Despite more than 250 different techniques for hypospadias repair, successful outcome depends mainly on the surgeon’s skills and the availability of appropriate tissue. In case of insufficient tissue, oral buccal mucosal grafts are one of the alternatives [
29]. Unique histological characteristics, such as thin lamina propria and thick epithelium, facilitate optimal vascular supply and inosculation [
29]. All substituted tissues from other origins (skin, bladder, or buccal mucosa) have their own limitations, which can increase complications like stricture formations and graft failure [
16]; furthermore, the amount of tissue harvested can be limited. Alternative sources of tissue have been proposed over the years, such as autologous cell cultures, matrices/scaffolds, and cell-seeded scaffolds [
2,
16]. Different progenitor cells have been used, harvested from either urine or adipose tissue. Thus far, the best results were obtained using in vitro expansion of cells from bladder washings, oral cavity, or tissue biopsies (bladder) [
2,
16]. Two strategies are available for urethral reconstruction using tissue engineering, the acellular matrix bioscaffold and the cell-seeded bioscaffold model. Biomaterials in genitourinary tissue engineering are either naturally derived (collagen, alginate, acellular tissue matrices like bladder submucosa) or synthetic polymers (polyglycolic acid, polyactid acid, polylactic-co-glycolic acid). The latter can be produced on a large scale but have the potential disadvantage of host versus graft reactions [
16]. Successful urethral repair was possible with acellular matrices in both rabbits and patients with failed hypospadias reconstruction as inlay urethral repairs [
16]. However, tubularized urethral repairs with acellular matrices resulted in graft contracture and stricture formation [
16]. Clinical experience in this area is still relatively scarce, and further research is needed before tissue-engineered urethral repair will become daily practice. Meanwhile, due to the above-mentioned characteristics, for over 20 years, oral mucosa is considered by most surgeons as the best and therefore the primary source of alternative tissue in complex hypospadias [
13].