Hep3Gel: A Shape-Shifting Extracellular Matrix-Based, Three-Dimensional Liver Model Adaptable to Different Culture Systems

Guagliano, G; Volpini, Cristina; Sardelli, Lorenzo; Bloise, Nora; Briatico‐Vangosa, Francesco; Cornaglia, Antonia Icaro; Dotti, Silvia; Villa, Riccardo; Visai, Livia; Pacheco, Daniela Peneda

doi:10.1021/acsbiomaterials.2c01226

Cited by 12 publications

(34 citation statements)

References 95 publications

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“…The temperature was set at 37 • C and controlled with a Peltier's plate and hood system. The final viscoelastic properties of the Hep3Gel and control materials at the end of crosslinking (24 h after the beginning of the reaction) has been previously reported [20].…”

Section: Time-dependent Rheological Characterizationmentioning

confidence: 89%

“…Hep3Gel was produced through alginate internal crosslinking, as previously described [20]. Then, immediately after the addition and mixing of GDL, samples were loaded into 3 ml pneumatic bioprinting cartridges (CELLINK, SE), capped with a 0.22 µm luer-lock syringe filter (Primo Filters, Euroclone, IT), and incubated until needed at 37 Two other hydrogels, the first one made with alginate only (ALG), and the second one made of a blend of alginate and gelatin (GEL), were produced as previously described, processed in the same way as Hep3Gel, and used as controls [20]. All the hydrogels described in this study were produced through alginate internal gelation, a detailed insight on the process to produce them is illustrated in figure S1.…”

Section: Preparation Of the Bioinksmentioning

confidence: 99%

“…Conversely, in the field of bioprinting, internal gelation has only been proposed as a pre-crosslinking strategy intended to improve the printability of alginate-based inks [19]. Internal, as opposed to external, gelation relies on triggering the progressive release of the Ca 2+ ions that are already homogeneously dispersed throughout the hydrogel precursor, not being directly available, thus achieving the gelation [20]. One of the most common strategies to produce alginate hydrogels with this technique involves suspending CaCO 3 within the hydrogel precursor and then dissolving it by lowering the pH, thus enabling the progressive release of Ca 2+ ions [12].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, with internal gelation, the crosslinking ions are released throughout the volume of the hydrogel precursor and, as a consequence, these hydrogels are characterized by a homogeneous degree of gelation throughout their structure. This avoids the uncontrolled formation of crosslinking gradients or core-shell structures which are typical of externally crosslinked hydrogels [20,22,23]. In this sense, the possibility to exert complete control over the viscoelastic properties of internally crosslinked alginate hydrogels makes them particularly interesting for applications in which constructs need to replicate a mechanical environment, as in the fabrication of in vitro models [24].…”

Section: Introductionmentioning

confidence: 99%

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Internally crosslinked alginate-based bioinks for the fabrication of in vitro hepatic tissue models

Guagliano,

Volpini,

Camilletti

et al. 2023

Biofabrication

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Bioprinting is a key technique to fabricate cell-laden volumetric constructs with controlled geometry. It can be used not only to replicate the architecture of a target organ but also to produce shapes that allow for the mimicry, in vitro, of specific desired features. Among the various materials suitable to be processed with this technique, sodium alginate is currently considered one of the most appealing because of its versatility. To date, the most widespread strategies to print alginate-based bioinks exploit external gelation as a primary process, by directly extruding the hydrogel-precursor solution into a crosslinking bath or within a sacrificial crosslinking hydrogel, where the gelation takes place. In this work, we describe the print optimization and the processing of Hep3Gel: an internally crosslinked alginate and ECM-based bioink for the production of volumetric hepatic tissue models. We adopted an unconventional strategy, by moving from the reproduction of the geometry and the architecture of liver tissue to the use of bioprinting to fabricate structures that can promote a high degree of oxygenation, as is the case with hepatic tissue. To this end, the design of structures was optimized by employing computational methods. The printability of the bioink was then studied and optimized through a combination of different a priori and a posteriori analyses. We produced 14-layered constructs, thus highlighting the possibility to exploit internal gelation alone to directly print self-standing structures with finely controlled viscoelastic properties. Constructs loaded with HepG2 cells were successfully printed and cultured in static conditions for up to 12 days, underlining the suitability of Hep3Gel to support mid/long-term cultures.

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Section: Time-dependent Rheological Characterizationmentioning

confidence: 89%

Section: Preparation Of the Bioinksmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Internally crosslinked alginate-based bioinks for the fabrication of in vitro hepatic tissue models

Guagliano,

Volpini,

Camilletti

et al. 2023

Biofabrication

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“…The combination of dECM‐based materials with other polymers such as alginate allowed the fine‐tuning of their mechanical properties. [ 119 ]…”

Section: Biomaterials As Essential Components Of Liver Disease Modelsmentioning

confidence: 99%

The Material World of 3D‐Bioprinted and Microfluidic‐Chip Models of Human Liver Fibrosis

Carvalho,

Bansal,

Barrias

et al. 2023

Advanced Materials

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Biomaterials are extensively used to mimic the cell‐matrix interactions, which are essential for cell growth, function and differentiation. This is particularly relevant when developing in vitro disease models of organs rich in extracellular matrix, like the liver. Liver disease involves a chronic wound‐healing response with formation of scar tissue known as liver fibrosis. At early stages, liver disease can be reverted, but as disease progresses, reversion is no longer possible, and there is no cure. Research for new therapies is hampered by the lack of adequate models that replicate the mechanical properties and biochemical stimuli present in the fibrotic liver. Fibrosis is associated with changes in the composition of the extracellular matrix that directly influence cell behavior. Biomaterials could play an essential role in better emulating the disease microenvironment. In this paper, the recent and cutting‐edge biomaterials used for creating in vitro models of human liver fibrosis are revised, in combination with cells, bioprinting and/or microfluidics. These technologies have been instrumental to replicate the intricate structure of the unhealthy tissue and promote medium perfusion that improves cell growth and function, respectively. A comprehensive analysis of the impact of material hints and cell‐material interactions in a 3D context is provided.This article is protected by copyright. All rights reserved

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Bioinspired Bioinks for the Fabrication of Chemomechanically Relevant Standalone Disease Models of Hepatic Steatosis

Guagliano,

Volpini,

Sardelli

et al. 2024

Adv Healthcare Materials

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Hepatotoxicity‐related issues are poorly predicted during preclinical trials, as their relevance is limited by the inadequacy to screen all the non‐physiological subclasses of the population. These pitfalls could be solved by implementing complex in vitro models of hepatic physiology and pathologies in the preclinical phase. To produce these platforms, we focused on extrusion‐based bioprinting, since it allows to manufacture tridimensional cell‐laden constructs with controlled geometries, in a high‐throughput manner. We propose different bioinks, whose formulation was tailored to mimic the chemomechanical environment of hepatic steatosis, the most prevalent hepatic disorder worldwide. Internally crosslinked alginate hydrogels were chosen as structural components of the inks. Their viscoelastic properties (G’ = 512‐730 Pa and G’’ = 94‐276 Pa, depending on frequency) were tuned to mimic those of steatotic liver tissue. Porcine hepatic ECM was introduced as a relevant biochemical cue. Sodium oleate was added to recall the accumulation of lipids in the tissue. Downstream analyses on 14‐layered bioprinted structures cultured for 10 days revealed the establishment of steatotic‐like features (intracellular lipid vesicles, viability decrease up to ≈50%) without needing external conditionings. The presented bioinks are thus suitable to fabricate complex models of hepatic steatosis to be implemented in a high‐throughput experimental frame.This article is protected by copyright. All rights reserved

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Hep3Gel: A Shape-Shifting Extracellular Matrix-Based, Three-Dimensional Liver Model Adaptable to Different Culture Systems

Cited by 12 publications

References 95 publications

Internally crosslinked alginate-based bioinks for the fabrication of in vitro hepatic tissue models

Internally crosslinked alginate-based bioinks for the fabrication of in vitro hepatic tissue models

The Material World of 3D‐Bioprinted and Microfluidic‐Chip Models of Human Liver Fibrosis

Bioinspired Bioinks for the Fabrication of Chemomechanically Relevant Standalone Disease Models of Hepatic Steatosis

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