## 1 Introduction  
The bottom-up tissue-engineering (TE) approach for the construction of implantable tissue of clinically relevant size relies on the paradigm of assembling building blocks that mimic native functional units into large tissue constructs. This addresses two of the main limitations in the top-down TE approach: (1) maintenance of mass transfer, i.e., the diffusion of nutrients and waste removal; and (2) fabrication of a controlled and functional histoarchitecture [1; 2]. With respect to the building blocks, cell spheroids, which are spherical microtissue assembled from monodispersed cells, are currently attracting considerable interest owing to their proximity to natural structures, cellular density, and organ-specific functions at a high level [3; 4; 5; 6]. However, the hurdles posed by these cellular elements become significant when scaling up towards construction of larger tissue. The first factor is the strength of the cellular elements, since it is difficult to maintain their structure, especially in perfusion-culture environments. Furthermore, cells seeded onto the internal sides of cellular elements may gradually die after assembly. This is due to the restriction of diffusion of oxygen, nutrients, and metabolic waste products beyond a thickness of 100-200 \(\upmu\)m without the ingrowth of vasculature [7, 8, 9]. [PERSON] used a polyurethane foam (PUF)/spheroid culture to differentiate embryonic stem (ES) cells of hepatic lineage, and cells spontaneously formed spherical multicellular aggregates (spheroids) in the pores of the PUF. However, cell number decreased after 15 days of culture [10]. We worked on spacing tissue elements with the inclusion of poly (l, l-lactide) (PLLA) fibers in cellular aggregates, which partly improved local mass transfer for cultured cells, but was still limited by aggregate disintegration during a prolonged period of perfusion culture [11]. Hence, the dual goals of identifying cellular elements of a well-designed hierarchic structure to promote culture-medium distribution, and developing greater mechanical strength to sustain under dynamic-flow conditions, are yet to be attained. The methodology of scaffold-based element construction, which is contrary to pure cell-based elements, is not merely to seed cells homogeneously onto a macroscopic, cell-instructive scaffold, but also to pattern the units of one tissue according to a predefined organization that guides the maturation of the TE construct towards a functional histoarchitecture, owing in part to the promotion of cellular self-sorting and self-assembly capabilities, and morphogenetic mechanisms [12, 13]. Several studies showed that the morphogenetic mechanism of the adhesion-guided self-assembly of cells can be harnessed in TE to obtain an anisotropic structure from isotropic aggregates made up of multiple cell types [14, 15, 16, 17]. Scaffolds have been subject to prolific research and development over the last thirty years and, in general, offer the advantage of optimal biocompatibility, cell attachment, and proliferation, while providing the biological, chemical, and mechanical cues to guide eventual cell differentiation and assembly into a 3D tissue construct. Scaffold-based tissue engineering has led to significant advancements in the reconstruction of various tissue types and organs, and, in some cases, has been translated into clinical practice [18, 19, 20]. Submillimeter-sized cylindrical modules of collagen were seeded with cells and then randomly assembled inside a perfusion chamber to form a macroscopic tissue construct called an \"organoid\" [21, 22, 23, 24]. The radius of each module was defined according to the diffusion limit of nutrients to avoid cell starvation in the absence of vascularization. Although the above-mentioned studies elucidated a promising approach, module contraction and deformation cannot be avoided during perfusion culture. In the present study, scaffold-based cell constructs were used as cellular tissue elements.