A foreign body reaction (FBR) is a typical tissue response to a foreign body within

biological tissue In biology, tissue is a biological organizational level between cells and a complete organ. A tissue is an ensemble of similar cells and their extracellular matrix from the same origin that together carry out a specific function. Organs are th ...

. It usually includes the formation of a foreign body granuloma. Tissue-encapsulation of an implant is an example, as is inflammation around a splinter. Foreign body granuloma formation consists of

protein adsorption Adsorption (not to be mistaken for ''absorption'') is the accumulation and adhesion of molecules, atoms, ions, or larger particles to a surface, but without surface penetration occurring. The adsorption of larger biomolecules such as proteins is of ...

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

, multinucleated

foreign body giant cell A foreign-body giant cell is a collection of fused macrophages (giant cell) which are generated in response to the presence of a large foreign body. This is particularly evident with catheters, parasites, or biomaterials that are inserted into th ...

s (macrophage fusion),

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

, and angiogenesis. It has also been proposed that the mechanical property of the interface between an implant and its surrounding tissues is critical for the host response. In the long term, the foreign body reaction results in encapsulation of the foreign body within a

calcified Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature Ma ...

shell. For example, a ''

lithopedion A lithopedion ( also spelled lithopaedion or lithopædion; from grc, λίθος "stone" and grc, παιδίον "small child, infant"), or stone baby, is a rare phenomenon which occurs most commonly when a fetus dies during an abdominal pregna ...

'' is a rare phenomenon which occurs most commonly when a

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

dies during an

abdominal pregnancy An abdominal pregnancy is a rare type of ectopic pregnancy where the embryo or fetus is growing and developing outside the womb in the abdomen, but not in the Fallopian tube (usual location), ovary or broad ligament. Because tubal, ovarian and ...

, is too large to be reabsorbed by the body, and calcifies.

Foreign body reaction to biomaterial implantation

Following

biomaterial A biomaterial is a substance that has been engineered to interact with biological systems for a medical purpose, either a therapeutic (treat, augment, repair, or replace a tissue function of the body) or a diagnostic one. As a science, biomateria ...

implantation, blood and body fluids contact the implant surface. Host

blood protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s adsorb onto the implant surface and a fibrin matrix forms. Acute and chronic

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

follow the initial blood protein deposition and matrix formation. Macrophages at the implant site fuse to form foreign body giant cells. Following the inflammatory response,

granulation Granulation is the process of forming grains or granules from a powdery or solid substance, producing a granular material. It is applied in several technological processes in the chemical and pharmaceutical industries. Typically, granulation invo ...

tissue form. The end stage of the foreign body reaction is the fibrous capsule formation around the implanted biomaterial. The

biocompatibility Biocompatibility is related to the behavior of biomaterials in various contexts. The term refers to the ability of a material to perform with an appropriate host response in a specific situation. The ambiguity of the term reflects the ongoing de ...

of the device affects the severity of the foreign body reaction. The foreign body reaction can lead to device failure. Host reactions to the implantation of a biomaterial device

Host reactions to the implantation of a biomaterial device

Protein adsorption

During blood-biomaterial interaction, blood proteins spontaneously adsorb to the biomaterial surface. The biomaterial surface properties affect the types, concentrations, and conformation of proteins that adsorb to the surface. The

Vroman effect The Vroman effect, named after Leo Vroman, describes the process of competitive protein adsorption to a surface by blood serum proteins. The highest mobility proteins generally arrive first and are later replaced by less mobile proteins that hav ...

can describe the time-dependent behavior of this protein adsorption. Surface-adsorbed proteins regulate inflammatory cell interaction and adhesion. The deposited proteins allow inflammatory cells to attach via

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...

s. The biomaterial surface can also recruit and activate complement proteins.

Immune recruitment

The composition and conformation of adsorbed proteins on the implant surface is critical to the foreign body reaction. For the first two days, neutrophils are the primary cell type that deposit on the implant surface. Neutrophils release degradative enzymes and reactive oxygen intermediates that damages the implant. Platelets from the blood-biomaterial interaction release

inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...

s that cause

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

s and macrophages to extravasate and migrate to the implant site. The degranulation and release of

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered ...

from

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

s further recruits macrophages to the biomaterial. Macrophages adhere to the biomaterial surface based on the surface protein deposits and produce cytokines that further recruit macrophages. Foreign body granuloma forms as immune cells accumulate on the biomaterial surface in an attempt to eliminate the biomaterial.

Macrophage fusion

Adherent macrophages at the implant site can fuse into a multinucleated cell called foreign body giant cell. Foreign body giant cell formation depends on the biomaterial surface properties and on the presence of

interleukin-4 The interleukin 4 (IL4, IL-4) is a cytokine that induces differentiation of naive helper T cells ( Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 ...

and interleukin-13. Foreign body giant cells release reactive oxygen intermediates,

degradative enzyme A degradative enzyme is an enzyme (in a broader sense a protein) which degrades biological molecules. Some examples of degradative enzymes: *Lipase, which digests lipids, *Carbohydrases, which digest carbohydrates (e.g., sugars), *Proteases, which d ...

s, and acid onto the biomaterial surface. Foreign body giant cells also attempt to engulf the biomaterial for degradation. Adherent macrophages and foreign body giant cells degrade biomaterials and can lead to device failure. Foreign body giant cells remain on the surface of the implanted device throughout the device's lifetime.

Fibrous capsule formation

The end-stage healing response is the fibrous encapsulation of the biomaterial. Macrophages and foreign body giant cells release cytokines that attract fibroblasts. Fibroblasts create a collagenous fibrous capsule to separate the biomaterial from the surrounding tissue. The fibrous capsule may hinder the device's function, such as drug diffusion for

drug delivery systems A route of administration in pharmacology and toxicology is the way by which a medication, drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance i ...

or normal

tissue regeneration In biology, regeneration is the process of renewal, restoration, and tissue growth that makes genomes, cells, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of rege ...

for

tissue engineering Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biolog ...

implants.

Engineering biomaterial to resist the foreign body reaction

The foreign body giant cell formation and the fibrous encapsulation of the implanted device can affect the function of the implanted device and lead to its failure. Reducing the foreign body reaction can promote better device performance and durability. Even though many types of implants cannot completely escape the foreign body reaction, there are many ways to engineer biomaterials to reduce the foreign body reaction. Reducing nonspecific protein adsorption is one important method to prevent fibrous encapsulation of the implant.

Modification of physical properties

The physical properties of the implant's surface, such as size, shape,

topology In mathematics, topology (from the Greek words , and ) is concerned with the properties of a geometric object that are preserved under continuous deformations, such as stretching, twisting, crumpling, and bending; that is, without closing ...

, and

strength Strength may refer to: Physical strength *Physical strength, as in people or animals * Hysterical strength, extreme strength occurring when people are in life-and-death situations *Superhuman strength, great physical strength far above human c ...

, influence protein adsorption and immune cell interactions with the implant. Generally, surface roughness induces greater protein adsorption and triggers greater immune response. Thicker cylindrical implants on the millimeter scale were shown to produce greater fibrous encapsulation. However, there may not be an absolute relationship between the modification of the biomaterial and the associated foreign body response, because some biomaterials intrinsically induce a stronger foreign body response than other biomaterials would.

Delivery of anti-inflammatory drugs

Implanted biomaterial can be loaded with different drugs to perform anti-inflammatory functions or promote angiogenesis to further integrate the implant with the host. The sustained release of certain anti-inflammatory drugs from the biomaterial, such as

dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...

, is shown to increase implant life by preventing inflammation and fibrosis.

Incorporation of bioactive molecules

Coating the implant surface with biomimetic biomaterial may reduce the foreign body reaction and reduce the device failure rate. Biomaterials that mimic the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...

can significantly reduce the inflammatory response as well as reduce foreign body giant cell formation.

Novel biomaterials

Developing materials that resist protein adsorption, fibrous encapsulation, or foreign body giant cell formation is important to resist the foreign body reaction. Commonly used biomaterials like

polyethylene glycol Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...

and polyhydroxyethylmethacrylate resist nonspecific protein adsorption but are easily degraded in the in vivo

oxidative Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

environment. Therefore, scientists are looking for new materials that intrinsically resist the foreign body reaction.

Zwitterionic materials

Zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups. : With amino acids, for example, in solution a chemical equilibrium wil ...

ic polymers are widely used in surface modification because they can inhibit non-specific protein adhesion. Zwitterionic hydrogels also promote angiogenesis in surrounding tissues. Commonly used zwitterionic materials include sulfobetaine, carboxybetaine, and

phosphorylcholine :''Phosphorylcholine refers to the functional group derived from phosphocholine. Also not to be confused with phosphatidylcholine.'' Phosphorylcholine (abbreviated ChoP) is the hydrophilic polar head group of some phospholipids, which is compose ...

. Zwitterionic polymers have the ability to reduce nonspecific adsorption of proteins and cells at biological interfaces. Zwitterionic coatings are often used to minimize the negative effects of foreign body response for implanted devices and improve the device's biocompatibility. The mechanism is related to surface charge balancing and creation of a strong hydration sphere. Zwitterionic coatings can be covalently attached by “grafting to” and “grafting from” methods. With “grafting to” methods, the surface is modified with the polymer after synthesis, whereas with “grafting from” methods, polymer is directly synthesized on a modified surface. Several “grafting to” methods have been used to covalently attach zwitterionic polymers to surfaces. Anderson group developed attachment to the surface via polydopamine conjugation. In this case, copolymer should contain a thiol group. Nazarova and coworkers synthesized MPC copolymers with 2-methacrylamido-D-glucose, N-vinylpyrrolidone, and N-vinyl-N-methyl-acetamide and grafted them onto the surface of carbon fibre biosorbent using γ-radiation. MPC copolymers with trimethoxysilylpropyl methacrylate can be thermally cured and self-crosslinked.

Modian fied alginates

Alginates Alginic acid, also called algin, is a naturally occurring, edible polysaccharide found in brown algae. It is hydrophilic and forms a viscous gum when hydrated. With metals such as sodium and calcium, its salts are known as alginates. Its colour ...

are widely used for their low cost, low toxicity, and tunability. However, implantation of only alginate will trigger serious foreign body reaction. There are a few

triazole A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial isomerism, depending on the positioning of the nitrogen atoms within t ...

-containing alginate derivative microspheres that remain clear of fibrotic deposition in mice, but more studies are required to explore the relationship between triazole groups and the inflammatory response.

Polypeptide materials

Polyethylene glycol peptides and zwitterionic peptides have immunomodulatory functions that help to resist the foreign body reaction.

Gallery

File:Pulmonary talcosis low mag cropped.jpg, A foreign-body response to

talc Talc, or talcum, is a clay mineral, composed of hydrated magnesium silicate with the chemical formula Mg3Si4O10(OH)2. Talc in powdered form, often combined with corn starch, is used as baby powder. This mineral is used as a thickening agent a ...

( talcosis) due to

intravenous drug use Drug injection is a method of introducing a drug into the bloodstream via a hollow hypodermic needle, which is pierced through the skin into the body (usually intravenously, but also at an intramuscular or subcutaneous location). Intravenous t ...

H&E stain Hematoxylin and eosin stain ( or haematoxylin and eosin stain or hematoxylin-eosin stain; often abbreviated as H&E stain or HE stain) is one of the principal tissue stains used in histology. It is the most widely used stain in medical diagnos ...

. File:Suture material.jpg, Foreign body giant cell reaction to nylon suture material File:Foreign body granuloma (labeled).jpg, Foreign body granuloma

References

External links

{{Cutaneous ketatosis, ulcer, atrophy, necrobiosis, and vasculitis Immune system disorders Granuloma