Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure

Reactive oxygen species(ROS)-associated oxidative stress,inflammation storm,and massive hepatocyte necrosis are the typical manifestations of acute liver failure(ALF),therefore specific therapeutic interventions are essential for the devastating disease.Here,we developed a platform consisting of versatile biomimetic copper oxide nanozymes(Cu NZs)-loaded PLGA nanofibers(Cu NZs@PLGA nanofibers)and decellularized extracellular matrix(dECM)hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells(hADMSCs-derived HLCs)(HLCs/Cu NZs@fiber/dECM).Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF,and reduce the massive accumulation of pro-inflammatory cytokines,herein efficiently preventing the deterioration of hepatocytes necrosis.Moreover,Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted HLCs.Meanwhile,HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF therapy.The dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of HLCs.In addition,the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host liver.Hence,HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF mice.This strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.

Can microfluidics address biomanufacturing challenges in drug/gene/cell therapies?

Translation of any inventions into products requires manufacturing.Development of drug/gene/cell delivery systems will eventually face manufacturing challenges,which require the establishment of standardized processes to produce biologically-relevant products of high quality without incurring prohibitive cost.Microfluidicu technologies present many advantages to improve the quality of drug/gene/cell delivery systems.They also offer the benefits of automation.What remains unclear is whether they can meet the scale-up requirement.In this perspective,we discuss the advantages of microfluidic-assisted synthesis of nanoscale drug/gene delivery systems,formation of microscale drug/cell-encapsulated particles,generation of genetically engineered cells and fabrication of macroscale drug/cell-loaded micro-/nano-fibers.We also highlight the scale-up challenges one would face in adopting microfluidic technologies for the manufacturing of these therapeutic delivery systems.