The liver, as the “chemical factory” of the human body, is responsible for more than 500 synthetic and metabolic functions, which are essential for life-sustaining activities. Liver transplantation has become a “lifesaver” for many patients when serious liver problems develop into end-stage. However, the severe shortage of donor livers has greatly limited the widespread use of liver transplantation.

In recent years, research on liver-like organs has become a new direction to overcome this problem, and a recent study published in Mater Today Bio 3D bioprinting lobule-like hepatorganoids with induced vascularization for orthotopic implantation has brought a major breakthrough in this field.

Liver-like organs are expected to solve the dilemma of insufficient liver donors, which not only mimic some of the liver's functions, but also can be standardized and industrially produced with the help of biofabrication technology to reduce the cost of treatment. In the study of liver-like organs, vascularization is a key factor affecting their function and survival. This is because an adequate vascular network can provide oxygen and nutrients to the organoid and maintain normal cellular metabolism and function. However, achieving in situ transplantation of vascularized liver-like organs still faces many challenges, such as the biofabrication precision is difficult to meet the demand of constructing microcapillary networks, the vascularized functional materials need to be optimized, and the key molecular mechanisms are not yet clear.

To address these issues, the research team conducted an in-depth study. Using 3D bioprinting technology, they successfully prepared lobular liver-like organs based on GelMA hydrogel, and further constructed vascularized lobular liver-like organs (VLH).

In the in vitro experiments, the lobular liver-like organ performed excellently. Its hypoxia level was significantly lower than that of other constructs, which meant that the cells could obtain more sufficient oxygen, creating favorable conditions for maintaining normal function. In terms of function, lobular liver-like organs had higher albumin and urea secretion. The high albumin secretion reflects its strong protein synthesizing ability, while the high urea secretion reflects good metabolic function, all of which fully proves the high activity of this type of organ.

Figure 1: Characterization of 3D printed lobule-like liver-like organs

For the vascularized lobular liver-like organ VLH, it was found to perform well in vivo.RNA sequencing results showed that the GAS6/AXL and LAMB3/ITGA3 signaling pathways, which play key roles in angiogenesis and cell proliferation, were significantly upregulated in VLH.

In the in situ transplantation experiments, the advantages of VLH were obvious. Compared with other types of liver-like organs, VLH survived longer in vivo. Serologic indices showed elevated levels of its serum markers, indicating that VLH was able to maintain its function effectively in vivo. Histological analysis also revealed that VLH was more vascularized after transplantation, and the rich vascular network provided sufficient oxygen and nutrients to the class organ, which strongly guaranteed the normal function of the class organ.

Figure 2: HUVECs and GelMA/NHS/VEGF synergistically induce vascularization of 3D printed lobular liver-like organs

Figure 3: Long-term viability maintenance after in situ implantation of vascularized lobular liver-like organs

This study is of landmark significance in that it innovatively realized 3D printing of lobular liver-like organs and successfully induced vascularization and performed in situ transplantation. Meanwhile, it reveals the key mechanisms to promote vascularization and maintain functional activity, which provides a brand new strategy and direction for the clinical treatment of liver diseases such as acute and chronic liver injury, and post hepatectomy liver function deficiency.

It is believed that with the continuous efforts of researchers, this achievement will gradually move from the laboratory to the clinic, bringing new hope to the majority of patients with liver diseases and promoting the field of liver disease treatment to new heights. In the future, we are looking forward to seeing more in-depth research and application based on this achievement, which will make greater contributions to the cause of human health.