Quantifying the kinetics and morphological changes of the fusion of spheroid building blocks

Susienka, Michael; Wilks, Benjamin T.; Morgan, Jeffrey R.

doi:10.1088/1758-5090/8/4/045003

Cited by 41 publications

(58 citation statements)

References 28 publications

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“…Prefabricated microtissues self‐assembled from cells in agarose micromolds are used as building blocks because they are stackable, can subsequently autofuse without external biomaterials, have organ cell density (scaffold‐free), form within hours, and can be made into various geometries and designs in lumen placements . The lumens within the planar microtissues allow us to build perfusable macrotissues by carefully aligning the lumens during stacking to form channels through the macrotissue.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we describe the Bio‐Pick, Place, and Perfuse (Bio‐P3), an integrated biofabrication‐bioreactor technology that semiautomatically constructs perfusable macrotissues with 100 million cells at physiological cell density within 2 h. Our approach makes use of prefabricated, modular, scaffold‐free microtissue building parts in customizable geometries with precisely placed holes that act as lumens . The Bio‐P3 grips, aligns, and stacks microtissues vertically onto a perfusable build‐platform.…”

Section: Introductionmentioning

confidence: 99%

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Perfused Organ Cell‐Dense Macrotissues Assembled from Prefabricated Living Microtissues

Cui

Wilks

et al. 2018

Adv. Biosys.

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Engineered tissues usually fall short of physiological cell densities and sizes, resulting in limited functional performance. Viability of large tissues is constrained by inadequate diffusion‐driven nutrient exchange. Methods to form large viable tissues are lacking and are constrained by diffusion‐driven nutrient exchange. Here, the use of the Bio‐Pick, Place, and Perfuse (Bio‐P3) is reported, an integrated biofabrication‐bioreactor platform that semiautomatically and rapidly assembles physiologically cell‐dense macrotissues with 100 million cells while being actively perfused. The Bio‐P3 grips, aligns, and stacks prefabricated, scaffold‐free microtissue parts with integrated lumens on a perfusable build‐platform. Parts spontaneously fuse into one continuous macrotissue with perfusable channels. Customizable microtissues are rapidly prepared up to centimeter‐scale with sustained functional performance. Computational models are developed and experimentally validated to elucidate the effects of perfusion rate and tissue geometry on convective nutrient transport in built macrotissues. It is shown that macrotissues constructed from human hepatocellular microtissues maintain geometry and function (albumin and urea secretion) over 5 days. The Bio‐P3 technology fabricates massive solid tissues with high cell numbers and densities to mimic human physiology for preclinical and clinical applications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Perfused Organ Cell‐Dense Macrotissues Assembled from Prefabricated Living Microtissues

Cui

Wilks

et al. 2018

Adv. Biosys.

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“…These structures that only encompass an intermediate complexity could then be bioprinted into more complex tissue and organ progenitors with geometries and patterns designed to instruct the formation of functional tissue . The fusion capability of multicellular spheroids representing such intermediate tissue modules has been characterized in detail and utilized in proof‐of‐principle studies for tissue generation . The bioprinting of such spheroids or microtissues into either 3D plotted or MEW‐generated thermoplastic polymer scaffolds has recently been proposed and demonstrated, facilitating the assembly into larger tissue units …”

Section: Strategies To Evolve From Shape To Functionmentioning

confidence: 99%

From Shape to Function: The Next Step in Bioprinting

et al. 2020

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In 2013, the “biofabrication window” was introduced to reflect the processing challenge for the fields of biofabrication and bioprinting. At that time, the lack of printable materials that could serve as cell‐laden bioinks, as well as the limitations of printing and assembly methods, presented a major constraint. However, recent developments have now resulted in the availability of a plethora of bioinks, new printing approaches, and the technological advancement of established techniques. Nevertheless, it remains largely unknown which materials and technical parameters are essential for the fabrication of intrinsically hierarchical cell–material constructs that truly mimic biologically functional tissue. In order to achieve this, it is urged that the field now shift its focus from materials and technologies toward the biological development of the resulting constructs. Therefore, herein, the recent material and technological advances since the introduction of the biofabrication window are briefly summarized, i.e., approaches how to generate shape, to then focus the discussion on how to acquire the biological function within this context. In particular, a vision of how biological function can evolve from the possibility to determine shape is outlined.

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“…Assuming an symmetric cell doublet is in mechanical equilibrium, the dependence of the contact angle between two cells on their surface tensions can be deduced using linear force balance at the vertex [13] [ Figure 2c]. Further 130 assuming, based on experimental observations [34,35,13], that the effect of ω is negligible in the high-tension limit, one can derive a relationship between γ m , γ c , and the doublet contact angle θ [Eq. 1].…”

Section: Simulation Of Cell Doubletsmentioning

confidence: 99%

Force-based three-dimensional model predicts mechanical drivers of cell sorting

Revell¹,

Blumenfeld

Chalut

2018

Preprint

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Many biological processes, including tissue morphogenesis, are driven by mechanical sorting. However, the primary mechanical drivers of cell sorting remain controversial, in part because there remains a lack of appropriate threedimensional computational methods to probe the mechanical interactions that drive sorting. To address this important issue, we developed a three-dimensional, local force-based simulation method to enable such investigation into the sorting mechanisms of multicellular aggregates. Our method utilises the subcellular element method, in which cells are modeled as collections of locally-interacting force-bearing elements, accommodating cell growth and cell division. We define two different types of intracellular elements, assigning different attributes to boundary elements to model a cell cortex, which mediates the interfacial interaction between different cells. By tuning interfacial adhesion and tension in each cell cortex, we can control and predict the degree of sorting in cellular aggregates. The method is validated by comparing the interface areas of simulated cell doublets to experimental data and to previous theoretical work. We then define numerical measures of sorting and investigate the effects of mechanical parameters on the extent of sorting in multicellular aggregates. Using this method, we find that a minimum adhesion is required for differential interfacial tension to produce inside-out sorting of two cell types with different mechanical phenotypes. We predict the value of the minimum adhesion, which is in excellent agreement with observations in several developmental systems. We also predict the level of tension asymmetry needed for robust sorting. The generality and flexibility of the method make it applicable to tissue self-organization in a myriad of biological processes, such as tumorigenesis and embryogenesis.Self-organization is a widely-studied feature of non-equilibrium systems across a great variety of fields [1,2,3]. In Biology, self-organized processes range in length-and time-scales from protein folding [4] to the dramatic murmurations of starlings [5]. Generically, these systems exhibit emergence of macroscopic order 5 from disordered states by the action of simple, local, inter-component interactions. Here we focus on one such a process of self-organization -cell sorting. Cell sorting in a multicellular aggregate (MCA) is critical for normal development of an embryo, and is also at the heart of pathologies such as metastastic growth of tumors. 10The spontaneous separation of mixtures of embryonic cells has long been thought to be driven by cells' differing "affinity" for one another [6]. Two primary drivers have been proposed to facilitate differential affinity: differential adhesion and differential interfacial tension.The differential adhesion hypothesis is a widely studied driver of cell sort-15 ing [7, 8,9]. It asserts that, in an MCA with multiple cell types, those with strong mutual adhesion adhere together better than cells with weaker mutual adhesion. The ...

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Quantifying the kinetics and morphological changes of the fusion of spheroid building blocks

Cited by 41 publications

References 28 publications

Perfused Organ Cell‐Dense Macrotissues Assembled from Prefabricated Living Microtissues

Perfused Organ Cell‐Dense Macrotissues Assembled from Prefabricated Living Microtissues

From Shape to Function: The Next Step in Bioprinting

Force-based three-dimensional model predicts mechanical drivers of cell sorting

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