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Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies...
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Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing

A special issue of Bioengineering (ISSN 2306-5354). This special issue belongs to the section "Regenerative Engineering".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 44459

Special Issue Editors

Dr. Diana Massai

E-Mail Website
Guest Editor
Solid and Fluid Biomechanics Group, PolitoBIOMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
Interests: bioreactors and culture devices; tissue engineering; regenerative medicine; stem cell production; bioprocess automation; biomedical engineering; fluid dynamics and mass transport modeling; multiscale mechanical characterization of biological tissues
Dr. Sara Mantero

E-Mail Website
Guest Editor
Laboratory of Biological Structure Mechanics (LaBS), Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
Interests: 3D bioprinting; regenerative medicine; bioreactor design; tissue engineering; biomaterials; in vitro models

Special Issue Information

Dear Colleagues,

The use of in vivo and in vitro animal models in biomedical research has been fundamental for achieving in-depth knowledge of development and disease mechanisms and for novel therapies testing, leading to ground-breaking progress in life sciences. However, besides the central ethical debate, animals are not always reliable as human-like models, their use can be extremely expensive, and in vivo systemic effects and high inter-subject variability do not allow controlling or obtaining real-time precise information on individual bioprocess parameters.

In our opinion, and according to EU legislation and several national and international initiatives such as 3R Centers and networks, it is time to develop advanced alternatives to animal testing and to encourage their application towards reduction, refinement, and even replacement (3R) of animal use for scientific purposes and in pre-clinical research.

The current Special Issue wants to highlight new and advanced bioengineering tools and technologies for developing better and more predictive alternative methods, whose integrated application could lead to a drastic reduction of animal use in the whole field of biomedical research, from basic research and tissue engineering studies to drug testing and toxicological screening.

Relevant methods include three-dimensional (3D) in vitro models mimicking cells, tissues, organs, and their physiological processes (e.g., based on human cells or induced pluripotent stem cells, functional biomaterials, organoids, engineered tissues, etc.). Of special interest are studies with novel bioreactors, microfluidics, and organ-on-chips that provide biomimetic, monitored, and controlled 3D in vitro culture conditions. New technologies for biological tissue characterization, or those designed as a test bench for identifying innovative pharmacological treatments and for testing new products, e.g., for cosmetic industry, will be included.

In addition, in silico models based on advanced computer modeling and artificial intelligence to unravel biological system complexity and to study diseases' mechanisms of action and related therapies (e.g., molecular and multiscale modeling from molecules to organs) are welcome.

This Issue is open for papers addressing the following topics:

  • 3D in vitro models of cells/tissues/organs;
  • Biomimetic bioreactors, microfluidics, and organ-on-chips;
  • Sensors and monitoring devices for 3D in vitro cultures;
  • Test bench technologies;
  • In silico approaches.

 We look forward to receiving your contributions for this Special Issue.

Dr. Diana Massai
Prof. Sara Mantero
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Bioengineering is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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20 pages, 3459 KiB  
Article
Kinetic Analysis of Lidocaine Elimination by Pig Liver Cells Cultured in 3D Multi-Compartment Hollow Fiber Membrane Network Perfusion Bioreactors
by Gerardo Catapano, Juliane K. Unger, Elisabetta M. Zanetti, Gionata Fragomeni and Jörg C. Gerlach
Bioengineering 2021, 8(8), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering8080104 - 23 Jul 2021
Cited by 1 | Viewed by 2885
Abstract
Liver cells cultured in 3D bioreactors is an interesting option for temporary extracorporeal liver support in the treatment of acute liver failure and for animal models for preclinical drug screening. Bioreactor capacity to eliminate drugs is generally used for assessing cell metabolic competence [...] Read more.
Liver cells cultured in 3D bioreactors is an interesting option for temporary extracorporeal liver support in the treatment of acute liver failure and for animal models for preclinical drug screening. Bioreactor capacity to eliminate drugs is generally used for assessing cell metabolic competence in different bioreactors or to scale-up bioreactor design and performance for clinical or preclinical applications. However, drug adsorption and physical transport often disguise the intrinsic drug biotransformation kinetics and cell metabolic state. In this study, we characterized the intrinsic kinetics of lidocaine elimination and adsorption by porcine liver cells cultured in 3D four-compartment hollow fiber membrane network perfusion bioreactors. Models of lidocaine transport and biotransformation were used to extract intrinsic kinetic information from response to lidocaine bolus of bioreactor versus adhesion cultures. Different from 2D adhesion cultures, cells in the bioreactors are organized in liver-like aggregates. Adsorption on bioreactor constituents significantly affected lidocaine elimination and was effectively accounted for in kinetic analysis. Lidocaine elimination and cellular monoethylglicinexylidide biotransformation featured first-order kinetics with near-to-in vivo cell-specific capacity that was retained for times suitable for clinical assist and drug screening. Different from 2D cultures, cells in the 3D bioreactors challenged with lidocaine were exposed to close-to-physiological lidocaine and monoethylglicinexylidide concentration profiles. Kinetic analysis suggests bioreactor technology feasibility for preclinical drug screening and patient assist and that drug adsorption should be accounted for to assess cell state in different cultures and when laboratory bioreactor design and performance is scaled-up to clinical use or toxicological drug screening. Full article
(This article belongs to the Special Issue Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing)
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12 pages, 13827 KiB  
Article
Microfluidic System for In Vivo-Like Drug Permeation Studies with Dynamic Dilution Profiles
by Thomas Lorenz, Mona Kirschke, Verena Ledwig, Stephan Reichl and Andreas Dietzel
Bioengineering 2021, 8(5), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering8050058 - 05 May 2021
Cited by 2 | Viewed by 3230
Abstract
Automated biomimetic systems for the preclinical testing of drugs are of great interest. Here, an in vitro testing platform for in vivo adapted drug absorption studies is presented. It has been designed with a focus on easy handling and the usability of established [...] Read more.
Automated biomimetic systems for the preclinical testing of drugs are of great interest. Here, an in vitro testing platform for in vivo adapted drug absorption studies is presented. It has been designed with a focus on easy handling and the usability of established cell cultivation techniques in standard well plate inserts. The platform consists of a microfluidic device, which accommodates a well plate insert with pre-cultivated cells, and provides a fluid flow with dynamic drug dilution profiles. A low-cost single-board computer with a touchscreen was used as a control unit. This provides a graphical user interface, controls the syringe pump flow rates, and records the transepithelial electrical resistance. It thereby enables automated parallel testing in multiple devices at the same time. To demonstrate functionality, an MDCK cell layer was used as a model for an epithelial barrier for drug permeation testing. This confirms the possibility of performing absorption studies on barrier tissues under conditions close to those in vivo. Therefore, a further reduction in animal experiments can be expected. Full article
(This article belongs to the Special Issue Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing)
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12 pages, 3488 KiB  
Article
Towards an In Vitro Retinal Model to Study and Develop New Therapies for Age-Related Macular Degeneration
by Beatrice Belgio, Federica Boschetti and Sara Mantero
Bioengineering 2021, 8(2), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering8020018 - 22 Jan 2021
Cited by 6 | Viewed by 3326
Abstract
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly worldwide. So far, the etiology and the progression of AMD are not well known. Animal models have been developed to study the mechanisms involved in AMD; however, according to [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly worldwide. So far, the etiology and the progression of AMD are not well known. Animal models have been developed to study the mechanisms involved in AMD; however, according to the “Three Rs” principle, alternative methods have been investigated. Here we present a strategy to develop a “Three Rs” compliant retinal three-dimensional (3D) in vitro model, including a Bruch’s membrane model and retina pigment epithelium (RPE) layer. First, tensile testing was performed on porcine retina to set a reference for the in vitro model. The results of tensile testing showed a short linear region followed by a plastic region with peaks. Then, Bruch’s membrane (BrM) was fabricated via electrospinning by using Bombyx mori silk fibroin (BMSF) and polycaprolactone (PCL). The BrM properties and ARPE-19 cell responses to BrM substrates were investigated. The BrM model displayed a thickness of 44 µm, with a high porosity and an average fiber diameter of 1217 ± 101 nm. ARPE-19 cells adhered and spread on the BMSF/PCL electrospun membranes. In conclusion, we are developing a novel 3D in vitro retinal model towards the replacement of animal models in AMD studies. Full article
(This article belongs to the Special Issue Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing)
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18 pages, 4331 KiB  
Article
Optimization of Co-Culture Conditions for a Human Vascularized Adipose Tissue Model
by Feipeng Yang, Ronald N. Cohen and Eric M. Brey
Bioengineering 2020, 7(3), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering7030114 - 17 Sep 2020
Cited by 26 | Viewed by 5659
Abstract
In vitro adipose tissue models can be used to provide insight into fundamental aspects of adipose physiology. These systems may serve as replacements for animal models, which are often poor predictors of obesity and metabolic diseases in humans. Adipose tissue consists of a [...] Read more.
In vitro adipose tissue models can be used to provide insight into fundamental aspects of adipose physiology. These systems may serve as replacements for animal models, which are often poor predictors of obesity and metabolic diseases in humans. Adipose tissue consists of a rich vasculature that is essential to its function. However, the study of endothelial cell–adipocyte interactions has been challenging due to differences in culture conditions required for the survival and function of each cell type. To address this issue, we performed an extensive evaluation of the cell culture media composition to identify the conditions optimal for the co-culture of endothelial cells and adipocytes. The effects of individual media factors on cell survival, proliferation, and differentiation were systematically explored. Several media factors were determined to disrupt the co-culture system. Optimized culture conditions were identified and used to generate a vascularized human adipose microtissue. An interconnected vascular network was established within an adipose micro-tissue, and the networks were anastomosed with perfused channels to form a functional network. In conclusion, media conditions were identified that enabled endothelial cell–adipocyte co-culture and were used to support the formation of a vascularized adipose tissue within a microfluidic device. Full article
(This article belongs to the Special Issue Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing)
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13 pages, 8735 KiB  
Article
Investigating Curcumin/Intestinal Epithelium Interaction in a Millifluidic Bioreactor
by Joana Costa, Vanessa Almonti, Ludovica Cacopardo, Daniele Poli, Simona Rapposelli and Arti Ahluwalia
Bioengineering 2020, 7(3), 100; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering7030100 - 26 Aug 2020
Cited by 8 | Viewed by 4105
Abstract
Multidrug resistance is still an obstacle for chemotherapeutic treatments. One of the proteins involved in this phenomenon is the P-glycoprotein, P-gp, which is known to be responsible for the efflux of therapeutic substances from the cell cytoplasm. To date, the identification of a [...] Read more.
Multidrug resistance is still an obstacle for chemotherapeutic treatments. One of the proteins involved in this phenomenon is the P-glycoprotein, P-gp, which is known to be responsible for the efflux of therapeutic substances from the cell cytoplasm. To date, the identification of a drug that can efficiently inhibit P-gp activity remains a challenge, nevertheless some studies have identified natural compounds suitable for that purpose. Amongst them, curcumin has shown an inhibitory effect on the protein in in vitro studies using Caco-2 cells. To understand if flow can modulate the influence of curcumin on the protein’s activity, we studied the uptake of a P-gp substrate under static and dynamic conditions. Caco-2 cells were cultured in bioreactors and in Transwells and the basolateral transport of rhodamine-123 was assessed in the two systems as a function of the P-gp activity. Experiments were performed with and without pre-treatment of the cells with an extract of curcumin or an arylmethyloxy-phenyl derivative to evaluate the inhibitory effect of the natural substance with respect to a synthetic compound. The results indicated that the P-gp activity of the cells cultured in the bioreactors was intrinsically lower, and that the effect of both natural and synthetic inhibitors was up modulated by the presence of flow. Our study underlies the fact that the use of more sophisticated and physiologically relevant in vitro models can bring new insights on the therapeutic effects of natural substances such as curcumin. Full article
(This article belongs to the Special Issue Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing)
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Review

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40 pages, 2988 KiB  
Review
Innovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing
by Patrick Bédard, Sara Gauvin, Karel Ferland, Christophe Caneparo, Ève Pellerin, Stéphane Chabaud and Stéphane Bolduc
Bioengineering 2020, 7(3), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering7030115 - 17 Sep 2020
Cited by 70 | Viewed by 17990
Abstract
Animal testing has long been used in science to study complex biological phenomena that cannot be investigated using two-dimensional cell cultures in plastic dishes. With time, it appeared that more differences could exist between animal models and even more when translated to human [...] Read more.
Animal testing has long been used in science to study complex biological phenomena that cannot be investigated using two-dimensional cell cultures in plastic dishes. With time, it appeared that more differences could exist between animal models and even more when translated to human patients. Innovative models became essential to develop more accurate knowledge. Tissue engineering provides some of those models, but it mostly relies on the use of prefabricated scaffolds on which cells are seeded. The self-assembly protocol has recently produced organ-specific human-derived three-dimensional models without the need for exogenous material. This strategy will help to achieve the 3R principles. Full article
(This article belongs to the Special Issue Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing)
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12 pages, 1803 KiB  
Review
Computational Biomechanics: In-Silico Tools for the Investigation of Surgical Procedures and Devices
by Emanuele Luigi Carniel, Ilaria Toniolo and Chiara Giulia Fontanella
Bioengineering 2020, 7(2), 48; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering7020048 - 30 May 2020
Cited by 19 | Viewed by 4981
Abstract
Biomechanical investigations of surgical procedures and devices are usually developed by means of human or animal models. The exploitation of computational methods and tools can reduce, refine, and replace (3R) the animal experimentations for scientific purposes and for pre-clinical research. The computational model [...] Read more.
Biomechanical investigations of surgical procedures and devices are usually developed by means of human or animal models. The exploitation of computational methods and tools can reduce, refine, and replace (3R) the animal experimentations for scientific purposes and for pre-clinical research. The computational model of a biological structure characterizes both its geometrical conformation and the mechanical behavior of its building tissues. Model development requires coupled experimental and computational activities. Medical images and anthropometric information provide the geometrical definition of the computational model. Histological investigations and mechanical tests on tissue samples allow for characterizing biological tissues’ mechanical response by means of constitutive models. The assessment of computational model reliability requires comparing model results and data from further experimentations. Computational methods allow for the in-silico analysis of surgical procedures and devices’ functionality considering many different influencing variables, the experimental investigation of which should be extremely expensive and time consuming. Furthermore, computational methods provide information that experimental methods barely supply, as the strain and the stress fields that regulate important mechano-biological phenomena. In this work, general notes about the development of biomechanical tools are proposed, together with specific applications to different fields, as dental implantology and bariatric surgery. Full article
(This article belongs to the Special Issue Towards 3R (Replacement, Reduction, Refinement) Approaches: Bioengineering Tools and Technologies as Advanced Alternatives to Animal Testing)
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