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.

Preparation of azidophenyl-low molecular chitosan derivative micro particles for enhance drug delivery.

Systems for delivering damaged tissue by immobilization of a bioactive substance or a protein drug for rapid recovery of a patient are being studied. To immobilize drugs using natural polymer, photo-immobilization method has been designed. Immobilization through photo-reaction is a new technology that stabilizes drugs or growth factors for sustained release. Introduction of photo-reactive functional groups into biocompatible natural polymers produces materials applicable to the medical field. Since chitosan is a natural polymer with stability and biocompatibility, this study attempts to use chitosan as a mediator of drug delivery. In addition, If the form of the immobilized biomaterial is made into a micro-sized particle, it can be utilized as an injectable material in addition to the stability of the photo-immobilization. In photo-immobilization in particle form, the probability of exposure to the enzyme in the body is lower than if it is injected into the body in the conventional free state. In addition, since it can be freely injected into a desired target site, it can be used for various medical applications. Therefore, it is expected that various effects of growth factors and drugs can be utilized and additional effects can be obtained by photo-immobilization together with various effects.

Preparation of drug-immobilized anti-adhesion agent using visible light-curable alginate derivative containing furfuryl group.

This study demonstrated the anti-adhesion and wound healing effect of a visible light curable anti-adhesion agent using an alginate derivative modified with a furfuryl moiety. Visible light-curable furfuryl alginate (F-Alg) was prepared in conjugation with alginate and furfurylamine by an amide coupling reaction, and the conjugated F-Alg was characterized by 1H NMR analysis. The cytotoxicity, cell adhesion, and cell permeability of the F-Alg were evaluated for use in anti-adhesion applications. Drug immobilization and protein release were assessed to verify whether the alginate derivatives and drugs were photo-immobilized. In in vivo anti-adhesion testing, the new anti-adhesion agent prepared in this study acted as a physical protective layer by forming a biofilm on the surgical site. Additionally, along with gradual decomposition of the photo-crosslinked alginate derivative, the immobilized drug was released, and additional effects such as accelerated wound healing are expected. Thus, visible light-curable F-Alg has good application potential as an anti-adhesion agent.

Osteogenic effectiveness of photo-immobilized bone morphogenetic protein-2 using different azidophenyl-natural polymer carriers in rat calvarial defect model.

The osteogenetic potential of photo-immobilized azdiophenyl (Az)-natural polymers as a carrier of bone morphogenetic protein-2 (BMP-2) was assessed in 56 rats randomized to four groups. The control group comprised implanted collagen sheet with BMP-2. In the three experimental groups, the implant comprised collagen sheet with photo-immobilized BMP-2 on Az-gelatin (Az-Gel), Az-O-carboxymethyl chitosan (Az-OMC), or Az­O­carboxymethyl low molecular chitosan (Az-LMC). Micro-computed tomography analysis revealed more regenerated bone in Az-Gel at 8weeks. Immunohistochemical analysis at 4weeks revealed that the positively expressed cellular ratio in RUNX2-stained cells was significantly higher in Az-Gel and Az-OMC groups. At 8weeks, only the Az-Gel group showed higher positively expressed cellular ratio compared with the control group. These results demonstrate the superior osteogenetic potential of photo-immobilized BMP-2 using Az-Gel carrier in a rat calvarial defect model compared with control group. Photo-immobilization of BMP-2 using Az-gelatin could be a more effective carrier system of BMP-2 than a chitosan-based carrier system.

Biocompatible, drug-loaded anti-adhesion barrier using visible-light curable furfuryl gelatin derivative.

Recently, many of studies have been attempted to determine how to decrease adhesion. To effectively prevent adhesion, decrease in unnecessary surgical procedures, prevention of contact with other tissue, and drug treatment for inflammation are required. However, current anti-adhesion materials have disadvantages. To solve current problems, we prepared a biocompatible drug-loaded anti-adhesion barrier using a visible-light curable furfuryl gelatin derivative. We used riboflavin as a photo-initiator in the photo-curing process. The biocompatibility of riboflavin was estimated compared with that of Rose Bengal. In addition, the curing ratio was measured to determine whether riboflavin initiated photo-curing. We also evaluated the curing ratio of riboflavin according to the concentration of F-gelatin and the photo-irradiation time. A drug used to decrease inflammation that causes adhesion should not disappear from the surgical site and should also be released consistently. For this, we observed the release profiles of photo-immobilized ibuprofen with different concentrations of F-gelatin. Because an anti-adhesion barrier should protect from bacterial infection we evaluated the protective ability of a barrier formed by F-gelatin. In conclusion, a drug-loaded anti-adhesion barrier was prepared using a visible-light curable furfuryl gelatin derivative, with riboflavin as a photo-initiator. We expect that this drug-loaded anti-adhesion barrier effectively decrease adhesion formation.

Visible and UV-curable chitosan derivatives for immobilization of biomolecules.

Chitosan, which has many biocompatible properties, is used widely in medical field like wound healing, drug delivery and so on. Chitosan could be used as a biomaterial to immobilize protein-drug. There are many methods to immobilize protein-drug, but they have some drawbacks such as low efficiency and denaturation of protein. Therefore, photo-immobilization method is suggested to immobilize protein-drug. Photo-immobilization method is simple-reaction and also needs no additional crosslinking reagent. There has been some effort to modify chitosan to have an ability of photo-immobilization. Generally, visible and UV light reactive chitosan derivatives were prepared. Various types of photo-curable chitosan derivatives showed possibility for application to medical field. For example, they showed ability for protein-immobilization and some of them showed wound-healing effect, anti-adhesive effect, or property to interact directly with titanium surface. In this study, we introduce many types of photo-curable chitosan derivative and their possibility of medical application.

Hybrid Natural Orifice Transluminal Endoscopic Surgery with Sentinel Lymph Node Navigation for Deep Early Gastric Cancer in the Fundic Region.

For patients refusing surgical treatment for deep early gastric cancer, hybrid natural orifice transluminal endoscopic surgery with sentinel lymph node navigation is a potential treatment option, particularly when the anatomic location of the cancer has low probability of lymph node metastasis. We report a case of deep early gastric cancer of the fundus beyond the endoscopic submucosal dissection indication that was treated by hybrid natural orifice transluminal endoscopic surgery with sentinel lymph node navigation. In a conventional approach, a total gastrectomy would have been needed; however, the patient refused surgical intervention. In this case, since the patient showed no positivity of the sentinel lymph node on intraoperative navigation, laparoscopic basin lymph node dissection was not performed. Hybrid natural orifice transluminal endoscopic surgery might be considered for specific regions such as the safety zone where lymph node metastases are less likely to occur.

An epidermal growth factor derivative with binding affinity for hydroxyapatite and titanium surfaces.

An epidermal growth factor (EGF) derivative with affinity for apatite and titanium surfaces was designed using a peptide moiety derived from salivary statherin, a protein that adheres to hydroxyapatite. Since the active sequence has two phosphoserine residues, the EGF derivative was prepared by organic synthesis, and a 54 residue peptide was successfully prepared using this method. Circular dichroism spectra indicated that the conformation of EGF was not significantly altered by the addition of the affinity peptide sequence and the mitogenic activity was only slightly reduced when compared with the wild-type protein. However, the binding affinity of the modified EGF to hydroxyapatite and titanium was significantly higher than the unmodified EGF. The phosphate groups in the affinity sequence contributed to the affinity of modified EGF to both apatite and titanium. The modified EGF significantly enhanced the growth of cells on hydroxyapatite and titanium. It was also demonstrated that the bound EGF enhanced the signal transduction for longer periods than unbound EGF. In conclusion, the modified EGF had significantly higher binding affinity for apatite and titanium than soluble EGF, and the bound EGF significantly enhanced cell growth by long-lasting activation of intracellular signal transduction.

Immobilization of bone morphogenetic protein on DOPA- or dopamine-treated titanium surfaces to enhance osseointegration.

Titanium was treated with 3,4-dihydroxy-L-phenylalanine (DOPA) or dopamine to immobilize bone morphogenetic protein-2 (BMP2), a biomolecule. DOPA and dopamine solutions turned into suspensions, and precipitates were produced at high pH. Both treatments produced a brown surface on titanium that was thicker at high pH than low pH. Dopamine produced a thicker layer than DOPA. The hydrophobicity of the surfaces increased after treatment with dopamine independent of pH. Furthermore, there were more amino groups in the layers formed at pH 8.5 than pH 4.5 in both treatments. Dopamine treatment produced more amino groups in the layer than DOPA. BMP2 was immobilized on the treated surfaces via a coupling reaction using carbodiimide. More BMP2 was immobilized on surfaces treated at pH 8.5 than pH 4.5 in both treatments. The immobilized BMP induced specific signal transduction and alkali phosphatase, a differentiation marker. Thus, the present study demonstrates that titanium treated with DOPA or dopamine can become bioactive via the surface immobilization of BMP2, which induces specific signal transduction.

PEGylated antibody in organic media.

Antibodies were covalently conjugated with poly(ethylene glycol) (PEG) and the properties of the PEGylated antibodies in organic media were investigated. Two types of monoclonal antibody were used in this study. One was a monoclonal antibody (abzyme) that was prepared against a hapten mimicking a transition state of hydrolysis. Another was a monoclonal antibody against estrogen, which is not soluble in water. By electrophoresis and mass spectral analysis, the covalent conjugation with PEG chains was confirmed. The PEGylated antibodies bound to antigens and the PEGylated abzyme catalyzed a hydrolysis reaction in an aqueous solution. The PEGylated antibodies were soluble in dichloromethane and acetone and interacted with antigen either in dichloromethane or in acetone. In conclusion, PEGylated antibodies can be employed as analytical tools for water-insoluble analytes.

Visible light-induced crosslinkable gelatin.

A novel visible light-crosslinkable porcine gelatin was prepared for gelation and micropatterning. The preparation employed a photo-oxidation-induced crosslinking mechanism. First, furfuryl groups were incorporated into the gelatin. Second, the modified gelatin was mixed in water with Rose Bengal, which is a visible light sensitizer. Irradiation by visible light solidified the aqueous solution. In addition, when the solution was cast on a plate, dried and photo-irradiated in the presence of a photomask a micropattern was formed that matched the micropattern on the photomask. The gelatin-immobilized regions enhanced cell adhesion. It was also confirmed that the gelatin incorporating furfuryl and Rose Bengal have no significant toxicity. The photo-crosslinkable gelatin was employed as a direct pulp capping material in the dental field. Considering these results, this system could be useful as a new type of visible light-induced crosslinkable biosealant.