Recent Advances in Chemically-Modified and Hybrid Carrageenan-Based Platforms for Drug Delivery, Wound Healing, and Tissue Engineering.

Recently, many studies have focused on carrageenan-based hydrogels for biomedical applications thanks to their intrinsic properties, including biodegradability, biocompatibility, resembling native glycosaminoglycans, antioxidants, antitumor, immunomodulatory, and anticoagulant properties. They can easily change to three-dimensional hydrogels using a simple ionic crosslinking process. However, there are some limitations, including the uncontrollable exchange of ions and the formation of a brittle hydrogel, which can be overcome via simple chemical modifications of polymer networks to form chemically crosslinked hydrogels with significant mechanical properties and a controlled degradation rate. Additionally, the incorporation of various types of nanoparticles and polymer networks into carrageenan hydrogels has resulted in the formation of hybrid platforms with significant mechanical, chemical and biological properties, making them suitable biomaterials for drug delivery (DD), tissue engineering (TE), and wound healing applications. Herein, we aim to overview the recent advances in various chemical modification approaches and hybrid carrageenan-based platforms for tissue engineering and drug delivery applications.

Recent Trends in Three-Dimensional Bioinks Based on Alginate for Biomedical Applications.

Three-dimensional (3D) bioprinting is an appealing and revolutionary manufacturing approach for the accurate placement of biologics, such as living cells and extracellular matrix (ECM) components, in the form of a 3D hierarchical structure to fabricate synthetic multicellular tissues. Many synthetic and natural polymers are applied as cell printing bioinks. One of them, alginate (Alg), is an inexpensive biomaterial that is among the most examined hydrogel materials intended for vascular, cartilage, and bone tissue printing. It has also been studied pertaining to the liver, kidney, and skin, due to its excellent cell response and flexible gelation preparation through divalent ions including calcium. Nevertheless, Alg hydrogels possess certain negative aspects, including weak mechanical characteristics, poor printability, poor structural stability, and poor cell attachment, which may restrict its usage along with the 3D printing approach to prepare artificial tissue. In this review paper, we prepare the accessible materials to be able to encourage and boost new Alg-based bioink formulations with superior characteristics for upcoming purposes in drug delivery systems. Moreover, the major outcomes are discussed, and the outstanding concerns regarding this area and the scope for upcoming examination are outlined.

A multifunctional nanocomposite spray dressing of Kappa-carrageenan-polydopamine modified ZnO/L-glutamic acid for diabetic wounds.

Sprayable bioadhesives with exceptional properties were developed for application in wound healing. In this study, a visible light-crosslinkable nanocomposite bioadhesive hydrogel with multifunctional properties was proposed. While methacrylated Kappa-carrageenan (KaMA), mimicking the natural glycosaminoglycan was applied as the hydrogel matrix, various concentrations of polydopamine modified ZnO (ZnO/PD) nanoparticles (0, 0.5, 1 and 2 wt%) was loaded in it to improve its mechanical, antibacterial and cellular properties. Moreover, L-glutamic acid was incorporated in the nanocomposite hydrogel network to accelerate wound healing. The nanocomposite hydrogels revealed significant mechanical property and recovery ability, comparable elasticity with human skin and great adhesiveness. For instance, the tensile strength of KaMA hydrogel enhanced from 64.1 ± 10 to 80.3 ± 8 kPa and elongation jumped from 20 ± 4% to 61 ± 5% after incorporation of 1 wt% ZnO/PD nanoparticles. The nanocomposite hydrogels demonstrated effectual blood clotting ability and biocompatibility, >95% cell viability after 3 days of incubation. In vivo experiments also suggested that L-glutamic acid loaded nanocomposite hydrogel considerably accelerated wound healing with superior granulation tissue thickness than control in a full-thickness skin defect model. Taken together, this visible-light crosslinking nanocomposite hydrogel with significant properties could be used to spray on a wound area to eliminate wound infection and accelerate wound healing process.

An adhesive and injectable nanocomposite hydrogel of thiolated gelatin/gelatin methacrylate/Laponite® as a potential surgical sealant.

Hemostatic adhesive hydrogels as sealants for surgical operations are one of the focus of the researches in the field of injectable materials. Herein, we evaluated the potential application of a mechanically robust nanocomposite hydrogel with significant adhesion strength and shorter blood clotting time. This hydrogel was composed of thiolated gelatin (Gel-SH) and gelatin methacrylate (GelMA) as the main matrix to support cell viability and proliferation, while polydopamine functionalized Laponite® (PD-LAP) were introduced to the structure to improve the mechanical properties, adhesion strength, and blood clotting. This hydrogel formed via Michael reaction between Gel-SH and GelMA, and covalent interaction between PD-LAP and hydrogel. Results revealed that presence of PD-LAP significantly controlled the swelling ratio, biodegradability, and mechanical properties of nanocomposite hydrogels. Tensile and compressive strength of nanocomposite hydrogels were measured in the range of 22-84 kPa and 54-153 kPa, respectively. Furthermore, nanocomposite hydrogels revealed excellent recovery ability, strong tissue adhesiveness and significantly less blood clotting time than Gel-SH/GelMA hydrogel (2.25 min). In the culture with L929 fibroblasts cells, viability more than 97% and high proliferation after 5 days of culture was estimated. The simplicity, low-cost, tunable mechanical properties, short blood clotting time, and cytocompatibility of the hydrogels composed of Gel-SH, GelMA, and PD-LAP highlight its potential as hemostat sealants.

Sprayable and injectable visible-light Kappa-carrageenan hydrogel for in-situ soft tissue engineering.

The aim of this study was to develop injectable and sprayable visible-light crosslinked Kappa-carrageenan (κCA) hydrogel and to investigate the role of polymer concentration (2, 4 and 6 wt%) and degree of methacrylation (6 and 12%) on its properties. It was found that, the average pore sizes, water content and swelling ratio of hydrogel were tunable by changing the methacrylate κCA (KaMA) concentration and methacrylation degree. Furthermore, the mechanical properties of KaMA could be noticeably modulated, depending on the formulation of hydrogel. Tensile and comprehensive modules were enhanced from 68 to 357 kPa and from 213 to 357 kPa, respectively, by increasing KaMA concentration from 2 to 6 wt% and methacrylation degree from 6 to 12%. Furthermore, with increasing methacrylation degree and polymer content, the absorbed energy and energy loss were increased. Moreover, recovery significantly enhanced from 27.3% to 74.4% with increasing polymer content from 2 to 6 wt%. Finally, visible-light crosslinked KaMA hydrogels not only was biocompatible, but also could promote HaLa cell and fibloblasts function. The visible-light crosslinked KaMA is thought to be an exclusive biomaterial as a sprayable hydrogel being able to cover skin injuries or to inject as a bio-printing material to in situ heal soft tissue damages.

An injectable mechanically robust hydrogel of Kappa-carrageenan-dopamine functionalized graphene oxide for promoting cell growth.

An injectable nanohybrid hydrogel with robust mechanical properties was developed based on Methacrylate-Kappa-carrageenan (KaMA)-dopamine functionalized graphene oxide (GOPD) for soft tissue engineering. KaMA-GOPD hydrogels revealed shear-thinning behavior and injectability through interaction of active catechol groups of dopamine with other moieties in the structure of hydrogels. In addition, these interactions promoted mechanical properties of hydrogels, depending on the GOPD content. Noticeably, encapsulation of 20 wt.% GOPD significantly enhanced compressive strength (8-folds) and toughness (6-folds) of KaMA. Furthermore, the hybrid hydrogel consisting of 20 wt.% GOPD significantly reduced energy loss from 70% (at KaMA) to about 61%, after a two-cycle compression test, while significantly enhanced recovery of the KaMA structure. Reinforcing the KaMA with 20 wt.% GOPD resulted in enhanced fibroblast proliferation (2.5-times) and spreading (5.7 times) after 5 days of culture. Based on these findings, KaMA-GOPD hydrogel could be used for cell delivery through the injection process and applied as a suitable bio-ink for 3D-bioproiting process.