**2.1 Introduction of reactive groups to induce cell–cell adhesions**

A general strategy for initiating user-controlled cell–cell interactions is to introduce reactive chemical groups on the cell surface. These chemical groups are not genetically coded and thus do not require genetic engineering to add them to the surface. Such chemical groups are introduced through the fusion of lipid vesicles containing the chemical reactive groups or through metabolic labeling with non-natural sugars bearing bioorthogonal functional groups with the cell [40]. For instance, complementarily reactive ketone and oxyamine groups or alkyne and azide groups can be introduced on the plasma membrane of cells [41]. Consequently, when cells with complementary reactive groups are mixed, the functional groups on the cell surfaces react and cells

are connected through covalent bonds [42, 43]. In general, so-called click reactions, that take place in water, do not form toxic side products and do not interfere with other functional groups found in biomolecules. Alternatively, noncovalent interactions with high specificity can be used to form cell–cell adhesions. For this purpose, the binding of biotin to streptavidin [44–46] or the hybridization of complementary single-stranded DNA [47–49] is employed. DNA-based cell–cell adhesions open the possibility to form diverse structures with varying cell types and cellular connectivity owing to the high specificity of these interactions; however, DNA adhesions show limited reversibility making migratory sorting impossible, and covalent and strong noncovalent links between cells permanently glue them together [50].
