Carrageenan based hydrogels for drug delivery, tissue engineering and wound healing
Introduction
Hydrogels are 3D networks of hydrophilic polymeric chains that have 90–99% water content and facilitate efficient oxygen and mass transfer (Seliktar, 2012). Over the past few decades, these hydrophilic networks have garnered unprecedented application in tissue engineering owing to their high biocompatibility, low immunogenicity and cytotoxicity, ease of functionalization and tuneable physicochemical properties (Hoffman, 2012; Saul & Williams, 2013). These polymeric systems are excellent substrates for cell transplantation and differentiation, endogenous regeneration, sustained drug delivery, bio prosthetics and wound healing (Saul & Williams, 2013; Hoffman, 2012; Seliktar, 2012; Anitha et al., 2014). The three dimensional network system of hydrogels mimics the microarchitecture of native tissue extracellular matrix (ECM) and thus provide in vivo niche like conditions for cell survival (Geckil, Xu, Zhang, Moon, & Demirci, 2010; Tibbitt & Anseth, 2009). Although a gamut of biopolymers have been employed in hydrogel biofabrication for cell encapsulation and targeted drug delivery, polysaccharide based biomaterials are extensively being studied due to their enhanced biological activity, biocompatibility and biodegradability, mechanical stability as well as scope for chemical modification. Recently, hydrogels based on marine derived polysaccharides such as alginate, agarose, chitosan, etc. have been widely employed in tissue engineering applications as they are available in abundance (Lee & Mooney, 2012; Varoni et al., 2012; Vignesh, Sivashanmugam et al., 2018). These biopolymers have known to possess a facile and efficient extraction procedure that makes them ideal to be produced in large scale.
In the present scenario, where scientists are in a quest for novel renewable polymers, the underexploited carrageenan (CRG) seaweeds belonging to marine red algae family are an interesting source of polysaccharides with distinctive structure and functional properties. Derived from Rhodophyceae, CRG is an anionic, sulphated polygalacton consisting of alternating long linear chains of α-1, 3 D-galactose and β-1, 4 3, 6-anhydro-galactose (3, 6-AG) with ester sulphates (15–40%) similar to naturally occurring glycosaminoglycans (Campo, Kawano, da Silva, & Carvalho, 2009). This seaweed based polysaccharide can be conventionally categorized into six basic forms depending on their sulphate content, source of extraction and solubility as Kappa (κ)-, Iota (ɩ)-, Lambda (λ)-, Mu (μ)-, Nu (ν)- and Theta (θ)-CRG (Fig. 1). Of these κ, ɩ and λ are of commercial importance due to their viscoelastic and gelling properties (Cunha & Grenha, 2016). CRG type, molecular weight, concentration and temperature determine the viscosity of CRG gels. Viscosity increases with increase in concentration of the CRG, as there is more interaction between the macromolecular chains and in the presence of cations the electrostatic repulsion between the sulphate groups are reduced. κ- and ɩ- CRGs form gels of increased apparent viscosity at low temperature and small salt concentrations. The viscosity of CRG gels decreases with increase in temperature (Anderson, Dolan, Lawson, Penman, & Rees, 1968). CRG is used far more widely than agar as emulsifier, gelling, thickening and stabilizing agent in pharmaceutical and industrial applications (Liu, Zhan, Wan, Wang, & Wang, 2015). Apart from its inflammatory and immunomodulatory properties, these polysaccharides are used as an anticancer (G. Zhou et al., 2004), antihyperlipidemic agents (Panlasigui, Baello, Dimatangal, & Dumelod, 2003) and also as herpes (Carlucci, Scolaro, & Damonte, 1999) and human papillomavirus inhibitors (Buck et al., 2006).
Among the commercially available CRGs, κ- and ɩ- CRG form three dimensional network of double helix via crosslinking of adjacent sulphate groups, while in λ-CRGs the sulphate groups do not undergo crosslinking and thus do not form gels (Campo et al., 2009). Upon cooling and in the presence of appropriate cation (K+, Ca2+), CRGs, kappa in particular undergo, coil to helix transition and helical aggregation to form thermotropic and ionotropic hydrogels. Thermogelation property of κ-CRG hydrogels has been used to develop novel injectable hydrogels systems. Generally, CRG based hydrogels formed are brittle in nature with high swelling ratios and poor mechanical stability under physiological conditions (Thakur et al., 2016). Chemical modification of the polymeric backbone can be used to overcome this drawback. CRG is known to possess multifarious functional groups such as hydroxyl/sulphate groups which make them an ideal choice for diverse chemical modifications (Campo et al., 2009). They have been oxidized (Zhu et al., 2017), oversulphated (Yuan et al., 2005), carboxmethylated (Aparna et al., 2017), acetylated (Yuan et al., 2005), methacrylated (Mihaila et al., 2013), as well as phosphorylated (Yuan et al., 2005). These modifications have not only proven that CRG is a robust polymer but have also endowed them with the improved physio-chemical properties, new specific functionalities and features. There are few excellent reviews that widely explored the basic properties of CRG such as structure, physiochemical properties, biological activities and chemical modifications (Campo et al., 2009; Liu et al., 2015). Further, few reviews have also focussed on CRG based drug delivery applications using blends and nanocomposites (Cunha & Grenha, 2016; Li, Ni, Shao, & Mao, 2014; Zia et al., 2017)
In this review, we specifically focus on the emerging trends in application of CRG as promising biomaterial. We provide an overview of the various forms of CRG based hydrogels for drug delivery, tissue engineering and wound healing. Administration of these hydrogels through various routes for drug delivery applications has been critically evaluated. Finally, we have provided our perspectives that promote this seaweed-derived polysaccharide as versatile and promising biomaterial for tissue engineering applications.
Section snippets
Different forms of carrageenan based hydrogels
CRG hydrogels are generally formed through thermoreversible gelation, ionic crosslinking as well as modification of CRG backbone with photocrosslinking methacrylate moieties (Fig. 2). These modifications are further explored to fabricate different forms of CRG hydrogels with interesting features.
Bone
Development of scaffolds and bone substitutes that provides structural and functional support in treating the bone defect remains the primary focus in the area of bone tissue engineering. CRG’s ability to allow apatite layer formation when incorporated with functional bioactive cues is well established (Daniel-Da-Silva, Lopes, Gil, & Correia, 2007; Kim et al., 2011). κ-CRG when incorporated into collagen-hydroxyapatite composite gel, increased its compressive strength (Feng et al., 2017). This
Conclusion and future perspective
In summary, application of CRG in drug delivery, tissue engineering and regenerative medicine is rapidly evolving due to its distinctive gelling mechanism, ample functional groups, strong water absorption and favourable physiochemical properties. By adopting variety of fabrication strategies to develop CRG based hydrogels, desired therapeutic potential could be achieved. Development of photocrosslinking hydrogels facilitated to overcome the physiological instability of CRG hydrogels. Floating
Acknowledgements
The authors are grateful for the support provided by Nanomission, Department of Science and Technology (DST), Government of India under the ‘M.Tech’ program (Ref. No. SR/NM/PG-01/2015).A. Sivashanmugam acknowledges the Council of Scientific and Industrial Research (CSIR) for the financial support through Senior Research Fellowship (SRF Award No. 09/963 (0038)2K17-EMR-I).
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