Human lung organoids develop into adult airway-like structures directed by physico-chemical biomaterial properties

Tissues derived from human pluripotent stem cells (hPSCs) often represent early stages of fetal development, but mature at the molecular and structural level when transplanted into immunocompromised mice. hPSC-derived lung organoids (HLOs) transplantation has been further enhanced with biomaterial scaffolds, where HLOs had improved tissue structure and cellular differentiation. Here, our goal was to define the physico-chemical biomaterial properties that maximally enhanced transplant efficiency, including features such as the polymer type, degradation, and pore interconnectivity of the scaffolds. We found that transplantation of HLOs on microporous scaffolds formed from poly (ethylene glycol) (PEG) hydrogel scaffolds inhibit growth and maturation, and the transplanted HLOs possessed mostly immature lung progenitors. On the other hand, HLOs transplanted on poly (lactide-co-glycolide) (PLG) scaffolds or polycaprolactone (PCL) led to tube-like structures that resembled both the structure and cellular diversity of an adult airway. Our data suggests that scaffold pore interconnectivity and polymer degradation contributed to the maturation, and we found that the size of the airway structures and the total size of the transplanted tissue was influenced by the material degradation rate. Collectively, these biomaterial platforms provide a set of tools to promote maturation of the tissues and to control the size and structure of the organoids.