Byung Hwi Kim

Surgical suture assembled with polymeric drug-delivery sheet for sustained, local pain relief

Surgical suture is a strand of biocompatible material designed for wound closure, and therefore can be a medical device potentially suitable for local drug delivery to treat pain at the surgical site. However, the preparation methods previously introduced for drug-delivery sutures adversely influenced the mechanical strength of the suture itself - strength that is essential for successful wound closure. Thus, it is not easy to control drug delivery with sutures, and the drug-delivery surgical sutures available for clinical use are now limited to anti-infection roles. Here, we demonstrate a surgical suture enabled to provide controlled delivery of a pain-relief drug and, more importantly, we demonstrate how it can be fabricated to maintain the mechanical strength of the suture itself. For this purpose, we separately prepare a drug-delivery sheet composed of a biocompatible polymer and a pain-relief drug, which is then physically assembled with a type of surgical suture that is already in clinical use. In this way, the drug release profiles can be tailored for the period of therapeutic need by modifying only the drug-loaded polymer sheet without adversely influencing the mechanical strength of the suture. The drug-delivery sutures in this work can effectively relieve the pain at the surgical site in a sustained manner during the period of wound healing, while showing biocompatibility and mechanical properties comparable to those of the original surgical suture in clinical use.

Acute suppression of TGF-ß with local, sustained release of tranilast against the formation of fibrous capsules around silicone implants

We propose the acute, local suppression of transforming growth factor beta (TGF-ß), a major profibrotic cytokine, to reduce fibrosis around silicone implants. To this end, we prepared silicone implants that were able to release tranilast, a TGF-ß inhibitor, in a sustained manner for 5 days or 15 days. We performed histologic and immunohistochemical analyses for 12 weeks after the implantation of the implants in living rats. The capsule thicknesses and collagen densities significantly decreased compared with those around the non-treated silicone implants. Notably, early suppression of TGF-ß affected the fibrogenesis that actually occurs at the late stage of wound healing. This change may be ascribed to the decrease in monocyte recruitment mediated by early TGF-ß during the acute inflammatory reaction. Thus, a significant decrease in differentiated macrophages was observed along with a decrease in the quantity of TGF-ß and fibroblasts during the subsequent inflammation stage; these changes led to a diminished fibrotic capsule formation.

Implantable batteryless device for on-demand and pulsatile insulin administration.

Many implantable systems have been designed for long-term, pulsatile delivery of insulin, but the lifetime of these devices is limited by the need for battery replacement and consequent replacement surgery. Here we propose a batteryless, fully implantable insulin pump that can be actuated by a magnetic field. The pump is prepared by simple-assembly of magnets and constituent units and comprises a drug reservoir and actuator equipped with a plunger and barrel, each assembled with a magnet. The plunger moves to noninvasively infuse insulin only when a magnetic field is applied on the exterior surface of the body. Here we show that the dose is easily controlled by varying the number of magnet applications. Also, pump implantation in diabetic rats results in profiles of insulin concentration and decreased blood glucose levels similar to those observed in rats treated with conventional subcutaneous insulin injections.

Prolonged, acute suppression of cysteinyl leukotriene to reduce capsular contracture around silicone implants

We hypothesize that periodically early, local suppression of cysteinyl leukotrienes (CysLTs), which are potent inflammatory mediators, can reduce the fibrotic capsular contracture around silicone implants. We tested this hypothesis with the silicone implants enabled with the sustained release of montelukast, a CysLT receptor antagonist, for 3 and 15days. In this work, we inserted each of the distinct implants into the pocket of the subpanniculus carnosus plane of living rats and performed histological and immunofluorescent (IF) analyses of the tissues biopsied at predetermined periods for 12weeks after implant insertion. The implants with montelukast exhibited significantly reduced polymorphonuclear leukocytes (i.e., PMNs), implying a concurrent reduction of CysLT. This effect was more prominent after long-term local montelukast exposure. Thus, fewer fibroblasts were recruited, thereby reducing transforming growth factor (TGF)-β and myofibroblasts in the tissue around the implant. Therefore, the fibrotic capsule formation, which was assessed using the capsule thickness and collagen density, decreased along with the myofibroblasts. Additionally, the tissue biopsied at the experimental end point exhibited significantly decreased mechanical stiffness. STATEMENT OF SIGNIFICANCE Capsular contracture is troublesome, making the tissues hardened around the silicone implant. This causes serious pain and discomfort to the patients, often leading to secondary surgery for implant replacement. To resolve this, we suggest a strategy of long-term, local suppression of cysteinyl leukotriene, an important mediator present during inflammation. For this, we propose a silicone implant abled to release a drug, montelukast, in a sustained manner. We tested our drug-release implant in living animals, which exhibited a significant decrease in capsule formation compared with the intact silicone implant. Therefore, we conclude that the sustained release of montelukast at the local insertion site represents a promising way to reduce capsular contracture around silicone implants.

Surgical suture braided with a diclofenac-loaded strand of poly(lactic- co -glycolic acid) for local, sustained pain mitigation

In this work, we propose a surgical suture that can sustainably release diclofenac (DF) for the local pain relief of surgical wounds. We separately fabricated a DF-loaded strand composed of a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), which was then braided with a surgical suture already in clinical use, i.e., VICRYL™. In this way, the drug-delivery suture presented herein could release DF in a sustained manner for 10days while maintaining the mechanical strength needed for wound closure. According to the in vivo results of an induced-pain animal model, the drug-delivery suture mitigated pain throughout the period of persistent pain. The histological analysis of tissue around the sutures showed that the drug-delivery suture exhibited biocompatibility comparable to that of the VICRYL™ suture in clinical use.

Protective effect of telomerase-based 16-mer peptide vaccine (GV1001) on inferior epigastric island skin flap survivability in ischaemia-reperfusion injury rat model

Abstract Background: Ischaemia-reperfusion injury (IRI) results in oxidative damage and a profound inflammatory reaction, leading to cell death. GV 1001 is a telomerase-based 16-mer peptide vaccine developed against cancer. However, it has also been reported to possess antioxidant and anti-inflammatory properties. The aim of this study was to determine if GV 1001 can reduce the negative effects caused by IRI in a rat skin flap model owing to its anti-oxidant and anti-inflammatory properties. Materials and methods: In order to evaluate the effect of GV 1001, 5 × 5 cm2 inferior epigastric artery based island skin flaps were dissected in 39 8-week-old Sprague-Dawley rats weighing 220–270 g. The rats were divided into three groups: (I) non-ischaemic group; (II) IRI with saline; and (III) IRI with 10 mg GV 1001 treatment. Drugs were administered intra-muscularly directly before and after ischaemia. Flap survival area, neutrophil infiltration, cytokine levels (interleukin [IL]-1, IL-6, and tumour necrosis factor-α), malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity were measured. Flap survivability was analysed at 7 days after surgery. Results: Flap survival area was significantly larger in group III than in group II. Cytokine release level was also significantly lower in group III. Neutrophil infiltration grade, MDA level, and SOD activity slightly decreased in Group III; however, the changes were not statistically significant. Conclusion: These results imply that GV 1001 exerts a protective effect against IRI through antioxidant effects, reducing reactive oxygen species, and suppressing the inflammatory cascade.

Implantable small device enabled with magnetic actuation for on-demand and pulsatile drug delivery

ABSTRACT We prepared an implantable device of small volume (SID) that is enabled with on‐demand, pulsatile drug release. The device was designed to be actuated via a magnetic field; hence, there was no need for a battery. The device was actuated when the magnet was applied from the outside and infused the drug solution outward via the outlet ports in the device. When there was no external magnetic field, no drug was released. In this work, we varied the amount of delivered drug by varying the number of outlet ports. Thus, as the number of outlet ports increased from one to three, the average amount of drug release per actuation increased from 60.7 ± 1.79 &mgr;g to 122.6 ± 1.27 &mgr;g. In addition, when the SID with three outlet ports (SID3) was actuated once and thrice, the amount of drug release increased from 123.0 ± 6.99 &mgr;g to 357.3 ± 9.70 &mgr;g, respectively, which was reproducible over 30 days. When the SID3 was implanted in living animals for 30 days, plasma drug concentration was measured to be 92–146 ng ml−1 or 210–363 ng ml−1 when the device was actuated once or three consecutive times, respectively. Graphical abstract Figure. No caption available.

Dual surface modification of PDMS-based silicone implants to suppress capsular contracture

In this study, we report a new physicochemical surface on poly(dimethylsiloxane) (PDMS)-based silicone implants in an effort to minimize capsular contracture. Two different surface modification strategies, namely, microtexturing as a physical cue and multilayer coating as a chemical cue, were combined to achieve synergistic effects. The deposition of uniformly sized microparticles onto uncured PDMS surfaces and the subsequent removal after curing generated microtextured surfaces with concave hemisphere micropatterns. The size of the individual micropattern was controlled by the microparticle size. Micropatterns of three different sizes (37.16, 70.22, and 97.64 μm) smaller than 100 μm were produced for potential application to smooth and round-shaped breast implants. The PDMS surface was further chemically modified by layer-by-layer (LbL) deposition of poly-l-lysine and hyaluronic acid. Short-term in vitro experiments demonstrated that all the PDMS samples were cytocompatible. However, lower expression of TGF-β and α-SMA, the major profibrotic cytokine and myofibroblast marker, respectively, was observed in only multilayer-coated PDMS samples with larger size micropatterns (70.22 and 97.64 μm), thereby confirming the synergistic effects of physical and chemical cues. An in vivo study conducted for 8 weeks after implantation in rats also indicated that PDMS samples with larger size micropatterns and multilayer coating most effectively inhibited capsular contracture based on analyses of tissue inflammation, number of macrophage, fibroblast and myofibroblast, TGF-β expression, collagen density, and capsule thickness. STATEMENT OF SIGNIFICANCE Although poly(dimethylsiloxane) (PDMS)-based silicone implants have been widely used for various applications including breast implants, they usually cause typical side effects called as capsular contracture. Prior studies have shown that microtexturing and surface coating could reduce capsular contracture. However, previous methods are limited in their scope for application, and it is difficult to obtain FDA approval because of the large and nonuniform size of the microtexture as well as the use of toxic chemical components. Herein, those issues could be addressed by creating a microtexture of size less than 100 m, with a narrow size distribution and using layer-by-layer deposition of a biocompatible polymer without using any toxic compounds. Furthermore, this is the first attempt to combine microtexture with multilayer coating to obtain synergetic effects in minimizing the capsular contracture.

Pattern-coated titanium bone fixation plate for dual delivery of vancomycin and alendronate

Metallic bone-fixation devices have been widely used in the treatment of fractured bones. However, there are still some unmet clinical needs associated with post-surgical infection and hampered bone repair. Therefore, to both prevent infection and enhance bone formation, we propose a titanium (Ti)-based bone plate for dual delivery of an antibiotic, vancomycin (VAN), and a bone-forming drug, alendronate (AL). In this work, we prepared the coating with a blend of a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), and a drug, VAN or AL. Instead of coating the whole surface, we patterned the coatings each in the shape of a dot, on a flat surface of the Ti bone plate currently in clinical use (BP0001-PT, U&I, Korea). This way, we could prevent detachment of the polymeric coating from the metallic plate surface while being immersed in an aqueous medium for 23 days. Both VAN and AL were released in a sustained manner for more than 28 days, maintaining their own activity without being influenced by their co-existence in the medium. Thus, the coated plate showed an antibacterial activity against Staphylococcus aureus, while also promoting osteoblast proliferation and alkaline phosphate activity in MG-63 cells. Therefore, we conclude that a Ti-based bone plate coated with patterned dots, each for delivery of VAN or AL, can be a promising strategy to allow for both antibacterial and bone-forming activities.