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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]

The restoration of damaged endothelium is promising to reduce side effects, including restenosis and thrombosis, in the stent treatment for vascular diseases. Current technologies based on drug delivery for these complications still do not satisfy patients due to invariant recurrence rate. Recently, even if one approach was applied to clinical trial to develop the firstly commercialized stent employing circulating endothelial progenitor cells (EPCs) in blood vessels, it resulted in failure in clinical trial. Based on instruction of the failed case, we designed an advanced EPC-capture stent covered with anti-CD146 antibody (Ab) immobilized silicone nanofilament (SiNf) for the highly efficient and specific capture of not early but late stage of EPCs. In vitro cell capture test demonstrates enhanced capture efficiency and adhesion morphology of late EPCs on the modified substrate. The modified substrates could capture 8 times more late EPCs and even 3 times more mesenchymal stem cells (MSCs) as compared to unmodified one. A porcine model with high similarity to human reproduced in vivo results ideally translated from in vitro cell capture results. As restenosis indicators, lumen area, neointimal rate and stenosis area for modified stents were reduced at the range of 30-60% as compared to those for bare metal stent (BMS). Fibrin score indicating thrombosis was lowered less than half as comparing to that on BMS. These inspiring results are attributed to ~2-fold increased endothelial coverage, determined by immuno-histological staining. Taken together, the CD146 Ab-armed nanofilamentous stent could show great performance in the reduction of thrombosis and restenosis through re-endothelialization due to highly efficient specific cell capture. STATEMENT OF SIGNIFICANCE: Stents have been developed from simple metal stents to functionalized stents for past decades. However, they have still risks to relapse the occlusion in stented arteries. In this paper, we describe the fabrication and optimization of cell capturing stents to maximize the effective re-endothelialization through the serial coating of silicone nanofilaments and anti-CD146 antibody. The nanofilaments increase the amount of coated antibodies and provide the anchoring points of circulating angiogenic cells for strong focal adhesion. We demonstrate high immobilizing ability of circulating angiogenic cells (endotheliali progenitor cells and mesenchymal stem cells) in vitro under similar shear stress to coronary arteries (15 dyne/cm2). Also, we show accelerating re-endothelialization and the efficient prevention of restenosis in porcine coronary arteries in vivo.

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: 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.

In the never ending search for novel advanced drug delivery systems that would overcome the drawbacks, such as inducing the immune system and low drug loading, of currently utilized exogenous nanomaterials, a group of highly biocompatible and versatile drug carriers stand out from the rest, the “lipid-based family” of drug carriers. This family of carriers are unique due to their high bio-mimicking ability of cell membranes, making their toxicity of low concern and the modification of their targeting ability an achievable task. Herein, we will focus our discussion on two main members of this family, the exosomes and the naturally derived supported lipid bilayers (SLBs), as drug delivery platforms that have caught the attention of researchers in recent years due to their wide range of potential applications in the arena of targeted delivery. The significance of this chapter is to inform the reader about the history, advantages, shortcomings, potential, and applications of these two naturally derived carriers in biomedicine.

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.

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.

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.

Vascular stent is tubular shaped medical device designed to treat occluded circulatory or digestive systems by opening the blocked vascular sites. Originally stents were made of bare metals, such as stainless steel and cobalt–chromium alloys, due to their inherent corrosion resistance and good mechanical properties. Damage of intimal layer during expansion of stent, however, have caused neointimal hyperplasia resulting in in-stent restenosis which is one of main complications of vascular stent treatment. Drug-eluting stents (DESs) were introduced to alleviate this restenosis by local delivery of anti-proliferative drugs to the implanted or inserted site. The DES systems have been developed over the years by making changes in its main component, namely, drug, polymeric coating layer and expandable scaffold. Nevertheless, late thrombosis caused by drugs themselves and polymeric coating layer still remains as a serious problem of DES systems. Numerous studies, therefore, consistently focus on more advanced DES systems to solve the current issues. In this mini review article, we cast an opinion on how to improve the potential of DES system by means of (i) summarizing the history of DES system developed so far and (ii) updating current advances for the future generation of DES system.

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.

Over the last decade, numerous biopolymers have received more attention in medical applications involving novel biomaterials because of their biocompatibility, biodegradability, and ease of processing. To date, many biopolymer-based functional composites have been developed to increase the value of raw biopolymers obtained from natural sources or microbial systems. This review article covers general information on various biopolymers, important methods for biopolymer-based composites preparation including their advantages and disadvantages, and surface topography for tissue engineering. In addition, this article provides comprehensive knowledge and highlights recent research on functional biopolymer composites used in various medical applications, such as tissue engineering comprising skin, bone, cartilage, vascular graft, and other organs, implantable medical devices including stent and barrier membrane, and some delivery systems of bioactive agents. Furthermore, the article presents a brief overview on several challenges and future scope in this field.

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.

The restoration of a damaged endothelium might be a fascinating way to reduce significantly late-thrombosis and restenosis in the stent treatment. It has been recently reported that the recruitment of endothelial progenitor cells (EPCs), capable for repairing a damaged endothelium, can be important in the vascular stent application. Therefore, we focused on the hypothesis that stromal cell-derived factor-1α (SDF-1α) acts as a key chemokine for the mobilization and recruitment of EPCs to the damaged endothelium lesion. In this study, the effect of SDF-1α released from a cobalt-chromium alloy (Co-Cr) plate, vascular stent material, was investigated on the recruitment of EPCs in vitro. Dopamine-conjugated heparin was synthesized to introduce heparin onto Co-Cr. Heparin-coated Co-Cr surfaces were examined by water contact angle and attenuated total reflectance-Fourier transform infrared (ATRFTIR) to prove successful coating of heparin. Finally, SDF-1α was bound to the coated heparin derivative. Amounts of loaded and released SDF-1α were measured by ELISA, and the recruited EPC by released SDF-1α was evaluated using two different migration assays. The quantity of SDF-1α bound to the heparin-modified surface increased in a concentration-dependent manner and SDF-1α was released over 28 days. Transwell migration assay revealed that soluble SDF-1α released from the heparin-coated Co-Cr induced significantly more EPC recruitment than bare Co-Cr and heparin-coated Co-Cr. More importantly, fibrin gel migration assay further demonstrated that EPCs evidently respond to heparin-based substrate with SDF-1α and this type of behaviors was surprisingly found at as low level as less 1 ng/day of SDF-1α. These results are strongly encouraging for further in vitro and in vivo studies. Open image in new window

Biomedical devices have come a long way since they were first introduced as a medically interventional methodology in treating various types of diseases. Different techniques were employed to make the devices more biocompatible and promote tissue repair; such as chemical surface modifications, using novel materials as the bulk of a device, physical topological manipulations and so forth. One of the strategies that recently gained a lot of attention is the use of tissue-inspired biomaterials that are coated on the surface of biomedical devices via different coating techniques, such as the use of extracellular matrix (ECM) coatings, extracted cell membrane coatings, and so on. In this chapter, we will give a general overview of the different types of tissue-inspired coatings along with a summary of recent studies reported in this scientific arena.

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.