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Comparing PET scans of more than 90 adults with and without mild cognitive impairment (MCI), Johns Hopkins Medicine researchers say relatively lower levels of the so-called “happiness” chemical, serotonin, in parts of the brain of those with MCI may play a role in memory problems including Alzheimer’s disease.
The findings, first published online Sept. 13 in the Journal of Alzheimer’s Disease, lend support to growing evidence that measurable changes in the brain happen in people with mild memory problems long before an Alzheimer’s diagnosis, and may offer novel targets for treatments to slow or stop disease progression.
“The study shows that people with mild cognitive impairment already display loss of the serotonin transporter. This measure that reflects serotonin degeneration is associated with problems with memory, even when we take into account in our statistical model MRI measures of neurodegeneration and PET measures of the amyloid protein that are associated with Alzheimer’s Disease,” says Gwenn Smith, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.
MCI describes the diagnostic stage between normal brain function in aging and Alzheimer’s Disease (AD). Symptoms of MCI include frequent forgetfulness of recent events, word finding difficulty, and loss of the sense of smell. Those with MCI may stay in this stage indefinitely, or progress to more severe forms of cognitive deficits, giving urgency to the search for predictive markers, and possible early prevention interventions, investigators say.
The investigators cautioned that their study showed a correlation between lower serotonin transporter levels and memory problems in MCI, and was not designed to show causation or the role of serotonin in the progression from MCI to AD. To answer these questions, further research is needed to study over time healthy controls and individuals with MCI to demonstrate the role of serotonin in disease progression.
For the study, the Hopkins scientists recruited 49 volunteers with MCI, and 45 healthy adults ages 55 and older who underwent an MRI to measure changes in brain structure and two positron emission tomography (PET) scans of their brains at Johns Hopkins between 2009 and 2022. The research team used PET scans to look specifically at the serotonin transporter — a neurotransmitter, or brain chemical long associated with positive mood, appetite and sleep — and to look at the amyloid-beta protein (Aβ) distribution in the brain. Aβ is thought to play a central role in the pathology of AD. Studies in mice done at Johns Hopkins have shown that serotonin degeneration occurs before the development of widespread beta-amyloid deposits in the brain. Loss of serotonin is often associated with depression, anxiety, and psychological disorders.
Researchers found that MCI patients had lower levels of the serotonin transporter, and higher levels of Aβ than healthy controls. The MCI patients had up to 25% lower serotonin transporter levels in cortical and limbic regions than healthy controls. In particular, they report, lower serotonin transporter levels were found in cortical, limbic, and subcortical regions of the brains in those with MCI, areas specifically responsible for executive function, emotion, and memory.

“The correlation we observed between lower serotonin transporters and memory problems in MCI is important because we may have identified a brain chemical that we can safely target that may improve cognitive deficits and, potentially, depressive symptoms,” says Smith. “If we can show that serotonin loss over time is directly involved in the transition from MCI to AD, recently developed antidepressant medications may be an effective way to improve memory deficits and depressive symptoms and thus, may be a powerful way forward to slow disease progression.”
Researchers say future studies include longitudinal follow up of individuals with MCI to compare serotonin degeneration to the increase in and Aβ levels, as well as the increase in levels of the Tau protein that is also associated with AD compared to healthy adults. They are also studying multi-modal antidepressant drugs to treat depression and memory deficits in hopes of mitigating and halting symptoms.
Other scientists at the Johns Hopkins University School of Medicine and Johns Hopkins Bloomberg School of Public Health who contributed to this research are Jennifer Coughlin, Robert Dannals, Neda Gould, Daniel Holt, Vidya Kamath, Michael Kraut, Hiroto Kuwabara, Jeannie Leoutsakos, Martin Lodge, Ayon Nandi, Najlla Nassery, Martin Pomper, Alena Savonenko, Haijuan Yan and Mark Yoon.
All authors have no conflicts to disclose.
This research was partly supported by the National Institutes of Health.

Mortality related to end stage liver disease is ranked as the 12th most common cause of death in the U.S. Liver transplantation remains the only treatment for end stage liver disease, but there is a critical shortage of organ donors, necessitating a dire need for new forms of treatment.
New research from Boston Medical Center and Boston University Chobanian & Avedisian School of Medicine’s Center for Regenerative Medicine (CReM) found evidence that a novel stem cell treatment, using mRNA technology encapsulated into nanoparticles (LNP) that was successfully used to produce the COVID-19 vaccines, may boost the natural repair mechanism of the liver to regress the diseased tissue caused by either an acute or chronic liver injury. Published in Cell Stem Cell, researchers identified a specific receptor present on the stem cells which can be recognized and activated by the ligand protein called vascular endothelial growth factor A (VEGFA).
“This potential treatment has important clinical implications for people suffering from chronic liver disease, allowing the liver to heal itself, and potentially avoiding the need for many liver transplants,” said corresponding author, Valerie Gouon-Evans, PhD, PharmD, Director of the Boston University Liver Biologist Program, Associate Professor at Boston University Chobanian & Avedisian School of Medicine, and CReM faculty. “It’s our hope that these findings, with further study, will be translated to clinical patient care to alleviate chronic liver disease and the need for transplants as a result of acute or chronic injury.”
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. But during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, researchers studied VEGFA as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion.
Researchers used mice and zebrafish liver disease models. In the zebrafish studies, the liver disease was created by inducing hepatocyte death with genetic and chemical intervention. The experimental group of fish was then exposed to overexpression of VEGFA while the control group was not. Researchers observed a significant increase of newly generated hepatocytes from the BEC-derived stem cells in the presence of VEGFA.
In the mouse study, the acute disease was induced with an overdose of the drug acetaminophen, and the chronic disease was promoted with a diet. The experimental groups were treated with 2 injections of VEGFA mRNA-LNP, while the control groups were injected with neutral mRNA-LNP. Researchers demonstrated that delivery of VEGFA mRNA-LNP in both acutely or chronically injured livers induced robust BEC-to-hepatocyte conversion with a five-fold increase compared to control-treated mice, and importantly full reversion of steatosis and fibrosis in the chronic model.
This treatment activates the stem cells of the liver, a subset of the biliary epithelial cells (BEC) lining up the liver biliary tree, so that they proliferate and generate new healthy hepatocytes, the functional cells of the liver.
Nearly 30% of severe cases of acetaminophen overdose require liver transplantation because the gold standard-of-care NAC currently used in the clinic to neutralize acetaminophen toxic metabolite has a very narrow time frame of efficiency. The data suggest VEGFA mRNA-LNP as an alternative treatment for severe acetaminophen intoxication that would prevent liver failure and, thus, the need for transplantation for the many overdosed patients who come too late to the ER.
This study has critical clinical implications establishing potential novel treatments for liver diseases by exploiting and optimizing the naturally occurring BEC-mediated repair mechanism of the liver to a clinically relevant extent by delivery of VEGFA into the liver using the clinically safe mRNA-LNPs.

Although SARS-CoV-2 is no longer a stranger to the immune system, new virus variants still pose a challenge. The working group led by Professor Dr Florian Klein, Director of the Institute of Virology at the University Hospital Cologne and the Faculty of Medicine, has now published two studies investigating how the antibody response to SARS-CoV-2 changes over time and how the immune system is preparing itself for new variants with clever strategies. The work has been published under the title ‘Enhanced SARS-CoV-2 humoral immunity following breakthrough infection builds upon the preexisting memory B cell pool’ in Science Immunology and under ‘Somatic hypermutation introduces bystander mutations that prepare SARS-CoV-2 antibodies for emerging variants” in Immunity.
In a process known as affinity maturation, antibodies can mature over time through the exchange (mutations) of individual amino acids, thus enabling them to better detect infectious pathogens. The working group led by Professor Klein has now been able to show that an Omicron infection induces a renewed immune response in vaccinated persons, which is primarily based on the reactivation of so-called memory B cells. Interestingly, the maturation process of the antibodies produced by these cells had already taken place long before Omicron emerged — so the immune system was already prepared. The results of the two studies show how strongly the first contact with SARS-CoV-2 influences the immune system and indicate the possibility that it is also prepared for future variants.
“Our first goal was to investigate how the antibody response in healthy subjects changes through a third vaccination against the original SARS-CoV-2 strain,” reports Svea Rose, a doctoral candidate and a first author. “We were initially surprised by the results. Although the third vaccination significantly increased the SARS-CoV-2 immune response overall, there was hardly any further maturation at the level of individual antibodies.” However, people who — like many — became infected with the Omicron variants BA.1 and BA.2 after vaccination were also examined. The re-analysis showed that memory B cells which were able to form antibodies neutralizing SARS-CoV-2 omicron now proliferate. “Interestingly, the immune cells directed against the Omicron variant were already present before contact with Omicron and were not induced by Omicron,” adds first author Dr Timm Weber. But that’s not all: At an early stage, the researchers found so-called broad neutralizing antibodies that can neutralize all new variants which have been tested.
At the same time, the working group looked at the molecular mechanism of affinity maturation. The clock was turned back and individual antibodies, which were isolated throughout the world in the first year of the pandemic, were restored to their original state, report the two lead authors Michael Korenkov and Dr Matthias Zehner in the study published in Immunity. As a result, the researchers were able to show that some of the modifications during affinity maturation are not deliberate, but happen randomly. Surprisingly, it was precisely these random modifications that were essential for the neutralization of Omicron variants. “The immune system expands the arsenal of existing antibodies by inserting arbitrary mutations and thus increases the likelihood of having a suitable antibody in the repertoire when a new virus variant appears,” explains Dr Christoph Kreer, who led the study together with Professor Klein. The group was able to use the new biological findings to modify a therapeutic antibody that was ineffective against Omicron in such a way that it could effectively neutralize Omicron variants again.
In summary, the work shows how the human immune system reacts to a new virus and its emerging variants. The newly isolated broad neutralizing antibodies are so effective that they could also be used therapeutically and preventively against newer Omicron variants.

Human noroviruses cause acute gastroenteritis, a global health problem for which there are no vaccines or antiviral drugs. Although most healthy patients recover completely from the infection, norovirus can be life-threatening in infants, the elderly and people with underlying diseases. Estimates indicate that human noroviruses cause approximately 684 million illnesses and 212,000 deaths annually.
“Human noroviruses are highly diverse,” said first author Dr. Wilhelm Salmen, a graduate student in Dr. B V Venkataram Prasad’s lab while he was working on this project and currently a postdoctoral fellow at the University of Michigan. “Noroviruses are categorized into10 groups, of which groups GI, GII, GIV, GVIII and GIX infect humans. Viruses in the GII.4 subgroup are the most predominant in human populations.”
Noroviruses also are notorious for periodically giving rise to new variants, particularly those of GII.4 norovirus, that can evade the immune response the body has developed against previous variants, like some flu viruses and coronaviruses do. The diversity of norovirus groups and the recurring emergence of new variants are some of the factors challenging the development of effective preventive and therapeutic approaches to control this serious disease.
In the current study published in the journal Nature Communications, Salmen, Prasad and their colleagues investigated a novel strategy to neutralize human noroviruses. They tested whether tiny antibodies produced by llamas, called nanobodies, could effectively neutralize human norovirus infection in the lab. The unexpected findings reveal that nanobodies could be developed as a therapeutic agent against human norovirus.
Llama nanobodies may give an upper hand
Llamas and related animals such as camels and alpacas, produce antibodies for protection against disease just like people do. However, compared to people’s antibodies, llama’s are about a tenth of the size of human antibodies. Llama’s nanobodies have been developed against viruses such as those causing hepatitis B, influenza, human immunodeficiency, polio and other diseases.
“Our collaborators from Argentina, Dr. Marina Bok and Dr. Viviana Parreño at the Institute of Virology and Technology Innovation, had prepared nanobodies from llamas that were inoculated with human norovirus-like particles from different strains,” Salmen said. “We worked with one nanobody named M4, which bound to the predominant GII.4 strain, testing its ability to neutralize different norovirus strains, that is, to prevent them from infecting human cells.”
The researchers tested the ability of the nanobodies to prevent live viruses from infecting human intestinal organoids or mini guts grown in the lab. Mini guts are models of human intestinal cells, closely representing actual small intestine tissue and its functions, that enable scientists to study how noroviruses work and to test potential therapies.

“It was really unexpected to see that the M4 nanobody not only interacted and neutralized the currently circulating pandemic GII.4 strain but also its older variants,” said Prasad, Alvin Romansky Chair in Biochemistry and professor in the Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology and the Department of Molecular Virology and Microbiology at Baylor. He also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center and corresponding author of the work.
The researchers used crystallography and other techniques to look closely at the interactions between nanobodies and noroviruses to try to understand how the M4 nanobody recognizes and neutralizes a variety of noroviruses when they expected it would recognize only the GII.4 strain used to generate M4.
“We discovered that this little nanobody can recognize a part of the norovirus that all the different noroviruses that we tested have in common,” Salmen said.
The team discovered that the M4 nanobody recognized a hidden pocket in the norovirus particles that would be exposed only when the particles underwent a structural change. “The traditional thinking is that viral particles are in a very stable compact state, but in reality these particles ‘breathe’ considerably,” Salmen said. “Recent studies have shown that the structure of norovirus particles is dynamic, alternating between a resting or compact conformation and a raised conformation.”
“We think that the raised state is important for the virus to bind to cells and infect them,” Prasad said. “We also think that when the viral particles are in the raised state, the hidden pocket is exposed and available for the nanobody to bind to it and, acting like a wedge, to keep the particle in an elevated, potentially unstable state, preventing it from collapsing back down into the compact, more stable resting state.”
“Our findings suggest that trapping the viral particles in an elevated, unstable state disassembles the particles, which kills the virus. This effectively would stop the infection as it blocks the transmission chain, preventing the virus from spreading from cell to cell,” Salmen said.

“This study is also remarkable in confirming that the human norovirus must change its 3D confirmation, from compact to raised, to infect people,” said co-author Dr. Mary Estes, Distinguished Service Professor of Virology and Microbiology and Cullen Foundation Endowed Chair at Baylor. She also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “Also, this work reveals the importance of considering viral particle dynamics when designing vaccines.”
Other contributors to this work include Liya Hu, Natthawan Chaimongkol, Khalil Ettayebi, Stanislav V. Sosnovtsev, Kaundal Soni, B. Vijayalakshmi Ayyar, Sreejesh Shanker, Frederick H. Neill, Banumathi Sankaran, Robert L. Atmar and Kim Y. Green. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Institute for Virology and Technology Innovation-Argentina, National Institutes of Health and Lawrence Berkeley Laboratory.
This study was supported in part by the National Institutes of Health grants P30 GM124169-01, P30 CA125123 and P01 AI057788, and a grant from the Robert Welch Foundation (Q1279). Further support was provided by a Fulbright Program grant and by the Division of Intramural Research, NIAID, NIH.

An unexpectedly high percentage of children, who were born with HIV and started treatment within 48 hours of life, exhibit biomarkers by 2 years of age that may make them eligible to test for medication-free remission, according to a multinational study published in Lancet HIV.
“Moving away from reliance on daily antiretroviral therapy (ART) to control HIV would be a huge improvement to the quality of life of these children,” said Protocol Co-Chair and senior author Ellen Chadwick, MD, former Director of Section of Pediatric, Adolescent and Maternal HIV Infection at Ann & Robert H. Lurie Children’s Hospital of Chicago and Professor of Pediatrics at Northwestern University Feinberg School of Medicine.
The proof-of-concept study was charged with replicating the case of HIV remission as seen in the “Mississippi baby” that was reported in 2013. In that case, the infant started ART at 30 hours of life, was treated for 18 months, and achieved 27 months of ART-free remission before the virus rebounded. Typically, if ART is stopped, the virus rebounds within a month.
The study included a three-drug ART regimen initiated within 48 hours of life, with the fourth drug added within 2-4 weeks. This is very early treatment compared to the standard of care where three-drug ART may not begin until 2- 3 months of age. In the U.S., however, based on earlier findings from this study, very early treatment is now the norm for infants at high risk of acquiring HIV infection from their mother.
“With earlier treatment, we hope to limit or prevent the establishment of viral reservoirs in the body. These viral reservoirs hold small amounts of hidden virus which are hard to reach with ART. By shrinking these reservoirs, we expect to increase the amount of time that patients can be in remission, without needing daily ART,” said co-author Jennifer Jao, MD, MPH, from Lurie Children’s, who is the Protocol Co-Chair with Dr. Chadwick. She is a Professor of Pediatrics at Northwestern University Feinberg School of Medicine and holds the Susan B. DePree Founders’ Board Professorship in Pediatric, Adolescent, and Maternal HIV Infection.
Dr. Chadwick adds: “Another benefit of smaller viral reservoirs might be that newer treatments such as long-acting antibody therapies or therapeutic vaccines could potentially be used instead of daily ART.”
“Our results show a higher percentage of children might be eligible to interrupt therapy than we expected, and the next step is to stop ART and see how many children actually achieve remission,” said Dr. Chadwick. “If even one child achieves remission, that would be considered a success. Today, newer more effective and better tolerated HIV medications are available for infants than when the study began, strengthening the prospect of limiting viral reservoirs and testing for possible remission in infants and children with HIV. Overall, this is an exciting advancement and an opportunity to change the course of pediatric HIV infection.”
The study was conducted in 11 countries — Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, USA, Zambia and Zimbabwe.
Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632-15 (IMPAACT LOC), UM1AI068616-15 (IMPAACT SDMC), and UM1AI106716-09 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Research at Ann & Robert H. Lurie Children’s Hospital of Chicago is conducted through Stanley Manne Children’s Research Institute, which is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is a nonprofit organization committed to providing access to exceptional care for every child. It is ranked as one of the nation’s top children’s hospitals by U.S. News & World Report. Lurie Children’s is the pediatric training ground for Northwestern University Feinberg School of Medicine.

Pancreatic ductal adenocarcinoma (PDAC), that arises from pancreatic epithelial cells, is the most common form of pancreatic cancer, with a very high mortality rate. This elevated mortality is associated with the unique tumor microenvironment (TME), known for increased resistance to chemotherapy and high metastatic potential. TME is characterized by the presence of a complex stromal structure comprising cancer-associated fibroblasts (CAFs), tumor endothelial cells (TECs), and a variety of immune cells.
CAFs are specific cells, primarily involved in the overall aggressiveness and spread of cancer cells. These cells can further be categorized into several types based on their cellular characteristics and roles, such as inflammatory, myo-fibroblastic, and antigen-presenting CAFs. Therefore, the development of a cell culture system for PDAC that mimics the unique TME involving different types of CAFs, is the need of the hour.
To this end, a research team from Japan attempted to create cancer cell organoid systems that can effectively resemble PDAC and act as a screening tool in anticancer research. Dr. Takeuchi Kenta, a research assistant at the Institute of Medical Science, including Associate Professor Tanimizu Naoki, and Professor Taniguchi Hideki, both from the Institute of Medical Science, The University of Tokyo, were involved in this novel research. Their research findings were published in volume 42, issue 11 of the Cell Reports journal on November 28, 2023.
Dr. Takeuchi Kenta briefly discusses his motivation behind the research. He says, “To reproduce the complexity of PDAC-TME in cell culture models is challenging. Therefore, we used human-induced pluripotent stem cell (hiPSC)-derived mesenchymal cells that can differentiate to multiple types of CAFs and established a novel PDAC organoid.”
The research team used patient-derived PDAC cells with hiPSC-derived endothelial and mesenchymal cells to create fused pancreatic cancer organoid (FPCO). This innovative approach yielded two distinct FPCOs, a proliferative FPCO (pFPCO), and a quiescent FPCO (qFPCO), which resemble a typical patient’s PDAC tissue. Notably, qFPCOs exhibited strong chemo-resistance capabilities, whereas pFPCOs could reproliferate after initial drug treatment. Using advanced techniques such as stem cell technology along with analyses like single cell RNA sequencing, and in-vitro cancer assays, the functional properties of the PDAC organoid system were studied and characterized.
Dr. Tanimizu Naoki concludes, “PDAC is a disease that often requires surgical resection and has no other viable treatment options. Also, anti-PDAC drugs have generally failed at different stages of clinical trials. Hence, PDAC organoids with unique TME profiles should be used for anticancer drug screening. Our PDAC model can help future research in cancer biology and in personalized healthcare.”

An international team of researchers including experts at the Indiana University School of Medicine has identified a protein found in the brains of people with frontotemporal dementia (FTD), discovering a new target for potential treatments for the disease.
According to the National Institutes of Health, FTD results from damage to neurons in the frontal and temporal lobes of the brain. People with this type of dementia typically present symptoms, including unusual behaviors, emotional problems, trouble communicating, difficulty with work or in some cases difficulty with walking, between the ages of 25 and 65.
Neurodegenerative disorders, including dementias and Amyotrophic Lateral Sclerosis (ALS), occur when specific proteins form amyloid filaments in the nerve cells of the brain and spinal cord. The multidisciplinary team of researchers — including members from the Medical Research Council (MRC) Laboratory of Molecular Biology, the IU School of Medicine and the University College London Queen Square Institute of Neurology — found that in cases of FTD, a protein called TAF15 forms these amyloid filaments in the cells of the brain and the spinal cord. On December 6, they published their findings in Nature.
Bernardino Ghetti, MD is a Distinguished Professor at the IU School of Medicine and has been studying neurodegenerative dementias for 50 years. As a lead neuropathologist on the project, Ghetti and his team studied the protein aggregates from brains donated by four people who had frontotemporal dementia and motor weakness. Together with their colleagues in the UK, IU researchers used neuropathologic and molecular techniques and cutting-edge cryo-electron microscopy (cryo-EM) at atomic resolution to discover the presence of the amyloid filaments made of TAF15 protein in multiple brain areas. However it is important to note that TAF15 amyloid affects also nerve cells of the motor system.
“This discovery represents an important breakthrough that recognizes TAF15 as a potential target for the development of diagnostic and therapeutic strategies toward a lesser-known form of frontotemporal lobar degeneration associated with frontotemporal dementia,” Ghetti said.
Additional authors on the study are the MRC Laboratory of Molecular Biology’s Stephan Tetter, Diana Arseni, Alexey G. Murzin, Sew Y. Peak-Chew and Benjamin Ryskeldi-Falcon; the University College London’s Yazead Buhidma and Tammaryn Lashley; and the IU School of Medicine’s Holly J. Garringer, Kathy L. Newell, Ruben Vidal and Liana G. Apostolova.
The study was in part funded by the NIH’s National Institute on Aging and National Instiute of Neurological Disorders and Stroke.

Engineers at Duke University and Harvard Medical School have developed a bio-compatible ink that solidifies into different 3D shapes and structures by absorbing ultrasound waves. Because it responds to sound waves rather than light, the ink can be used in deep tissues for biomedical purposes ranging from bone healing to heart valve repair.
This work appears on December 7 in the journal Science.
The uses for 3D-printing tools are ever increasing. Printers create prototypes of medical devices, design flexible, lightweight electronics, and even engineer tissues used in wound healing. But many of these printing techniques involve building the object point-by-point in a slow and arduous process that often requires a robust printing platform.
To circumvent these issues over the past several years, researchers developed a photo-sensitive ink that responds directly to targeted beams of light and quickly hardens into a desired structure. While this printing technique can substantially improve the speed and quality of a print, researchers can only use transparent inks for the prints, and biomedical purposes are limited, as light can’t reach beyond a few millimeters deep into tissue.
Now, Y. Shrike Zhang, associate bioengineer at Brigham and Women’s Hospital and associate professor at Harvard Medical School, and Junjie Yao, associate professor of biomedical engineering at Duke, have developed a new printing method called deep-penetrating acoustic volumetric printing, or DVAP, that resolves these problems. This new technique involves a specialized ink that reacts to soundwaves rather than light, enabling them to create biomedically useful structures at unprecedented tissue depths.
“DVAP relies on the sonothermal effect, which occurs when soundwaves are absorbed and increase the temperature to harden our ink,” explained Yao, who designed the ultrasound printing technology for DVAP. “Ultrasound waves can penetrate more than 100 times deeper than light while still spatially confined, so we can reach tissues, bones and organs with high spatial precision that haven’t been reachable with light-based printing methods.”
The first component of DVAP involves a sonicated ink, called sono-ink, that is a combination of hydrogels, microparticles and molecules designed to specifically react to ultrasound waves. Once the sono-ink is delivered into the target area, a specialized ultrasound printing probe sends focused ultrasound waves into the ink, hardening portions of it into intricate structures. These structures can range from a hexagonal scaffold that mimics the hardness of bone to a bubble of hydrogel that can be placed on an organ.

“The ink itself is a viscous liquid, so it can be injected into a targeted area fairly easily, and as you move the ultrasound printing probe around, the materials in the ink will link together and harden,” said Zhang, who designed the sono-ink in his lab at the Brigham. “Once it’s done, you can remove any remaining ink that isn’t solidified via a syringe.”
The different components of the sono-ink enable the researchers to adjust the formula for a wide variety uses. For example, if they want to create a scaffold to help heal a broken bone or make up for bone loss, they can add bone mineral particles to the ink. This flexibility also allows them to engineer the hardened formula to be more durable or more degradable, depending on its use. They can even adjust the colors of their final print.
The team conducted three tests as a proof-of-concept of their new technique. The first involved using the ink to seal off a section in a goat’s heart. When a human has nonvalvular atrial fibrillation, the heart won’t beat correctly, causing blood to pool in the organ. Traditional treatment often requires open-chest surgery to seal off the left atrial appendage to reduce the risk of blood clots and heart attack.
Instead, the team used a catheter to deliver their sono-ink to the left atrial appendage in a goat heart that was placed in a printing chamber. The ultrasound probe then delivered focused ultrasound waves through 12 mm of tissue, hardening the ink without damaging any of the surrounding organ. Once the process was complete, the ink was safely bonded to the heart tissue and was flexible enough to withstand movements that mimicked the heart beating.
Next, the team tested the potential for DVAP’s use for tissue reconstruction and regeneration. After creating a bone defect model using a chicken leg, the team injected the sono-ink and hardened it through 10 mm of sample skin and muscle tissue layers. The resulting material bonded seamlessly to the bone and didn’t negatively impact any of the surrounding tissues.
Finally, Yao and Zhang showed that DVAP could also be used for therapeutic drug delivery. In their example, they added a common chemotherapy drug to their ink, which they delivered to sample liver tissue. Using their probe, they hardened the sono-ink into hydrogels that slowly release the chemotherapy and diffuse into the liver tissue.
“We’re still far from bringing this tool into the clinic, but these tests reaffirmed the potential of this technology,” said Zhang. “We’re very excited to see where it can go from here.”
“Because we can print through tissue, it allows for a lot of potential applications in surgery and therapy that traditionally involve very invasive and disruptive methods,” said Yao. “This work opens up an exciting new avenue in the 3D printing world, and we’re excited to explore the potential of this tool together.”

A new method, developed at Karolinska Institutet, KTH Royal Institute of Technology and SciLifeLab in Sweden, can identify unique immune cell receptors and their location in tissue, a study published in the journal Science reports. The researchers predict that the method will improve the ability to identify which immune cells contribute to disease processes and open up opportunities to develop novel therapies for numerous diseases.
Immune cells such as T and B cells are central to the body’s defence against both infections and tumours. Both types of immune cells express unique receptors that specifically recognise different parts of unwanted and foreign elements, such as bacteria, viruses and tumours. Each immune cell and its progeny has its own specific receptors, and in each human body there are billions of different immune cells with unique receptors.
Researchers at Karolinska Institutet, KTH Royal Institute of Technology and SciLifeLab have now developed a method that is able to both identify the different B and T cell receptors and reveal their location in human tissue.
Many areas of application
“Since activated immune cells are often found close to the targets that they attack, we want to be able to map the cells that are indeed closest to a tumour or infection,” says Camilla Engblom, assistant professor at the Department of Medicine (Solna), Karolinska Institutet and one of the study’s three lead authors along with Kim Thrane, KTH/SciLifeLab, and Qirong Lin, Karolinska Institutet. “It hasn’t been possible to identify both B och T cell receptors in their microenvironments using previous methods.”
According to Dr Engblom, there is a wide range of areas in which the new technique can be put to clinical use in the future.
“In cancer, the method can identify T cells that potentially attack the tumour,” she says. “They could then be used as cell therapy against cancer. We can also identify unique receptors on the B cells that are released as antibodies in specific areas of the tumour. These antibodies can be produced in the lab with relative ease and eventually give rise to novel therapies. Another field is autoimmune diseases, where the immune system attacks healthy tissue. The new technique could be used to identify the immune cells that do this and increase the chances of finding exactly what it is they attack.”
An important step forward

Jeff Mold, one of the principal investigators of the study and researcher at the Department of Cell and Molecular Biology at Karolinska Institutet, sees the new method as an important step forward.
“Identifying these unique immune receptors is like trying to find a needle in a haystack, especially when it comes to autoimmune diseases,” he says. “With most current methods, you destroy the tissue, which means not only that you get different immune cells mixed up, but also that some cells die in the process. With this method, we preserve the cells where they are and we can see cells that would otherwise have been lost.”
Dr Mold believes that the ability to identify B cells is arguably the main benefit of this new method.
“T cells have been a popular research target, while the B cells have been a little overlooked, especially in cancer,” he says. “But now we can track how B cells develop and expand direct in tissue.”
The study was financed by the Swedish Research Council, the Swedish Cancer Society and the EU research and innovation programme Horizon 2020.
Potential conflicts of interest: Camilla Engblom, Kim Thrane, Jeff Mold, Jonas Frisén, Joakim Lundeberg and Qirong Lin are inventors of a patent that covers this work. Camilla Engblom, Kim Thrane, Qirong Lin, Alma Andersson, Hosein Toosi, Sami Saarenpää, Jeff Mold, Joakim Lundeberg and Jonas Frisén are scientific consultants for 10x Genomics, which holds intellectual property rights to this technology. Jeff Mold holds shares in Pacific Biosciences.

Facts: Spatial transcriptomics of immune cells
The method of spatial transcriptomics was developed in 2016 by professors Jonas Frisén at Karolinska Institutet and Joakim Lundeberg at KTH Royal Institute of Technology, who are co-authors of this study. It was named “Method of the Year 2020” by the journal Nature Methods.
The new method is an upgrade of the original method that now makes it possible for researchers to map the immune cells’ receptors and their exact location in tissue, which was previously not possible to do for B and T cells at the same time.

A new study focused on wearable health monitors underscores an entrenched problem in the development of new health technologies — namely, that a failure to understand race means the way these devices are developed and tested can exacerbate existing racial health inequities.
“This is a case study that focuses on one specific health monitoring technology, but it really highlights the fact that racial bias is baked into the design of many of these technologies,” says Vanessa Volpe, co-author of the study and an associate professor of psychology at North Carolina State University.
“The way that we understand race, and the way that we put that understanding into action when developing and using health technologies, is deeply flawed,” says Beza Merid, corresponding author of the study and an assistant professor of science, technology, innovation and racial justice at Arizona State University.
“Basically, the design of health technologies that purport to provide equitable solutions to racial health disparities often define race as a biological trait, when it’s actually a social construct,” Merid says. “And the end result of this misunderstanding is that we have health technologies that contribute to health inequities rather than reducing them.”
To explore issues related to the way the development and testing of health tech can reinforce racism, the researchers focused specifically on photoplethysmographic (PPG) sensors, which are widely used in consumer devices such as Fitbits and Apple watches. PPG sensors are used in wearable technologies to measure biological signals, such as heart rate, by sending a signal of light through the skin and collecting data from the way in which the light is reflected back to the device.
For the study, the researchers drew on data from clinical validation studies for a wearable health monitoring device that relied on PPG sensors. The researchers also used data from studies that investigated the ways in which skin tone affects the accuracy of PPG “green light” sensors in the context of health monitoring. Lastly, the researchers looked at wearable device specification and user manuals and data from a lawsuit filed against a health technology manufacturer related to the accuracy of technologies that relied on PPG sensors.
“Essentially, we synthesized and interpreted data from each of these sources to take a critical look at racial bias in the development and testing of PPG sensors and their outputs, to see if they matched guidelines for responsible innovation,” Volpe says.

“These studies identified challenges with PPG sensors for people with darker skin tones,” says Merid. “We drew on scholarship exploring how innovative technologies can reproduce racial health inequities to dig more deeply into how and why these challenges exist. Our own expertise in responsible innovation and structural racism in technology guided our approach. If people are developing technologies with the goal of reducing harm to people’s health, how and why do these technologies end up with flaws that can exacerbate that harm?”
The findings suggest there are significant challenges when it comes to “race correction” in health technologies.
“Race correction” is a broad term that applies not only to technologies, but also involves correcting or adjusting health risk scores used to make decisions about the relative risk of disease and the allocation of health care resources.
“Race correction assumes that we can develop technologies or health risk scoring algorithms to first quantify and then ‘remove’ the effect of biological race from the equation,” says Merid. “But doing so assumes race is a biological difference that needs to be corrected for to achieve equitable health for all. This prevents us from treating the real thing that needs to be corrected — the system of racism itself (e.g., differential treatment and access to health care, systematic socioeconomic disenfranchisement).”
“For example, many — if not most — health technologies that use PPG sensors claim to be designed for use by everyone,” Volpe says. “But in reality those technologies are less accurate for people with darker skin tones. We argue that the systematic exclusion and erasure of those with darker skin tones in the development and testing of wearable technologies that are supposed to democratize and improve health for all can be a less visible form of race correction. In other words, the development process itself reflects the system of racism. The end result is a technological ‘solution’ that fails to deliver equity and is instead characteristic of the very system that created the problem.
“Race corrections assume that we have to make adjustments based on race as a biological construct,” Volpe says. “But we should be adjusting racism as a system so that the technologies developed work and are responsible and equitable for everyone — in both their development and their consequences.”
“Innovation can introduce unintended consequences,” Merid says. “Rather than coming up with a solution, you can potentially just introduce a new suite of problems. This is a longstanding challenge for trying to develop technological solutions to social problems.
“Hopefully, this work contributes to our understanding of the ways that race correction is problematic,” says Merid. “We also hope that this work advances the idea that assumptions about race in the health field are deeply problematic, whether we’re talking about health technology, diagnoses or access to care. Lastly, we need to be mindful about the ways in which emerging health technologies can be harmful.”