Engineering an artificial tissue conventionally involves seeding healthy cells into a preformed, porous and biodegradable scaffold. The utility of such constructs, as a potential organ source to alleviate donor shortages, is limited however by the absence of an internal vascular supply, difficulties in achieving high density uniform seeding and loss of tissue specific cell function over time. Here we outline the concept of modular tissue engineering, a biomimetic strategy to assemble scaleable, high cell density, vascularised tissues containing multiple cell types, demonstrate proof of principle and theoretically analyze the limitations of a modular strategy. To create a modular construct, instead of seeding a preformed scaffold, cells are encapsulated within microscale modular components, the outer surface of which is covered with a layer of endothelial cells. Modules are then assembled into a larger structure (here a tube) to form a construct which is permeated by a network of interconnected endothelial cell lined channels to facilitate blood perfusion and nutrient delivery.

Through a systematic process of materials selection, collagen, human umbilical vein endothelial cells (HUVEC) and HepG2 cells, a human hepatoma cell line, were identified as suitable components for module formation. A method, which involved cutting and shaping the modules within a tubular mold, was developed to fabricate sub-mm collagen cylinders containing encapsulated HepG2 cells which could be seeded with a surface layer of HUVEC. Cells remained viable within both individual modules and assembled modular constructs for 7 days. Construct perfusion was achieved at physiological pressure differences and at flow rates which generated physiologically relevant levels of shear stress on the HUVEC surface layer. At medium to high flow rates however, construct compaction did occur. The seeded HUVEC exhibited a non-thrombogenic phenotype on collagen modules, prolonged clot formation in whole blood-module mixtures, and enabled blood perfusion of an assembled modular construct with no increase in platelet loss compared to background levels. Modular tissue engineering offers a feasible strategy for the development of clinically significant whole organ replacements and potentially transforms the conventional cell seeding/porous scaffold paradigm of tissue engineering.