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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 (31 March 2020) | Viewed by 44103

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Prof. Dr. Feng-Huei Lin

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Guest Editor

Institute of Biomedical Engineering and Nano-Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan
Interests: biomaterials; tissue engineering; regenerative medicine
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Feza Korkusuz

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Department of Sports Medicine, Medical Faculty, Hacettepe University, Sihhiye, Ankara 06100, Turkey

Special Issue Information

Dear Colleagues,

The present Special Issue focuses on the ‘’Translation of Cells, Nanomaterials and Signaling Molecules into Regenerative Medicine’’, highlighting the current state and future prospects of the new generation of multifunctional bio-nanomaterials, based on organic and inorganic nanostructures and different natural or synthetic biopolymers/ceramics, for tissue engineering and regeneration applications. The impact of nanotechnology has helped to improve the efficacy of available therapeutics with the possibility to control specific cell functions by modulating material properties. Nanotechnology enables the development of new systems that mimic the complex, hierarchical structure of the native tissue. The confluence of nanotechnology and biology can address several biomedical problems, and can revolutionize the field of health and medicine.

Regenerative medicine requires functional/physical platforms, scaffolds with specific properties concerning the morphology, chemistry of the surface, and interconnectivity to promote cell adhesion and proliferation. This Special Issue is focused on nanomaterial synthesis, development, and characterization, with specific attention paid to the correlation between material properties and stem cell interactions. In particular, contributions focused on polymeric/ceramic nanocomposites, nanotopography, and nanoparticles will be considered, which promise an exciting future at the interface of chemistry, biology, and material science.

Prof. Dr. Feng-Huei Lin
Prof. Dr. Feza Korkusuz
Guest Editors

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Keywords

nanomedicine
nanotechnology
nanomaterial synthesis
microfluidics
tissue engineering
regenerative medicine
stem cell
biomaterial

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Published Papers (10 papers)

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Research

18 pages, 2858 KiB

Open AccessArticle

Evaluating Oxygen Tensions Related to Bone Marrow and Matrix for MSC Differentiation in 2D and 3D Biomimetic Lamellar Scaffolds

by Esen Sayin, Erkan Türker Baran, Ahmed Elsheikh, Vivek Mudera, Umber Cheema and Vasif Hasirci

Int. J. Mol. Sci. 2021, 22(8), 4010; https://doi.org/10.3390/ijms22084010 - 13 Apr 2021

Cited by 10 | Viewed by 3018

Abstract

The physiological O₂ microenvironment of mesenchymal stem cells (MSCs) and osteoblasts and the dimensionality of a substrate are known to be important in regulating cell phenotype and function. By providing the physiologically normoxic environments of bone marrow (5%) and matrix (12%), we assessed their potential to maintain stemness, induce osteogenic differentiation, and enhance the material properties in the micropatterned collagen/silk fibroin scaffolds that were produced in 2D or 3D. Expression of osterix (OSX) and vascular endothelial growth factor A (VEGFA) was significantly enhanced in the 3D scaffold in all oxygen environments. At 21% O₂, OSX and VEGFA expressions in the 3D scaffold were respectively 13,200 and 270 times higher than those of the 2D scaffold. Markers for assessing stemness were significantly more pronounced on tissue culture polystyrene and 2D scaffold incubated at 5% O₂. At 21% O₂, we measured significant increases in ultimate tensile strength (p < 0.0001) and Young’s modulus (p = 0.003) of the 3D scaffold compared to the 2D scaffold, whilst 5% O₂ hindered the positive effect of cell seeding on tensile strength. In conclusion, we demonstrated that the 3D culture of MSCs in collagen/silk fibroin scaffolds provided biomimetic cues for bone progenitor cells toward differentiation and enhanced the tensile mechanical properties. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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22 pages, 4117 KiB

Open AccessArticle

A Dynamic Hanging-Drop System for Mesenchymal Stem Cell Culture

by Shu-Wei Huang, Shian-Chiuan Tzeng, Jem-Kun Chen, Jui-Sheng Sun and Feng-Huei Lin

Int. J. Mol. Sci. 2020, 21(12), 4298; https://doi.org/10.3390/ijms21124298 - 16 Jun 2020

Cited by 35 | Viewed by 6447

Abstract

There have been many microfluid technologies combined with hanging-drop for cell culture gotten developed in the past decade. A common problem within these devices is that the cell suspension introduced at the central inlet could cause a number of cells in each microwell to not regularize. Also, the instability of droplets during the spheroid formation remains an unsolved ordeal. In this study, we designed a microfluidic-based hanging-drop culture system with the design of taper-tube that can increase the stability of droplets while enhancing the rate of liquid exchange. A ring is surrounding the taper-tube. The ring can hold the cells to enable us to seed an adequate amount of cells before perfusion. Moreover, during the period of cell culture, the mechanical force around the cell is relatively low to prevent stem cells from differentiate and maintain the phenotype. As a result of our hanging system design, cells are designed to accumulate at the bottom of the droplet. This method enhances convenience for observation activities and analysis of experiments. Thus, this microfluid chip can be used as an in vitro platform representing in vivo physiological conditions, and can be useful in regenerative therapy. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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14 pages, 9637 KiB

Open AccessArticle

Three-Dimensional Printed Porous Titanium Screw with Bioactive Surface Modification for Bone–Tendon Healing: A Rabbit Animal Model

by Yu-Min Huang, Chih-Chieh Huang, Pei-I Tsai, Kuo-Yi Yang, Shin-I Huang, Hsin-Hsin Shen, Hong-Jen Lai, Shu-Wei Huang, San-Yuan Chen, Feng-Huei Lin and Chih-Yu Chen

Int. J. Mol. Sci. 2020, 21(10), 3628; https://doi.org/10.3390/ijms21103628 - 21 May 2020

Cited by 23 | Viewed by 4976

Abstract

The interference screw fixation method is used to secure a graft in the tibial tunnel during anterior cruciate ligament reconstruction surgery. However, several complications have been reported, such as biodegradable screw breakage, inflammatory or foreign body reaction, tunnel enlargement, and delayed graft healing. Using additive manufacturing (AM) technology, we developed a titanium alloy (Ti₆Al₄V) interference screw with chemically calcium phosphate surface modification technology to improve bone integration in the tibial tunnel. After chemical and heat treatment, the titanium screw formed a dense apatite layer on the metal surface in simulated body fluid. Twenty-seven New Zealand white rabbits were randomly divided into control and additive manufactured (AMD) screw groups. The long digital extensor tendon was detached and translated into a tibial plateau tunnel (diameter: 2.0 mm) and transfixed with an interference screw while the paw was in dorsiflexion. Biomechanical analyses, histological analyses, and an imaging study were performed at 1, 3, and 6 months. The biomechanical test showed that the ultimate pull-out load failure was significantly higher in the AMD screw group in all tested periods. Micro-computed tomography analyses revealed early woven bone formation in the AMD screw group at 1 and 3 months. In conclusion, AMD screws with bioactive surface modification improved bone ingrowth and enhanced biomechanical performance in a rabbit model. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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11 pages, 4382 KiB

Open AccessArticle

Enhancement of Neurite Outgrowth by Warming Biomaterial Ultrasound Treatment

by Jung-Chih Chen, Chao-Ming Su, Gin-Shin Chen, Chin-Chun Lai, Ching-Yun Chen, Kurt Ming-Chao Lin, Feng-Huei Lin and Guo-Chung Dong

Int. J. Mol. Sci. 2020, 21(6), 2236; https://doi.org/10.3390/ijms21062236 - 23 Mar 2020

Cited by 2 | Viewed by 3780

Abstract

Ultrasound is a method for enhancing neurite outgrowth because of its thermal effect. In order to reach the working temperature to enhance neurite outgrowth, long-time treatment by ultrasound is necessary, while acknowledging that the treatment poses a high risk of damaging nerve cells. To overcome this problem, we developed a method that shortens the ultrasonic treatment time with a warming biomaterial. In this study, we used Fe₃O₄ nanoparticle-embedded polycaprolactone (PCL) as a sonosensitized biomaterial, which has an excellent heating rate due to its high acoustic attenuation. With this material, the ultrasonic treatment time for enhancing neurite outgrowth could be effectively shortened. Ultrasonic treatment could also increase neuronal function combined with the warming biomaterial, with more promoter neuronal function than only ultrasound. Moreover, the risk of overexposure can be avoided by the use of the warming biomaterial by reducing the ultrasonic treatment time, providing better effectiveness. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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17 pages, 5027 KiB

Open AccessArticle

The Bioactive Core and Corona Synergism of Quantized Gold Enables Slowed Inflammation and Increased Tissue Regeneration in Wound Hypoxia

by Lu-Chen Yeh, Shu-Ping Chen, Fang-Hsuean Liao, Te-Haw Wu, Yu-Ting Huang and Shu-Yi Lin

Int. J. Mol. Sci. 2020, 21(5), 1699; https://doi.org/10.3390/ijms21051699 - 2 Mar 2020

Cited by 8 | Viewed by 3117

Abstract

The progress of wound regeneration relies on inflammation management, while neovascular angiogenesis is a critical aspect of wound healing. In this study, the bioactive core and corona synergism of quantized gold (QG) were developed to simultaneously address these complicated issues, combining the abilities to eliminate endotoxins and provide oxygen. The QG was constructed from ultrasmall nanogold and a loosely packed amine-based corona via a simple process, but it could nonetheless eliminate endotoxins (a vital factor in inflammation also called lipopolysaccharides) and provide oxygen in situ for the remodeling of wound sites. Even while capturing endotoxins through electrostatic interactions, the catalytic active sites inside the nanogold could maintain its surface accessibility to automatically transform the overexpressed hydrogen peroxide in hypoxic wound regions into oxygen. Since the inflammatory stage is an essential stage of wound healing, the provision of endotoxin clearance by the outer organic corona of the QG could slow inflammation in a way that subsequently promoted two other important stages of wound bed healing, namely proliferation and remodeling. Relatedly, the efficacy of two forms of the QG, a liquid form and a dressing form, was demonstrated at wound sites in this study, with both forms promoting the development of granulation, including angiogenesis and collagen deposition. Thus, the simply fabricated dual function nanocomposite presented herein not only offers reduced batch-to-batch variation but also increased options for homecare treatments. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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16 pages, 3437 KiB

Open AccessArticle

ZnO Nanoparticles Induced Caspase-Dependent Apoptosis in Gingival Squamous Cell Carcinoma through Mitochondrial Dysfunction and p70S6K Signaling Pathway

by Shih-Wei Wang, Chien-Hsing Lee, Ming-Shen Lin, Chih-Wen Chi, Yu-Jen Chen, Guo-Shou Wang, Kuang-Wen Liao, Li-Pin Chiu, Shu-Hui Wu, Dong-Ming Huang, Luke Chen and Yung-Shuen Shen

Int. J. Mol. Sci. 2020, 21(5), 1612; https://doi.org/10.3390/ijms21051612 - 26 Feb 2020

Cited by 65 | Viewed by 5560

Abstract

Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, food additives, pigments, rubber manufacture, and electronic materials. Several studies have shown that ZnO-NPs inhibit cell growth and induce apoptosis by the production of oxidative stress in a variety of human cancer cells. However, the anti-cancer property and molecular mechanism of ZnO-NPs in human gingival squamous cell carcinoma (GSCC) are not fully understood. In this study, we found that ZnO-NPs induced growth inhibition of GSCC (Ca9-22 and OECM-1 cells), but no damage in human normal keratinocytes (HaCaT cells) and gingival fibroblasts (HGF-1 cells). ZnO-NPs caused apoptotic cell death of GSCC in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation. Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs. In addition, ZnO-NPs increased the intracellular reactive oxygen species and specifically superoxide levels, and also decreased the mitochondrial membrane potential. ZnO-NPs further activated apoptotic cell death via the caspase cascades. Importantly, anti-oxidant and caspase inhibitor clearly prevented ZnO-NP-induced cell death, indicating the fact that superoxide-induced mitochondrial dysfunction is associated with the ZnO-NP-mediated caspase-dependent apoptosis in human GSCC. Moreover, ZnO-NPs significantly inhibited the phosphorylation of ribosomal protein S6 kinase (p70S6K kinase). In a corollary in vivo study, our results demonstrated that ZnO-NPs possessed an anti-cancer effect in a zebrafish xenograft model. Collectively, these results suggest that ZnO-NPs induce apoptosis through the mitochondrial oxidative damage and p70S6K signaling pathway in human GSCC. The present study may provide an experimental basis for ZnO-NPs to be considered as a promising novel anti-tumor agent for the treatment of gingival cancer. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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19 pages, 7777 KiB

Open AccessArticle

An Engineered Gene Nanovehicle Developed for Smart Gene Therapy to Selectively Inhibit Smooth Muscle Cells: An In Vitro Study

by Ling-Yi Cheng, Yu-Chi Wang, Ming-Hong Chen, Fu-I Tung, Kuan-Ming Chiu and Tse-Ying Liu

Int. J. Mol. Sci. 2020, 21(4), 1530; https://doi.org/10.3390/ijms21041530 - 24 Feb 2020

Cited by 2 | Viewed by 3375

Abstract

In-stent restenosis is a serious concern for patients treated through the stenting procedure, although this can be solved using drug-eluting stents and/or drug-eluting balloon catheters. However, the chemical agents released from the drug-eluting layer for inhibiting smooth muscle cell (SMC) migration are inevitably associated with damage to vascular endothelial cell (ECs). The present in vitro study used a distinct strategy, in which a smart gene (phEGR1-PKCδ, an engineered plasmid consists of an SMC-specific promoter (human early growth response 1, hEGR1 promoter) ligated with a gene encoding apoptosis-inducing protein (protein kinase C-delta, PKCδ) was incorporated into a novel gene vehicle (Au cluster-incorporated polyethylenimine/carboxymethyl hexanoyl chitosan, PEI-Au/CHC) to form the PEI-Au/CHC/phEGR1-PKCδ complex, which was proposed for the selective inhibition of SMC proliferation. It was found that the cell viability of SMCs receiving the PEI-Au/CHC/phEGR1-PKCδ complex under simulated inflammation conditions was significantly lower than that of the ECs receiving the same treatment. In addition, the PEI-Au/CHC/phEGR1-PKCδ complex did not demonstrate an inhibitory effect on EC proliferation and migration under simulated inflammation conditions. Finally, the PEI-Au/CHC/phEGR1-PKCδ complexes coated onto a balloon catheter used in percutaneous transluminal coronary angioplasty (PTCA) could be transferred to both the ECs and the SMC layer of Sprague Dawley (SD) rat aortas ex vivo. These preliminary in vitro results suggest that the newly developed approach proposed in the present study might be a potential treatment for reducing the incidence rate of in-stent restenosis and late thrombosis in the future. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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14 pages, 3296 KiB

Open AccessArticle

CharXgen-Activated Bamboo Charcoal Encapsulated in Sodium Alginate Microsphere as the Absorbent of Uremic Toxins to Retard Kidney Function Deterioration

by Cheng-Jui Lin, Chiao-Yin Sun, Chih-Jen Wu, Chau-Chung Wu, Vincent Wu and Feng-Huei Lin

Int. J. Mol. Sci. 2020, 21(4), 1257; https://doi.org/10.3390/ijms21041257 - 13 Feb 2020

Cited by 6 | Viewed by 5103

Abstract

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are two protein bound uraemic toxins accumulated in chronic kidney disease (CKD) and associated with adverse outcomes. The purpose of this study isto evaluate the effect of the new activated charcoal, CharXgen, on renal function protection and lowering serum uraemic toxins in CKD animal model. The physical character of CharXgen was analyzed before and after activation procedure by Scanning Electron Microscope (SEM) and X-ray diffractometer (XRD). The effect of CharXgen on biochemistry and lowering uremic toxins was evaluated by in vitro binding assay and CKD animal model. CharXgen have high interior surface area analyzed by SEM and XRD and have been produced from local bamboo after an activation process. CharXgen was able to effectively absorb IS, p-cresol and phosphate in an in vitro gastrointestinal tract simulation study. The animal study showed that CharXgen did not cause intestine blackening. Serum albuminand liver function did not change after feeding with CharXgen. Moreover, renal function was improved in CKD rats fed with CharXgen as compared to the CKD group, and there were no significant differences in the CKD and the CKD + AST-120 groups. Serum IS and PCS were higher in the CKD group and lower in rats treated with CharXgen and AST-120. In rats treated with CharXgen, Fibroblast growth factor 23 was significantly decreased as compared to the CKD group. This change cannot be found in rats fed with AST-120.It indicates that CharXgen is a new safe and non-toxic activated charcoal having potential in attenuating renal function deterioration and lowering protein-bound uraemic toxins. Whether the introduction of this new charcoal could further have renal protection in CKD patients will need to be investigated further. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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16 pages, 2775 KiB

Open AccessArticle

Biomimetic Synthesis of Nanocrystalline Hydroxyapatite Composites: Therapeutic Potential and Effects on Bone Regeneration

by Chih-Hsiang Fang, Yi-Wen Lin, Feng-Huei Lin, Jui-Sheng Sun, Yuan-Hung Chao, Hung-Ying Lin and Zwei-Chieng Chang

Int. J. Mol. Sci. 2019, 20(23), 6002; https://doi.org/10.3390/ijms20236002 - 28 Nov 2019

Cited by 47 | Viewed by 4760

Abstract

The development of a novel alloplastic graft with both osteoinductive and osteoconductive properties is still necessary. In this study, we tried to synthesize a biomimetic hydroxyapatite microspheres (gelatin/nano-hydroxyapatite microsphere embedded with stromal cell-derived factor-1: GHM-S) from nanocrystalline hydroxyapatites and to investigate their therapeutic potential and effects on bone regeneration. In this study, hydroxyapatite was synthesized by co-precipitation of calcium hydroxide and orthophosphoric acid to gelatin solution. The microbial transglutaminase was used as the agent to crosslink the microspheres. The morphology, characterization, and thermal gravimetric analysis of microspheres were performed. SDF-1 release profile and in vitro biocompatibility and relative osteogenic gene expression were analyzed, followed by in vivo micro-computed tomography study and histological analysis. The synthesized hydroxyapatite was found to be similar to hydroxyapatite of natural bone tissue. The stromal cell-derived factor-1 was embedded into gelatin/hydroxyapatite microsphere to form the biomimetic hydroxyapatite microsphere. The stromal cell-derived factor-1 protein could be released in a controlled manner from the biomimetic hydroxyapatite microsphere and form a concentration gradient in the culture environment to attract the migration of stem cells. Gene expression and protein expression indicated that stem cells could differentiate or develop into pre-osteoblasts. The effect of bone formation by the biomimetic hydroxyapatite microsphere was assessed by an in vivo rats’ alveolar bone defects model and confirmed by micro-CT imaging and histological examination. Our findings demonstrated that the biomimetic hydroxyapatite microsphere can enhance the alveolar bone regeneration. This design has potential be applied to other bone defects. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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16 pages, 8196 KiB

Open AccessArticle

In Vitro and In Vivo Evaluations of Mesoporous Iron Particles for Iron Bioavailability

by Jung-Feng Lin, Chau-Chung Wu, Yu-Jiun Liao, Subhaini Jakfar, Zi-Biao Tang, Jhewn-Kuang Chen and Feng-Huei Lin

Int. J. Mol. Sci. 2019, 20(21), 5291; https://doi.org/10.3390/ijms20215291 - 24 Oct 2019

Cited by 10 | Viewed by 3350

Abstract

Chronic renal failure involving hemodialysis results in blood loss during filtration. Iron deficiency and iron deficiency anemia can result. A compensatory increase in iron dosage has many side effects including discomfort. Elemental iron is a highly-pure iron source, which reduces the frequency of dosages; the solubility decreases with increased particle size or pore size. In this study, synthesized mesoporous iron particles (MIPs) were used to relieve iron deficiency anemia. Their bioavailability was measured in vitro by a Caco-2 cell model and in vivo in iron-deficient rats. In vitro bioavailability of MIPs was examined by measuring ferritin content in the Caco-2 cell model. Iron uptake of MIPs was significantly higher than commercial iron particles, which were less porous. In vivo bioavailability of MIPs was examined by measuring body weight gain and red blood cell-related parameters, compared with the bioavailability of standard drug ferrous sulfate in iron-deficient anemic rats. Finally, average hemoglobin content and hemoglobin regeneration efficiency were significantly higher in anemic rats supplemented with commercial iron particles, compared to anemic controls. In the 28-day oral toxicity test, MIPs were not significantly toxic to rat physiology or tissue histopathology. Thus, MIPs may allow effective recovery of hemoglobin in iron deficiency anemia. Full article

(This article belongs to the Special Issue Bio-Engineering and Nano-Medicine)

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