Natural Biomaterials

Natural biomaterials for scaffold fabrication include both purified ECM proteins, such as collagen, elastin, ECM derivatives, such as Matrigel™ and small intestinal submucosa (SIS™) acellular matrix, as well as materials derived from marine plants and crustaceans, such as alginate and chitosan. Natural biomaterials more closely mimic, than synthetic polymers, both function and structure of the native extracellular environment. Natural biomaterials, such as collagens, are largely conserved among different species and provide a readily available source of materials for tissue engineering. Importantly, when used as 3D matrices - either as hydrogels or as fibrous or porous scaffolds - these materials can serve as ubiquitous (but occasionally also species-or tissue-specific) templates for cell attachment, growth and differentiation.

Matrigel™, an ECM derivative isolated from the murine Engelbreth-Holm-Swarm (EHS) sarcoma, is a complex mixture of basement membrane proteins, mostly laminin and type IV collagen, which also contains a large number of essential growth factors and cytokines. Unlike artificial synthetic scaffolds, Matrigel™ provides a natural, biocompatible environment [36], which induces organotypic differentiation of cells cultured on or in this hydrogel, because of the complexity of its composition and its viscoelastic properties. Given its biological complexity, Matrigel™ provides an excellent differentiative environment for in-vitro tissue engineering application; its use in vivo in animal models is mainly restricted to syngeneic mice. Sheets made of the acellularized porcine SIS are in clinical use as well-tolerated, xenogeneic scaffolds, inducing variable degrees of tissue-specific remodeling in the organ or tissue into which it is placed [37]. SIS is mostly composed of type I collagen, though it has some type III and type IV collagen in addition to other ECM molecules, such as fibronectin, hyaluronic acid, chondroitin sulfate A and B, heparin, and heparin sulfate, and some growth factors, such as basic fibroblast growth factor (bFGF), transforming growth factor (TGF), and vascular endothelial growth factor (VEGF) [37].

Collagen and elastin are two key structural ECM components in many tissues [8, 13]. These proteins are important modulators of the physical properties of many types of engineered scaffolds, affecting cellular attachment, growth and responses to mechanical stimuli [38, 39]. Matthews et al. [40] and Boland et al. [41] were the first to generate 3D micro- and nano-fibrous scaffolds from collagen and elastin for cardiovascular tissue engineering by electrospinning (see below). Tropoelastin, the cellular precursor of elastin, is secreted from elastogenic cells as a 60-kDa monomer that is subjected to oxidation by lysyl oxidase. Subsequent proteinprotein associations give rise to massive macroarrays of elastin, for example, in the inner elastic lamina of arterial blood vessels. As a consequence, elastin is a substantially insoluble protein network that displays elasticity, resilience, and biological persistence. Soluble elastin is typically available either as fragmented elastin in the form of alpha- and kappa-elastin [42], or through expression of the natural monomer, tropoelastin [43]. Recently, tropoelastin was also electrospun into scaffolds for tissue engineering purposes [9].

Alginate hydrogels (generally 1%, w/v in water) can change their physical state towards hydrogel, depending on the cross-linker and calcium chloride concentration [44]. Due to their versatile viscoelastic properties and adjustable porosity (> 80%), alginate scaffolds have been used for a number of diverse tissue engineering applications such as the liver [45] or pancreas. Alginate scaffolds could also provide a charged surface environment to facilitate the 3D culturing of cardiac cells, and can also be used for regeneration and healing of the myocardium after heart failure [46].

The complexity ofthe ECM composition in situ makes it difficult to fully emulate the "organ-specific environment" ex vivo, either by design and/or synthesis. However, the use of natural biomaterials, either alone or in combination with other natural or synthetic polymers, such as collagen/glycosaminoglycans or collagen/PLGA, may improve the biocompatibility of the ensuing scaffolds by reducing inflammatory responses in vivo and improving initial cell attachment and differentiation. Cells growing in such an instructive environment are stimulated to remodel this "provisional matrix" in a tissue-specific fashion; thus, these "naturally intelligent matrices" provide the necessary cues for organotypic differentiation and assembly of engineered tissue constructs.

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