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Light has attracted significant attention as a promising tool in the biomedical and cosmetic industries. However, little is known about the cytotoxic effects of conventional light sources based on their physical effects such as temperature and luminance. Here, the cytotoxic effects of representative light sources, a light-emitting diode (LED) and an organic light-emitting diode (OLED), were studied with human adipose-derived stem cells (hADSCs). Regardless of the identical light energy conditions, LED group induced a higher apoptotic activity in hADSCs than the OLED group due to its significant heat generation compared to OLED as further demonstrated with heat shock protein family gene expression. Additionally, we further confirmed the effect of luminance by irradiating light from LED and OLED under the same temperature and energy conditions. Increased cell proliferation was confirmed in the OLED group, and a significant expression of intracellular reactive oxygen species was observed in the LED group without showing heat shock protein upregulation. Taken together, the differences in cytotoxicity and cellular response after LED irradiation compared with OLED irradiation can be varied with temperature and luminance control. This study suggests that OLED based device could be an alternative and promising light source for future biomedical and cosmetic applications.

BACKGROUND: To prevent unsolved problems of medical devices, we hypothesized that combinatorial effects of zwitterionic functional group and anti-bacterial metal ions can reduce effectively the thrombosis and bacterial infection of polymeric biomaterials. In this research, we designed a novel series of zwitterionic polyurethane (zPU) additives to impart anti-thrombotic properties to a polyvinyl chloride (PVC) matrix. METHODS: We have synthesized zPUs by combination of various components and zPUs complexed with metal ions. Zwitterion group was prepared by reaction with 1,3-propane sultone and Nmethyldiethanolamine and metal ions were incorporated into sulfobetaine chains via molecular complexation. These zPU additives were characterized using FT-IR, 1H-NMR, elemental analysis, and thermal analysis. The PVC film blended with zPU additives were prepared by utilizing a solvent casting and hot melting process. RESULTS: Water contact angle demonstrated that the introduction of zwitterion group has improved hydrophilicity of polyurethanes dramatically. Protein adsorption test resulted in improved anti-fouling effects dependent on additive concentration and decreases in their effects by metal complexation. Platelet adhesion test revealed anti-fouling effects by additive blending but not significant as compared to protein resistance results. CONCLUSION: With further studies, the synthesized zPUs and zPUs complexed with metal ions are expected to be used as good biomaterials in biomedical fields. Based on our results, we can carefully estimate that the enhanced anti-fouling effect contributed to reduced platelet adhesion. GRAPHIC ABSTRACT: Schematic explanation of the effect of zwitterionic polyurethane additives for blood-compatible and anti-bacterial bulk modification. [Image: see text]

Engineering an endothelium-mimetic surface has been one of long-lasting topics to develop ideal cardiovascular devices. The aim of the study was to investigate the potential use of a model of lipid bilayers that not only come from membranes extracted from endothelial cells (ECs) but also embedded with a type of organoselenium lipid enabling it to catalyze the generation of nitric oxide (NO). Herein, the titanium-cloaking in lipid bilayers extracted from ECs was prepared to propose a promising idea for the development of endovascular implants. For this purpose, we synthesized and characterized a lipidic molecule containing selenium and verified enough catalytic activity for the NO generation in the presence of S-nitrosothiols (RSNO) as endogenous NO precursors. We demonstrated the fabrication process of tethered lipid bilayers, from membrane extraction to vesicle fusion, and validated the successful formation of the layer and the catalyst insertion. The resulting bilayer presented endothelium-similar properties including the NO generation and cellular interactions. The catalyst inserted into the bilayer provided an unexampled result in the release period and kinetics of NO, likely similar to the native endothelial system. Using three different cells including EC, smooth muscle cell (SMC), and macrophage, it was demonstrated that the membrane responds selectively to each cell in the manner of promotive, suppressive, and nonimmunoreactive, respectively. Taken together, the fundamental study on obtained results not only provides understanding of the kinetics of designed NO catalyst and cellular interactions of reassembled membranes but also suggests very useful data on rational design and development of many vascular implantable devices, even expandable toward to nonvascular biointerfacing devices.

The aim of this study was to investigate the feasibility and potential use of tethered lipid bilayer (tLB) membranes with a lipophilic nitric oxide (NO) donor (10-nitrooleate) incorporated into the bilayer to achieve the controlled release of NO from tLB membrane-anchored on a metal surface. NO releasing tLB membranes were prepared via two steps: (1) tethering phospholipids on a metal surface and (2) fusing NO donor containing liposomes with the lipids pre-tethered on the surface. Surface analyses using Fourier transform infrared (FTIR), fluorescent and confocal and atomic force microscopy (AFM) were utilized to prove the successful tLB formation on titanium surface. Bovine serum albumin and fibrinogen tests showed minimum adsorption on the tLB samples when compared with bare titanium plates. After the incorporation of 10-nitrooleate into the bilayer, the samples exhibited sustained NO release profiles up to 24 h. In vitro cell study demonstrated that NO releasing tLB has pleiotropic effects on endothelial cells and smooth muscle cells. Finally, these results open up a door for the potential use of bioactive gas releasing tLB for biomedical devices.

Background Human adipose-derived stem cells (hADSCs) have been used in various fields of tissue engineering because of their promising therapeutic efficacy. However, the stemness of hADSCs cannot be maintained for long durations, and their therapeutic cellular functions, such as paracrine factor secretion decrease during long-term cell culture. To facilitate the use of long-term-cultured hADSCs (L-ADSCs), we designed a novel therapeutic anti-senescence ion-delivering nanocarrier (AIN) that is capable of recovering the therapeutic properties of L-ADSCs. In the present study, we introduced a low-pH-responsive ion nanocarrier capable of delivering transition metal ions that can enhance angiogenic paracrine factor secretion from L-ADSCs. The AINs were delivered to L-ADSCs in an intracellular manner through endocytosis. Results Low pH conditions within the endosomes induced the release of transition metal ions (Fe) into the L-ADSCs that in turn caused a mild elevation in the levels of reactive oxygen species (ROS). This mild elevation in ROS levels induced a downregulation of senescence-related gene expression and an upregulation of stemness-related gene expression. The angiogenic paracrine factor secretion from L-ADSCs was significantly enhanced, and this was evidenced by the observed therapeutic efficacy in response to treatment of a wound-closing mouse model with conditioned medium obtained from AIN-treated L-ADSCs that was similar to that observed in response to treatment with short-term-cultured adipose-derived stem cells. Conclusions This study suggests a novel method and strategy for cell-based tissue regeneration that can overcome the limitations of the low stemness and therapeutic efficacy of stem cells that occurs during long-term cell culture. Graphical Abstract

BACKGROUND: Owing to the tumor-targeted migration capacity of human mesenchymal stem cells (hMSCs), they have been combined with nanoparticles for photothermal therapy. However, the low viability of hMSCs following transplantation remains a problem. Here, we developed iron (Fe) ion-releasing gold (Au) nanoparticles (IIAuNPs) for advanced tumor-targeted photothermal therapy using hMSCs. METHODS: IIAuNPs were designed to undergo degradation under low pH conditions, such as the endosomal microenvironment, for Fe ion release in hMSCs. After evaluating the properties of IIAuNP, the IIAuNP concentration for treating hMSCs was optimized in terms of cytotoxicity. In vitro cell migration and antiapoptotic factor secretion were observed in hMSCs. Additionally, IIAuNPs-treated hMSCs were intravenously injected into tumor-bearing mice, and enhanced tumor targeting based on improved cell viability and cell migration was evaluated. Three days after the injection, the mice were irradiated with 660 nm laser to confirm the enhanced photothermal effect. RESULTS: In vitro studies revealed that treating hMSCs with an optimum concentration of IIAuNPs enhanced cell migration and anti-apoptotic gene expression through intracellular Fe ion delivery. The viability of hMSCs under hypoxic cell culture conditions that mimic the in vivo microenvironment was also improved when hMSCs were treated with IIAuNPs, compared to hMSCs without IIAuNPs treatment. IIAuNPs-treated hMSCs showed significantly enhanced tumor-targeting efficiency and subsequent photothermal effect compared to hMSCs without IIAuNP treatment. CONCLUSION: Our results suggest that our metal-ion-releasing photothermal nanoparticles may provide a promising platform for future photothermal therapies and related applications.

Drug-eluting stents (DESs) have been used for the treatment of cardiovascular diseases including stenosis. However, in-stent restenosis, thrombosis, and delayed re-endothelialization represent challenges for their clinical applications. Here, we demonstrate a novel work to overcome these limitations through surface modification technology. The cobalt-chromium (Co-Cr) surface was modified with antioxidants such as gallic acid (GA) and rutin (Ru) and the corresponding persulfates derivatives (i.e., GAS, and RuS) through a simple conjugation procedure. Various analyses tools such as ATR-FTIR, XPS, water contact angle, SEM, and AFM characterized the functionalized surface. The surface characterization confirmed that the antioxidant and the additional persulfates were successfully bonded to the Co-Cr surface. The results of in vitro endothelial cells proved that the persulfates derivatives showed the highest tendency to get rapid re-endothelialization especially RuS. In addition, it showed inhibition to smooth muscle cells (SMCs) as compared to control Co-Cr substrate. The persulfates modified substrates reduced the amount of adsorbed fibrinogen and albumin with higher stability to fetal bovine serum. Moreover, platelet study also demonstrated that Ru and RuS presented lower platelet adhesion with round shape morphology, whereas the control Co-Cr adhere and activate many platelets with pseudopodium morphology. Moreover, these modification processes did not cause any inflammatory responses. In conclusion, it is believed that the persulfates flavonoids have a great potential in the field of drug-eluting stents and blood contacting medical implants to improve blood compatibility, suppress SMCs, and get rapid re-endothelialization.

Synthetic biodegradable polymers including poly(lactide-co-glycolide) (PLGA) have been widely used as alternatives to metallic implantable materials in the orthopedic field due to their superior biocompatibility and biodegradability. However, weak mechanical properties of the biodegradable polymers and inflammatory reaction caused by the acidic degradation products have limited their biomedical applications. In this study, we have developed a PLGA composite containing beta-tricalcium phosphate (β-TCP) and magnesium hydroxide (Mg(OH)2) as additives to improve mechanical, osteoconductivity, and anti-inflammation property of the biopolymer composite simultaneously. The β-TCP has an osteoconductive effect and the Mg(OH)2 has a pH neutralizing effect. The PLGA/inorganic composites were uniformly blended via a twin extrusion process. The mechanical property of the PLGA/β-TCP/Mg(OH)2 composite was improved compared to the pure PLGA. In particular, the addition of Mg(OH)2 suppressed the inflammatory reaction of normal human osteoblast (NHOst) cells and also inhibited the differentiation of pre-osteoclastic cells into osteoclasts. Moreover, synergistically upregulated late osteogenic differentiation of NHOst cells was observed on the PLGA/β-TCP/Mg(OH)2 composite. Taken all together, we believe that the use of β-TCP and Mg(OH)2 as additives with synthetic biodegradable polymers has great potential by the synergistic effect in orthopedic applications.

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 10.24 N, while that of PDO stent was 5.64 N. Deteriorations of tensile strength, elastic modulus and elongation during degradation test were also delayed on PDO/PLLA group. Hyaluronic acid–dopamine conjugate and BaSO4/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.

Fibroblast-derived extracellular matrix (fECM)-supported scaffolds made up of poly(lactic-co-glycolic acid) were prepared with the enhanced preservation of ECM components by composites with magnesium hydroxide nanoparticles (MH NPs), and were applied for the renal tissue regeneration. MH NP utilization resulted in an increased ECM protein amount, decreased scaffold degradation, and surface hydrophilic modification. These effects were correlated with the improved adhesion and viability of renal proximal tubule epithelial cells on the scaffold. In vivo experiments demonstrated effects of fECM and MH NPs on renal regeneration. The number of glomeruli was the largest in the ECM scaffold with MH NPs as compared to the pristine scaffold and ECM scaffold without MH NPs. Quantitative PCR analysis exhibited less inflammation (IL-1β, TNF-α, and IL-6) and fibrosis-related (vimentin, collagen I, and α-SMA) markers, whereas opposite results were found in regeneration-related markers (Pax2, vWf, Wt1, and Emx2). The concentration of renal function-related molecules, creatinine and blood urea nitrogen diminished in the ECM scaffold with MH NPs. All results indicate that MH NPs utilization for the renal regenerative scaffold is effective for in vitro and in vivo environments and is, therefore, a good model for regeneration of kidneys and other tissues, and organs.

Catechol-conjugated chitosan (CCs), used as tissue adhesive, wound dressing, and hemostatic materials, has been drawing much more attention. However, most CCs tissue adhesives exhibit poor adhesion strength, and few studies on optimization of cohesion and adhesion strength of CCs derivatives have been conducted. This work focused on the balance between cohesion and adhesion strength of catechol-conjugated chitosan (CCs) derivatives via different mechanisms of chemical and enzymatic conjugation. CCs derivatives were characterized regarding its mechanical property, cytotoxicity, platelet adhesion and wound healing test. Mechanical properties could be optimized by the degree of catechol substitution, pH and the presence of oxidizing agent, resulting in that the highest value of adhesive shear strength to the porcine tissue is 64.8 ± 5.7 kPa. In addition, CCs derivatives exhibit decreased toxicity and promoted in vivo wound healing effects as comparing to a commercially available adhesive (Dermabond®). All the results demonstrate that CCs derivatives can be used as well-optimized tissue adhesives as well as a hemostat.

Biodegradable polymers, such as poly(L-lactide) (PLLA), are very useful in many biomedical applications. However, their degradation by-products have been much of a concern as they are the sources of inflammatory reactions in the body. In this work, we suggest a novel composite system composed of PLLA and oligolactide-grafted magnesium hydroxide (Mg-OLA) that can overcome drawbacks caused by poor mechanical properties and inflammatory response of PLLA for biomedical applications. Mg-OLAs were synthesized by ring opening polymerization and the structure, morphology, pH change, thermal, and mechanical properties were analyzed using FTIR, SEM, pH meter, TGA, and UTM. In particular, the tensile strength and modulus of PLLA/Mg80-OLA20 (0–20 wt%) were higher than those of PLLA/magnesium hydroxide. The PLLA/Mg80-OLA20 composite was also very effective in neutralizing the acidic environment caused by the degradable by-product of the PLLA matrix. In vitro cell viability and the expression levels of COX-2 and IL-6 proteins in the PLLA composites were also evaluated. Cell viability increased to around 100% with increasing the amount of Mg80-OLA20 from 0 to 20 wt%. The expression levels of IL-6 and COX-2 were reduced dramatically when increasing the proportion of Mg80-OLA20 from 0 to 50 wt%. As a result, the incorporation of Mg-OLAs into the PLLA matrix could reinforce the mechanical properties as well as reduce the inflammatory response of the hybrid PLLA. Therefore, this hybrid composite system blending oligomer-grafted magnesium hydroxide in biodegradable polymers would be a promising strategy for avoiding current fatal problems in biomedical applications.

Bulk blending is considered as one of the most effective and straightforward ways to improve the hemo-compatibility of blood-contacting polymeric biomaterials among many surface modification methods. Zwitterionic structure-, glycocalyx-like structure-, and heparin-like structure-based oligomers have been synthesized as additives and blended with base polymers to improve the blood compatibility of base polymers. Fluorinated end- and side-functionalized oligomers could promote the migration of functionalized groups to the surface of biomedical polymers without changing their bulk properties, and it highly depends on the number and concentration of functional groups. Moreover, oligomers having both zwitterion and fluorine are receiving considerable attention due to their desirable phase separation, which can avoid undesired protein adsorption and platelet adhesion. The surface analysis of the surface-modified materials is usually investigated by analytical tools such as contact angle measurement, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Blood compatibility is mainly evaluated via platelet adhesion and protein adsorption test, and the result showed a significant decrease in the amount of undesirable adsorption. These analyses indicated that surface modification using bulk blending technique effectively improves blood compatibility of polymeric biomaterials.

Atherosclerotic plaques within the vasculature may eventually lead to heart failure. Currently, cardiac stenting is the most effective and least invasive approach to treat this disease. However, in-stent restenosis is a complex chronic side effect of stenting treatment. This study used coronary stents coated with stem cells secreting angiogenic growth factors via an inducible genome-editing system to reduce stent restenosis and induce re-endothelialization within the artery. The characteristics of the cells and their adhesion properties on the stents were confirmed, and the stents were transplanted into a swine model to evaluate restenosis and the potential therapeutic use of stents with stem cells. Restenosis was evaluated using optical coherence tomography (OCT), microcomputed tomography (mCT) and angiography, and re-endothelialization was evaluated by immunostaining after cardiac stent treatment. Compared to a bare metal stent (BMS) or a parental umbilical cord blood-derived mesenchymal stem cell (UCB-MSC)-coated stent, the stents with stem cells capable of the controlled release of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) successfully reduced restenosis within the stent and induced natural re-endothelialization. Furthermore, UCB-MSCs exhibited the ability to differentiate into endothelial cells in Matrigel, and HGF and VEGF improved this differentiation. Our study indicates that stents coated with UCB-MSCs secreting VEGF/HGF reduce the restenosis side effects of cardiac stenting with improved re-endothelialization.

Drug-eluting stents (DESs) are used to treat cardiovascular diseases such as atherosclerosis. The anti-proliferative drug released from the DES suppress the proliferation of smooth muscle cells and reduced in-stent restenosis. However, a burst release of the drug in the early stages and degradation morphology of the polymer coating represent major disadvantages, which might increase the incidence of in-stent restenosis and/or thrombosis under in vivo clinical studies. To solve these problems, in this study, a double-layer coating system composed of poly(lactide) (PLLA) bottom layer and poly(lactide-co-glycolide) (PLGA) top layer are used for the fabrication of DES. PLLA bottom layer was firstly coated on the metal surface followed by oxygen ion beam treatment. It was found that increasing the ion beam exposure time, increased the roughness of PLLA surface with a nanoscale pocket (or hole)-like structure. The top layer coating represented a mixture of PLGA and paclitaxel (PTX) with 5, 10, and 20% PTX contents. The coating was performed through ultrasonic spray technique, and the morphology showed not only a smooth and uniform surface but also no irregularities were observed at zero day. The drug release and degradation morphology for single-layer (PLGA/PTX) and double-layer (PLLA/PLGA/PTX) coatings were compared. The drug release from the double-layer stainless steel (SS) group showed a slower and controlled drug release for all PTX content samples as compared to single-layer SS group. Moreover, the degradation morphology of double-layer SS group presented a smoother and uniform surface after 12 weeks of degradation under physiological conditions. Therefore, an oxygen ion beam technique with double-layer coating system could effectively control the drug release, i.e., prevent initial burst drug release, and improve the degradation morphology of biodegradable polymer-based DESs.

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 in vitro 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 in vivo 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. Statement of Significance 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 in vivo 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.

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- co-glycolide), by using oligo(lactide)-grafted magnesium hydroxide (Mg(OH)2) nanoparticles, which neutralize the acidic environment. In particular, we demonstrated that incorporating the modified Mg(OH)2 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)2 nanoparticles may be useful to extend the applicability and improve clinical success of biodegradable devices used in various biomedical fields.

Five different shapes of magnesium hydroxide (Mg(OH)2) particles (Plate-S, Plate-N, Disk, Whisker, and Fiber) were synthesized and added to biopolymer (i.e., Poly(lactic-co-glycolic acid) (PLGA)) composite to improve their mechanical and biological properties. The PLGA composite films including Mg(OH)2 particles were prepared by a solvent casting method. Their mechanical and biological properties were compared according to the composites containing different shapes of Mg(OH)2 particles. Among them, the fiber shape of Mg(OH)2 provided the highest mechanical strength, and anti-inflammation and anti-bacterial activity to PLGA films among other forms. This study demonstrated a new strategy for the design of biomaterials by controlling the form of inorganic additives.

For the development of anti-thrombotic biomaterials, blending a surface migrating oligomer (SMO) in a biomedical polymer has been focused as a promising alternative way to conventional coatings. In this study, novel SMOs with the polyurethane backbone containing zwitterion and fluorine were synthesized and blended it with polyvinyl chloride (PVC) to confer synergistic anti-thrombotic performance through anti-fouling effect. Studies using elemental analysis, FT IR, 1H NMR and ion chromatography demonstrated the successful incorporation of sulfobetaine and fluorine in the SMOs. The thermal analysis characterized PVC/SMO-blended films with varied glass transition temperatures. X-ray photoelectron spectroscopy represented high compositions of sulfur and fluorine atoms at the surface of SMOs-blended PVCs, proving that SMOs effectively migrated toward the surface during the film preparation. The SMOs-blended PVC films not only improved resistivity to the adsorption of albumin and fibrinogen but also inhibited the adhesion and activation of human platelets, meaning enhanced anti-fouling effect and thereby anti-thrombogenicity. In particular, the SMOs-blended PVCs with both sulfobetaine and fluorine were synergistically effective in the reduction in cell/platelet adhesion and protein adsorption. In summary, our results give a positive cue that the novel type of SMOs containing both sulfobetaine and fluorinated segments can be a promising material for anti-thrombogenic surface modification in cardiovascular applications.

In the present study, a novel synthetic tissue adhesive material capable of sealing wounds without the use of any crosslinking agent was developed by conjugating thermosensitive hexanoyl glycol chitosan (HGC) with gallic acid (GA). The degree of N-gallylation was manipulated to prepare GA-HGCs with different GA contents. GA-HGCs demonstrated thermosensitive sol-gel transition behavior and formed irreversible hydrogels upon natural oxidation of the pyrogallol moieties in GA, possibly leading to GA-HGC crosslinks through intra/intermolecular hydrogen bonding and chemical bonds. The GA-HGC hydrogels exhibited self-healing properties, high compressive strength, strong tissue adhesive strength and biodegradability that were adjustable according to the GA content. GA-HGCs also presented excellent biocompatibility and wound healing effects. The results of in vivo wound healing efficacy studies on GA-HGC hydrogels indicated that they significantly promote wound closure and tissue regeneration by upregulating growth factors and recruiting fibroblasts compared to the untreated control group.

Silicone rubber is widely used in various biomedical fields. However, the silicone surface is known to cause biofouling and thrombosis issues due to its higher hydrophobic property. In this study, to improve its antifouling property and blood compatibility, silicone rubber was modified by coating of hyaluronic acid (HA) or poly(ethylene glycol) (PEG). To enhance adhesive property of HA and PEG on the silicone surface, HA and PEG were modified by introducing the amino groups of dopamine (DA) to the carboxyl group of each polymer. The modified HA (HA-DA) and PEG (PEG-DA) were confirmed by 1H nuclear magnetic resonance (NMR) and the coated surfaces were characterized with contact angle, X-ray photoelectron spectroscopy (XPS), and micro-bicinchoninic acid (micro-BCA) analyses. To compare antifouling property and blood compatibility, adsorbed proteins, adhered platelets, and anticoagulation on the modified surfaces were evaluated by fluorescence microscopy, scanning electron microscopy, and activated partial thromboplastin time (APTT) assay, respectively. The property of cell adhesion on the modified surface was evaluated by NIH 3T3 fibroblast as a model cell system. Protein, platelet, and fibroblast showed low adsorption and adhesion on the modified silicone rubber surfaces compared to the unmodified one. Especially, the third coated silicone rubber surfaces were found to strongly resist protein adsorption as well as platelet and fibroblast adhesion. These results indicated that the antifouling property and blood compatibility were enhanced significantly on HA-DA and PEG-DA immobilized silicone rubbers. Therefore, these modified silicone rubbers can be used in various biomedical applications.

Nitric oxide (NO) is crucial for body homeostasis at moderate levels, but cytotoxic at high levels, thus making it a potential candidate for anticancer therapies and antibacterial surface coatings. To date, NO use has been limited due to its very short half-life. Many strategies have been utilized in an attempt to control the half-life of NO, including (but not limited to) lipid-based carriers, due to their biocompatibility and versatility. Areas covered: In this review, we discuss the latest studies that aimed to control the release of NO via a variety of lipid-based delivery carriers, such as liposomes (echogenic and normal) and microbubbles. In addition, we discuss the different types of NO donors used to control and target the release of NO. Expert opinion: Achieving a NO releasing lipid-based systems to mimic the natural release rate of NO remains a challenging task. Many promising strategies are still to be tackled, such as NO release supported lipid bilayers using GPx mimicking catalysts instead of vesicles, or the use of lipophillic NO donors such as nitrooleate instead of the conventional hydrophilic NO donors. These new strategies may present us with better alternatives to the previously published systems.

Several developments are in progress for improving the performance of drug-eluting stents (DESs) including use of biodegradable polymers, polymer-free DES, fully bioabsorbable stents, and so on. The commercially available DESs still suffer from polymer defects that could affect the performance of a DES through a series of adverse events such as coating delamination and/or peeling-off that lead to non-uniform local drug distribution, restenosis, and thrombosis. The goal of this work was to enhance the stability of drug-in-polymer matrix coating on a stent metal surface through surface modification. The cobalt–chromium (Co–Cr) surface was chemically modified using poly(dopamine) (PDA) nano-coating and poly(L-lactide) (PLLA) nano-brush in order to be applied to a biodegradable polymer-coated DES. The biodegradable polymer loaded with sirolimus was coated using an ultrasonic spray coating instrument. The coating morphology on all samples showed a very smooth and uniform coating. The stability of the coating was evaluated for 2 months under the circulation system in which the drug-in-polymer coating on the PLLA brush-modified stent presented the most stable coating behavior as compared to other samples. The in vitro sirolimus release study from both unmodified and modified stents was studied in phosphate-buffered saline (PBS), and the modified stents showed slower sirolimus release profile as compared to unmodified stents. In vivo study was performed in a porcine coronary artery injury model for 28 days. The percentage of in-stent restenosis area (ISR) for PLLA brush-modified sirolimus-eluting stent (SES) decreased significantly as compared to unmodified SES and bare metal stent (BMS). This study demonstrated that the modification of stent surface using PLLA brushes affects in vitro and in vivo performance effectively to be applied for biodegradable polymercoated DES.

The sustained or controlled release of nitric oxide (NO) can be the most promising approach for the suppression or prevention of restenosis and thrombosis caused by stent implantation. The aim of this study is to investigate the feasibility in the potential use of layer-by-layer (LBL) coating with a NO donor-containing liposomes to control the release rate of NO from a metallic stent. Microscopic observation and surface characterizations of LBL-modified stents demonstrate successful LBL coating with liposomes on a stent. Release profiles of NO show that the release rate is sustained up to 5 d. In vitro cell study demonstrates that NO release significantly enhances endothelial cell proliferation, whereas it markedly inhibits smooth muscle cell proliferation. Finally, in vivo study conducted with a porcine coronary injury model proves the therapeutic efficacy of the NO-releasing stents coated by liposomal LBL technique, supported by improved results in luminal healing, inflammation, and neointimal thickening except thrombo-resistant effect. As a result, all these results demonstrate that highly optimized release rate and therapeutic dose of NO can be achieved by LBL coating and liposomal encapsulation, followed by significantly efficacious outcome in vivo.

Drug-eluting stents (DESs) have been used to treat coronary artery diseases by placing in the arteries. However, current DESs still suffer from polymer coating defects such as delamination and peeling-off that follows stent deployment. Such coating defects could increase the roughness of DES and might act as a source of late or very late thrombosis and might increase the incident of restenosis. In this regard, we modified the cobalt–chromium (Co–Cr) alloy surface with hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA) or hydrophobic poly(2-hydroxyethyl methacrylate)-grafted-poly(caprolactone) (PHEMA-g-PCL) brushes. The resulting surfaces were biocompatible and biodegradable, which could act as anchoring layer for the drug-in-polymer matrix coating. The two modifications were characterized by ATR-FTIR, XPS, water contact angle measurements, SEM and AFM. On the control and modified Co–Cr samples, a sirolimus (SRL)-containing poly(D,L-lactide) (PDLLA) were ultrasonically spray-coated, and the drug release was examined for 8 weeks under physiological conditions. The results demonstrated that PHEMA as a primer coating improved the coating stability and degradation morphology, and drug release profile for short-term as compared to control Co–Cr, but fails after 7 weeks in physiological buffer. On the other hand, the hydrophobic PHEMA-g-PCL brushes not only enhanced the stability and degradation morphology of the PDLLA coating layer, but also sustained SRL release for long-term. At 8-week of release test, the surface morphologies and release profiles of coated PDLLA layers verified the beneficial effect of hydrophobic PCL brushes as well as their thickness on coating stability. Our study concludes that 200 nm thickness of PHEMA-g-PCL as interfacial layer affects the stability and degradation morphology of the biodegradable coating intensively to be applied for various biodegradable-based DESs.

Polymer-based drug-eluting stents (DESs) represented attractive application for the treatment of cardiovascular diseases; however, polymer coating has caused serious adverse responses to tissues such as chronic inflammation due to acidic by-products. Therefore, polymer-free DESs have recently emerged as promising candidates for the treatment; however, burst release of drug(s) from the surface limited its applications. In this study, we focused on delivery of therapeutic drug from polymer-free (or -less) DESs through surface modification using cobalt oxide nanowires (Co3O4 NWs) to improve and control the drug release. The results demonstrated that Co3O4 NWs could be simply fabricated on cobalt–chromium substrate by ammonia-evaporation-induced method. The Co3O4 NWs were uniformly arrayed with diameters of 50–100 nm and lengths of 10 µm. It was found that Co3O4 NWs were comparatively stable without any delamination or change of the morphology under in vitro long-term stability using circulating system. Sirolimus was used as a model drug for studying in vitro release behavior under physiological conditions. The sirolimus release behavior from flat cobalt–chromium showed an initial burst (over 90%) after one day. On the other hand, Co3O4 NWs presented a sustained sirolimus release rate for up to seven days. Similarly, the polymer-less specimens on Co3O4 NWs substrates sustained sirolimus release for a longer-period of time when compared to flat Co–Cr substrates. In summary, the current approach of using Co3O4 NWs-based substrates might have a great potential to sustain drug release for drug-eluting implants and medical devices including stents.

The appropriate anti-adhesive effect of polymers on cells or tissues in the body is one of the essential requirements of maintaining health and protecting the body from trauma and foreign bodies. Regulating the anti-adhesive properties of biomedical polymers against cells has been considered a pivotal parameter in developing polymeric biomaterials for biomedical applications such as artificial blood vessels and cell encapsulation. Meanwhile, tissue adhesion barriers that can physically isolate wounds and thus effectively prevent the formation of tissue adhesion have been a hot topic in both research and industrial fields. This review describes the comprehensive knowledge and recent research efforts on polymers for anti-adhesion to both cells and tissues. The basic concepts and mechanisms for the design and performance of anti-adhesive polymers are introduced in terms of both cell and tissue. Polymer-based approaches for anti-adhesion to cells or tissues are then extensively discussed.

Objectives/Hypothesis This study was conducted to determine whether a surface-modified tracheal T-tube can prevent tracheal stenosis in a rabbit model. Study Design Animal model study. Methods We designed surface-modified tracheal T-tubes in which silicone rubber was modified by coating it with hyaluronic acid (HA) or polyethylene glycol (PEG). Sixteen rabbits were divided into four insertion groups: normal, silicone tube, silicone tube coated with HA, and silicone tube coated with PEG. Surface-modified tubes were inserted into the tracheal lumen after a scraping injury on the inner tracheal mucosa around the preformed tracheostoma. Laryngoscopy was performed to evaluate formation of stenosis in the trachea. Histological examinations were performed to evaluate epithelial thickness, inflammatory response, and fibrosis. Results Endoscopic finding showed that the HA- and PEG-coated tube groups had less granulation tissue in the trachea than the noncoated tube group. Greater epithelialization was observed in the noncoated tube group than in the normal group. HA- and PEG-coated tube groups showed a tendency to decreasing epithelialization compared with the noncoated tube group. More inflammatory cells were observed in the noncoated tube group than in the normal group, and fewer inflammatory cells were observed in the HA- and PEG-coated tube groups than in the noncoated tube group. The noncoated tube group showed a greater area of fibrosis than the HA- and PEG-coated tube groups. Conclusions A surface-modified tracheal T-tube may have a favorable effect on reducing tracheal stenosis in a rabbit model. We suggest that local application of HA and PEG should be further researched for prevention of tracheal stenosis. Our rabbit model could be helpful in providing an additional scenario for evaluating new strategies to prevent tracheal stenosis. Level of Evidence NA Laryngoscope, 125:1465–1471, 2015

Two kinds of magnesium hydroxide (Mg(OH)2) rods (Mg-Rod, 150 and 350 nm in size) and plates (Mg-PL, 60 and 300 nm) were prepared, and blended with poly(L-lactide) (PLLA) to obtain PLLA/Mg(OH)2 composites to investigate the effect of the shape and size of Mg(OH)2 particles. The structure, morphology, pH change, thermal and mechanical properties, cytotoxicity, and inflammation of Mg(OH)2 control and PLLA/Mg(OH)2 composites were evaluated. PLLA/Mg-Rod150 (30%) composite showed a 50% higher tensile strength and a 45% improved modulus as compared with PLLA/Mg-PL300 30% composite. Although Mg-Rods displayed similar cell viability (above 80%) as compared to Mg-PLs, the expression levels of TNF-α from Mg-PL60 gradually increased with increasing concentrations from 1 to 300 μg. This indicates that Mg-PL60 had a potential cytotoxicity due to endocytosis. In addition, the byproduct of PLLA/Mg-Rods composite was more effectively neutralized than that of the PLLA/Mg-PLs composite, but cell viability and the expression levels of TNF-α were similar. Therefore, the use of our PLLA/Mg-Rod composite system would be a promising strategy to prevent the current fatal problems in biomedical applications including biodegradable implants such as stents.

Crack prevention of biodegradable polymer coatings on drug-eluting stents was investigated by introducing a nano-coupled layer at the interface between the metal surface and the polymer coating layer using surface-initiated ring-opening polymerization of ε-caprolactone. Poly(d,l-lactide-co-glycolide) coating on cobalt-chromium control and ricinoleic acid-poly(caprolactone)–grafted cobalt-chromium was carried out using electrospraying. The cracking of the biodegradable polymer coating on drug-eluting stents during ballooning was addressed by introducing a nano-coupled interlayer on the cobalt-chromium surface. The ricinoleic acid-poly(caprolactone) nano-coupled interlayer and poly(d,l-lactide-co-glycolide)-coated top layer were characterized using attenuated total reflection Fourier transform infrared, contact angle, ellipsometry, X-ray photoelectron spectroscopy, and atomic force microscopy. Based on scratch tests, the nano-coupled samples had stronger interfacial adhesion compared to the control sample without the nano-coupled layer. Scanning electron microscope images indicated that the cracking on the poly(d,l-lactide-co-glycolide) coating was addressed. Introducing a nano-coupling interlayer may be an important strategy to preventing polymer coating cracking on drug-eluting stents.

Sirolimus (SRL) release from the biodegradable poly(l-lactic-co-glycolic acid) (PLGA) matrix was investigated for the application of drug-eluting stents (DES). In particular, this study focused on whether various organic solvents affect the interaction between SRL and PLGA and the formation of microstructures during ultrasonic coating. The SRL-loaded PLGA coated by tetrahydrofuran or acetone showed a significant initial burst, whereas that from acetonitrile was constantly released during a period of 21 days. On the basis of these results, the interactions at the molecular level of SRL with the polymer matrix were estimated according to various organic solvents. Although the topographies of the coated surface were obviously different, the correlation between surface roughness and SRL release was very poor. Irrespective of organic solvents, FT-IR data showed significantly weak SRL-PLGA interactions. From the result of wide-angle X-ray diffraction, it was confirmed that SRL was dispersed in an amorphous state in the polymer matrix after ultrasonic coating. The glass-transition temperature was also influenced by organic solvents, resulting in a plasticizing effect. The particle size of SRL appeared to determine the release profile from the PLGA matrix, which was the combination of diffusion and polymer degradation at an SRL size of more than 800 nm and the Fickian release at that of less than 300 nm. Therefore, organic solvents can lead to a heterogeneous microstructure in the SRL-loaded PLGA matrix, which is at or near the surface, consisting of aggregated drug- and polymer-rich regions. It is expected that the drug release can be controlled by physicochemical properties of organic solvents, and this study can be used effectively for localized drug release in biomedical devices such as drug-eluting stents.

During the balloon expansion of several commercially available drug-eluting stents, various types of defects in the polymer layer have been observed. The aim of this study is to prevent these defects by increasing the interfacial adhesion between the metal substrate and the drug-in-polymer matrix using poly(caprolactone) (PCL) brushes onto a cobalt-chromium (Co-Cr or CC) alloy surface. The chemical modification of the Co-Cr surface was accomplished by grafting ricinoleic acid (RA) onto the metal substrate followed by surface-initiated ring opening polymerization of ε-caprolactone. The unmodified, RA-grafted (CC-RA), and PCL-grafted Co-Cr substrates (CC-RA-PCL3D and CC-RA-PCL6D) were characterized by various surface analyses. Poly(d,l-lactide) containing sirolimus was spray coated onto the unmodified and modified substrates. The adhesion property of the polymer coating on the PCL-grafted surfaces was improved compared to those of other samples. Among all of the drug-in-polymer coated samples, both CC-RA-PCL3D and CC-RA-PCL6D exhibited a stabilized drug release profile over 49 days. It was also revealed that CC-RA-PCL6D showed the slowest drug release of all the samples. On the basis of these results, the proposed nanocoupling method has shown not only improved adhesion of the drug-in-polymer matrix to the Co-Cr substrate but also controlled drug release.

Biodegradable polymers such as poly(L-lactide) (PLLA) have been widely utilized as materials for biomedical applications. However, the relatively poor mechanical properties of PLLA and its acid-induced cell inflammation brought about by the acidic byproducts during biodegradation pose severe problems. In this study, these drawbacks of PLLA are addressed using a stereocomplex structure, where oligo-D-lactide-grafted magnesium hydroxide (MgO-ODLA) is synthesized by grafting d-lactide onto the surface of magnesium hydroxide, which is then blended with a PLLA film. The structure, morphology, pH change, thermal and mechanical properties, in-vitro cytotoxicity, and inflammation effect of the MgO-ODLAs and their PLLA composites are evaluated through various analyses. The PLLA/MgO70-ODLA30 (0-20 wt%) composite with a stereocomplex structure shows a 20% increase in its tensile strength and an improvement in the modulus compared to its oligo-L-lactide (PLLA/MgO70-OLLA30) counterpart. The interfacial interaction parameter of PLLA/MgO70-ODLA30 (5.459) has superior properties to those of PLLA/MgO70-OLLA30 (4.013) and PLLA/Mg(OH)2 (1.774). The cell cytotoxicity and acid-induced inflammatory response are suppressed by the neutralizing effect of the MgO-ODLAs. In addition, the inflammatory problem caused by the rapid acidification of the stereocomplex structure is also addressed. As a result, the stereocomplex structure of the MgO-ODLA/PLLA composite can be used to overcome the problems associated with the biomedical applications of PLLA films.

【In the current study, a drug-eluting stent coated with biodegradable polymers and sirolimus was developed by using an ultrasonic nanocoater and characterized in aspects of surface smoothness and coating thickness. In addition, in vitro release profiles of sirolimus by changing top coating layer with different biodegradable polymers were investigated. Smooth surfaces with variable thickness could be fabricated by optimizing polymer concentration, flow rate, nozzle-tip distance, gas pressure, various solvents and ultrasonic power. Smooth surface could be generated by using volatile solvents (acetone, chloroform, and methylene chloride) or post-treating with solvent vapor. Coating thickness could be controlled by varying injection volume or polymer concentration, and higher concentration could reduce the coating time while obtaining the same thickness. The thickness measurement was the most effectively performed by a conventional cutting method among three different methods that were investigated in this study. Release profiles of sirolimus were effectively controlled by changing polymers for top layer. PLGA made the release rate 3 times faster than PDLLA and PLLA and all top layers prevented burst release at the initial phase of profiles. Our results will provide useful and informative knowledge for developing drug-eluting stents, especially coated with biodegradable polymers.】

Specific biodegradable polymers having shape-memory properties through "polymer-blend" method are investigated and their shape-switching in body temperature (37 °C) is characterized. Poly(L-lactide-co-caprolactone) (PLCL) and poly(L-lactide-co-glycolide) (PLGA) are dissolved in chloroform and the films of several blending ratios of PLCL/PLGA are prepared by solvent casting. The shape-memory properties of films are also examined using dynamic mechanical analysis (DMA). Among the blending ratios, the PLCL50/PLGA50 film shows good performance of shape-fixity and shape-recovery based on glass transition temperature. It displays that the degree of shape recovery is 100% at 37 °C and the shape recovery proceeds within only 15 s. In vitro biocompatibility studies are shown to have good blood compatibility and cytocompatibility for the PLCL50/PLGA50 films. It is expected that this blended biodegradable polymer can be potentially used as a material for blood-contacting medical devices such as a self-expended vascular polymer stents and vascular closure devices in biomedical applications.

Poly(D,L-lactic-co-glycolic acid) (PLGA) has been widely used as a biodegradable polymer in the fabrication of porous polymer scaffolds, but it is hydrolyzed into acidic by-products such as glycolic acid and lactic acid in the human body. Magnesium hydroxide nanoparticles (Mg-NPs) were incorporated into a PLGA scaffold in order to neutralize the acidic environment caused by the hydrolysis of PLGA, thereby reducing the cytotoxicity and inflammatory response. In this study, three-dimensional porous scaffolds blended with 30% Mg-NP were fabricated using gas foaming (PLGA/Mg/NaHCO3), salt leaching (PLGA/Mg/NaCl), and freeze drying (PLGA/Mg/Ice), and their structures, morphologies, pH change, thermal properties, and mechanical properties were analyzed by Fourier transform infrared spectroscopy, scanning electron microscopy, pH meter, thermogravimetric analysis, and a universal testing machine. The porosity of the PLGA/Mg/Ice scaffold was higher at about 10-13 wt% than those of the PLGA/Mg/NaCl or PLGA/Mg/NaHCO3 scaffolds. The Mg-NP content of the PLGA/Mg/NaHCO3 scaffold remained lower than those of the other scaffolds at about 63%. As a result of this loss of Mg-NP, the PLGA/Mg/NaHCO3 scaffold was confirmed to have lower cell viability (about 70%) than the PLGA/Mg/Ice scaffold (about 100%), owing to the reduced neutralizing effect. Although the PLGA/Mg/Ice and PLGA/Mg/NaCl scaffolds showed similar cell viability, the NaCl of the PLGA/Mg/NaCl scaffold exhibited slight toxicity in the body. The expression level of interleukin-6 (IL-6) was significantly decreased in the PLGA/Mg/Ice scaffold than in the PLGA/Ice scaffold, but the PLGA/Mg/Ice scaffold exhibited an IL-6 expression level that was about 10% lower than that of the PLGA/Mg/ NaCl scaffold. Consequently, the addition of Mg-NP/Ice could conceivably reduce the expression level of IL-6 in PLGA scaffolds. This anti-inflammatory PLGA/Mg/Ice scaffold is therefore expected to show great promise when used as a template in tissue engineering. Open image in new window

Combination chemotherapy using more than two therapeutic agents with different modes of action is a promising strategy that can be used to enhance the therapeutic efficacy of cancer treatment, even though it is a complicated treatment modality. The aim of this study was to investigate how a novel multidrug nanocarrier is effective for combination chemotherapy in vitro and, more specifically, whether combined agents with different modes of action and physicochemical properties show synergistic cytotoxicity with the use of this nanocarrier. A heparin-Pluronic (Hep-Pr) nanogel encapsulating both paclitaxel and DNase was shown to be efficient for intracellular delivery with respect to size, encapsulation efficiency, and intracellular uptake/fates. As a result of these properties, a Hep-Pr nanogel combined with paclitaxel and DNase exhibited a dose-dependent synergistic cytotoxicity compared to single drug and free-drug treatments, whose combination indices were 0.93 and 0.45 at higher concentrations (250 and 500 μg/mL). Therefore, Hep-Pr nanogels have the potential to deliver multitherapeutic agents with different characteristics and thereby enhance the therapeutic efficacy of combination cancer chemotherapy.

Various drug-eluting stents (DESs) have been developed to prevent restenosis after stent implantation. However, DES still needs to improve the drug-in-polymer coating stability and control of drug release for effective clinical treatment. In this study, the cobalt-chromium (CoCr) alloy surface was coated with biodegradable poly(D,L-lactide) (PDLLA) and sirolimus (SRL) mixed with hydrophilic Pluronic F127 additive by using ultrasonic spray coating system in order to achieve a stable coating surface and control SRL release. The degradation of PDLLA/SRL coating was studied under physiological solution. It was found that adding F127 reduced the degradation of PDLLA and improved the coating stability during 60days. The effects of organic solvent such as chloroform and tetrahydrofuran (THF) on the coating uniformity were also examined. It was revealed that THF produced a very smooth and uniform coating compared to chloroform. The patterns of in vitro drug release according to the type of organic solvent and hydrophilic additive proposed the possibility of controllable drug release design in DES. It was found that using F127 the drug release was sustained regardless of the organic solvent used. In addition, THF was able to get faster and controlled release profile when compared to chloroform. The structure of SRL molecules in different organic solvents was investigated using ultra-small angle neutron scattering. Furthermore, the structure of SRL is concentration-dependent in chloroform with tight nature under high concentration, but concentration-independent in THF. These results strongly demonstrated that coating stability and drug release patterns can be changed by physicochemical properties of various parameters such as organic solvents, additive, and coating strategy.

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.

Background Biodegradable poly(L-lactic acid) (PLLA) is one of the most widely used polymer in biomedical devices, but it still has limitations such as inherent brittleness and acidic degradation products. In this work, PLLA blends with poly(L-lactide-ε-caprolactone) (PLCL) and Mg(OH)2 were prepared by the thermal processing to improve their physico-mechanical and thermal properties. In addition, the neutralizing effect of Mg(OH)2 was evaluated by degradation study. Results The elongation of PLLA remarkably increased from 3 to 164.4 % and the glass transition temperature (Tg) of PLLA was slightly reduced from 61 to 52 °C by adding PLCL additive. Mg(OH)2 in polymeric matrix not only improved the molecular weight reduction and mechanical strength of PLLA, but also neutralized the acidic byproducts generated during polyester degradation. Conclusions Therefore, the results demonstrated that the presence of PLCL and Mg(OH)2 additives in PLLA matrix could prevent the thermal decomposition and control degradation behavior of polyester.

A series of hybrid nanocomposites containing poly(L-lactide) (PLLA) and polyhedral oligomeric silsesquioxane (POSS) was prepared by solvent casting method for the enhancement of the mechanical properties of PLLA. One of them was mixed by only a physical blending between PLLA and POSS to form PLLA/POSS nanocomposite that did not show considerable improvement. In the other hand, two types of PLLA-POSS additives were synthesized via the ring-opening polymerization of L-lactide in the presence of POSS in different content. On these additives, POSS played as not only an initiator for the ring-opening polymerization reaction due to its hydroxyl functional groups on the surface but also a type of hybrid filler for PLLA/PLLA-POSS nanocomposite after mixing with PLLA matrix. PLLA/PLLA-POSS composite showed significant improvement in mechanical properties because of covalent bonding between PLLA and POSS. In particular, the tensile modulus has been apparently increased in PLLA/5PLLA-5POSS nanocomposites (1,449 MPa) with respect to PLLA control (498 MPa). SEM and XRD data indicated that the dispersion of PLLA-modified POSS was better than that of POSS in PLLA matrix. Although the contact angle was not significantly different, the protein adsorption and platelet adhesion are reduced slightly in PLLA/PLLA-POSS nanocomposite as compared to those of PLLA control and PLLA/POSS. Therefore, it is expected that biodegradable POSS nanocomposite may be helpful to be utilized in biomedical devices such as drug-eluting stents and artificial implants. Open image in new window

In this study, in situ–forming quercetin-conjugated heparin hydrogels to be used to coat metal surfaces for blood compatibility were developed and characterized. Four units of quercetin and poly(ethylene glycol)–tyramine were conjugated per heparin for blood compatibility and hydrogel formation, respectively. The product, quercetin-conjugated heparin–poly(ethylene glycol)–tyramine, was cross-linked in situ via an enzymatic reaction using horseradish peroxidase and hydrogen peroxide to form a hydrogel. The physicochemical properties, such as the gelation time and swelling/degradation time as well as the release kinetics of quercetin, were controlled by changing the catalytic concentrations. The quercetin-conjugated heparin hydrogel, when adhered to a metal surface, enhanced blood compatibility and reduced platelet adhesion by 77%. The release of quercetin inhibited the proliferation of smooth muscle cells. The quercetin-conjugated heparin–poly(ethylene glycol)–tyramine hydrogel is a promising biomaterial with a stable-coated metal surface, with enhanced blood compatibility and antiproliferation effects.

Surface-modified poly(L-lactic acid) (PLLA) films and scaffolds were treated with plasma discharge in oxygen gas and subsequently subjected to in situ grafting of acrylic acid (AA) in order to increase the cell compatibility. The surface of AA-grafted PLLA was converted to hydroxyapatite (HA)-deposited PLLA in stimulated body fluid (SBF). After the samples were immersed in phosphate-buffered saline (PBS), fetal bovine serum (FBS), normal saline, or cell medium, the water contact angles were significantly reduced on the surface of HA-deposited PLLA. Chondrocyte and osteoblast showed a higher attachment and cell proliferation on HA-deposited surfaces and in particular, it was confirmed that chondrocyte was considerably influenced by HA. However, osteoblast showed better cell proliferation on the surfaces immersed in FBS, cell medium or HA-deposited surface. In addition, the cell proliferation in 3D scaffolds was much higher than that on film type, irrespective of chondrocyte and osteoblast. Therefore, such surface-modified PLLAs are expected to be useful as organic-inorganic hybrid scaffolds in the regeneration of cartilage and bone.

The shell cross-linked micelles composed of tyramine-conjugated 4-arm poly(propylene oxide)–poly(ethylene oxide) was developed as a carrier for controlled drug delivery. The shell cross-linked tyramine-conjugated 4-arm poly(propylene oxide)–poly(ethylene oxide) micelles were prepared by an enzyme-mediated reaction using horseradish peroxidase and hydrogen peroxide. The physicochemical properties, size distribution, morphologies, and thermal properties of the shell cross-linked tyramine-conjugated 4-arm poly(propylene oxide)–poly(ethylene oxide) micelles were characterized to confirm the micelle formation and controllable properties dependent on the concentration of the catalysts. The in vitro cytocompatibility of the micelles was investigated using NIH3T3 fibroblast cells, and the shell cross-linked tyramine-conjugated 4-arm poly(propylene oxide)–poly(ethylene oxide) micelles showed low cytotoxicity. The in vitro hydrophobic drug release behavior from the shell cross-linked tyramine-conjugated 4-arm poly(propylene oxide)–poly(ethylene oxide) micelles was controllable with a sustained release behavior. Therefore, the shell cross-linked tyramine-conjugated 4-arm poly(propylene oxide)–poly(ethylene oxide) micelles via enzyme-mediated reaction have potential as nanocarriers for controlled drug delivery.

Three-dimensional scaffolds like hydrogels can be used for cell and drug delivery and have become a major research focus in tissue engineering. Presently, we investigated the regenerative potency of platelet-rich plasma (PRP) combined with a chondrocyte/hydrogel composite scaffold in the repair of articular cartilage defects using a rabbit model. Primary isolated joint chondrocytes from the trachlear groove of rabbit were cultured in hydrogels as follows; hydrogel (2900 Pa or 5900 Pa)+chondrocytes and hydrogel+chondrocytes+PRP for in vitro analysis and in vivo implantation. The 5900 Pa hydrogel markedly increased cellular viability and development in a time-dependent manner. Furthermore, the hydrogels attenuated the expression of SOX-9, aggrecan, and type II collagen. PRP-containing hydrogels produced an immediate increase in mRNA levels of cannabinoid receptor (CB)1 and CB2, compared with control and PRP-free hydrogels. Osteochondral defects were enhanced recovery with formation of cartilage and perichondrium in the 5900 Pa hydrogel+chondrocytes+PRP. Hydrogel may provide a suitable environment for proliferation and maturation of joint chondrocytes in relation to the gelation density and bioactive sources like PRP resulting in improvement for cartilage regeneration.

Rapid re-endothelialization of damaged vessel lining efficiently prevents restenosis and thrombosis and restores original vascular functions. In this study, we designed a novel metallic stent with a heparin-modified surface and used different methods, including 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and divinyl sulfone (DVS), to load growth factors. First we loaded heparin into a dopamine-conjugated hyaluronic acid (HA) coating to serve as a growth factor reservoir. In a second step, we took advantage of the heparin-binding domain of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) to gain advanced re-endothelialization capabilities. We demonstrated that DVS technique offered higher amount of growth factor loading. In vitro assessment also showed better capillary-like structure formation and localized gap junctions when DVS coating was employed. This study suggested that growth factor loaded stent modified by HA and heparin provided the advantage to rapid and tight restoration of endothelium.

A method of securing the adhesion of biodegradable polymer coating was investigated for drug-eluting metal stents, using surface-initiated ring-opening polymerization (SI-ROP) of L-lactide. Introduction of oligolactide on the stainless steel (SS) surface was successful and the thickness of the oligolactide grafts remained on the nanometer scale, as determined by ellipsometry. The presence of an oligolactide graft was also identified using attenuated total reflection-Fourier transform infrared (ATR-FTIR) and electron spectroscopy for chemical analysis (ESCA). On top of the grafts, poly(D,L-lactide-co-glycolide) (PLGA) coating was carried out on different substrates such as SS control, plasma-treated SS, and lactide-grafted (referred to as a nanocoupled) SS using electrospraying. When the adhesion forces were measured with a scratch tester, the nanocoupled SS showed the strongest interfacial adhesion between polymer coating layer and metal substrate. The outcome of the peel-off test was also consistent with the result of the scratch test. When degradation behavior of the polymer coating in vitro was examined for up to 4 weeks in a continuous fluid flow, the SEM images demonstrated that polymer degradation was obvious due to hydration and swelling of the polymer matrix. Although the matrix completely disappeared after 4 weeks for SS control and plasma-treated substrates, the nanocoupled SS was persistent with some polymer matrix. In addition, the release profiles of SRL-loaded PLGA coating appeared slightly different between control and nanocoupled groups. This work suggested that the concept of nanocoupling remarkably improved the interfacial adhesion stability between metal surface and polymer layer and controlled drug release, and showed the feasibility of drug-eluting stents.

Improving the efficacy of drug delivery via nanocarriers has been a major issue in the field of intravenous delivery. In this study, a polymeric nanogel was developed to enhance the stability, redox responsiveness, and the efficacy for intracellular protein delivery. The thiolated heparin-Pluronic conjugate was self-assembled and oxidized to form a disulfide-crosslinked nanogel network under a diluted aqueous condition. The disulfide-crosslinked heparin-Pluronic (DHP) nanogels with encapsulated RNase A were characterized by in vitro release and cytotoxicity tests depending on the existence of glutathione (GSH). The DHP nanogels exhibited reduced hydrodynamic size, higher encapsulation degree, and augmentable release responding to the GSH concentration. The ctotoxicity data confirmed that DHP nanogels were more effective for the intracellular delivery of RNase A compared to non-crosslinked nanogel.