Vinodh
Rajendra
,
Yang
Chen
and
Michael A.
Brook
*
Department of Chemistry, McMaster University, 1280 Main St. W., Hamilton, ON, Canada L8S 4M1. E-mail: mabrook@mcmaster.ca; Fax: +1 905 522 2509; Tel: +1 905 525 9140
First published on 21st December 2009
The controlled generation of hydrophilic structures within hydrophobic polymers can be challenging. Very few examples of such structures have been described for silicones. We now report that such structures can be encoded in the air-contacting layer of a silicone elastomer by the formation of silica domains from tetraethoxysilane, optionally in the presence of poly(ethylene glycol) (PEG), using a surface active aminopropylsilicone catalyst and moisture cure. The control of the relative modulus at the upper versus lower layers and the degree and type of hydrophilic structuring requires control over the efficiency of delivery of water to the core of the pre-elastomer, which is facilitated by the surface active catalyst and may additionally be manipulated by the addition of PEG.
Silicone elastomers have also been broadly used as components in drug delivery systems. With rare exception,8–10only hydrophobic drugs that readily diffuse through silicones have been delivered, either internally or topically.11The delivery of hydrophilic drugs from silicones, by contrast, requires internal structuring of the silicone such that water can penetrate, and the hydrophilic drug can then escape the body of the silicone elastomer. Such structuring has previously been achieved by the use of proteins,8 or the use of surfactants generated by the drug itself.9
The objective of the current study was to develop synthetic strategies that would permit the structuring of silicones in two different ways. First, it should be possible to control the hydrophilicity and roughness of the interface that would ultimately contact a biological environment and, second, the silicone elastomer proximal to the external interface should be internally structured so that the modulus can be controlled and that hydrophilic domains can be incorporated, which would ultimately mediate the release profile of hydrophilic drugs. Both elements should affect in a positive way the biocompatibility of silicone elastomers.
The strategy adopted makes use of previous observations9 that poly(ethylene glycol) (PEG), a polymer widely recognized for its biocompatibility,12 can be incorporated in silicones to facilitate water ingress and subsequent rates of bioactive release. Although there have been several studies in which internal structuring of two different domains was accomplished using covalent linkages,13,14 we chose to use PEG that was not chemically tethered to the silicone. Instead, structuring was provided by the presence of silica synthesized in situ during polymerization. We describe below the preparation of silicone elastomers with structurally controlled surface chemistry, morphology and, additionally, internal structuring of the silicone in the vicinity of the air interface, by use of a combination of cure kinetics and surface-active agents.
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Fig. 1 Structure of DC 3225c. |
Compound | Controls (entries 1–5)a | Varying TEOS (entries 6–10) | Varying catalyst (entries 11–13) | Controls at 90% humidity (entries 14–18) | Varying TEOS at 90% humidity (entries 19–23) | 1% DC 3225C (entry 24) | 5% DC 3225C (entries 25–27) |
---|---|---|---|---|---|---|---|
a Refers to specific formulations described in more detail on Table 2. | |||||||
PDMS | 2.125–1.625 (85–65%) | 2.000–1.500 (80–60%) | 1.900–1.750 (76–70%) | 2.125–1.625 (85–65%) | 2.000–1.500 (80–60%) | 1.725 (69%) | 1.775–1.700 (71–68%) |
TEOS | 0.125–0.625 (5–25%) | 0.125–0.625 (5–25%) | 0.375 (15%) | 0.125–0.625 (5–25%) | 0.125–0.625 (5–25%) | 0.375 (15%) | 0.375 (15%) |
Aminopropyl-terminated PDMS | 0.250 (10%) | 0.250 (10%) | 0.100–0.250 (4–10%) | 0.250 (10%) | 0.250 (10%) | 0.250 (10%) | 0.100–0.175 (4–7%) |
PEG | 0 | 0.125 (5%) | 0.125 (5%) | 0 | 0.125 (5%) | 0.125 (5%) | 0.125 (5%) |
DC 3225C | 0 | 0 | 0 | 0 | 0 | 0.025 (1%) | 0.125 (5%) |
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Fig. 2 Preparation of elastomers for fluorescence microscopy. |
Scanning electron microscope (SEM) images of elastomers were obtained using a JEOL 7000F SEM at an accelerating voltage of 5 kV. Energy dispersive X-ray (EDX) analysis was performed on the JEOL 7000F SEM at 10 kV. When obtaining cross sections, elastomers were initially frozen in liquid nitrogen and then fractured before mounting.
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Fig. 3 General chemical equation for RTV silicone crosslinking. |
Hydrophilic domains were to be introduced into the elastomer using two strategies: silica formed from TEOShydrolysis, as noted above, and the use poly(ethylene glycol), which was optionally added into the pre-elastomer formulation. It was recognized that efficient distribution of the PEG into the silicone, particularly as channels rather than droplets, might require the presence of surface-active agents because of the near immiscibility of the two materials. Therefore, a siliconesurfactant based on PEG and silicones (DC 3225C) was optionally added to the pre-elastomer mixture. Thus, mixing the precursors (Table 1, Table 2), placing them in an open vessel lined with a Teflon® film and allowing them to cure at ambient temperature for up to 4 days led to translucent or opaque silicone elastomers.
Entry | Elastomera | Translucent or opaque | Phase separation | Homogeneous (Y/N) | Surface hardnessb | Bottom hardnessb |
---|---|---|---|---|---|---|
a For more detailed formulations, see Table 1. b Arbitrary hardness scale where 1 = viscous liquid, 5 = shore A hardness of 40, 10 = hard/brittle rubber. | ||||||
Effect of TEOS | Humidity = 20–30% | |||||
Samples | Without PEG | |||||
1 | 5% TEOS | T | Liquid on surface | Y | 3 | 3 |
2 | 10% TEOS | T | None | N | 5 | 3 |
3 | 15% TEOS | T | None | N | 7 | 4 |
4 | 20% TEOS | T | None | N | 8 | 2 |
5 | 25% TEOS | T | None | N | 10 | 1 |
Samples | Containing PEG | |||||
6 | 5% TEOS | O | Liquid on surface | Y | 4 | 4 |
7 | 10% TEOS | O | None | N | 5 | 4 |
8 | 15% TEOS | O | None | N | 7 | 4 |
9 | 20% TEOS | O | None | N | 8 | 4 |
10 | 25% TEOS | O | None | N | 10 | 5 |
Effect of catalyst | Humidity = 20–30% | |||||
11 | 10% Cat. | O | None | N | 7 | 4 |
12 | 7% Cat. | O | None | N | 6 | 4 |
13 | 4% Cat. | O | None | Y | 5 | 5 |
Effect of humidity | Humidity = 90% | |||||
Samples | Without PEG | |||||
14 | 5% TEOS | T | Liquid on surface | Y | 4 | 4 |
15 | 10% TEOS | T | None | Y | 5 | 5 |
16 | 15% TEOS | T | None | Y | 5 | 5 |
17 | 20% TEOS | T | None | N | 6 | 5 |
18 | 25% TEOS | T | None | N | 8 | 4 |
Samples | Containing PEG | |||||
19 | 5% TEOS | O | Liquid on surface | Y | 4 | 4 |
20 | 10% TEOS | O | None | Y | 5 | 5 |
21 | 15% TEOS | O | None | Y | 5 | 5 |
22 | 20% TEOS | O | None | N | 6 | 5 |
23 | 25% TEOS | O | None | N | 6 | 5 |
Effect of surfactant | Humidity = 20–30% | |||||
24 | 1% S, 10% Cat. | O | None | N | 7 | 5 |
25 | 5% S, 10% Cat. | O | None | N | 7 | 5 |
26 | 5% S, 7% Cat. | O | None | N | 6 | 5 |
27 | 5% S, 4% Cat. | O | None | Y | 5 | 5 |
Our objective was to create surface-modified silicones with hydrophilic domains, which could be accomplished by controlling the relative rates of crosslinking, silica formation, and the rates of diffusion of reagents through the uncured mixture. The silicones formulated here cured slowly and, only exceptionally, led to homogenous materials. In general, the elastomer cured asymmetrically, generating an elastomer with a higher modulus proximal to the air-contacting surface, and softer elastomers beneath. The natures of the silicones produced were examined as a function of aminopropylsilicone catalyst, water, and TEOS concentrations.
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Fig. 4 A: Nitrogen (catalyst) concentration (XPS) at surface with varying TEOS concentrations at different take-off angles (the 15% sample was examined at 2 different angles than the other samples). B: Ninhydrin staining showing presence of catalyst preferentially at the air interface. |
Angular-dependent XPS measurements also showed that the amine preferentially resided at the air interface. As noted above, asymmetry of the elastomer increased with TEOS concentration. Asymmetry correlated inversely with the amine concentration at the air interface (Fig. 4, see also ESI† ): more highly asymmetric materials exhibited lower surface levels of amine. In the case of the elastomer prepared with only 5 wt% TEOS (Table 2, entry 6), a viscous liquid phase separated from the elastomer. 1H NMR spectra showed that the phase-separated liquid contained ∼40 mg of catalyst (of 250 mg, 16%), ∼12.5 mg of PEG (of 125 mg, 10%) and less than ∼21.3 mg of PDMS (of 2.0 g, Table 1, Table 2, about 1%).
The preferential presence of the amine at the interface, a consequence of efficient migration to the interface which has previously been seen with aminopropyltrialkoxysilanes in epoxypolymers,19 manifests itself in various ways. The aminopropylsilicone, while less effective than the traditional and more efficient tin- or titanium-based RTV catalysts, still facilitates both curing of the silicone and formation of silica. Appropriate formulation thus permits simultaneous control of surface morphology, roughness and hydrophilicity: at pH values near neutrality, amine groups will be protonated leading to surface charge and, as discussed below in more detail, surface active species that may assist in geometric control of the silica formed.
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Fig. 5 A: Roughness of surfaces with increasing crosslinker by profilometry (Table 2, entries 6–10). B: Roughness of surfaces with increasing crosslinker at 90% RH by profilometry (Table 2, entries 14–23). C: Wavelength of elastomers cured at 90% RH (Table 2, entries 16, 17, 19–23). |
There was an inverse trend between catalyst concentration and roughness. With the crosslinker TEOS concentration fixed at 15 wt%, elastomers were prepared using catalyst concentrations between 4 and 10%. The highly inhomogeneous elastomers prepared at 10% and 7% catalyst, respectively, exhibited roughnesses of 2.86 μm and 2.16 μm (Fig. 6A, ESI† ). By contrast, the homogenous elastomer prepared with 4% catalyst had an Rq value of 364 nm, making it significantly smoother than those prepared with higher catalyst levels (Fig. 6B).
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Fig. 6 Profilometry images of elastomers prepared with 15% TEOS and A: 10% catalyst (Table 2, entry 11), B: 4% catalyst (Table 2, entry 13). Scale bars represent 50 μm. C: SEM image of elastomer prepared with 25% TEOS, 10% catalyst, and 90% RH (entry 23). Scale bar represents 1 mm. |
Atmospheric moisture also had a significant impact on the surface roughness of the elastomers. When the same formulations as those just described were cured at high humidity (90% RH) random structures on the surface did not form and instead highly corrugated, macroscopic wave structures formed on elastomers (Fig. 5B,C). These waves could be readily seen by eye, with wavelengths of up to 880 μm (Fig. 6C, ESI† ). In the absence of PEG, only pre-elastomers containing 15% or 20% crosslinker developed these structures. In the presence of PEG, however, all elastomer formulations developed waves but with shorter wavelengths and greater amplitudes than when PEG was absent (Fig. 5B,C).
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Fig. 7 Fluorescence images of elastomers with varying amount of crosslinker. A: 5%. B: 15%. C: 25% (Table 2, entries 6, 8 and 10). Scale bar = 500 μm. |
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Fig. 8 Fluorescence images of elastomers prepared with 15% TEOS and A: 1% surfactant (S), 10% catalyst (C), B: 5% (S) 10% (C), C: 5% (S) 7% (C), D: 5% (S) 4% (C) (Table 2, entries 24–27). Scale bar = 500 μm. |
In the silicone elastomers described above, the use of an atypical (slow) catalyst, aminopropylsilicone, in low viscosity, unfilled RTV systems, alters the cure profile significantly. Only in cases where water ingress is appreciably faster than either crosslinking or silica formation is a homogeneous silicone formed. Such cases occurred at high RH, low TEOS concentrations and/or low catalyst concentrations. Even in such cases, however, inhomogeneity can result if the water must travel relatively long distances through the silicone. For example, the low surface area/volume sample (1 × 1 × 4.5 cm deep) gave a highly cured elastomer only to a depth of about 0.5 cm even with cure at 90% RH. Thus, in general, crosslinking and silica formation occurred faster, and to a greater extent, at the air interface of these silicones.
The structural features of greatest interest of these asymmetric cured silicones are: interfacial hydrophilicity, roughness, and internal structuring. The synthetic parameters that allowed their control (Table 2) are examined in turn. The amine catalyst (Fig. 3) has a nitrogen content about 4.4 atom%. As seen from Fig. 4, the surfaces of the cured silicone elastomer can be highly enriched in catalyst (nearly 25% of the material present) at the upper interface.19 The degree to which the upper interface is populated by amines is a function of the catalyst concentration, and of the TEOS and water concentrations. More rapid cure and higher concentrations of TEOS were associated with decreased catalyst presence at the interface. The catalyst thus diffuses to the interface unless extensive silica formation occurs more rapidly. Amine groups near neutral pH are protonated in aqueous media, which will impact both on the cure chemistry (see below) and the chemistry of the interface. Cationic surfaces have been proposed to be beneficial with biomaterials because they support cell growth (following adsorption of plasma proteins).
Higher concentrations of TEOS, and of catalyst, but lower water concentrations led to high degrees of crosslinking and of silica formation at the air interface (Fig. 9). At ambient humidity, the reactions at the interface, and diffusion of the reagents within the silicone to the surface, occur more rapidly than water vapor can diffuse into the silicone. At the extreme, with high levels of catalyst and TEOS under relatively dry conditions, rough, brittle layers form on top of nearly uncured silicone elastomers. Decreasing concentrations of either TEOS or catalyst, or increased water concentrations enhanced the thickness of the more highly cured and filled upper layer. Note that thicker overlayers were formed when PEG was present in the formulations. The hydrophilic nature of PEG provides a mechanism to deliver water further into the silicone than in its absence. That is, PEG lowers the barrier for water transmission such that the ratio of internal vs. surface crosslinking/silica formation is increased. Thus, as a consequence of the clear differences in reaction rates between cure/silica formation and the diffusion of moisture, it is possible to control both the modulus of the silicone at the air interface and the interfacial hydrophilicity.
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Fig. 9 Asymmetry caused by increasing crosslinker. With increasing TEOS concentration, A: dispersed silica particles, B: assembled into ribbons, and then, C: into three-dimensional networks. |
At low humidity, very rough surfaces were observed at high concentrations of TEOS. Highly reticulated brittle surfaces, comprised mostly of silica, are unable to anneal during cure, leading to rough, kinetically formed structures. By contrast, when excess water was present, and particularly when PEG was present to deliver water into the core of the elastomer, well-defined waves could be clearly seen even by eye at the external interface. The wavelength (up to nearly 1 mm) and amplitude (up to 250μm, see ESI† ) of these waves were affiliated with much lower surface crosslink densities, but higher than the underlayers. Such waves, particularly on silicone elastomer surfaces, have previously been examined by a variety of authors.23–27 During cure, two elastomer layers form. The higher modulus elastomer at the air interface shrinks and the resulting waves are a consequence of yielding of the lower modulus underlayer. As seen from Fig. 5, the amplitude and wavelength of the surface can be manipulated over a large range particularly by changing the TEOS concentration, which directly correlates both with chemical crosslinking, and physical crosslinking via the silica particles.
Two features in particular controlled the nature of the internal hydrophilic structuring: TEOS concentration and the presence of surface-active species. As the concentration of TEOS increased, isolated particles first became linear ‘ribbons’ and then three-dimensional network structures (Fig. 7B,C, Fig. 9, ESI† ). The facility for 3D structuring increased with catalyst concentration (data not shown) and when silicone/PEGsurfactants were added (3225C, Fig. 8).
Two independent but closely related processes are occurring during hydrolysis and condensation: crosslinking of the siliconepolymer, and formation of silica due to the large excess of TEOS present. Of course, these processes are not mutually exclusive. While a single TEOS atom could lead to a 3- or 4-armed branch point (Fig. 3), condensation of the silicone can occur with silicic acid oligomers or silica ribbons/particles. Reinforcement of the silicone can also occur through physical interactions with silica. We focus now on the formation of silica.
The hydrolysis of TEOS is very slow at neutral pH. By contrast, rates increase rapidly away from pH 7. This pH sensitivity has been exploited to control silica structuring in various ways, perhaps most famously in the formation of model silicacolloids by Stöber, in which TEOS is hydrolyzed in ethanol with ammonia catalysis.28 We propose that analogous pH control is provided by the amino group on the aminopropylsilicone catalyst to facilitate hydrolysis/condensation of TEOS, yielding silica, primarily in particulate form.
The organization of the hydrophilic silica/PEG domains can be understood by considering the templated synthesis of meso- and macroporous silica from TEOS using surfactants. Perhaps best known of these are the syntheses of zeolites such as MCM-41 in which surfactants such as CTAB create cylinders around which silica synthesis occurs.29 Normally, such syntheses are undertaken in hydrophilic solvents, which may be aqueous or alcohol based, although strategies for assembly in organic solvents have been elegantly reviewed by Morris and Weigel.30
As with any of the templating processes used to prepare zeolites and other mineral species, a surface-active material guides the assembly of these structures by interactions occurring, in part, between complementary charged species. We propose, in the silicone elastomers formed using aminopropylsilicone catalysts, that the ammonium ions on the catalyst can interact with silanolates on silica surfaces (see model in Fig. 10). The polar silica interface is stabilized in the hydrophobic silicone elastomer matrix by such an interaction. Similar types of interactions, although based on non-ionic/polar interactions can occur when the siliconesurfactant 3225C is present (Fig. 8, Fig. 10). Such interactions have been used to direct the assembly and porosity of silica particles31 and silica monoliths.32As the concentration of surfactant is increased, the hydrophilic silica domain size is decreased (Fig. 8).
The biocompatibility of silicone species relies on interactions that take place at the interface of the device. As shown above, the use of a surface active catalyst in an RTV system, in combination with control of crosslinker and water concentrations, permits the preparation of elastomer surfaces with controlled geometry and with internal hydrophilic structuring. We shall report in due course on the biocompatibility of such systems per se, and the ability to release hydrophilic bioactive species from the structured silicones.
Footnotes |
† Electronic supplementary information (ESI) available: 1H NMR of liquid separated from the 5% TEOS elastomer (Table 2, entry 6), N atm% XPS data for over and underlayers as a function of TEOS concentration (Table 2, entries 7–10), surface profilometry images (Table 2, entries 6–10), Table of amplitudes and SEM images of surface waves (Table 2, entries 19–21), fluorescence microscope images (Table 2, entries 11–13). See DOI: 10.1039/b9py00220k |
‡ Surface profilometry provides roughness as Rq, ![]() |
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