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Abstract Over the past decade, three-dimensional (3D) bioprinting has made significant progress, transforming into a key innovation in tissue engineering. Despite the early strides, critical challenges remain in 3D bioprinting that must be addressed to accelerate clinical translation. In particular, there is still a long way to go before functionally-mature, clinically-relevant tissue equivalents are developed. Current limitations range from the sub-optimal bioink properties and degree of biomimicry of bioprintable architectures, to the lack of stem/progenitor cells for massive cell expansion, and fundamental knowledge regardingin vitroculturing conditions. In addition to these problems, the absence of guidelines and well-regulated international standards is creating uncertainty among the biofabrication community stakeholders regarding the reliable and scalable production processes. This review aims at exploring the latest developments in 3D bioprinting approaches, including various additive manufacturing techniques and their applications. A thorough discussion of common bioprinting techniques and recent progresses are compiled along with notable recent studies. Later we discuss the current challenges in clinical application of 3D bioprinting and the major bottlenecks in the commercialization of 3D bioprinted tissue equivalents, including the longevity of bioprinted organs, meeting biomechanical requirements, and the often underrated ethical and legal aspects. Amidst the progress of regulatory efforts for regenerative medicine, we also present an overview of the current regulatory concerns which should be taken into account to translate bioprinted tissues into clinical practice. At last, this review emphasizes future directions in 3D bioprinting that includes the transformative ideas such as bioprinting in microgravity and the integration of artificial intelligence. The study concludes with a discussion on the need for collaborative efforts in resolving the technical and regulatory constraints to improve the quality, reliability, and reproducibility of bioprinted tissue equivalents to ultimately accomplish their successful clinical implementation. 

Abstract Aspiration-assisted freeform bioprinting (AAfB) has emerged as a promising technique for precise placement of tissue spheroids in three-dimensional (3D) space enabling tissue fabrication. To achieve success in embedded bioprinting using AAfB, an ideal support bath should possess shear-thinning behavior and yield-stress to facilitate tight fusion and assembly of bioprinted spheroids forming tissues. Several studies have demonstrated support baths for embedded bioprinting in the past few years, yet a majority of these materials poses challenges due to their low biocompatibility, opaqueness, complex and prolonged preparation procedures, and limited spheroid fusion efficacy. In this study, to circumvent the aforementioned limitations, we present the feasibility of AAfB of human mesenchymal stem cell (hMSC) spheroids in alginate microgels as a support bath. Alginate microgels were first prepared with different particle sizes modulated by blending time and concentration, followed by determination of the optimal bioprinting conditions by the assessment of rheological properties, bioprintability, and spheroid fusion efficiency. The bioprinted and consequently self-assembled tissue structures made of hMSC spheroids were osteogenically induced for bone tissue formation. Alongside, we investigated the effects of peripheral blood monocyte-derived osteoclast incorporation into the hMSC spheroids in heterotypic bone tissue formation. We demonstrated that alginate microgels enabled unprecedented positional accuracy (∼5%), transparency for visualization, and improved fusion efficiency (∼97%) of bioprinted hMSC spheroids for bone fabrication. This study demonstrates the potential of using alginate microgels as a support bath for many different applications including but not limited to freeform bioprinting of spheroids, cell-laden hydrogels, and fugitive inks to form viable tissue constructs.