Farshid Guilak, right, and co-author Alison Ross show prototype of living hip replacement (Robert Boston, Washington University in St. Louis)
19 July 2016. A process combining stem cells, industrial weaving, and gene therapy to grow replacement joint cartilage for osteoarthritis is shown in lab tests to also prevent inflammation from returning. A team from Washington University in St. Louis and biomaterials company Cytex Therapeutics in Durham, North Carolina demonstrate their technology in yesterday’s issue of Proceedings of the National Academy of Sciences (paid subscription required).
Researchers from the lab of orthopedic surgery professor Farshid Guilak at Washington University’s medical school are seeking better ways to treat osteoarthritis, the most common form of arthritis, affecting some 27 million people in the U.S. Symptoms often appear gradually and become worse with age, but are aggravated by overuse, obesity, previous injuries, and in some cases genetics. Treatments for osteoarthritis usually aim at relieving pain, since no cure is yet found.
While osteoarthritis affects mainly older individuals, it can occur in people as young as 25. The techniques developed by Guilak and colleagues are designed primarily for younger people with the condition, for whom normal joint replacement surgery would be a temporary solution, since replacement joints do not last more than 20 years. Another replacement surgery runs risks of bone damage and infection.
In their paper, the team created a synthetic, hip ball joint made from poly-epsilon-caprolactone, or PCL, fibers, a long-lasting biocompatible polymer. The fibers are woven into 3-D hemispheric scaffolds, about 22 millimeters in diameter, with the structure and properties of cartilage using industrial weaving techniques adapted by Cytex Therapeutics. Cytex is a spin-off enterprise from Duke University in Durham; Guilak is also president of Cytex and formerly a faculty member at Duke.
The fiber scaffolds are then seeded with stem cells derived from adipose or fat tissue from the patient, thus removing the risk for immune rejection. The stem cells are cultured and induced to develop into cartilage, which can replace the patient’s damaged cartilage.
The researchers took the process one step further. The team also coated the PCL fibers with Interleukin-1 Receptor Antagonist or IL-1Ra genes, using benign viruses to deliver the genes, which were transferred into the stem cells. IL-1Ra genes have anti-inflammatory properties blocking signals from Interleukin-1 proteins that promote inflammation.
In lab tests, the team tested identical synthetic cartilage samples treated with Il-1 proteins. The cartilage sample without IL-1Ra genes expressed inflammatory enzymes, while the cartilage receiving the IL-1Ra genes did not produce those enzymes.
“We’ve developed a way to resurface an arthritic joint using a patient’s own stem cells to grow new cartilage,” says Guilak in a university statement, “combined with gene therapy to release anti-inflammatory molecules to keep arthritis at bay. Our hope is to prevent, or at least delay, a standard metal and plastic prosthetic joint replacement.”
The researchers say they began tests of the technology with lab animals, and expect human clinical trials could start in 3 to 5 years.
Tracking injected mesenchymal stem cells in lab mouse with magnetic nanoparticles (Magnetic Insight Inc.)
18 July 2016. A spin-off enterprise from University of California in Berkeley, developing a medical imaging technology with magnetic nanoparticles, is raising $3 million in start-up funding. Magnetic Insight Inc. in Alameda, California says the new financing supplements the $12 million it already raised before start-up.
The company licenses a technology developed in the UC-Berkeley lab of engineering professor Steven Conolly that detects magnetic tracers made with nanoscale particles — 1 nanometer equals 1 billionth of a meter — sent into tissue to diagnose medical conditions. Conolly is a co-founder of Magnetic Insight and a scientific advisor, with company CEO Anna Christensen and chief technologist Patrick Goodwill. The company began initially at StartX, an accelerator for start-up enterprises related to Stanford University; both Conolly and Goodwill got graduate degrees at Stanford.
Magnetic Insight’s technology sends non-radioactive and non-toxic iron oxide nanoparticle tracers into tissue, where they are detected by a magnetic field. Superparamagnetic iron oxide or SPIO particles, as small as 60 nanometers, are already used as contrast agents for MRI scans. Because iron oxide in the particles is not found in the body, the particles can be traced with a high degree of accuracy.
The magnetic field can also direct the movement of nanoparticles, with a location and direction determined by a free field point. When the magnetic direction of the nanoparticle changes, it sends a signal detected by a receiver. Those signals can then be aggregated and displayed as a quantitative image. Conolly with colleagues at Berkeley and Magnetic Insight demonstrated the technology tracking stem cells in lab mice in a paper published in January 2016.
The new financing is seed-round funds led by Sand Hill Angels, a group of Silicon Valley investors supporting innovative start-ups in Internet, information technology, clean tech, consumer, and life sciences. The StartX Fund and other angel investors participated in the financing. Magnetic Insight says it already raised some $12 million in research funding, prior to company start-up, as well as Small Business Innovation Research grants from NIH.
The new funding is expected to support development of Momentum, the company’s lead product. Momentum is a magnetic nanoparticle imaging system designed for preclinical applications, including cell tracking, monitoring vascular functions, cancer, and immunology research. The company also markets Vivotrax, magnetic particle imaging tracers for research, not clinical use.
18 July 2016. A clinical trial testing the safety of treatments derived from patients’ stem cells also shows patients with amyotrophic lateral sclerosis, or ALS, were able to slow the progression of their disease compared to those taking a placebo. Early results of the trial were reported by BrainStorm Cell Therapeutics Inc., in Petach Tikvah, Israel, developer of the treatments.
ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder where neurons or nerve cells controlling muscles in the body begin to waste away, and can no longer send or receive signals from the brain or spinal cord. As the nerve cells stop functioning, the muscles in the limbs, and later speech and breathing muscles, begin weakening and eventually stop functioning. Most people with the disease die of respiratory failure.
BrainStorm’s NurOwn technology, licensed from Tel Aviv University, extracts stem cells from the patient’s bone marrow that are transformed into cells supporting development of nerve cells. These transformed stem cells, says the company, secrete proteins called neurotrophic factors that protect nerve cells, as well as encourage their growth and interactions with muscles. Because the original cells come from the patient, they have little risk of rejection by the immune system.
The clinical trial is an intermediate-stage study conducted at 3 sites in the U.S. Some 48 patients with ALS were randomly assigned to receive either a single NurOwn treatment or a placebo. The trial’s primary objective is to test for the treatments’ safety and tolerability. However, the study team also recorded indicators of efficacy, namely a rating scale measuring decline of various muscle and communications functions, and slow vital capacity, a measure of normal respiratory function, before the treatments and at 10 points over 24 weeks.
BrainStorm reported results from the functional rating scales, specifically changes in scores as marked on a graph over time, where changes in the slope of the curve recording the functional decline can be precisely measured. The results show smaller declines in function, as measured by the slope of the curve over 24 weeks, for patients receiving NurOwn treatments, both in the point scores on the scale and percentages, from before the treatments, compared to patients receiving a placebo.
The company also broke out for a separate analysis ALS patients with a faster rate of decline from the disease — about half of the participants — since those with a slower rate of decline would likely experience a smaller benefit from the treatments. Among patients with faster progressing disease, those receiving the stem cell treatments show higher functional rating scale percentages at each testing point, than patients receiving the placebo.
BrainStorm says the treatments were largely safe and well-tolerated, with adverse events considered mild or moderate. Participants receiving NurOwn and placebo treatments experienced some kind of reaction, with adverse events happening somewhat more frequently among those receiving stem calls than placebo recipients. Adverse events included local treatment site and back pain, fever, headaches, and joint pain. No deaths were reported and all patients completed the trial.
The results, say BrainStorm, show the company can proceed on a late-stage study, with a larger patient population and multiple treatments.
Clinic in Haiti treating cholera patients in 2010 (Kendra Helmer, USAID)
15 July 2016. A new challenge seeks technologies and solutions to reduce child mortality and improve the health of children in low-resource regions of the world. The competition, sponsored by the pharmaceutical company GlaxoSmithKline and advocacy group Save The Children, has a total purse of $1 million and a deadline for submissions of 7 September 2016.
The challenge is conducted by InnoCentive in Waltham, Massachusetts that conducts open-innovation, crowdsourcing competitions for corporate and organization sponsors. Free registration is required to see details of the competition.
GlaxoSmithKline and Save The Children are in the fourth year of their partnership to find innovations in health care that reduce child deaths in developing countries, focusing on mortality of children under the age of 5. The competition is open to organizations in low- and middle-income countries, as defined by the World Bank. Organizations in these countries developing innovative practices or technologies designed to deliver health care to children considered difficult to reach are encouraged to submit proposals, or they can be nominated by other groups or individuals.
Examples of winning entries from previous years — the annual competition began in 2013 — include:
– An organization in Vietnam uses smartphones and computers to keep track of vaccine stocks, register pregnant women and newborns, and send text-message reminders to mothers to vaccinate themselves and their children.
– A medical college in Malawi invented a device that eases breathing difficulties of children with respiratory disorders. The college is sending trainers to expand use of the device in hospitals in Tanzania, Zambia, and South Africa.
– A company in Kenya developed a mobile health management system that improves maternal and child care in that country, providing real-time data on medicines and disease trends, to support health planning decisions for some 500,000 patients.
– An organization in Uganda trains health micro-entrepreneurs to go door-to-door distributing products such as fortified foods and solar lights, and educating residents on healthy practices. The group now reaches more than 3 times the number of traveling educators and families served.
InnoCentive calls the competition an electronic request-for-partners challenge that requires a proposal explaining materials or expertise to be provided, in this case technologies or solutions to improve child health in low-resource regions of the world. Participants in the challenge are asked not to provide confidential information in their proposals. Sponsors and participants will negotiate scope of work and other contract terms separately, and while transfers of intellectual property are not required, these arrangements are usually included in the contract.
GlaxoSmithKline and Save The Children expect to award up to $400,000 for the most innovative and effective solutions. The deadline for submissions is 7 September 2016.
Induced pluripotent stem cells reprogrammed from human skin (California Institute for Regenerative Medicine)
15 July 2016. An academic-industry team in Europe designed and tested new processes that can simplify and streamline production of human stem cells in large quantities. Researchers from Uppsala University in Sweden, University of Nottingham in the U.K., and GE Healthcare in Uppsala reported on this innovation on 13 July in the journal Nature Communications.
Health care providers, research labs, and drug companies are increasing their use of human pluripotent stem cells for regenerative medicine, tissue engineering, and drug screening, as well as therapeutic uses in the clinic. These stem cells can develop and transform into a wide range of mature cell types in the body, but current culturing processes for growing and reproducing stem cells are too expensive to scale-up to large quantities, or do not easily support advanced applications, such as cloning.
The search for more efficient stem cell production processes began in the lab of molecular biologist Cecilia Annerén at Uppsala University, who is also marketing manager for cell cultures at GE Healthcare in Uppsala. Sara Pijuan-Galitó, who led the project, started the study as a postdoc in Uppsala, and continues the work now as a research fellow at Nottingham’s stem cell biology group.
Pijuan-Galitó and colleagues began with a commercially-available stem cell culture medium called Essential-8, which is not derived from other animal components, known-as xeno-free, or other feeder cells that may carry viruses to contaminate the stem cells. The team then supplemented Essential-8 with inter-alpha-inhibitor, an abundant protein in blood, already tested as a treatment for inflammation and other disorders.
For the researchers, however, inter-alpha-inhibitor has another desirable property: it activates cell differentiation pathways for transformation into multiple adult cell types, as shown previously in tests with stem cells from mice. In lab tests, the team found that adding inter-alpha-inhibitor to Essential-8 provided a culturing medium that induces attachment and growth of both human embryonic and adult pluripotent stem cells.
The key benefits of combining inter-alpha-inhibitor and Essential-8, however, are that it can grow and differentiate stem cells on plain lab plastic surfaces, without bioactive coatings, as well as support cloning tasks. Moreover, it can improve the survival of stem cells in harsh conditions. “It is the first stem cell culture method that does not require a pre-treated biological substrate for attachment,” says Pijuan-Galitó in a Nottingham statement, “and therefore, is more cost and time-efficient and paves the way for easier and cheaper large-scale production.”
Annerén adds, “As coating is a time-consuming step and adds cost to human stem cell culture, this new method has the potential to save time and money in large-scale and high-throughput cultures, and be highly valuable for both basic research and commercial applications.”
GE Healthcare has more than a passing interest in stem cell production. On the same day the paper appeared, GE Healthcare announced the acquisition of Biosafe Group SA, a supplier of cell bioprocessing systems. In April, GE and Mayo Clinic formed a joint venture known as Vitruvian Networks to develop software and manufacturing systems supporting cell and gene therapies.
Rendering of three amyloid plaques (Fisher Center for Alzheimer’s Research Foundation)
14 July 2016. Researchers in New York applied an imaging technique that visualizes the build-up of amyloid-beta plaques in the brain associated with Alzheimer’s disease. The team from the lab of Rockefeller University neuroscientist Paul Greengard published its findings in today’s issue of the journal Cell Reports.
Alzheimer’s diseaseis progressive neurodegenerative disease affecting growing numbers of older people worldwide. People with Alzheimer’s disease often have deposits ofabnormal substancesin spaces between brain cells, known as amyloid-beta peptides, as well as misfolded tangles of proteins inside brain cells known as tau. Up to now, these accumulations in the brain were not clearly or precisely visualized, which can hamper diagnosis and treatment of Alzheimer’s disease.
The Rockefeller team, led by researcher Marc Flajolet and funded in part by the Fisher Center for Alzheimer’s Research, adapted a visualization method known as immunolabeling-enabled three-dimensional imaging of solvent-cleared organs, or iDisco, designed for large and high-volume tissue samples. The iDisco techniques, developed in a related Rockefeller lab, quickly and inexpensively labels characteristic antibodies associated with tissue, which enables the simultaneous color highlighting of different tissue types, including neurons and blood vessels, as well as build-ups of proteins such as amyloid-beta.
Flajolet and colleagues first used iDisco techniques to visualize brains of lab mice, up to 27 months in age, induced with Alzheimer’s disease. The researchers were able to identify amyloid-beta and tau accumulations in the mouse brains, as well as blood vessels and glial or immune-system cells in the brain. The team coupled their visualizations with automated detection, mapping, and quantification of plaque build-ups in the mice.
The team then applied iDisco methods to slices of frozen brains from deceased humans with Alzheimer’s disease. The researchers say the human samples needed no special preparation, and returned 3-D images showing as expected a more complex brain than those in mice. More importantly for understanding Alzheimer’s disease, the images revealed large 3-D amyloid patterns that the researchers believe can help establish different types or stages of Alzheimer’s disease.
“A better understanding of these plaques,” says Flajolet in a university statement, “as well as other key features of Alzheimer’s in the brain, might contribute to efforts to develop better targeted drugs, or allow us to rethink the drugs we have now. That’s what we hope for.”
The following video, courtesy of Fisher Center for Alzheimer’s Research Foundation, shows some of the brain images captured by iDisco techniques.
Scanning electron micrograph of HIV particles infecting a human T cell (NIH.gov)
14 July 2016. A device implanted under the skin that provides 60 days of antiretroviral drugs to prevent HIV infection is in development at Houston Methodist Research Institute. Tests of the refillable device with animals to prepare for human clinical trials are funded by a 5-year, $4 million grant from National Institute of Allergy and Infectious Diseases, or NIAID, part of National Institutes of Health.
A team led by Houston Methodist nanomedicine engineering professor Alessandro Grattoni is seeking to solve a continuing problem with adherence to drugs that prevent HIV infection among some individuals at high risk. Antiretroviral drugs can be taken by people to prevent HIV infection, but for various reasons (including side effects), taking HIV medicines every day and exactly as prescribed is sometimes difficult to sustain.
Grattoni and colleagues in the institute’s nanomedicine department developed a device, implanted under the skin, with nanoscale channels that diffuse drug compounds through membranes into the blood stream. Early versions of the device, known as a nanochannel delivery system, can sustain delivery of drugs in lab animals without pumps, valves, or a power supply. Among the early tests, the device delivered the drug tenofovir alafenamide for treating HIV for 21 days.
In the new project, the Houston Methodist team — with colleagues from University of Texas Medical School, M.D. Anderson Cancer Center, University of Houston, Baylor College of Medicine, and University of Colorado in Denver — will reconfigure the nanochannel delivery system to sustain delivery of an HIV prevention drug, including refills, for 60 days in monkeys. The drug is a combination of tenofovir alafenamide fumarate and emtricitabine, marketed as Truvada by Gilead Sciences as a pre-exposure prevention medication for HIV.
In addition, the team will test the ability of the sustained-release drugs to prevent infection of simian-human immunodeficiency virus, similar to HIV, in monkeys. The researchers will also test a remote-control feature that deactivates the device, as well as document chemical responses in the animals’ bodies to the implant and delivered drugs.
The developers already demonstrated that the nanochannel delivery system can administer more than HIV drugs. Grattoni’s lab is testing the device with hormone replacement, cancer prevention and treatment, mental disorders, drug abuse, and metabolic syndrome. NanoMedical Systems in Austin, Texas licenses the technology from Houston Methodist for commercialization.
A similar nanochannel delivery system is being tested as well aboard the International Space Station, evaluating nanoscale drug diffusion in microgravity conditions. The device was part of a resupply payload launched on 8 April 2016 with a SpaceX rocket.
13 July 2016. The personal genetics company 23andMe is offering a new analytical service for researchers that determines genotypes, or genetic variations, of individuals taking part in their studies. The Mountain View, California enterprise says its genotyping service for researchers includes collecting specimens and returning results of the analysis to individual study participants.
The new service, says the company, aims to simplify the process of collecting genetic data in research studies. Researchers, with studies approved by institutional review boards that govern research with human subjects, can employ the 23andMe service to collect saliva specimens, extract DNA, determine genetic variations through tests and reagents, return data and project reports to investigators, and return personal analytical reports to study participants.
The company says the genotyping service can also be combined with its iPhone app for researchers wanting to use mobile devices for data collection. As reported in Science & Enterprise, 23andMe unveiled in March 2016 a software module for Apple’s ResearchKit platform that makes it possible to add genetics data to iPhone apps used in medical research. ResearchKitis an open-source framework for collecting medical data with surveys or sensors connected to iPhones.
The 23andMe genotyping service is being pilot tested with researchers at University of California in San Diego, University of Southern California, Washington University in St. Louis, and McMaster University in Hamilton, Ontario, Canada. The company says pilot tests include research on smoking cessation, cognitive impairment in glioma patients, as well as addictions and psychiatric disorders.
The company says the genotyping service could make it easier for investigators to recruit participants by making it simple for individuals to collect saliva samples at home and return them to 23andMe for analysis. Participants would also receive their individual results collected for the research study as well as be eligible for 23andMe reports on ancestry, wellness, unique traits, and inherited conditions.
“Typically, research studies don’t return any data to the participants,” says 23andMe vice-president Ruby Gadelrab in a company statement. “We’ve enabled researchers to give results back to participants in the form of the 23andMe experience, which we believe is a huge advantage in recruiting.”
Roots with soil microbes (Stephen Temple, New Mexico State University, USDA)
13 July 2016. A plant science center and crop science company are developing a large-scale X-ray imaging system to measure root development in plants. Financial aspects of the agreement between Donald Danforth Plant Science Center in St. Louis and Valent Biosciences in Libertyville, Illinois were not disclosed.
The Danforth Center is a not-for-profit institute studying plant science. In June, researcher Chris Topp received a 4-year, $1.43 million grant from National Science Foundation to study root systems of maize — the formal name for corn — including development of advanced imaging technologies to better track root system development. The new agreement with Valent BioSciences, a subsidiary of Sumitomo Chemical Company in Tokyo, supplements the NSF award.
Topp’s lab studies root growth dynamics, especially the response to environmental stresses like drought and competition underground for nutrients. Its work includes development of better technologies to measure and document root system architecture, including computational biology and quantitative genetics, as well as advanced imaging technologies: X-rays, optical, and CT and PET scanning.
Valent BioSciences specializes in biorational products, defined as structurally similar and functionally identical to a biologically occurring substances, whether biologically derived or synthetic. Among its products are those addressing the rhizosphere, the biochemical interactions between roots and soil. In 2015, the company acquired Mycorrhizal Applications Inc., a producer of fungal spores to improve soil health and increase plants’ nutrient and water uptake.
The NSF award calls for Topp and colleagues to investigate root systems of maize, called the “hidden half” of plants, where water and nutrients are acquired. Root systems of maize are considered superior in acquiring nitrogen, and the project proposes applying technologies from medicine and industry, including X-ray and optical imaging, to document and measure the root architecture of maize.
In their joint project, Valent and the Danforth Center are expected to develop a large-scale X-ray imaging system for non-invasive root measurements, which the partners say will be the first system of its kind dedicated to academic plant science. Up to now, plant scientists had to take plants out of the ground to observe root systems.
In addition to the imaging project, Valent and the Danforth Center are collaborating in SyMyco Inc., a joint venture to improve and restore natural fungi that improve root system performance.
12 July 2016. Ingredients in pomegranate fruit, once metabolized in the gut, are found in tests with lab mice to protect cells against aging. A team from École Polytechnique Fédérale de Lausanne, or EPFL, in Switzerland and the spin-off enterprise Amazentis SA published its findings yesterday in the journal Nature Medicine (paid subscription required).
Pomegranates are native to South Asia and grown throughout the Middle East, as well as warmer regions in the Americas. Various health benefits are attributed to pomegranates, but up to now, little hard evidence of these benefits were found. The EPFL-Amazentis team investigated the benefits of a molecule derived from pomegranates known as urolithin A to strengthen the energy function in cells.
Urolithin A does not come directly from pomegranates, but is a product of metabolism by microbes in the gut of ellagitannins, bioactive nutrients in pomegranates, as well as some other fruit and nuts including black and red raspberries, strawberries, walnuts, and almonds. Once produced in the gut, urolithin A is processed in the liver.
The researchers, led by EPFL physiologist Johan Auwerx and Chris Rinsch, CEO of Amazentis, tested urolithin A’s effects on mitophagy, a process of degrading and recycling mitochondria, the energy centers of cells. As organisms age, damaged mitochondria accumulate in cells, which over time contributes to sarcopenia, a weakening of muscle mass, characteristic of the aging process. Amazentis cites data indicating 30 percent of people age 60 and over and half of those 80 and over experience sarcopenia. Urolithin A is believed to restore mitophagy, thus helping cells recycle damaged mitochondria.
The team tested first with C. elegans, a well-studied model species of roundworms with a short life span. The results show exposure to urolithin A increased the life span of C. elegans by 45 percent, compared to similar worms not exposed. During their longer life span, the C. elegans exposed to urolithin A maintained normal mobility and respiratory functions.
In tests with two sets of lab mice, one older and one younger group, the researchers found similar results. The mice exposed to urolithin A showed more recycling of damaged mitochondria than comparison groups not exposed. In addition, among older mice, the exposed group showed 42 percent more exercise endurance than the comparison group.
Auwerx believes the tests with two very different kinds of species bodes well for eventual success of urolithin A with humans. “Species that are evolutionarily quite distant, such as C elegans and the rat,” says Auwerx in an EPFL statement, “react to the same substance in the same way. That’s a good indication that we’re touching here on an essential mechanism in living organisms.”
Amazentis is developing a product with urolithin A to improve cell health among older individuals. The company started its first clinical trials of its urolithin A product, with results expected in 2017. Auwerx tells more about the research in the following video.
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