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* Improving cell transplantation after spinal cord injury: When, where and how?

Spinal cord injuries are mostly caused by trauma, often incurred in road traffic or sporting incidents, often with devastating and irreversible consequences, and unfortunately having a relatively high prevalence (250,000 patients in the USA; 80% of cases are male). One currently explored approach to restoring function after spinal cord injury is the transplantation of olfactory ensheathing cells (OECs) into the damaged area. The hope is that these will encourage the repair of damaged neurons, but does it work? And if so, how can it be optimized?

According to a systematic analysis of the literature published this week in PLOS Biology, after experimental spinal cord injury, transplanting OECs into the site of damage does indeed significantly improve locomotor performance. To reach this conclusion, Ralf Watzlawick, Jan Schwab, and their colleagues at the Ohio State University Wexner Medical Center, Charité Universtaetsmedizin Berlin and the CAMARADES consortium (Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies), analyzed 49 studies, published between 1949 and 2014, which included 62 experiments involving 1164 animals.

Restoration of function after spinal cord injury remains one of the most formidable challenges in regenerative medicine, but cell transplantation into the spinal cord represents a promising treatment strategy. OECs are considered particularly suitable for transplantation because they have been shown to be neuro-protective and to promote neuro-regeneration in different settings, and can be extracted from the patient’s own nasal cavity, thereby minimizing the chances of graft rejection and avoiding the need for immunosuppressive drugs.

However, reports in the literature about the efficacy of transplantation of OECs for treatment of spinal cord injury have been contradictory. Therefore, to investigate the in vivo evidence for the efficacy of this procedure, the authors implemented a systematic review and meta-analysis of the literature. Importantly, the authors set out to explore the potential influence of variations in experimental approaches and unreported data.

“We felt that after more than two decades since the discovery that OECs elicit effects on neural plasticity in vivo, it was time to test their effects by appropriate methodology beyond reproduction,” the authors argued.

The data analysed by the authors justify the use of OECs as a cellular substrate to develop and to optimize minimally invasive and secure protocols for repairing damaged spinal cord. They also identified several aspects of the cell transplantation procedure that could have a significant impact on the size of the therapeutic effect, including: the time-point of application, the use of surgical micro-dissection to “refresh” the scar tissue, the localization of transplanted cells, the number of injections, the injected volume, and the dose of cells administered.

Importantly, by using state-of-the-art statistical methods the authors also found that the impact of publication bias (due to selective failure to report results) was minimal, further supporting the translational potential of this approach.

Despite being focussing on OECs, the findings may be of more general relevance for optimizing the transplantation of other cell types after spinal cord injury.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160531165224.htm  Original web page at Science Daily

 

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New imaging method makes gall bladder removals, other procedures more safe

UCLA researchers have discovered an optimal way to image the bile ducts during gallbladder removal surgeries using a tested and safe dye and a real-time near-infrared florescence laparoscopic camera, a finding that will make the procedure much safer for the hundreds of thousands of people who undergo the procedure each year.

The new imaging procedure can also be used any time surgeons look laparoscopically at the liver and surrounding anatomy.

The gallbladder and liver can be hard to access and visualize when the areas around them are inflamed or surrounded by fat. Using the conventional imaging technique, in which the bile ducts are not as clearly delineated, injuries to the ducts can occur. Those injuries sometimes remain undetected during the surgery, which can lead to serious problems for the patients, said study first author Dr. Ali Zarrinpar, an assistant professor of surgery in the Division of Liver and Pancreas Transplantation.

“Removal of the gallbladder is one of the most commonly performed operations in the United States, with more than 100,000 surgeries performed each year. Injuries to the bile ducts, which carry bile from the liver to the intestines, are rare. But when they do occur, the outcomes can be quite serious and cause life-long consequences,” Zarrinpar said. “Gallbladder removals are one of the most litigated cases in general surgery because of these injuries. Any technique that can reduce the rate of bile duct injury and increase the safety of the operation is good for patients and for surgeons.”

The study appears March 10, 2016 in the early online edition of the peer-reviewed journal Surgical Innovations.

The dye, called indocyanine green (ICG), is approved by the U.S. Food and Drug Administration and has been in use medically for 60 years. The near-infrared florescence laparoscopic camera also is approved for use in colorectal surgeries. This is the first study to optimize the timing and dosing of the dye using his device, Zarrinpar said.

After being injected into a vein, ICG is taken up by the liver and excreted into the bile. The laparoscopic device then detects the fluorescence of the dye in the bile ducts and superimposes that image onto the conventional white light image that surgeons use routinely. This augmented image improves the surgeons’ visualization of the bile ducts, making it easier for them to identify the appropriate anatomy.

Prior to this study, it was unclear just how long before the procedure the dye had to be injected and exactly how much for optimal imaging. Timing, and dosage, often varied widely among practioners. Sometimes, patients got the ICG injected the day prior to their surgery, requiring an extra doctor visit.

However, Zarrinpar and his team found that the dye could be injected as little as 25 to 30 minutes before with good result, although one to four hours prior did improve the image. They also found that patients could receive much less of the dye than many were getting, allowing them to clear the substance in the bile from their bodies much more quickly.

The finding also could lead to a reduction in the number of “open” gallbladder removals and partial liver resections. When the surgeons have trouble visualizing the bile duct and surrounding anatomy, they often will switch from laparoscopic to open surgeries, which make it easier to avoid injuring the bile duct but result in a more difficult and lengthy recovery time for patients.

The prospective UCLA study, which took six months, was small, with 37 patients enrolled. Going forward, Zarrinpar is working to put together a much larger clinical trial to confirm his findings and see if the imaging process and the resulting benefits are cost effective, Zarrinpar said.

“This study provides guidance on the timing and dosing of indocyanine green with respect to anticipated visualization of the biliary tree,” the study states. “NIRFC is practical and effective in delineating extrahepatic biliary anatomy during laparoscopic biliary and hepatic operations, and its use should therefore be considered over traditional methods.”

https://www.sciencedaily.com/releases/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160310164857.htm  Original web page at Science Daily

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New surgical tool keeps orthopedic procedures on target

New fiber optic guide-wire will enable surgeons to perform highly accurate hip fracture and spinal fusion surgery with minimal side effects. Common orthopedic procedures, such as hip and pelvic fracture surgery as well as spinal fusion, require the accurate positioning of a thin metallic wire to guide the positioning of a fixating screw. However, the surgical procedure is often hampered by deflection, bending and even breakage of the guide-wire, which then requires repair while complicating and prolonging the recovery of patients.

“This is a significant challenge,” said Prof. Meir Liebergall, head of the Department of Orthopedic Surgery at Hadassah Medical Center, “as complications in guide-wire positioning could lead to revision surgeries and increase hospitalization time and cost.”

To address this challenge, Prof. Liebergall partnered with a multidisciplinary team of medical doctors, along with engineering and business students, from The Hebrew University’s BioDesign: Medical Innovation program.

They identified a solution: by creating a system that provides real-time indication of deflection or bending of the guide-wire, the surgeon will be able to adjust the procedure before damage occurs.

The team developed BendGuide, an opto-electronic drilling system that monitors and detects minute changes in guide-wire trajectory during surgery. It allows surgeons to correct drilling trajectories during the procedure itself. The system eliminates guide-wire bending or breakage and significantly reduces operation time and enhances safety.

“This is an elegant technological solution to a complex problem,” said Prof. Yaakov Nahmias, director of The Hebrew University’s Alexander Grass Center for Bioengineering and the BioDesign program. “The group model and proof-of-concept experiments showed they could detect even miniscule changes in guide-wire trajectory.”

BendGuide uses a fiber bundle with a reflecting laser beam that enables detection of small deflections in wire trajectory. At a fully-aligned state, the beam power hits the center of the detector array. When deflected, mirror misalignment causes the power to spread differentially across the fiber bundle.

The market for computer-aided navigation systems for surgery is growing fast. The potential market is estimated at $500 million annually in the United States alone. BendGuide aims to become an integral part of this market, which is expected to grow further with the aging population.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/02/160223132717.htm  Original web page at Science Daily

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* Karolinska Institute to cut ties with controversial surgeon

The Karolinska Institute (KI) in Stockholm is ending its association with acclaimed but controversial surgeon Paolo Macchiarini, who pioneered transplants of artificial windpipes but has been accused of ethical breaches in his work.

Macchiarini’s contract will not be renewed when it runs out in November 2016, the Karolinska announced, and he has been asked to use his remaining time to phase out his research there. Macchiarini’s head of department is also responsible for ensuring that “the work of his research group is dismantled”, the institute says.

The 4 February decision comes after revelations in a Swedish documentary that Macchiarini conducted operations in Krasnodar, Russia, on at least one patient who was not life-threateningly ill, and that he misrepresented the success of his prosthetic grafts in scientific publications. The programme has created uproar in Sweden, and led the KI to announce earlier this week that it was looking into the case.

Now, the Karolinska has “lost confidence” in Macchiarini, explains Claes Keisu, a press officer for the institute. “He has overexploited Karolinska’s brand in his work in Krasnodar. His activities there has undermined KI’s reputation and damaged the public’s and the scientific community’s trust in KI,” Keisu says.

The institute is also looking into discrepancies in the surgeon’s CV, adds Keisu. Those allegations were first made in a Vanity Fair article.

The surgeon’s work was hailed as a game-changer in regenerative medicine when, in 2011, he implanted a plastic artificial trachea, using bioengineered stem cells, into a patient whose own windpipe had been damaged. Over the next three years, he carried out seven more synthetic trachea implantations — two more at the Karolinska, one in Illinois and four in Russia, where he heads a tissue engineering project. Six of the eight patients have died (from causes unrelated to the transplants, Macchiarini says), and one has been in intensive care since the procedure.

The documentary, made by SVT, Sweden’s national broadcaster, was aired in January. It suggested that in Russia, Macchiarini implanted a trachea into a woman who was not in a life-threatening condition. That was news to the Karolinska’s vice-chancellor Anders Hamsten, who said in a statement that the institute would never have approved Macchiarini’s activities in Russia if they were as the documentary describes.

Five months ago, Hamsten had cleared Macchiarini of allegations of misconduct in research papers — after an independent investigation had found the surgeon guilty. The institute has not yet decided whether to reopen that investigation. But on 4 February it said it would open an external investigation into its own handling of the Macchiarini case, to be led by a lawyer and medical researchers who have not yet been appointed. Swedish prosecutors are also investigating the three procedures carried out at Karolinska, but have not made any charges.

Macchiarini, a visiting professor at the KI since 2010, has not yet responded to Nature’s requests for comment after the latest Karolinska announcement. After the documentary, he said that he was “in the process of presenting all the multidisciplinary conference discussions that were had around each patient’s case — along with the ethical committee decisions that approved them — to the Karolinska Institute”.

Nature doi:10.1038/nature.2016.19315

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/karolinska-institute-to-cut-ties-with-controversial-surgeon-1.19315  Original web page at Nature

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* Freezing nerves prior to knee replacement improves outcomes, study finds

The first study of its kind has found that freezing nerves before knee replacement surgery combined with traditional pain management approaches significantly improves patient outcomes. The results of the preliminary retrospective study led by Vinod Dasa, MD, Associate Professor of Clinical Orthopaedics at LSU Health New Orleans School of Medicine, were published online Feb. 10, 2016, in the journal, The Knee.

The study, a retrospective chart review, investigated the cases of 100 patients with advanced osteoarthritis requiring total knee replacement in Dr. Dasa’s LSU Health New Orleans orthopaedic practice. Half of them were treated with standard multiple pain management options, before cryoneurolysis (nerve freezing) was introduced to the practice. The first 50 patients to undergo cryneurolysis in addition to multimodal pain management comprised the treatment group, which was compared to the control group who had standard therapy alone. The treatment and control groups were similar in terms of gender, age and body mass index. The only difference is that the treatment group received cryoneurolysis via an FDA-approved handheld device five days prior to surgery. The KOOS (Knee Injury and Osteoarthritis Outcome Score), PROMS (Patient-reported Outcomes Measurement Information System), WOMAC (Western Ontario and McMaster Universities Arthritis Index) and Oxford Knee Score were used to measure outcomes.

“Patients in the treatment group had significantly shorter hospital stays, were prescribed significantly fewer opioids during the first 12 weeks post-operatively and had significantly fewer knee symptoms,” notes Dr. Vinod Dasa, Associate Professor of Clinical Orthopaedics at LSU Health New Orleans School of Medicine.

The ability to decrease hospital length of stay following total knee replacement should substantially reduce costs for hospitals and payers. In the present study, only 6% of patients treated with cryoneurolysis prior to surgery stayed in the hospital for two or more days compared to 67% of patients who did not receive this treatment. Similarly, almost half of patients treated with cryoneurolysis were discharged on the same day of surgery compared with only 14% in the control group. The shorter length of stay of the patients in the treatment group may be due to better local control of pain and a reduced need for nerve blocks that can impair motor function, as well as reduced use of opioids for pain control, which allows patients to walk and function well enough to go home sooner.

Approximately 600,000 knee replacements are performed each year, and this number is expected to increase in coming years. Although knee replacements usually are very successful in the long term, patients often experience a significant amount of pain during the immediate post-operative period, which can be a major hindrance to effective rehabilitation and restoration of function following surgery

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/02/160211185928.htm Original web page at Science Daily

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Can stem cell technology be harnessed to generate biological pacemakers?

Although today’s pacemakers are lifesaving electronic devices, they are limited by their artificial nature. For example, their parts can fail or they can become infected. In addition, the devices require regular maintenance, must be replaced periodically, and can only approximate the natural regulation of a heartbeat. A Review article published on November 20 in Trends in Molecular Medicine highlights the promise and limitations of new methods based on stem cell and reprogramming technologies to generate biological pacemakers that might one day replace electronic pacemakers.

“Theoretically, biological pacemakers, which are composed of electrically active cells that can functionally integrate with the heart, could provide natural heart rhythm regulation without the need for indwelling hardware,” says author Vasanth Vedantham, of the University of California, San Francisco.

To create biological pacemakers, one approach is to coax stem cells to become specialized cardiac pacemaker cells that are normally found within the sinoatrial node of the heart. These are then transplanted into an ailing heart to restore pacemaking function. Another promising approach is to directly reprogram supporting cells, already present in the heart–for instance, fibroblasts (e.g., connective tissue)–and convert them into pacemaker cells to restore cardiac function.

Vedantham states that initial large animal studies on biological pacemakers have generated promising results but that much more work remains ahead before biological pacing can be actually considered a clinically viable therapy. For example, researchers need to better understand the mechanisms controlling the development and maintenance of pacemaker cells in the sinoatrial node, just as they must develop ways to compare experimental biological pacemaker tissue with bona fide sinoatrial node tissue. Also, scientists will need to improve the methods used to deliver cells to desired locations within the heart, as well as the recovery of specific individual cells for detailed characterization and functional analyses.

“Biological pacemakers must meet a very high standard of performance to supplant electronic pacemakers,” Vedantham says. “Because even a few seconds without a heartbeat can lead to serious consequences, a biological pacemaker would need to exhibit very robust and reliable performance. It remains to be determined whether this will be technically feasible. Despite such challenges, the field is poised for rapid progress over the next few years,” he adds.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/11/151120182815.htm  Original web page at Science Daily

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Engineers develop new method to repair elephant tusks

A new resin is replacing the metal ring typically used to prevent cracks from furthering down an elephant’s tusk. When Birmingham Zoo veterinarians approached researchers from the University of Alabama at Birmingham School of Engineering to help them stop a crack from growing in their oldest elephant’s tusk, the engineers saw an opportunity to use their expertise in materials science to improve the industry standard for the repair process.

Cracks in elephants’ tusks have historically been repaired by adhering a metal ring to the tusk in order to stabilize the crack and prevent it from growing any farther up the tusk. The Birmingham Zoo asked the director of UAB’s Materials Processing and Applications Development Center, Brian Pillay, Ph.D., to do just that, for Bulwagi, a 35-year-old male African elephant in their care.

Pillay’s immediate response was to innovate the process, and apply some of the science the lab uses in other materials processes to create a new, more robust and seamless treatment for the crack.

“When the team at the Zoo asked me to create this metal ring, I thought, ‘we can do better,'” Pillay said. “We can use what we know about materials development to make something that will work better for the elephant.”

“This is something that’s bridging the gap between what Dr. Pillay’s lab does working with industrial settings and what we do working with a biologic situation,” said Richard Sim, DVM, associate veterinarian at the Zoo. “It’s a first of its kind in that way — combining engineering that would normally be used in structures like bridges and applying it to an elephant.”

A cracked tusk can become infected and pose problems for an elephant. Tusks with cracks that are left untreated may ultimately have to be removed. “An open crack is a site for infection, as a tusk is basically a tooth,” Pillay said. “Imagine having a crack in your tooth — it’s rather painful for the elephants as well.”

The Zoo’s team of veterinarians, animal care specialists and curators worked with students and researchers from UAB to prepare, then apply, the composite fiberglass and carbon-fiber band and resin on Bulwagi’s tusk.

“We worked with Dr. Pillay’s lab to practice applying this product on a PVC pipe to start off with as a model,” Sim said. “I went down to the UAB lab on two occasions to really try to hammer out the details of how this was actually going to work. The first time I went down, we had a very successful practice session; but our idea of how we were going to apply it to a real-life setting was just not going to work for the elephant.”

Through training with MPAD staff engineer Ben Willis, Sim and Pillay’s team worked to perfect the process, and the end result was successful. “We put a number of layers of carbon fiber and fiberglass around the tusk, and then used a vacuum pump to suck the resin, kind of like an epoxy, up into that product, and it set and became a really hard structure that is going to resist the forces that resulted in the crack,” Sim said. “No one has done this before, so it’s our hope that this will be a process that will stand the test of time.”

“It’s the latest in technology, and it’s a great deal lighter, stronger and tougher than steel,” Pillay said. “The standard ring that would have been traditionally used is four to five times heavier than what Bulwagi has now. This is a significantly better solution.”

Tusk cracks are fairly common in elephants, because a great deal of pressure is put on the tusk as the elephants use them to interact with their environment and other elephants, so the repair process is something that will always be in demand.

While Bulwagi may eventually lose his tusk because of the progression of this particular crack, UAB and the Zoo sought to use this development process as a way to help other elephants in the future.

“Our hope is that we came up with something that will help a lot of elephants moving forward,” Pillay said.

The team’s next step is to wait and see how, and whether, the crack continues to develop over time, to evaluate how their creation will work for other elephants.

“Right now it’s just a waiting game, but we feel good about what we created and are looking forward to seeing if it can help other elephants,” Pillay said. “We’re hopeful that when vets first observe cracks, they will be able to go in and replicate this procedure to prevent the cracks from growing any farther and save the elephants’ tusks.”

Regardless of the outcome, this project has served another purpose — fostering collaboration between two Birmingham organizations.

“Having a partnership with the Greater Birmingham area is a model we use in caring for our animals,” Sim said. “It can only benefit us by employing the expertise of our community to help with issues that are outside of the scope of what we can do here.”

“It’s a perfect partnership, with the Zoo’s environmental responsibility to protect and care for the animals,” Pillay said. “At UAB, we do a lot of work in terms of human care; but it’s great to be able to take some of that technology and apply it to the animal world.

“Working with the Zoo to innovate and create something that serves to benefit animals has been tremendously rewarding for our team of researchers and students. For our students, specifically, it’s opening their eyes to how diverse the engineering industry can be. Being able work on a project like this as undergraduate and graduate students has been invaluable for their career development.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/11/151117182006.htm  Original web page at Science Daily

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New ‘Tissue Velcro’ could help repair damaged hearts

Engineers at the University of Toronto just made assembling functional heart tissue as easy as fastening your shoes. The team has created a biocompatible scaffold that allows sheets of beating heart cells to snap together just like Velcro™. “One of the main advantages is the ease of use,” says biomedical engineer Professor Milica Radisic, who led the project. “We can build larger tissue structures immediately before they are needed, and disassemble them just as easily. I don’t know of any other technique that gives this ability.”

Growing heart muscle cells in the lab is nothing new. The problem is that too often, these cells don’t resemble those found in the body. Real heart cells grow in an environment replete with protein scaffolds and support cells that help shape them into long, lean beating machines. In contrast, lab-grown cells often lack these supports, and tend to be amorphous and weak. Radisic and her team focus on engineering artificial environments that more closely imitate what cells see in the body, resulting in tougher, more robust cells.

Two years ago, Radisic and her team invented the Biowire, in which heart cells grew around a silk suture, imitating the way real muscle fibres grow in the heart. “If you think of single fibre as a 1D structure, then the next step is to create a 2D structure and then assemble those into a 3D structure,” says Boyang Zhang a PhD candidate in Radisic’s lab. Zhang and Miles Montgomery, another PhD student in the lab, were co-lead authors on the current work, published today in Science Advances.

Zhang and his colleagues used a special polymer called POMaC to create a 2D mesh for the cells to grow around. It somewhat resembles a honeycomb in shape, except that the holes are not symmetrical, but rather wider in one direction than in another. Critically, this provides a template that causes the cells to line up together. When stimulated with an electrical current, the heart muscle cells contract together, causing the flexible polymer to bend.

Next the team bonded T-shaped posts on top of the honeycomb. When a second sheet is placed above, these posts act like tiny hooks, poking through the holes of honeycomb and clicking into place. The concept the same as the plastic hooks and loops of Velcro™, which itself is based on the burrs that plants use to hitch their seeds to passing animals.

Amazingly, the assembled sheets start to function almost immediately. “As soon as you click them together, they start beating, and when we apply electrical field stimulation, we see that they beat in synchrony,” says Radisic. The team has created layered tissues up to three sheets thick in a variety of configurations, including tiny checkerboards.

The ultimate goal of the project is to create artificial tissue that could be used to repair damaged hearts. The modular nature of the technology should make it easier to customize the graft to each patient. “If you had these little building blocks, you could build the tissue right at the surgery time to be whatever size that you require,” says Radisic. The polymer scaffold itself is biodegradable; within a few months it will gradually break down and be absorbed by the body.

Best of all, the technique is not limited to heart cells. “We use three different cell types in this paper; cardiomyocytes, fibroblasts and endothelial cells, but conceptually there is really no limitation,” says Radisic. That means that other researchers could use the scaffold to build layered structures that imitate a variety of tissues, livers to lungs. These artificial tissues could be used to test out new drugs in a realistic environment.

Moreover, the ability to assemble and disassemble them at will could enable scientists to get much more detailed information on cell response than is currently possible. “You could take middle layer out, to see what the cells look like,” says Radisic. “Then you could apply a molecule that will cause differentiation or proliferation or whatever you want, to just that layer. Then you could put it back into the tissue, to see how it interacts with the remaining layers.”

The next step is to test how well the system functions in vivo. Radisic and her team are collaborating with medical researchers in order to design implantation experiments that will take the project one step closer to the clinic.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/08/150828142946.htm  Original web page at Science Daily

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Patient satisfaction is good indicator of success after spinal surgery

The researchers analyzed one-year follow-up data on 1,645 patients undergoing surgery for degenerative disease of the upper (cervical) and lower (lumbar) spine. Before and one year after surgery, the patients were evaluated using standard rating scales for disability and neck, back, arm and leg pain.

Based on a spinal surgery satisfaction scale, 83 percent of patient said they were satisfied with the outcomes of surgery one year later. The researchers wanted to see whether any of the factors evaluated before surgery could predict whether patients would be satisfied or dissatisfied with their outcomes.

After adjustment for a wide array of patient-specific factors, several specific predictors were identified. Patients who didn’t have at least a 15 percent improvement on a standard disability rating scale — considered to be the “minimal clinically important difference” — were four times more likely to be dissatisfied with their surgical outcomes.

Patients who didn’t achieve minimal clinically important differences in pain scores were about three times more likely to be dissatisfied with the results of surgery. Patients who were on Medicaid or uninsured also had lower satisfaction rates, as did those with higher initial pain and disability scores.

Patients with depression or anxiety before surgery were less likely to achieve clinically meaningful improvement, and had lower satisfaction rates. However, after adjustment for initial pain and disability scores, these mental health factors were not significant predictors.

Patient satisfaction scores are increasingly used as measures of the quality of medical care — and as a determinant of reimbursement for care provided. “Identifying modifiable factors that improve satisfaction is of utmost importance,” according to Dr. Devin and coauthors.

The new study shows that patient satisfaction ratings after surgery for spinal degenerative disease line up well with the level of improvement in pain and disability achieved. The researchers write, “Surgical ineffectiveness was a strong independent predictor of dissatisfaction.”

But the results also show a significant impact of initial pain and disability, suggesting that patients with more severe spinal degenerative disease are less likely to be satisfied with the results of surgery. Insurance status also seems to have an impact — Medicaid recipients or uninsured patients may have lower satisfaction rates even if they do improve clinically.

The study may provide tools to help identify individuals at risk of dissatisfaction and to improve the delivery of spine care, Dr. Devin and coauthors believe. They conclude, “Individualizing the patient preoperative counseling on the basis of these patient-specific factors can improve patient satisfaction with outcomes.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/07/150724084854.htm  Original web page at Science Daily

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* A highly specialized procedure that lengthens bones can prevent the need for amputations in selected patients who have suffered severe fractures

The standard limb-lengthening technique requires patients to be fitted with a device called a circular external fixator. The device consists of a rigid frame made of stainless steel and high-grade aluminum. Three rings surround the lower leg and are secured to the bone in order to manipulate bone fragments with stainless-steel pins.

The study examined an alternative technique that employed an internal titanium rod in addition to the external fixator. Researchers compared the standard technique with this alternative technique in trauma patients who underwent lengthening of the tibia (shinebone). The alternative technique significantly reduced the amount of time patients had to spend in the external fixator (from 11 months to seven months). Preventing amputation is known as limb salvage. A prerequisite for salvaging an arm or a leg is the ability to regenerate missing bone.

Limb lengthening is used to replace missing bone or to lengthen or straighten deformed bones. Patients include children born with birth defects and patients who have suffered severe fractures or bone cancer. In trauma patients, broken bones can become infected, requiring surgeons to remove the infected segment. In bone cancer patients, the surgeon takes out a segment of bone in order to remove the tumor. The limb-lengthening technique enables the patient to grow back the section of bone lost to infection or tumor.

Limb lengthening works on a principle known as distraction osteogenesis. Four times a day, the external fixator pulls apart two bone segments, and new bone tissue fills in the gap. As a result, the bone lengthens at a rate of about 1 mm. per day. Bones can be lengthened by between 15 percent and 25 percent of their original length at a time.

Once the new bone tissue is formed, it takes several more months until it fully regenerates. In the standard limb-lengthening technique, the patient wears the external fixator until the bone completely matures, in order to support the weight of the limb. In the alternative technique, the surgeon implants a titanium rod inside the bone, in order to reduce the amount of time the patient must spend in the external fixator.

The study was conducted at the Hospital for Special Surgery, where Dr. Bernstein completed a fellowship in limb lengthening and complex reconstruction. The study included 58 trauma patients who underwent limb lengthening. Thirty patients were treated with the standard technique. Twenty-eight patients were treated with the alternative technique, which combined the external fixator with the titanium rod implantation. In both groups, the average limb lengthening was 2.1 in.

There was no statistically significant difference in the severity or number of complications between both groups, and good-to-excellent results were found in all patients. Wearing an external fixator can irritate the skin and cause infections at the pin sites. Also, it’s difficult to wear clothes over the device, and sleeping can be uncomfortable.

“As soon as we get patients out of the external frame they feel better,” Dr. Bernstein said. “Limb deformity surgeons are trying their best to make it a bit easier for patients, without compromising the safety of the procedure.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/07/150717120438.htm  Original web page at Science Daily

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* Ultrasound accelerates skin healing, especially for diabetics and the elderly

Healing times for skin ulcers and bedsores can be reduced by a third with the use of low-intensity ultrasound, scientists from the University of Sheffield and University of Bristol have found. Researchers from the University of Sheffield’s Department of Biomedical Science discovered the ultrasound transmits a vibration through the skin and wakes up cells in wounds helping to stimulate and accelerate the healing process

More than 200,000 patients in the UK suffer with chronic wounds every year at a cost of over £3.1 billion to the NHS. The ultrasound treatment, which also reduces the chance of wounds getting infected, is particularly effective when treating diabetics and the elderly. There are 11 million over-65s, three million diabetics, and 10 million smokers in the UK — all of whom are likely to suffer problems with healing wounds. A quarter of diabetics suffer from skin ulcers, particularly foot ulcers, due to the loss of sensation and circulation in the legs.

Lead author of the study Dr Mark Bass, from the University’s Centre for Membrane Interactions and Dynamics (CMIAD), said: “Skin ulcers are excruciatingly painful for patients and in many cases can only be resolved by amputation of the limb.

“Using ultrasound wakes up the cells and stimulates a normal healing process. Because it is just speeding up the normal processes, the treatment doesn’t carry the risk of side effects that are often associated with drug treatments.

The pioneering study, which is published in the Journal of Investigative Dermatology, was carried out in collaboration with the School of Biochemistry at the University of Bristol, the Wound Biology Group at the Cardiff Institute of Tissue Engineering and Repair, and the orthopaedic company, Bioventus LLC.

Dr Bass added: “Now that we have proven the effectiveness of ultrasound we need to explore the signal further. We have found that the ultrasound signal we currently use is effective, but it is possible that by refining the treatment we could improve the effects even further. “Because ultrasound is relatively risk free we could expect to see it in broad clinical use within three or four years.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/07/150712203837.htm  Original web page at Science Daily

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* Statins show promise to reduce major complications following lung surgery

Statins have been shown to reduce complications from cardiovascular surgery. To determine whether statins might also help those undergoing major lung surgeries, a team of researchers conducted a well-designed study that randomized patients to receive either a statin or placebo before and after surgery. They found that patients undergoing major lung resection experienced fewer complications overall, however, the differences between groups for specific complications or changes in inflammatory markers failed to reach statistical significance

Statins have been shown to reduce complications from cardiovascular surgery. To determine whether statins might also help those undergoing major lung surgeries, a team at Memorial Sloan Kettering Cancer Center conducted a well-designed study that randomized patients to receive either a statin or placebo before and after surgery. They found that patients undergoing major lung resection experienced fewer complications overall, however, the differences between groups for specific complications or changes in inflammatory markers failed to reach statistical significance, according to a report in the Journal of Thoracic and Cardiovascular Surgery, the official publication of the American Association for Thoracic Surgery (AATS).

Because encouraging trends were observed, the authors have called for further evaluation in a larger multicenter, randomized, controlled trial. In an Editorial Commentary that accompanied the report, Betty C. Tong, M.D., of the Division of Cardiovascular and Thoracic Surgery of Duke University Medical Center (Durham, NC), concurred. ‘Imagine all the people who could potentially have benefited from the knowledge gained by this trial had it accrued as originally intended. With continued enthusiasm and surgeon commitment to multicenter clinical trials, we will be able to elucidate further the role of therapies such as this in preventing complications after lung resection,’ noted Tong.

The original study design called for 480 patients to be enrolled. In part because previously unpublished data on the efficacy of the statin (atorvastatin) to reduce postoperative atrial fibrillation were released soon after the trial began and it became challenging to find patients who were not taking the drug, only 164 patients were randomized into two groups.

Total postoperative complications occurred in 22 percent of patients receiving placebo and 12 percent patients receiving the statin. While the difference was not statistically significant, the composite of major pulmonary and cardiovascular complication rates in those who underwent more extensive surgeries (anatomic lung resections) were three-fold higher in placebo-treated patients than those who received the statin and the difference was statistically significant.

While other complications including pneumonia, acute respiratory failure, myocardial infarction, deep vein thrombosis, and mortality were more frequent in the placebo group compared to the statin group, the differences were not statistically significant. Postoperative rates of atrial fibrillation in the atorvastatin group were cut by almost half (from 27 to 14 percent), but the change, while perhaps clinically meaningful, was not statistically significant. In addition, no differences were found in plasma levels of markers of inflammation, such as C-reactive protein, tumor necrosis factor-α, or myeloperoxidase. ‘These promising results in patients undergoing anatomic pulmonary resection merit further evaluation in a larger multicenter, randomized, controlled trial before recommendation as standard clinical practice,’ explained lead author David Amar, M.D., of the Departments of Anesthesiology and Critical Care Medicine, and co-principal investigator Bernard Park, M.D., of the Department of Surgery at Memorial Sloan Kettering Cancer Center (New York).

In light of the increasing use of statins, including during the perioperative period for cardiac and thoracic surgery, and their low potential for adverse effects, Neel R. Sodha, M.D., and Frank W. Sellke, M.D., of the Division of Cardiothoracic Surgery of Alpert Medical School of Brown University (Rhode Island) prepared an Expert Review of the clinical evidence of perioperative statin use. ‘A review of the research shows that slightly more than half the studies [done for cardiac surgery] support the anti-inflammatory effect of statins. Clinical studies are confounded because most patients proceeding to cardiac or thoracic surgery are receiving statins to reduce the progression of coronary artery disease. Therefore, it is difficult to know whether statins also reduce postoperative complications. Conclusions regarding the relationship of statins to clinical outcomes cannot be drawn based on current data,’ stated Sodha and Sellke.

They point to wide variation among reports concerning the magnitude of the reduction in inflammatory parameters. Noting that the two trials (including that of Amar and colleagues) investigating the effect of statins in thoracic surgery produced discordant results, they concluded that ‘this inconsistency lends more weight to the need for caution in using statins for the sole purpose of minimizing perioperative inflammation.’

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/06/150622182503.htm  Original web page at Science Daily

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* Researchers hack a teleoperated surgical robot to reveal security flaws

How safe is that robot doing your surgery? Researchers easily hacked a next generation teleoperated surgical robot to test how easily a malicious attack could hijack remotely-controlled operations in the future and to offer security solutions. UW reseachers mounted cyberattacks while study participants used the Raven II surgical robotic system to move rubber blocks on a pegboard. To make cars as safe as possible, we crash them into walls to pinpoint weaknesses and better protect the people who use them.

That’s the idea behind a series of experiments conducted by a University of Washington engineering team who hacked a next generation teleoperated surgical robot — one used only for research purposes — to test how easily a malicious attack could hijack remotely-controlled operations in the future and to make those systems more secure. Real-world teleoperated robots, which are controlled by a human who may be in another physical location, are expected to become more commonplace as the technology evolves. They’re ideal for situations that are dangerous for people: fighting fires in chemical plants, diffusing explosive devices or extricating earthquake victims from collapsed buildings.

Outside of a handful of experimental surgeries conducted remotely, doctors typically use surgical robots today to operate on a patient in the same room using a secure, hardwired connection. But telerobots may one day routinely provide medical treatment in underdeveloped rural areas, battlefield scenarios, Ebola wards or catastrophic disasters happening half a world away. In two recent papers, UW BioRobotics Lab researchers demonstrated that next generation teleoperated robots using nonprivate networks — which may be the only option in disasters or in remote locations — can be easily disrupted or derailed by common forms of cyberattacks. Incorporating security measures to foil those attacks, the authors argue, will be critical to their safe adoption and use.

“We want to make the next generation of telerobots resilient to some of the threats we’ve detected without putting an operator or patient or any other person in the physical world in danger,” said lead author Tamara Bonaci, a UW doctoral candidate in electrical engineering.

To expose vulnerabilities, the UW team mounted common types of cyberattacks as study participants used a teleoperated surgical robot developed at the UW for research purposes to move rubber blocks between pegs on a pegboard. By mounting “man in the middle” attacks, which alter the commands flowing between the operator and robot, the team was able to maliciously disrupt a wide range of the robot’s functions — making it hard to grasp objects with the robot’s arms — and even to completely override command inputs. During denial-of-service attacks, in which the attacking machine flooded the system with useless data, the robots became jerky and harder to use.

In some cases, the human operators were eventually able to compensate for those disruptions, given the relatively simple task of moving blocks. In situations where precise movements can mean the difference between life and death — such as surgery or a search and rescue extrication — these types of cyberattacks could have more serious consequences, the researchers believe. With a single packet of bad data, for instance, the team was able to maliciously trigger the robot’s emergency stop mechanism, rendering it useless

The tests were conducted with the Raven II, an open source teleoperated robotic system developed by UW electrical engineering professor Blake Hannaford and former UW professor Jacob Rosen, along with their students. Raven II, currently manufactured and sold by Seattle-based Applied Dexterity Inc., a UW spin-out, is a next generation teleoperated robotic system designed to support research in advanced techniques of robotic-assisted surgery. The system is not currently in clinical use and is not approved by the FDA. The surgical robots that are FDA-approved for clinical use today, which typically allow a surgeon to remove tumors, repair heart valves or perform other procedures in a less invasive way, use a different communication channel and typically do not rely on publicly available networks, which would make the cyberattacks the UW team tested much harder to mount.

But if teleoperated robots will be used in locations where there’s no secure alternative to networks or other communication channels that are easy to hack, it’s important to begin designing and incorporating additional security features now, the researchers argue. “If there’s been a disaster, the network has probably been damaged too. So you might have to fly a drone and put a router on it and send signals up to it,” said Howard Chizeck, UW professor of electrical engineering and co-director of the UW BioRobotics Lab.

“In an ideal world, you’d always have a private network and everything could be controlled, but that’s not always going to be the case. We need to design for and test additional security measures now, before the next generation of telerobots are deployed.” Encrypting data packets that flow between the robot and human operator would help prevent certain types of cyberattacks. But it isn’t effective against denial-of-service attacks that bog down the system with extraneous data. With video, encryption also runs the risk of causing unacceptable delays in delicate operations.

The UW team is also developing the concept of “operator signatures,” which leverage the ways in which a particular surgeon or other teleoperator interacts with a robot to create a unique biometric signature. By tracking the forces and torques that a particular operator applies to the console instruments and his or her interactions with the robot’s tools, the researchers have developed a novel way to validate that person’s identity and authenticate that the operator is the person he or she claims to be. Moreover, monitoring those actions and reactions during a telerobotic procedure could give early warning that someone else has hijacked that process.

“Just as everyone signs something a little bit differently and you can identify people from the way they write different letters, different surgeons move the robotic system differently,” Chizeck said. “This would allow us to detect and raise the alarm if all of a sudden someone who doesn’t seem to be operator A is maliciously controlling or interfering with the procedure.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/05/150507145332.htm#  Original web page at Science Daily

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When teeth and hands connect, bites may be beastly

Hand injuries are frequently caused by human and animal bites, prompting as many as 330,000 emergency department visits in the United States each year. A literature review appearing in the January issue of the Journal of the American Academy of Orthopaedic Surgeons (JAAOS) outlines the potential complications of human and animal bites to the hand, the importance of early injury assessment, and the use of antibiotic and other treatment methods to avoid infection, permanent disability, and amputation.

“Although many people may be reluctant to immediately go to a doctor, all bites to the hand should receive medical care,” said orthopaedic surgeon and lead study author Stephen A. Kennedy, MD. “And while routine antibiotics are not necessarily recommended for other bite wounds, they are recommended for a bite to the hand to reduce the risk of infection and disability.” Human bites to the hand–while accounting for only two to three percent of all hand bite injuries–can occur during altercations and include wounds caused by punching type contact with the mouth or teeth, domestic abuse, or accidentally during sports, play, or other activities. Human bites to the fingers and hand that penetrate through the skin can transmit infection through oral flora, or saliva, which contains more than 600 bacterial species.

Animals also have saliva containing a broad range of bacteria. Adult dog jaws, especially among larger breeds, are capable of exerting a bite force of more than 300 pounds, and when combined with the variety and sharpness of their teeth–designed to clamp, hold, tear, and crush food–can cause significant injuries to hand and finger ligaments, tendons, and bones. Cats do not have the jaw strength of dogs; however, their sharp, narrow teeth also can cause serious injury. An estimated 30 percent to 50 percent of cat bites are complicated by infections, which can occur as early as three hours after injury in approximately 50 percent of the infection cases. Infections due to dog bites typically occur at less than half the rate of cat bites.

If a hand-to-mouth injury or bite occurs: Inspect the hand carefully for any puncture wounds. Even a small wound can inject virulent bacteria under the skin. If there is a puncture wound of any size, wash as soon as possible with soap and water then seek medical advice.

If you see redness, feel increasing pain over time or see red streaking up the hand or arm (or along a tendon), these are signs of a significant infection and immediate medical attention is needed. Prompt treatment, ideally within 24 hours of an animal or human bite, can prevent serious injury or infection: Symptoms of infection include erythema (redness), edema (swelling), progressive pain, and fever. The patient’s medical, immunization, and recent antibiotic history, as well as the timing and location of injury, should be considered when determining treatment. Patients who have prosthetic joints are at risk of an infection “seeding,” or anchoring, at the site of the metal, ceramic, or plastic device.

The size and depth of the wound and the amount of devitalized (dead) tissue should be assessed along with potential damage to neurovascular structures and tendons, underlying fractures, the presence of exposed bone and/or infection, and the integrity of the joint. All patients with hand bites should receive antibiotic treatment, which can lower the infection rate from an average of 28 percent to 2 percent. Open wounds may need to be surgically irrigated and débrided (cleaned, including removal of unhealthy or dead tissue).

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/01/150105125838.htm

Original web page at Science Daily

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Long-term complication rate low in nose job using patient’s own rib cartilage

Autologous rib cartilage is the preferred source of graft material for rhinoplasty because of its strength and ample volume. However, using rib cartilage for dorsal augmentation to build up the bridge of the nose has been criticized for its tendency to warp and issues at the cartilage donor site, such as pneumothorax (a collapsed lung) and postoperative scarring. Jee Hye Wee, M.D., of the National Medical Center, Seoul, South Korea, and co-authors reviewed the available medical literature to evaluate complications associated with autologous rib cartilage and rhinoplasty. Authors identified 10 studies involving 491 patients with an average follow-up across all studies of 33.3 moths. Results indicate that combined complication rates from the studies were 3.08 percent for warping, 0.22 percent for resorption, 0.56 percent for infection, 0.39 percent for displacement, 5.45 percent for hypertrophic chest scarring (keloids), 0 percent for pneumothorax and 14.07 percent for revision surgery. “The overall long-term complications associated with autologous rib cartilage use in rhinoplasty were low. Because warping and hypertrophic chest scarring had relatively high rates, surgeons should pay more attention to reduce these complications. … Future analysis should include studies with larger pools of patients, clearer definitions of complications and longer-term follow-up to obtain more reliable results,” the study concludes.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2014/11/141127212325.htm Original web page at Science Daily

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*Australian doctors transplant first circulatory death human heart

The St Vincent’s Hospital Heart Lung Transplant Unit has carried out the world’s first distant procurement of hearts donated after circulatory death (DCD). These hearts were subsequently resuscitated and then successfully transplanted into patients with end-stage heart failure.

Transplant Units until now have relied solely on donor hearts from brain-dead patients whose hearts are still beating. The use of DCD hearts, where the heart is no longer beating, represents a paradigm shift in organ donation and will herald a major increase in the pool of available hearts for transplantation. St Vincent’s has recently transplanted two patients using DCD hearts both of whom have recovered extremely well. The DCD transplants were carried out following pioneering basic and translational research undertaken by the Victor Chang Cardiac Research Institute and St Vincent’s Hospital, who have jointly developed a special preservation solution that together with the use of a novel portable console to house, resuscitate and transport donor hearts; has made this milestone achievable. The ex vivo Organ Care System (OCS — TransmedicsTM) involves the Transplant retrieval team connecting the donor heart to a sterile circuit where it is kept beating and warm thereby limiting the detrimental effects of cold ischaemia (a period where the heart is dormant without oxygen and nutrients) that occurs with the standard organ preservation mode of packing the heart on ice in an Esky. Once housed inside the portable device, the heart is reanimated, preserved and able to be functionally assessed until it is ready to be placed inside the recipient. Coined the “Heart in a box,” for the past several months the OCS has provided the transplant surgeons greater versatility with regard to both organ preservation and resuscitation. This has enabled the St Vincent’s Transplant Unit to conduct several regular heart transplants this year through more long distance organ retrievals and most importantly, retrieval of “marginal hearts,” that is, brain death hearts previously regarded as being unsuitable for transplantation. This portable OCS technology will help significantly in mitigating the significant disparity that remains between the increasing number of patients with end-stage heart failure on the transplant waiting list and the number of suitable donor-hearts that are available. Whilst the use of DCD organs has already made an enormous positive impact on liver, kidney and lung transplantation, it has to date not been possible to use DCD hearts. This is the first time internationally that human heart transplantation has been achieved with hearts donated following circulatory death and procured at a distance with portable organ preservation technology. In acknowledging the significance of this milestone for his Unit, Professor Peter MacDonald, Medical Director of the St Vincent’s Heart Transplant Unit, Head of the Transplantation Research Laboratory at the Victor Chang Institute and Professor of Medicine at UNSW said, “In many respects this breakthrough represents a major inroad to reducing the shortage of donor organs. As we mark the 30th anniversary of the St Vincent’s Heart Lung Transplant Unit and the 20th anniversary of the Victor Chang Institute this year, this is a timely breakthrough. In all our years, our biggest hindrance has been the limited availability of donor organs.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/10/141024144822.htm  Original web page at a Science Daily

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World’s first child born after uterus transplantation

In a ground-breaking research project at the University of Gothenburg, seven Swedish women have had embryos reintroduced after receiving wombs from living donors. Now the first transplanted woman has delivered a baby — a healthy and normally developed boy. The world-unique birth was acknowledged in The Lancet on 5 October. The uterus transplantation research project at the University of Gothenburg started in 1999 and has been evaluated in over 40 scientific articles. The goal of the Gothenburg project is to enable women who were born without a womb or who have lost their wombs in cancer surgery to give birth to their own children. Nine women in the project have received a womb from live donors — in most cases the recipient’s mother but also other family members and close friends. The transplanted uterus was removed in two cases, in one case due to a serious infection and in the other due to blood clots in the transplanted blood vessels. The seven remaining women have in 2014 tried to become pregnant through a process where their own embryos, produced through IVF, are reintroduced to the transplanted uterus. The first early pregnancy was confirmed in the spring after a successful first pregnancy attempt in a woman in her mid-30s, a little over a year after her transplantation. In early September, the woman successfully delivered a baby by caesarean section, making her the first woman in the world to deliver a child from a transplanted uterus. Her uterus was donated by a 61-year-old unrelated woman. The caesarean section had to be performed earlier than planned: the woman developed preeclampsia in week 32 of her pregnancy and the CTG indicated that the baby was under stress. A caesarean section was performed in accordance with normal clinical routines so as not to risk the health of the mother and child. According to Professor Mats Brännström, who performed the caesarean section, the perfectly healthy newborn boy is developing normally. The baby weighed 1,775 grams (3 lbs14.6 oz) at birth, which is normal size considering the gestational age at delivery. The baby screamed right away and has not required any other care than normal clinical observation at the neonatal unit. The mother and child are both doing well and have returned home. The new parents are of course very happy and thankful,’ says Professor Mats Brännström, who is leading the research project. The reason for the woman’s preeclampsia is unknown, but it may be due to her immunosuppressive treatment combined with the fact that she is missing one kidney. The age of the donated womb may also be a factor. Also, preeclampsia is generally more common among women who have become pregnant through IVF treatment.’

The woman has had three mild rejection episodes since the transplant, one of which occurred during the pregnancy. The rejection episodes, which are often seen also in other types of transplants, could be stopped with immunosuppressive treatment. The research team followed the pregnancy closely, carefully monitoring the growth and development of the foetus with a special focus on the blood supply to the uterus and umbilical cord. ‘There were concerns that the blood supply may be compromised since we had reattached the blood vessels to the womb. But we did not notice anything unusual concerning the function of the uterus and the foetus, and the pregnancy followed all normal curves,’ says Brännström. ‘It gives us scientific evidence that the concept of uterus transplantation can be used to treat uterine factor infertility, which up to now has remained the last untreatable form of female infertility. It also shows that transplants with a live donor are possible, including if the donor is past menopause,’ says Brännström. Several research teams around the world have been awaiting the results of the Gothenburg study in order to launch similar observational studies. The pregnancy attempts are ongoing with the other six women in the project.

http://www.sciencedaily.com/  Science Dail

http://www.sciencedaily.com/releases/2014/10/141007092110.htm Original web page at Science Daily

 

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Regenerative medicine approach improves muscle strength, function in leg injuries; Derived from pig bladder

Damaged leg muscles grew stronger and showed signs of regeneration in three out of five men whose old injuries were surgically implanted with extracellular matrix (ECM) derived from pig bladder, according to a new study conducted by researchers at the University of Pittsburgh School of Medicine and the McGowan Institute for Regenerative Medicine. Early findings from a human trial of the process and from animal studies were published today in Science Translational Medicine. When a large volume of muscle is lost, typically due to trauma, the body cannot sufficiently respond to replace it, explained senior investigator Stephen F. Badylak, D.V.M., Ph.D., M.D., professor of surgery at Pitt and deputy director of the McGowan Institute, a joint effort of Pitt and UPMC. Instead, scar tissue can form that significantly impairs strength and function. Pig bladder ECM has been used for many years as the basis for medical products for hernia repair and treatment of skin ulcers. It is the biologic scaffold that remains left behind after cells have been removed. Previous research conducted by Dr. Badylak’s team suggested that ECM also could be used to regenerate lost muscle by placing the material in the injury site where it signals the body to recruit stem and other progenitor cells to rebuild healthy tissue. “This new study is the first to show replacement of new functional muscle tissue in humans, and we’re very excited by its potential,” Dr. Badylak said. “These are patients who can’t walk anymore, can’t get out of a car, can’t get up and down from a chair, can’t take steps without falling. Now we might have a way of helping them get better.” For the Muscle Tendon Tissue Unit Repair and Reinforcement Reconstructive Surgery Research Study, which is sponsored by the U.S. Department of Defense and is continuing to enroll new participants, five men who had at least six months earlier lost at least 25 percent of leg muscle volume and function compared to the uninjured limb underwent a customized regimen of physical therapy for 12 to 26 weeks until their function and strength plateaued for a minimum of two weeks.

Then, study lead surgeon J. Peter Rubin, M.D., UPMC Professor and chair of plastic surgery, Pitt School of Medicine, surgically implanted a “quilt” of compressed ECM sheets designed to fill into their injury sites. Within 48 hours of the operation, the participants resumed physical therapy for up to 26 additional weeks. The researchers found that three of the participants, two of whom had thigh injuries and one a calf injury, were stronger by 20 percent or more six months after the surgery. One thigh-injured patient improved on the “single hop test” by 1,820 percent, and the other had a 352 percent improvement in a chair lift test and a 417 percent improvement in the single-leg squat test. Biopsies and scans all indicated that muscle growth had occurred. Two other participants with calf injuries did not have such dramatic results, but both improved on at least one functional measure and said they felt better. “This work represents an important step forward in our ability to repair tissues and improve function with materials derived from natural proteins. There will be more options to help our patients,” Dr. Rubin said. The study also showed six months after an injury, mice treated with ECM showed signs of new muscle growth while untreated mice appeared to form typical scars.

http://www.sciencedaily.com/   Science Daily

May 27, 2014

http://www.sciencedaily.com/releases/2014/04/140430143016.htm  Original web page at Science Daily

 

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* Engineers grow functional human cartilage in lab

Researchers at Columbia Engineering announced today that they have successfully grown fully functional human cartilage in vitro from human stem cells derived from bone marrow tissue. Their study, which demonstrates new ways to better mimic the enormous complexity of tissue development, regeneration, and disease, is published in the April 28 Early Online edition of Proceedings of the National Academy of Sciences (PNAS). “We’ve been able — for the first time — to generate fully functional human cartilage from mesenchymal stem cells by mimicking in vitro the developmental process of mesenchymal condensation,” says Gordana Vunjak-Novakovic, who led the study and is the Mikati Foundation Professor of Biomedical Engineering at Columbia Engineering and professor of medical sciences. “This could have clinical impact, as this cartilage can be used to repair a cartilage defect, or in combination with bone in a composite graft grown in lab for more complex tissue reconstruction.” For more than 20 years, researchers have unofficially called cartilage the “official tissue of tissue engineering,” Vunjak-Novakovic observes. Many groups studied cartilage as an apparently simple tissue: one single cell type, no blood vessels or nerves, a tissue built for bearing loads while protecting bone ends in the joints. While there has been great success in engineering pieces of cartilage using young animal cells, no one has, until now, been able to reproduce these results using adult human stem cells from bone marrow or fat, the most practical stem cell source. Vunjak-Novakovic’s team succeeded in growing cartilage with physiologic architecture and strength by radically changing the tissue-engineering approach. The general approach to cartilage tissue engineering has been to place cells into a hydrogel and culture them in the presence of nutrients and growth factors and sometimes also mechanical loading. But using this technique with adult human stem cells has invariably produced mechanically weak cartilage. So Vunjak-Novakovic and her team, who have had a longstanding interest in skeletal tissue engineering, wondered if a method resembling the normal development of the skeleton could lead to a higher quality of cartilage.

Sarindr Bhumiratana, postdoctoral fellow in Vunjak-Novakovic’s Laboratory for Stem Cells and Tissue Engineering, came up with a new approach: inducing the mesenchymal stem cells to undergo a condensation stage as they do in the body before starting to make cartilage. He discovered that this simple but major departure from how things were usually? being done resulted in a quality of human cartilage not seen before. Gerard Ateshian, Andrew Walz Professor of Mechanical Engineering, professor of biomedical engineering, and chair of the Department of Mechanical Engineering, and his PhD student, Sevan Oungoulian, helped perform measurements showing that the lubricative property and compressive strength — the two important functional properties — of the tissue-engineered cartilage approached those of native cartilage. The researchers then used their method to regenerate large pieces of anatomically shaped and mechanically strong cartilage over the bone, and to repair defects in cartilage. “Our whole approach to tissue engineering is biomimetic in nature, which means that our engineering designs are defined by biological principles,” Vunjak-Novakovic notes. “This approach has been effective in improving the quality of many engineered tissues — from bone to heart. Still, we were really surprised to see that our cartilage, grown by mimicking some aspects of biological development, was as strong as ‘normal’ human cartilage.” The team plans next to test whether the engineered cartilage tissue maintains its structure and long-term function when implanted into a defect. “This is a very exciting time for tissue engineers,” says Vunjak-Novakovic. “Stem cells are transforming the future of medicine, offering ways to overcome some of the human body’s fundamental limitations. We bioengineers are now working with stem cell scientists and clinicians to develop technologies that will make this dream possible. This project is a wonderful example that we need to ‘think as a cell’ to find out how exactly to coax the cells into making a functional human tissue of a specific kind. It’s emblematic of the progress being driven by the exceptional young talent we have among our postdocs and students at Columbia Engineering.”

http://www.sciencedaily.com/  Nature

May 27, 2014

http://www.sciencedaily.com/releases/2014/04/140430142820.htm  Original web page at Nature

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Surgeons develop personalized 3-D printed kidney to simulate surgery prior to cancer operation

Kidney cancers are the eighth most common cancer affecting adults, accounting for around 3% of all cancers in Europe; In 2012 it was estimated that there would be approximately 84.400 new cases of Kidney cancer with 34,700 deaths. It is usually treated surgically, but the operations can be stressful, and speed and accuracy are essential. The ability to produce exact 3-dimensional models of objects means that 3D printing is set to revolutionize many fields. Now a group of surgeons from Kobe University in Japan has combined the 3D imaging capabilities of Computer Tomography, with 3D printing, to produce exact scale model of kidneys prior to surgery. This allows surgeons to practice surgery in difficult kidney cancer cases. So far they have produced ten 3D kidney models to assist in kidney cancer operations. The group used computer tomography to produce a 3D scan of a diseased kidney. They then fed this information into a commercially-available 3D printer to produce a 3D model of the diseased kidney. As the scan is personalized for each patient, this meant that the surgeons were able to construct a 3D scale model of each individual’s kidney cancer. The model — which was printed using two different materials- allowed the surgeons to accurately determine the margins of the kidney tumors. The 3D printed organ model was made of transparent material so that the blood vessels could be seen from the outside, meaning that surgeons could see the exact position of the blood vessels prior to surgery. This allowed the surgeons to simulate surgery on the kidney tumor prior to real surgery. The surgery itself was then performed robotically. Presenting the work at the European Association of Urology congress in Stockholm, lead researcher Dr Yoshiyuki Shiga said: “The use of this “hands-on” model system gave us a 3D anatomical understanding of the kidney and the tumor. This enabled the surgeon to work on a smaller area. This is important, as it means that the area where the blood supply is interrupted during surgery can be reduced, in fact we found that the shortest interruption time was only 8 minutes, compared to a normal average of 22 minutes. We also found that where we had to remove part of the kidney, the fact that we knew the exact location of the blood vessels helped us greatly. At the moment this is still an expensive technique, adding between $500 and $1500 to the cost of surgery, but we hope that if it is more widely used then costs will fall.”

http://www.sciencedaily.com/  Science Daily

May 13, 2014

http://www.sciencedaily.com/releases/2014/04/140414100801.htm  Original web page at Science Daily

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Stem cell findings may offer answers for some bladder defects, disease

For the first time, scientists have succeeded in coaxing laboratory cultures of human stem cells to develop into the specialized, unique cells needed to repair a patient’s defective or diseased bladder. The breakthrough, developed at the UC Davis Institute for Regenerative Cures and published today in the scientific journal Stem Cells Translational Medicine, is significant because it provides a pathway to regenerate replacement bladder tissue for patients whose bladders are too small or do not function properly, such as children with spina bifida and adults with spinal cord injuries or bladder cancer. “Our goal is to use human stem cells to regenerate tissue in the lab that can be transplanted into patients to augment or replace their malfunctioning bladders,” said Eric Kurzrock, professor and chief of the division of pediatric urologic surgery at UC Davis Children’s Hospital and lead scientist of the study, which is titled “Induction of Human Embryonic and Induced Pluripotent Stem Cells into Urothelium.” To develop the bladder cells, Kurzrock and his UC Davis colleagues investigated two categories of human stem cells. In their key experiments, they used induced pluripotent stem cells (iPS cells), which were derived from lab cultures of human skin cells and umbilical blood cells that had been genetically reprogrammed to convert to an embryonic stem cell-like state. If additional research demonstrates that grafts of bladder tissue grown from human stem cells will be safe and effective for patient care, Kurzrock said that the source of the grafts would be iPS cells derived from a patient’s own skin or umbilical cord blood cells. This type of tissue would be optimal, he said, because it lowers the risk of immunological rejection that typifies most transplants.

In their investigation, Kurzrock and his colleagues developed a protocol to prod the pluripotent cells into becoming bladder cells. Their procedure was efficient and, most importantly, the cells proliferated over a long period of time — a critical element in any tissue engineering application. “What’s exciting about this discovery is that it also opens up an array of opportunities using pluripotent cells,” said Jan Nolta, professor and director of the UC Davis Stem Cell program and a co-author on the new study. “When we can reliably direct and differentiate pluripotent stem cells, we have more options to develop new and effective regenerative medicine therapies. The protocols we used to create bladder tissue also provide insight into other types of tissue regeneration.” UC Davis researchers first used human embryonic stem cells obtained from the National Institutes of Health’s repository of human stem cells. Embryonic stem cells can become any cell type in the body (i.e., they are pluripotent), and the team successfully coaxed these embryonic stem cells into bladder cells. They then used the same protocol to coax iPS cells made from skin and umbilical cord blood into bladder cells, called urothelium, that line the inside of the bladder. The cells expressed a very unique protein and marker of bladder cells called uroplakin, which makes the bladder impermeable to toxins in the urine. The UC Davis researchers adjusted the culture system in which the stem cells were developing to encourage the cells to proliferate, differentiate and express the bladder protein without depending upon signals from other human cells, said Kurzrock. In future research, Kurzrock and his colleagues plan to modify the laboratory cultures so that they will not need animal and human products, which will allow use of the cells in patients.

Kurzrock’s primary focus as a physician is with children suffering from spina bifida and other pediatric congenital disorders. Currently, when he surgically reconstructs a child’s defective bladder, he must use a segment of their own intestine. Because the function of intestine, which absorbs food, is almost the opposite of bladder, bladder reconstruction with intestinal tissue may lead to serious complications, including urinary stone formation, electrolyte abnormalities and cancer. Developing a stem cell alternative not only will be less invasive, but should prove to be more effective, too, he said. Another benefit of the UC Davis study is the insight it may provide about the pathways of bladder cancer, which is diagnosed in more than 70,000 Americans each year, according to the National Cancer Institute. “Our study may provide important data for basic research in determining the deviations from normal biological processes that trigger malignancies in developing bladder cells,” said Nolta. More than 90 percent of patients who need replacement bladder tissue are adults with bladder cancer. Kurzrock said “cells from these patients’ bladders cannot be used to generate tissue grafts because the implanted tissue could carry a high risk of becoming cancerous. On the other hand, using bladder cells derived from patients’ skin may alleviate that risk. Our next experiments will seek to prove that these cells are safer.”

http://www.sciencedaily.com/  Science Daily

April 15, 2014

http://www.sciencedaily.com/releases/2014/03/140321164856.htm  Original web page at Science Daily

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Stem cell transplant shows ‘landmark’ promise for treatment of degenerative disc disease

Stem cell transplant was viable and effective in halting or reversing degenerative disc disease of the spine, a meta-analysis of animal studies showed, in a development expected to open up research in humans. Recent developments in stem cell research have made it possible to assess its effect on intervertebral disc (IVD) height, Mayo Clinic researchers reported in a scientific poster today at the 30th Annual Meeting of the AmericanAcademy of Pain Medicine. “This landmark study draws the conclusion in pre-clinical animal studies that stem cell therapy for disc degenerative disease might be a potentially effective treatment for the very common condition that affects people’s quality of life and productivity,” said the senior author, Wenchun Qu, MD, PhD, of the Mayo Clinic in Rochester, Minn. Dr. Qu said not only did disc height increase, but stem cell transplant also increased disc water content and improved appropriate gene expression. “These exciting developments place us in a position to prepare for translation of stem cell therapy for degenerative disc disease into clinical trials,” he said. The increase in disc height was due to restoration in the transplant group of the nucleus pulposus structure, which refers to the jelly-like substance in the disc, and an increased amount of water content, which is critical for the appropriate function of the disc as a cushion for the spinal column, the researchers concluded.

The researchers performed a literature search of MEDLINE, EMBASE and PsycINFO databases and also manually searched reference lists for original, randomized, controlled trials on animals that examined the association between IVD stem cell transplant and the change of disc height. Six studies met inclusion criteria. Differences between the studies necessitated the use of random-effects models to pool estimates of effect. What they found was an over 23.6% increase in the disc height index in the transplant group compared with the placebo group (95% confidence interval [CI], 19.7-23.5; p < 0.001). None of the 6 studies showed a decrease of the disc height index in the transplant group. Increases in the disc height index were statistically significant in all individual studies. The authors commented that it is time to turn attention to the much-needed work of determining the safety, feasibility, efficacy of IVD stem cell transplant for humans. “A hallmark of IVD degenerative disease is its poor self-repair capacity secondary to the loss of IVD cells. However, current available treatments fail to address the loss of cells and cellular functions. In fact, many invasive treatments further damage the disc, causing further degeneration in the diseased level or adjacent levels,” said the lead study author Jason Dauffenbach, DO. “The goal of tissue engineering using stem cells is to restore the normal function and motion of the diseased human spine.”

http://www.sciencedaily.com/  Science Daily

April 1, 2014

http://www.sciencedaily.com/releases/2014/03/140308094811.htm  Original web page at Science Daily

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Stem cell therapy following meniscus knee surgery may reduce pain, restore meniscus

A single stem cell injection following meniscus knee surgery may provide pain relief and aid in meniscus regrowth, according to a novel study appearing in the January issue of the Journal of Bone and Joint Surgery (JBJS). More than one million knee arthroscopy procedures are performed each year in the U.S. primarily for the treatment of tears to the meniscus — the wedge-shaped pieces of cartilage that act as “shock absorbers” between the thighbone and shinbone in the knee joint. In the first-of-its-kind study, “Adult Human Mesenchymal Stem Cells (MSC) Delivered via Intra-Articular Injection to the Knee, Following Partial Medial Meniscectomy,” most patients who received a single injection of adult stem cells following the surgical removal of all or part of a torn meniscus, reported a significant reduction in pain. Some patients, 24 percent of one MSC group and 6 percent of another, experienced at least a 15 percent increase in meniscal volume at one year. There was no additional increase in meniscal volume at year two. “The results demonstrated that high doses of mesenchymal stem cells can be safely delivered in a concentrated manner to a knee joint without abnormal tissue formation,” said lead study author C. Thomas Vangsness, Jr., MD. “No one has ever done that before.” In addition, “the patients with arthritis got strong improvement in pain” and some experienced meniscal regrowth.

Specific Study Details The study involved 55 patients, ages 18 to 60, who underwent a partial medial meniscectomy (the surgical removal of all or part of a torn meniscus) at seven medical institutions. Patients were randomly placed in one of three treatment groups: Group A patients (18) received a “low-dose” injection of 50 million stem cells within seven to 10 days after meniscus surgery; Group B patients (18), a higher dose of 100 million stem cells; and the “control group (19),” sodium hyaluronate only. Patients were assessed to evaluate safety, meniscus regeneration through MRI and X-ray images, overall condition of the knee joint and clinical outcomes through two years. While most of the patients had some arthritis, patients with severe (level three or four) arthritis, in the same compartment as the meniscectomy, were excluded from the study. “The results of this study suggest that mesenchymal stem cells have the potential to improve the overall condition of the knee joint,” said Dr. Vangsness. “I am very excited and encouraged” by the results. With the success of a single injection, “it begs the question: What if we give a series of injections?”

http://www.sciencedaily.com/  Science Daily February 4, 2014

http://www.sciencedaily.com/releases/2014/01/140116130957.htm  Original web page at Science Daily

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Stem cells used to model disease that causes abnormal bone growth

Researchers have developed a new way to study bone disorders and bone growth, using stem cells from patients afflicted with a rare, genetic bone disease. The approach, based on Nobel-Prize winning techniques, could illuminate the illness, in which muscles and tendons progressively turn into bone, and addresses the similar destructive process that afflicts a growing number of veterans who have suffered blast injuries — including traumatic amputations or injuries to the brain and nervous system. This insidious hardening of tissues also grips some patients following joint replacement or severe bone injuries. The disease model, described in a new study by a UC San Francisco-led team, involves taking skin cells from patients with the bone disease, reprogramming them in a lab dish to their embryonic state, and deriving stem cells from them. Once the team derived the stem cells, they identified a cellular mechanism that drives abnormal bone growth in the thus-far untreatable bone disease, called fibrodysplasiaossificans progressiva (FOP). Furthermore, they found that certain chemicals could slow abnormal bone growth in the stem cells, a discovery that might help guide future drug development.

Clinically, the genetic and trauma-caused conditions are very similar, with bone formation in muscle leading to pain and restricted movement, according to the leader of the new study, Edward Hsiao, MD, PhD, an endocrinologist who cares for patients with rare and unusual bone diseases at the UCSF Metabolic Bone Clinic in the Division of Endocrinology and Metabolism. The human cell-based disease model is expected to lead to a better understanding of these disorders and other illnesses, Hsiao said. “The new FOP model already has shed light on the disease process in FOP by showing that the mutated gene can affect different steps of bone formation,” Hsiao said. “These different stages represent potential targets for limiting or stopping the progression of the disease, and may also be useful for blocking abnormal bone formation in other conditions besides FOP. The human stem-cell lines we developed will be useful for identifying drugs that target the bone-formation process in humans.” The team’s development of, and experimentation with, the human stem-cell disease model for FOP, published in the December issue of the Orphanet Journal of Rare Diseases, is a realization of the promise of research using stem cells of the type known as induced pluripotent stem (iPS) cells, immortal cells of nearly limitless potential, derived not from embryos, but from adult tissues.

Shinya Yamanaka, MD, PhD, a UCSF professor of anatomy and a senior investigator with the UCSF-affiliated Gladstone Institutes, as well as the director of the Center for iPSCell Research and Application (CiRA) and a principal investigator at Kyoto University, shared the Nobel Prize in 2012 for discovering how to make iPS cells from skin cells using a handful of protein “factors.” These factors guide a reprogramming process that reverts the cells to an embryonic state, in which they have the potential to become virtually any type of cell. Because injuries and surgeries can trigger rapid bone formation in FOP patients, obtaining tissue samples for extensive lab study is extremely difficult. Human iPS cells provide a unique solution by allowing the creation of the needed tissues in the lab. Hsiao and colleagues carefully gathered skin samples from donors, and then grew the skin cells in culture before converting them into iPS cells using the methods created by Yamanaka. In addition to providing an alternative to embryonic stem cells for potential use in regenerating diseased tissues, iPS cells are being used to learn more about diseases, especially diseases driven by mutated genes. Unlike the skin cells from which they originated, the human iPS cells created from FOP patients show increased cartilage formation and increased bone mineralization, two critical steps that are necessary to form mature bone. Bone morphogenetic proteins (BMPs) play a central role in the bone formation within muscle. FOP results from a gene mutation that causes a defect in the receptor protein to which BMPs bind, thereby increasing bone formation. “These cells will be a key tool for finding ways to stimulate and control human bone growth for regenerative medicine or bone repair,” Hsiao said. “The iPS cells may also help us identify treatments for more common diseases, such as atherosclerosis and vascular calcification, because the same bone morphogenetic protein pathways are involved in these medical conditions.”

http://www.sciencedaily.com/  Science Daily February 4, 2014

http://www.sciencedaily.com/releases/2014/01/140108093250.htm  Original web page at Science Daily

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Faster surgery may be better for hip fractures

The speed of surgery after a hip fracture may have a significant impact on outcomes for older patients, and faster may be better, say researchers at McMaster University. For seniors, hip fractures can cause serious complications that may result in death or admission to long-term care facilities for some people who previously lived at home. Hip fractures cause pain, bleeding and immobility and activate patient’s coagulation and stress systems which can lead to medical complications in people awaiting surgery. In many countries, including Canada, waits for hip surgery can be 24 hours or longer, mainly because of pre-surgery clearance procedures and lack of operating rooms. However, during the scientific study of 60 people aged 45 years or older in Canada and India, half received accelerated surgery within six hours and half had standard care of surgery 24 hours after diagnosis with a hip fracture. Among patients receiving standard care, 47% suffered a major complication of death, heart attack, stroke, pneumonia, blood clot or major bleeding event. However, only 30% of the patients in the accelerated surgery group suffered one of these complications. “We believe that the shortest time possible to treatment may provide the greatest potential for benefit, as is the case in acute heart attack and stroke,” said Dr. P.J. Devereaux, an associate professor of medicine and epidemiology at the Michael G. DeGroote School of Medicine at McMaster and co-principal investigator of the pilot trial. Dr. Mohit Bhandari, a professor of surgery of the McMaster medical school and co-principal investigator, added: “This pilot provides encouraging evidence that accelerated surgery may substantially improve outcomes in these patients.”

Science Daily
December 10, 2013

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Molecule critical to healing wounds identified

Skin provides a first line of defense against viruses, bacteria and parasites that might otherwise make people ill. When an injury breaks that barrier, a systematic chain of molecular signaling launches to close the wound and re-establish the skin’s layer of protection. A study led by researchers from the University of Pennsylvania’s School of Dental Medicine and published in the Journal of Cell Biology now offers a clearer explanation of the role of one of the players in the wound-healing process, a molecule called FOX01. Contrary to what had been expected, FOX01 is critical to wound healing, providing researchers with a possible new target for drugs that could help speed that process for people with impaired wound healing. Senior author Dana Graves is a professor in Penn Dental Medicine’s Department of Periodontics and is vice dean for scholarship and research. He collaborated on the study with Penn’s Bhaskar Ponugoti, Fanxing Xu, Chenying Zhang, Chen Tian and Sandra Pacio. A critical element of wound healing involves the movement of keratinocytes, the primary cells comprising the epidermis, or the outer layer of skin. Previous research had found that FOX01 was expressed at higher levels in wounds, but scientists did not understand what role the molecule was playing. In other scenarios, such as in cancer cells, FOX01 promotes cell death and interferes with the cell reproduction, two actions that would seem to be detrimental to healing.

To investigate the role of FOX01 in wound healing, Graves and colleagues bred mice that lacked the protein in their keratinocytes and then observed the wound healing process in these mice compared to mice with normal FOX01. “We thought that deleting FOX01 would speed up the wound-healing process,” Graves said, “but in fact it had the opposite effect.” The mice that lacked FOX01 showed significant delays in healing. Whereas all wounds on control mice were healed after one week, all of the experimental mice still had open wounds. Digging deeper into this counterintuitive finding, the researchers examined the effect of reducing FOX01 levels on other genes known to play a role in cell migration. They found that many of these genes were significantly reduced, notably TGF-β1, a critical growth factor in wound repair. When the team added TGF-β1 to cells lacking FOX01, the cells behaved normally and produced the proper suite of molecules needed for healing, indicating that FOX01 acts upstream of TGF-β1 in the signaling pathway triggered during the healing process. Further experimenting revealed that mice lacking FOX01 had evidence of increased oxidative stress, which is detrimental to wound healing. “The wound healing environment is a stressful environment for the cell,” Graves said. “It appears that upregulation of FOX01 helps protect the cell against oxidative stress.”

The fact that FOX01 behaves in this unexpected way could have to do with the specialized microenvironment of a cell in a wound, Graves noted. While FOX01 does indeed promote cell death when it is highly activated, it does the opposite when moderately activated. Which activity it promotes depends on the environment in which it is acting. Taken together, the study’s findings demonstrate that FOX01 plays an integral role in two key processes in wound healing: activation of TGF-β1 and protecting the cell against oxidative damage. Its involvement in these aspects of healing make it a potential target for pharmaceuticals that could help speed healing. “If you had a small molecule that increased FOX01 expression, you might be able to upregulate TGF-β1 as well as protect against the oxidative stress associated with wound healing,” Graves said.

Science Daily
December 10, 2013

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New ligament discovered‬ in the human knee

Two knee surgeons at University Hospitals Leuven have discovered a previously unknown ligament in the human knee. This ligament appears to play an important role in patients with anterior cruciate ligament (ACL) tears. ‪Despite a successful ACL repair surgery and rehabilitation, some patients with ACL-repaired knees continue to experience so-called ‘pivot shift’, or episodes where the knee ‘gives way’ during activity. For the last four years, orthopedic surgeons Dr Steven Claes and Professor Dr Johan Bellemans have been conducting research into serious ACL injuries in an effort to find out why. Their starting point: an 1879 article by a French surgeon that postulated the existence of an additional ligament located on the anterior of the human knee. That postulation turned out to be correct: the Belgian doctors are the first to identify the previously unknown ligament after a broad cadaver study using macroscopic dissection techniques. Their research shows that the ligament, which was given the name anterolateral ligament (ALL), is present in 97 per cent of all human knees. Subsequent research shows that pivot shift, the giving way of the knee in patients with an ACL tear, is caused by an injury in the ALL ligament. Some of the conclusions were recently published in the Journal of Anatomy. The Anatomical Society praised the research as “very refreshing” and commended the researchers for reminding the medical world that, despite the emergence of advanced technology, our knowledge of the basic anatomy of the human body is not yet exhaustive. ‪The research questions current medical thinking about serious ACL injuries and could signal a breakthrough in the treatment of patients with serious ACL injuries. Dr Claes and Professor Bellemans are currently working on a surgical technique to correct ALL injuries. Those results will be ready in several years.

Science Daily
November 26, 2013

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Gene and stem cell therapy combination could aid wound healing

Johns Hopkins researchers, working with elderly mice, have determined that combining gene therapy with an extra boost of the same stem cells the body already uses to repair itself leads to faster healing of burns and greater blood flow to the site of the wound. Their findings offer insight into why older people with burns fail to heal as well as younger patients, and how to potentially harness the power of the body’s own bone marrow stem cells to reverse this age-related discrepancy. “As we get older, it is harder for our wounds to heal,” says John W. Harmon, M.D., a professor of surgery at the Johns Hopkins University School of Medicine, who will present his findings to the American College of Surgeons’ Surgical Biology Club on Sunday. “Our research suggests there may be a way to remedy that.” To heal burns or other wounds, stem cells from the bone marrow rush into action, homing to the wound where they can become blood vessels, skin and other reparative tissue. The migration and homing of the stem cells is organized by a protein called Hypoxia-Inducible Factor-1 (HIF-1). In older people, Harmon says, fewer of these stem cells are released from the bone marrow and there is a deficiency of HIF-1. The protein was first discovered about 15 years ago at Johns Hopkins by Gregg L. Semenza, M.D., Ph.D., one of Harmon’s collaborators.

Harmon and his colleagues first attempted to boost the healing process in mice with burn wounds by increasing levels of HIF-1 using gene therapy, a process that included injecting the rodents with a better working copy of the gene that codes for the protein. That had worked to improve healing of wounds in diabetic animals, but the burn wound is particularly difficult to heal, and that approach was insufficient. So they supplemented the gene therapy by removing bone marrow from a young mouse and growing out the needed stem cells in the lab. When they had enough, they injected those supercharged cells back into the mice. After 17 days, there were significantly more mice with completely healed burns in the group treated with the combination therapy than in the other groups, Harmon says. The animals that got the combination therapy also showed better blood flow and more blood vessels supplying the wounds. Harmon says a wound treatment like this that uses a patient’s own cells is promising because the patient would be less likely to reject them as they would cells from someone else. Meanwhile, he says, HIF-1 gene therapy has been safely used in humans with sudden lack of blood flow to a limb. “It’s not a stretch of the imagination to think this could someday be used in elderly people with burns or other difficult wounds,” Harmon says.

Johns Hopkins researchers from the Department of Plastic and Reconstructive Surgery report that a type of stem cell found easily in fat cells and also in bone marrow promoted nerve regeneration in rats with paralyzing leg injuries and in some of the rodents that received hind-leg transplants. The findings mark a step forward in understanding how mesenchymal stem cells (MSCs) may improve nerve regeneration after injury and limb transplant, while potentially minimizing the need for lifelong immunosuppression after reconstructive surgery to replace a lost limb, say study leaders W.P. Andrew Lee, M.D., and Gerald Brandacher, M.D. Such immunosuppressive drug therapy carries many unwanted side effects. “Mesenchymal stem cells may be a promising add-on therapy to help damaged nerves regenerate,” says John Pang, a medical student at the Johns Hopkins University School of Medicine, who is expected to present the findings on Wednesday. “We obviously need to learn much more, but we are encouraged by what we learned from these experiments.” MSCs most frequently become bone, cartilage and fat in the bodies of mammals, and researchers have been able to coax them in test tubes into becoming nerve cells and skin that lines blood vessels and tissue.

Notably, MSCs are not recognized by the body as foreign, making them less likely to trigger an immune system response or attack. Instead, these stem cells appear to secrete proteins that suppress the immune system in specific ways. Pang says it is those properties researchers hope to harness and use to not only regenerate nerve cells, but also to help transplant patients avoid immunosuppressant drugs. The Johns Hopkins team notes that harvesting MSCs is a relatively simple procedure, because accessible stores are found in body fat. They can also be extracted from bone marrow, a slightly more complicated process. The Johns Hopkins researchers experimented with three groups of rats: those whose femoral nerves were cut and repaired; those that received a hind-leg transplant from the same biological type of rat; and animals that received a transplant from a different type. Some rats had MSCs injected directly into the sciatic nerve, while others received them intravenously into the bloodstream. After 16 weeks, the researchers say the rats with severed and repaired nerves treated with MSCs showed significant improvements in nerve regrowth and nerve signaling. Those with transplants from similar rats appeared to also show benefit. The rats whose transplants came from dissimilar rodent types — the situation most similar to a human transplant from a cadaver — rejected their new limbs.

Science Daily
October 29, 2013

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Fat grafting helps patients with scarring problems

Millions of people with scars suffer from pain, discomfort, and inability to perform regular activities. Some may have to revert to addicting pain medicine to get rid of their ailments. Now, and with a new methodology, such problems can be treated successfully. A technique using injection of the patient’s own fat cells is an effective treatment for hard, contracted scars resulting from burns or other causes, reports a study in the September issue of The Journal of Craniofacial Surgery, edited by Mutaz B. Habal, MD, FRCSC, and published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health. Dr. Marco Klinger and coauthors of Università degli Studi di Milano report good results with fat grafting in hundreds of patients with difficult-to-treat scars causing pain and limited motion. “For scar treatment, where medical and surgical therapies seem to be ineffective especially in the long term, autologous fat graft has proven to be a new chance to repair tissue damage,” the researchers write. “Fat Grafting Shows Promise as Treatment for Scars” Dr. Klinger and colleagues used autologous fat grafting to treat persistent scarring problems in nearly 700 patients over six years. (“autologous” means using the patient’s own tissues.) All patients had abnormal, painful scars causing hardening or tightening of the skin, often with limitation of motion. The scars — resulting from burns, surgery, or other causes — had not improved with other treatments.

The fat grafting procedure began with liposuction to collect a small amount of the patient’s own fat tissue — usually from the abdomen or hips. After processing, surgeons reinjected the fat cells under the skin in the area of scarring. Fat was distributed in different directions, with the goal of creating a “web” of support for scarred, damaged skin. Fat grafting led to significant improvement “both from an aesthetic and functional point of view,” according to Dr. Klinger and co-authors. The skin in the scarred area became “softer and more flexible and extensible, and very often color seemed similar to the surrounding unharmed skin.” After fat grafting, the patients had decreased pain and increased scar elasticity. Improvement began within two weeks, continued through three months, and persisted through one year and beyond. In a subgroup of patients, objective testing of skin hardness and clinical ratings by doctors and patients provided further evidence of treatment benefits. Fat cells lead to improved function as well as appearance. For example, in patients with scarring after burns to the face, fat grafting led to improved facial motion.

Fat grafting helped solve other difficult surgical problems as well. In one case, a breast cancer patient was left with hard, painful scars after complications from breast reconstruction. Treatment with fat grafting allowed a successful second breast reconstruction to be performed. In recent years, there has been renewed interest in techniques using the patient’s own fat for reconstructive and cosmetic plastic surgery. The new experience suggests that fat grafting may provide an effective new “regenerative medicine” technique for patients with difficult-to-treat scars. It’s not yet clear exactly how fat grafting exerts its benefits in scarred tissues. One factor may be the fact that fat tissue includes stem cells, which can develop into many different types of cells active in the wound healing and tissue repair process.

Science Daily
October 15, 2013

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Glass scaffolds help heal bone, show promise as weight-bearing implants

Researchers at Missouri University of Science and Technology have developed a type of glass implant that could one day be used to repair injured bones in the arms, legs and other areas of the body that are most subject to the stresses of weight. This marks the first time researchers have shown a glass implant strong enough to bear weight can also integrate with bone and promote bone growth, says lead researcher Dr. Mohamed N. Rahaman, professor of materials science and engineering at Missouri S&T. In previous work, the Missouri S&T researchers developed a glass implant strong enough to handle the weight and pressure of repetitive movement, such as walking or lifting. In their most recent study, published in the journal Acta Biomaterialia, the research team reported that the glass implant, in the form of a porous scaffolding, also integrates with bone and promotes bone growth. This combination of strength and bone growth opens new possibilities for bone repair, says Rahaman, who also directs Missouri S&T’s Center for Biomedical Science and Engineering, where the research was conducted. “Right now, there is no synthetic material that is practical for structural bone repair,” Rahaman says.

Conventional approaches to structural bone repair involve either the use of a porous metal, which does not reliably heal bone, or a bone allograft from a cadaver. Both approaches are costly and carry risks, Rahaman says. He thinks the type of glass implant developed in his center could provide a more feasible approach for repairing injured bones. The glass is bioactive, which means that it reacts when implanted in living tissue and convert to a bone-like material. In their latest research, Rahaman and his colleagues implanted bioactive glass scaffolds into sections of the calvarial bones (skullcaps) of laboratory rats, then examined how well the glass integrated with the surrounding bone and how quickly new bone grew into the scaffold. The scaffolds are manufactured in Rahaman’s lab through a process known as robocasting — a computer-controlled technique to manufacture materials from ceramic slurries, layer by layer — to ensure uniform structure for the porous material. In previous studies by the Missouri S&T researchers, porous scaffolds of the silicate glass, known as 13-93, were found to have the same strength properties as cortical bone. Cortical bones are those outer bones of the body that bear the most weight and undergo the most repetitive stress. They include the long bones of the arms and legs. But what Rahaman and his colleagues didn’t know was how well the silicate 13-93 bioactive glass scaffolds would integrate with bone or how quickly bone would grow into the scaffolding.

“You can have the strongest material in the world, but it also must encourage bone growth in a reasonable amount of time,” says Rahaman. He considers three to six months to be a reasonable time frame for completely regenerating an injured bone into one strong enough to bear weight. In their studies, the S&T researchers found that the bioactive glass scaffolds bonded quickly to bone and promoted a significant amount of new bone growth within six weeks. While the skullcap is not a load-bearing bone, it is primarily a cortical bone. The purpose of this research was to demonstrate how well this type of glass scaffolding — already shown to be strong — would interact with cortical bone. Rahaman and his fellow researchers in the Center for Biomedical Science and Engineering are now experimenting with true load-bearing bones. They are now testing the silicate 13-93 implants in the femurs (leg bones) of laboratory rats. In the future, Rahaman plans to experiment with modified glass scaffolds to see how well they enhance certain attributes within bone. For instance, doping the glass with copper should promote the growth of blood vessels or capillaries within the new bone, while doping the glass with silver will give it antibacterial properties.

Science Daily
August 6, 2013

Original web page at Science Daily