The research, now published in Nature journal, was conducted by Dr. Swarup Deb, M.Sc. student Noam Raab, Prof. Moshe Goldstein, and Dr. Moshe Ben Shalom, all from the Raymond & Beverly Sackler School of Physics & Astronomy at Tel Aviv University, and Dr. Wei Cao, Prof. Michael Urbakh and Prof. Oded Hod from the Chemistry School at TAU, and Prof. Leeor Kronik from the Weizmann Institute.

"We are fascinated by how the atoms in a condensed matter order, how electrons mix with the atoms, and whether external stimulus can manipulate the atomic order and the electric charge distribution." Dr. Moshe Ben Shalom

Turning to Crystals

"We are fascinated by how the atoms in a condensed matter order, how electrons mix with the atoms, and whether external stimulus can manipulate the atomic order and the electric charge distribution," says Dr. Moshe Ben Shalom, head of the Quantum Layered Matter Group.

"Answering these questions is challenging due to the enormous number of atoms and electrons, even in the tiniest devices of our most advanced technologies. One of the tricks is to study crystals, which contain much smaller units, each including only a few atoms and electrons."

"While crystals are made of many identical units, repeated periodically in space, their properties are entirely deduced from the one unit-cell symmetry and the details of the few atoms it captures. And still, it is challenging to understand and predict these details since the electrons spread over all the atoms simultaneously as determined by their joint quantum mechanical interactions."

One way to probe the atomic order and the electronic charge distribution is to break the symmetry of the cells to induce internal electric fields. Crystals with permanent internal electric fields are called "polar crystals". In 2020 the same lab at TAU reported a novel polar crystal by stacking together two layers of a van der Waals crystal, with each layer only one atom thick.

"The natural order in which these crystals grow is symmetric, with each successive layer rotated by 180 degrees compared to the previous one. Here, one type of atoms is positioned precisely above the other type. Conversely, the artificial crystals assembled in the lab are not rotated, resulting in a slight shift between the layers, thus straying away from the fully symmetric configurations. This non-symmetric crystal structure forces electrons to jump from one layer to another, forming a permanent electric field between them," recaps Dr. Ben Shalom.

Ladder ferroelectrics

"We are now developing such tunneling devices in a stealth phase company called Slide-Tro LTD, established with the University and an external investor. We believe that a wide slew of devices from low power electronics to robust non-volatile memories are feasible with this technology." Dr. Moshe Ben Shalom

"The Thinnest Possible"

"Crucially, the group found that applying external electric fields makes the layers slide back and forth to match the direction of the electron's jump with the external field orientation. They named the phenomena 'interfacial ferroelectricity' and pointed out the unique domain-wall motion that governs the 'Slide-Tronics' response," explains Ben Shalom.

"The ferroelectric response we discovered is in a two-atoms thick system, the thinnest possible. It is therefore highly appealing for information technologies which are based on electronic quantum tunneling," says Ben Shalom.  

"We are now developing such tunneling devices in a stealth phase company called Slide-Tro LTD, established with the University and an external investor. We believe that a wide slew of devices from low power electronics to robust non-volatile memories are feasible with this technology."

Climbing the Crystalline Ladder

"From a fundamental science perspective, the discovery pointed us to new questions: How does the electric charge order? And how does the electric potential grow if we stack additional layers to further break or restore the symmetry of the crystals? In other words, instead of thinning down crystals as was vastly explored to date, we could now assemble new polar crystals, layer by layer, and probe the electric potential at any step of the crystalline ladder."

In the experiment, the researchers compared adjacent few layers thick domains with different back / forward shifts between the various layers, resulting in different polarization orientations. For example, in four layers (with three polar interfaces), there are four allowed configurations: all pointing up ↑↑↑, one down and two up ↑↑↓, two down and one up ↑↓↓, and all down ↓↓↓.

"We were excited to find a ladder of distinct electric potentials which are separated by nearly even steps, such that each step can be used as an independent information unit," says Noam Rab, a student conducting the measurements.

"This is very different from any polar thin film known to date, where the polarization magnitude is very sensitive to many surface effects and where the polar orientation switches at once between two potentials only”.

"Sliding and Climbing a Ladder-Ferroelectric": The periodic crystal is made of two different atoms, repeating with constant separations in each horizontal layer. Sliding the layers to the right or left positions, to position the red atom above the blue (or vice versa), makes electrons jump up (or down) between the layers. Unlike common polar crystals, the interfacial ferroelectric system exhibits distinct, evenly spaced electric potential steps which can serve as individual information units.

"The most likely directions of future research that we envision is manipulating more electronic orders like magnetism and superconductivity by sliding different crystal symmetries to form novel Ladder-Multiferroics." Dr. Wei Cao

According to Dr. Swarup Deb, a leading author of the paper, the researchers found that, "the internal electric fields remain substantial even if we add external electrons to the system to make it both conductive and polar. Typically, the external charge screens off the internal polarization, but in the present interfacial ferroelectrics, the extra electrons could only flow along the layers without jumping between them too much, to mute down the out-of-plane electric field”.

Dr. Wei Cao, one of the other leading authors adds: “With the help of theoretical calculations based on quantum mechanical principles, we identified the precise distribution of the polar charge and the conducting charge. The former is highly confined to the interfaces between the layers and hence protected from external perturbations."

"The calculations allowed us to predict which crystals are most resilient to the extra charge and how to design even better Ladder-Ferroelectrics. The most likely directions of future research that we envision is manipulating more electronic orders like magnetism and superconductivity by sliding different crystal symmetries to form novel Ladder-Multiferroics."

The groundbreaking study was conducted by experts from TAU's Maurice and Gabriela Goldschleger School of Dental Medicine, led by Prof. Lihi Adler-Abramovich and Dr. Michal Halperin-Sternfeld, in collaboration with Prof. Itzhak Binderman, Dr. Rachel Sarig, Dr. Moran Aviv, and researchers from the University of Michigan in Ann Arbor. The paper was published in the Journal of Clinical Periodontology.

Prof. Adler-Abramovich: "Small bone defects, such as fractures, heal spontaneously, with the body restoring the lost bone tissue. The problem begins with large bone defects. In many cases, when substantial bone loss results from tumor resection (removal by surgery), physical trauma, tooth extraction, gum disease or inflammation around dental implants, the bone is unable to renew itself. In the current study, we developed a hydrogel that mimics the natural substances in the extracellular matrix of bones, stimulating bone growth and reactivating the immune system to accelerate the healing process."

The researchers explain that the extracellular matrix is the substance surrounding our cells, providing them with structural support. Every type of tissue in our body has a specific extracellular matrix consisting of suitable substances with the right mechanical properties. The new hydrogel has a fibrillary structure that mimics that of the extracellular matrix of the natural bone. Furthermore, it is rigid, thus enabling the patient’s cells to differentiate into bone-forming cells.

WATCH: Lab of Bioinspired Materials: A Tour with TAU Prof. Lihi Adler-Abramovich

"As can be expected, the extracellular matrix of our bones is quite rigid," says Prof. Adler-Abramovich. "In our study, we produced a hydrogel that mimics this specific matrix in both chemical and physical properties. At the nanometric level, the cell can attach itself to the gel, gaining structural support and receiving relevant mechanical signals from the fibers. At first, to test these properties, we grew cells in a 3D model of the gel. Then we examined the impact of the hydrogel on model animals with large bone defects that could not heal spontaneously. We monitored them for two months with various methods, including Micro C.T. To our delight, the bone defects were fully corrected through regeneration, with the bones regaining their original thickness, and generating new blood vessels."

According to Prof. Adler-Abramovich, the innovative gel has extensive clinical applications in both orthopedic and dental medicine: "When we lose teeth due to extensive damage or bacterial infections, the standard treatment is dental implants. Implants, however, must be anchored in a sufficient amount of bone, and when bone loss is too substantial, physicians implant additional bone from a healthy part of the body – a complex medical procedure. Another option is adding bone substitutes from either human or animal sources, but these might generate an immune response. I hope that in the future the hydrogel we have developed will enable faster, safer, and simpler bone restoration."  

The study was led by Prof. Neta Erez of the Department of Pathology at TAU's Sackler Faculty of Medicine, and researchers from her group: Lea Monteran, Dr. Nour Ershaid, Yael Zait, and Ye'ela Scharff, in collaboration with Prof. Iris Barshack of the Sheba Medical Center and Dr. Amir Sonnenblick of the Tel Aviv Sourasky (Ichilov) Medical Center. The paper was published in Nature Communications. The study was funded by ERC, the Israel Cancer Association, and the Emerson Cancer Research Fund.

The Dark Side of Chemo

"In many cases of breast cancer, surgical removal of the primary tumor is followed by a chemotherapy regimen intended to kill any remaining malignant cells – either left behind by the surgeon or already colonizing in other organs," explains Prof. Erez. "However, while effectively killing cancer cells, chemotherapy also has some undesirable and even harmful side effects, including damage to healthy tissues. The most dangerous of these, is probably internal inflammations that might paradoxically help remaining cancer cells to form metastases in distant organs. The goal of our study was to discover how this happens and try to find an effective solution."

To this end, the researchers created an animal model for breast cancer metastasis. The animals received the same treatment as human patients: surgical removal of the primary tumor, then chemotherapy, followed by monitoring to detect metastatic relapse as early as possible. The disturbing results: metastatic tumors were detected in the lungs of a large percentage of the treated animals - similar to the percentage found in the control group.

"In humans, this interval between chemotherapy and detection of metastatic tumors is an inaccessible 'black box.' Working with an animal model, we could check what happens inside this 'box'." Prof. Neta Erez

 

What's Going on Inside the "Black Box"?

To decipher these adverse effects, the researchers examined the animals' lungs at an intermediate stage – when tiny micro-metastases may have already developed, but even advanced imaging technologies like CT cannot detect them.

"In humans, this interval between chemotherapy and detection of metastatic tumors is an inaccessible 'black box'," says Prof. Erez. "Working with an animal model we could check what happens inside this 'box'."

"We discovered a previously unknown mechanism: the chemotherapy generates an inflammatory response in connective tissue cells called 'fibroblasts', causing them to summon immune cells from the bone marrow. This, in turn, creates an inflammatory environment that supports the micro-metastases, helping them grow into full-fledged metastatic tumors. In this way, the chemotherapy, administered as a means for combating cancer, achieves the opposite result."

The researchers also identified the mechanism through which fibroblasts recruit immune cells, and 'train' them to support the cancer. "We found that in response to chemotherapy, the fibroblasts secrete 'complement proteins' – proteins that mediate cell recruitment and intensify inflammation, often by summoning white blood cells to damaged or infected areas, a process called chemotaxis," notes Prof. Erez. "When the immune cells reach the lungs, they create an inflammatory environment that supports cancer cells and helps them grow."

"We identified an inflammatory mechanism through which chemotherapy inadvertently supports the growth of metastatic tumors, and also discovered an effective solution: combining chemotherapy with an inflammation inhibitor." Prof. Neta Erez

Potential to Save Many Lives

To combat this newly discovered process, the researchers combined the chemotherapy administered to the animals with a drug that blocks the activity of complement proteins.

The results were very encouraging: following the combined treatment, the percentage of lab models developing no metastases rose from 32% to 67%; and the percentage of those with extensive cancer colonization in their lungs decreased from 52% with regular chemotherapy to 6% when the inflammation inhibitor was added.

"We discovered the mechanism behind a severe problem in the treatment of breast cancer: many patients develop metastatic tumors following removal of the primary tumor plus chemotherapy," says Prof. Erez, and concludes: "We identified an inflammatory mechanism through which chemotherapy inadvertently supports the growth of metastatic tumors, and also discovered an effective solution: combining chemotherapy with an inflammation inhibitor. We hope that our findings will enable more effective treatment for breast cancer, and perhaps other types of cancer as well – to prevent metastatic relapse and save numerous lives worldwide."  

The breakthrough was made under the leadership of doctoral student Inbar Fischer, from the laboratory of Dr. Boaz Barak of Tel Aviv University’s Sagol School of Neuroscience and School of Psychological Sciences. The research was published in the International Journal of Molecular Sciences.

Considered Safe

Fischer and Barak explain that hyperbaric medicine is a form of therapy in which patients are treated in special chambers where the atmospheric pressure is higher than the pressure we experience at sea level, and in addition are delivered 100 percent oxygen to breathe.

Hyperbaric medicine is considered safe and is already being used to treat a long list of medical conditions, including here in Israel. In recent years, scientific evidence has been accumulating that unique protocols of hyperbaric treatments improve the supply of blood and oxygen to the brain, thereby improving brain function.

Improving Brain Function

“The medical causes of autism are numerous and varied, and ultimately create the diverse autistic spectrum with which we are familiar," explains Dr. Barak:. "About 20% of autistic cases today are explained by genetic causes, that is, those involving genetic defects, but not necessarily ones that are inherited from the parents. Despite the variety of sources of autism, the entire spectrum of behavioral problems associated with it are still included under the single broad heading of ‘autism,’ and the treatments and medications offered do not necessarily correspond directly to the reason why the autism developed.”

In the preliminary phase of the study, a girl carrying the mutation in the SHANK3 gene, which is known to lead to autism, received treatments in the pressure chamber, conducted by Prof. Shai Efrati, director of the Sagol Center for Hyperbaric Medicine at the Shamir “Assaf Harofeh” Medical Center, faculty member at the Sagol School of Neuroscience, and a partner in the study. After the treatments, it was evident that the girl’s social abilities and brain function had improved considerably.

In the next stage, and in order to comprehend the success of the treatment more deeply, the team of researchers at Dr. Barak’s laboratory sought to understand what being in a pressurized chamber does to the brain. To this end, the researchers used lab models carrying the same genetic mutation in the SHANK3 gene as that carried by the girl who had been treated. The experiment comprised a protocol of 40 one-hour treatments in a pressure chamber over several weeks.

“We discovered that treatment in the oxygen-enriched pressure chamber reduces inflammation in the brain and leads to an increase in the expression of substances responsible for improving blood and oxygen supply to the brain, and therefore brain function," explains Dr. Barak. "In addition, we saw a decrease in the number of microglial cells, immune system cells that indicate inflammation, which is associated with autism."

 Increased Social Interest

“Beyond the neurological findings we discovered, what interested us more than anything was to see whether these improvements in the brain also led to an improvement in social behavior, which is known to be impaired in autistic individuals,” adds Dr. Barak. “To our surprise, the findings showed a significant improvement in the social behavior of the animal models of autism that underwent treatment in the pressure chamber compared to those in the control group, who were exposed to air at normal pressure, and without oxygen enrichment. The animal models that underwent treatment displayed increased social interest, preferring to spend more time in the company of new animals to which they were exposed in comparison to the animal models from the control group.”

Inbar Fischer concludes, “the mutation in the animal models is identical to the mutation that exists in humans. Therefore, our research is likely to have clinical implications for improving the pathological condition of autism resulting from this genetic mutation, and likely also of autism stemming from other causes. Because the pressure chamber treatment is non-intrusive and has been found to be safe, our findings are encouraging and demonstrate that this treatment may improve these behavioral and neurological aspects in humans as well, in addition to offering a scientific explanation of how they occur in the brain.”