Painless technology could one day replace some phlebotomy blood draws as the go-to specimen-collection method for clinical laboratory testing and health monitoring
Clinical laboratories have long sought a non-invasive way to do useful medical laboratory testing without the need for either a venipuncture or a needle stick. Now engineers at the McKelvey School of Engineering at Washington University in St. Louis in Missouri have developed a disposable microneedle patch that one day could be a painless alternative to some blood draws for diagnostics tests and health monitoring.
The technology uses an easy-to-administer low-cost patch that can be applied to the skin like an adhesive bandage. The patch is virtually painless because the microneedles are too small to reach nerve receptors. Another unique aspect to this innovative approach to collecting a specimen for diagnostic testing is that the Washington University in St. Louis (WashU) research team designed the microneedle patch to include plasmonic-fluor. These are ultrabright gold nanolabels that light up target protein biomarkers and can make the biomarkers up to 1,400 times brighter at low concentrations, compared to traditional fluorescent labels.
The patch, states a WashU news release, “… can be applied to the skin, capture a biomarker of interest and, thanks to its unprecedented sensitivity, allow clinicians to detect its presence.”
The technology is low cost, easy for clinicians or patients themselves to use, and could eliminate the need for a trip to patient service center where a phlebotomist would draw blood for clinical laboratory testing, the news release states.
“We have created a platform technology that anyone can use. And they can use it to find their own biomarker of interest,” study leader Srikanth Singamaneni, PhD (above), Lilyan and E. Lisle Hughes Professor in the Department of Mechanical Engineering and Materials Sciences at Washington University in St. Louis, said in the WashU news release. Singamaneni and his colleagues are developing a new specimen collection method that might someday be widely used by clinical laboratories. (Photo copyright: Washington University in St. Louis.)
“We used the microneedle patch in mice for minimally invasive evaluation of the efficiency of a cocaine vaccine, for longitudinal monitoring of the levels of inflammatory biomarkers, and for efficient sampling of the calvarial periosteum [a skull membrane]—a challenging site for biomarker detection—and the quantification of its levels of the matricellular protein periostin, which cannot be accurately inferred from blood or other systemic biofluids,” the researchers wrote. “Microneedle patches for the minimally invasive collection and analysis of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring.”
Mark Prausnitz, PhD, Regents’ Professor, J. Erskine Love Jr. Chair in Chemical and Biomolecular Engineering, and Director of the Center for Drug Design, Development, and Delivery at Georgia Tech, told WIRED, “Blood is a tiny fraction of the fluid in our body. Other fluids should have something useful—it’s just hard to get those fluids.”
“Previously, concentrations of a biomarker had to be on the order of a few micrograms per milliliter of fluid,” said Zheyu (Ryan) Wang, a PhD candidate in Srikanth Singamaneni’s lab at McKelvey School of Engineering and a lead author of the paper, in the WashU news release. By using plasmonic-fluor, researchers were able to detect biomarkers on the order of picograms per milliliter—one millionth of the concentration.
“That’s orders of magnitude more sensitive,” Wang said.
Unlike blood, dermal interstitial fluid often does not contain high enough concentrations of biomarkers to be easily detectable. To overcome this hurdle, the Washington University in St. Louis research team developed a microneedle patch with plasmonic-fluor—ultrabright gold nanolabels (above)—which lit up target protein biomarkers, making them roughly 1,400 times brighter at low concentrations than when using traditional fluorescent labels commonly used in many medical laboratory tests. (Photo copyright: Washington University in St. Louis.)
Can Microneedles Be Used as a Diagnostic Tool?
As reported in WIRED, the polystyrene patch developed by Srikanth Singamaneni’s lab at McKelvey School of Engineering removes interstitial fluid from the skin and turns the needles into “biomarker traps” by coating them with antibodies known to bind to specific proteins, such as Interleukin 6 (IL-6). Once the microneedles are mixed with plasmonic-fluor, the patch will glow if the IL-6 biomarkers are present.
The development of such a highly sensitive biomarker-detection method means skin becomes a potential pathway for using microneedles to diagnose conditions, such as myocardial infarction or to measure COVID-19 antibodies in vaccinated persons.
“Now we can actually use this tool to understand what’s going on with interstitial fluid, and how we’re going to be able to use it to answer healthcare-related or medical problems,” Maral Mousavi, PhD, Assistant Professor of Biomedical Engineering, Viterbi School of Engineering at the University of Southern California, told WIRED. “I think it has the potential to be that kind of a game changer.”
Because the WashU study is a proof-of-concept in mice, it may be many years before this technology finds its way to clinical application. Many skin biomarkers will need to be verified for direct links to disease before microneedle patches will be of practical use to clinicians for diagnostics. However, microneedle patch technology has already proven viable for the collection of blood.
In 2017, Massachusetts-based Seventh Sense Biosystems (7SBio) received 510(k) clearance for a new microneedle blood collection device. Called TAP, the device is placed on the upper arm and blood collection starts with a press of a button. The process takes two to three minutes.
Initially, the FDA clearance permitted only healthcare workers to use the device “to collect capillary blood for hemoglobin A1c (HbA1c) testing, which is routinely used to monitor blood sugar levels in diabetic or pre-diabetic patients,” a Flagship Pioneering news release noted.
Then, in 2019, the FDA extended its authorization “to include blood collection by laypersons. Regulators are also allowing the device to be used ‘at-home’ for wellness testing,” a 7SBio news release stated. This opened the door for a microneedle device to be used for home care blood collection.
“No one likes getting blood drawn, but blood is the single-most important source of medical information in healthcare today, with about 90% of all diagnostic information coming from blood and its components,” Howard Weisman, former CEO of 7SBio and current CEO of PaxMedica, a clinical-stage biopharmaceutical company, said in the Flagship Pioneering news release. “TAP has the potential to transform blood collection from an inconvenient, stressful, and painful experience to one people can do themselves anywhere, making health monitoring much easier for both healthcare professionals and patients.”
As microneedle technology continues to evolve, clinical laboratories should expect patches to be used in a growing number of drug delivery systems and diagnostic tests. But further research will be needed to determine whether interstitial fluid can provide an alternate pathway for diagnosing disease.
This new technology could replace needle biopsies and allow physicians to detect rejection of transplanted organs earlier, saving patients’ lives
Anatomic pathologists
may be reading fewer biopsy reports for patients with organ transplants in the
future. That’s thanks to a new technology that may be more sensitive to and
capable of detecting organ rejection earlier than traditional needle biopsies.
When clinicians can detect organ transplant rejection
earlier, patients survive longer. Unfortunately, extensive organ damage may
have already occurred by the time rejection is detected through a traditional
needle biopsy. This led a group of researchers at Emory University School of Medicine to
search for a better method for detecting organ rejection in patients with transplants.
The Emory researchers describe the method and technology
they devised in a paper published in Nature Biomedical
Engineering, titled, “Non-Invasive Early Detection of Acute Transplant
Rejection Via Nanosensors of Granzyme B Activity.” The new technology could
make it easier for clinicians to detect when a patient’s body is rejecting a
transplanted organ at an earlier time than traditional methods.
This technology also provides a running measure of processes,
so clinicians have more powerful tools for deciding on the most appropriate
dosage of immunosuppressant
drugs.
“Right now, most tests are aimed at organ dysfunction, and
sometimes they don’t signal there is a problem until organ function is below 50
percent,” Andrew
Adams, MD, PhD Co-Principal Investigator and an Associate Professor of Surgery
at Emory University School of Medicine, in a Georgia
Institute of Technology news release.
How the Technology Works
The method that Adams and his colleagues tested involves the
detection of granzyme B,
a serine protease
often found in the granules of natural killer cells
(NK cells) and cytotoxic
T cells. “Before any organ damage can happen, T cells have to produce granzyme
B, which is why this is an early detection method,” said Gabe Kwong, PhD, Assistant
Professor in the Wallace H. Coulter Department of Biomedical Engineering at
Georgia Tech and Emory University, in the news release.
The new technology is made up of sensor nanoparticles in the
shape of a ball with iron oxide in the middle. Amino acids stick out of the
ball like bristles. Each amino acid has a fluorescent molecule attached to the
tip.
The nanoparticles are injected into the patient. Their size
prevents them from gathering in the patient’s tissue or from being flushed out
through the kidneys. They are designed to accumulate in the tissue of the
transplanted organ.
If the T cells in the transplanted organ begin to produce
granzyme B, the amino acids break away from the nanoparticles, releasing the
fluorescent molecules attached to their tips. Those molecules are small enough
to be processed through the kidneys and can be detected in the patient’s urine.
Pathologists Play Crucial Role on Transplant Teams
Anatomical pathologists (histopathologists in the UK) are key
members of transplant teams for many reasons, including their ability to assess
biopsies. The current method for detecting organ transplant rejection involves
needle biopsies. It is considered the gold standard.
However, according to a paper published in the International
Journal of Organ Transplantation Medicine: “Although imaging studies
and laboratory findings are important and helpful in monitoring of the
transplanted liver, in many circumstances they are not sensitive enough. For
conditions such as rejection of the transplant, liver histology remains the
gold-standard test for the diagnosis of allograft dysfunction. Therefore,
histopathologic assessments of allograft liver
biopsies have an important role in managing patients who have undergone liver
transplantation.”
There are two main problems with needle biopsies. The first,
as mentioned above, is that they don’t always catch the rejection soon enough.
The second is that the needle may cause damage to the transplanted organ.
“The biggest risk of a biopsy is bleeding and injury to the transplanted organ,” noted Andrew Adams, MD, PhD (above), Co-Principal Investigator and an Associate Professor of Surgery at Emory University School of Medicine, in the Georgia Tech news release. “Then there’s the possibility of infection. You’re also just taking a tiny fraction of the transplanted organ to determine what’s going on with the whole organ, and you may miss rejection or misdiagnose it because the needle didn’t hit the right spot,” he added.
And, according to Kwong, even though biopsies are the gold
standard, the results represent one moment in time. “The biopsy is not
predictive. It’s a static snapshot. It’s like looking at a photo of people in
mid-jump. You don’t know if they’re on their way up or on their way down. With
a biopsy, you don’t know whether rejection is progressing or regressing.”
Future Directions of Emory’s Research
The research conducted by Adams and Kwong, et al, is in its
early stages, and the new technology they created won’t be ready to be used on patients
for some time. Nevertheless, there’s reason to be excited.
Nanoparticles are not nearly as invasive as a needle biopsy.
Thus, risk of infection or damaging the transplanted organ is much lower. And Emory’s
technology would allow for much earlier detection, as well as giving clinicians
a better way to adjust the dose of immunosuppressant drugs the patient takes.
“Adjusting the dose is very difficult but very important
because heavy immunosuppression increases occurrence of infections and patients
who receive it also get cancer more often,” said Kwong. The new technology
provides a method of measuring biological activity rates, which would give
clinicians a clearer picture of what’s happening.
The Emory team’s plan is to enhance the new sensors to
detect at least one other major cause of transplant rejection—antibodies. When
a patient’s body rejects a transplanted organ, it produces antibodies to
neutralize what it sees as a foreign entity.
“Antibodies kill their target cells through similar types of
enzymes. In the future, we envision a single sensor to detect both types of
rejection,” said Kwong.
Adams adds, “This method could be adapted to tease out
multiple problems like rejection, infection, or injury to the transplanted
organ. The treatments for all of those are different, so we could select the
proper treatment or combination of treatments and also use the test to measure
how effective treatment is.”
This line of research at Emory University demonstrates how
expanding knowledge in a variety of fields can be combined in new ways. As this
happens, medical laboratories not only get new biomarkers that can be
clinically useful without the need for invasive procedures like needle biopsies,
but these same biomarkers can guide the selection of more effective therapies.
This new atlas of leukemia proteomes may prove useful for medical laboratories and pathologists providing diagnostic and prognostic services to physicians treating leukemia patients
Researchers at the University of Texas at San Antonio (UTSA) and the University of Texas MD Anderson Cancer Center created the online atlases—categorized into adult and pediatric datasets—to “provide quantitative, molecular hallmarks of leukemia; a broadly applicable computational approach to quantifying heterogeneity and similarity in molecular data; and a guide to new therapeutic targets for leukemias,” according to the Leukemia Atlases website.
In building the Leukemia Proteome Atlases, the researchers identified and classified protein signatures that are present when patients are diagnosed with AML. Their goal is to improve survival rates and aid scientific research for this deadly disease, as well as develop personalized, effective precision medicine treatments for patients.
To perform the study, the scientists looked at the proteomic screens of 205
biopsies of patients with AML and analyzed the genetic, epigenetic, and
environmental diversity in the cancer cells. Their analysis “revealed 154 functional
patterns based on common molecular pathways, 11 constellations of correlated
functional patterns, and 13 signatures that stratify the outcomes of patients.”
Amina Qutub, PhD, Associate Professor at UTSA and one of the authors of the research, told UTSA Today, “Acute myelogenous leukemia presents as a cancer so heterogeneous that it is often described as not one, but a collection of diseases.”
“To decipher the clues found in proteins from blood and bone marrow of leukemia patients, we developed a new computer analysis—MetaGalaxy—that identifies molecular hallmarks of leukemia,” noted Amina Qutub, PhD (above), UTSA Professor of Biomedical Engineering and one of the UTSA study’s authors. “These hallmarks are analogous to the way constellations guide navigation of the stars: they provide a map to protein changes for leukemia,” she concluded. (Photo copyright: UTSA.)
To better understand the proteomic levels associated with AML, and share their work globally with other scientists, the researchers created the Leukemia Proteome Atlases web portal. The information is displayed in an interactive format and divided into adult and pediatric databases. The atlases provide quantitative, molecular hallmarks of AML and a guide to new therapeutic targets for the disease.
The NCI predicts there will be approximately 21,540 new
cases of AML diagnosed this year. They will account for about 1.2% of all new
cancer cases. The disease will be responsible for approximately 10,920 deaths in
2019, or 1.8% of all cancer deaths. In 2016, there were an estimated 61,048
people living with AML in the US.
“Our ‘hallmark’ predictions are being experimentally tested
through drug screens and can be ‘programmed’
into cells through synthetic manipulation of proteins,” Qutub continued. “A
next step to bring this work to the clinic and impact
patient care is testing whether these signatures lead to the aggressive growth
or resistance to chemotherapy observed in
leukemia patients.
“At the same time, to rapidly accelerate research in
leukemia and advance the hunt for treatments,
we provide the hallmarks in an online compendium [LeukemiaAtlas.org] where fellow
researchers and oncologists worldwide can build from the resource, tools, and
findings.”
By mapping AML patients from the proteins present in their
blood and bone marrow, the researchers hope that healthcare professionals will
be able to better categorize patients into risk groups and improve treatment
outcomes and survival rates for this aggressive form of cancer.
The Leukemia Proteome Atlases are another example of the
trend where researchers work together to compile data from patients and share
that information with other scientists and medical professionals. Hopefully, having
this type of data readily available in a searchable database will enable
researchers—as well as clinical laboratory scientists and pathologists—to gain
a better understanding of AML and benefit cancer patients through improved
diagnosis, treatment, and monitoring.
