CN107003311A - 疟疾检测 - Google Patents
疟疾检测 Download PDFInfo
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- CN107003311A CN107003311A CN201580062659.2A CN201580062659A CN107003311A CN 107003311 A CN107003311 A CN 107003311A CN 201580062659 A CN201580062659 A CN 201580062659A CN 107003311 A CN107003311 A CN 107003311A
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Abstract
本发明提供了通过磁力分离、溶解和光谱分析来检测作为血液样本中疟疾的指标的疟原虫色素的存在。
Description
本发明涉及检测具有磁性质的目标物质的样本的装置和方法,尤其是,检测作为疟疾感染指标的全血或组织中的疟原虫色素的装置和方法。
对疟疾的早期准确诊断是有效的疾病管理和疟疾监测所必需的。因缺乏简易、价格实惠且准确的诊断方法,使得常见的预防措施是“发烧等于疟疾,除非证明并非如此”。这导致疟疾的推定过度、非疟疾发烧的误管理以及有限资源的浪费,并且造成耐药性。
通过对厚和薄的血涂片进行显微检查来对疟疾感染进行的准确检测和定量高度依赖于操作人员的训练和技能;这还需要不是总能得到的设备和工作条件,尤其是在乡村环境中。基于抗原-抗体反应进行的快速诊断测试(RDT)需要较低的技能和设备,但是通常是昂贵的,并且对于低水平疟疾而言缺乏足够的灵敏度。其他推荐的检测系统尚未发现适于实际在野外条件下广泛使用。例如,US 2012/0257199 A1公开了在样本中的悬浮磁性纳米粒子的表面上吸附β-正铁血红素并且在样本上使用磁场富集以增加拉曼光谱中得到的信号,而WO 2008/056171 A2公开了将差分吸收信号用于经受强度变化磁场的血液中的β-正铁血红素的p和s偏振光。
因此,仍然需要用于检测疟疾感染存在的改进方法和装置。
根据一个方面,本发明提供了一种检测样本中的具有磁性质形式的目标物质的方法,其如权利要求1所限定。其他从属权利要求中定义了其他方面。从属权利要求定义了优选或替代的实施方式。
具有磁性质形式的目标物质可以是有机磁性物质;其可以是疟原虫色素或β-正铁血红素。
疟原虫色素是由一些嗜血寄生虫消化血液时形成的副产物。诸如疟原虫等这些血液寄生生物体消化血红蛋白并且释放出大量游离血红素,其是血红蛋白的非蛋白成分。血红素是由包含在杂环卟啉环的中心的铁原子组成的辅基。游离血红素具有细胞毒性,所以寄生虫将其转化成被称为疟原虫色素的不溶性结晶形式。由于在寄生虫生命周期的给定阶段中,血液中的疟原虫色素的浓度与寄生物血症的水平之间存在关联性,所以对血液样本中的疟原虫色素的准确且灵敏的定量能够检测低水平或早期阶段感染的疟疾。
β-正铁血红素是类似于疟原虫色素的合成物质。β-正铁血红素表现出与疟原虫色素相似的性质,包括分光性质和磁性质,并且可用于模拟疟原虫色素的行为。
该方法可用于对样本中的疟原虫色素或β-正铁血红素的浓度进行检测或定量和/或能够进行检测或定量,所述浓度≤0.12μg/mL,优选地≤0.10μg/mL,更优选地≤0.08μg/mL并且甚至更优选地≤0.06μg/mL或≤0.05μg/mL和/或介于这些浓度中的一个和2μg/mL或2.5μg/mL的浓度之间。对0.12μg/mL的疟原虫色素浓度的检测能够实现200个寄生虫/μl的寄生物血症(如世界卫生组织所推荐的)的检测,而0.05μg/mL的疟原虫色素浓度的检测能够实现80个寄生虫/μl的寄生物血症的检测。这些灵敏度水平(特别地,较低的水平)能够实现疟疾的早期检测,从而大大方便了患者治疗。
用于分析的样本的体积可以≤1mL,优选地≤750μL,更优选地≤500μL并且甚至更优选地≤300μL。因此,只需要从将受试者采集非常少量的血液样本。特别地,在微流体系统中,用于分析的样本的体积可以是10μL~50μL。可通过静脉穿刺或手指针刺来收集分析样本。通过血液穿刺而收集的血液体积可足够进行分析。
样本分析的时间(例如,从注入样本到接收到最终数据)可以是不超过10分钟,优选地不超过8分钟;更优选地不超过6分钟或不超过5分钟。如此将比显微术明显更快速地提供结果。
该样本可包括水性或有机溶剂溶液和/或悬浮液。样本可包括生物基质或源自生物基质的水性或有机溶剂溶液和/或悬浮液。生物基质可包括流体、细胞、组织、提取物、溶解产物、原核生物或真核生物培养细胞、上清液和/或溶解产物、渗析样本、微量渗析样本。样本可包括人和动物的体液或组织,例如,全血、裂解全血、血清、血浆、尿液、精液、红细胞和/或白细胞悬浮液或溶解产物、离解和/或裂解的组织、活体解剖样本、头发、指甲。
在疟疾的成熟期间,当红细胞中裂殖体的浓度较高时,细胞自然裂解,并且疟原虫色素将与感染新红细胞的裂殖体同时地释放到血液中。使用包括全血(或裂解全血)而非分离后或纯化后的红细胞的样本的一个优点在于,这样能够分析存在的全部疟原虫色素,包括(i)仍然在红血细胞内的疟原虫色素;(ii)之前已经从红血细胞释放的疟原虫色素;以及(iii)通常高水平地已经掺入巨噬细胞、单核细胞和白细胞中的疟原虫色素。
样本优选地包括裂解全血。优先使用的任何裂解溶液具有中性pH或者略偏酸性;这样避免了疟原虫色素或β-正铁血红素在全血样本中的溶解。例如,可用Tris缓冲溶液(pH7)、Triton X-100和皂苷来使全血样本裂解。可遵循“Simple and InexpensiveFluorescence-Based Technique for High-Throughput Antimalarial Drug Screening”(M.Smikstein等人,Antimicrob.Agents Chemother.,2004,第48卷,第1803页)中描述的方法来制备裂解溶液。其他可能的裂解溶液包括不同pH(优选地,酸性或中性)的低渗缓冲液。可在样本中添加DNase(通常,10~100μg/mL)和RNase(10~100μg/mL),从而由于释放核酸物质而降低粘度。可在经历裂解的所有样本中添加核酸酶和/或蛋白酶抑制剂。可能的裂解方法包括:可能使用玻璃珠进行的机械破裂、液体均化、冻融、杵臼;所有这些方法都可在伴随或不伴随超声处理的情况下应用。优选地,样本包括已经使用裂解溶液进行裂解(也就是说,化学裂解)并且尚未进行机械裂解的全血;这样简化了样本的制备。
在将目标物质与样本磁力分离之前,可纯化样本。此种纯化可包括全都能够与液-液或液-固相提取结合的过滤、离心、沉淀、直接分配、反相、离子、亲水性、亲和、凝胶渗透或体积排阻色谱或电泳。然而,优选地,不需要或不执行此种纯化。
可将待分析样本引入载流体中,载流体可包括水、有机溶液、水溶液,例如,尤其是浓度大于或等于大约0.3%、0.6%或0.9%的氯化钠(NaCl)水溶液。优选地,载流体是水,尤其是纯化水。这样可提供简化处理。
在磁力分离之后,可通过收集流体来收集目标物质进行分析。收集流体优选地包含其中溶解了分离出的目标物质的成分以得到可分析的溶液。溶解的目标物质优选地是未磁化形式,即,溶解导致磁性质的丧失。收集流体可包括含有诸如氢氧化钙、氢氧化镁、氢氧化钠、氢氧化铵、有机季铵氢氧化物、氨、有机胺等碱化剂的水溶液。优选的收集流体是氢氧化钠溶液。收集流体的浓度可大于或等于0.1M和/或小于或等于1M;例如可使用0.4M的NaOH溶液。这些溶液是容易得到的,只需要标准实验室使用注意事项并且其浓度可避免产生可能堵塞设备(尤其是设备中横截面小的部分,例如,任何开关阀)的盐沉淀的风险。
载流体和/或收集流体可包含一种或多种添加剂,例如:
-抗氧化剂,例如,生育酚、三烯酚、抗坏血酸或异抗坏血酸或盐、合成抗氧化剂(包丁基化羟基甲苯和丁基化羟基苯甲醚)或天然酚类成分(包括黄烷酮、黄酮醇、来自香精油、咖啡酸和阿魏酸的一元酚(百里香酚、香芹酚、丁香油酚...)、来自葡萄酒和红酒的类黄酮和原花青素、迷迭香族二萜酸、橄榄油羟基酪醇、木质素降解产物和木酚素、可适于减少装置内部部件腐蚀的还原酮类(尤其是使用金属微球时);还可添加柠檬酸、磷酸或富马酸或金属螯合剂,以有赋予抗氧化效果;
-表面活性剂,例如,组合或非组合的非离子表面活性剂(聚西托醇1000、十六十八醇、鲸蜡醇、椰子酰胺、椰油酰胺、igepal ca-630、异鲸蜡醇聚醚-20、月桂基葡糖苷、单月桂酸甘油酯、窄范围乙氧基化物、nonidet p-40、壬基酚聚醚-9、壬基酚聚醚、np-40、八乙二醇单十二烷基醚、n-辛基-β-d-硫代吡喃葡萄糖苷、辛基葡糖苷、油醇、五乙二醇单十二烷基醚、泊洛沙姆、泊洛沙姆407、聚甘油聚蓖麻酸酯、多山梨醇酯、多山梨醇酯20、多山梨醇酯80、皂苷类、山梨聚糖单硬脂酸酯、山梨聚糖三硬脂酸酯、硬脂醇、triton x-100)、阳离子表面活性剂(苯扎氯铵、苄索氯铵、bronidox、西曲溴铵、西曲氯铵、二甲基双十八烷基氯化铵、月桂基甲基葡糖聚醚-10、羟丙基二甲基氯化铵、四甲基氢氧化铵)和/或阴离子表面活性剂(十二烷基硫酸铵、磺基琥珀酸二辛酯钠、MBAS试剂、全氟丁烷磺酸、全氟壬酸、全氟辛烷磺酸、全氟辛酸、月桂基硫酸钾、皂苷类、皂、皂替代品、十二烷基硫酸钠、十二烷基苯磺酸钠、月桂醇醚硫酸钠、月桂酰肌氨酸钠、肉豆蔻醇聚醚硫酸钠、烷醇聚醚硫酸钠、硬脂酸钠),尤其是适于促进冲洗装置的内部部件以减少会随时间推移引起寄生虫分析信号的污染的表面活性剂;
-辅色素,例如,类黄酮、花色素苷、花青素和/或肉桂衍生物,尤其是将使通过分子缔合的疟原虫色素的可检测性增强的化学品;
-抗微生物剂,例如,叠氮化物、苯甲酸衍生物(包括羟基化物、醚、酯和/或盐)、山梨酸、乙酸、硫衍生物(包括硫化物和亚硫酸盐)、氮衍生物(包括亚硝酸盐和硝酸盐)、磺酰胺、抗生素、噻苯咪唑,尤其是能够适宜地防止溶液中的微生物生长的抗微生物剂;
-增粘剂、增稠剂或胶凝剂,例如,金合欢树胶和衍生物、乙酰化单甘油酯、单甘油酯和二甘油酯的乙酰化酒石酸乙酯、琼脂、藻胶、藻酸、藻酸铵、卡拉胶铵、红藻胶铵、磷酸化甘油酯铵盐、阿拉伯半乳聚糖、面包酵母聚糖、藻酸钙、卡拉胶钙、羧甲基纤维素、角豆胶、卡拉胶、纤维素胶、明胶、结兰胶、瓜尔胶、阿拉伯树胶、羟基化卵磷脂、羟丙基纤维素、羟丙基甲基纤维素、爱尔兰苔琼酯糖、卡拉亚胶、乳酸化单甘油酯和二甘油酯、脂肪酸的乳酰酯、卵磷脂、刺槐豆胶、甲基纤维素、甲基乙基纤维素、燕麦胶、果胶、脂肪酸聚甘油酯、交酯化蓖麻油脂肪酸的聚甘油酯、聚氧乙烯(20)山梨聚糖单油酸酯(聚山梨酯80)、聚氧乙烯(20)山梨聚糖单硬脂酸酯(聚山梨酯60)、聚氧乙烯(20)山梨聚糖三硬脂酸酯(聚山梨酯65)、聚氧乙烯(8)硬脂酸酯、藻酸钾、卡拉胶钾、藻酸丙二醇酯、甲基纤维素的丙二醇醚、丙二醇单脂肪酸酯、藻酸钠、磷酸钠铝、羧甲基纤维素钠、卡拉胶钠、纤维素乙二醇酸钠、硬脂酰-2-乳酸钠、硬脂酸钠、酒石酸钠、三磷酸钠、山梨聚糖单硬脂酸酯、山梨聚糖三油酸酯、山梨聚糖三硬脂酸酯、硬脂基单甘油酯基柠檬酸酯、脂肪酸的蔗糖酯、黄蓍胶、黄原胶,尤其是将使溶液的粘性增加的化学物。
样本的目标物质的磁力分离可包括磁力分离柱中进行的分离,尤其是包含磁性或可磁化颗粒(特别是微球,如含钢或铁的微球)的磁力分离柱。微球的直径可以为≥0.3mm或≥0.1mm和/或≤1mm或≤2mm。这些粒径避免了用精细保持栅格或过滤器来将颗粒保持在柱内的需要,这样将防止堵塞的风险,特别是在样本包含悬浮液的情况下。
磁力柱可容易地进行拆解并重新组装,例如,以方便可磁化颗粒的替换。可磁化颗粒可进行周期性替换,以例如在腐蚀和/或沉积物和/或污染物积聚的情况下保持装置的功效和/或精度。在替换可磁化颗粒之前进行的分析次数可以是≥10或≥15;其可以是≤1000。
磁力柱的内径可以是≥0.5mm或≥1mm和/或≤15mm或≤10mm。柱的长度可以是≥5mm或≥1cm和/或≤12cm或≤10cm。柱优选地由非磁性材料(例如,诸如聚丙烯等塑料材料)制成。
例如,可通过一个或多个永磁体向磁力分离柱施加外部磁场。分离柱处的磁场强度可以是≥0.2T或≥1T;其可以是≤8T或≤10T。
该系统可被配置为微流体系统。因此,可以使磁力柱、微球、磁场和待测试样本的大小适应于微流体系统。尤其是,在这种情况下,磁性颗粒可以是纳米颗粒或纳米球。磁性颗粒可以是如上所述的微球,或者优选地,具有更小直径的微球。在该情况下,微球的直径可以是≥50μm或≥100μm和/或≤500μm或≤400μm或≤300μm。磁力柱可具有例如提供为集成式流体槽(flow cell)的一部分的微珠储罐的形式。集成式流体槽可包括与光学窗口流体连接的微珠储罐。
微珠储罐的大小可近似于标准的显微镜载玻片。其可具有以下尺寸:长度≥30mm或≥45mm或≥60mm或≥70mm和/或≤150mm或≤120mm或≤90mm;和/或宽度≥15mm或≥20mm和/或≤60mm或≤45mm或≤30mm;和/或厚度≥1mm或≥2mm或≥4mm和/或≤15mm或≤12mm或≤10mm或≤8mm。集成式流体槽的元件之间的连接管或路径的直径可以是≥20μm或≥50μm和/或≤200μm或≤150μm。集成式流体槽可基本上是平面的;其可提供单用途装置或多用途装置,其例如适于分析至少约10个样本和/或至多约50个样本。流体槽可由聚合物(例如,PMMA(聚(甲基丙烯酸甲酯))或PDMS(聚二甲基硅氧烷)制成。集成式流体槽可包括:第一部分,例如基体,通过机加工、雕刻或模制到表面中而在基体中设置流体回路,例如作为在一个面处开口的回路;以及第二部分,例如,盖体,其例如通过覆盖在基体上与基体互补,例如以密封设置在第一部分上的回路的开口面。流体回路的微珠储罐可填充可磁化颗粒,例如,钢颗粒或纳米颗粒,之后通过将第二部分设置在第一部分上方并且密封来组装流体槽。例如,可通过取下盖体来拆解流体槽,并且随后重新组装,以替换可磁化的微粒。
对可分析溶液进行光谱分析以检测溶解的目标物质的过程可包括光学分析;其可包括吸收光谱。从源发出的辐射可穿过可分析溶液,以给出由传感器接收的衰减信号。选择源和传感器以涵盖能够检测目标物质的存在和(优选)数量的波长。
优选地,使用准单色光来进行光谱分析,即,具有窄带宽的光,例如,在80nm、50nm、20nm或10nm的带宽内具有其能量的至少80%的光。可使用准单色光源和/或传感器。在一个优选实施方式中,使用在约380nm、约405nm或约620nm的波长发射的准单色二极管。另选地,可使用单色光。疟原虫色素的吸收光谱表现出多个峰(图1)。疟原虫色素强吸收波长在330nm~410nm的范围内的辐射并且较弱地吸收波长在600nm~640nm的范围内的辐射。第一波段是灵敏度所关注的,第二波段是特异性所关注的。因此,使用对应的准单色光源能够使用稳固的、简化的但提供良好灵敏度或选择性的构造和设备。例如,发光二极管可以是低功率二极管;其可与流动的可分析流体相邻地设置,而不需要用光纤传输。通过使用裂解全血在约380nm、约405nm或约620nm处检测疟原虫色素可实现特别的优势;可使用这种组合来灵敏地检测疟原虫色素和/或避免来自样本的干扰或遮蔽指示疟原虫色素信号的不期望的寄生虫信号。光传感器可以是能够在所选择波长下进行检测的光敏传感器。因此,用于检测目标物质的光谱分析的波长可包括:≥300nm或≥320nm或≥340nm或≥350nm或≥360nm和/或≤440nm或≤430nm或≤420nm或≤410nm的波长;或者≥580nm或≥590nm或≥600nm和/或≤650nm或≤640nm或≤630nm的波长。
可使用波长集中在以上范围内的单色或准单色发射器。
优选地,在光谱分析中使用的通过可分析溶液的辐射路径可选择为≥3mm、≥20mm、≥30mm或≥40mm;这样有助于提高检测的灵敏度。例如,可通过在流动路径中布置“Z”部分并且将辐射经过“Z”的较长部分,而使辐射可经过可分析溶液的流动路径的一部分。
该方法可包括:
-第一分离阶段,在该分离阶段中,例如,通过使样本经过磁力分离器并且将磁性形式的目标材料保持在分离器内,而将目标材料与样本磁力分离;和/或
-第二分析阶段,在该分析阶段中,例如,通过在溶液中溶解和洗脱,而从磁力分离器中除去目标材料,以提供可分析溶液;和/或
-第三冲洗阶段,在该冲洗阶段中,冲洗磁力分离器,以备其后续使用。
优选地,对在溶液中包含目标物质的分析溶液进行光谱分析。
可例如通过注入、尤其是通过入口(例如通过注入阀或隔膜)注入,而将待分析样本引入载流体的流动路径中。这样有助于将样本引入装置中,而不需要在其操作中断或拆解。
现在,将仅以示例方式参照附图来描述本发明的实施方式,在附图中:
图1是疟原虫色素的UV-可见光吸收光谱;
图2是分析装置的示意性代表实施方式;
图3是借助程序PcLab2000从包含β-正铁血红素的裂解全血样本得到的色谱图;以及
图4是借助程序PcLab2000从疟疾污染的裂解全血样本得到的色谱图。
图5是集成式流体槽形式的微流体系统的示意性平面图。
图2的分析装置包括:
1和2:装配有第一注射器1和第二注射器2的来自KR Analytica的双通道注射泵,第一注射器包含用作载流体的水,第二注射器2包含用作收集、溶解和洗脱流体的0.4M氢氧化钠(NaOH)溶液,注射泵被设置成各个注射器中产生0.5mL/分钟的恒定流;
3:注射器1和开关阀之间的连接管;
4:注射器2和开关阀之间的连接管;
5:用于注入样本的进入隔膜;
6:得自Rheodyne TitanMX的开关阀;
7:开关阀到处置口的连接管;
8:开关阀和柱之间的连接管;
9:包括聚丙烯柱的磁力分离柱,长度为约60mm且内径为约4mm,包含约4g的直径为约0.5mm的钢微球;
10:产生强度为约0.65T的磁场的永磁体(得自Miltenyi Biotec的MidiMACS磁体);
11:柱和流体槽之间的连接管;
12:用作光源的准单色发光二极管(405nm);
13:流体槽(包括针对高于210nm波长的UV-可见光二氧化硅窗口的得自OceanOptics的“SMA Z-cell”);
14:流体槽到处置口的连接管;
15:光传感器;
16:信号放大器和伏特计。
按照在“An iron-carboxylate bond links the heme units of malariapigment”(AFG Slater等人,Proc.Nati.Acad.Sci.USA,第88卷,第325-329页)中描述的改良方法来执行β-正铁血红素的合成。通过用0.4N氢氧化钠(NaOH)溶液溶解0.592g的氯化血红素来制备45.4mM正铁血红素的原液,从而得到所述溶液的20mL溶液。用90mL的水稀释10mL的原液,以得到100mL的4.54mM的正铁血红素溶液,此后添加2%丙酸,以得到pH为4的反应介质。在封闭容器中,使混合物在过滤之前在恒温浴内在70℃下反应18小时。收集过滤后的剩余物并且在37℃的烘箱中干燥24小时。然后,将β-正铁血红素晶体保持在4℃的冰箱中。
为了模拟人全血样本中的疟疾(疟原虫色素晶体)的检测,将待测试样本制为β-正铁血红素在未受污染的全血样本中的悬浮液。在进行全血样本分析之前,用Tris缓冲的(pH7)Triton X-100和皂苷溶液来裂解全血样本。遵循由“Simple and InexpensiveFluorescence-Based Technique for High-Throughput Antimalarial Drug Screening”(M.Smikstein等人,Antimicrob.Agents Chemother.,2004,第48卷,第1803页)中描述的方法的改良工序来制备裂解溶液。首先,制备100mL的Tris缓冲溶液。在将12.11g的三(羟基甲基)氨基甲烷溶解在60mL的水中并且添加HCl(盐酸)得到pH为7的溶液之后,继续添加水,以得到100mL的Tris缓冲溶液。通过在10mg的皂苷和1mL的Triton X-100中添加必要量的Tris缓冲溶液来得到100mL的裂解溶液。将该裂解溶液保持在4℃的冰箱中并且在7天内使用。通过用裂解溶液进行1/2稀释并且反应30分钟来执行全血样本的裂解。
在第一分离阶段开始时,用开关阀(6)来稳定装置,开关阀被设置成将来自注射器(1)的载流体引导至通过磁性柱(9)的流动路径,并且将来自注射器(2)的收集流体从开关阀(6)送到处置口。
将包含β-正铁血红素晶体的300μL裂解全血样本注入隔膜(5)中。当样本是悬浮液时,应该在注入之前进行振荡,以确保所注入样本是均质的。在该第一阶段期间,持续大约21/2分钟后,来自注射器(1)的水经过连接管(3)并且携带所注入样本通过开关阀(6)并且通过连接管(8),到达磁性柱的入口。当载流体所输送的样本经过柱中的磁化钢微球时,样本中的磁性β-正铁血红素晶体将吸附于并保持在磁化微球上。
在该分离阶段结束时,装置切换到第二分析阶段,第二分析阶段持续大约21/2分钟。在该分析阶段中,切换开关阀(6),使得来自注射器(1)的载流体从开关(6)送到处置口,并且来自注射器(2)的收集流体由开关(6)引导通过连接管(8),到达分离柱(9)的入口。选择收集溶液,使得其在经过微球时收集并且洗脱在分离阶段期间由微球保持的β-正铁血红素晶体,以提供可分析溶液,在该实施方式中,可分析溶液包括溶解在氢氧化钠收集溶液中的β-正铁血红素晶体。
分离柱的出口经由连接管(11)连接到流体槽(13),在此从窄带宽二极管发射出的光(中心405nm)穿过可分析溶液并且衰减透射光信号落在光传感器(15)上。衰减光信号中检测到的光吸收提供了样本中溶解的β-正铁血红素或疟原虫色素晶体的存在和数量的指标。光传感器(15)的输出端连接到信号放大器和伏特计(16),随后连接到被配置成处理并显示信号的计算机。
从流体槽(13)排出的流体通过连接管(14)送到处置口。
在分析阶段结束时,装置切换到第三冲洗阶段,在冲洗阶段期间,开关阀(6)将来自注射器(2)的收集流体从引导至处置口,并且将来自注射器的载流体通过连接管(8)引导至分离柱(9)。
图3是借助程序PcLab2000从包含β-正铁血红素的裂解全血样本得到的色谱图,其显示了信号振幅(y轴,单位:伏)随时间(x轴,单位:秒)的变化关系。箭头(18)指示开关阀何时切换,以从分离阶段过渡到分析阶段。峰(19)对应于分析溶液中检测的β-正铁血红素。该峰(19)的表面积与样本中β-正铁血红素的浓度相关。
图4是借助程序PcLab2000从使用上述过程分析的疟疾污染的裂解全血样本得到的色谱图。
为了确定样本中的疟原虫色素(或β-正铁血红素)的数量,可以制作初步校准曲线,尤其是使用包含已知数量的β-正铁血红素的校准样本来形成初步校准曲线。例如,校准曲线指示疟原虫色素的浓度与(可使用Graph Pad软件来确定的)对应于疟原虫色素的峰信号下方的表面积的变化关系,或者在简化的不太精确的替代方式中,指示疟原虫色素的浓度与吸收信号中对应于疟原虫色素的峰信号的最大强度的变化关系。
装置的简化和稳固性有助于其用于野外情况。以不显著依赖于操作人员技能的高水平灵敏度来得到可靠结果的快捷性也是有利的。
图5是集成式流体槽形式的微流体系统的示意性表示,集成式流体槽26具有76mm的长度和26mm的宽度,其包含:
20:载流体的入口
21:收集流体的入口
22:样本的入口
23:微珠储罐
24:光学窗口
25:出口/处置口
并且,其包含微珠储罐和光学窗口,处于平面流体槽或晶片形式。平面流体槽适于与至少(i)位于永磁体上方或夹在一对平面永磁体之间的其微珠储罐以及(ii)布置在光学窗口处的光发射器和光传感器一起使用。可改变磁体的几何构型及其定位,以确保合适的磁场。a)从载流体、收集流体和样本的入口通向微珠储罐的入口、b)从微珠储罐的出口通向光学窗口的入口和c)从光学窗口的出口通向出口/处置口的连接通道或连接管具有100μm的直径。微珠储罐容纳直径为200μm的可磁化钢微粒。
从外部容器提供载流体和收集流体并且例如对各种流体使用蠕动泵将其泵送通过流体槽。使用包含止回阀的蠕动泵避免了连续流体循环和诸如图2的分析装置描述的带有中间处置口(7)的开关阀(6)的需要。可经由微量吸管(例如,微量吸管)或玻璃毛细管引入待分析样本。
该装置可被设置为包括以下部件的套盒(kit):一个或多个流体槽26,其填充有磁性微粒;外部磁体,尤其是永磁体;蠕动泵;光发射器和关联的光传感器;信号处理设备和用于显示结果的界面屏,优选为触摸屏界面。
微流体系统提供了适于小样本量的野外使用的特别紧凑的、低成本的、快速分析系统。
Claims (14)
1.一种检测样本中的目标物质的方法,所述样本包含具有磁性质形式的目标物质,所述方法包括以下步骤:
-将磁性形式的所述目标物质与所述样本磁力分离;
-溶解分离的磁性形式的所述目标物质,以提供包含所述目标物质的可分析溶液;
-对所述可分析溶液进行光谱分析,以检测所述目标物质。
2.根据权利要求1所述的方法,其中,所述目标物质包括疟原虫色素或β-正铁血红素。
3.根据前述权利要求中任一项所述的方法,其中,所述方法包括对血液样本中的疟原虫色素进行检测和定量的方法,以检测疟疾感染和/或评估和/或定量寄生虫血症。
4.根据前述权利要求中任一项所述的方法,其中,所述样本包括裂解全血样本。
5.根据前述权利要求中任一项所述的方法,其中,磁性形式的所述目标物质与所述样本磁力分离的过程包括施加强度为0.2~10T的磁场。
6.根据前述权利要求中任一项所述的方法,其中,磁性形式的所述目标物质与所述样本磁力分离的过程包括使所述样本经过磁力分离柱中的磁性颗粒,尤其是磁化含铁颗粒。
7.根据前述权利要求中任一项所述的方法,其中,溶解分离的磁性形式的所述目标物质以提供可分析溶液的过程包括溶解在水溶液中,所述水溶液包含选自由氢氧化钙、氢氧化镁、氢氧化钠、氢氧化铵、有机季铵氢氧化物、氨、有机胺及其组合组成的组中的碱化剂。
8.根据前述权利要求中任一项所述的方法,其中,所述光谱分析包括光学吸收光谱,其中,从光源发射出的光穿过所述可分析溶液,以提供由光传感器接收的衰减的透射光。
9.根据权利要求8所述的方法,其中,通过所述透射光的吸光率得到所述样本中的目标物质量的指标。
10.根据前述权利要求中任一项所述的方法,其中,对所述可分析溶液进行光谱分析以检测所溶解的磁性目标物质的过程包括分析准单色光,尤其是包括波长范围为350nm~420nm或600nm~640nm中的准单色光。
11.根据前述权利要求中任一项所述的方法,其中,具有磁性质的所述目标物质包括疟原虫色素,并且所述方法能够检测所述样本中小于0.1μg/mL、优选小于0.08μg/mL的疟原虫色素的浓度。
12.一种用于检测液体样本中目标物质的存在的装置,所述液体样本包含具有磁性质形式的目标物质,所述装置包括:
-磁力分离器,所述磁力分离器具有在样本入口和样本出口之间的样本流动路径,所述磁力分离器流动路径经过保持在所述磁力分离器内的磁性元件,尤其是可磁化微球;以及
-光谱分析仪,所述光谱分析仪具有在样本入口和样本出口之间的样本流动路径,所述磁力分离器的样本出口与所述光谱分析仪的样本入口流体连接,所述光谱分析仪流动路径包括检测区,并且所述光谱分析仪包括:辐射发射器,尤其是准单色光发射器;和传感器,所述辐射发射器被配置为将辐射发射至所述检测区中,所述传感器被配置为检测所述检测区处的辐射。
13.根据权利要求12所述的装置,其中,所述装置还包括以下部件中的一个或多个:隔膜入口,所述隔膜入口能够将样本或载流体引入流动路径中;源,尤其是注射器,所述源适于将载流体引入所述磁力分离器中;源,尤其是注射器,所述源适于将收集和/或溶解流体引入所述磁力分离器中;流体流动装置,尤其是泵,所述流体流动装置适于通过所述装置产生流体的流动;辐射源,尤其是准单色光源,所述辐射源适于发射通过待分析样本的流动路径的辐射;传感器,所述传感器适于检测已通过所述待分析样本的所述流动路径的辐射;信号处理设备,所述信号处理设备适于基于所述光谱分析仪的输出来提供所述样本中的所述目标物质的存在和/或数量的指标。
14.根据权利要求12~13中的任一项所述的装置,其中,所述装置连接到信号分析仪,所述信号分析仪被配置为基于所述光谱分析仪的输出信号来提供所述样本中的所述目标物质的数量的指标。
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US11740203B2 (en) | 2019-06-25 | 2023-08-29 | Hemex Health, Inc. | Diagnostics systems and methods |
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WO2023138162A1 (zh) * | 2022-01-18 | 2023-07-27 | 北京流荧生物科技有限公司 | 样本检测方法、装置、系统、电子设备及计算机可读介质 |
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