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Platelets Engineered to Deliver, Transcribe RNA

Red blood cells and platelets

Red blood cells held together with platelets, in blue, and fibrin, in yellow (

5 November 2015. A biochemistry lab at University of British Columbia developed a technique for supercharging blood platelets with genetic material, enabling these cells to deliver therapies through the blood stream. The team led by biochemist and molecular biologist Christian Kastrup published its findings this week in the journal Angewandte Chemie International Edition (paid subscription required).

Kastrup and colleagues in Vancouver, Canada are seeking a way to expand the use of platelets as healing mechanisms. Platelets are cells in the blood whose function is to stop bleeding from broken blood vessels. The cells respond to signals of a damaged blood vessel from a protein known as thrombin and accumulate at the site forming a clot, which slows the blood flow. The clot forms by platelets depositing a natural polymer called fibrin at the point of damage, which changes the shape of the platelets and lets them clump together in a clot to staunch the blood flow.

The team considers platelets a promising vehicle for more functions because of their simple structure.  These cells do not have a nucleus, thus they have no nucleic acids such as DNA carrying genetic codes that get transcribed into RNA with instructions for cells to produce proteins. The researchers are seeking a more efficient way of delivering these RNA instructions to cells with nuclei, known as eukaryotic cells, than some existing (and inefficient) gene therapy or synthetic biology methods.

The UBC team started with current work on protocells, round synthetic cell replicas with fatty acid membranes called liposomes and enzymes from RNA that promote RNA growth and replication. Protocell technology is being developed for therapies, but so far is not working directly with live eukaryotic cells.

To meet this objective, the researchers adapted the functions of protocells to platelets. They devised a technique for injecting RNA with nanoscale liposomes into platelets, then activating the RNA with light beams. In lab tests, their technique succeeded in delivering RNA to platelets, then activating and transcribing the RNA into proteins. The researchers say this is the first time the process was induced inside mammalian cells, rather than protocells.

“Platelets are a basic component of blood,” says Kastrup in a university statement, “so they make an excellent way to deliver therapies to people with uncontrollable internal bleeding, or inflammatory diseases, or dangerous clots.” But this capability, he adds, can also be extended to conditions other than blood disorders. “We’ve gotten platelets to make their own RNA,” notes Kastrup. “Our next step is getting them to make therapeutic RNA, or therapeutic proteins.”

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Wearable Asthma Trigger Detector in Development

Child with asthma

(Tradimus, Wikiimedia Commons)

4 November 2015. A wearable device that detects conditions triggering asthma attacks in children is being developed by a team of engineers and behavioral scientists. The four-year project brings together sensor designers at University of Maryland-Baltimore County and psychologists at Southern Methodist University in Dallas, funded by a $2 million grant from National Institute of Biomedical Imaging and Bioengineering, part of National Institutes of Health.

Asthma is chronic condition, where the airways become inflamed and narrow, causing people with asthma to experience wheezing, shortness of breath, tightness in the chest, and coughing for periods of time. Centers for Disease Control and Prevention estimates that in 2010 some 18.7 million adults had asthma, along with 7 million children.

This device is being designed for children. It’s expected to have sensors that detect environmental factors, called triggers, causing people with asthma to react, such as pollution, pollen, dust, smoke, and pet hair. In addition, the device will also watch for physiological triggers, including physical activity levels and emotional stress. Some detectors today can identify one or, at most, a few asthma triggers, but no comprehensive device yet exists.

The new system plans to incorporate work on biomedical sensors done by UMBC’s Center for Advanced Sensor Technology that so far developed a portable system, but in this project aims to miniaturize the device further to the size of a pendant that children can wear.  The goal of the device is to provide children and their parents more objective data on the conditions that trigger asthma attacks, so they can avoid those situations or take appropriate action before the attacks become too severe.

“The monitoring system will help patients objectively determine when and why they experienced the asthma symptoms,” says Yordon Kostov, assistant director of Center for Advanced Sensor Technology and project leader for UMBC in a university statement.

The project team includes SMU health psychologists Thomas Ritz and Alicia Meuret, since stress can worsen the severity of asthma attacks, particularly in children. Ritz estimates 25 to 30 percent of patients have asthma symptoms triggered by emotional stimuli.

In an SMU statement Meuret notes her earlier work includes “developing a treatment that addresses hyperventilation using portable CO2 measurement devices, and teaching patients who suffer from panic disorders to normalize their CO2 levels and stop hyperventilating.” Team members expect a version of those instructions to be included in the trigger detection device.

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3-D Printing Devised for Blood Vessel Implants

3-D printed blood vessel components

Co-author Samantha Paulsen holds a plate of 3-D printed blood vessel components. A red dye is injected into the vessels to make them visible. (Jeff Fitlow, Rice University)

3 November 2015. A medical and engineering team developed a technique for three-dimensional printing of blood vessels that deliver oxygen and nutrients quickly to regenerated tissue. Researchers from Rice University in Houston and University of Pennsylvania in Philadelphia published a description of their work in a recent issue of the journal Tissue Engineering Part C: Methods (paid subscription required).

A team of bioengineers from the lab of Jordan Miller at Rice and surgeons led by Pavan Atluri at Penn’s medical school devised the 3-D printing technique to address a weakness in regenerative medicine, slow growth of blood vessels in the body to support engineered tissue or organ implants. That natural growth process can take days for blood vessels to grow from nearby tissue around implanted scaffolds, which can starve cells inside the live engineered tissue before they connect to the circulatory system.

Miller, Atluri, and colleagues took a different approach in addressing this problem: rather than wait for blood vessels to grow to the implanted tissue, create and implant new blood vessel connections. The researchers studied the transplant process to identify key components needed by surgeons to connect engineered tissue in the body. “What a surgeon needs in order to do transplant surgery isn’t just a mass of cells,” says Miller in a Rice statement, “the surgeon needs a vessel inlet and an outlet that can be directly connected to arteries and veins.”

In earlier work, Miller and colleagues at Penn and MIT designed a process for 3-D printing of sugar into temporary glass-like biocompatible filaments lined with cells from blood vessels through which pumped blood could flow. In lab tests, the filaments provided immediate oxygen and nutrients to liver cells from lab animals in engineered tissue samples, with the sugar filaments later dissolving.

In the new study, the Rice team used 3-D printing to create a network of sugar filaments for blood vessels into a mold with silicone gel. Silicone is a flexible polymer approved for breast and other implants. After the silicone gel hardens, the sugar filaments dissolves leaving tiny channels, about 1 millimeter across, through which blood can flow. As noted by Miller, the 3-D printed components each have a required inlet and outlet, with main vessels branching into smaller vessels.

Surgeons at Penn, led by Atluri, tested the silicone blood vessel components in lab rats. The surgeons attached the silicone components to the femoral artery, the main blood vessel feeding the leg, and a graft in the hind limb of the animals. Using doppler imaging, the researchers then measured blood flow from the artery through the implanted component to the leg. The team reports the implanted blood vessel components can withstand normal pumping pressure, and remain open for up to three hours.

“This study provides a first step toward developing a transplant model for tissue engineering where the surgeon can directly connect arteries to an engineered tissue,” says Miller. “In the future we aim to utilize a biodegradable material that also contains live cells next to these perfusable vessels for direct transplantation and monitoring long term.”

The Rice lab uses an open-source RepRap 3-D printer. Miller is designated a core developer for RepRap printers and contributes the lab’s findings to the RepRap community.

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Artificial Kidney Implant Gains $6 Million Funding

Implanted artificial kidney

Illustration of proposed implanted artificial kidney (University of California in San Francisco)

3 November 2015. A collaboration of engineering and medical researchers is developing an implantable artificial kidney to reduce the need for dialysis in people with kidney failure awaiting a transplant. The four-year project combining teams from University of California in San Francisco with Vanderbilt University in Nashville, is funded by a $6 million grant from National Institute of Biomedical Imaging and Bioengineering, part of National Institutes of Health.

The occurrence of kidney failure — also known as end-stage renal disease — is increasing in the U.S., as the population ages and becomes heavier, leading to high blood pressure and diabetes, the two leading causes of kidney disease. According to National Kidney Foundation, some 26 million people in the U.S. have kidney disease, leading to 47,000 deaths per year, making it the 9th leading cause of death. Men, African-Americans, and Hispanic-Americans are more likely to get kidney disease.

Once kidneys fail, dialysis or transplant is needed. National Kidney Foundation says about 450,000 people in the U.S. are on dialysis, requiring 3 visits a week for hours at a time. In addition, some 185,000 Americans have a transplanted kidney, but fewer than 17,000 per year will receive a transplant, despite a waiting list of 122,000. About 12 people a day in the U.S. die waiting for a kidney transplant.

The artificial kidney implant is meant to give an alternative to dialysis for people with failed kidneys as they await a transplant. The new project brings together work at UC-San Francisco led by bioengineering professor Shuvo Roy, and nephrologist/engineer William Fissell at Vanderbilt, on the school’s medical and bioengineering faculties. Roy, Fissell, and other colleagues aim to apply advances in microelectromechanical systems and nanotechnology to construct a self-contained miniaturized device that resides inside the recipient’s body.

UC-San Francisco’s Kidney Project, directed by Roy, is working on key components of the proposed device. One of those elements is a silicon filter for removing waste products from blood, which with nanoscale pores in the silicon membrane can provide more uniform filtering than now offered in conventional dialysis machines.

Another key component is a bioreactor with tubule cells from human kidneys that perform metabolic functions needed to maintain healthy pH and potassium levels in the blood. A version of the bioreactor in an external device, developed with collaborator David Humes at University of Michigan, when combined with finer-grained filtration, increased survival rates of kidney failure patients in a hospital intensive care unit, compared to dialysis alone.

Roy, Fissell, and colleagues plan to use non-reactive coatings on the implanted device, which the researchers say will remove a need for patients to take drugs to suppress their immune systems. Tests so far show the bioreactor can last up to 60 days under simulated conditions. Early preclinical tests of the silicon filters will test their performance and ability to stay clot-free for 30 days. The grant is expected to be divided about equally between optimizing the filters and the bioreactor.

While the artificial kidney implant device is still in development, it is already designated for review by the Food and Drug Administration under the agency’s Expedited Access Pathway program. That program is designed to speed review of medical devices that address unmet needs for life threatening or debilitating diseases. FDA seeks to reduce the time and cost of review of review for designated devices, without compromising standards of safety or effectiveness.

Roy and Fissell have ownership stakes in Silicon Kidney LLC, a start-up enterprise in San Francisco that aims to commercialize the silicon membrane technology developed in the artificial kidney project.

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Technique Developed to Extend Peptide Lifetimes

Transthyretin protein

Transthyretin protein structure (TFoss, Wikimedia Commons)

3 November 2015. A pharmacy lab at University of the Pacific developed a technique for extending the longevity of peptides, short amino acid chains found in many biologic drugs. The discovery from the lab of pharmacy professor Mamoun Alhamadsheh is described in this month’s issue of Nature Reviews Drug Discovery, and earlier in Nature Chemical Biology (paid subscriptions required).

Peptides are a vast potential source for engineered biologic drugs, and the building blocks of many new medications. Because of their small size and chemistry, peptides can be aimed precisely at target receptors, often with fewer side effects.

In their native state, however, peptides degrade quickly in the blood and kidneys, and are cleared from the body. As a result, to be effective peptides need to be taken frequently and in larger dosages. To increase their longevity in the body and avoid more frequent administration, peptides are sometimes combined with other compounds into macromolecules, which can interfere with binding to their target receptors, thus reducing their effects.

Alhamadsheh and colleagues in Stockton, California take a different path to extending peptide lifetimes. “In our approach,” says Alhamadsheh in a university statement, “we tagged peptides with a compound that enables it to hitch a ride on a larger protein in blood. This allows the peptides to avoid degradation and survive in the body much longer.”

The Pacific team engineered their peptides to bind with the protein transthyretin. This protein is produced mainly in the liver, and transported throughout the body carrying vitamin A and the hormone thyroxine. By binding with transthyretin, peptides are protected against degradation from enzymes in the blood, while maintaining their potency.

The researchers tested their technology in the lab with a peptide that stimulates receptors for gonadotropin-releasing hormone or GnRH, produced in the pituitary gland. Their tests show binding the peptide with transthyretin extends its lifetime, without compromising its binding ability.

In the Nature Chemical Biology article, the authors report filing for a patent on the technology.

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Computer Model Devised to Predict Drug Side Effects

Pills on table

(e-Magine Art/Flickr)

2 November 2015. A systems biology lab developed a prototype computer model that can test for potential side effects of drugs from an individual’s blood sample. The team led by bioengineering professor Bernhard Palsson at University of California in San Diego published its proof-of-concept results last week in the journal Cell Systems.

Palsson and first author Aarash Bordbar are founders of the San Diego start-up enterprise Sinopia Biosciences, developing a computational platform for modeling of biological processes involving blood cells. The journal paper reports as well that Palsson and co-author Neema Jamshidi hold a patent on large-scale data-driven kinetic modeling as applied to individuals.

The team from Palsson’s systems biology lab at UC-San Diego are seeking better ways of predicting a person’s reactions to drugs, which can be highly personalized as a result of genetic and metabolic factors. A tool for predicting reactions to drugs can help personalize the choice of medications, avoid adverse effects for individuals, and better identify candidates for clinical drug trials.

Because of the complexity of predicting a drug’s side effects, the UC-San Diego team needed to devise a kinetic model that addresses the dynamics of multiple interacting variables. The researchers constructed the model combining data from whole-genome sequencing and metabolism of red blood cells that determines the ability of blood to exchange oxygen and carbon dioxide to and from the lungs and tissues in the body. The team chose red blood cells for the prototype, because of their relative simplicity and availability in blood samples, as well as the rich platform offered by the cells to find indicators of drug side effects.

The researchers drew blood samples of about 8 milliliters (0.27 fluid ounces) from 24 volunteers, then built individualized predictive models based on their genomic profiles and red blood cell metabolism. The individual kinetic models use Mass Action Stoichiometric Simulation, a kinetic modeling approach developed by Palsson and Jamshidi, based on network models. They then tested the models with a simulated dose of the anti-viral hepatitis C drug ribavirin, which in 8 to 10 percent of cases induces anemia, or decrease in the number of red blood cells.

“A goal of our predictive model is to pinpoint specific regions in the red blood cell that might increase susceptibility to this side effect,” says Brodbar in a university statement, “and predict what will potentially happen to any particular patient on this drug over time.” With their model, tests of the simulated ribavirin dose identified 2 of the 24 volunteers with a predisposition to developing anemia from the drug.

For next steps, the UC-San Diego team plans to expand the number of individuals providing blood samples to hundreds as well as develop predictive models to cover more complex platelet cells. They eventually want to design a liver cell model, since a majority of drugs are metabolized in the liver, which also is where most side effects originate.

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Trial Testing MRI Depression Treatment with Teens

Brain map illustration

(Arthur Toga, UCLA/

2 November 2015. A new clinical trial is recruiting adolescents with major depressive disorder to test a therapy using magnetic resonance imaging impulses. The study is testing the NeuroStar TMS Therapy System, already approved for adult patients with major depressive disorder who do not respond to medications.

Depression is a widespread condition, which when it becomes persistent or severe, can interfere with normal family and work life, and lead to disability. National Institute of Mental Health estimates in 2013, 15.7 million adults in the U.S., or 6.7 percent of the adult population, suffered a major depressive episode in the previous 12 months. Data from the National Comorbidity Survey-Adolescent Supplement in 2010 show about 22 percent of adolescents suffer from severe mental disorders, half of which (11%) are mood disorders, often with symptoms different from adults.

Neuronetics Inc., in Malvern, Pennsylvania, developed its NeuroStar system harnessing magnetic resonance imaging or MRI impulses it calls transcranial magnetic stimulation that targets areas of the brain known to under-perform in people with depression. The company says the MRI impulses stimulate nerve cells in under-performing areas of the brain to release more neurotransmitters, signaling chemicals in the brain blocked or reduced in people with depression.

Transcranial magnetic stimulation or TMS therapy is given through a curved device containing a magnetic coil placed on the head and emitting MRI impulses. Each treatment lasts about 37 minutes, with treatments continuing 5 days a week for up to 6 weeks.

People receiving TMS therapies report feeling a tapping sensation on the head and hearing a clicking sound. The company reports the most common adverse effects are a temporary mild to moderate pain near the treatment area.

FDA approved the NeuroStar TMS system in 2008 for adults with major depressive disorder who do not respond to antidepressant medications. Neuronetics says more than 650 physicians now provide the therapy, which so far treated some 25,000 patients.

The new clinical trial is enrolling 100 individuals in the U.S. and Canada, age 12 to 21, with continuing major depressive disorder episodes, and who show a resistance to antidepressant medications. Participants will be randomly assigned to receive NeuroStar TMS treatments or a sham treatment, essentially the NeuroStar device without the magnetic coil. After an initial 6-week period, participants will be evaluated for symptoms of depression with a standard assessment scale.

Participants who do not improve from the initial treatments will be given an opportunity to receive or continue NeuroStar TMS treatments for another 6 weeks. Individuals taking part in the trial will then be assessed after 6 months, and receive follow-up treatments as needed during that period. The study team at 11 sites in the U.S. and 1 site in Canada, will also look for acute and long-term safety issues.

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Biotech, Accelerator to Partner on Glaucoma Treatment

Woman's eyes

(Public Domain Pictures, Pixabay)

30 October 2015. A new eye-drop treatment for the underlying causes of glaucoma is being developed in a collaboration between a biotechnology enterprise spun-off from Northwestern University and a company that acquires biomedical research assets. Financial aspects of the deal between Mannin Research Inc. in Toronto, Ontario, Canada and Q BioMed Inc. in New York were not disclosed.

Mannin Research is commercializing a technology developed in the lab of Susan Quaggin, a nephrologist and cardiovascular researcher at Northwestern University in Chicago. Quaggin, also Mannin’s chief scientist, studies signaling pathways affecting microvascular development, including genetic disruptions in vascular networks in the eyes associated with glaucoma. A September 2014 article in Journal of Clinical Investigation, with Quaggin as senior author, describes the technology and tests with lab mice induced with the genetic mutations resulting in glaucoma symptoms.

Glaucoma is the name given to a collection of eye conditions that result in damage to the optic nerve that in advanced stages can lead to vision loss. According to statistics cited by Glaucoma Research Foundation, glaucoma affects more than 3 million people in the U.S., accounting for 9 to 12 percent of all cases of blindness. Blindness from glaucoma is 6 to 8 times more common among people of African descent in the U.S. than Caucasians. It is also the second leading cause of blindness in the world, according to World Health Organization.

In most cases of glaucoma, abnormally high intraocular pressure results in the optic nerve damage. A blood vessel known as Schlemm’s canal drains fluid from the front of the eye, and when that vessel is blocked, due to mutation or over time, intraocular pressure can build up. Current treatments consist of eye drops or surgery to relieve pressure on the eyes.

Mannin Research plans to develop eye drops that repair and restore the normal flow of fluid in Schlemm’s canal, thus addressing the root cause of glaucoma rather than temporarily relieving intraocular pressure. The company says its technology is the only approach targeting this mechanism.

Q BioMed calls itself a biomedical acceleration and development company that acquires the rights to technologies from science-based enterprises and provides expansion capital to help those enterprises take their discoveries to market. Under the agreement, Q BioMed is licensing Mannin’s technology platform, with an option to acquire Mannin’s technology later on.

Q BioMed is publicly traded and offers stock-market investors opportunities to invest in biomedical enterprises, which are mainly privately owned, without becoming angel or venture investors. The company started in August 2015, and the deal with Mannin Research appears to be its first transaction.

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New Design Advances Lithium-Air Battery

EV charging station

Electric vehicle charging station (Steve Jurvetson, Flickr)

30 October 2015. A research group at University of Cambridge in the U.K. unveiled a new design that meets some of the obstacles plaguing lithium-air batteries, considered a major improvement over lithium-ion batteries now used to power mobile devices, computers, and electric cars. The team from the lab of chemistry professor Clare Grey published its findings in today’s issue of the journal Science (paid subscription required).

Lithium-ion batteries use a negative electrode made of graphite, like the carbon in pencils, and a positive electrode of a metal oxide, in an electrolyte solution of lithium salt and organic solvent. The movement of lithium ions between the electrodes creates the electric current. The light weight of lithium-ion batteries makes them attractive for mobile devices and electric cars, where weight is a key issue. Plus, they hold their charge for extended periods and have no “memory effect” requiring a complete discharge, a problem with earlier battery chemistries.

Nonetheless, lithium-ion batteries have some drawbacks, particularly a low energy density requiring frequent recharging, which creates problems when applying the technology to electric cars and grid-scale storage for intermittent renewable energy sources. Lithium-air batteries, where the lithium ions react with oxygen to create the current, are considered a possible alternative, since in lab tests they demonstrate a maximum energy density up to 10 times that of lithium-ion batteries.

Creating a practical battery with 10 times the energy density of current batteries would give electric cars, for example, about the same range as gasoline-powered cars, thus alleviating the range-anxiety keeping many electric car buyers out of showrooms. But the lithium-air battery comes with its own set of issues, including lower stability and efficiency, as well as unexpected chemical reactions.

Grey and colleagues addressed these issues by changing the materials in the electrolyte and electrode. The lithium-air battery described in the paper adds lithium iodide and water to the electrolyte, generating lithium hydroxide rather than lithium peroxide in earlier versions. By producing lithium hydroxide, the battery shows increased stability from fewer unwanted chemical reactions after multiple charging/recharging cycles.

The new battery also has a negative graphene oxide electrode, a porous carbon material one atom in thickness. The pores in the graphene electrode capture larger lithium hydroxide crystals that increase the efficiency of the battery. The increased efficiency was measured by a sharply reduced voltage gap between charging and recharging, which translates to an efficiency of 93 percent, closer to lithium-ion batteries. The researchers report being able to recharge the battery so far more than 2,000 times.

Based on lab tests, the Cambridge team believes their battery could be configured for electric vehicles with one-fifth the weight and cost of today’s lithium-ion car batteries. However, some serious issues still need to be addressed, with practical versions still several years away. The lab battery uses pure oxygen rather than ordinary air that contains nitrogen, carbon dioxide, and water as well, all of which can react with metal electrodes. In addition, the metal electrode in the demonstrator grows thin metal fibers that can short-circuit or even explode the battery.

“What we’ve achieved is a significant advance for this technology and suggests whole new areas for research, says Grey in a university statement. “We haven’t solved all the problems inherent to this chemistry, but our results do show routes forward towards a practical device.”

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Trial Underway Testing Breast Cancer Surgical Aid

Breast self exam

(National Cancer Institute)

29 October 2015. An early-stage clinical trial is recruiting participants to test a peptide that illuminates tumor cells to be removed in breast cancer surgery. The study is testing the experimental product made by Avelas Biosciences Inc., a biotechnology company in La Jolla, California.

The clinical trial is enrolling individuals with primary, non-recurring breast cancer, scheduled for mastectomy or lumpectomy surgery at University of California in San Francisco. The study is testing an engineered peptide, a short chain of amino acids, code-named AVB-620, which lights up and changes the color of tumor cells to distinguish the cancer from healthy tissue, and make the tumor easier to remove during surgery.

AVB-620 is the lead product from Avelas’s technology platform developing cell-penetrating peptides that act on enzymes produced by cancer cells. The company licenses research on cell-penetrating peptides from the lab of neuroscientist Roger Tsien at UC-San Diego. Tsien, a winner of the Nobel Prize for chemistry in 2008, studies cell signaling in neuron and cancer cells, responding to engineered molecules, such as those in AVB-620, as well as photochemical manipulation.

The trial plans to recruit 39 patients at UC-San Francisco and Moores Cancer Center at UC-San Diego. Its main goal is to assess the safety and tolerability of AVB-620, after a single dose of the peptide with an intravenous infusion. The study is also looking for activity of AVB-620 in the body, and determine the dosage needed to generate a fluorescence signal in tumor and lymph node tissue, as well as further image analysis.

“Currently, surgeons have no simple or reliable way to determine boundaries of tumors in real time during surgery,” says Jasmine Wong, a breast cancer surgeon and site leader for the study at UC-San Francisco, in an Avelas statement. “We face a delicate balancing act between removing too much tissue, which can lead to an unacceptable cosmetic outcome, and not removing enough tissue, which means subsequent surgeries will be needed.”

Highlighting tumor cells and distinguishing them from healthy tissue is the objective of an optical device tested in a clinical trial reported last month. In this case, the trial tested a hand-held wand designed by physician and engineering professor Stephan Boppart at University of Illinois in Champaign, and developed by Diagnostic Photonics Inc., a spin-off company co-founded by Boppart. As reported in Science & Enterprise, the results show a high correlation between the images from the device and pathologist reviews of diseased and healthy tissue.

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