Spheroids may be used as building b

Spheroids may be used as building blocks for scaffold-based and scaffold-free strategies (Figure 2). Seeding scaffolds with spheroids combines the classical approach of an implantable, shaped matrix for the filling of tissue defects with the beneficial regenerative properties of spheroids. The scaffold helps to fix individual spheroids in position and provides a defined geometry for their directed 3D assembly into larger tissues. This approach has already been used to fabricate tissue constructs for the replacement of cartilage [71], skin [72], myocardium [73], and the anterior cruciate ligament [74]. Moreover, spheroids exhibit potent angiogenic and vasculogenic capacity and serve as efficient vascularization units in porous scaffolds for bone tissue engineering [33]. Zhang et al. [75] designed nonadhesive scaffolds based on amide- bonded PLGA and chitosan, which even stimulate the in situ assembly of seeded single MSCs to spheroids in the scaffold pores. After implantation into knee articular cartilage defects of rabbits, these constructs promote hyaline-like cartilage regeneration with reduced fibrous tissue forma- tion when compared to adhesive control scaffolds overgrown with single MSCs [75].