Pigment particle's life-cycle

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1. Background

Pigment retention is a topic that might seem straightforward at first glance, with many artists discussing it confidently. However, this confidence may be misleading, as the underlying processes are quite complex. To inform this article, we have compiled insights from interviews with over 36 artists who have become the highest earners in their respective regions after careers spanning two to four years. The content has also been reviewed, refined, and augmented by a dermatologist, two chemists, and an expert in cellular biology. Throughout the development of this article, it has become evident that many professional artists have only explored pigment retention superficially, finding many of the details presented here to be novel.

The interviews utilized for this article were conducted between 2020 and 2024, with related research projects continuing. Of the artists interviewed, 24 were based in the European Union, six in the UK, three in the US, and the remainder in various Asian countries. Most specialize in the Powder Brows technique and frequently advise clients on matters of pigment retention.

2. From the bottle to lymphatic system

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.

In this article, we will trace the journey of pigment-colorant particles from the bottle to their ultimate locations within the human body. We'll distill the intricate biological interactions into five principal pathways that a pigment particle may undertake upon entering the dermal layer.

Immediate Phagocytosis and Transportation to the Lymphatic System

This route involves the prompt uptake of pigment particles by phagocytic cells, which swiftly transport them away from the implantation site to the lymphatic system. This is the most natural way for the body’s innate immune system to react to the trauma caused by the penetration of the dermis.

Wrong ways: Migration, reaching Hypodermis or blood vessels

This less desired scenario occurs when particles penetrate too deeply beyond the reticular dermis. Depending on their properties, these particles may persist for an extended period within the lipid-rich environment of the hypodermis. Similarly, a direct transfer to the blood vessels is uncommon and typically necessitates particular conditions.

Engulfment and Residence within Dermal Macrophages

In this scenario, macrophages engulf pigment particles and remain within the dermal layer, serving as long-term repositories for the pigment. This process potentially contributes to the longevity of the colorant in the skin.

Agglomeration and Encapsulation by Fibroblasts

Pigment particles may cluster and become encapsulated by fibroblasts, forming a fibrotic shell that isolates the pigment within the dermal extracellular matrix (ECM). This encapsulation can affect the pigment's long-term stability and its visibility within the skin.

Integration into the Extracellular Matrix (ECM)

Some pigment particles get trapped within the ECM, which comprises various proteins and polysaccharides providing structural support to cells. This entrapment can stabilize the pigment particles, diminishing their movement and influencing their fading rate over time.

In the following detailed review, we'll delve into each pathway to enhance our understanding of the biological and chemical determinants affecting pigment particle behavior post-implantation. We'll consider the influence of particle size, shape, and chemical makeup on their destiny and explore the body's immune mechanisms that may either degrade or retain these pigments within the skin.

Our comprehensive examination seeks to clarify the intricate interaction between introduced pigments and the skin's biological systems. The aim is to present an informative narrative of the "life cycle" of pigment particles used in semi-permanent makeup applications, from insertion to potential fading or persistence.

3. Immediate Phagocytosis

Macrophage Involvement and Phagocytosis

The human body has complex defense mechanisms to protect against foreign entities, a response that is triggered when pigment is introduced into the skin during semi-permanent makeup procedures.

At the outset, the body mounts a generalized immune response, mobilizing various cells like macrophages, histiocytes, and neutrophils to the insertion site. Macrophages, in particular, are key players in phagocytosis, the process by which cells ingest foreign particles. Capable of engulfing particles much larger than their own size, macrophages can phagocytize entities up to 10 micrometers. Given that the size of common pigment particles used in semi-permanent makeup typically measures around 500 nm in diameter, they are well within the size range that macrophages can handle. Post-ingestion, some macrophages may become sessile and integrate into the dermis, where they can retain pigment particles long-term.

Debunking Common Misconceptions

It is crucial to clarify some misconceptions prevalent among semi-permanent makeup artists regarding the body's immune response to pigment particles.

Particle versus Molecule

There is often confusion between the terms 'molecule' and 'particle'. Pigment molecules have distinct properties from the larger particles they form. It is the particle that is relevant when considering how the body interacts with pigment, not the individual molecules or atoms that comprise it.

Size and Phagocytosis

Contrary to intuitive belief, it is not the smaller particles but rather the larger ones, those over 0.5 μm, that are more efficiently phagocytized by macrophages. Particles smaller than 100-200 nm may avoid phagocytosis due to their size, but other cellular uptake mechanisms, such as pinocytosis or receptor-mediated endocytosis, may still operate. These processes contribute to the pigment's gradual fading from the skin over time. Initially, however, small-sized particles may indeed avoid phagocytosis.

Immunogenic Response

The immune response is triggered not solely by the chemical properties of the pigment but by the physical disruption of the skin's integrity due to the needle's penetration. This trauma activates the innate immune response, with neutrophils being among the first responders attempting to clear the pigment, which is often beyond their capability.

Pigment in the Lymphatic System

It is important to recognize that some pigment particles migrate to the lymphatic system. Once pigment particles enter the lymph nodes, they tend to remain there indefinitely. The lymph nodes do not possess mechanisms to break down or expel these pigments, which explains why ink particles can be detected in lymph nodes post-mortem.

In summary, the initial fate of pigment particles introduced into the skin is often dictated by the body's immune response. Macrophages play a pivotal role through phagocytosis, and smaller immune cells, like neutrophils, may struggle to manage larger pigment particles.

4. Migration and Misplacement

Intravascular Entry

The accidental introduction of pigment particles into the blood vessels is a rare but possible complication during semi-permanent makeup procedures, mainly when working in areas with "cold" skin tones where capillaries are more visible. While less likely to occur in eyebrow treatments, the risk is heightened during eyeliner procedures due to the vascular nature of the eyelids. Experienced artists may attempt to mitigate this by gently massaging the area to move particles away from the capillaries and applying anesthetics to constrict the blood vessels. In severe cases of vascular intrusion, it may be prudent to cease the procedure.

Reaching the Hypodermis

Another pathway that can lead to undesired results is the migration of pigment particles into the hypodermis, resulting in a phenomenon known as "blowout." The chemical composition of the pigment plays a pivotal role in this event. Organic pigments rich in hydrocarbons (up to 50% of their composition) are particularly prone to this because of their lipophilic nature. These particles have an affinity for the lipid-rich environment of the hypodermis, where carbon-hydrogen bonds thrive amidst fats and oils. Should the artist penetrate beyond the reticular dermis, pigment particles can migrate to this deeper layer and find a conducive environment for persistence.

Longevity of Particles in the Hypodermis

Pigment particles, especially organic ones, can remain embedded in the hypodermis for extended periods. Their stability in this layer is largely due to the lipophilic interactions between the organic components of the pigment and the lipid environment of the hypodermis. This compatibility enables the particles to blend with the surrounding tissue, resisting the body's attempts to metabolize or mobilize them. Consequently, pigments that reach the hypodermis can manifest as stubborn, long-lasting discolorations that resist fading. The body's limited regenerative activity in the hypodermis further contributes to the permanence of these pigments, as the slow cellular turnover in this layer does not favor the natural elimination of foreign substances.

Therefore, the misplacement of pigment particles into the hypodermis is an outcome that practitioners strive to avoid. Understanding the structural and chemical nature of pigments can help artists prevent such complications and ensure the pigments remain within the desired layers of the skin.

5. Residence in Dermal Macrophages

Engulfment and Residence within Dermal Macrophages

Macrophages play a pivotal role in determining the retention, migration, or degradation of these pigments, and their actions can lead to various outcomes, including the transportation of pigment particles to lymph nodes or their retention within the skin.

Becoming stationary

Some macrophages, once they have ingested pigment particles, may become stationary and integrate into the dermis, becoming long-term repositories for these pigments. It is an oversimplification, however, to say that these macrophages merely "die" and remain in the dermis with their engulfed contents. The reality is that the science of phagocytosis and subsequent macrophage behavior is complex and still under active investigation.

Chemical Reactions Inside Macrophages

As for the chemical reactions inside macrophages, there is no simple or balanced reaction formula for the degradation of iron oxide or carbon pigment particles. The process is complex and involves a variety of enzymes and reactive species. Here is a simplified description.

Inside the Phagolysosome. When a pigment particle is enclosed within a phagosome, and this vesicle fuses with a lysosome, the particle is exposed to a harsh, acidic environment and a variety of digestive enzymes and reactive species like reactive oxygen species (ROS).
Digestion of Organic Pigments. These enzymes and ROS can sometimes break down organic pigments into smaller molecules. This process can vary widely depending on the chemical structure of the pigment.
Stability of Inorganic Pigments. Inorganic pigments like iron oxides are generally more stable and resist breakdown within the phagolysosome. They may change their oxidation state but are not degraded in the same way as organic molecules. For example, the redox state of iron in iron oxide might be altered, but the particle remains largely intact.
Carbon Pigments. Carbon, being elemental and not a compound, does not react in a way that a simple chemical formula can represent. It is inert and resists chemical reactions under physiological conditions.

Thus, the response of pigment particles to the body’s immune system and their fate within it is a highly complex and dynamic process. What we do understand is that upon ingestion of pigment particles, some macrophages undergo functional changes. Rather than transporting the pigment to the lymphatic system, these cells retain the pigment in situ. It is not that they die, but rather that they enter a state of reduced activity, holding onto the pigment without actively degrading it as they might with pathogens like bacteria.

Over time, a macrophage’s ability to retain the pigment may diminish. Since the bone marrow continually replenishes macrophages, there is a dynamic process of release and re-engulfment of pigment particles within the skin. If a macrophage releases a particle and a new macrophage does not immediately capture it, this particle may eventually migrate to the lymphatic system.

Interactions Within Macrophages and Particle Fate

The impact of enzymes within macrophages on pigment particles can vary depending on the particle's chemical composition. Enzymatic reactions could potentially break down certain pigment particles, altering their structure and color.

Additionally, a new macrophage may engulf the same particle and, in some cases, transport it to the lymphatic system. The lifespan of a macrophage holding onto a pigment particle can differ widely, influenced by factors such as the local tissue environment and the macrophage's activation state. As macrophages are part of a renewable cell population, their involvement in pigment retention is both transient and sustained.

The life cycle of a pigment particle within dermal macrophages is characterized by phases of retention, possible degradation, and eventual release. This cyclical process is moderated by the body's ongoing production of macrophages. While some macrophages become repositories for pigment particles, others may serve as vehicles for their removal to the lymphatic system. The understanding of this cellular ballet is crucial for practitioners seeking to predict the longevity and fading of pigments used in the Powder Brows procedure.

6. Encapsulation by Fibroblasts

Specialized Immune Response

Following the initial innate response, the immune system's more specialized mechanisms, involving T-lymphocytes and B-lymphocytes, start to address the presence of foreign pigments. T-lymphocytes may target cells that have ingested pigment, while B-lymphocytes can produce antibodies. The role of B-lymphocytes in pigment response is less direct, as antibody-mediated pigment neutralization is not a primary reaction in semi-permanent makeup.

Agglomeration and Particle Dynamics

Concurrently, pigment particles within the skin may undergo agglomeration. Individual skin properties, such as age, oiliness, collagen strength, and overall skin condition, influence this complex phenomenon. Contrary to oversimplified notions that "small black particles are quickly removed," agglomeration is a nuanced process dependent on the particle's chemical nature. Smaller particles can form larger aggregates through chemical interactions and physical entanglements. These agglomerates, or clusters of aggregated particles, when large enough, can become stabilized within the skin's fibrous network, often through interactions with fibroblasts.

Stabilization and Encapsulation by Fibroblasts

Fibroblasts, cells responsible for producing the extracellular matrix (ECM) and collagen, may encapsulate these pigment aggregates. Upon the introduction of pigment, fibroblasts become activated and may differentiate into myofibroblasts, a cell type with enhanced contractile properties crucial for tissue repair and encapsulation processes.

Myofibroblasts will migrate towards pigment aggregates and encapsulate them with ECM components such as collagen, elastin, and fibronectin, creating a fibrotic capsule around the pigment clusters.

Functions and Remodeling of the Fibrotic Capsule

The resulting fibrotic capsule serves multiple protective functions. It mechanically isolates the pigment, minimizing its reactivity and shielding it from the immune system. However, this encapsulation is not permanent. The fibrotic capsule can remodel over time, influenced by enzymatic activity and physical forces, potentially releasing the pigment particles into the dermal environment.

The fibroblast-mediated encapsulation of pigment particles represents a critical, albeit dynamic, endpoint for pigment retention within the skin. The particles' journey through the immune system and subsequent stabilization in the dermal layer underscores the intricate balance between the biological environment of the skin and the physicochemical nature of the pigments used in semi-permanent makeup. Understanding these interactions provides valuable insights for artists aiming to predict and control the outcomes of their work.

7. Retention in Extracellular Matrix

The pigment encapsulation within the dermal layers is culminated by its integration into the extracellular matrix (ECM), a scaffold composed of proteins and polysaccharides that not only supports but also actively engages with skin cells. The ECM, abundant in collagen, elastin, and glycosaminoglycans, transcends mere structural support to play pivotal roles in cell signaling and tissue repair. Pigment particles introduced during semi-permanent makeup interact with this matrix, which may lead to their entrapment by various means.

When we are discussing such retention, we have to once again take into account the potential aggregation and agglomeration of pigment particles. The better the conditions are from the chemical perspective for any bonds to appear between the particles, the higher the chances are for the formation of aggregates and clusters that have a higher probability of being entrapped in parts of the dermis, such as ECM.

Mechanisms of Entrapment in the ECM

Physical Adsorption. The adherence of pigment particles to the ECM is influenced by their size, surface charge, and the charged domains of ECM proteins. These interactions anchor the particles physically within the matrix.

Mechanical Interlocking. Like net-capturing objects, the ECM's fibrous network can ensnare pigment particles. This mechanical capture is more likely when the ECM density is high, and particle geometry is conducive to entrapment.
Biochemical Anchoring. ECM proteins can bind pigment particles through specialized interactions, providing additional stability and hindering migration.
Tissue Remodeling. Post-pigmentation, the ECM often increases its synthesis around the introduced pigment, reinforcing the particle's anchorage within this newly formed matrix.

Implications of ECM Entrapment

Longevity and Stability. Entrapment within the ECM generally leads to prolonged retention and stability of pigment, mitigating the risks of migration and degradation.

Immunological Shielding. Though not as protective as fibroblast encapsulation, ECM entrapment provides a degree of concealment from the immune system, contributing to the longevity of the pigment.

The entrapment of pigment within the ECM underscores a critical aspect of pigment longevity in semi-permanent makeup. It showcases a dynamic interplay between the pigments and the biological components of the skin, each influencing the other to maintain a delicate equilibrium.

8. Additional Factors

What else influences pigment retention in the skin

Pigment retention in the skin is inherently a transient process, albeit sometimes prolonged. Eventually, as a foreign material within the body, pigment is destined for the lymphatic system and subsequent removal, a process that is only halted by the finite lifespan of the human organism.

Pigmentation retention, especially concerning semi-permanent makeup such as Powder Brows, is a complex, dynamic process. It is susceptible to many variables, including, but not limited to, the following.

Biochemical Alterations. Medication, hormonal fluctuations, and radiation exposure can trigger changes in the skin's chemical environment.
Enzymatic Activity. The body's natural enzymatic processes incessantly degrade foreign substances, including pigment agglomerates and particles.
Further immune Response. The immune system continuously surveys and reacts to non-self entities, working to break down and clear pigments.
UV Radiation. Exposure to ultraviolet light catalyzes photochemical reactions, leading to the breakdown of pigment particles. Resistance to UV light varies based on the inherent lightfastness of the pigment, its chemical composition, and particle size.
Environmental Factors. Elements such as titanium dioxide (TiO2) present in the skin can amplify the photodegradation of pigments due to their photocatalytic properties.
Cell Turnover The skin's natural exfoliation process can lead to the loss of more superficially implanted pigments over time.
Oxidative Stress: Reactive oxygen species (ROS) generated in the skin, possibly due to environmental stressors or metabolic processes, can chemically alter pigments, leading to their breakdown.
Chemical Interactions: Interactions with other chemical compounds, whether endogenously produced or externally applied (e.g., skincare products), can modify pigments and facilitate their degradation.
Exocytosis Macrophages and other phagocytic cells can ingest and, in some cases, expel pigment particles back into the interstitial fluid where they can be washed away by lymphatic drainage.

Exocytosis explained

Exocytosis is a cellular process where cells eject materials that they cannot process or need to eliminate. For macrophages dealing with pigment particles, such as those from tattoo ink or semi-permanent makeup, this process unfolds when the macrophage engulfs the particle but cannot degrade it. The macrophage then transports the particle to its membrane and expels it into the surrounding interstitial fluid. From there, the particle can be swept away by the lymphatic system, ultimately reaching the lymph nodes. While some particles are trapped in the lymph nodes, others may continue through the lymphatic system and either re-enter the bloodstream or be excreted. This mechanism demonstrates the macrophage’s role in managing foreign particles and maintaining the cell's balance.

In essence, the persistence of pigment within the skin is contingent upon a delicate balance of external influences and internal physiological processes. Each of these factors contributes to the gradual fading of pigmentation, underscoring the temporality of semi-permanent makeup applications.

9. Conclusions

When the pigment particle enters the skin, there is always traumatization that initiates the innate Immunogenic Response. After that, the five most common scenarios happen to the pigment particle. Immediate Phagocytosis and Migration to the Lymphatic System: Upon skin penetration, innate immune mechanisms are triggered, and pigment particles may be swiftly engulfed by phagocytes - primarily macrophages, and transported to the lymphatic system for further processing or permanent residence.

Migration and Reaching the Hypodermis or Blood Vessels. Particles that bypass initial phagocytic capture can inadvertently migrate to the hypodermis or, less commonly, into capillaries. Particles in the hypodermis may persist due to their chemical affinity for the lipid-rich environment or because they are beyond the typical reach of immune surveillance.

Engulfment and Residence within Dermal Macrophages. Some macrophages ingest pigment particles and become long-term repositories within the dermis. The lifetime of these macrophages and their pigment cargo can vary, influenced by factors such as the particle's resistance to enzymatic degradation and the dynamic state of immune cells in the dermis.

Agglomeration and Encapsulation by Fibroblasts. Aggregated pigment particles can become encapsulated by fibroblasts, leading to the formation of a fibrotic capsule. This process contributes to the longevity of the pigment's visibility, as the encapsulated particles are mechanically isolated and immunologically concealed.

Integration into the Extracellular Matrix (ECM). Pigment particles may also integrate into the ECM, where they can be physically trapped and biochemically anchored, further contributing to pigment stability and retention.

Over time, the particle that has remained in the dermis may be affected by several additional factors that facilitate its eventual removal from the skin. Most prominent of those are the skin’s biochemical alterations, the body’s enzymatic activity, further immune responses, UV radiation, environmental factors, cell turnover, oxidative stress, chemical interactions, and exocytosis.

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