Abstract
Cholangiocarcinoma (CCA), a biliary tract malignancy, accounts for 20% of all liver cancers. There are several existing methods for diagnosis of CCA, though they are generally expensive, laborious, and suffer from low detection rates. Herein we first developed a means of partially purifying human bile for consequent injection into a microfluidic chip. Then, the novel microfluidic system, which featured 1) a cell capture module, 2) an immunofluorescence (IF) staining module featuring two CCA-specific biomarkers, and 3) an optical detection module for visualization of antibody probes bound to these CCA marker proteins, was used to detect bile duct cancer cells within partially purified bile samples. As a proof of concept, CCA cells were successfully captured and identified from CCA cell cultures, blood samples inoculated with CCA cells, and clinical bile specimens. In 7.5 ml of bile, this system could detect >2, 0, and 1 positive cells in advanced stage patients, healthy patients, and chemotherapy-treated patients, respectively. In conclusion, our microfluidic system could be a promising tool for detection of cancer cells in bile, even at the earliest stages of CCA when cancer cells are at low densities relative to the total population of epithelial cells.
Highlights
Several methods exist for diagnosis of CCA, including blood tests[8], abdominal sonography[9], computed tomography scans[3], magnetic resonance imaging[3], and endoscopic retrograde choledochopancreatography[9]
The on-chip process started from the incubation between epithelial-enrich immunomagnetic beads (EpiEnrich beads, anti-epithelial cell adhesion molecule (EpCAM) antibodies coated beads) and the cell pellets to capture the target cancer cells in bile (Figure 1(b))
We have shown that the developed microfluidic system can successfully detect CCA cells in bile
Summary
Several methods exist for diagnosis of CCA, including blood tests[8], abdominal sonography[9], computed tomography scans[3], magnetic resonance imaging[3], and endoscopic retrograde choledochopancreatography[9]. CCA is difficult to diagnose in its early stages with existing bio-imaging methods, since the gallbladder and biliary tracts are deep inside the abdomen. Most CCAs are diagnosed in their later stages by endoscopic methods such as laparoscopy and cholangioscopy; these common, painful processes are characterized by low detection rates and require expensive instrumentation and large biopsies[3, 9]. A previous work investigated biliary cytology with 100 patients and separated them into two groups, including group 1 for bile cytology test only and group 2 for combining bile and brush cytology tests to diagnosis whether they were invasive by cancer[12]. Treat patients in the early stages of CCA given the low sensitivity of such histology-based approaches. Detection of circulating tumor cells (CTCs) has been recognized as a valid approach for cancer
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