Surface-Modifying Polymers for Blood-Contacting Polymeric Biomaterials.

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.

Tissue-Inspired Interfacial Coatings for Regenerative Medicine.

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.

Nitric Oxide Releasing Coronary Stent: A New Approach Using Layer-by-Layer Coating and Liposomal Encapsulation.

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.

A poly(lactide) stereocomplex structure with modified magnesium oxide and its effects in enhancing the mechanical properties and suppressing inflammation.

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.

Effect of solvent on drug release and a spray-coated matrix of a sirolimus-eluting stent coated with poly(lactic-co-glycolic acid).

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.

Reinforcement of interfacial adhesion of a coated polymer layer on a cobalt-chromium surface for 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.

Heparin-conjugated pluronic nanogels as multi-drug nanocarriers for combination chemotherapy.

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.

Sustained cytoplasmic delivery and anti-viral effect of PLGA nanoparticles carrying a nucleic acid-hydrolyzing monoclonal antibody.

PURPOSE: Cytoplasmic delivery of a monoclonal antibody (mAb) with nucleic acid-hydrolyzing activity (3D8 scFv) using poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) was investigated for persistent anti-viral effect. METHODS: 3D8 scFv-loaded PLGA (3D8-PLGA) NPs were prepared via a double emulsion method that was previously optimized. Flow cytometry and confocal microscopy was carried out to confirm the cellular uptake and cytoplasmic localization. immunochemical and fluorescence resonance energy transfer (FRET) assays tested the cytoplasmic release and hydrolyzing effect of 3D8 scFv, respectively. Anti-viral activity test was performed using MTT assay with vesicular stomatitis virus (VSV)-infected HeLa cells. RESULTS: 3D8-PLGA NPs were much more effectively taken into cells in dose- and time-dependent manner and localized in the cytosolic region, compared to free 3D8 scFv. 3D8 scFv was released and hydrolyzed RNAs in the cytoplasm, exhibiting the maxima at a period of time (12-24 h). Anti-viral activity test revealed that 3D8-PLGA NP has dose- and time-dependent anti-viral effect and the maximum effect at the dose of 2 mg/ml and the incubation of 3 days. CONCLUSIONS: Cytoplasmic delivery of 3D8 scFv via PLGA NPs could enhance the viability of infected cells in sustained manner due to preserved activity, much improved cellular uptake and sustained release.

Surface-Modifying Effect of Zwitterionic Polyurethane Oligomers Complexed with Metal Ions on Blood Compatibility.

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. Schematic explanation of the effect of zwitterionic polyurethane additives for blood-compatible and anti-bacterial bulk modification.

Improvement of interfacial adhesion of biodegradable polymers coated on metal surface by nanocoupling.

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.

Thermosensitive gallic acid-conjugated hexanoyl glycol chitosan as a novel wound healing biomaterial.

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.

In situ forming hydrogels based on tyramine conjugated 4-Arm-PPO-PEO via enzymatic oxidative reaction.

Over the past decades, hydrogels have been widely studied as biomaterials for various biomedical applications like implants, drugs and cell delivery carriers because of their high biocompatibility, high water contents and excellent permeability for nutrients and metabolites. Especially, in situ forming hydrogel systems have received much attention because of their easy application based on minimal invasive techniques. Chemical cross-linking systems fabricated using enzymatic reactions have various advantages, such as high biocompatibility and easy control of reaction rates under mild condition. In this study, we report enzyme-triggered injectable and biodegradable hydrogels composed of Tetronic-tyramine conjugates. The Tetronic-tyramine conjugates were synthesized by first reacting Tetronic with succinic anhydride and subsequent conjugation with tyramine using DCC/NHS as coupling reagents. The chemical structure of Tetronic-succinic anhydride-tyramine (Tet-SA-TA) copolymer was characterized by (1)H NMR and FTIR. The hydrogels were prepared from a Tet-SA-TA solution above 3 wt % in the presence of horseradish peroxidase (HRP) and H(2)O(2) under physiological conditions. Their mechanical property, gelation time, swelling ratio and degradation time were evaluated at different polymer, HRP, and H(2)O(2) concentrations. In addition, a cyto-compatibility study was performed using the MC3T3-E1 cell line. In the cytotoxicity test, it was clear that the Tet-SA-TA hydrogel had no apparent cytotoxicity except for the hydrogel formed with 0.25 wt % H(2)O(2) due to the cytotoxicity of residual H(2)O(2). In conclusion, the obtained results demonstrated that the Tet-SA-TA hydrogel has great potential for use as an injectable scaffold for tissue engineering and as a drug carrier for controlled drug delivery systems.

Balanced adhesion and cohesion of chitosan matrices by conjugation and oxidation of catechol for high-performance surgical adhesives.

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.

Synergistically enhanced osteoconductivity and anti-inflammation of PLGA/ß-TCP/Mg(OH)2 composite for orthopedic applications.

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 (ß-TCP) and magnesium hydroxide (Mg(OH)2) as additives to improve mechanical, osteoconductivity, and anti-inflammation property of the biopolymer composite simultaneously. The ß-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/ß-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/ß-TCP/Mg(OH)2 composite. Taken all together, we believe that the use of ß-TCP and Mg(OH)2 as additives with synthetic biodegradable polymers has great potential by the synergistic effect in orthopedic applications.

Hyper-branched poly(poly(ethylene glycol)methacrylate)-grafted surfaces by photo-polymerization with iniferter for bioactive interfaces.

A new hyper-branched surface in which three species of architectures were constructed as stem chain, branched stem and twig chain-grafted branched chain of poly(poly(ethylene glycol)methacrylate) (poly(PEGMA)) by photo-polymerization using dithiocarbamyl group (DC) as iniferter was prepared and characterized. For these surfaces, radical copolymerization of styrene and an iniferter-activated chain that was previously synthesized was performed for using as base materials for surface coating. On a DC-activated surface, hyper-branched poly(PEGMA) was introduced by photo-polymerization and dithiocarbamylation. All modified surfaces were analyzed by X-ray photoelectron spectroscopy (XPS) and water contact angle measurements. Our results demonstrated that a highly hyper-branched graft architecture of poly(PEGMA) can be constructed on PU surface by photo-polymerization using dithiocarbamyl group as iniferter, in which first, second and third generation gave stem chain, branched chain and twig chain of poly(PEGMA), respectively. Our hyper-branched surfaces could be regulated by photo-irradiation time and might be controlled by feed amounts or other reaction conditions. This highly dense architecture of PEG chain with hydrophilicity and chain mobility, grafted on surface, is expected to be effectively utilized in bio-implantable substrates or micro- or nano-patterned surfaces for immobilization of bioactive molecules in biomedical fields.

Controlled dual release of basic fibroblast growth factor and indomethacin from heparin-conjugated polymeric micelle.

This work describes the development of heparinized polymeric micelle as a novel injectable carrier for the dual drug delivery that can simultaneously release basic fibroblast growth factor (bFGF) and indomethacin (IMC), which can promote the regeneration of damaged tissue and prevent the inflammatory response after implantation. Tetronic-PCL-heparin for the preparation of heparinized polymeric micelle was synthesized by introducing PCL as a biodegradable linkage on Tetronic, following the conjugation of heparin. The mean diameter of the formed TCH micelle was around 114 nm and increases in the micelle size after single and dual drug loading were observed. Loading efficiencies of IMC and bFGF were 30.9% and 70.5%, respectively. In vitro dual drug release profiles from TCH micelles were investigated. IMC was more slowly released from dual drug-loaded micelle over 3 weeks as compared with single drug-loaded one. bFGF was released over 2 months in a controlled manner. Therefore, the release profile results support that TCH micelle could not only incorporate a hydrophobic drug into the core but also bind with bFGF to heparin that exists on its outer shell. The TCH micelle will have enhanced therapeutic effects on the target site which may be required the multi-function of drugs to use.

Nanoaggregate of thermosensitive chitosan-Pluronic for sustained release of hydrophobic drug.

A thermo-sensitive chitosan-Pluronic copolymer (CP) was prepared by grafting mono-carboxyl Pluronic onto the chitosan using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and N-hydroxysuccinimide (NHS). Indomethacin (IMC)-loaded nanoaggregate (NA) was prepared using the synthesized CP by the direct dissolution method. The critical aggregate concentration (CAC), hydrodynamic size and surface morphology of the prepared CP nanoaggregate (CPNA) were characterized by fluorescence spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM), respectively. The resulting CAC and the average diameter of CPNA were about 0.31 g/l and 120 nm, indicating high structural stability of CPNA and size favorable for intravenous delivery of drugs. In vitro release test of the IMC encapsulated into CPNA showed sustained release rate of IMC as compared with that from Pluronic micelle. Therefore, we can conclude that our CPNA can be a novel type of superior drug carrier for sustained delivery of hydrophobic drugs.

Versatile effects of magnesium hydroxide nanoparticles in PLGA scaffold-mediated chondrogenesis.

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.

Sustained drug release using cobalt oxide nanowires for the preparation of polymer-free drug-eluting stents.

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.

Modified Magnesium Hydroxide Nanoparticles Inhibit the Inflammatory Response to Biodegradable Poly(lactide- co-glycolide) Implants.

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.