Kang Ju Lee

Spatially discrete thermal drawing of biodegradable microneedles for vascular drug delivery

Spatially discrete thermal drawing is introduced as a novel method for the fabrication of biodegradable microneedles with ultra-sharp tip ends. This method provides the enhanced control of microneedle shapes by spatially controlling the temperature of drawn polymer as well as drawing steps and speeds. Particular focus is given on the formation of sharp tip ends of microneedles at the end of thermal drawing. Previous works relied on the fracture of polymer neck by fast drawing that often causes uncontrolled shapes of microneedle tips. Instead, this approach utilizes the surface energy of heated polymer to form ultra-sharp tip ends. We have investigated the effect of such temperature control, drawing speed, and drawing steps in thermal drawing process on the final shape of microneedles using biodegradable polymers. XRD analysis was performed to analyze the effect of thermal cycle on the biodegradable polymer. Load-displacement measurement also showed the dependency of mechanical strengths of microneedles on the microneedle shapes. Ex vivo vascular tissue insertion and drug delivery demonstrated microneedle insertion to tunica media layer of canine aorta and drug distribution in the tissue layer.

Impact insertion of transfer-molded microneedle for localized and minimally invasive ocular drug delivery.

It has been challenging for microneedles to deliver drugs effectively to thin tissues with little background support such as the cornea. Herein, we designed a microneedle pen system, a single microneedle with a spring-loaded microneedle applicator to provide impact insertion. To firmly attach solid microneedles with 140 μm in height at the end of macro-scale applicators, a transfer molding process was employed. The fabricated microneedle pens were then applied to mouse corneas. The microneedle pens successfully delivered rhodamine dye deep enough to reach the stromal layer of the cornea with small entry only about 1000 μm(2). When compared with syringes or 30 G needle tips, microneedle pens could achieve more localized and minimally invasive delivery without any chances of perforation. To investigate the efficacy of microneedle pens as a way of drug delivery, sunitinib malate proven to inhibit in vitro angiogenesis, was delivered to suture-induced angiogenesis model. When compared with delivery by a 30 G needle tip dipped with sunitinib malate, only delivery by microneedle pens could effectively inhibit corneal neovascularization in vivo. Microneedle pens could effectively deliver drugs to thin tissues without impairing merits of using microneedles: localized and minimally invasive delivery.

Perivascular biodegradable microneedle cuff for reduction of neointima formation after vascular injury

Restenosis often occurs at the site of vascular grafting and may become fatal for patients. Restenosis at anastomosis sites is due to neointimal hyperplasia (NH) and difficult to treat with conventional treatments. Such abnormal growth of smooth muscle cells in tunica media of vascular tissue can be reduced by delivering anti-proliferation drugs such as paclitaxel (PTX) to the inner vascular layer. Drug eluting stents (DES) or drug eluting balloon (DEB) have been developed to treat such vascular diseases. However, they are less efficient in drug delivery due to the drug loss to blood stream and inadequate to be applied to re-stenotic area in the presence of stent or anastomosis sites. Recently, we have introduced microneedle cuff (MNC) as perivascular delivery devices to achieve high delivery efficiency to tunica media. In this study, we investigated in vivo microneedle insertion and efficacy in treating NH using a rabbit balloon injury model. Microneedle shape was optimized for reliable insertion into tunica media layer. Uniform distribution of PTX in tunica media delivered by MNC devices was also confirmed. Animal study demonstrated significant NH reduction by MNC treatments and much higher delivery efficiency than flat type devices.

Rapid and repeatable fabrication of high A/R silk fibroin microneedles using thermally-drawn micromolds

Thermal drawing is a versatile rapid prototyping method that can freely form microneedle (MN) structures with ultra-high aspect ratio without relying on any complex and expensive process. However, it is still challenging to repeatedly produce MNs with identical shapes using this thermal drawing due to small fluctuations in processing conditions such as temperatures, drawing speeds, drawing heights, or parallelism in the drawing setup. In addition, thermal drawing is only applicable to thermoplastic materials and most natural biomaterials are incompatible with this method. Thus, we propose use of thermal drawing to fabricate master molds with high aspect ratios and replicate the shape by micromolding. In this work, high A/R MNs with various body profiles were fabricated by thermal drawing and replicated to silk fibroin (SF) MNs multiple times using micromolding. The original MN shape was precisely copied to the SF MNs. Methanol treatment enhanced the mechanical strength of SF MNs up to about 113% more depending on the treatment duration. We also demonstrated that methanol exposure time could effectively control drug release rates from SF MNs.

Controlled release of bupivacaine HCl through microchannels of biodegradable drug delivery device.

Local and prolonged delivery of local analgesics is much desired for post-operative pain management. For delivery of local analgesics at a constant rate over couple of days, a microfluidic device comprised of a drug reservoir and microchannels for drug release was developed using a biodegradable polymer, 85/15 poly(lactic-co-glycolic acid). Unlike conventional methods relying on material property, this device enables convenient modulation of the release speed of drugs by a simple change of the channel geometry such as the length and cross-sectional area. Bupivacaine was selected as our model local analgesic drug and its diffusional transport through microchannels was studied using the microfluidic devices. However, since the salt form of bupivacaine, bupivacaine hydrochloride, has pH-dependent solubility, its precipitation in microchannels had an adverse impact on the release performance of the microfluidic drug delivery devices. Thus, in this investigation, the diffusional transport and precipitation of bupivacaine hydrochloride in microfluidic channels were studied using in vitro release experiments and optical analysis. Furthermore, a concept of co-delivery of bupivacaine hydrochloride together with acidic additives was demonstrated to achieve a zero-order delivery of bupivacaine hydrochloride without the clogging of microchannels by its precipitation.

A Biodegradable Microneedle Cuff for Comparison of Drug Effects through Perivascular Delivery to Balloon-Injured Arteries

Restenosis at a vascular anastomosis site is a major cause of graft failure and is difficult to prevent by conventional treatment. Perivascular drug delivery has advantages as drugs can be diffused to tunica media and subintima while minimizing the direct effect on endothelium. This in vivo study investigated the comparative effectiveness of paclitaxel, sirolimus, and sunitinib using a perivascular biodegradable microneedle cuff. A total of 31 New Zealand white rabbits were used. Rhodamine was used to visualize drug distribution (n = 3). Sirolimus- (n = 7), sunitinib- (n = 7), and paclitaxel-loaded (n = 7) microneedle cuffs were placed at balloon-injured abdominal aortae and compared to drug-free cuffs (n = 7). Basic histological structures were not affected by microneedle devices, and vascular wall thickness of the device-only group was similar to that of normal artery. Quantitative analysis revealed significantly decreased neointima formation in all drug-treated groups (p < 0.001). However, the tunica media layer of the paclitaxel-treated group was significantly thinner than that of other groups and also showed the highest apoptotic ratio (p < 0.001). Proliferating cell nuclear antigen (PCNA)-positive cells were significantly reduced in all drug-treated groups. Sirolimus or sunitinib appeared to be more appropriate for microneedle devices capable of slow drug release because vascular wall thickness was minimally affected.

Transfer-molded wrappable microneedle meshes for perivascular drug delivery

&NA; After surgical procedures such as coronary/peripheral bypass grafting or endarterectomy for the treatment of organ ischemia derived from atherosclerosis, intimal hyperplasia (IH) which leads to restenosis or occlusion at the site of graft anastomosis frequently occurs. In order to inhibit IH caused by abnormal growth of smooth muscle cells (SMCs) in tunica media, various perivascular drug delivery devices are reported for delivery of anti‐proliferation drugs into vascular tissue. However, there still remain conflicting requirements such as local and unidirectional delivery vs device porosity, and conformal tight device installation vs pulsatile expansion and constriction of blood vessels. In this study, a biodegradable microneedle (MN) array is developed on a flexible woven surgical mesh using a transfer molding method. Mechanical properties of ‘wrappable’ MN meshes are investigated and compared to the properties of blood vessels. Ex vivo and in vivo animal studies demonstrate enhanced drug delivery efficiency, efficacy for IH reduction, and safety of MN mesh. In particular, MN mesh showed significantly reduced neointiamal formation (11.1%) compared to other competitive groups (23.7 and 22.2%) after 4‐week in vivo animal study. Additionally, wrappable MN meshes effectively suppressed side effects such as IH due to mechanical constriction, loss of toxic drug to the surroundings, and cell death that were frequently observed with other previous perivascular drug delivery devices. Graphical abstract Figure. No caption available.

Linear Micro-patterned Drug Eluting Balloon (LMDEB) for Enhanced Endovascular Drug Delivery

In-stent restenosis (ISR) often occurs after applying drug eluting stents to the blood vessels suffering from atherosclerosis or thrombosis. For treatment of ISR, drug eluting balloons (DEB) have been developed to deliver anti-proliferative drugs to the lesions with ISR. However, there are still limitations of DEB such as low drug delivery efficiency and drug loss to blood flow. Although most researches have focused on alteration of drug formulation for more efficient drug delivery, there are few studies that have attempted to understand and utilize the contact modality of DEB drug delivery. Here, we developed a linear micro-patterned DEB (LMDEB) that applied higher contact pressure to enhance drug stamping to vascular tissue. Ex vivo and in vivo studies confirmed that higher contact pressure from micro-patterns increased the amount of drug delivered to the deeper regions of vessel. Finite element method simulation also showed significant increase of contact pressure between endothelium and micro-patterns. Quantitative analysis by high performance liquid chromatography indicated that LMDEBs delivered 2.3 times higher amount of drug to vascular tissue in vivo than conventional DEBs. Finally, efficacy studies using both atherosclerotic and ISR models demonstrated superior patency of diseased vessels treated with LMDEB compared to those treated with DEB.

High-resolution imaging of microneedles in biological tissue with optical coherence tomography

Optical coherence tomography (OCT) allows non-invasive, cross-sectional optical imaging of biological tissue with high spatial resolution and acquisition speed. In principle, it is analogous to ultrasound imaging, but uses near-infrared light instead of ultrasound, measuring the time-delay of back-scattered light from within biological tissue. Compared to ultrasound imaging, it exhibits superior spatial resolution (1~10 um) and high sensitivity. Therefore, OCT has been applied to a wide range of applications such as cellular imaging, ophthalmology and cardiology. Here, we describe a novel application of OCT technology in visualizing microneedles embedded in tissue that is developed to deliver drugs into the dermis without the injection mark in the human skin. Detailed three-dimensional structural images of microneedles and biological tissues were obtained. Examining structural modification of microneedles and tissues during insertion process would enable to evaluate performance of various types of microneedles in situ.

Effect of Surfactants on the Controlled Release of Bupivacaine HCl from Biodegradable Microfluidic Devices

Key Words: Drug Delivery(약물전달), Biodegradable(생분해성), Bupivacaine(부피바케인), Micro-Fluidic(마이크로유체), Surfactant(계면활성제)초록: 마이크로유체구조를기반으로하는약물전달장치는마이크로유체채널형상의간단한변형만으로약물분출량을쉽게조절할수있는장점이있다. 그러나디바이스제작에사용된생분해성고분자85/15poly(lactic-co-glycolic acid) (85/15PLGA)의 소수성 기질 때문에 약물전달 장치내부로의 releasemedium의유입이원활하게이루어지지않으며그결과, 디바이스의임플랜트후초기의약물분출에영향을줄것으로예상된다. 따라서surfactant인polyethylene-glycol600 (PEG600)과Tween80을이용하여micro-channel의표면처리를한디바이스와surfactant를사용하지않은디바이스를각각제작하여약물전달실험을하였으며, 이를바탕으로마이크로유체채널의기하학적형상에따른국소마취제의일종인bupivacaine HCl(BHCl)의분출속도제어를입증하였다.Abstract: We investigated the diffusive transport of bupivacaine HCl through the microchannels of microfluidic drugdelivery devices. In the biodegradable microfluidic drug delivery devices developed in this research, the drug releaserate can be controlled by simply modulating the geometrical parameters of the microchannels, such as the length,number, and cross-sectional area of the microchannels, when the microchannels are used as paths for drug release.However, the hydrophobic nature of a biodegradable polymer, 85/15 poly(lactic-co-glycolic acid), hinders the infiltrationof a release medium (phosphate-buffered saline) through the microchannels into the reservoir of a device that containsbupivacaine HCl, at the early stage of drug release. This can have an adverse effect on the early stage release of localanalgesic compounds from the device. In this study, microfluidic channels were surface-treated with surfactants such asPEG600 and Tween80, and the effects of the surfactants on the release performance are presented and analyzed.