Publications by authors named "Jeong-Kee Yoon"

29 Publications

  • Page 1 of 1

Advanced Human BBB-on-a-Chip: A New Platform for Alzheimer's Disease Studies.

Adv Healthc Mater 2021 08 2;10(15):e2002285. Epub 2021 Jun 2.

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.

The blood-brain barrier (BBB) is a unique vascular structure that serves as a molecular transport gateway for the maintenance of brain homeostasis. Chronic disruption or breakdown of the BBB reportedly leads to neurodegenerative diseases. Nonetheless, research on human BBB pathophysiology and drug development remains highly dependent on studies using inherently different animals. Moreover, more studies have shown that animal models are not appropriate in modeling Alzheimer's disease (AD), underlining the importance of in vitro models of the human BBB with physiological relevance. In this review, recent advances in human BBB-on-a-chip technologies are highlighted and their potential for pathogenesis studies and drug prescreening for AD treatment are discussed.
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http://dx.doi.org/10.1002/adhm.202002285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349886PMC
August 2021

Microvascularized tumor organoids-on-chips: advancing preclinical drug screening with pathophysiological relevance.

Nano Converg 2021 Apr 13;8(1):12. Epub 2021 Apr 13.

School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, 08826, Republic of Korea.

Recent developments of organoids engineering and organ-on-a-chip microfluidic technologies have enabled the recapitulation of the major functions and architectures of microscale human tissue, including tumor pathophysiology. Nevertheless, there remain challenges in recapitulating the complexity and heterogeneity of tumor microenvironment. The integration of these engineering technologies suggests a potential strategy to overcome the limitations in reconstituting the perfusable microvascular system of large-scale tumors conserving their key functional features. Here, we review the recent progress of in vitro tumor-on-a-chip microfluidic technologies, focusing on the reconstruction of microvascularized organoid models to suggest a better platform for personalized cancer medicine.
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http://dx.doi.org/10.1186/s40580-021-00261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042002PMC
April 2021

Dilation-Responsive Microshape Programing Prevents Vascular Graft Stenosis.

Small 2021 05 17;17(18):e2007297. Epub 2021 Mar 17.

Department of Medical Engineering, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Shape memory materials have been successfully applied to minimally invasive implantation of medical devices. However, organ-movement-specific shape programing at a microscale level has never been demonstrated despite significant unmet needs. As vein-to-artery grafting induces vein dilation and stenosis, a polymeric self-enclosable external support (SES) is designed to wrap the vascular out-wall. Its micropores are programmed to increase sizes and interconnections upon dilation. Vessel dilation promotes venous maturation, but overdilation induces stenosis by disturbed blood flow. Therefore, the unique elastic shape-fixity of SES provides a foundation to enable a stable microscale shape transition by maintaining the vein dilation. The shape transition of micropore architecture upon dilation induces beneficial inflammation, thereby regenerating vasa vasorum and directing smooth muscle cell migration toward adventitia with the consequent muscle reinforcement of veins. This game-changer approach prevents the stenosis of vein-to-artery grafting by rescuing ischemic disorders and promoting arterial properties of veins.
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http://dx.doi.org/10.1002/smll.202007297DOI Listing
May 2021

Advanced Fabrication Techniques of Microengineered Physiological Systems.

Micromachines (Basel) 2020 Jul 28;11(8). Epub 2020 Jul 28.

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.

The field of organs-on-chips (OOCs) has experienced tremendous growth over the last decade. However, the current main limiting factor for further growth lies in the fabrication techniques utilized to reproducibly create multiscale and multifunctional devices. Conventional methods of photolithography and etching remain less useful to complex geometric conditions with high precision needed to manufacture the devices, while laser-induced methods have become an alternative for higher precision engineering yet remain costly. Meanwhile, soft lithography has become the foundation upon which OOCs are fabricated and newer methods including 3D printing and injection molding show great promise to innovate the way OOCs are fabricated. This review is focused on the advantages and disadvantages associated with the commonly used fabrication techniques applied to these microengineered physiological systems (MPS) and the obstacles that remain in the way of further innovation in the field.
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http://dx.doi.org/10.3390/mi11080730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464561PMC
July 2020

Nanovesicles derived from iron oxide nanoparticles-incorporated mesenchymal stem cells for cardiac repair.

Sci Adv 2020 May 1;6(18):eaaz0952. Epub 2020 May 1.

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

Because of poor engraftment and safety concerns regarding mesenchymal stem cell (MSC) therapy, MSC-derived exosomes have emerged as an alternative cell-free therapy for myocardial infarction (MI). However, the diffusion of exosomes out of the infarcted heart following injection and the low productivity limit the potential of clinical applications. Here, we developed exosome-mimetic extracellular nanovesicles (NVs) derived from iron oxide nanoparticles (IONPs)-incorporated MSCs (IONP-MSCs). The retention of injected IONP-MSC-derived NVs (IONP-NVs) within the infarcted heart was markedly augmented by magnetic guidance. Furthermore, IONPs significantly increased the levels of therapeutic molecules in IONP-MSCs and IONP-NVs, which can reduce the concern of low exosome productivity. The injection of IONP-NVs into the infarcted heart and magnetic guidance induced an early shift from the inflammation phase to the reparative phase, reduced apoptosis and fibrosis, and enhanced angiogenesis and cardiac function recovery. This approach can enhance the therapeutic potency of an MSC-derived NV therapy.
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http://dx.doi.org/10.1126/sciadv.aaz0952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195131PMC
May 2020

Anti-Atherogenic Effect of Stem Cell Nanovesicles Targeting Disturbed Flow Sites.

Small 2020 04 2;16(16):e2000012. Epub 2020 Apr 2.

Department of Medical Engineering, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.

Atherosclerosis development leads to irreversible cascades, highlighting the unmet need for improved methods of early diagnosis and prevention. Disturbed flow formation is one of the earliest atherogenic events, resulting in increased endothelial permeability and subsequent monocyte recruitment. Here, a mesenchymal stem cell (MSC)-derived nanovesicle (NV) that can target disturbed flow sites with the peptide GSPREYTSYMPH (PREY) (PMSC-NVs) is presented which is selected through phage display screening of a hundred million peptides. The PMSC-NVs are effectively produced from human MSCs (hMSCs) using plasmid DNA designed to functionalize the cell membrane with PREY. The potent anti-inflammatory and pro-endothelial recovery effects are confirmed, similar to those of hMSCs, employing mouse and porcine partial carotid artery ligation models as well as a microfluidic disturbed flow model with human carotid artery-derived endothelial cells. This nanoscale platform is expected to contribute to the development of new theragnostic strategies for preventing the progression of atherosclerosis.
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http://dx.doi.org/10.1002/smll.202000012DOI Listing
April 2020

Hydrogel cross-linking-programmed release of nitric oxide regulates source-dependent angiogenic behaviors of human mesenchymal stem cell.

Sci Adv 2020 02 26;6(9):eaay5413. Epub 2020 Feb 26.

Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Angiogenesis is stimulated by nitric oxide (NO) production in endothelial cells (ECs). Although proangiogenic actions of human mesenchymal stem cells (hMSCs) have been extensively studied, the mechanistic role of NO in this action remains obscure. Here, we used a gelatin hydrogel that releases NO upon crosslinking by a transglutaminase reaction ("NO gel"). Then, the source-specific behaviors of bone marrow versus adipose tissue-derived hMSCs (BMSCs versus ADSCs) were monitored in the NO gels. NO inhibition resulted in significant decreases in their angiogenic activities. The NO gel induced pericyte-like characteristics in BMSCs in contrast to EC differentiation in ADSCs, as evidenced by tube stabilization versus tube formation, 3D colocalization versus 2D coformation with EC tube networks, pericyte-like wound healing versus EC-like vasculogenesis in gel plugs, and pericyte versus EC marker production. These results provide previously unidentified insights into the effects of NO in regulating hMSC source-specific angiogenic mechanisms and their therapeutic applications.
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http://dx.doi.org/10.1126/sciadv.aay5413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043909PMC
February 2020

Microchannel network hydrogel induced ischemic blood perfusion connection.

Nat Commun 2020 01 30;11(1):615. Epub 2020 Jan 30.

Department of Medical Engineering, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Angiogenesis induction into damaged sites has long been an unresolved issue. Local treatment with pro-angiogenic molecules has been the most common approach. However, this approach has critical side effects including inflammatory coupling, tumorous vascular activation, and off-target circulation. Here, the concept that a structure can guide desirable biological function is applied to physically engineer three-dimensional channel networks in implant sites, without any therapeutic treatment. Microchannel networks are generated in a gelatin hydrogel to overcome the diffusion limit of nutrients and oxygen three-dimensionally. Hydrogel implantation in mouse and porcine models of hindlimb ischemia rescues severely damaged tissues by the ingrowth of neighboring host vessels with microchannel perfusion. This effect is guided by microchannel size-specific regenerative macrophage polarization with the consequent functional recovery of endothelial cells. Multiple-site implantation reveals hypoxia and neighboring vessels as major causative factors of the beneficial function. This technique may contribute to the development of therapeutics for hypoxia/inflammatory-related diseases.
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http://dx.doi.org/10.1038/s41467-020-14480-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992688PMC
January 2020

Interleukin-4 Gene Transfection and Spheroid Formation Potentiate Therapeutic Efficacy of Mesenchymal Stem Cells for Osteoarthritis.

Adv Healthc Mater 2020 03 24;9(5):e1901612. Epub 2020 Jan 24.

School of Chemical and Biological Engineering, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.

Osteoarthritis (OA) is a painful intractable disease that significantly affects patients' quality of life. However, current therapies, such as pain killers and joint replacement surgery, do not lead to cartilage protection. Mesenchymal stem cells (MSCs) have been proposed as an alternative strategy for OA therapy because MSCs can secrete chondroprotective and anti-inflammatory factors. However, interleukin-4 (IL-4), a potent anti-inflammatory cytokine, is barely produced by MSCs, and MSC therapy suffers from rapid MSC death following intra-articular implantation. MSCs in spheroids survive better than naïve MSCs in vitro and in vivo. IL-4-transfected MSCs in spheroids (IL-4 MSC spheroid) show increased chondroprotective and anti-inflammatory effects in an OA chondrocyte model in vitro. Following intra-articular implantation in OA rats, IL-4 MSC spheroids show better cartilage protection and pain relief than naïve MSCs. Thus, IL-4 MSC spheroid may potentiate the therapeutic efficacy of MSCs for OA.
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http://dx.doi.org/10.1002/adhm.201901612DOI Listing
March 2020

Nasolacrimal stent with shape memory as an advanced alternative to silicone products.

Acta Biomater 2020 01 7;101:273-284. Epub 2019 Nov 7.

Department of Medical Engineering, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address:

Epiphora is the overflow of tears typically caused by obstruction or occlusion of the nasolacrimal duct. More attention is required to address this global health issue owing to the increase in air pollution. Implantation of a silicone stent is the preferred treatment for epiphora; however, introducing a silicone stent into a narrow duct with complex geometry is challenging as it requires guidance by a sharp metal needle. Additionally, silicone can cause adverse reactions such as biofilm formation and tear flow resistance due to its extreme hydrophobicity. To overcome these problems, in this study we developed a new type of biocompatible shape memory polymer (SMP) stent with elasticity capacity for self-expansion. First, SMPs in the form of x%poly(ε-caprolactone)-co-y%poly(glycidyl methacrylate) (x%PCL-y%PGMA) were synthesized via ring opening polymerization by varying the molar ratio of PCL (x%) and PGMA (y%). Second, the shape memory and mechanical properties were tuned by controlling the crosslinking degree and concentration of x%PCL-y%PGMA solution to produce a test type of SMP stent. Lastly, this 94%PCL-06%PGMA stent exhibited more standout critical functions in a series of in vitro and in vivo experiments such as a cell growth-supporting level of biocompatibility with nasal epithelial cells without significant inflammatory responses, better resistance to biofilm formation, and more efficient capacity to drain tear than the silicone control. Overall, 94%PCL-06%PGMA can be suggested as a superior alternative to the currently used materials for nasolacrimal stents. STATEMENT OF SIGNIFICANCE: Silicone intubation (stenting) has been widely used to treat nasolacrimal duct obstruction, however, it can cause adverse clinical effects such as bacterial infection; presents procedural challenges because of the curved nasolacrimal duct structure; and shows poor drainage efficiency stemming from the highly hydrophobic nature of silicone. In this work, we describe an innovative shape memory polymer (SMP) as a superior alternative to conventional silicone-based materials for nasolacrimal duct intubation. We demonstrate the clear advantages of the SMP over conventional silicone, including a much higher drainage capacity and superior resistance to bacterial infection.
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http://dx.doi.org/10.1016/j.actbio.2019.11.001DOI Listing
January 2020

Development of a Shape-Memory Tube to Prevent Vascular Stenosis.

Adv Mater 2019 Oct 27;31(41):e1904476. Epub 2019 Aug 27.

Department of Medical Engineering, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.

Inserting a graft into vessels with different diameters frequently causes severe damage to the host vessels. Poor flow patency is an unresolved issue in grafts, particularly those with diameters less than 6 mm, because of vessel occlusion caused by disturbed blood flow following fast clotting. Herein, successful patency in the deployment of an ≈2 mm diameter graft into a porcine vessel is reported. A new library of property-tunable shape-memory polymers that prevent vessel damage by expanding the graft diameter circumferentially upon implantation is presented. The polymers undergo seven consecutive cycles of strain energy-preserved shape programming. Moreover, the new graft tube, which features a diffuser shape, minimizes disturbed flow formation and prevents thrombosis because its surface is coated with nitric-oxide-releasing peptides. Improved patency in a porcine vessel for 18 d is demonstrated while occlusive vascular remodeling occurs. These insights will help advance vascular graft design.
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http://dx.doi.org/10.1002/adma.201904476DOI Listing
October 2019

Potential roles of aquaporin 9 in the pathogenesis of endometriosis.

Mol Hum Reprod 2019 07;25(7):373-384

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.

Aquaporins (AQPs) are involved in cell migration, proliferation and carcinogenesis in tumor development and physiologic inflammatory processes, but their associations with endometriosis have not been fully evaluated. In this study, tissue samples were obtained from women undergoing laparoscopic surgery for endometriosis and other benign conditions. Analysis of expressions of AQP subtypes in eutopic and ectopic endometrium of patients with endometriosis (Eu-EMS and Ect-EMS, respectively) and eutopic endometrium of control patients without endometriosis (Eu-CTL) were performed using the NanoString nCounter System and western blotting. Human endometrial stromal cells (HESCs) were cultured and transfected with the siRNA of the AQP of interest. Among the AQP1-9 subtypes, endometrial expression of AQP2 and AQP8 was significantly increased, whereas AQP9 expression was significantly decreased in the Eu-EMS group compared to the Eu-CTL group. Comparison of expression of AQP2, AQP8 and AQP9 among Eu-EMS, Ect-EMS and Eu-CTL groups revealed significant differences for only AQP9. Expression of AQP9 in the Eu-EMS group was decreased compared with that in Eu-CTL. After transfection of AQP9 siRNA in HESCs, expressions of MMP2 and MMP9 were significantly elevated. Increased expression of phosphorylated ERK 1/2 and phosphorylated p38 MAPK proteins after transfection was also confirmed using western blot analysis. Increased migration and invasion potentials of HESCs after transfection were determined by migration and wound healing assays. These findings suggest that AQP9 may be involved in the pathogenesis of endometriosis and warrant further investigation as a potential therapeutic target for treating endometriosis.
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http://dx.doi.org/10.1093/molehr/gaz025DOI Listing
July 2019

Experimental Tracheal Replacement Using 3-dimensional Bioprinted Artificial Trachea with Autologous Epithelial Cells and Chondrocytes.

Sci Rep 2019 02 14;9(1):2103. Epub 2019 Feb 14.

Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Sedaemun-gu, Seoul, 03722, Republic of Korea.

Various treatment methods for tracheal defects have been attempted, such as artificial implants, allografts, autogenous grafts, and tissue engineering; however, no perfect method has been established. We attempted to create an effective artificial trachea via a tissue engineering method using 3D bio-printing. A multi-layered scaffold was fabricated using a 3D printer. Polycaprolactone (PCL) and hydrogel were used with nasal epithelial and auricular cartilage cells in the printing process. An artificial trachea was transplanted into 15 rabbits and a PCL scaffold without the addition of cells was transplanted into 6 rabbits (controls). All animals were followed up with radiography, CT, and endoscopy at 3, 6, and 12 months. In the control group, 3 out of 6 rabbits died from respiratory symptoms. Surviving rabbits in control group had narrowed tracheas due to the formation of granulation tissue and absence of epithelium regeneration. In the experimental group, 13 of 15 animals survived, and the histologic examination confirmed the regeneration of epithelial cells. Neonatal cartilage was also confirmed at 6 and 12 months. Our artificial trachea was effective in the regeneration of respiratory epithelium, but not in cartilage regeneration. Additional studies are needed to promote cartilage regeneration and improve implant stability.
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http://dx.doi.org/10.1038/s41598-019-38565-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375946PMC
February 2019

Association Between Impairment of DNA Double Strand Break Repair and Decreased Ovarian Reserve in Patients With Endometriosis.

Front Endocrinol (Lausanne) 2018 21;9:772. Epub 2018 Dec 21.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Repair of DNA double strand break (DSB) is an important mechanism for maintaining genetic stability during a DNA damage event. Although, a growing body of recent evidence suggests that DNA DSBs and related repair mechanisms may be important in ovarian aging and in various cancers, there are few reports in endometriosis. We, therefore, examined expression levels of genes pertaining to DNA DSB repair in patients with endometriosis to assess the potential effects on ovarian reserves. A total of 69 women undergoing laparoscopic surgery for endometriosis and other benign conditions was included; endometriosis group ( = 38) vs. controls ( = 31). DNA DSBs in endometrial and ovarian tissues of both groups were compared via immunohistochemistry, aimed at γ-H2AX expression. To gauge genotoxin-induced DNA DSBs in endometrial stromal cells, γ-H2AX expression was determined by western blot after HO treatment of cultured endometrial stromal cells (endometriosis group and controls) and Ishikawa cell-line cultures. Endometrial and ovarian tissue levels of BRCA1, BRCA2, Rad51, and ATM (ataxia-telangiectasia mutated) mRNA expression were also compared. Correlations between expression levels of genes of interest and serum anti-müllerian hormone (AMH) levels were assessed as well. Expression of γ-H2AX in immunostained endometrial and ovarian tissue preparations was greater in the endometriosis group, compared with controls. After HO treatment, γ-H2AX expression levels were also significantly greater in cultured stromal cells of the endometriosis group and in the Ishikawa cell line than in controls. Endometrial expression of and mRNA proved significantly lower in the endometriosis group (vs. controls), as did ovarian expression of and mRNA. Serum AMH concentration showed a significant correlation with ovarian mRNA expression in women with endometriosis ( = 0.03). In women with endometriosis, expression levels of various genes implicated in DSB repair are decreased and ovarian expression correlates with.
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http://dx.doi.org/10.3389/fendo.2018.00772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308303PMC
December 2018

Microneedle Vascular Couplers with Heparin-Immobilized Surface Improve Suture-Free Anastomosis Performance.

ACS Biomater Sci Eng 2018 Nov 29;4(11):3848-3853. Epub 2018 Oct 29.

Department of Medical Engineering, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.

To make up for the shortcomings of the suture-based approach and current coupler devices including long suturing time, exhaustive training, additional mechanical setting, and narrow working windows for size and type of diverse vessel types, a new, suture-free microneedle coupler was developed in this study. The needle shape for improved anastomosis performance and the condition for antithrombotic surface immobilization were determined. In particular, the polymer materials help to maintain healthy phenotypes of main vascular cell types. The performance in rabbit and porcine models of end-to-end vascular anastomosis indicate that this device can serve as a potent alternative to the current approaches.
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http://dx.doi.org/10.1021/acsbiomaterials.8b01097DOI Listing
November 2018

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

Therapeutic Efficacy-Potentiated and Diseased Organ-Targeting Nanovesicles Derived from Mesenchymal Stem Cells for Spinal Cord Injury Treatment.

Nano Lett 2018 08 13;18(8):4965-4975. Epub 2018 Jul 13.

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

Human mesenchymal stem cell (hMSC)-derived exosomes have been spotlighted as a promising therapeutic agent for cell-free regenerative medicine. However, poor organ-targeting ability and insufficient therapeutic efficacy of systemically injected hMSC-exosomes were identified as critical limitations for their further applications. Therefore, in this study we fabricated iron oxide nanoparticle (IONP)-incorporated exosome-mimetic nanovesicles (NV-IONP) from IONP-treated hMSCs and evaluated their therapeutic efficacy in a clinically relevant model for spinal cord injury. Compared to exosome-mimetic nanovesicles (NV) prepared from untreated hMSCs, NV-IONP not only contained IONPs which act as a magnet-guided navigation tool but also carried greater amounts of therapeutic growth factors that can be delivered to the target cells. The increased amounts of therapeutic growth factors inside NV-IONP were attributed to IONPs that are slowly ionized to iron ions which activate the JNK and c-Jun signaling cascades in hMSCs. In vivo systemic injection of NV-IONP with magnetic guidance significantly increased the amount of NV-IONP accumulating in the injured spinal cord. Accumulated NV-IONP enhanced blood vessel formation, attenuated inflammation and apoptosis in the injured spinal cord, and consequently improved spinal cord function. Taken together, these findings highlight the development of therapeutic efficacy-potentiated extracellular nanovesicles and demonstrate their feasibility for repairing injured spinal cord.
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http://dx.doi.org/10.1021/acs.nanolett.8b01816DOI Listing
August 2018

Direct Control of Stem Cell Behavior Using Biomaterials and Genetic Factors.

Stem Cells Int 2018 10;2018:8642989. Epub 2018 May 10.

Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul, Republic of Korea.

Stem cells have recently emerged as an important candidate for cell therapy. However, some major limitations still exist such as a small quantity of cell supply, senescence, and insufficient differentiation efficiency. Therefore, there is an unmet need to control stem cell behavior for better clinical performance. Since native microenvironment factors including stem cell niche, genetic factors, and growth factors direct stem cell fate cooperatively, user-specified settings are required to understand the regulatory roles and effects of each factor, thereby applying the factors for improved cell therapy. Among others, various types of biomaterials and transfection method have been employed as key tools for development of the settings. This review focuses on the current strategies to improve stemness maintenance, direct differentiation, and reprogramming using biomaterials and genetic factors without any aids from additional biochemicals and growth factors.
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http://dx.doi.org/10.1155/2018/8642989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971247PMC
May 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

Synergistic Therapeutic Effect of Three-Dimensional Stem Cell Clusters and Angiopoietin-1 on Promoting Vascular Regeneration in Ischemic Region.

Tissue Eng Part A 2018 04 26;24(7-8):616-630. Epub 2017 Sep 26.

1 Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology , Seoul, Republic of Korea.

Peripheral artery disease (PAD) is an ischemic disease characterized by reduced blood flow to the legs, feet, and hands. Human mesenchymal stem cells are an attractive cell source to treat PAD in regenerative medicine. However, in clinical applications, the use of adult stem cells has several limitations, such as low cell viability and low therapeutic efficiency. In this study, we described an innovative method of culturing three-dimensional stem cell clusters (Angiocluster™ [AC]), demonstrated the potential for ACs to differentiate into vascular cells, and assessed the synergistic effects of ACs and angiopoietin-1 (Ang-1) on angiogenesis in ischemic animal models. ACs were formed by culturing human adipose-derived stem cells (hASCs) on a maltose-binding protein-linked basic fibroblast growth factor-immobilized polystyrene surface. ACs released various angiogenic factors, such as vascular endothelial growth factor and interleukin-8, and could differentiate into endothelial lineage cells. However, ACs did not secrete Ang-1, which is an essential component of vascular maturation and anti-inflammation. ACs were combined with Ang-1 and were transplanted into the ischemic lesions of mice for 28 days. Most of the mice receiving the AC + Ang-1 treatment exhibited limb salvage and exhibited similar blood perfusion ratio compared to normal limb. The combination therapy of AC and Ang-1 enhanced angiogenic efficacy by increasing blood vessel regeneration and facilitating the implantation of stem cells into host vessels. Importantly, fibrotic collagen was observed in most of the groups after 28 days of treatment, except for the AC + Ang-1 group. This indicates that the combination therapy is synergistic in minimizing ischemic fibrosis and muscle degeneration. Our results demonstrate that the combination therapy significantly enhanced tissue regeneration and angiogenic efficacy of hASCs and may have wide applications in regenerative medicine.
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http://dx.doi.org/10.1089/ten.TEA.2017.0260DOI Listing
April 2018

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

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

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

Therapeutic angiogenesis using tumor cell-conditioned medium.

Biotechnol Prog 2016 03 23;32(2):456-64. Epub 2016 Jan 23.

School of Chemical and Biological Engineering, Seoul National University, Seoul, 151-744, Republic of Korea.

Stem cell-conditioned medium (CM), which contains angiogenic factors that are secreted by stem cells, represents a potential therapy for ischemic diseases. Along with stem cells, tumor cells also secrete various angiogenic factors. Here, tumor cells as a cell source of CM for therapeutic angiogenesis was evaluated and the therapeutic efficacy of tumor cell CM in mouse hindlimb ischemia models was demonstrated. CM obtained from a human fibrosarcoma HT1080 cell line culture was compared with CM obtained from a human bone marrow-derived mesenchymal stem cell (MSC) culture. HT1080 CM contained higher concentrations of angiogenic factors compared with MSC CM, which was attributable to the higher cell density that resulted from a much faster growth rate of HT1080 cells compared with MSCs. For use in in vitro and in vivo angiogenesis studies, HT1080 CM was diluted such that HT1080 CM and MSC CM would have the same cell number basis. The two types of CMs induced the same extent of human umbilical vein endothelial cell (HUVEC) proliferation in vitro. The injection of HT1080 CM into mouse ischemic limbs significantly improved capillary density and blood perfusion compared with the injection of fresh medium. Although the therapeutic outcome of HT1080 CM was similar to that of MSC CM, the preparation of CM by tumor cell line culture would be much more efficient due to the faster growth and unlimited life-time of the tumor cell line. These data suggest the potential application of tumor cell CM as a therapeutic modality for angiogenesis and ischemic diseases. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:456-464, 2016.
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http://dx.doi.org/10.1002/btpr.2226DOI Listing
March 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

Graphene enhances the cardiomyogenic differentiation of human embryonic stem cells.

Biochem Biophys Res Commun 2014 Sep 22;452(1):174-80. Epub 2014 Aug 22.

Engineering Research Institute, Seoul National University, Seoul, Republic of Korea; School of Chemical and Biological Engineering, Seoul National University, Seoul, Republic of Korea; Institute of Bioengineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea. Electronic address:

Graphene has drawn attention as a substrate for stem cell culture and has been reported to stimulate the differentiation of multipotent adult stem cells. Here, we report that graphene enhances the cardiomyogenic differentiation of human embryonic stem cells (hESCs) at least in part, due to nanoroughness of graphene. Large-area graphene on glass coverslips was prepared via the chemical vapor deposition method. The coating of the graphene with vitronectin (VN) was required to ensure high viability of the hESCs cultured on the graphene. hESCs were cultured on either VN-coated glass (glass group) or VN-coated graphene (graphene group) for 21 days. The cells were also cultured on glass coated with Matrigel (Matrigel group), which is a substrate used in conventional, directed cardiomyogenic differentiation systems. The culture of hESCs on graphene promoted the expression of genes involved in the stepwise differentiation into mesodermal and endodermal lineage cells and subsequently cardiomyogenic differentiation compared with the culture on glass or Matrigel. In addition, the culture on graphene enhanced the gene expression of cardiac-specific extracellular matrices. Culture on graphene may provide a new platform for the development of stem cell therapies for ischemic heart diseases by enhancing the cardiomyogenic differentiation of hESCs.
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http://dx.doi.org/10.1016/j.bbrc.2014.08.062DOI Listing
September 2014

Incorporation of gold-coated microspheres into embryoid body of human embryonic stem cells for cardiomyogenic differentiation.

Tissue Eng Part A 2015 Jan 8;21(1-2):374-81. Epub 2014 Sep 8.

1 Engineering Research Institute, Seoul National University , Seoul, Republic of Korea.

Human embryonic stem cells (hESCs) are a useful cell source for cardiac regeneration by stem cell therapy. In this study, we show that incorporation of gold-coated microspheres into hESC-derived embryoid bodies (EBs) enhances the cardiomyogenic differentiation process of pluripotent embryonic stem cells. A polycaprolactone (PCL) microsphere surface was coated with gold. Either gold-coated PCL microspheres (AuMS) or PCL microspheres (MS) were incorporated into hESC-derived EBs. AuMS and MS were not cytotoxic. AuMS promoted the expression of genes for mesodermal and cardiac mesodermal lineage cells, both of which are intermediates in the process of cardiac differentiation of hESCs on day 4 and the expression of cardiomyogenic differentiation markers on day 14 compared to MS. AuMS also enhanced gene expression of cardiac-specific extracellular matrices. Incorporation of gold-coated MS into hESC-derived EBs may provide a new platform for inducing cardiomyogenic differentiation of pluripotent embryonic stem cells.
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http://dx.doi.org/10.1089/ten.TEA.2014.0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293129PMC
January 2015

Graphene-regulated cardiomyogenic differentiation process of mesenchymal stem cells by enhancing the expression of extracellular matrix proteins and cell signaling molecules.

Adv Healthc Mater 2014 Feb 15;3(2):176-81. Epub 2013 Aug 15.

School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Korea.

The potential of graphene as a mesenchymal stem cell (MSC) culture substrate to promote cardiomyogenic differentiation is demonstrated. Graphene exhibits no sign of cytotoxicity for stem cell culture. MSCs are committed toward cardiomyogenic lineage by simply culturing them on graphene. This may be attributed, at least partially, to the regulation of expression levels of extracellular matrix and signaling molecules.
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http://dx.doi.org/10.1002/adhm.201300177DOI Listing
February 2014
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