3.1. Collagen
Collagen is the most abundant protein in the body, representing a third of total proteins and the main component of ECM
[31][32][102,103]. The use of collagen in tissue engineering is common due to its many advantages such as biocompatibility, cell adhesion sites, biodegradability, nonimmunogenicity, availability, and hydrophilicity. Collagen is the most commonly used natural material for VTE, as it is the main ECM component of the vascular wall, responsible for load carrying and pressure resistance
[33][104]. Its use for vascular graft fabrication dates back to 1986
[34][20], and, with time, more complex TEVGs were fabricated with collagen as the core biomaterial
[33][35][36][104,105,106]. Recent research works have shown the different advances made in the use of collagen for TEVGs production, achieving collagen constructs with better mechanical properties
[379][3810][3911]. The use of collagen still presents limitations, however, due to the excellent biological, potential it is still one of the most interesting natural materials for TEVG production.
3.2 Gelatin
Gelatin is a material derived from the denaturation of collagen’s triple helix. Thanks to its biocompatibility, biodegradability, low cytotoxicity, immunogenicity, and, finally, low cost, gelatin has been widely used as a biomaterial for tissue engineering. A disadvantage of gelatin is related to the need for chain reticulation in order to maintain its stability, thus it is mainly used in the functionalized form: gelatin methacryloyl (GelMA) and is often reticulated with other materials
[40][41][24,112]. Still, different works have shown the potential of gelatin biomaterials for VTE
[113] [115][4212][43][44], and its use in combination with other materials for VTE is promising to enhance biological properties and endothelialization.
3.3. Fibrin
Fibrin is the active and insoluble form of fibrinogen, a protein involved in the coagulation cascade and wound healing. Because of its adhesive properties, it is widely used as a sealant in biomedical applications
[45][118]. It is an interesting material for scaffold design, both in gel and fiber form and it can be isolated from a patient’s plasma, representing an interesting option in terms of personalized tailored biomaterials, limiting immunological reaction risks
[46][45]. Fibrin fibers can closely replicate the structure of ECM and guide cell functions and remodeling
[47][119] so, it is frequently found used in combination with other materials for VTE purposes
[4813][4914][50] [123]. Fibrin undoubtedly demonstrates many advantages for TEVGs’ production, especially because of the possibility of obtaining it from patients’ blood. However, the studies performed still use it in combination with other materials in order to achieve the necessary mechanical properties.
3.4. Elastin
Elastin is a protein of the connective tissue responsible for tissue elasticity. The tropoelastin fibers provide recoil to tissues that undergo stretching forces and in the vascular tissue, elastin plays both a mechanical and biosensing role, allowing for elastic expansion and contraction. Moreover, elastin plays a role in the inhibition of SMCs’ hyperproliferation and has antithrombotic properties
[51][126]. Collagen and elastin are also often used in combination for VTE, as they are both major components of blood vessels and elastin is used to provide elasticity to the scaffold. These types of scaffolds present higher porosity and structural features that promote their use for small-caliber TEVGs, while stimulating endothelialization and preventing SMCs’ hyperplasia
[40][24]. Aside from collagen and elastin composites, elastin has been widely reported to increase the elastic properties of TEVGs in combination with other materials
[52][132]. Even though the use of elastin retains the limitation of its insolubility, its use has gained interest in the field of VTE, demonstrating the ability to improve mechanical and biological properties and decreasing platelet adhesion.
3.5. Silk
Silk is a versatile biopolymer mainly produced by insects. This natural material is extremely resistant to traction, aside from being very biocompatible, and has been broadly used for surgical sutures. In recent decades, silk has also gathered interest for the production of bioscaffolds in VTE, because it demonstrates interesting advantages such as controllable biodegradation, low immunogenicity, extraordinary mechanical strength, and wide scaffolding applications, as it can be used in the form of films, hydrogels, nanofibers, and nanoparticles. Moreover, it is an easily accessible material, both eco-sustainable and low cost
[5315][5416]. Silk can be used alone or in combination with other materials for TEVGs
[136] [83] [5517][56][57], demonstrating its suitability for this application.
3.6. Chitosan
Chitosan is a linear polysaccharide derived from chitin’s partial deacetylation, found in the exoskeleton of arthropods. Structurally, chitosan is very similar to glycosaminoglycans contained in the ECM, and as a biomaterial it presents several advantages: it is easily sterilisable, low cost, bioactive, and highly hydrophilic. Its degradability can be controlled, and, notably, it has antibacterial and antifungal properties. Thus, it was also explored as a scaffold for TEVGs production. However, its mechanical properties are far from resembling those of native blood vessels; to overcome this limitation, chitosan is often reticulated with other polymers
[24,140,141] [40][58][5918][60].
Chitosan shows unique antibacterial and antithrombogenic properties; therefore, it is used in VTE to improve these aspects when they are lacking in other materials. However, it remains difficult to find uses for chitosan as a sole material for TEVG production. With further innovations in manufacturing and modifications, technologies may bring research closer to improving its use for VTE.
3.7. Decellularized Extracellular Matrix
Decellularized vessels were explored as a means to obtain a tubular scaffold directly from the vessel, and this strategy has led to the development of several vascular grafts, which have indeed reached clinical trials. However, decellularized extracellular matrix (dECM) derived from other tissue sources can also be used for scaffold production. In particular, after decellularization, the matrix can be further processed in order to be solubilized, then used as hydrogels, bioinks, or electrospinning solution. dECM is one of the most bioactive materials that can be found, as it is the one that most closely resembles the native ECM environment. In VTE, it has been widely used, both alone and in combination with other materials, to enhance their mechanical properties and provide them with superior bioactivity
[145,146,147] [149][61][62][63][64][65][6519].
4. Conclusions
In a context where CDVs are the main cause of death in the world and vessel substitution or bypass are often required, VTE has been shown to be a promising alternative to autologous vascular grafts. Although it is a challenge to replicate the necessary biological and mechanical properties, great progress has been made in the production of TEVGs. New fabrication techniques, insights into biomaterial design, and innovative tissue maturation strategies have led to improved results. Natural materials have received more attention due to their innate bioactivity, and, thanks to the progress made in the past decades, some of the problems tied to their use have been overcome. In particular, the advances in fabrication techniques have allowed better manipulation and tailorability of natural materials, which were significant challenges in the use of biological materials; at the same time, many research works reported herein also demonstrated results in obtaining natural-based TEVGs with appropriate mechanical properties for blood vessel replacement. Astonishingly, many research works even reported the production of small-caliber TEVGs made with natural materials, an achievement that has challenged researchers for many years. These innovations have also led to many works obtaining promising results with in vivo experimentation using natural-based TEVGs. Biomaterials like collagen and elastin remain the top choices when it concerns biomaterials for VTE; some collagen products have reached the market, such as Artegraft
® or ProCol
®, while new manufacturing techniques, such as electrospinning and 3D printing, are taking over and being used more frequently to obtain highly controlled graft ultrastructures. However, challenges with the use of all-natural TEVGs still remain, such as the ability to obtain functional and effective vascular grafts (encompassing both biological and mechanical properties, made of a single and natural component) and if—and when—most of these will be able to achieve commercialization. However, considering the positive advances reported herein, TEVGs from natural material scaffolds show potential for being translated from research to clinical practice in the near future, while other natural TEVGs, such as cell-derived TEVGs or hybrid TEVGs, have already been utilized in human trials
[66][67][68][152,153,154].