Biomaterial-based cell delivery strategies to promote liver regeneration

Abstract

Chronic liver disease and cirrhosis is a widespread and untreatable condition that leads to lifelong impairment and eventual death. The scarcity of liver transplantation options requires the development of new strategies to attenuate disease progression and reestablish liver function by promoting regeneration. Biomaterials are becoming an increasingly promising option to both culture and deliver cells to support in vivo viability and long-term function. There is a wide variety of both natural and synthetic biomaterials that are becoming established as delivery vehicles with their own unique advantages and disadvantages for liver regeneration. We review the latest developments in cell transplantation strategies to promote liver regeneration, with a focus on the use of both natural and synthetic biomaterials for cell culture and delivery. We conclude that future work will need to refine the use of these biomaterials and combine them with novel strategies that recapitulate liver organization and function in order to translate this strategy to clinical use.

Fig. 1

Biomaterials can be combined with cells and biomolecules for transplantation to treat chronic liver disease. Biomaterials are injectable, biocompatible, degradable and provide physical support and biological cues to transplanted cells to promote their survival and differentiation. Created with BioRender (www.biorender.com)

Fig. 2

Silk fibroin scaffolds provide support for adipose-derived stem cell (ADSC) and bone marrow stem cell (BMSC) survival and liver-specific function both in vitro and in vivo. a 2D and 3D light scattering confocal microscopy images of ADSCs and BMSCs (GFP, green) 5 days after encapsulation in the scaffold. Scale bar = 200 μm. b Fluorescence of ADSCs and BMSCs in the silk fibroin scaffolds implanted into mouse livers demonstrating cell survival up to 30 days. Adapted with permission from Ref [182]

Fig. 3

Recellularized liver ECM scaffolds conjugated with homogenized liver ECM promote HepG2 cell proliferation and liver-specific function following transplantation into the mouse liver. a Whole liver, H&E, and ultramicroscopic images of decellularized liver scaffold (DLS) with and without conjugated liver ECM (Conj-DLS). Conj-DLS had more ECM and thicker collagen fibres compared to the DLS. b Semi-quantitative analysis of Ki67+ cells in DLS and conj-DLS demonstrating higher number of Ki67+ cells in conj-DLS compared to DLS. c Representative immunofluorescent images and analysis of ALB, CK19, and HGF expression after hepatic transplantation. I = implanted tissue, s = surrounding liver. Scale bar = 100 μm. Adapted with permission from Ref [189]

Fig. 4

Function of primary hepatocytes in electrospun PLGA scaffolds is improved with the addition of collagen 1. Scanning electron micrographs (SEM) of primary human hepatocytes within electrospun PLGA scaffolds after 14 days of culture in (a) unmodified PLGA, b PLGA with high [collagen], c PLGA with low [collagen], d PLGA with high [fibronectin] and e PLGA with low [fibronectin], scale bar = 50 μm. Insets: representative H&E stained hepatocytes within scaffolds, scale bar = 20 μm. f In vitro albumin secretion by hepatocytes cultured in PLGA scaffolds with/without collagen/fibronectin compared to sandwich culture. g In vitro urea synthesis of hepatocytes cultured in PLGA scaffolds with/without. Adapted with permission from Ref [201]