Tunable Mechanical, Antibacterial, and Cytocompatible Hydrogels

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Tunable mechanical, Antibacterial and Cytocompatible Hydrogels Based on a Functionalized Dual Network of Metal Coordination Bonds and Covalent Crosslinking Xin Yi, Jiapeng He, Xiaolan Wang, Yu Zhang, Guoxin Tan, Zhengnan Zhou, Junqi Chen, Dafu Chen, Renxian Wang, Wei Tian, Peng Yu, Lei Zhou, and Chengyun Ning ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b18821 • Publication Date (Web): 30 Jan 2018 Downloaded from http://pubs.acs.org on January 31, 2018

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Tunable mechanical, Antibacterial and Cytocompatible Hydrogels Based on a Functionalized Dual Network of Metal Coordination Bonds and Covalent Crosslinking Xin Yi1,5, Jiapeng He2,5, Xiaolan Wang4, Yu Zhang4, Guoxin Tan3, Zhengnan Zhou3, Junqi Chen2,5, Dafu Chen6, Renxian Wang6, Wei Tian6, Peng Yu2,5, Lei Zhou2,5*, Chengyun Ning2,5* 1

School of Medicine, South China University of Technology, Guangzhou, China

2

School of Materials Science and Engineering, South China University of Technology, Guangzhou,

China 3

Institute of Chemical Engineering and Light Industry, Guangdong University of Technology,

Guangzhou, China 4

Hospital of Orthopedics, Guangzhou General Hospital of Guangzhou Military Command of PLA,

Guangzhou, 510010, China. 5

Guangdong Key Laboratory of Biomedical Sciences and Engineering, South China University of

Technology, Guangzhou 510006, China. 6

Laboratory of Bone Tissue Engineering, Beijing Research institute of Traumatology and

Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, China. *Corresponding Author. E-mail addresses: [email protected] (L Zhou), [email protected] (Prof. CY Ning). X. Yi and J. He contributed equally to this paper.

Abstract Tissue engineering has become a rapidly developing field of research because of the increased demand from regenerative medicine, and hydrogels are a promising tissue engineering scaffold due to their three-dimensional structures. In this study, we constructed novel hydrogels of gelatin methylacrylic (GelMA) hydrogels modified with histidine and Zn2+ (GelMA-His-Zn(II)), which possessed fascinating antibacterial properties and tunable mechanical properties due to the formation of a functionalized dual network of covalent crosslinking and metal coordination bonds. The introduction of metal coordination bonds not only improves the strength of the gelatin methylacrylic (GelMA) hydrogels with covalent crosslinking but also makes their mechanical properties tunable via adjustments to the concentration of Zn2+. The synergistic effect of the Zn2+ and the imidazole groups gives the GelMA-His-Zn(II) hydrogels fascinating antibacterial properties (up to 100% ACS Paragon Plus Environment

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inhibition). Counting the colony forming units (CFUs) and compression tests confirmed the fascinating antibacterial abilities and tunable mechanical properties, respectively, of the GelMA-His-Zn(II) hydrogels. In addition, Cell Counting Kit-8 (CCK-8) assays, cytoskeletal staining assays and live/dead assays confirmed the excellent cytocompatibility of the GelMA-His-Zn(II) hydrogels. Therefore, the GelMA-His-Zn(II) hydrogels are promising for applications in tissue engineering. Keyword: Dual network, Metal coordination, Antibacterial hydrogel, Cytocompatibility, Tunable mechanical properties 1. Introduction With increased demand for surgeries due to athletic activity-related injuries, diseases, and aging, the need for regenerative medicine is increasing. Tens of billions of dollars per year are spent to treat the approximately 35 million musculoskeletal injuries sustained each year

1-3

. Therefore, tissue

engineering has attracted increasing attention, and one of the challenges inherent in tissue engineering is replicating the complex three-dimensional (3D) structures of most tissues, such as skeletal muscle heart, bone, tendon, ligament, artery, and nervous system tissues, as their structures are critical to their function 4. Both natural and synthetic hydrogels are of great interest as engineered tissue materials due to their 3D structures because they can absorb and retain a large amount of water 5

, their mass transfer properties are similarly to those of natural tissues 5, and they can be formed into

different shapes 6. In particular, GelMA hydrogels, which have the advantages of both natural and synthetic biomaterials, have become popular in the field of tissue engineering 7. More specifically, GelMA hydrogels contain gelatin as their backbone, which gives them cell-responsive characteristics such as appropriate cell adhesion sites and proteolytic degradability

8-10

. GelMA hydrogels are also

cytocompatible, inexpensive and technically simple to prepare 7. Moreover, researchers have shown that methacrylation and photocrosslinking can be used to tune the mechanical and chemical properties of GelMA hydrogels including their applicability in the creation of 3D microarchitectures 9, 11-12

.

However, GelMA hydrogels do not have intrinsic antibacterial properties, which severely restrict their use in tissue engineering. To date, several strategies have been proposed to give GelMA hydrogels antibacterial characteristics. Zhao et al. reported that silver nanoparticles can be loaded onto the surface of the materials to give them antimicrobial activities 13. Moreover, a short cationic ACS Paragon Plus Environment


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antimicrobial peptide (AMP) known as HHC-36 has been investigated as an antimicrobial component for the surface modification of GelMA hydrogels due to its broad-spectrum antimicrobial activity against common Gram-positive and Gram-negative bacteria and enhanced efficacy compared to traditional antibiotics

14-17

. However, these surface modification and drug loading methods are

generally time-consuming and require complex, multistep procedures. Imidazole groups and imidazole analogs, antibacterial moieties that exist in various biomolecules such as histidine, histamine and natural products

18

, have generated substantial interest over the years due to their

antimicrobial properties. Some imidazole derivatives such as cimetidine, etomidate, ketoconazole and metronidazole have been used as drug therapies to treat bacterial infections 19-20. In addition, Zn possess excellent antibacterial abilities 21-22, and it is an important trace element in human biological functions 23-24. Our previous study have proved Zn2+ can produce reactive oxygen species which can damage the protein and cell wall, and kill the bacterias ultimately 25. Tang et al. have reported the incorporation of Zn into bioglasses and Ca–P and Ca–Si systems can enhance their antibacterial properties 26-28. The mechanical properties of materials are another important consideration for the engineering of tissue scaffolds, and mechanical properties play crucial roles in regulating the interactions between cells and extracellular matrices and directing the phenotype and genotype of the cells. However, GelMA hydrogels suffer from poor mechanical properties 29, which need to be improved to make these hydrogels applicable in tissue engineering. On one hand, GelMA hydrogels can be mixed with other polymers, such as hyaluronic acid

30

, silk fibroin

31

and gellan gum

32

, to improve their

mechanical properties. On the other hand, the mechanical properties of GelMA hydrogels can also be improved by introducing nanomaterials, such as graphene oxide

33

and carbon nanotubes 34, into the

gel. However, with these methods, it is difficult to prepare GelMA hydrogels with tunable mechanical properties. Now, dual network, due to excellent performance, have attracted increasing attention. Yang et al. have fabricated an extremely tough and rapidly recoverable double network hydrogels

35

. Bu et al. have constructed a double network hydrogels with good biocompatibility 36.

So, we want to form a dual network with covalent bonds and metal coordination bonds to improve the mechanical properties of the GelMA hydrogels, and to afford GelMA hydrogels with tunable mechanical properties via adjustments to the amount of metal coordination bonds. Most importantly, a promising tissue engineering scaffold should have both excellent ACS Paragon Plus Environment

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antibacterial properties and tunable mechanical properties. We herein report a new family of GelMA-His-Zn(II) hydrogels based on the three-dimensional structures of GelMA hydrogels that possess potent antibacterial properties and tunable mechanical properties. This result was achieved using the functionalized dual network present in GelMA-His-Zn(II) hydrogels that consists of the covalent bonds of GelMA and the metal coordination bonds between Zn2+ and the imidazole groups. On one hand, the zinc and imidazole groups not only have antibacterial activities but are also beneficial to human health and have low cytotoxicities. On the other hand, the dual network composed of covalent bonds and metal coordination bonds gives the GelMA-His-Zn(II) hydrogels improved and tunable mechanical properties. The antibacterial rate of the GelMA-His-Zn(II) hydrogels is much higher than that of GelMA hydrogels, and it can be as high as 100%. The compression moduli of the GelMA-His-Zn(II) hydrogels can be adjusted from 3.5 to 7.8 KPa, which match the modulus of some tissue, such as nerve and cardiac tissue 37. The moduli do not appreciably change after five repeated loadings to 80% strain. In addition, the GelMA-His-Zn(II) hydrogels possesses brilliant cytocompatibility. A Cell Counting Kit-8 assay and cytoskeletal staining assay proved MC3T3-E1 cells can proliferate, adhere, and spread normally after co-culture with the GelMA-His-Zn(II) hydrogels, and the average cell spreading area and OD value of cells co-cultured with the GelMA-His-Zn(II) hydrogels were noticeably higher than those of cells cultured with GelMA hydrogels. A live/dead assay also showed that the cytotoxicity of the GelMA-His-Zn(II) hydrogels toward MC3T3-E1 cells is acceptable, and the average live cell number with the GelMA-His-Zn(II) hydrogels was higher than that of the GelMA hydrogels. Finally, the GelMA-His-Zn(II) hydrogels can be used to prepare three-dimensional structures, which is significant for tissue engineering. Therefore, the GelMA-His-Zn(II) hydrogels show promise for use in tissue engineering. 2. Materials and methods 2.1 Materials and reagents Gelatin, methacrylic anhydride, histidine, acryloyl chloride and zinc sulfate were purchased from Aladdin Reagent Company (Shanghai, China). Mesenchymal stem cells (MC3T3-E1) were purchased from American Type Culture Collection. Calcein-AM, propidium iodide (PI), 4, 6-diamidino-2-phenylindole (DAPI), F-actin and a CCK-8 kit were purchased from Biyuntian biotechnology CO. LTD. All other chemical reagents were of analytical reagent grade and were used ACS Paragon Plus Environment


without further purification. 2.2 Synthesis of gelatin methylacrylic monomer The synthesis of GelMA monomers was reported previously 9, and the synthetic pathway is shown in Fig. 1a. First, 0.5 g of gelatin was added to 50 mL of PBS at 60 °C, and the solution was stirred until the gelatin had dissolved. Second, 4 mL of methacrylic anhydride was added to the above solution at 50 °C at a rate of 0.2 mL/min, and the solution was stirred for 3 h until it became milk white. Third, the solution was poured under stirring into PBS to stop the reaction. Finally, the mixed solution was poured into a dialysis bag, and placed in deionized water at 50 °C for one week to obtain pure gelatin methylacrylic monomer. Samples were freeze dried and stored at -20 °C until further use. 2.3 Synthesis of N-Acryloyl-L-Histidine monomer Fig. 1b shows the synthesis of N-acryloyl-L-histidine (N-Acry-L-His). Firstly, 3 g of histidine was added to 7 mL of NaOH solution, and the solution was stirred until the histidine dissolved. Then, 1.6 mL of acryloyl chloride was added to the above solution while protected from light, and after reacting 1 h, concentrated HCl was used to adjust the pH of the solution to 3. Finally, acetone ethyl alcohol and deionized water were added successively to wash the mixture 3 times, and after washing, the product was placed in a refrigerator -80 °C for 24 h to obtain pure N-Acry-L-His. 2.4 Preparation of GelMA-His-Zn(II) hydrogels Fig. 1c shows the synthesis of GelMA-His-Zn(II) hydrogels. First, GelMA monomer (10 w/v%) and N-Acry-L-His (10 w/v%) were dissolved in 50 mL of phosphate-buffered saline (pH=7) at 40 °C. Then, the photoinitiator (0.5 w/v%) was added to the above solution, and the mixture was stirred for 10 minutes. The mixture was transferred to a 24-well cell culture plate with 300 µL of solution per well, and the plate was placed under UV light for 20 seconds. Finally, 1 mL of zinc sulfate solutions at certain concentrations was added to each well. The solutions soaked for 2 h at room temperature, and then each well was washed with phosphate-buffered saline 3 times. By adjusting the concentration of zinc sulfate solution from 12 to 48 mmol/L, different GelMA-His-Zn(II) hydrogels were synthesized as shown in Table 1. Samples were stored at -4 °C until further use. Fig. 1d also shows the dual-network architecture of the GelMA-His-Zn(II) hydrogels with covalent bonds and metal coordination bonds, which gives the GelMA-His-Zn(II) hydrogels excellent antibacterial properties and tunable mechanical properties. In addition, the synthesis of the GelMA, GelMA-His ACS Paragon Plus Environment

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and GelMA-Zn(II) hydrogels followed a procedure similar to what was used for the GelMA-His-Zn(II) hydrogels, and Fig. 1c shows the synthesis and single network architecture of the GelMA hydrogels. Table. 1 the concentration of Zn(II) of GelMA-His and GelMA hydrogels Hydrogel name C Zn(II) (mmol/L) GelMA-His 0 GelMA-Zn(II)-1 12 GelMA-Zn(II)-2 24 GelMA-Zn(II)-3 48 GelMA-His-Zn(II)-1 12 GelMA-His-Zn(II)-2 24 GelMA-His-Zn(II)-3 48

Fig. 1 The synthesis of (a) GelMA and (b) N-Acry-L-His. The network architectures of (c) GelMA hydrogels with a single network of covalent bonds and (d) GelMA-His-Zn(II) hydrogels with a dual network of metal coordination and covalent bonds.



3. Results and Discussion

Fig. 2 SEM images of (a) a GelMA hydrogel and (b) a GelMA-His-Zn(II)-1 hydrogel. (c) Swelling rate and (d) weight loss rate of the GelMA, GelMA-His and GelMA-His-Zn(II) hydrogels. The microstructural features of hydrogels play a crucial role in the mechanical properties of hydrogels, and we found significant differences in the microstructures of the hydrogels (Fig. 2a and Fig. 2b). Notably, GelMA hydrogels were inhomogeneous and comprised a mixture of voids interspersed with denser material. In contrast, the microstructures of the GelMA-His-Zn(II) hydrogels were more homogenous and showed smaller voids. The average pore sizes of the GelMA and GelMA-His-Zn(II) hydrogels were 20 µm and 10 µm, respectively. The smaller and more uniform distribution of pores could be a key reason for the superior mechanical properties of the GelMA-His-Zn(II) hydrogels. Besides，both GelMA and GelMA-His-Zn(II) hydrogels possessed 3D porous structure, which is useful in tissue engineering. The degree of swelling of the hydrogels is related to the pore size and the amount of metal coordination bonds, which ultimately affects the mechanical strength of the material. As shown in Fig. 2c, the degree of swelling of the GelMA hydrogels modified with histidine (GelMA-His) is 30%, which is lower than that of the GelMA hydrogels (36%). This result may be attributed to the introduction of N-acryloyl-L-histidine, which decreased the pore size. In addition, when the


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GelMA-His hydrogels were immersed in zinc sulfate solution, the degree of swelling of the hydrogels decreased to as low as 24%. This result showed that the formation of a metal coordination bond between Zn2+ and the imidazole group can decrease the degree of swelling, and increasing the number of metal coordination bonds results in a lower degree of swelling. Degradation rate is a key factor in determining the service life of the tissue engineering scaffold, and it is affected by the amount of the crosslinking and metal coordination bonds. Fig. 2d shows that the weight loss of the GelMA-His hydrogels is lower than that of the GelMA hydrogels, which can be attributed to the higher crosslinking density in the GelMA-His. Moreover, Fig. 2d also shows that presence of the metal coordination bonds can decrease the degradation rate of the GelMA-His-Zn(II) hydrogels relative to that of the GelMA-His hydrogels, and more metal coordination bonds result in a slower degradation rate.

Fig. 3 1H NMR spectra of (a) GelMA and gelatin (b) N-Acryloyl-L-histidine and histidine. (c) FTIR spectrum of GelMA and GelMA-His. (d) EDS of GelMA-His-Zn(II). The 1H NMR spectra of gelatin and GelMA was shown in Fig. 3a. Comparing the spectra of gelatin and GelMA, new signals can be observed at 5.35 ppm and 5.59 ppm, corresponding to the



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two protons of methacrylate double bond. Therefore we confirmed that methacrylate has been successfully grafted to the gelatin molecules, and the degree of methylacrylation of GelMA was 79.2% by quantitative 1H NMR analysis. The 1H NMR spectra of histidine and N-Acry-L-Hist was shown in Fig. 3b. Comparing the 1H NMR spectra of histidine and N-Acry-L-Hist, new signals can be observed at 5.7~6.11 and 6.21 ppm, corresponding to the two protons of acrylamide double bond. Therefore we confirmed that acryloyl chloride has been successfully grafted to the gelatin molecules. Besides, Fig. S1 shown the 13C NMR spectra of N-Acryloyl-L-histidine. The peak of 126.8 ppm and 131.1 ppm is attributed to the C=C, and the peak of 166.8 ppm is attributed to the –CCN. Both of it were come from the acryloyl chloride molecule. Therefore, the

13

C NMR of N-Acry-L-His also

proved that acryloyl chloride has been successfully grafted to the gelatin molecules (Fig. S1). The FTIR spectra of GelMA and GelMA-His was shown in Fig. 3c, the characteristic peaks at 3320 cm-1 and 3314 cm-1 can be ascribed to the stretching vibration of N-H bands. The characteristic peaks at 1660 cm-1 and 1640 cm-1 can be ascribed to the stretching vibration of C=O bands. The characteristic peaks at 1550 cm-1 and 1243 cm-1 can be ascribed to the stretching vibration of N-H bands. The characteristic peaks at 1086 cm-1 and 840 cm-1 can be ascribed to the bending vibration and stretching vibration of –CCN bands in imidazole ring. The characteristic peaks at 635 cm-1 can be ascribed to the vibration of imidazole ring. This result suggested that N-Acry-L-His was successfully incorporated into the GelMA. Although the GelMA-His-Zn(II) hydrogels were washed several times, free zinc still can be detected in the freeze-dried hydrogels by EDS (Fig. 3d). Comparing the EDS of the GelMA-His and GelMA-His-Zn(II) confirmed that the Zn2+ formed metal coordination bonds with the imidazole groups (Fig. S2).

Fig. 4 (a) Compressive stress–strain profiles of the GelMA-His-Zn(II) and GelMA-Zn(II) hydrogels


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with different concentrations of zinc ions. (b) Compression modulus of the hydrogels. Fig. 4 shows typical compressive stress–strain curves of the GelMA-His-Zn(II) and GelMA-Zn(II) hydrogels. The GelMA-His-Zn(II) hydrogels show significantly higher compression moduli than those of the GelMA-Zn(II) (Fig. S3). Briefly, the moduli of the GelMA-His-Zn(II)-1, GelMA-His-Zn(II)-2 and GelMA-His-Zn(II)-3 hydrogels were approximately 3.4, 3.3 and 5.8-fold greater than those of the GelMA-Zn(II)-1, GelMA-Zn(II)-2 and GelMA-Zn(II)-3 hydrogels, respectively. This result is attributable to the formation of metal coordinate bonds between the Zn2+ and the imidazole groups, and the dual bonding network gives the hydrogels higher moduli than those of a single binding network. In addition, Fig. 4b shows (red curve) that the compression moduli of the GelMA-His-Zn(II) hydrogels increase with increasing concentrations of zinc sulfate. This result shows that the compression moduli of the GelMA-His-Zn(II) hydrogels can be tuned by adjusting the metal coordination bond density, and the ability to tune the compression modulus of the material means it can be aligned with the mechanical properties of a greater number of types of tissue. However, the compression modulus of the GelMA-Zn(II) hydrogel did not change noticeably with increasing concentrations of zinc sulfate.

Fig. 5 Compressive stress–strain profiles for repeated loading to 80% strain (five cycles at 0.5 N min−1 as shown, inset) of (a) GelMA-His-Zn(II)-1 hydrogels and (b) GelMA hydrogels. A distinctive and advantageous feature of metal coordination bonds is their ability to withstand repeated loading. To quantitatively investigate this ability in the GelMA and GelMA-His-Zn(II) hydrogels, repetitive loading was tested. Stress–strain profiles under the same cyclic compressive strain overlapped with each other, and no appreciable change in the moduli between loading cycles was observed, indicating elastic recovery at 80% strain (Fig. 5a). Moreover, the hysteresis energy



(i.e., the energy consumed due to internal bond failure

38

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) was notably higher for the

GelMA-His-Zn(II) hydrogels (Fig. 5a) than for the GelMA hydrogels (Fig. 5a), indicating energy dissipation due to forceful induction of metal coordination bond failure. In addition, with repeated application of 80% strain, Mullins-type softening (i.e., reductions in moduli and strain energy) was not observed in the GelMA-His-Zn(II) hydrogels. Thus, the GelMA-His-Zn(II) hydrogels effectively leverage the primary metal coordination bonds to prevent internal rupture of the covalent bonds and maintain their moduli even without lengthy recovery times like those needed with other types of crosslinking (e.g., ionic DNs)

39-40

. Taken together, these results indicate that metal coordination

bonds within the GelMA-His-Zn(II) hydrogels immediately repair themselves between loading cycles and contribute substantially to energy consumption throughout loading, which enables the GelMA-His-Zn(II) hydrogels to withstand repetitive loadings in rapid succession like what occurs in biological tissues.

Fig. 6 (a) and (b) Bacterial colonies of S. aureus and E. coli after co-culture with GelMA GelMA-His, GelMA-His-Zn(II)-1, GelMA-His-Zn(II)-2 and GelMA-His-Zn(II)-3 hydrogels, respectively. (c) and (d) antibacterial rate (AR) of S. aureus and E. coli respectively, n=4, **p

Tunable Mechanical, Antibacterial, and Cytocompatible Hydrogels

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