Tuesday 6 December 2011
Monday 5 December 2011
Spatiotemporal Signals Guide Stem Cell Changes Enabling Engineering Of Cartilage Replacements
A lab discovery is a step toward implantable replacement cartilage, holding promise for knees, shoulders, ears and noses damaged by osteoarthritis, sports injuries and accidents.
Self-assembling sheets of mesenchymal stem cells permeated with tiny beads filled with growth factor formed thicker, stiffer cartilage than previous tissue engineering methods, researchers at Case Western Reserve University have found. A description of the research is published in the Journal of Controlled Release.
"We think that the capacity to drive cartilage formation using the patient's own stem cells and the potential to use this approach without lengthy culture time prior to implantation makes this technology attractive," said Eben Alsberg, associate professor in the departments of Biomedical Engineering and Orthopaedic Surgery, and senior author of the paper.
Alsberg teamed with biomedical engineering graduate students Loran D. Solorio and Phuong N. Dang, undergraduate student Chirag D. Dhami, and Eran L. Vieregge, a student at Case Western Reserve School of Medicine.
The team put transforming growth factor beta-1 in biodegradable gelatin microspheres distributed throughout the sheet of stem cells rather than soak the sheet in growth factor.
The process showed a host of advantages, Alsberg said.
The microspheres provide structure, similar to scaffolds, creating space between cells that is maintained after the beads degrade. The spacing results in better water retention - a key to resiliency.
The gelatin beads degrade at a controllable rate due to exposure to chemicals released by the cells. As the beads degrade, growth factor is released to cells at the interior and exterior of the sheet, providing more uniform cell differentiation into neocartilage.
The rate of microsphere degradation and, therefore, cell differentiation, can be tailored by the degree to which the microsphere are cross-linked. Within the microspheres, the polymer is connected by a varying number of threads. The more of these connections, or cross-links, the longer it takes for enzymes the cell secretes to enter and break down the material.
The researchers made five kinds of sheets. Those filled with: sparsely cross-linked microspheres containing growth factor, highly cross-linked microspheres containing growth factor, sparsely cross-linked microspheres with no growth factor, highly cross-linked microspheres with no growth factor, and a control with no microspheres. The last three were grown in baths containing growth factor.
After three weeks in a petri dish, all sheets containing microspheres were thicker and more resilient than the control sheet. The sheet with sparsely crosslinked microspheres grew into the thickest and most resilient neocartilage.
The results indicate that the sparsely cross-linked microspheres, which degraded more rapidly by cell-secreted enzymes, provided a continuous supply of growth factor throughout the sheets that enhanced the uniformity, extent, and rate of stem cell differentiation into cartilage cells, or chondrocytes.
The tissue appeared grossly similar to articular cartilage, the tough cartilage found in the knee: rounded cells surrounded by large amounts of a matrix containing glycosaminoglycans. Called GAG for short, the carbohydrate locks water ions in the tissue, which makes the tissue pressure-resistant.
Testing also showed that this sheet had the highest amount of type II collagen - the main protein component of articular cartilage.
Although the sheet was significantly stiffer than control sheets, the mechanics still fell short of native cartilage. Alsberg's team is now working on a variety of ways to optimize the process and make replacement cartilage tough enough for the wear and tear of daily life.
One major advantage of this system is that it may avoid the troubles and expense of growing the cartilage fully in the lab over a long period of time, and instead permit implantation of a cartilage sheet into a patient more rapidly.
Because the sheets containing microspheres are strong enough to be handled early during culturing, the researchers believe sheets just a week or two old could be used clinically. The mechanical environment within the body could further enhance cartilage formation and increase strength and resiliency of the tissue, completing maturation.
Source:
Self-assembling sheets of mesenchymal stem cells permeated with tiny beads filled with growth factor formed thicker, stiffer cartilage than previous tissue engineering methods, researchers at Case Western Reserve University have found. A description of the research is published in the Journal of Controlled Release.
"We think that the capacity to drive cartilage formation using the patient's own stem cells and the potential to use this approach without lengthy culture time prior to implantation makes this technology attractive," said Eben Alsberg, associate professor in the departments of Biomedical Engineering and Orthopaedic Surgery, and senior author of the paper.
Alsberg teamed with biomedical engineering graduate students Loran D. Solorio and Phuong N. Dang, undergraduate student Chirag D. Dhami, and Eran L. Vieregge, a student at Case Western Reserve School of Medicine.
The team put transforming growth factor beta-1 in biodegradable gelatin microspheres distributed throughout the sheet of stem cells rather than soak the sheet in growth factor.
The process showed a host of advantages, Alsberg said.
The microspheres provide structure, similar to scaffolds, creating space between cells that is maintained after the beads degrade. The spacing results in better water retention - a key to resiliency.
The gelatin beads degrade at a controllable rate due to exposure to chemicals released by the cells. As the beads degrade, growth factor is released to cells at the interior and exterior of the sheet, providing more uniform cell differentiation into neocartilage.
The rate of microsphere degradation and, therefore, cell differentiation, can be tailored by the degree to which the microsphere are cross-linked. Within the microspheres, the polymer is connected by a varying number of threads. The more of these connections, or cross-links, the longer it takes for enzymes the cell secretes to enter and break down the material.
The researchers made five kinds of sheets. Those filled with: sparsely cross-linked microspheres containing growth factor, highly cross-linked microspheres containing growth factor, sparsely cross-linked microspheres with no growth factor, highly cross-linked microspheres with no growth factor, and a control with no microspheres. The last three were grown in baths containing growth factor.
After three weeks in a petri dish, all sheets containing microspheres were thicker and more resilient than the control sheet. The sheet with sparsely crosslinked microspheres grew into the thickest and most resilient neocartilage.
The results indicate that the sparsely cross-linked microspheres, which degraded more rapidly by cell-secreted enzymes, provided a continuous supply of growth factor throughout the sheets that enhanced the uniformity, extent, and rate of stem cell differentiation into cartilage cells, or chondrocytes.
The tissue appeared grossly similar to articular cartilage, the tough cartilage found in the knee: rounded cells surrounded by large amounts of a matrix containing glycosaminoglycans. Called GAG for short, the carbohydrate locks water ions in the tissue, which makes the tissue pressure-resistant.
Testing also showed that this sheet had the highest amount of type II collagen - the main protein component of articular cartilage.
Although the sheet was significantly stiffer than control sheets, the mechanics still fell short of native cartilage. Alsberg's team is now working on a variety of ways to optimize the process and make replacement cartilage tough enough for the wear and tear of daily life.
One major advantage of this system is that it may avoid the troubles and expense of growing the cartilage fully in the lab over a long period of time, and instead permit implantation of a cartilage sheet into a patient more rapidly.
Because the sheets containing microspheres are strong enough to be handled early during culturing, the researchers believe sheets just a week or two old could be used clinically. The mechanical environment within the body could further enhance cartilage formation and increase strength and resiliency of the tissue, completing maturation.
Source:
Case Western Reserve University. "Spatiotemporal Signals Guide Stem Cell Changes Enabling Engineering Of Cartilage Replacements." Medical News Today. MediLexicon, Intl., 5 Dec. 2011. Web.
5 Dec. 2011. <http://www.medicalnewstoday.com/releases/238648.php>
5 Dec. 2011. <http://www.medicalnewstoday.com/releases/238648.php>
Case Western Reserve University. (2011, December 5). "Spatiotemporal Signals Guide Stem Cell Changes Enabling Engineering Of Cartilage Replacements." Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/238648.php.
http://www.medicalnewstoday.com/releases/238648.php.
Genetic sequencing could help match patients with biomarker-driven cancer trials, treatments
"We're talking about more than just examining a few genes where mutations are known to occur, or even about a hundred genes," says co-lead investigator Dan Robinson, Ph.D., a post-doctoral fellow at MCTP. "We're talking about the ability to sequence more than 20,000 genes and look not just for individual genetic mutations, but at combinations of mutations."
The exploratory study, known as the Michigan Oncology Sequencing Project (MI-ONCOSEQ), found that identifying a patient's "mutational landscape" provides a promising approach for identifying which trials may best help a patient, the researchers say. Their findings were recently published in Science Translational Medicine.
"High-throughput sequencing harnesses the latest technological advances to process millions of pieces of genetic information, allowing us to map a cancer's genetic aberrations," says co-lead investigator Sameek Roychowdhury, M.D., Ph.D., a clinical lecturer in hematology and oncology at the U-M Medical School. "Using this technique to identify biomarker-driven treatment options really opens the door for personalized oncology, but it also presents a number of logistical challenges, chief among them making the results available cost-effectively and in a clinically relevant timeframe."
"A decade or two ago, this type of sequencing would have cost many millions or even billions of dollars, but the technology is advancing so rapidly, we're now talking in terms of thousands -- which makes widespread use a real possibility," he adds.
Cancer can arise from a variety of genetic alterations including rearrangements, additions, deletions and substitutions within the genetic code.
"Different sequencing processes are required to find different types of alterations," Roychowdhury says. "But to be cost-effective, there must be a balancing act between a broad analysis and a deep analysis."
The study began by testing the researchers' sequencing strategy on prostate cancer tumors that had been grown in mice. Later, two patients were enrolled in a clinical pilot: one with colorectal cancer and one with melanoma. Potential clinical trials were identified for both patients.
However, the researchers caution, not all patients will match an existing study. Some patients with a given mutation may be excluded because they have, for example, prostate cancer, but a trial is only enrolling breast cancer patients. The researchers believe that this approach also provides an opportunity to approach clinical trials in a new way, moving from a tissue-specific focus toward genetic aberrations shared across cancer types.
Still, enrolling in a trial does not guarantee a patient will benefit from the treatment, the researchers caution.
Hurdles to widespread implementation include the need for a multidisciplinary Sequencing Tumor Board to interpret the complex sequencing results, management of the necessary computational resources, and a process for dealing with incidental genetic findings revealed by the sequencing -- such as a risk for hemochromatosis, a genetic disorder that causes the body to absorb too much iron.
Achieving a four-week turnaround time for results is important because that's how long patients are usually required to wait for unsuccessful treatments to leave their systems before starting a clinical trial.
"Once some of the practical and technological hurdles are cleared, we envision an array of mutation and pathway-based trials for available targeted therapies, with eligibility based on molecular assessment," says senior investigator Arul Chinnaiyan, M.D., Ph.D., director of MCTP, Howard Hughes Medical Institute Investigator, and S.P. Hicks Professor of Pathology at the U-M Medical School. "Moreover, if patients are treated with matching targeted therapies and develop secondary resistance, it could also help reveal the mechanisms of resistance and inform future trials for combination therapies."
Chinnaiyan says the work was made possible only by collaboration and teamwork. U-M physicians Moshe Talpaz, M.D., Stephen Gruber, M.D., Ph.D., and Kenneth Pienta, M.D. played key roles in the clinical implementation of this exploratory protocol, he notes.
Researchers hope this type of sequencing will become more widely available over the next 5 to 10 years. Cancer patients are encouraged to speak to their doctors about clinical trial opportunities.
Published: Wednesday, November 30, 2011 - 22:33 in Health & Medicine
Source: University of Michigan Health System
Subscribe to:
Posts (Atom)