Synthetic biomaterials present many advantages, such as their low cost, ability to be highly tunable and form the desired geometry [73,74,75]. They also present some drawbacks, such as their difference in composition and organisation compared to a natural extracellular matrix (ECM), which can impact adhesion, proliferation and differentiation of cells [76]. Indeed, the low diversity of the components used to produce these biomaterials appears simplistic compare to the numerous components of a native ECM. Nevertheless, significant progress has been made with the functionalisation of synthetic biomaterials in the last decades. For many applications, the use of hydrogels is interesting, and recent studies have shown a potential for them functionalised with different peptides to recreate, at least in part, the microenvironment of the target tissues [77]. This kind of functionalised hydrogels could support cell growth/differentiation, as well as vehicles for the delivery of stem cells, drugs or bioactive proteins.

Contrarily to synthetic materials, natural biomaterials used as scaffolds, especially those using elements coming from ECM [78], provide better adapted environments for migration, proliferation and differentiation of cells when used under appropriate conditions. Nevertheless, these biomaterials generally have weaker mechanical properties compared to native ECM. Indeed, the mechanical properties of ECM are not only due to the molecules it is composed of, but also, more importantly, because the organisation of these molecules in the matrix.

Among other promising biomaterials, decellularised tissues are becoming more and more attractive with new protocols of decellularisation [79]. Indeed, it seems convenient to use the complexity of native materials to repair themselves. Decellularising tissues to remove antigenic molecules responsible for immunological response and potential pathogens before being recellularised with patient’s cells allows tissue production, which is very close to the autograft or even better if the disease’s causal effect is also corrected. Decellularisation of tissue can be obtained by successive hypo/hypertonic shocks, combined or not with the addition of detergents, to destroy the cell membrane [80]. Enzymes can be used to remove proteins and nucleic acids. The tissue can originate from a human cadaver or be obtained from animals.

Nevertheless, several problems slow down the use of such prostheses: Ethical problems and various regulatory issues, such as the risk of immune reaction in ineffective/incomplete decellularisation. However, the main problem remains the ability to maintain the ECM architecture that provides good mechanical and biological characteristics to the graft. Indeed, heavy decellularisation can induce a loss of the native matrix architecture and its non-immunogen components, whereas weak decellularisation could be insufficient to obtain a safe biomaterial [81,82,83]. In the past, ECM was largely disorganised or modified by the decellularisation process, losing the mechanical properties, resistance, elasticity and cell differentiation potential. An increasing number of protocols are emerging to reduce these problems, but more studies are needed to obtain a clear view for this option [84]. Recently a novel approach to functionalise decellularised tissues has been proposed to improve endothelial cell adhesion and accelerates endothelialisation, which is an important point, due to the need to rapidly provide oxygen and nutrients to grafts to ensure positive outcomes. This goal is achieved through selective immobilisation of REDV tetrapeptides [85].

Several groups have attempted urethral substitution using TE cell-free matrices, such as bladder acellular matrix graft (BAMG) and small intestinal submucosa (SIS) or cellularised matrices [86,87,88,89,90,91,92,93]. These matrices are prepared from native tissues by decellularising and sterilising them. As shown in rabbits by Dorin et al., a significant problem of acellular matrices is that urothelial regeneration is limited to 0.5 cm, which compromises success in more complex cases, such as long strictures [94]. Synthetic polymers have also shown advantages (poly-l-lactic acid, (PLLA) and poly(lactic-co-glycolic) acid, (PLGA)) for forming low-cost, biocompatible, three-dimensional (3D) organs with controlled mechanical properties. However, synthetic scaffolds without functionalisation by peptides do not allow the proper differentiation of epithelial cells into well-organised tissue. Indeed, contrarily to natural matrices, they cannot recreate the target organ microenvironment, especially adequate ECM-cell interaction (e.g., lack integrin-binding peptide sequence, failure in synchronisation between degradation rate and matrix neo-deposition) [73,95,96]. No long-term experiment has been performed with a significant number of patients. Currently, protocols developed are not used in clinics despite the media coverage of some, signalling the immaturity of the works, which must continue to be improved [97]. TE substitutes that contain autologous cells in addition to an extracellular matrix, close to the native one, are more promising. The main advantage of this method is that a large graft of autologous cells can be produced with a limited sample, such as a piece of oral or bladder mucosa. Indeed, the extracted cells can be grown in vivo, seeded on the biomaterial and implanted with a very low risk of rejection. Studies have also reported that stem cells can be obtained from urine, making this approach potentially useful [98,99]. A downfall of this method is that after long periods of culture to obtain well-differentiated tissues, the exogenous matrices become challenging to manipulate and lose their mechanical and physical properties. Despite significant progress in urethral TE, very few teams have performed clinical trials and published their results to date [100] (Table 1). However, the four clinical trials conducted to date show promising results in a limited number of patients with long-segment and/or complex stenosis [97,101,102,103,104]. While these models are certainly far from a “plug and play” alternative with consistently reproducible results, they could offer an alternative for complex cases requiring long segment urethral replacement [105].

Vaginal abnormalities represent a significant health problem for women because nearly 1% of women will suffer from the pathologies mentioned previously, resulting in significant psychological impacts. Interestingly, tissue engineering is an area that aims to replace or regenerate dysfunctional tissues and organs with autologous cells, biomaterials or a combination of both. The success of vaginal reconstruction in these patients largely depends on the use of a sufficiently large tissue substrate that adequately fulfils the physiological functions of the vagina. Prior techniques have often relied on autologous tissues, such as the intestine or skin, often associated with complications, due to the physiological differences inherent to these substrates. To improve results, a variety of biodegradable substitutes, including collagen matrices and a decellularised bladder submucosa, have been used for vaginal replacement [102,134]. Reconstructions using these substitutes have generally failed, due to functional, structural, mechanical or biocompatibility issues. Using the patient’s vaginal tissue for reconstruction would be the most elegant and effective solution, but this has often not been possible, due to the relative scarcity of healthy vaginal tissue for autologous transplantation. There is a substantial clinical need to develop technologies to facilitate the regeneration of injured or diseased tissues and organs. The relentless prevalence of trauma, congenital abnormalities and diseases, such as cancer, is driving demand, becoming increasingly urgent as the world’s population grows and ages. A wide variety of tissues and organs would benefit from engineering-based repairing or regeneration. Several graft materials have been used to line the surgically created neovaginal cavity, including myocutaneous flaps or intestinal segments, full-thickness or split-thickness skin grafts, amniotic membrane, peritoneum, buccal mucosa and vaginal epithelial tissue [135,136,137,138,139,140,141,142,143]. These techniques are associated with contraction and/or stenosis of the graft, which may require long-term dilation. Oral mucosa vaginoplasties are associated with donor site morbidities, due to the large volume of tissue taken to create the neovagina. In addition, the amount of tissue that can be harvested from a donor site is limited, which can be problematic, especially for significant defects. To overcome these difficulties, alternative methods of vaginal reconstruction have been explored. Few groups have attempted TE vaginal reconstruction using acellular and cellular matrices of natural or synthetic origin [144,145,146,147,148,149] (Table 2). The tissues were transplanted into mice, rabbits and humans. However, further preclinical and clinical studies are needed, due to the limited number of subjects included in these studies. It remains challenging to determine whether the optimal technique was used.