Acellular Extracellular Matrix Bio-ink Build Tissue And Organ-Specific Microenvironment

Tissue engineering is a revolutionary strategy to rebuild new organs or tissues through the use of various biomedical technologies. Traditional methods mainly focus on the use of biological materials. Such as biocompatible synthetic high molecular polymers, natural/synthetic hydrogels, and further supplement cells through inoculation or recruitment from the patient, with sufficient physical chemistry in the patient’s body Stimulations. Such as biologically active factors, shear/cyclic stress, electrical stimulation, and impulse force.

Although significant progress has been made in tissue engineering technology centered on biomaterials in the past 30 years, a large number of challenges still remain: 1.Designing hydrogels to generalize the highly dynamic and fluid microenvironments that exist in various tissues and organs. 2. Reconstruction of functional units in organs. 3.Promote the formation of vascular networks in engineered tissues.

In this regard, biological manufacturing methods based on biological materials have attracted widespread attention, and these methods can optimize cells, materials, and desired structures in any position. This comprehensive strategy can promote cell maturation, cell signaling, and enhance the vascularization required for the cell assembly process. In addition, biological materials that are beneficial to cells (such as hydrogels composed of extracellular matrix components) can strengthen the interaction between cells and matrix, trigger the tissue and organ-specific differentiation process to restore the original cell function.

Recently, the team of Professor Dong-Woo Cho and Jinah Jang from Pohang University of Science and Technology and Yonsei University published an article entitled “Decellularized Extracellular Matrix-based Bioinks for Engineering Tissue-and Organ-specific Microenvironments” in Chemical Reviews. And applications are summarized.

Most shear-thinning hydrogels ( PEG-based materials, GelMA, sodium alginate, collagen, HA-based materials, and acellular matrix) are widely used as materials for bio-ink components. In addition, the biological activity cues in the bio-ink (binding sites, embedded soluble factors) directly trigger cells to induce tissue morphogenesis.

Bio-inks require a specific range of parameters, including viscosity, yield stress, and response at dynamic frequencies. Physical methods are usually simple, but it is difficult to speed up the cross-linking of collagen. Ionic cross-linking mainly uses calcium ions, which may hinder the propagation of calcium-based signals in cardiomyocytes and neurons.

On the other hand, chemical methods can achieve controllable cross-linking, thereby rapidly strengthening the structure, but the biocompatibility of the material is less than using physical methods due to the small number of binding sites. Therefore, the printed unit cannot fully display the inherent morphology and function of the cells in the body. Tailoring existing hydrogel platforms for different applications requires changing their physical and chemical properties (stiffness, yield stress). However, shaped fidelity and bio-inks cellular affinity are often mutually constrained, which brings a challenge to the design of bio-inks.

Researchers applied various chemical modification methods (methacrylate, diacrylate) to overcome this challenge. Recently, chemically modified ECM-based hydrogels (GelMA, diacrylate-HA) meet the requirements of biological functionality and mechanical tunability compared to other hydrogels.

Although these hydrogels provide suitable features to print cell-carrying constructs, the process requires a certain level of biological functionality needed to support a niche environment of multiple cells.

In this sense, decellularized tissue and organ extracellular matrix (dECM) can play a synergistic role in supporting various cells in any composition. An important feature of dECM, which distinguishes it from other biological materials, is that it provides a unique spatial distribution of structural and functional components. The proposed bionic method for generating printable dECM-based hydrogels contributes to specific physiological properties.

However, the understanding of the naturally occurring tissue-specific components and the location of each ECM component in tissues and organs is crucial. Therefore, it is necessary to conduct systematic research on dECM-based bio-inks to understand how it affects cell function, which in turn determines cell fate and tissue development process in vitro.

This review aims to discuss the new paradigm of bio-ink based on tissue and organ-specific dECM, so as to summarize the inherent microenvironment in 3D cell printing structures.

This review can also be used for the toolbox of biomedical engineers who want to understand the beneficial properties of dECM-based bioinks and a set of basic standards for printing functional human functional tissues. The second part summarizes the biophysical, biochemical, and biological characteristics of the extracellular matrix. The third part introduces how to process, disinfect, and generate a printable dECM hydrogel, and then the fourth part verifies its constituents and composition. The fifth part summarizes the precautions for 3D cell printing based on dECM hydrogel, the emergence and progress of 3D cell printing technology, and the application of various tissue and organ printing. Further, summarize and look forward to the future and challenges of bio-ink based on dECM with some viewpoints.

Extracellular matrix organization
Progress of dECM bio-ink in cell 3D printing
Application of acellular matrix bio-ink from heart
Application of Cartilage-derived Acellular Matrix Bio-ink
Application of acellular matrix bio-ink from skeletal muscle
Application of kidney-derived acellular matrix bio-ink

Biological manufacturing methods based on biological materials have gained widespread attention in recent years. Among them, 3D cell printing is a pioneering technology used to promote highly generalized unique characteristics of complex human tissues and organs, and it has a high degree of process flexibility and versatility. Bio-ink, a combination of hydrogel and cells that can be printed, can be used to create 3D cell-printed structures.

The biological activity clues of bio-ink directly trigger cells to induce tissue morphogenesis. Among various printable hydrogels, tissue and organ-specific decellularized extracellular matrix (dECM) can play a synergistic role to support multiple cells of any composition by promoting specific physiological properties.

This review aims to explore the new paradigm of dECM-based bio-inks to reproduce the inherent internal microenvironment in 3D cell printing structures.