Bioengineered In Vitro Models for Biomedical Applications

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Biomedical Engineering and Materials".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 37542

Special Issue Editor

Biomimetic Systems for Cell Engineering, Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain
Interests: bioengineering; oral drug delivery; 3D in vitro models; hydrogels; tissue microenvironment; intestinal barrier

Special Issue Information

Dear Colleagues,

Recent advances in cell biology and bioengineering techniques have radically changed the cellular models used in biomedicine. Conventional flat monolayers grown on plastic dishes have been replaced by three-dimensional (3D) cultures that better represent the physiology and topography of human tissues. These advanced in vitro cultures usually involve the use of bioengineered materials that act as cell culture scaffolds, mimicking the extracellular matrix and tissue microenvironment. In recent years, the development of new biomaterials, novel microfabrication technologies and biosensors, and their integration into microfluidic setups and bioreactors have opened up new landscapes in cell culture and tissue modeling. Organoids, microengineered scaffolds or organ-on-chip devices, among others, have been used in a wide range of biomedical applications, such as disease modeling, cell barriers, drug and nanomedicine development, or regenerative medicine. In this Special Issue, we aim to gather the latest advances in these biomimetic models of human tissues, including but not limited to new biomaterials (e.g., hydrogels, bioresponsive materials); advances in biofabrication techniques (e.g., 3D bioprinting, high-resolution microfabrication); co-culture 3D models (e.g., vascularized models, stromal and immune components); microphysiological systems (e.g., multiscale engineered systems, (multi)organ-on-chip); and their applications in biomedicine. Original works are welcome as well as reviews on the field.

Dr. María García-Díaz
Guest Editor

Manuscript Submission Information

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Keywords

  • biomaterials
  • in vitro models
  • organ-on-chip
  • scaffolds
  • tissue barriers
  • hydrogels
  • tissue engineering
  • 3D printing
  • microfabrication
  • tissue microenvironment

Published Papers (10 papers)

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Research

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13 pages, 23600 KiB  
Article
Viscous Cervical Environment-on-a-Chip for Selecting High-Quality Sperm from Human Semen
by Manhee Lee, Jin Woo Park, Dongwon Kim, Hyojeong Kwon, Min Jeong Cho, Eun Ji Lee, Tai Eun Shin, Dae Keun Kim, Seungki Lee, Do Gyeung Byeun, Jung Jae Ko, Jae Ho Lee and Jung Kyu Choi
Biomedicines 2021, 9(10), 1439; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101439 - 10 Oct 2021
Cited by 4 | Viewed by 2898
Abstract
When ejaculated sperm travels through the vagina to the uterus, mucus secreted by the cervical canal generally filters out sperm having low motility and poor morphology. To investigate this selection principle in vivo, we developed a microfluidic sperm-sorting chip with a viscous medium [...] Read more.
When ejaculated sperm travels through the vagina to the uterus, mucus secreted by the cervical canal generally filters out sperm having low motility and poor morphology. To investigate this selection principle in vivo, we developed a microfluidic sperm-sorting chip with a viscous medium (polyvinylpyrrolidone: PVP) to imitate the biophysical environment mimic system of the human cervical canal. The material property of the PVP solution was tuned to the range of viscosities of cervical mucus using micro-viscometry. The selection of high-quality human sperm was experimentally evaluated in vitro and theoretically analyzed by the convection-diffusion mechanism. The convection flow is shown to be dominant at low viscosity of the medium used in the sperm-sorting chip when seeded with raw semen; hence, the raw semen containing sperm and debris convectively flow together with suppressed relative dispersions. Also, it was observed that the sperm selected via the chip not only had high motilities but also normal morphologies and high DNA integrity. Therefore, the biomimetic sperm-sorting chip with PVP medium is expected to improve male fertility by enabling the selection of high-quality sperm as well as uncovering pathways and regulatory mechanisms involved in sperm transport through the female reproductive tract for egg fertilization. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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16 pages, 3873 KiB  
Article
Differentiation of Adipose-Derived Stem Cells into Vascular Smooth Muscle Cells for Tissue Engineering Applications
by Alvaro Yogi, Marina Rukhlova, Claudie Charlebois, Ganghong Tian, Danica B. Stanimirovic and Maria J. Moreno
Biomedicines 2021, 9(7), 797; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070797 - 09 Jul 2021
Cited by 7 | Viewed by 2779
Abstract
Synthetic grafts have been developed for vascular bypass surgery, however, the risks of thrombosis and neointimal hyperplasia still limit their use. Tissue engineering with the use of adipose-derived stem cells (ASCs) has shown promise in addressing these limitations. Here we further characterized and [...] Read more.
Synthetic grafts have been developed for vascular bypass surgery, however, the risks of thrombosis and neointimal hyperplasia still limit their use. Tissue engineering with the use of adipose-derived stem cells (ASCs) has shown promise in addressing these limitations. Here we further characterized and optimized the ASC differentiation into smooth muscle cells (VSMCs) induced by TGF-β and BMP-4. TGF-β and BMP-4 induced a time-dependent expression of SMC markers in ASC. Shortening the differentiation period from 7 to 4 days did not impair the functional property of contraction in these cells. Stability of the process was demonstrated by switching cells to regular growth media for up to 14 days. The role of IGFBP7, a downstream effector of TGF-β, was also examined. Finally, topographic and surface patterning of a substrate is recognized as a powerful tool for regulating cell differentiation. Here we provide evidence that a non-woven PET structure does not affect the differentiation of ASC. Taken together, our results indicate that VSMCs differentiated from ASCs are a suitable candidate to populate a PET-based vascular scaffolds. By employing an autologous source of cells we provide a novel alternative to address major issues that reduces long-term patency of currently vascular grafts. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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19 pages, 2953 KiB  
Article
A Tissue-Engineered Tracheobronchial In Vitro Co-Culture Model for Determining Epithelial Toxicological and Inflammatory Responses
by Luis Soriano, Tehreem Khalid, Fergal J. O’Brien, Cian O’Leary and Sally-Ann Cryan
Biomedicines 2021, 9(6), 631; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060631 - 02 Jun 2021
Viewed by 3451
Abstract
Translation of novel inhalable therapies for respiratory diseases is hampered due to the lack of in vitro cell models that reflect the complexity of native tissue, resulting in many novel drugs and formulations failing to progress beyond preclinical assessments. The development of physiologically-representative [...] Read more.
Translation of novel inhalable therapies for respiratory diseases is hampered due to the lack of in vitro cell models that reflect the complexity of native tissue, resulting in many novel drugs and formulations failing to progress beyond preclinical assessments. The development of physiologically-representative tracheobronchial tissue analogues has the potential to improve the translation of new treatments by more accurately reflecting in vivo respiratory pharmacological and toxicological responses. Herein, advanced tissue-engineered collagen hyaluronic acid bilayered scaffolds (CHyA-B) previously developed within our group were used to evaluate bacterial and drug-induced toxicity and inflammation for the first time. Calu-3 bronchial epithelial cells and Wi38 lung fibroblasts were grown on either CHyA-B scaffolds (3D) or Transwell® inserts (2D) under air liquid interface (ALI) conditions. Toxicological and inflammatory responses from epithelial monocultures and co-cultures grown in 2D or 3D were compared, using lipopolysaccharide (LPS) and bleomycin challenges to induce bacterial and drug responses in vitro. The 3D in vitro model exhibited significant epithelial barrier formation that was maintained upon introduction of co-culture conditions. Barrier integrity showed differential recovery in CHyA-B and Transwell® epithelial cultures. Basolateral secretion of pro-inflammatory cytokines to bacterial challenge was found to be higher from cells grown in 3D compared to 2D. In addition, higher cytotoxicity and increased basolateral levels of cytokines were detected when epithelial cultures grown in 3D were challenged with bleomycin. CHyA-B scaffolds support the growth and differentiation of bronchial epithelial cells in a 3D co-culture model with different transepithelial resistance in comparison to the same co-cultures grown on Transwell® inserts. Epithelial cultures in an extracellular matrix like environment show distinct responses in cytokine release and metabolic activity compared to 2D polarised models, which better mimic in vivo response to toxic and inflammatory stimuli offering an innovative in vitro platform for respiratory drug development. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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16 pages, 6033 KiB  
Article
Degeneration of Aortic Valves in a Bioreactor System with Pulsatile Flow
by Naima Niazy, Mareike Barth, Jessica I. Selig, Sabine Feichtner, Babak Shakiba, Asya Candan, Alexander Albert, Karlheinz Preuß, Artur Lichtenberg and Payam Akhyari
Biomedicines 2021, 9(5), 462; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050462 - 23 Apr 2021
Cited by 5 | Viewed by 2202
Abstract
Calcific aortic valve disease is the most common valvular heart disease in industrialized countries. Pulsatile pressure, sheer and bending stress promote initiation and progression of aortic valve degeneration. The aim of this work is to establish an ex vivo model to study the [...] Read more.
Calcific aortic valve disease is the most common valvular heart disease in industrialized countries. Pulsatile pressure, sheer and bending stress promote initiation and progression of aortic valve degeneration. The aim of this work is to establish an ex vivo model to study the therein involved processes. Ovine aortic roots bearing aortic valve leaflets were cultivated in an elaborated bioreactor system with pulsatile flow, physiological temperature, and controlled pressure and pH values. Standard and pro-degenerative treatment were studied regarding the impact on morphology, calcification, and gene expression. In particular, differentiation, matrix remodeling, and degeneration were also compared to a static cultivation model. Bioreactor cultivation led to shrinking and thickening of the valve leaflets compared to native leaflets while gross morphology and the presence of valvular interstitial cells were preserved. Degenerative conditions induced considerable leaflet calcification. In comparison to static cultivation, collagen gene expression was stable under bioreactor cultivation, whereas expression of hypoxia-related markers was increased. Osteopontin gene expression was differentially altered compared to protein expression, indicating an enhanced protein turnover. The present ex vivo model is an adequate and effective system to analyze aortic valve degeneration under controlled physiological conditions without the need of additional growth factors. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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18 pages, 6305 KiB  
Article
Development and Angiogenic Potential of Cell-Derived Microtissues Using Microcarrier-Template
by Gerard Rubí-Sans, Irene Cano-Torres, Soledad Pérez-Amodio, Barbara Blanco-Fernandez, Miguel A. Mateos-Timoneda and Elisabeth Engel
Biomedicines 2021, 9(3), 232; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030232 - 25 Feb 2021
Cited by 5 | Viewed by 2529
Abstract
Tissue engineering and regenerative medicine approaches use biomaterials in combination with cells to regenerate lost functions of tissues and organs to prevent organ transplantation. However, most of the current strategies fail in mimicking the tissue’s extracellular matrix properties. In order to mimic native [...] Read more.
Tissue engineering and regenerative medicine approaches use biomaterials in combination with cells to regenerate lost functions of tissues and organs to prevent organ transplantation. However, most of the current strategies fail in mimicking the tissue’s extracellular matrix properties. In order to mimic native tissue conditions, we developed cell-derived matrix (CDM) microtissues (MT). Our methodology uses poly-lactic acid (PLA) and Cultispher® S microcarriers’ (MCs’) as scaffold templates, which are seeded with rat bone marrow mesenchymal stem cells (rBM-MSCs). The scaffold template allows cells to generate an extracellular matrix, which is then extracted for downstream use. The newly formed CDM provides cells with a complex physical (MT architecture) and biochemical (deposited ECM proteins) environment, also showing spontaneous angiogenic potential. Our results suggest that MTs generated from the combination of these two MCs (mixed MTs) are excellent candidates for tissue vascularization. Overall, this study provides a methodology for in-house fabrication of microtissues with angiogenic potential for downstream use in various tissue regenerative strategies. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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16 pages, 3400 KiB  
Article
Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses
by Jessica Oi-Ling Tsang, Jie Zhou, Xiaoyu Zhao, Cun Li, Zijiao Zou, Feifei Yin, Shuofeng Yuan, Man-Lung Yeung, Hin Chu and Jasper Fuk-Woo Chan
Biomedicines 2021, 9(1), 88; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9010088 - 18 Jan 2021
Cited by 14 | Viewed by 3263
Abstract
Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We [...] Read more.
Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We established the human small intestinal organoids as a novel platform for characterizing the viral replication kinetics and evaluating candidate antivirals for enteroviruses. The organoids supported productive replication of enterovirus (EV)-A71, coxsackievirus B2, and poliovirus type 3, as evidenced by increasing viral loads, infectious virus titers, and the presence of cytopathic effects. In contrast, EV-D68, which mainly causes respiratory tract infection in humans, did not replicate significantly in the organoids. The differential expression profiles of the receptors for these enteroviruses correlated with their replication kinetics. Using itraconazole as control, we showed that the results of various antiviral assays, including viral load reduction, plaque reduction, and cytopathic effect inhibition assays, were highly reproducible in the organoids. Moreover, itraconazole attenuated virus-induced inflammatory response in the organoids, which helped to explain its antiviral effects and mechanism. Collectively, these data showed that the human small intestinal organoids may serve as a robust platform for investigating the pathogenesis and evaluating antivirals for enteroviruses. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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16 pages, 9706 KiB  
Article
An In-Vitro Analysis of Peri-Implant Mucosal Seal Following Photofunctionalization of Zirconia Abutment Materials
by Masfueh Razali, Wei Cheong Ngeow, Ros Anita Omar and Wen Lin Chai
Biomedicines 2021, 9(1), 78; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9010078 - 15 Jan 2021
Cited by 11 | Viewed by 2485
Abstract
The presence of epithelial and connective tissue attachment at the peri-implant–soft tissue region has been demonstrated to provide a biological barrier of the alveolar bone from the oral environment. This barrier can be improved via surface modification of implant abutment materials. The effect [...] Read more.
The presence of epithelial and connective tissue attachment at the peri-implant–soft tissue region has been demonstrated to provide a biological barrier of the alveolar bone from the oral environment. This barrier can be improved via surface modification of implant abutment materials. The effect of photofunctionalization on creating a bioactive surface for the enhancement of the epithelial and connective tissue attachment of zirconia implant abutment’s peri-implant mucosal interface using organotypic model has not been investigated. Therefore, this study aimed to evaluate the soft tissue seal around peri-implant mucosa and to understand the effect of photofunctionalization on the abutment materials. Three types of abutment materials were used in this study; yttria-stabilized zirconia (YSZ), alumina-toughened zirconia, and grade 2 commercially pure titanium (CPTi) which were divided into nontreated (N-Tx) and photofunctionalized group (UV-Tx). The three-dimensional peri-implant mucosal model was constructed using primary human gingival keratinocytes and fibroblasts co-cultured on the acellular dermal membrane. The biological seal was determined through the concentration of tritiated water permeating the material–soft tissue interface. The biological seal formed by the soft tissue in the N-Tx group was significantly reduced compared to the UV-treated group (p < 0.001), with YSZ exhibiting the lowest permeability among all materials. Photofunctionalization of implant abutment materials improved the biological seal of the surrounding soft tissue peri-implant interface. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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Review

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66 pages, 8463 KiB  
Review
Natural Polymers in Heart Valve Tissue Engineering: Strategies, Advances and Challenges
by Diana Elena Ciolacu, Raluca Nicu and Florin Ciolacu
Biomedicines 2022, 10(5), 1095; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051095 - 08 May 2022
Cited by 14 | Viewed by 6405
Abstract
In the history of biomedicine and biomedical devices, heart valve manufacturing techniques have undergone a spectacular evolution. However, important limitations in the development and use of these devices are known and heart valve tissue engineering has proven to be the solution to the [...] Read more.
In the history of biomedicine and biomedical devices, heart valve manufacturing techniques have undergone a spectacular evolution. However, important limitations in the development and use of these devices are known and heart valve tissue engineering has proven to be the solution to the problems faced by mechanical and prosthetic valves. The new generation of heart valves developed by tissue engineering has the ability to repair, reshape and regenerate cardiac tissue. Achieving a sustainable and functional tissue-engineered heart valve (TEHV) requires deep understanding of the complex interactions that occur among valve cells, the extracellular matrix (ECM) and the mechanical environment. Starting from this idea, the review presents a comprehensive overview related not only to the structural components of the heart valve, such as cells sources, potential materials and scaffolds fabrication, but also to the advances in the development of heart valve replacements. The focus of the review is on the recent achievements concerning the utilization of natural polymers (polysaccharides and proteins) in TEHV; thus, their extensive presentation is provided. In addition, the technological progresses in heart valve tissue engineering (HVTE) are shown, with several inherent challenges and limitations. The available strategies to design, validate and remodel heart valves are discussed in depth by a comparative analysis of in vitro, in vivo (pre-clinical models) and in situ (clinical translation) tissue engineering studies. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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34 pages, 4505 KiB  
Review
In Vitro Disease Models of the Endocrine Pancreas
by Marko Milojević, Jan Rožanc, Jernej Vajda, Laura Činč Ćurić, Eva Paradiž, Andraž Stožer, Uroš Maver and Boštjan Vihar
Biomedicines 2021, 9(10), 1415; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101415 - 08 Oct 2021
Cited by 3 | Viewed by 4266
Abstract
The ethical constraints and shortcomings of animal models, combined with the demand to study disease pathogenesis under controlled conditions, are giving rise to a new field at the interface of tissue engineering and pathophysiology, which focuses on the development of in vitro models [...] Read more.
The ethical constraints and shortcomings of animal models, combined with the demand to study disease pathogenesis under controlled conditions, are giving rise to a new field at the interface of tissue engineering and pathophysiology, which focuses on the development of in vitro models of disease. In vitro models are defined as synthetic experimental systems that contain living human cells and mimic tissue- and organ-level physiology in vitro by taking advantage of recent advances in tissue engineering and microfabrication. This review provides an overview of in vitro models and focuses specifically on in vitro disease models of the endocrine pancreas and diabetes. First, we briefly review the anatomy, physiology, and pathophysiology of the human pancreas, with an emphasis on islets of Langerhans and beta cell dysfunction. We then discuss different types of in vitro models and fundamental elements that should be considered when developing an in vitro disease model. Finally, we review the current state and breakthroughs in the field of pancreatic in vitro models and conclude with some challenges that need to be addressed in the future development of in vitro models. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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27 pages, 6827 KiB  
Review
Microvascular Tissue Engineering—A Review
by Jernej Vajda, Marko Milojević, Uroš Maver and Boštjan Vihar
Biomedicines 2021, 9(6), 589; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060589 - 21 May 2021
Cited by 15 | Viewed by 5794
Abstract
Tissue engineering and regenerative medicine have come a long way in recent decades, but the lack of functioning vasculature is still a major obstacle preventing the development of thicker, physiologically relevant tissue constructs. A large part of this obstacle lies in the development [...] Read more.
Tissue engineering and regenerative medicine have come a long way in recent decades, but the lack of functioning vasculature is still a major obstacle preventing the development of thicker, physiologically relevant tissue constructs. A large part of this obstacle lies in the development of the vessels on a microscale—the microvasculature—that are crucial for oxygen and nutrient delivery. In this review, we present the state of the art in the field of microvascular tissue engineering and demonstrate the challenges for future research in various sections of the field. Finally, we illustrate the potential strategies for addressing some of those challenges. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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