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Cell-Biomaterial Interaction

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (20 September 2018) | Viewed by 143091

Special Issue Editors

Department of Chemistry, Biology and Biotechnology, Biochemistry and Molecular Biology Unit, University of Perugia, Via del Giochetto, 06126 Perugia, Italy
Interests: stem cell–biomaterial interaction; mecchanotransduction; stem cell reprogramming; gene/stem cell therapy; regenerative medicine; lysosomal storage disorders; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
National Research Council, Institute of Science and Technology for Ceramics, Roma, Italy
Interests: tissue engineering; nanomedicine; cell–material interaction; 3D biomaterials; cell therapy; cell biology; magnetic nanoparticles
Special Issues, Collections and Topics in MDPI journals
National Research Council of Italy Institute of Science and Technology for Ceramics (ISTEC-CNR), Via Granarolo 64, I-48018 Faenza, Italy
Interests: cellular and molecular biology; material science; nanotechnology; tissue engineering and regenerative medicine; 2D and 3D cellular models; cell/biomaterial interaction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is great interest in generating artificial tissues as biological substitutes in regenerative medicine applications and nanomedicine. Efforts have been made in designing advanced biofunctional systems by combining cells (e.g., stem cells, differentiated cells, induce pluripotent stem cells) and biomaterials. It is well-known that cells recognize and interact with biomaterials in different forms (e.g., nanoparticles, 3D scaffold, coating, film), through a plethora of plasma membrane proteins that activate a signal cascade, steering cells toward a selected behavior. Therefore, developing innovative biomaterials with peculiar physico-chemical properties, focusing on specific architectures/porosity is instrumental to tune cell fate. Moreover, a specific biodecoration of a material with biomolecules/drugs could further enhance the bioactivity of a material itself, reflecting on an improved cellular response.

This Special Issue focuses on several aspects of the cell/biomaterial interaction, and we invite contributions of reviews and/or original papers reporting recent efforts in the field of biomaterials applications.

Dr. Sabata Martino
Dr. Silvia Panseri
Dr. Monica Montesi|
Guest Editors

Manuscript Submission Information

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Keywords

  • cell-material interaction
  • biomaterials
  • regenerative medicine
  • stem cells
  • cell therapy
  • nanomedicine
  • cell fate
  • nanoparticles
  • 3D scaffold
  • biofunctionalization

Published Papers (30 papers)

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17 pages, 9530 KiB  
Article
Establishing Liposome-Immobilized Dexamethasone-Releasing PDMS Membrane for the Cultivation of Retinal Pigment Epithelial Cells and Suppression of Neovascularization
by Tzu-Wei Lin, Yueh Chien, Yi-Ying Lin, Mong-Lien Wang, Aliaksandr A. Yarmishyn, Yi-Ping Yang, De-Kuang Hwang, Chi-Hsien Peng, Chih-Chien Hsu, Shih-Jen Chen and Ke-Hung Chien
Int. J. Mol. Sci. 2019, 20(2), 241; https://doi.org/10.3390/ijms20020241 - 09 Jan 2019
Cited by 9 | Viewed by 3942
Abstract
Age-related macular degeneration (AMD) is the eye disease with the highest epidemic incidence, and has great impact on the aged population. Wet-type AMD commonly has the feature of neovascularization, which destroys the normal retinal structure and visual function. So far, effective therapy options [...] Read more.
Age-related macular degeneration (AMD) is the eye disease with the highest epidemic incidence, and has great impact on the aged population. Wet-type AMD commonly has the feature of neovascularization, which destroys the normal retinal structure and visual function. So far, effective therapy options for rescuing visual function in advanced AMD patients are highly limited, especially in wet-type AMD, in which the retinal pigmented epithelium and Bruch’s membrane structure (RPE-BM) are destroyed by abnormal angiogenesis. Anti-VEGF treatment is an effective remedy for the latter type of AMD; however, it is not a curative therapy. Therefore, reconstruction of the complex structure of RPE-BM and controlled release of angiogenesis inhibitors are strongly required for sustained therapy. The major purpose of this study was to develop a dual function biomimetic material, which could mimic the RPE-BM structure and ensure slow release of angiogenesis inhibitor as a novel therapeutic strategy for wet AMD. We herein utilized plasma-modified polydimethylsiloxane (PDMS) sheet to create a biomimetic scaffold mimicking subretinal BM. This dual-surface biomimetic scaffold was coated with laminin and dexamethasone-loaded liposomes. The top surface of PDMS was covalently grafted with laminin and used for cultivation of the retinal pigment epithelial cells differentiated from human induced pluripotent stem cells (hiPSC-RPE). To reach the objective of inhibiting angiogenesis required for treatment of wet AMD, the bottom surface of modified PDMS membrane was further loaded with dexamethasone-containing liposomes via biotin-streptavidin linkage. We demonstrated that hiPSC-RPE cells could proliferate, express normal RPE-specific genes and maintain their phenotype on laminin-coated PDMS membrane, including phagocytosis ability, and secretion of anti-angiogenesis factor PEDF. By using in vitro HUVEC angiogenesis assay, we showed that application of our membrane could suppress oxidative stress-induced angiogenesis, which was manifested in decreased secretion of VEGF by RPE cells and suppression of vascularization. In conclusion, we propose modified biomimetic material for dual delivery of RPE cells and liposome-enveloped dexamethasone, which can be potentially applied for AMD therapy. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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20 pages, 3602 KiB  
Article
Polybenzyl Glutamate Biocompatible Scaffold Promotes the Efficiency of Retinal Differentiation toward Retinal Ganglion Cell Lineage from Human-Induced Pluripotent Stem Cells
by Ta-Ching Chen, Pin-Yi She, Dong Feng Chen, Jui-Hsien Lu, Chang-Hao Yang, Ding-Siang Huang, Pao-Yang Chen, Chen-Yu Lu, Kin-Sang Cho, Hsin-Fu Chen and Wei-Fang Su
Int. J. Mol. Sci. 2019, 20(1), 178; https://doi.org/10.3390/ijms20010178 - 05 Jan 2019
Cited by 19 | Viewed by 5558
Abstract
Optic neuropathy is one of the leading causes of irreversible blindness caused by retinal ganglion cell (RGC) degeneration. The development of induced pluripotent stem cell (iPSC)-based therapy opens a therapeutic window for RGC degeneration, and tissue engineering may further promote the efficiency of [...] Read more.
Optic neuropathy is one of the leading causes of irreversible blindness caused by retinal ganglion cell (RGC) degeneration. The development of induced pluripotent stem cell (iPSC)-based therapy opens a therapeutic window for RGC degeneration, and tissue engineering may further promote the efficiency of differentiation process of iPSCs. The present study was designed to evaluate the effects of a novel biomimetic polybenzyl glutamate (PBG) scaffold on culturing iPSC-derived RGC progenitors. The iPSC-derived neural spheres cultured on PBG scaffold increased the differentiated retinal neurons and promoted the neurite outgrowth in the RGC progenitor layer. Additionally, iPSCs cultured on PBG scaffold formed the organoid-like structures compared to that of iPSCs cultured on cover glass within the same culture period. With RNA-seq, we found that cells of the PBG group were differentiated toward retinal lineage and may be related to the glutamate signaling pathway. Further ontological analysis and the gene network analysis showed that the differentially expressed genes between cells of the PBG group and the control group were mainly associated with neuronal differentiation, neuronal maturation, and more specifically, retinal differentiation and maturation. The novel electrospinning PBG scaffold is beneficial for culturing iPSC-derived RGC progenitors as well as retinal organoids. Cells cultured on PBG scaffold differentiate effectively and shorten the process of RGC differentiation compared to that of cells cultured on coverslip. The new culture system may be helpful in future disease modeling, pharmacological screening, autologous transplantation, as well as narrowing the gap to clinical application. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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11 pages, 7071 KiB  
Article
Co-Culturing Human Adipose Derived Stem Cells and Schwann Cells on Spider Silk—A New Approach as Prerequisite for Enhanced Nerve Regeneration
by Annika Resch, Sonja Wolf, Anda Mann, Tamara Weiss, Alexandra-Larissa Stetco and Christine Radtke
Int. J. Mol. Sci. 2019, 20(1), 71; https://doi.org/10.3390/ijms20010071 - 24 Dec 2018
Cited by 22 | Viewed by 4332
Abstract
Fast recovery is crucial for a successful nerve repair and an optimal functional outcome after peripheral nerve injury. Regarding donor site morbidity, autologous transplantation shows great limitations, which urge the need for alternative options in nerve reconstruction. Spider silk was reported as an [...] Read more.
Fast recovery is crucial for a successful nerve repair and an optimal functional outcome after peripheral nerve injury. Regarding donor site morbidity, autologous transplantation shows great limitations, which urge the need for alternative options in nerve reconstruction. Spider silk was reported as an advantageous material for cell adhesion, migration and proliferation, and its use in conduits is of great interest, especially in combination with cells to improve nerve regeneration. We here described the behavior of a co-culture of human Schwann cells and human adipose-derived stem cells (ADSCs) on spider silk as a new approach. After characterized by immunostaining ADSCs and Schwann cells were seeded in the co-culture on a spider silk scaffold and observed for 21 days. Results showed that cells were attached to the silk and aligned along the silk fibers. With further culture time, cells migrated along the silk and increased in number and formed an almost confluent cell layer. In immunostaining, results suggest that the cell layer was equally composed of ADSCs and Schwann cells. In conclusion, we showed that by providing a guiding structure for directed growth and cells to support nerve regeneration and remyelination, a valid alternative to autologous nerve grafts could have been found. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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18 pages, 3259 KiB  
Article
Titanium Dioxide Nanoparticles Enhance Leakiness and Drug Permeability in Primary Human Hepatic Sinusoidal Endothelial Cells
by Jie Kai Tee, Li Yang Ng, Hannah Yun Koh, David Tai Leong and Han Kiat Ho
Int. J. Mol. Sci. 2019, 20(1), 35; https://doi.org/10.3390/ijms20010035 - 21 Dec 2018
Cited by 17 | Viewed by 4422
Abstract
Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the blood compartment from the hepatic cells, regulating hepatic vascular tone and portal pressure amidst changes in the blood flow. In the presence of pathological conditions, phenotypic changes in LSECs contribute to [...] Read more.
Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the blood compartment from the hepatic cells, regulating hepatic vascular tone and portal pressure amidst changes in the blood flow. In the presence of pathological conditions, phenotypic changes in LSECs contribute to the progression of chronic liver diseases, including the loss of endothelial permeability. Therefore, modulating LSECs offers a possible way to restore sinusoidal permeability and thereby improve hepatic recovery. Herein, we showed that titanium dioxide nanoparticles (TiO2 NPs) could induce transient leakiness in primary human hepatic sinusoidal endothelial cells (HHSECs). Interestingly, HHSECs exposed to these NPs exhibited reduced protein kinase B (Akt) phosphorylation, an important protein kinase which regulates cell attachment. Using a 3D co-culture system, we demonstrated that TiO2 NPs diminished the attachment of HHSECs onto normal human hepatic cell LO2. To further illustrate the significance of leakiness in liver sinusoids, we showed that NP-induced leakiness promoted Sunitinib transport across the HHSEC layer, resulting in increased drug uptake and efficacy. Hence, TiO2 NPs have the potential to modulate endothelial permeability within the specialized sinusoidal endothelium, especially during events of fibrosis and occlusion. This study highlighted the possible use of inorganic NPs as a novel strategy to promote drug delivery targeting the diseased liver. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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16 pages, 3478 KiB  
Article
Nonlinear Cellular Mechanical Behavior Adaptation to Substrate Mechanics Identified by Atomic Force Microscope
by Keyvan Mollaeian, Yi Liu, Siyu Bi, Yifei Wang, Juan Ren and Meng Lu
Int. J. Mol. Sci. 2018, 19(11), 3461; https://doi.org/10.3390/ijms19113461 - 04 Nov 2018
Cited by 19 | Viewed by 4027
Abstract
Cell–substrate interaction plays an important role in intracellular behavior and function. Adherent cell mechanics is directly regulated by the substrate mechanics. However, previous studies on the effect of substrate mechanics only focused on the stiffness relation between the substrate and the cells, and [...] Read more.
Cell–substrate interaction plays an important role in intracellular behavior and function. Adherent cell mechanics is directly regulated by the substrate mechanics. However, previous studies on the effect of substrate mechanics only focused on the stiffness relation between the substrate and the cells, and how the substrate stiffness affects the time-scale and length-scale of the cell mechanics has not yet been studied. The absence of this information directly limits the in-depth understanding of the cellular mechanotransduction process. In this study, the effect of substrate mechanics on the nonlinear biomechanical behavior of living cells was investigated using indentation-based atomic force microscopy. The mechanical properties and their nonlinearities of the cells cultured on four substrates with distinct mechanical properties were thoroughly investigated. Furthermore, the actin filament (F-actin) cytoskeleton of the cells was fluorescently stained to investigate the adaptation of F-actin cytoskeleton structure to the substrate mechanics. It was found that living cells sense and adapt to substrate mechanics: the cellular Young’s modulus, shear modulus, apparent viscosity, and their nonlinearities (mechanical property vs. measurement depth relation) were adapted to the substrates’ nonlinear mechanics. Moreover, the positive correlation between the cellular poroelasticity and the indentation remained the same regardless of the substrate stiffness nonlinearity, but was indeed more pronounced for the cells seeded on the softer substrates. Comparison of the F-actin cytoskeleton morphology confirmed that the substrate affects the cell mechanics by regulating the intracellular structure. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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21 pages, 5217 KiB  
Article
In Vitro Screening of Molecularly Engineered Polyethylene Glycol Hydrogels for Cartilage Tissue Engineering using Periosteum-Derived and ATDC5 Cells
by Abhijith K. Kudva, Frank P. Luyten and Jennifer Patterson
Int. J. Mol. Sci. 2018, 19(11), 3341; https://doi.org/10.3390/ijms19113341 - 26 Oct 2018
Cited by 11 | Viewed by 4095
Abstract
The rapidly growing field of tissue engineering and regenerative medicine has brought about an increase in demand for biomaterials that mimic closely the form and function of biological tissues. Therefore, understanding the cellular response to the changes in material composition moves research one [...] Read more.
The rapidly growing field of tissue engineering and regenerative medicine has brought about an increase in demand for biomaterials that mimic closely the form and function of biological tissues. Therefore, understanding the cellular response to the changes in material composition moves research one step closer to a successful tissue-engineered product. With this in mind, polyethylene glycol (PEG) hydrogels comprised of different concentrations of polymer (2.5%, 4%, 6.5%, or 8% (w/v)); different protease sensitive, peptide cross-linkers (VPMSMRGG or GPQGIWGQ); and the incorporation or lack of a peptide cell adhesion ligand (RGD) were screened for their ability to support in vitro chondrogenesis. Human periosteum-derived cells (hPDCs), a mesenchymal stem cell (MSC)-like primary cell source, and ATDC5 cells, a murine carcinoma-derived chondrogenic cell line, were encapsulated within the various hydrogels to assess the effects of the different formulations on cellular viability, proliferation, and chondrogenic differentiation while receiving exogenous growth factor stimulation via the medium. Through the results of this screening process, the 6.5% (w/v) PEG constructs, cross-linked with the GPQGIWGQ peptide and containing the RGD cell binding molecule, demonstrated an environment that consistently supported cellular viability and proliferation as well as chondrogenic differentiation. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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14 pages, 2789 KiB  
Article
Quercitrin Nanocoated Implant Surfaces Reduce Osteoclast Activity In Vitro and In Vivo
by Alba Córdoba, Nahuel Manzanaro-Moreno, Carme Colom, Hans J. Rønold, Staale P. Lyngstadaas, Marta Monjo and Joana M. Ramis
Int. J. Mol. Sci. 2018, 19(11), 3319; https://doi.org/10.3390/ijms19113319 - 25 Oct 2018
Cited by 26 | Viewed by 3671
Abstract
In this study, the effect on osteoclast activity in vitro and in vivo of titanium implants that were coated with quercitrin was evaluated. Titanium surfaces were covalently coated with the flavonoid quercitrin. The effect of the surfaces on osteoclastogenesis was first tested in [...] Read more.
In this study, the effect on osteoclast activity in vitro and in vivo of titanium implants that were coated with quercitrin was evaluated. Titanium surfaces were covalently coated with the flavonoid quercitrin. The effect of the surfaces on osteoclastogenesis was first tested in vitro on RAW264.7 cells that were supplemented with receptor activator of nuclear factor kappa-B ligand (RANKL) to generate osteoclast-like cells by tartrate-resistant acid phosphatase (TRAP) inmunostaining after five days of culture, and by analysis of the mRNA expression levels of markers related to bone resorption after seven days of culture. A rabbit tibial model was used to evaluate the in vivo biological response to the implant surfaces after eight weeks of healing, analyzing the lactate dehydrogenase (LDH) and the alkaline phosphatase (ALP) activities in the wound fluid that were present at the implant interface and the peri-implant bone mRNA expression levels of several markers related to inflammation, bone resorption and osteoblast-osteoclast interaction. No differences between groups and control surfaces were found in the wound fluid analyses. Moreover, quercitrin implant surfaces significantly decreased the expression of osteoclast related genes in vitro (Trap, CalcR, Ctsk, H+ATPase, Mmp9) and in vivo (Ctsk, H+ATPase, Mmp9) as well as the expression of RankL in vivo. Moreover, quercitrin surfaces were not cytotoxic for the cells. Thus, quercitrin implant surfaces were biocompatible and decreased osteoclastogenesis in vitro and in vivo. This could be used to improve the performance of dental implants. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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21 pages, 4567 KiB  
Article
Effect of Cross-Linking Density on the Structures and Properties of Carbodiimide-Treated Gelatin Matrices as Limbal Stem Cell Niches
by Jui-Yang Lai, Li-Jyuan Luo and David Hui-Kang Ma
Int. J. Mol. Sci. 2018, 19(11), 3294; https://doi.org/10.3390/ijms19113294 - 23 Oct 2018
Cited by 12 | Viewed by 3850
Abstract
Given that human amniotic membrane is a valuable biological material not readily available for corneal epithelial tissue engineering, gelatin is considered as a potential alternative to construct a cellular microenvironment. This study investigates, for the first time, the influence of cross-linking density of [...] Read more.
Given that human amniotic membrane is a valuable biological material not readily available for corneal epithelial tissue engineering, gelatin is considered as a potential alternative to construct a cellular microenvironment. This study investigates, for the first time, the influence of cross-linking density of carbodiimide-treated gelatin matrices on the structures and properties of artificial limbal stem cell niches. Our results showed that an increase in the carbodiimide concentration from 1.5 to 15 mM leads to an upward trend in the structural and suture strength of biopolymers. Furthermore, increasing number of cross-linking bridges capable of linking protein molecules together may reduce their crystallinity. For the samples treated with 50 mM of cross-linker (i.e., the presence of excess N-substituted carbodiimide), abundant N-acylurea was detected, which was detrimental to the in vitro and in vivo ocular biocompatibility of gelatin matrices. Surface roughness and stiffness of biopolymer substrates were found to be positively correlated with carbodiimide-induced cross-link formation. Significant increases of integrin β1 expression, metabolic activity, and ABCG2 expression were noted as the cross-linker concentration increased, suggesting that the bulk crystalline structure and surface roughness/stiffness of niche attributed to the number of cross-linking bridges may have profound effects on a variety of limbal epithelial cell behaviors, including adhesion, proliferation, and stemness maintenance. In summary, taking the advantages of carbodiimide cross-linking-mediated development of gelatin matrices, new niches with tunable cross-linking densities can provide a significant boost to maintain the limbal stem cells during ex vivo expansion. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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18 pages, 3390 KiB  
Article
Dendrimeric Poly(Epsilon-Lysine) Delivery Systems for the Enhanced Permeability of Flurbiprofen across the Blood-Brain Barrier in Alzheimer’s Disease
by Shafq Al-azzawi, Dhafir Masheta, Anna L. Guildford, Gary Phillips and Matteo Santin
Int. J. Mol. Sci. 2018, 19(10), 3224; https://doi.org/10.3390/ijms19103224 - 18 Oct 2018
Cited by 34 | Viewed by 4257
Abstract
Alzheimer’s disease (AD) is a progressive brain disorder and age-related disease characterised by abnormal accumulation of β-amyloid (Aβ). The development of drugs to combat AD is hampered by the lack of therapeutically-active molecules able to cross the blood-brain barrier (BBB). It is agreed [...] Read more.
Alzheimer’s disease (AD) is a progressive brain disorder and age-related disease characterised by abnormal accumulation of β-amyloid (Aβ). The development of drugs to combat AD is hampered by the lack of therapeutically-active molecules able to cross the blood-brain barrier (BBB). It is agreed that specifically-designed carriers, such as dendrimers, could support the drug penetration across the BBB. The aim of this study was to design biocompatible and biodegradable dendrimeric delivery systems able to carry Flurbiprofen (FP), as drug for AD treatment, across the BBB and liberate it at the target tissue. These dendrons were synthesised using solid-phase peptide synthesis method and characterised by mass spectrometry and fourier-transform infrared spectroscopy (FTIR). The results revealed successful synthesis of dendrons having FP been integrated during the synthesis at their branching ends. Cytotoxicity assays demonstrated the biocompatibility of the delivery systems, whereas HPLC analysis showed high percentages of permeability across an in vitro BBB model for FP-integrated dendrons. Results also revealed the efficiency of drug conjugates on the γ-secretase enzyme in target cells with evidence of eventual drug release by hydrolysis of the carrier. This study demonstrates that the coupling of FP to dendrimeric delivery systems can successfully be achieved during the synthesis of the poly(epsilon-lysine) macromolecules to improve the transport of the active drug across the BBB. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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22 pages, 11148 KiB  
Article
Ether-Oxygen Containing Electrospun Microfibrous and Sub-Microfibrous Scaffolds Based on Poly(butylene 1,4-cyclohexanedicarboxylate) for Skeletal Muscle Tissue Engineering
by Nora Bloise, Emanuele Berardi, Chiara Gualandi, Elisa Zaghi, Matteo Gigli, Robin Duelen, Gabriele Ceccarelli, Emanuela Elsa Cortesi, Domiziana Costamagna, Giovanna Bruni, Nadia Lotti, Maria Letizia Focarete, Livia Visai and Maurilio Sampaolesi
Int. J. Mol. Sci. 2018, 19(10), 3212; https://doi.org/10.3390/ijms19103212 - 17 Oct 2018
Cited by 29 | Viewed by 4639
Abstract
We report the study of novel biodegradable electrospun scaffolds from poly(butylene 1,4-cyclohexandicarboxylate-co-triethylene cyclohexanedicarboxylate) (P(BCE-co-TECE)) as support for in vitro and in vivo muscle tissue regeneration. We demonstrate that chemical composition, i.e., the amount of TECE co-units (constituted of polyethylene [...] Read more.
We report the study of novel biodegradable electrospun scaffolds from poly(butylene 1,4-cyclohexandicarboxylate-co-triethylene cyclohexanedicarboxylate) (P(BCE-co-TECE)) as support for in vitro and in vivo muscle tissue regeneration. We demonstrate that chemical composition, i.e., the amount of TECE co-units (constituted of polyethylene glycol-like moieties), and fibre morphology, i.e., aligned microfibrous or sub-microfibrous scaffolds, are crucial in determining the material biocompatibility. Indeed, the presence of ether linkages influences surface wettability, mechanical properties, hydrolytic degradation rate, and density of cell anchoring points of the studied materials. On the other hand, electrospun scaffolds improve cell adhesion, proliferation, and differentiation by favouring cell alignment along fibre direction (fibre morphology), also allowing for better cell infiltration and oxygen and nutrient diffusion (fibre size). Overall, C2C12 myogenic cells highly differentiated into mature myotubes when cultured on microfibres realised with the copolymer richest in TECE co-units (micro-P73 mat). Lastly, when transplanted in the tibialis anterior muscles of healthy, injured, or dystrophic mice, micro-P73 mat appeared highly vascularised, colonised by murine cells and perfectly integrated with host muscles, thus confirming the suitability of P(BCE-co-TECE) scaffolds as substrates for skeletal muscle tissue engineering. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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15 pages, 4347 KiB  
Article
PEG-Plasma Hydrogels Increase Epithelialization Using a Human Ex Vivo Skin Model
by Randolph Stone II, John T. Wall, Shanmugasundaram Natesan and Robert J. Christy
Int. J. Mol. Sci. 2018, 19(10), 3156; https://doi.org/10.3390/ijms19103156 - 13 Oct 2018
Cited by 21 | Viewed by 4111
Abstract
In vitro cell culture methods are used extensively to study cellular migration, proliferation, and differentiation, which play major roles in wound healing but the results often do not translate to the in vivo environment. One alternative would be to establish an ex vivo [...] Read more.
In vitro cell culture methods are used extensively to study cellular migration, proliferation, and differentiation, which play major roles in wound healing but the results often do not translate to the in vivo environment. One alternative would be to establish an ex vivo model utilizing human discarded skin to evaluate therapies in a more natural setting. The purpose of this study was to institute such a model by creating ‘wounds’ in the center of a piece of discarded skin and treating them with three different biomaterials: collagen, polyethylene glycol (PEG)-fibrin, or PEG-platelet free plasma (PFP). Explants were cultured for 14 days with supernatant and microscopy images collected every 3 days to assess cytotoxicity and epithelialization. After 14 days, the explants were fixed, sectioned, and stained for cytokeratin-10 (CK-10), alpha-smooth muscle actin (α-SMA), and wheat germ (WG). Compared to controls, similar levels of cytotoxicity were detected for 12 days which decreased slightly at day 14. The PEG-PFP hydrogel-treated wounds epithelialized faster than other treatments at days 6 to 14. A 6-8 cell layer thick CK-10+ stratified epidermis had developed over the PEG-PFP hydrogel and cells co-stained by WG and α-SMA were observed within the hydrogel. An ex vivo model was established that can be used practically to screen different therapies exploring wound healing. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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17 pages, 3426 KiB  
Article
Generation of a 3D Liver Model Comprising Human Extracellular Matrix in an Alginate/Gelatin-Based Bioink by Extrusion Bioprinting for Infection and Transduction Studies
by Thomas Hiller, Johanna Berg, Laura Elomaa, Viola Röhrs, Imran Ullah, Katrin Schaar, Ann-Christin Dietrich, Munir A. Al-Zeer, Andreas Kurtz, Andreas C. Hocke, Stefan Hippenstiel, Henry Fechner, Marie Weinhart and Jens Kurreck
Int. J. Mol. Sci. 2018, 19(10), 3129; https://doi.org/10.3390/ijms19103129 - 12 Oct 2018
Cited by 102 | Viewed by 10396
Abstract
Bioprinting is a novel technology that may help to overcome limitations associated with two-dimensional (2D) cell cultures and animal experiments, as it allows the production of three-dimensional (3D) tissue models composed of human cells. The present study describes the optimization of a bioink [...] Read more.
Bioprinting is a novel technology that may help to overcome limitations associated with two-dimensional (2D) cell cultures and animal experiments, as it allows the production of three-dimensional (3D) tissue models composed of human cells. The present study describes the optimization of a bioink composed of alginate, gelatin and human extracellular matrix (hECM) to print human HepaRG liver cells with a pneumatic extrusion printer. The resulting tissue model was tested for its suitability for the study of transduction by an adeno-associated virus (AAV) vector and infection with human adenovirus 5 (hAdV5). We found supplementation of the basic alginate/gelatin bioink with 0.5 and 1 mg/mL hECM provides desirable properties for the printing process, the stability of the printed constructs, and the viability and metabolic functions of the printed HepaRG cells. The tissue models were efficiently transduced by AAV vectors of serotype 6, which successfully silenced an endogenous target (cyclophilin B) by means of RNA interference. Furthermore, the printed 3D model supported efficient adenoviral replication making it suitable to study virus biology and develop new antiviral compounds. We consider the approach described here paradigmatic for the development of 3D tissue models for studies including viral vectors and infectious viruses. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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16 pages, 3678 KiB  
Article
Granulin A Synergizes with Cisplatin to Inhibit the Growth of Human Hepatocellular Carcinoma
by Gan Qiao, Huanli Xu, Cong Li, Xiao Li, Ammad Ahmad Farooqi, Yuming Zhao, Xiaohui Liu, Ming Liu, Dimitrios Stagos and Xiukun Lin
Int. J. Mol. Sci. 2018, 19(10), 3060; https://doi.org/10.3390/ijms19103060 - 07 Oct 2018
Cited by 19 | Viewed by 3550
Abstract
Cisplatin is one of the most potent chemotherapy drugs widely used for cancer treatment. However, due to resistance and toxicity, the application of cisplatin for the treatment of hepatocellular carcinoma (HCC) is limited. Our previous study has shown that granulin A (GRN A), [...] Read more.
Cisplatin is one of the most potent chemotherapy drugs widely used for cancer treatment. However, due to resistance and toxicity, the application of cisplatin for the treatment of hepatocellular carcinoma (HCC) is limited. Our previous study has shown that granulin A (GRN A), an anticancer peptide, is able to interact with enolase1 (ENO1) and inhibit the growth of HCC in vitro. In the present study, we studied the synergistic effect of the combination of cisplatin and GRN A for the inhibitory effect on HCC. An 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and Chou-Talalay approaches revealed that the combination of GRN A and cisplatin displayed potent synergistic effect. The colony formation and cell viability of HCC cells were inhibited significantly in cells treated with the combination of cisplatin and GRN A, compared with cells treated with cisplatin or GRN A alone. Overexpression of ENO1 diminished the synergistic effect of GRN A and cisplatin in HCC cells. The combination of the two drugs exhibited a more obvious inhibitory effect on cancer cell apoptosis, as analyzed by the cytometry flow, mitochondrial membrane potential (MMP) and western blot analysis. An in vivo study confirmed that the combined use of the two drugs displayed more potent antitumor activity compared to mice treated with cisplatin and GRN A alone; the inhibitory rate of tumor growth was 65.46% and 68.94%, respectively, in mice treated with GRN A and cisplatin. However, the inhibitory rate increased to 86.63% in mice treated with the combination of the two drugs. This study provides evidence that the combination of GRN A and cisplatin is able to sensitize the liver cancer to cisplatin, and that targeting ENO1 is a promising approach for enhancing the antitumor activity of cisplatin. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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14 pages, 3592 KiB  
Article
A Disposable Photovoltaic Patch Controlling Cellular Microenvironment for Wound Healing
by Hyeon-Ki Jang, Jin Young Oh, Gun-Jae Jeong, Tae-Jin Lee, Gwang-Bum Im, Ju-Ro Lee, Jeong-Kee Yoon, Dong-Ik Kim, Byung-Soo Kim, Suk Ho Bhang and Tae Il Lee
Int. J. Mol. Sci. 2018, 19(10), 3025; https://doi.org/10.3390/ijms19103025 - 04 Oct 2018
Cited by 10 | Viewed by 4112
Abstract
Electrical stimulation (ES) is known to affect the wound healing process by modulating skin cell behaviors. However, the conventional clinical devices that can generate ES for promoting wound healing require patient hospitalization due to large-scale of the extracorporeal devices. Herein, we introduce a [...] Read more.
Electrical stimulation (ES) is known to affect the wound healing process by modulating skin cell behaviors. However, the conventional clinical devices that can generate ES for promoting wound healing require patient hospitalization due to large-scale of the extracorporeal devices. Herein, we introduce a disposable photovoltaic patch that can be applied to skin wound sites to control cellular microenvironment for promoting wound healing by generating ES. In vitro experiment results show that exogenous ES could enhance cell migration, proliferation, expression of extracellular matrix proteins, and myoblast differentiation of fibroblasts which are critical for wound healing. Our disposable photovoltaic patches were attached to the back of skin wound induced mice. Our patch successfully provided ES, generated by photovoltaic energy harvested from the organic solar cell under visible light illumination. In vivo experiment results show that the patch promoted cutaneous wound healing via enhanced host-inductive cell proliferation, cytokine secretion, and protein synthesis which is critical for wound healing process. Unlike the current treatments for wound healing that engage passive healing processes and often are unsuccessful, our wearable photovoltaic patch can stimulate regenerative activities of endogenous cells and actively contribute to the wound healing processes. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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17 pages, 2967 KiB  
Article
Topical Delivery of Senicapoc Nanoliposomal Formulation for Ocular Surface Treatments
by Jie Liang Phua, Aihua Hou, Yuan Siang Lui, Tanima Bose, George Kanianthara Chandy, Louis Tong, Subbu Venkatraman and Yingying Huang
Int. J. Mol. Sci. 2018, 19(10), 2977; https://doi.org/10.3390/ijms19102977 - 29 Sep 2018
Cited by 15 | Viewed by 4808
Abstract
Topical ophthalmologic treatments have been facing great challenges with main limitations of low drug bioavailability, due to highly integrative defense mechanisms of the eye. This study rationally devised strategies to increase drug bioavailability by increasing ocular surface residence time of drug-loaded nanoliposomes dispersed [...] Read more.
Topical ophthalmologic treatments have been facing great challenges with main limitations of low drug bioavailability, due to highly integrative defense mechanisms of the eye. This study rationally devised strategies to increase drug bioavailability by increasing ocular surface residence time of drug-loaded nanoliposomes dispersed within thermo-sensitive hydrogels (Pluronic F-127). Alternatively, we utilized sub-conjunctival injections as a depot technique to localize nanoliposomes. Senicapoc was encapsulated and sustainably released from free nanoliposomes and hydrogels formulations in vitro. Residence time increased up to 12-fold (60 min) with 24% hydrogel formulations, as compared to 5 min for free liposomes, which was observed in the eyes of Sprague-Dawley rats using fluorescence measurements. Pharmacokinetic results obtained from flushed tears, also showed that the hydrogels had greater drug retention capabilities to that of topical viscous solutions for up to 60 min. Senicapoc also remained quantifiable within sub-conjunctival tissues for up to 24 h post-injection. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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14 pages, 2592 KiB  
Article
Tuning Nanopore Diameter of Titanium Surfaces to Improve Human Gingival Fibroblast Response
by Maria Del Mar Ferrà-Cañellas, Maria Antonia Llopis-Grimalt, Marta Monjo and Joana Maria Ramis
Int. J. Mol. Sci. 2018, 19(10), 2881; https://doi.org/10.3390/ijms19102881 - 22 Sep 2018
Cited by 14 | Viewed by 3513
Abstract
The aim of this study was to determine the optimal nanopore diameter of titanium nanostructured surfaces to improve human gingival fibroblast (hGF) response, with the purpose of promoting gingiva integration to dental implant abutments. Two TiO2 nanoporous groups with different diameters (NP-S [...] Read more.
The aim of this study was to determine the optimal nanopore diameter of titanium nanostructured surfaces to improve human gingival fibroblast (hGF) response, with the purpose of promoting gingiva integration to dental implant abutments. Two TiO2 nanoporous groups with different diameters (NP-S ~48 nm and NP-B ~74 nm) were grown on Ti foils using an organic electrolyte containing fluoride by electrochemical oxidation, varying the applied voltage and the interelectrode spacing. The surfaces were characterized by scanning electron microscope (SEM), atomic force microscopy (AFM), and contact angle. The hGF were cultured onto the different surfaces, and metabolic activity, cytotoxicity, cell adhesion, and gene expression were analyzed. Bigger porous diameters (NP-B) were obtained by increasing the voltage used during anodization. To obtain the smallest diameter (NP-S), apart from lowering the voltage, a lower interelectrode spacing was needed. The greatest surface area and number of peaks was found for NP-B, despite these samples not being the roughest as defined by Ra. NP-B had a better cellular response compared to NP-S. However, these effects had a significant dependence on the cell donor. In conclusion, nanoporous groups with a diameter in the range of 74 nm induce a better hGF response, which may be beneficial for an effective soft tissue integration around the implant. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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16 pages, 4710 KiB  
Article
Comparison of Cytomorphometry and Early Cell Response of Human Gingival Fibroblast (HGFs) between Zirconium and New Zirconia-Reinforced Lithium Silicate Ceramics (ZLS)
by María Rizo-Gorrita, Irene Luna-Oliva, María-Ángeles Serrera-Figallo, José-Luis Gutiérrez-Pérez and Daniel Torres-Lagares
Int. J. Mol. Sci. 2018, 19(9), 2718; https://doi.org/10.3390/ijms19092718 - 11 Sep 2018
Cited by 16 | Viewed by 4094
Abstract
New zirconia-reinforced lithium silicate ceramics (ZLS) could be a viable alternative to zirconium (Y-TZP) in the manufacture of implantological abutments—especially in aesthetic cases—due to its good mechanical, optical, and biocompatibility properties. Although there are several studies on the ZLS mechanical properties, there are [...] Read more.
New zirconia-reinforced lithium silicate ceramics (ZLS) could be a viable alternative to zirconium (Y-TZP) in the manufacture of implantological abutments—especially in aesthetic cases—due to its good mechanical, optical, and biocompatibility properties. Although there are several studies on the ZLS mechanical properties, there are no studies regarding proliferation, spreading, or cytomorphometry. We designed the present study which compares the surface, cellular proliferation, and cellular morphology between Y-TZP (Vita YZ® T [Vita Zahnfabrik (Postfach, Germany)]) and ZLS (Celtra® Duo [Degudent (Hanau-Wolfgang, Germany)]). The surface characterization was performed with energy dispersive spectroscopy (EDS), scanning electron microscopy (SEM), and optical profilometry. Human gingival fibroblasts (HGFs) were subsequently cultured on both materials and early cellular response and cell morphology were compared through nuclear and cytoskeletal measurement parameters using confocal microscopy. The results showed greater proliferation and spreading on the surface of Y-TZP. This could indicate that Y-TZP continues to be a gold standard in terms of transgingival implant material: Nevertheless, more in vitro and in vivo research is necessary to confirm the results obtained in this study. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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15 pages, 2712 KiB  
Article
Differential and Interactive Effects of Substrate Topography and Chemistry on Human Mesenchymal Stem Cell Gene Expression
by Qiongfang Li, Bo Zhang, Naresh Kasoju, Jinmin Ma, Aidong Yang, Zhanfeng Cui, Hui Wang and Hua Ye
Int. J. Mol. Sci. 2018, 19(8), 2344; https://doi.org/10.3390/ijms19082344 - 09 Aug 2018
Cited by 24 | Viewed by 4114 | Correction
Abstract
Variations in substrate chemistry and the micro-structure were shown to have a significant effect on the biology of human mesenchymal stromal cells (hMSCs). This occurs when differences in the surface properties indirectly modulate pathways within numerous signaling networks that control cell fate. To [...] Read more.
Variations in substrate chemistry and the micro-structure were shown to have a significant effect on the biology of human mesenchymal stromal cells (hMSCs). This occurs when differences in the surface properties indirectly modulate pathways within numerous signaling networks that control cell fate. To understand how the surface features affect hMSC gene expression, we performed RNA-sequencing analysis of bone marrow-derived hMSCs cultured on tissue culture-treated polystyrene (TCP) and poly(l-lactide) (PLLA) based substrates of differing topography (Fl: flat and Fs: fibrous) and chemistry (Pr: pristine and Am: aminated). Whilst 80% of gene expression remained similar for cells cultured on test substrates, the analysis of differentially expressed genes (DEGs) revealed that surface topography significantly altered gene expression more than surface chemistry. The Fl and Fs topologies introduced opposite directional alternations in gene expression when compared to TCP control. In addition, the effect of chemical treatment interacted with that of topography in a synergistic manner with the Pr samples promoting more DEGs than Am samples in all gene ontology function groups. These findings not only highlight the significance of the culture surface on regulating the overall gene expression profile but also provide novel insights into cell-material interactions that could help further design the next-generation biomaterials to facilitate hMSC applications. At the same time, further studies are required to investigate whether or not the observations noted correlate with subsequent protein expression and functionality of cells. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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7 pages, 1325 KiB  
Communication
Hydroxyl Radical-Suppressing Mechanism and Efficiency of Melanin-Mimetic Nanoparticles
by Koichiro Hayashi, Atsuto Tokuda and Wataru Sakamoto
Int. J. Mol. Sci. 2018, 19(8), 2309; https://doi.org/10.3390/ijms19082309 - 07 Aug 2018
Cited by 1 | Viewed by 3135
Abstract
Harnessing melanins to scavenge free radicals in vivo may yield treatment methods for inflammatory disorders. Furthermore, elucidation of the mechanism underlying melanin-mediated suppression of free radicals, which is yet unclear, is warranted. Herein, we chemically synthesized melanin-mimetic nanoparticles (MeNPs) and investigated the mechanism [...] Read more.
Harnessing melanins to scavenge free radicals in vivo may yield treatment methods for inflammatory disorders. Furthermore, elucidation of the mechanism underlying melanin-mediated suppression of free radicals, which is yet unclear, is warranted. Herein, we chemically synthesized melanin-mimetic nanoparticles (MeNPs) and investigated the mechanism underlying their use. MeNPs efficiently suppressed hydroxyl radicals by converting some MeNP hydroxyl groups to ketone groups. Furthermore, they suppressed hydroxyl radicals produced by lipopolysaccharide-treated Kupffer cells involved in hepatic cirrhosis pathogenesis, without causing significant cytotoxicity. The present results indicate the suitability of MeNPs to treat hepatic cirrhosis; however, further in vivo studies are warranted to determine their treatment efficacy. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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16 pages, 4371 KiB  
Article
Evaluation of BMP-2 Enhances the Osteoblast Differentiation of Human Amnion Mesenchymal Stem Cells Seeded on Nano-Hydroxyapatite/Collagen/Poly(l-Lactide)
by Shuhong Wu, Zhili Xiao, Jinlin Song, Min Li and Wenhua Li
Int. J. Mol. Sci. 2018, 19(8), 2171; https://doi.org/10.3390/ijms19082171 - 25 Jul 2018
Cited by 31 | Viewed by 5416
Abstract
Background: The aim of this study is to evaluate the effects of recombinant human bone morphogenetic protein 2 (rhBMP-2), human amnion mesenchymal stem cells (hAMSCs), and nanohydroxyapatite/collagen/poly(l-lactide) (nHAC/PLA) in tissue engineering to provide potential approaches for periodontal bone regeneration. Methods: hAMSCs [...] Read more.
Background: The aim of this study is to evaluate the effects of recombinant human bone morphogenetic protein 2 (rhBMP-2), human amnion mesenchymal stem cells (hAMSCs), and nanohydroxyapatite/collagen/poly(l-lactide) (nHAC/PLA) in tissue engineering to provide potential approaches for periodontal bone regeneration. Methods: hAMSCs were isolated from discarded amniotic membrane samples and cultured in vitro. Alkaline phosphatase (ALP) staining and alizarin red staining were performed to evaluate the osteoblast (OB) differentiation ability of hAMSCs. Three groups were divided: the experimental group (cells transfected with pcDNA3.1-rhBMP-2), the blank group (cells without gene transfection), and the control group (cells transfected with empty plasmid). RT-PCR and western blot were used to examine whether rhBMP-2 has been successfully expressed. 3-(4,5)-dimethylthiahiazol(-z-y1)-3,5-di-phenytetrazo-liumromide assay (MTT) was done to detect the effect of rhBMP-2 on hAMSCs seeded on nHAC/PLA. ALP activity, mineral formation assay, calcium, phosphate and osteocalcin (OCN) content, and OCN and RUNX2 expression of hAMSCs were detected to evaluate osteogenic differentiation capability of rhBMP-2 on hAMSCs seeded on nHAC/PLA. Results: hAMSCs exhibited intense ALP staining, obvious calcium deposition, and mineralization nodules, and rhBMP-2 were highly expressed in the experimental group. The proliferation of the hAMSCs with rhBMP-2 on nHAC/PLA was significantly higher than the cells without rhBMP-2, and the cells all increased in a time-dependent manner. rhBMP-2 significantly increased the OCN and phosphate content, mineral formation, ALP activity, osteogenic biomarkers OCN, and Runx2, and decreased calcium content in hAMSCs seeded on the nHAC/PLA scaffold. Conclusions: This finding demonstrated that hAMSCs has an ideal OB differentiation ability. rhBMP-2 facilitates the proliferation and osteogenesis of hAMSCs. The nHAC/PLA could act as a good scaffold for hAMSCs seeding, proliferation, and osteogenic differentiation. The application of rhBMP-2, nHAC/PLA, and hAMSCs in tissue engineering may offer promising possibilities for periodontal bone regeneration. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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19 pages, 3661 KiB  
Article
Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure
by Uliana De Simone, Marianna Roccio, Laura Gribaldo, Arsenio Spinillo, Francesca Caloni and Teresa Coccini
Int. J. Mol. Sci. 2018, 19(7), 1993; https://doi.org/10.3390/ijms19071993 - 08 Jul 2018
Cited by 33 | Viewed by 4284
Abstract
Since nanoparticles (NPs) can translocate to the brain and impact the highly vulnerable central nervous system (CNS), novel in vitro tools for the assessment of NP-induced neurotoxicity are advocated. In this study, two types of CNS spheroids have been developed from human D384 [...] Read more.
Since nanoparticles (NPs) can translocate to the brain and impact the highly vulnerable central nervous system (CNS), novel in vitro tools for the assessment of NP-induced neurotoxicity are advocated. In this study, two types of CNS spheroids have been developed from human D384 astrocyte- and SH-SY5Y neuronal-like cells, and optimized in combination with standard assays (viability readout and cell morphology) to test neurotoxic effects caused by Fe3O4NPs, as NP-model, after short- (24–48 h; 1–100µg/ml) and long-term repeated exposure (30days; 0.1–25µg/ml). Short-term exposure of 3D-spheroids to Fe3O4NP induced cytotoxicity at 10 µg/mL in astrocytes and 25 µg/mL neurons. After long-term repeated dose regimen, spheroids showed concentration- and time-dependent cell mortality at 10 µg/mL for D384 and 0.5 µg/mL for SH-SY5Y, indicating a higher susceptibility of neurons than astrocytes. Both spheroid types displayed cell disaggregation after the first week of treatment at ≥0.1 µg/mL and becoming considerably evident at higher concentrations and over time. Recreating the 3D-spatial environment of the CNS allows cells to behave in vitro more closely to the in vivo situations, therefore providing a model that can be used as a stand-alone test or as a part of integrated testing strategies. These models could drive an improvement in the species-relevant predictivity of toxicity testing. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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11 pages, 2855 KiB  
Communication
Phenotype and Viability of MLO-Y4 Cells Is Maintained by TGFβ3 in a Serum-Dependent Manner within a 3D-Co-Culture with MG-63 Cells
by Katharina Jähn, Deborah J. Mason, Jim R. Ralphs, Bronwen A.J. Evans, Charles W. Archer, R. Geoff Richards and Martin J. Stoddart
Int. J. Mol. Sci. 2018, 19(7), 1932; https://doi.org/10.3390/ijms19071932 - 30 Jun 2018
Cited by 5 | Viewed by 4586
Abstract
The osteocyte network inside the bone matrix is of functional importance and osteocyte cell death is a characteristic feature of pathological bone diseases. Osteocytes have emerged as key regulators of bone tissue maintenance, yet maintaining their phenotype during in vitro culture remains challenging. [...] Read more.
The osteocyte network inside the bone matrix is of functional importance and osteocyte cell death is a characteristic feature of pathological bone diseases. Osteocytes have emerged as key regulators of bone tissue maintenance, yet maintaining their phenotype during in vitro culture remains challenging. A 3D co-culture system for osteocytes with osteoblasts was recently presented, enabling the determination of more physiological effects of growth factors on cells in vitro. MLO-Y4 cells were embedded within a type I collagen gel and cultured in the presence of surface MG-63 cells. Co-culture was performed in the presence or absence of TGFβ3. Gene expression by quantitative PCR, protein expression by fluorescent immunohistochemistry and cell viability tests were performed. The 3D co-culture induced cell differentiation of MG-63 cells seen by increased type I collagen and osteocalcin mRNA expression. TGFβ3 maintained osteocyte differentiation of MLO-Y4 cells during co-culture as determined by stable E11 and osteocalcin mRNA expression till day 4. Interestingly, most of the effects of TGFβ3 on co-cultured cells were serum-dependent. Also, TGFβ3 reduced cell death of 3D co-cultured MLO-Y4 cells in a serum-dependent manner. This study shows that 3D co-culture upregulates differentiation of MG-63 cells to a more mature osteoblast-like phenotype; while the addition of TGFβ3 maintained the characteristic MLO-Y4 osteocyte-like phenotype and viability in a serum-dependent manner. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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15 pages, 5274 KiB  
Article
Ubidecarenone-Loaded Nanostructured Lipid Carrier (UB-NLC): Percutaneous Penetration and Protective Effects Against Hydrogen Peroxide-Induced Oxidative Stress on HaCaT Cells
by Jianmin Wang, Huiyun Wang and Qiang Xia
Int. J. Mol. Sci. 2018, 19(7), 1865; https://doi.org/10.3390/ijms19071865 - 25 Jun 2018
Cited by 6 | Viewed by 3837
Abstract
The objective of the investigation was to evaluate the percutaneous penetration of a ubidecarenone-loaded nanostructured lipid carrier (UB-NLC) and to illuminate the protective effects of UB-NLC for amelioration of hydrogen peroxide-induced oxidative damage on HaCaT cells. Ubidecarenone (UB) was encapsulated in a nanostructured [...] Read more.
The objective of the investigation was to evaluate the percutaneous penetration of a ubidecarenone-loaded nanostructured lipid carrier (UB-NLC) and to illuminate the protective effects of UB-NLC for amelioration of hydrogen peroxide-induced oxidative damage on HaCaT cells. Ubidecarenone (UB) was encapsulated in a nanostructured lipid carrier (NLC), which was manufactured by homogenization. The morphological and dimensional properties of the prepared UB-NLC were studied by freeze-fracture transmission electron microscopy (FF-TEM) and photon correlation spectroscopy (PCS). Percutaneous penetration of UB-NLC was carried out by the Franz diffusion cells method. The change of cellular morphology was identified through a non-invasive time-lapse imaging system. The assessment was achieved via the evaluation of the levels of oxidative stress markers: reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA). Percutaneous penetration of UB loaded in NLC formulation was enhanced in comparison to free UB. Preincubation of HaCaT cells with UB-NLC attenuated the level of intracellular generation of ROS. Lipid peroxidation was diminished by UB-NLC via inhibition of MDA formation. Pretreatment of cells with UB-NLC reestablished the activity of cellular antioxidant enzymes (SOD and GSH-PX). On the basis of the investigation conducted, results suggest that formulating UB as NLC is advantageous for topical delivery and treatment of oxidative stress-induced human diseases. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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17 pages, 51034 KiB  
Article
Biofunctionalized Scaffold in Bone Tissue Repair
by Francesca Diomede, Marco D’Aurora, Agnese Gugliandolo, Ilaria Merciaro, Tiziana Orsini, Valentina Gatta, Adriano Piattelli, Oriana Trubiani and Emanuela Mazzon
Int. J. Mol. Sci. 2018, 19(4), 1022; https://doi.org/10.3390/ijms19041022 - 29 Mar 2018
Cited by 65 | Viewed by 5454
Abstract
Bone tissue engineering is based on bone grafting to repair bone defects. Bone graft substitutes can contribute to the addition of mesenchymal stem cells (MSCs) in order to enhance the rate and the quality of defect regeneration. The stem cell secretome contains many [...] Read more.
Bone tissue engineering is based on bone grafting to repair bone defects. Bone graft substitutes can contribute to the addition of mesenchymal stem cells (MSCs) in order to enhance the rate and the quality of defect regeneration. The stem cell secretome contains many growth factors and chemokines, which could affect cellular characteristics and behavior. Conditioned medium (CM) could be used in tissue regeneration avoiding several problems linked to the direct use of MSCs. In this study, we investigated the effect of human periodontal ligament stem cells (hPDLSCs) and their CM on bone regeneration using a commercially available membrane scaffold Evolution (EVO) implanted in rat calvarias. EVO alone or EVO + hPDLSCs with or without CM were implanted in Wistar male rats subjected to calvarial defects. The in vivo results revealed that EVO membrane enriched with hPDLSCs and CM showed a better osteogenic ability to repair the calvarial defect. These results were confirmed by acquired micro-computed tomography (CT) images and the increased osteopontin levels. Moreover, RT-PCR in vitro revealed the upregulation of three genes (Collagen (COL)5A1, COL16A1 and transforming growth factor (TGF)β1) and the down regulation of 26 genes involved in bone regeneration. These results suggest a promising potential application of CM from hPDLSCs and scaffolds for bone defect restoration and in particular for calvarial repair in case of trauma. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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Review

Jump to: Research

30 pages, 2788 KiB  
Review
Small Molecules Enhance Scaffold-Based Bone Grafts via Purinergic Receptor Signaling in Stem Cells
by Patrick Frank Ottensmeyer, Markus Witzler, Margit Schulze and Edda Tobiasch
Int. J. Mol. Sci. 2018, 19(11), 3601; https://doi.org/10.3390/ijms19113601 - 14 Nov 2018
Cited by 21 | Viewed by 6952
Abstract
The need for bone grafts is high, due to age-related diseases, such as tumor resections, but also accidents, risky sports, and military conflicts. The gold standard for bone grafting is the use of autografts from the iliac crest, but the limited amount of [...] Read more.
The need for bone grafts is high, due to age-related diseases, such as tumor resections, but also accidents, risky sports, and military conflicts. The gold standard for bone grafting is the use of autografts from the iliac crest, but the limited amount of accessible material demands new sources of bone replacement. The use of mesenchymal stem cells or their descendant cells, namely osteoblast, the bone-building cells and endothelial cells for angiogenesis, combined with artificial scaffolds, is a new approach. Mesenchymal stem cells (MSCs) can be obtained from the patient themselves, or from donors, as they barely cause an immune response in the recipient. However, MSCs never fully differentiate in vitro which might lead to unwanted effects in vivo. Interestingly, purinergic receptors can positively influence the differentiation of both osteoblasts and endothelial cells, using specific artificial ligands. An overview is given on purinergic receptor signaling in the most-needed cell types involved in bone metabolism—namely osteoblasts, osteoclasts, and endothelial cells. Furthermore, different types of scaffolds and their production methods will be elucidated. Finally, recent patents on scaffold materials, as wells as purinergic receptor-influencing molecules which might impact bone grafting, are discussed. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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17 pages, 1353 KiB  
Review
Cellular Signaling Pathways Activated by Functional Graphene Nanomaterials
by Anna Piperno, Angela Scala, Antonino Mazzaglia, Giulia Neri, Rosamaria Pennisi, Maria Teresa Sciortino and Giovanni Grassi
Int. J. Mol. Sci. 2018, 19(11), 3365; https://doi.org/10.3390/ijms19113365 - 27 Oct 2018
Cited by 24 | Viewed by 4126
Abstract
The paper reviews the network of cellular signaling pathways activated by Functional Graphene Nanomaterials (FGN) designed as a platform for multi-targeted therapy or scaffold in tissue engineering. Cells communicate with each other through a molecular device called signalosome. It is a transient co-cluster [...] Read more.
The paper reviews the network of cellular signaling pathways activated by Functional Graphene Nanomaterials (FGN) designed as a platform for multi-targeted therapy or scaffold in tissue engineering. Cells communicate with each other through a molecular device called signalosome. It is a transient co-cluster of signal transducers and transmembrane receptors activated following the binding of transmembrane receptors to extracellular signals. Signalosomes are thus efficient and sensitive signal-responding devices that amplify incoming signals and convert them into robust responses that can be relayed from the plasma membrane to the nucleus or other target sites within the cell. The review describes the state-of-the-art biomedical applications of FGN focusing the attention on the cell/FGN interactions and signalosome activation. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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16 pages, 3378 KiB  
Review
Hydrogel Cryopreservation System: An Effective Method for Cell Storage
by Chaocan Zhang, Youliang Zhou, Li Zhang, Lili Wu, Yanjun Chen, Dong Xie and Wanyu Chen
Int. J. Mol. Sci. 2018, 19(11), 3330; https://doi.org/10.3390/ijms19113330 - 25 Oct 2018
Cited by 48 | Viewed by 8121
Abstract
At present, living cells are widely used in cell transplantation and tissue engineering. Many efforts have been made aiming towards the use of a large number of living cells with high activity and integrated functionality. Currently, cryopreservation has become well-established and is effective [...] Read more.
At present, living cells are widely used in cell transplantation and tissue engineering. Many efforts have been made aiming towards the use of a large number of living cells with high activity and integrated functionality. Currently, cryopreservation has become well-established and is effective for the long-term storage of cells. However, it is still a major challenge to inhibit cell damage, such as from solution injury, ice injury, recrystallization and osmotic injury during the thawing process, and the cytotoxicity of cryoprotectants. Hence, this review focused on different novel gel cryopreservation systems. Natural polymer hydrogel cryopreservation, the synthetic polymer hydrogel cryopreservation system and the supramolecular hydrogel cryopreservation system were presented, respectively. Due to the unique three-dimensional network structure of the hydrogel, these hydrogel cryopreservation systems have the advantages of excellent biocompatibility for natural polymer hydrogel cryopreservation systems, designability for synthetic polymer hydrogel cryopreservation systems, and versatility for supramolecular hydrogel cryopreservation systems. To some extent, the different hydrogel cryopreservation methods can confine ice crystal growth and decrease the change rates of osmotic shock in cell encapsulation systems. It is notable that the cryopreservation of complex cells and tissues is demanded in future clinical research and therapy, and depends on the linkage of different methods. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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15 pages, 1767 KiB  
Review
Allogeneic Mesenchymal Stem Cells and Biomaterials: The Perfect Match for Cardiac Repair?
by Inigo Perez-Estenaga, Felipe Prosper and Beatriz Pelacho
Int. J. Mol. Sci. 2018, 19(10), 3236; https://doi.org/10.3390/ijms19103236 - 19 Oct 2018
Cited by 21 | Viewed by 5300
Abstract
Coronary heart disease is the leading cause of death worldwide with huge socio-economic consequences. Cell therapy, and particularly mesenchymal stem cells (MSC), are considered a promising option to treat this disorder, due to their robust trophic and immunomodulatory properties. However, limitations such as [...] Read more.
Coronary heart disease is the leading cause of death worldwide with huge socio-economic consequences. Cell therapy, and particularly mesenchymal stem cells (MSC), are considered a promising option to treat this disorder, due to their robust trophic and immunomodulatory properties. However, limitations such as their low rate of engraftment and poor survival after administration into the heart have precluded their large-scale clinical use. Nevertheless, the combination of MSC with polymer-made scaffolds or hydrogels has proven to enhance their retention and, therefore, their efficacy. Additionally, their allogeneic use could permit the creation of ready-to-use cell patches able to improve their feasibility and promote their application in clinical settings. In this review, the experimental and clinical results derived from the use of MSC in cardiac pathology, as well as advances in the bioengineering field to improve the potential of therapeutic cells, are extensively discussed. Additionally, the current understanding of the heart response to the allogeneic MSC transplants is addressed. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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16 pages, 4518 KiB  
Review
The Potential of Intrinsically Magnetic Mesenchymal Stem Cells for Tissue Engineering
by Fransiscus F. A. Kerans, Lisa Lungaro, Asim Azfer and Donald M. Salter
Int. J. Mol. Sci. 2018, 19(10), 3159; https://doi.org/10.3390/ijms19103159 - 14 Oct 2018
Cited by 17 | Viewed by 4608
Abstract
The magnetization of mesenchymal stem cells (MSC) has the potential to aid tissue engineering approaches by allowing tracking, targeting, and local retention of cells at the site of tissue damage. Commonly used methods for magnetizing cells include optimizing uptake and retention of superparamagnetic [...] Read more.
The magnetization of mesenchymal stem cells (MSC) has the potential to aid tissue engineering approaches by allowing tracking, targeting, and local retention of cells at the site of tissue damage. Commonly used methods for magnetizing cells include optimizing uptake and retention of superparamagnetic iron oxide nanoparticles (SPIONs). These appear to have minimal detrimental effects on the use of MSC function as assessed by in vitro assays. The cellular content of magnetic nanoparticles (MNPs) will, however, decrease with cell proliferation and the longer-term effects on MSC function are not entirely clear. An alternative approach to magnetizing MSCs involves genetic modification by transfection with one or more genes derived from Magnetospirillum magneticum AMB-1, a magnetotactic bacterium that synthesizes single-magnetic domain crystals which are incorporated into magnetosomes. MSCs with either or mms6 and mmsF genes are followed by bio-assimilated synthesis of intracytoplasmic magnetic nanoparticles which can be imaged by magnetic resonance (MR) and which have no deleterious effects on MSC proliferation, migration, or differentiation. The stable transfection of magnetosome-associated genes in MSCs promotes assimilation of magnetic nanoparticle synthesis into mammalian cells with the potential to allow MR-based cell tracking and, through external or internal magnetic targeting approaches, enhanced site-specific retention of cells for tissue engineering. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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19 pages, 1221 KiB  
Review
3D Bone Biomimetic Scaffolds for Basic and Translational Studies with Mesenchymal Stem Cells
by Cristina Sobacchi, Marco Erreni, Dario Strina, Eleonora Palagano, Anna Villa and Ciro Menale
Int. J. Mol. Sci. 2018, 19(10), 3150; https://doi.org/10.3390/ijms19103150 - 13 Oct 2018
Cited by 27 | Viewed by 4305
Abstract
Mesenchymal stem cells (MSCs) are recognized as an attractive tool owing to their self-renewal and differentiation capacity, and their ability to secrete bioactive molecules and to regulate the behavior of neighboring cells within different tissues. Accumulating evidence demonstrates that cells prefer three-dimensional (3D) [...] Read more.
Mesenchymal stem cells (MSCs) are recognized as an attractive tool owing to their self-renewal and differentiation capacity, and their ability to secrete bioactive molecules and to regulate the behavior of neighboring cells within different tissues. Accumulating evidence demonstrates that cells prefer three-dimensional (3D) to 2D culture conditions, at least because the former are closer to their natural environment. Thus, for in vitro studies and in vivo utilization, great effort is being dedicated to the optimization of MSC 3D culture systems in view of achieving the intended performance. This implies understanding cell–biomaterial interactions and manipulating the physicochemical characteristics of biomimetic scaffolds to elicit a specific cell behavior. In the bone field, biomimetic scaffolds can be used as 3D structures, where MSCs can be seeded, expanded, and then implanted in vivo for bone repair or bioactive molecules release. Actually, the union of MSCs and biomaterial has been greatly improving the field of tissue regeneration. Here, we will provide some examples of recent advances in basic as well as translational research about MSC-seeded scaffold systems. Overall, the proliferation of tools for a range of applications witnesses a fruitful collaboration among different branches of the scientific community. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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