Publications by authors named "Suk Ho Bhang"

92 Publications

Delivery of a spheroids-incorporated human dermal fibroblast sheet increases angiogenesis and M2 polarization for wound healing.

Biomaterials 2021 Jun 7;275:120954. Epub 2021 Jun 7.

School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea. Electronic address:

Low cell engraftment is a major problem in tissue engineering. Although various methods related with cell sheets have been attempted to resolve the issue, low cell viability due to oxygen and nutrient depletion remains an obstacle toward advanced therapeutic applications. Cell therapy using fibroblasts is thought of as a good alternative due to the short doubling times of fibroblasts together with their immunomodulatory properties. Furthermore, three-dimensional (3D) fibroblasts exhibit unique angiogenic and inflammation-manipulating properties that are not present in two-dimensional (2D) forms. However, the therapeutic effect of 3D fibroblasts in tissue regeneration has not been fully elucidated. Macrophage polarization has been widely studied, as it stimulates the transition from the inflammation to the proliferation phase of wound healing. Although numerous strategies have been developed to achieve better polarization of macrophages, the low efficacy of these strategies and safety issues remain problematic. To this end, we introduced a biocompatible flat patch with specifically designed holes that form a spheroids-incorporated human dermal fibroblast sheet (SIS) to mediate the activity of inflammatory cytokines for M2 polarization and increase angiogenic efficacy. We further confirmed in vivo enhancement of wound healing with an SIS-laden skin patch (SISS) compared to conventional cell therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120954DOI Listing
June 2021

Poly(amino ester)-Based Polymers for Gene and Drug Delivery Systems and Further Application toward Cell Culture System.

Macromol Biosci 2021 Jun 12:e2100106. Epub 2021 Jun 12.

School of Chemical Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Various synthetic polymers based on poly(amino ester) (PAE) are suggested as candidates for gene and drug delivery owing to their pH-responsiveness, which contributes to efficient delivery performance. PAE-based pH-responsive polymers are more biodegradable and hydrophilic than other types of pH-responsive polymers. The functionality of PAE-based polymers can be reinforced by using different chemical modifications to improve the efficiency of gene and drug delivery. Additionally, PAE-based polymers are used in many ways in the biomedical field, such as in transdermal delivery and stem cell culture systems. Here, the recent novel PAE-based polymers designed for gene and drug delivery systems along with their further applications toward adult stem cell culture systems are reviewed. The synthetic tactics are contemplated and pros and cons of each type of polymer are analyzed, and detailed examples of the different types are analyzed.
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http://dx.doi.org/10.1002/mabi.202100106DOI Listing
June 2021

Stem Cell-Engineered Nanovesicles Exert Proangiogenic and Neuroprotective Effects.

Materials (Basel) 2021 Feb 25;14(5). Epub 2021 Feb 25.

School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Korea.

As a tissue regeneration strategy, the utilization of mesenchymal stem cells (MSCs) has drawn considerable attention. Comprehensive research using MSCs has led to significant preclinical or clinical outcomes; however, improving the survival rate, engraftment efficacy, and immunogenicity of implanted MSCs remains challenging. Although MSC-derived exosomes were recently introduced and reported to have great potential to replace conventional MSC-based therapeutics, the poor production yield and heterogeneity of exosomes are critical hurdles for their further applications. Herein, we report the fabrication of exosome-mimetic MSC-engineered nanovesicles (MSC-NVs) by subjecting cells to serial extrusion through filters. The fabricated MSC-NVs exhibit a hydrodynamic size of ~120 nm, which is considerably smaller than the size of MSCs (~30 μm). MSC-NVs contain both MSC markers and exosome markers. Importantly, various therapeutic growth factors originating from parent MSCs are encapsulated in the MSC-NVs. The MSC-NVs exerted various therapeutic effects comparable to those of MSCs. They also significantly induced the angiogenesis of endothelial cells and showed neuroprotective effects in damaged neuronal cells. The results collectively demonstrate that the fabricated MSC-NVs can serve as a nanosized therapeutic agent for tissue regeneration.
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http://dx.doi.org/10.3390/ma14051078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956182PMC
February 2021

Development of pH-Responsive Polymer Coating as an Alternative to Enzyme-Based Stem Cell Dissociation for Cell Therapy.

Materials (Basel) 2021 Jan 20;14(3). Epub 2021 Jan 20.

School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Korea.

Cell therapy usually accompanies cell detachment as an essential process in cell culture and cell collection for transplantation. However, conventional methods based on enzymatic cell detachment can cause cellular damage including cell death and senescence during the routine cell detaching step due to an inappropriate handing. The aim of the current study is to apply the pH-responsive degradation property of poly (amino ester) to the surface of a cell culture dish to provide a simple and easy alternative method for cell detachment that can substitute the conventional enzyme treatment. In this study, poly (amino ester) was modified (cell detachable polymer, CDP) to show appropriate pH-responsive degradation under mild acidic conditions (0.05% (w/v) CDP, pH 6.0) to detach stem cells (human adipose tissue-derived stem cells (hADSCs)) perfectly within a short period (less than 10 min). Compared to conventional enzymatic cell detachment, hADSCs cultured on and detached from a CDP-coated cell culture dish showed similar cellular properties. We further performed in vivo experiments on a mouse hindlimb ischemia model (1.0 × 10 cells per limb). The in vivo results indicated that hADSCs retrieved from normal cell culture dishes and CDP-coated cell culture dishes showed analogous therapeutic angiogenesis. In conclusion, CDP could be applied to a pH-responsive cell detachment system as a simple and easy nonenzymatic method for stem cell culture and various cell therapies.
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http://dx.doi.org/10.3390/ma14030491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864336PMC
January 2021

Dual Ion Releasing Nanoparticles for Modulating Osteogenic Cellular Microenvironment of Human Mesenchymal Stem Cells.

Materials (Basel) 2021 Jan 15;14(2). Epub 2021 Jan 15.

School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Korea.

In this study we developed a dual therapeutic metal ion-releasing nanoparticle for advanced osteogenic differentiation of stem cells. In order to enhance the osteogenic differentiation of human mesenchymal stem cells (hMSCs) and induce angiogenesis, zinc (Zn) and iron (Fe) were synthesized together into a nanoparticle with a pH-sensitive degradation property. Zn and Fe were loaded within the nanoparticles to promote early osteogenic gene expression and to induce angiogenic paracrine factor secretion for hMSCs. In vitro studies revealed that treating an optimized concentration of our zinc-based iron oxide nanoparticles to hMSCs delivered Zn and Fe ion in a controlled release manner and supported osteogenic gene expression (RUNX2 and alkaline phosphatase) with improved vascular endothelial growth factor secretion. Simultaneous intracellular release of Zn and Fe ions through the endocytosis of the nanoparticles further modulated the mild reactive oxygen species generation level in hMSCs without cytotoxicity and thus improved the osteogenic capacity of the stem cells. Current results suggest that our dual ion releasing nanoparticles might provide a promising platform for future biomedical applications.
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http://dx.doi.org/10.3390/ma14020412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830414PMC
January 2021

Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells.

Nano Converg 2020 Oct 16;7(1):34. Epub 2020 Oct 16.

School of Chemical Engineering, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.

Cell therapy based on human adipose derived stem cells (hADSCs) is a known potential therapeutic approach to induce angiogenesis in ischemic diseases. However, the therapeutic efficacy of direct hADSC injection is limited by a low cell viability and poor cell engraftment after administration. To improve the outcomes of this kind of approach, various types of nanoparticles have been utilized to improve the therapeutic efficacy of hADSC transplantation. Despite their advantages, the adverse effects of nanoparticles, such as genetic damage and potential oncogenesis based on non-degradable property of nanoparticles prohibit the application of nanoparticles toward the clinical applications. Herein, we designed a transition metal based inorganic nanocluster able of pH-selective degradation (ps-TNC), with the aim of enhancing an hADSC based treatment of mouse hindlimb ischemia. Our ps-TNC was designed to undergo degradation at low pH conditions, thus releasing metal ions only after endocytosis, in the endosome. To eliminate the limitations of both conventional hADSC injection and non-degradable property of nanoparticles, we have collected conditioned medium (CM) from the ps-TNC treated hADSCs and administrated it to the ischemic lesions. We found that intracellular increment of transition metal ion upregulated the hypoxia-inducible factor 1α, which can induce vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expressions. Based on the molecular mechanism, the secretion of VEGF and bFGF by ps-TNC treated hADSCs showed a significant improvement compared to that of untreated cells. Injecting the CM collected from ps-TNC treated hADSCs into the mouse hindlimb ischemia model (ps-TNC-CM group) showed significantly improved angiogenesis in the lesions, with improved limb salvage and decreased muscle degeneration compared to the group injected with CM collected from normal hADSCs (CM group). This study suggests a novel strategy, combining a known angiogenesis molecular mechanism with both an improvement on conventional stem cell therapy and the circumvention of some limitations still present in modern approaches based on nanoparticles.
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http://dx.doi.org/10.1186/s40580-020-00244-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567771PMC
October 2020

NIR-vis-Induced pH-Sensitive TiO Immobilized Carbon Dot for Controllable Membrane-Nuclei Targeting and Photothermal Therapy of Cancer Cells.

ACS Appl Mater Interfaces 2020 Aug 12;12(34):37929-37942. Epub 2020 Aug 12.

Department of Green Bio Engineering, Korea National University of Transportation, Chungju 380-702, Republic of Korea.

This study investigated a selective and sensitive theragnosis system for the specific targeting of the membrane and nuclei based on visible-light and pH-responsive TiO-integrated cross-linked carbon dot (C-CD/TiO) for tumor detection and controllable photothermal therapy. The cross-linking system was formed by boronate ester linkages between the TiO-immobilized Dopa-decyl (D-CD) and zwitterionic-formed CD (Z-CD) for nuclear targeting, which showed fluorescence "off" at physiological pH. The fluorescence recovered to the "on" state in acidic cancer cells owing to cleavages of the boronate ester bonds, resulting in the disruption of the Förster resonance energy transfer that generated different CDs useful for tumor-selective biosensors and therapy. D-CD, which is hydrophobic, can penetrate the hydrophobic sites of the cell membrane; it caused a loss in the hydrophobicity of these sites after visible-light irradiation. This was achieved by the photocatalytic activity of the TiO modulating energy bandgap, whereas the Z-CD targeted the nucleus, as confirmed by merged confocal microscopy images. D-CD augmented by photothermal heat also exhibited selective anticancer activity in the acidic tumor condition but showed only minimal effects at a normal site at pH 7.4. After C-CD/TiO injection to an tumor model, C-CD/TiO efficiently ablated tumors under NIR light irradiation. The C-CD/TiO group showed up-regulation of the pro-apoptotic markers such as and in tumor. This material exhibited its potential as a theragnostic sensor with excellent biocompatibility, high sensitivity, selective imaging, and direct anticancer activity via photothermal therapy.
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http://dx.doi.org/10.1021/acsami.0c11979DOI Listing
August 2020

Bio-application of Inorganic Nanomaterials in Tissue Engineering.

Adv Exp Med Biol 2020 ;1249:115-130

School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi, Republic of Korea.

Inorganic nanomaterials or nanoparticles (INPs) have drawn high attention for their usage in the biomedical field. In addition to the facile synthetic and modifiable property of INPs, INPs have various unique properties that originate from the components of the INPs, such as metal ions that are essential for the human body. Apart from their roles as components of the human body, inorganic materials have unique properties, such as magnetic, antibacterial, and piezoelectric, so that INPs have been widely used as either carriers or inducers. However, most of the bio-applicable INPs, especially those consisting of metal, can cause cytotoxicity. Therefore, INPs require modification to alleviate the harmful effect toward the cells by controlling the release of metal ions from INPs. Even though many attempts have been made to modify INPs, many things, including the side effects of INPs, still remain as obstacles in the bio-application, which need to be elucidated. In this chapter, we introduce novel INPs in terms of their synthetic method and bio-application in tissue engineering.
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http://dx.doi.org/10.1007/978-981-15-3258-0_8DOI Listing
December 2020

Endosome-triggered ion-releasing nanoparticles as therapeutics to enhance the angiogenic efficacy of human mesenchymal stem cells.

J Control Release 2020 08 23;324:586-597. Epub 2020 May 23.

School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address:

Here, we report that Fe ions delivered into human mesenchymal stem cells (hMSCs) by bioreducible metal nanoparticles (NPs) enhance their angiogenic and cell-homing efficacy by controlling ion-triggered intracellular reactive oxygen species (ROS) and improve cell migration, while reducing cytotoxicity. Endosome-triggered iron-ion-releasing nanoparticles (ETIN) were designed to be low-pH responsive to take advantage of the low-pH conditions (4-5) of endosomes for in situ iron-ion release. Due to the different redox potentials of Fe and Au, only Fe could be ionized and released from our novel ETIN, while Au remained intact after ETIN endocytosis. Treatment with an optimal amount of ETIN led to a mild increase in intracellular ROS levels in hMSCs, which enhanced the expression of HIF-1α, a key trigger for angiogenic growth factor secretion from hMSCs. Treatmetn of hMSCs with ETIN significantly enhanced the expression of angiogenesis- and lesion-targeting-related genes and proteins. Transplantation of ETIN-treated hMSCs significantly enhanced angiogenesis and tissue regeneration in a wound-closing mouse model compared with those in untreated mice and mice that underwent conventional hMSC transplantation.
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http://dx.doi.org/10.1016/j.jconrel.2020.05.038DOI Listing
August 2020

Facile Aqueous-Phase Synthesis of Bimetallic (AgPt, AgPd, and CuPt) and Trimetallic (AgCuPt) Nanoparticles.

Materials (Basel) 2020 Jan 7;13(2). Epub 2020 Jan 7.

Department of Chemical Engineering, College of Engineering, Kyung Hee University, Yongin 17104, Korea.

Multi-metallic nanoparticles continue to attract attention, due to their great potential in various applications. In this paper, we report a facile aqueous-phase synthesis for multi-metallic nanoparticles, including AgPt, AgPd, CuPt, and AgCuPt, by a co-reduction method within a short reaction time of 10 min. The atomic ratio of bimetallic nanoparticles was easily controlled by varying the ratio of each precursor. In addition, we found that AgCuPt trimetallic nanoparticles had a core-shell structure with an Ag core and CuPt shell.
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http://dx.doi.org/10.3390/ma13020254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013979PMC
January 2020

A fibronectin-coated gold nanostructure composite for electrochemical detection of effects of curcumin-carrying nanoliposomes on human stomach cancer cells.

Analyst 2020 Jan 5;145(2):675-684. Epub 2019 Dec 5.

School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea. and Integrative Research Center for Two-Dimensional Functional Materials, Institute of Interdisciplinary Convergence Research, Chung-Ang University, Seoul 06974, Republic of Korea.

Curcumin, which is produced by the medicinal herbaceous plant Curcuma longa, has been widely investigated for use as a potential anticancer drug. In this study, the potential toxicity of curcumin-carrying nanoliposomes (curcumin-NLC) toward human stomach cancer cells (MKN-28) was investigated using a new cell-based electrochemical sensing platform. To satisfy both biocompatibility and electroconductivity of the electrodes, the density of the gold nanostructure and the coating conditions of extracellular matrix proteins (fibronectin and collagen) were optimized. The developed platform enabled the successful adhesion and long-term growth of stomach cancer cells on the chip surface, allowing label-free and real-time monitoring of cell viability in a quantitative manner. According to the electrochemical results, both bare curcumin and curcumin-NLC showed toxicity toward MKN-28 cells in the concentration range of 10-100 μM, which was consistent with the results obtained from a conventional colorimetric method (CCK-8). Remarkably, at a low concentration range (<50 μM), this electrochemical platform determined the decrease in cell viability to be approximately 22.8%, 33.9% and 53.1% in the presence of 10, 30, and 50 μM of curcumin-NLC, respectively, compared with the 1.3%, 18.5%, and 28.1% determined by CCK-8, making it 1.7-2 times more sensitive than the conventional colorimetric assay. Hence, it can be concluded that the newly developed fibronectin-coated electroconductive platform is highly promising as an electrochemical detection tool for the sensitive and precise assessment of the anticancer effects of various food-derived compounds with low toxicity.
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http://dx.doi.org/10.1039/c9an01553aDOI Listing
January 2020

Facile aqueous-phase synthesis of Ag-Cu-Pt-Pd quadrometallic nanoparticles.

Nano Converg 2019 Dec 2;6(1):38. Epub 2019 Dec 2.

Department of Chemical Engineering, College of Engineering, Kyung Hee University, Yongin, 17104, Republic of Korea.

Ag-Cu-Pt-Pd quadrometallic nanoparticles which small Pt and Pd nanoparticles were attached on the surface of AgCu Janus nanoparticles were firstly synthesized by sequential reduction of Pt and Pd precursor in the presence of Janus AgCu bimetallic nanoparticles as seeds in an aqueous solution. Even though there was a small amount of CuO on the surface, the synthesized nanoparticles were mainly composed of four independent metallic part, not alloy parts. By theoretical calculation and growth mechanism study, we found that different reducing rate between Ag and Cu and sequential reduction of Pt and Pd precursors would be key roles for the formation of the quadrometallic nanoparticles.
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http://dx.doi.org/10.1186/s40580-019-0208-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885459PMC
December 2019

Synthesis of Sub 3 nm-Sized Uniform Magnetite Nanoparticles Using Reverse Micelle Method for Biomedical Application.

Materials (Basel) 2019 Nov 22;12(23). Epub 2019 Nov 22.

Department of Chemical Engineering, Kyung Hee University, Yongin 17104, Korea.

We report a synthetic method for small and uniform FeO (magnetite) nanoparticles under mild conditions. Spherical sub-3 nm-sized magnetite nanoparticles were prepared via reverse micelles composed of oleylamine, F127, xylene, and water for the reaction of iron(III) stearate with hydrazine at a reaction temperature of 90 °C in air atmosphere. These synthesized magnetite nanoparticles exhibited good size uniformity. By controlling experimental conditions, we could easily control both size and size uniformity of these magnetite nanoparticles. We further investigated whether FeO could be used in biomedical applications. Cytotoxicity of FeO was evaluated with human adipose-derived stem cells (hADSCs). Our results showed that the number of hADSCs did not significantly decrease when these cells were treated with FeO nanoparticles at a concentration of up to 9 μg/mL. Apoptotic activity and cell proliferation of hADSCs treated with FeO nanoparticles were similar to those of hADSCs without any treatment. This novel method could be used for synthesizing uniform and biocompatible FeO nanoparticles with further biomedical applications.
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http://dx.doi.org/10.3390/ma12233850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926741PMC
November 2019

Reduction-Triggered Paclitaxel Release Nano-Hybrid System Based on Core-Crosslinked Polymer Dots with a pH-Responsive Shell-Cleavable Colorimetric Biosensor.

Int J Mol Sci 2019 Oct 28;20(21). Epub 2019 Oct 28.

Department of Chemical and Biological Engineering, Korea National University of Transportation, Chungju 380-702, Korea.

Herein, we describe the fabrication and characterization of carbonized disulfide core-crosslinked polymer dots with pH-cleavable colorimetric nanosensors, based on diol dye-conjugated fluorescent polymer dots (L-PD), for reduction-triggered paclitaxel (PTX) release during fluorescence imaging-guided chemotherapy of tumors. L-PD were loaded with PTX (PTX loaded L-PD), via π-π stackings or hydrophobic interactions, for selective theragnosis by enhanced release of PTX after the cleavage of disulfide bonds by high concentration of glutathione (GSH) in a tumor. The nano-hybrid system showed fluorescence quenching behavior with less than 2% of PTX released under physiological conditions. However, in a tumor microenvironment, the fluorescence recovered at an acidic-pH, and PTX (approximately 100% of the drug release) was released efficiently out of the matrix by reduction caused by the GSH level in the tumor cells, which improved the effectiveness of the cancer treatment. Therefore, the colorimetric nanosensor showed promising potential in distinguishing between normal and cancerous tissues depending on the surrounding pH and GSH concentrations so that PTX can be selectively delivered into cancer cells for improved cancer diagnosis and chemotherapy.
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http://dx.doi.org/10.3390/ijms20215368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862247PMC
October 2019

Enhancing the Wound Healing Effect of Conditioned Medium Collected from Mesenchymal Stem Cells with High Passage Number Using Bioreducible Nanoparticles.

Int J Mol Sci 2019 Sep 28;20(19). Epub 2019 Sep 28.

School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Korea.

Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect; however, hMSCs have several limitations, such as low viability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternative method for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associated with hMSCs, a CM can be easily mass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number; whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) expression. Through this mechanism, AuFe NPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.
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http://dx.doi.org/10.3390/ijms20194835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801963PMC
September 2019

Upconverting Oil-Laden Hollow Mesoporous Silica Microcapsules for Anti-Stokes-Based Biophotonic Applications.

ACS Appl Mater Interfaces 2019 Jul 17;11(30):26571-26580. Epub 2019 Jul 17.

Department of Chemical and Environmental Engineering , Pusan National University , Busan 46241 , Korea.

A recyclable, aqueous phase functioning and biocompatible photon upconverting system is developed. Hollow mesoporous silica microcapsules (HMSMs) with ordered radial mesochannels were employed, for the first time, as vehicles for the post-encapsulation of oil phase triplet-triplet annihilation upconversion (TTA-UC), with the capability of homogeneous suspension in water. In-depth characterization of such upconverting oil-laden HMSMs (UC-HMSMs) showed that the mesoporous silica shells reversibly stabilized the encapsulated UC oil in water to allow efficient upconverted emission, even under aerated conditions. In addition, the UC-HMSMs were found to actively bind to the surface of human mesenchymal stem cells without significant cytotoxicity and displayed upconverted bright blue emission under 640 nm excitation, indicating a potential of our new TTA-UC system in biophotonic applications. These findings reveal the great promise of UC-HMSMs to serve as ideal vehicles not only for ultralow-power in vivo imaging but also for stem cell labeling, to facilitate the tracking of tumor cells in animal models.
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http://dx.doi.org/10.1021/acsami.9b06620DOI Listing
July 2019

Enhanced Anti-Cancer Effects of Conditioned Medium from Hypoxic Human Umbilical Cord-Derived Mesenchymal Stem Cells.

Int J Stem Cells 2019 Jul;12(2):291-303

Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background And Objectives: There have been contradictory reports on the pro-cancer or anti-cancer effects of mesenchymal stem cells. In this study, we investigated whether conditioned medium (CM) from hypoxic human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) (H-CM) showed enhanced anti-cancer effects compared with CM from normoxic hUC-MSCs (N-CM).

Methods And Results: Compared with N-CM, H-CM not only strongly reduced cell viability and increased apoptosis of human cervical cancer cells (HeLa cells), but also increased caspase-3/7 activity, decreased mitochondrial membrane potential (MMP), and induced cell cycle arrest. In contrast, cell viability, apoptosis, MMP, and cell cycle of human dermal fibroblast (hDFs) were not significantly changed by either CM whereas caspase-3/7 activity was decreased by H-CM. Protein antibody array showed that activin A, Beta IG-H3, TIMP-2, RET, and IGFBP-3 were upregulated in H-CM compared with N-CM. Intracellular proteins that were upregulated by H-CM in HeLa cells were represented by apoptosis and cell cycle arrest terms of biological processes of Gene Ontology (GO), and by cell cycle of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In hDFs, negative regulation of apoptosis in biological process of GO and PI3K-Akt signaling pathway of KEGG pathways were represented.

Conclusions: H-CM showed enhanced anti-cancer effects on HeLa cells but did not influence cell viability or apoptosis of hDFs and these different effects were supported by profiling of secretory proteins in both kinds of CM and intracellular signaling of HeLa cells and hDFs.
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http://dx.doi.org/10.15283/ijsc19002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657944PMC
July 2019

A Disposable Photovoltaic Patch Controlling Cellular Microenvironment for Wound Healing.

Int J Mol Sci 2018 Oct 4;19(10). Epub 2018 Oct 4.

Department of BioNano Technology, Gachon University, Seongnam 13120, Korea.

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.
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http://dx.doi.org/10.3390/ijms19103025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213857PMC
October 2018

Bioreducible Polymer Micelles Based on Acid-Degradable Poly(ethylene glycol)-poly(amino ketal) Enhance the Stromal Cell-Derived Factor-1α Gene Transfection Efficacy and Therapeutic Angiogenesis of Human Adipose-Derived Stem Cells.

Int J Mol Sci 2018 Feb 9;19(2). Epub 2018 Feb 9.

School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Korea.

Adipose-derived stem cells (ADSCs) have the potential to treat ischemic diseases. In general, ADSCs facilitate angiogenesis by secreting various pro-angiogenic growth factors. However, transplanted ADSCs have a low therapeutic efficacy in ischemic tissues due to their poor engraftment and low viability. Stromal cell-derived factor-1α (SDF-1α) improves the survival rate of stem cells transplanted into ischemic regions. In this study, we developed acid-degradable poly(ethylene glycol)-poly(amino ketal) (PEG-PAK)-based micelles for efficient intracellular delivery of plasmid DNA. The was successfully delivered into human ADSCs (hADSCs) using PEG-PAK micelles. Transfection of increased , vascular endothelial growth factor, and basic fibroblast growth factor gene expression and decreased apoptotic activity in hADSCs cultured under hypoxic conditions in comparison with conventional gene transfection using polyethylenimine. -transfected hADSCs also showed significantly increased and VEGF expression together with reduced apoptotic activity at 4 weeks after transplantation into mouse ischemic hindlimbs. Consequently, these cells improved angiogenesis in ischemic hindlimb regions. These PEG-PAK micelles may lead to the development of a novel therapeutic modality for ischemic diseases based on an acid-degradable polymer specialized for gene delivery.
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http://dx.doi.org/10.3390/ijms19020529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855751PMC
February 2018

Therapeutic Angiogenesis via Solar Cell-Facilitated Electrical Stimulation.

ACS Appl Mater Interfaces 2017 Nov 27;9(44):38344-38355. Epub 2017 Oct 27.

Department of BioNano Technology, Gachon University , Seongnam 13120, Republic of Korea.

Cell therapy has been suggested as a treatment modality for ischemic diseases, but the poor survival and engraftment of implanted cells limit its therapeutic efficacy. To overcome such limitation, we used electrical stimulation (ES) derived from a wearable solar cell for inducing angiogenesis in ischemic tissue. ES enhanced the secretion of angiogenic growth factors and the migration of mesenchymal stem cells (MSCs), myoblasts, endothelial progenitor cells, and endothelial cells in vitro. In a mouse ischemic hindlimb model, ES generated by a solar cell and applied to the ischemic region promoted migration of MSCs toward the ischemic site and upregulated expression of angiogenic paracrine factors (vascular endothelial, basic fibroblast, and hepatocyte growth factors; and stromal cell-derived factor-1α). Importantly, solar cell-generated ES promoted the formation of capillaries and arterioles at the ischemic region, attenuated muscle necrosis and fibrosis, and eventually prevented loss of the ischemic limb. Solar cell ES therapy showed higher angiogenic efficacy than conventional MSC therapy. This study shows the feasibility of using solar cell ES as a novel treatment for therapeutic angiogenesis.
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http://dx.doi.org/10.1021/acsami.7b13322DOI Listing
November 2017

A wet-tolerant adhesive patch inspired by protuberances in suction cups of octopi.

Nature 2017 06;546(7658):396-400

School of Chemical Engineering, Sungkyunkwan University, Suwon, Kyunggi-do 16419, South Korea.

Adhesion strategies that rely on mechanical interlocking or molecular attractions between surfaces can suffer when coming into contact with liquids. Thus far, artificial wet and dry adhesives have included hierarchical mushroom-shaped or porous structures that allow suction or capillarity, supramolecular structures comprising nanoparticles, and chemistry-based attractants that use various protein polyelectrolytes. However, it is challenging to develop adhesives that are simple to make and also perform well-and repeatedly-under both wet and dry conditions, while avoiding non-chemical contamination on the adhered surfaces. Here we present an artificial, biologically inspired, reversible wet/dry adhesion system that is based on the dome-like protuberances found in the suction cups of octopi. To mimic the architecture of these protuberances, we use a simple, solution-based, air-trap technique that involves fabricating a patterned structure as a polymeric master, and using it to produce a reversed architecture, without any sophisticated chemical syntheses or surface modifications. The micrometre-scale domes in our artificial adhesive enhance the suction stress. This octopus-inspired system exhibits strong, reversible, highly repeatable adhesion to silicon wafers, glass, and rough skin surfaces under various conditions (dry, moist, under water and under oil). To demonstrate a potential application, we also used our adhesive to transport a large silicon wafer in air and under water without any resulting surface contamination.
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http://dx.doi.org/10.1038/nature22382DOI Listing
June 2017

Stretchable Piezoelectric Substrate Providing Pulsatile Mechanoelectric Cues for Cardiomyogenic Differentiation of Mesenchymal Stem Cells.

ACS Appl Mater Interfaces 2017 Jul 28;9(27):22101-22111. Epub 2017 Jun 28.

Department of Materials Science and Engineering, Yonsei University , Seoul 03722, Republic of Korea.

Ex vivo induction of cardiomyogenic differentiation of mesenchymal stem cells (MSCs) before implantation would potentiate therapeutic efficacy of stem cell therapies for ischemic heart diseases because MSCs rarely undergo cardiomyogenic differentiation following implantation. In cardiac microenvironments, electric pulse and cyclic mechanical strain are sequentially produced. However, no study has applied the pulsatile mechanoelectric cues (PMEC) to stimulate cardiomyogenic differentiation of MSCs ex vivo. In this study, we developed a stretchable piezoelectric substrate (SPS) that can provide PMEC to human MSCs (hMSCs) for cardiomyogenic differentiation ex vivo. Our data showed that hMSCs subjected to PMEC by SPS underwent promoted cardiac phenotype development: cell alignment and the expression of cardiac markers (i.e., cardiac transcription factors, structural proteins, ion channel proteins, and gap junction proteins). The enhanced cardiac phenotype development was mediated by the upregulation of cardiomyogenic differentiation-related autocrine factor expression, focal adhesion kinase, and extracellular signal-regulated kinases signaling pathways. Thus, SPS providing electrical and mechanical regulation of stem cells may be utilized to potentiate hMSC therapies for myocardial infarction and provide a tool for the study of stem cell biology.
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http://dx.doi.org/10.1021/acsami.7b03050DOI Listing
July 2017

Topography-Guided Control of Local Migratory Behaviors and Protein Expression of Cancer Cells.

Adv Healthc Mater 2017 Aug 16;6(16). Epub 2017 May 16.

School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea.

In vivo cancer cell migration and invasion are directed by biophysical guidance mechanisms such as pre-existing microtracks and basement membrane extracellular matrices. Here, this paper reports the correlation of the local migratory behavior of cancer cells and the biochemical signal expression using the topography that can guide or inhibit cell behaviors. To this end, the local apparent migration and the protein expression level are investigated with respect to the topographical feature size (flat, nanoline, and microline) and orientation (microline, microconcentric, and microradial) with the collectively migrating (A431) and individually migrating (MDA-MB-231 and U-87-MG) cancer cells. The results show that the migration and the protein expression of focal adhesion kinase, rho-associated protein kinase, and extracellular signal-regulated kinase are localized in the periphery of cell colony. Furthermore, the inhibition of migratory behavior at the periphery recues the protein expression, while the guidance of migration enhances the aforementioned protein expression. The results may imply the employ of biophysical inhibitory factors can help to control invasiveness of cancer cells during the progression state.
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http://dx.doi.org/10.1002/adhm.201700155DOI Listing
August 2017

Tocilizumab-Alendronate Conjugate for Treatment of Rheumatoid Arthritis.

Bioconjug Chem 2017 04 13;28(4):1084-1092. Epub 2017 Feb 13.

Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH) , 77 Cheongam-ro, Nam-gu, Pohang 790-784, Korea.

An autoimmune disease of rheumatoid arthritis (RA) causes severe inflammation on the synovial membrane, which results in the destruction of articular cartilage and bone. Here, Tocilizumab (TCZ)-Alendronate (ALD) conjugate is synthesized for the early intervention of RA. A humanized monoclonal antibody of TCZ shows an immunosuppressive effect, targeting interleukin-6 (IL-6) receptor in the RA pathogenesis. ALD is an anti-inflammatory bisphosphonate drug which can bind to the exposed bone surface. ALD is conjugated selectively to N-glycan on Fc region of TCZ using a chemical linker of 3-(2-pyridyldithio)propionyl hydrazide (PDPH)-poly(ethylene glycol)-N-hydroxysuccinimide (PDPH-PEG-NHS). The successful synthesis of TCZ-ALD conjugate is corroborated by H NMR, the purpald assay, mass spectrometry (MS), and high performance liquid chromatography (HPLC). In vitro binding affinity and cell viability tests confirmed the biological activity of TCZ-ALD conjugate. Furthermore, in vivo efficacy of TCZ-ALD conjugate is confirmed by microcomputed tomography (CT), histology, and Western blot analyses for the treatment of RA.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00008DOI Listing
April 2017

Enhanced Bone Repair by Guided Osteoblast Recruitment Using Topographically Defined Implant.

Tissue Eng Part A 2016 Apr 31;22(7-8):654-64. Epub 2016 Mar 31.

1 School of Chemical and Biological Engineering, Seoul National University , Seoul, Republic of Korea.

The rapid recruitment of osteoblasts in bone defects is an essential prerequisite for efficient bone repair. Conventionally, osteoblast recruitment to bone defects and subsequent bone repair has been achieved using growth factors. Here, we present a methodology that can guide the recruitment of osteoblasts to bone defects with topographically defined implants (TIs) for efficient in vivo bone repair. We compared circular TIs that had microgrooves in parallel or radial arrangements with nonpatterned implants for osteoblast migration and in vivo bone formation. In vitro, the microgrooves in the TIs enhanced both the migration and proliferation of osteoblasts. Especially, the microgrooves with radial arrangement demonstrated a much higher efficiency of osteoblast recruitment to the implants than did the other types of implants, which may be due to the efficient guidance of cell migration toward the cell-free area of the implants. The expression of the intracellular signaling molecules responsible for the cell migration was also upregulated in osteoblasts on the microgrooved TIs. In vivo, the TI with radially defined topography demonstrated much greater bone repair in mouse calvarial defect models than in the other types of implants. Taken together, these results indicate that implants with physical guidance can enhance tissue repair by rapid cell recruitment.
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http://dx.doi.org/10.1089/ten.TEA.2015.0417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840921PMC
April 2016

Microscale Soft Patterning for Solution Processable Metal Oxide Thin Film Transistors.

ACS Appl Mater Interfaces 2016 Mar 8;8(11):7205-11. Epub 2016 Mar 8.

Department of BioNano Technology, Gachon University , Seongnam, Gyeonggi-Do 461-701, South Korea.

We introduce a microscale soft pattering (MSP) route utilizing contact printing of chemically inert sub-nanometer thick low molecular weight (LMW) poly(dimethylsiloxane) (PDMS) layers. These PDMS layers serve as a release agent layer between the n-type Ohmic metal and metal oxide semiconductors (MOSs) and provide a layer that protects the MOS from water in the surrounding environment. The feasibility of our MSP route was experimentally demonstrated by fabricating solution processable In2O3, IZO, and IGZO TFTs with aluminum (Al), a typical n-type Ohmic metal. We have demonstrated patterning gaps as small as 13 μm. The TFTs fabricated using MSP showed higher field-effect-mobility and lower hysteresis in comparison with those made using conventional photolithography.
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http://dx.doi.org/10.1021/acsami.5b10847DOI Listing
March 2016

Enhancing Therapeutic Efficacy and Reducing Cell Dosage in Stem Cell Transplantation Therapy for Ischemic Limb Diseases by Modifying the Cell Injection Site.

Tissue Eng Part A 2016 Feb 29;22(3-4):349-62. Epub 2016 Jan 29.

1 School of Chemical and Biological Engineering, Seoul National University , Seoul, Republic of Korea.

In conventional stem cell transplantation therapies for ischemic limb diseases, stem cells are generally transplanted into the ischemic region (IR), and most of the transplanted cells undergo hypoxia-mediated cell death. Due to massive cell death, the therapeutic efficacy is reduced and a high dose of stem cells is necessitated for the therapies. In this study, we investigated whether the therapeutic efficacy can be improved and the cell dosage can be reduced in the therapy for limb ischemia simply by modifying the stem cell injection site to a site where cell engraftment is improved and blood vessel sprouting is efficiently stimulated. Human mesenchymal stem cells (hMSCs) cultured under hypoxic condition, which simulates cells transplanted to IR, underwent extensive cell death in vitro. Importantly, cell death was significantly attenuated when hMSCs adhered first under normoxic condition for 24 h and then were exposed to hypoxic condition, which simulates cells transplanted to the border zone (BZ) in the upper thigh and migrated to IR. hMSCs, at doses of 2 × 10(5) or 2 × 10(6) cells, were injected into the IR or BZ of 5-week-old female athymic mice after ischemic hindlimb induction. Compared with human mesenchymal stem cell (hMSC) transplantation to the IR of mouse ischemic limbs, transplantation to the BZ significantly enhanced cell engraftment and paracrine factor secretion, which effectively stimulated vessel sprouting, enhanced blood perfusion in IR, and enabled the cell dosage reduction. Therefore, modification of the stem cell transplantation site would improve the current stem cell therapies for ischemic limb diseases in terms of cell dosage reduction and therapeutic efficacy enhancement.
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http://dx.doi.org/10.1089/ten.tea.2015.0119DOI Listing
February 2016

Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2.

Arterioscler Thromb Vasc Biol 2016 Jan 19;36(1):86-96. Epub 2015 Nov 19.

Department of Pediatrics (C.P., H.S.C.), Children's Heart Research and Outcomes Center (C.P.), Molecular and Systems Pharmacology Program (C.P.), Emory University School of Medicine, Atlanta; Department of Pharmacology, College of Medicine, University of Illinois at Chicago, IL (T.M.K., N.U., M.U-F.); School of Chemical Engineering, Sungkyunkwan University, Korea (S.H.B.); School of Chemical and Biological Engineering, Seoul National University, Seoul, Korea (B-S.K.); Korea Advanced Institute of Science and Technology, Korea (D.J.L., D-S.L.); RIKEN BioResource Center, Japan (H.M.); the Departments of Pathology and Immunology (T-J.L., F.L., K.C.), Ophthalmology and Visual Sciences (R.N., I.P-R., R.S.A.), Developmental Biology (S.S.O., D.M.O.), Biochemistry and Molecular Biophysics (B. C.), Developmental, Regenerative, and Stem cell Biology Program (D.M.O., R.S.A., K.C.), Washington University School of Medicine, MO.

Objective: Comprehensive understanding of the mechanisms regulating angiogenesis might provide new strategies for angiogenic therapies for treating diverse physiological and pathological ischemic conditions. The E-twenty six (ETS) factor Ets variant 2 (ETV2; aka Ets-related protein 71) is essential for the formation of hematopoietic and vascular systems. Despite its indispensable function in vessel development, ETV2 role in adult angiogenesis has not yet been addressed. We have therefore investigated the role of ETV2 in vascular regeneration.

Approach And Results: We used endothelial Etv2 conditional knockout mice and ischemic injury models to assess the role of ETV2 in vascular regeneration. Although Etv2 expression was not detectable under steady-state conditions, its expression was readily observed in endothelial cells after injury. Mice lacking endothelial Etv2 displayed impaired neovascularization in response to eye injury, wounding, or hindlimb ischemic injury. Lentiviral Etv2 expression in ischemic hindlimbs led to improved recovery of blood perfusion with enhanced vessel formation. After injury, fetal liver kinase 1 (Flk1), aka VEGFR2, expression and neovascularization were significantly upregulated by Etv2, whereas Flk1 expression and vascular endothelial growth factor response were significantly blunted in Etv2-deficient endothelial cells. Conversely, enforced Etv2 expression enhanced vascular endothelial growth factor-mediated endothelial sprouting from embryoid bodies. Lentiviral Flk1 expression rescued angiogenesis defects in endothelial Etv2 conditional knockout mice after hindlimb ischemic injury. Furthermore, Etv2(+/-); Flk1(+/-) double heterozygous mice displayed a more severe hindlimb ischemic injury response compared with Etv2(+/-) or Flk1(+/-) heterozygous mice, revealing an epistatic interaction between ETV2 and FLK1 in vascular regeneration.

Conclusions: Our study demonstrates a novel obligatory role for the ETV2 in postnatal vascular repair and regeneration.
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http://dx.doi.org/10.1161/ATVBAHA.115.306430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690812PMC
January 2016

Mesenchymal Stem Cells Aggregate and Deliver Gold Nanoparticles to Tumors for Photothermal Therapy.

ACS Nano 2015 Oct 11;9(10):9678-90. Epub 2015 Sep 11.

School of Chemical Engineering, Sungkyunkwan University , Suwon 440-746, Republic of Korea.

Gold nanoparticles (AuNPs) have been extensively studied for photothermal cancer therapy because AuNPs can generate heat upon near-infrared irradiation. However, improving their tumor-targeting efficiency and optimizing the nanoparticle size for maximizing the photothermal effect remain challenging. We demonstrate that mesenchymal stem cells (MSCs) can aggregate pH-sensitive gold nanoparticles (PSAuNPs) in mildly acidic endosomes, target tumors, and be used for photothermal therapy. These aggregated structures had a higher cellular retention in comparison to pH-insensitive, control AuNPs (cAuNPs), which is important for the cell-based delivery process. PSAuNP-laden MSCs (MSC-PSAuNPs) injected intravenously to tumor-bearing mice show a 37-fold higher tumor-targeting efficiency (5.6% of the injected dose) and 8.3 °C higher heat generation compared to injections of cAuNPs after irradiation, which results in a significantly enhanced anticancer effect.
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http://dx.doi.org/10.1021/acsnano.5b02207DOI Listing
October 2015

pH-triggered release of manganese from MnAu nanoparticles that enables cellular neuronal differentiation without cellular toxicity.

Biomaterials 2015 Jul 9;55:33-43. Epub 2015 Apr 9.

School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea; Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 151-744, Republic of Korea; Bio-MAX Institute, Institute of Chemical Processes, Engineering Research Institute, Seoul National University, Seoul 151-744, Republic of Korea. Electronic address:

At high concentrations, manganese (Mn) promotes cellular neurodevelopment but causes toxicity. Here, we report that Mn ion at high concentrations can be delivered to pheochromocytoma 12 (PC12) cells using gold nanoparticles (AuNPs) to enhance cellular neurodevelopment without toxicity. Mn(2+) release from AuNPs was designed to be pH-responsive so that low pH condition of the cell endosomes can trigger in situ release of Mn(2+) from AuNPs after cellular uptake of Mn-incorporated AuNPs (MnAuNPs). Due to the differences in reduction potentials of Mn and Au, only Mn ionized and released while Au remained intact when MnAuNPs were uptaken by cells. Compared to PC12 cells treated with a high concentration of free Mn(2+), PC12 cells treated with an equal concentration of MnAuNPs resulted in significantly enhanced cellular neurodevelopment with decreased apoptosis and necrosis. Treatment with a high concentration of free Mn(2+) led to an abrupt consumption of a large amount of ATP for the intracellular transport of Mn(2+) through the ion channel of the cell membrane and to mitochondrial damage caused by the high intracellular concentration of Mn(2+), both of which resulted in cell necrosis and apoptosis. In contrast, MnAuNP-treated cells consumed much smaller amount of ATP for the intracellular transport of MnAuNPs by endocytosis and showed pH-triggered in situ release of Mn(2+) from the MnAuNPs in the endosomes of the cells, both of which prevented the cell death caused by ATP depletion and mitochondrial damage. To our knowledge, this is the first report on the use of AuNPs as a vehicle for pH-responsive, intracellular delivery of metal ion, which may open a new window for drug delivery and clinical therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2015.03.025DOI Listing
July 2015