Microfluidic concentration and separation of circulating tumor cell clusters from large blood volumes.,Lab on a Chip

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Microfluidic concentration and separation of circulating tumor cell clusters from large blood volumes.
Lab on a Chip ( IF 6.1 ) Pub Date : 2020-01-14 , DOI: 10.1039/c9lc01122f
Jon F Edd ₁ , Avanish Mishra ₂ , Taronish D Dubash ₃ , Stefan Herrera ₂ , Ridhwan Mohammad ₂ , E Kendall Williams ₂ , Xin Hong ₄ , Baris R Mutlu ₂ , John R Walsh ₁ , Fernanda Machado de Carvalho ₄ , Berent Aldikacti ₁ , Linda T Nieman ₄ , Shannon L Stott ₅ , Ravi Kapur ₆ , Shyamala Maheswaran ₃ , Daniel A Haber ₇ , Mehmet Toner ₈

Affiliation

BioMEMS Resource Center, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
BioMEMS Resource Center, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA and Harvard Medical School, Boston, MA 02115, USA.
Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
BioMEMS Resource Center, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA and Harvard Medical School, Boston, MA 02115, USA.
MicroMedicine, Inc., Waltham, MA 02451, USA.
Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA and Harvard Medical School, Boston, MA 02115, USA and Howard Hughes Medical Institute, Bethesda, MD 20815, USA.
BioMEMS Resource Center, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. and Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.

Circulating tumor cells (CTCs) are extremely rare in the blood, yet they account for metastasis. Notably, it was reported that CTC clusters (CTCCs) can be 50-100 times more metastatic than single CTCs, making them particularly salient as a liquid biopsy target. Yet they can split apart and are even rarer, complicating their recovery. Isolation by filtration risks loss when clusters squeeze through filter pores over time, and release of captured clusters can be difficult. Deterministic lateral displacement is continuous but requires channels not much larger than clusters, leading to clogging. Spiral inertial focusing requires large blood dilution factors (or lysis). Here, we report a microfluidic chip that continuously isolates untouched CTC clusters from large volumes of minimally (or undiluted) whole blood. An array of 100 μm-wide channels first concentrates clusters in the blood, and then a similar array transfers them into a small volume of buffer. The microscope-slide-sized PDMS device isolates individually-spiked CTC clusters from >30 mL per hour of whole blood with 80% efficiency into enumeration (fluorescence imaging), and on-chip yield approaches 100% (high speed video). Median blood cell removal (in base-10 logs) is 4.2 for leukocytes, 5.5 for red blood cells, and 4.9 for platelets, leaving less than 0.01% of leukocytes alongside CTC clusters in the product. We also demonstrate that cluster configurations are preserved. Gentle, high throughput concentration and separation of circulating tumor cell clusters from large blood volumes will enable cluster-specific diagnostics and speed the generation of patient-specific CTC cluster lines.

中文翻译：

微流体浓缩和从大量血液中分离循环肿瘤细胞簇。

循环肿瘤细胞（CTC）在血液中极其罕见，但它们却导致了转移。值得注意的是，据报道，CTC 簇 (CTCC) 的转移性比单个 CTC 高 50-100 倍，这使得它们作为液体活检目标特别突出。然而，它们可能会分裂，而且更加罕见，这使得它们的恢复变得更加复杂。随着时间的推移，当簇挤过过滤器孔时，通过过滤进行隔离可能会造成损失，并且捕获的簇的释放可能很困难。确定性横向位移是连续的，但需要的通道不比簇大很多，从而导致堵塞。螺旋惯性聚焦需要较大的血液稀释因子（或裂解）。在这里，我们报道了一种微流控芯片，它可以从大量最低限度（或未稀释）的全血中连续分离出未受影响的 CTC 簇。100 μm 宽的通道阵列首先集中血液中的簇，然后类似的阵列将它们转移到少量缓冲液中。显微镜载玻片大小的 PDMS 设备可从每小时超过 30 mL 的全血中分离出单独加标的 CTC 簇，计数效率为 80%（荧光成像），片上产量接近 100%（高速视频）。血细胞去除率中位数（以 10 为底数）为白细胞 4.2、红细胞 5.5、血小板 4.9，产品中与 CTC 簇一起留下的白细胞不足 0.01%。我们还证明了集群配置被保留。温和、高通量的浓缩以及从大量血液中分离循环肿瘤细胞簇将实现簇特异性诊断并加速患者特异性 CTC 簇系的生成。

更新日期：2020-02-13

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