Magnetically actuating implantable pump for the on-demand and needle-free administration of human growth hormone.

A bolus of human growth hormone (hGH) is often prescribed for the treatment of growth hormone deficiency, which requires frequent injections in current clinical settings. This painful needle-involved delivery often results in poor patient compliance, leading to low medication adherence and poor clinical outcomes. Therefore, we propose a magnetically actuating implantable pump (MAP) that can infuse an accurate dose of hGH only at the time of non-invasive magnet application from the skin. The MAP herein could reproducibly infuse 20.6 ±â€¯0.9 µg hGH per actuation without any leak at times without actuation. The infused amount increased proportionally with an increase in the number of actuations. When the MAP was implanted and actuated with a magnet in animals with growth hormone deficiency for 21 days, the profiles of plasma hGH concentration and insulin-like growth factor (IGF)-1, as well as changes in body weight, were similar to those observed in animals treated with conventional subcutaneous hGH injections. Therefore, we anticipate that the MAP fabricated in this study can be a non-invasive alternative to administer hGH without repeated and frequent needle injections.

Magnetically-driven implantable pump for on-demand bolus infusion of short-acting glucagon-like peptide-1 receptor agonist.

For type 2 diabetic patients, short acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) is often prescribed with frequent needled injections. Long-acting GLP-1 RA for less frequent injections do not mimic physiologic secretion of GLP-1. Therefore, an implantable pump is proposed in this work, which can deliver a short-acting GLP-1 RA, exenatide, without needles and batteries. The implanted pump can infuse an accurate amount of exenatide bolus only when a noninvasive magnetic force is applied from outside the body. The pump includes a safety feature of patterned magnets for actuation to prevent accidental infusion possibly caused by a general household magnet. The reservoir for exenatide is made of a flexible biomaterial and thus, a negative pressure build-up in the reservoir can be prevented even after multiple actuations and almost all drug consumption (~ 94%). This allows a reproducible drug dose for a longer period after implantation, hence less frequent replenishment procedures. The pump is also equipped with an intermediate container with two distinct check-valves and thus, the reservoir of exenatide can be further separated and better prevented from infiltration of the bodily fluid surrounding the implanted pump. When tested in Goto-Kakizaki rats, the pump demonstrates the efficacy of exenatide similar to conventional subcutaneous injections. Therefore, the pump can be promising for patient-friendly, optimal delivery of short-acting GLP-1 RA that better follows the physiologic secretion profile of GLP-1.

Elastic net of polyurethane strands for sustained delivery of triamcinolone around silicone implants of various sizes.

We propose an elastic net made of a biocompatible polymer to wrap silicone implants of various sizes, which also allows for the sustained release of an anti-inflammatory drug, triamcinolone, to prevent fibrosis. For this, we first prepared a strand composed of a mixture of polyurethane and triamcinolone via electrospinning, which was then assembled to prepare the elastic drug-delivery net (DDN). The DDN was prepared to just fit for wrapping the small silicone implant sample herein, but was also able to wrap a sample 7 times as large at 72% strain due to the elastic property of polyurethane. The DDN exhibited sustained drug release for 4 weeks, the profile of which was not very different between the intact and strained DDNs. When implanted in a subcutaneous pocket in living rats, the DDN-wrapped silicone implant samples showed an obvious antifibrotic effect due to the sustained release of triamcinolone. Importantly, this effect was similar for the small and large silicone samples, both wrapped with the same DDN. Therefore, we conclude that this drug-loaded net made of an elastic, biocompatible polymer has high potential for sustained drug delivery around silicone implants manufactured in various sizes.

Silicone Implant Coated with Tranilast-Loaded Polymer in a Pattern for Fibrosis Suppression.

Pathologic fibrosis around silicone implants is problematic, and thus, these implants have been coated with a mixture of a biocompatible polymer and antifibrotic drug for sustained drug release to prevent fibrosis. However, a coating applied over an entire surface would be subject to mechanical instability as the implant would be severely crumpled for implant insertion. Therefore, in this work, we proposed localized, patterned coating dots, each composed of poly(lactic-co-glycolic acid) (PLGA) and tranilast, to be applied on the surface of silicone implants. The drug loaded in the pattern-coated implant herein was well retained after a cyclic tensile test. Due to the presence of PLGA in each coating dot, the tranilast could be released in a sustained manner for more than 14 days. When implanted in a subcutaneous pocket in living rats for 12 weeks, compared with the intact implant, the pattern-coated implant showed a decreased capsule thickness and collagen density, as well as less transforming growth factor-ß (TGF-ß) expression and fewer fibroblasts; importantly, these changes were similar between the surfaces with and without the coating dots. Therefore, we conclude that the pattern-coating strategy proposed in this study can still effectively prevent fibrosis by maintaining the physical stability of the coatings.

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

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 ±â€¯1.79 µg to 122.6 ±â€¯1.27 µg. In addition, when the SID with three outlet ports (SID3) was actuated once and thrice, the amount of drug release increased from 123.0 ±â€¯6.99 µg to 357.3 ±â€¯9.70 µg, 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.

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-ß 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-ß 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.

Silicone breast implant modification review: overcoming capsular contracture.

BACKGROUND: Silicone implants are biomaterials that are frequently used in the medical industry due to their physiological inertness and low toxicity. However, capsular contracture remains a concern in long-term transplantation. To date, several studies have been conducted to overcome this problem. This review summarizes and explores these trends. MAIN BODY: First, we examined the overall foreign body response from initial inflammation to fibrosis capsule formation in detail and introduced various studies to overcome capsular contracture. Secondly, we introduced that the main research approaches are to inhibit fibrosis with anti-inflammatory drugs or antibiotics, to control the topography of the surface of silicone implants, and to administer plasma treatment. Each study examined aspects of the various mechanisms by which capsular contracture could occur, and addressed the effects of inhibiting fibrosis. CONCLUSION: This review introduces various silicone surface modification methods to date and examines their limitations. This review will help identify new directions in inhibiting the fibrosis of silicone implants.

Surgical suture releasing macrophage-targeted drug-loaded nanoparticles for an enhanced anti-inflammatory effect.

A surgical suture is a medical device to close the wound site of skin and organs but excessive inflammation surrounding the suture can disrupt the wound healing process. Although post-operative prescription of anti-inflammatory drugs is used to manage the inflammation, the need for local drug delivery systems has been rising because of low bioavailability and fast clearance of drugs. In this work, we proposed a new strategy for a local anti-inflammatory device by incorporating macrophage-targeted anti-inflammatory nanoparticles into the suture. For macrophage-targeted anti-inflammatory nanoparticles, poly(lactic-co-glycolic) nanoparticles were loaded with anti-inflammatory drug diclofenac and decorated with polyethylene glycol and macrophage-targeting ligand mannose. These anti-inflammatory nanoparticles released diclofenac sustainably, and targeted activated macrophages efficiently. After nanoparticle optimization, a suture was coated with multiple layers of macrophage-targeted anti-inflammatory nanoparticles using a dip coating process. The suture releasing macrophage-targeted anti-inflammatory nanoparticles showed an enhanced anti-inflammatory effect in both macrophage culture and excisional wound healing animal models compared to a free drug molecule-coated suture. These results suggest that anti-inflammatory nanoparticle-coated sutures have great potential as an effective local delivery system to reduce inflammation and pain at the wound site.

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.

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.

Cartilage suspension using a poly (lactic-co-glycolic) acid system.

BACKGROUND: This study aims to determine whether a bar-like implant made of poly lactic-co-glycolic acid (PLGA) could be used for cartilage suspension and whether the implant would be suitable for rhinoplasty. METHODS: Three types of in vivo animal experiments were performed. First, the ear cartilage was incised in a full-thickness pattern, and the PLGA system was placed between the upper and lower cartilage to offer support to the tissue. Second, after the ear cartilage was forcibly bent, an implant was placed in the cartilage. For these rabbits, the outer aspect of the ear cartilage was assessed at 2, 4, 8, 10, and 12 weeks postoperatively. In addition, tissue samples were collected for histological evaluation 12 weeks after surgery. Third, the bar-like nasal implant was used for nasal septal suspension. We obtained micro-computed tomography (CT) images and evaluated the inflammatory reaction at 12 weeks postoperatively. RESULTS: The results of both the ear suspension and bending retention tests revealed that the characteristic shapes of the cartilage were well preserved at 12 weeks postoperatively. Moreover, no abnormal inflammatory reaction was present in any site in the experimental group. We successfully implanted the bar-like nasal implant in the rabbit's septum, and no complications occurred. Furthermore, the physical examination and the micro-CT images did not reveal any nasal obstruction or inflammation. CONCLUSIONS: We confirmed that an implant made of PLGA can be maintained in the cartilage tissue and believe that this can be applied in rhinoplasty as an alternative to autologous cartilage.

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)-ß 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.

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

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.

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 micro-chip for controlled delivery of diclofenac sodium.

We prepared an implantable micro-chip enabled for controlled delivery of diclofenac sodium (DS). The micro-chip was made of poly(methyl methacrylate), where a pair of micro-channels and micro-wells was embedded to serve as a drug diffusion barrier and a reservoir, respectively. For this purpose, the micro-channel and micro-well were filled with a water-soluble polymer, polyethylene glycol and a fine powder of DS, respectively. To modulate the drug release profile, we varied both the cross-sectional area and length of the micro-channels. Thus, the average rate and onset time of drug release could be varied from 0.32%/day to 3.68%/day and from day 0.5 to day 8, respectively, as the cross-sectional area to length ratio (i.e., A/L) of the micro-channels increased from 0.0026 mm to 0.0280 mm. To achieve both almost immediate onset and zero-order release of DS, we also prepared a micro-chip embedded with multiple pairs of the micro-wells and the micro-channels of different dimensions. In this work, a single micro-chip equipped with the micro-channels with A/Ls of 0.0280 mm, 0.0217 mm and 0.0108 mm exhibited almost zero-order drug release for 31 days (R2>0.996) after the release onset on day 0.5. When the resulting micro-chip was implanted in living rats, the drug concentration in the blood could be maintained at 148 ng/ml-225 ng/ml for the first 23 days while showing good biocompatibility.

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.