a 2D culture. However, it was in 1956 that Robert Ehrmann and George Gey published a method to reconstitute collagen extracted from rat-tail tendons as a transparent gel (Ehrmann and Gey, 1956). In their original paper, 29 cells lines and tissues were tested and, in most cases, cells grew and survived better on top of collagen dried on 2D dishes than on glass or plasma clots. At that time, Mandl et al. (1953) isolated collagenase from Clostridium histolyticum and, four years later, Lasfargues (1957) established a method using collagenase to dissociate adult mouse mammary gland tissue, generating mammary organoids (duct fragments) devoid of fibroblasts and adipocytes. This was the rationale that led to the establishment of a method to produce millions of viable hepatocytes by Berry and Friend (1969) by perfusing livers with this same collagenase. Adult and embryonic hepatocytes, as well as other cell types, were shown to grow better on collagen, but in most cases cells were losing their differentiation functions after one or more days in culture (Bissell and Tilles, 1971). Michalopoulos and Pitot (1975) determined in 1975 that it was possible to trigger differentiation of specific epithelial cells, such as hepatocytes, by modifying the behavior of
