Circuit boards in your brain. They sound like something out of a popular sci-fi film, but they’re here. In recent years, researchers have made significant progress toward the use of neural implants to restore the function of the brain in patients with a variety of neurological disorders.
Image 1. A concept rendering of a neural implant.
These implantable devices can influence brain function either chemically or electrically (Image 1). Because they are implanted in the brain, the surgical procedures necessary for their insertion are high-risk and complex. As a result, the devices are intended to stay inside the patient for years. However, as we have learned in class, the implantation of the foreign device generates an acute immune response, which can be detrimental to its function.
When a biomaterial is first introduced to the body, it is coated with proteins, the composition of which depends on the surface characteristics of the material like charge, hydrophobicity, and polarity. Over time, the protein reorganizes into a crystallized monolayer on the surface which then interacts with cells. Cells recognize both the chemical and mechanical properties of the biomaterial, which leads to varying degrees of an immune response (Image 2). In many cases, implanted biomaterials result in an initial inflammatory response in the neighboring microenvironment. If this inflammation is chronic, the implant can lead to fibrosis, an accumulation of scar tissue.
Image 2. How cells can interact with the protein coating to recognize a foreign biomaterial.
Specifically, in the brain, researchers have characterized the immune response to neural implants as astrogliosis, the creation of a scar surrounding the implant by glial cells. The immune response is classified into the acute and chronic phases, as we have learned in class. In the acute phase, which happens within the first week of implantation, the microglia release pro-inflammatory cytokines that initiate an immune response to the implanted device. While the inflammatory mechanism protects the tissue, it damages neuron functionality in the vicinity of the device, and thus reduces its efficacy.
In the chronic phase, which occurs at time points over four weeks, a glial scar begins to form at increased density around the device. Astrocytes with upregulated glial fibrillary acidic protein and chondroitin sulfate proteoglycans surround the implant and isolate the rest of the neural tissue from the device. Researchers have compared this to the scar formation process that takes place when implants are inserted in other locations of the body as well, which has been a significant barrier to implant longevity as well in implanted insulin pumps.
Recent studies have demonstrated, though, that motion on the micron-scale of the device at the site of implantation is a significant driver of glial scar formation, particularly in the chronic phase of response. The friction between the implant and surrounding tissue generates local strain on the surrounding cells, upregulating molecules involved in fibrosis. A study published by a group from the Massachusetts Institute of Technology (MIT) sought to reduce the local strain experienced by the surrounding neural tissue by coating a device with a PEG hydrogel prior to implantation. Because PEG hydrogels are highly tunable in terms of thickness and elastic modulus, making them prime candidates to coat inserted implants. The group at MIT tested in vitro the reduction in strain after coating with the hydrogel in an implantation model and studied the effects of the hydrogel on the production of scar tissue in an in vivo mouse model.
Image 3. Results from in vitro local strain testing demonstrating the reduced strain in hydrogel-coated neural probes. Two modes of displacement were studied: side to side and in and out.
Their results were successful in demonstrating the ability of the hydrogel coating to improve neural implant performance. The in vitro study found that the PEG hydrogel significantly reduced local strain from the motion of the implant (Image 3). Coated implants saw drastically less displacement when moved in both the side-to-side and in-and-out motion regimes. Thicker coating corresponded with greater absorption of motion, and thus lower local strain. The study also found that in vivo, coated implants led to a reduction in scar formation. However, the study identified a key tradeoff. While the hydrogel coating reduced scar formation, the data was compared with glass probes of the same diameter. Experiments revealed that a decrease in the size of the implant significantly reduced scarring and increased local neural density. As a result, increasing the diameter of a neural implant by coating the device with a hydrogel may not, in fact, be as effective in reducing scar tissue formation, and both the factors of mechanical strain and the size of the device must be considered in its design.
This study demonstrates the applications of the concepts we have discussed in lecture in an important field of research. Understanding how surrounding tissue will interact with implanted biomaterials is crucial to determining the efficacy of a medical device. When this goes wrong, the device could be rejected by the body, leading to extensive tissue damage. I believe a natural next step in the research published by the group at MIT is identifying the risk/reward to coating a neural implant with a hydrogel vs. reducing its size. It would be valuable to develop a model to optimize the probe size/thickness coating for a variety of applications, including those outside of the brain. As we have learned in class, it could also be useful to embed nanoparticle-encapsulated anti-inflammatory therapeutics in the coated hydrogel to further reduce scar formation.
Article:
- Spencer, K., Sy, J., Ramadi, K., Graybiel, A., Langer, R., & Cima, M. (2017). Characterization of Mechanically Matched Hydrogel Coatings to Improve the Biocompatibility of Neural Implants. Scientific Reports, 7(1). doi: 10.1038/s41598-017-02107-2