POSS-Containing Bioinspired Adhesives with Enhanced Mechanical

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POSS-Containing Bioinspired Adhesives with Enhanced Mechanical and Optical Properties for Biomedical Applications Irawan Pramudya, Catalina Gomez Rico, Choogon Lee, and Hoyong Chung Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.6b00805 • Publication Date (Web): 01 Nov 2016 Downloaded from http://pubs.acs.org on November 3, 2016

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POSS-Containing Bioinspired Adhesives with Enhanced Mechanical and Optical Properties for Biomedical Applications Irawan Pramudya†, Catalina G. Rico†, Choogon Lee‡, Hoyong Chung†* †Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, Florida 32310, United States ‡Department of Biomedical Sciences, Florida State University, Tallahassee, Florida, 32306, United States KEYWORDS Adhesive, Biomedical adhesive, Polyhedral Oligomeric Silsesquioxane, POSS, Bioinspired adhesive, DOPA, Catechol, terpolymer adhesive.

ABSTRACT

A new terpolymer adhesive, poly(2-methoxyethyl acrylate-co-N-methacryloyl 3,4-dihydroxyl-Lphenylalanine-co-heptaisobutyl

substituted

polyhedral

oligomeric

silsesquioxane

propylmethacrylate) (poly(MEA–co–MDOPA–co–MPOSS) was synthesized by thermally initiated radical polymerization. In this study, we investigated the effect of the POSS component 1

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on adhesion, mechanical, and optical properties of the catechol-group containing bioinspired adhesives. The terpolymer contains the catechol group which is known to improve the adhesion properties of polymers. Only a very small amount of the POSS-containing monomer, MPOSS, was included, 0.5 mole %. In the presence of POSS, the synthesized poly(MEA–co–MDOPA–co– MPOSS) demonstrated strong adhesion properties, 23.2 ± 6.2 J/m2 with 0.05 N preloading and 300 second holding time, compared to many previously-prepared catechol-containing adhesives. The mechanical properties (Young’s modulus and stress at 10% strain) of the POSS-containing terpolymer showed significant increases (6-folds higher) over the control polymer which does not contain POSS. Optical transmittance of the synthesized terpolymer was also improved significantly in the visible light range, 450 – 750 nm. Cell testing with human embryonic kidney cells (HEK293A) indicates that the new terpolymer is a promising candidate in biomedical adhesives without acute cytotoxicity. The synthesized poly(MEA–co–MDOPA–co–MPOSS) is the first example of POSS-containing pressure sensitive bioinspired adhesive for biomedical applications. The study of poly(MEA–co–MDOPA–co–MPOSS) demonstrated a convenient method to enhance two important properties, mechanical and optical properties, by the addition of very small amount of POSS. Based upon this study, it was found that POSS can be used to strengthen mechanical properties of bioinspired adhesive without the need for a covalent crosslinking step.

INTRODUCTION Biomedical adhesive polymers are an important class of chemical compounds, which have recently found use in many diverse applications.1-2 The most extensively studied application of 2


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biomedical adhesives is tissue adhesion.3 Commonly proposed applications of tissue adhesives are aimed toward the replacement of conventional wound closure methods such as sutures and staples.4 Besides wound closure, biomedical adhesive have also found use as sealants,5 hemostatic agents,6 wound dressings,7 and drug delivery.8 Because of such a high practical value in diverse fields of medicine, many commercial biomedical adhesives have been developed. The most commonly used commercial biomedical adhesives are cyanoacrylate-based products such as Indermil®, Dermabond®, Histoacryl®, and Omnex®.9 However, the cyanoacrylate-based adhesives are limited to use on outer skin, and the adhesive generates stiff adhesion layers on soft tissue. Other effective commercial biomedical adhesives are natural protein-based dual component adhesives including BioGlue®, Tisseel®, CryoSeal®, and Crosseal®.10 The proteinbased adhesives utilize rapid crosslinking event between protein and crosslinkers to bind separated tissues. BioGlue®, for example, has two components, a purified bovine serum albumin and glutaraldehyde. These two components are stored separately in a dual-barrel syringe and are mixed in an applicator tip (mixing tip) upon injection.11 However, the dual component system may cause inconvenience to users, and according to recent reports, the crosslinking agent, glutaraldehyde, may pose some safety concerns.12 In addition to strong adhesion properties, a precise control of mechanical properties is an important aspect of any biomedical adhesive. This is because different human tissues have different levels of mechanical strength, such as hard tissue (bone, tooth, cartilage) and soft tissue (most other organs). Another important requirement of biomedical adhesives is a preciselycontrollable crosslinking rate. If the crosslinking rate is too fast, a medical device under using may be permanently fixed to the tissue. If the crosslinking is too slow, the adhesive would not successfully bind separated tissues. For these reasons, there exists a strong need for new 3


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advanced functional materials in the biomedical adhesive field to overcome the above mentioned issues. In recent times, 3,4-dihydroxy-L-phenylalanine (DOPA) containing adhesives have gained extensive interest mainly compared to conventional biomedical adhesives due to their strong wet adhesion properties and enhanced strong adhesion properties. DOPA is a modified amino acid which is found in marine organisms such as mussels and sandcastle worms which is an essential contributor of the strong adhesion properties of plaque proteins.13-14 The essential chemical functionality of DOPA is a catechol group. These wet adhesion properties are greatly beneficial in biomedical adhesives because water significantly weakens the typical adhesion bond. The human body contains more than 60% or water. Internal organs are water-wet by blood, interstitial fluid, mucus, and different types of liquids.15 Because of this wet environment, DOPA containing biomedical have the potential to outperform other biomedical adhesives for internal use. However, the DOPA moiety alone does not always strengthen the adhesion properties of all polymers and/or materials. The DOPA including catechol functionality must be integrated within well-defined polymers that present optimum viscoelastic properties, cohesion bond formation (crosslinking), water compatibility, and mechanical strength.16-19 The DOPA can be synergic only when it is incorporated into well-understood and controllable polymers with defined structures and functionalities. Polyhedral oligomeric silsesquioxane (POSS) is an organic/inorganic hybrid material consisting of a silicon-oxygen (Si8O12) cage.20 The silica-like nano sized cage (1-3 nm) is functionalized by organic groups such as alkyl, aryl, hydroxyl, epoxy, allyl, acrylate, amino, thiol, silyl, fluoro, and cyano groups. Because of the small size of the silica-like cage and organic substituents, the POSS can show excellent compatibility to most organic polymers via blending, 4


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graft copolymerization, and polymerization. Considerable mechanical property enhancements have been reported with POSS-containing polymers. Herein the nano-sized POSS cages act as nanoparticle fillers in a bulk polymer matrix. Thus, the well-dispersed nano-sized POSS cages generate a large surface-to-volume ratio, which promotes the enhancement of mechanical properties.21-23 In addition to the mechanical property enhancement, incorporation of POSS provides extraordinary thermal stability, flame retardancy, antioxidative properties, physical crosslinking points, anti-biodegradable properties, low dielectric properties, and biocompatibility.21, 24-26 POSS also can increase the optical transparency of polymer composites, which have found application in display electronic devices and ophthalmic applications.27-30 In this report, we have incorporated POSS into DOPA-containing bioinspired adhesives via copolymerization. The biomedical adhesive should demonstrate strong cohesion after two separate substrates are affixed. Also the adhesive should have a certain degree of mechanical strength (viscosity) for use as a pressure sensitive adhesive or injectable adhesive. If the mechanical strength is too weak, the adhesive will be mislocated from a target area. Weak mechanical properties can also cause localized collection of pressure sensitive adhesive on a backing material during storage due to gravity. Of particular importance with live human subjects is the ubiquity of uneven surfaces, with constant circulation and mobility in the presence of various fluids. Thus, the mechanical strength of an adhesive is essential to locate an adhesive a target point. A commonly used method to enhance mechanical properties and cohesion is covalent crosslinking. However, covalent crosslinking generally reduces adhesion properties due to strengthened stiffness.19, 31 Because of this, there is a strong need for mechanically enhanced adhesives without the use of covalent crosslinking. Although there is a chance that a catechol may undergo uncontrolled crosslinking that can cause mechanical property changes in certain 5


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polymer systems,32 the described POSS containing polymer is a well-known route for the exhibition of precise and systematic control over mechanical properties. In addition to mechanical strength, the optical transparency of biomedical adhesives is also important, because high light transmittance increases observation capability through the adhesive and/or sealant. Ophthalmic applications of biomedical adhesives, for example, fundamentally require a high optical transparency.28-30 By employing POSS in the bioinspired adhesive, both mechanical properties and optical transparency were increased without sacrificing pressure sensitive adhesion properties. These results demonstrate that a DOPA containing bioinspired adhesive can be modified in a controlled manner to produce significantly advanced properties (enhanced mechanical and optical properties) via convenient free radical copolymerization methods.

EXPERIMENTAL SECTION Materials. All chemicals were purchased from Sigma-Aldrich Ltd. and TCI America. All chemicals were used without further purification unless otherwise stated. All organic solvents were degassed with bubbling dry nitro-gen gas in the presence of molecular sieves. Characterization. The 1H NMR (Proton Nuclear Magnetic Resonance), 13C NMR, 29Si NMR samples were analyzed in a Bruker Avance III 400 MHz spectrometer. Polymer molecular weights and dispersities were determined on an Agilent – Wyatt combination gel permeation chromatography (GPC) instrument containing 3 successive Agilent PLgel Mixed C columns, an Agilent 1260 infinity series pump, degasser, and autosampler. The Wyatt detection unit hosts a 6


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Dawn Heleos 8+ 8-angle light scattering detector and Optilab TrEX refractive index detector. Dimethyl formamide (DMF) with 0.025M LiBr was used as the eluent of GPC and a flow rate was 1 mL / min. The sample analysis temperature was room temperature, 23 oC. The transmittance spectra was obtained from PerkinElmer UV-vis spectrometer (model: Lambda 950). Infrared spectroscopy was obtained from a PerkinElmer Spectrum 100 FT-IR spectrometer equipped with diamond ATR accessory. Shimadzu tensile-compression tester (model: EZ-LX) equipped with a 200 N force transducer (Model: SM-200N-168) was used to perform uniaxial indentation adhesion test and compression test. Synthesis of N-methacryloyl 3,4-dihydroxyl-L-phenylalanine (MDOPA). To a solution of Na2B4O7*10 H2O (19.1 g, 50 mmol, 1.0 equiv.) in degassed H2O (500 mL) was added L-DOPA (9.96 g, 0.05 mol, 1.0 equiv.). The pH was then adjusted to ~9-10 with Na2CO3 (10.6 g), and the solution was degassed for 5 min. and was kept under N2 atmosphere with stirring. Reaction was cooled to 0 oC, and methacryloyl chloride (4.8 mL, 65 mmol, 1.3 equiv.) was added dropwise (pH after addition was ~7.0 and was adjusted to ~9-10 by the addition of additional 5.3 g of Na2CO3). Reaction was then degassed for 10 min. and was then kept at room temperature for 2 hours while stirring vigorously. Reaction was then acidified with concentrated HCl (~30 mL) to pH of 2.0 and was then extracted 4 times with 150 mL of ethyl acetate and organic fractions were combined and washed twice with 0.1 M HCl and twice with brine. Organic layers were then dried under magnesium sulfate and the product was collected using rotary evaporator. Crude product had brown / green appearance, and was used as is if pure by 1H NMR. In some cases isolated product was contaminated with methacrylic acid, which was removed using column chromatography (gradient elution 5 - 15 % MeOH / CHCl3).

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Synthesis of poly(MEA–co–MDOPA–co–MPOSS) (1). Dry THF was degassed for at least 15 min by bubbling nitrogen prior to use. A 2-methoxyethyl acrylate (MEA) was purified by passing through a short plug of basic aluminum oxide to remove inhibitors and then filtering the solution via 0.45 µm pore size syringe filter. To a 100 mL round bottom flask (or 50 mL scintillation vial), were added: MDOPA (1000 mg, 3.77 mmol, 0.145 equiv.), degassed THF (4 mL) and MEA (2.7 mL, 21.2 mmol, 0.85 equiv.). To a separate vial was added Heptaisobutyl substituted POSS-(1-Propylmethacrylate) (MPOSS, Aldrich catalog number: 534633, CAS# 307531-94-8) (118.5 mg, 0.13 mmol, 0.005 equiv.), AIBN (124 mg, 0.7 mmol, 0.03 equiv.) and THF (4 mL) and the mixture was transferred to the main reaction vessel via syringe. The reaction was then heated to 70 oC and stirred for 16 h under a seal of septa cap which was wrapped using sticky tape. Reaction was then quenched by the exposure to air, cooled down and purified by precipitation from ice-cold Et2O (~300 mL). Polymer was then dissolved in DCM and precipitated again from Et2O and was then dried in the vacuum oven overnight. The polymer had MDOPA incorporation of ~9-12 % and POSS incorporation of 0.5-0.7 % as determined by 1H NMR. Proton NMR is shown in Figure 1. Molecular weight and molecular weight distribution are presented in Table 1. Other characterization results, 13C NMR, 29Si NMR, and FT-IR results are displayed in the supporting information. Overall yield of polymerizations was slightly different for each batch lying near to 80 %. Synthesis of poly(MEA–co–MDOPA) (2). Same conditions were used, except the ratios used for the synthesis were: MDOPA (0.15 equiv.), MEA (0.85 equiv.), AIBN (0.03 equiv.). The polymers produced contained 9-13 % of MDOPA in their composition as determined by 1H NMR.

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Synthesis of poly(MEA–co–MPOSS) (3). Same conditions were used. The ratios were: MEA (0.995 equiv.), MPOSS (0.005 equiv.). The polymers contained 0.5 % of MPOSS as determined by 1H NMR. Compression testing. Compression testing was per-formed using trapezium EZ-LX tensilecompression tester (Shimadzu Corp.) equipped with a force transducer (200 N capacity, Model SM-200N-168). The samples of 1-2 were prepared by spreading out an 2-3 mm layer of polymer on a glass plate, then pressurizing the polymer using 10 N force (Non-stick patch from bandage was used between the pressurizer and polymer to prevent adhesion.). Samples were cut using razorblade to form similar size cuboids (~6-8 x 6-8 x 2-3 mm). The amount of polymers used for the samples was 200-250 mg per sample (using smaller amounts (40-60 mg)) of polymers led to significant errors). Accurate measurements of samples were recorded using calipher up to 0.01 mm. The pressure probe was then lowered so that there is small gap between pressure cap and polymer sample and samples were pressurized at 1 mm/min compression rate. The forcedisplacement curves were analyzed for >= 0.2 N range. Young’s modulus was calculated by measuring the slope (Δy / Δx) of the stress strain curve over 1 % of displacement in the early linear phase of stress / strain graph. Five measurements were recorded for 1 and 4 measurements were recorded for 2. Adhesion testing. Adhesion testing was performed using trapezium EZ-LX tensile tester equipped with 7 mm diameter aluminum spherical probe (see Figure 2. for a photo). The polyurethane cuboids were spin coated using solution of 1, 3 in THF 360 mg / mL (polymer coating layer thickness: 2 µm). THF was completely removed by drying. THF was not observed in 1H NMR after the coating process. The probe was pressed against the sample with a preload of 0.01-0.05 N, then it was held for 30-600 seconds and retracted with a velocity of 0.017-1.7 9


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mm/s. The adhesion work was calculated by dividing the area of stress-strain curve over the maximum contact area (1/4 of the surface area of the probe). Each test was performed at least 3 times. Optical transmittance testing. The synthesized polymer samples (100 mg) were sandwiched between transparent Mylar® films and compressed with 180 N force. The com-pressed and flatten samples were characterized by UV-vis spectrometer (PerkinElmer, Lambda 950) to measure transmittance. The characterization was performed 8 times for each polymer (UV-vis spectra available in supporting information). Cell testing. The synthesized poly(MEA–co–MDOPA–co–MPOSS) was further purified against ultra-purified DI water (water purifier: Barnstead Nanopure) with using Spectra/Por® Dialysis tube (molecular weight cut-off 1kD) to remove all small molecules that can be potentially harmful to live cells. The poly(MEA–co–MDOPA–co–MPOSS) was dissolved in methanol first and then placed in the dialysis tub prior to staring dialysis for 2 days. During the dialysis, not significantly visible precipitation was formed in the tube. The polymer was then recovered by freeze dryer (FreeZone® -105°C 4.5L Benchtop Freeze Dry System, Labconco®). The purified 50 mg of poly(MEA–co–MDOPA–co–MPOSS) was dissolved in 1 ml of methanol and the pH was adjusted to 7.0 by adding 40 µl of NaOH (0.4375 M). The polymer solution was then sterilized using UV light for 30 minutes. After sterilization, 50 µl of terpolymer solution was added to HEK293A cells in a 35 mm dish containing 2 ml DMEM supplemented with 10% FBS. The cells were incubated with terpolymer for 48 hours before they were inspected by an optical microscope. Cell morphology and adhesion were assessed for measuring cytotoxicity of the chemical and compared with those of control cells with vehicle only. The same number of cells were seeded in both dishes. 10


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RESULTS AND DISCUSSION Synthesis of polymers. Three different polymers (1-3) from MDOPA, MEA and MPOSS monomers were polymerized using thermally initiated free radical polymerization: 3 mole % AIBN in THF at 70oC (Scheme 1). Scheme 1. Synthesis of polymers 1-3; polymer 1: poly(MEA–co–MDOPA–co–MPOSS), polymer 2: poly(MEA–co–MDOPA), and polymer 3: poly(MEA–co–MPOSS)

The initial molar ratios used for polymerization were: 85 % of MEA, 14.5 % of MDOPA and 0.5 % of MPOSS for polymer 1. The repeating unit ratio was previously determined elsewhere after extensive testing to deliver the best adhesion properties.17-19, 33 This report will demonstrate the fixed molar ratio between MEA, MDOPA, and MPOSS. The polymer 2 contains no MPOSS and was prepared as a control to study the effect of MPOSS concentration. Eighty five mole percent of MEA and 15 mole % of MDPOA were polymerized to form polymer 2. Polymer 3 has a monomer feed of 99.5 mole % of MEA and 0.5 mole % of MPOSS. In polymer 3, MDOPA was not included to investigate the effect of the catechol group on the adhesion properties of the developed polymers. The incorporation of MDOPA in the final polymers was slightly lower in 11


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polymers 1 and 2 than the initial ratio used (9-12 % for polymer 1 and 9-13 % for polymer 2).

Polymer (1) poly(MEA–co–MDOPA– co–MPOSS) (2) poly(MEA–co–MDOPA) (3) poly(MEA–co–MPOSS)

Mn MALS (g/mol)

Mn NMR. (g/mol)

PDI

MEA/MDOPA/MPOSS (Monomer feed)

MEA/MDOPA/MPOSS (Polymer, 1H NMR)

6900

5300

1.87

85/14.5/0.5

87.3-90.5/9-12/0.5-0.7

7900

5100

1.77

85/15/0

87-91/9-13/0

3900

4600

1.80

99.5/0/0.5

99.5/0/0.5

Polymer 1 had the MPOSS molar ratio of 0.5-0.7 % and polymer 3 had MPOSS ratio of exactly 0.5 % as determined by 1H NMR. The molecular weights (g/mole) and molecular weight distribution (polydispersity index, PDI) of all polymers were determined by GPC-MALS and 1H NMR (Table 1). Polymer 3 had a number average molecular weight of 3,900 g/mol with PDI of 1.80. Number average molecular weights were determined by 1H NMR by using the ratio of end group and polymer repeating units. The presence of MDOPA repeating units in polymers was confirmed by the identification of broad aromatic protons at 6.67-6.53 ppm, 6.50-6.40 ppm (in DMSO-d6), and the presence of MPOSS was confirmed by presence of -Si-CH2- protons at 0.640.54 ppm, and -CH(CH3)2 doublet at 0.92 ppm (Figure 1). The 1H NMR spectra of the described polymers are shown in the Supporting Information with assignments. Polymer synthesis was performed by thermally-initiated free radical polymerization. The repeating unit ratio of the prepared polymers were determined by the input ratio of monomers without significant changes. The observed PDI was quite broad, 1.80, as is typical of free radical polymerization. Table 1. Polymer characterization of prepared polymers 1-3.

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O

O O

NH

HOOC

z

y

x O

O

O HO

Si RO O Si Si O O O

OH

R

a)

R

Si O

HOOC

R Si OOO Si

Si

O RO Si R

R

y

x O

O

O NH

O

O HO

OH

b)

z

y O

O O

O

O Si RO O Si Si O O O

R

c)

R

Si O

O

R Si OOO

Si

Si

O RO Si R

R

Figure 1. 1H NMR spectra of (a) poly(MEA-co-MDOPA-co-MPOSS, (b) poly(MEA-coMDOPA), and (c) poly(MEA-co-MPOSS). MEA was chosen as the bulk monomer for our current studies because of its excellent biocompatibility and adhesion properties. The monomer was present at 85 mol % of the synthesized polymers. Polar functional groups as well as a low glass transition temperature (Tg), -34 oC, make MEA as extensively used adhesive component34-35 Also, excel-lent biocompatibility of MEA has been demonstrated by in vitro cytotoxicity tests.36-37 The outstanding blood compatibility of poly(MEA) has received attention in diverse biomedical applications.38-39 Aside from MEA, MDOPA contains a catechol group which shows strong wet adhesion properties in produced terpolymer adhesives. The MPOSS component in the polymer has an important role in the mechanical and optical property improvements in adhesives. 13


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The incorporation of POSS in organic polymers generates hybrid polymers that demonstrate a synergy between organic and inorganic components from the silicone-based POSS moiety. More specifically, POSS provides enhanced strength (modulus), toughness, allows for greater processibility, chemical/thermal stability and biocompatibility.20-21, 25-26 In this report, we focused our attention on the enhancement of mechanical strength (modulus) and optical transmittance of the adhesive. Mechanical strength is an important aspect of adhesives, and even more so for pressure sensitive adhesives. A pressure sensitive adhesive typically has two major parts: an adhesive layer and backing materials. Generally, a soft adhesive layer is coated on a backing material, which can be accomplished single sided or both sides depending on the specific application.40-41 Typical examples are Scotch Tape® and Post-it®. Without suitable mechanical strength on a backing material, the adhesive will be dislocated easily from the target area by flowing. Also, an adhesive which is too soft can be collected to a specific site of a backing material during storage due to gravity. In addition, biomedical adhesives are expected to be used at temperatures higher than ambient temperature (human body temperature, 37.5 oC). Thus, low Tg adhesive polymers can be too easily dislocated from a target area under conditions found within the human body. Therefore, maintaining a stable mechanical strength without sacrificing adhesion properties is a very practical concern. This report demonstrates that the incorporation of a very small amount (0.5 mole %) of POSS into the polymer structure is a very simple and convenient way to enhance the overall mechanical strength of an adhesive.

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Figure 2. Picture of uniaxial indentation test of spin coated layer of poly(MEA–co–MDOPA– co–MPOSS) on a polyurethane substrate; The probe was holding for 30 seconds at a constant preload of 0.05 N. 0.10

Displacement (mm)

0.05 -2

-1

0

0.00 -0.05

Force (N)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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-0.10 -0.15 -0.20

Polymer 1 Polymer 3 Bare PU

Work of Adhesion

-0.25 -0.30

Figure 3. Force-displacement curve of polymer 1, 3, and bare polyurethane at 0.5 N preload with holding time 30 seconds. The gray colored area below x-axis represents work of adhesion (J/m2) of each polymer.

Adhesion Testing. The adhesion properties of the novel polymer, poly(MEA–co–MDOPA– co–MPOSS), was measured under various conditions. The performed adhesion property test was uniaxial indentation of a non-flat spherical aluminum probe on an adhesive film as shown in Figure 2. The synthesized adhesive was coated on a commercially available polyurethane backing material (BJB Enterprises, F-105 A/B). The backing material, polyurethane, was carefully selected to represent mechanical strength (Young’s modulus of 40 kPa) of typical 15


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human soft tissues. The polyurethane modulus is very close to human skin, cornea, and tendon tissue.42-44 Other measured commercial polyurethanes were listed in the Supporting Information with their Young’s moduli (Table S1). We separately investigated the effects of three different factors – preloading, holding time, and retraction velocity on polymers 1 and 3 to measure the effect that the catechol group from had on the adhesion properties of the described MEA polymer (Figure 3 and 4). Adhesion testing revealed significant bulk property effects from both monomers, MDOPA and MPOSS. The MDOPA contributed to enhance the work of adhesion in all conditions (Figure 3 and 4). Herein, the work of adhesion (J/m2) is a measurement of energy per unit area which is a comprehensive concept of the energy being used through interfacial failure and the energy being dissipated in the bulk matrix of the polymer adhesive.45-46 The enhancement of adhesion property with DOPA moiety has been extensively reported.13-14, 16 The obtained force-displacement in Figure 3 illustrates the difference in work of adhesion. Integration of the curve below the x-axis represents work of adhesion, and their numerical values are displayed in Figure 4. We further investigated two variables that can have an effect on adhesion properties in indentation adhesion tests: preloading force and contact-holding time with preload. First, we varied the holding time of the probe at 0.05 N preload and retraction speed of 1.7 mm/s. Interestingly, at a holding time of 30 second, 1 had 45 % higher adhesion work than 3 (4.34 ± 1.27 J/m2 vs. 3.01 ± 0.5 J/m2), as expected. However, at a holding time of 300 second, the difference in adhesion strength between 1 and 3 was much more pronounced - almost 5-fold (23.2 ± 6.2 J/m2 vs. 4.96 ± 0.77 J/ m2). Additional increasing of the holding time to 600 s diminished the difference of adhesion works between polymer 1 and 3 to 91 % (6.43 ± 1.08 J/m2 vs. 3.36 ± 0.68 J/m2). Although the reasoning of this phenomenon is still under investigation, 16


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presumably this trend is due to a lack of adhesive polymer between probe and backing material, polyurethane. During the excessive holding time (600 seconds), the non-flat spherical probe may push the adhesive polymers out of the contact area. In other words, the coated polymer relocated out of the contact area by the preload force. This phenomenon results in a smaller amount of adhesive polymer between the probe and backing material with a holding time of 600 seconds, compared to a 300 seconds holding time, inducing low work of adhesion. Secondly, we investigated the dependence of adhesion work with respect to the retraction velocity. Figure 4 (c) shows that the adhesion work is directly related to retraction velocity. A similar dependence was observed for both polymers 1 and 3, wherein increasing the retraction velocity led to an increase of adhesion work. The stronger resistance to debonding under high retraction velocity is an important requirement for pressure sensitive adhesives. The stronger resistance (higher work of adhesion) to debonding occurs because of the resistance to internal energy dissipation of the viscoelastic adhesive polymers.19, 31, 47 Hence, pressure sensitive adhesives can keep the adhesion bonding between substrates against rapid debonding processes. In contrast, slow debonding causes efficient internal energy dissipation within the matrix of viscoelastic adhesive polymers yielding low debonding energy (work of adhesion). Consequently, the synthesized adhesive polymers shows desirable behavior for pressure sensitive adhesives.

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(a)

Poly(MEA-co-MDOPA-co-MPOSS) (1) Poly(MEA-co-MPOSS) (3)

(b)

20

10

0

Poly(MEA-co-MDOPA-co-MPOSS) (1) Poly(MEA-co-MPOSS) (3) 6

Work of adhesion (J/m2)


30

30

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0.017

Holding time (s)

(c) 6


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0.17

1.7

Retraction velocity (mm/s)

Poly(MEA-co-MDOPA-co-MPOSS) (1) Poly(MEA-co-MPOSS) (3)

4

2

0

0.01

0.025

0.05

Preload (N)

Figure 4. Adhesion testing results. The dependence of adhesion work on holding time (a), retraction velocity (b), and preload (c). Lastly, we investigated the effects of adhesion strength with respect to different preloads. In these experiments, the sample was held for 30 s and then retracted at a rate of 1.7 mm/s. The most pronounced difference between adhesion properties of polymer 1 and 3 was only evident with a preload of at least 0.05 N. At a preload strength of 0.01 N, the polymers performed similarly, while at a preload of 0.025 N, 1 had only slightly better adhesion that 3 (2.72 ± 0.46

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J/m2 vs. 2.23 ± 0.14 J/m2). This trend shows that sufficient force on polymer 1 has to be used to make it useful as an adhesive. Compression testing. Having established that MDOPA can enhance the adhesion properties in MEA-MDOPA based polymers, we then decided to investigate effects of MPOSS on the terpolymer adhesive system. We hypothesized that using small amount of MPOSS in the adhesive system would increase its mechanical strength, but that such a polymer should still retain the necessary adhesion properties. The newly developed poly(MEA–co–MDOPA–co– MPOSS) demonstrates much better adhesion properties (work of adhesion) than many other precedent bioinspired adhesives in spite of the presence of POSS (Note that there are slight differences in detailed experimental conditions). Those precedent examples include: catecholcontaining amino acid based poly(ester urea) - 33.1 mJ/m2,48 Poly(ethylene glycol) (PEG) crosslinked catechol bearing poly(2-hydroxyethyl methacrylate) – 3.0 J/m2,49 Polydopamine/epoxy thin film – 112.1 mJ/m2,50 and DOPA modified PEG-Polylactide block copolymer - 413 mJ/m2.51 In addition to these, the work of adhesion of synthetic polypeptides to diverse substrates are laid in the range of 15 – 140 mJ/m2.52-54 Thus, the developed poly(MEA– co–MDOPA–co–MPOSS) is competitive in the context of the area of biomedical adhesives.

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1000 Poly(MEA-co-MDOPA-co-MPOSS) (1) Poly(MEA-co-MDOPA) (2)

900 3

800

-1

Compression strangth (kPa g cm )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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700 600 500

100

0

Modulus

Stress at 10 %

Figure 5. Compression testing results of polymer 1 and 2; compression strength (kPa) was normalized by density of samples (g/cm3). Performing compression tests using a cylindrical 200 N probe indeed showed that the mechanical properties of adhesive 1, when compared to adhesive 2 had a superior Young’s modulus (612 ± 341 kPa g-1 cm3 vs. 102 ± 40 kPa g-1 cm3), and much higher stress at 10 % strain (62.6 ± 23 kPa g-1 cm3 vs. 12.1 ± 5.08 kPa g-1 cm3). Also, when subjected to the compression test, adhesive 1 appeared to have more rigid structure than adhesive 2. Polymer 2 demonstrated some elastomeric behavior – after compression it slowly returned to the previous shape. According to these results, it is demonstrated that very small amount, 0.5 mole %, of POSS can enhance mechanical properties (Young’s modulus and stress at 10 % strain) very efficiently. Optical properties. The optical transmittance of the poly(MEA–co–MDOPA–co–MPOSS) (1) was measured compared to the non-POSS containing control example, poly(MEA–co–MDOPA) (2). Polymer 1 demonstrates clearly enhanced transmittance over the visible range from 320 nm to 800 nm. A similar optical transmittance enhancement was consistently observed by multiple reports.27-30, 55-57 Silicone-based materials have a high optical transparency; and because POSS is a nano scale silicone-oxygen cage, the prepared POSS containing polymer shows overall 20


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enhanced optical transmittance by reduced light absorption through POSS. In addition, the high compatibility of the isobutyl group functionalized POSS to other polymer segments contribute to prevent phase separation or crystalline domain formation within the overall polymer matrix.58 Thus, the POSS containing polymer shows high optical transparency because the prepared polymer does not possess any domains that are similar in size to visible light wavelengths.55 Note that the test samples were prepared by high stress compression between optically transparent Mylar® films. Although this particular sample preparation method cannot be exactly applied to ordinary biomedical applications, the difference of optical transmittance via incorporation of a small amount of POSS is significant. In particular, the increased transmittance in the visible light range of 450 – 750 nm, implies that the new adhesive can be used in various optical devices and ophthalmic applications.

100

Transmittance (%)

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80

Poly(MEA-co-MDOPA) Poly(MEA-co-MDOPA-co-MPOSS) 60

0 400

500

600

700

800

Wavelength (nm)

Figure 6. Optical transmittance of poly(MEA–co–MDOPA–co–MPOSS) and poly(MEA–co– MDOPA) films from UV-vis spectrometer; all other characterization results are available in the Supporting Information. 21


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Cell experiments To test if poly(MEA–co–MDOPA–co–MPOSS) is cytotoxic in vitro, human embryonic kidney (HEK293A) cells were treated with the terpolymer for 48 hours. The terpolymer was dissolved in methanol and then further diluted with DMEM cell medium (ATTC, Dulbecco’s Modified Eagle Medium). After treatment for 48 hours, cell morphology was observed under an optical microscope as shown in Figure 7. The cell morphology was not apparently different between the treated and control cells suggesting that the terpolymer is not cytotoxic. Although additional in vitro/in vivo testing with various cell lines is needed before clinical application, these results suggest that the developed poly(MEA–co–MDOPA–co– MPOSS) represents a promising new wave of biomedical adhesives.

Figure 7. Cell morphology of (a) methanol (control) and (b) polymer 1 after 48 hours incubation with human embryonic kidney (293-HEK) cells; n=6.

CONCLUSION In this study, poly(MEA–co–MDOPA–co–MPOSS) was synthesized to investigate the effect of POSS on the properties of bioinspired adhesives. Only a small amount of POSS, 0.5 mole %, resulted in a significant enhancement of polymer mechanical properties (Young’s modulus and stress at 10% strain) and optical transmittance in the visible light region. The POSS-containing 22


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terpolymer, poly(MEA–co–MDOPA–co–MPOSS) competes very well with other catechol containing bioinspired adhesives previously reported in the literature. The cytocompatability of this terpolymer with HEK293 cells implies that the new terpolymer is a promising candidate for biomedical applications. Our study has uncovered that small amounts of POSS can be used as a convenient tool to tune multiple properties, mechanical and optical, without sacrificing other original adhesion characteristics of common catechol containing adhesives. ASSOCIATED CONTENT Supporting Information. Supporting information available – 1H, 13C, 29Si NMR spectra of polymers, FTIR spectrum of polymer, mechanical property tests of commercial polyurethanes, and UV-vis spectra of optical transmittance test. AUTHOR INFORMATION Corresponding Author *Email: [email protected] Funding Sources This work was supported by the Florida State University Energy and Materials Hiring initiative and FSU Department of Chemical and Biomedical Engineering. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT 23


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