Introduction

The human body is a complicated piece of machinery that has taken scientists centuries to understand, and we still don’t know everything about it. Each part of the machine is equally complicated and yet works in sync with the rest of the body. One main part of this machine is the immune system, which works to protect the body from foreign materials such as implants or pathogens. The area of implants especially is an interesting one that many scientists are still exploring.

The study of implants is a diverse and varied field ranging from breast implants to prosthetics, to insulin monitors for the diabetic. They are all made up of different biomaterials, in different shapes, sizes, and structures, but they all also have one thing in common. None can stay in the body permanently. The human body has evolved a response to implants such that it protects the body from both splinters and heart monitors in the same way: the Foreign Body Response.

The Foreign Body Response (FBR), also called the Foreign Body Reaction, has five main steps that ultimately surround the implant in a capsule of collagen, or a structural tissue protein, and isolate it from the rest of the environment, many times damaging the implant in the process. At a certain point, doctors will have to remove and replace the implant from the body because it is now sitting useless in the body. Currently, the longest-lasting implants in the human body are breast implants, which can last anywhere from ten to twenty years before they must be replaced. Scientists in multiple companies are working to reduce or eliminate the foreign body response when it comes to implants, and have had varying success. The five steps of the FBR are:

1. Inflammation and Protein Adsorption
2. Macrophages
3. Foreign Body Giant Cells
4. Fibroblasts
5. Angiogenesis

Step 1: Inflammation and Protein Adsorption

The first step in the Foreign Body Response is protein adsorption. After an implant is injected into the body, it immediately gains a thin layer of proteins that surround it and adhere to the biomaterial surface and form a matrix through a process known as protein adsorption. The purpose of these proteins is to identify the biomaterial and interact with the immune system. Different proteins adhere to the biomaterial depending on its qualities, such as size, shape, and material, thus modulating the response of the immune system towards the foreign biomaterial.

Then, inflammation occurs around the biomaterial in order to start isolating it from its environment. Acute inflammation is the first to occur, sequentially followed by chronic inflammation. In acute inflammation, neutrophils, a type of white blood cell, are released along with macrophages, a large, phagocytic blood cell. Cells that are phagocytic use the process of phagocytosis to ‘eat’ foreign pathogens and keep the body safe. Then, chronic inflammation starts. An identifier of chronic inflammation is the presence of mononuclear cells, or cells with a single, rounded nucleus, at the implant site. This response is common when it comes to implants, however, the persistence of inflammation past three weeks is a good indicator of infection.

Step 2: Macrophages

After inflammation comes one of the most important steps in the process: macrophages, and what they do. The presence of the host proteins that adsorbed to the surface of the biomaterial allows for the complement system to be activated; a system responsible for interacting with and removing foreign substances in vivo, or in real life. Once the system is activated, macrophages must be recruited and brought to the implant site. This move is in response to certain chemoattractants, proteins that attract certain types of cells to them. When a biomaterial is injected into the body, it first interacts with blood before protein adsorption can occur, and this reaction between the platelets in the blood releases chemoattractants responsible for recruiting macrophages. Furthermore, once macrophages are at the implant site, they can release more chemoattractants that attract other macrophages.

The macrophage now needs to bind to the surface of the biomaterial. To do this, it interacts with a special category of receptors known as integrins. Integrins are a type of membrane receptor that mediates interactions between the cell and other cells, and are attached to the biomaterial surface through protein adsorption. The macrophages are thus able to easily bind to the biomaterial surface by binding to the adsorbed integrin receptors on the surface. It is as though macrophages and the specific integrin receptors are magnets that are attracted to one another. Once macrophages bind to the surface of the biomaterial, a signal is sent using a transduction pathway throughout the cell that changes macrophage behavior and adhesion to the surface. These signals change the cytoskeletal arrangements of the macrophages on the surface until they form specialized adhesion structures known as podosomes. This is done through a focal adhesion kinase which activates once the integrin receptors are connected to the macrophages.

This process makes it hard for scientists to create biomaterials that will last; however, they have found some loopholes. The integrin signaling not only changes the cytoskeletal arrangement of the macrophages but it controls the cell cycle, and thus, cell death. If the biochemistry of the biomaterial surface is right, the interaction of that surface with the integrins and the macrophages can be detrimental to the life cycle of the macrophages. This interaction can cause the macrophages to undergo a process known as anoikis, where a cell detaches from its supportive matrix on the biomaterial surface and thus causes the cell to go through apoptosis, or programmed cell death. Scientists have thus been working on creating surfaces that do not promote adhesion so that the macrophages that attempt to attach to the biomaterial surface can instead slip off and underdog anoikis and then apoptosis, leaving the biomaterial safe.

Step 3: Foreign Body Giant Cells

The next step in the Foreign Body Response is the formation of Foreign Body Giant Cells (FBGCs). FBGCs are formed when macrophages fuse to form giant cells vital to the FBR. Certain factors are necessary for the macrophages to fuse in the FBGCs. Mannose receptors, or receptors that are expressed on macrophages and other cells, are important for this fusion, as are certain binding molecules that must be present. This makes macrophage fusion dependent on the biomaterial surface—the right proteins have to be adsorbed so that the adherent macrophages can use them to fuse into foreign body giant cells. It is yet another area where scientists have worked hard to create surfaces that do not allow for the right proteins to be adsorbed onto the surface, thus halting or at least slowing down the FBR.

A consequence of the formation of foreign body giant cells, however, is that many times it can lead to the degradation of the foreign implant. Macrophages and FBGCs can release mediators of degradation, degradative enzymes, and certain acids into the small area between adherent cells and the biomaterial surface. These chemicals are good for destroying unwanted implants such as splinters, but a blockage for scientists who are trying to keep the implant safe. Thus, they stay hard at work on making sure that the chemistry and material of the implant are as resistant to degradation as possible. This degradation of the surface of the biomaterial can lead to it failing, which can severely harm people when it comes to, for example, heart implants. This is also why scientists use antioxidants on implants: to stop the oxidation process that would break the device apart.

Step 4: Fibroblasts

Now that macrophages and foreign body giant cells are formed and adhered to the surface of the biomaterial, what do they do? To understand this, we need to look deeper into macrophage activation. Macrophages are inactive most of the time unless activated by chemoattractants or a pathogen. However, macrophages have two states of activation. The first is classic activation, which occurs when fighting pathogens such as viruses and bacteria. In this state, inflammatory cytokine proteins are upregulated, anti-inflammatory cytokines are inhibited, and nitrous oxide is produced. In the alternative activation state, inflammatory cytokines are inhibited, anti-inflammatory cytokines are upregulated, and more mannose receptors than average are produced. Once macrophages and FBGCs have adhered to the surface of the biomaterial, they attempt to phagocytose, or ‘eat’, the foreign object. Most of the time, the implant is too large to be phagocytosed, so the macrophages secrete cytokines that bring inflammatory and wound healing cells to the area. Over time, as the inflammatory and wound healing cells do their job, the macrophages slowly shift from a state of classic activation to alternative activation.

Step 5: Angiogenesis

What do the wound-healing cells that the macrophages recruit do? They perform the final step in the Foreign Body Response, which is to create a capsule of collagen, a main structural protein of human tissue, around the implant. This is done mostly through angiogenesis, or the body’s process of developing new blood vessels and creating fibroblasts to heal the skin. These fibroblasts create collagen to surround the implant, and the process of angiogenesis develops new blood vessels from pre-existing ones that go around the implant. Not only do the macrophages bring these wound-healing cells to the site, but alternatively activated macrophages overexpress certain extracellular matrix (ECM) proteins important to tissue remodeling. These same ECM proteins are also important when healing wounds and cuts in the body. This fibrous capsule that ultimately forms around the implant acts as a bubble that keeps the implant isolated from the rest of the body, and many times interferes with the implant’s function, rendering it useless.

Conclusion

The Foreign Body Response is such a complicated reaction that it is amazing that we humans evolved to respond in this manner. From an inflammatory response, to the recruitment of macrophages, to the formation of foreign body giant cells, to the creation of a fibrous capsule around the foreign implant, each step has multiple substeps and requires specific chemicals, cells, and states of being. Furthermore, the fact that scientists have been able to hold off such a potent reaction for anywhere from 10-20 years in the human body is a miracle of science that we are still improving upon. Most of these implants and biomaterials are made at the scale of 10^-9, because that is the size of proteins in the body, and as such, some call this the field of nanobiomaterials and nanotechnology. Nanobiomaterials can be split into five categories: nanoparticles, nanoporous scaffolds, nanopatterned surfaces, nanofibers and nanowires, and carbon nanotubes. Each one has a different effect on the body, and by modulating the size, shape, function, material, chemical, and effect on the body, scientists have been able to craft remarkable cures for different ailments. Nothing is perfect, and this is still an emerging field, but the possibilities are limitless. Making the nanobiomaterials is easy—conquering the Foreign Body Response? That’s a challenge.

References

James A., Analiz R., & David C. (2007). Foreign Body Reaction to Biomaterials. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2327202/

Foreign Body Granuloma. (2020, March 31). Retrieved from https://en.wikipedia.org/wiki/Foreign_body_granuloma

Nikki Agrawal (2019). 3 – 1.30 – The Foreign Body Response. Retrieved from https://docs.google.com/document/d/1DHFzSgI4K-Emn43MafkYfR2EuDRHjkj5B_Fx4eqTon0/edit?usp=sharing

Molecular Events in the Foreign Body Response. (2020, June 5). Retrieved from https://medicine.yale.edu/lab/kyriakides/research/molecularevents/