Synergistic effect of anti-platelet and anti-inflammation of drug-coated Co–Cr substrates for prevention of initial in-stent restenosis

Lih, Eugene,Jung, Jee Won,Joung, Yoon Ki,Ahn, Dong June,Han, Dong Keun Elsevier 2016 Colloids and Surfaces B Vol.140 No.-

<P><B>Abstract</B></P> <P>Antiplatelet and antithrombotic therapies are systematically considered to prevent restenosis following coronary stent implantation. Currently, patients receiving medicated stents are prescribed to orally take anticoagulants and antiplatelet drugs such as aspirin (ASP) and prasugrel (PRAS). Propolis (PROP) known as a natural organic compound was recently evaluated for its antiplatelet activity, antibiotics and immunomodulatory activities. In this study, antiplatelet drug-coated Co–Cr substrates were prepared with biodegradable poly(<SMALL>D</SMALL>,<SMALL>L</SMALL>-lactide) (PDLLA) containing ASP, PRA, or PROP using electrospray and the blood compatibility of the different substrates was investigated by measuring protein adsorption and platelet adhesion. In addition, the anti-inflammatory properties of the modified Co–Cr surfaces were assessed by measuring IL-8 and IL-6 expression levels in human endothelial cell cultures. Drug-coated surfaces were found to resist the adsorption of fibrinogen when compared to bare Co–Cr or PDLLA-coated Co–Cr. Interestingly, ASP- and PROP-containing substrates not only showed reduced adhesion of platelets and delayed coagulation time, but also drastically reduced the expression level of IL-8 and IL-6. Such results are supported that ASP- or PROP-coated Co–Cr can be potentially used as a stent material to mitigate early stage of restenosis. The developed coating materials might be an interesting alternative to systemic anticoagulant therapies prescribed after stent implantation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Antiplatelet drug-coated Co–Cr substrates were prepared by using electrospray. </LI> <LI> Aspirin- and propolis-coated Co–Cr reduced platelet adhesion and activation. </LI> <LI> Aspirin- and propolis-coated Co–Cr have anti-inflammatory effect. </LI> <LI> Non-metabolized prasugrel on the stent does not cause any of these effects directly. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>The asprin (ASP)- and propolis (PROP)-coated cobalt–chrome (Co–Cr), reducing adhesion of platelets and the expression levels of inflammatory factors, can be potentially used as a coronary stent material to mitigate early stage of restenosis.</P> <P>[DISPLAY OMISSION]</P>

Modified Magnesium Hydroxide Nanoparticles Inhibit the Inflammatory Response to Biodegradable Poly(lactide-<i>co</i>-glycolide) Implants

Lih, Eugene,Kum, Chang Hun,Park, Wooram,Chun, So Young,Cho, Youngjin,Joung, Yoon Ki,Park, Kwang-Sook,Hong, Young Joon,Ahn, Dong June,Kim, Byung-Soo,Kwon, Tae Gyun,Jeong, Myung Ho,Hubbell, Jeffrey A.,H American Chemical Society 2018 ACS NANO Vol.12 No.7

<P>Biodegradable polymers have been extensively used in biomedical applications, ranging from regenerative medicine to medical devices. However, the acidic byproducts resulting from degradation can generate vigorous inflammatory reactions, often leading to clinical failure. We present an approach to prevent acid-induced inflammatory responses associated with biodegradable polymers, here poly(lactide-<I>co</I>-glycolide), by using oligo(lactide)-grafted magnesium hydroxide (Mg(OH)<SUB>2</SUB>) nanoparticles, which neutralize the acidic environment. In particular, we demonstrated that incorporating the modified Mg(OH)<SUB>2</SUB> nanoparticles within degradable coatings on drug-eluting arterial stents efficiently attenuates the inflammatory response and in-stent intimal thickening by more than 97 and 60%, respectively, in the porcine coronary artery, compared with that of drug-eluting stent control. We also observed that decreased inflammation allows better reconstruction of mouse renal glomeruli in a kidney tissue regeneration model. Such modified Mg(OH)<SUB>2</SUB> nanoparticles may be useful to extend the applicability and improve clinical success of biodegradable devices used in various biomedical fields.</P> [FIG OMISSION]</BR>

Biomimetic Porous PLGA Scaffolds Incorporating Decellularized Extracellular Matrix for Kidney Tissue Regeneration

Lih, Eugene,Park, Ki Wan,Chun, So Young,Kim, Hyuncheol,Kwon, Tae Gyun,Joung, Yoon Ki,Han, Dong Keun American Chemical Society 2016 ACS APPLIED MATERIALS & INTERFACES Vol.8 No.33

<P>Chronic kidney disease is now recognized as a major health problem, but current therapies including dialysis and renal replacement have many limitations. Consequently, biodegradable scaffolds to help repairing injured tissue are emerging as a promising approach in the field of kidney tissue engineering. Poly(lactic-co-glycolic acid) (PLGA) is a useful biomedical material, but its insufficient biocompatibility caused a reduction in cell behavior and function. In this work, we developed the kidney-derived extracellular matrix (ECM) incorporated PLGA scaffolds as a cell supporting material for kidney tissue regeneration. Biomimetic PLGA scaffolds (PLGA/ECM) with different ECM concentrations were prepared by an ice particle leaching method, and their physicochemical and mechanical properties were characterized through various analyses. The proliferation of renal cortical epithelial cells on the PLGA/ECM scaffolds increased with an increase in ECM concentrations (0.2, 1, 5, and 10%) in scaffolds. The PLGA scaffold containing 10% of ECM has been shown to be an effective matrix for the repair and reconstitution of glomerulus and blood vessels in partially nephrectomized mice in vivo, compared with only PLGA control. These results suggest that not only can the tissue-engineering techniques be an effective alternative method for treatment of kidney diseases, but also the ECM incorporated PLGA scaffolds could be promising materials for biomedical applications including tissue engineered scaffolds and biodegradable implants.</P>

Heparin Conjugated PLGA-PEG-PLGA as a Bioactive Hydrogel for Tissue Regeneration

Eugene Lih,Jin Woo Bae,Dong Hyun Go,Ki Dong Park 한국고분자학회 2006 한국고분자학회 학술대회 연구논문 초록집 Vol.2006 No.10

A Bioinspired Scaffold with Anti-Inflammatory Magnesium Hydroxide and Decellularized Extracellular Matrix for Renal Tissue Regeneration

Lih, Eugene,Park, Wooram,Park, Ki Wan,Chun, So Young,Kim, Hyuncheol,Joung, Yoon Ki,Kwon, Tae Gyun,Hubbell, Jeffrey A.,Han, Dong Keun American Chemical Society 2019 ACS central science Vol.5 No.3

<▼1><P/><P>Kidney diseases are a worldwide public health issue. Renal tissue regeneration using functional scaffolds with biomaterials has attracted a great deal of attention due to limited donor organ availability. Here, we developed a bioinspired scaffold that can efficiently induce renal tissue regeneration. The bioinspired scaffold was designed with poly(lactide-<I>co</I>-glycolide) (PLGA), magnesium hydroxide (Mg(OH)<SUB>2</SUB>), and decellularized renal extracellular matrix (ECM). The Mg(OH)<SUB>2</SUB> inhibited materials-induced inflammatory reactions by neutralizing the acidic microenvironment formed by degradation products of PLGA, and the acellular ECM helped restore the biological function of kidney tissues. When the PLGA/ECM/Mg(OH)<SUB>2</SUB> scaffold was implanted in a partially nephrectomized mouse model, it led to the regeneration of renal glomerular tissue with a low inflammatory response. Finally, the PLGA/ECM/Mg(OH)<SUB>2</SUB> scaffold was able to restore renal function more effectively than the control groups. These results suggest that the bioinspired scaffold can be used as an advanced scaffold platform for renal disease treatment.</P></▼1><▼2><P>PLGA scaffold with Mg(OH)<SUB>2</SUB> and renal ECM facilitates kidney reconstruction (histological structure and biological function) by neutralizing the acidic microenvironment and improving biocompatibility.</P></▼2>

Rapidly curable chitosan-PEG hydrogels as tissue adhesives for hemostasis and wound healing

Lih, Eugene,Lee, Jung Seok,Park, Kyung Min,Park, Ki Dong Elsevier 2012 ACTA BIOMATERIALIA Vol.8 No.9

RGD-Conjugated In Situ Forming Hydrogels as Cell-Adhesive Injectable Scaffolds

Ngoc Quyen Tran,정윤기,Eugene Lih,박경민,박기동 한국고분자학회 2011 Macromolecular Research Vol.19 No.3

In this study, a bioactive hydrogel was prepared from a chitosan derivative and Arg-Gly-Asp (RGD)-conjugated polypseudorotaxane, which is a cell-adhesive extracellular matrix. Chitosan was modified with 4-hydroxy phenyl acetic acid to obtain a water-soluble product for enzymatic cross-linking. Tyramine-terminated polypseudorotaxane (PRx) was prepared from the inclusion complex of a tyramine-terminated poly(ethylene glycol) backbone,and α-cyclodextrin (α-CD). Gly-Arg-Gly-Asp-Ser (GRGDS) was conjugated to the PRx using 4-nitrophenyl chloroformate (NPC) and partially carboxylated with succinic anhydride. The structure of the PRx-RGD and 4-hydroxylphenylacetamide chitosan (CHPA) was characterized by ^1H NMR and FTIR spectroscopy. The RGD content in PRx-RGD was determined to be 0.19%. PRx-RGD and CHPA solution was crosslinked to form a bioactive hydrogel in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H_2O_2), which exhibited rapid gelation (~20sec). An in vitro cell culture was carried out with L929 mouse fibroblasts for 1 and 3 days. The results showed that fibroblasts adhered better and appeared to be more biocompatible on the RGD-conjugated hydrogel than the hydrogel without RGD. The combined results highlight the potential use of this bioactive hydrogel as an injectable scaffold in tissue engineering applications.

Biodegradable sheath-core biphasic monofilament braided stent for bio-functional treatment of esophageal strictures

Han, Cheol-Min,Lih, Eugene,Choi, Seul-Ki,Bedair, Tarek M.,Lee, Young-Jae,Park, Wooram,Han, Dong Keun,Son, Jun Sik,Joung, Yoon Ki Elsevier 2018 Journal of industrial and engineering chemistry Vol.67 No.-

<P><B>Abstract</B></P> <P>In this study, a polydioxanone (PDO) and poly(L-lactic acid) (PLLA) sheath-core biphasic monofilament was designed to develop an esophageal stent with improved mechanical properties and controlled biodegradability. The radial force of PDO/PLLA sheath-core stent was 10.24N, while that of PDO stent was 5.64N. Deteriorations of tensile strength, elastic modulus and elongation during degradation test were also delayed on PDO/PLLA group. Hyaluronic acid–dopamine conjugate and BaSO<SUB>4</SUB>/PDO conjugate coating layers provided improved tissue adhesion strength and reasonable X-ray contrast, respectively. Taken all together, the sheath-core filaments with tissue adhesive and radiopaque properties will be useful in designing esophageal stents.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

<i>In situ</i> formation of enzyme-free hydrogels <i>via</i> ferromagnetic microbead-assisted enzymatic cross-linking

Bae, Jin Woo,Kim, Bae Young,Lih, Eugene,Choi, Jong Hoon,Lee, Yunki,Park, Ki Dong The Royal Society of Chemistry 2014 Chemical communications Vol.50 No.89

<P><I>In situ</I> formation of horseradish peroxidase (HRP)-free gelatin hydrogels was achieved <I>via</I> ferromagnetic microbead-assisted enzymatic cross-linking. Gelation time and mechanical stiffness of the hydrogels can be tuned <I>in situ</I>, which makes HRP-free gelatin hydrogels suitable for injectable cell delivery.</P> <P>Graphic Abstract</P><P>This work reports a new <I>in situ</I> enzymatic crosslinking method to prepare mechanically tunable hydrogels not possessing an enzyme. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c4cc04436c'> </P>

Versatile effects of magnesium hydroxide nanoparticles in PLGA scaffold–mediated chondrogenesis

Park, Kwang-Sook,Kim, Byoung-Ju,Lih, Eugene,Park, Wooram,Lee, Soo-Hong,Joung, Yoon Ki,Han, Dong Keun Elsevier 2018 ACTA BIOMATERIALIA Vol.73 No.-

<P><B>Abstract</B></P> <P>Artificial scaffolds made up of various synthetic biodegradable polymers have been reported to have many advantages including cheap manufacturing, easy scale up, high mechanical strength, convenient manipulation, and molding into an unlimited variety of shapes. However, the synthetic biodegradable polymers still have the insufficiency for cartilage regeneration owing to their acidic degradation products. To reduce acidification by degradation of synthetic polymers, we incorporated magnesium hydroxide (MH) nanoparticles into porous polymer scaffold not only to effectively neutralize the acidic hydrolysate but also to minimize the structural disturbance of scaffolds. The neutralization effect of poly(D,L-lactic-co-glycolic acid; PLGA)/MH scaffold was confirmed with the maintenance of neutral pH, contrary to a PLGA scaffold with low pH. Further, the scaffolds were applied to evaluate the chondrogenic differentiation of the human bone marrow mesenchymal stem cells. In <I>in vitro</I> study, the PLGA/MH scaffold enhanced the chondrogenesis markers and reduced the calcification, compared to the PLGA scaffold. Additionally, the PLGA/MH scaffold reduced the release of inflammatory cytokines, compared to the PLGA scaffold, as the cell death decreased. Moreover, the addition of MH reduced necrotic cell death at the early stage of chondrogenic differentiation. Further, the necrotic cell death by the PLGA scaffold was mediated by cleavage of caspase-1, the so-called interleukin 1-converting enzyme, and MH alleviated it as well as nuclear factor kappa B expression. Furthermore, the PLGA/MH scaffold highly supported chondrogenic healing of rat osteochondral defect sites in <I>in vivo</I> study. Therefore, it was suggested that a synthetic polymer scaffold containing MH could be a novel healing tool to support cartilage regeneration and further treatment of orthopedic patients.</P> <P><B>Statement of Significance</B></P> <P>Synthetic polymer scaffolds have been widely utilized for tissue regeneration. However, they have a disadvantage of releasing acidic products through degradation. This paper demonstrated a novel type of synthetic polymer scaffold with pH-neutralizing ceramic nanoparticles composed of magnesium hydroxide for cartilage regeneration. This polymer showed pH-neutralization property during polymer degradation and significant enhancement of chondrogenic differentiation of mesenchymal stem cells. It reduced not only chondrogenic calcification but also release of proinflammatory cytokines. Moreover, it has an inhibitory effect on necrotic cell death, particularly caspase-1-mediated necrotic cell death (pyroptosis). In <I>in vivo</I> study, it showed higher healing rate of the damaged cartilage in a rat osteochondral defect model. We expected that this novel type of scaffold can be effectively applied to support cartilage regeneration and further treatment of orthopedic patients.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>