Animal models for cartilage repair.

Cartilage lesions still represent an unsolved problem: despite the efforts of the basic and translational research, the regeneration of this tissue is far from being reached (1-3). Articular cartilage lesions can be divided in two main groups: superficial or partial defects and full-thickness defects (4, 5). Partial lesions are not able to self-heal because multipotent cells from the bone marrow cannot reach the area leading to a progressive degeneration of the tissue (6). Conversely, full-thickness injuries possess greater chances to heal because subchondral bone involvement allows for the migration of mesenchymal cells, which fill the damaged area (7, 8). However, healing occurs through the formation of a fibrocartilaginous tissue, which has different biomechanical and biological properties (9). Native hyaline cartilage has indeed specific biomechanical properties, which confer resistance to compressive and shear stresses; the reparative fibrocartilaginous tissue lacks these abilities, therefore, the surrounding healthy cartilage progressively degenerates. In the past years, several therapeutic strategies have been developed to restore the damaged cartilage, bone marrow stimulation (chondroabrasion, drilling, micro- or nano-fractures) and more recently, tissue engineering approaches (10-14). Some of these latter procedures have already been applied in clinical practice such as matrix-induced autologous chondrocyte implantation (MACI) (15) or osteochondral scaffold implantation (16). Generally, tissue engineering approaches are based on the combination of three main elements: cells (i.e. primary chondrocytes or multipotent mesenchymal cells), biocompatible scaffolds (i.e. polymers, composites, ceramics) and signaling molecules (i.e. growth factors). Moreover, several culture conditions (i.e. static or dynamic cultures) and biomechanical stimuli can be applied during the in vitro culture to promote tissue maturation (17-19). However, an in vivo culture is mandatory to validate a new engineered construct as the in vitro phase lacks the essential in vivo environmental stimuli and because the in vivo culture allows for the testing of the biocompatibility and safety of a new material (18, 19). Moreover, preclinical animal models are crucial to understand the molecular mechanisms of cartilage lesions favoring the development of new regenerative strategies (20, 21). in vivo studies on animal models should focus on the analysis of the cellular component, analyzing the maintenance of the cellular phenotype and the tumorigenicity; on the evaluation of the biocompatibility, toxicity and degradation of the biomaterial and on the assessment of the engineered construct. In this manuscript, we will review the most common preclinical animal models, which are used to understand cartilage biology and therefore to develop new tissue engineering strategies. We will focus on both small and large animal models highlighting their peculiarities, advantages and drawbacks.