Current Concepts in Capsular Contracture: Pathophysiology, Prevention, and Management

Abstract

Over 400,000 women in the United States alone will have breast implant surgery each year. Although capsular contracture represents the most common complication of breast implant surgery, surgeons continue to debate the precise etiology. General agreement exists concerning the inflammatory origin of capsular fibrosis, but the inciting events triggering the inflammatory cascade appear to be multifactorial, making it difficult to predict why one patient may develop capsular contracture while another will not. Accordingly, researchers have explored many different surgical, biomaterial, and medical therapies to address these multiple factors in an attempt to prevent and treat capsular contracture. In the current paper, we aim to inform the reader on the most up-to-date understanding of the pathophysiology, prevention, and treatment of capsular contracture.

All foreign bodies placed in the body elicit an inflammatory response via the foreign body reaction resulting in either fibrous encapsulation or incorporation of the implanted biomaterial. Immediately following placement of a breast implant, a fibrous capsule forms surrounding the device. ¹ The extent of the soft tissue reaction surrounding the implant depends on several factors such as the plane of insertion, incision used, surface texture of the implant, and previous radiation treatment. ¹ Under normal circumstances the capsule remains benign and presents no concerns. However, in response to sustained inflammation, the capsule becomes fibrotic, culminating in capsular contracture that causes significant pain and deformity around the breast implant. ¹

Each year, over 400,000 women in the United States alone will have breast implant surgery for either breast augmentation or reconstruction following mastectomy. ² In breast augmentation, capsular contracture affects 1.9% of patients with submuscular implants and 9.6% of patients with subglandular implants; in breast reconstruction capsular contracture affects up to 8.7% of patients with prepectoral reconstruction with acellular dermal matrix (ADM) and up to 13.9% of patients with subpectoral implants. ^{3 4 5 6 7} These numbers increase substantially in radiated patients, with up to 40% of patients receiving post-mastectomy radiotherapy suffering from capsular contracture. ³ Despite the high incidence of capsular contracture, an effective treatment remains elusive with up to 54% of surgically managed capsular contracture cases recurring. ^{8 9}

Although capsular contracture represents the most common complication of breast implant surgery, surgeons continue to debate the precise etiology. General agreement exists concerning the inflammatory origin of capsular fibrosis, but the inciting events triggering the inflammatory cascade appear to be multifactorial making it difficult to predict why one patient may develop capsular contracture while another will not. Accordingly, researchers have explored many different surgical, biomaterial, and medical modalities to address these multiple factors in an attempt to prevent and treat capsular contracture.

In the current paper, we aim to inform the reader on the most up-to-date understanding of the pathophysiology, prevention, and treatment of capsular contracture.

Cellular and Molecular Origin of Capsular Contracture

The breast implant capsule forms via a foreign body reaction which begins within minutes of implantation by proceeding through the following phases: blood–material interaction, surface provisional matrix formation, acute inflammation, chronic inflammation, foreign body giant cell formation, and fibrous capsule formation. ^{10 11} The resulting capsule contains three layers: an inner cellular layer comprised primarily of fibroblasts, T-cells, and macrophages; a vascular middle layer of loose connective tissue; and an outer vascular layer of dense connective tissue. ^{12 13} The foreign body response, particularly the inflammatory phase, is tightly regulated. In certain cases, external factors such as chronic implant micromotion, biofilm, or silicone particulate shedding may prolong the inflammatory phase leading to sustained inflammation and eventually capsular fibrosis. ^{11 14 15 16 17}

The inflammatory phase of the foreign body reaction begins with recruitment of innate immune cells from the vasculature in neighboring tissues, such as pectoralis muscle or breast gland, to the implant interface. ¹⁰ Soon after initiation of the inflammatory response macrophages become the dominant cell type in the developing breast implant capsule. Macrophage subpopulations are generally divided into the proinflammatory M1 phenotype or the prorepair M2 phenotype. ^{18 19} Classically activated (M1) macrophages are CD68 + NOS2+ cells that are primed in response to bacterial peptides, IFN-γ, and TNF-α. ^{19 20} Upon activation, the M1 macrophages express the proinflammatory cytokines NOS2, TNF-α, IL-6, IL-1β, and IL-8 via the STAT3 and NF-κβ signaling pathways. ^{19 20} The M1 macrophages are present in greater numbers in the earlier acute phases of inflammation and are responsible for clearing debris. ²⁰ The alternatively activated (M2 or “wound healing”) macrophages are present in greater numbers later in the foreign body reaction and promote the transition from inflammation to capsule formation. ²⁰ The M2 macrophages are CD68 + CD206+ cells activated by IL-4 and IL-13, and stimulate fibroblast recruitment, angiogenesis, and extracellular matrix production by secreting vascular endothelial growth factor, transforming growth factor -β, and epidermal growth factor receptor ligands. ^{19 20} M2 macrophage activation leads to less capsular contracture while sustained M1 macrophage activation induces fibrosis. ^{13 21}

The Th1, Th17, and Th2 effector T-cell adaptive immune responses also play an important role in breast implant capsule inflammation and fibrosis. Th1 signaling is proinflammatory and associated with the M1 macrophage phenotype. Th1 effector cells characteristically express interferon-γ and contribute to breast implant capsular contracture. ^{12 22} Th2 effector cells express IL-4 and IL-13. Th2 signaling is linked to the M2 macrophage phenotype and participates in wound repair. ²³ Th17 signaling is also proinflammatory and together with the Th1 response also contributes to capsular contracture. ^{22 23} Th17 effector T-cells are activated by IL-1 and IL-6 and express IL-17. ²³ Multiple studies both in vivo and in vitro demonstrate a correlation between Th17 signaling and capsular fibrosis ^{22 23}

Studies characterizing the inflammatory response around breast implants have compared contracted to noncontracted capsules. Contracted capsules possess greater numbers of macrophages and T-cell infiltrates at the implant interface and collections of T cells around the capsule vasculature. ^{12 24} Th1/Th17 T cells dominate the T-cell population in contracted capsules compared with noncontracted capsules and express greater levels of the cytokines TGF-β, IL-1, IL-6, and IL-17. ^{22 23} Although these data are key to our fundamental understanding of capsular contracture, they fail to address other variables that clinically impact the rate of capsular contracture including plane of insertion, implant texture, ADM placement, or associated biofilm.

The clinical observation that breast implant insertion plane impacts capsular contracture rates could be mediated by differences in periprosthetic inflammation dependent on the tissue type adjacent to the breast implant. An early study describes more macrophages present in capsules adjacent to breast gland compared with muscle. ²⁴ Limited other data exist directly comparing the specific inflammatory response in the breast implant capsule based on adjacent tissue type. However, capsule adjacent to ADM compared with capsule against muscle in the same breast shows significantly reduced inflammation and cellularity in capsule against ADM. ^{25 26 27 28} This, coupled with the fact that ADM appears to reduce capsular contracture, raises the possibility that adjacent tissues drive periprosthetic inflammation, and that ADM shields the implant from this inflammatory response. ^{8 9} Another plane-specific consideration is that breast parenchyma also possesses low levels of bacterial colonization. ²⁹ This could activate innate immunity at the implant interface more than muscle and would be consistent with the increased capsular contracture rate observed in subglandular breast augmentation. ^{3 5 30} Collectively, these data all suggest that the adjacent tissue type could locally direct periprosthetic inflammation, which could in turn explain the difference in capsular contracture observed clinically based on implant insertion plane.

Despite advances in the understanding of inflammation in breast implant capsules, the inflammatory impact of adjacent tissues remain a significant gap in knowledge. The specific M1 and M2 innate immune responses and Th1/Th2/Th17 adaptive immune responses along with their associated cytokine expression seem to play an important role in the development of breast implant capsule and associated contracture. Further characterization of these inflammatory patterns will provide additional fundamental understanding of breast implant capsule development and the etiology of capsular contracture; these findings could potentially direct targeted surgical management of capsular contracture and facilitate bioengineering of increasingly biocompatible materials.

Etiology of Capsular Contracture

Two main theories have been proposed to explain the development of a capsular contracture:

1. Subclinical bacterial infection/biofilm.

2. Chronic inflammation.

Subclinical Bacterial Infection/Biofilm

Early studies showed an association between subacute periprosthetic infections and capsular contracture through cultures obtained in open capsulotomy patients. ^{31 32 33} Multiple species of bacteria have been shown to possibly lead to capsular contracture including Propionibacterium acnes , E. coli , Staphylococcus epidermis , and others. ^{34 35} The most common detected bacteria were Staphylococcus spp. , in particular Staphylococcus epidermidis. Subsequently, once a link between periprosthetic fibrosis and infection was established, capsular contracture rates decreased owing to the introduction of antimicrobial washes of the implant and the breast pocket. ^{35 36} This has changed practice, with surgeons now routinely using either a triple-antibiotic solution or a povidone-based solution to wash the implant and irrigate the pocket preimplantation. ³⁴ Antimicrobial precautions have advanced and continue to dominate the literature in terms of optimum prevention strategies. ³⁷

The underlying pathophysiology of this theory states that in response to a biofilm, persistent inflammation occurs at the interface of the capsule and implant. Biofilm is a latent bacterial subclinical infection, resistant to typical antimicrobials, and capable of eliciting a very robust immune response. By definition, a biofilm is composed of microbes adherent to a surface living within an extracellular polymeric substance and demonstrate antibiotic recalcitrance despite known susceptibility. ³⁶ Bacteria adhere to breast implants in a sessile state, and consequently often do not grow in culture. ³⁶ This likely results in under-reporting of the contribution of bacterial infection to capsular contracture since these subclinical biofilms often go undiagnosed.

Breast implants are primed to allow for biofilm deposition. ^{38 39} Biofilms have been shown to adhere to breast implants more easily due to the hydrophilic nature of the implant, large surface area (which is further increased with textured implants), and diminished host response due to surgery. ^{39 40} One study inoculated porcine model implants with Staphylococcus epidermidis and demonstrated that the inoculated pockets were strongly associated with biofilm and capsular contracture. ¹⁵ As the body tries to eliminate the pathogens through continued inflammatory expression, macrophages and lymphocytes secrete proinflammatory mediators and proteases. This cycle perpetuates creating a milieu for ongoing inflammation and fibrosis of the periprosthetic capsule.

Chronic Inflammation

Another leading hypothesis for the development of capsular contracture centers on chronic inflammation in a manner analogous to a hypertrophic scarring. In certain situations, there exist increased levels of proinflammatory mediators in the periprosthetic capsule that drive fibrosis. Hematoma or increase in residual blood in the pocket represents a powerful medium for bacterial growth and also have been shown to carry a very high concentration of proinflammatory cytokines. ⁴¹ This could occur acutely from surgical dissection or in rare cases after erosion of vessels in the capsule. ^{41 42} Accordingly, clinical observations reveal a link between hematoma and capsular contracture formation. ⁴² Furthermore, seroma and pocket infection likewise increase the risk of capsular contracture via a similar mechanism. Residual seroma fluid, rich in inflammatory mediators, can also predispose to bacterial infection and biofilm formation. ⁴³ Similarly, silicone present in the capsular space also promote inflammation. In older generations of breast implants, silicone bleeding was much more common than with today's cohesive gels. As such, silicone bleeding and rupture correlated with increased rates of capsular contracture due to an increased inflammatory response. ⁴⁴ While newer generations of breast implants shed less silicone than previous generations, evidence exists showing residual silicone in capsule biopsies. ⁴⁴ Lastly, there is some discussion that patients prone to hypertrophic scars (keloids and hypertrophic scars) may also increase their risk of developing a capsular contracture. ⁴¹ These patients often have an increased circulating proinflammatory cytokines and thus can continue to mount an exaggerated immune response.

Radiation

Another factor contributing to capsular contracture is post-mastectomy radiation therapy (PMRT). In addition to inducing contracture of the capsule, PMRT also contributes to fibrosis of the surrounding tissues. A higher rate of capsular contracture was found in response to PMRT in both prepectoral and subpectoral breast reconstruction; prepectoral patients receiving PMRT had a 16.1% incidence of capsular contracture compared with 3.5% of patients who did not while in subpectoral breast reconstruction 52.2% of patients receiving PMRT developed capsular contracture versus 3.5% of patients who did not. ³

PMRT in subpectoral reconstruction causes scarring of the pectoralis major muscle, which culminates in increased pain, implant displacement, and a higher rate of capsular contracture. ^{45 46} However, prepectoral implant placement leaves the pectoralis major in its anatomical position under the implant. As a result, any scarring or fibrotic changes within the muscle will occur under the device culminating in reduced contracture of the capsule overlying the implant. Patients undergoing subpectoral breast reconstruction with PMRT have been shown to have a capsular contracture rate three-times higher, and more severe (Baker grades III–IV), than patients undergoing prepectoral breast reconstruction with PMRT. ³

Histological studies have demonstrated significantly greater elastin and total cellular infiltrates in native capsules following PMRT, with little difference in collagen content and α-smooth muscle actin staining than nonirradiated counterparts. ⁴⁷ Additionally, radiation changes may cumulate in indurated and fibrotic skin and aberrant pectoralis attachments, which must be differentiated from capsular contracture. ⁴⁶

Clinical Implications of Capsular Contracture

Classification

Capsular contracture exists on a spectrum. Given the progressive multifactorial etiology of capsular contracture, each patient may experience the capsule differently. In some cases, severe capsular contracture case may present as a hardened, distorted, and painful breast. However, it is possible that none or all of these symptoms may be present. Capsular contracture, as one review article mentions, has become a generic term for the collation of capsule-related complaints. To help objectify and grade the severity, both the Baker and then Baker-Spear classifications were created. ^{48 49}

Baker Classification Augmentation

• Grade I: the breast is normally soft and looks natural.

• Grade II: the breast is a little firm but looks normal.

• Grade III: the breast is firm and looks abnormal (visible distortion).

• Grade IV: the breast is hard, painful, and looks abnormal (greater distortion).

Baker-Spear Classification Reconstruction

• Class IA: Soft, nonvisible implant.

• Class IB: Soft but visible implant.

• Class II: Implant with mild firmness.

• Class III: Implant with moderate firmness.

• Class IV: Excessively firm and symptomatic breast.

The grading systems mentioned above have sparked some controversy, especially in the reconstructive literature due to the fact that no validation studies have been performed. ⁴⁸ One study which utilized two independent plastic surgeons found that the interobserver reliability of the Baker grading scale is quite poor. ⁴⁸ This is likely due to the broad spectrum of clinical presentations associated with each strata of the classification. For example, one patient with bilateral firm breasts without pain and distortion might be quite pleased with her results and can be graded a Baker III. ⁴⁸ However, another might have mild contracture surrounding her implants, or a Baker II classification, and be dissatisfied with the result.

Other grading scales have been proposed; however, they attempt to objectify the grading. One example utilized applanation tonometry to identify the pressure of the capsule. ⁵⁰ One study looked at magnetic resonance imaging and ultrasound evaluation of breasts to determine if capsular thickness correlated with Baker classification. ⁵¹ Although in this study it did show a correlation, patients with thin capsules may present with severe distortion and vice versa. Additionally, there are some mimickers of capsular contracture, such as a fibrotic muscle, overfilled saline implant, and possibly newly highly cohesive form-stable gel implants. While these classifications attempt to describe the severity of capsular contracture, surgeons should only intervene if the patient is truly bothered by the result.

Factors Contributing to Capsular Contracture

There are many measures taken at different steps of the surgical procedure to limit the risk of capsular contracture. These all attempt to minimize risk of bacterial contamination and subsequent periprosthetic inflammation.

Preoperative Preparation

First, to limit bacterial contamination, extra care should be taken, and elimination of contamination sources must be done. Preoperatively patients should be screened for methicillin-resistant Staphylococcus aureus (MRSA). If the patient is a carrier, they should undergo 5-day course of topical mupirocin and daily chlorhexidine body scrubs. All patients should also receive a chlorhexidine scrub the night prior to surgery. Immediately preoperatively, patients should be prepped and draped in the usual fashion using chlorhexidine prep and nipple shields should be placed to avoid contamination with the ducts, and preoperative prophylactic antibiotics should be administered. ⁵²

Surgical Technique

Surgical technique correlates with rates of capsular contracture. Optimization of incision location, plane of implant insertion, and manipulation of the implant are all linked to variability in the incidence of periprosthetic fibrosis.

During breast augmentation, an inframammary incision results in lower rates of capsular contracture compared with a periareolar incision. This is due to the fact that it avoids the nipple areolar complex and dissection through the breast gland, which harbors endogenous bacterial colonization. ⁵³ One meta-analysis demonstrated a significantly higher rate of capsular contracture in periareolar incisions compared with inframammary incisions (odds ratio, 1.91; 95% confidence interval, 1.06–3.43, p  = 0.03). ⁵⁴

The decision to place the implant under the gland or pectoralis muscle also impact the development of capsular contracture. While other clinical considerations exist to direct the plane of insertion, these should be weighed against the risk of capsular contracture. The most recent meta-analyses and systematic reviews of the literature show that 1.9% of patients with submuscular implants and 9.6% of patients with subglandular implants develop capsular fibrosis. ^{4 6} In contrast, during breast reconstruction submuscular implant poses a greater risk of capsular contracture, affecting up to 8.7% of patients with prepectoral reconstruction with ADM and up to 13.9% of patients with subpectoral reconstruction. ^{5 6}

Intraoperative maneuvers and manipulation of the breast implant can also reduce the risk of capsular contracture by utilizing the “14-point plan. ^{55 56 57} Steps 1 to 7 have already been described, and they include administering proper prophylactic antibiotics, avoiding periareolar incisions, using nipple shields, atraumatic dissection of a subpectoral pocket, meticulous hemostasis, and utilization of a triple antibiotic solution on the implant and breast pocket.

The remaining steps focus on minimizing time of implant opening, changing surgical gloves, cleaning instruments. By using a funnel or barrier device while inserting the implant, the surgeon will decrease the chance of bacterial colonization of the device. One study evaluated how using the Keller funnel could affect capsular contracture through a peri areolar incision and found that it significantly decreased capsular contracture by 87%. ⁵⁸ Another study using the Keller funnel with an IMF incision found a 54% decrease; however, the rates of capsular contracture were already low at 1.49% without the funnel and 0.86% with the funnel. ⁵⁹

Pocket irrigation with an antimicrobial solution has taken importance in the literature. There has been much debate over the optimal solution for irrigation. The original gold standard, Adams' Triple Antibiotic solution, contains 1 g of cefazolin, 80 mg of gentamicin, 50,000 IU of bacitracin, and 500 mL of normal saline. ⁵⁷ However, newer in vitro studies have found that povidone–iodine only or povidone–iodine containing triple-antibiotic solutions are more effective at significantly decreasing planktonic species and biofilm production. ^{60 61} In addition to irrigating the breast implant pocket, these solutions can also be injected into the implant packaging to address potential bacterial attraction due to an electrostatic charge imparted on opening the sterile package. ³⁵

Layered closure of the incision must be performed to prevent implant exposure or inadvertent contamination. Postoperative antibiotics aimed at reducing periprosthetic infections have not been shown to change the rates of capsular contracture; however, higher lever evidence is required. ⁶² Postoperative breast massage has not been proven to be an effective method for prevention. ⁶³

Additional adjuncts to the 14-point plan also offer promise to further reduce the risk of capsular fibrosis. Beyond the recommendation for meticulous hemostasis, our group has shown that topical application of transexamic acid to the breast implant pocket lowers capsular contraction rates. Following mastectomy or pocket dissection with meticulous hemostasis, we place topical TXA (3 g in 70 mL of normal saline) in the breast pocket for 5 minutes. ⁶⁴ In a nearly complete randomized controlled trial, we observe significantly reduced hematoma rates, drain output, and time to drain removal. These all collectively reduce the inflammatory burden in the periprosthetic space, which we hypothesize are the reasons for the observed reduction in capsular contracture.

Implant Factors

For patients exploring breast implant surgery, a variety of types of implants are available. The main choices include the surface texture and the material filling the implant. While use of textured implants has declined substantially owing to concerns about developing BIA-ALCL, newer micro- and nanotextured implants have recently come to market restoring this option for patients and surgeons alike. ⁶⁵ Additionally, patients may choose between silicone gel or saline-filled implants.

Regarding implant fill, there exists discrepancy in the literature comparing the capsular contracture rates between saline and silicone filled devices. For saline implants, one study demonstrated a 20.8% capsular contracture rate with saline implants, while another paper showed that the risk with saline implants was half of that with silicone implants. ^{59 66} However, the meta-analysis stating that capsular contracture rates were effectively lower in saline compared with silicone implants has been criticized due to the variability and quality of the studies included. ⁵⁹ Owing to the relative abundance of silicone implant use, the data concerning capsular contracture in these devices is more reliable but still carries some variability. Overall, the capsular contracture rate with silicone implants ranges from approximately 2 to 10%. ⁴²

Compared with smooth prostheses, textured implants lead to lower rates of capsular contracture. This may occur due to the fact that smooth implants allow for the fibroblasts within the capsule to align to the surface of the implant in a planar arrangement, readily allowing for contraction. The rationale behind the manufacturing of textured silicone implants relates to the ability of the irregular surface texture to disrupt this planar arrangement, thereby reducing the risk of capsular contracture. Smooth implants, however, are said to allow for the planar alignment of the myofibroblasts and collagen to allow for easier contraction. ⁶⁷ It has been shown that the greatest decrease in capsular contracture rates while using textured implants has been when placed in the subglandular plane. ^{68 69 70} In breast reconstruction, a systematic review and meta-analysis found no significant difference between textured and smooth devices in terms of capsular contracture, however, the risk of infection was increased in the textured group. ⁷¹

A significant reduction in the use of textured implants has occurred as plastics surgeons gained improved understanding of the link to developing BIA-ALCL. Additionally, a cohort study also suggests that in breast reconstruction patients, textured implants may be linked to a significantly higher rate of cancer recurrence. ⁷² In light of these risks and the potential benefits of textured implants, new nanotexturing has been developed in an attempt to strike a balance between risk of BIA-ALCL and capsular contracture. ⁷³ Early studies using these implants have demonstrated a high complication rate in comparison to previous generation of textured implants, but allude to a learning curve for the difference. ⁷³

Management of Capsular Contracture

Surgical Modification of the Capsule

The gold standard treatment for capsular contracture involves compete capsulectomy with site change and implant exchange; however, this procedure carries morbidity, especially in the submuscular plane, and is more difficult to perform than capsulotomy or partial capsulectomy. Open capsulotomy involves incision and release of tethered, pathologic capsule. Both techniques are associated with a variable recurrence rate ranging from 0 to 54%. ⁷⁴ Two studies comparing capsulotomy to capsulectomy found no difference in recurrence rates. ⁷⁴ There is conflicting evidence for total versus partial capsulectomy. Site change of the implant has been associated with lower capsular contracture rates when compared with capsulectomy/capsulotomy alone. ⁷⁴ Implant exchange has been shown to lower capsular contracture rates, with or without site change. Interestingly, as reported in one review article, exchange to smooth implants from textured was associated with lower capsular contracture rates. Wan and Rohrich, after reviewing the evidence found no conclusive evidence to support the reported gold standard of capsulectomy and site change. ⁸

Acellular Dermal Matrix

Insertion of ADM following capsulectomy for treatment of capsular contracture has emerged as a promising therapy to reduce recurrence. ⁷⁵ ADM was originally used in breast reconstruction as an integrative regenerative tissue matrix to help facilitate and expand the soft tissue envelope of the mastectomy. In its first uses in breast reconstruction, it served as an inferior pole sling attached to the pectoralis, thus, obviating the need for rectus and serratus fascia to be raised. In one study evaluating the use of direct-to-implant breast reconstruction in the subpectoral plane with an ADM sling, the authors found an incidence of capsular contracture of 4%. ⁷⁶

ADM is thought to inhibit the development of capsular contracture via two mechanisms: (1) by impeding interaction of cells and inflammatory mediators from the adjacent tissues with the implant surface, and (2) by effectively forming an island within the surrounding capsule, thus interfering with the centripetal contractions of the neighboring capsular tissue. The effects of ADM on capsule formation have been studied in animal models that demonstrated that implants with ADM exhibited less thick capsule formation. ⁷⁷ Concerning breast augmentation, a recent study by Hidalgo and Weinstein demonstrated that the use of ADM in select cases successfully treated capsular contracture in over 85% of the patients. ⁹ Several studies evaluating subpectoral reconstruction showed decreased capsular contracture rates with the use of ADM compared with or without-ADM. ⁷⁷ In prepectoral breast reconstruction, one review compared capsular contracture data with and without ADM and found that ADM significantly reduced capsular contracture. ⁷⁸ However, the studies that did not use ADM were all performed with older generation implants, thinner mastectomy flaps, and lack of understanding of capsular contracture prevention strategies. ⁷⁸ Moreover, in the reconstructive procedures, ADM is predominantly placed at the first stage with tissue expander placement. Capsulotomies are then performed at the second stage, which also address capsular contracture at that time. Another recent review compared all surgical meshes (synthetic, xenograft, and allograft) and found that there was a decrease in capsular contracture compared with historic no-mesh prepectoral reconstructions; however, no subgroup analysis was performed comparing nonregenerative tissue matrices. ⁷⁹ It must be noted, however, that ADM does increase the risk of seroma, pocket infection, and cost of the procedure. ⁸⁰ Further high-quality studies are required to more accurately measure the effectiveness of ADM in reducing capsular contracture.

Experimental/Medical Preventions

Based on the role that inflammation is thought to play in capsular contracture development, multiple experimental medications have been studied. Pirfenidone, as an antifibrotic and anti-inflammatory drug has been investigated and found a reduction of capsular contracture by modulating TGF-beta levels. ⁸¹ This was shown to decrease severity of existing capsule and continued its effect after medication discontinuation. Leukotriene antagonists have also been studied as a prevention and treatment for capsular contracture. A recent meta-analysis demonstrated that leukotriene antagonists (montelukast and zafirlukast) have significant effects in treating and preventing capsular contracture. ⁸² Of note, leukotriene antagonists are known for their possible liver toxicity and must be monitored. Myofibroblasts have been found to express estrogen receptors, which can be modulated with the administration of antiestrogenic medications. One study sampled capsules of women who underwent breast reconstruction and found a higher incidence of grade III-IV contractures in patients who did not have antiestrogenic therapy ( p  < 0.001), suggesting that estrogen suppression could work to decrease capsular contracture. ⁸³ Additionally, studies in animal models suggest that various medications such as Vitamin E, colchicine, botox, chitosan, collagenases, omega 3, and doxycycline could potentially be used to prevent the development of capsular contracture. ^{84 85 86 87 88 89 90} Despite the promise of these experimental therapies, most have not yet been explored in human trials. Continued investigations into novel therapies such as those described here are exciting and could help to substantially improve biologic response to implants and in turn reduce morbidity associated with periprosthetic fibrosis.

Conclusion

In conclusion, understanding the pathophysiology of capsular contracture is of paramount importance to continue to improve surgical and aesthetic outcomes. Sustained periprosthetic inflammation causes increased scarring and possible contraction/distortion. Continued research into the precise mechanisms underlying the etiology of capsular contracture and the source of inflammation will allow us to better explain why some patients experience capsular contracture while others do not, and also to develop novel medical, surgical, and biomaterial strategies to improve biocompatibility of breast implants.