How to Restore Vital Cellular Functions to Pigs one Hour After Death

Within minutes of the final heartbeat, a cascade of biochemical events triggered by a lack of blood flow, oxygen, and nutrients begins to destroy a body’s cells and organs. But a team of Yale scientists has found that massive and permanent cellular failure doesn’t have to happen so quickly.

Using a new technology the team developed that delivers a specially designed cell-protective fluid to organs and tissues, the researchers restored blood circulation and other cellular functions in pigs a full hour after their deaths, they report in the Aug. 3 edition of the journal Nature. The findings may help extend the health of human organs during surgery and expand availability of donor organs, the authors said.

All cells do not die immediately, there is a more protracted series of events,” said David Andrijevic, associate research scientist in neuroscience at Yale School of Medicine and co-lead author of the study. “It is a process in which you can intervene, stop, and restore some cellular function.”The research builds upon an earlier Yale-led project that restored circulation and certain cellular functions in the brain of a dead pig with technology dubbed BrainEx. Published in 2019, that study and the new one were led by the lab of Yale’s Nenad Sestan, Professor of Neuroscience.

If we were able to restore certain cellular functions in the dead brain, an organ known to be most susceptible to ischemia [inadequate blood supply], we hypothesized that something similar could also be achieved in other vital transplantable organs,” Sestan said.

In the new study — which involved senior author Sestan and colleagues Andrijevic, Zvonimir Vrselja, Taras Lysyy, and Shupei Zhang, all from Yale — the researchers applied a modified version of BrainEx called OrganEx to the whole pig. The technology consists of a perfusion device similar to heart-lung machines — which do the work of the heart and lungs during surgery — and an experimental fluid containing compounds that can promote cellular health and suppress inflammation throughout the pig’s body. Cardiac arrest was induced in anesthetized pigs, which were treated with OrganEx an hour after death.

Six hours after treatment with OrganEx, the scientists found that certain key cellular functions were active in many areas of the pigs’ bodies — including in the heart, liver, and kidneys — and that some organ function had been restored. For instance, they found evidence of electrical activity in the heart, which retained the ability to contract.

We were also able to restore circulation throughout the body, which amazed us,” Sestan said.

Normally when the heart stops beating, organs begin to swell, collapsing blood vessels and blocking circulation, he said. Yet circulation was restored and organs in the deceased pigs that received OrganEx treatment appeared functional at the level of cells and tissueUnder the microscope, it was difficult to tell the difference between a healthy organ and one which had been treated with OrganEx technology after death,” Vrselja said.

Source: https://news.yale.edu/

Drug Prevents Breast Cancer Recurrence and Metastasis

Even when detected early, some cancers are more aggressive and more fatal than others. This is the case, for example, with triple negative breast cancer which accounts for 10 to 15% of all breast cancers. This cancer affects 1,000 patients per year in Belgium, while the figure worldwide is 225,000. Around half of the patients will develop local recurrences and metastases, regardless of the treatment they receive. No specific treatment is currently capable of preventing these two events. Patients suffering from pervasive triple negative breast cancer have only a one-in-ten chance of a cure. In 2014, Pierre Sonveaux, a researcher at the University of Louvain (UCLouvain) Institute for experimental and clinical research, succeeded in demonstrating the principle that it was possible to prevent the appearance of melanoma tumour metastases in mice. However, the experimental molecules used at the time were far from being drugs.

Since then, the UCLouvain researcher and his team, including post-doctoral researcher Tania Capeloa, have continued their work thanks in particular to sponsorship obtained by the UCLouvain Foundation. They have now succeeded in establishing that a drug developed for diseases other than cancer, MitoQ, avoids the appearance of metastases in 80% and local recurrences of human breast cancer in 75% of cases in mice. Conversely, most of the mice not treated suffered a recurrence of their cancer, which spread.

To do this, the researchers treated mice affected by human breast cancer. They treated them as hospital patients are treated, i.e. by combining surgery with a carefully dosed cocktail of standard chemotherapies. However, the UCLouvain researchers supplemented this standard treatment with the new molecule, MitoQ. They not only demonstrated that the administration of MitoQ is compatible with standard chemotherapies, but also that this innovative treatment prevents both relapses and metastases of breast cancer in mice. “We expected to be able to block the metastases, says Pierre Sonveaux enthusiastically. But preventing the recurrence of the cancer was totally unexpected. Getting this type of result is a huge motivation for us to carry on.” In short, this is a giant step given that the three main causes of cancer mortality are recurrences, the spread of the cancer caused by metastasis and resistance to treatment. And that there is currently no other known molecule capable of acting like MitoQ.

How does it work? Cancers consist of two types of cancerous cells: those that proliferate and are sensitive to clinical treatments and those that are dormant and that bide their time. Such cells are more harmful. The problem? These cancerous stem cells are resistant to clinical treatments. They result in metastases and if, unfortunately, cancer surgery fails to remove them all, they cause recurrences. These relapses are currently treated using chemotherapy. However, this tends to be relatively ineffective owing to the resistance to treatment developed by the tumorous cells . This is where the important discovery of the UCLouvain scientists comes in: the molecule MitoQ stops cancerous stem cells from awakening.

What next? MitoQ has already come through the first clinical phase successfully. It has been tested on healthy patients, both men and women, and proves to be only slightly toxic (nausea, vomiting). In addition, its behaviour is known. What next? The discovery made by the UCLouvain scientists opens wide the path for the clinical 2 phase, intended to demonstrate the efficacy of the new treatment in cancer patients.

Source: https://uclouvain.be/
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https://www.thebrighterside.news

Tiny Bubbles Destroy Tumours in Seven Minutes

Following her diagnosis with liver cancer last June, 68-year-old Sheila Riley braced herself for painful and gruelling treatmentsSurgery, chemotherapy, radio-therapy and even ablation — where heat is used to destroy tumours — are some of medicine’s most effective tools against cancer, but the potential side-effects can be hard to bear. In fact, Sheila was spared these thanks to a radical new form of therapy that uses tiny bubbles of gas to destroy tumours within minutes and doesn’t leave a mark on the body. She was one of the first patients in the UK to undergo histotripsy, where focused ultrasound waves are directed from outside the body to destroy tumours by generating thousands of exploding gas bubbles. So rapid is the procedure that her tumour was obliterated painlessly — in under seven minutes.

It was amazing,’ says the grandmother of eight, who had the treatment last August at St James’s University Hospital in Leeds. ‘I didn’t need any medication — not even painkillers afterwards,’ adds Sheila, who lives in Bradford with her partner Frank, 70. ‘I was able to go shopping the next day, and two days after my treatment I was out with friends. It didn’t even leave a mark on my skin.

It is now hoped the procedure can help those with tumours in other parts of the bodyHistotripsy was pioneered by researchers at the University of Michigan in the U.S. and relies on a process called cavitation — creating an empty space inside something solid — to eradicate cancer. First, a beam of ultrasound energy is directed through the skin to the tumour site. As the beam hits the targeted spot, it activates thousands of pockets of gas that occur naturally in tissue throughout the body, even tumours, as a result of the respiratory process. These tiny pockets of gas are usually dormant, but when blasted with the sound waves, they expand, vibrate and explode, forming a high-energy cloud of microbubbles in the tumour. As they rapidly expand and collapse, the bubbles break up surrounding cancerous tissue, liquifying it into a solution that then gets passed out of the body as waste.

Unlike existing treatments such as microwave ablation, where a heat-generating probe is used to ‘cook’ tumour cells, there is no heat that might damage surrounding healthy tissue, making cavitation potentially safer. This capacity for ultrasound to destroy tissue has been known about for years but was not previously adopted as a cancer treatment because it was too difficult to control the bubble clouds and avoid damaging healthy tissue.

However, the process has now been fine-tuned and the energy source can be better directed inside the tumour, avoiding the risk of nearby healthy tissue or organs being affected. An international trial is now under way looking at histotripsy for liver cancer. The chief investigator, Professor Tze Min Wah, a senior consultant interventional radiologist at St James’s University Hospital, believes cavitation could transform cancer treatment. ‘Rather than using heat, radiation or surgery to remove the tumour, the bubble cloud created by histotripsy is so powerful that it ruptures the tumour but doesn’t damage the tissue around it,’ she says.

Source: https://www.dailymail.co.uk/

Augmented Reality (AR) Revolutionizes Surgery

Dr Stephen Quinn, a gynaecologist at hospitals in the NHS Trust Imperial College, appears on TV show to help a patient, Hilda, with a condition causing her swollen abdomen. After taking careful scans of Hilda’s body, the team are able to show her the growths, called fibroids, that are behind her pain.

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I’ve spent a lot of my career looking at MRI scans of pelvises, and having these images is extremely helpful in clinic,” said Quinn. “But using augmented reality just took that to a whole different level. It was fantastic being able to to fully visualise exactly what was going on in the pelvis ahead of the surgery to remove the fibroids.”

Unfortunately, the technology is a way off being available on the NHS, but Quinn said AR’s use could be commonplace within the next decade.

For the show, radiologists at Imperial hospitals provided artists with in-depth scans of each patient. Dr Dimitri Amiras, a musculoskeletal consultant radiologist at Imperial, also worked on the experiment.

First, patients would undergo routine scans. “In order to define what the organ is and where the pathology is, that’s all done by radiologists. We are the ones to identify it and look at the imaging techniques work out what is good tissue, what’s bad tissue,” said Amiras. “Then, once we’ve got those images with relevant bits identified, digital artists may draw around them or even use artificial intelligence to make all the pretty pictures and the shiny stuff.”

Once finished, the patients and doctors would wear an AR device to ‘see’ the body part in front of them. Each was 3D, and could be zoomed in or out, rotated, and compared to the same areas on a healthy individual.

Source: https://www.sciencefocus.com/

Robot Performs much Better than Humans at Surgery

For years, the world of medicine has been steadily advancing the art of robot-assisted procedures, enabling doctors to enhance their technique inside the operating theatre. Now US researchers say a robot has successfully performed keyhole surgery on pigs all on its own without the guiding hand of a human. Furthermore, they add, the robot surgeon produced “significantly better” results than humans.

Smart Tissue Autonomous Robot (Star) carried out laparoscopic surgery to connect two ends of an intestine in four pigs. The robot excelled at the procedure, which requires a high level of precision and repetitive movements

Axel Krieger, of Johns Hopkins University, said it marked the first time a robot had performed laparoscopic surgery without human help. “Our findings show that we can automate one of the most intricate and delicate tasks in surgery: the reconnection of two ends of an intestine,” he said. “The Star performed the procedure in four animals and it produced significantly better results than humans performing the same procedure.”

Connecting two ends of an intestine is a challenging procedure in gastrointestinal surgery, requiring a surgeon to apply stitches – or sutures – with high accuracy and consistency. Even a slight hand tremor or misplaced stitch can result in a leak that could result in a patient suffering fatal complications. Krieger, an assistant professor of mechanical engineering at Johns Hopkins, helped create the robot, a vision-guided system designed specifically to suture soft tissue. It improves a 2016 model that repaired a pig’s intestines, but required a large incision to access the intestine and more guidance from humans.
Experts say new features allow for improved surgical precision, including specialised suturing tools and imaging systems that provide more accurate visualisations of the surgical field.
Source: https://www.theguardian.com/

Successful Transplant of Porcine Heart into Adult Human

In a first-of-its-kind surgery, a 57-year-old patient with terminal heart disease received a successful transplant of a genetically-modified pig heart and is still doing well three days later. It was the only currently available option for the patient. The historic surgery was conducted by University of Maryland School of Medicine (UMSOM) faculty at the University of Maryland Medical Center (UMMC), together known as the University of Maryland Medicine.

This organ transplant demonstrated for the first time that a genetically-modified animal heart can function like a human heart without immediate rejection by the body. The patient, David Bennett, a Maryland resident, is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits. He had been deemed ineligible for a conventional heart transplant at UMMC as well as at several other leading transplant centers that reviewed his medical records.

 “It was either die or do this transplant. I want to live. I know it’s a shot in the dark, but it’s my last choice,” said Mr. Bennett, the patient, a day before the surgery was conducted. He had been hospitalized and bedridden for the past few months.  I look forward to getting out of bed after I recover.

The U.S. Food and Drug Administration granted emergency authorization for the surgery on New Year’s Eve through its expanded access (compassionate use) provision. It is used when an experimental medical product, in this case the genetically-modified pig’s heart, is the only option available for a patient faced with a serious or life-threatening medical condition. The authorization to proceed was granted in the hope of saving the patient’s life.

“This was a breakthrough surgery and brings us one step closer to solving the organ shortage crisis. There are simply not enough donor human hearts available to meet the long list of potential recipients,” said Bartley P. Griffith, MD, who surgically transplanted the pig heart into the patient. Dr. Griffith is the Thomas E. and Alice Marie Hales Distinguished Professor in Transplant Surgery at UMSOM. “We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future.”

Considered one of the world’s foremost experts on transplanting animal organs, known as xenotransplantation, Muhammad M. Mohiuddin, MD, Professor of Surgery at UMSOM, joined the UMSOM faculty five years ago and established the Cardiac Xenotransplantation Program with Dr. Griffith. Dr. Mohiuddin serves as the program’s Scientific/Program Director and Dr. Griffith as its Clinical Director.

“This is the culmination of years of highly complicated research to hone this technique in animals with survival times that have reached beyond nine months. The FDA used our data and data on the experimental pig to authorize the transplant in an end-stage heart disease patient who had no other treatment options,” said Dr. Mohiuddin.The successful procedure provided valuable information to help the medical community improve this potentially life-saving method in future patients.

Source: https://www.medschool.umaryland.edu/

Glue Seals Bleeding Organs in Seconds

Inspired by the sticky substance that barnacles use to cling to rocks, MIT engineers have designed a strong, biocompatible glue that can seal injured tissues and stop bleeding. The new paste can adhere to surfaces even when they are covered with blood, and can form a tight seal within about 15 seconds of application. Such a glue could offer a much more effective way to treat traumatic injuries and to help control bleeding during surgery, the researchers say.

We are solving an adhesion problem in a challenging environment, which is this wet, dynamic environment of human tissues. At the same time, we are trying to translate this fundamental knowledge into real products that can save lives,” says Xuanhe Zhao, a professor of mechanical engineering and civil and environmental engineering at MIT and one of the senior authors of the study. Finding ways to stop bleeding is a longstanding problem that has not been adequately solved, Zhao says. Sutures are commonly used to seal wounds, but putting stitches in place is a time-consuming process that usually isn’t possible for first responders to perform during an emergency situation. Among members of the military, blood loss is the leading cause of death following a traumatic injury, and among the general population, it is the second leading cause of death following a traumatic injury.

In recent years, some materials that can halt bleeding, also called hemostatic agents, have become commercially available. Many of these consist of patches that contain clotting factors, which help blood to clot on its own. However, these require several minutes to form a seal and don’t always work on wounds that are bleeding profusely. Zhao’s lab has been working to address this problem for several years

For their new tissue glue, the researchers once again drew inspiration from the natural world. This time, they focused their attention on the barnacle, a small crustacean that attaches itself to rocks, ship hulls, and even other animals such as whales. These surfaces are wet and often dirty — conditions that make adhesion difficult. “This caught our eye,” Yuk says. “It’s very interesting because to seal bleeding tissues, you have to fight with not only wetness but also the contamination from this outcoming blood. We found that this creature living in a marine environment is doing exactly the same thing that we have to do to deal with complicated bleeding issues.” The researchers’ analysis of barnacle glue revealed that it has a unique composition. The sticky protein molecules that help barnacles attach to surfaces are suspended in an oil that repels water and any contaminants found on the surface, allowing the adhesive proteins to attach firmly to the surface.

The MIT team decided to try to mimic this glue by adapting an adhesive they had previously developed. This sticky material consists of a polymer called poly(acrylic acid) embedded with an organic compound called an NHS ester, which provides adhesion, and chitosan, a sugar that strengthens the material. The researchers froze sheets of this material, ground it into microparticles, and then suspended those particles in medical grade silicone oil.

Christoph Nabzdyk, a cardiac anesthesiologist and critical care physician at the Mayo Clinic in Rochester, Minnesota, is also a senior author of the paper, which appears today in Nature Biomedical Engineering. MIT Research Scientist Hyunwoo Yuk and postdoc Jingjing Wu are the lead authors of the study.

Source: https://news.mit.edu/

Gene Therapy Treats Eye Disease whithout Surgery

A new gene therapy could eventually provide an alternative treatment for Fuchs’ endothelial corneal dystrophy, a genetic eye disease that affects roughly one in 2,000 people globally. Currently, the only treatment is corneal transplant, a major surgery with associated risks and potential complications.

When you do a transplant you make a huge difference for that person, but it’s a big deal for the patient with lots of visits, lots of eye drops, lots of co-pays, and if you had a medical treatment that did not require surgery, that would be great,” says Bala Ambati, a research professor at the University of Oregon who led an eight-year study involving the development of the gene therapy. “Not only could it help patients who need a transplant, but it could also help a lot of other people who could have used that (corneal) tissue.

For the study in the journal eLife, investigators focused on a rare, early-onset version of the disease and carried out the research in mice. They used CRISPR-Cas9, a powerful tool for editing genomes, to knock out a mutant form of a protein that is associated with the disease.

Fuchs’ dystrophy occurs when cells in the corneal layer called the endothelium gradually die off and stressed cells produce structures known as guttae. These cells normally pump fluid from the cornea to keep it clear, but when they die, fluid builds up, the cornea gets swollen, and vision becomes cloudy or hazy.

We were able to stop this toxic protein expression and study it in a mouse model,” says coauthor Hiro Uehara, a senior research associate in the Ambati lab. “We confirmed that (in mice who received it), our treatment was able to rescue loss of corneal endothelial cells, reduce guttata-like structures, and preserve the corneal endothelial cell pump function.

Corneal cells are non-reproducing, meaning you’re born with all of the cells you will ever have, Ambati says. One of the challenges of the study involved using CRISPR gene editing technology on such cells, a process that is technically difficult.

Uehara developed an innovative workaround that increases the utility of the CRISPR technology and could eventually lead to treatments for other diseases involving non-reproducing cells, including some neurologic diseases, immune diseases, and certain genetic disorders affecting the joints. The study marks the first time that researchers have applied the technique, called start codon disruption, to non-reproducing cells.

Source: https://accelerate.uoregon.edu/

Skin and Bones Repaired by Bioprinting

Fixing traumatic injuries to the skin and bones of the face and skull is difficult because of the many layers of different types of tissues involved, but now, researchers have repaired such defects in a rat model using bioprinting during surgery, and their work may lead to faster and better methods of healing skin and bones.

Schematic of the skin and bone bioprinting process. After scanning, the bone and then skin layers are bioprinted creating a layered repair with bone, a barrier layer, and dermis and epidermis

This work is clinically significant,” said Ibrahim T. Ozbolat, Associate Professor of Biomedical Engineering and Neurosurgery, Penn State. “Dealing with composite defects, fixing hard and soft tissues at once, is difficult. And for the craniofacial area, the results have to be esthetically pleasing.

Currently, fixing a hole in the skull involving both bone and soft tissue requires  using bone from another part of the patient’s body or a cadaver. The bone must be covered by soft tissue with blood flow, also harvested from somewhere else, or the bone will die. Then surgeons need to repair the soft tissue and skin. Ozbolat and his team used extrusion bioprinting and droplet bioprinting of mixtures of cells and carrier materials to print both bone and soft tissueThere is no surgical method for repairing soft and hard tissue at once,” said Ozbolat. “This is why we aimed to demonstrate a technology where we can reconstruct the whole defect — bone to epidermis — at once.”

The researchers attacked the problem of bone replacement first, beginning in the laboratory and moving to an animal model. They needed something that was printable and nontoxic and could repair a 5-millimeter hole in the skull. The “hard tissue ink” consisted of collagen, chitosan, nano-hydroxyapatite and other compounds and mesenchymal stem cells — multipotent cells found in bone marrow that create bone, cartilage and bone marrow fat. The hard tissue ink extrudes at room temperature but heats up to body temperature when applied. This creates physical cross-linkage of the collagen and other portions of the ink without any chemical changes or the necessity of a crosslinker additive.

The researchers used droplet printing to create the soft tissue with thinner layers than the bone. They used collagen and fibrinogen in alternating layers with crosslinking and growth enhancing compounds. Each layer of skin including the epidermis and dermis differs, so the bioprinted soft tissue layers differed in composition. Experiments repairing 6 mm holes in full thickness skin proved successful. Once the team understood skin and bone separately, they moved on to repairing both during the same surgical procedure. “This approach was an extremely challenging process and we actually spent a lot of time finding the right material for bone, skin and the right bioprinting techniques,” said Ozbolat.

The scientists have reported their results in Advanced Functional Materials.

Source: https://news.psu.edu/

3D printing becoming a surgical game changer

Imagine 1,000 puzzle pieces without any picture of what it’s ultimately supposed to look like. With few, if any, reference points, the challenge of fitting them together would be daunting. That’s what surgeons often confront when a patient suffering from a traumatic injury or condition has a portion of their body that is dramatically damaged or changed. The “puzzle” can be exponentially harder when the injuries involve a person’s face or skull – areas of the human anatomy that are complex, difficult to surgically navigate, and often require both functional and near-perfect cosmetic repair.

Now, thanks to high-tech equipment that is sometimes not much bigger than a home printer, UC Davis Health physicians are enhancing their capabilities and mapping out surgeries in ways that benefit patients and surgical outcomes.

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3D printing, which for us means manufacturing that’s accurate, affordable and on-site, can be a game changer in health care,” said David Lubarsky, vice chancellor for Human Health Sciences and CEO of UC Davis Health, who is very encouraged by the university’s newest technology initiatives and promising results.

The new device is a specialized but fairly affordable printer that produces three-dimensional models of an individual’s skull or body part. The 3D models enable a surgeon to visualize, practice and then perform the reconstructive surgery while saving time and increasing precision.

Facial reconstructive surgery involves intricate anatomy within an extremely narrow operative field in which to maneuver our instruments,” said E. Bradley Strong, a professor of otolaryngology who specializes in facial reconstructive surgery. “Being able to print out a high-resolution 3D model of the injury, allows us to do detailed preoperative planning and preparation that is more efficient and accurate. We can also use these patient specific models in the operating room to improve the accuracy of implant placement.”

The 3D printer used by Strong and his colleagues for the past year is about the size of a mini-refrigerator and costs approximately $4,000. It uses the imaging data from a patient’s computed tomography (CT) scans to provide the modeling output information. Like an inkjet printer, the 3D version spits out layer upon layer of material over a period of hours, sometimes taking nearly a day to complete, depending on the complexity of the model. The finished replica can save time during surgery, which means less time on the operating table for a patient and potentially a better outcome.

By creating a 3D model prior to surgery, Strong is able to bend and customize generic surgical plates into patient-specific shapes that fit perfectly for each individual patient.

Source: https://health.ucdavis.edu/