Introduction of biomedical devices in the body, such as electrodes for treating Parkinson’s disease or glucose monitors for diabetics, produces an immune response where cells surround the object with scar tissue in a process known as fibrosis. This scarring disrupts the effectiveness of the device and may cause failure. One solution is to use immunosuppressive drugs to reduce the fibrosis response, though this affects the body’s ability to fight off infection. Other side effects, including fatigue or even cancer, may also result! By delivering incredibly small immunosuppressant doses to the tissue directly around the implant, it is possible to avoiding compromising the patient’s immune system entirely, as the drugs will be diluted in the blood stream and broken down by the body. These methods are mostly successful, but drugs are typically used up within two months. Once depleted, fibrosis will progress as normal. Now, bioengineers at MIT have developed a new method for long-term local drug delivery around implants based on drug crystallization that suppresses the immune response in rodents and monkeys for at least 6 months.

The new method for long-term delivery involves formation of a crystal, where drug molecules are arranged in a dense, repeating pattern. After first identifying which immunosuppressive compound they wanted to use, GW2580, the authors figured out how to crystallize this drug and found that the amount of crystallized and uncrystallized drug, along with crystal size, could be used to control the release rate of the drug. By incorporating these crystals in devices that perform biomedical functions, like electrical stimulation, sensing or release of additional non-crystalline drugs, the researchers hoped to prevent the local fibrosis response for longer than other methods.

The authors then turned to animals, implanting drug-containing gel capsules in mice and monkeys and measuring fibrosis levels up to six months. All crystal-containing capsules were fibrosis-free at all points, and drug remained even at six months, so these devices could potentially suppress fibrosis for even longer. Blood levels of the immunosuppressant drug were found to be low, so the patient’s immune system was not compromised. Next, the researchers asked about the ability of their method to preserve the function of biomedical devices by implanting spheres with crystalline drug and rat pancreatic cells, which produce insulin, into diabetic mice. The crystal-containing spheres helped maintained blood sugar levels up to 15 months, while devices without drugs or with non-crystalline drugs couldn’t maintain proper blood sugar levels beyond 35 or 70 days. This method was then tested in two multicomponent devices: a glucose monitoring system and a muscle stimulation device. In all cases, including the crystalline drug substantially reduced fibrosis around implants and preserved function for several weeks.

The results of these studies suggest that including crystallized immunosuppressants during device implantation is an effective method to suppress the immune response produced by external objects for at least several months. It’s important to mention that the number of materials used in biomedical devices is substantially larger than that tested here, though the glucose sensor and muscle stimulation device both contain several different materials each, and other immunosuppressive drugs may be necessary to reduce fibrosis for different devices or sites of implantation. Many biologically active materials are notoriously difficult to crystallize due to their large size, so finding the proper conditions for reliable crystal formation for each new drug might take a while. Additionally, while preventing fibrosis up to over a year is a substantial improvement over one month, the crystal will eventually dissolve, so this is not a permanent solution. Even so, the possibility of using drug crystals in a variety of biomedical devices provides a simple solution to a problem that has plagued the bioengineering community for decades.

Managing Correspondent: Andrew T. Sullivan

Press Articles: A better way to encapsulate islet cells for diabetes treatment, Science Daily, Phys.org

A novel way to encapsulate islet cells for treatment of diabetes, News Medical Life Sciences

Original Journal Article: “Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations,” Nature Materials

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