Engineering nanoparticles that are benign by design

Computer simulation of a lipid corona around a 5-nanometer nanoparticle showing ammonium-phosphate ion pairing.

Study provides insight into how nanoparticles interact with biological systems

Personal electronic devices — smartphones, computers, TVs, tablets, screens of all kinds — are a significant and growing source of the world’s electronic waste. Many of these products use nanomaterials, but little is known about how these modern materials and their tiny particles interact with the environment and living things.

Now a research team of Northwestern University chemists and colleagues from the national Center for Sustainable Nanotechnology has discovered that when certain coated nanoparticles interact with living organisms it results in new properties that cause the nanoparticles to become sticky. Fragmented lipid coronasform on the particles, causing them to stick together and grow into long kelp-like strands. Nanoparticles with 5-nanometer diameters form long structures that are microns in size in solution. The impact on cells is not known.

“Why not make a particle that is benign from the beginning?” said Franz M. Geiger, professor of chemistry in Northwestern’s Weinberg College of Arts and Sciences. He led the Northwestern portion of the research.

“This study provides insight into the molecular mechanisms by which nanoparticles interact with biological systems,” Geiger said. “This may help us understand and predict why some nanomaterial/ligand coating combinations are detrimental to cellular organisms while others are not. We can use this to engineer nanoparticles that are benign by design.”

Why not make a particle that is benign from the beginning?”
Franz Geiger
chemist

Using experiments and computer simulations, the research team studied polycation-wrapped gold nanoparticles and their interactions with a variety of bilayer membrane models, including bacteria. The researchers found that a nearly circular layer of lipids forms spontaneously around the particles. These “fragmented lipid coronas” have never been seen before.

The study points to solving problems with chemistry. Scientists can use the findings to design a better ligand coating for nanoparticles that avoids the ammonium-phosphate interaction, which causes the aggregation. (Ligands are used in nanomaterials for layering.)

“By integrating a broad range of analyses and models, this study is a breakthrough in understanding how nanoparticles interact with our environment,” said Carol Bessel, director of the National Science Foundation‘s chemistry division, which funded the research. “This approach may allow chemists to predict new nanoparticle risks, triggering design improvements that avoid negative environmental impacts.”

The results will be published Oct. 18 in the journal Chem.

Geiger is the study’s corresponding author. Other authors include scientists from the Center for Sustainable Nanotechnology’s other institutional partners. Based at the University of Wisconsin-Madison, the center studies engineered nanomaterialsand their interaction with the environment, including biological systems — both the negative and positive aspects.

“The nanoparticles pick up parts of the lipid cellular membrane like a snowball rolling in a snowfield, and they become sticky,” Geiger said. “This unintended effect happens because of the presence of the nanoparticle. It can bring lipids to places in cells where lipids are not meant to be.”

The experiments were conducted in idealized laboratory settings that nevertheless are relevant to environments found during the late summer in a landfill — at 21-22 degrees Celsius and a couple feet below ground, where soil and groundwater mix and the food chain begins.

By pairing spectroscopic and imaging experiments with atomistic and coarse-grain simulations, the researchers identified that ion pairing between the lipid head groups of biological membranes and the polycations’ ammonium groups in the nanoparticle wrapping leads to the formation of fragmented lipid coronas. These coronas engender new properties, including composition and stickiness, to the particles with diameters below 10 nanometers.

The study’s insights help predict the impact that the increasingly widespread use of engineered nanomaterials has on the nanoparticles’ fate once they enter the food chain, which many of them may eventually do.

“New technologies and mass consumer products are emerging that feature nanomaterials as critical operational components,” Geiger said. “We can upend the existing paradigm in nanomaterial production towards one in which companies design nanomaterials to be sustainable from the beginning, as opposed to risking expensive product recalls — or worse — down the road.”

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Biodegradable implant provides electrical stimulation that speeds nerve regeneration

The wireless device naturally absorbs into the body after a week or two.
CREDIT
Northwestern University

Researchers demonstrate first example of a bioelectronic medicine

Northwestern University and Washington University School of Medicine have developed the first example of a bioelectronic medicine: an implantable, biodegradable wireless device that speeds nerve regeneration and improves the healing of a damaged nerve.

The collaborators — materials scientists and engineers at Northwestern and neurosurgeons at Washington University — developed a device that delivers regular pulses of electricity to damaged peripheral nerves in rats after a surgical repair process, accelerating the regrowth of nerves in their legs and enhancing the ultimate recovery of muscle strength and control. The size of a dime and the thickness of a sheet of paper, the wireless device operates for about two weeks before naturally absorbing into the body.

The scientists envision that such transient engineered technologies one day could complement or replace pharmaceutical treatments for a variety of medical conditions in humans. This type of technology, which the researchers refer to as a “bioelectronic medicine,” provides therapy and treatment over a clinically relevant period of time and directly at the site where it’s needed, thereby reducing side effects or risks associated with conventional, permanent implants.

“These engineered systems provide active, therapeutic function in a programmable, dosed format and then naturally disappear into the body, without a trace,” said Northwestern’s John A. Rogers, a pioneer in bio-integrated technologies and a co-senior author of the study. “This approach to therapy allows one to think about options that go beyond drugs and chemistry.”

Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery in the McCormick School of Engineering and Northwestern University Feinberg School of Medicine.

The research will be published Oct. 8 in the journal Nature Medicine.

While the device has not been tested in humans, the findings offer promise as a future therapeutic option for nerve injury patients. For cases requiring surgery, standard practice is to administer some electrical stimulation during the surgery to aid recovery. But until now, doctors have lacked a means to continuously provide that added boost at various time points throughout the recovery and healing process.

“We know that electrical stimulation during surgery helps, but once the surgery is over, the window for intervening is closed,” said co-senior author Dr. Wilson “Zack” Ray, an associate professor of neurosurgery, of biomedical engineering and of orthopedic surgery at Washington University. “With this device, we’ve shown that electrical stimulation given on a scheduled basis can further enhance nerve recovery.”

Over the past eight years, Rogers and his lab have developed a complete collection of electronic materials, device designs and manufacturing techniques for biodegradable devices with a broad range of options that offer the potential to address unmet medical needs. When Ray and his colleagues at Washington University identified the need for electrical stimulation-based therapies to accelerate wound healing, Rogers and colleagues at Northwestern went to their toolbox and set to work.

They designed and developed a thin, flexible device that wraps around an injured nerve and delivers electrical pulses at selected time points for days before the device harmlessly degrades in the body. The device is powered and controlled wirelessly by a transmitter outside the body that acts much like a cellphone-charging mat. Rogers and his team worked closely with the Washington University team throughout the development process and animal validation.

The Washington University researchers then studied the bioelectronic device in rats with injured sciatic nerves. This nerve sends signals up and down the legs and controls the hamstrings and muscles of the lower legs and feet. They used the device to provide one hour per day of electrical stimulation to the rats for one, three or six days or no electrical stimulation at all, and then monitored their recovery for the next 10 weeks.

They found that any electrical stimulation was better than none at all at helping the rats recover muscle mass and muscle strength. In addition, the more days of electrical stimulation the rats received, the more quickly and thoroughly they recovered nerve signaling and muscle strength. No adverse biological effects from the device and its reabsorption were found.

“Before we did this study, we weren’t sure that longer stimulation would make a difference, and now that we know it does, we can start trying to find the ideal time frame to maximize recovery,” Ray said. “Had we delivered electrical stimulation for 12 days instead of six, would there have been more therapeutic benefit? Maybe. We’re looking into that now.”

By varying the composition and thickness of the materials in the device, Rogers and colleagues can control the precise number of days it remains functional before being absorbed into the body. New versions can provide electrical pulses for weeks before degrading. The ability of the device to degrade in the body takes the place of a second surgery to remove a non-biodegradable device, thereby eliminating additional risk to the patient.

“We engineer the devices to disappear,” Rogers said. “This notion of transient electronic devices has been a topic of deep interest in my group for nearly 10 years — a grand quest in materials science, in a sense. We are excited because we now have the pieces — the materials, the devices, the fabrication approaches, the system-level engineering concepts — to exploit these concepts in ways that could have relevance to grand challenges in human health.”

The research study also showed the device can work as a temporary pacemaker and as an interface to the spinal cord and other stimulation sites across the body. These findings suggest broad utility, beyond just the peripheral nervous system.

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Treating fibrosis, that is estimated to cause 35 to 40 percent of deaths in the world, with precision medicine

Cirrhosis of the liver with hepatic steatosis and chronic hepatitis

Normal scar tissue forms to heal an internal wound and quietly retreats when the job is done. But in many common diseases — kidney, liver and lung fibrosis — the scar tissue goes rogue and strangles vital organs. These diseases are largely untreatable and ultimately fatal.

A new Northwestern Medicine study has newly identified a trigger of some fibrotic diseases and an experimental compound to treat it.

Fibrosis — a progressive scarring and hardening of internal organs — is estimated to cause 35 to 40 percent of deaths in the world. Fibrotic diseases include diabetic kidney fibrosis, alcoholic liver cirrhosishepatitis C, pulmonary fibrosis and nonalcoholic fatty liver disease, which may lead to fibrosis of the liver, the leading cause of liver transplant.

In one subset of human fibrosis cells, scientists discovered a delinquent gang of molecules that continually shouted at an immune receptor — the antennae on the cell — to produce scar tissue instead of quieting down and allowing the scar tissue to go back to sleep.

Scientists collaborated with a University of Colorado researcher who used crystallography and computer modeling to predict a molecule that could block the receptor that leads to the uncontrolled scarring. When they tested the molecule, T53, in three different mouse models of fibrosis, the abnormality was significantly reversed.

Our study opens a new door into fibrosis by looking at it as an aberrant innate immune response and suggesting a novel approach to treat it.”
Dr. John Varga
Director of the Northwestern Scleroderma Program

“Our study opens a new door into fibrosis by looking at it as an aberrant innate immune response and suggesting a novel approach to treat it,” said senior author Dr. John Varga, director of the Northwestern Scleroderma Program and the John and Nancy Hughes Distinguished Professor of Rheumatology at Northwestern University Feinberg School of Medicine.

The paper was published July 12 in the Journal of Clinical Investigation Insight.

“The leading cause of liver failure in western world is obesity and that’s because of liver fibrosis,” Varga said. “In the U.S., many of these diseases are lifestyle or age dependent. As we get fatter or older, they get worse.”

Most fibrotic disease likely begins as normal repair of an injury, scientists said. “But if the immune system produces too much of an initial scar, it can’t go back to normal,” Varga said. “You have an unhealed scar that keeps growing and can wipe out the entire organ.”

Not everyone’s fibrosis is caused by the same abnormality, Varga said. If the compound, T53, is eventually developed into an approved drug, it would be targeted to patients with the specific genetic signature identified in the study.

“There is an emerging direction for treating fibrosis with precision medicine,” said first author Swati Bhattacharyya, research associate professor of medicine in rheumatology and scientific director of the Scleroderma Research Laboratory at Feinberg. “Some people live with fibrotic disease for 30 years while others die in two years. We need to identify the rapid progressors from the slow progressors. That’s where precision medicine becomes really critical.”

“The results of this study are encouraging,” Varga said. “We are not saying this compound is ready to be a drug. It’s an initial compound that would need to be developed and tweaked. It would need significant funding to go to the next step.”

Learn more: Why internal scars won’t stop growing

 

 

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A drug compound that stops cancer cells from spreading throughout the body

(Left to right) Ryan Gordon, Ph.D., Raymond Bergan, M.D., Zhenzhen Zhang, Ph.D., M.P.H., Limin Zhang, Ph.D., Graham Fowler and Abhi Pattanayak in the OHSU Bergan Basic Research Laboratory. A multidisciplinary team has discovered a drug compound that stops cancer cells from spreading throughout the body. (OHSU/Kristyna Wentz-Graff)

Via a mouse model, OHSU physician-scientists lead effort to hone a drug that inhibits cancer cells from spreading to other areas in the body

Fighting cancer means killing cancer cells. However, oncologists know that it’s also important to halt the movement of cancer cells before they spread throughout the body. New research, published today in the journal Nature Communications, shows that it may be possible to freeze cancer cells and kill them where they stand.

Raymond Bergan, M.D., Division Chief of Hematology and Medical Oncology and professor of medicine at OHSU, says that the majority of cancer treatment therapies today are directed toward killing cancer. To date, he says, no one has developed a therapy that can stop cancer cells from moving around the body.

“For the vast majority of cancer—breast, prostate, lung, colon, and others—if it is detected early when it is a little lump in that organ and it has not spread, you will live. And generally, if you find it late, after it has spread throughout your body, you will die,” says Bergan, also the associate director of medical oncology in the OHSU Knight Cancer Institute and director of the OHSU Bergan Basic Research Laboratory. “Movement is key: the difference is black and white, night and day. If cancer cells spread throughout your body, they will take your life. We can treat it, but it will take your life.”

For that reason, the study of cancer cell movement, or motility, has been the focus of his group’s research for several decades.

Stopping cancer cell movement

In 2011, Bergan and team took a novel approach to their research by working with chemists to jointly discover a drug that will inhibit the movement of cancer cells.

The Nature Communications paper outlines the multidisciplinary team’s work with KBU2046, a compound that was found to inhibit cell motility in four different human cell models of solid cancer types: breast, prostate, colon and lung cancers.

“We used chemistry to probe biology to give us a perfect drug that would only inhibit the movement of cancer cells and wouldn’t do anything else,” Bergan says. “That basic change in logic lead us to do everything we did.”

A multidisciplinary team

The team of investigators includes Bergan’s team at OHSU, a chemist from Northwestern University as well as researchers from Xiamen University in China, the University of Chicago, and the University of Washington.

Ryan Gordon, Ph.D., research assistant professor in the OHSU School of Medicine and co-director of the Bergan lab, says drawing upon the strengths of this cross-functional group was key to the research’s success.

“As we identified areas we were lacking, we looked at new cutting-edge technologies, and if there was something that didn’t meet our needs, we developed new assays to address our needs,” he says.

The lab of Karl Scheidt, Ph.D., professor of chemistry and professor of pharmacology; director of the Center for Molecular Innovation and Drug Discovery; and executive director of the NewCures accelerator at Northwestern University, was responsible for the design and creation of new molecules which were then evaluated by Bergan’s team for their ability to inhibit cell motility. Using chemical synthesis approaches, Scheidt and team accessed new compounds that minimized motility in tumor cells, with few side effects and very low toxicity.

“We’ve taken a clue provided by nature and through the power of chemistry created an entirely new way to potentially control the spread of cancer,” Scheidt says. “It’s been a truly rewarding experience working together as a team toward ultimately helping cancer patients.”

Refining the drug

Bergan notes the process for narrowing down the specific drug compound was a process of refinement.

“We started off with a chemical that stopped cells from moving, then we increasingly refined that chemical until it did a perfect job of stopping the cells with no side effects,” he says. “All drugs have side effects, so you look for the drug that is the most specific as possible. This drug does that.”

Bergan says the key to this drug was engaging the heat shock proteins—the “cleaners” of a cell. “The way the drug works is that it binds to these cleaner proteins to stop cell movement, but it has no other effect on those proteins.”

He says it is a very unusual, unique mechanism that “took us years to figure out.”

“Initially, nobody would fund us,” Bergan says. “We were looking into a completely different way of treating cancer.”

Next step: testing the drug in humans

Ultimately, Gordon says the goal of this research is to look for a new therapeutic to benefit humans.

“The eventual promise of this research is that we’re working toward developing a therapeutic that can help manage early stage disease, preventing patients from getting the more incurable later-stage disease,” he says.

He’s quick to note this work has not been tested in humans, and doing so will require both time and money. The team’s best estimate is that will take about two years and five million dollars of funding. They are currently raising money to do IND (investigational new drug) enabling studies, a requirement to conduct a clinical trial of an unapproved drug or an approved product for a new indication or in a new patient population.

In addition, Drs. Bergan and Scheidt have founded a company, Third Coast Therapeutics, aimed to bring this type of therapy to patients.

“Our eventual goal is to be able to say to a woman with breast cancer: here, take this pill and your cancer won’t spread throughout your body. The same thing for patients with prostate, lung, and colon cancer,” Bergan says. “This drug is highly effective against four cancer types (breast, colon, lung, prostate) in the in vitro model so far. Our goal is to move this forward as a therapy to test in humans.”

Bergan says his team feels lucky to have the opportunity to conduct this challenging research at the OHSU Knight Cancer Institute, an institute dedicated to novel approaches to detecting and treating cancer.

“What early detection is trying to do is detect an early, lethal lesion. Cancers are lethal because they move,” he says. “This drug is designed to stop that movement.”

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Shape-conforming hydrogel bandage accelerates healing in diabetic wounds

Stained epidermis cells cultured on the A5G81 peptide.

Shape-conforming hydrogel leverages the body’s own healing mechanisms rather than releasing drugs or biologics

A simple scrape or sore might not cause alarm for most people. But for diabetic patients, an untreated scratch can turn into an open wound that could potentially lead to a limb amputation or even death.

A Northwestern University team has developed a new device, called a regenerative bandage, that quickly heals these painful, hard-to-treat sores without using drugs. During head-to-head tests, Northwestern’s bandage healed diabetic wounds 33 percent faster than one of the most popular bandages currently on the market.

Guillermo Ameer
Guillermo Ameer

“The novelty is that we identified a segment of a protein in skin that is important to wound healing, made the segment and incorporated it into an antioxidant molecule that self-aggregates at body temperature to create a scaffold that facilitates the body’s ability to regenerate tissue at the wound site,” said Northwestern’s Guillermo Ameer, who led the study. “With this newer approach, we’re not releasing drugs or outside factors to accelerate healing. And it works very well.”

Because the bandage leverages the body’s own healing power without releasing drugs or biologics, it faces fewer regulatory hurdles. This means patients could see it on the market much sooner.

The research was published today, June 11, in the Proceedings of the National Academy of Sciences. Although Ameer’s laboratory is specifically interested in diabetes applications, the bandage can be used to heal all types of open wounds.

An expert in biomaterials and regenerative engineering, Ameer is the Daniel Hale Williams Professor of Biomedical Engineering in the McCormick School of Engineering, professor of surgery in the Feinberg School of Medicine and director of Northwestern’s new Center for Advanced Regenerative Engineering (CARE).

The difference between a sore in a physically healthy person versus a diabetic patient? Diabetes can cause nerve damage that leads to numbness in the extremities. People with diabetes, therefore, might experience something as simple as a blister or small scratch that goes unnoticed and untreated because they cannot feel it to know it’s there. As high glucose levels also thicken capillary walls, blood circulation slows, making it more difficult for these wounds to heal. It’s a perfect storm for a small nick to become a limb-threatening — or life-threatening — wound.

The secret behind Ameer’s regenerative bandage is laminin, a protein found in most of the body’s tissues including the skin. Laminin sends signals to cells, encouraging them to differentiate, migrate and adhere to one another. Ameer’s team identified a segment of laminin — 12 amino acids in length — called A5G81 that is critical for the wound-healing process.

“This particular sequence caught our eye because it activates cellular receptors to get cells to adhere, migrate and proliferate,” Ameer said. “Then we cut up the sequence to find the minimum size that we needed for it to work.”

By using such a small fragment of laminin rather than the entire protein, it can be easily synthesized in the laboratory — making it more reproducible while keeping manufacturing costs low. Ameer’s team incorporated A5G81 into an antioxidant hydrogel bandage that it previously developed in the laboratory.

The bandage’s antioxidant nature counters inflammation. And the hydrogel is thermally responsive: It is a liquid when applied to the wound bed, then rapidly solidifies into a gel when exposed to body temperature. This phase change allows it to conform to the exact shape of the wound — a property that helped it out-perform other bandages on the market.

“Wounds have irregular shapes and depths. Our liquid can fill any shape and then stay in place,” Ameer said. “Other bandages are mostly based on collagen films or sponges that can move around and shift away from the wound site.”

Patients also must change bandages often, which can rip off the healing tissue and re-injure the site. Ameer’s bandage, however, can be rinsed off with cool saline, so the regenerating tissue remains undisturbed.

Not only will the lack of drugs or biologics make the bandage move to market faster, it also increases the bandage’s safety. So far, Ameer’s team has not noticed any adverse side effects in animal models. This is a stark difference from another product on the market, which contains a growth factor linked to cancer.

“It is not acceptable for patients who are trying to heal an open sore to have to deal with an increased risk of cancer,” Ameer said.

Next, Ameer’s team will continue to investigate the bandage in a larger pre-clinical model.

Learn more: Regenerative bandage accelerates healing in diabetic wounds

 

 

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