Synthesis and characterization of PIL/pNIPAAm hybrid hydrogels

Sylvia Pfensig, Daniela Arbeiter, Klaus-Peter Schmitz, Niels Grabow, Thomas Eickner and Sabine Illner

Abstract

In this study, varying amounts of NIPAAm and an ionic liquid (IL), namely 1-vinyl-3-isopropylimidazolium bromide ([ViPrIm]+[Br]), have been used to synthesize hybrid hydrogels by radical emulsion polymerization. Amounts of 70/30%, 50/50%, 30/70%, 15/85% and 5/95% (wt/wt) of PIL/pNIPAAm were used to produce hybrid hydrogels as well as the parental hydrogels. The adhesive strength was investigated and evaluated for mechanical characterization. Thermal properties of resulting hydrogels have been investigated using differential scanning calorimetry (DSC) in a default heating temperature range (heating rate 10 K min−1). The presence of poly ionic liquids (PIL) in the polymer matrix leads to a moved LCST (lower critical solution temperature) to a higher temperature range for certain hybrid hydrogels PIL/pNIPAAm. While pNIPAAm exhibits an LCST at 33.9 ± 0.3°C, PIL/pNIPAAm 5/95% and PIL/pNIPAAm 15/85% were found to have LCSTs at 37.6 ± 0.9°C and 52 ± 2°C, respectively. This could be used for controlled drug release that goes along with increasing body temperature in response to an implantation caused infection.

1 Introduction

Hydrogels, as a separate class of polymers, are three-dimensional linked structures. They build a network of covalent and non-covalent interactions, gaining considerably in volume in the presence of water.

Biomaterials used as biocompatible coatings for implants have to support tissue integration and should offer antibacterial properties at once. Hydrogels as coatings for biomedical implants are similar to human tissue and often exhibit very good biocompatibility [1]. Furthermore, hydrogels offer inclusion and transportation of drugs [2]. The characterization of stimuli-responsive hydrogels, with an enhanced swelling behaviour responding to a change in environmental variables like temperature or pH, allows further applications, e.g. for controlled drug release [3]. Disadvantages of hydrogels are weak mechanical properties, but amazingly the toughness and fatigue resistance can be improved by crosslinking copolymerization [4].

In this study, we report first the copolymerization of the ionic liquid (IL) [ViPrIm]+[Br] with NIPAAm. Whereas pNIPAAm is the best investigated thermo-responsive hydrogel with an LCST transition at 32°C [5], [6], the N-vinylimidazolium based IL [ViPrIm]+[Br] is a less researched attractive co-monomer in biomedical applications.

Ionic liquids are classified as organic salts and existent in liquid texture at temperatures lower than 100°C without the presence of water. Specific properties can be set by structural modification [7]. By free radical polymerization of e.g. reactive vinyl groups in the presence of a crosslinker and a strong oxidizing agent stable parental and hybrid hydrogel with a defined shape can be successfully synthesized. The aim was to generate hybrid hydrogels with varied swelling properties using two different monomers with reactive vinyl and acryl groups for copolymerization. As key parameter for biomedical application the adhesive strength on implant surfaces was investigated on a specially built test setup. To investigate LCST transition as an endothermic process differential scanning calorimetry (DSC) was used.

2 Material and methods

2.1 Synthesis

In a first step, the IL 1-vinyl-3-isopropyl-imidazolium bromide ([ViPrIm]+[Br]) was prepared following a procedure already described [8].

Hybrid hydrogels have been synthesized by using varying amounts of N-isopropylacrylamide (NIPAAm) and [ViPrIm]+[Br]. Defined masses were mixed and dissolved in distilled water. Constant amounts of N,N′-methylene-bisacrylamide (MBAA) as crosslinker, ammonium peroxidesulfate (APS) as initiator and tetramethylethylenediamine (TEMED) as catalyst were added subsequently for radical polymerization into optional shapes.

Figure 1 illustrates the amounts of basic raw materials for synthesis of hybrid hydrogels PIL/pNIPAAm. The materials and chemicals have been purchased from Sigma-Aldrich (St Louis, MO, USA) and used as received.

Figure 1:
Figure 1:

Amounts of components for synthesis of hydrogels PIL and pNIPAAm and hybrid hydrogels PIL/pNIPAAm 1/2/3/4/5.

Citation: Current Directions in Biomedical Engineering 2, 1; 10.1515/cdbme-2016-0004

2.2 Characterization of adhesive strength

To simulate the connection of hydrogels to the surface of cardiovascular implants, a determination of their adhesive strength was established in dependence on DIN SPEC 91063:2011-07.

Parental hydrogels of PIL and pNIPAAm and hybrid hydrogels PIL/pNIPAAm 1/2/3 have been manufactured by casting the solution into a mold (Figure 2), where the gel polymerized for approximately 10–20 min covered by a glass plate. The stainless steel surface of the appliance wasn’t biofunctionalyzed before and no coupling agents or adhesives were used.

Figure 2:
Figure 2:

Appliance of stainless steel to determine the adhesive strength of hydrogels.

Citation: Current Directions in Biomedical Engineering 2, 1; 10.1515/cdbme-2016-0004

The sticky tape was removed and the free flap was fixed between the upper clamping jaws, while the appliance itself was placed between the lower clamping jaws of the tensile testing machine Zwick/Roell BT1-FR2.5TN.D14 (Zwick, Ulm, Germany). The sample was peeled off of the rail for at least 50 mm under uniaxial strain with a testing speed of 20 mm min1. To evaluate the test results the peel off strength (σA) is calculated as the difference of the measured peel off force (FAb) and the sample width (b0):

σA=FAb/b0

2.3 Thermal characterization

Differential scanning calorimetry was used for investigation of the basic raw materials NIPAAm and [ViPrIm]+[Br] and to compare thermal properties of parental hydrogels pNIPAAm and PIL with those of developed hybrid hydrogels PIL/pNIPAAm. The thermo-behaviour of all samples was monitored on a DSC1 STARe System (Mettler-Toledo, Gießen, Germany).

In a first instance, the melting temperature of NIPAAm and [ViPrIm]+[Br] was investigated. For each material a sample of approximately 5–10 mg was placed on aluminium DSC plates and sealed. Surrounded by nitrogen the samples were heated from 20°C to 200°C at 10 K min1.

Furthermore, three samples of parental hydrogels PIL and pNIPAAm and hybrid hydrogels PIL/pNIPAAm 1/2/3/4/5 have been analysed, respectively. Samples of approximately 5–10 mg were exempted of excessive water after swelling in PBS buffer solution (pH 7.38) for 24 h and weighed on a microscale before DSC measurement. Placed on aluminium plates and sealed as well, thermal scans of the samples were conducted at 10 K min1 to determine their LCST values as an endothermic peak during a process of heating from 0°C to 80°C.

3 Results

3.1 Adhesive strength

A test to determine the adhesive strength was executed for parental hydrogels PIL and pNIPAAm and for hybrid hydrogels PIL/pNIPAAm 1/2/3.

PIL and PIL/pNIPAAm 1 hydrogels couldn’t be peeled off without multiple cracks from the very first. For pNIPAAm, PIL/pNIPAAm 2 and PIL/pNIPAAm 3 it was feasible to peel off the hydrogels completely without a crack. The peel off strength (σA) of those hydrogels was lower than the tensile strength. The following Table 1 represents the calculated peel off strength (σA) of hydrogels.

Table 1:

Peel off strength (σA) of hydrogels PIL/pNIPAAm 2/3 and pNIPAAm as the difference of measured peel off force and sample width (10 mm).

HydrogelMass ratio (wt%)σA (N/10 mm)
PIL/pNIPAAm 250/500.04
PIL/pNIPAAm 330/700.09
pNIPAAm0/1000.11

3.2 Thermal characterization

The heat flow of basic raw materials NIPAAm and [ViPrIm]+[Br] was studied as a function of increasing temperature to determine the melting temperatures of both materials (Figure 3). Figure 3 illustrates a sharp endothermic melting peak around 50–70°C for NIPAAm. In contrast, [ViPrIm]+[Br] exhibited a broad melting peak in the range 155–170°C. The maximum of each peak indicated the melting point, respectively.

Figure 3:
Figure 3:

Heat flow as a function of increasing temperature and melting point (MP), respectively of a sample of NIPAAm (12.45 mg) and [ViPrIm]+[Br] (16.88 mg) at 10 K min1 using DSC.

Citation: Current Directions in Biomedical Engineering 2, 1; 10.1515/cdbme-2016-0004

Figure 4 illustrates the heat flow of swollen parental and hybrid hydrogels as a function of increasing temperature in a range 10–80°C. A lower critical solution temperature for pNIPAAm as well as PIL/pNIPAAm 5 and PIL/pNIPAAm 4 was shown.

Figure 4:
Figure 4:

Heat flow as a function of increasing temperature of the swollen hydrogels at 10 K min1 using DSC. LCST of pNIPAAm and PIL/pNIPAAm 4/5 is illustrated.

Citation: Current Directions in Biomedical Engineering 2, 1; 10.1515/cdbme-2016-0004

While the hybrid hydrogels PIL/pNIPAAm 5 and PIL/pNIPAAm 4 exhibited broad LCST transitions (35–44°C and 40–60°C), pNIPAAm showed its relatively sharp characteristically LCST around 34°C. In Table 2, a review of LCST of investigated hydrogels is given (n = 3). The hydrogels PIL and PIL/pNIPAAm 1/2/3 exhibited a broad and featureless DSC profile within the temperature range.

Furthermore all hybrid hydrogels and PIL exhibited an artefact as a small and sharp exothermic peak around 26°C.

Table 2:

Measured LCST of investigated hydrogels pNIPAAm and PIL/pNIPAAm 4/5 (mean ± SD).

HydrogelMass ratio (wt%)σA (N/10 mm)
PIL/pNIPAAm 415/8552 ± 2
PIL/pNIPAAm 55/9537.6 ± 0.9
pNIPAAm0/10033.9 ± 0.3

4 Discussion

In the presented study hybrid hydrogels of pNIPAAm and PIL were synthesized successfully by adding crosslinker, initiator and catalyst to a solution of the main components.

The adhesive strength of hydrogels to a stainless steel substrate was investigated to simulate the connection of hydrogels to the surface of cardiovascular implants. No peel off strength (σA) could be calculated for PIL and PIL/pNIPAAm 1 hydrogels. The tensile strength was higher than interconnections within the hydrogel matrix so that the hydrogels disintegrated. In a first test, increasing peel off strength was observed for hybrid hydrogels with higher amount of pNIPAAm. To make a clear assessment about the correlation between peel off strength and the behaviour of hydrogels as coatings for implant surfaces, further tests will be necessary.

For thermal characterization, DSC was used determining material properties as the melting point. Furthermore, hydrogels have been investigated on existence of LCST transition. No explicit statement for an artefact that all hydrogels exhibited around 26°C could be made. The thermo-responsive hydrogel pNIPAAm showed a characteristically LCST at 33.9 ± 0.3°C. Hybrid hydrogels with high amounts of NIPAAm exhibited a shifted and broader endothermic peak indicating LCST transition. The hybrid hydrogel PIL/pNIPAAm 5 with an amount of 5% IL and 95% NIPAAm exhibited an LCST at 37.6 ± 0.9°C, while PIL/pNIPAAm 4 with an amount of 15% IL and 85% NIPAAm exhibited an LCST at 52 ± 2°C. Thus, it could be revealed, that LCST of pNIPAAm can be influenced and shifted to higher temperatures by copolymerization with the IL 1-vinyl-3-isopropylimidazolium bromide.

In conclusion, hybrid hydrogels of NIPAAm and [ViPrIm]+[Br] have been synthesized successfully in different mass ratios with new deviating material properties. Characterization of adhesive strength of parental and hybrid hydrogels exhibited significant differences. Thermal characterization by DSC demonstrated, that LCST of pNIPAAm can be influenced significantly by co-polymerization of NIPAAm with [ViPrIm]+[Br]. This allows an adjustment of LCST and might be useful for controlled drug release to treat infection after medical implantation that goes along with increasing body temperature.

Built on these findings, a continuative evaluation containing the thermo-responsive swelling behavior and further mechanical characteristics of the hybrid hydrogels will be published.

Acknowledgement

Financial support by the Federal Ministry of Education and Research (BMBF) within RESPONSE “Partnership for Innovation in Implant Technology” is gratefully acknowledged.

Author’s Statement

Research funding: The author state no funding involved. Conflict of interest: Authors state no conflict of interest. Material and Methods: Informed consent: Informed consent is not applicable. Ethical approval: The conducted research is not related to either human or animal use.

References

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    Buwalda SJ, Boere KWM, Dijkstra PJ, Feijen J, Vermonden T, Hennink WE. Hydrogels in a historical perspective: from simple networks to smart materials. J Control Release. 2014;190:254–73.

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    Caló E, Khutoryanskiy VV. Biomedical applications of hydrogels: a review of patents and commercial products. Eur Polym J. 2015;65:252–67.

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    Chung J, Yokoyama M, Aoyagi T, Sakurai Y, Okano T. Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers. J Control Release. 1998;53:119–30.

  • [4]

    Sun J-Y, Zhao X, Illeperuma WRK, Chaudhuri O, oh KH, Mooney DJ, et al. Highly stretchable and tough hydrogels. Nature. 2012;489:133–6.

  • [5]

    Heskins M, Guillet JE. Solution properties of poly(N-isopropylacrylamide). J Macromol Sci. 1968;A2:1441–55.

  • [6]

    Schild HG, Tirrel DA. Microcalorimetric detection of lower critical solution temperatures in aqueous polymer solutions. J Phys Chem. 1990;94:4352–6.

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    Angell AC, Ansari Y, Zhao Z. Ionic liquids. Past, present and future. Faraday Discuss. 2012;514:9–27.

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    Pinaud J, Vignolle J, Gnanou Y, Taton D. Poly(N-heterocyclic-carbene)s and their CO 2 adducts as recyclable polymer-supported organocatalysts for benzoin condensation and transesterification reactions. Macromolecules. 2011;44:1900–8.

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  • [1]

    Buwalda SJ, Boere KWM, Dijkstra PJ, Feijen J, Vermonden T, Hennink WE. Hydrogels in a historical perspective: from simple networks to smart materials. J Control Release. 2014;190:254–73.

  • [2]

    Caló E, Khutoryanskiy VV. Biomedical applications of hydrogels: a review of patents and commercial products. Eur Polym J. 2015;65:252–67.

  • [3]

    Chung J, Yokoyama M, Aoyagi T, Sakurai Y, Okano T. Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers. J Control Release. 1998;53:119–30.

  • [4]

    Sun J-Y, Zhao X, Illeperuma WRK, Chaudhuri O, oh KH, Mooney DJ, et al. Highly stretchable and tough hydrogels. Nature. 2012;489:133–6.

  • [5]

    Heskins M, Guillet JE. Solution properties of poly(N-isopropylacrylamide). J Macromol Sci. 1968;A2:1441–55.

  • [6]

    Schild HG, Tirrel DA. Microcalorimetric detection of lower critical solution temperatures in aqueous polymer solutions. J Phys Chem. 1990;94:4352–6.

  • [7]

    Angell AC, Ansari Y, Zhao Z. Ionic liquids. Past, present and future. Faraday Discuss. 2012;514:9–27.

  • [8]

    Pinaud J, Vignolle J, Gnanou Y, Taton D. Poly(N-heterocyclic-carbene)s and their CO 2 adducts as recyclable polymer-supported organocatalysts for benzoin condensation and transesterification reactions. Macromolecules. 2011;44:1900–8.

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Current Directions in Biomedical Engineering is an open access journal and closely related to the journal Biomedical Engineering - Biomedizinische Technik. CDBME is a forum for the exchange of knowledge in the fields of biomedical engineering, medical information technology and biotechnology/bioengineering for medicine and addresses engineers, natural scientists, and clinicians working in research, industry, or clinical practice.

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  • View in gallery

    Amounts of components for synthesis of hydrogels PIL and pNIPAAm and hybrid hydrogels PIL/pNIPAAm 1/2/3/4/5.

  • View in gallery

    Appliance of stainless steel to determine the adhesive strength of hydrogels.

  • View in gallery

    Heat flow as a function of increasing temperature and melting point (MP), respectively of a sample of NIPAAm (12.45 mg) and [ViPrIm]+[Br] (16.88 mg) at 10 K min1 using DSC.

  • View in gallery

    Heat flow as a function of increasing temperature of the swollen hydrogels at 10 K min1 using DSC. LCST of pNIPAAm and PIL/pNIPAAm 4/5 is illustrated.