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3. From Bottle to the Red in Brows

To understand the entire process that leads from the application of pigment to a reddish hue in brows, we'll delve into the following steps:

Introduction of Iron Oxide Pigment Particles into the Skin

We explore how pigment particles containing iron oxide are initially introduced into the skin layers through the semi-permanent makeup procedure.

Immune System Response to Pigment Particles

We break this down into three sub-points to discuss how the immune system reacts to the introduced pigments.

Macrophage Involvement. We discuss how a portion of the pigment particles is engulfed by white blood cells, specifically macrophages, through the process of phagocytosis.
Fibroblast Encapsulation. We describe how another portion of pigment particles is encapsulated by fibroblasts within the skin.
Extracellular Matrix Entrapment. We explain how a remaining portion of the pigment particles becomes trapped in the extracellular matrix of the skin.

Ferritin and Iron Oxide Interactions

We explore how ferritin, a protein that stores and releases iron, interacts with the iron oxide molecules in the pigment. Highlight how this interaction causes a change in the oxidation level of the iron oxide, which leads to the reflection of reddish, pinkish, or "rusted" light, thereby causing the brows to take on a reddish hue.

4. Iron oxides

Introduction of Iron Oxide Pigment Particles into the Skin

Iron oxide pigments are classified as inorganic pigments, often referred to as mineral or hybrid pigments. These designations imply that the base component of the colorant is iron oxide. It's crucial to differentiate this from organic pigments, which are carbon-based and have a different set of properties and behaviors in the skin.

Composition of the Pigment

In the final pigment product, a liquid carrier, often called the cosmetic base, holds the colorant in a stable form. This carrier is a complex mixture consisting of solubles, binders, additives, and stabilizers. The colorant component gives the pigment its color and can be either organic or inorganic in nature.

For pigments considered inorganic (or mineral or hybrid), several forms of iron oxides are commonly used:
CI 77499 - Black Iron Oxides (Ferrous Black) or Iron (II) oxide
CI 77491 - Red Iron Oxides (Ferrous Red)
CI 77492 - Yellow Iron Oxides (Ferrous Yellow)

Specific Iron Oxides: Fe2O3 and Fe3O4

When looking at iron oxides that may contribute to a reddish hue, we focus on Fe2O3, also known as Hematite, and Fe3O4, known as Magnetite.

Fe2O3 (Hematite). This form of iron oxide is often related to red and brown colors and has a high potential for causing a reddish hue in semi-permanent makeup.
Fe3O4 (Magnetite). This is generally black or brownish-black and might not directly contribute to a reddish hue but can darken the overall color of the pigment, potentially affecting the shade in the long term.

5. Immune System Response

A pigment particle and four directions: Hypodermis, Migration to blood vessels, Lymph, Phagocytosis, Fibroblast Encapsulation, Extracellular Matrix Entrapment, on the left and an attractive woman in red on the right.

Macrophages and Phagocytosis

The human body is an intricate system with numerous built-in safeguards against damage and foreign invasion. In the realm of semi-permanent makeup, the pigment inserted into the skin essentially becomes an alien entity that the immune system works to expel.

Initially, the body's immune response to introducing pigment is non-specific, and it deploys a host of immune cells, such as macrophages, histiocytes, and neutrophils, to the site. Among these, macrophages lead to phagocytosis, or engulfing, of the pigment particles. Macrophages are highly versatile and can consume particles up to 10 micrometers in size, thus readily ingesting common pigment particles, which are usually around 500 nm in diameter. After ingestion, some macrophages die off and become part of the dermal landscape, essentially becoming a long-term storage vessel for the pigment.

Specialized Immunity

As the immune response matures, specific immunity comes into play, featuring specialized immune cells like T-lymphocytes and B-lymphocytes. T-lymphocytes function by recognizing and destroying cells displaying foreign antigens, including those that have ingested pigment. B-lymphocytes, on the other hand, can produce antibodies that neutralize the pigment, although this is less commonly implicated in the context of semi-permanent makeup.

Pigment in the Lymphatic System

It's worth noting that some pigment particles are transported to the lymph nodes. Once in the lymphatic system, these particles generally remain there permanently, as the lymph nodes lack the mechanisms to expel further or break down these materials. That is, by the way, the reason that some ink particles can sometimes be found during the autopsy.

Note on Macrophage Lifespan

The duration for which a macrophage "lives" can vary, typically from days to months, depending on the tissue environment and its activation state. However, because macrophages are continually regenerated from precursors in the bone marrow, their role in pigment retention remains dynamic yet persistent over time.

Transfer to the Lymphatic System

There are experts who believe that the removal of iron oxide particles, relatively heavy particles that, in some cases, can even range in diameter from 500 nm to 1000 nm, get removed to lymph vessels and at the moments when one macrophage dies and figuratively “drops the ball” (the iron oxide particle). The body has the next macrophage ready to catch it, but when it cannot engulf it immediately, the pigment particle gets removed from the lymphatic system.

Given these intricate mechanisms, the persistence of semi-permanent makeup pigment in the skin is not solely due to its chemical composition but is also a result of complex interactions with the immune system's various components.

Pigment Encapsulated in Fibroblast

The process of fibroblast encapsulation is crucial for stabilizing pigments within the skin. After pigment application, molecules cluster together and are gradually enveloped by fibroblasts, the connective tissue cells responsible for producing the extracellular matrix and collagen. Triggered by the skin's healing response, fibroblasts detect the foreign pigment particles and transform into myofibroblasts.

These myofibroblasts, known for their role in wound closure, mobilize towards the pigment clusters to begin encapsulation, secreting a mix of structural proteins like collagen. This forms a fibrotic capsule that isolates the clusters, reduces potential chemical reactivity, and shields them from immune detection.

However, this encapsulation isn't permanent. Over time, the capsule may remodel, altering the pigment's appearance as particles can be released and potentially transported to the lymph system. This balance between stability and change is a delicate interplay, ensuring the pigment's longevity in the skin.

Pigment Stabilization in the Extracellular Matrix (ECM)

Pigment particles settle into the skin's extracellular matrix (ECM), a rich weave of proteins and sugars that bolster cells and facilitate healing. This network doesn't just support but can also ensnare pigment through various methods.

Physical Adsorption: ECM fibers can grip pigment particles based on size and charge, anchoring them in place.
Mechanical Interlocking: The ECM's dense lattice can trap particles, somewhat like a net catching its targets.
Biochemical Anchoring: Specialized ECM proteins can form chemical bonds with pigments, securing them even further.
Tissue Remodeling: Post-pigmentation, the ECM may ramp up its output around the pigment, creating a stronger hold within this freshly made matrix.

These processes ensure pigments last longer, remain stable, and are somewhat shielded from the immune response, maintaining the integrity and appearance of semi-permanent makeup.

6. Ferritin and Iron Oxide Interactions

Iron oxides like Fe2O3 and Fe3O4 have historically been criticized for turning rusty, causing eyebrows to adopt a reddish hue. Ferritin, which binds to iron and other metals, is indeed a factor in this change.

What Happens to Iron Oxide Particles in the Skin

When iron oxides serve as colorants in semi-permanent pigments and are introduced into the skin, various biochemical and physicochemical reactions occur. These reactions might lead to changes in pigment color over time. Iron oxides like Fe2O3 (hematite) and Fe3O4 (magnetite) are generally stable. However, under certain conditions, they can undergo oxidation or other chemical reactions that affect the stability of the pigment's color.

Understanding Ferritin

Ferritin acts like a biological magnet, attracting iron ions and catalyzing a chemical reaction that can degrade iron oxide pigments. This leads to a reddish or rusty appearance. The longer the pigment remains in the skin, the more susceptible it becomes to this transformation due to the ongoing activity of ferritin.

Iron Storage and Degradation

Ferritin functions to store iron in a non-toxic form and to deposit it safely. When ferritin aggregates, it transforms into a toxic form of iron called hemosiderin. The ferritin protein structure is complex, consisting of 24 protein subunits that form a hollow nanocage with multiple metal-protein interactions. Inside this ferritin shell, iron ions form crystallites with phosphate and hydroxide ions, resembling ferrihydrite. A single ferritin complex can store around 4500 iron (Fe3+) ions.

Factors Contributing to Oxidation

The skin is not a static environment; it's dynamic and rich in biological molecules, enzymes, and cellular components. Ferritin, a protein that stores iron, can play a key role in the oxidation process. It can interact with iron ions, catalyzing oxidation reactions. Environmental factors like UV light exposure, along with physiological factors such as pH and enzymatic activity, can also influence oxidation.

7. A Chemical Explanation

Reactions with ferritin

Iron oxides in the skin can react with ferritin, leading to the formation of ferric ions (Fe3+). These ions can react with oxygen and other elements, undergoing redox reactions that alter the iron's oxidation state. This change manifests as a shift in color from the original hue to a reddish or rusty one.

The generalized simplified reaction can be expressed as:
Fe2O3 + ferritin → Fe3+ + O2 + other products

This reaction alters the iron oxide's form and bonding characteristics, affecting its optical properties and causing the "red brow" phenomenon.

Differences in reactions of hematite and magnetite

Both iron oxides, Fe2O3 (hematite) and Fe3O4 (magnetite) interact with ferritin, albeit through different mechanisms due to their distinct oxidative states and properties.

Fe2O3 (Hematite) and Ferritin. Fe2O3 commonly interacts with ferritin through the Fenton reaction, where Fe3+ ions from Fe2O3 are reduced to Fe2+ and subsequently stored in the ferritin core. Here, the Fe3+ ions in the Fe2O3 are enzymatically reduced to Fe2+ by ferric reductases present in cells. Once reduced, these ions are captured by ferritin and stored as ferrihydrite within its hollow cavity.
Fe3O4 (Magnetite) and Ferritin. Fe3O4 contains both Fe2+ and Fe3+ ions. Because ferritin is designed to store Fe3+ in its mineral core, the Fe2+ ions must first be oxidized to Fe3+ before storage. However, the Fe3+ ions in magnetite can be directly incorporated into ferritin through similar enzymatic reduction mechanisms as those involved in interacting with Fe2O3. The presence of Fe2+ complicates the issue and may require further redox reactions mediated by cellular mechanisms, including the action of ferroxidase enzymes that facilitate the oxidation of Fe2+ to Fe3+.

Distinctive Interactions

The two different forms of iron in Fe3O4 add an extra layer of complexity. Because Fe3O4 is magnetic and possesses unique electronic properties, its interaction with biological molecules like ferritin can be influenced by external magnetic fields and other physicochemical factors. Thus, the encapsulation or biochemical transformation of Fe3O4 may involve other proteins or biological components beyond ferritin, depending on the specific cellular context.

Photostability and Lightfastness

When it comes to iron oxides used in mineral or non-organic pigments, we should note, additonally, that black pigment is the one that remains in the skin the longest. Many artists have made this empirical observation even if the marketing material of pigment producers claims that all their iron oxides have the same photostability properties.

Black Iron Oxide (CI 77499) is generally stable under UV light and does not break down easily. Similarly, red iron oxide (CI 77491) demonstrates good stability against UV light. However, it has a slightly different electronic structure compared to black iron oxide, which could make it susceptible to photo-induced redox reactions under very intense UV radiation. Yellow iron oxide (CI 77492) exhibits relatively good photostability. However, its chromophoric properties may make it slightly more susceptible to photochemical reactions under high UV exposure over extended periods.

Reasons for lightfastness

Iron oxides are compounds of iron and oxygen that exhibit strong chemical bonds between the atoms. The synthetic production of iron oxides allows for the creation of pure, uniform pigments with controlled properties. These pigments are known to be extremely lightfast, which means they resist fading when exposed to light, including sunlight and artificial light sources.

Crystalline Structure

The lightfastness of chemically produced iron oxide pigments can be attributed to their stable crystalline structure and the nature of the iron-oxygen bond, which absorbs and reflects light without undergoing significant structural changes. When these pigments absorb light photons, the energy is dissipated as heat rather than causing the pigment to break down or change. This property makes iron oxide pigments reliable for applications where durability and color retention are essential, such as inks, paints, and, of course, semi-permanent makeup.

Synthetic vs. Natural Iron Oxide

Synthetic iron oxide pigments, unlike their natural counterparts mined from the earth with varied particle sizes and potential impurities, are engineered for consistency and purity. This is why both iron oxide black (CI 77499) and iron oxide red (CI 77491) display excellent UV resistance and high photostability, boasting the highest lightfastness index (8). They are specifically designed not to degrade through photonic reactions due to UV light exposure.

Biochemical Interactions and Pigment Degradation

Despite their photostability, these pigments can undergo changes in the skin due to biochemical interactions. For instance, Fe^2+ may be oxidized to Fe^3+, altering its electronic structure and thus the pigment's optical properties, leading to a color shift. Within the skin's biologically active environment, redox reactions can occur, facilitated by factors such as light, oxygen, and biological catalysts like ferritin. Ferritin can bind to iron in the pigments and catalyze reactions that may result in pigment degradation or a change in color.

Therefore, while iron oxide pigments are synthesized to resist light-induced degradation, it is the complex biochemical reactions in the skin, particularly those involving proteins such as ferritin, that are the primary contributors to changes in oxidation state, leading to the degradation or color shifts observed in semi-permanent makeup applications.

Conclusion of the causes

In simple terms, the iron oxides in semi-permanent pigments can interact with ferritin in the body. This interaction can lead to chemical reactions that change the iron's oxidation state. As a result, the altered form of iron can diffract light differently, causing the pigment to take on a reddish, pinkish, or rusty hue.

8. Solutions to red brows

Silica and Stabilizing Iron Oxide Pigments

To address the issue of iron oxide molecules interacting with ferritin (or, as a matter of fact, any other similar agent leading to changes in oxidation state), chemists turned to the concept of modifying the Iron oxide molecules. By fusing mineral iron oxide molecules with organic polymetal silica, a protective "coating" was achieved. This coating functions much like a barrier, akin to how a rubber glove or condom works. Let us explore that next.

Initial solution

Initially, this coating technique was developed in the field of industrial coatings to protect metals against environmental degradation. Recognizing its potential, experts in the field of semi-permanent makeup pigments adopted this approach. The silica coating acts as a shield, preventing the iron oxide from reacting with ferritin and thus neutralizing the risk of the pigment turning red post-application.

The creation of “protective coating"

This protective "coating" is created by fusing mineral iron oxide molecules with organic polymetal silica. Initially, this coating technique was developed in the field of industrial coatings to protect metals from environmental degradation. Here, silica-based coatings, specifically using tetraethoxysilane (TEOS) and mercaptopropyltrimethoxysilane (MPTMS), were employed to surface modify iron oxide magnetic nanoparticles. These coatings were extensively characterized and found to offer stability against environmental factors and high temperatures. Recognizing the success of this approach, experts in the field of semi-permanent makeup pigments adapted it. Now, the silica coating acts as a shield, preventing the iron oxide from reacting with ferritin, thus neutralizing the risk of the pigment turning red post-application.

9. Silanization

In the realm of advanced materials science, the process of fusing mineral iron oxide molecules with organic polymetal silica is essentially a surface modification technique designed to enhance the chemical stability and functional properties of iron oxide. This technique is known as “silanization.”

General overview of the process

Preparation of Silane Coupling Agents. Tetraethoxysilane (TEOS) and mercaptopropyltrimethoxysilane (MPTMS) are typically used as silane coupling agents. These agents are prepared in a solvent, often ethanol or another alcohol, sometimes with the addition of water and an acid or base catalyst.
Surface Activation. Iron oxide particles are often cleaned and activated, usually by treating them with an acid or a base, to ensure that the silane coupling agents can readily bond with their surface.
Silanization. The activated iron oxide particles are mixed with the prepared silane coupling agent solution. The reaction conditions, like temperature and time, are controlled to facilitate the bonding of the silica groups to the surface of iron oxide particles. This creates a covalent bond between the iron oxide surface and the silane coupling agent.

Chemical Reactions

The precise formula of the reaction can vary depending on the specific silane coupling agent used, but for a general idea, consider the reaction with TEOS:

Fe2O3+(EtO)4Si→Fe2O3−Si(OEt)3

Here, EtO refers to the ethoxy group.

For MPTMS, the formula might look something like:

Fe2O3+(CH3O)3Si−CH2−CH2−CH2−SH→Fe2O3−Si(OCH3)2−CH2−CH2−CH2−SH

The "Si(OCH3)2" group, in this case, represents the coupling agent covalently bonded to the iron oxide, while the "SH" group is a functional handle that can be used for further modification.

This silanization process results in a silica-based coating that acts as a protective barrier around the iron oxide, shielding it from unwanted reactions with substances like ferritin, which is crucial in applications like semi-permanent makeup pigments.

Notes by a chemist who reviewed and fact-checked the article: The exact chemical formulae provided are more representative of a simplified reaction scheme. The actual process may involve several stages, including hydrolysis and condensation reactions, where ethoxy groups (EtO) or methoxy groups (CH3O) from silanes are replaced by hydroxyl groups upon reaction with water, which then form covalent bonds with the surface hydroxyl groups on the iron oxide particles.

Additionally. it is important to note that while a silica coating generally protects iron oxide particles from direct interaction with proteins like ferritin, the overall longevity and appearance of pigments in semi-permanent makeup also depend on factors such as pigment formulation, application technique, and individual skin properties.

10. Conclusions

The reason why brows "turn red" is not solely a matter of the number of iron oxide particles in the skin, which is often the cause of a bluish color when it comes to carbon particles. While the issue with carbon black is largely a physical, and more specifically optical, phenomenon, the "red" pigment issue is more related to biochemistry. Essentially, it's due to the modification of iron oxides within the skin over time.

The potential for a reddish hue is linked to two specific iron oxidesFe2O3 (Hematite - Red Iron Oxide - CI 77491) and Fe3O4 (Magnetite - Black Iron Oxide - CI 77499). Both are commonly used in inorganic pigments due to their larger particle size and excellent photostability. Among the iron oxides, Black Iron Oxide remains in the skin the longest, compared to other types like Red (CI 77491) and Yellow (CI 77492).

When a pigment containing iron oxides is implanted during a Powder Brows or microblading procedure, the pigment particles generally undergo one of four fates: they are either immediately removed via lymph vessels, engulfed by macrophages (white blood cells) through phagocytosis, encapsulated by fibroblasts, or entrapped in the extracellular matrix (ECM).

Iron oxide particles within the skin interact with ferritin, a protein the body produces. This interaction can lead to chemical reactions that alter the iron's oxidation state. Consequently, the modified form of iron can diffract light differently, causing the pigment to take on a reddish, pinkish, or rusty hue.

To prevent such interactions, one solution is to modify the iron oxide at the molecular level to inhibit its interaction with ferritin. Additionally, stabilizing the yellow and red iron oxides (if used along with black) can ensure similar particle size and photostability, leading to more uniform fading of the brows. The key to solving the "red" brows issue lies in the molecular modification of iron oxides.

One way to accomplish this is through the process of silanization, originally developed for the coating industry. This involves fusing mineral iron oxide molecules with organic polymetal silica. Though the resulting pigment can be termed a "hybrid," this nomenclature is unregulated in the field of semi-permanent makeup, allowing for alternative descriptions based on functional properties.

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1. Background

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3. From Bottle to the Red in Brows

Introduction of Iron Oxide Pigment Particles into the Skin

Immune System Response to Pigment Particles

Ferritin and Iron Oxide Interactions

4. Iron oxides

Introduction of Iron Oxide Pigment Particles into the Skin

Composition of the Pigment

Specific Iron Oxides: Fe2O3 and Fe3O4

5. Immune System Response

Macrophages and Phagocytosis

Specialized Immunity

Pigment in the Lymphatic System

Note on Macrophage Lifespan

Transfer to the Lymphatic System

Pigment Encapsulated in Fibroblast

Pigment Stabilization in the Extracellular Matrix (ECM)

6. Ferritin and Iron Oxide Interactions

What Happens to Iron Oxide Particles in the Skin

Understanding Ferritin

Iron Storage and Degradation

Factors Contributing to Oxidation

7. A Chemical Explanation

Reactions with ferritin

Differences in reactions of hematite and magnetite

Distinctive Interactions

Photostability and Lightfastness

Reasons for lightfastness

Crystalline Structure

Synthetic vs. Natural Iron Oxide

Biochemical Interactions and Pigment Degradation

Conclusion of the causes

8. Solutions to red brows

Silica and Stabilizing Iron Oxide Pigments

Initial solution

The creation of “protective coating"

9. Silanization

General overview of the process

Chemical Reactions

10. Conclusions