Anti-senescence ion-delivering nanocarrier for recovering therapeutic properties of long-term-cultured human adipose-derived stem cells.

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.

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.

Anti-fibrotic and anti-stricture effects of biodegradable biliary stents braided with dexamethasone-impregnated sheath/core structured monofilaments.

Endoscopic biliary stent insertion has been widely used for the treatment of benign biliary stricture (BBS). Thus, the development of stent materials in the perspectives of structure, mechanical properties, and biocompatibility has been also studied. However, conventional metal and plastic stents have several disadvantages, such as repeated procedures to remove or exchange them, dislodgment, restenosis, biocompatibility, and poor mechanical properties. Sustainable effectiveness, attenuation and prevention of fibrosis, and biocompatibility are key factors for the clinical application of stents to BBS treatment. In addition, loading drugs could show synergistic effects with stents' own performance. We developed a dexamethasone-eluting biodegradable stent (DBS) consisting of a sheath/core structure with outstanding mechanical properties and sustained release of dexamethasone, which maintained its functions in a BBS duct over 12 weeks in a swine model. The insertion of our DBS not only expanded BBS areas but also healed secondary ulcers as a result of the attenuation of fibrosis. After 16 weeks from the insertion, BBS areas were totally improved, and the DBS was degraded and thoroughly disappeared without re-intervention for stent removal. Our DBS would be an effective clinical tool for non-vascular diseases. STATEMENT OF SIGNIFICANCE: This study describes the insertion of a drug-eluting biodegradable stent (DBS) into the bile duct. The sheath/core structure of DBS confers substantial durability and a sustained drug release profile. Drug released from the DBS exhibited anti-fibrotic effects without inflammatory responses in both in vitro and in vivo experiments. The DBS maintained its function over 12 weeks after insertion into the common bile duct, expanding benign biliary stricture (BBS) and reducing inflammation to heal secondary ulcers in a swine BBS model. After 16 weeks from the DBS insertion, the DBS thoroughly disappeared without re-intervention for stent removal, resulting in totally improved BBS areas. Our findings not only spotlight the understanding of the sheath/core structure of the biodegradable stent, but also pave the way for the further application for non-vascular diseases.

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.

Silica-Based Advanced Nanoparticles For Treating Ischemic Disease.

Recently, various attempts have been made to apply diverse types of nanoparticles in biotechnology. Silica nanoparticles (SNPs) have been highlighted and studied for their selective accumulation in diseased parts, strong physical and chemical stability, and low cytotoxicity. SNPs, in particular, are very suitable for use in drug delivery and bioimaging, and have been sought as a treatment for ischemic diseases. In addition, mesoporous silica nanoparticles have been confirmed to efficiently deliver various types of drugs owing to their porous structure. Moreover, there have been innovative attempts to treat ischemic diseases using SNPs, which utilize the effects of Si ions on cells to improve cell viability, migration enhancement, and phenotype modulation. Recently, external stimulus-responsive treatments that control the movement of magnetic SNPs using external magnetic fields have been studied. This review addresses several original attempts to treat ischemic diseases using SNPs, including particle synthesis methods, and presents perspectives on future research directions.

Detection and quantification of the metabolite Ac-Tß1-14 in in vitro experiments and urine of rats treated with Ac-Tß4: A potential biomarker of Ac-Tß4 for doping tests.

Thymosin ß4 (Tß4) was reported to exert various beneficial bioactivities such as tissue repair, anti-inflammation, and reduced scar formation, and it is listed on the prohibited substances in sports by the World Anti-Doping Agency. However, no metabolism studies of Tß4 were reported yet. Previously, our lab reported in in vitro experiment that a total of 13 metabolites were found by using multiple enzymes, and six metabolites (Ac-Tß31-43 , Ac-Tß17-43 , Ac-Tß1-11 , Ac-Tß1-14 , Ac-Tß1-15 , and Ac-Tß1-17 ) were confirmed by comparing with the synthetic standards. This study was aimed at identifying new metabolites of Tß4 leucine aminopeptidase (LAP), human kidney microsomes (HKM), cultured huvec cells, and rats after administration of Tß4 protein to develop biomarkers for detecting doping drugs in sports. A method for detecting and quantifying Ac-Tß1-14 was developed and validated using Q-Exactive orbitrap mass spectrometry. The limit of detection (LOD) and limit of quantification (LOQ) of the Ac-Tß1-14 were 0.19 and 0.58 ng/mL, respectively, and showed a good linearity (r2 = 0.9998). As a result, among the six metabolites above, Ac-Tß1-14 , as a common metabolite, was found in LAP, HKM, huvec cells exposed to Tß4, and the urine of rats intraperitoneally treated with 20-mg/kg Tß4. And the metabolite Ac-Tß1-14 was quantitatively determined by 48 h in rats, with the highest concentration occurring between 0 and 6 h. Ac-Tß1-14 was not detected in non-treated control groups, including human blank urine. These results suggest that Ac-Tß1-14 in urine is a potential biomarker for screening the parent Tß4 in doping tests.

Challenges and advances in materials and fabrication technologies of small-diameter vascular grafts.

The arterial occlusive disease is one of the leading causes of cardiovascular diseases, often requiring revascularization. Lack of suitable small-diameter vascular grafts (SDVGs), infection, thrombosis, and intimal hyperplasia associated with synthetic vascular grafts lead to a low success rate of SDVGs (< 6 mm) transplantation in the clinical treatment of cardiovascular diseases. The development of fabrication technology along with vascular tissue engineering and regenerative medicine technology allows biological tissue-engineered vascular grafts to become living grafts, which can integrate, remodel, and repair the host vessels as well as respond to the surrounding mechanical and biochemical stimuli. Hence, they potentially alleviate the shortage of existing vascular grafts. This paper evaluates the current advanced fabrication technologies for SDVGs, including electrospinning, molding, 3D printing, decellularization, and so on. Various characteristics of synthetic polymers and surface modification methods are also introduced. In addition, it also provides interdisciplinary insights into the future of small-diameter prostheses and discusses vital factors and perspectives for developing such prostheses in clinical applications. We propose that the performance of SDVGs can be improved by integrating various technologies in the near future.

Subaqueous 3D stem cell spheroid levitation culture using anti-gravity bioreactor based on sound wave superposition.

BACKGROUND: Recently, various studies have revealed that 3D cell spheroids have several advantages over 2D cells in stem cell culture. However, conventional 3D spheroid culture methods have some disadvantages and limitations such as time required for spheroid formation and complexity of the experimental process. Here, we used acoustic levitation as cell culture platform to overcome the limitation of conventional 3D culture methods. METHODS: In our anti-gravity bioreactor, continuous standing sonic waves created pressure field for 3D culture of human mesenchymal stem cells (hMSCs). hMSCs were trapped and aggerated in pressure field and consequently formed spheroids. The structure, viability, gene and protein expression of spheroids formed in the anti-gravity bioreactor were analyzed by electron microscope, immunostaining, polymerase chain reaction, and western blot. We injected hMSC spheroids fabricated by anti-gravity bioreactor into the mouse hindlimb ischemia model. Limb salvage was quantified to evaluate therapeutic efficacy of hMSC spheroids. RESULTS: The acoustic levitation in anti-gravity bioreactor made spheroids faster and more compact compared to the conventional hanging drop method, which resulted in the upregulation of angiogenic paracrine factors of hMSCs, such as vascular endothelial growth factor and angiopoietin 2. Injected hMSCs spheroids cultured in the anti-gravity bioreactor exhibited improved therapeutic efficacy, including the degree of limb salvage, capillary formation, and attenuation of fibrosis and inflammation, for mouse hindlimb ischemia model compared to spheroids formed by the conventional hanging drop method. CONCLUSION: Our stem cell culture system using acoustic levitation will be proposed as a new platform for the future 3D cell culture system.

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.

Metal Ion Releasing Gold Nanoparticles for Improving Therapeutic Efficiency of Tumor Targeted Photothermal Therapy.

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.

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.

In situ forming and rutin-releasing chitosan hydrogels as injectable dressings for dermal wound healing.

An in situ gel-forming system composed of rutin- and tyramine-conjugated chitosan derivatives, horseradish peroxidase (HRP), and hydrogen peroxide (H(2)O(2)) was prepared and applied to dermal wound repair. Rutin was employed to enhance production and accumulation of extracellular matrix in the healing process. In vitro study demonstrates that released rutin significantly enhanced cell proliferation as compared with media without rutin. In vivo wound healing study was performed by injecting hydrogels on rat dorsal wounds with a diameter of 8 mm for 14 days. Histological results demonstrated that rutin-conjugated hydrogel exhibited enhancement of wound healing as compared with treatments with PBS, hydrogel without rutin, and a commercialized wound dressing (Duoderm). More specifically, rutin-conjugated hydrogels induced better defined formation of neo-epithelium and thicker granulation, which is closer to the original epithelial tissue. As a result, this study suggests that the in situ gel-forming system can be a promising injectable gel-type wound dressing.

Endothelial Cell-Derived Tethered Lipid Bilayers Generating Nitric Oxide for Endovascular Implantation.

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.

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.