European Journal of Pharmaceutics and Biopharmaceutics
Research paperSpatially discrete thermal drawing of biodegradable microneedles for vascular drug delivery
Graphical abstract
Spatially-discrete temperature control during thermal drawing of biodegradable polymers allows for the formation of microneedles with ultrasharp tips and various body profiles that are suitable for drug delivery to tunica media layer of blood vessels.
Introduction
Microneedles have demonstrated enhanced efficacy by delivering various therapeutic compounds through skin barriers with advantages such as self-administration, pain-free injection, and enhanced safety [1], [2], [3]. Microneedles have typically been fabricated using metals, ceramics, or polymers. Ceramic or metal microneedles have been fabricated by chemical etching or laser cutting [4], [5], [6], [7], [8], [9]. On the other hand, polymer microneedles were generally constructed by casting polymer melt or solution in micro-molds [10], [11], [12], [13], [14]. However, negative cavities of micro-molds have relatively low aspect ratios (depth over area) that limit the creation of microneedles with high aspect ratio.
Recently, a thermal drawing method was developed to create hollow metal [15] or solid polymer microneedles with high aspect ratio [16], [17]. In this method, heated polymer is vertically drawn by a metal pillar structure at a controlled speed. After a cooling step, the neck is fractured by fast drawing, and microneedle structure is formed. Closer investigation into the apex of microneedles fabricated in this way reveals that the fracturing step results in rather flat or elongated apex. Such uncontrolled tip geometry seriously limits the insertion capability of microneedles into target tissues. However, despite the recent development of thermal drawing processes for microneedles, relatively less attention was paid to how sharp tips can be formed when the thermal drawing process is used for microneedle fabrication.
Synthetic biodegradable polymers such as poly (lactic acid) (PLA), poly (glycolic acid) (PGA), or their copolymers, poly (lactic-co-glycolic acid) (PLGA) have been popular for the fabrication of medical implants, drug delivery systems, and tissue scaffolds [18], [19], [20]. Biodegradable polymers have also been employed in microneedle fabrication by micro-molding or casting [10], [11], [12], [13]. Microneedles made of biodegradable polymers can be left in human body and deliver drugs over an extended period of time depending on their degradation speed and delivery mechanisms. When such biodegradable devices are fabricated by thermal processing, it is important to confirm that the original physical and chemical properties of the materials remain unchanged. In particular, crystallization during thermal processing or hydrolysis from the exposure to humidity due to sudden temperature change during a thermal cycle can easily change the critical properties of biodegradable polymers such as degradation time, molecular weight, and mechanical strength. When thermal drawing is used to fabricate biodegradable microneedles, it inevitably exposes biodegradable polymers to a thermal cycle. The effect of the thermal cycle on the property of biodegradable polymer needs to be monitored before and after the process.
Microneedles have mainly been used to deliver therapeutic molecules through skin as mentioned previously. Our recent work showed the potential of microneedles for drug delivery to vascular tissues to treat atherosclerosis or intimal hyperplasia [17]. Cuff-shaped devices containing an array of microneedles were fabricated and tested in vivo for the perivascular delivery of model drugs to the internal layers such as tunica adventitia and media. Among many challenges, it was the most critical to have microneedles that could penetrate the vascular tissues at a minimal force. The insertion capability was strongly dependent on the strength and tip shape of microneedles. However, regardless of the convenience of the thermal drawing method to fabricate high aspect ratio microneedles, the mechanism of sharp tip formation and the shape optimization for strength improvement were not studied in detail.
In this report, we introduce spatially discrete thermal drawing (SDTD) process to fabricate biodegradable microneedles with sharp tip ends for vascular drug delivery. In this process, temperatures of the top and bottom sides of microneedles are controlled separately to allow for more precise modulation of the shape of microneedles including tip geometry. Configuration of an SDTD system is explained in detail and the operation steps are discussed. Then, the formation of microneedle tips is investigated under various thermal boundary conditions, and the dependency on drawing speeds is also discussed. First, standard “cold drawing fracture (CDF)” mechanism is demonstrated, and the resulting shape is discussed. This neck fracture method produces either a flat tip end or an elongated tip depending on the fracture speed. To avoid the formation of such less ideal geometry for microneedle tips, heating from micro-pillars, is demonstrated and analyzed as an improved way to form the sharp apex of microneedles. As an alternative way to adjust the tip shape of microneedles, post-annealing is employed, and the effect on the final shape is analyzed. Furthermore, in order to investigate the effect of thermal processes on PLGA, X-ray diffraction (XRD) analysis was performed, and the results were discussed. Using the SDTD process, microneedles of two different shapes (slender and bullet-shaped microneedles) were fabricated, and their mechanical strengths were measured and compared for their insertion into vascular tissues such as artery and vein ex vivo.
Section snippets
Materials
Biodegradable polymers, 90/10PGLA (Mw = 268,267 Da) and 30/70PGLA (Mw = 69,900 Da), were generously donated by Samyang Corporation, Republic of Korea. 50/50PLGA (5050 DLG 1A, Mw = 5.7 kDa) was purchased from Lakeshore Biomaterials, Birmingham, AL. Dimethyl sulfoxide (product no. D0457, DMSO) and rhodamine B (product no. R0050, RB) were purchased from Samchun Chemical Inc., Republic of Korea. Stainless steel pillar array structures were fabricated by electrical discharge machining (EDM). Each pillar had
Thermal drawing of microneedles
Thermal drawing is a simple and robust process that can produce microneedle structures with high aspect ratio by drawing polymer melt. A micro-pillar makes a contact on polymer melt and draws up the polymer melt until it reaches to the desired height (Fig. 2). After the drawn polymer forms a microneedle shape, the polymer is disconnected at the neck to form the tip ends of microneedles. There are a number of parameters that affect the final shape of microneedles fabricated by this thermal
Discussion
Thermal drawing is a robust process to fabricate polymeric microneedles with high aspect ratio. However, microneedles fabricated by this approach typically have either flat or enlarged tip ends since microneedle tips are shaped by CDF [21]. When relatively ductile polymer such as PLGA is drawn as microneedles in this study, microneedle tips by CDF can be stretched plastically before the fracture, producing undesirable tip geometry as shown in Fig. 4, Fig. 5. Although previous reports emphasized
Conclusions
SDTD process was introduced as a novel method to fabricate biodegradable microneedles with sharp tip ends. Unlike conventional thermal drawing, separate control of temperatures at both top and bottom of drawn polymer enabled the fine modulation of microneedle geometry and the formation of “ultra sharp” tip ends. The effect of heating direction and drawing speed on the formation of the tip ends of microneedles was analyzed. In particular, the formation of sharp tip ends based on surface energy
Acknowledgements
This research was supported by a research grant of the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (A085136). C.K.C. and K.J.L. thank the financial support from the Yonsei University Institute of HRD Program for Nano/Micro Mechanical Engineering, a Brain Korea 21 program, Republic of Korea. The authors thank Dr. Young Joo Koh at Samyang Corporation for the kind donation of biodegradable polymers and helpful discussions.
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2021, International Journal of PharmaceuticsCitation Excerpt :Spatial discrete thermal drawing, an upgraded version of thermal drawing (Lee et al., 2015b), is a new method for preparing biodegradable microneedles with super-tips. This method controls the shape of the microneedles by spatially controlling the temperature of the stretched polymer, the stretching step and the speed, which can make up for the defect that the tip of the microneedles manufactured by traditional thermal drawing is not sharp (Choi et al., 2013). Similar to the drawing lithography method, this method can produce microneedles with high aspect ratio.