Hyaluronic acid methacrylate/pancreatic extracellular matrix as a potential 3D printing bioink for constructing islet organoids.

Abstract

Islet transplantation has poor long-term efficacy because of the lack of extracellular matrix support and neovascularization; this limits its wide application in diabetes research. In this study, we develop a 3D-printed islet organoid by combining a pancreatic extracellular matrix (pECM) and hyaluronic acid methacrylate (HAMA) as specific bioinks. The HAMA/pECM hydrogel was validated in vitro to maintain islet cell adhesion and morphology through the Rac1/ROCK/MLCK signaling pathway, which helps improve islet function and activity. Further, in vivo experiments confirmed that the 3D-printed islet-encapsulated HAMA/pECM hydrogel increases insulin levels in diabetic mice, maintains blood glucose levels within a normal range for 90 days, and rapidly secretes insulin in response to blood glucose stimulation. In addition, the HAMA/pECM hydrogel can facilitate the attachment and growth of new blood vessels and increase the density of new vessels. Meanwhile, the designed 3D-printed structure was conducive to the formation of vascular networks and it promoted the construction of 3D-printed islet organoids. In conclusion, our experiments optimized the HAMA/pECM bioink composition and 3D-printed structure of islet organoids with promising therapeutic effects compared with the HAMA hydrogel group that can be potentially used in clinical applications to improve the effectiveness and safety of islet transplantation in vivo. STATEMENT OF SIGNIFICANCE: The extraction process of pancreatic islets can easily cause damage to the extracellular matrix and vascular system, resulting in poor islet transplantation efficiency. We developed a new tissue-specific bioink by combining pancreatic extracellular matrix (pECM) and hyaluronic acid methacrylate (HAMA). The islet organoids constructed by 3D printing can mimic the microenvironment of the pancreas and maintain islet cell adhesion and morphology through the Rac1/ROCK/MLCK signaling pathway, thereby improving islet function and activity. In addition, the 3D-printed structures we designed are favorable for the formation of new blood vessel networks, bringing hope for the long-term efficacy of islet transplantation.