Hydrogel with Antifouling and Bacteria Releasing Properties

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Materials and Interfaces

“Janus-Featured” Hydrogel with Antifouling and Bacteria Releasing Properties Jiahui Wu, Dong Zhang, Xiaomin He, Yang Wang, Shengwei Xiao, Feng Chen, Ping Fan, Mingqiang Zhong, Jun Tan, and Jintao Yang Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.9b02984 • Publication Date (Web): 20 Aug 2019 Downloaded from pubs.acs.org on August 21, 2019

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“Janus-Featured” Hydrogel with Antifouling and Bacteria Releasing Properties

Jiahui Wu†, Dong Zhang†, ¶, Xiaomin He†, Yang Wang†, Shengwei Xiao†, Feng Chen†, Ping Fan†, Mingqiang Zhong†, Jun Tan‡* and Jintao Yang†*

† College of Materials Science& Engineering Zhejiang University of Technology, Hangzhou 310014, P. R. China

‡ College of Biological, Chemical Science and Technology Jiaxing University, Jiaxing 314001, P. R. China ¶

Department of Chemical and Biomolecular Engineering The University of Akron, Akron, Ohio 44325, USA

*Corresponding Author: J.T. [email protected]; J.Y. [email protected]

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ABSTRACT “Janus-featured” hydrogels with different structure and function for each layer can be particularly important in diverse application. However, very few research has been conducted on multifunctional “Janus featured” hydrogel, and significant challenge for simple, rapid and efficient fabrication of such hydrogels remains. Herein, “Janus featured” polyHEAA (poly(N-hydroxyethyl acrylamide)) hydrogel loaded with modified silica nanoparticle was fabricated by a supergravity method. Silica nanoparticles grafted with polyDVBAPS (poly(3-(dimethyl(4-vinylbenzyl) ammonio) propyl sulfonate)) were first prepared and then introduced into progel of polyHEAA hydrogel. During the formation of the hydrogel, a supergravity resulted from centrifugation was applied, from which silica nanoparticles moved to one side of the hydrogel, forming “Janus-featured” hydrogels, i.e. a pristine polyHEAA layer and a composite layer. These two layers showed different properties, where the prinstine polyHEAA layer showed excellent antifouling property by resisting the bacteria adsorption (< 106 cells/cm2) for up to 5 days, and the nanoparticle-loaded hydrogel layer showed excellent bacteria release properties by releasing > 94% adherent bacteria upon a simply treatment of 2.0 M NaCl solution for 10 min. Additional, the hydrogel showed good biocompatibility, as indicated by the cell viability of ~85%. Through this work, we expect that our interesting strategy may provide a new method for the fabrication of “Janus featured” hydrogel and hopefully offers reference significance for the design of hydrogel-based wound dressing in the near future.

Key words: “Janus-Featured” hydrogel, polyzwitterionic brushes, salt-responsive, antifouling

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1. INTRODUCTION Materials with Janus structure as an emerging concept have attracted widespread attention result from its wide range applications over the past years. Generally, “Janus” stems from ancient, two-faced Roman god, which tries to describe the two faces with asymmetry properties nowadays.1 Because the nature of asymmetry often endows material itself further diverse performances, Janus materials currently have already designed in various fields, such as interface catalysis2-3, compatibilization4-5, humidity stress sensor6, actuators7-8 , oil/water separation9, etc., and have become a research hotspot in the field of interfacial science. Newly asymmetric Janus material have been intensively developed in recent years

10-14.

The

application of Janus structures material is broadened, and the forms are diversely include papers, sheets, membranes and hydrogel. Among these material, Janus hydrogel have received widespread attention in recent years due to its special structure and property15. The asymmetry structure and property have been further used for exploring the effects chirality on cell behavior, tissue engineering and responsive soft robots. Several methods have been developed for the fabrication of Janus hydrogel, including copolymerizing opposite property monomer with the double bond groups introduced onto a hydrogel surface previously16, combining two different hydrogels17 and using two different hydrophilic/hydrophobic plate molds during gelation18. Although many advances in this field have been achieved, some challenges still remain, in particular, simple, rapid, and efficient fabrication methods are highly desirable. Due to the intrinsic transparence, softness, and biocompatibility, the use of hydrogel as wound dressing shows great potential in real-world applications as compared to other materials

19-21.

Many

efforts have been made on newly hydrogel wound dressings with superior antifouling property to 3


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improve the traditional wound dressings 22-27. Hydrogel wound dressings have got great development in recent years, from single function to multifunction and become smarter, such as stimuli-responsive hydrogels

28-34.

However, the preparation methods for antibacterial wound dressing are complicate.

Moreover, almost all hydrogel wounding dressings with single function or multi-function are uniform in their structures. Interestingly, anisotropic or Janus-featured hydrogel seems to have more potential to build novel platform for wound dressing. Normally, the wound has been cleaned and sterilized before coating the wound dressing. Therefore, the most important function for the dressing side contacting with the wound, in the initial period, is providing a moist and isolated environment for cell growth, tissue repair and defending outer bacteria intrude, and the side exposed to the air should prevent the adhesion of bacteria and release the bacteria adsorbed on the surface from outer environment to defend the bacteria invasion. Based on previous efforts on antibacterial hydrogels from our group35, herein, we tried to present a universal strategy that effectively integrate the “Janus featured” structure into the hydrogel to achieve more interesting design. A kind of “Janus-featured” multi-functional hydrogel with long-term bacteria resistance and salt-responsive capability was fabricated by supergravity method under a certain centrifugal force. Salt-responsive silica nanoparticles were firstly synthesized by Stöber way and subsequently graft of polyzwitterionic brushes using surface-initiated atom transition radical polymerization (SI-ATRP). Sequential aggregation and distribution of silica nanoparticles grafted with polyDVBAPS (poly(3-(dimethyl(4-vinylbenzyl) ammonio) propyl sulfonate)) in polyHEAA under supergravity force enabled construction of “Janus-featured” hydrogel with different function for each layer. Due to the long-term and ultralow fouling property of polyHEAA, the hydrogel exhibited effective bacteria resistance for a long period of time (up to 5 days). More 4



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interestingly, the inevitably/eventually attached bacteria from outer environment can be removed by the conformation change and hydration of polyzwitterionic brush in 2.0 M NaCl solution for 10 min, achieving the surface regeneration in the nanoparticle aggregation side. Overall, our strategy is not just to come up with one-step preparation of “Janus-featured” hydrogel endowed with dual biological functions, but also develop a platform for novel hydrogel-based wound dressing by introducing more biocompatible agents into “Janus-featured” system.

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2. EXPERIMENTAL SECTION

Scheme 1. Schematic illustration of the fabrication of SNPs-g-polyDVBAPS and “Janus featured”-featured polyHEAA@SNPs-g-polyDVBAPS hydrogel based on supergravity method. First, salt-responsive nanoparticles grafted polyzwitterionic brushes (SNPs-g-polyDVBAPS) were synthesized by SI-ATRP. The size of the nanoparticle was increased because the chain segments of grafted polymer brushes could be extended in saline. When these nanoparticles switch to water system, the particle size decreased due to the contraction of the chain segments. Moreover, this trend was reversible and can also be observed in “Janus-featured” polyHEAA@SNPs-g-polyDVBAPS hydrogel. Here, due to the supergravity provided during the polymerization, the salt-responsive nanoparticles can aggregate on the one layer of the hydrogel and present unique 6



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“Janus-featured” structures.

2.1 Materials. Tetraethyl orthosilicate, ammonium hydroxide (27 %), 2-bromoisobutyryl bromide, 4-Vinlybenzyl chloride (90 %), dimethylamine solution (40 wt % in H2O ), 1,3-propane sultone (98%), 2,2,2-trifluoroethanol, 3-Aminopropyltriethoxysilane (APTES), copper(I) bromide (CuBr, 98 %) and phosphate buffer saline (PBS, pH 7.4, 0.15 M, 138 mM NaCl, 2.7 mM KCl), potassium persulfate (KPS), 2-bromoisobutyryl bromide and N,N,N',N'-Tetramethyl ethylenediamine (TEMED) were purchased from Sigma-Aldrich (Shanghai), Co. and used as received. N, N’-Methylenebisacrylamide (MBA, 99%) were obtained from Aladdin (Shanghai). 3-(dimethyl (4-vinylbenzyl) ammonium) propyl sulfonate (DVBAPS) as the monomer was synthesized according to our previous report. N-(2-hydroxyethyl)acrylamide (HEAA, stabilized with MEHQ, 98%), Tris[2-(dimethylamino)-ethyl]amine (Me6TREN, 99.0 %) were purchased from TCI Co., Ltd. Water used in these experiments was purified by a Millipore water purification system with a minimum resistivity of 18.0 MΩ cm. All other reagents and solvents were commercially obtained at extra-pure grade and were used as received without any purification. 2.2 Preparation of SNPs-g-polyDVBAPS via the SI-ATRP method. Silicon nanoparticle with an average diameter of ~163 nm was synthesized by traditional Stöber way. Cleaned silicon nanoparticles was dispersed in ethanol (45 ml), and ammonium hydroxide (50 μL) was added to adjust the pH of the solution. APTES (0.4 ml, 1.7 mmol) was added to the reaction system dropwisely. Stirring the solution for about 12 h under 60 °C. Aminated silicon nanoparticle was collected under 8000 centrifugal speed. Aminated silicon nanoparticle was dispersed in toluene (50 ml). 2-bromoisobutyryl bromide (0.25 ml) was injected to the solution under 0 °C. The mixture reacted under 0 °C for 30 minutes, and then reacted at room temperature for about 12 h. The reaction 7


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product was collected under the centrifugal speed of 8000 rpm and then dried at 50 °C in a vacuum oven. PolyDVBAPS-based brushes were synthesized by SI-ATRP from initiator-functionalized silicon nanoparticle surface (Scheme 1). Typically, the monomer (3.92 mmol), SNPs-Br (4 mg), 2, 2, 2-Trifluoroethanol (4 mL), water (3 mL), Me6TREN (14 μL) were added carefully into the reaction tube. The oxygen in mixture was removed by bubbling through a stream of nitrogen for 30 min. Then, syringing the mixture into another reaction tube containing a 14 mg portion of CuBr (0.098 mmol) under nitrogen protection. The tube was subjected to evacuation-nitrogen purging and kept at 60 °C temperature for the SI-ATRP reaction for pre-specified time. The reaction was terminated by exposed to air and cooled down to the room temperature. Finally, polyDVBAPS-grafted silicon nanoparticles was dispersed in water and centrifuge for several cycles to remove the free polymer absorbed on its surface, then vacuum drying for 24 hours at 80 °C. 2.3

Synthesis

of

“Janus-featured”

polyHEAA@

SNPs-g-polyDVBAPS

hydrogel.

SNPs-g-polyDVBAPS (0.004 g), KPS (0.05 g) and MBA (0.004 g) was added to the mixing solution of HEAA (0.83 g) and deionized water (1 ml) at room temperature. The solution was stirred for pre-specified time to fully disperse the solid particle. Then, TEMED (2.5 μL) as accelerator was added to the solution. The mixed solutions were gently injected into a gap of glass-mold separated by a piece of polytetrafluoroethylene (PTFE) space at once. The distance between two glass-mold was 1 mm. Then the glass-mold was placed vertically in a centrifuge tube and the polymerization was carried out under 3000× centrifugation rate for 20 min. After about 12 h, the “Janus featured” hydrogels were swelled in deionized water to remove unreactive material. 2.4 Nanoparticle and hydrogel characterization by FT-IR. Fourier transform infrared spectra of 8



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the SNPs, SNPs-Br and SNPs-g-PolyDVBAPS recorded on Nicolet 6700 spectrophotometer, with the samples dried and dispersed in KBr pellets. FT-IR measurement was also used to evaluate the chemical structure of freeze-dried “Janus featured” hydrogel with resolution at 4 cm−1 and scans at 32. 2.5 Nanoparticle characterization by TG. Thermo gravimetric analysis was performed using a TA Q5000 IR thermal analyzer measured in a temperature range of 25-800 °C at a heating rate of 10 °C/min under a N2 atmosphere. 2.6 Nanoparticle size characterization by DLS. Dynamic light scattering was conducted on a NanoBrook Omni in a glass cuvette, using a He-Ne (633 nm) laser at room temperature. 2.7 Nanoparticle and hydrogel morphology by SEM. The morphology of SNPs-Br, and SNPs-g-PolyDVBAPS nanoparticles and “Janus featured” polyHEAA@ SNPs-g-polyDVBAPS hydrogel was analyzed using a field emission scanning electron microscope (SEM, Hitachi SU-1510). The nanoparticles were ultrasonically dispersed uniformly in saline solution, dropped on a tin foil paper and then dry. The “Janus featured” hydrogel was soaked in water for a long time to fully swell, and then freeze-dried for 24 hours after frozen. The sample were sputter coated with a thin layer of gold to improve the surface conductivity before observing. The morphology of the hydrogel was characterized by observing the fracture section of the freeze-dried hydrogel using SEM (FEI Nova Nano 450). 2.8 Nanoparticle core-shell structure by TEM. The core-shell structure of SNPs-g-PolyDVBAPS was observed by transmission electron microscopy (TEM, JEOL JEM-100CX II) with an accelerating voltage of 300 kV. The polymer brush attached nanoparticles were uniformly dispersed ultrasonically in saline solution, and 10 μL of the nanoparticle solution was dipped on the 9


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carbon-coated copper grid and subsequently placing it onto a piece of filter paper to remove excess solvent. 2.9 Bacteria attachment and release. Escherichia coli (E. coli, Gram negative) and Staphylococcus aureus (S. aureus, Gram positive) were used to investigate the bacteria attaching and releasing effects of the hydrogel in this work. E. coli and S. aureus were incubated overnight at 37 °C on Luria-Bertanni (LB, OXOID) agar plate. A single colony of each bacteria was used to inoculate 20 mL of LB separately under shaking, and then diluted to the suitable optical density of ∼0.10 (E. coli) and ∼0.05 (S. aureus) at 600 nm respectively. The layered hydrogel samples were cut into square (15 mm ×15 mm) and then sterilized under UV light for 10 min before placing into 12-well plate containing 3 ml of bacterial suspension and incubated at 37 °C. The incubated time and cycle time for E. coli and S. aureus was 24 h, 120 h and 12 h, 60 h respectively. To test the bacteria releasing effect of the “Janus featured” hydrogel, 2 M salt solution was added in the 12-well plate and shaking for 10 min. Then the “Janus featured” hydrogel was rinsed with PBS, and treated with LIVE/DEAD BacLight kit (Thermo Fisher Scientific Inc., NY) for imaging. The rest of “Janus featured” hydrogels were used for the next cycle test. In the next cycle, the procedure and observation method were same to way used in the first cycle. Each “Janus featured” hydrogel was directly observed by Axio Observer. A1 fluorescence microscope (Carl Zeiss Inc., Germany) with a 40×lens. 2.10 Cytotoxicity tests. SH-SY5Y human neuroblastoma cells were cultured in the medium containing 10% fetal bovine serum and 1% antibiotics (penicillin-streptomycin) at 37 °C with 5% CO2. After the cells reached a certain number, 0.25% trypsin-EDTA solution was added to make the cells detached from the culture flask. The harvested cells were resuspended in PBS solution to the density of 1.0 × 104 cells/ml. The cells suspension were added into 24-well plate with cutted pure 10



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polyHEAA hydrogel disk and polyHEAA@SNPs-g-polyDVBAPS disk. After cocultured for 24 h, the culture medium was removed and then 20 μL of the 3-[4, 5-Dimethyl-thiazol-2-yl]-2, 5-Diphenyltetrazolium bromide solution (MTT, 5 mg/ml) was added and incubated for 4 h with 5% CO2 at 37 °C. Then, 150 μL biological dimethyl sulfoxide (DMSO) was added to dissolve the formazan crystals. And the absorbance density of formazan solution was measured using a microplate reader (Bio-Rad 680, USA) at the wavelength of 570 nm. All experiments were recorded for six times and the cell viability was calculated by the control sample. 3. RESULTS AND DISCUSSION The first yet significant step of the construction of Janus-featured hydrogel is to design suitable salt-responsive silica nanoparticles. As shown in Scheme 1, initiators for ATRP were grafted onto silica nanoparticles by the condensation between Si-OH of silane in solution and OH on silica nanoparticles. In SI-ATRP system, CuBr is used as catalyst, and Me6TREN is used as ligand to enhance the solubility and activity of CuBr. Upon the catalytic effect of CuBr, C-Br bonds in the initiators were split, forming the free radicals which can initiate the polymerization of the monomers, as a result, polyDVBAPS brush grafted on silica nanoparticles was prepared

36-37.To

confirm the

successful graft of polyDVBAPS onto the silica nanoparticle surface, chemical compositions of the modified surface were analyzed by FT-IR. As shown in Figure 1a, three absorption bands were appeared at 1100 cm−1 (Si−O stretching), 953 cm−1 (Si−OH bending), and 800 cm−1 (Si−O−Si bending) from bare SNPs. After introducing initiator, a doublet at 1390 and 1370 cm-1, where characteristic of the deformation of two methyl groups in 2-bromoisobutyrate residues located at, can be discerned. After grafting polyDVBAPS brush to the surface of SNPs, frequency of bending vibration of carbon-hydrogen on benzene at 605 cm-1~900 cm-1 , aryl sulfonate ion stretching 11


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vibration frequency at 1048 cm-1~1193 cm-1 and benzene ring skeleton stretching vibration frequency at 1650 cm-1 is appeared. These results verified the successful fabrication of SNPs-g-polyDVBAPS. The successful attachment of ATRP initiator and polyDVBAPS brush to SNPs surface can be further confirmed by TGA measurement. As shown in Figure 1b, a weight loss of 11.8% for the SNPs was attributed to the physically adsorbed water on the silica surface. There exists ~3.9 wt % difference in the weight retentions at 800 °C between SNPs and 2-bromoisobutyrate-functionalized silica nanoparticles (SNPs-Br). If the mass retention of SNPs at 800 °C was used as the reference and assumed the density of the SNPs was same to that of bulk silica (2.07 g/cm3), we can approximately calculated the grafting density of ATRP initiators at the surface of silica nanoparticles (163 nm of diameter) to be ∼11.9 nm2 / initiator. For the SNPs-g-polyDVBAPS microspheres with the grafted polymer brushes, the weight loss was 50.5% with two distinct weight loss stages between 100 and 600 °C. The first weight loss until 250 °C was also caused by the evaporation of the physically adsorbed water or solvent, and the second major weight loss from 250 to 600 °C was assigned to the decomposition of the polymer component in the shell layer of the corresponding microspheres.

Figure 1. a) Fourier transform infrared (FT-IR) spectra and b) Thermo gravimetric analysis (TGA) of bare SNPs, SNPs-Br, and SNPs-g-polyDVBAPS. TGA was performed under a N2 atmosphere at a heating rate of 10 °C/min. 12



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DLS were used to characterize the size change of hybrid silica nanoparticles before and after grafting with polyDVBAPS chains. After modified, the hydrodynamic diameter of silica nanoparticle increased from ~163 nm for SNPs to ~244 nm for SNPs-g-polyDVBAPS as shown in Figure 2. The DLS analysis of SNPs-g-polyDVBAPS revealed a narrow size distribution with an average diameter of 244 nm in 0.3 M NaCl solution, about 53 nm larger than that of the SNPs-Br. Note that the salt concentration below 0.3 M would not lead a uniform dispersion of these nanoparticle in solution. And the size of nanoparticles can be effectively controlled.

Figure 2. Hydrodynamic diameter of SNPs, SNPs-Br, and SNPs-g-polyDVBAPS measured by DLS.

Morphologies of SNPs-Br, SNPs-g-polyDVBAPS were observed by both of TEM and SEM (Figure. 3). In SEM images, explicit particles for SNPs-Br is observed. On the contrary, the particles for SNPs-g-polyDVBAPS are blurry. This phenomenon was attributed to the bad electricity of polymer brush attached on the surface of silica particle. From TEM images, it is obvious that a polymer shell, with an average thickness of ~7.3 nm, surrounding each nanoparticle. The consequence of size change between SNPs and SNPs-g-polyDVBAPS analyzed by DLS and TEM was distinctly different. We assumed this difference result from the two kind conformation status, which the polyDVBAPS was more stretchable in solution than in dry condition. The collapsed and

13


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contracted conformation lead the size of SNPs-g-polyDVBAPS in dry status was much smaller than that in solution.

Figure 3. SEM images of a) SNPs-Br, b) SNPs-g-polyDVBAPS and TEM images of c) SNPs-g-polyDVBAPS.

According to the previous research, polyDVBAPS chains can undergo conformation change from collapse to straight when switching solution from water to brine due to anti-polyelectrolyte effect35. The hydrodynamic diameter of SNPs-g-polyDVBAPS in aqueous dispersion as a function of NaCl concentration show the salt-responsive behavior of the polymer chains on the nanoparticle surface. To investigate the salt-responsive behavior of the polymer chains, the hydrodynamic diameter of the nanohybrids was studied in different salt concentration range from 0.3 to 4.0 M. From Figure 4a, the polyDVBAPS brush is very sensitive to salt concentration. The relationship between SNPs-g-polyDVBAPS size and salt concentration is almost linearly related. The hydrodynamic diameter of SNPs-g-polyDVBAPS increase from ~245 nm to ~465 nm when the outer salt concentration change from 0.3 M to 4.0 M. And as shown in Figure 4b, the hydrodynamic diameter of SNPs-g-polyDVBAPS in low concentration and high concentration NaCl solution shows well reversibility. This swelling behavior can be ascribed to the anti-polyelectrolyte effect of DVBAPS repeating units. In water, there exist strong electrostatic inter/intrachain dipole−dipole inter-action. Therefore, the conformation of polyDVBAPS was collapsed. However, when salts are introduced in solution, the counterions adsorb and penetrate into polymer brushes, destroy the

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electrostatic inter/intrachain dipole−dipole inter-action, and thus induce the more extended chain conformations.

Figure 4. a) The size of SNPs-g-polyDVBAPS as a function of salt concentration in aqueous solution (the inset scheme shows the salt-responsiveness of the block copolymer chains on the nanoparticle surface), b) Reversible size change switching for SNPs-g-polyDVBAPS in 0.3 and in 4.0 M NaCl solution.

The above results indicated the successful graft of salt responsive polyDVBAPS brush to the silica nanoparticle surface and more importantly it showed excellent salt responsive behavior and good reversibility. Based on the huge conformation change between water and salt water, the bacteria adhered onto the hydrogel surface loaded SNPs-g-polyDVBAPS can be released. This responsive comformation change of polymer brush has been widely used for constructing bacteria releasing surface

38-41.

Moreover, Because of the intrinsically hydrophilic property, polyHEAA has

been extensively used for fabricating antifouling matrix material 42-43. This antifouling capacity, also known as a “passive” antibacterial strategy. Hence, we used polyHEAA hydrogel and SNPs-g-polyDVBAPS to fabricate “Janus featured” hydrogel with antifouling and bacteria releasing effects for each layer by supergravity method. We tested the antifouling and bacteria releasing properties to further verify the successful fabrication of “Janus featured” hydrogel. FT-IR and SEM was used to verify the successful construction of “Janus featured” hydrogel. Before conducting test, the hydrogel was freeze in refrigerator for 1 h at -80 °C and then freeze drying for 24 h to get dry sample. The “upper” and “bottom” is represent pure polyHEAA layer and 15


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SNPs-g-polyDVBAPS loaded layer respectively. As shown in Figure 5, the infrared absorption peak of pure polyHEAA layer was same with the upper layer. However, the bottom layer has new absorption peak at 1098 cm-1 which attributed Si−O stretching. The results indicated that SNPs-g-polyDVBAPS was tended to aggregate on the one layer under the effect of supergravity force during gelation process.

Figure 5. FT-IR spectra of pure polyHEAA hydrogel and the different layer of “Janus featured” polyHEAA@SNPs-g-polyDVBAPS hydrogel (“Upper” represent pure polyHEAA layer, “Bottom” represent polyHEAA loaded with SNPs-g-polyDVBAPS layer).

The “Janus featured” structure of the hydrogel was further characterized by SEM. As shown in Figure 6, it is obvious to see the different pore structure between upper and bottom layer. And the pore size of pure polyHEAA layer was much bigger than the bottom layer. As a matter of fact, this phenomenon was attributed to the complex interactions between polyHEAA network and polyDVBAPS brushes in bottom layer, such as anti-polyelectrolyte effect induced physical entanglement, nucleation effect induced by SNPs, and rebalancing of hydrogen bonds after charge introduction, which finally result in “Janus featured” small network structure. Therefore, the pure polyHEAA layer swells bigger with respect to the layer of the nanoparticle loading during swelling. From the enlarged graph on the right, we can further see the different characteristics between two 16



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layers. The nanoparticles only exist at the bottom layer. Further compared with the smooth surface of pure polyHEAA layer, the surface of SNPs-g-polyDVBAPS loaded layer seems to be much rougher. This rough structural feature further exposes the salt-responsive layer and allows the chain segment conformation to change unsoundly.

Figure 6. SEM images of “Janus featured” polyHEAA@SNPs-g-polyDVBAPS hydrogel (upper layer represent pure polyHEAA, bottom layer represent polyHEAA loaded with SNPs-g-polyDVBAPS) after freeze drying.

The

antifouling

capability,

and

regeneration

efficiency

of

“Janus

featured”

polyHEAA@SNPs-g-polyDVBAPS hydrogel were evaluated by co-culturing the hydrogel with bacteria solution for a preoptimized time. PolyHEAA, polyHEAA@SNPs-g-polyDVBAPS represent pure polyHEAA layer and nanoparticles loaded layer respectively. Figure 7 shows the fluorescence microscopy images of E. coli and S. aureus on the two layer of hydrogels and the corresponding statistical result of bacterial density on the surfaces. Differing from the pure polyHEAA layer which has better antifouling effects at a consistent bacteria density of ~1*106 cells/cm2 up to 5 days for E. coli, the introduction of SNPs-g-polyDVBAPS slightly deteriorates the polyHEAA antifouling 17


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performance. SNPs-g-polyDVBAPS loaded polyHEAA layer shows higher bacteria density above ~1*106 cells/cm2. This phenomenon was caused by the increased roughness and decreased hydrophilic of SNPs-g-polyDVBAPS loaded polyHEAA layer. However, it should be noted that both two layer of polyHEAA@SNPs-g-polyDVBAPS “Janus featured” hydrogels showed a very low surface accumulation of bacterial cells (120 h and 60 h for E. coli and S. aureus) compared with normal material because of the excellent antifouling property of polyHEAA components. The S. aureus attachment status on different layer of “Janus featured” hydrogel showed similar trends with E. coli. The bacteria releasing effect of bottom layer was investigated by treating 2.0 M NaCl to “Janus featured” hydrogel after long-term cocultured. Figure 8 a” and b” shows the bacteria density on different layer of polyHEAA@ SNPs-g-polyDVBAPS “Janus featured” hydrogel before and after 2.0 M NaCl treatment. Pure polyHEAA layer does not show bacteria releasing function. SNPs-g-polyDVBAPS loaded polyHEAA layer shows good bacterial release property. It can release ~94 % of E. coli and ~92 % of S. aureus. PolyDVBAPS brushes, which grafting to the surface of silica nanoparticle, have huge conformation change from collapse to straight when exterior solution switched from water to 2.0 M NaCl. In water, interaction force was so strong that induced the chain collapsed, while in salt solution, electrostatic interactions was dominant to induce extended chain conformation and higher hydration extent by counter ions. The conformation change and increased hydration extent of the polyDVBAPS brush were believed to supply the driving force to release the attached bacteria.

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Figure 7. Fluorescence microscopy images of E. coli and S. aureus on polyHEAA layer, polyHEAA@SNPs-g-polyDVBAPS layer upon different incubation time, followed by treatment with 2.0 M NaCl solution.

Figure 8. a), b) Total bacterial densities and a’), b’) densities of live and dead bacteria of E. coli and S. aureus,on polyHEAA layer, polyHEAA@SNPs-g-polyDVBAPS layer upon different incubation time; and a”), b”) bacterial densities before and after the treatment of 2.0 M NaCl solution..

To further investigate the surface regeneration function of SNPs-g-polyDVBAPS loaded polyHEAA layer, the bacteria cocultured measurements were conducted for three cycles. As shown in Figure 9, the density of attached bacteria improve gradually with cocultured time increase in each 19


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test cycle. The release ratios are ~94 %, ~95, ~92 % % for E. coli, and ~95 %, ~94 %, ~92 % for S. aureus, respectively. It indicated that the nanoparticle loaded layer has excellent bacteria removal function after the treatment of 2.0 M NaCl solution.

Figure 9. Fluorescence microscopy images of a) E. coli and b) S. aureus with different optimized cocultured time, followed by treatment with 2.0 NaCl solution. Furthermore, histogram of bacteria density statistics of a’) E. coli and b’) S. aureus were provided on the right. Here, three cocultured cycles were conducted.

Since there was a potential application value of distinct hybrid hydrogel for wound dressing, we further

investigated

the

cytotoxicity

of

such

typically


polyHEAA@SNPs-g-polyDVBAPS hydrogel. Generally, the cytotoxicity performance was recorded by using MTT (3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium Bromide) assay with SH-SY5Y cell lines for 24 h. Here, in order to establish baseline of live cells, the absorbance of the media solution containing cultured cells was firstly measured and carried out with normalization processing. The controlled group was mainly regarded as 100 % of cells being viable. And we further recorded the absorbance value of treatment groups, including cells cocultured with pure polyHEAA hydrogel disks and cocultured with polyHEAA@SNPs-g-polyDVBAPS hydrogel disks. Here, to avoid the inter interference between two layers, we used pure polyHEAA hydrogel and uniform polyHEAA@SNPs-g-polyDVBAPS hydrogel to represent the different layer of 20




hydrogel.

As

shown

in

Figure

10,

both

Page 22 of 27

pure

polyHEAA

and

polyHEAA@SNPs-g-polyDVBAPS hydrogel presented relatively low cytotoxicity to SH-SY5Y cells, as evidenced by ~89% and ~85% cell viability for 24 h cocultured with cells (Figure 10a). Therefore, to better understand for cytotoxicity, we tried to transfer cell viability to cytotoxicity. The formula was defined and listed as below (Eq. 1). And we can see this defined cytotoxicity was ~11% and ~15% for pure polyHEAA, polyHEAA@SNPs-g-polyDVBAPS hydrogel, respectively. These results completely demonstrated that our “Janus featured” hydrogel possessed superb biocompatibility and bio-toxicity, which presented ideal practical application prospect for wound dressings. 𝐶𝐶𝑦𝑡𝑜𝑡𝑜𝑥𝑖𝑐𝑖𝑡𝑦% = 1 ― 𝐶𝑉𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦%

(Eq. 1)

Figure 10. a) Cell viability and b) Specially defined cytotoxicity for coculture groups with pure polyHEAA and polyHEAA@SNPs-g-polyDVBAPS hydrogel disks after the normalization processing of controlled group.

4. CONCLUSION In summary, a novel and universal strategy to fabricate “Janus-featured” hydrogel was developed. We demonstrated the feasibility of constructing “Janus-featured” hydrogel with different function for each layer by introducing SNPs-g-polyDVBAPS to polyHEAA through centrifugal force and investigated how the “Janus-featured” structure affect the antifouling and bacteria releasing function. It showed that the “Janus-featured” hydrogel with different function for each layer could be readily controlled. The pure polyHEAA layer showed excellent antifouling effect. The introduction 21


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of SNPs-g-polyDVBAPS nanoparticles slightly decreased the antifouling effect compared with pure polyHEAA layer, however, the salt-responsive properties used for bacteria releasing were well endowed to the one layer of polyHEAA hydrogel. The polyHEAA@SNPs-g-polyDVABAPS “Janus-featured” hydrogel has outstanding antifouling and bacteria releasing effect for each layer at the same time. Moreover, this hybrid gel still maintains a relatively low cytotoxicity (~15%). We believe that this strategy will provide the basis for design and fabrication of “Janus-featured” hydrogel with specific properties in the near future, especially in the field of wound dressing. ACKNOWLEDGEMENTS. J.Y. thanks financial support from Natural Science Foundation of China (No. 51673175), Natural Science Foundation of Zhejiang Province (LY16E030012), and Zhejiang Top Priority Discipline of Textile Science and Engineering (2015KF06).

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Table of Content

26


Hydrogel with Antifouling and Bacteria Releasing Properties

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