Research

Size Matters for Particles in Bloodstream

UConn Engineering Professor’s Findings Could Mean More Effective Cancer Drugs

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream.

UConn researchers used a fluorescence microscope to illuminate a microfluidic device that simulates a blood vessel to observe and measure how particles of different sizes behave in the bloodstream. Their findings could aid the development of more effective cancer drugs. Photo: Anson Ma


A UConn engineering professor has uncovered new information about how particles behave in our bloodstream, an important advancement that could help pharmaceutical scientists develop more effective cancer drugs.

Making sure cancer medications reach the leaky blood vessels surrounding most tumor sites is a critical aspect of treatment and drug delivery. While surface chemistry, molecular interactions, and other factors come into play once drug-carrying particles arrive at a tumor, therapeutic medication doesn’t do much good if it never reaches its intended target.

Anson Ma, assistant professor of chemical and biomolecular engineering, used a microfluidic channel device to observe, track, and measure how individual particles behaved in a simulated blood vessel.

Ma says he wanted to learn more about the physics influencing a particle’s behavior as it travels in human blood, and to determine which particle size might be the most effective for delivering drugs to their targets. His experimental findings mark the first time such quantitative data has been gathered. The study appeared in the Oct. 4, 2016 issue of the Biophysical Journal.

Using a fluorescence microscope, Ma was able to see particles moving in the simulated blood vessel in what could be described as a vascular “Running of the Bulls.” Red blood cells race through the middle of the channel as the particles — highlighted under the fluorescent light — get carried along in the rush, bumping and bouncing off the blood cells until they are pushed to open spaces, called the cell-free layer, along the vessel’s walls.

What Ma found was that larger particles — the optimum size appeared to be about 2 microns — were most likely to get pushed closer to the blood vessel wall, where their chances of carrying medication into a tumor site are greatest. The research team also determined that 2 microns was the largest size that should be used if particles are going to have any chance of going through the leaky blood vessel walls into the tumor site.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, reducing the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

“When it comes to using particles for the delivery of cancer drugs, size matters,” Ma says. “When you have a bigger particle, the chance of it bumping into blood cells is much higher, there are a lot more collisions, and they tend to get pushed to the blood vessel walls.”

The results were somewhat surprising. In preparing their hypothesis, the research team estimated that smaller particles were probably the most effective since they would move the most in collisions with blood cells, much like what happens when a small ball bounces off a larger one. But just the opposite proved true. The smaller particles appeared to skirt through the mass of moving blood cells and were less likely to experience the “trampoline” effect and get bounced to the cell-free layer, says Ma.

Ma proposed the study after talking to a UConn pharmaceutical scientist about drug development at a campus event five years ago.

“We had a great conversation about how drugs are made and then I asked, ‘But how can you be sure where the particles go?’” Ma recalls, laughing. “I’m an engineer. That’s how we think. I was curious. This was an engineering question. So I said, ‘Let’s write a proposal!’”

The proposal was funded by the National Science Foundation’s Early-concept Grants for Exploratory Research, or EAGER, program, which supports exploratory work in its early stages on untested, but potentially transformative, research ideas or approaches.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, Ma says, which in turn will further reduce the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

The findings were particularly meaningful for Ma, who lost two of his grandparents to cancer and who has long wanted to contribute to cancer research in a meaningful way as an engineer.

The results may also be beneficial in bioimaging, where scientists and doctors want to keep particles circulating in the bloodstream long enough for imaging to occur. In that case, smaller particles would be better, says Ma.

Moving forward, Ma would like to explore other aspects of particle flow in the circulatory system, including how particles behave when they pass through a constricted area, such as from a blood vessel to a capillary. Capillaries are only about 7 microns in diameter. The average human hair is 100 microns.

“We have all of this complex geometry in our bodies,” says Ma. “Most people just assume there is no impact when a particle moves from a bigger channel to a smaller channel because they haven’t quantified it. Our plan is to do some experiments to look at this more carefully, building on the work that we just published.”

Ventilator-Associated Pneumonia Still a Concern, Study Says

mask holds oxygen mask to face


Contrary to data published by the Centers for Disease Control and Prevention, ventilator-associated pneumonia rates in hospital intensive care units have not declined significantly since 2005, according to a new study out of the UConn School of Medicine.

The study, published in the Journal of the American Medical Association, found that about 10 percent of critically ill patients placed on a ventilator develop ventilator-associated pneumonia (VAP). The finding is based on reviews of charts from hospitals across the country from 2005-2013.

“VAP is not going away; it still affects approximately one in 10 ventilated patients,” says the study’s lead author, Dr. Mark L. Metersky of UConn Health’s Division of Pulmonary and Critical Care Medicine. “Our findings are in stark contrast to the CDC’s report of a marked decline in VAP rates that had some believing it may no longer be an important problem.”

Researchers reviewed data compiled by the Medicare Patient Safety Monitoring System from a representative sampling of 1,856 critically ill Medicare patients, ages 65 and older, who needed two or more days of mechanical ventilation.

While the VAP rates were stable throughout that time, the rates did not correlate with the CDC’s National Healthcare Safety Network reported rates, which suggest declining rates between 2006 and 2012 in both medical and surgical ICUs. The rate of VAP is one of the metrics for patient safety and health care delivery quality that many hospitals are scored on nationally.

VAP is not going away … Our findings are in stark contrast to the CDC’s report of a marked decline in VAP rates that had some believing it may no longer be an important problem.

Patients in need of mechanical ventilation are often the most critically ill in a medical or surgical ICU hospital setting. Research has shown that up to 15 percent of patients who get it may die from VAP.
The study authors examined the prevalence of VAP in patients on a ventilator following a heart attack,
heart failure, pneumonia, or major surgery. These types of patients are at higher risk for developing pneumonia, a bacterial infection, due to the need for a tube extending down their throat and into their lungs to help them breathe.

“We have not beaten this,” says Metersky. “Current hospital interventions that are used in an attempt to prevent VAP are not working. VAP is still a significant issue, and needs more examination into how we survey its occurrence and report it, along with more research into how best to prevent this type of pneumonia in vulnerable patient populations.”

The higher-than-expected VAP rates may be leading patients to experience complications or death from their lung infection or spend more time on a ventilator or in the ICU, slowing recovery. It may also increase use of antibiotics, leading to potential resistance, and increase health care costs due to longer hospital stays.

Metersky collaborated on the study with colleagues at Qualidigm, Harvard Medical School, and Harvard School of Public Health. It was supported by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services.

Lab Notes – Spring 2017

For MRSA, Resistance is Futile

UConn medicinal chemists have designed experimental antibiotics that kill Methicillin-resistant Staphylococcus aureus (MRSA), a common and often deadly bacteria that causes skin, lung, and heart infections. The new antibiotics disable the bacteria’s vitamin B9 enzyme. Without vitamin B9, the bacteria can’t make essential amino acids and they die. Not only do the new antibiotics kill regular MRSA, they also kill types of the bacteria with unusual antibiotic-resistance genes that had never been seen before in the U.S. And that’s no accident: the chemists designed the antibiotics to latch on to the enzyme so cleverly that if it changed enough to elude them, it would no longer be able to do its job with vitamin B9. This could make the new antibiotics resistant to, well, resistance. The research was published in the Dec. 22, 2016 issue of Cell Chemical Biology.

MRSA colonies are shown on a blood agar plate.


State’s Leading Institutions Launch International Effort to Advance Metabolic Research

overweight 3D model running with target on metabolic area

UConn, Yale University, and The Jackson Laboratory (JAX) have partnered with the Weizmann Institute of Science, a prestigious counterpart in Israel, to fill a research void in metabolic diseases that affect billions of people worldwide. The goal of the newly formed Metabolic Research Alliance is to unite the expertise of the institutions on research projects that swiftly move investigations into clinical application and commercialization. The Alliance will employ a novel approach to coordinating existing and new expertise in the areas of immunology, cell biology, microbiota, and the rapidly evolving field of genomics. While investigations will initially focus on obesity and diabetes, the research projects will eventually pursue solutions to additional metabolic diseases.


Innovative Imaging Could Save Sight

Connecticut Innovations has awarded $500,000 to a team of UConn researchers to speed the process to commercialization of the biomarker probe they’re developing to detect a precursor to blindness. The team — led by Royce Mohan, associate professor of neuroscience at UConn Health, and including assistant professor of neuroscience Paola Bargagna-Mohan and UConn School of Pharmacy medicinal chemistry professor Dennis Wright — is developing a fluorescent small molecule imaging reagent to help identify preclinical stages of ocular fibrosis, which is associated with an aggressive form of age-related macular degeneration (AMD) that causes rapid vision loss. AMD is the leading cause of blindness in the U.S. The method would both enable earlier intervention and allow physicians to monitor the progress and effectiveness of interventions before it’s too late.


DOACs Safer Than Warfarin, Study Shows

Patients who suffered blunt traumatic intracranial hemorrhage (ICH) associated with direct oral anticoagulants (DOACs) had significantly lower mortality rates and lower rates of operative intervention compared with a similar group taking warfarin, a study published in the November issue of Trauma and Acute Surgery by researchers from UConn, Saint Francis Hospital and Medical Center, and Trinity College shows. Although DOACs have been an increasingly popular alternative to warfarin for anticoagulation, physicians have worried their use might lead to an increase in patient mortality from uncontrollable bleeding, according to the study. The study, based on data on 162 patients in the St. Francis Trauma Quality Improvement Program database, aimed to help close a gap in research on DOAC safety.

bloodclot in vein

Lab Notes – Fall 2016

‘Morrbid’ RNA Could Be Key to Asthma Treatment

No.2 Pencil eraser erasing a piece of an RNA strand

Researchers have discovered a potential therapeutic target for inflammatory disorders that are characterized by abnormal myeloid cell lifespan, such as asthma, Churg-Strauss syndrome, and hypereosinophilic syndrome. Investigators including Adam Williams of UConn Health and The Jackson Laboratory named the novel long non-coding RNA ‘Morrbid’ (Myeloid RNA Regulator of Bim-Induced Death). They discovered that Morrbid tightly controls how long circulating myeloid cells live — which is key to maintaining the balance between fighting infection and exacerbating inflammation — by overriding a signaling mechanism that prevents premature immune cell death. In mice, deleting the gene helped protect them against inflammation and immunopathology. The findings were published online in Nature, Aug. 15, 2016.


Parents Living Longer is Good News for Offspring, Study Says

Father and young son laugh together and hug

A new study led by the University of Exeter and co-authored by the UConn Center on Aging, among other international contributors, shows that how long a person’s parents live can help predict how long the offspring will live, and how healthy the child will be as he or she ages. The study of 186,000 participants, aged 55 to 73 years and followed for up to eight years, is the largest of its kind. It found that a person’s chance of survival increased by 17 percent for each decade that at least one parent lived beyond age 70, and that those with longer-lived parents had lower rates of heart disease and other circulatory conditions, as well as cancer. The study was published in the Journal of the American College of Cardiology, Aug. 15, 2016.


PRP Limits Ill Effects of Osteoarthritis Treatment

red blood cells

Giving platelet-rich plasma (PRP) to patients undergoing treatment for osteoarthritis may limit the negative effects of the drugs used to manage their symptoms, according to a new study led by Dr. Augustus Mazzocca, director of the UConn Musculoskeletal Institute, and the University of Pittsburgh Medical Center. Osteoarthritis is the most common chronic condition of the joints, causing pain, stiffness, and swelling in approximately 27 million Americans. Powerful anti-inflammatory medicines and local anesthetics relieve pain and improve range of motion, but can also lead to tissue degeneration. In the study, published in the August issue of The American Journal of Sports Medicine, researchers found combining PRP with these treatments significantly reduced their toxic effect on the cells and even improved their proliferation.


Bath Salts 101: Pharmacist Explains Party Drugs

Synthetic party drugs with dangerous hallucinogenic properties, such as those sold commercially as “bath salts,” continue to pose a significant public health risk around the country. C. Michael White — head of the Department of Pharmacy Practice in UConn’s School of Pharmacy — published a comprehensive review of synthetic cathinones in the June 2016 issue of The Journal of Clinical Pharmacology to help clinicians recognize signs of abuse and properly treat patients with adverse events, ranging from psychosis to heart disease, from the drugs. This is the third in a series of articles on drugs including molly/ecstasy and GHB that he wrote to support clinicians. He is currently working on an assessment of synthetic marijuana.

dirty spoon holds 'bath salt' drug

Lab Notes – Summer 2016

Researchers Reveal a Secret of Sepsis

human cell rendering

Severe bacterial infections can push the human body into sepsis, a life-threatening cascade of inflammation and cell death that can be difficult to cure. In the May 19 issue of Cell, immunologist Vijay Rathinam and colleagues at UConn Health proposed an explanation for how bacteria trigger such a dangerous reaction: The human cells aren’t really being invaded. They just think they are, at least when sepsis is caused by gram-negative bacteria. Gram-negative bacteria secrete vesicles of lipopolysaccharides (LPS) that can get inside human cells and set off alarms. When the cell detects the LPS, it thinks a bacterium has slipped past its defenses and self-destructs, spilling inflammatory cytokines that prompt the bacteria to emit more LPS, setting off a vicious cycle.


Nanoparticles: guided missiles for drug delivery

Powerful drugs such as chemotherapy and steroids can be devastatingly effective against their intended targets — but they have a tendency to devastate other, healthy body systems as well. UConn chemist Jessica Rouge is working to make these medications more discriminating in their action by bundling them into guided nanoparticles. Her lab is developing aptamers, molecules that bind to a specific target proteins or cell receptors, that can be attached to the nanoparticles to guide them straight to damaged or diseased cells. This approach could help cancer patients avoid the worst side effects of chemotherapy. It could also be useful for asthmatics who need steroidal anti-inflammatory drugs. With this strategy, the drugs could be sent straight to the lungs, side-stepping side effects completely.


Walnuts May Improve Your Colon Health

a walnut in its shell

Eating walnuts may change gut bacteria in a way that suppresses colon cancer. A team of researchers from UConn Health and The Jackson Laboratory for Genomic Medicine found that mice that ate 7-10.5 percent of their total calories as walnuts (about an ounce per day for humans) developed fewer colon cancers. Walnuts are packed with compounds known to be important nutritionally, but it may be as a whole food that they pack the most significant anti-cancer punch against colon cancer, the third most common cancer in the world. The research, supported in part by the California Walnut Commission and the American Institute for Cancer Research, was published May 23 in the journal Cancer Prevention Research. UConn Health Center for Molecular Medicine cancer researcher Dan Rosenberg and colleagues are now working on a long-term study in humans.


Congestive Heart Failure plus Type 2 Diabetes Worse Than We Knew

Diabetes blood Sugar monitor and test strip

Data from more than 5,300 patients with Type 2 diabetes has shown that these patients face a one-in-four chance of dying within 18 months of being hospitalized for congestive heart failure, according to the global EXAMINE study, led by UConn Health professor of medicine Dr. William B. White. Patients with Type 2 diabetes have two to three times the heart disease risk of the general population. White hopes the results inspire patients and doctors to focus more on preventing cardiovascular disease. The findings were presented June 11 at the American Diabetes Association’s (ADA) annual meeting in New Orleans and published online in the ADA journal Diabetes Care.

Lab Notes – Spring 2016

Studying Dirty Diapers for Clues About Premature Babies

A team of UConn researchers is working on minimizing stress for premature babies by analyzing one of the most extensive sources of information these patients provide: poop. Fully one in nine babies born in the U.S. arrives prematurely, and the measures necessary to keep them alive are numerous, often painful, and may have long-term effects, including lower IQs and neurodevelopmental challenges. In an ongoing study by nursing professor Xiaomei Cong and microbiologist Joerg Graf, preemies’ fecal samples are collected to study each patient’s microbiome. The researchers chart the patterns in the gut microbiome and compare them to the babies’ daily procedures, medications, feeding, and parental contact, looking for correlations between microbiome dynamics and babies’ outcomes.


Researchers Pinpoint Bone Disease-causing Gene

Fragile bones are usually an old person’s affliction, but sometimes children are born with them. Hajdu-Cheney is a particularly terrible form of inherited bone disease, in which sufferers’ bones begin to soften and fracture early, often in childhood. Now, a team of researchers led by Dr. Ernesto Canalis, director of the Center for Skeletal Research at UConn Health, has shown in mice that a specific gene can cause the disease. Overabundant bone-absorbing cells may be causing the characteristic bone loss, the researchers reported in the Jan. 22 issue of The Journal of Biological Chemistry. The researchers hope to find a potential treatment, perhaps by slowing the development or activity of the cells that absorb old bone.


Researchers up one in antibacterial cat-and-mouse game

UConn pathobiologists have discovered that vibrio bacteria have a special protein that sounds the alarm when it detects antibiotics in the beta-lactams family, such as penicillins and cephalosporins. The protein, called histidine kinase, alerts the bacteria to produce an antibiotic-fighting enzyme called beta-lactamase. The researchers reported their discovery in the Feb. 1 edition of Proceedings of the National Academy of Sciences. They don’t yet know the mechanism for how the protein senses antibiotics, but now that they know it exists, they will work on a way to disable it by developing drugs that can desensitize the bacteria — so that they don’t respond to the alarm.


Diagnose sickle cell disease with your phone

A few drops of blood inserted into a tube on a smartphone could be all that’s necessary to diagnose sickle cell disease, UConn biomedical engineers reported in Scientific Reports on Oct. 22. A hereditary disease, sickle cell affects people across Africa and the U.S. If undiagnosed, it can cause silent strokes and life-long damage, but current techniques for screening newborns are cumbersome and require specialized training. UConn’s Stephanie Knowlton and Savas Tasoglu, working with colleagues at Yale, MIT, and Harvard, have invented a sickle cell testing device that can be plugged into an Android phone and easily interpreted by a non-specialist. They’re now working on expanding the device to work for other diseases.

A device to analyze blood for sickle cell disease

Lab Notes – Winter 2015

Cancer Cells Unreceptive to Vitamin D

Many human colon cancers may not express receptors for vitamin D, limiting vitamin D’s protective role against colon cancer to the early stages of the disease, report Charles Giardina and colleagues at UConn’s Department of Molecular and Cell Biology and Center for Molecular Medicine in the April 14 issue of Cancer Prevention Research. The researchers observed that adenomas in the colons of mice tended to repress vitamin D receptors, while having elevated Class I histone deacetylases (HDAC). However, HDAC inhibitors may reactivate the vitamin D receptors. They propose that vitamin D could still be protective against colon cancer, but how its receptors are expressed and inhibited in cancer cells needs more examination. Read the article at Cancer Prevention Research.

a group of vitamin D suppliments


Rogue X Chromosomes Uncovered in Farmington

Humans only need the genes from one X chromosome to be healthy. The extra one gets trussed up and shut down in the earliest stages of development. But female human embryonic stem cells growing in the lab sometimes reactivate their second X. They express extra genes, fouling up experiments and scuttling potential therapies. Now, researchers including UConn’s Marc Lalande and a team from Paris Diderot University have found a marker, and potentially a mechanism, for how the extra X reactivates – and they have an idea on how to prevent it. They describe their findings in the May 7 issue of Cell Stem Cell.


Friends are Unreliable Sources for Drinking Studies

In recent years, researchers have turned to friends of people in alcohol studies to verify what the subjects report about their drinking habits. People in the same social situations are sought out, in part, because of the inherent impairment caused by alcohol. But according to a UConn study published in Addictive Behaviors, friends don’t seem to provide any new information. In fact, they typically underreport what their acquaintances consume. The finding supports the so-called “protective effect” of friends described in other research. A growing availability of other evidence – hair and fingernail samples, for example – may provide better strategy for corroborating the amount of alcohol study subjects consume, says author Michael Fendrich, associate dean of the School of Social Work.


She Smells Him, She Smells Him Not

Mice rely on their noses to help them navigate the world. But high levels of progesterone “blind” receptors in the noses of female mice to male pheromones, UConn Health’s John Peluso and other colleagues, led by Dr. Lisa Stowers of The Scripps Research Institute, report in the June 4 issue of Cell. Female mice have high levels of progesterone during the infertile phase of their reproductive cycles, and tend to be indifferent or even aggressive toward males. But during the fertile phase, progesterone levels drop and estrogen rises, and their nasal receptors again respond to male pheromones, the researchers found. Female mice in their fertile phase are friendly and sexually receptive towards males – perhaps because they can smell them.

mouse