|
|
xv | |
Foreword |
|
xxi | |
Preface |
|
xxv | |
|
|
1 | (50) |
|
1 Circulating Tumor Cells and Historic Perspectives |
|
|
3 | (30) |
|
|
1.1 Early Studies on Cancer Dormancy Led to the Development of a Sensitive Assay for CTCs (1970--1998) |
|
|
3 | (3) |
|
1.2 Modern Era for Counting CTCs: 1998--2007 |
|
|
6 | (1) |
|
1.3 Proof of Malignancy of CTCs |
|
|
7 | (1) |
|
1.4 New Experiments Involving CTCs |
|
|
7 | (1) |
|
1.5 Clinical Cancer Dormancy |
|
|
8 | (2) |
|
1.6 Human Epidermal Growth Factor Receptor 2 (HER2) Gene Amplification can be Acquired as Breast Cancer Progresses |
|
|
10 | (1) |
|
1.7 uPAR and HER2 Co-amplification |
|
|
11 | (1) |
|
1.8 Epithelial--Mesenchymal Transition (EMT) |
|
|
12 | (2) |
|
1.9 New Instruments to Capture CTCs |
|
|
14 | (1) |
|
|
15 | (3) |
|
|
18 | (15) |
|
|
20 | (13) |
|
2 Introduction to Microfluidics |
|
|
33 | (18) |
|
|
|
|
33 | (3) |
|
|
33 | (1) |
|
|
34 | (1) |
|
|
34 | (1) |
|
2.1.4 Advantages of Microfluidics |
|
|
35 | (1) |
|
|
36 | (3) |
|
|
36 | (1) |
|
|
37 | (1) |
|
|
38 | (1) |
|
|
39 | (4) |
|
|
39 | (1) |
|
2.3.2 Fabrication Methods |
|
|
40 | (1) |
|
|
40 | (1) |
|
|
41 | (1) |
|
|
42 | (1) |
|
|
42 | (1) |
|
2.4 Functional Components in Microfluidic Devices |
|
|
43 | (3) |
|
|
43 | (1) |
|
|
43 | (1) |
|
2.4.1.2 Nonmechanical Pumps |
|
|
44 | (1) |
|
|
44 | (1) |
|
|
45 | (1) |
|
|
46 | (1) |
|
|
46 | (5) |
|
|
47 | (4) |
|
PART II ISOLATION METHODS |
|
|
51 | (262) |
|
3 Ensemble-decision Aliquot Ranking (eDAR) for CTC Isolation and Analysis |
|
|
53 | (32) |
|
|
|
|
|
53 | (2) |
|
3.2 Individual Components and Analytical Performance of eDAR |
|
|
55 | (14) |
|
|
55 | (4) |
|
|
59 | (1) |
|
3.2.2.1 Active Sorting Scheme Based on an On-Chip Solenoid |
|
|
59 | (1) |
|
3.2.2.2 Active Sorting Scheme Based on an Off-Chip Solenoid |
|
|
60 | (3) |
|
3.2.3 On-Chip Purification |
|
|
63 | (1) |
|
3.2.3.1 Purification via Integrated Planar Filter |
|
|
63 | (1) |
|
3.2.3.2 Purification via Microfabricated Slits |
|
|
64 | (1) |
|
3.2.4 Secondary Labeling and the Enumeration of CTCs |
|
|
65 | (2) |
|
3.2.5 Characterization and Analytical Performance of eDAR |
|
|
67 | (2) |
|
3.3 Application and Downstream Analyses of eDAR |
|
|
69 | (11) |
|
3.3.1 Enumeration of CTCs from Cancer Patients using eDAR |
|
|
69 | (2) |
|
3.3.2 Downstream Analysis of CTCs Isolated by eDAR |
|
|
71 | (4) |
|
3.3.3 Automated High-Throughput Counting of CTCs -- A "Simplified" Version of eDAR |
|
|
75 | (5) |
|
3.4 Conclusion and Perspective |
|
|
80 | (5) |
|
|
81 | (4) |
|
4 Sinusoidal Microchannels with High Aspect Ratios for CTC Selection and Analysis |
|
|
85 | (42) |
|
|
|
|
|
85 | (5) |
|
|
85 | (2) |
|
4.1.2 Overview of CTC Selection Modalities and Assay Metrics |
|
|
87 | (3) |
|
4.2 Parallel Arrays of High-Aspect-Ratio, Sinusoidal Microchannels for CTC Selection |
|
|
90 | (24) |
|
4.2.1 Production of CTC In Vitro Diagnostic Devices in Thermoplastics |
|
|
91 | (3) |
|
4.2.2 Activation of High-Aspect-Ratio Microchannels for Efficient Ab Immobilization |
|
|
94 | (5) |
|
4.2.3 CTC Selection in Sinusoidal Microchannels from a Fluid Dynamics Perspective |
|
|
99 | (1) |
|
4.2.3.1 Centrifugal Forces in Curved Microchannels |
|
|
100 | (4) |
|
4.2.3.2 Transient Dynamics of CTC-Ab Binding |
|
|
104 | (3) |
|
4.2.4 Parallel Arrays for High-Throughput Sample Processing |
|
|
107 | (7) |
|
4.3 Clinical Applications of Sinusoidal CTC Microchip |
|
|
114 | (4) |
|
|
118 | (9) |
|
|
119 | (1) |
|
|
119 | (8) |
|
5 Cell Separation using Inertial Microfluidics |
|
|
127 | (20) |
|
|
|
|
127 | (1) |
|
5.2 Device Fabrication and System Setup |
|
|
128 | (1) |
|
5.3 Inertial Focusing in Microfluidics |
|
|
129 | (3) |
|
5.4 Cancer Cell Separation in Straight Microchannels |
|
|
132 | (4) |
|
5.5 Cancer Cell Separation in Spiral Microchannels |
|
|
136 | (6) |
|
|
142 | (5) |
|
|
142 | (5) |
|
6 Morphological Characteristics of CTCs and the Potential for Deformability-Based Separation |
|
|
147 | (26) |
|
|
|
|
147 | (1) |
|
6.2 Limitations of Antibody-based CTC Separation Methods |
|
|
148 | (1) |
|
6.3 Morphological and Biophysical Differences Between CTCs and Hematological Cells |
|
|
149 | (4) |
|
6.4 Historical and Recent Methods in CTC Separation Based on Biophysical Properties |
|
|
153 | (2) |
|
6.5 Microfluidic Ratchet for Deformability-Based Separation of CTCs |
|
|
155 | (5) |
|
6.5.1 Microfluidic Ratchet Mechanism |
|
|
155 | (1) |
|
6.5.2 Design of the Microfluidic Ratchet |
|
|
156 | (2) |
|
6.5.3 Validation of the Microfluidic Ratchet Mechanism |
|
|
158 | (1) |
|
6.5.4 Viability of Cells Enriched by the Microfluidic Ratchet Mechanism |
|
|
159 | (1) |
|
6.6 Resettable Cell Trap for Deformability-based Separation of CTCs |
|
|
160 | (5) |
|
6.6.1 Resettable Cell Trap Mechanism |
|
|
160 | (3) |
|
6.6.2 Validation of the Resettable Cell Trap Device |
|
|
163 | (1) |
|
6.6.3 Application of the Resettable Cell Trap for CTC Enrichment |
|
|
164 | (1) |
|
|
165 | (8) |
|
|
166 | (7) |
|
7 Microfabricated Filter Membranes for Capture and Characterization of Circulating Tumor Cells (CTCs) |
|
|
173 | (10) |
|
|
|
|
|
|
173 | (1) |
|
7.2 Size-based Enrichment of Circulating Tumor Cells |
|
|
174 | (3) |
|
7.3 Comparison Between Size-based CTC Isolation and Affinity-based Isolation |
|
|
177 | (1) |
|
7.4 Characterization of CTCs Captured by Microfilters |
|
|
178 | (2) |
|
7.4.1 Genomic Analysis of CTCs Enriched by Microfabricated Filter Membrane |
|
|
178 | (1) |
|
7.4.2 Gene Expression Analysis of CTC Enriched by Microfabricated Filter Membrane |
|
|
179 | (1) |
|
7.4.3 Functional Characterization of CTCs Enriched by Microfabricated Filter Membrane |
|
|
180 | (1) |
|
|
180 | (3) |
|
|
181 | (2) |
|
8 Miniaturized Nuclear Magnetic Resonance Platform for Rare Cell Detection and Profiling |
|
|
183 | (18) |
|
|
|
|
|
|
|
|
183 | (1) |
|
|
184 | (7) |
|
8.2.1 Magnetic Nanoparticles with High Transverse Relaxivity |
|
|
185 | (3) |
|
8.2.2 Bioorthogonal Strategy for Efficient MNP Labeling |
|
|
188 | (1) |
|
8.2.3 Miniaturized NMR Probe |
|
|
188 | (3) |
|
8.3 Clinical Application of μNMR for CTC Detection and Profiling |
|
|
191 | (5) |
|
8.3.1 Quad-Marker Assay Integrated with μNMR |
|
|
192 | (1) |
|
8.3.2 Comparison of Biomarkers in CTC and Bulk Tumor Cell |
|
|
192 | (4) |
|
|
196 | (5) |
|
|
196 | (5) |
|
9 Nanovelcro Cell-Affinity Assay for Detecting and Characterizing Circulating Tumor Cells |
|
|
201 | (26) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
202 | (5) |
|
9.1.1 Circulating Tumor Cells |
|
|
202 | (1) |
|
9.1.2 Current CTC Capture Methods |
|
|
202 | (3) |
|
9.1.3 The Evolution of NanoVelcro Cell-Affinity Assays |
|
|
205 | (1) |
|
9.1.4 Nanostructured Substrates for Cell Biology |
|
|
206 | (1) |
|
9.2 Proof-of-Concept Demonstration of NanoVelcro Cell-Affinity Substrates |
|
|
207 | (2) |
|
9.2.1 Stationary NanoVelcro CTC Assay |
|
|
207 | (1) |
|
9.2.2 General Applicability of NanoVelcro CTC Substrates |
|
|
207 | (2) |
|
9.3 First-Generation NanoVelcro Chips for CTC Enumeration |
|
|
209 | (5) |
|
9.3.1 Device Configuration of First-Generation NanoVelcro Chips |
|
|
209 | (3) |
|
9.3.2 Clinical Utility of First-Generation NanoVelcro Chips |
|
|
212 | (1) |
|
9.3.3 An Alternative Capture Agent, Aptamer |
|
|
213 | (1) |
|
9.4 Second-Generation NanoVelcro-LMD Technology for Single CTC Isolation |
|
|
214 | (5) |
|
9.4.1 Preparation of PLGA NanoVelcro Chips |
|
|
215 | (1) |
|
9.4.2 NanoVelcro-LMD Technology and Mutational Analysis |
|
|
215 | (1) |
|
9.4.3 NanoVelcro-LCM Technology and Whole Exome Sequencing |
|
|
215 | (4) |
|
9.5 Third-Generation Thermoresponsive NanoVelcro Chips |
|
|
219 | (1) |
|
9.6 Conclusions and Future Perspectives |
|
|
220 | (7) |
|
|
221 | (1) |
|
|
221 | (6) |
|
10 Acoustophoresis in Tumor Cell Enrichment |
|
|
227 | (22) |
|
|
|
|
|
|
227 | (3) |
|
|
227 | (2) |
|
10.1.2 System Specification |
|
|
229 | (1) |
|
10.2 Factors Determining Acoustophoresis Cell Separation |
|
|
230 | (4) |
|
|
231 | (1) |
|
10.2.2 Acoustic Radiation Force |
|
|
231 | (1) |
|
10.2.3 Trajectory of a Cell |
|
|
232 | (1) |
|
10.2.4 The MicroChannel Flow Profile |
|
|
233 | (1) |
|
10.3 Acoustophoresis System for Separating Cells |
|
|
234 | (5) |
|
10.3.1 Acoustophoresis Chip |
|
|
234 | (1) |
|
10.3.2 Actuation of Ultrasound |
|
|
234 | (1) |
|
|
234 | (2) |
|
10.3.4 Sample Preparation and Analysis |
|
|
236 | (1) |
|
10.3.4.1 Blood and Cancer Cell Preparation |
|
|
236 | (1) |
|
|
236 | (1) |
|
|
237 | (1) |
|
10.3.5.1 Varying the Flow Rate |
|
|
237 | (1) |
|
10.3.5.2 Cancer Cell Number |
|
|
237 | (1) |
|
10.3.5.3 Cancer Cell Diversity |
|
|
237 | (2) |
|
10.4 Acoustophoresis Platform for Clinical Sample Processing |
|
|
239 | (5) |
|
10.4.1 The Acoustophoresis Chip |
|
|
239 | (2) |
|
|
241 | (1) |
|
10.4.2.1 Pressure-Driven Flow |
|
|
241 | (1) |
|
10.4.2.2 Operation of the Flow System for Cell Separation |
|
|
241 | (1) |
|
10.4.3 Temperature Control System |
|
|
242 | (1) |
|
10.4.4 Software Interface |
|
|
242 | (1) |
|
10.4.5 System Calibration using Microbeads |
|
|
243 | (1) |
|
|
244 | (1) |
|
10.5 Unperturbed Cell Survival and Phenotype after Microchip Acoustophoresis |
|
|
244 | (2) |
|
|
246 | (3) |
|
|
246 | (3) |
|
11 Photoacoustic Flow Cytometry for Detection and Capture of Circulating Melanoma Cells |
|
|
249 | (18) |
|
|
|
|
|
|
249 | (5) |
|
11.1.1 Biomedical Photoacoustics |
|
|
251 | (1) |
|
11.1.2 Photoacoustic Flow Cytometry |
|
|
251 | (3) |
|
11.2 Current Methods for Detection and Capture of CMCs |
|
|
254 | (5) |
|
11.2.1 Two-Phase Flow for Cell Capture |
|
|
255 | (1) |
|
11.2.2 Photoacoustic Flow Cytometer |
|
|
256 | (1) |
|
11.2.3 Blood Sample Preparation |
|
|
256 | (2) |
|
|
258 | (1) |
|
11.2.5 Results of CMC Capture Study |
|
|
259 | (1) |
|
|
259 | (2) |
|
11.3.1 Extension to Nonpigmented CTCs |
|
|
260 | (1) |
|
|
261 | (6) |
|
|
262 | (5) |
|
12 Selectin-Mediated Targeting of Circulating Tumor Cells for Isolation and Treatment |
|
|
267 | (20) |
|
|
|
|
267 | (4) |
|
|
267 | (3) |
|
12.1.2 Circulating Tumor Cells |
|
|
270 | (1) |
|
12.2 CTC Capture by E-selectin |
|
|
271 | (2) |
|
12.3 Applications for E-selectin in Cancer Diagnosis and Treatment |
|
|
273 | (5) |
|
12.3.1 E-Selectin Capture for Drug Efficacy Testing |
|
|
273 | (1) |
|
12.3.2 E-Selectin for use in Targeted Cancer Therapy |
|
|
274 | (4) |
|
|
278 | (9) |
|
|
279 | (8) |
|
13 Aptamer-Enabled Tumor Cell Isolation |
|
|
287 | (14) |
|
|
|
|
287 | (1) |
|
13.2 Aptamers and their Biomedical Applications |
|
|
288 | (2) |
|
13.2.1 Identification of Aptamers |
|
|
288 | (1) |
|
13.2.2 Aptamers versus Antibodies |
|
|
289 | (1) |
|
|
290 | (1) |
|
13.3 Aptamer-based Tumor Cell Isolation |
|
|
290 | (7) |
|
13.3.1 Aptamers with Microfluidics |
|
|
290 | (1) |
|
|
290 | (3) |
|
13.3.1.2 Surface Functionalization |
|
|
293 | (1) |
|
13.3.1.3 Tumor Cell Isolation |
|
|
293 | (1) |
|
13.3.1.4 Instrument Setup |
|
|
293 | (1) |
|
13.3.2 Aptamers with Nanoparticles |
|
|
294 | (1) |
|
13.3.3 Aptamers with Innovative Schemes |
|
|
295 | (1) |
|
13.3.4 Aptamers for CTC Isolation |
|
|
296 | (1) |
|
13.4 Conclusion and Outlook |
|
|
297 | (4) |
|
|
297 | (4) |
|
14 Depletion of Normal Cells for CTC Enrichment |
|
|
301 | (12) |
|
|
|
|
|
|
|
|
301 | (1) |
|
14.2 Estimates of Number and Type of Cells in Blood |
|
|
302 | (1) |
|
14.3 Summary of Examples of Negative Depletion |
|
|
303 | (2) |
|
|
303 | (1) |
|
14.3.2 Removal of Normal Nucleated Cells |
|
|
304 | (1) |
|
14.4 Types of Cells Observed After Depletion of Normal Cells |
|
|
305 | (1) |
|
14.5 Incomplete Depletion of Normal Cells |
|
|
305 | (5) |
|
|
310 | (3) |
|
|
311 | (2) |
|
PART III POST-ISOLATION ANALYSIS AND CLINICAL TRANSLATION |
|
|
313 | (52) |
|
15 Tumor Heterogeneity and Single-cell Analysis of CTCs |
|
|
315 | (14) |
|
|
|
|
315 | (1) |
|
|
316 | (2) |
|
15.3 Single-Cell Analysis of CTCs and CTC Heterogeneity |
|
|
318 | (1) |
|
15.4 Gene Expression Analysis |
|
|
319 | (2) |
|
|
321 | (2) |
|
15.6 Conclusion: Clinical Implications and Future Perspectives |
|
|
323 | (6) |
|
|
324 | (5) |
|
16 Single-Cell Molecular Profiles and Biophysical Assessment of Circulating Tumor Cells |
|
|
329 | (22) |
|
|
|
|
|
|
|
|
|
|
329 | (2) |
|
|
331 | (5) |
|
16.2.1 Single-Cell Molecular Profiling |
|
|
331 | (1) |
|
16.2.1.1 High-Throughput Single-Cell qRT-PCR using Microfluidic BioMark™ HD |
|
|
332 | (1) |
|
16.2.1.2 Single-Cell Transcriptome Analysis using Gene Expression Microarray |
|
|
332 | (1) |
|
16.2.1.3 Single-Cell RNA-Seq |
|
|
333 | (1) |
|
16.2.2 Probing Cellular Biophysical Properties of Single Cells |
|
|
333 | (1) |
|
16.2.2.1 The Instruments for Biophysical Assessment of Single Cells |
|
|
333 | (3) |
|
16.2.2.2 The Biophysical Parameters of Single Cells |
|
|
336 | (1) |
|
|
336 | (6) |
|
16.3.1 Single-cell Molecular Profiling of CTCs |
|
|
336 | (5) |
|
16.3.2 Analysis of Nanomechanical Phenotypes of Single CTCs |
|
|
341 | (1) |
|
|
342 | (9) |
|
|
343 | (8) |
|
17 Directing Circulating Tumor Cell Technologies Into Clinical Practice |
|
|
351 | (14) |
|
|
|
|
|
351 | (1) |
|
|
352 | (4) |
|
17.2.1 Prognostic CTC Biomarkers |
|
|
353 | (2) |
|
17.2.2 Predictive CTC Biomarkers |
|
|
355 | (1) |
|
17.2.3 Pharmacodynamic CTC Biomarkers |
|
|
355 | (1) |
|
17.2.4 Diagnostic CTC Biomarkers |
|
|
356 | (1) |
|
17.2.5 Surrogate CTC Biomarkers |
|
|
356 | (1) |
|
|
356 | (1) |
|
17.3.1 Translated Technologies |
|
|
357 | (1) |
|
17.4 Translating Technology |
|
|
357 | (3) |
|
17.4.1 The Technology Side |
|
|
358 | (2) |
|
|
360 | (1) |
|
|
360 | (5) |
|
|
361 | (4) |
|
PART IV COMMERCIALIZATION |
|
|
365 | (36) |
|
18 DEPArray™ Technology for Single CTC Analysis |
|
|
367 | (10) |
|
|
|
|
18.1 Challenges in Molecular Profiling of CTCs |
|
|
367 | (1) |
|
18.2 DEPArray™ Technology Solution |
|
|
368 | (1) |
|
18.3 DEPArray™ for Single Tumor Cell Analysis |
|
|
369 | (4) |
|
18.4 Clinical Significance in Single CTC Profiling |
|
|
373 | (1) |
|
|
374 | (3) |
|
|
374 | (3) |
|
19 CELLSEARCH® Instrument, Features, and Usage |
|
|
377 | (24) |
|
|
|
|
|
|
377 | (2) |
|
19.2 Principles of CELLSEARCH® |
|
|
379 | (1) |
|
19.3 EpCAM Density and CTC Capture |
|
|
380 | (3) |
|
19.4 Clinical Applications of CELLSEARCH® CTCs |
|
|
383 | (7) |
|
|
383 | (1) |
|
19.4.2 Expanding Enumeration |
|
|
384 | (1) |
|
19.4.3 CTC Enumeration and Clinical Utility |
|
|
385 | (2) |
|
19.4.4 Characterization of CTCs using CELLSEARCH® |
|
|
387 | (3) |
|
19.5 Beyond EpCAM Capture |
|
|
390 | (1) |
|
|
391 | (10) |
|
|
394 | (7) |
|
|
401 | (2) |
Circulating Tumor Cell Glossary |
|
403 | (20) |
|
|
Index |
|
423 | |