High Sensitivity and High Throughput Magnetic Flow CMOS Cytometers With 2D Oscillator Array and Inter-Sensor Spectrogram Cross-Correlation
High Sensitivity and High Throughput Magnetic Flow CMOS Cytometers With 2D Oscillator Array and Inter-Sensor Spectrogram Cross-Correlation
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DOI：
10.1109/tbcas.2024.3367668
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发表时间：
2024-08-01
影响因子：
5.1
通讯作者：
Sengupta，Kaushik
中科院分区：
文献类型：
--
作者：
Tang，Hao;Venkatesh，Suresh;Sengupta，Kaushik
在本文中，我们提出了一种集成流式细胞仪，该流式细胞仪采用65纳米CMOS工艺，基于双频振荡器的二维磁传感器阵列，芯片封装有微流体控制。传感器架构和所提出的阵列信号处理允许不受抑制的高通量样品流动，而无需对单个传感器进行流体动力学聚焦。为了克服灵敏度和特异性的挑战，这是作为一个交易与高贯穿，我们执行两个级别的信号处理。首先，利用磁性标记细胞有望以延时方式依次激发一系列传感器的事实，我们执行传感器频谱图的站点间相互关联，这使我们能够大大抑制误检测的可能性，从而使理论灵敏度达到罕见细胞或循环肿瘤细胞检测所需的亚ppm水平。此外，我们实现了两种不同的方法来抑制奇异传感器的相关低频漂移——一种是芯片上的传感器参考，另一种是利用超顺磁磁珠的磁化率的频率依赖性，我们部署作为标签。我们在一个采用65纳米CMOS技术的77传感器阵列上演示了这些技术，该阵列采用带有磁性标记介电颗粒的微流体封装，并培养淋巴瘤癌细胞。
In the paper, we present an integrated flow cytometer with a 2D array of magnetic sensors based on dual-frequency oscillators in a 65-nm CMOS process, with the chip packaged with microfluidic controls. The sensor architecture and the presented array signal processing allows uninhibited flow of the sample for high throughput without the need for hydrodynamic focusing to a single sensor. To overcome the challenge of sensitivity and specificity that comes as a trade off with high throughout, we perform two levels of signal processing. First, utilizing the fact that a magnetically tagged cell is expected to excite sequentially an array of sensors in a time-delayed fashion, we perform inter-site cross-correlation of the sensor spectrograms that allows us to suppress the probability of false detection drastically, allowing theoretical sensitivity reaching towards sub-ppM levels that is needed for rare cell or circulating tumor cell detection. In addition, we implement two distinct methods to suppress correlated low frequency drifts of singular sensors—one with an on-chip sensor reference and one that utilizes the frequency dependence of the susceptibility of super-paramagnetic magnetic beads that we deploy as tags. We demonstrate these techniques on a 77 sensor array in 65 nm CMOS technology packaged with microfluidics with magnetically tagged dielectric particles and cultu lymphoma cancer cells.