Nanoparticles can turn off genes in bone marrow cells

Using these new particles, researchers could develop treatments for heart disease and other conditions.

Using specialized nanoparticles, MIT engineers have developed a way to turn off specific genes in cells of the bone marrow, which play an important role in producing blood cells. These particles could be tailored to help treat heart disease or to boost the yield of stem cells in patients who need stem cell transplants, the researchers say.

This type of genetic therapy, known as RNA interference, is usually difficult to target to organs other than the liver, where nanoparticles would tend to accumulate. The MIT researchers were able to modify their particles in such a way that they would accumulate in the cells found in the bone marrow.

“If we can get these particles to hit other organs of interest, there could be a broader range of disease applications to explore, and one that we were really interested in this paper was the bone marrow. The bone marrow is a site for hematopoiesis of blood cells, and these give rise to a whole lineage of cells that contribute to various types of diseases,” says Michael Mitchell, a former MIT postdoc and one of the lead authors of the study.

In a study of mice, the researchers showed that they could use this approach to improve recovery after a heart attack by inhibiting the release of bone marrow blood cells that promote inflammation and contribute to heart disease.

Marvin Krohn-Grimberghe, a cardiologist at the Freiburg University Heart Center in Germany, and Maximilian Schloss, a research fellow at Massachusetts General Hospital, are also lead authors of the paper, which appears today in Nature Biomedical Engineering. The paper’s senior authors are Daniel Anderson, a professor of chemical engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and Matthias Nahrendorf, a professor of radiology at MGH.

Targeting the bone marrow

RNA interference is a strategy that could potentially be used to treat a variety of diseases by delivering short strands of RNA that block specific genes from being turned on in a cell. So far, the biggest obstacle to this kind of therapy has been the difficulty in delivering it to the right part of the body. When injected into the bloodstream, nanoparticles carrying RNA tend to accumulate in the liver, which some biotech companies have taken advantage of to develop new experimental treatments for liver disease.

Anderson’s lab, working with MIT Institute Professor Robert Langer, who is also an author of the new study, has previously developed a type of polymer nanoparticles that can deliver RNA to organs other than the liver. The particles are coated with lipids that help stabilize them, and they can target organs such as the lungs, heart, and spleen, depending on the particles’ composition and molecular weight.

“RNA nanoparticles are currently FDA-approved as a liver-targeted therapy but hold promise for many diseases, ranging from Covid-19 vaccines to drugs that can permanently repair disease genes,” Anderson says. “We believe that engineering nanoparticles to deliver RNA to different types of cells and organs in the body is key to reaching the broadest potential of genetic therapy.”

In the new study, the researchers set out to adapt the particles so that they could reach the bone marrow. The bone marrow contains stem cells that produce many different types of blood cells, through a process called hematopoiesis. Stimulating this process could enhance the yield of hematopoietic stem cells for stem cell transplantation, while repressing it could have beneficial effects on patients with heart disease or other diseases.

“If we could develop technologies that could control cellular activity in bone marrow and the hematopoietic stem cell niche, it could be transformative for disease applications,” says Mitchell, who is now an assistant professor of bioengineering at the University of Pennsylvania.

The researchers began with the particles they had previously used to target the lungs and created variants that had different arrangements of a surface coating called polyethylene glycol (PEG). They tested 15 of these particles and found one that was able to avoid being caught in the liver or the lungs, and that could effectively accumulate in endothelial cells of the bone marrow. They also showed that RNA carried by this particle could reduce the expression of a target gene by up to 80 percent.

The researchers tested this approach with two genes that they believed could be beneficial to knock down. The first, SDF1, is a molecule that normally prevents hematopoietic stem cells from leaving the bone marrow. Turning off this gene could achieve the same effect as the drugs that doctors often use to induce hematopoietic stem cell release in patients who need to undergo radiation treatments for blood cancers. These stem cells are later transplanted to repopulate the patient’s blood cells.

“If you have a way to knock down SDF1, you can cause the release of these hematopoietic stem cells, which could be very important for a transplantation so you can harvest more from the patient,” Mitchell says.

The researchers showed that when they used their nanoparticles to knock down SDF1, they could boost the release of hematopoietic stem cells fivefold, which is comparable to the levels achieved by the drugs that are now used to enhance stem cell release. They also showed that these cells could successfully differentiate into new blood cells when transplanted into another mouse.

“We are very excited about the latest results,” says Langer, who is also the David H. Koch Institute Professor at MIT. “Previously we have developed high-throughput synthesis and screening approaches to target the liver and blood vessel cells, and now in this study, the bone marrow. We hope this will lead to new treatments for diseases of the bone marrow like multiple myeloma and other illnesses.”

Combatting heart disease

The second gene that the researchers targeted for knockdown is called MCP1, a molecule that plays a key role in heart disease. When MCP1 is released by bone marrow cells after a heart attack, it stimulates a flood of immune cells to leave the bone marrow and travel to the heart, where they promote inflammation and can lead to further heart damage.

In a study of mice, the researchers found that delivering RNA that targets MCP1 reduced the number of immune cells that went to the heart after a heart attack. Mice that received this treatment also showed improved healing of heart tissue following a heart attack.

“We now know that immune cells play such a key role in the progression of heart attack and heart failure,” Mitchell says. “If we could develop therapeutic strategies to stop immune cells that originate from bone marrow from getting into the heart, it could be a new means of treating heart attack. This is one of the first demonstrations of a nucleic-acid-based approach of doing this.”

At his lab at the University of Pennsylvania, Mitchell is now working on new nanotechnologies that target bone marrow and immune cells for treating other diseases, especially blood cancers such as multiple myeloma.

The research was funded in part by the National Institutes of Health, the European Union’s Horizon 2020 research and innovation program, the MGH Research Scholar Program, a Burroughs Wellcome Fund Career Award at the Scientific Interface, a Koch-Prostate Cancer Foundation Award in Nanotherapeutics, the Koch Institute Marble Center for Cancer Nanomedicine, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Enhancing quantum dot solar cell efficiency to 11.53%

Figure 1. Shown above is the structure of CQDSC and the optical redistribution profiles of devices by TMF optical simulation. Credit: Professor Sung-Yeon Jang, UNIST

A novel technology that can improve the efficiency of quantum dot solar cells to 11.53% has been unveiled. Published in the February 2020 issue of Advanced Energy Materials, it has been evaluated as a study that solved the challenges posed by the generation of electric currents from sunlight by solar cells by enhancing the hole extraction.

A research team, led by Professor Sung-Yeon Jang in the School of Energy and Chemical Engineering at UNIST has developed a photovoltaic device that maximizes the performance of quantum dot solar cells by using organic polymers.

Solar cells use a characteristic of which electrons and holes are generated in the absorber layer. The free free electrons and hole then move through the cell, creating and filling in holes. It is this movement of electrons and holes that generate electricity. Therefore, creating multiple electron-hole pairs and transporting them are an important consideration in the design of efficient solar cells.

The research team switched one side of the quantum dot solar cells to organic hole transport materials (HTMs) to better extract and transport holes. This is because the newly-developed organic polymer not only possesses superior hole extracting ability, but also prevents electrons and holes from recombining, which allow efficient transport of holes to the anode.

Generally, quantum dot solar cells combine electron-rich quantum dots (n-type CQDs) and hole-rich quantum dots (p-type QDs). In this work, the research team developed organic π‐conjugated polymer (π‐CP) based HTMs, which can achieve performance superior to that of state‐of‐the‐art HTM, p‐type CQDs. The molecular engineering of the π‐CPs alters their optoelectronic properties, and the charge generation and collection in colloidal quantum dot solar cells (CQDSCs), using them are substantially improved.

As a result, the research team succeeded in achieving power conversion efficiency (PCE) of 11.53% with decent air‐storage stability. This is the highest reported PCE among CQDSCs using organic HTMs, and even higher than the reported best solid‐state ligand exchange‐free CQDSC using pCQD‐HTM. “From the viewpoint of device processing, device fabrication does not require any solid‐state ligand exchange step or layer‐by‐layer deposition process, which is favorable for exploiting commercial processing techniques,” noted the research team.

“This study solves the problem of hole transport, which has been the major obstacle for the genration of electric currents in quantum dot solar cells,” says Professor Jang. “This work suggests that the molecular engineering of organic π‐CPs is an efficient strategy for simultaneous improvement in PCE and processability of CQDSCs, and additional optimization might further improve their performance.”

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Explore further

Light on efficiency loss in organic solar cells

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More information: Muhibullah Al Mubarok et al. Molecular Engineering in Hole Transport π‐Conjugated Polymers to Enable High Efficiency Colloidal Quantum Dot Solar Cells, Advanced Energy Materials (2020). DOI: 10.1002/aenm.201902933

Journal information: Advanced Energy Materials

Provided by Ulsan National Institute of Science and Technology

Breakthrough Quantum-Dot Transistors Open the Door to a Host of Innovative Electronics

By depositing gold (Au) and Indium (In) contacts, researchers create two crucial types of quantum dot transistors on the same substrate, opening the door to a host of innovative electronics. Credit: Los Alamos National Laboratory/University of California, Irvine

Quantum dot logic circuits provide the long-sought building blocks for innovative devices, including printable electronics, flexible displays, and medical diagnostics.

Researchers at Los Alamos National Laboratory and their collaborators from the University of California, Irvine have created fundamental electronic building blocks out of tiny structures known as quantum dots and used them to assemble functional logic circuits. The innovation promises a cheaper and manufacturing-friendly approach to complex electronic devices that can be fabricated in a chemistry laboratory via simple, solution-based techniques, and offer long-sought components for a host of innovative devices.

“Potential applications of the new approach to electronic devices based on non-toxic quantum dots include printable circuits, flexible displays, lab-on-a-chip diagnostics, wearable devices, medical testing, smart implants, and biometrics,” said Victor Klimov, a physicist specializing in semiconductor nanocrystals at Los Alamos and lead author on a paper announcing the new results in the October 19, 2020, issue of Nature Communications.

For decades, microelectronics has relied on extra-high purity silicon processed in a specially created clean-room environment. Recently, silicon-based microelectronics has been challenged by several alternative technologies that allow for fabricating complex electronic circuits outside a clean room, via inexpensive, readily accessible chemical techniques. Colloidal semiconductor nanoparticles made with chemistry methods in much less stringent environments are one such emerging technology. Due to their small size and unique properties directly controlled by quantum mechanics, these particles are dubbed quantum dots. 

A colloidal quantum dot consists of a semiconductor core covered with organic molecules. As a result of this hybrid nature, they combine the advantages of well-understood traditional semiconductors with the chemical versatility of molecular systems. These properties are attractive for realizing new types of flexible electronic circuits that could be printed onto virtually any surface including plastic, paper, and even human skin. This capability could benefit numerous areas including consumer electronics, security, digital signage, and medical diagnostics.  

A key element of electronic circuitry is a transistor that acts as a switch of electrical current activated by applied voltage. Usually transistors come in pairs of n- and p-type devices that control flows of negative and positive electrical charges, respectively. Such pairs of complementary transistors are the cornerstone of the modern CMOS (complementary metal oxide semiconductor) technology, which enables microprocessors, memory chips, image sensors, and other electronic devices.

The first quantum dot transistors were demonstrated almost two decades ago. However, integrating complementary n- and p-type devices within the same quantum dot layer remained a long-standing challenge. In addition, most of the efforts in this area have focused on nanocrystals based on lead and cadmium. These elements are highly toxic heavy metals, which greatly limits practical utility of the demonstrated devices.

The team of Los Alamos researchers and their collaborators from the University of California, Irvine have demonstrated that by using copper indium selenide (CuInSe₂) quantum dots devoid of heavy metals they were able to address both the problem of toxicity and simultaneously achieve straightforward integration of n- and p-transistors in the same quantum dot layer. As a proof of practical utility of the developed approach, they created functional circuits that performed logical operations.

The innovation that Klimov and colleagues are presenting in their new paper allows them to define p- and n-type transistors by applying two different types of metal contacts (gold and indium, respectively). They completed the devices by depositing a common quantum dot layer on top of the pre-patterned contacts. “This approach permits straightforward integration of an arbitrary number of complementary p- and n-type transistors into the same quantum dot layer prepared as a continuous, un-patterned film via standard spin-coating,” said Klimov.

Reference: “Solution-processable integrated CMOS circuits based on colloidal CuInSe₂ quantum dots” by Hyeong Jin Yun, Jaehoon Lim, Jeongkyun Roh, Darren Chi Jin Neo, Matt Law and  Victor I. Klimov, 19 October 2020, Nature Communications.
DOI: 10.1038/s41467-020-18932-5

Funding: This work was supported by the Laboratory Directed Research and Development (LDRD) program at Los Alamos National Laboratory under project 20200213DR and the University of California (UC) Office of the President under the UC Laboratory Fees Research Program Collaborative Research and Training Award LFR-17-477148.

Lithium-Ion Battery Research “Flowers” at Stoney Brook University – ‘3D Nano-Flowers’ Accelerate Battery Performance

 

 

A scanning electron microscope image of lithium titanate (lithium, titanium, oxygen) “nanoflowers.”

Lithium-ion batteries work by shuffling lithium ions between a positive electrode (cathode) and a negative electrode (anode) during charging and in the opposite direction during discharging.

Our smartphones, laptops, and electric vehicles conventionally employ lithium-ion batteries with anodes made of graphite, a form of carbon.

Lithium is inserted into graphite as you charge the battery and removed as you use the battery.

While graphite can be reversibly charged and discharged over hundreds or even thousands of cycles, the amount of lithium it can store (capacity) is not enough for energy-intensive applications.

For example, electric cars can only travel so far before they need to be recharged. In addition, graphite cannot be charged or discharged at very high rates (power). Because of these limitations, scientists have been on the hunt for alternative anode materials.

 

One such promising anode material is lithium titanate (LTO), which contains lithium, titanium, and oxygen. In addition to its high-rate capability, LTO has good cycling stability and maintains empty sites within its structure to accommodate lithium ions. However, LTO conducts electricity poorly, and lithium ions are slow to diffuse into the material.

“Pure LTO has moderate usable capacity but can deliver power quickly,” said Amy Marschilok, an associate professor in the Department of Chemistry and an adjunct faculty member in the Department of Materials Science and Chemical Engineering at Stony Brook University—where she also serves as deputy director of the Center for Mesoscale Transport Properties (m2M)—and Energy Storage Division manager and scientist in the Interdisciplinary Science Department at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory.

“High-rate battery materials are appealing for applications where you want to use stored energy quickly, over minutes—such as electric vehicles, portable power tools, and emergency power supply systems.”

Marschilok is part of an interdisciplinary Brookhaven Lab–Stony Brook team that began collaborating on LTO research in 2014. In their latest effort, they increased the capacity of LTO by 12 percent by adding chlorine through a process known as doping.

“Controlled doping can change the electronic and structural properties of a material,” explained Stanislaus Wong, distinguished professor in the Department of Chemistry at Stony Brook University, where he is also the principal investigator in charge of the student-based team comprising the Wong Group.

“In my group, we are interested in developing and using chemistry to direct favorable structure-property correlations.

For LTO, the incorporation of dopant atoms can increase electrical conductivity and expand the crystal lattice, such that the channel for lithium ions to migrate becomes wider. Scientists have been testing out many different types of dopants, but chlorine has not been explored as much.”

To make “chlorine-doped” LTO, the team used a solution-based method called hydrothermal synthesis. In hydrothermal synthesis, scientists add a solution containing relevant precursors (materials that react to form the desired product) in water, place the mixture in a sealed vessel, and expose it to relatively modest temperatures and pressures for a certain duration. In this case, to enable a scaling up of their procedure, the scientists selected a liquid-based titanium precursor instead of the solid titanium foil that had been previously used in these types of reactions.

Following the hydrothermal synthesis of both pure LTO and chlorine-doped LTO for 36 hours, they performed additional chemical processing steps to isolate the desired materials.

The team’s imaging studies using scanning electron microscopy (SEM) at the Electron Microscopy Facility of Brookhaven’s Center for Functional Nanomaterials (CFN) revealed that both sample types were characterized by “flower-shaped” nanostructures.

This result suggested that the chemical treatment did not destroy the original structure.

“Our novel synthesis approach facilitates a more rapid, uniform, and efficient reaction for the large-scale production of these 3-D nanoflowers,” said Wong. “This relatively unique kind of architecture has a high surface area, with flower-like “petals” radially disseminating from a central core. This structure provides multiple pathways for lithium ions to access the material.

By varying the concentration of chlorine, lithium, and precursor; the purity of the precursor; and the reaction time, the scientists found the optimal conditions for making highly crystalline nanoflowers.

At the CFN, the team performed several characterization experiments based on how the samples interact with x-rays and electrons: x-ray diffraction to obtain crystallinity information and chemical composition, SEM to visualize morphology (shape), energy-dispersive x-ray spectroscopy to map the distribution of elements, and x-ray photoelectron spectroscopy (XPS) to confirm chemical composition and derive chemical oxidation states.

“The XPS data are key in this study because they prove that titanium—which ordinarily exists in LTO as 4+, meaning four electrons have been removed—is reduced to 3+,” said Xiao Tong, a staff scientist in the CFN Interface Science and Catalysis Group.

“This change in chemical state is significant because the material transforms from an insulator to a semiconductor, increasing electrical conductivity and lithium-ion mobility.”

With the optimized samples, the scientists performed several electrochemical tests. They found that chlorine-doped LTO has more usable capacity under a high-rate condition in which the battery discharges in 30 minutes. This improvement was maintained over more than 100 charge/discharge cycles.

“Chlorine-doped LTO is not only better initially but also remains stable over time,” said Marschilok.

To understand why this improvement occurred, the team turned to computational theory, modeling the structural and electronic changes that arise from chlorine doping.

“When we do basic science experiments, we need to understand what we observe to see how the material is functioning and gain insights on how to improve the material’s performance,” explained Ping Liu, a chemist in Brookhaven’s Chemistry Division who was led the theoretical studies.

“Theory is a very effective way to achieve such mechanistic understanding, especially for complex materials like LTO.”

In calculating the most energetically stable geometry of LTO with chlorine doping, the team found that chlorine prefers to substitute sites where oxygen sits in the LTO structure.

“This substitution throws one electron to the system, causing electronic redistribution,” said Liu. “It causes titanium, which interacts directly with chlorine, to be reduced from 4+ to 3+, consistent with the experimental XPS results.

We also did calculations that showed once chlorine is substituted for oxygen, more lithium can be inserted into LTO during discharge. Chlorine is bigger than oxygen, so it provides an enlarged tunnel for lithium transport.”

Next, the team is studying how the microscopic structure of the 3-D nanoflowers affects transport. They also are exploring other atomic-level substitutions in both anode and cathode materials that may lead to improved transport.

“Improving both the electronic and ionic conductivity through one process is often challenging,” said Marschilok. “But beyond improving the performance of any one material, at m2M, we’re always thinking about designing model studies that can show the scientific community ways to develop new battery materials in a comprehensive way.

The combination of material synthesis, advanced material characterization, and computational theory, as well as the collaboration between Stony Brook and Brookhaven, are strengths of m2M’s work.”

This research—published in a special issue on “Low Temperature Solution Route Approaches to Oxide Functional Nanoscale Materials” in Chemistry–A European Journal—was funded as part of m2M, an Energy Frontier Research Center supported by the DOE Office of Science, Basic Energy Sciences. The scientists performed the theoretical calculations using computational resources at the CFN and the Scientific Data and Computing Center, part of Brookhaven’s Computational Science Initiative.

The CFN is a DOE Office of Science User Facility. Some co-authors were also supported by the National Science Foundation Graduate Research Fellowship and the William and Jane Knapp Chair for Energy and the Environment at Stony Brook University.

Some Good News for Start-Ups as a Tough 2020 Comes to a Close – SEC Changes Crowdfunding Regulation – Increases Maximum Funding

Companies raising money through regulation crowdfunding can now raise up to $5 million, the United States Securities and Exchange Commission announcedMonday.

Previously, entrepreneurs had a limit of $1.07 million for regulation crowdfunding. Regulation crowdfunding provides entrepreneurs with an exemption from the SEC’s registration requirements for securities-based crowdfunding, according to the SEC website. 

This means that entrepreneurs can raise up to a certain amount of their securities without having to register the transaction with the SEC. Before, that amount was $1.07, and now it’s $5 million.

The amendment passed by the SEC comes after there’s been more conversation around expanding opportunities to invest in startups. Last month, the SEC changed another rule, expanding its definition of an accredited investor.

Accredited investors previously had to meet certain income and wealth requirements. Now, the SEC has expanded that pool to other individuals who may not meet the income and wealth requirements, but have other proof of “financial sophistication,” according to Newsday.

Illustration: Dom GuzmanStay up to date with recent funding rounds, acquisitions, and more with the Crunchbase Daily

Special Note:

Canadian securities regulators are contemplating increasing the Startup Crowdfunding capital raising limit from CDN$250K (twice per calendar year) to CDN$1.5+ million.

Especially in these challenging times, I am hoping that Canadian regulators will follow suit soon and help Canadian private markets capital formation for entrepreneurs and retail investors.

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