ABSTRACT
While tissue engineering holds great potential to regenerate damaged tissues in the body, we have yet to realize much clinically relevant success [30,48]. As of today, only several tissue-engineered products are successful used in clinic, such as skin and cartilage replacement [35,62,108]. The lack of successful in vitro engineered tissues is due to multiple challenges that we are facing today in tissue engineering field [31,48]. One of the most significant challenges is the inability to create vascularized tissues [59,83,89]. Without vascular supplies, engineered tissues cannot grow more than a few hundred microns in size, which is also known as the diffusion limit [25]. There are reports of in vitro culture of large tissue-engineered constructs that can be sufficiently supplied with oxygen and nutrients by perfusion bioreactors [45,85]. However, after implanting these tissues, the diffusion processes are still limited due to the distance between capillaries and the center of the
construct. In vivo, nearly all tissues are supplied with nutrients and oxygen by a highly branched network of blood vessels, which are then subdivided in the tissue into small capillaries. The maximum distance between these capillaries is 200 μm, which correlates with the diffusion limit of oxygen [10].
