Influencing the macrophages immediately after injury may affect the whole cascade of biochemical events that occurs after nerve damage, potentially eliminating the need to directly stimulate the growth of axons using nerve growth factors. If the results of this first-ever study can be applied to humans, they could one day lead to a new strategy for treating peripheral nerve injuries that typically result from trauma, surgical resection of tumors or radical prostectomy.
“Both scar formation and healing are the end results of two different cascades of biological processes that result from injuries,” said Ravi Bellamkonda, Carol Ann and David D. Flanagan professor in the Wallace H. Coulter Department of Biomedical Engineering and member of the Regenerative Engineering and Medicine Center at Georgia Tech and Emory University. “In this study, we show that by manipulating the immune system soon after injury, we can bias the system toward healing, and stimulate the natural repair mechanisms of the body.”
Beyond nerves, researchers believe their technique could also be applied to help regenerate other tissue – such as bone. The research was supported by the National Institutes of Health (NIH), and reported online Sept. 26, 2012, by the journal Biomaterials.
After injury, macrophages that congregate at the site of the injury operate like the conductor of an orchestra, controlling processes that remove damaged tissue, set the stage for repair and encourage the replacement of cells and matrix materials, said Nassir Mokarram, a Ph.D. student in the Coulter Department of Biomedical Engineering and Georgia Tech’s School of Materials Science and Engineering. Converting the macrophages to a “pro-healing” phenotype that secretes healing compounds signals a broad range of other processes – the “players” in the symphony analogy.
“If you really want to change the symphony’s activity from generating scarring to regeneration of tissue, you need to target the conductor, not just a few of the players, and we think macrophages are capable of being conductors of the healing symphony,” said Mokarram.
Macrophages are best known for their role in creating inflammation at the site of injuries. The macrophages and other immune system components battle infection, remove dead tissue – and often create scarring that prevents nerve regeneration. However, these macrophages can exist in several different phenotypes depending on the signals they receive. Among the macrophage phenotypes are two classes – M2a and M2c – that encourage healing.
Bellamkonda’s research team used an interleukin 4 (IL-4) cytokine to convert macrophages within the animal model to the “pro-healing” phenotypes. They placed a gel that released IL-4 into hollow polymeric nerve guides that connected the ends of severed animal sciatic nerves that had to grow across a 15 millimeter gap to regenerate. The IL-4 remained in the nerve guides for 24 hours or less, and had no direct influence on the growth of nerve tissue in this short period of time.Three weeks after the injury, the nerve guides that released IL-4 were almost completely filled with re-grown axons. The treated nerve guides had approximately 20 times more nerve regeneration than the control channels, which had no IL-4-treated macrophages.
Research is now underway to develop the technique for determining how soon after injury the macrophages should be treated, and what concentration of IL-4 would be most effective.
“We believe immune cells are the ‘master knobs’ that modulate the biochemical cascade downstream,” Mokarram said. “They are among the ‘first-responders’ to injury, and are involved for almost the whole regeneration process, secreting several factors that affect other cells. With IL-4, we are doing something very early in the process that is triggering a cascade of events whose effects last longer.”
Tissue engineering approaches have focused on encouraging the growth of nerve cells, using special scaffolds and continuous application of nerve growth factors over a period of weeks. Instead, the Bellamkonda group believes that influencing the immune system soon after injury could provide a simpler and more effective treatment able to restore nerve function.
“Beyond neural tissue engineering, the implications of this approach can be significant for other types of tissue engineering,” said Mokarram. “Neural tissue may be just a model.”
As part of their paper, the researchers defined a state they termed “regenerative bias” that predicts the probability of a regenerative outcome. The Bellamkonda group discovered that when it quantified the ratio of healing macrophages to scar-promoting macrophages at the site of injury early after the injury, the ratio – or regenerative bias – predicted whether or not the nerve regenerated after many weeks.
“The significance of this finding is that IL-4 and other factors may be used to make sure the regenerative bias is high so that nerves, and perhaps other tissues, can regenerate on their own after injury,” Bellamkonda said.
The research team also included Alishah Merchant, Vivek Mukhatyar and Gaurangkumar Patel, all from the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.
This research was supported by the National Institutes of Health under grants NS44409, NS65109 and 1R41NS06777. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National lnstitutes of Health.
CITATION: Mokarram N, et al., Effect of modulating macrophage phenotype on peripheral nerve repair, Biomaterials (2012), http://dx.doi.org/10.1016/j.biomaterials.2012.08.050Research News & Publications Office
John Toon | Newswise Science News
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy