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LSPR生物传感器在临床医学检测应用中的研究进展

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文章导航 > 光电工程 > 2017 Vol. 44 > No. 2 > 152-160

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段瑞岐, 于秀章, 兰竹, 等. LSPR生物传感器在临床医学检测应用中的研究进展[J]. 光电工程, 2017, 44(2): 152-160. doi: 10.3969/j.issn.1003-501X.2017.02.003
引用本文: 段瑞岐, 于秀章, 兰竹, 等. LSPR生物传感器在临床医学检测应用中的研究进展[J]. 光电工程, 2017, 44(2): 152-160. doi: 10.3969/j.issn.1003-501X.2017.02.003
shu
Duan Ruiqi, Yu Xiuzhang, Lan Zhu, et al. Research progress in applications of LSPR biosensor for clinical medicine detection[J]. Opto-Electronic Engineering, 2017, 44(2): 152-160. doi: 10.3969/j.issn.1003-501X.2017.02.003
Citation: Duan Ruiqi, Yu Xiuzhang, Lan Zhu, et al. Research progress in applications of LSPR biosensor for clinical medicine detection[J]. Opto-Electronic Engineering, 2017, 44(2): 152-160. doi: 10.3969/j.issn.1003-501X.2017.02.003
shu

LSPR生物传感器在临床医学检测应用中的研究进展

    • 四川大学华西第二医院妇产科；出生缺陷与相关妇儿疾病教育部重点实验室，成都 610041

  • 基金项目:
    国家自然科学基金资助项目(61505126)
详细信息
    通讯作者: 郄明蓉, E-mail: qmrjzz@126.com

  • 中图分类号: O539;R508

Research progress in applications of LSPR biosensor for clinical medicine detection

    • Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education; Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China

  • Fund Project:
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    摘要

  • 肿瘤标志物在人类医学及恶性肿瘤的早期诊断、治疗监测及预后评估方面具有重要作用。目前血清肿瘤标志物的检测方法主要有放射免疫法(RIA)，酶联免疫吸附法(ELISA)及化学发光免疫法(CLEIA)等，这些方法各自存在放射性污染、操作繁琐、检测时间长、价格昂贵等缺点，限制了血清肿瘤标志物在临床医学及肿瘤检测中的应用。新近出现的基于局域表面等离子体共振效应(LSPR)的传感器因在生物医学检测领域极具优势而成为研究热点。基于局域表面等离子体共振效应的生物传感器，利用贵金属纳米结构对周围介质环境变化敏感的基本原理，可将生物分子吸附引发的金属纳米颗粒外界介质折射率的改变转化为可测量的LSPR峰值吸收波长有规律的移动以实现对传感器表面样品的检测，具备检测灵敏度高、特异性好、免标记、设备便携、成本低的优点，具备临床检测潜力。但到目前为止，利用此传感器检测与疾病及肿瘤相关的肿瘤标志物的类似研究报道较少。在本文中，我们针对LSPR生物传感器的传感原理、国内外的研究进展以及我们在此方面的主要研究成果进行了综述。

    Tumor biomarker plays an important role in early diagnosis, treatment evaluation, and prognosis prediction for human medicine and cancers. At present, the human serum tumor biomarker detection methods mainly include radioimmunoassay (RIA), enzyme linked immunosorbent assay (ELISA), and chemiluminescence immunoassay (CLEIA), which have disadvantages of radioactive contamination, complicated operation, and long detection time and high cost. Various issues exist in these methods which limit its widespread applications in clinic screening. Recently, biosensors based on localized surface plasmon resonance (LSPR) have attracted much research attention for their remarkable superiority in the domain of biomedicine detection. The LSPR biosensor, a novel type of optical fiber-based biosensor, uses an optical fiber or optical fiber bundle to transform biological recognition information into analytically useful signals in the LSPR spectrum, which is suitable for clinical detection because of the advantages of high sensitivity, high specificity, label free, portable equipment and lower cost. However, up to now, there was little progress on the report of the detection of tumor biomarkers associated diseases and tumors by using this LSPR biosensor. In this paper, the principle and research progress of local surface plasmon resonance biosensor, as well as the main findings of our study in the detection of tumor markers are reviewed.

    • Overview

  • Abstract: Tumor biomarker plays an important role in early diagnosis, treatment evaluation, and prognosis prediction for human medicine and cancers. At present, the human serum tumor biomarker detection methods have defections, such as radioactive contamination, complicated operation, long detection time and high cost, which limit the widespread applications in clinic screening. The LSPR biosensor, a novel type of optical fiber-based biosensor, uses an optical fiber or optical fiber bundle to transform biological recognition information into analytically useful signals in the LSPR spectrum, which is suitable for clinical detection because of the advantages of high sensitivity, high specificity, label free, portable equipment and lower cost. In this paper, the principle and research progress of local surface plasmon resonance biosensor, especially the main findings of our study group, are reviewed.

    In this work, the physical characteristics of metal nanostructure were calculated and simulated by discrete dipole approximation (DDA). Combining with reactive ion etching (RIE), nanosphere lithography (NSL) was applied to produce the triangle nanostructures. Eventually, a triangle silver nanostrure array with high refractive index sensitivity was produced. Meanwhile, a primitive ultraviolet-visible spectrometer was constructed to make spectro-analysis. An effective biological sensitive layer was fabricated on the surface of nanostructures by means of 11-mercaptoundecanoic acid (MUA) amine couple method.

    To explore the clinical applications of this LSPR biosensor, we firstly used it to detect the microalbuminuria. The anti-human albumin antibody was immobilized on the sensor surface. Different concentrations of commercial albumin and albumin in urine samples from patients were determined according to the peak of LSPR extinction spectra. The biosensor displayed a detection limit of 1 ng/ml and wide dynamic range from 1 ng/ml to 1 mg/ml. Secondly, the anti-HE4 antibody as a probe, which could distinctly recognize HE4, an important ovarian tumor marker, was effectively assembled onto the nanochip surface. Human serum samples were detected and compared using an enzyme-linked immunosorbent assay. The linear range was between 10 pM and 10000 pM, with a detection limit of 4 pM and an excellent correlation between it and enzyme-linked immunosorbent assay. Thirdly, we made a functionalized chip surface with monoclonal anti-SCCa antibodies on the silver nanoparticles for distinct detection of SCCa. Different concentrations of SCCa were successfully tested in both buffer and human serum, with a linear quantitative detection range of 0.1~1000 pM. Lastly, the specific DNA probe was immobilized on the nanochip surface. Wild-type and mutant p53 DNA was detected. The low detection limit was 10 nM, with a wide dynamic range (10 nM~10 μM). Importantly, this sensor could effectively discriminate against single base mutations. By comparing with traditional methods, the advantage of the LSPR biosensor, such as wider detection range, label free, simple operation and short time was clear. It could provide a promising platform for developing clinical diagnostic applications.

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  • 图 1  LSPR传感检测示意图[7].

    Figure 1.  Schematic principle of LSPR sensor [7].

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    图 2  LSPR纳米传感器检测人脑脊液样本[16]. (a)利用抗体三明治方法检测人脑脊液样本的芯片表面化学反应过程. (b)传感器检测老年人脑脊液样本的波谱图. B1~B3:功能化银纳米加入100 nM anti-ADDL(100 mM EDC活化) (B1)，加入老年人脑脊液样本(B2)以及再次加入100 nM anti-ADDL (B3)的波谱图. (c)传感器检测老年患者脑脊液样本的波谱图. C1~C3:功能化银纳米加入100 nM anti-ADDL(100 mM EDC活化) (C1)，加入老年人脑脊液样本(C2)以及再次加入100 nM anti-ADDL (C3)的波谱图.

    Figure 2.  Analysis of human CSF samples using a sandwich assay and the LSPR nanosensor[16]. (a) Surface chemistry for the possible ADDL detection in human CSF samples using the antibody "sandwich"assay. (b) Aging patient: LSPR spectra for each step of the assay. Ag nanoparticles after functionalization with 100 nM anti-ADDL (100 mM EDC) (B1), CSF (B2), 100 nM anti-ADDL (B3). (c) AD patient: LSPR spectra for each step of the assay. Ag nanoparticles after functionalization with 100 nM anti-ADDL (100mM EDC) (C1), CSF(C2), 100 nM anti-ADDL (C3). All measurements were collected in a N2 environment.

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    图 3  (a) 随机有序圆柱形纳米粒子阵列的离散圆形区域25 mm玻片相机图像. (b)每个圆形区域随机有序纳米圆柱阵列玻片示意图[18].

    Figure 3.  (a) Camera imaging of a 25 mm glass slide patterned with discrete circular regions of randomly ordered cylindrical nanoparticle arrays using a shadow mask. (b) Schematic showing randomly ordered nano-cylinder arrays within each circular region on the glass slide [18].

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    图 4  LSPR纳米传感芯片检测白蛋白过程[26]. (a)芯片玻璃基底. (b)采用NSL技术在芯片表面合成点阵排列的纳米颗粒. (c)纳米表面自主装11-MUA层. (d)孵育EDC和NHS，活化表面巯基. (e)固定白蛋白抗体. (f)不同浓度的标准品和样品与芯片进行免疫分析检测.

    Figure 4.  Design of LSPR nanobiosensor for albumin detection [26]. (a) Glass substrate. (b) Surface-confined sliver nanoparticles were synthesized using NSL. (c) The nanoparticles were incubated in MUA solution to form a SAM. (d) The substrates were incubated in EDC/NHS. (e) Anti-albumin antibody (10 mg/ml) immobilized the substrate. (f) Varying the concentrations of the albumin or the samples on the substrates completed the albumin immunoassay.

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    图 5  研究中搭建的消光谱实验测试平台.

    Figure 5.  Test platform for extinction spectrum experiment.

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    图 6  LSPR传感芯片测定1 μg/ml的白蛋白的波谱图[26]. A:原始基线值. B:巯基化合物在芯片表面形成自组装单分子层(SAM)后的波峰值. C:交联剂作用后的波峰值. D:固定抗白蛋白抗体的波峰值. E: 1 μg/ml白蛋白反应上样波谱图.

    Figure 6.  Specific LSPR extinction spectrum for 1μg/ml albumin detection [26]. A: Ag nanoparticles before chemical modification. B: MUA (1 mM). C: EDC/NHS solution. D: antibody (10 mg/ml). E: albumin (1 mg/ml). All spectra were collected in air.

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    图 7  LSPR传感器测定临床患者标本的波谱图[26]. A:原始基线值. B:固定抗白蛋白抗体的波峰值. C:轻度子痫前期患者尿液稀释后检测出来的微量蛋白尿的波峰值.

    Figure 7.  Specific LSPR extinction spectrum for patient albumin detection [26]. A: Ag nanoparticles before chemical modification. B: antibody. C: clinical sample. All spectra were collected in air environment.

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    图 8  LSPR传感器检测100 pM SCCA的波谱图[31]. A:原始基线值. B: MUA在芯片表面形成SAM后的波峰值. C:固定单克隆抗体的波峰值. D: 100 pM SCCA反应点样后的波谱图.

    Figure 8.  Specific LSPR extinction spectrum for 100 pM SCCA detection [31]. A: Bare silver nanochip. B: Modification of 1 mM MUA. C: Incubation with 10 μg/mL monoclonal anti-SCCa. D: Detection of 100 pM SCCa.

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    图 9  LSPR传感芯片测定HE4的波谱图[36]. A:原始基线值. B: 11-MUA自组装单分子层. C:固定10 μg/ml抗HE4单克隆抗体. D:与500 pM的HE4标准品进行抗原抗体反应(Δλmax+14.48 nm).

    Figure 9.  Specific LSPR extinction spectrum for HE4 detection [36]. A: Bare silver nanochip. B: 1 mM 11-mercaptoundecanoic acid. C: functionalized biosensor with 10 μg/mL antibody. D: 500 pM HE4.

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    图 10  构建检测p53基因突变的LSPR纳米生物传感器[43]. (a)利用NSL方法在玻璃基底上制备三角柱银纳米. (b)在银纳米表面修饰MUA形成自组装层. (c) EDC/NHS催化下将末端修饰氨基的DNA探针固定在纳米表面. (d)固定探针与目标序列杂交.

    Figure 10.  (a) Triangular Ag nanoparticles were fabricated on a glass substrate using NSL. (b) The nanoparticles were modified with MUA to form a SAM. (c) Amine-terminated DNA probes were immobilized on the MUA-coated nanoparticles with EDC/NHS activation. (d) Target DNA was hybridized with the immobilized probe.

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收稿日期:  2016-10-24
修回日期:  2016-12-28
刊出日期:  2017-02-15

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