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Recapitulation of multiscale structure–function properties of cells, cell‐secreted extracellular matrix, and 3D architecture of natural tissues is central to engineering biomimetic tissue substitutes. Toward achieving biomimicry, a variety of biofabrication processes have been developed, which can be broadly classified into five categories—fiber and fabric formation, additive manufacturing, surface modification, remote fields, and other notable processes—each with specific advantages and limitations. The majority of biofabrication literature has focused on using a single process at a time, which often limits the range of tissues that could be created with relevant features that span nano to macro scales. With multiscale biomimicry as the goal, development of hybrid biofabrication strategies that synergistically unite two or more processes to complement each other's strengths and limitations has been steadily increasing. This work discusses recent literature in this domain and attempts to equip the reader with the understanding of selecting appropriate processes that can harmonize toward creating engineered tissues with appropriate multiscale structure–function properties. Opportunities related to various hybridization schemes and a future outlook on scale‐up biofabrication have also been discussed.

This article is categorized under:

Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement

 

3D bioprinting has been evolving as an important strategy for the fabrication of engineered tissues for clinical, diagnostic, and research applications. A major advantage of bioprinting is the ability to recapitulate the patient-specific tissue macro-architecture using cellular bioinks. The effectiveness of bioprinting can be significantly enhanced by incorporating the ability to preferentially organize cellular constituents within 3D constructs to mimic the intrinsic micro-architectural characteristics of native tissues. Accordingly, this work focuses on a new non-contact and label-free approach called ultrasound-assisted bioprinting (UAB) that utilizes acoustophoresis principle to align cells within bioprinted constructs. We describe the underlying process physics and develop and validate computational models to determine the effects of ultrasound process parameters (excitation mode, excitation time, frequency, voltage amplitude) on the relevant temperature, pressure distribution, and alignment time characteristics. Using knowledge from the computational models, we experimentally investigate the effect of selected process parameters (frequency, voltage amplitude) on the critical quality attributes (cellular strand width, inter-strand spacing, and viability) of MG63 cells in alginate as a model bioink system. Finally, we demonstrate the UAB of bilayered constructs with parallel (0°–0°) and orthogonal (0°–90°) cellular alignment across layers. Results of this work highlight the key interplay between the UAB process design and characteristics of aligned cellular constructs, and represent an important next step in our ability to create biomimetic engineered tissues.

 

In attempts to engineer human tissues in the lab, bio-mimicking the cellular arrangement of natural tissues is critical to achieve the required biological and mechanical form and function. Although biofabrication employing cellular bioinks continues to evolve as a promising solution over polymer scaffold based techniques in creating complex multi-cellular tissues, the ability of most current biofabrication processes to mimic the requisite cellular arrangement is limited. In this study, we propose a novel biofabrication approach that uses forces generated by bulk standing acoustic waves (BSAW) to non-deleteriously align cells within viscous bioinks. We computationally determine the acoustic pressure pattern generated by BSAW and experimentally map the effects of BSAW frequency (0.71, 1, 1.5, 2 MHz) on the linear arrangement of two types of human cells (adipose-derived stem cells and MG63) in alginate. Computational results indicate a non-linear relationship between frequency and acoustic pressure amplitude. Experimental results demonstrate that the spacing between adjacent strands of aligned cells is affected by frequency (p < 0.0001), and this effect is independent of the cell type. Lastly, we demonstrate a synergistic technique of gradual crosslinking in tandem with the BSAW-induced alignment to entrap cells within crosslinked hydrogels. This study represents an advancement in engineered tissue biofabrication aimed at bio-mimicry.