Evidence for the Use of Acellular Dermal Matrix in Implant-Based Breast Reconstruction

Abstract

Acellular dermal matrices (ADMs) are tissue grafts that have been specially processed to remove all cellular components. These machined biological scaffolds have become popular in a variety of surgical settings due to their rapid incorporation into living tissue. As ADMs are highly malleable and cause minimal inflammation, they have come to serve as a useful tool in implant-based breast reconstruction procedures. The major benefits of using an ADM in this setting include superior initial breast contouring, decreased risk of capsular contracture after implant insertion, and consistent sustained positioning of the reconstructed breast. Despite these advantages, these tissue grafts are foreign to the host, and postoperative complications following ADM insertion, including infection and seroma, have been well documented. When considering using ADMs in this setting, it is important to first consider patient-specific factors that could preclude their use, such as low body mass index, small breasts, or a history of radiation exposure to the breast tissue. ADM grafts are also expensive, which may present another barrier to their use. Review of the literature ultimately suggests a continued role for ADMs in implant-based breast reconstruction, and continued research in this field is warranted.

An acellular dermal matrix (ADM) is a processed tissue graft created from either donated human cadaveric tissue or animal skin tissue. To create a graft, donated tissue goes through a series of steps to be decellularized. What remains is a tissue matrix comprised only of the supporting structures of the original material—the basement membrane, cellular matrix, and bundled collagen fibers. ^{1 2} The ADM can then be implanted in a manner that delivers minimal risk and optimal strength; the cellular components that typically cause graft rejection or a nidus for infection have been removed, while the support structure that remains facilitates efficient incorporation of transplanted tissue at the recipient site. ^{1 2} ADMs act as biological scaffold, promoting angiogenesis and allowing for accelerated tissue ingrowth and cellular repopulation, thus inducing tissue regeneration. ¹ Given their regenerative capabilities, ADMs were first utilized in 1992 as a dermal substitute for the treatment of severe burns. They have also been described and applied as a soft-tissue replacement option, and they were first associated with breast reconstruction when used as a mesh to reinforce the fascial defect following TRAM flap breast reconstruction. ³ ADMs have since been utilized with increasing frequency in the field of breast surgery, and they have proven to be useful in the setting of tissue expander and implant placement during primary breast reconstruction. ⁴

The utilization of breast reconstruction surgery has increased over the last two decades. In 2017, the American Cancer Society estimated that 252,710 new cases of invasive breast cancer would be diagnosed, ⁵ and that there would be a total of 3.1 million living breast cancer survivors in the United States. ⁶ Mastectomy, both unilateral and bilateral, has become an increasingly common management approach to treat breast cancer over the past decade. ^{7 8} Of those patients who elect treatment with mastectomy, approximately 70% will subsequently undergo implant-based reconstruction. ⁹ Given these trends, there has been a 39% increase in breast reconstruction procedural volume since 2000, with 109,256 breast reconstruction procedures occurring in 2016 alone. ^{5 10} Of these, tissue expander followed by implant reconstruction accounted for 79,019 cases, and 58,310 breast reconstructive procedures utilized ADMs. ¹⁰

The traditional immediate two-stage implant-based breast reconstruction entails placement of a tissue expander in a total submuscular pocket. Placement under the pectoralis muscle provides vascularized tissue layer between the tissue expander and the mastectomy flap, which protects against mastectomy flap necrosis. While this reconstructive option is a current mainstay of treatment, its limitations include lack of lower pole and inferolateral breast expansion, increased time for subsequent expansion, increased pain experienced upon expansion, and, commonly, reoperative pocket modification at a later date. ¹⁰ These limitations presented a need for innovation which ADMs have, at least in part, been utilized to fill. ADMs are widely used in immediate direct-to-implant postmastectomy breast reconstruction as reliable, time-efficient, and potentially less expensive alternatives to tissue expander–implants and free flap surgeries. ¹

In a submuscular approach, ADM-assisted reconstruction involves suturing an ADM graft between the inferior border of the surgically released pectoralis major muscle and the inframammary fold to provide support and coverage of the implant in the lower pole of the breast. ⁷ This placement secures the expander or implant securely under the pectoralis muscle and allows for intraoperative contour shaping. In addition to decreasing the morbidity associated with complete submuscular pocket dissection, the properties of the ADMs allow for incorporation of the allograft to the native skin with minimal fibrosis or contracture. Moreover, the high tensile strength and low elasticity of the graft allow for pressure that accumulates during insert expansion to be applied to the graft rather than directly to the patient's healing mastectomy flaps.

Acellular Dermal Matrices Available for Use

A variety of ADM products are available on the market ( Table 1 ). AlloDerm (Allergan, distributed by BioHorizons) is the most popular ADM overall, largely due to the abundance of research and evidence reporting favorable outcomes with its use. ¹¹ For instance, in a head-to-head comparison between AlloMax (Bard Davol Inc.) and AlloDerm in a murine model, AlloDerm grafts had superior neovascularization, tissue infiltration, fibroblast proliferation, and inflammatory reaction when compared with AlloMax. ¹² ADM selection is also influenced by the compiled historical experience from myriad reconstructive surgeons. Other than familiarity with the product, however, there are several differences between products that require consideration before utilizing them in surgery. These considerations include, but are not limited to, the following: original species source of the graft, treatments used to prepare the graft to which the patient may be sensitive (e.g., antibiotic exposure), the process by which the matrix was sterilized (or are only made “aseptic”), and the product's shelf life. Intraoperatively, the surgeon should also consider product-specific preparation time and note that some ADMs require specific orientation, and particular care will need to be taken to recognize the substrate's polarity during grafting. These relative pros and cons provide comparison points when deciding between products, and they are succinctly summarized in Table 1 , which was adapted from Cheng and Saint-Cyr. ¹¹ Generally, the human-based products have been found to cause less inflammation when utilized intraoperatively than porcine or bovine grafts. ¹¹ Additionally, newer ADMs need less rehydration before use than older ADM designs.

Table 1. Summary of the characteristics, prices, and considerations for acellular dermal matrices and their alternatives.

Product	AlloDerm Ready to Use	AlloDerm	AlloMax (Neoform)	DermACELL	DermaMatrix	Flex HD	Permacol	Seri Scaffold	Strattice	SurgiMend PRS	Veritas	Vicryl Mesh
Type	Biologic	Biologic	Biologic	Biologic	Biologic	Biologic	Biologic	Synthetic	Biologic	Biologic	Biologic	Synthetic
Manufacturer	Allergan	Allergan	Bard/Davol	Stryker	MTF/Synthes	MTF/Synthes	Medtronic	Allergan	Allergan	Integra	Baxter	Ethicon
Source	Human	Human	Human	Human	Human	Human	Porcine	Purified silk	Porcine	Fetal bovine	Fetal bovine pericardium	Synthetic (polyglactin 910)
Preparation	Rinse in NS or LR	2 baths of warm NS or LR	Room temp. NS	None	Room temp. NS or LR	None	None	Room temp. NS or LR	Room temp. NS or LR	Room temp. NS	None	None
Prep. time	2 min	10–40 min	3 min	None	<3 min	None	None		2 min	60 s	None	None
Sterility	Yes	No	Yes	No	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Orientation	Yes	Yes	No	Yes	Yes	Yes	No	No	No	No	No	No
Shelf life	2 y	2 y	5 y	2 y	3 y	3 y	3 y	3 y	18 mo	3 y	3 y	–
Approximate price per cm 2 a	–	$28	–	$34	28.51–$31.94	$27.31–$34.76	21.63	–	$24.65–$30.76	$23	–	–
Key considerations	Short prep time	Well studied, recognized by insurance	Short prep time, only sterile human ADM, long shelf life	Cost	Short prep time, multiple thicknesses	Cost	Nonhuman	Short prep time, cannot use if silk allergy	Short prep time, nonhuman, short shelf life	Short prep time, nonhuman	Short prep time, nonhuman	Short prep time

Abbreviations: LR, lactated Ringer's solution; MTF, musculoskeletal transplant foundation; NS, normal saline.

^a Cheng and Saint-Cyr. ¹²

Advantages of Acellular Dermal Matrix Use

One advantage of performing ADM-assisted breast reconstruction is the documented decrease in postoperative capsular contracture (CC) rates. ^{12 13 14 15} To definitively measure the effect of ADM use on CC, Salzberg et al published a report summarizing their experience over 13 years with patients who underwent ADM utilization in direct-to-implant exchange. With a mean follow-up time of 4.7 years, they reported a CC rate of 0.8%, all of which occurred within the first 2 years postoperatively. ¹⁶ These findings suggest that CC is a relatively early event in the postoperative course of ADM-assisted breast reconstructions, and it does not appear to progress after approximately 2 years since operation. A separate meta-analysis of studies over the past decade further supports the finding of ADM-associated decreased CC rates, citing the incidence of CC with ADMs at 0.6% by a pooled analysis of 16 studies. This is a 3- to 40-fold lower incidence than the CC rates reported in the literature following traditional breast implantation, which range from 3 to 25%. ¹⁶ Of note, the rate of CC associated with silicone implants typically reported in the breast augmentation literature is cited around 15%. ¹⁷ Importantly, though, ADM use does not necessarily prevent CC; it has been found that smaller implants (< 400 mL) and postoperative irradiation are both greater predictors than ADM use for the development of CC. ¹⁶

It is hypothesized that these lower CC rates are the result of decreased inflammation. ¹⁸ Basic science research supports this theory; in vitro, AlloDerm has been shown to decrease production of interleukin (IL)-1B, IL-6, IL-8, and vascular endothelial growth factor from mononuclear cells. ¹⁹ Histological studies have been performed to further characterize the local tissue capsular response after use of ADM in the setting of breast reconstruction surgery. One study using Matracell (LifeNet Health) decellularized regenerative matrix examined capsule samples at the time of second-stage reconstruction. Capsules showed less inflammation and less fibrosis in samples containing ADMs compared with samples without ADMs. In this study, the reading pathologists were blinded, which lends additional credibility to these findings. ²⁰ Leong et al further supported the theory that ADMs limit capsular formation by showing decreased inflammatory changes, fibroblast activity, collagen I deposition, and capsular fibrosis in AlloDerm capsule samples. ²¹

Besides the benefits of decreased incidence of CC, ADM-based approaches also provide superior control of inframammary fold positioning compared with alternative techniques. Vardanian et al reported that ADM-based immediate breast reconstruction had a trend toward fewer inframammary fold–related postoperative concerns, but the noted difference was not statistically significant. ²² The explanation of this finding is multifactorial. First, the interposition of an ADM reduces musculofascial dissection, as there is little to no need to elevate the serratus anterior or rectus abdominus muscle fascia. Second, compared with reconstruction without ADM, ADM use in immediate breast reconstruction provides for greater initial fill volumes of implants, which in turn reduces the number of the subsequent fills necessary to optimize volume as well as decreases the overall duration of time to maximum tissue expansion. ^{1 4 23 24 25 26 27}

This decreased “return to normal appearance time” is advantageous, as it has been linked to psychological benefit for the patient. Specifically, a prospective study showed that immediate breast reconstruction after mastectomy had a protective effect in patients, as they experienced a decreased period of psychosocial distress, poor body image, and diminished sexual well-being compared with those waiting for delayed breast reconstrution. ²⁸ For greater detail, a review of ADM's perceived advantages in prosthetic breast reconstruction was published by JoAnna Nguyen et al, ²⁹ who synthesized the levels of supporting evidence for each purported advantage. ^{4 25 26 30 31 32 33 34 35 36 37 38}

Disadvantages of Acellular Dermal Matrix Use

Clear benefit has been established for the use of ADMs in breast reconstruction surgery. However, with their increasing popularity and incorporation into surgical practice, disadvantages of ADMs have also been observed. The incidence of postoperative complications with ADM use has been debated in the literature. In 2013, Davila et al conducted a multivariate analysis of short-term complications, comparing ADM-based breast reconstruction to submuscular tissue expander–based breast reconstruction. They found that the total complications and reconstruction-related complications were similar between the two cohorts (5.5 vs. 5.3%, p  = 0.68 and 4.7 vs. 4.3%, p  = 0.39, respectively). ³⁹ However, this finding was called into question in 2015 when Zhao et al conducted a meta-analysis comparing postoperative complications of tissue expander/implant breast reconstruction using ADMs to complications in studies without ADM use. They found that incorporation of ADMs increased the incidence of overall complications (odds ratio [OR]: 1.33 compared with control), hematoma/seroma formation (OR: 1.66), and infection (OR: 1.47). ⁴⁰ Exact rate of seroma formation following ADM use was then quantified in 2010, with rates of 14.1 versus 2.7% reported when comparing ADM to non-ADM breast reconstruction, respectively. ²⁶ Similarly, the same study showed the rates of infection after ADM use to be 8.9 versus 2.1% for those patients who did not receive ADM. ²⁶ However, in 2011, a separate retrospective review of 331 patients reported only a 1.5% seroma rate and a 3.0% infection rate following immediate single-stage implant reconstructions with ADM. ⁴¹ An additional 2011 study of 470 total patients reported a 6.9% overall wound infection rate in the ADM cohort compared with 2.5% in the non-ADM cohort, but the difference was not statistically significant. ⁴²

In 2015, Selber et al performed a critical evaluation of risk factors and early complications in over 500 two-stage implant-based breast reconstructions using ADMs. This study found that the strongest independent predictor of seroma was obesity; the use of ADM only became predictive of seroma when larger pieces were used. Selber et al also compared outcomes between the human and bovine ADMs and found no statistically significant differences in complications including tissue expander explantation, seroma, infection, and mastectomy skin flap necrosis when analyzing both products. ⁴³

The large variance (range, 3.2–48.7%) in total complication profiles reported throughout the literature triggered Kim et al to perform a meta-analysis in 2015 of complications of human ADMs and submuscular tissue expanders for breast reconstruction. They showed an increased rate of total complications, seroma, infection, and flap necrosis in cases using human ADMs when compared with submuscular reconstructions. While rates of hematoma were found to be greater in the submuscular cohort, the rate of reconstructive failure was comparable in both cohorts. ⁴⁴

Lee et al also performed a meta-analysis of 23 studies comparing the outcome of ADM use with traditional submuscular technique from 2011 to 2014. They claimed that systematic reviews published prior to 2011 were conducted during a relatively early, experimental period, since ADM was introduced in implant-based reconstruction in 2005. By analyzing publications only after 2011, the aim of their study was to demonstrate outcome data for ADM use during a time when refined surgical techniques were consistently being applied. Previously published studies had shown significantly increased risks of infection (relative risk [RR]: 1.42), seroma (RR: 1.41), and mastectomy flap necrosis (RR: 1.44) with ADM use compared with no ADM use. In their study, Lee et al reported significantly enhanced risks of infection and seroma with ADM use. Their study also reinforced the benefit of decreased CC (RR: 0.26) and decreased implant malposition (RR: 0.21) with ADM use. In contradiction of earlier reviews that had shown a nonsignificant trend toward increased risk of necrotic complications and implant loss in the ADM group compared with the non-ADM group, their study results suggested that the risk of implant loss was not significantly affected by ADM use. They concluded that although the use of ADMs increases the overall risk of complications, surgical refinement of ADM implantation has made it so that these complications can often be controlled without implant removal. ⁴⁵

Cost Analysis

A more practical consideration when choosing between ADMs for use in breast reconstruction is cost. For private payers, this may be less of a factor, but different insurance plans can fluctuate widely when determining the patient cost of different ADMs. Permacol (Medtronic) is the cheapest ADM listed for use at 21.63 USD/cm ² , and DermACELL (Stryker) is the most expensive at 34.00 USD/cm ² . The remaining price points are similar to that of AlloDerm, which has a listing price of 28.00 USD/cm ² . ADM prices are compared in Table 1 , which provides a practical comparison of different ADMs available in the marketplace. ¹¹

Serrurier et al argued that using ADMs for direct-to-implant breast reconstruction may potentially simplify the procedure, but would not necessarily be associated with decreased complications or a better cosmetic outcome, and would come with an increased overall cost of procedure ranging from 35.5 to 47.7%. They recognize that breast reconstruction is more challenging without the use of ADM for lower pole support, but once the technique is mastered without ADM use, then it can be quicker and more cost-effective than using any other form of lower pole support. They also point out that many novel products are likely to be unaffordable in low- and middle-income countries. ⁴⁶

Polyglactin 910, or Vicryl mesh, has been researched as a lower-cost alternative to ADMs that would serve the same purpose during surgery. Rodriguez-Unda et al conducted a systematic review in 2015 and concluded that Polyglactin 910 is both safe and effective. When compared with ADMs, Polyglactin 910 has been found to be approximately 10 times less expensive than ADMs on the market, and this material has also been shown to have lower complication rates when compared with those associated with ADMs. ⁴⁷ Specifically, rates of infection following utilization of Polyglactin 910 for general surgical purposes, including hernia repair, were reported at 2.6%, with a rate of reconstruction failure reported at 3.2% and rate of seroma formation reported at 1.3%. In a study of 38 patients who utilized Vicryl mesh in the setting of breast reconstruction, rates of infection were 2.6% for nonirradiated patients and 37.5% for irradiated patients. ⁴⁸ This study concluded that ADMs may be superior to Vicryl mesh in the irradiated population, but Vicryl mesh may provide a more cost-effective alternative for nonirradiated patients. No studies to date, however, have directly compared outcomes in breast reconstruction utilizing Polyglactin 910 versus ADMs.

The decision to forego utilization of ADM in breast reconstruction surgery may be appropriate for certain patients and conditions. In 2014, Jordan et al designed an algorithmic approach for the selective use of ADMs in two-stage breast reconstruction that incorporated the patient's body mass index (BMI), breast size, radiation history, and intraoperative factors such as sentinel lymph node biopsy results, pectoralis integrity/width, and flap vascularity. All of these variables were taken into account in their creation of a decision-making tool to help guide the use of ADM in the reconstructive surgery ( Fig. 1 ). ⁴⁹ Preoperatively, their model suggests that radiation history should be considered a contraindication to ADM use, while postoperative radiation should not. Independently, patients with a low BMI and small breasts should also not receive ADMs. Barring these clear contraindications, they advise that the decision to use ADMs should be left to the physician's discretion, except in patients with a high BMI and large breasts, who the authors proposed had a clear positive indication for ADM use during the reconstruction. Intraoperatively, if a sentinel lymph node biopsy was positive, then an ADM should be utilized during the reconstruction, and poor flap vascularity should disqualify ADM use. Even with good flap vascularity, if there is no relative skin excess for reconstruction, ADMs also should not be utilized. If, however, good flap vascularity is observed intraoperatively and there is an appropriate amount of skin excess available, an ADM should be considered. Final intraoperative considerations pertain to pectoralis muscle anatomy. Any time pectoralis muscle integrity is compromised during surgery; an ADM should be encouraged as part of the reconstruction if no other contraindications exist. However, if the pectoralis muscle is not compromised, the use of ADMs during reconstruction remains at the discretion of the surgeon. Similarly, an intact but small pectoralis muscle would benefit from ADM support. However, if there is an intact but large pectoralis muscle, ADM use should also be left to clinician judgment. Jordan et al implemented these decision-making principles in a 372-person prospective cohort study. They found that adopting this selective decision-making algorithm to guide ADM use in breast reconstruction resulted in a 48% reduction in the use of ADMs in inappropriate circumstances. This judicious ADM use resulted in substantial cost savings without significantly impacting surgical outcomes, including incidence of infection, seroma, flap necrosis, explantation, or aesthetic scores. ⁴⁹

Fig. 1.

Flowchart describing an algorithmic approach for the selective use of acellular dermal matrices in two-stage breast reconstruction.

Final Considerations

Considerations of other postoperative sequelae following ADM implantation have also been measured. McCarthy et al conducted a multicenter, blinded, randomized controlled trial designed to evaluate the effectiveness of ADM in the setting of tissue expander/implant reconstruction, specifically investigating the effects of ADM use on postoperative pain experienced by patients. ⁵⁰ No differences were seen in postoperative pain compared with controls ( p  = 0.19). There was similarly no difference in postoperative narcotic use in either cohort ( p  = 0.38).

It is important to consider the effects of conflicts of interest (COI) on the reported literature currently available. In 2014, Lopez et al investigated the impact of COI in plastic surgery regarding the use of ADMs in implant-based breast reconstruction. ⁵¹ Their analysis identified 35 abstracts that represented a total of 2,852 patients in studies where the authors had a COI, and only 1,864 patients in studies where the authors had no COI. From this division alone, surgical complications were found to be less common in studies with a COI than those without COI. With this in mind, and given the conflicting data reported in this field to date, future ADM studies should consider using COI in their exclusion criteria to ensure that reported results are as accurate as possible.

Conclusion

As reconstructive breast surgery techniques continue to develop, expectations from both surgeons and patients are driving the field toward patient-specific approaches with the safest and most efficient reconstruction technique, the lowest morbidity, and the best aesthetic outcomes. ADMs have been shown to be useful for the precise, long-lasting placement of tissue expanders, and studies have repeatedly demonstrated that ADM use is associated with decreased CC rates. These benefits must be balanced, however, with an increased risk of infection and of overall surgical complication. Current literature supports the use of ADMs in practice, but surgeons must weigh considerations of cost and patient eligibility when deciding whether or not an ADM is indicated.