Soft-Nanoparticle Functionalization of Natural Hydrogels for Tissue Engineering Applications

Abstract

Tissue engineering has emerged as an important research area that provides numerous research tools for the fabrication of biologically functional constructs that can be used in drug discovery, disease modeling, and the treatment of diseased or injured organs. From a materials point of view, scaffolds have become an important part of tissue engineering activities and are usually used to form an environment supporting cellular growth, differentiation, and maturation. Among various materials used as scaffolds, hydrogels based on natural polymers are considered one of the most suitable groups of materials for creating tissue engineering scaffolds. Natural hydrogels, however, do not always provide the physicochemical and biological characteristics and properties required for optimal cell growth. This review discusses the properties and tissue engineering applications of widely used natural hydrogels. In addition, methods of modulation of their physicochemical and biological properties using soft nanoparticles as fillers or reinforcing agents are presented.

Keywords: nanofunctionalization; natural hydrogels; soft nanoparticles; tissue engineering.

Figure 1.

Alginate-based hydrogels in tissue engineering applications. (a) The use of alginate for engineering IPN hydrogels with various materials or its use as a sacrificial network for creating fibers from polymers and protein-based hydrogels. (b) SEM image of IPN fibers of GelMA and alginate (left) and the removal of alginate from the construct to fabricate pure GelMA fibers (right). (c) Cellular morphology shown by F-actin staining in IPN fibers of GelMA and alginate (left) and GelMA fibers after the removal alginate from the network (right). Reproduced with permission.^[62] Copyright 2015, John Wiley and Sons. (d) The use of alginate for carrying PRP as a source of biological factors in tissue engineering. The hydrogel fibers could be printed in the presence of CaCl₂ mist on dry substrates. (e) The effect of PRP encapsulated in alginate in releasing angiogenic factors facilitating vascularization. Reproduced with permission.^[6] Copyright 2018, John Wiley and Sons.

Figure 2.

Protein-based hydrogels as scaffolding materials for tissue engineering. (a-c) The growth of endothelial cells cultured in vascular-like organizations in different protein-based hydrogels including Matrigel (a), GelMA (b), Collagen (c). The patterns of cellular migration into the hydrogel constructs were fundamentally different. Among them, only collagen supported the formation of tubular sprouts. Reproduced with permission.^[64] Copyright 2016, John Wiley and Sons. (d) The density of cells within the original patterns was also dependent on the material. (e,f) The fabrication of highly elastic hydrogel networks from photocrosslinkable methacrylated tropoelastin (MeTro). The fabricated hydrogel showed excellent torsional resilience. Reproduced with permission.^[66] Copyright 2015, John Wiley and Sons.

Figure 3.

Five main nanofunctionalization techniques with their relative examples (Adapted from ^[46]): 1. hydrogel formation in a nanoparticle suspension, 2. gel formation using nanoparticles, polymers, and distinct gelator molecules, 3. cross-linking using nanoparticles to form hydrogels, 4. physical incorporation after gelation of nanoparticles into the hydrogel matrix, and 5. formation of reactive nanoparticle within a preformed gel. (a) Schematic of the usage of the photo catalyst, titania nano sheets, for gelation. Reproduced with permission.^[136] (b) Schematic illustration of 3D porous silicon-nanoparticles/conductive polymer hydrogel. Reproduced with permission.^[137] (c) Cross-linking using semiconductor nanoparticles, monomer, and clay nanostructure to form nanoparticle-hydrogel composites with enhanced mechanical properties. Reproduced with permission.^[139] (d) The switch between its swollen and shrunken states resulting in the construction of a gold-nanoparticle/hydrogel composite. Reproduced with permission.^[140] (e) Preparation of Ag/PAAm hydrogel composite without using thiols. Reproduced with permission.^[143] Hydrogel nanofunctionalization with gold nanoparticles resulting in catalytic hydrogels. Reproduced with permission.^[144] Copyright 2014, American Chemical Society.

Figure 4.

The schematic representation of (a) convergent and (b) divergent synthesis of dendrimers. (c) Schematic of autologous bone marrow mesenchymal stem cell–liposome complex. Reproduced with permission.^[167] (d) Synthesis of the CHPOA/hydrogel block by Michael addition. (e) Schematic representation of nanogels releasing FGF18 and BMP2 after disintegration. Reproduced with permission.^[168] Copyright 2009, American Chemical Society.