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Biophysics: Geometry supersedes simulations

Ludwig-Maximilians-Universitaet (LMU) in Munich physicists have introduced a new method that allows biological pattern-forming systems to be systematically characterized with the aid of mathematical analysis. The trick lies in the use of geometry to characterize the dynamics.

Many vital processes that take place in biological cells depend on the formation of self-organizing molecular patterns. For example, defined spatial distributions of specific proteins regulate cell division, cell migration and cell growth. These patterns result from the concerted interactions of many individual macromolecules. Like the collective motions of bird flocks, these processes do not need a central coordinator. Hitherto, mathematical modelling of protein pattern formation in cells has been carried out largely by means of elaborate computer-based simulations. Now, LMU physicists led by Professor Erwin Frey report the development of a new method which provides for the systematic mathematical analysis of pattern formation processes, and uncovers the their underlying physical principles. The new approach is described and validated in a paper that appears in the journal Physical Review X.

The study focuses on what are called ‘mass-conserving’ systems, in which the interactions affect the states of the particles involved, but do not alter the total number of particles present in the system. This condition is fulfilled in systems in which proteins can switch between different conformational states that allow them to bind to a cell membrane or to form different multicomponent complexes, for example. Owing to the complexity of the nonlinear dynamics in these systems, pattern formation has so far been studied with the aid of time-consuming numerical simulations. “Now we can understand the salient features of pattern formation independently of simulations using simple calculations and geometrical constructions,” explains Fridtjof Brauns, lead author of the new paper. “The theory that we present in this report essentially provides a bridge between the mathematical models and the collective behavior of the system’s components.”

The key insight that led to the theory was the recognition that alterations in the local number density of particles will also shift the positions of local chemical equilibria. These shifts in turn generate concentration gradients that drive the diffusive motions of the particles. The authors capture this dynamic interplay with the aid of geometrical structures that characterize the global dynamics in a multidimensional ‘phase space’. The collective properties of systems can be directly derived from the topological relationships between these geometric constructs, because these objects have concrete physical meanings — as representations of the trajectories of shifting chemical equilibria, for instance. “This is the reason why our geometrical description allows us to understand why the patterns we observe in cells arise. In other words, they reveal the physical mechanisms that determine the interplay between the molecular species involved,” says Frey. “Furthermore, the fundamental elements of our theory can be generalized to deal with a wide range of systems, which in turn paves the way to a comprehensive theoretical framework for self-organizing systems.”

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Bio-based communication networks could control cells in the body to treat conditions

Like electronic devices, biological cells send and receive messages, but they communicate through very different mechanisms. Now, scientists report progress on tiny communication networks that overcome this language barrier, allowing electronics to eavesdrop on cells and alter their behavior — and vice versa. These systems could enable applications including a wearable device that could diagnose and treat a bacterial infection or a capsule that could be swallowed to track blood sugar and make insulin when needed.

The researchers will present their results today at the American Chemical Society (ACS) Fall 2020 Virtual Meeting & Expo.

“We want to expand electronic information processing to include biology,” says principal investigator William E. Bentley, Ph.D. “Our goal is to incorporate biological cells in the computational decision-making process.”

The new technology Bentley’s team developed relies on redox mediators, which move electrons around cells. These small molecules carry out cellular activities by accepting or giving up electrons through reduction or oxidation reactions. Because they can also exchange electrons with electrodes, thereby producing a current, redox mediators can bridge the gap between hardware and living tissue. In ongoing work, the team, which includes co-principal investigator Gregory F. Payne, Ph.D., is developing interfaces to enable this information exchange, opening the way for electronic control of cellular behavior, as well as cellular feedback that could operate electronics.

“In one project that we are reporting on at the meeting, we engineered cells to receive electronically generated information and transmit it as molecular cues,” says Eric VanArsdale, a graduate student in Bentley’s lab at the University of Maryland, who is presenting the latest results at the meeting. The cells were designed to detect and respond to hydrogen peroxide. When placed near a charged electrode that generated this redox mediator, the cells produced a corresponding amount of a quorum sensing molecule that bacteria use to signal to each other and modulate behavior by altering gene expression.

In another recent project, the team engineered two types of cells to receive molecular information from the pathogenic bacteria Pseudomonas aeruginosa and convert it into an electronic signal for diagnostic and other applications. One group of cells produced the amino acid tyrosine, and another group made tyrosinase, which converts tyrosine into a molecule called L-DOPA. The cells were engineered so this redox mediator would be produced only if the bacteria released both a quorum sensing molecule and a toxin associated with a virulent stage of P. aeruginosa growth. The size of the resulting current generated by L-DOPA indicated the amount of bacteria and toxin present in a sample. If used in a blood test, the technique could reveal an infection and also gauge its severity. Because this information would be in electronic form, it could be wirelessly transmitted to a doctor’s office and a patient’s cell phone to inform them about the infection, Bentley says. “Ultimately, we could engineer it so that a wearable device would be triggered to give the patient a therapeutic after an infection is detected.”

The researchers envision eventually integrating the communication networks into autonomous systems in the body. For instance, a diabetes patient could swallow a capsule containing cells that monitor blood sugar. The device would store this blood sugar data and periodically send it to a cell phone, which would interpret the data and send back an electronic signal directing other cells in the capsule to make insulin as needed. As a step toward this goal, VanArsdale developed a biological analog of computer memory that uses the natural pigment melanin to store information and direct cellular signaling.

In other work, Bentley’s team and collaborators including Reza Ghodssi, Ph.D., recently designed a system to monitor conditions inside industrial bioreactors that hold thousands of gallons of cell culture for drug production. Currently, manufacturers track oxygen levels, which are vital to cells’ productivity, with a single probe in the side of each vessel. That probe can’t confirm conditions are uniform everywhere in the bioreactor, so the researchers developed “smart marbles” that will circulate throughout the vessel measuring oxygen. The marbles transmit data via Bluetooth to a cell phone that could adjust operating conditions. In the future, these smart marbles could serve as a communication interface to detect chemical signals within a bioreactor, send that information to a computer, and then transmit electronic signals to direct the behavior of engineered cells in the bioreactor. The team is working with instrument makers interested in commercializing the design, which could be adapted for environmental monitoring and other uses.

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Nanocatalysts that remotely control chemical reactions inside living cells

The enzymes responsible for catalytic reactions in our body’s biological reactions are difficult to use for diagnosis or treatment as they react only to certain molecules or have low stability. Many researchers anticipate that if these issues are ameliorated or if artificial catalysts are developed to create a synergetic effect by meeting the enzymes in the body, there will be new ways to diagnose and treat diseases. In particular, if artificial catalysts that respond to external stimuli such as magnetic fields are developed, new treatment methods that remotely control bioreactions from outside the body can become a reality.

The research team led by Professor In Su Lee of the Department of Chemistry at POSTECH has developed a remote magnetic-sensitive artificial catalyst called MAG-NER, which shows high catalytic efficiency within living cells. The study was published as the supplementary cover paper for Nano Letters, an international journal on nanotechnology.

The research team mimicked the structure of vesicles, an organelle within a cell, and synthesized a magnetic-catalyst-combined nanoreactor with iron-oxide nanoparticles and palladium catalysts inside a hollow silica nanoshell.

When MAG-NER encounters an alternating magnetic field, iron-oxide nanoparticles inside cause magnetic field-induced heat and activate only the palladium catalyst without raising the exterior temperature. The research team succeeded in implementing the catalytic reaction with high efficiency, which transforms non-fluorescent reactants into fluorescent products through implanting MAG-NER into living cells then applying alternating magnetic fields. The research team also confirmed that the catalyst of MAG-NER can remain active for long periods of time without being contaminated by biomolecules in cells and does not affect the cells’ survival.

Using MAG-NER, it is anticipated that diagnosis and treatment methods, that can artificially remote control the cell’s functions, can be developed as artificial molecules can be synthesized or chemical reactions can be induced within cells using magnetic fields that are harmless to the body.

Professor In Su Lee who led the research explained, “This research is a result of utilizing the hallow nanoreactor materials that our lab has been developing over the years and is valued as an innovative chemical tool that will advance biomedical and biological research.”

This research was conducted with the support from the National Research Foundation’s Research Leader Program (Creative Research).

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Photonic crystal light converter

Spectroscopy is the use of light to analyze physical objects and biological samples. Different kinds of light can provide different kinds of information. Vacuum ultraviolet light is useful as it can aid people in a broad range of research fields, but generation of that light has been difficult and expensive. Researchers created a new device to efficiently generate this special kind of light using an ultrathin film with nanoscale perforations.

The wavelengths of light you see with your eyes constitute a mere fraction of the possible wavelengths of light that exist. There’s infrared light which you can feel in the form of heat, or see if you happen to be a snake, that has a longer wavelength than visible light. At the opposite end is ultraviolet (UV) light which you can use to produce vitamin D in your skin, or see if you happen to be a bee. These and other forms of light have many uses in science.

Within the UV range is a subset of wavelengths known as vacuum ultraviolet light (VUV), so called because they are easily absorbed by air but can pass through a vacuum. Some VUV wavelengths in the region of around 120-200 nanometers are of particular use to scientists and medical researchers as they can be used for chemical and physical analyses of different materials and even biological samples.

However, there is more to light than a wavelength. For VUV to be truly useful, it also needs to be twisted or polarized in a manner called circular polarization. Existing methods to produce VUV, such as using particle accelerators or laser-driven plasmas, have many drawbacks, including cost, scale and complexity. But also, these can only produce untwisted linear polarized VUV. If there was a simple way to make circular polarized VUV, it would be extremely beneficial. Assistant Professor Kuniaki Konishi from the Institute for Photon Science and Technology at the University of Tokyo and his team may just have the answer.

“We have created a simple device to convert circularly polarized visible laser light into circularly polarized VUV, twisted in the opposite direction,” said Konishi. “Our photonic crystal dielectric nanomembrane (PCN) consists of a sheet made from an aluminium oxide-based crystal (?-Al2O3) only 48 nm thick. It sits atop a 525 micrometer-thick sheet of silicon which has 190 nm-wide holes cut into it 600 nm apart.”

To our eyes the PCN membrane just looks like a flat featureless surface, but under a powerful microscope the pattern of perforations can be seen. It looks a little like the holes in a showerhead which increase the water pressure to make jets.

“When pulses of circularly polarized blue laser light with a wavelength of 470 nm shine down these channels in the silicon, the PCN acts on these pulses and twists them in the opposing direction,” said Konishi. “It also shrinks their wavelengths to 157 nm which is well within the range of VUV that is so useful in spectroscopy.”

With short pulses of circularly polarized VUV, researchers can observe fast or short-lived physical phenomena at the submicrometer scale that are otherwise impossible to see. Such phenomena include the behaviors of electrons or biomolecules. So this new method to generate VUV can be useful to researchers in medicine, life sciences, molecular chemistry and solid state physics. Although a similar method has been demonstrated before, it produced less useful longer wavelengths, and did so using a metal-based film which is subject to rapid degradation in the presence of laser light. PCN is far more robust to this.

“I am pleased that through our study of PCN, we found a new and useful application for circularly polarized light conversion, generating VUV with the intensity required to make it ideal for spectroscopy,” said Konishi. “And it was surprising that the PCN membrane could survive the repeated bombardment of laser light, unlike previous metal-based devices. This makes it suitable for lab use where it may be used extensively over long periods. We did this for basic science and I hope to see many kinds of researchers make good use of our work.”

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Quantum body scanner? What happens when vector vortex beams meet scattering media

Propagate light through any kind of medium — be it free space or biological tissue — and light will scatter. Robustness to scattering is a common requirement for communications and for imaging systems. Structured light, with its use of projected patterns, is resistant to scattering, and has therefore emerged as a versatile tool. In particular, modes of structured light carrying orbital angular momentum (OAM) have attracted significant attention for applications in biomedical imaging.

OAM is an internal property of light conferring a characteristic doughnut shape to the spatial profile. The polarization profile of OAM modes of light can also be structured. Superimpose two OAM modes, and you can get a vector vortex beam (VVB) characterized by a doughnut intensity distribution in the beam cross-section, and with spatially variant polarization. VVBs are considered suitable and advantageous for quantum applications in medical technology.

An innovative cancer scanner

An international team of researchers recently published a comprehensive study of VVB transmission in scattering media. The team is collaborating under the aegis of the European Union’s FET-OPEN project Cancer Scan, which proposes to develop a radically new unified technological concept of biomedical detection deploying new ideas in quantum optics and quantum mechanics. The new concept is based on unified transmission and detection of photons in a three-dimensional space of orbital angular momentum, entanglement, and hyperspectral characteristics. Theoretically, these elements can contribute to developing a scanner that can screen for cancer and detect it in a single scan of the body, without any risk of radiation.

As explained in their report, the team implemented a flexible platform to generate VVBs and Gaussian beams, and investigated their propagation through a medium that mimics the features of biological tissue. They demonstrate and analyze the degradation of both the spatial profile and polarization pattern of the different modes of light.

Ready, aim, scatter

For both Gaussian beams and VVBs, the authors remark that spatial profiles undergo an abrupt change as the concentration of the medium increases beyond 0.09%: a sudden swift decrease in contrast. The authors observe that the change is due to the presence of a uniform background caused by the scattered components of the beams.

Investigating the polarization profiles, they found that VVB behavior is quite different from that of the Gaussian beams. Gaussian beams present a uniform polarization pattern that is unaffected by the scattering process. In contrast, VVBs present a complex distribution of polarization on the transverse plane. The team observed that a portion of the VVB signal becomes completely depolarized when it passes through scattering media, but a portion of the signal preserves its structure.

These insights into how interaction with scattering media can affect the behavior of structured OAM light represent a step forward in exploring how it may interact with biological tissue. The team hopes that their comprehensive study will stimulate further investigation into the effects of light-scattering tissue-mimicking media, to advance the quest for innovative biomedical detection technology.

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New molecular tool precisely edits mitochondrial DNA

The genome in mitochondria — the cell’s energy-producing organelles — is involved in disease and key biological functions, and the ability to precisely alter this DNA would allow scientists to learn more about the effects of these genes and mutations. But the precision editing technologies that have revolutionized DNA editing in the cell nucleus have been unable to reach the mitochondrial genome.

Now, a team at the Broad Institute of MIT and Harvard and the University of Washington School of Medicine has broken this barrier with a new type of molecular editor that can make precise C* G-to-T* A nucleotide changes in mitochondrial DNA. The editor, engineered from a bacterial toxin, enables modeling of disease-associated mitochondrial DNA mutations, opening the door to a better understanding of genetic changes associated with cancer, aging, and more.

The work is described in Nature, with co-first authors Beverly Mok, a graduate student from the Broad Institute and Harvard University, and Marcos de Moraes, a postdoctoral fellow at the University of Washington (UW).

The work was jointly supervised by Joseph Mougous, UW professor of microbiology and an investigator at the Howard Hughes Medical Institute (HHMI), and David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute, professor of chemistry and chemical biology at Harvard University, and HHMI investigator.

“The team has developed a new way of manipulating DNA and used it to precisely edit the human mitochondrial genome for the first time, to our knowledge — providing a solution to a long-standing challenge in molecular biology,” said Liu. “The work is a testament to collaboration in basic and applied research, and may have further applications beyond mitochondrial biology.”

Agent of bacterial warfare

Most current approaches to studying specific variations in mitochondrial DNA involve using patient-derived cells, or a small number of animal models, in which mutations have occurred by chance. “But these methods pose major limitations, and creating new, defined models has been impossible,” said co-author Vamsi Mootha, institute member and co-director of the Metabolism Program at Broad. Mootha is also an HHMI investigator and professor of medicine at Massachusetts General Hospital.

While CRISPR-based technologies can rapidly and precisely edit DNA in the cell nucleus, greatly facilitating model creation for many diseases, these tools haven’t been able to edit mitochondrial DNA because they rely on a guide RNA to target a location in the genome. The mitochondrial membrane allows proteins to enter the organelle, but is not known to have accessible pathways for transporting RNA.

One piece of a potential solution arose when the Mougous lab identified a toxic protein made by the pathogen Burkholderia cenocepacia. This protein can kill other bacteria by directly changing cytosine (C) to uracil (U) in double-stranded DNA.

“What is special about this protein, and what suggested to us that it might have unique editing applications, is its ability to target double-stranded DNA. All previously described deaminases that target DNA work only on the single-stranded form, which limits how they can be used as genome editors,” said Mougous. His team determined the structure and biochemical characteristics of the toxin, called DddA.

“We realized that the properties of this ‘bacterial warfare agent’ could allow it to be paired with a non-CRISPR-based DNA-targeting system, raising the possibility of making base editors that do not rely on CRISPR or on guide RNAs,” explained Liu. “It could enable us to finally perform precision genome editing in one of the last corners of biology that has remained untouchable by such technology — mitochondrial DNA.”

“Taming the beast”

The team’s first major challenge was to eliminate the toxicity of the bacterial agent — what Liu described to Mougous as “taming the beast” — so that it could edit DNA without damaging the cell. The researchers divided the protein into two inactive halves that could edit DNA only when they combined.

The researchers tethered the two halves of the tamed bacterial toxin to TALE DNA-binding proteins, which can locate and bind a target DNA sequence in both the nucleus and mitochondria without the use of a guide RNA. When these pieces bind DNA next to each other, the complex reassembles into its active form, and converts C to U at that location — ultimately resulting in a C* G-to-T* A base edit. The researchers called their tool a DddA-derived cytosine base editor (DdCBE).

The team tested DdCBE on five genes in the mitochondrial genome in human cells and found that DdCBE installed precise base edits in up to 50 percent of the mitochondrial DNA. They focused on the gene ND4, which encodes a subunit of the mitochondrial enzyme complex I, for further characterization. Mootha’s lab analyzed the mitochondrial physiology and chemistry of the edited cells and showed that the changes affected mitochondria as intended.

“This is the first time in my career that we’ve been able to engineer a precise edit in mitochondrial DNA,” said Mootha. “It’s a quantum leap forward — if we can make targeted mutations, we can develop models to study disease-associated variants, determine what role they actually play in disease, and screen the effects of drugs on the pathways involved.”

Future developments

One goal for the field now will be to develop editors that can precisely make other types of genetic changes in mitochondrial DNA.

“A mitochondrial genome editor has the long-term potential to be developed into a therapeutic to treat mitochondrial-derived diseases, and it has more immediate value as a tool that scientists can use to better model mitochondrial diseases and explore fundamental questions pertaining to mitochondrial biology and genetics,” Mougous said.

The team added that some features of DdCBE, such as its lack of RNA, may also be attractive for other gene-editing applications beyond the mitochondria.

This work was supported in part by the Merkin Institute of Transformative Technologies in Healthcare, NIH (R01AI080609, U01AI142756, RM1HG009490, R35GM122455, R35GM118062, and P30DK089507), Defense Threat Reduction Agency (1-13-1-0014), and University of Washington Cystic Fibrosis Foundation

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Measuring a tiny quasiparticle is a major step forward for semiconductor technology

A team of researchers led by Sufei Shi, an assistant professor of chemical and biological engineering at Rensselaer Polytechnic Institute, has uncovered new information about the mass of individual components that make up a promising quasiparticle, known as an exciton, that could play a critical role in future applications for quantum computing, improved memory storage, and more efficient energy conversion.

Published today in Nature Communications, the team’s work brings researchers one step closer to advancing the development of semiconductor devices by deepening their understanding of an atomically thin class of materials known as transitional metal dichalcogenides (TMDCs), which have been eyed for their electronic and optical properties. Researchers still have a lot to learn about the exciton before TMDCs can successfully be used in technological devices.

Shi and his team have become leaders in that pursuit, developing and studying TMDCs, and the exciton in particular. Excitons are typically generated by energy from light and form when a negatively charged electron bonds with a positively charged hole particle.

The Rensselaer team found that within this atomically thin semiconductor material, the interaction between electrons and holes can be so strong that the two particles within an exciton can bond with a third electron or hole particle to form a trion.

In this new study, Shi’s team was able to manipulate the TMDCs material so the crystalline lattice within would vibrate, creating another type of quasiparticle known as a phonon, which will strongly interact with a trion. The researchers then placed the material within a high magnetic field, analyzed the light emitted from the TMDCs from the phonon interaction, and were able to determine the effective mass of the electron and hole individually.

Researchers previously assumed there would be symmetry in mass, but, Shi said, the Rensselaer team found these measurements were significantly different.

“We have developed a lot of knowledge about TMDCs now,” Shi said. “But in order to design an electronic or optoelectronic device, it is essential to know the effective mass of the electrons and holes. This work is one solid step toward that goal.”

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Artificial pieces of brain use light to communicate with real neurons

Researchers have created a way for artificial neuronal networks to communicate with biological neuronal networks. The new system converts artificial electrical spiking signals to a visual pattern than is then used to entrain the real neurons via optogenetic stimulation of the network. This advance will be important for future neuroprosthetic devices that replace damages neurons with artificial neuronal circuitry.

A prosthesis is an artificial device that replaces an injured or missing part of the body. You can easily imagine a stereotypical pirate with a wooden leg or Luke Skywalker’s famous robotic hand. Less dramatically, think of old-school prosthetics like glasses and contact lenses that replace the natural lenses in our eyes. Now try to imagine a prosthesis that replaces part of a damaged brain. What could artificial brain matter be like? How would it even work?

Creating neuroprosthetic technology is the goal of an international team led by by the Ikerbasque Researcher Paolo Bonifazi from Biocruces Health Research Institute (Bilbao, Spain), and Timothée Levi from Institute of Industrial Science, The University of Tokyo and from IMS lab, University of Bordeaux. Although several types of artificial neurons have been developed, none have been truly practical for neuroprostheses. One of the biggest problems is that neurons in the brain communicate very precisely, but electrical output from the typical electrical neural network is unable to target specific neurons. To overcome this problem, the team converted the electrical signals to light. As Levi explains, “advances in optogenetic technology allowed us to precisely target neurons in a very small area of our biological neuronal network.”

Optogenetics is a technology that takes advantage of several light-sensitive proteins found in algae and other animals. Inserting these proteins into neurons is a kind of hack; once they are there, shining light onto a neuron will make it active or inactive, depending on the type of protein. In this case, the researchers used proteins that were activated specifically by blue light. In their experiment, they first converted the electrical output of the spiking neuronal network into the checkered pattern of blue and black squares. Then, they shined this pattern down onto a 0.8 by 0.8 mm square of the biological neuronal network growing in the dish. Within this square, only neurons hit by the light coming from the blue squares were directly activated.

Spontaneous activity in cultured neurons produces synchronous activity that follows a certain kind of rhythm. This rhythm is defined by the way the neurons are connected together, the types of neurons, and their ability to adapt and change.

“The key to our success,” says Levi, “was understanding that the rhythms of the artificial neurons had to match those of the real neurons. Once we were able to do this, the biological network was able to respond to the “melodies” sent by the artificial one. Preliminary results obtained during the European Brainbow project, help us to design these biomimetic artificial neurons.”

They tuned the artificial neuronal network to use several different rhythms until they found the best match. Groups of neurons were assigned to specific pixels in the image grid and the rhythmic activity was then able to change the visual pattern that was shined onto the cultured neurons. The light patterns were shown onto a very small area of the cultured neurons, and the researchers were able to verify local reactions as well as changes in the global rhythms of the biological network.

“Incorporating optogenetics into the system is an advance towards practicality,” says Levi. “It will allow future biomimetic devices to communicate with specific types of neurons or within specific neuronal circuits.” The team is optimistic that future prosthetic devices using their system will be able to replace damaged brain circuits and restore communication between brain regions. “At University of Tokyo, in collaboration with Pr Kohno and Dr Ikeuchi, we are focusing on the design of bio-hybrid neuromorphic systems to create new generation of neuroprosthesis,” says Levi.

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Spinal cord gives bio-bots walking rhythm

Miniature biological robots are making greater strides than ever, thanks to the spinal cord directing their steps.

University of Illinois at Urbana-Champaign researchers developed the tiny walking “spinobots,” powered by rat muscle and spinal cord tissue on a soft, 3D-printed hydrogel skeleton. While previous generations of biological robots, or bio-bots, could move forward by simple muscle contraction, the integration of the spinal cord gives them a more natural walking rhythm, said study leader Martha Gillette, a professor of cell and developmental biology.

“These are the beginnings of a direction toward interactive biological devices that could have applications for neurocomputing and for restorative medicine,” Gillette said.

The researchers published their findings in the journal APL Bioengineering.

To make the spinobots, the researchers first printed the tiny skeleton: two posts for legs and a flexible “backbone,” only a few millimeters across. Then, they seeded it with muscle cells, which grew into muscle tissue. Finally, they integrated a segment of lumbar spinal cord from a rat.

“We specifically selected the lumbar spinal cord because previous work has demonstrated that it houses the circuits that control left-right alternation for lower limbs during walking,” said graduate student Collin Kaufman, the first author of the paper. “From an engineering perspective, neurons are necessary to drive ever more complex, coordinated muscle movements. The most challenging obstacle for innervation was that nobody had ever cultured an intact rodent spinal cord before.”

The researchers had to devise a method not only to extract the intact spinal cord and then culture it, but also to integrate it onto the bio-bot and culture the muscle and nerve tissue together — and do it in a way that the neurons form junctions with the muscle.

The researchers saw spontaneous muscle contractions in the spinobots, signaling that the desired neuro-muscular junctions had formed and the two cell types were communicating. To verify that the spinal cord was functioning as it should to promote walking, the researchers added glutamate, a neurotransmitter that prompts nerves to signal muscle to contract.

The glutamate caused the muscle to contract and the legs to move in a natural walking rhythm. When the glutamate was rinsed away, the spinobots stopped walking.

Next, the researchers plan to further refine the spinobots’ movement, making their gaits more natural. The researchers hope this small-scale spinal cord integration is a first step toward creating in vitro models of the peripheral nervous system, which is difficult to study in live patients or animal models.

“The development of an in vitro peripheral nervous system — spinal cord, outgrowths and innervated muscle — could allow researchers to study neurodegenerative diseases such as ALS in real time with greater ease of access to all the impacted components,” Kaufman said. “There are also a variety of ways that this technology could be used as a surgical training tool, from acting as a practice dummy made of real biological tissue to actually helping perform the surgery itself. These applications are, for now, in the fairly distant future, but the inclusion of an intact spinal cord circuit is an important step forward.”

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Unique physical, chemical properties of cicada wings

Biological structures sometimes have unique features that engineers would like to copy. For example, many types of insect wings shed water, kill microbes, reflect light in unusual ways and are self-cleaning. While researchers have dissected the physical characteristics that likely contribute to such traits, a new study reveals that the chemical compounds that coat cicada wings also contribute to their ability to repel water and kill microbes.

The scientists report their findings in the journal Advanced Materials Interfaces.

The researchers looked at the physical traits and chemical characteristics of the wings of two cicada species, Neotibicen pruinosus and Magicicada casinnii. N. pruinosus is an annual cicada; M. casinnii emerges from the soil once every 17 years. Previous studies have shown that both species have a highly ordered pattern of tiny pillars, called nanopillars, on their wings. The nanopillars contribute to the wings’ hydrophobicity — they shed water better than a raincoat — and likely play a role in killing microbes that try to attach to the wings.

“We knew a lot about the surface structure of cicada wings before this study, but we knew very little about the chemistry of those structures,” said Marianne Alleyne, an entomology professor at the University of Illinois at Urbana-Champaign who led the study with analytical chemist Jessica Román-Kustas, of the Sandia National Laboratories in Albuquerque, New Mexico; Donald Cropek, of the U.S. Army Corps of Engineers’ Construction Engineering Research Laboratory; and Nenad Miljkovic, a professor of mechanical science and engineering at Illinois.

To study nanopillar chemistry, Román-Kustas developed a method to gradually extract the compounds on the surface without damaging the overall structure of the wings. She placed each wing in solvent in an enclosed chamber and slowly microwaved each one.

“We extracted all these different compounds over different time periods, and then we analyzed what came off,” Román-Kustas said. “And we also looked at the corresponding changes in the nanopillar structure.”

The effort revealed that cicada wings are coated in a stew of hydrocarbons, fatty acids and oxygen-containing molecules like sterols, alcohols and esters. The oxygen-containing molecules were most abundant deeper in the nanopillars, while hydrocarbons and fatty acids made up more of the outermost nanopillar layers.

“Finding these particular molecules on the surface is not a surprise,” Alleyne said. “Hydrocarbons and fatty acids on insect cuticle is fairly common.”

The ratio of surface chemicals differed between the two cicada species, as did their nanopillar structures.

The study revealed that altering the surface chemicals also changed the nanopillar structure. In the N. pruinosis cicadas, the nanopillars began to shift in relation to one another as the chemicals were extracted, and later shifted back to a more parallel configuration. This also changed the wings’ wettability and anti-microbial characteristics.

The wings of the M. cassinni cicadas had shorter nanopillars and a higher proportion of hydrophobic compounds on their surface. Their nanopillar configuration orientation did not change as a result of extracting their surface chemicals.

While preliminary, the new findings offer insight into the interplay of structure and chemistry in determining function, Alleyne said. By dissecting these characteristics, the researchers hope to one day design artificial structures with some of the same surface traits. Finding materials that shed water and kill microbes, for example, would be useful in many applications, from agriculture to medicine, she said.

Alleyne is also an affiliate of the Beckman Institute for Advanced Science and Technology at Illinois.

The U.S. Army Corps of Engineers’ Construction Engineering Research Laboratory, National Science Foundation and the Japanese Ministry of Education, Culture, Sports, Science, and Technology supported this research.

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