Circulating tumor cell capturing techniques and devices

Abstract

Candidate cells, such as circulating tumor cells (CTCs), present with blood are captured using a multiple stage device, having successive stages configured to deviate candidate cells out of the blood while slowing down the flow rates of the deviated resultant for easier capture of CTCs through progressive stages. The devices can include separation channel and deviation channels formed of micro-post patterns dimensioned to deviate different desired candidate cells for analysis.

What is claimed is: 
     
         1 . A device for separating candidate cells from a carrier fluid, the device comprising:
 a separation channel to receive the carrier fluid having a first flow rate and to provide for an isolation fluid, wherein the separation channel is configured to deflect the candidate cells from the carrier fluid into the isolation fluid; and   a capture stage coupled to the separation channel through a coupling stage, wherein the coupling stage is configured to collect the isolation fluid and reduce the flow rate of the isolation fluid and deflected candidate cells, and wherein the capture stage is configured to capture the deflected candidate cells over a sampling period.   
     
     
         2 . The device of  claim 1 , wherein the separation channel maintains a laminar flow of the carrier fluid and the isolation fluid. 
     
     
         3 . The device of  claim 1 , wherein the separation channel is a deviation channel comprising a micro-post pattern dimensioned to deviate the candidate cells based on cell size. 
     
     
         4 . The device of  claim 1 , wherein the separation channel is a deviation channel comprising a micro-post pattern dimensioned to deviate the candidate cells from the remaining cells in the carrier fluid. 
     
     
         5 . The device of  claim 1 , wherein the first flow rate is at or below a normal blood flow rate for a patient. 
     
     
         6 . The device of  claim 1 , wherein the separation channel is a deviation channel that deviates only candidate cells into the isolation fluid. 
     
     
         7 . The device of  claim 1 , wherein the separation channel propagates the carrier fluid at the first flow rate from an inlet to the separation channel to an outlet from the separation channel. 
     
     
         8 . The device of  claim 1 , wherein the separation channel is a deviation channel that deflects the candidate cells based on antibody deflection created in the deviation channel using patterned angled lines on opposing channel walls of the deviation channel, where the patterned angled lines are chosen to deviate the candidate cells by transient adhesion to included antibodies, thereby slowing down the candidate cells and deflecting the candidate cells at an angle. 
     
     
         9 . The device of  claim 1 , wherein the capture stage comprises a micro-post pattern dimensioned to capture the candidate cells. 
     
     
         10 . The device of  claim 1 , wherein the separation stage has a first outlet for egressing the carrier fluid at the first flow rate and a second outlet for egressing the isolation fluid and deviated candidate cells at the first flow rate. 
     
     
         11 . The device of  claim 10 , wherein the coupling stage is coupled to the second outlet and reduces the flow rate of the isolation fluid and deviated candidate from the first flow rate to a second flow rate less than the first flow rate. 
     
     
         12 . The device of  claim 11 , wherein the second flow rate is at least 10× slower than the first flow rate. 
     
     
         13 . The device of  claim 11 , where the coupling stage comprises:
 a first slow down stage coupled to the second output and configured to slow down the flow rate of the isolation fluid and deviated candidate cells from the first flow rate to a second flow rate lower than the first flow rate; and   a second separation stage coupled to the first slow down stage to further deviate the candidate cells, the second separation stage having a third outlet supporting flow at the second flow rate and a fourth outlet supporting flow at a third flow rate lower than the second flow rate.   
     
     
         14 . The device of  claim 1 , wherein the carrier fluid is blood and the candidate cells are circulating tumor cells. 
     
     
         15 . The device of  claim 1 , wherein the carrier fluid is blood and the candidate cells are cancer cells. 
     
     
         16 . The device of  claim 15 , wherein the cancer cells are epithelial cells, endothelial cells, neurons, hepatocytes, nephrons, glial cells, muscle cells, skin cells, adipcytes, fibroblasts, chondrocytes, osteocytes, or osteoblasts. 
     
     
         17 . The device of  claim 15 , where the cancer cells express at least one marker of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, or Wilm's tumor. 
     
     
         18 . The device of  claim 1 , wherein the capture stage is to allow cell growth of the deviated candidate cells. 
     
     
         19 . The device of  claim 1 , wherein the carrier fluid is blood, the device further comprises:
 an extraction stage to collect the blood from a blood-vessel of a patient, into the separation channel; and   an insertion stage to re-introduce the blood into the vessel after deviation of the candidate cells, where the blood is re-introduced substantially at or up to the first flow rate.   
     
     
         20 . The device of  claim 19 , further comprising a first peristaltic pump coupled to the extraction stage to normalize flow of the carrier fluid to the first flow rate. 
     
     
         21 . The device of  claim 20 , further comprising a second micro-pump coupled to the insertion stage to normalize flow of the carrier fluid back into the vessel at a nominal blood flow rate for the vessel. 
     
     
         22 . The device of  claim 1 , wherein the carrier fluid is blood and the isolation fluid is a water solution, a saline solution, or a water and saline solution. 
     
     
         23 . The device of  claim 1 , wherein the separation channel is configured to deflect at least 90% of the candidate cells in the carrier fluid into the isolation fluid. 
     
     
         24 . A method of analyzing candidate cells captured in the capture stage of the device of  claim 1 , the method comprising applying at least one of an optical analysis, visual inspection, automated counting, microscopy, magnetic detection, or electrical detection to at least some of the captured candidate cells. 
     
     
         25 . A wearable circulating tumor cell capture device, the device comprising:
 a mounting for releasable attaching the device to an exterior of a patient;   an extraction lumen coupled to a vessel of the patient to continuously receive blood, at a normal blood flow rate, over a sampling period;   a separation channel coupled to receive the blood at the normal blood flow rate and configured to deflect circulating tumor cells from the blood into an isolation channel and configured to maintain blood at the normal blood flow rate in main flow channel, where the separation channel blocks white blood cells and red blood cells from deflection into the isolation channel;   a capture stage coupled to the isolation channel and configured to collect the deflected candidate cells over the sampling period; and   an insertion lumen coupled to the vessel to re-introduce blood into the vessel at an acceptable blood flow rate.   
     
     
         26 . The device of  claim 25 , wherein the sampling period is less than an hour. 
     
     
         27 . The device of  claim 25 , wherein the sampling period is at least an hour. 
     
     
         28 . The device of  claim 27 , wherein the sampling period is between 1 hour and 24 hours. 
     
     
         29 . The device of  claim 25 , wherein at a blood flow rate through the device of approximately 4 ML/min, the capture stage collected over 90% of circulating tumor cells within the received blood over a sampling period. 
     
     
         30 . The device of  claim 25 , further comprising a first peristaltic pump coupled to the extraction lumen to normalize flow of the blood into the separation channel. 
     
     
         31 . The device of  claim 25 , further comprising a second peristaltic pump coupled to the insertion lumen to normalize flow of the blood back into the vessel. 
     
     
         32 . The device of  claim 31 , wherein the second peristaltic pump is coupled to receive blood from the main flow channel of the separation channel. 
     
     
         33 . The device of  claim 25 , further comprising a housing enclosing at least the separation channel and the capture stage. 
     
     
         34 . The device of  claim 25 , wherein the separation channel comprises a micro-post pattern formed of an array of micro-posts. 
     
     
         35 . The device of  claim 25 , wherein the separation channel deflects the circulating tumor cells based on antibody deflection created in the deviation channel using patterned angled lines on opposing channel walls of the deviation channel, where the patterned angled lines are chosen to deviate the candidate cells by transient adhesion to included antibodies, thereby slowing down the candidate cells and deflecting the candidate cells at an angle. 
     
     
         36 . The device of  claim 25 , wherein the circulating tumor cells express at least marker one of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, or Wilm's tumor. 
     
     
         37 . The device of  claim 25 , wherein the separation channel is configured to deflect at least 90% of the circulating tumor cells in the blood flowing into the device over the sampling period. 
     
     
         38 . A method for capturing circulating tumor cells from blood, the method comprising:
 maintaining blood flow at a normal blood flow rate and in a laminarized profile;   deviating the circulating tumor cells from blood, while the blood is flowing at the normal blood flow rate;   slowing the deviated circulating tumor cells; and   capturing the slowed deviated circulating tumor cells.   
     
     
         39 . The method of  claim 38 , wherein deviating the circulating tumor cells comprises using a micro-post patterned channel to concentrate circulating tumor cells in a region of the micro-post patterned channel. 
     
     
         40 . The method of  claim 39 , wherein slowing the deviated circulating tumor cells comprises slowing the circulating tumor cells flowing from the region of the micro-post patterned channel. 
     
     
         41 . The method of  claim 40 , wherein the micro-post patterned channel comprises a plurality of micro-posts in an arrayed patterned, 
     
     
         42 . The method of  claim 40 , wherein at least some of the plurality of micro-posts are functionalized with an antibody. 
     
     
         43 . The method of  claim 38 , wherein deviating the circulating tumor cells comprises using an antibody rolling deflection to concentrate circulating tumor cells in a region of the micro-post patterned channel. 
     
     
         44 . The method of  38 , wherein capturing the slowed deviated circulating tumor cells comprises using a micro-post patterned stage configured to retain the circulating tumor cells. 
     
     
         45 . The method of  claim 38 , wherein the circulating tumor cells express at least one marker of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, or Wilm's tumor. 
     
     
         46 . A device for characterizing cells within blood, the device comprising:
 a plurality of deviation stages each functionalized to deviate cells within the blood based on a different morphological, mechanical, physical or biological characteristic; and   a plurality of capture stages, each coupled to a different combination of the plurality of deviation stages, such that each capture stage corresponds to a different combination of physical and/or biological characteristics.   
     
     
         47 . The device of  claim 46 , wherein each of the plurality of deviation stages are antibody-rolling deviation stages. 
     
     
         48 . The device of  claim 46 , wherein each of the plurality of capture stages are micro-post patterned stages. 
     
     
         49 . The device of  claim 46 , further comprising a plurality of cell detection readout stages each positioned to detect the presence of cells within a corresponding one of the capture stages. 
     
     
         50 . The device of  claim 49 , wherein each cell detection readout stage comprises a pixel sensor array. 
     
     
         51 . The device of  claim 49 , wherein each cell detection readout stage automatically examines for cells in the corresponding capture stage. 
     
     
         52 . The device of  claim 51 , wherein each cell detection readout stage automatically examines the corresponding capture stage at periodic time intervals. 
     
     
         53 . The device of  claim 49 , wherein each cell detection readout stage automatically counts the number of cells captured in the corresponding capture stage. 
     
     
         54 . A candidate cell analysis device comprising:
 a deviation stage configured to deflect candidate cells from blood while the blood is flowing at normal patient blood flow rate, where the candidate cells are deflected into a blood-free solution;   a slow down stage to slow the flow rate of the blood free solution having the candidate cells; and   a capture stage coupled to the slow down stage to collect at least some of the candidate cells against further flow; and   a cell detection readout device positioned to detect whether the candidate cells have been captured in the capture stage.   
     
     
         55 . The device of  claim 54 , wherein the cell detection readout device comprises a pixel sensor array. 
     
     
         56 . The device of  claim 54 , wherein the cell detection readout device automatically examines the capture stage to determine if candidate cells have been captured. 
     
     
         57 . The device of  claim 56 , wherein the cell detection readout device automatically examines the capture stage at periodic time intervals. 
     
     
         58 . The device of  claim 54 , wherein the cell detection readout device automatically counts the number of candidate cells captured in the capture stage. 
     
     
         59 . The device of  claim 54 , wherein the cell detection readout device automatically analyzes captured candidate cells to determine cell type. 
     
     
         60 . The device of  claim 54 , wherein the candidate cells are cancer cells. 
     
     
         61 . The device of  claim 60 , wherein the cancer cells are epithelial cells, endothelial cells, neurons, hepatocytes, nephrons, glial cells, muscle cells, skin cells, adipcytes, fibroblasts, chondrocytes, osteocytes, or osteoblasts. 
     
     
         62 . The device of  claim 60 , where the cancer cells express at least one marker of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, or Wilm's tumor. 
     
     
         63 . A circulating tumor cell capture device, the device comprising:
 a separation channel to receive blood from a vessel of a patient at the normal blood flow rate and configured to deflect circulating tumor cells from the blood into an isolation channel and configured to maintain blood at the normal blood flow rate in main flow channel, where the separation channel blocks white blood cells and red blood cells from deflection into the isolation channel; and   a capture stage coupled to the isolation channel and configured to collect the deflected candidate cells over the sampling period.   
     
     
         64 . The device of  claim 63 , further comprising an extraction lumen device coupled to a vessel of the patient to continuously receive blood, at a normal blood flow rate, over a sampling period and coupled to transmit the blood to the separation channel at the normal blood flow rate. 
     
     
         65 . The device of  claim 64 , further comprising a first peristaltic pump coupled to the extraction lumen to normalize flow of the blood into the separation channel. 
     
     
         66 . The device of  claim 63 , wherein the separation channel is configured to deflect at least 90% of the circulating tumor cells in the blood flowing into the device over the sampling period. 
     
     
         67 . The device of  claim 63 , further comprising a housing enclosing at least the separation channel and the capture stage. 
     
     
         68 . The device of  claim 63 , wherein the separation channel comprises a micro-post pattern formed of an array of micro-posts. 
     
     
         69 . The device of  claim 63 , wherein the separation channel deflects the circulating tumor cells based on antibody deflection created in the deviation channel using patterned angled lines on opposing channel walls of the deviation channel, where the patterned angled lines are chosen to deviate the candidate cells by transient adhesion to included antibodies, thereby slowing down the candidate cells and deflecting the candidate cells at an angle. 
     
     
         70 . The device of  claim 63 , wherein the circulating tumor cells express at least marker one of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, or Wilm's tumor.