Tag Archives: University of California at San Diego (UCSD)

Tiny sponges lure coronavirus away from lung cells

This research approach looks promising as three news releases trumpeting the possibilities indicate. First, there’s the June 17, 2020 American Chemical Society (ACS) news release,

Scientists are working overtime to find an effective treatment for COVID-19, the illness caused by the new coronavirus, SARS-CoV-2. Many of these efforts target a specific part of the virus, such as the spike protein. Now, researchers reporting in Nano Letters have taken a different approach, using nanosponges coated with human cell membranes –– the natural targets of the virus –– to soak up SARS-CoV-2 and keep it from infecting cells in a petri dish.

To gain entry, SARS-CoV-2 uses its spike protein to bind to two known proteins on human cells, called ACE2 and CD147. Blocking these interactions would keep the virus from infecting cells, so many researchers are trying to identify drugs directed against the spike protein. Anthony Griffiths, Liangfang Zhang and colleagues had a different idea: making a nanoparticle decoy with the virus’ natural targets, including ACE2 and CD147, to lure SARS-CoV-2 away from cells. And to test this idea, they conducted experiments with the actual SARS-CoV-2 virus in a biosafety level 4 lab.

The researchers coated a nanoparticle polymer core with cell membranes from either human lung epithelial cells or macrophages –– two cell types infected by SARS-CoV-2. They showed that the nanosponges had ACE2 and CD147, as well as other cell membrane proteins, projecting outward from the polymer core. When administered to mice, the nanosponges did not show any short-term toxicity. Then, the researchers treated cells in a dish with SARS-CoV-2 and the lung epithelial or macrophage nanosponges. Both decoys neutralized SARS-CoV-2 and prevented it from infecting cells to a similar extent. The researchers plan to next test the nanosponges in animals before moving to human clinical trials. In theory, the nanosponge approach would work even if SARS-CoV-2 mutates to resist other therapies, and it could be used against other viruses, as well, the researchers say.

In this illustration, a nanosponge coated with a human cell membrane acts as a decoy to prevent a virus from entering cells. Credit: Adapted from Nano Letters 2020, DOI: 10.1021/acs.nanolett.0c02278

There are two research teams involved, one at Boston University and the other at the University of California at San Diego (UC San Diego or UCSD). The June 18, 2020 Boston University news release (also on EurekAlert) by Kat J. McAlpine adds more details about the research, provides some insights from the researchers, and is a little redundant if you’ve already seen the ACS news release,

Imagine if scientists could stop the coronavirus infection in its tracks simply by diverting its attention away from living lung cells? A new therapeutic countermeasure, announced in a Nano Letters study by researchers from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the University of California San Diego, appears to do just that in experiments that were carried out at the NEIDL in Boston.

The breakthrough technology could have major implications for fighting the SARS-CoV-2 virus responsible for the global pandemic that’s already claimed nearly 450,000 lives and infected more than 8 million people. But, perhaps even more significantly, it has the potential to be adapted to combat virtually any virus, such as influenza or even Ebola.

“I was skeptical at the beginning because it seemed too good to be true,” says NEIDL microbiologist Anna Honko, one of the co-first authors on the study. “But when I saw the first set of results in the lab, I was just astonished.”

The technology consists of very small, nanosized drops of polymers–essentially, soft biofriendly plastics–covered in fragments of living lung cell and immune cell membranes.

“It looks like a nanoparticle coated in pieces of cell membrane,” Honko says. “The small polymer [droplet] mimics a cell having a membrane around it.”

The SARS-CoV-2 virus seeks out unique signatures of lung cell membranes and latches onto them. When that happens inside the human body, the coronavirus infection takes hold, with the SARS-CoV-2 viruses hijacking lung cells to replicate their own genetic material. But in experiments at the NEIDL, BU researchers observed that polymer droplets laden with pieces of lung cell membrane did a better job of attracting the SARS-CoV-2 virus than living lung cells. [emphasis mine]

By fusing with the SARS-CoV-2 virus better than living cells can, the nanotechnology appears to be an effective countermeasure to coronavirus infection, preventing SARS-CoV-2 from attacking cells.

“Our guess is that it acts like a decoy, it competes with cells for the virus,” says NEIDL microbiologist Anthony Griffiths, co-corresponding author on the study. “They are little bits of plastic, just containing the outer pieces of cells with none of the internal cellular machinery contained inside living cells. Conceptually, it’s such a simple idea. It mops up the virus like a sponge.”

That attribute is why the UC San Diego and BU research team call the technology “nanosponges.” Once SARS-CoV-2 binds with the cell fragments inside a nanosponge droplet–each one a thousand times smaller than the width of a human hair–the coronavirus dies. Although the initial results are based on experiments conducted in cell culture dishes, the researchers believe that inside a human body, the biodegradable nanosponges and the SARS-CoV-2 virus trapped inside them could then be disposed of by the body’s immune system. The immune system routinely breaks down and gets rid of dead cell fragments caused by infection or normal cell life cycles.

There is also another important effect that the nanosponges have in the context of coronavirus infection. Honko says nanosponges containing fragments of immune cells can soak up cellular signals that increase inflammation [emphases mine]. Acute respiratory distress, caused by an inflammatory cascade inside the lungs, is the most deadly aspect of the coronavirus infection, sending patients into the intensive care unit for oxygen or ventilator support to help them breathe.

But the nanosponges, which can attract the inflammatory molecules that send the immune system into dangerous overdrive, can help tamp down that response, Honko says. By using both kinds of nanosponges, some containing lung cell fragments and some containing pieces of immune cells, she says it’s possible to “attack the coronavirus and the [body’s] response” responsible for disease and eventual lung failure.

At the NEIDL, Honko and Griffiths are now planning additional experiments to see how well the nanosponges can prevent coronavirus infection in animal models of the disease. They plan to work closely with the team of engineers at UC San Diego, who first developed the nanosponges more than a decade ago, to tailor the technology for eventual safe and effective use in humans.

“Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets,” said Liangfang Zhang, a UC San Diego nanoengineer and leader of the California-based team, according to a UC San Diego press release. “Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys.”

When the novel coronavirus first appeared, the idea of using the nanosponges to combat the infection came to Zhang almost immediately. He reached out to the NEIDL for help. Looking ahead, the BU and UC San Diego collaborators believe the nanosponges can easily be converted into a noninvasive treatment.

“We should be able to drop it right into the nose,” Griffiths says. “In humans, it could be something like a nasal spray.”

Honko agrees: “That would be an easy and safe administration method that should target the appropriate [respiratory] tissues. And if you wanted to treat patients that are already intubated, you could deliver it straight into the lung.”

Griffiths and Honko are especially intrigued by the nanosponges as a new platform for treating all types of viral infections. “The broad spectrum aspect of this is exceptionally appealing,” Griffiths says. The researchers say the nanosponge could be easily adapted to house other types of cell membranes preferred by other viruses, creating many new opportunities to use the technology against other tough-to-treat infections like the flu and even deadly hemorrhagic fevers caused by Ebola, Marburg, or Lassa viruses.

“I’m interested in seeing how far we can push this technology,” Honko says.

The University of California as San Diego has released a video illustrating the nanosponges work,

There’s also this June 17, 2020 University of California at San Diego (UC San Diego) news release (also on EurekAlert) by Ioana Patringenaru, which offers extensive new detail along with, if you’ve read one or both of the news releases in the above, a few redundant bits,

Nanoparticles cloaked in human lung cell membranes and human immune cell membranes can attract and neutralize the SARS-CoV-2 virus in cell culture, causing the virus to lose its ability to hijack host cells and reproduce.

The first data describing this new direction for fighting COVID-19 were published on June 17 in the journal Nano Letters. The “nanosponges” were developed by engineers at the University of California San Diego and tested by researchers at Boston University.

The UC San Diego researchers call their nano-scale particles “nanosponges” because they soak up harmful pathogens and toxins.

In lab experiments, both the lung cell and immune cell types of nanosponges caused the SARS-CoV-2 virus to lose nearly 90% of its “viral infectivity” in a dose-dependent manner. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

Instead of targeting the virus itself, these nanosponges are designed to protect the healthy cells the virus invades.

“Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets. Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys,” said Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering.

His lab first created this biomimetic nanosponge platform more than a decade ago and has been developing it for a wide range of applications ever since [emphasis mine]. When the novel coronavirus appeared, the idea of using the nanosponge platform to fight it came to Zhang “almost immediately,” he said.

In addition to the encouraging data on neutralizing the virus in cell culture, the researchers note that nanosponges cloaked with fragments of the outer membranes of macrophages could have an added benefit: soaking up inflammatory cytokine proteins, which are implicated in some of the most dangerous aspects of COVID-19 and are driven by immune response to the infection.

Making and testing COVID-19 nanosponges

Each COVID-19 nanosponge–a thousand times smaller than the width of a human hair–consists of a polymer core coated in cell membranes extracted from either lung epithelial type II cells or macrophage cells. The membranes cover the sponges with all the same protein receptors as the cells they impersonate–and this inherently includes whatever receptors SARS-CoV-2 uses to enter cells in the body.

The researchers prepared several different concentrations of nanosponges in solution to test against the novel coronavirus. To test the ability of the nanosponges to block SARS-CoV-2 infectivity, the UC San Diego researchers turned to a team at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) to perform independent tests. In this BSL-4 lab–the highest biosafety level for a research facility–the researchers, led by Anthony Griffiths, associate professor of microbiology at Boston University School of Medicine, tested the ability of various concentrations of each nanosponge type to reduce the infectivity of live SARS-CoV-2 virus–the same strains that are being tested in other COVID-19 therapeutic and vaccine research.

At a concentration of 5 milligrams per milliliter, the lung cell membrane-cloaked sponges inhibited 93% of the viral infectivity of SARS-CoV-2. The macrophage-cloaked sponges inhibited 88% of the viral infectivity of SARS-CoV-2. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

“From the perspective of an immunologist and virologist, the nanosponge platform was immediately appealing as a potential antiviral because of its ability to work against viruses of any kind. This means that as opposed to a drug or antibody that might very specifically block SARS-CoV-2 infection or replication, these cell membrane nanosponges might function in a more holistic manner in treating a broad spectrum of viral infectious diseases. I was optimistically skeptical initially that it would work, and then thrilled once I saw the results and it sunk in what this could mean for therapeutic development as a whole,” said Anna Honko, a co-first author on the paper and a Research Associate Professor, Microbiology at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL).

In the next few months, the UC San Diego researchers and collaborators will evaluate the nanosponges’ efficacy in animal models. The UC San Diego team has already shown short-term safety in the respiratory tracts and lungs of mice. If and when these COVID-19 nanosponges will be tested in humans depends on a variety of factors, but the researchers are moving as fast as possible.

“Another interesting aspect of our approach is that even as SARS-CoV-2 mutates, as long as the virus can still invade the cells we are mimicking, our nanosponge approach should still work. I’m not sure this can be said for some of the vaccines and therapeutics that are currently being developed,” said Zhang.

The researchers also expect these nanosponges would work against any new coronavirus or even other respiratory viruses, including whatever virus might trigger the next respiratory pandemic.

Mimicking lung epithelial cells and immune cells

Since the novel coronavirus often infects lung epithelial cells as the first step in COVID-19 infection, Zhang and his colleagues reasoned that it would make sense to cloak a nanoparticle in fragments of the outer membranes of lung epithelial cells to see if the virus could be tricked into latching on it instead of a lung cell.

Macrophages, which are white blood cells that play a major role in inflammation, also are very active in the lung during the course of a COVID-19 illness, so Zhang and colleagues created a second sponge cloaked in macrophage membrane.

The research team plans to study whether the macrophage sponges also have the ability to quiet cytokine storms in COVID-19 patients.

“We will see if the macrophage nanosponges can neutralize the excessive amount of these cytokines as well as neutralize the virus,” said Zhang.

Using macrophage cell fragments as cloaks builds on years of work to develop therapies for sepsis using macrophage nanosponges.

In a paper published in 2017 in Proceedings of the National Academy of Sciences, Zhang and a team of researchers at UC San Diego showed that macrophage nanosponges can safely neutralize both endotoxins and pro-inflammatory cytokines in the bloodstream of mice. A San Diego biotechnology company co-founded by Zhang called Cellics Therapeutics is working to translate this macrophage nanosponge work into the clinic.

A potential COVID-19 therapeutic The COVID-19 nanosponge platform has significant testing ahead of it before scientists know whether it would be a safe and effective therapy against the virus in humans, Zhang cautioned [emphasis mine]. But if the sponges reach the clinical trial stage, there are multiple potential ways of delivering the therapy that include direct delivery into the lung for intubated patients, via an inhaler like for asthmatic patients, or intravenously, especially to treat the complication of cytokine storm.

A therapeutic dose of nanosponges might flood the lung with a trillion or more tiny nanosponges that could draw the virus away from healthy cells. Once the virus binds with a sponge, “it loses its viability and is not infective anymore, and will be taken up by our own immune cells and digested,” said Zhang.

“I see potential for a preventive treatment, for a therapeutic that could be given early because once the nanosponges get in the lung, they can stay in the lung for some time,” Zhang said. “If a virus comes, it could be blocked if there are nanosponges waiting for it.”

Growing momentum for nanosponges

Zhang’s lab at UC San Diego created the first membrane-cloaked nanoparticles over a decade ago. The first of these nanosponges were cloaked with fragments of red blood cell membranes. These nanosponges are being developed to treat bacterial pneumonia and have undergone all stages of pre-clinical testing by Cellics Therapeutics, the San Diego startup cofounded by Zhang. The company is currently in the process of submitting the investigational new drug (IND) application to the FDA for their lead candidate: red blood cell nanosponges for the treatment of methicillin-resistant staphylococcus aureus (MRSA) pneumonia. The company estimates the first patients in a clinical trial will be dosed next year.

The UC San Diego researchers have also shown that nanosponges can deliver drugs to a wound site; sop up bacterial toxins that trigger sepsis; and intercept HIV before it can infect human T cells.

The basic construction for each of these nanosponges is the same: a biodegradable, FDA-approved polymer core is coated in a specific type of cell membrane, so that it might be disguised as a red blood cell, or an immune T cell or a platelet cell. The cloaking keeps the immune system from spotting and attacking the particles as dangerous invaders.

“I think of the cell membrane fragments as the active ingredients. This is a different way of looking at drug development,” said Zhang. “For COVID-19, I hope other teams come up with safe and effective therapies and vaccines as soon as possible. At the same time, we are working and planning as if the world is counting on us.”

I wish the researchers good luck. For the curious, here’s a link to and a citation for the paper,

Cellular Nanosponges Inhibit SARS-CoV-2 Infectivity by Qiangzhe Zhang, Anna Honko, Jiarong Zhou, Hua Gong, Sierra N. Downs, Jhonatan Henao Vasquez, Ronnie H. Fang, Weiwei Gao, Anthony Griffiths, and Liangfang Zhang. Nano Lett. 2020, XXXX, XXX, XXX-XXX DOI: https://doi.org/10.1021/acs.nanolett.0c02278 Publication Date:June 17, 2020 Copyright © 2020 American Chemical Society

This paper appears to be open access.

Here, too, is the Cellics Therapeutics website.

Bringing a technique from astronomy down to the nanoscale

A January 2, 2020 Columbia University news release on EurekAlert (also on phys.org but published Jan. 3, 2020) describes research that takes the inter-galactic down to the quantum level,

Researchers at Columbia University and University of California, San Diego, have introduced a novel “multi-messenger” approach to quantum physics that signifies a technological leap in how scientists can explore quantum materials.

The findings appear in a recent article published in Nature Materials, led by A. S. McLeod, postdoctoral researcher, Columbia Nano Initiative, with co-authors Dmitri Basov and A. J. Millis at Columbia and R.A. Averitt at UC San Diego.

“We have brought a technique from the inter-galactic scale down to the realm of the ultra-small,” said Basov, Higgins Professor of Physics and Director of the Energy Frontier Research Center at Columbia. Equipped with multi-modal nanoscience tools we can now routinely go places no one thought would be possible as recently as five years ago.”

The work was inspired by “multi-messenger” astrophysics, which emerged during the last decade as a revolutionary technique for the study of distant phenomena like black hole mergers. Simultaneous measurements from instruments, including infrared, optical, X-ray and gravitational-wave telescopes can, taken together, deliver a physical picture greater than the sum of their individual parts.

The search is on for new materials that can supplement the current reliance on electronic semiconductors. Control over material properties using light can offer improved functionality, speed, flexibility and energy efficiency for next-generation computing platforms.

Experimental papers on quantum materials have typically reported results obtained by using only one type of spectroscopy. The researchers have shown the power of using a combination of measurement techniques to simultaneously examine electrical and optical properties.

The researchers performed their experiment by focusing laser light onto the sharp tip of a needle probe coated with magnetic material. When thin films of metal oxide are subject to a unique strain, ultra-fast light pulses can trigger the material to switch into an unexplored phase of nanometer-scale domains, and the change is reversible.

By scanning the probe over the surface of their thin film sample, the researchers were able to trigger the change locally and simultaneously manipulate and record the electrical, magnetic and optical properties of these light-triggered domains with nanometer-scale precision.

The study reveals how unanticipated properties can emerge in long-studied quantum materials at ultra-small scales when scientists tune them by strain.

“It is relatively common to study these nano-phase materials with scanning probes. But this is the first time an optical nano-probe has been combined with simultaneous magnetic nano-imaging, and all at the very low temperatures where quantum materials show their merits,” McLeod said. “Now, investigation of quantum materials by multi-modal nanoscience offers a means to close the loop on programs to engineer them.”

The excitement is palpable.

Caption: The discovery of multi-messenger nanoprobes allows scientists to simultaneously probe multiple properties of quantum materials at nanometer-scale spatial resolutions. Credit: Ella Maru Studio

Here’s a link to and a citation for the paper,

Multi-messenger nanoprobes of hidden magnetism in a strained manganite by A. S. McLeod, Jingdi Zhang, M. Q. Gu, F. Jin, G. Zhang, K. W. Post, X. G. Zhao, A. J. Millis, W. B. Wu, J. M. Rondinelli, R. D. Averitt & D. N. Basov. Nature Materials (2019) doi:10.1038/s41563-019-0533-y Published: 16 December 2019

This paper is behind a paywall.

The latest and greatest in gene drives (for flies)

This is a CRISPR (clustered regularly interspaced short palindromic repeats) story where the researchers are working on flies. If successful, this has much wider implications. From an April 10, 2019 news item on phys.org,

New CRISPR-based gene drives and broader active genetics technologies are revolutionizing the way scientists engineer the transfer of specific traits from one generation to another.

Scientists at the University of California San Diego have now developed a new version of a gene drive that opens the door to the spread of specific, favorable subtle genetic variants, also known as “alleles,” throughout a population.

The new “allelic drive,” described April 9 [2019] in Nature Communications, is equipped with a guide RNA (gRNA) that directs the CRISPR system to cut undesired variants of a gene and replace it with a preferred version of the gene. The new drive extends scientists’ ability to modify populations of organisms with precision editing. Using word processing as an analogy, CRISPR-based gene drives allow scientists to edit sentences of genetic information, while the new allelic drive offers letter-by-letter editing.

An April 9, 2019 University of California at San Diego (UCSD) news release (also on EurekAlert) by Mario Aguilera, which originated the news item, delves into this technique’s potential uses while further explaining the work


In one example of its potential applications, specific genes in agricultural pests that have become resistant to insecticides could be replaced by original natural genetic variants conferring sensitivity to insecticides using allelic drives that selectively swap the identities of a single protein residue (amino acid).

In addition to agricultural applications, disease-carrying insects could be a target for allelic drives.

“If we incorporate such a normalizing gRNA on a gene-drive element, for example, one designed to immunize mosquitoes against malaria, the resulting allelic gene drive will spread through a population. When this dual action drive encounters an insecticide-resistant allele, it will cut and repair it using the wild-type susceptible allele,” said Ethan Bier, the new paper’s senior author. “The result being that nearly all emerging progeny will be sensitive to insecticides as well as refractory to malaria transmission.”

“Forcing these species to return to their natural sensitive state using allelic drives would help break a downward cycle of ever-increasing and environmentally damaging pesticide over-use,” said Annabel Guichard, the paper’s first author.

The researchers describe two versions of the allelic drive, including “copy-cutting,” in which researchers use the CRISPR system to selectively cut the undesired version of a gene, and a more broadly applicable version referred to as “copy-grafting” that promotes transmission of a favored allele next to the site that is selectively protected from gRNA cleavage.

“An unexpected finding from this study is that mistakes created by such allelic drives do not get transmitted to the next generation,” said Guichard. “These mutations instead produce an unusual form of lethality referred to as ‘lethal mosaicism.’ This process helps make allelic drives more efficient by immediately eliminating unwanted mutations created by CRISPR-based drives.”

Although demonstrated in fruit flies, the new technology also has potential for broad application in insects, mammals and plants. According to the researchers, several variations of the allelic drive technology could be developed with combinations of favorable traits in crops that, for example, thrive in poor soil and arid environments to help feed the ever-growing world population.

Beyond environmental applications, allelic drives should enable next-generation engineering of animal models to study human disease as well as answer important questions in basic science. As a member of the Tata Institute for Genetics and Society (TIGS), Bier says allelic drives could be used to aid in environmental conservation efforts to protect vulnerable endemic species or stop the spread of invasive species.

Gene drives and active genetics systems are now being developed for use in mammals. The scientists say allelic drives could accelerate new laboratory strains of animal models of human disease that aid in the development of new cures.

Here’s a link to and a citation for the paper,

Efficient allelic-drive in Drosophila by Annabel Guichard, Tisha Haque, Marketta Bobik, Xiang-Ru S. Xu, Carissa Klanseck, Raja Babu Singh Kushwah, Mateus Berni, Bhagyashree Kaduskar, Valentino M. Gantz & Ethan Bier. Nature Communicationsvolume 10, Article number: 1640 (2019) DOI: https://doi.org/10.1038/s41467-019-09694-w Published 09 April 2019

This paper is open access.

For anyone new to gene drives, I have a February 8, 2018 posting that highlights a report from the UK on the latest in genetic engineering, which provides a definition for [synthetic] gene drives, and if you scroll down about 75% of the way, you’ll also find excerpts from an article for The Atlantic by Ed Yong on gene drives as proposed for a project in New Zealand.

Biohybrid cyborgs

Cyborgs are usually thought of as people who’ve been enhanced with some sort of technology, In contemporary real life that technology might be a pacemaker or hip replacement but in science fiction it’s technology such as artificial retinas (for example) that expands the range of visible light for an enhanced human.

Rarely does the topic of a microscopic life form come up in discussion about cyborgs and yet, that’s exactly what an April 3, 2019 Nanowerk spotlight article by Michael Berger describes in relationship to its use in water remediation efforts (Note: links have been removed),

Researchers often use living systems as inspiration for the design and engineering of micro- and nanoscale propulsion systems, actuators, sensors, and robots. …

“Although microrobots have recently proved successful for remediating decontaminated water at the laboratory scale, the major challenge in the field is to scale up these applications to actual environmental settings,” Professor Joseph Wang, Chair of Nanoengineering and Director, Center of Wearable Sensors at the University California San Diego, tells Nanowerk. “In order to do this, we need to overcome the toxicity of their chemical fuels, the short time span of biocompatible magnesium-based micromotors and the small domain operation of externally actuated microrobots.”

In their recent work on self-propelled biohybrid microrobots, Wang and his team were inspired by recent developments of biohybrid cyborgs that integrate self-propelling bacteria with functionalized synthetic nanostructures to transport materials.

“These tiny cyborgs are incredibly efficient for transport materials, but the limitation that we observed is that they do not provide large-scale fluid mixing,” notes Wang. ” We wanted to combine the best properties of both worlds. So, we searched for the best candidate to create a more robust biohybrid for mixing and we decided on using rotifers (Brachionus) as the engine of the cyborg.”

These marine microorganisms, which measure between 100 and 300 micrometers, are amazing creatures as they already possess sensing ability, energetic autonomy, and provide large-scale fluid mixing capability. They are also are very resilient and can survive in very harsh environments and even are one of the few organisms that have survived via asexual reproduction.

“Taking inspiration from the science fiction concept of a cybernetic organism, or cyborg – where an organism has enhanced abilities due to the integration of some artificial component – we developed a self-propelled biohybrid microrobot, that we named rotibot, employing rotifers as their engine,” says Fernando Soto, first author of a paper on this work (Advanced Functional Materials, “Rotibot: Use of Rotifers as Self-Propelling Biohybrid Microcleaners”).

This is the first demonstration of a biohybrid cyborg used for the removal and degradation of pollutants from solution. The technical breakthrough that allowed the team to achieve this task is based on a novel fabrication mechanism based on the selective accumulation of functionalized microbeads in the microorganism’s mouth: The rotifer serves not only as a transport vessel for active material or cargo but also acting as a powerful biological pump, as it creates fluid flows directed towards its mouth

Nanowerk has made this video demonstrating a rotifer available along with a description,

“The rotibot is a rotifer (a marine microorganism) that has plastic microbeads attached to the mouth, which are functionalized with pollutant-degrading enzymes. This video illustrates a free swimming rotibot mixing tracer particles in solution. “

Here’s a link to and a citation for the paper,

Rotibot: Use of Rotifers as Self‐Propelling Biohybrid Microcleaners by Fernando Soto, Miguel Angel Lopez‐Ramirez, Itthipon Jeerapan, Berta Esteban‐Fernandez de Avila, Rupesh, Kumar Mishra, Xiaolong Lu, Ingrid Chai, Chuanrui Chen, Daniel Kupor. Advanced Functional Materials DOI: https://doi.org/10.1002/adfm.201900658 First published: 28 March 2019

This paper is behind a paywall.

Berger’s April 3, 2019 Nanowerk spotlight article includes some useful images if you are interested in figuring out how these rotibots function.

Transparent graphene electrode technology and complex brain imaging

Michael Berger has written a May 24, 2018 Nanowerk Spotlight article about some of the latest research on transparent graphene electrode technology and the brain (Note: A link has been removed),

In new work, scientists from the labs of Kuzum [Duygu Kuzum, an Assistant Professor of Electrical and Computer Engineering at the University of California, San Diego {UCSD}] and Anna Devor report a transparent graphene microelectrode neural implant that eliminates light-induced artifacts to enable crosstalk-free integration of 2-photon microscopy, optogenetic stimulation, and cortical recordings in the same in vivo experiment. The new class of transparent brain implant is based on monolayer graphene. It offers a practical pathway to investigate neuronal activity over multiple spatial scales extending from single neurons to large neuronal populations.

Conventional metal-based microelectrodes cannot be used for simultaneous measurements of multiple optical and electrical parameters, which are essential for comprehensive investigation of brain function across spatio-temporal scales. Since they are opaque, they block the field of view of the microscopes and generate optical shadows impeding imaging.

More importantly, they cause light induced artifacts in electrical recordings, which can significantly interfere with neural signals. Transparent graphene electrode technology presented in this paper addresses these problems and allow seamless and crosstalk-free integration of optical and electrical sensing and manipulation technologies.

In their work, the scientists demonstrate that by careful design of key steps in the fabrication process for transparent graphene electrodes, the light-induced artifact problem can be mitigated and virtually artifact-free local field potential (LFP) recordings can be achieved within operating light intensities.

“Optical transparency of graphene enables seamless integration of imaging, optogenetic stimulation and electrical recording of brain activity in the same experiment with animal models,” Kuzum explains. “Different from conventional implants based on metal electrodes, graphene-based electrodes do not generate any electrical artifacts upon interacting with light used for imaging or optogenetics. That enables crosstalk free integration of three modalities: imaging, stimulation and recording to investigate brain activity over multiple spatial scales extending from single neurons to large populations of neurons in the same experiment.”

The team’s new fabrication process avoids any crack formation in the transfer process, resulting in a 95-100% yield for the electrode arrays. This fabrication quality is important for expanding this technology to high-density large area transparent arrays to monitor brain-scale cortical activity in large animal models or humans.

“Our technology is also well-suited for neurovascular and neurometabolic studies, providing a ‘gold standard’ neuronal correlate for optical measurements of vascular, hemodynamic, and metabolic activity,” Kuzum points out. “It will find application in multiple areas, advancing our understanding of how microscopic neural activity at the cellular scale translates into macroscopic activity of large neuron populations.”

“Combining optical techniques with electrical recordings using graphene electrodes will allow to connect the large body of neuroscience knowledge obtained from animal models to human studies mainly relying on electrophysiological recordings of brain-scale activity,” she adds.

Next steps for the team involve employing this technology to investigate coupling and information transfer between different brain regions.

This work is part of the US BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative and there’s more than one team working with transparent graphene electrodes. John Hewitt in an Oct. 21, 2014 posting on ExtremeTech describes two other teams’ work (Note: Links have been removed),

The solution [to the problems with metal electrodes], now emerging from multiple labs throughout the universe is to build flexible, transparent electrode arrays from graphene. Two studies in the latest issue of Nature Communications, one from the University of Wisconsin-Madison and the other from Penn [University of Pennsylvania], describe how to build these devices.

The University of Wisconsin researchers are either a little bit smarter or just a little bit richer, because they published their work open access. It’s a no-brainer then that we will focus on their methods first, and also in more detail. To make the arrays, these guys first deposited the parylene (polymer) substrate on a silicon wafer, metalized it with gold, and then patterned it with an electron beam to create small contact pads. The magic was to then apply four stacked single-atom-thick graphene layers using a wet transfer technique. These layers were then protected with a silicon dioxide layer, another parylene layer, and finally molded into brain signal recording goodness with reactive ion etching.

PennTransparentelectrodeThe researchers went with four graphene layers because that provided optimal mechanical integrity and conductivity while maintaining sufficient transparency. They tested the device in opto-enhanced mice whose neurons expressed proteins that react to blue light. When they hit the neurons with a laser fired in through the implant, the protein channels opened and fired the cell beneath. The masterstroke that remained was then to successfully record the electrical signals from this firing, sit back, and wait for the Nobel prize office to call.

The Penn State group [Note: Every reearcher mentioned in the paper Hewitt linked to is from the University of Pennsylvania] in the  used a similar 16-spot electrode array (pictured above right), and proceeded — we presume — in much the same fashion. Their angle was to perform high-resolution optical imaging, in particular calcium imaging, right out through the transparent electrode arrays which simultaneously recorded in high-temporal-resolution signals. They did this in slices of the hippocampus where they could bring to bear the complex and multifarious hardware needed to perform confocal and two-photon microscopy. These latter techniques provide a boost in spatial resolution by zeroing in over narrow planes inside the specimen, and limiting the background by the requirement of two photons to generate an optical signal. We should mention that there are voltage sensitive dyes available, in addition to standard calcium dyes, which can almost record the fastest single spikes, but electrical recording still reigns supreme for speed.

What a mouse looks like with an optogenetics system plugged in

What a mouse looks like with an optogenetics system plugged in

One concern of both groups in making these kinds of simultaneous electro-optic measurements was the generation of light-induced artifacts in the electrical recordings. This potential complication, called the Becqueral photovoltaic effect, has been known to exist since it was first demonstrated back in 1839. When light hits a conventional metal electrode, a photoelectrochemical (or more simply, a photovoltaic) effect occurs. If present in these recordings, the different signals could be highly disambiguatable. The Penn researchers reported that they saw no significant artifact, while the Wisconsin researchers saw some small effects with their device. In particular, when compared with platinum electrodes put into the opposite side cortical hemisphere, the Wisconsin researchers found that the artifact from graphene was similar to that obtained from platinum electrodes.

Here’s a link to and a citation for the latest research from UCSD,

Deep 2-photon imaging and artifact-free optogenetics through transparent graphene microelectrode arrays by Martin Thunemann, Yichen Lu, Xin Liu, Kıvılcım Kılıç, Michèle Desjardins, Matthieu Vandenberghe, Sanaz Sadegh, Payam A. Saisan, Qun Cheng, Kimberly L. Weldy, Hongming Lyu, Srdjan Djurovic, Ole A. Andreassen, Anders M. Dale, Anna Devor, & Duygu Kuzum. Nature Communicationsvolume 9, Article number: 2035 (2018) doi:10.1038/s41467-018-04457-5 Published: 23 May 2018

This paper is open access.

You can find out more about the US BRAIN initiative here and if you’re curious, you can find out more about the project at UCSD here. Duygu Kuzum (now at UCSD) was at  the University of Pennsylvania in 2014 and participated in the work mentioned in Hewitt’s 2014 posting.

Humans can distinguish molecular differences by touch

Yesterday, in my December 18, 2017 post about medieval textiles, I posed the question, “How did medieval artisans create nanoscale and microscale gilding when they couldn’t see it?” I realized afterwards that an answer to that question might be in this December 13, 2017 news item on ScienceDaily,

How sensitive is the human sense of touch? Sensitive enough to feel the difference between surfaces that differ by just a single layer of molecules, a team of researchers at the University of California San Diego has shown.

“This is the greatest tactile sensitivity that has ever been shown in humans,” said Darren Lipomi, a professor of nanoengineering and member of the Center for Wearable Sensors at the UC San Diego Jacobs School of Engineering, who led the interdisciplinary project with V. S. Ramachandran, director of the Center for Brain and Cognition and distinguished professor in the Department of Psychology at UC San Diego.

So perhaps those medieval artisans were able to feel the difference before it could be seen in the textiles they were producing?

Getting back to the matter at hand, a December 13, 2017 University of California at San Diego (UCSD) news release (also on EurekAlert) by Liezel Labios offers more detail about the work,

Humans can easily feel the difference between many everyday surfaces such as glass, metal, wood and plastic. That’s because these surfaces have different textures or draw heat away from the finger at different rates. But UC San Diego researchers wondered, if they kept all these large-scale effects equal and changed only the topmost layer of molecules, could humans still detect the difference using their sense of touch? And if so, how?

Researchers say this fundamental knowledge will be useful for developing electronic skin, prosthetics that can feel, advanced haptic technology for virtual and augmented reality and more.

Unsophisticated haptic technologies exist in the form of rumble packs in video game controllers or smartphones that shake, Lipomi added. “But reproducing realistic tactile sensations is difficult because we don’t yet fully understand the basic ways in which materials interact with the sense of touch.”

“Today’s technologies allow us to see and hear what’s happening, but we can’t feel it,” said Cody Carpenter, a nanoengineering Ph.D. student at UC San Diego and co-first author of the study. “We have state-of-the-art speakers, phones and high-resolution screens that are visually and aurally engaging, but what’s missing is the sense of touch. Adding that ingredient is a driving force behind this work.”

This study is the first to combine materials science and psychophysics to understand how humans perceive touch. “Receptors processing sensations from our skin are phylogenetically the most ancient, but far from being primitive they have had time to evolve extraordinarily subtle strategies for discerning surfaces—whether a lover’s caress or a tickle or the raw tactile feel of metal, wood, paper, etc. This study is one of the first to demonstrate the range of sophistication and exquisite sensitivity of tactile sensations. It paves the way, perhaps, for a whole new approach to tactile psychophysics,” Ramachandran said.

Super-Sensitive Touch

In a paper published in Materials Horizons, UC San Diego researchers tested whether human subjects could distinguish—by dragging or tapping a finger across the surface—between smooth silicon wafers that differed only in their single topmost layer of molecules. One surface was a single oxidized layer made mostly of oxygen atoms. The other was a single Teflon-like layer made of fluorine and carbon atoms. Both surfaces looked identical and felt similar enough that some subjects could not differentiate between them at all.

According to the researchers, human subjects can feel these differences because of a phenomenon known as stick-slip friction, which is the jerking motion that occurs when two objects at rest start to slide against each other. This phenomenon is responsible for the musical notes played by running a wet finger along the rim of a wine glass, the sound of a squeaky door hinge or the noise of a stopping train. In this case, each surface has a different stick-slip frequency due to the identity of the molecules in the topmost layer.

In one test, 15 subjects were tasked with feeling three surfaces and identifying the one surface that differed from the other two. Subjects correctly identified the differences 71 percent of the time.

In another test, subjects were given three different strips of silicon wafer, each strip containing a different sequence of 8 patches of oxidized and Teflon-like surfaces. Each sequence represented an 8-digit string of 0s and 1s, which encoded for a particular letter in the ASCII alphabet. Subjects were asked to “read” these sequences by dragging a finger from one end of the strip to the other and noting which patches in the sequence were the oxidized surfaces and which were the Teflon-like surfaces. In this experiment, 10 out of 11 subjects decoded the bits needed to spell the word “Lab” (with the correct upper and lowercase letters) more than 50 percent of the time. Subjects spent an average of 4.5 minutes to decode each letter.

“A human may be slower than a nanobit per second in terms of reading digital information, but this experiment shows a potentially neat way to do chemical communications using our sense of touch instead of sight,” Lipomi said.

Basic Model of Touch

The researchers also found that these surfaces can be differentiated depending on how fast the finger drags and how much force it applies across the surface. The researchers modeled the touch experiments using a “mock finger,” a finger-like device made of an organic polymer that’s connected by a spring to a force sensor. The mock finger was dragged across the different surfaces using multiple combinations of force and swiping velocity. The researchers plotted the data and found that the surfaces could be distinguished given certain combinations of velocity and force. Meanwhile, other combinations made the surfaces indistinguishable from each other.

“Our results reveal a remarkable human ability to quickly home in on the right combinations of forces and swiping velocities required to feel the difference between these surfaces. They don’t need to reconstruct an entire matrix of data points one by one as we did in our experiments,” Lipomi said.

“It’s also interesting that the mock finger device, which doesn’t have anything resembling the hundreds of nerves in our skin, has just one force sensor and is still able to get the information needed to feel the difference in these surfaces. This tells us it’s not just the mechanoreceptors in the skin, but receptors in the ligaments, knuckles, wrist, elbow and shoulder that could be enabling humans to sense minute differences using touch,” he added.

This work was supported by member companies of the Center for Wearable Sensors at UC San Diego: Samsung, Dexcom, Sabic, Cubic, Qualcomm and Honda.

For those who prefer their news by video,

Here’s a link to and a citation for the paper,

Human ability to discriminate surface chemistry by touch by Cody W. Carpenter, Charles Dhong, Nicholas B. Root, Daniel Rodriquez, Emily E. Abdo, Kyle Skelil, Mohammad A. Alkhadra, Julian Ramírez, Vilayanur S. Ramachandran and Darren J. Lipomi. Mater. Horiz., 2018, Advance Article DOI: 10.1039/C7MH00800G

This paper is open access but you do need to have opened a free account on the website.

Mimicking the sea urchin’s mouth and teeth for space exploration

Researchers at the University of California at San Diego (UCSD) have designed a new device for use in space exploration that is based on the structure and mechanics of a sea urchin’s mouth and teeth. From a May 2, 2016 news item on ScienceDaily,

The sea urchin’s intricate mouth and teeth are the model for a claw-like device developed by a team of engineers and marine biologists at the University of California, San Diego to sample sediments on other planets, such as Mars. The researchers detail their work in a recent issue of the Journal of Visualized Experiments.

A May 2, 2016 UCSD press release (also on EurekAlert), which originated the news item, expands on the theme by hearkening back to Aristotle (a Greek philosopher),

The urchin’s mouthpiece was first described in detail by the Greek philosopher Aristotle, earning it the nickname “Aristotle’s lantern.” It is comprised of an intricate framework of muscles and five curved teeth with triangle-shaped tips that can scrape, cut, chew and bore holes into the toughest rocks—a colony of sea urchins can destroy an entire kelp forest by churning through rock and uprooting seaweed.  The teeth are arranged in a dome-like formation that opens outwards and closes inwards in a smooth motion, similar to a claw in an arcade prize-grabbing machine.

The news release goes on to describe the methodology,

Bio-inspiration for the study came from pink sea urchins (Strongylocentrotus fragilis), which live off the West Coast of North America, at depths ranging from 100 to 1000 meters in the Pacific Ocean. The urchins were collected for scientific research by the Scripps Institution of Oceanography at UC San Diego.

Researchers extracted the urchins’ mouthpieces, scanned them with microCT, essentially a 3D microscopy technique, and analyzed the structures at the National Center for Microscopy and Imaging Research at the School of Medicine at UC San Diego. This allowed engineers to build a highly accurate model of the mouthpiece’s geometry.

Researchers also used finite element analysis to investigate the structure of the teeth, a method that allowed them to determine the importance of the keel to the teeth’s performance.

Engineers then turned the microCT data into a user-friendly file that a team of undergraduate engineering students at UC San Diego used to start iterating prototypes of the claw-like device, under the supervision of Ph.D. students in McKittrick’s lab.

The first iteration was very close to the mouthpiece’s natural structure, but didn’t do a very good job at grasping sand.  In the second iteration, students flattened the pointed end of the teeth so the device would scoop up sand better. But the device wasn’t opening quite right. Finally, on the third iteration, they connected the teeth differently to the rest of the device, which allowed it to open much easier. The students were able to quickly modify each prototype by using 3D printers in the UC San Diego Design Studio.

The device was then attached to a remote-controlled small rover. The researchers first tested the claw on beach sand, where it performed well. They then used the claw on sand that simulates Martian soil in density and humidity (or lack thereof). The device was able to scoop up sand efficiently. Researchers envision a fleet of mini rovers equipped with the claw that could be deployed to collect samples and bring them back to a main rover. Frank hopes that this design will be of interest to NASA [US National Aeronautics and Space Administraton] and SpaceX [a private enterprise for designing, manufacturing, and launching craft bound for space].

Here’s a link to and a citation for the paper,

A Protocol for Bioinspired Design: A Ground Sampler Based on Sea Urchin Jaws by Michael B. Frank, Steven E. Naleway, Taylor S. Wirth, Jae-Young Jung, Charlene L. Cheung, Faviola B. Loera, Sandra Medina, Kirk N. Sato, Jennifer R. A. Taylor, Joanna McKittrick. Journal of Visualized Experiments, 2016; (110) DOI: 10.3791/53554 Date Published: 4/24/2016

This paper and its video are behind a paywall. For those unfamiliar with the Journal of Visualized Experiments (JOVE), it is focused largely on videos which demonstrate the various techniques and protocols being described in the accompanying papers.

The researchers have made an introductory video available courtesy of UCSD,