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1751-6161/$ - see frohttp://dx.doi.org/10

$Selected parts oDay at the Summa

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1Present addressShanghai 200127, C

Research Paper

New biomaterial as a promising alternative to siliconebreast implants$

Goy Teck Lima,1, Stephanie A. Valenteb, Cherie R. Hart-Spicerc,Mary M. Evancho-Chapmand, Judit E. Puskasa,e, Walter I. Hornef, Steven P. Schmidtd,n

aDepartment of Chemical and Biomolecular Engineering, University of Akron, Akron, OH 44325, USAbDepartment of Surgery, Summa Health System, Akron City Hospital, 525 East Market Street, Akron, OH 44304, USAcDepartment of Pathology and Laboratory Medicine, Summa Health System, Akron City Hospital, 525 East Market Street, Akron,

OH 44304, USAdDivision of Surgical Education and Research, Department of Surgery, Summa Health System, Akron City Hospital, 525 East Market Street,

Akron, OH 44304, USAeDepartment of Polymer Science, University of Akron, Akron, OH 44325, USAfComparative Medicine Unit, Northeast Ohio Medical University (formerly Northeastern Ohio Universities Colleges of Medicine and

Pharmacy), 4209 State Route 44, Rootstown, OH 44272, USA

a r t i c l e i n f o

Article history:

Received 11 November 2012

Received in revised form

20 January 2013

Accepted 28 January 2013

Available online 9 February 2013

Keywords:

Breast implants

Biopolymers

SIBS

Mechanical properties

In vivo biocompatibility

Histological study

nt matter & 2013 Elsevie.1016/j.jmbbm.2013.01.02

f this work were presenteHealth System, 2009.hor. Tel.: þ1 330 375 3693schmidts@summahealth: Exponent Science and Thina.

a b s t r a c t

One in eight American women develops breast cancer. Of the many patients requiring

mastectomy yearly as a consequence, most elect some form of breast reconstruction. Since

2006, only silicone breast implants have been approved by the FDA for the public use.

Unfortunately, over one-third of women with these implants experience complications as

a result of tissue-material biocompatibility issues, which may include capsular contrac-

ture, calcification, hematoma, necrosis and implant rupture. Our group has been working

on developing alternatives to silicone. Linear triblock poly(styrene-b-isobutylene-b-

styrene) (SIBS) polymers are self-assembling nanostructured thermoplastic rubbers,

already in clinical practice as drug eluting stent coatings. New generations with a branched

(arborescent or dendritic) polyisobutylene core show promising potential as a biomaterial

alternative to silicone rubber. The purpose of this pre-clinical research was to evaluate the

material-tissue interactions of a new arborescent block copolymer (TPE1) in a rabbit

implantation model compared to a linear SIBS (SIBSTAR 103T) and silicone rubber. This

study is the first to compare the molecular weight and molecular weight distribution,

tensile properties and histological evaluation of arborescent SIBS-type materials with

silicone rubber before implantation and after explantation.

& 2013 Elsevier Ltd. All rights reserved.

r Ltd. All rights reserved.5

d at the 2008 Annual Meeting of Society for Biomaterials and the 17th Annual Postgraduate

; fax: þ1 330 375 4648..org (S.P. Schmidt).echnology Consulting Co. Ltd, You You International Plaza, Suite 2305-2306, 76 Pujian Road,

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 648

1. Introduction

Breast implantation, either for augmentation or reconstruc-

tion, is among the most commonly performed plastic surgical

procedures in the US (American Society of Plastic Surgeons,

2011). In 2010, an estimated 296,000 women in the United

States underwent elective breast augmentation surgery

(American Society of Plastic Surgeons, 2011). Additionally in

2009, over 250,000 women were newly diagnosed with breast

cancer (American Cancer Society, 2009). Of these women who

eventually undergo mastectomy for breast cancer, many will

opt for some form of breast reconstruction, an option which

may require the use of breast implants. Furthermore, with

the increase in prophylactic mastectomies occurring as a

result of the better understanding of breast cancer genetics,

the demand for superior and safe breast reconstruction

materials has increased.

Since 2006, only breast implants made with silicone shells

have been approved by the Food and Drug Administration

(FDA) for the public use. Unfortunately, 34% of women with

these implants experience some form of complication that

may include capsular contracture, calcification, hematoma,

necrosis, or implant rupture with material leakage. To better

appreciate the complications related to breast implants,

understanding the chemistry and material properties of

silicones is necessary (Puskas and Chen, 2004; Fruhstorfer

et al., 2004, Puskas and Luebbers, 2012). Silicone breast

implants consist of a rubbery silicone shell and a filler

material of either silicone gel or saline solution. Silicone is

the generic description of synthetic polymers containing

repeat Si–O bonds in their backbone. The viscosity of this

type of material depends on the polymer’s chain length

(molecular weight) and chain length distribution. The silicone

rubber shell is produced by crosslinking high molecular

weight long chains. In addition, the shell is reinforced with

silica nanoparticles because silicone rubber alone is too weak

(�1–3 MPa tensile strength) (Puskas and Chen, 2004).

The breast implant shells provide strength whereas the gel

filling gives bulk and consistency. The first generation silicone

gel implants used in the 1960s–1970s had the thickest shells

and the most viscous gel. They felt too firm compared with

natural breast tissue, so the shell thickness and gel viscosity

were reduced in the second generation implants, which were

introduced in the early 1980s. This resulted, however, in rupture

of the shell and gel bleed into surrounding tissues. As a result,

they were pulled from the market from 1992 to 2006. The third

generation silicone breast implants used today consist of shells

of intermediate thickness filled with silicone gel of medium

viscosity or saline solution. Saline filled implants have a less

natural feeling and tend to wrinkle under the skin.

Although they have been reintroduced for usage by the

FDA in 2006, most women with silicone-based breast

implants will still experience some form of complication.

These complications appear to occur more frequently in

patients receiving implants for breast reconstruction versus

augmentation (National Research Center for Women &

Families, 2006). The reasons behind this difference are not

clear although one can speculate that it may be due to more

trauma and tissue/skin loss associated with mastectomy.

Such complications in both cases include wound contracture,

infection, bruising, hematoma, calcification, necrosis of the

overlying skin, pain, and eventual implant rupture with

subsequent material leakage (National Research Center for

Women & Families, 2006; Gherardini et al., 2004). In addition

to local complications, silicone implants have also been

associated with joint pain and morning stiffness, neurologi-

cal symptoms, hair loss and rashes (National Research Center

for Women & Families, 2006). Capsule contraction, the result

of scar tissue that forms around the implant, causes the

breast to harden and become painful, and is the main

complication of silicone breast implants with a reported

incidence as high as 74% (Ersek, 1991).

Leakage, also called ‘‘gel bleed’’, of silicone gel from the

implant due to mechanical failure or high permeability of the

shell (inherent material properties) is a common, often unno-

ticed, problem whose consequences are not yet clear, but

which does lead to the eventual implant removal. Recent

findings indicate a statistically significant link between MRI-

diagnosed extra-capsular silicone gel and fibromyalgia as well

as other connective tissue diseases, but the majority of

scientific studies find no such association (National Research

Center for Women & Families, 2006; Beekman et al., 1997;

Peters et al., 1999; Ikeda et al., 1999; Flassbeck et al., 2003).

Thus far, no material has been identified which can absolutely

prevent capsule formation or gel leakage. Research shows that

the longer an implant is in place, the higher the risk of

complications. It is estimated that after 10–15 years from the

initial surgery, nearly all breast implantation patients require

reoperation to remove or replace the implants (National

Research Center for Women & Families, 2006).

Although reports concerning the possible adverse effects

of silicones used in implantation surfaced shortly after their

introduction, silicone rubber remains the only breast implant

shell material used in clinical practice today; all other

materials [polyethylene, poly(tetrafluoro ethylene), polyur-

ethane] were recalled from the market. Implants with alter-

native fillers [soybean oil, poly(vinyl pyrrolidone) and

poly(vinyl alcohol) hydrogels] were also recalled (Piza-Katzer

et al., 2002). Clearly a new biomaterial with improved bio-

compatibility and mechanical properties is needed as an

alternative to silicone breast implants.

The emergence of a novel class of biomaterials developed

by our group—branched polyisobutylene (PIB)-based block

copolymer thermoplastic rubbers (Cadieux et al., 2003; El

Fray et al., 2006; Foreman et al., 2007, 2008; Kennedy and

Puskas, 2004; Kennedy et al., 1990; Pinchuk et al., 2008; Puskas

and Chen, 2004; Puskas and Kwon, 2006; Puskas et al., 2001,

2004a, 2004b, 2005, 2006, 2007, 2009a, 2009b, 2009c) offers the

possibility of an alternative, potentially more successful

material for breast reconstruction. The first generation of

PIB-based thermoplastic rubbers, linear poly(styrene-b-iso-

butylene-b-styrene) (SIBS for simplicity) (Kennedy et al., 1990)

received FDA approval for use as the polymeric coating on

drug-eluting coronary stents after 15 years of comparative

biocompatibility testing (Pinchuk et al., 2008; Ranade et al.,

2005; US FDA, 2004). The exceptional biocompatibility of SIBS

and similar PIB-based polymers can primarily be attributed to

its surface being covered by a thin (�10 nm) inert layer of PIB

(Puskas and Kwon, 2006).

Fig. 1 – Architecture of (a) SIBSTAR 103T and (b) TPE1. Wavy

lines are polyisobutylene rubber segments; rectangles are

polystyrene plastic segments.

9

3 45 25

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 6 49

SIBS-type block copolymers are self-assembling nanostruc-

tured thermoplastic rubbers that do not need chemical cross-

linking. They exhibit a unique combination of desirable

properties for breast prostheses such as good mechanical

properties, exceptional biocompatibility and biostability, as

well as very low permeability (El Fray et al., 2006; Foreman

et al., 2007, 2008; Gotz et al., 2012; Kennedy and Puskas, 2004;

Kennedy et al., 1990; Pinchuk et al., 2008; Puskas and Chen,

2004; Puskas and Kwon, 2006; Puskas et al., 2001, 2004a, 2004b,

2005, 2006, 2007, 2009a, 2009b, 2009c; Ranade et al., 2005; US

FDA, 2004). Despite the desirable properties of the first gen-

eration SIBS, it is a linear thermoplastic rubber with reduced

shape retention capacity (Puskas et al., 2009c). As an alter-

native, Puskas et al. (2001), (2004b) developed a new generation

of SIBS polymers with a randomly branched (arborescent)

structure (arbIBS) (see Fig. 1). Since these polymers are made

by living carbocationic polymerization, the mechanical proper-

ties can be tailored by the molecular weights (number average

molecular weight Mn and weight average molecular weight Mw)

molecular weight distribution (Mw/Mn) of the PIB block, and the

composition of the polymers (hard block content) (Puskas and

Kwon, 2006). Representatives of the third generation polymer

family exhibited improved fatigue and shape retention proper-

ties (Puskas et al., 2004a, 2009b, 2009c; Gotz et al., 2012).

The purpose of this pre-clinical research study was to

evaluate in vivo tissue and material interactions of a third

generation polymer (TPE1) compared to commercial SIBS

(SIBSTAR 103T) and silicone controls using a rabbit implanta-

tion model. We selected tests recommended by the US FDA

for the materials to be used in alternative breast implants (US

FDA, 2006). Specifically, the Mw, Mn and Mw/Mn, and ultimate

elongation and breaking forces were measured before

implantation and after explantation to assess the mechanical

performance and stability of the alternative polymer, and

implant pathology was investigated after explantation to

assess polymer–tissue interaction. These data are necessary

before testing an entire new device.

Fig. 2 – Dimensions of the microdumbbell specimen (all

values are in mm).

2. Materials and methods

2.1. Polymer preparation

To prepare the materials for implantation, the as-received

pellets of SIBS (SIBSTAR 103T by Kaneka Corp.) were

compression-molded into 1-mm sheets twice using a hot

press to yield a flat sheet. Kaptons (polyimide) sheets were

used as substrates for the compression molding and liquid

nitrogen was applied at the end to detach the molded

materials from the Kaptons substrate. TPE1 was synthesized

as reported (Puskas and Kwon, 2006), and compression

molded. Silicone rubber (MED-4050) sheet reinforced with

silica was used as supplied from NuSil Technology. Micro-

dumbbells (see Fig. 2) were then cut from the sheets using a

hydraulic press and a cutting mold. Table 1 summarizes the

basic properties of the materials. All microdumbbells were

sterilized with ethylene oxide prior to cytotoxicity testing and

rabbit implantations.

2.2. Size exclusion chromatography (SEC)

Molecular weights (Mn, Mw) and molecular weight distribu-

tions (Mw/Mn) of the polymers were determined both before

implantation and after explantation by SEC using a Waters

system equipped with six Styragel-HR columns (HR0.5, HR1,

HR3, HR4, HR5 and HR6) thermostated at 35 1C, a Dawn EOS

18 angle laser light scattering (MALLS) detector (Wyatt Tech-

nology), an Optilab DSP refractive index (RI) detector (Wyatt

Technology) thermostated at 40 1C, a 2487 Dual Absorbance

UV detector (Waters), a quasi-elastic light scattering (QELS)

detector (Wyatt Technology), and a Viscostar viscosity detec-

tor (Wyatt Technology). Tetrahydrofuran, freshly distilled

from CaH2, was employed as the mobile phase and was

delivered at 1 mL/min. ASTRA software (Wyatt Technology)

was used to process the data. The dn/dc values (refractive

index increment) of the materials were calculated from

composition data obtained by Nuclear Magnetic Resonance

spectroscopy (Puskas and Kwon, 2006; Tomkins, 2006). MWs

calculated using these dn/dc values agreed well with those

obtained assuming 100% mass recovery on the columns.

Table 1 – Properties of implant materials.

Polymer Polymer designation Polystyrene content (wt%) Mn (g/mol) Mw/Mn

SIBS SIBSTAR 103T 34.2 107,000 1.34

arbIBS TPE1 23.1 114,100 2.30

Silicone MED-4050 Silicone – – –

Head Spine

Fig. 3 – Locations of incision for microdumbbell implants on

the back of the rabbit.

Fig. 4 – Microdumbbells at the end of 2-week implantation.

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 650

2.3. Tensile testing

Tensile testing was performed both before implantation and

after explantation using a testing rig (Instron 5567) with a

1000-N load cell and crosshead speed of 500 mm/min, accord-

ing to ASTM D412-06a (ASTM International, 2006). The tensile

strain was measured by a long-travel extensometer attached

to the mid-section of the microdumbbell with a gauge length

of 10 mm between the clips. Load and extensometer calibra-

tions were performed prior to the testing. The accuracy of the

extensometer was checked with an Instron gauge to fall

within an error of 2% in the range of the measured strain.

To prevent specimen slippage off the fixture, a pair of

hydraulic clamps was employed to secure the specimen

during testing. The results were engineering stress and strain

values (i.e., relative to initial cross section and initial clip

distance). Pristine materials (SIBSTAR 103T, TPE1 and Sili-

cone) and those harvested from the implant study were

tested.

2.4. Cytotoxicity testing

Prior to animal implants, in vitro cytotoxicity testing to

determine the safety of the polymers was conducted and all

polymers met criteria. The tests were conducted as described

in ISO 10993-5. The sample test volume was 20 times the

volume of the polymer sample (US FDA, 2006; Munoz-Robledo

et al., 2009).

2.5. Rabbit study

All animal care and surgical procedures were conducted in

accordance with the regulations and approval of the North-

east Ohio Medical University (formerly Northeastern Ohio

Universities Colleges of Medicine and Pharmacy)—Institu-

tional Animal Care and Use Committee and in compliance

with standards issued by the United States Department of

Agriculture, Public Health Service and the American Associa-

tion for Accreditation of Laboratory Animal Care. Two 2-week

implantation experiments were performed in a randomized

double-blinded manner using 6 New Zealand white, 6–8 lb,

adult female rabbits (Myrtle’s Rabbitry). Anesthesia was

induced with ketamine (35 mg/kg, IM), xylazine (5 mg/kg IM)

and glycopyrrolate (0.1 mg/kg, IM.); subsequent delivery of

isoflurane (0.5–2.5%) was used to maintain anesthesia

throughout surgery. The analgesic ketoprofen (1–3 mg/kg,

IM) was administered before anesthesia and 24 h post-

surgery. Each rabbit’s back and chest wall were clipped,

shaved, and prepared for aseptic surgery with an alcohol

and betadine solution followed by application of adhesive

surgical barrier.

Each rabbit had eight microdumbbells placed (Fig. 3) with

four TPE1 microdumbbells on one side, and two SIBS and

Silicone microdumbbells each on the other side. The

implants were placed under sterile conditions into the sub-

cutaneous plane of the rabbit’s lateral thoracic wall. An 8-mm

Atrium vascular graft tunneling catheter was used to uni-

formly pass the dumbbells between the subcutaneous and

muscular plane. The dorsal end of each dumbbell was

sutured to the underlying muscle using 2-0 Sofsilk (Syneture)

to limit implant movement, and the skin incisions were

closed using 4-0 Vicryl (Ethicon).

At the end of the 2-week implant period, the rabbits were

euthanized according to American Veterinary Medical Asso-

ciation standards. For histological evaluation, the implants

were harvested with surrounding capsules intact (Fig. 4) and

placed into neutral buffered formalin. For tensile testing and

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 6 51

SEC, harvested implants were cleaned and thoroughly dried.

An equal number of material samples were provided for both

histology and material characterization, i.e., two TPE1, one

SIBSTAR 103T, and one Silicone. The materials and the

locations of the microdumbbells placed in the rabbits were

unknown to the histology and material testing teams prior to

their examination.

2.6. Implant pathology

The tissue samples were sectioned horizontally in two places

with two pieces per sample submitted for histology review.

Only the soft tissue was evaluated. Of the 24 samples

received, two had only one section submitted, due to minimal

amounts of surrounding capsular tissue present on the

implants. The tissue pieces were submitted cut-side down

to evaluate the changes present in the tissue adjacent to the

synthetic materials. Tissue was processed using standard

procedures and was embedded in paraffin wax blocks. The

blocks were all cut into 4 mm thick sections by the same

histology technician and stained using a standard hematox-

ylin and eosin stain. The slides were examined by a single

pathologist who assessed the subcutaneous tissue reactions

using six categories including acute inflammation (presence

of polymorphonuclear neutrophils), chronic inflammation

(presence of mononuclear leukocytes), granulation tissue

formation, foreign body reaction and foreign body giant cell

formation, fibrous capsule formation, and presence of infec-

tion. Fibrous capsule formation was evaluated based on

visual inspection, with the study pathologist assessing the

amount of fibrosis present, as well as the progression of the

fibrous capsule from immature proliferating fibroblasts to

more mature, collagenized fibrosis and scar tissue. Evidence

of infection was determined by the presence of bacterial

overgrowth in the tissue. All six parameters were graded on a

0 to 4 scale with 0 being no evidence of entity being evaluated

and 4 being extensive evidence.

2.7. Statistical evaluation

Sigmstat, SyStat Corporation (ver 3.1) statistical software was

utilized to evaluate study data. The student t-test was used to

30 35 40 45 50

Rel

ativ

e Sc

ale

Retention time (min)

PristineSIBSTAR 103T

SIBSTAR 103T(1 Implant)

SIBSTAR 103T(2 Implant)

Fig. 5 – (a) Light scattering, and (b) refractive index

evaluate the material testing data and paired t-tests on ranks

were used to evaluate the pathology data. po0.05 was

considered statistically significant.

3. Results

3.1. Size exclusion chromatography

Figs. 5 and 6 show the light scattering (LS) and refractive index

(RI) traces from the SEC analysis of pristine and explanted

samples of SIBSTAR 103T and TPE1, respectively. Our high

resolution SEC shows that pristine SIBSTAR 103T has a high

molecular weight shoulder (peak MW¼211,600 g/mol) with

about twice the MW of the main peak (peak MW¼102,600

g/mol), indicating some coupling of the linear triblock chains

during manufacturing. Comparison of the LS and RI traces

before implantation and after explantation shows no changes.

From both implantation studies, the average Mn¼106,100 g/mol

and Mw/Mn¼1.39 of explanted SIBSTAR 103T agree very well

with those of the pristine material (Mn¼107,000 g/mol and Mw/

Mn¼1.34). For TPE1, both LS and RI traces have multimodal

peaks. LS is more sensitive to high MW so the LS traces show

more clearly three peaks at MW¼474,100 g/mol, 172,200 g/mol

and 59,600 g/mol. The traces of the explanted samples remain

identical to the traces of the pristine material. The explanted

TPE1 had an average Mn¼112,000 g/mol and Mw/Mn¼2.32,

which are in close agreement with the measured values

(Mn¼114,100 g/mol and Mw/Mn¼2.30) and the published data

(Mn¼118,800 g/mol and Mw/Mn¼2.38) (Puskas and Kwon, 2006)

of the pristine material.

3.2. Tensile testing

Fig. 7a presents the stress–strain responses of pristine SIB-

STAR 103T, TPE1 and Silicone from the tensile testing. Table 2

provides the moduli at 100%, 200% and 300% strain, ultimate

tensile strength and tensile strain (average values of at least 5

specimens, together with the calculated standard deviations)

of these tested pristine materials. Both SIBS and Silicone have

higher moduli at 100%, 200% and 300% strain than TPE1. The

notable differences in the moduli data between TPE1 and

SIBSTAR 103T are observed because of the higher polystyrene

PristineSIBSTAR 103T

SIBSTAR 103T(1 Implant)

SIBSTAR 103T(2 Implant)

30 35 40 45 50

Rel

ativ

e Sc

ale

Retention time (min)

trace of pristine and explanted SIBSTAR 103T.

Fig. 7 – Tensile stress–strain plots of (a) pristine materials, and (b) explanted materials (solid and dotted lines correspond to

samples from the 1st and 2nd implant, respectively). All samples tested at 500 mm/min.

Table 2 – Tensile data of pristine materials.

Material Stress at (MPa) Ultimate tensile strength (MPa) Ultimate tensile strain (%)

100% strain 200% strain 300% strain

Silicone 1.870.1 2.470.0 3.070.1 10.270.2 845723

SIBSTAR 103T 1.570.1 3.070.3 7.571.0 18.170.9 506720

TPE1 0.670.0 1.070.1 1.970.2 9.270.3 544728

PristineTPE1

30 35 40 45 50

Rel

ativ

e Sc

ale

Retention time (min)

PristineTPE1

TPE1(1 Implant)

TPE1 (2 Implant)

TPE1(1 Implant)

TPE1(2 Implant)

30 35 40 45 50

Rel

ativ

e Sc

ale

Retention time (min)

Fig. 6 – (a) Light scattering, and (b) refractive index trace of pristine and explanted TPE1.

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 652

(PS) content of the latter. Both SIBSTAR 103T and TPE1 have a

similar range of ductility, as shown by their ultimate tensile

strains, but TPE1 is much softer than SIBSTAR 103T or

Silicone at lower strains. However, both SIBSTAR and TPE1

shows strain stiffening—it is well-known that PIB-based

rubbers undergo strain-induced crystallization, similarly to

natural rubber (Kaszas, 1993; Xu and Mark, 1995). Silicone

and TPE1 show similar ultimate strengths, both lower than

that of SIBSTAR 103T. The stress–strain plots of the harvested

implant materials from the first (solid lines) and second

(dotted lines) implant studies are presented in Fig. 7b. The

tensile behavior of the explanted materials was similar from

both implant studies. Fig. 8 provides comparative ultimate

tensile strength and strain data of pristine and explanted

materials from the two implants. The strength and ductility

of Silicone are reduced after the 2-week implantation. This

agrees with earlier reports of decreasing tensile strength and

elongation data for explanted breast implant shells

(Greensmith et al., 1963; Marotta et al., 2002). However from

both implantation studies, both explanted SIBSTAR 103T and

TPE1 exhibited improved tensile strength and strain at break.

3.3. Implant pathology

Infection was not identified in any of the three tested materi-

als (see Table 3). There was no difference in the amount of

Table 3 – Pathology data.

Histology parameter TPE1 (7st.dev.) SIBSTAR 103T (7st.dev.) Silicone (7st.dev.)

Acute inflammation 0.1770.39 0.5070.55 0.0070.0

Chronic inflammation 1.4670.72 1.8370.41 1.3370.52

Fibrous capsule 0.9270.51 1.0070.00 0.6770.52

Foreign body giant cells 0.9670.75 0.5070.55 0.8370.75

Granulation tissue 0.2570.45 0.8370.75 1.0070.90

Infection 0.0070.00 0.0070.00 0.0070.00

Score legend: 0¼none; 1¼minimal; 2¼mild; 3¼moderate; 4¼extensive.

Fig. 8 – (a) Ultimate tensile strength, and (b) ultimate tensile strain of pristine and explanted materials.

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 6 53

acute inflammation or fibrous capsule formation between the

TPE1 and Silicone samples. Both showed no evidence of acute

inflammation and minimal fibrous capsule formation. In

addition, there was no difference in the amount of acute

inflammation when comparing the TPE1 and SIBSTAR 103T

samples. No significant difference was found between any of

the three samples when evaluating the amount of chronic

inflammation. The TPE1 and SIBSTAR 103T samples also

showed no difference in the amount of fibrous capsule

formation. One of the twelve TPE1 samples did show histolo-

gically identifiable foreign material. However, the differences

in foreign body giant cell reaction between the samples were

not statistically significant. Overall, the TPE1 samples tended

to have less granulation tissue formation compared to Silicone

and SIBSTAR 103T. Fig. 9 shows representative photomicro-

graphs of fibrous capsule formation, granulation tissue forma-

tion, and foreign body giant cells from each of the three study

materials. Chronic inflammation is also shown in the granula-

tion tissue formation images. Since there was no significant

acute inflammation or infection present, images of these

findings are not represented.

4. Discussion

Breast augmentation and reconstruction surgeries are com-

mon procedures, and the only approved prosthetic implant

material is silicone for these procedures. With the high rate

of complications related to silicone implants, an alternative

material is imperative. The biostability of linear SIBS has

been demonstrated in the pre-clinical evaluation of the

TransluteTM coating of the Taxus stent using SEC analysis

(US FDA, 2004). Our high resolution SEC data of SIBSTAR 103T

before and after the two-week implantation agree with this

conclusion. The data from TPE1 verify that this material is

also biostable in vivo.

TPE1 has lower tensile strength and elongation than the

medical grade Silicone rubber investigated, while it is much

softer with significantly lower moduli values at low strain.

This is desirable in the intended application. The silicone gel

filling swells the silicone shell of the implants and makes it

softer. That is why the gel-filled implants are more natural

than the saline-filled implants. With more PS content, SIB-

STAR 103T is consequently harder and has higher tensile

strength than TPE1. It was chosen as a reference material

because it is commercially available and is similar to the FDA-

approved TransluteTM SIBS. The tensile data show that the

explanted TPE1 exhibited improved ultimate tensile strength

and strain, with almost no increase in standard deviation.

This improvement may be attributed to improved phase

separation between the PIB and PS domains under the in

vivo conditions of 38.5–40.0 1C [rabbit rectal temperature

(Harkness and Wagner, 1995)]. SIBSTAR 103T showed similar

improvement, which also can be explained with improved

phase separation. In contrast, significant reduction was seen

in the average tensile strength and ductility of Silicone with a

high standard deviation after a mere 2-week implantation.

Our findings agree with earlier reports of reduced tensile

Fig. 9 – Photomicrographs of representative tissue samples.

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 654

properties of explanted silicone implant shells (Marotta et al.,

2002). This can be explained by the post-curing of Silicone at

the elevated temperature in vivo. It is known that beyond an

upper limit, increasing crosslink density decreases the ulti-

mate tensile properties of cured rubbers (Flory, 1953;

Greensmith et al., 1963).

The data presented here show that TPE1 is a very promising

biocompatible candidate for breast implants. In addition, TPE1

is based on PIB, which has the lowest permeability of all known

rubbers (Puskas et al., 2004a, 2005), and can potentially help to

prevent the leakage of the silicone gel which may provoke

inflammatory responses in patients. From our pathology results

presented in Table 3, TPE1 exhibited no significant differences

compared to silicone in the subcutaneous tissue reaction, i.e.,

acute and chronic inflammatory responses, fibrous capsule

formation, foreign body giant cell formation and infection,

while experiencing less granulation tissue formation. The

excellent tissue–material interactions of TPE1 may be attributed

to the lower surface energy of PIB that forms a thin layer on the

surface of the material (Puskas and Kwon, 2006). Preliminary

implant studies with a carbon nanocomposite of a TPE1-type

polymer revealed even more improved biocompatibility, with

no eosinophils present in the capsules after 6 months of

implantation (Puskas et al., 2010). In addition, our studies with

silica, carbon and clay nanocomposites of TPE1-type materials

show that the static and dynamic mechanical properties of the

polymer can dramatically be improved by the nanofillers

(Puskas et al., 2010; Lim et al., 2009).

5. Conclusions

We have shown that our new generation polymer, TPE1, is a

promising alternative to silicone rubber for implant applica-

tions. However, further investigation is warranted to deter-

mine if TPE1 and similar materials are more biocompatible

than silicone in the long-term. Previous studies have found

that the most significant contributor to capsular contracture

is the length of time the implant is in the body (Brandon

et al., 2003a). It has also been shown that gel bleed through

the silicone shell considerably weakens the shell over time

(Brandon et al., 2003b). Our current study is limited by its

relatively short two week duration, but the pilot results

justify moving forward with additional long-term rabbit

studies with TPE1-type polymers and nanocomposites.

Acknowledgements

The authors would like to acknowledge the Animal

Care—Comparative Medicine Unit at Northeast Ohio Medical

University for providing the surgical facilities for the animal

j o u r n a l o f t h e m e c h a n i c a l b e h a v i o r o f b i o m e d i c a l m a t e r i a l s 2 1 ( 2 0 1 3 ) 4 7 – 5 6 55

studies in this work. The supportive work in surgical proce-

dures by Maureen Cheung, Tristan Ula and Aaron Clark

(Summa Health System), histology processing by Jackie Beach

(Summa Health System), and polymer testing by Sara Porosky

(University of Akron) are all gratefully appreciated by the

authors.

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