Alginate-based self-healing hydrogels assembled by dual cross-linking strategy: Fabrication and evaluation of mechanical properties

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Abstract

One way to enhance the poor mechanical properties of the self-healing hydrogels based on host-guest (HG) interaction is employing the dual cross-linking method. Here, the alginate-based hydrogels based on HG complexation were prepared through the modification of alginate (ALG) polysaccharide with beta-cyclodextrin (βCD) and adamantane (Ad) as host and guest groups with different grafting values, respectively. The porous structure was confirmed for all ALG-CD:ALG-Ad hydrogels. The average pore size of ALG-CD1:ALG-Ad1 hydrogel cross-linked by HG interactions was 288 μm. Mechanical properties of the alginate-based HG hydrogels were improved by incorporating Ca2+ ions in their structure through dual cross-linking methodology. The maximum modulus of the porous dual-crosslinked hydrogel was reached up to 6500 Pa. The healing time of less than 5 s was obtained for the alginate-based hydrogels. The fabricated hydrogels can be used in 3D printing, tissue engineering, and drug delivery systems due to their biocompatibility and shear-thinning behavior.

Introduction

In recent decades, application of the polymeric materials in various fields has increased significantly and life without polymers is unimaginable. However, usually cracks and micro-cracks occur when using polymeric materials. Self-repairing materials as a significant type of smart materials show the ability to auto-heal cracks or micro-cracks without human participation or in the presence of external stimulates. This ability increases the life-time of materials and reduces the replacing and repairing costs [1], [2], [3]. Generally, application of pre-embedded healing agents (extrinsic healing method) in self-healing materials is not repeatable and they can heal only one time. Therefore, researchers turned to the use of reversible interactions (intrinsic healing method) to make self-healing materials. Reversible interactions can be used in two ways including covalent and non-covalent interactions. Covalent interactions such as disulfide bonds [4], [5], reversible photodimerization [6], [7], [8], boronate ester bond [9], [10], the Diels–Alder reaction [11], [12], [13], acylhydrazone bond [14], [15], imine bond [16], diselenide bond [17], trithiocarbonates [18], and alkoxyamine bond, have a relatively low healing speed and need a specific external stimulus. So, non-covalent interactions including host-guest (HG) complexation [19], [20], [21], ionic bonds [22], [23], [24], π-π stacks [25], hydrogen bonds [26], [27], stereocomplex crystallization [28], metal-ligand bonds [29], LCST/UCST-based interactions [30], [31], and sol-gel transition controlled by ultrasound, are more powerful and applicable for proposing self-healable materials. There are three main strategies to fabricate the self-healing polymers such as main-chain recognition (polyrotaxane), side-chain recognition, and sequential recognition. 3D structure polymer networks (hydrogels) can be cross-linked physically (non-covalent bonds), chemically, or a combination of these two methods that have many applications in biological fields [32], [33], [34]. Host-guest (HG) complexation can be used to fabricate hydrogels with self-healing ability due to the reversible healing process, high healing rate, and high selectivity for guest molecules. But, the mechanical strength of HG hydrogels is weak because of their non-covalent nature. HG-based self-healing materials have various applications in designing stimuli-responsive systems, shape-memory materials, coatings (anti-bacterial, UV-blocking, food packaging), optical sensing [35] and imaging, artificial muscles [36], wound and tissue healing, biomedical applications [37], 3D bioprinting [38], gene and drug delivery, 3D printing [39], electroconductive polymers, cell therapy [40], bone tissue engineering [41], commercial painting, and nanocomposites. Among different host molecules such as cucurbiturils [42], [43], [44], crown ethers [45], [46], [47], calixarenes [48], pillararenes [49], and cyclodextrins [50], [51], β-cyclodextrin “a cyclic non-toxic oligosaccharide with hydrophobic cavity and hydrophilic surface” has attracted the attention of many scientists because of the biocompatibility, low cost, commercial availability, ability to form an inclusion complex with different guest molecules, and easy modification. There were reported different guest groups such as adamantane [52], ferrocene [53], azobenzene [54], imidazole [55], benzyl [56], N-isopropylacrylamide [57], cationic alkyl chains [58], arylazopyrazole [59], benzotriazole [60], amino acids [61], phenolphthalein [62], and l-methanol [63] that can form inclusion complex with βCD cavity. There are several factors to fabricate HG complexes including the size matching of the guest molecules with βCD cavity, hydrophobic interactions between guests and the internal surface of the βCD cavity, and solvent. The main driving force to make the HG complexes is the release of water molecules out of the CD cavity. Water molecules must be replaced with more non-polar guest molecules in solution to create non-polar-non-polar interactions, reduce the CD ring pressure, and fabricate a more stable state with lower energy [64]. This convenient net energetic driving is necessary to insert the guest molecule into the CD cavity. The adamantane can form a stable inclusion complex with the β-CD cavity and has a high binding constant (Ka) of 3.5 × 104 with the β-CD cavity compared to other guest molecules [65]. Alginate, a biological polysaccharide extracted from seaweeds, has a linear chain structure of (1–4)-linked α-L-guluronic acid (G) and β-D-mannuronic acid (M) residues, giving it biocompatibility, hydrophilicity, and nontoxicity [66]. Moreover, alginate has a high density of carboxylate and hydroxyl groups which can be modified with different functional groups, such as sulfonic or amine groups [67], [68], [69], [70]. For example, Xu et al. prepared an electroconductive HG-based hydrogel using adamantane-modified sulfated alginate and poly-βCD for 3D cell culture application [71]. Miao et al. fabricated a self-healable thermos-responsive hydrogel based on HG inclusion complex of alginate grafted with βCD and Pluronic® F108 copolymer [72].

Due to the emergence and novelty of the self-healing materials, addressing the challenges associated with this field, such as their poor mechanical properties, is as important as the application. For this reason, researchers have used various methods to solve this challenge including the addition of nanomaterials, use of β-CD bilayer vesicles, β-CD dimer, β-CD trimer, poly-β-cyclodextrin, and HG macromer, application of dual cross-linking methods, and increasing the number of host and guest sites [65]. Most researchers used covalent dual cross-links to address this challenge, but we used ionic cross-links, which could be a positive step in the development of this field. 1-(p-toluenesulfonyl)imidazole (Ts-Im), mono-6A-(p-toluenesulfonyl)-6A-deoxy-β-cyclodextrin (CD-OTs), and β-cyclodextrin-ethylenediamine (CD-EDA) were synthesized, respectively. βCD and adamantane as host and guest groups were grafted on the backbone of alginate biopolymer with different grafting values. Self-healing hydrogels were formed and Ca2+ ions as ionic cross-linker were used to enhance the mechanical strength of the hydrogels. In addition to improve the poor mechanical properties, we also obtained a very good repairing rate. In most cases, thickening of the hydrogel decreases the repairing ability, but we solved this problem by increasing the grafting percentage. Final biocompatible self-healing hydrogels can be used for designing biomedical systems such as tissue engineering and drug-delivery systems.

Section snippets

Materials

Sodium alginate (viscosity of 15–25 cP, 1% in H2O), p-toluenesulfonyl chloride, imidazole, β-cyclodextrin, NH4Cl, N-hydroxysuccinimide (NHS), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), ethylenediamine, and dialysis bag (12,000 MWCO) were obtained from Sigma Aldrich (Germany). Calcium chloride and 1-aminoadamantane hydrochloride ≥99% were obtained from Merck. CH2Cl2 was dried over calcium hydride under reflux for 24 h. All the other solvents including hexane, ethyl

Synthesis and characterization of host polymers

To fabricate the host polymer, the CD-OTs was synthesized through the reaction of Ts-Im with βCD (Scheme 1). Then the CD-OTs was amine-functionalized with ethylenediamine to form CD-EDA. Finally, the alginate (ALG) backbone was modified with CD-EDA to fabricate the host polymer. The successful synthesis of Ts-Im was confirmed with 1H NMR analysis (Fig. S1). Peaks at 2.38, 7.98–8, and 7.49 ppm respectively correspond to the methyl group, H4, and H5 of the tosyl ring. Signals at 8.40, 7.76, and

Conclusion

In the present study, the alginate biocompatible polymer was modified with adamantane (Ad) and natural βCD groups, and the self-healing hydrogels based on the HG interactions were fabricated. βCD and Ad groups at two levels (6.1 mmol for ALG-Ad1, 8.8 mmol for ALG-Ad2 and 3.5 mmol for ALG-CD1, 6 mmol for ALG-CD2) were grafted onto the alginate backbone and the effect of grafting value on the mechanical properties was investigated. Also, to prepare the self-healing HG hydrogel with enhanced

CRediT authorship contribution statement

Zahra Mohamadnia: Supervision, Conceptualization, Editing the manuscript.

Masoumeh Mohamadhoseini: Investigation, Methodology, Writing, Original draft preparation.

Author contributions

Masoumeh Mohamadhoseini performed the experimental investigations. Zahra Mohamadnia made substantial contributions to research design and interpretation of data.

Acknowledgment

The authors wish special thanks to Dr. Ehsan Ahadi Akhlaghi and Dr. Mania Maleki for their technical support, and the Institute for Advanced Studies in Basic Sciences (IASBS) for its financial and spiritual support.

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