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Key Points Different tissues have unique and specialized extracellular matrix (ECM) components and organization, which enables each ECM to carry out tissue-specific roles, including structural support, the transmission of forces and macromolecular filtration. The architecture of the ECM is highly organized, which partly arises from the innate properties of its constituent molecules and their interactions and partly from the activities of the resident cells. The fibrous (collagens and elastin) and glycoprotein (fibronectin, proteoglycans and laminins) macromolecules that constitute the ECM have evolved structures and chemical properties that are particularly suited to their specific biological functions in their respective tissues. Each class of ECM molecule is designed to interact with another class to produce unique physical and signalling properties that support tissue structure, growth and function. Small, modular subunits form homopolymers and heteropolymers that become supramolecular assemblies with highly specialized organization. Collagens are the major proteins of the ECM. The structural hallmark of all collagens is the triple helix, which is a right-handed helix of three polypeptide α-chains (homotrimers and heterotrimers), each of which contains one or more regions that are characterized by the repeating amino acid motif Gly-X-Y, where X and Y can be any amino acid. The assembly of fibrillar collagen involves multiple complex intracellular and extracellular post-translational steps from the translational product to a fibrillar structure that is capable of withstanding tensile forces. The unique mechanical properties of fibrillar collagen are mainly controlled by the collagen structure, which shows the importance of the relationship between three-dimensional protein structure and the resulting ECM function. The primary biological function of proteoglycans derives from the biochemical and hydrodynamic characteristics of the glycosaminoglycan (GAG) components of the molecules, which are long, negatively charged, linear chains of disaccharide repeats that bind water to provide hydration and compressive resistance. Heparan sulphate proteoglycans (HSPGs) are a major part of the basement membrane and chondroitin sulphate proteoglycans (CSPGs) can be found in cartilage and in neural ECMs. The laminin family of large, mosaic glycoproteins are primarily located in basal lamina and some mesenchymal compartments, and they mediate interactions between cells via cell surface receptors (such as integrins and dystroglycan) and other components of the ECM through the modular domains within the laminin molecule. Similarly, many ECM proteins interact with cells through crucial connections with the multidomain protein fibronectin, which is secreted as a large glycoprotein that assembles via cell-mediated processes into fibrillar structures around cells. The production and assembly of the ECM follow different temporal and spatial patterns in various tissues, with load-bearing tissues such as tendons showing highly ordered, fibrillar structures and the continually evolving brain showing a less organized, GAG-rich ECM. Therefore, disruption of the relative abundance of ECM proteins or their interactions with one another has important consequences for the behaviour and the fate of cells within that tissue. The molecules that are associated with the extracellular matrix (ECM) in different tissues, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled, determine the structure and the organization of the ECM. The resultant biochemical and biophysical properties of the ECM dictate its tissue-specific functions. The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.

Animal cells in tissues are supported by biopolymer matrices, which typically exhibit highly nonlinear mechanical properties. While the linear elasticity of the matrix can significantly impact cell mechanics and functionality, it remains largely unknown how cells, in turn, affect the nonlinear mechanics of their surrounding matrix. Here, we show that living contractile cells are able to generate a massive stiffness gradient in three distinct 3D extracellular matrix model systems: collagen, fibrin, and Matrigel. We decipher this remarkable behavior by introducing nonlinear stress inference microscopy (NSIM), a technique to infer stress fields in a 3D matrix from nonlinear microrheology measurements with optical tweezers. Using NSIM and simulations, we reveal large long-ranged cell-generated stresses capable of buckling filaments in the matrix. These stresses give rise to the large spatial extent of the observed cell-induced matrix stiffness gradient, which can provide a mechanism for mechanical communication between cells.

Over the past decade, organoids have emerged as a prevalent and promising research tool, mirroring the physiological architecture of the human body. However, as the field advances, the traditional use of animal or tumor-derived extracellular matrix (ECM) as scaffolds has become increasingly inadequate. This shift has led to a focus on developing synthetic scaffolds, particularly hydrogels, that more accurately mimic three-dimensional (3D) tissue structures and dynamics in vitro. The ECM–cell interaction is crucial for organoid growth, necessitating hydrogels that meet organoid-specific requirements through modifiable physical and compositional properties. Advanced composite hydrogels have been engineered to more effectively replicate in vivo conditions, offering a more accurate representation of human organs compared to traditional matrices. This review explores the evolution and current uses of decellularized ECM scaffolds, emphasizing the application of decellularized ECM hydrogels in organoid culture. It also explores the fabrication of composite hydrogels and the prospects for their future use in organoid systems.

[Display omitted] Decellularized extracellular matrix (d-ECM) serves as an ideal scaffold for constructing artificial ovaries, a promising approach to fertility preservation for patients experiencing premature ovarian failure. The biomechanical properties of d-ECM are crucial for the development and maturation of follicles. However, there is no standardized or comprehensive framework for evaluating the various decellularization methods proposed in the literature. In this study, we developed a novel decellularization protocol for porcine ovaries using liquid nitrogen and hypertonic saline methods, comparing its effectiveness against conventional chemical and enzymatic techniques through histological analysis, quantitative assessments and biomechanical testing. Histological analyses demonstrated that our d-ECM protocols effectively removed cellular and nuclear materials (at least 95% reduction) while preserving the structural integrity of elastin and collagen fibers (maximum 15% reduction). Furthermore, tensile testing results indicated that the novel decellularization methods using liquid nitrogen and hypertonic saline retained mechanical properties most similar to those of the fresh group. Our findings expand the evaluation of decellularization techniques by incorporating the biomechanical properties of d-ECM. Additionally, we provide valuable insights for enhancing decellularization methods and identifying optimal scaffolds for artificial ovaries.

This study deliberated the effect of ultrasonic treatment on collagen self-assembly behavior and collagen fibril gel properties. Bovine bone collagen I which had undergone ultrasonic treatment with different power (0–400 W) and duration (0–60 min) was analyzed. SDS-PAGE and spectroscopic analysis revealed that ultrasonic treatment decreased collagen molecular order degree and the number of hydrogen bonds, stretching collagen telopeptide regions while maintaining the integrity of the collagen triple-helical structure. Ultrasonic treatment (p ≤ 200 W, t ≤ 15 min) dispersed the collagen aggregates more evenly, and accelerated collagen self-assembly rate with a decreased but more homogeneous fibril diameter (82.78 ± 16.47–115.52 ± 19.51 nm) and D-periodicity lengths (62.1 ± 2.9–66.5 ± 1.8 nm) than that of the untreated collagen (119.15 ± 27.89 nm; 66.5 ± 1.8 nm). Meanwhile, ultrasonic treatment (p ≤ 200 W, t ≤ 15 min) decreased the viscoelasticity index and gel strength, enhancing thermal stability and promoting specific surface area and porosity of collagen fibril gels than that of the untreated collagen fibril gel. These results testified that collagen self-assembly behavior and collagen fibril gel properties can be regulated by ultrasonic treatment through multi-hierarchical structural alteration. This study provided a new approach for controlling in vitro collagen fibrillogenesis process so as to manufacture novel desirable collagen-based biomaterials with propitious performances for further valorization.

The generation of a tissue-specific intestinal hydrogel derived from the native intestine has the potential to support and promote the growth of intestinal organoids. In this study, we aimed to develop hydrogels derived exclusively from intestinal extracellular matrix (ECM) or composites comprised of intestinal ECM combined with alginate that allow for greater tuning of the hydrogel properties. A novel mouse intestinal decellularization protocol was developed and the ECM characterized. Our analyses demonstrate that our protocol effectively removed cellular and nuclear content while preserving key ECM components including collagens, glycosaminoglycans, fibronectin and laminin. When the decellularized small intestine (DSI) was used to generate hydrogels, the resulting ECM showed bioactivity as demonstrated by metabolic and pro-proliferative effects on NIH 3T3 murine fibroblasts. Importantly, our novel DSI hydrogels also supported murine intestinal and colonic organoid growth similar to Matrigel® controls. These studies demonstrate that murine tissue-specific DSI hydrogels can provide a supportive environment for the culture of intestinal and colonic organoids in vitro .

The incidence of liver diseases is high worldwide. Many factors can cause liver fibrosis, which in turn can lead to liver cirrhosis and even liver cancer. Due to the shortage of donor organs, immunosuppression, and other factors, only a few patients are able to undergo liver transplantation. Therefore, how to construct a bioartificial liver that can be transplanted has become a global research hotspot. With the rapid development of three-dimensional (3D) bioprinting in the field of tissue engineering and regenerative medicine, researchers have tried to use various 3D bioprinting technologies to construct bioartificial livers in vitro. In terms of the choice of bioinks, liver decellularized extracellular matrix (dECM) has many advantages over other materials for cell-laden hydrogel in 3D bioprinting. This review mainly summarizes the acquisition of liver dECM and its application in liver 3D bioprinting as a bioink with respect to availability, printability, and biocompatibility in many aspects and puts forward the current challenges and prospects.

Scaffolds used in tissue engineering can be obtained from synthetic or natural materials, always focusing the effort on mimicking the extracellular matrix of human native tissue. In this study, a decellularization process is used to obtain an acellular, biocompatible non-cytotoxic human pericardium graft as a bio-substitute. An enzymatic and hypertonic method was used to decellularize the pericardium. Histological analyses were performed to determine the absence of cells and ensure the integrity of the extracellular matrix (ECM). In order to measure the effect of the decellularization process on the tissue’s biological and mechanical properties, residual genetic content and ECM biomolecules (collagen, elastin, and glycosaminoglycan) were quantified and the tissue’s tensile strength was tested. Preservation of the biomolecules, a residual genetic content below 50 ng/mg dry tissue, and maintenance of the histological structure provided evidence for the efficacy of the decellularization process, while preserving the ECM. Moreover, the acellular tissue retains its mechanical properties, as shown by the biomechanical tests. Our group has shown that the acellular pericardial matrix obtained through the super-fast decellularization protocol developed recently retains the desired biomechanical and structural properties, suggesting that it is suitable for a broad range of clinical indications.

Hydrogels with protein–polysaccharide combinations are widely used in the field of tissue engineering, as they can mimic the in vivo environments of native tissues, specifically the extracellular matrix (ECM). However, achieving stability and mechanical properties comparable to those of tissues by employing natural polymers remains a challenge due to their weak structural characteristics. In this work, we optimized the fabrication strategy of a hydrogel composite, comprising gelatin and sodium alginate (Gel-SA), by varying reaction parameters. Magnetite (Fe3O4) nanoparticles were incorporated to enhance the mechanical stability and structural integrity of the scaffold. The changes in hydrogel stiffness and viscoelastic properties due to variations in polymer mixing ratio, crosslinking time, and heating cycle, both before and after nanoparticle incorporation, were compared. FTIR spectra of crosslinked hydrogels confirmed physical interactions of Gel-SA, metal coordination bonds of alginate with Ca2+, and magnetite nanoparticles. Tensile and rheology tests confirmed that even at low magnetite concentration, the Gel-SA-Fe3O4 hydrogel exhibits mechanical properties comparable to soft tissues. This work has demonstrated enhanced resilience of magnetite-incorporated Gel-SA hydrogels during the heating cycle, compared to Gel-SA gel, as thermal stability is a significant concern for hydrogels containing gelatin. The interactions of thermoreversible gelatin, anionic alginate, and nanoparticles result in dynamic hydrogels, facilitating their use as viscoelastic acellular matrices.

The tissue‐specific heart decellularized extracellular matrix (hdECM) demonstrates a variety of therapeutic advantages, including fibrosis reduction and angiogenesis. Consequently, recent research for myocardial infarction (MI) therapy has utilized hdECM with various delivery techniques, such as injection or patch implantation. In this study, a novel approach for hdECM delivery using a wet adhesive paintable hydrogel is proposed. The hdECM‐containing paintable hydrogel (pdHA_t) is simply applied, with no theoretical limit to the size or shape, making it highly beneficial for scale‐up. Additionally, pdHA_t exhibits robust adhesion to the epicardium, with a minimal swelling ratio and sufficient adhesion strength for MI treatment when applied to the rat MI model. Moreover, the adhesiveness of pdHA_t can be easily washed off to prevent undesired adhesion with nearby organs, such as the rib cages and lungs, which can result in stenosis. During the 28 days of in vivo analysis, the pdHA_t not only facilitates functional regeneration by reducing ventricular wall thinning but also promotes neo‐vascularization in the MI region. In conclusion, the pdHA_t presents a promising strategy for MI treatment and cardiac tissue regeneration, offering the potential for improved patient outcomes and enhanced cardiac function post‐MI. The heart decellularized extracellular matrix (hdECM) is one well‐known factor for the myocardial infarction (MI) regeneration. Here, a novel hdECM delivery method using paintable hydrogel with no size or shape limitations on application is shown. It exhibits stable wet cardiac tissue adhesion that is easily regulated with a simple treatment. Moreover, it demonstrates angiogenesis and MI regeneration abilities upon in vivo implantation.