Automated 3D bioassembly of micro-tissues for biofabrication of hybrid tissue engineered constructs

Mekhileri, Naveen Vijayan; Lim, Khoon S.; Brown, Gabriella C. J.; Mutreja, Isha; Schon, Benjamin S.; Hooper, Gary J.; Woodfield, Tim B. F.

doi:10.1088/1758-5090/aa9ef1

Cited by 157 publications

(180 citation statements)

References 85 publications

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“…The advantages of MEW include solvent‐free processing and avoidance of the chaotic fiber deposition often seen in electrospinning. Bioprinting approaches for cell hierarchy have been reinforced with extruded, stiffer structures that reinforce the bioink and aid with in vitro handling and extend a processing window for such hydrogels . The reinforcing of matrices and bioinks with much smaller, low‐micrometer scale fibers on matrices has recently been of particular interest .…”

Section: Electrophysiological Properties Of Glyrs Determined From Reimentioning

confidence: 99%

3D Electrophysiological Measurements on Cells Embedded within Fiber‐Reinforced Matrigel

Schaefer

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Bakırcı

et al. 2019

Adv Healthcare Materials

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of the matrix. [9] Mechanical properties such as the stiffness of the 3D surrounding environment are known to affect differentiation of certain cells, [10] and are believed to be critical for neuronal maturation and neurotransmission. [9] More discrete and higher resolved structures, such as those made with additive manufacturing (AM) [11] and electrojetting technology, [12] are promising to provide reproducible conditions. Electrojetting uses electrostatic forces to fabricate monodispersed, nanomicro particles in a simple, versatile, and cost-effective method for drug delivery and tissue engineering applications. [13] Electrospinning allows processability for polymer solutions and polymer melts. [14] In addition, polymer melts can be directly written using a programmable path in a technique known as melt electrowriting (MEW). [15] The precise placement of low-micrometer diameter fibers that are stackable using additive manufacturing principles are achievable using MEW (Figure 1a,b). The advantages of MEW include solvent-free processing and avoidance of the chaotic fiber deposition often seen in electrospinning. Bioprinting approaches for cell hierarchy have been reinforced with extruded, stiffer structures [16] that reinforce the bioink and aid with in vitro handling [17] and extend a processing window for such hydrogels. [16,17] The reinforcing of matrices and bioinks with much smaller, low-micrometer scale fibers on matrices has recently been of particular interest. [18,19] Using MEW, [15] well-ordered, small diameter fibers can be distributed throughout a matrix in low volume fractions and provide significant increase in overall mechanical properties. [18][19][20] Furthermore, the mechanics of MEW fiber-reinforced hydrogels can be modulated further with sinusoidal direct-writing of the fibers. [18] Since the fiber diameter made using MEW can be readily changed with the nozzle mass flow rate and/or the collection speed, the diameter of the printed fiber can be significantly altered. [21] Therefore, MEW reinforcement of matrices (such as Matrigel shown here) have the potential to regulate the environment of cells through both mechanotransductive [22] or haptotaptic [23] cues.An experimentally designed in vitro 3D structure for electrophysiological studies requires a relevant receptor model, with the inhibitory glycine receptor (GlyR) used in this study. The GlyR is a pentameric, ligand gated ion channel, which belongs to the superfamily of Cys-loop receptors. [24] Upon binding of 2D electrophysiology is often used to determine the electrical properties of neurons. In the brain however, neurons form extensive 3D networks. Thus, performing electrophysiology in a 3D environment provides a closer situation to the physiological condition and serves as a useful tool for various applications in the field of neuroscience. In this study, 3D electrophysiology is established within a fiber-reinforced matrix to enable fast readouts from transfected cells, which are often used as model systems for 2D electrophysiology. Usin...

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Section: Electrophysiological Properties Of Glyrs Determined From Reimentioning

confidence: 99%

3D Electrophysiological Measurements on Cells Embedded within Fiber‐Reinforced Matrigel

Schaefer

Janzen

Bakırcı

et al. 2019

Adv Healthcare Materials

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“…The method consists of four main steps: (a) the injection of the fibrin components including the cells into the silicone tube, (b) the gelation process, (c) the ejection of the gel after polymerization and (d) the stretching of the resulting fiber. We expect that already existing solutions for automated pipetting, handling, collection, gripping of samples and controlled linear displacement could be assembled to create an ad‐hoc automated system for the production of the fibers in a sterile, closed environment (Bhuthalingam, Lim, Irvine, & Venkatraman, ; Bartolo, Domingos, Gloria, & Ciurana, ; P. F. Costa et al, ; Kikuchi et al, ; Mekhileri et al, ). A GMP conform production is facilitated by the limited number of parts in contact with the materials composing the fibers and the commercial availability of GMP‐conform cell‐work stations.…”

Section: Discussionmentioning

confidence: 99%

A bench‐top molding method for the production of cell‐laden fibrin micro‐fibers with longitudinal topography

et al. 2019

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Tissue‐engineered constructs have great potential in many intervention strategies. In order for these constructs to function optimally, they should ideally mimic the cellular alignment and orientation found in the tissues to be treated. Here we present a simple and reproducible method for the production of cell‐laden pure fibrin micro‐fibers with longitudinal topography. The micro‐fibers were produced using a molding technique and longitudinal topography was induced by a single initial stretch. Using this method, fibers up to 1 m in length and with diameters of 0.2–3 mm could be produced. The micro‐fibers were generated with embedded endothelial cells, smooth muscle cell/fibroblasts or Schwann cells. Polarized light and scanning electron microscopy imaging showed that the initial stretch was sufficient to induce longitudinal topography in the fibrin gel. Cells in the unstretched control micro‐fibers elongated randomly in both the floating and encapsulated environments, whereas the cells in the stretched micro‐fibers responded to the introduced topography by adopting a similar orientation. Proof of concept bottom‐up tissue engineering (TE) constructs are shown, all displaying various anisotropic organization of cells within. This simple, economical, versatile and scalable approach for the production of highly orientated and cell‐laden micro‐fibers is easily transferrable to any TE laboratory.

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“…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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Automated 3D bioassembly of micro-tissues for biofabrication of hybrid tissue engineered constructs

Cited by 157 publications

References 85 publications

3D Electrophysiological Measurements on Cells Embedded within Fiber‐Reinforced Matrigel

3D Electrophysiological Measurements on Cells Embedded within Fiber‐Reinforced Matrigel

A bench‐top molding method for the production of cell‐laden fibrin micro‐fibers with longitudinal topography

From Shape to Function: The Next Step in Bioprinting

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