Implant Texture and Capsular Contracture: A Review of Cellular and Molecular Pathways

Abstract

Background:

Capsular contracture (CC) is a leading cause of morbidity in implant-based breast surgery. Implant surface texture has been implicated in CC development, yet its etiopathogenesis remains unclear. We conducted a systematic review to determine the influence of implant surface texture on cellular and molecular mechanisms involved in the etiopathogenesis of CC.

Methods:

A systematic review of the MEDLINE, Embase, Web of Science, and Scopus databases was completed to examine the influence of implant texture on cellular and molecular pathways leading to CC. Excluded articles were reviews and those examining solely the clinical presentation of CC.

Results:

Development of CC includes prolonged inflammation, increased myofibroblast density, parallel arrangement of collagen fibers, and biofilm formation. When compared with textured implants, smooth implants are associated with reduction in parallel collagen, capsule thickness, and sheer frictional force. Microtextured implants trigger a reduced macrophage response and decreased fibroblast activation as compared with smooth and macrotextured surfaces. Bacterial counts on microtextured and smooth surfaces are significantly lower than that of macrotextured surfaces. Both micro- and macrotextured implants have increased matrix metalloproteinases and activation of tumor necrosis factor α pathway, with increased activation of the transforming growth factor β1 pathway relative to smooth implants.

Conclusions:

Implant surface texture alters the cellular and molecular mechanisms in the chronic inflammatory process leading to CC. Given the complex biological system of cellular and molecular events in CC, a mathematical model integrating these influences may be optimal to deduce the etiopathogenesis.

Takeaways

Question: Does breast implant surface texture influence cellular and molecular mechanisms involved in the development of capsular contracture (CC)?

Findings: Our literature review indicated that CC is typically associated with changes observed around smooth implants. Smooth and macrotextured implants differ in the bacterial attachment, macrophage levels, collagen orientation, and various other cellular and molecular reactions observed around each implant surface.

Meaning: Surface texture alters the cellular and molecular mechanisms, leading to CC. The complexity of these interrelated mechanistic processes suggests that mathematical models may assist in testing hypotheses for CC etiopathogenesis.

INTRODUCTION

Since the introduction of silicone breast implants in the 1960s,¹ implant-based breast surgery has become an integral component of plastic surgery practice.² Among implant-related complications,³ capsular contracture (CC) remains the most common and challenging complication, leading to reoperation and patient dissatisfaction.^4,5 Despite the prevalence and irreversible nature of CC, there remains a gap in our knowledge of its etiopathogenesis. Various causative mechanisms have been proposed to explain the transition from a normal capsule to a fibrous contracted capsule.^2–4,6–8 Chronic inflammation of the periprosthetic tissue is hypothesized to be a hallmark of this transition, stimulated by subclinical bacterial infection with biofilm formation, hematoma, or seroma.⁵ The cellular and molecular mechanisms of this prolonged inflammatory response are not well characterized.⁵ Aberrant macrophage and T-cell signaling are putative causal factors.⁵ Although observational clinical studies suggest surface texture may mitigate CC, the impact of surface texture on the inflammatory cellular response and risk of CC remains unknown.^6,7,9,10 Meta-analyses have shown that textured implant surfaces are superior to smooth surfaces in decreasing the rate of early CC in subglandular breast augmentation.^6,7 Another systematic review reported comparable rates of CC for textured and smooth implants in a subpectoral plane.⁹ Limited long-term safety outcome data exist to evaluate the influence of implant texture on CC.¹⁰

CC is a complex disease stemming from networks of cellular, chemical, and mechanical factors. In this setting, verbal arguments alone fail to provide definitive explanations. Mathematical models can help improve insight and understanding.^11,12 Models can rigorously test hypotheses for what sets up the initial triggering stimulus; the risk factors involved; and how physiological, immunological, and genetic factors contribute to risks of developing CC. Exploring a suite of hypotheses using mathematical models is significantly simpler, faster, and cheaper than clinical trials.¹³ Moreover, models can point to specific clinical trial strategies and identify possible measures to reduce risks. A caveat, however, is that biological data and cell-level experimental observations (from in vitro and in vivo animal studies or humans) are needed to ground those models in reality.¹⁴

This study aimed to provide a comprehensive summary of current evidence on the influence of implant surface texture on molecular mechanisms in the development of CC. The results of this study will be used to inform mathematical modeling of CC development on a cellular and molecular level, which can later be tested in vitro and in vivo. This review may also provide plausible hypotheses worthy of future investigation to understand the impact of breast implant texture on the pathogenesis of CC.

METHODS

In accordance with the methodological checklist by Prisma,¹⁵ this systematic review was conducted to synthesize the evidence on the role of implant surface texture in the development of CC on molecular and cellular levels. Study identification was conducted in two parts: database and manual search. MEDLINE (Ovid), Embase (Ovid), Web of Science, and Scopus were queried using search terms for breast implantation, implant texture, cellular pathways, molecular pathways, and capsular contracture. Identified articles were screened based on predefined criteria. Two reviewers conducted abstract and title screening based on two criteria: published in English and examined a molecular/cellular pathway by which breast implant texture influences CC. Excluded articles were reviews, those examining solely clinical presentation of CC, and studies without access to the full text. Following this initial screening, full-text screening was conducted to generate a shortlist of studies to utilize for data extraction. A third reviewer was consulted in case of discrepancies between the two reviewers.

Quality appraisal and data extraction were completed by two reviewers. Data were collected on study details (authors and year of publication), study characteristics (study design, methodology, and sample number), molecular pathways and targets in normal and pathologic states (cells, proteins, etc), study limitations, and future directions of research regarding the implicated pathways as suggested by authors. Reference lists of published reviews and included articles were reviewed to ensure the robustness of our systematic review.

Narrative analysis of the collated data was performed by constructing a summary of evidence on the cellular and molecular mechanisms by which implant surface texture influences CC development.

RESULTS

On June 22, 2023 four databases were searched for articles, and the search parameters yielded 359 articles. Of this list, 164 duplicates were removed and 195 underwent an initial title and abstract screening. A full-text review of 88 articles was conducted and 74 of them were used for data extraction (Fig. 1). (See appendix, Supplemental Digital Content 1, which shows the list of 74 articles included in systematic review. http://links.lww.com/PRSGO/D201.)

Fig. 1.

Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) flow diagram demonstrating the number of articles screened and removed. After final review, 74 articles remained for final inclusion and data extraction. Adapted from Page et al.¹⁵

NORMAL CAPSULE DEVELOPMENT

A silicone implant induces an inflammatory response characterized by infiltration of platelets, macrophages, foreign body giant cells, plasma cells, and lymphocytes.¹⁶ This inflammatory cascade begins with the infiltration of platelets that produce transforming growth factor-β (TGF- β), platelet-derived growth factor, chemokine ligand 4, leukotriene, and interleukin-1 (IL-1).^17,18 These factors recruit and activate macrophages, which stimulate fibroblast recruitment, proliferation, and trans-differentiation into myofibroblasts.¹⁷Polymorphonuclear leukocytes, namely neutrophil, eosinophil, basophil, and mast cells, are recruited by cytokines and produce cysteinyl leukotrienes, which further stimulate polymorphonuclear leukocyte productions as well as migration and proliferation of fibroblast.¹⁹Foreign body giant cells form as a result of failed macrophage phagocytosis of the implant. Giant cells produce reactive oxygen species and TGF- β, which further attract fibroblasts.¹⁷ Macrophages and giant cells can also produce matrix metalloproteinases (MMPs) that degrade extracellular matrix (ECM) and have both inflammatory and proinflammatory functions. MMP9 deficiency is associated with abnormal ECM deposition, suggesting a proinflammatory role,²⁰ and also reduces IL-2 response (antiinflammatory).²¹ MMP2 overexpression is associated with dysfunctional wound healing,²² and MMP2, -3, -7 also increase the bioavailability of TGF- β.²¹ Roles of cellular and molecular processes involved in CC development are summarized here (Fig. 2).

Fig. 2.

Cellular and molecular players involved in the development of CC. IFN, interferon. Created with BioRender.com.

TEXTURED VERSUS SMOOTH IMPLANTS

Capsules of smooth and textured implants differ in their composition; smooth implant capsules are associated with lower collagen amount,²³ reduced thickness,^23,24 increased parallel arrangement of collagen,^23,25 and reduced sheer frictional force.²⁶ Textured implants are associated with more ridged and less continuous capsules⁸ with more compact collagen arrangement,²⁴ and thicker capsular epithelium⁸ when compared with smooth implant capsules. Synovial metaplasia²⁴ and increased cell death²⁶ are more commonly observed in capsules surrounding macrotexturized implants than smooth implants.

CAPSULAR CONTRACTURE

In CC, a pliable capsule is transformed into a fibrotic capsule with possible deformity and pain.³ CC is characterized by a double layer, with an inner layer composed of fibrocytes and histiocytes and a thicker outer layer of collagen bundles in a parallel array, with vascular components and loose connective tissue.²⁷ Theories for the formation of double layers include (1) mechanical shear stress that causes microtrauma, inducing fibrosis,²⁸ and (2) biofilm formation around the implant that induces inflammation that causes weakening of the capsule.²⁹ CC development is hypothesized to occur secondary to increased duration of inflammation,¹ increased vascularization,³⁰ increased contractility of myofibroblasts,^31,32 and parallel collagen fiber arrangement, which is necessary for myofibroblasts to exert enough force on the capsule.^31,33–35 Evidence of the cellular and molecular pathways in CC development according to implant surface texture is summarized here (Fig. 3).

Fig. 3.

Summary of differences in cellular and molecular processes leading to CC in smooth vs textured implant surfaces. Created with BioRender.com.

HOW DOES IMPLANT TEXTURE AFFECT MACROPHAGE BEHAVIOR AND MYOFIBROBLAST TRANS-DIFFERENTIATION?

Fibroblast to myofibroblast trans-differentiation is critical for CC development.³⁶ Fibroblast density in textured and smooth implant capsules seems to be similar. Berniz et al showed increased myofibroblast density in implants with higher texturization,²³ but Zhang et al observed decreased myofibroblast proliferation in macrotexturized versus smooth implants.³⁸ Polyurethene macrotexturized and microtexturization^37,38 are associated with decreased trans-differentiation of fibroblasts to myofibroblasts relative to smooth implants.¹⁶

Macrophages play an important role in the promotion of myofibroblast trans-differentiation of fibroblasts.^39,40 There are two subtypes of macrophages. The proinflammatory subtype M1 produces IL-6, IL-12, and TNF, as well as antimicrobial molecules, reactive oxygen, and nitrogen species.^39,41 Prolonged M1 macrophage exposure can lead to fibrous encapsulation of foreign material.⁴² M2 macrophages reduce inflammation and encourage wound repair, partially through the TGF-β1, which promotes the differentiation of fibroblasts into myofibroblasts.^39,40 Macrophage density is lower in capsules of smooth versus textured implants, despite higher levels of macrophage precursors (monocytes). Siltex, Silk Surface (microtexturized), and micropolyurethane (macrotexturized) textured surfaces are exceptions, having the lowest macrophage counts.^23,43 The relative abundance of M1 proinflammatory and M2 antiinflammatory macrophages has been investigated according to implant texture. Santanelli di Pompeo et al reported a lower percentage of M2 antiinflammatory macrophages in macrotextured implants when compared with smooth implants.¹⁰ Choi et al demonstrated a higher level of M2 macrophages in microtextured than in smooth implants.³⁷

DOES IMPLANT TEXTURE INFLUENCE BACTERIAL COMPOSITION AND BIOFILM FORMATION?

Gram-negative bacteria have been implicated in the pathogenesis of CC.²⁷ Common bacteria isolates include coagulase-negative staphylococci (41%), Escherichia coli (10%), and Staphylococcus aureus (8%).²⁷ Higher implant texturization is associated with Staphylococcus epidermidis and Ralstonia pickettii biofilm formation.⁴⁴ Bacterial level is significantly lower on microtextured and smooth surfaces than on macrotextured surfaces.⁴⁵ The architecture of biofilms also differs for a single bacterial phenotype according to implant texture. S. aureus biofilms are dense and thick on the surface of the macrotextured implants, whereas these biofilms are patchy on the surface of the smooth and microtextured implants.⁴⁵ The adherence of S. epidermidis was also shown to be greater on the macrotextured than microtextured and smooth surfaces.⁴⁵

DOES IMPLANT TEXTURE INFLUENCE INFLAMMATORY MEDIATORS OF CAPSULAR CONTRACTURE?

Tumor Necrosis Factor-α

Produced mainly by activated macrophages, the transcription factor tumor necrosis factor (TNF) α has a proinflammatory effect by the activation of downstream nuclear factor (NF) κB and mitogen-activated protein kinases (MAPK) signaling pathways and production of proinflammatory cytokines IL-6 and IL-8.^46,47 TNF-α expression was observed to be higher in human macrophages cultured on highly textured surface implants when compared with smooth.⁴⁸ Interestingly, polyurethane surfaces, when compared with other macrotextured devices, demonstrate higher expression of NFκB-p65, a component of the proinflammatory NF-κB transcription factor downstream of TNF- α.¹⁶

Transforming Growth Factor-β

TGF-β1 is a transcription factor that has both proinflammatory and antiinflammatory properties through activations of the SMAD, NF-κB and MAPK pathways.⁴⁹ TGF-β1 increases T helper cells’ differentiation when joined by IL-6, and it promotes IL-9- and IL-10-producing T cells when combined with IL-4. On the other hand, TGF-β1 also has antiinflammatory effects.⁵⁰In fibroblasts of normal capsules, TGF-β1 was shown to be upregulated on smooth relative to textured implant surfaces.^51,52

Interleukin-4

Interleukin 4 (IL-4) acts as an immune regulator that is important for leukocyte survival, Th2-mediated immunity, and activation of macrophage through an alternative pathway.⁵³ Kim et al investigated the effect of additional IL-4 implant coating on the development of capsular contracture in mice models. They concluded that implants with IL-4 coating have decreased thickness, collagen density, fibroblast, myofibroblast, and M1 macrophages. An increase in the M2 macrophage population was also observed.⁴² With the change in macrophage population to favor M2 macrophages, as well as significantly reduced proinflammatory cytokines, IL-4 was shown to decrease inflammatory response and resultant fibrosis and capsular contracture.⁴² No comparison of IL-4 coating on different surface textures could be identified.

Cysteinyl Leukotrienes

The proliferation and migration of fibroblasts associated with inflammation are mediated by cysteinyl leukotrienes (CysLTs).⁵⁴ In the setting of chronic inflammation, CysLTs result in an upregulation of fibroblast to myofibroblast differentiation and collagen synthesis, increasing the contractile and fibrotic forces.⁵⁴ The mechanistic uncertainty and prevalence of CC has encouraged use of CysLT inhibitors in preventing CC development. Postoperative prophylaxis with CysLT inhibitors, including montelukast and zafirlukast, has been explored for its purported benefit of reducing CC risk. In mouse models, montelukast results in implant capsules being thinner, with lower collagen density, lower numbers of fibroblasts and myofibroblasts, and lower TGF-β.⁵⁴ Clinical studies support decreased rates and severity of CC in those receiving montelukast and zafirlukast versus untreated patients.

Matrix Metalloproteinases

While the main function of matrix metalloproteinases (MMPs) is ECM degradation and removal, the involvement of MMPs in CC pathogenesis has not been fully elucidated. Normal capsules have increased MMP3 expression when compared with contracted capsules.⁸ Also, textured implants have higher MMP3 expression when compared with smooth.⁸ MMP2, MMP9, or MMP12 are similar in smooth and microtextured implants; however, MMP9 and MMP12 are heavily upregulated in macrotextured implants.⁵⁵ Tissue inhibitor of metalloproteinase (TIMP) is a known inhibitor of MMPs. TIMP4 expression was found to be heavily upregulated in smooth implants.⁵⁵ Together, these findings suggest a higher MMP/TIMP ratio in textured implants, which suggests lower MMP-mediated ECG degradation in capsules around textured implants.

A summative table outlines differences in levels of cells and cytokines around smooth and textured implants (Table 1).

Table 1.

Summary of the Differences in the Levels of Cells and Cytokines around Smooth and Textured Implants

Implant Texture
Smooth		Textured
Higher	Lower	Higher	Lower
TGF-β1	Macrophages	MMP3, MMP9, MMP12	Myofibroblasts
IL-6, IL-4, IL-9, IL-10		TNF-α
Th-17		IL-6
Myofibroblasts		Macrophages
Monocytes

A comparison of changes in cytokine and cell levels observed around smooth and textured implants.

DISCUSSION

The influence of implant surface texture on cellular and molecular mechanisms in CC development is supported by current evidence. Cellular composition, signaling, differentiation, and behavior are affected by implant texture: there are more antiinflammatory macrophages, higher MMP-mediated ECM degradation, increased TNF-α mediated inflammation in textured than in smooth implants. The severity of capsular contracture mirrors the levels of macrophages, fibroblasts, with a resultant cascade of effects on pro- and antiinflammatory cytokines including IL-4, TNF-α, and TGF-β1. Also, smooth implants demonstrate parallel collagen arrangement while textured implants demonstrate a disrupted capsular collagen arrangement. With this multitude of plausible interrelated cellular and molecular processes contributing to CC development, it is challenging to decipher this complex biologic system leading to a pathologic capsule.

Mathematical models can help decipher complex biologic processes and elucidate the conditions leading to normal versus pathologic health outcomes.⁵⁸ Mathematical modeling of CC development may be a feasible approach to evaluate the plausible interplay of many factors, including surface texture. Models have been applied to explore the roles of macrophages, myofibroblasts,¹⁴ and collagen⁵⁹ in wound contraction, and recently, in CC.⁶¹ So far, the effects of surface implant texture and cell-to-cell forces^56,57,60 are yet to be modeled, one of our current goals.

A model can probe specific hypotheses for causal factors.⁶¹ For example, one hypothesis posits that increased inflammation elevates the risk of CC. However, is inflammation enough, on its own, to do so, or are there important feedback loops that could be targeted by drugs to ameliorate the outcome? Models can identify the key rate parameters, genetics, physiology, and medical history that interact with perioperative conditions to result in CC risk. For example, a 50% reduction in macrophage recruitment to the implant surface could decrease or abrogate CC risk. Therefore, a pharmaceutical agent capable of reducing macrophage recruitment would be beneficial to be evaluated in a clinical trial. The mathematical model provides guidance on the pharmacologic effect size required to anticipate a clinically meaningful difference in CC development. A model can unravel the distinct roles of intrinsic (genetic and physiological) parameters, versus stimuli or insults that put an otherwise healthy patient on a trajectory towards CC.⁶¹

Although mathematical models can help our understanding of CC etiopathogenesis, further quantitative and qualitative observations on which to base model hypotheses are needed.¹⁴ While no single model is “the truth,” exploring a suite of hypotheses using model-based arguments is significantly simpler, faster, and cheaper than costly experimental studies or clinical trials. Moreover, alternate models can help guide experimental studies by pointing to specific data needed to narrow down the list of hypothetical causative factors, thereby saving cost and time.

LIMITATIONS

There are limitations inherent in the methodology of this study as a systematic review. The evidence summarized is limited by published work, which are limited in cohort size and processes assessed,⁶² partly due to funding and time.⁴² The majority of the studies report findings based on in vitro or animal studies, and evidence derived from the immune and inflammatory response of rats and rabbits differ from the normal human response.^23,63 Lastly, the Baker grading system used to classify the degree of CC is subjective in its nature and can potentiate the level of discrepancies in reporting and classifying the pathways observed.⁶⁴

CONCLUSIONS

Despite prophylactic and therapeutic interventions, CC remains a prominent complication. With inflammatory processes central to this CC development, this review supports that implant surface texture influences the cellular and molecular processes leading to the pathologic transition. This complex biologic system of interrelated mechanisms in CC etiology highlights an opportunity for applying mathematical modeling to help understand these processes and guide targeted hypothesis-testing in human tissue.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.