明的优选实施方案如图2所示的刺激器所采用的电路的框图;
图5A和5B为依据本发明的优选实施方案如图1或图2所示的刺激器所采用的不同工作模式的示意图;
图6为依据本发明的优选实施方案与药物传递体系同步工作时,如图1或图2所示的刺激器的一种工作模式的示意图;
图7为依据本发明的优选实施方案如图1所示的刺激器所采用的电路的框图,其中刺激器由外部控制器和采用调制器和解调器的能源驱动;
图8描述了依据本发明的优选实施方案图7电路所采用的调制器和解调器的示意性功能;
图9、10A和10B为依据本发明的优选实施方案可植入性刺激器所采用的其它电路的框图;
图11和12为依据本发明的优选实施方案所收集的实验数据的棒图;
图13为依据本发明的优选实施方案用于血管的一种传感器的示意图。
具体实施方式
依据本发明的一个优选实施方案,图1为一种用于刺激患者蝶腭神经节(SPG)6或其它副交感神经部位的、全部可植入的刺激器4的示意图。图1中显示了人的鼻腔2,刺激器4植入在SPG6的附近。由SPG6中发出的副交感神经元的分支延伸至脑中和脑前动脉(图中未显示)。优选地,一个或多个相对较短的电极7从刺激器4中发出,伸展至与SPG6或受SPG6支配的神经(如神经节后副交感神经束)相接触或处于其附近。
对于某些应用,刺激器4被植入位于鼻腔底部的骨腭顶部上。任选或附加地,在口腔的顶部将刺激器4植于骨腭的下表面。在此情况下,从刺激器发出的一个或多个柔性电极7穿过腭骨或位于软骨之后,使得其处于刺激SPG或其副交感神经束的部位。同样任选或附加地,刺激器可直接安装在SPG和/或其神经节后副交感神经束上。
对于某些应用,将刺激器4以可拆卸的方式安装在一个刚性或略为柔软的导引棒(图中未显示)的远端,然后将导引棒插入患者的鼻道,直至刺激器被恰当定位,由此将刺激器传送到鼻腔2中理想的位置。如果合适,采用荧光透视法、X-射线引导、细内窥镜手术(FES)技术或其它本领域已知的导引技术,或联合使用上述技术,可以使置放过程更容易。优选地,在插入过程中同时测量环境温度和/或脑部血流。例如,可以采用放置于患者前额上的激光多普勒仪或跨颅多普勒仪测量脑部血流。通过激活装置,一般而言需同时检测脑部血流,可以验证电极是否恰当地植入到了适当的神经结构之上。
某些分子从脑血管进入大脑受到BBB的阻断。毛细血管的内皮、血管的质膜以及星形胶质细胞的末梢均对大脑摄入分子起到阻碍作用。BBB一般仅允许小分子(如分子量小于200Da的亲水性分子和分子量小于500Da的亲脂性分子)通过体循环进入大脑。
依据本发明的一个优选实施方案,刺激器4电流诱导的副交感神经活化克服了大脑毛细血管内皮和质膜对分子跨BBB运动的阻碍。因此,在某些应用中,刺激器4可用于暂时性显著去除血液和大脑间药物传递的障碍。例如,刺激器可以周期性地施加电流约2min,然后休息约1至20min。
人们推测在BBB性质改变中有两个神经递质—血管活性肠多肽(VIP)和一氧化氮(NO)起到了重要的作用(乙酰胆碱也可能起作用)。VIP是一种短肽,NO是一种气体分子。VIP被认为是易化血浆蛋白渗出(PPE)的重要因素,而NO则与血管舒张有关。对于某些应用,如果合适,为达到选择性影响这些神经递质的一种或全部,刺激器4被设计成可以改变施加于SPG上的电流参数的模式。例如,不同频率的副交感神经刺激可能诱导出不同的分泌—低频时造成NO分泌,高频(例如大于10Hz)时造成肽(VIP)分泌。
对于其它一些应用,为达到阻断受作用组织中副交感神经的活动的目的,施加恒定直流或电压缓慢递增的信号。或者在频率高于10Hz的条件下进行刺激也可得到类似的结果,因为这可以耗竭神经递质。因此,为造成类似化学阻断SPG总体效应的血管收缩,刺激器4可以被设置成诱导电阻断副交感神经的形式。例如,血管收缩效应可以用于受控地防止或倒转偏头痛的形成。现有技术中采用药物(如利多卡因)诱导SPG阻断,这种方法与电疗偏头痛的技术相悖。
依据本发明的一个优选实施方案,图2为位于患者体外的刺激器控制单元8的示意图。优选地,至少一个柔性电极10从控制单元8中发出,穿过患者鼻孔12,到达鼻腔14中接近SPG 6的位置。
可以认为电极7(图1)和10可能包含一个或多个,例如两个电极,或一个微电极束。对于刺激器4包含一个可作为电极的金属盒的情况,一般采用单电极7,以单极性模式工作。不论所采用电极总个数的多少,典型地,仅有一个或二个伸至SPG 6之处。其它电极7或10或刺激器的金属盒优选暂时性或永久性地被植入而与鼻腔2的其它部位相接触。
各电极7和/或10优选包含合适的导电材料,例如生理上可接受的材料,如银、铱、铂、铂铱合金、钛、镍钛合金、或镍铬合金。对于某些应用,一个或多个电极的长度在约1至5mm之间,直径在约50至100μm之间。各电极优选采用生理可接受的材料绝缘,如聚乙烯、聚氨酯、或这两种材料的共聚物。电极优选采用螺旋形状,以达到更好接触的目的,或者可以带一个钩状末端,用于钩住SPG或其附近区域。任选或附加地,如果合适,电极可包含简单线状电极、安装弹簧的“鳄鱼”电极、或粘性电极。
在本发明的一个优选实施方案中,除电极末端被制成具有大的表面积形式外,各电极7和/或10具有基本光滑的表面。例如,电极末端可被镀上多孔性铂。任选或附加地,至少是电极7或10的末端,和/或刺激器4的金属盒包含一层含有抗炎药物,如磷酸倍氯米松钠或磷酸倍氯米松的涂层。或者这种抗炎药物也可以经注射或其它方法给药。
依据本发明的一个优选实施方案,图3为用于刺激器4(图1所示)的电路的框图,包括植入单元20和外部单元30。植入单元20优选包含一个反馈模块22和一个或多个传感或信号施加电极24。典型地,植入单元20也包含一个电磁耦合器26,它从外部单元30中的电磁耦合器28处接收能量和/或二者间发生数据信号交换。
外部单元30优选包含一个微处理器32,用于接收外部控制信号34(如来自医生或患者的信号)和来自反馈模块22的反馈信号36。控制信号34可以包括,例如操作参数,如操作方案;病人参数,如体重;或信号参数,如施加于SPG之上的信号的预定频率和幅值。如果合适,控制信号34可以包含紧急超控信号,这些信号由患者或护理人员输入,以中止刺激或按预定程序修正刺激的模式。微处理器32优选处理控制信号34和反馈信号36以确定通过电极24施加的电流的一个或多个参数。与这种参数确定相呼应,微处理器32典型地生成一个由电磁耦合器28传递至电磁耦合器26的电磁控制信号42。控制信号42优选相当于通过电极24施加到SPG 6的所需电流和电压,并且在一个优选实施方案中利用控制信号42诱导驱动电极。电磁耦合器26和28和/或单元20或30中的其它电路的配置可以决定施加到预定组织上信号(如一系列脉冲)的强度、频率、波形、单相或多相模式、直流补偿。
典型地,微处理器32由电池44或其它任选直流电源提供能源。由电池44提供接地或设置独立的地线46。如果合适,微处理器32生成显示信号38,用于驱动外部单元30中的显示模块40。典型但不是必须地,激活显示模块是为了显示反馈模块22生成的反馈数据,或是为外部单元提供一个用户界面。
植入单元20优选包装在采用钛、铂或环氧树脂或其它生理上可接受材料制成的盒子中。如果盒子由金属制成,则该盒子可以作为一个接地电极,因此,刺激作用典型地以单相模式进行。此外,如果盒子由生理上可接受的塑料材料制成,典型地,为了向SPG施加电流需要驱动两个电极24。
对于某些应用,通过一个或多个电极施加到预定组织(如SPG)上的波形包含指数衰变波、斜上或斜下波、方波、正弦波、锯齿波、直流分量,以及现有技术中已知的其它任何适用于施加于组织之上的波形。任选或附加地,波形中可以包含一个或多个短形或矩形脉冲—各脉冲的持续时间优选小于1ms。一般而言,在外部单元30和植入单元20的初始测试期中确定其适当的波形和参数。对于某些应用,通过单元20刺激SPG期间和/或非激活(即停机)期间的测量,依据所测结果对波形进行大幅度的更新。
在偏头痛的治疗中,为阻断传出副交感神经的信息传播,波形可以采取缓慢改变形状的模式,例如慢锯齿波,或恒定的直流水平。
依据本发明的一个优选实施方案,图4为如图2所示刺激器8所采用的电路的框图。外部单元50包含一个由电池54或其它直流电源供能的微处理器52。接地可以由电池54或独立的地线56承担。微处理器52优选接收控制和反馈信号58和68(类似于上述的信号34和36),并且相应地生成通过一个或多个电极66向SPG或其它组织传递的刺激信号64。典型但不是必须地,反馈信号68包含通过一个和多个电极66测量的反馈电信号,和/或来自位于患者脑部或身体其它部位之上的其它传感器的反馈信号。如果合适,微处理器52生成显示信号60,该驱动显示模块62向病人或医生显示相关数据。典型地,一些或全部电极66被暂时性植入患者(如中风后的病人)体内,通过连接外部单元和植入单元的导线直接进行驱动。
依据本发明的一个优选实施方案,图5A是一个示意图,显示了图1-4所示一种或多种装置的一种工作模式。优选地,通过位于SPG上或头部其它部位(如鼻腔内)的温度传感器监测所施加刺激的效应。如图5A所示,对于一阶模式(开/关)的刺激,SPG或相关组织的刺激开始于T1,这可以通过温度测量值升高反应出来(因为血液流量增大)。一旦温度上升至预定的或发生显著变化的阈值(如37℃)时,中止刺激(时间T2),此时相应于温度下降。如果合适,当温度下降至设定的或动力学确定的点时,重新开始刺激(T3)。优选地,为达到最佳治疗的目的,需要对每个病人设定恰当的温度或其它生理学参数。如果合适,控制信号也可以由病人发出,例如当出现偏头痛时开始刺激。
依据本发明的一个优选实施方案,图5B是一个示意图,显示了图1-4所示一种或多种装置的一种工作模式。在这个实施方案中,为达到所需的效果,施加到SPG上的波形的幅值相应于测量温度在连续的一系列数值(S1)间或分立的一系列数值(S2)间变化。可以理解的是,为了使植入装置达到最佳疗效,其它测自头部的反馈参数或(如颅内压和/或大脑血流)以及所测的身体参数(如心率)和病人主观输入的参数(如偏头痛=3/5)可以与温度测量值一起使用或单独使用。
依据本发明的一个优选实施方案,图6是一个示意图,显示了图1-4所示一种或多种装置的一种工作模式。在这个实施方案中,在开始SPG刺激的时间T1之前,对病人恒速给药,如通过静脉。这种作法的有利之处在于血液中预先形成了高的药物浓度,使得药物透过BBB进入大脑的速度相对更快,而不需要为等待血药浓度达到适当数值而延长提高BBB通透性的刺激时间。此外,对于某些应用,在SPG开始之前或之后单次注射一大丸剂的药物也是理想的。典型地,根据作用于大脑的各药物的生物化学特性,医生决定给药和刺激联合使用的方案。
依据本发明的一个优选实施方案,图7为一示意图,显示用于副交感神经刺激的电路,这种电路与图1所示实施方案联合使用时特别有用。外部单元80包括由电池84和/或交流电源提供能源的微处理器82。由电池84或任选的地线86为微处理器82提供接地。
在一个典型的操作模式中,外部控制信号88被输入微处理器82中,同时从一个或多个生物传感器106中发出的反馈信号108也进入微处理器82中,典型地,这些生物传感器置于植入单元100附近或其它部位或位于患者体内。相应于信号88和108,如上所述,微处理器82优选生成一个驱动显示器90的显示信号。此外,微处理器82优选处理外部控制信号88和反馈信号108,以确定输出信号92的参数,其中输出信号受调制器94调节。所生成的输出信号优选驱动电流通过电磁耦合器96,该电磁耦合器96诱导驱动植入单元100中的电磁耦合器98。如果合适,电磁耦合器98耦合的解调器102随即生成一个信号103,用于向SPG或其它组织驱动电流。
优选地,生物传感器106可以包括可植入的或外部的医疗装置,例如以下的一种或多种:
·血流传感器,
·温度传感器,
·化学传感器,
·超声传感器,
·跨颅多普勒(TCD)仪,
·激光—多普勒仪,
·系统或颅内血压传感器(例如,包含一个固定在大脑血管上
的压电晶体,可以检测指征栓塞的突发血液升高),
·一种动力学传感器,包含例如一个加速度、速度或水平传感
器(如水银开关),用于指征身体配置,如身体状况的突然改
变(如虚脱)
·脑电图(EEG)传感器,包括安装或植入到患者头部的EEG
电极,用于指征神经学特征,如中风或偏头痛症状的改变,
·血管堵塞传感器(如以下图13所述传感器),
·其它适用于体现本发明这个实施方案或其它实施方案目的的
生理指标检测仪。
依据本发明的一个优选实施方案,图8为一个示意图,描述了调制器94和/或解调器102的操作模式。如左图所示,图7中信号92的幅值和频率可以含有某些数值;对于这些幅值和频率进行调制使得信号103具有不同的特征。
依据本发明的一个优选实施方案,图9为一个示意图,描述了另外一种刺激SPG的装置。在该实施方案中,基本上所有的处理和信号生成都是由植入病人体内的电路执行的,并且优选地,与外部单元111中的控制器122的通讯仅是间断进行的。植入单元110优选包含一个装有电池114的微处理器112。微处理器112生成信号116,该信号通过至少一个电极118刺激SPG。从生物传感器(未显示)和/或电极118发出的反馈信号120被微处理器112接收,并依据该信号修正刺激参数。优选地,微处理器112和控制器122之间通过电磁耦合器126和124联系,以达到交换数据和改变参数的作用。优选地,通过电磁耦合器电池114可以诱导充电。
依据本发明的一个优选实施方案,图10A是刺激器150的示意图。优选地,基本上所有的电子元件(包括具有可充电电源的电子电路158)被包覆在一个生理可接受的金属盒子154中。感应线圈156和至少一个电极162优选通过馈通耦合器160与电路耦合。感应线圈优选通过环氧树脂涂层隔离,使得电磁耦合效能更高。
依据本发明的一个优选实施方案,图10B显示可植入刺激器的另一种构造。优选地,基本上所有的电子元件(包括感应线圈176和具有可充电电源的电子电路178)被包覆在一个生理可接受的金属盒子174中。优选通过一个或多个馈通,使得在至少一个电极182和电子电路间,以及感应线圈176和其它通讯感应线圈(图中未作显示)之间发生耦合。
参考图10A和10B,电子电路158和178的能量源可以包含例如原电池、充电电池、或超级电容器。对于采用充电电池或超级电容器的应用,任何供能方法均可用于对能量源充装能量,例如(此处不作界定)标准的诱导充电方法或微型电机械能转换器,将病人运动的动能转换成电能。此外,外部光源(如简单的LED、激光二极管或其它光源)可以被导向至电子电路的光电电池上。此外,超声能量可以被导向至植入单元,转换后用于充电。
依据本发明的一个优选实施方案,图11和12为大鼠实验所得数据的棒图。常规监测物质在体内的生物分布的技术包括监测放射标记示踪剂的存在和浓度。这些示踪剂为结合有目标物质的常见元素(如Tc、In、Cr、Ga和Gd)的不稳定同位素。示踪剂的化学性质被用作对具有类似生理化学性质的其它物质行为的预测,选择的依据是被评价的某种特殊生物学机制。典型地,病人或实验动物被放在γ照相机中,或者可以收集目标组织样本并将其放入井型计数器中。根据本实验的目的,由于井型计数法灵敏度和空间分辩力高,实验中选用井型计数器。采用99Tc-DTPA(结合锝99同位素的DTPA分子)进行系列实验。99Tc-DTPA的分子量为458Da,亲脂性为负值,电核为+1。这些数值与标准化学疗法中的药物如三苯氧胺、鬼臼亚乙苷和药薯十分相似。
图11和12显示了利用常规大脑取样技术(图11)和剥离大脑技术(图12)获得的99Tc-DTPA穿透实验数据。各图中X轴代表实验次数,Y轴定义为[(脑半球放射性)/(脑半球重量)]/[(总注射放射量)/(动物体重)]。所得的结果表明对于大鼠大脑99Tc-DTPA穿透能力平均提高了2.5倍。需要指出的是,这些数据是通过单向刺激SPG得到的。本发明的发明者认为,与单向刺激SPG相比,双向刺激SPG差不多可以使药物穿透能力加倍。
在图11和12中,一些动物被标记为对照动物,其它动物被标记为实验动物。在各组中,左和右半球分别被测量,各棒的高度代表指定动物指定脑半球的标准放射量(定义如上)。图11共显示了四个测试脑半球和四个对照脑半球的结果。图12显示了六个测试脑半球和十四个对照脑半球的结果。棒图中对照和测试棒相互毗邻并不意味着它们是一个对照和测试脑半球对。
依据本发明的一个优选实施方案,图13为声学或光学栓塞检测装置202的示意图,它们用于例如为上述微处理器或其它装置提供反馈信号。优选在一个大血管200(如颈内动脉或静脉)上安置检测单元进行检测,其中检测单元包含声学或光学发射器/接收器206和一个任选的反射面。天然的生理流体可以作为装置和血管间的调节流体。优选地,发射器/接收器发出超声或电磁信号,信号经反射后被接收,处理器对接收信号的变化进行分析以确定是否存在新生成的栓塞。此外,将发射器置于血管的一侧而将接收器置于血管的另一侧。在这两种情况下,在某些应用中将更多个这样的装置202置于血管之上,其目的是改善检测栓塞的成功率,有可能预测栓塞在血管中的运动方向,降低误报(即误检测)的机率。
本发明的实施方案可能具有多种医学用途。例如,为治疗大脑肿瘤化疗药物需进入大脑组织。大多数的化疗药物分子量为200-1200Da,因此,它们通过血脑屏障(BBB)的转运受到极大的限制。为克服BBB的阻碍作用,现有技术中以及在利用颈动脉中滴注高渗物质,目的是短时间(如25min)打开BBB的紧密连接,在此期间进行给药。这种方法并不简单—它是一种侵入性的手段,需要进行麻醉,需要随后的精心治疗并且相对昂贵。由于这些原因,这种颈动脉中滴注仅在极少数的医疗机构中使用,尽管一些报道称接受这种方式的化学疗法可以显著提高患者的平均寿命。
优选地,本发明易化药物跨BBB传递并同时因此提高化疗效能的实施方案也可以减少或消除需要放疗的可能性。应当指出的是,大脑受到辐射是文献中讨论的、出现长期认知缺陷或其它问题的主要原因。
如本发明优选实施方案所提出的,提高药物转运效能也是治疗其它疾病如帕金森氏病、阿尔茨海默氏病和其它神经系统疾病的主要因素。对于某些应用,利用此处所描述的技术可以易化多种生长因子的跨BBB转运。生长因子一般为可以促进神经元生长的大分子,可以用于治疗退行性疾病,如帕金森氏病、阿尔茨海默氏病和运动神经元疾病(如LouGehrig病)。
本发明的其它优选应用包括易化药物的跨BBB转运,目的是为了治疗脑部炎症,如免疫低下病人大脑的感染性疾病。类似地,使用本发明的方法和装置,艾滋病的治疗药物可以更为有效地穿过BBB进入大脑中的作用部位。本发明一些实施方案的其它应用包括穿过BBB转运用于基因治疗药物的病毒(例如,用于治疗帕金森氏病)。类似地,此处所描述的方法和装置可以用于治疗大脑代谢异常,如GM2神经节苷脂沉积症。
本发明一些优选实施方案的其它方面涉及调节大脑血流。每年约有750,000美国人受到中风的侵扰。中风是美国第三大致死原因,每年造成约160,000人死亡。在美国有超过三百万人从中风中存活,其中有二百万人受跛性麻痹(crippling paralysis)、语言丧失和记忆力下降困扰。约有85%中风是局部缺血,即血管被堵塞并且局部缺氧。完全丧失血液供应的大脑区域被部分缺血的第二区域所包围,该区域的活力也处在危险之中。第二区域是本发明一些实施方案的主要作用区域—刺激SPG将舒张其血管并且明显改善了该区域存活的可能性。如果间隔时间足够短(即中风后几小时以内),由于血栓还没有固化,血管舒张有可能重新向组织引入血液,有可能对于中风核心区也产生帮助。此外,SPG刺激可能使栓塞从大血管移向小血管,从而仅造成脑部较小区域丧失血液供应(否则则有可能在血栓原地丧失血液供应)。
基于人口的研究显示约5%的男人和16%的妇女受到偏头痛的侵扰。其中80%的人具有某种程度的头痛相关的病残。已知副交感神经阻断(与刺激相反)可以造成血管收缩。本发明的一个实施方案利用电方法诱导血管收缩效应并用于治疗偏头痛。例如,可以采用阻断神经通讯的技术,如施加缓慢变化的电压,或者在某些情况中施加反相的直流电压。
为增加平均寿命,阿尔茨海默氏病已经称为不能和财政负担的主要因素。进几年来,血管因素被认为是该病的主要致病机制。现今治疗方法主要集中在一条线上—拟胆碱药物,这些药物大多数情况下可以减缓病人认知能力的衰退。如本发明优选实施方案中所提出的那样,SPG刺激被认为是可以增加大脑的血液和氧供应,因此也有助于病人的治疗。对于这种用途,可以在病人鼻腔内植入永久性刺激器,用于长期间歇性的治疗。
本领域的技术人员应当认识到本发明并不仅局限于以上所示和所描述的内容。本发明的范围包括上述的多种特征的组合和亚组合,同时也包括现有技术中没有的但经本领域技术人员阅读过以上描述后所构想出的变化和变体。例如,图中所示的被包覆在一个盒子中的元件在某些应用中可以被放置在多个分立的单元中。类似地,图中所示的装置中通讯和能量传递通过无线方式耦合,当然也可以采用有线方式进行耦合。图中所示装置中的通讯和能量传递通过有线方式耦合,当然也可以采用无线方式进行耦合。
Claims (72)
1、一种用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以诱导患者血脑屏障(BBB)通透性增加的作用部位。
2、一种用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以诱导患者大脑血流增加的作用部位。
3、一种用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以诱导患者大脑血流降低的作用部位。
4、一种用于修正病人大脑性能的装置,其包括:
一个或多个电极,该电极适用于作用一个选自于以下组中的部位上:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;以及
一个控制单元,该控制单元适用于驱动所述一个或多个电极,将电流施加到可以抑制SPG副交感活动的作用部位。
5、如权利要求1-4之一所述的装置,其中所述一个或多个电极适用于在患者体内的植入期为大于约一个月。
6、如权利要求1-4之一所述的装置,其包括用于连接所述控制单元和一个或多个电极的导线,其中控制单元适用于在患者体外驱动所述一个或多个电极。
7、如权利要求1-4之一所述的装置,其中控制单元适用于通过无线通讯的方式在患者体外驱动所述一个或多个电极。
8、如权利要求7所述的装置,其中包含一个用于耦合所述控制单元和一个或多个电极的电磁耦合器。
9、如权利要求7所述的装置,其中所述控制单元与一个或多个电极是通过光电方式联系的。
10、如权利要求7所述的装置,其中所述控制单元与一个或多个电极是通过声光方式联系的。
11、如权利要求1-4之一所述的装置,其中所述控制单元植入患者的鼻腔。
12、如权利要求1-4之一所述的装置,其中所述一个或多个电极植入患者的鼻腔。
13、如权利要求1-4之一所述的装置,其中所述一个或多个电极中至少有一个电极包含柔性电极,该柔性电极适用于插入患者鼻孔并延伸至作用部位。
14、如权利要求1-4之一所述的装置,其包括至少一个生物传感器,该传感器用于测量患者的生理学参数并产生响应信号,其中控制单元适用于根据上述信号修正施加电流的参数。
15、如权利要求14所述的装置,其中生物传感器包含血流传感器。
16、如权利要求14所述的装置,其中生物传感器包含温度传感器
17、如权利要求14所述的装置,其中生物传感器包含化学传感器。
18、如权利要求14所述的装置,其中生物传感器包含超声传感器。
19、如权利要求14所述的装置,其中生物传感器包含跨颅多普勒(TCD)仪。
20、如权利要求14所述的装置,其中生物传感器包含激光—多普勒仪。
21、如权利要求14所述的装置,其中生物传感器包含全身血压传感器。
22、如权利要求14所述的装置,其中生物传感器包含颅内血压传感器。
23、如权利要求22所述的装置,其中颅内血压传感器包含一种固定在大脑血管上的检测单元,而且控制单元适用于分析信号以决定是否有指示血管堵塞的血压变化的症状。
24、如权利要求14所述的装置,其中生物传感器包含动力学传感器。
25、如权利要求24所述的装置,其中控制单元适用于分析信号以决定是否有患者身体配置改变的症状。
26、如权利要求14所述的装置,其中生物传感器包含脑电图(EEG)传感器。
27、如权利要求14所述的装置,其中生物传感器包含血管堵塞传感器。
28、如权利要求1所述的装置,其中控制单元适用于调节电流,使得BBB通透性增加时易化药物透过BBB吸收。
29、如权利要求2所述的装置,其中控制单元适用于调节电流,使得血管直径增加,致使血管位于某一部位的栓塞从该部位移走。
30、如权利要求2所述的装置,其中控制单元适用于驱动一个或多个电极施加对抗中风症状的电流。
31、如权利要求4所述的装置,其中控制单元适用于驱动一个或多个电极施加对抗偏头痛病人症状的电流。
32、一种用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以诱导患者血脑屏障(BBB)通透性增加的作用部位。
33、一种用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以诱导患者大脑血流增加的作用部位。
34、一种用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以诱导患者大脑血流降低的作用部位。
35、一种用于修正病人大脑性能的方法,其包括:
由以下组中选择一个作用部位:患者的蝶腭神经节(SPG)和传入或传出SPG的神经束;然后
将电流施加到可以诱导抑制SPG活动的部位。
36、如权利要求32-35之一所述的方法,其中部位选择包括在该部位植入电极,电极在患者体内的植入期大于一个月。
37、如权利要求32-35之一所述的方法,其中部位选择包括在该部位植入电极,而且电流的施加包括从患者体外与电极进行有线联系。
38、如权利要求32-35之一所述的方法,其中部位选择包括在该部位植入电极,而且电流的施加包括从患者体外与电极进行无线联系。
39、如权利要求38所述的方法,其中所述联系包括通过电磁耦合进行联系。
40、如权利要求38所述的方法,其中所述联系包含通过光电耦合进行联系。
41、如权利要求38所述的方法,其中所述联系包含通过声电耦合进行联系。
42、如权利要求32-35之一所述的方法,其中电流的施加包含将一个控制单元植入患者的鼻腔。
43、如权利要求32-35之一所述的方法,其中电流的施加包含将一个或多个电极植入患者的鼻腔。
44、如权利要求43所述的方法,其中植入包含将一个或多个柔性电极插入患者鼻孔。
45、如权利要求32-35之一所述的方法,其包括测量患者的生理学参数并产生响应信号,其中电流的施加包括根据该信号修正所施加电流的参数。
46、如权利要求45所述的方法,其中测量包含测量患者的血流。
47、如权利要求45所述的方法,其中测量包含测量患者的温度。
48、如权利要求45所述的方法,其中测量包含测量某一化学物质的存在。
49、如权利要求45所述的方法,其中测量包含测量超声能。
50、如权利要求45所述的方法,其中测量包含执行跨颅多普勒(TCD)操作。
51、如权利要求45所述的方法,其中测量包含执行激光—多普勒操作。
52、如权利要求45所述的方法,其中测量包含测量患者的全身血压。
53、如权利要求45所述的方法,其中测量包含测量患者的颅内血压。
54、如权利要求53所述的方法,其中测量颅内血压包含将可生成信号的检测单元固定在大脑血管上,然后分析该信号以决定血管中是否存在栓塞的症状。
55、如权利要求45所述的方法,其中测量包含测量患者的动力学素因。
56、如权利要求55所述的方法,其中测量动力学素因包含测量患者的身体素因改变的症状。
57、如权利要求45所述的方法,其中测量包含测量脑电图(EEG)数据。
58、如权利要求45所述的方法,其中测量包含检测患者血管中是否存在血栓。
59、如权利要求32所述的方法,其中施加电流包括设置电流,使得BBB通透性增加时易化药物透过BBB的吸收。
60、如权利要求33所述的方法,其中施加电流包括设置电流使得血管直径增加,致使血管位于某一部位的栓塞从该部位移走。
61、如权利要求33所述的方法,其中施加电流包括施加对抗中风症状的电流。
62、如权利要求35所述的方法,其中施加电流包括施加对抗偏头痛病人症状的电流。
63、如权利要求32-35之一所述的方法,其中部位选择包括在该部位植入电极,电极在患者体内的植入期不小于一周。
64、如权利要求1-4之一所述的装置,其中一个或多个电极适用于在患者体内的植入期不小于一周。
65、一种血管装置,其包括:
一个检测单元,适用于固定于患者血管上并生成相应于血管能量的信号;以及
一个控制单元,适用于分析上述信号以决定血管中是否存在栓塞的症状。
66、如权利要求65所述的装置,其中检测单元中包含一个能量发射器和一个能量接收器。
67、如权利要求65所述的装置,其中能量发射器包括一个超声发射器。
68、如权利要求65所述的装置,其中能量发射器包括一个电磁能发射器。
69、一种检测方法,其包括:
将一个检测单元固定于患者血管上;
生成相应于血管能量的信号;然后
分析上述信号以决定血管中是否存在栓塞的症状。
70、如权利要求69所述的方法,其中信号生成包含向血管传送能量。
71、如权利要求70所述的方法,其中信号生成包含向血管传送超声能。
72、如权利要求70所述的方法,其中信号生成包含向血管传送电磁能。
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2001
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- 2001-05-07 CA CA002408097A patent/CA2408097A1/en not_active Abandoned
- 2001-05-07 EP EP01929945A patent/EP1286621A4/en not_active Withdrawn
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2004
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2006
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2007
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Also Published As
Publication number | Publication date |
---|---|
WO2001085094A2 (en) | 2001-11-15 |
JP4311904B2 (ja) | 2009-08-12 |
US20040210269A1 (en) | 2004-10-21 |
US7120489B2 (en) | 2006-10-10 |
AU5662001A (en) | 2001-11-20 |
US20070142875A1 (en) | 2007-06-21 |
US20040015068A1 (en) | 2004-01-22 |
EP1286621A2 (en) | 2003-03-05 |
EP1286621A4 (en) | 2009-01-21 |
US20110184494A1 (en) | 2011-07-28 |
US7729759B2 (en) | 2010-06-01 |
US7877147B2 (en) | 2011-01-25 |
US7190998B2 (en) | 2007-03-13 |
JP2004508847A (ja) | 2004-03-25 |
CA2408097A1 (en) | 2001-11-15 |
WO2001085094A3 (en) | 2002-03-28 |
US20060276854A1 (en) | 2006-12-07 |
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