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Applications of Polymer, Composite, and Coating Materials
Mussel-inspired tissue adhesive hydrogel based on polydopaminechondroitin sulfate complex for growth-factor-free cartilage regeneration Lu Han, Menghao Wang, Pengfei Li, Donglin Gan, Liwei Yan, Jielong Xu, Kefeng Wang, Liming Fang, Chun Wai Chan, Hongping Zhang, Huipin Yuan, and Xiong Lu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b05314 • Publication Date (Web): 27 Jul 2018 Downloaded from http://pubs.acs.org on July 28, 2018
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ACS Applied Materials & Interfaces
Mussel-inspired tissue adhesive hydrogel based on polydopamine-chondroitin sulfate complex for growth-factor-free cartilage regeneration
Lu Han1, Menghao Wang1, Pengfei Li1, Donglin Gan1, Liwei Yan1, Jielong Xu1, Kefeng Wang2, Liming Fang3, Chun Wai Chan4, Hongping Zhang5, Huipin Yuan6, Xiong Lu1* 1
Key Lab of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, China 2
National Engineering Research Center for Biomaterials, Genome Research Center for Biomaterials, Sichuan University, Chengdu 610064, Sichuan, China 3
4
Department of Polymer Science and Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China 5
Engineering Research Center of Biomass Materials, Ministry of Education, School of Materials Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China
6
College of Physical Science and Technology, Sichuan University, Chengdu 610064, Sichuan, China
* Corresponding Author Tel.: +86-28-87634023 Fax: +86-28-87601371 Email address:
[email protected] Keywords: mussel inspired; chondroitin sulfate; hydrogel; chondrocyte; tissue adhesive; cartilage tissue engineering
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Abstract. Glycosaminoglycans-based hydrogels are widely used for cartilage repair because glycosaminoglycans are the main component of cartilage extracellular matrix (ECM) and can maintain chondrocytes functions. However, most of glycosaminoglycans-based hydrogels are negatively charged and cell repellant, and they cannot host cells or favor tissue regeneration. Inspired by mussel chemistry, we designed a polydopamine-chondroitin sulfatepolyacrylamide (PDA-CS-PAM) hydrogel with tissue adhesiveness and super mechanical properties for growth-factor free cartilage regeneration. Thanks to the abundant reactive catechol groups on the PDA, a cartilage-specific PDA-CS complex was formed by self-assembly of PDA and CS, and then the PDA-CS complex was homogenously incorporated into an elastic hydrogel network. This catechol group-enriched PDA-CS complex endowed the hydrogel with good cell affinity and tissue adhesiveness to facilitate cell adhesion and tissue integration. Compared with bare CS, the PDA-CS complex in the hydrogel was more effective in exerting its functions on adhered cells to upregulate chondrogenic differentiation. Because of the synergistic effects of non-covalent interactions caused by the PDA-CS complex and covalently crosslinked PAM network, the hydrogel exhibited super resilience and toughness, meeting the mechanical requirement of cartilage repair. Collectively, this tissue-adhesive and tough PDA-CS-PAM hydrogel with good cell affinity creates a growth factor-free and biomimetic microenvironment for chondrocyte growth and cartilage regeneration, and sheds light on the development of growth-factor-free biomaterials for cartilage repair.
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1. Introduction Articular cartilage has poor tissue regenerative and reparative ability following injury or degenerative diseases because of the avascular properties of cartilage, which make cartilage repair a great challenge in clinics 1. Hydrogels, due to their high water content and structural resemblance to natural soft biological tissues 2-4, are promising candidates for cartilage repair. Hydrogels have adequate mechanical strength and swelling kinetics, facilitating the diffusion of nutrients and metabolites, so as to provide biomimetic ECM environment similar to native cartilage
5-6
. Various hydrogels that were formed by chemically or physically crosslinked
polymers from natural or synthetic sources have been developed for biological and biomedical applications 7. Synthetic polymer-based hydrogels, such as poly(ethylene glycol), poly(vinyl alcohol), polyglycolic acid, and polyacrylamide, possess high mechanical properties, but these materials are relatively bio-inert and lack bioactivity. Thus, commonly reported hydrogels based on synthetic polymers are not able to provide an ideal environment for cell adhesion, inducing chondrogenic induction, and cartilage matrix remodeling support 8. To improve the bioactivity of these hydrogels, researchers have introduced bioactive molecules such as transforming growth factors
9-11
and peptides
12-13
into the hydrogel, and
the bioactive molecules immobilized in hydrogels show remarkably enhanced biological functionalities. However, the biological activity of these bioactive molecules is not easy to be preserved during hydrogel processing 14-15, which limits their practical applications.
Natural polymer-based hydrogels, such as collagen, agarose, silk fibroin, chitosan, alginate, gelatin, elastin, hyaluronic acid (HA), and chondroitin sulfate (CS), show excellent biological activity, including cell signaling and cell-interactive properties 8. Among them, CS is a type 3
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of sulfated glycosaminoglycan composed of alternating units of β-1,4-linked glucuronic acid and β-1,3-N-acetyl-D-glucosamine 16. It is the main component of cartilage ECM and other tissues in the body, and plays an important role in regulating cell functions, such as cell migration and receptor binding 17. CS-based hydrogels have been shown to have good wound healing ability and biological activity at the cellular level, which may help to restore arthritic joint function 18-20. However, native CS-based hydrogels are limited in certain clinical studies (e.g., cartilage regeneration) due to their low mechanical properties and short-term duration in vivo 7. In addition, because of its negative charge and lack of adhesive motifs, CS exhibits weak cell affinity for chondrocytes, fibroblasts, and hippocampal neurons 21. Therefore, it is imperative to develop a CS-based hydrogel for cartilage repair, which has not only enhanced mechanical properties, but also good cell/tissue affinity.
Recently, polydopamine (PDA), with structural similarity to marine mussel secreted adhesion proteins, was proven to have strong adhesion to various substrates 22-24 especially to enhance cell attachment and proliferation
25-26
. The high adhesiveness of PDA is attributed to the
active catechol groups on PDA that facilitate cell adhesion through conjunction with reactive groups (amino groups, carboxyl groups, and catechol groups) on cell membranes 27. Indeed, previous studies have reported mussel-inspired hydrogels that exhibit sufficient adhesion to diverse types of materials, especially cells and tissue. For instance, Lee et al. 26 fabricated the chitosan/pluronic hydrogel as tissue adhesives formed by catechol-functionalized chitosan. Cho et al.
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functionalized hyaluronic acid (HA) with dopamine to form a tissue adhesive
catechol-modified HA hydrogel for invasive cell therapy. These mussel-inspired hydrogels 4
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have typically been prepared by chemical and physical crosslinking of catechol groups on the polymer chains. Thus, the physicochemical and mechanical properties of these hydrogels are highly dependent on the catechol conjugation degree. However, the relatively low conjugation degree of catechol groups (
