The considerations on selecting the appropriate decellularized ECM for specific regeneration demands

Abstract

An ideal biomaterial should create a customized tissue-specific microenvironment that can facilitate and guide the tissue repair process. Due to its good biocompatibility and similar biochemical properties to native tissues, decellularized extracellular matrix (dECM) generally yields enhanced regenerative outcomes, with improved morphological and functional recovery. By utilizing various decellularization techniques and post-processing protocols, dECM can be flexibly prepared in different states from various sources, with specifically customized physicochemical properties for different tissues. To initiate a well-orchestrated tissue-regenerative response, dECM exerts multiple effects at the wound site by activating various overlapping signaling pathways to promote cell adhesion, proliferation, and differentiation, as well as suppressing inflammation via modulation of various immune cells, including macrophages, T cells, and mastocytes. Functional tissue repair is likely the main aim when employing the optimized dECM biomaterials. Here, we review the current applications of different kinds of dECMs in an attempt to improve the efficiency of tissue regeneration, highlighting key considerations on developing dECM for specific tissue engineering applications.

Keywords: Decellularized extracellular matrix biomaterials; Physicochemical properties; Tissue engineering; Underlying mechanisms on dECM-mediated regeneration process.

Graphical abstract

Fig. 1

Advantages and shortcomings of dECM derived from cells, hard and soft tissues.

Fig. 2

Two common dECM-based biomaterial types: solid-state and soluble-state. (ECM, extracellular matrix; dECM, decellularized extracellular matrix; 3D, three-dimensional).

Fig. 3

The notable physicochemical properties of four solid-state dECMs. (ECM, extracellular matrix; dECM, decellularized extracellular matrix).

Fig. 4

The notable physicochemical properties of two soluble-state dECMs. (dECM, decellularized extracellular matrix).

Fig. 5

Illustration of dECM to promote pro-regeneration immune response, cell adhesion, proliferation and differentiation via triggering various biochemical signals. (MMPs, metalloproteinases).

Fig. 6

Application of cell-derived dECM in tissue engineering. (A) hTERT-immortalized human mesenchymal line with constitutive expression of human BMP-2 transgene (MB cells) was dynamically seeded, differentiated to the chondrogenic lineage and subsequently induced to apoptosis and lyophilized to produce dECM. (B) After 6-week implantation into the rat mandibular defect, much more new bone formation in both the inner and outer regions could be observed with the above dECM. (C) Quantitative assessment of osteointegration and new bone volume formation. Reproduced with permission [90]. Copyright 2021, Wiley. (D) Bioactive glass–Poly(lactide-co-glycolide) (BG-PLG) composite scaffolds were coated with mesenchymal stem cells (MSC)-secreted extracellular matrix (ECM). (E) ECM coating enhanced MSC metabolic activity and (F) increased cell-secreted osteocalcin. Reproduced with permission [92]. Copyright 2016, ACS.

Fig. 7

Tissue-derived dECM for cardiac and skeletal muscle tissue engineering. (A) Primary cardiomyocytes isolated from neonatal rats were encapsulated in bioinks composed of hdECM. The bioinks were sequentially printed using an extrusion-based 3D bioprinter and cultured either statically or dynamically. Enhanced maturation of cardiomyocytes in hdECM was observed. (B) Enhanced maturation of cardiomyocytes in dECM when cultured dynamically. Reproduced with permission [96]. Copyright 2019, Elsevier. (C) Schematic illustration of 3D skeletal muscle construct generated using a combination of direct cellular reprogramming, decellularization of muscle tissue, and fibril alignment technique. After 4-week implantation into a volumetric muscle loss injury mouse mode, (D) HE, Masson's trichrome staining and (E) quantitative measurement suggested that this aligned muscle constructs significantly reduced fibrosis while promoting de novo muscle regeneration in damaged muscle tissue. Reproduced with permission [106]. Copyright 2021, Wiley.

Fig. 8

Tissue-derived dECM for bone tissue engineering. (A) Schematic illustration of the bilayered construct design (upper: cartilage layer; bottom: bone layer), and the pathway of chondrogenesis and endochondral ossification. (B) Representative histological images of H&E, Safranin-O/fast green, Masson, type Ⅱ, I collagen and OCN staining of the osteochondral defect area at 12 weeks after surgery. IF: interface; NA: native area; RC: repaired cartilage; RB: repaired bone. (C) Expression of cartilage-related genes and bone-related genes of the regenerated osteochondral tissue at 12 weeks post-surgery. Reproduced with permission [109]. Copyright 2022, Elsevier. (D) Decellularized fish scale and chitosan were combined to produce a highly porous bio-composite scaffold with enhanced osteogenic activity. (E) SEM images of the biomineralized matrix on the scaffolds. Reproduced with permission [114]. Copyright 2019, Elsevier.