Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep 6:8:2041731417726464.
doi: 10.1177/2041731417726464. eCollection 2017 Jan-Dec.

Crosslinking method of hyaluronic-based hydrogel for biomedical applications

Sureerat Khunmanee  1 , Younghyen Jeong  1 , Hansoo Park  1
Affiliations

Crosslinking method of hyaluronic-based hydrogel for biomedical applications

Sureerat Khunmanee et al. J Tissue Eng. .

Abstract

In the field of tissue engineering, there is a need for advancement beyond conventional scaffolds and preformed hydrogels. Injectable hydrogels have gained wider admiration among researchers as they can be used in minimally invasive surgical procedures. Injectable gels completely fill the defect area and have good permeability and hence are promising biomaterials. The technique can be effectively applied to deliver a wide range of bioactive agents, such as drugs, proteins, growth factors, and even living cells. Hyaluronic acid is a promising candidate for the tissue engineering field because of its unique physicochemical and biological properties. Thus, this review provides an overview of various methods of chemical and physical crosslinking using different linkers that have been investigated to develop the mechanical properties, biodegradation, and biocompatibility of hyaluronic acid as an injectable hydrogel in cell scaffolds, drug delivery systems, and wound healing applications.

Keywords: Hyaluronic acid; crosslinking method; tissue engineering.

PubMed Disclaimer

Conflict of interest statement

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Hyaluronic acid structure showing the disaccharide repeat units and sites for chemical modification.
Figure 2.
Figure 2.
Coupling reagents for the activation of hyaluronic acid (HA)-COOH.
Figure 3.
Figure 3.
Crosslinking agents for modification of –OH groups.
Figure 4.
Figure 4.
Synthesis of oxidized hyaluronic acid (HA)-gelatin hydrogels: (a) crosslinking of HA and gelatin by ethyl(dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS), (b) HAG polymer oxidation by sodium periodate, and (c) Oxi-HAG-ADH hydrogel synthesis, with imines bonding oxi-HAG and ADH.
Figure 5.
Figure 5.
Commonly utilized vinyl groups in thiol-Michael addition reactions.
Figure 6.
Figure 6.
(a) Synthesis protocol of thiol-modified hyaluronic acid (HA-SH). (b) 1H-NMR (D2O) spectra of HA and HA-SH (Mw = 0.1 MDa, Ds = 37.47%). (c) Biocompatibility of HA-SH polymers (Mw = 0.3 MDa, Ds = 55.44%) for chondrocytes, 3T3 cells and L929 cells after 48 h of co-culture (n = 3). (d) SEM micrograph of HA-SH hydrogel (Mw = 0.3 MDa, Ds = 55.44%, 3.0% (w/v)). (e) Image of HA-SH solution (Mw = 0.3 MDa, Ds = 55.44%, 3.0% (w/v)). (f) Image of HA-SH hydrogel. (g) Image of HA-SH solution derived from the decomposition of HA-SH hydrogel with DTT (100 mM). Source: Reproduced with permission. Copyright 2016, Elsevier B.V.
Figure 7.
Figure 7.
(a) Schematic illustration to show formation of a hydrogel through click chemistry. (b) Gelation time of the hyaluronic acid/chondroitin sulfate (HA/CS)/gelatin click hydrogel as a function of CuCl concentration. (c) Macroscopic and (d) microscopic images of the hydrogel taken with a digital camera and by cryo-SEM at −195°C, respectively. (e) 1H HR-MAS NMR spectra of the hydrogel. Source: Reproduced with permission. Copyright 2011 Acta Materialia Inc.
Figure 8.
Figure 8.
Schematic representation of hyaluronic acid (HA)/pluronic hydrogels. (a) Slightly crosslinked three-dimensional network formation of HA/Pluronic hydrogels and their sol-gel transition behavior. (b) Sol-gel transition curves of HA/Pluronic hydrogels (∇) and HADN-L + Plu-SH hydrogels (○). Pluronic F127 hydrogel (●) was used as control. Source: Reproduced with permission. Copyright 2010, Royal Society of Chemistry.
Figure 9.
Figure 9.
Reaction scheme and idealized structure of the Fe-hyaluronic acid (FeHA) network.
Figure 10.
Figure 10.
Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining of collagen type II in hADSC after 14 days of in vitro culture in hyaluronic acid (HA) and HA/sodium alginate (SAL) interpenetrating polymeric network (IPN) scaffolds. Scale bar = 20 μm. Source: Reproduced with permission. Copyright 2013, Elsevier B.V.
Figure 11.
Figure 11.
Intracellular uptake and distribution of UnTHCPSi and UnTHCPSi–HA+ nanoparticles. TEM images and the corresponding numerically organized magnifications of ultra-thin sections of MDA-MB-231 and MCF-7 breast cancer cells exposed to UnTHCPSi and UnTHCPSi–HA+ at a concentration of 50 μg/mL, for 6 h at 37°C are shown. The conjugation of HA+ onto the surface of the UnTHCPSi nanoparticles has been shown to significantly enhance the interaction and consequently the uptake of the nanoparticles by both MDA-MB-231 and MCF-7 breast cancer cells. The nanoparticles associated with the cells are highlighted by blue arrows. Scale bars are 5 μm. Source: Reproduced with permission. Copyright 2014, Royal Society of Chemistry.
Figure 12.
Figure 12.
Representative photographs of antimicrobial activities of PVA-HA membranes showing the appearance of microbial inhibition zones formed against seeded Staphylococcus aureus, Candida albicans, and Escherichia coli. Source: Reproduced with permission. Copyright 2015, Sociedade Brasileira de Quimica.
See this image and copyright information in PMC

References

    1. Wang H, Heilshorn SC. Adaptable hydrogel networks with reversible linkages for tissue engineering. Adv Mater 2015; 27(25): 3717–3736. - PMC - PubMed
    1. Kim IL, Mauck RL, Burdick JA. Hydrogel design for cartilage tissue engineering: a case study with hyaluronic acid. Biomaterials 2011; 32(34): 8771–8782. - PMC - PubMed
    1. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer 2008; 49(8): 1993–2007.
    1. Sivashanmugam A, Arun Kumar R, Vishnu Priya M, et al. An overview of injectable polymeric hydrogels for tissue engineering. Eur Polym J 2015; 72: 543–565.
    1. Burdick JA, Prestwich GD. Hyaluronic acid hydrogels for biomedical applications. Adv Mater 2011; 23(12): H41–H56. - PMC - PubMed