Advances in decellularized extracellular matrix bioinks for regenerative medicine applications

Abstract

Organ transplantation serves as a critical life-saving intervention. However, the persistent global shortage of donor organs continues to result in high mortality rates. This pressing clinical challenge has fueled the search for alternative therapeutic strategies. Among these strategies, three-dimensional (3D) bioprinting has emerged as a transformative technology capable of fabricating complex tissue constructs using bioinks composed of living cells and supportive biomaterials. Notably, recent advancements have highlighted the incorporation of decellularized extracellular matrix (dECM) as a bioactive component, significantly enhancing biocompatibility, structural integrity, cellular support, and the formation and maturation of vascular networks. In this review, we detail the pivotal role of the ECM as a dynamic reservoir of biochemical signals and mechanical cues that regulate cellular behavior through mechanotransduction. These processes guide essential functions including gene expression, tissue development, and remodeling, thereby ensuring tissue-specific mechanical properties such as elasticity and tensile strength. We highlight how dECM-based bioinks can retain the native structural and molecular features of the ECM, making them ideal for replicating physiologically relevant microenvironments. Representative studies demonstrate the successful application of dECM bioinks in engineering complex in vitro 3D tissue models. Furthermore, we address current challenges in tissue engineering, including the standardization of bioink formulations, the refinement of decellularization techniques, and the enhancement of the mechanical and architectural properties of scaffolds. Finally, we explore emerging solutions—such as artificial intelligence-guided optimization, in situ bioprinting, and the development of patient-specific bioinks—as promising avenues to overcome current limitations and drive the clinical translation of 3D-bioprinted tissues.

Keywords

Decellularized extracellular matrix / Decellularized extracellular matrix-based bioinks / Regenerative medicine / Three-dimensional bioprinting / Tissue regeneration / Vascularization

Funding

This study was supported by the NSERC Discovery grant program (No. RGPIN-2017-04044), the NSERC Alliance grant program (No. 590667-2023), the NSERC CREATE training grant in 3D Printing Technology and Materials (No. 565179-2022), the CIHR Project grant program (No. 460840), and the B.C. Ministry of Forests, New Frontiers in Research Fund, Transformation Grant, “Mend the Gap” (No. NFRFT-2020-00238), and the Nanotherapeutics cluster at the University of Victoria.

Conflict of Interest

Dr. Willerth is the C.E.O. and co-founder of Axolotl Biosciences, a biotechnology company that sells novel bioinks. The rest of the authors declare they have no competing interests.

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