Unconventional strategies for liver tissue engineering: plant, paper, silk and nanomaterial-based scaffolds.

The paper highlights how significant characteristics of liver can be modeled in tissue-engineered constructs using unconventional scaffolds. Hepatic lobular organization and metabolic zonation can be mimicked with decellularized plant structures with vasculature resembling a native-hepatic lobule vascular arrangement or silk blend scaffolds meticulously designed for guided cellular arrangement as hepatic patches or metabolic activities. The functionality of hepatocytes can be enhanced and maintained for long periods in naturally fibrous structures paving way for bioartificial liver development. The phase I enzymatic activity in hepatic models can be raised exploiting the microfibrillar structure of paper to allow cellular stacking creating hypoxic conditions to induce in vivo-like xenobiotic metabolism. Lastly, the paper introduces amalgamation of carbon-based nanomaterials into existing scaffolds in liver tissue engineering. Plain Language Summary Unconventional scaffolds have the potential to meet the current challenges in liver tissue engineering- loss of hepatic morphology and functions over long-term culture, absence of native-like cell-cell and cell-matrix interactions, organization of hepatocytes into lobular structures exhibiting metabolic variations-which hinder pharmaceutical analysis, regenerative therapies and artificial organ development. Paper with cellulose microfibril network develops cellular aggregates with hypoxic conditions that influence enzymes of xenobiotic metabolism proving to be a better scaffold for hepatotoxicity testing compared with conventional monolayers in tissue culture plates. Decellularized plant stems provide already-built vasculature to be exploited for the development of intricate vessel networks that exist in hepatic lobules aiding in regenerative medicine for hepatic pathologies. Fibrous plant structures are excellent materials for the immobilization of hepatocytes and improve albumin secretion enabling their use in bioartificial liver development. Biomimicry of metabolic zonation in hepatic lobules can be achieved with perfusion culture using silk blend scaffolds with varying proportions of the liver matrix that orchestrate cellular function. The mechanical properties of silk allow the fabrication of structures that resemble liver anatomy to generate native-like hepatic lobules. Nanomaterials have immense potential as a component of composite material development for scaffolds to achieve improved predictive ability in pharmacokinetics. Most of these unconventional scaffolds have the added advantage of being readily available, accessible, affordable and sustainable for liver tissue engineering applications. Conclusively, the shift of attention away from conventional scaffolds poses a promising future in the field of tissue engineering. Graphical Abstract Article highlights Limitations of 2D culture: Current 2D culture practices cannot achieve the complexity of hepatic tissue including metabolic zonation, lobular organization, extensive vasculature, existence of multiple cell types. Splenic scaffold: Spleen proves to be the excellent choice of decellularized organ for liver tissue regeneration, however, this cross-organ recellularization procedure is not ideal for clinical translation. Plant-based scaffold: Selecting plant material that matches hepatic tissue mechanical properties and anatomical features including the channel arrangements (central vein and portal triad) help hepatic regeneration and pathological modeling. Naturally fibrous plant materials have the potential to be excellent platforms for bioartificial liver development based on high hepatocyte adherence and function. Paper-based scaffold: Hepatocyte culture on functionalized filter paper forms a physiologically more relevant model for hepatotoxicity assessment particularly because of higher activity of drug metabolizing enzymes. Silk-based scaffold: Hepatic lobular organization that supports metabolic zonation can be mimicked by varying ECM content in silk blend scaffolds to create native-like oxygen and nutrient gradient. CNT-based scaffold: Exceptional properties of carbon nanotubes make them ideal to mimic liver ECM allowing formation of hepatic spheroids with in vivo like characteristics- bile canaliculi, polarity and drug clearance. [ABSTRACT FROM AUTHOR]