One more medical miracle in a decade-long series of phenomenal innovative research …

Biological sutures: Hair-thin threads seeded with stem cells (marked in red and blue) could help heal the heart.    Credit: Gaudette Lab, WPI

Polymer threads coated with stem cells might one day heal damaged cardiac muscle

MIT Technology Review, December 16, 2010, by Emily Singer  —  Over the last decade, scientists have experimented with using stem cells to heal or replace the scarred tissue that mars the heart after a heart attack. While the cells do spur some level of repair in animals, human tests have resulted in modest or transient benefits at best. Now researchers have developed a new kind of biological sutures, made from polymer strands infused with stem cells, that might help surmount two major obstacles to using stem cells to heal the heart: getting the cells to the right spot and keeping them there long enough to trigger healing.

Scientists from the Worcester Polytechnic Institute, in Massachusetts, have shown that cells derived from human bone marrow, known as mesenchymal stem cells, can survive on the threads and maintain their ability to differentiate into different cell types after being sewn through a collagen matrix that mimics tissue. Preliminary tests in rats suggest that the technology helps the cells survive in the heart.

“This is an out-of-the-box approach,” says Charles Murry, a director of the Center for Cardiovascular Biology at the University of Washington, who was not involved in the study. “Putting cells on thread—once you hear it, it seems simple. But I’ve been in this field for 15 years, and I never thought of it.”

One major challenge has been to get an adequate number of cells to remain in the area of injury. For example, in human studies of injected mesenchymal stem cells, only one percent to about 10 percent of injected cells remained at the site after injection. “Presumably the cells will be much happier if they have something to adhere to than if you just put them in and left them to fend for themselves,” says Murry.

Glenn Gaudette and collaborators at Worcester Polytechnic created the sutures with hair-thin threads made of fibrin, a protein polymer that the body uses to initiate wound healing and a common ingredient in tissue engineering. The microthread technology was developed by George Pins, associate professor of bioengineering at the institute.

The strands are transferred to a tube filled with stem cells and growth solution; the tube slowly rotates, so the stem cells can adhere to the full circumference of the suture. Once populated by cells, the suture is attached to a surgical needle.

About 10,000 mesenchymal cells can inhabit a two-centimeter length of bundled threads. Scientists can vary the size of the bundle, and the speed at which the material breaks down, depending on the application.

“This new technique provides a wonderful tool for cell delivery for cardiac repair and for electrical problems as well, where you might want to create a new electrical path,” says Ira Cohen, director of the Institute for Molecular Cardiology at Stony Brook University in New York. Cohen has collaborated previously with Gaudette but was not involved in this project.

Gaudette’s team is now studying the sutures in rats, to determine how long the cells remain at the injury site, and whether they can help heal tissue. One question that remains to be answered is whether the technology can be scaled up to deliver the hundreds of millions of cells needed to repair the heart wall.

While both animal and human studies show that mesenchymal cells can boost heart function, it’s not clear how. The predominant idea is that the cells, rather than forming new tissue themselves, release growth factors and other molecules that spur the growth of new blood vessels. They may also signal resident cells to begin dividing in order to grow new tissue.

Tissue engineers are developing a number of different methods for delivering stem cells to a wounded heart, including growing patches of beating heart muscle. But Gaudette hopes that biological sutures will prove more versatile than patches, and ultimately less invasive. Because of the threadlike structure, the material has the potential to be delivered via a catheter that passes through a vein.

The research is also part of a larger trend to combine stem cells with tissue engineering and novel biomaterials to help cells grow more naturally and to improve their survival rate once implanted. “If you think of the heart as a damaged piece of material—a concept that I think is gaining traction—you’re not going to want to randomly introduce cells,” says Kenneth Chien, director of the Cardiovascular Research Center at Massachusetts General Hospital. “We want to force cells to go where we want and align the way we want.” He likens this approach to that of a skilled tailor who repairs a sweater using the same thread and stitching as the existing material.

While Gaudette’s study focused on mesenchymal stem cells, other researchers are pursuing the same approach with other cell types, such as cardiac myocytes, which make up the heart’s striated muscle. “Presumably you could make threads of vascular cells, cardiac muscle cells, or multiple cell types,” says Murry. “The greater limitation comes to how big a hole you can make in the heart to drag through a cable of cells.”

Biomedicine

Mending muscle: Hair-thin threads like the ones shown here were seeded with muscle cells and implanted into wounds to help heal muscle in mice.   Credit: Tissue Engineering/Mary Ann Liebert

Doctors can’t do much in cases of severe muscle damage. New research shows that hair-thin threads might help

MIT Technology Review, December 16, 2010, by Emily Singer  —  Researchers have repaired large muscle wounds in mice by growing and implanting “microthreads” coated with human muscle cells. The microthreads—made out of the same material that triggers the formation of blood clots—seem to help the cells grow in the proper orientation, which is vital for rebuilding working muscle tissue.

“We hypothesize that cells migrate along these scaffolds, which act like a conduit,” says George Pins, associate professor of bioengineering at Worcester Polytechnic Institute. Pins developed the microthread technology. The implanted cells quickly integrate into the existing muscle and reduce formation of scar tissue. “The cells grow into the space where muscle used to be, but they grow in a guided way.”

Currently, there’s not much doctors can do when someone suffers massive injury to a muscle, such as in a car crash or an explosion. Thick bands of scar tissue can form in the wound, leaving the muscle severely and permanently impaired.

Scientists are developing numerous approaches to creating replacement muscle, including growing patches of cells in a dish, injecting stem cells into damaged muscle, and implanting cell-seeded scaffolds designed to mimic native tissue. While all of these efforts show promise for certain applications, one of the major challenges has been growing enough cells in the correct structure to heal large muscle wounds.

“Muscle alignment is very important,” says Kevin “Kit” Parker, a bioengineer at Harvard University who wasn’t involved in the research. “You want the sarcomeres [the basic functional unit of muscle] to be aligned, that’s how you get muscle contractions.”

Pins and his collaborators, including Ray Page, an assistant professor at WPI’s Bioengineering Institute, aim to solve this problem by growing cells along microthreads. These hair-thin strands are made of fibrin, a protein polymer that the body uses to initiate wound healing, and a common ingredient in tissue engineering. To make the microthreads, the researchers simultaneously extrude fibrinogen, the building block of fibrin, and thrombin, an enzyme that catalyzes the soluble fibrinogen proteins into a polymer, from two small tubes. (Microthreads are also being studied for other applications, such as growing patches of heart muscle to repair damage after heart attacks.)

The threads were seeded with human muscle cells derived from tissue discarded during surgery. Prior to seeding, Page’s team grew the cells under conditions that pushed them to de-differentiate—or to become more juvenile, less specialized cells—which in turn made them better able to regenerate.

To test the technology in mice, researchers cut out about 30 percent of the animals’ tibialis anterior muscle, which lies at the front of the lower leg. They then implanted cell-seeded microthreads into the wound. (The diameter of the thread, about 50 to 100 microns, is five to 10 times the size of the cells.)

Researchers believe that the fibrin scaffold sends signaling cues that mimic native wound healing, binding to growth factors and other molecules found in blood clots. It also attracts an enzyme that breaks down the fibrin, releasing fibrinogen proteins that signal the surrounding cells to migrate in and grow new tissue, says Pins.

The cells appeared to integrate into the host tissue in just a couple of days. After a week, the microthreads began to degrade, and researchers saw that muscle fibers had grown into the area left behind. At 10 weeks, the wound bed was full of human cells, which looked like mature muscle fibers. Page presented the research at a bioengineering symposium at WPI earlier this month.

The researchers are now trying to determine whether the new tissue behaves like normal muscle. Early evidence suggests that the implants also spurred the growth of native muscle cells, though Page says they still need to confirm this.

In addition, mice implanted with microthreads had much less scar tissue than animals left to heal on their own. The microthreads “dramatically reduced the amount of collagen [the major component of scar tissue] deposited in the wound area,” says Page. “Instead of collagen, we see a lot of [well-organized] muscle tissue.”

Page says that while other scientists have been able to repair muscle to a certain extent, the WPI technology healed a much larger area of injury than previous research. This may be because the microthreads help solve one of the major challenges in growing larger swaths of new tissue—drawing in an adequate supply of blood, vital for cell survival. “One of the reasons we wanted to investigate microthreads was, we felt having space between threads would give room for vasculature to form and for muscle cells to grow,” says Page.

Harvard’s Parker, who is growing heart muscle using even smaller fibers, agrees, adding that few people in tissue engineering are taking this approach. “If I put a solid chunk of meat in there, the center will become hypoxic [or oxygen-starved],” says Parker. “If I leave space between the cells, it is easier to recruit local blood vessels.”

Biomedicine

Regenerating a joint: A joint-shaped scaffold (top) attracts many more stem cells when it is infused with a protein growth factor (second from bottom) than without (second from top). The bottom image shows natural cartilage.   Credit: Jeremy Mao

A chemical-infused scaffold generates new tissue by attracting stem cells

MIT Technology Review, December  16, 2010, by Karen Weintraub  —  Today’s titanium replacement joints work very well for 10 to 15 years, but replacing them after they’ve worn out is a challenge for both patient and surgeon. A team of researchers from Columbia University proposes a way around that problem: by implanting a scaffold that encourages the patient’s own stem cells to regrow the joint.

In research published this week in The Lancet, the researchers demonstrate that the technology–a joint-shaped scaffold infused with a growth factor protein–works in rabbits. About a month after the implant, the animals began using their injured forelimbs again, and at two months the animals moved almost as well as similarly aged healthy rabbits. The study is the first to show that an entire joint can be repaired while being used.

“They used the potential of the body as a bioreactor, instead of doing everything in the petri dish,” says Patrick H. Warnke, a professor of surgery at Bond University. Warnke wrote a commentary on the Columbia study for The Lancet. While the connection between bone and the titanium in existing implants wears out over time, the hope for this alternative approach is that the new bone formed by the stem cells will create a more natural and durable connection, and that the scaffold itself would disintegrate over time.

The procedure, so far tested only in rabbits, still has a long way to go before it could be used in people, according to senior author Jeremy J. Mao, and a half-dozen scientists not involved in the research. It’s still not clear how well the approach would work for human-sized joints, or in animals, like humans, that put more pressure on their joints.

In the study, the researchers first imaged the damaged forelimb joint and then created a three-dimensional picture of it, explains Mao, a professor of biomedical engineering at Columbia University Medical Center. They used a bioprinter to “print out” a precisely accurate, three-dimensional copy of the joint, but criss-crossed it with tiny interconnecting microchannels to serve as a scaffold for new bone and cartilage growth. The surgical implantation was the same used to insert titanium implants in people, Mao says.

Thanks to the added growth factor protein, the rabbit’s own stem cells naturally migrated into the scaffold and regenerated both the cartilage and the bone beneath it.

The success is somewhat surprising. “I wouldn’t have thought in a normal weight-bearing joint that you could [replace the newly forming] cartilage while the joint is being loaded,” says Howard Seeherman, chief scientific officer for tissue repair at Pfizer. Seeherman says he would have expected the cartilage to just wear off when weight was put on the joint.

The research reflects a new trend in tissue engineering. “People are starting to think that if you simply build the microenvironment inside the body, the innate cells may be able to take this microenvironment and make the tissue,” says Ali Khademhosseini, a tissue engineering expert and assistant professor at Harvard Medical School and Brigham and Women’s Hospital. The approach has several advantages, he says. It’s impossible to re-create in a dish the array of signaling chemicals the body uses to generate the diverse cell types in different tissue, and it’s much easier to get approval from regulatory agencies to implant a scaffold than whole tissue.

Mao says he next wants to test the procedure in goats, which are a better model for human osteoarthritis than rabbits. Goats consistently put more of their body weight on their limbs. Though rabbits put weight on their forelimbs, humans put far more on their knees and hips, and it is not yet clear whether the procedure would survive such pressure.

Rabbits, particularly young ones, are also known for their regenerative abilities. Mao says the 23 rabbits used in the study were skeletally mature, and the three control rabbits–with injuries but no surgical repair–did not regrow joints. Rabbits who received the scaffold but not the growth factor saw some new growth, but not nearly as much as the ones who got the growth factor.

Pending regulatory guidelines, consumer privacy concerns and unclear return on investment present adoption hurdles

NEW YORK, Dec. 16, 2010 – As many life sciences companies begin to test the waters of online social networking, 65 percent of surveyed life sciences company professionals say their company uses or plans to use social networks at a company level in some capacity, while a surprising 35 percent report no plans to do so, according to a new Deloitte report titled, “To Friend or Not? New Insights About Social Networks in the Life Sciences Industry.”

Survey respondents say undefined Food and Drug Administration (FDA) guidelines, consumer privacy concerns and a lack of a clearly demonstrated return on investment are the top three hurdles to widespread adoption.

“The abundance of regulatory and risk restrictions are causing some life sciences companies to cautiously and slowly explore online social networks,” said Terry Hisey, vice chairman and life sciences sector leader, Deloitte LLP. “Innovative companies are beginning to leverage online social networks of physicians, patients and scientists to explore unprecedented opportunity to collect information, communicate important information and collaborate externally.”

Despite the potential risks that could be associated with online social networking, half (50 percent) of surveyed respondents who report they are responsible for managing risk related to online social networks, say their companies do not have a formal risk policy in place and 43 percent do not have procedures for managing adverse events.

“While many are waiting for more comprehensive guidelines on social networking to be released by the FDA, the potential for risk is great in the world of social media,” added Chris Franck, principal, Deloitte Consulting LLP, who serves Deloitte’s life sciences and health care clients. “Implementing and clearly communicating formal procedures for engaging with customers and managing the risks of social networking are important factors for life sciences companies to address to protect brand integrity.”

Future investment
Even after the FDA guidelines for social networking are issued, more than half (53 percent) of respondents still expect a significant amount of confusion around how life sciences companies can engage with social networks. Another 46 percent of respondents will continue to use social networks but won’t increase investment until the FDA provides guidance. More than one-third of respondents (38 percent) are waiting for the FDA to issue guidance before making any investment. Nearly three in 10 respondents (28 percent), said their companies are waiting to see what ROI other companies get. However, the majority (73 percent) expect the budget allocated for social networking will increase over the next three years.

Additional findings from the report that surveyed marketing/brand management professionals include:

Approximately 44 percent have an informal strategy for social networking that is not documented and/or fully supported by leadership, while 32 percent have no strategy at all.

Survey respondents use social networking to disseminate information (51 percent), proactively seek information (42 percent), or to react or respond to pertinent information posted on an online social network (23 percent).

One in five (20 percent) are indifferent to using social networking.

Hisey concluded, “Our survey findings demonstrate that the bulk of the use for social networking now is geared largely towards marketing. However, there are additional strategic applications beyond pure marketing still to evolve, such as conducting market research cheaper and faster; working with foundations to mobilize patients; improving peer-to-peer education through cost-effective medical education; determining the right patient reported outcomes; and providing data to help speed-up clinical trials. It will be interesting to see how the future of online social networking continues to evolve in the life sciences industry over the next five years.”

Methodology
Executive interviews were conducted with life sciences company executives, Health 2.0 executives, and academics. To supplement qualitative findings, Deloitte surveyed 208 life sciences industry professionals who are involved in marketing and/or compliance and risk management to get attitudes and behaviors relating to social network use in the industry. Respondents from the pharmaceutical, biotechnology, medical device, and diagnostics industries were surveyed between June 22, 2010 and July 6, 2010 via a web-based questionnaire. Professionals with marketing and compliance and risk responsibilities were selected based on their company’s core business and their day-to-day roles, and then asked to self describe their title and function. Respondents were categorized as “marketing” or “risk management” based on degree to which they were involved in brand management and risk and compliance in their day-to-day jobs. The web-based questionnaire consisted of 35 questions about the use and perceptions of social networks in their company and business units and was divided into a section focused to marketing professionals and a separate section focused to risk management professionals.

See Graphics, below on NETWORKS

The Importance of Networking 5 Examples

Web site

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Contagion of TB

The Internet

Yeast Proteins

For Immediate Release: Dec. 16, 2010
erica.jefferson@fda.hhs.gov

FDA begins process to remove breast cancer indication from Avastin label
Drug not shown to be safe and effective in breast cancer patients

The U.S. Food and Drug Administration announced today that the agency is recommending removing the breast cancer indication from the label for Avastin (bevacizumab) because the drug has not been shown to be safe and effective for that use.

The agency is making this recommendation after reviewing the results of four clinical studies of Avastin in women with breast cancer and determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.

In July 2010, after reviewing all available data an independent advisory committee, composed primarily of oncologists, voted 12-1 to remove the breast cancer indication from Avastin’s label.

“After careful review of the clinical data, we are recommending that the breast cancer indication for Avastin be removed based on evidence from four independent studies,” Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Subsequent studies failed to confirm the benefit observed in the original trial. None of the studies demonstrated that patients receiving Avastin lived longer and patients receiving Avastin experienced a significant increase in serious side effects. The limited effects of Avastin combined with the significant risks led us to this difficult decision. The results of these studies are disappointing. We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.”

Removing the breast cancer indication from the Avastin label will be a process. This is the first step. The drug itself is not being removed from the market and today’s action will not have any immediate impact on its use in treating breast cancer. Today’s action will not affect the approvals for colon, kidney, brain, and lung cancers.

Oncologists currently treating patients with Avastin for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

The agency has informed Genentech, Avastin’s manufacturer, of its proposal to withdraw marketing approval of the drug for breast cancer. Genentech has not agreed to remove the breast cancer indication voluntarily, so the agency has issued a Notice of Opportunity for a Hearing, which permits Genentech to request a public hearing if it wishes to contest the agency’s determination. The company has 15 days to request a hearing; if it does not do so, the hearing will be waived, and FDA will begin proceedings to remove the breast cancer indication.

Avastin, in combination with chemotherapy (paclitaxel), was approved in February 2008 under the FDA’s accelerated approval program, based on the results of a clinical trial known as “E2100,” which evaluated the drug in patients who had not received chemotherapy for their metastatic HER2-negative breast cancer. Under the accelerated approval program, a drug may be approved based on clinical data that suggest the drug has a meaningful clinical benefit, with more information being needed to confirm this.  The program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted.

After the accelerated approval of Avastin for breast cancer, Genentech completed additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on “progression-free survival” without evidence of an improvement in overall survival or a clinical benefit to patients sufficient to outweigh the risks. The small increase in “progression-free survival” reflects a small, temporary effect in slowing tumor growth.

Avastin has also been associated with several other serious and potentially life-threatening side effects including the risk of stroke, wound healing complications, organ damage or failure; and the development of a neurological condition called reversible posterior leukoencephalopathy syndrome (RPLS), characterized by high blood pressure, headaches, confusion, seizures, and vision loss from swelling of the brain.

On the basis of all available data relating to the use of Avastin to treat metastatic breast cancer, the agency has determined that the risks of the drug outweigh the benefits for this use.

FDA is open to working with Genentech on any proposals to conduct additional studies of Avastin in patients with metastatic breast cancer designed to identify a population of patients in which the drug’s benefits exceed the risks.

For more information:

FDA: Bevacizumab (marketed as Avastin) Information
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm193900.htm

NCI: Breast Cancer
http://www.cancer.gov/cancertopics/types/breast