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Clinical Laboratories and Pathology Groups

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Clinical Laboratories and Pathology Groups

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US Hospitals Continue to Be Squeezed by Shortage of Nurses, Rising Salaries

It is more than a shortage of nurses, as most clinical laboratories report the same shortages of medical technologists and increased labor costs

Just as hospital-based clinical laboratories are unable to hire and retain adequate numbers of medical technologists (MTs) and clinical laboratory scientists (CLSs), the nursing shortage is also acute. Compounding the challenge of staffing nurses is the rapid rise in the salaries of nurses because hospitals need nurses to keep their emergency departments, operating rooms, and other services open and treating patients while also generating revenue.

The nursing shortage has been blamed on burnout due to the COVID-19 pandemic, but nurses also report consistently deteriorating conditions and say they feel undervalued and under-appreciated, according to Michigan Advance, which recently covered an averted strike by nurses at 118-bed acute care McLaren Central Hospital in Mt. Pleasant and 97-bed teaching hospital MyMichigan Medical Center Alma, both in Central Michigan.

“Nurses are leaving the bedside because the conditions that hospital corporations are creating are unbearable. The more nurses leave, the worse it becomes. This was a problem before the pandemic, and the situation has only deteriorated over the last three years,” said Jamie Brown, RN, President of the Michigan Nurses Association (MNA) and a critical care nurse at Ascension Borgess Hospital in Kalamazoo, Michigan Advance reported.

Jamie Brown, RN

“The staffing crisis will never be adequately addressed until working conditions at hospitals are improved,” said Jamie Brown, RN (above), President of the Michigan Nurses Association in a press release. Brown’s statement correlates with claims by laboratory technicians about working conditions in clinical laboratories all over the country that are experiencing similar shortages of critical staff. (Photo copyright: Michigan Nurses Association.)

Nurse Understaffing Dangerous to Patients

In the lead up to the Michigan nurses’ strike, NPR reported on a poll conducted by market research firm Emma White Research LLC on behalf of the MNA that found 42% of nurses surveyed claimed “they know of a patient death due to nurses being assigned too many patients.” The same poll in 2016 found only 22% of nurses making the same claim.

And yet, according to an MNA news release, “There is no law that sets safe RN-to-patient ratios in hospitals, leading to RNs having too many patients at one time too often. This puts patients in danger and drives nurses out of the profession.”

Other survey findings noted in the Emma White Research memo to NPR include:

  • Seven in 10 RNs working in direct care say they are assigned an unsafe patient load in half or more of their shifts.
  • Over nine in 10 RNs say requiring nurses to care for too many patients at once is affecting the quality of patient care.
  • Requiring set nurse-to-patient ratios could also make a difference in retention and in returning qualified nurses to the field.

According to NPR, “Nurses across the state say dangerous levels of understaffing are becoming the norm, even though hospitals are no longer overwhelmed by COVID-19 patients.”

Thus, nursing organizations in Michigan, and the legislators who support change, have proposed the Safe Patient Care Act which sets out to “to increase patient safety in Michigan hospitals by establishing minimum nurse staffing levels, limiting mandatory overtime for RNs, and adding transparency,” according to an MNA news release.

Huge Increase in Nursing Costs

Another pressure on hospitals is the rise in the cost of replacing nurses with temporary or travel nurses to maintain adequate staffing levels.

In “Hospital Temporary Labor Costs: a Staggering $1.52 Billion in FY2022,” the Massachusetts Health and Hospital Association noted that “To fill gaps in staffing, hospitals hire registered nurses and other staff through ‘traveler’ agencies. Traveler workers, especially RNs in high demand, command higher hourly wages—at least two or three times more than what an on-staff clinician would earn. Many often receive signing bonuses. In Fiscal Year 2019, [Massachusetts] hospitals spent $204 million on temporary staff. In FY2022, they spent $1.52 billion—a 610% increase. According to the MHA survey, approximately 77% of the $1.52 billion went to hiring temporary RNs.”

It’s likely this same scenario is playing out in hospitals all across America.

Are Nursing Strikes a Symptom of a Larger Healthcare Problem?

In “Nurses on Strike Are Just the Tip of the Iceberg. The Care Worker Shortage Is About to Touch Every Corner of the US Economy,” Fortune reported that nationally the US is facing a shortage of more than 200,000 nurses.

“But the problem is much bigger,” Fortune wrote. “Care workers—physicians, home health aides, early childhood care workers, physician assistants, and more—face critical challenges as a result of America’s immense care gap that may soon touch every corner of the American economy.”

Clinical laboratories are experiencing the same shortages of critical staff due in large part to the same workplace issues affecting nurses. Dark Daily covered this growing crisis in several ebriefings.

In “Forbes Senior Contributor Covers Reasons for Growing Staff Shortages at Medical Laboratories and Possible Solutions,” we covered an article written by infectious disease expert Judy Stone, MD, in which she noted that factors contributing to the shortage of medical technologists and other clinical laboratory scientists include limited training programs in clinical laboratory science, pay disparity, and staff retention.

We also covered in that ebrief how the so-called “Great Resignation” caused by the COVID-19 pandemic has had a severe impact on clinical laboratory staffs, creating shortages of pathologists as well as of medical technologists, medical laboratory technicians, and other lab scientists who are vital to the nation’s network of clinical laboratories.

And in “Clinical Laboratory Technician Shares Personal Journey and Experience with Burnout During the COVID-19 Pandemic,” we reported on the personal story of Suzanna Bator, a former laboratory technician with the Cleveland Clinic and with MetroHealth System in Cleveland, Ohio. Bator shared her experiences in an essay for Daily Nurse that took a personalized, human look at the strain clinical laboratory technicians were put under during the SARS-CoV-2 pandemic. Her story presents the quandary of how to keep these critical frontline healthcare workers from experiencing burnout and leaving the field.

Did Experts See the Shortages Coming?

Hospitals across the United States—and in the UK, according to Reuters—are facing worker strikes, staff shortages, rising costs, and uncertainty about the future. Just like clinical laboratories and other segments of the healthcare industry, worker burnout and exhaustion in the wake of the COVID-19 pandemic are being cited as culprits for these woes.

But was it predictable and could it have been avoided?

“One of the big things to clear up for the public is that … we saw the writing on the wall that vacancies were going to be a problem for us, before the pandemic hit our shores,” Christopher Friese, PhD, professor of Nursing and Health Management Policy at the University of Michigan (UM), told NPR. Friese is also Director of the Center for Improving Patient and Population Health at UM.

Effects of the COVID-19 pandemic, and staffing shortages exasperated by it, will be felt by clinical laboratories, pathology groups, and the healthcare industry in general for years to come. Creative solutions must be employed to avoid more staff shortages and increase employee retention and recruitment.

Ashley Croce

Related Information:

Amid Burnout and Exhaustion, Nurses at Two Mid-Michigan Hospitals OK New Contracts

‘Everyone Is Exhausted and Burned Out’: McLaren Central Nurses Authorize Potential Strike

New Poll Shows a Nurse-to-Patient Ratio Law Could Be Key to Addressing Staffing Crisis

42% of Michigan Nurses Say High Patient Load Led to Deaths

Michigan Nurses Report More Patients Dying Due to Understaffing, Poll Finds

COVID-19’s Impact on Nursing Shortages, the Rise of Travel Nurses, and Price Gouging

Survey of Registered Nurses Living or Working in Michigan

This Nursing Shortage Requires Innovative Solutions

Nurses on Strike Are Just the Tip of the iceberg. The Care Worker Shortage Is About to Touch Every Corner of the US Economy

Workers Stage Largest Strike in History of Britain’s Health Service

Nursing Shortage by State: Which US States Need Nurses the Most and Which Ones Will Have Too Many?

Japanese Researchers Create Inexpensive Palm-Size Microfilter That Captures Circulating Tumor Cells from Minute Amounts of Blood

Its low cost may advance liquid biopsy cancer testing used by anatomic pathologists and improve outcomes by speeding time to diagnosis and treatment

Researchers in Japan say they have created a circulating tumor cell (CTC) detection solution that is inexpensive and easy to run. Such a device would be of huge interest to investors and companies wishing to develop clinical laboratory tests that use circulating tumor cells in the blood to identify patients with cancer.

In a proof-of-concept study, researchers at Kumamoto University (KU) in Japan have developed and tested a microfilter device they claim can separate and capture CTCs in blood without large equipment, a KU news release reported.

According to Medgadget, the device is an “inexpensive, convenient, and highly sensitive filter that can successfully work in samples containing as few as five tumor cells in one milliliter of blood and does not require expensive equipment or reagents, unlike certain pre-existing cell capture technologies.”

This Technology Could Give Pathologists a Less-Invasive Cancer Test

As medical laboratory scientists and anatomic pathologists know, a CTC test is less invasive than tissue biopsy, which benefits patients. Furthermore, such a CTC test may enable earlier detection of cancer and start of treatment improving odds for success.

Still, there are many pitfalls to overcome when the challenge is to detect cancer cells in a milliliter (about .03 fluid ounce) of blood. As Medgadget put it, “A needle in a haystack doesn’t even come close.”

“Cancer cell count in the blood of cancer patients is extremely low. If these cells are easily detectable, cancer diagnosis may be possible by simply using a blood test, thus reducing patient burden,” the researchers wrote in their paper.

The KU scientists published their findings in Talanta, the international journal of pure and applied analytical chemistry, titled, “Detection of Cancer Cells in Whole Blood Using a Dynamic Deformable Microfilter and a Nucleic Acid Aptamer.”

Yuta Nakashima, PhD

“This work demonstrates that our microfilter device can accurately detect trace amounts of cancer cells in blood,” said study leader Yuta Nakashima, PhD (above), Associate Professor, Department of Mechanical System Engineering at Kumamoto University, in the news release. “We expect it will be adopted for cancer diagnosis and treatment, including for early diagnosis of cancers that cannot be detected by imaging like CT and PET scans, post-operative follow-up, recurrence monitoring, and tailor-made treatments. In the future, we plan to use blood samples donated by cancer patients to verify the practical and clinical application of the method,” he added. Were it to become available, such a CTC test would be a boon for clinical laboratories and anatomic pathologists engaged in cancer diagnostics and treatment. (Photo copyright: Kumamoto University.)

How Does the CTC Filter Device Work?

The KU scientists created a palm-size “cancer detection device using a microfilter and nucleic acid aptamer,” the paper said, adding:

  • The microfilter was made with photolithography, electroforming, and three-dimensional (3D) printing.
  • It includes slits to enable a deformation with force of blood pumping through the device.
  • As blood flows over the microfilter, cancer cells bind to the nucleic acid aptamer.
  • Force of blood flow opens microfilter slits, pushing away the healthy cells.
  • Cancer cells are left on the microfilter.

To test the microfilter the researchers used one milliliter of blood that was “spiked with cancer cells,” according to the paper. Findings include:

  • Detection of five CTCs in one milliliter of blood. 
  • Blood cell removal rate of 98% suggested “no blood cells were absorbed by the microfilter,” the news release said.
  • The method “showed higher accuracy than the CellSearch System,” the Talanta paper noted.

The KU research team compared their microfluidic device to CellSearch, an FDA-cleared system for detecting CTCs from a blood sample. 

CellSearch enables “identification, isolation, and enumeration of CTCs of epithelial origin,” according to Menarini Silicon Biosystems of Castel Maggiore, Italy. It works from a blood sample of 7.5 millimeters with “high level of sensitivity and specificity,” notes the company’s website.

According to Menarini, labs offering CellSearch CTC testing include:

CTC Tests Progress, But More to Do

The UK scientists admit that their research needs further study. Nakashima indicated he plans to test blood samples donated by cancer patients in subsequent device trials.

However, a separate CTC study published in Oncology Letters, titled, “Detection of Circulating Tumor Cells: Advances and Critical Concerns,” suggested that CellSearch and another CTC assay, Gilupi CellCollector, are “limited in their clinical application, largely due to their low sensitivity.”  

“Although great progress has been made, there is a long way to go before CTC-based liquid biopsy is widely used as a routine test in clinical application,” the authors of that study noted.

Nevertheless, even with more to do, liquid biopsy testing has come a long way, as multiple Dark Daily eBriefs reported over the years.

If the KU scientists succeed in bringing to market a microfilter that can reduce the cost of CTC detection by clinical laboratories while also improving cancer diagnostics, that will have a huge impact on cancer patients and is worthy of clinical laboratory leaders’ attention.    

Donna Marie Pocius

Related Information:

Microfilter Device Capable of Detecting Trace Amounts of Cancer Cells in One mL of Blood

Inexpensive Filter Isolates Circulating Tumor Cells

Detection of Cancer Cells in Whole Blood Using a Dynamic Deformable Microfilter and a Nucleic Acid Aptamer

Detection of Circulating Tumor Cells: Advances and Critical Concerns

Dark Daily: Liquid Biopsy

University Researchers Develop Microfluidic Device That Partitions Cancer Cells According to Size in Effort to Create a Useful Liquid Biopsy Method

Could a fast, cheap, and accurate liquid biopsy diagnostic cancer test soon be available to clinical laboratories and anatomic pathology groups?

What if medical laboratories worldwide could perform a simple liquid biopsy diagnostic test that detected cancer in its various forms? Such a test, if affordable and accurate, would be a boon to histopathology and clinical pathology laboratories. Until now, though, such a test has proven to be elusive. But, researchers at the University of Illinois at Chicago (UIC) and Queensland University of Technology (QUT) in Australia think they may have such a technology in hand.

The researchers unveiled a diagnostic device that uses microfluidic technology to identify cell types in blood by their size. The device also “can isolate individual cancer cells from patient blood samples,” according to a news release.

The ability to isolate circulating tumor cells could enable clinical laboratories to perform diagnostic cancer tests on liquid biopsies and blood samples. Dark Daily reported on various studies involving liquid biopsies—an alternative to invasive and costly cancer diagnostic procedures, such as surgery and tissue biopsies—in previous e-briefings.

The new device differs from other microfluidic technologies that rely on biomarkers to attach to tumor cells (aka, affinity separation), New Atlas reported. Papautsky co-authored a research paper on their findings published in Nature: Microsystems and Nanoengineering.

“This new microfluidics chip lets us separate cancer cells from whole blood or minimally diluted blood. Our device is cheap and doesn’t require much specimen preparation or dilution, making it fast and easy-to-use,” said Ian Papautsky, PhD, Professor of Bioengineering at University of Illinois at Chicago, in the news release. He is shown above with members of the Papautsky Lab, which has been developing “microfluidic systems and point- of-care sensors for public health applications.” (Photo copyright: University of Illinois at Chicago.)

Searching for ‘Purity’

The UIC and QUT researchers were motivated by the information-rich nature of circulating tumor cells. They also saw opportunity for escalated “purity” in results, as compared to past studies.

In the paper, they acknowledged the work of other scientists who deployed microfluidic technology affinity-based methods to differentiate tumor cells in blood. Past studies (including previous work by the authors) also explored tumor cells based on size and difference from white blood cells.

“While many emerging systems have been tested using patient samples, they share a common shortcoming: their purity remains to be significantly improved. High purity is in strong demand for circulating tumor cell enumeration, molecular characterization, and functional assays with less background intervention from white blood cells,” the authors wrote in their paper.

How the Device Works

The scientists say their system leverages “size-dependent inertial migration” of cells. According to the news release:

  • Blood passes through “microchannels” formed in plastic in the device;
  • “Inertial migration and shear-induced diffusion” separate cancer cells from blood;
  • Tiny differences in size determine a cell’s attraction to a location; and
  • Cells separate to column locations as the liquid moves.

In other words, the device works as a filter sorting out, in blood samples, the circulating tumor cells based on their unique size, New Atlas explained.

93% of Cancer Cells Recovered by Device

When the researchers tested their new device:

  • Researchers placed 10 small-cell-lung cancer cells into five-milliliter samples of healthy blood;
  • The blood was then flowed through the device; and
  • 93% of the cancer cells were recovered.

“A 7.5 milliliter tube of blood, which is typical volume for a blood draw, might have 10 cancer cells and 35- to 40-billion blood cells. So, we are really looking for a needle in a haystack,” Papautsky stated in the news release.

The graphic above illustrates how, in the lab, the microfluidic device enabled the researchers to separate out cancer cells in six of the eight lung cancer samples they studied. (Graphic copyright: Ian Papautsky, PhD/University of Illinois at Chicago/New Atlas.)

“We report on a novel multi-flow microfluidic system for the separation of circulating tumor cells with high purity. The microchannel takes advantage of inertial migration of cells. The lateral migration of cells strongly depends on cell size in our microchannel, and label-free separation of circulating tumor cells from white blood cells is thus achieved without sophisticated sample predation steps and external controls required by affinity-based and active approaches,” the researchers wrote in their paper.

The device could one day aid physicians in precision medicine and the development of targeted treatment plans for patients, reported Genetic Engineering and Biotechnology News.

Other Microfluidic Diagnostic Devices

The researchers plan wider trials and the addition of biomarkers to enable cancer DNA detection, New Atlas reported, which described the UIC/QUT study as part of a “new wave of diagnostics.”

Another novel liquid biopsy approach to cancer detection is under development at the University of Queensland. It involves a unique nano-scale DNA signature that appeared in breast cancer and other cancer studies. (See, “University of Queensland Researches May Have Found a Universal Biomarker That Identifies Cancer in Various Human Cells in Just 10 Minutes!Dark Daily, May 20, 2019.)

And researchers developed a “labyrinth” label-free microfluidic device that enabled white blood cells and circulating tumor cells to separate during a study at the University of Michigan. (See, “University of Michigan Researchers Use ‘Labyrinth’ Chip Design in Clinical Trial to Capture Circulating Tumor Cells of Different Cancer Types,” Dark Daily, February 2, 2018.)

With so much focus on liquid biopsy research, it may be possible for medical laboratories to one day not only diagnose cancer through blood tests, but also to find the disease earlier and in a more precise way than with traditional tissue sample analysis.

—Donna Marie Pocius

Related Information:

New Microfluidic Device Can Detect Cancer Cells in Blood

Microfluidic Device Promises Cheap and Fast Detection of Cancer Cells in Blood

Isolation of Circulating Tumor Cells in Non-Small-Lung Cancer Patients Using a Multi-Flow Microfluidic Channel

Liquid Biopsies Become Cheap and Easy with New Microfluidic Device

University of Queensland Researchers May Have Found a Universal Biomarker that Identifies Cancer in Various Human Cells in Just 10 Minutes

University of Michigan Researchers Use Labyrinth Chip Design in Clinical Trial to Capture Circulating Tumor Cells of Different Cancer Types

Dark Daily: Liquid Biopsy

How DNA Databases Help Investigators Solve Crimes; Will Clinical Laboratories Be Asked to Help?

Studies show consumer genealogy databases are much broader than is generally known. If your cousins are in such a database, it’s likely you are too

Recent news stories highlighted crime investigators who used the DNA data in consumer genetic genealogy databases to solve cold cases. Though not widely known, such uses of direct-to-consumer DNA databases is becoming more commonplace, which might eventually lead to requests for clinical laboratories to assist in criminal investigations involving DNA data.

Case in point: investigators found the Golden State Killer, a serial killer/rapist/burglar who terrorized multiple California counties over a dozen years in the 1970s to 1980s, after uploading a DNA sample from the crime scene to GEDmatch, an open-data genomics database that features tools for genealogy research. They made the arrest after discovering a distant relative’s DNA in the genealogy database and matching it to the suspect, CBS News revealed in a 60 Minutes Overtime online report.

These and other investigators are using a technique called familial DNA testing (AKA, DNA Profiling), which enables them to use genetic material from relatives to solve crimes.

Clinical laboratories oversee DNA databases. Could DNA databases—developed and managed over years by medical laboratories for patient care—be subpoenaed by law enforcement investigating crimes?

The question raises many issues for society and for labs, including privacy responsibilities and appropriate use of genetic information. On the other hand, the genetic genie is already out of the bottle.

Leveraging Familia DNA to Solve Crimes a New Trend

“The solving of the Golden State Killer case opened this method up as a possibility, and other crime labs are taking advantage of it. Clearly, a trend has started,” Ruth Dickover, PhD, Director of Forensic Science, University of California, Davis, told the Los Angeles Times.

Indeed, the use of familial DNA testing is moving forward. The Verge reported 19 cold case samples have been identified in recent familial DNA testing and public database searches. It also said two new published studies may propel the technique further.

One study, published in the journal Science, suggests nearly every American of European ancestry may soon be identified through familial DNA testing.

The other study, published in Cell, shows that a person’s relatives can be detected when forensic DNA data are compared with consumer genetic databases.

Professor Noah Rosenberg and postdoctoral research fellow Jaehee Kim.

Noah Rosenberg, PhD (above left), Professor of Population Genetics and Society Biology at Stanford University, is shown above working with Jaehee Kim, PhD (right), a Postdoctoral Research Fellow in Biology, on math that could be used to track down relatives in genealogy databases based on forensic DNA. “This could be a way of expanding the reach of forensic genetics, potentially for solving even more cold cases. But at the same time, it could be exposing participants in those databases to forensic searches they might not have anticipated,” he told Wired. (Photo copyright: Stanford University/L.A. Cicero.)

15 Million People Already in Genealogy Databases

Researchers at Columbia University in New York and Hebrew University of Jerusalem told Science they were motivated by the recent trend of investigations leveraging third-party consumer genomics services to find criminals. But they perceived a gap.

“The big limitation is coverage. And even if you find an individual it requires complex analysis from that point,” Yaniv Erlich, PhD, Associate Professor at Columbia and Chief Science Officer at MyHeritage, told The Verge. MyHeritage is an online genealogy platform.

Others offering consumer genetic testing and family history exploration include 23andMe and Ancestry. As of April 2018, more than 15 million people have participated in direct-to-consumer genetic testing, the researchers noted.

The study aimed to find the likelihood that a person can be identified using a long-range familial search. It included these steps and findings:

  • Statistical analysis of 1.28 million people in the MyHeritage database;
  • Pairs of people with “identity-by-descent” were removed to avoid bias, such as first cousins and closer relationships;
  • Researchers aimed at finding a third cousin or closer relatives for each person in the database;
  • 60% of the 1.28 million people were matched with a third cousin or closer relative.

“We project that about 60% of the searches for individuals of European-descent will result in a third cousin or closer match, which can allow their identification using demographic identifiers. Moreover, the technique could implicate nearly any US individual of European descent in the near future,” the researchers wrote.

In an interview with Wired, Erlich added, “The takeaway is it doesn’t matter if you’ve been tested or not tested. You can be identified because the databases already cover such large fractions of the US—at least for European ancestry.”

Matching Forensic and Consumer Genetic Data

Meanwhile, the study published in Cell by researchers at Stanford University, University of California, Davis, and the University of Michigan also suggests investigators could compare forensic DNA samples with consumer genetic databases to find people related to criminals.

That study found:

  • 30% to 32% of people in a forensic database could be related to a child or parent in a consumer database;
  • 35% to 36% could be tied to a sibling.

These studies reveal that genetic data and familial DNA testing can help law enforcement find suspects, which is a good thing for society. But people who uploaded DNA data to some direct-to-consumer databases may find themselves caught up in searches they do not know about. So may their cousins.

Dark Daily recently covered other similar studies that showed it takes just one person’s DNA to reveal genetic information on an entire family. (See, “The Problems with Ancestry DNA Analyses,” October 18, 2018.) These developments in the use of DNA databases to identify criminals should be an early warning to clinical laboratories building databases of genetic information that, at some future point, law enforcement agencies might want access to those databases as part of ongoing criminal investigations.

—Donna Marie Pocius

Related Information:

Could Your DNA Help Solve a Cold Case?

So Many People Have Had Their DNA Sequenced That They’ve Put Other People’s Privacy in Jeopardy

The DNA Technique That Caught the Golden State Killer is More Powerful than We Thought

Identity Inference of Genomic Data Using Long-Range Familial Searches

Statistical Detection of Relatives Typed with Disjoint Forensic and Biomedical Loci

Genome Hackers Show No One’s DNA is Anonymous Anymore

Stanford Researchers Discover a New Way to Find Relatives from Forensic DNA

The Problems with Ancestry DNA Analyses

University of Michigan Researchers Use “Labyrinth” Chip Design in Clinical Trial to Capture Circulating Tumor Cells of Different Cancer Types

Research goal was to isolate circulating tumor cells in venipuncture samples with improved purity compared to standard spiral chips

Many research teams are pursuing the goal of creating assays that detect circulating tumor cells (CTCs) that would allow earlier and more accurate diagnosis of cancer. Now comes news of a unique technology developed at the University of Michigan (U-M) Ann Arbor that showed promised in an early study.

The method of using CTCs to diagnose cancer in patients, while further analyzing specific characteristics of a given cancer case, shows promise as an innovative tool for clinical laboratories and oncologists. However, current approaches face challenges when it comes to proving accuracy and establishing thresholds that might indicate the need for further action.

Researchers at U-M believe they may have solved that problem. They created “Labyrinth,” a “label-free microfluidic device” that condenses 637mm of channels—including 11 loops and 56 corners—onto a 500μm-wide chip that uses inertia and Dean flow to separate white blood cells and CTCs from venipuncture samples at rates as high as 2.5ml per minute. These results improve upon the traditional spiral chip design.

Publishing their findings in Cell Systems, first author of the study Eric Lin, PhD, noted, “With the recent advances in tools for genomic characterization, it is more compelling than ever to look at the tumor heterogeneity to understand tumor progression and resistance to therapies. The Labyrinth device enabled high yields of CTCs without the bias induced by antibody-based selection, allowing the identification of true biological tumor heterogeneity.”

The graphic above, taken from the University of Michigan study, demonstrates the “High-throughput and label-free Labyrinth device that enables single CTC isolation and gene expression characterization.” According to the researchers, “Labyrinth offers a cell-surface marker-independent single-cell isolation platform to study heterogeneous CTC subpopulations.” The U-M study shows promise in creating tools for oncologist and clinical laboratory cancer treatment. (Image copyright: University of Michigan/Cell Systems.)

Challenges in the Isolation of CTCs

The Labyrinth chip is not the first device to assist in isolating CTCs. The U-M study notes that while immune-affinity capture is a validated approach to prognosis, therapeutic monitoring and molecular diagnostics, it does not work with all cancer cases. The researchers also note the method creates challenges in single-cell analysis later.

Existing label-free methods of isolation, such as deterministic lateral displacement, microfluidic flow fractionation, and acoustic-based separation, avoid these concerns but face issues of their own. The researchers noted, “Issues encountered with these approaches include pore clogging, high-pressure drop, pre-fixation to prevent CTC loss, low throughput, and excessive non-specific cell retention.”

The researchers further clarified that a major factor separating the Labyrinth chip from other methods is the ability to identify CTC subpopulations without the need for manual selection based on positive or negative protein expression. Thus, improving the ability to conduct further single-cell analysis from the results. Testing of the Labyrinth chip involved a variety of cancer cell lines, including:

·       Human breast (MCF-7);

·       Pancreatic (PANC-1);

·       Prostate (PC-3); and,

·       Lung (H1650).

And while standard spiral chips are already a common method for conducting size-based sorting, the purity of results is less than ideal with thousands of other cells remaining in the sample.

The researchers reported that the Labyrinth chip recovered 91.5% (plus or minus 0.9%) of cancer cells and removed 91.4% (plus or minus 3.3%) of white blood cells in a spiked buffer test.

“Bigger cells, like most cancer cells, focus pretty fast due to the curvature. But the smaller the cell is, the longer it takes to get focused,” Sunitha Nagrath, PhD, Associate Professor of Chemical Engineering and a lead developer of the Labyrinth chip, stated in a U-M news release. “The corners produce a mixing action that makes the smaller white blood cells come close to the equilibrium position much faster.”

Labyrinth also supports a series configuration of multiple chips. While testing two chips in series, researchers noted “a two-log improvement in tumor cell enrichment over the single Labyrinth.” They claim this is a higher purity than other label-free methods they studied, while adding only five minutes to processing times.

Sunitha Nagrath, PhD (above), is an Associate Professor of Chemical Engineering at the University of Michigan, and one of the lead developers of the Labyrinth chip. “You cannot put a box around these cells,” she noted in the U-M news release. “The markers for them are so complex, there is no one marker we could target for all these stages.” (Photo copyright: University of Michigan.)

Current Testing Using the Labyrinth Chip

The chip is already in use in a clinical trial for an aggressive form of breast cancer by Max Wicha, MD, Madeline and Sidney Forbes Professor of Oncology, Founding Director Emeritus, University of Michigan Comprehensive Cancer Center, and co-author of the Cell Systems study, who lead the study along with Nagrath.

The trial involves the attempted activation of adult system cells by blocking the signaling molecule interleukin-6. Wicha suspects the molecule enables cancer stem cells as well. “We think that this may be a way to monitor patients in clinical trials,” he said in the U-M news release. “Rather than just counting the cells, by capturing them, we can perform molecular analysis [to] know what we can target with treatments.”

The news release further highlights how this chip is specifically suited to such a task. As cancer stem cells transition from stem-like cells to more ordinary cell types, their gene expression shifts as well. This creates an issue when using conventional cell targeting. Nagrath notes this concern, stating, “The markers for [cancer stem cells] are so complex, there is no one marker we could target for all these stages.”

The Labyrinth chip shows potential for overcoming one of the biggest hurdles to leveraging CTCs to diagnose cancers and develop personalized therapies. Currently, the chip can output to Fluidigm, DEPArray by Silicon Biosystems, and RainDance Technologies’ RainDrop Digital PCR System.

The U-M researchers hope that future research will yield additional applications and compatible systems to further improve the ability for medical laboratories to use CTCs in the early detection and monitoring of cancer cases.

—Jon Stone

Related Information:

‘Labyrinth’ Chip Could Help Monitor Aggressive Cancer Stem Cells

High-throughput Microfluidic Labyrinth for the Label-free Isolation of Circulating Tumor Cells

Novel Labyrinth Chip Monitors Cancer Stem Cells in Clinical Trial

‘Labyrinth’ Device Sorts Cancer Cells from Healthy Blood

This Awesome Blood Labyrinth Is the Newest Method for Catching Cancer Cells

Labyrinth Chip Has the Potential to Lead to Customized Cancer Treatments