Background
Since skin- and nipple-sparing mastectomies (SSM/NSM) have proven to be oncologically
safe procedures, the number of immediate breast reconstruction (BR) procedures has
substantially increased [1 ]. With SSM and NSM, the gland
is completely removed and the skin envelope preserved, facilitating subsequent
reconstruction. Historically, BR was performed in less than 25 % of all breast
cancer (BC) patients [2 ]. Whilst autologous BR used to be
the treatment of choice, the last decade has seen a shift from autologous BR towards
implant-based breast reconstruction (IBBR), which is now used in 37 % of all BC
patients in the USA [2 ]. As the number of autologous
procedures has remained approximately the same, the increase in the number of
immediate BR procedures can be primarily attributed to an increase in
implant/expander reconstructions. Whether these data can be transferred to Germany
is debatable, as the reimbursement systems in Germany differ from those in the US.
The reimbursement of complex reconstructive procedures (pedicle and free flaps) is
not the same in the US as in Germany, and these procedures are reimbursed
proportionally less than IBBR, contributing to an increase in IBBR procedures [3 ]. Reasons for the increase in IBBR in Germany include
increasing numbers of prophylactic contralateral mastectomies, improvements in the
safety of silicone implants, a higher patient acceptance of silicone implants and
the development of new surgical procedures and products for IBBR. Compared to
autologous BR procedures, donor site morbidity has improved and the extent of
surgery required and patient morbidity have decreased [4 ], [5 ], [6 ]. With
the development of biological matrices and synthetic meshes, patients who were
initially unsuited for, or who did not desire, autologous BR can now be offered
implant-based reconstruction.
In IBBR the implant is usually placed in a sub-pectoral pocket. The pectoral muscle
serves as cover towards the maximal thinned out mastectomy flap. Implant coverage
can often be achieved only for the upper and lower medial quadrant. No tissue from
the pectoral muscle is usually available for the lower lateral part to provide
additional cover or support the implant. This can lead to increased implant
palpability with a lack of support and subsequent skin erosion. Additional coverage
can be obtained by mobilizing the serratus or the anterior layer of the rectus
muscle. But this approach involves even more trauma to native tissue and may
technically not be possible in all patients. Thin patients, in particular, have no
reserves to mobilize extra tissue at the lower lateral part where the breast is most
vulnerable. The introduction of biological matrices (acellular dermal matrix [ADM])
into breast surgery has helped to resolve surgical restrictions in IBBR by allowing
the surgeon to cover the implant even when native skin cover is insufficient. In
addition to offering additional coverage, these products help to fix the pectoralis
major muscle to the inframammary fold and stabilize the implant pocket laterally,
without destroying additional tissue. Since the first reports on the use of ADMs in
IBBR by Breuing et al., further supporting biological and synthetic materials have
been introduced. To prevent any misunderstanding, in our review we use the terms
“matrices” for biological materials and “meshes” for synthetic materials. Both
materials are used in oncological patients. The aim of this review was to give an
overview of the different materials available for IBBR in Germany and discuss their
use in clinical practice.
Approved Materials for Breast Reconstruction in Germany
In Germany, seven biological matrices and three synthetic meshes have been approved
for use in IBBR procedures. The different types and synthetic features are shown in
[Tables 1 ] and [2 ], and
the available products are discussed in more detail below.
Table 1 Overview of synthetic meshes approved for breast
reconstruction in Germany.
TiLOOP® Bra extralight
SERAGYN BR®
TIGR® Mesh (non-permanent scaffold)
n. a.: not available, cm: centimeter, mm: millimeter; N:
Newton
Material
titanium-coated polypropylene (30–50 nm)
resorbable part: polyglycol acid –
caprolacton
non-resorbable part:
polypropylene
fast resorbing fiber is a copolymer of lactide, glycolide
and trimethylene carbonate
slow-resorbing fiber is
a copolymer of lactide and trimethylene carbonate (completely
absorbed after 3 years)
Filament
monofilament
monofilament
warp-knitted polymers
Base weight (g/m2 )
16
n. a.
–
85
–
28 (resorbable within 90–120 days)
Pore size (mm)
≥ 1.0
1 at the time of implantation 1 × 2 at 4 months
–
2
–
4
Strength (mm)
0.2
0.5 (before resorption) 0.2 (after resorption)
n. a.
Filament diameter
65 µm
0.15 mm
0.51 mm
Tensile strength (grab test)
37 N/cm –
67 N/cm (before resorption) 41 N/cm (after resorption)
86.6 N/cm
Physiological elasticity at 16 N/cm
23 %
lengthwise: 14 %/crossways 50 % (before
resorption) lengthwise: 25 %/crossways 69 % (after
resorption)
7 %
Table 2 Overview of biological meshes approved for breast
reconstruction in Germany.
Strattice™
epiflex®
Permacol™
SurgiMend® PRS
ALLOMAX™
Flex HD®
DermaMatrix®
n. a.: not available, cm: centimeter, mm: millimeter, N:
Newton
Source
porcine- derived matrix (non-cross-linked)
human skin (non-cross-linked)
porcine dermal matrix (cross-linked)
fetal bovine dermal collagen (non-cross-linked)
human- derived matrix (non-cross-linked)
human allograft skin (non-cross-linked)
human skin (non-cross-linked)
Decellularization/processing
n. a.
n. a.
n. a.
n. a.
acetone, hyper/hypotonic baths, H2 O2 ,
NaOH
hypertonic bath
sodium chloride and detergent, disinfected with acidic and
antiseptic reagents
Sterilization
electron beam radiation
peracetic acid-based sterilization
gamma radiation
ethylene oxide
gamma radiation
decontamination with ethanol and peracetic acid (not terminally
sterilized)
disinfection solution
Thickness
1–2 mm
> 0.3 and > 0.8 mm
0.5–1.5 cm
0.4–0.75 and 0.75–1.54 mm
0.8–1.8 mm
0.4–0.8 mm and 0.8–1.7 mm and 1.8 mm
0.2–04 mm and 0.4–0.8 mm and 0.8–1.7 mm
and 1.7+ mm
Tensile strength (grab test)
270 N/cm
70 N/cm
66 N/cm
432 N/cm
290 N/cm
929 N/cm
146 N/cm
Physiological elasticity at 16 N/cm
9.6 %
n. a.
13.1 %
6.4 %
26.2 %
21.2 %
n. a.
Synthetic meshes
TiLOOP® Bra
The TiLOOP® Bra (pfm medical, Cologne, Germany) is the most commonly used
synthetic mesh in Germany. It is made of non-resorbable, titanized,
lightweight polypropylene (PP) with a monofilament structure ([Fig. 1 ]). Titanium coating has been found to
reduce inflammatory reaction, and there is significantly less shrinkage
compared to identical, non titanium-coated, heavyweight PP meshes [7 ]. There were only three citations for the TiLOOP®
Bra in PubMed. A single case report with histological evaluation of the
TiLOOP® Bra reported only a mild inflammatory reaction and endothelial cells
with good neovascularization [8 ]. Clinical
evaluation of a TiLOOP® Bra mesh after 2½ months showed that the
mesh fibers had embedded well in the surrounding tissue. An in vitro study
and real-time cell analysis confirmed the good biocompatibility of the
TiLOOP® Bra [9 ]. First clinical results indicate
that TiLOOP® Bra and other synthetic meshes should be predominantly used in
primary cases [10 ]. A large retrospective
multicenter study of 231 procedures revealed seroma rates of only 4.8 %, but
mesh explantation had to be performed in 7.8 %, and revisionary surgery was
needed in 13.4 % [11 ].
Fig. 1 a to j Demonstration of synthetic meshes and
biological matrices. a TiLOOP®Bra, b SERAGYN® BR,
c TIGR® Matrix, d Strattice™, e Permacol™,
f ALLOMAX™, g Epiflex®, h Surgimend® PRS,
i FLEXHD®, j DermaMatrix®.
SERAGYN® BR
The SERAGYN® BR mesh (SERAG WIESSNER, Naila, Germany) is a tightly woven,
partially resorbable mesh. The resorbable part is absorbed within 90–120
days while the non-resorbable part remains in place for additional support.
Although surgeons have reported more difficult intraoperative handling due
to its firmer characteristics, in vitro investigation and real-time cell
analysis at our institute showed that the biocompatibility of the SERAGYN®
BR mesh was similar to that of the TiLOOP® Bra [9 ]. With the exception of a summary reporting its use in 23 patients,
no clinical data are available for SERAGYN® BR [12 ].
TIGR® Matrix
TIGR® Matrix (Novus Scientific AB, Uppsala, Sweden) is a long-term resorbable
synthetic mesh. The product description “matrix” is misleading, as the term
is generally used to refer to biological products. Although, TIGR® Matrix is
completely resorbable, it was classified as a synthetic mesh in our review
because it is manufactured synthetically. After implantation, the synthetic
fibers degrade at different rates by bulk hydrolysis ([Fig. 2 ]). It provides additional support in the first six months,
and complete resorption is achieved after three years. In vivo
investigations in a three-year preclinical implantation study revealed good
biocompatibility with the formation of blood vessels and well structured
collagen fibers [13 ]. Data on TIGR® Matrix are
predominantly available for hernia surgery. No clinical data are available
with the exception of a retrospective study (LoE4) of 62 patients (112
breasts), which reported a complication rate of 19 % (10.7 % in regards to
operated breasts) [14 ]. A clinical evaluation of
this mesh is being performed at Akademikliniken in Stockholm, Sweden. Final
results are not yet available.
Fig. 2 Metabolic pathway of the TIGR® Matrix.
Biological matrices
Strattice™
Strattice™ (LifeCell Corp., Branchburg, NJ, USA) is a terminally sterilized
porcine-derived ADM denuded of antigenic cells ([Fig. 1 ]) [15 ]. A complex proprietary
process is performed to remove cells and key components believed to play an
important role in the xenogenic rejection process without destroying the
biochemical components needed for reinforcement. The Strattice™ encourages
tissue regeneration, acting like a scaffold to be repopulated and
revascularized by the host [16 ]. There are 17
citations in PubMed on the use of the Strattice™ in BR. A publication by
Spears et al. (LoE 4) investigating mainly revisionary breast surgeries
(92 %) reported an overall complication rate of 5.3 % [17 ]. Long-term studies over 3.5 years (LoE 4) in 105 BR reported
a total complication rate of 8.6 % [18 ].
Permacol™
Like Strattice™, Permacol™ is a porcine-derived collagen tissue matrix from
which cell debris, DNA and RNA are removed, leaving behind an acellular
dermal scaffold. During processing, Permacol™ is cross-linked, presumably to
increase tensile strength compared to non-cross-linked ADMs. However, the
cross-linking process changes the individual collagen strands, resulting in
a less flexible matrix. Permacol™ has been primarily used in abdominal
hernia repair, and clinical reports on its use in BR are not available.
ALLOMAX™
ALLOMAX™ (BARD, Davol Inc., Warwick, RI, USA) is a non-cross-linked,
regenerative collagen matrix derived from human dermis. During processing,
all non-collagenous cell components are removed, leaving behind a sterile
matrix of elastin fibers. The trademarked Tutoplast™ process first removes
lipids, red and white blood cells and disrupts cell membranes, using an
osmotic treatment to remove cellular components. Immunogenic formations are
removed by an oxidative treatment. In vitro, high concentrations of vascular
endothelial growth factor were found and blood vessel formation was observed
[19 ]. In vitro investigations comparing
Alloderm™ and ALLOMAX™ showed greater neovascularization, tissue
infiltration, fibroblast proliferation and inflammatory reaction for
Alloderm™. Clinical results for ALLOMAX™ are not available. ALLOMAX™ was
formerly marketed as NeoForm® (Mentor®, Santa Barbara, CA, USA). A
publication by Losken on the use of NeoForm® in 31 breasts reported no
postoperative complications and vascular integration after three months
[20 ].
Epiflex®
Epiflex® (Deutsches Institut für Zell- und Gewebeersatz [DIZG] gGmbH, Berlin,
Germany) is the only ADM approved as a drug in Europe. It is derived from
human skin and undergoes a complex decellularization process, leaving behind
a collagen matrix with low residual levels of genomic material insufficient
to provoke an immune reaction. Histological analysis showed good cell
infiltration with neoangiogenesis and tissue regeneration [21 ]. Clinical data on the use of Epiflex® in BR
are not available in PubMed. Epiflex® is identical to DermaMatrix® and
FlexHD®, and the clinical results for these products are transferable.
SurgiMend® PRS
SurgiMend® PRS (TEI, Biosciences, Inc., Boston, MA, USA) is derived from
fetal bovine dermal collagen and is rich in type III collagen. Collagen III
is prominent in embryologic development and wound healing. It is the only
biological mesh with fenestration, theoretically allowing fluid
accumulations around the implant to drain into the surrounding tissue.
Histological examination showed a decreased inflammatory response compared
to other bovine-derived matrices [22 ]. Four
months after SurgiMend® PRS implantation, adequate vascularization with CD31
positive cells was observed [23 ]. There are four
publications available in PubMed on SurgiMend®. The largest cohort reported
on in a study by Butterfield consisted of 222 patients who had immediate
IBBR with SurgiMend® [24 ]. Complication rates did
not differ from those reported for Alloderm™ reconstructions. Seromas were
the most commonly observed complications, with an incidence of 8.3 %. A
recent publication on 95 procedures using SurgiMend® described 3.2 %
hematomas, 7.5 % seromas and a re-operation rate of 2.1 % [25 ].
FlexHD®
FlexHD® (MTF/Ethicon, Inc., Somerville, NJ, USA) is an acellular hydrated
dermis derived from cadaveric human allograft skin. During sterile
processing, this matrix undergoes an aseptic process, removing the epidermis
and dermis but maintaining the extracellular matrix responsible for tissue
strength. In contrast to Epiflex®, which is deep-frozen, FlexHD® is
conserved in alcohol. The study by Orenstein et al. found an increased
inflammatory response for FlexHD® compared to Alloderm™ [26 ]. However, no difference in inflammation,
neovascularization, adhesion or fibrous tissue was observed compared to
Strattice™ [27 ]. Clinical experiences are
mentioned in only 2 publications. In one large study of 547 BR procedures in
382 consecutive women, the majority (81 %) of whom had immediate
reconstruction, no difference in complications was observed between
Alloderm™ and FlexHD® [28 ]. The overall rate of
return to the operating room was 8.6 %. Surgical site infections occurred in
9.7 %, seromas in 6.0 % and implant loss in 6.9 %. Although complication
rates were comparable, an increased risk for implant loss was seen for the
FlexHD® group in multivariate analysis (p = 0.042). In 284 BR procedures
using AlloDerm™, DermaMatrix™ or FlexHD™, no significant differences in
complication rates were observed [29 ]. In
patients without ADM reconstruction, complications rates were much lower
compared to the three ADM groups (2 vs. 10 %).
DermaMatrix®
DermaMatrix® (MTF/Synthes CMF, West Chester, PA, USA) is derived from human
skin and undergoes an equivalent manufacturing process to that of FlexHD®
during which the epidermis and dermis are removed. After implantation, cells
promoting neovascularization and fibroblast deposits infiltrate the matrix.
A retrospective study of 50 patients who had immediate expander BR using
Alloderm™ or DermaMatrix® showed a comparable overall complication rate of
4 % [30 ]. Neovascularization was similar for
Alloderm™ and DermaMatrix®.
Discussion
Biological matrices and synthetic meshes are increasingly being incorporated into
breast surgery. Many different materials are available, but it is still unclear
which material is best. The most data is available for Alloderm™, a human-derived
dermis used in the USA but not approved in Europe. Prospective randomized trials are
not available for any matrix or mesh. Use of particular matrices or meshes depends
predominately on single surgeon experiences or retrospective studies. No data is
available which would indicate that any matrix is superior to others, and the
potential increase in the number of seromas and the subsequent infections,
inflammatory reactions and cases with capsular contraction are unknown. So far, the
available publications show similar complication rates compared to IBBR without ADM
or meshes [31 ]. Complication rates range between
17.7–29.0 % for the titanium-coated mesh and 0–32 % for biological matrices, whereas
complications after IBBR without additional use of a matrix/mesh are reported to be
about 15 % [16 ], [31 ], [32 ], [33 ], [34 ], [35 ], [36 ].
Comparing individual studies results in a methodological bias which is partially
responsible for the conflicting outcomes and the large range of reported
complications. Defining complications using retrospective analysis is tricky, and
direct comparisons are difficult. A meta-analysis by Sbitany and Serletti found no
differences in infection rates of patients undergoing BR using ADM compared to those
with no ADM [37 ]. In contrast, Kim et al. found
significant differences in seroma rates and overall complications in patients with
IBBR using ADM [38 ]. The products used differ with regard
to their manufacturing processes, and clinically significant differences in seroma
formation rates were found for different matrices [39 ].
For synthetic meshes, only two strong publications reporting seroma rates of
1.8–4.8 % are available [10 ], [11 ]. Due to the limited number of publications, these numbers need to be
interpreted carefully, and differences between synthetic meshes and biological
matrices are speculative. One reason for the different seroma formation rates could
be attributable to the surface properties of the respective materials. Biological
matrices have smooth surfaces, permitting increased fluctuation between the matrix
and subcutaneous tissue and resulting in the development of seromas. Synthetic
meshes have rougher surfaces compared to ADMs, allowing for a potentially faster
interaction between the mesh and the subcutaneous tissue, with less fluctuation and
a consequent decrease in seroma formation. However, the rough surface can also serve
as an additional stimulus for seromas. To what extent the different coatings of the
synthetic meshes influence seroma formation rates remains unclear.
From a clinical perspective and based on our own experiences, synthetic meshes should
be used preferentially in primary cases with “sufficient” soft tissue. Defining
“sufficient” soft tissue is difficult; there are no clinical guidelines. Evaluating
the soft tissue left in situ after SSM/NSM depends on the personal assessment of
each surgeon. No metric data have been evaluated in any scientific publication on
biological matrices or synthetic meshes. Therefore, it is not possible to provide
metric recommendations on the use of specific materials for certain soft tissue
thicknesses.
A retrospective study examining the postoperative results of IBBR using TiLOOP® Bra
indicated an increased risk of complications for secondary BR [11 ]. Synthetic meshes are much thinner than biological matrices and not
suitable for soft tissue replacement. They are useful in primary cases to define the
inframammary fold, stabilize the implant laterally and prevent the implant from
bottoming out [40 ]. Especially in secondary cases or
revisionary breast surgery (aesthetic or reconstructive), the skin-soft tissue
conditions are poor, compared to primary cases. Here, biological matrices could
serve as a better alternative ([Table 3 ]). The downside
of biological matrices is that they are far more expensive than synthetic meshes.
Both materials are valuable for BR but are not covered by the German Diagnosis
Related Group (DRG) system and involve additional costs. With evolving surgical
procedures, it is essential that costs and postoperative outcomes are taken into
account. Single-stage implant reconstruction with ADM is associated with lower costs
compared to two-stage expander/implant reconstruction, even when the probability of
complications is factored into the analysis [41 ]. A study
by Krishnan et al. compared patients undergoing immediate autologous BR to patients
undergoing IBBR using ADM. A cost-effectiveness analysis showed that ADM was not
cost-effective compared to autologous BR when the complication rate for autologous
dermal flaps was below 20 percent [42 ]. A systemic review
of infections after BR comparing autologous flaps to implant-based BR analyzed
39 406 BR and found comparable infection rates of 5.28 % for implant-based and
4.70 % for autologous BR procedures [43 ]. Biological
matrices should preferably be used in single-stage IBBR, as increased complications
were observed for two-stage implant reconstructions [34 ].
Table 3 Recommendations for the application of synthetic
meshes or biological matrices in implant-based breast
reconstruction.
Indication and benefits
Synthetic meshes
Biological matrix
X: recommended; XX: preferably recommended; –: not recommended,
MRM: modified radical mastectomy
Skin- and nipple-sparing mastectomy
XX
XX
Inherent breast deformities
X
X
Implant-associated breast deformities
X
XX
Implant exchange
XX
XX
Fixation of the pectoralis major muscle
XX
XX
Control of implant position
XX
XX
Implant support
X
XX
Implant coverage
–
XX
Additional soft tissue replacement
–
XX
Implant-based breast reconstruction after MRM
–
XX
Breast reconstruction after radiotherapy
–
X
Delayed immediate breast reconstruction (mastectomy with expander
→ radiation → final implant exchange)
–
XX
Decreased frequency of capsular contraction
unknown
unknown
In irradiated breasts, biological matrices and IBBR seem to give acceptable results
[44 ]. If radiation therapy is indicated after
mastectomy, immediate delayed reconstruction (SSM/NSM with expander reconstruction
followed by radiation therapy and subsequent expander to implant exchange) with ADM
can be an alternative for patients desiring immediate BR instead of secondary BR. In
an experimental study of rats, radiated implants covered with ADM had less capsular
tensile strength, less inflammatory cell invasion, less thinning of the ADM and less
pseudoepithelium formation [45 ]. These results suggest
that the use of ADM in immediate delayed BR could reduce radiation-associated
inflammation and decrease the incidence of capsular formations. These data need
careful interpretation and BR should be delayed when radiation therapy is indicated
after mastectomy [46 ]. In irradiated patients, secondary
BR with autologous tissue remains the procedure of choice.
A surgical alternative to the described matrices and meshes is available for patients
with large, ptotic breasts where the patientʼs own autologous dermal tissue can be
used by de-epithelizing the inferior mastectomy flap. This flap can then be used in
the same way as a matrix/meshes to stabilize the implant pocket and protect the
implant [47 ].
When deciding on the choice of material to be used during surgery, proper
preoperative assessment is essential. Both product groups should be available during
surgery to allow the surgeon to make the “right” decision.
If it is doubtful whether an attractive postoperative result can be created using
implants, an experienced breast surgeon needs to discuss autologous reconstruction
in advance with the patient [48 ]. Although biological
matrices and synthetic meshes can facilitate BR, they are not “miracle products”
capable of solving every problem associated with IBBR. Some manufacturers may argue
that their product is superior to others, but long-term results, for example the
incidence of lasting complications such as capsule contraction, are still pending
for all materials presented here. Especially in complicated reconstructive
situations with poor soft tissue conditions, autologous procedures are preferable as
they usually have lower complication rates when performed by experienced surgeons in
high-volume hospitals [49 ], [50 ].
It is essential to evaluate the need for a supplementary product preoperatively. It
is also important to keep in mind that only biological matrices should be used for
soft tissue replacement. Synthetic meshes can serve as auxiliary supports to define
the inframammary fold and stabilize the implant pocket but are not meant to be used
as tissue replacement. If possible, the surgeon should abstain from using a second
product, as the use of two foreign bodies (implant and matrix/mesh) will increase
graft reaction and possible complications. Biological matrices and synthetic meshes
have an important part to play in breast reconstruction in selected patients.