logo logo
Determination of the mechanical properties of polymeric microneedles by micromanipulation. Du Guangsheng,Zhang Zhihua,He Penghui,Zhang Zhibing,Sun Xun Journal of the mechanical behavior of biomedical materials Precise characterization of the mechanical properties of polymeric microneedles is crucial for their successful penetration into skin and delivery of the loaded active ingredients. However, most available strategies for this purpose are based on compression of the whole patch, which only provide the average rupture force of the needles and can not give information on the variations across individual microneedles in the patch. In this study, we determined the mechanical strength of individual microneedles of two types of hyaluronic acid microneedles with or without loaded model drugs using a micromanipulation technique. The applied force as a function of displacement of the microneedles was recorded, which was used to determine the rupture displacement, rupture force, and then to derive and calculate normal stress-deformation curve, rupture stress and Young's modulus of individual microneedles. The obtained data suggest that the molecular weight of the polymer and the loading of drug into the microneedles can significantly affect the rupture behavior and mechanical properties of the microneedles, which provides a foundation for preparing sufficiently strong microneedles for controlled drug delivery. 10.1016/j.jmbbm.2021.104384
Microneedles with Tunable Dissolution Rate. Kathuria Himanshu,Lim Dennis,Cai Junyu,Chung Bong Geun,Kang Lifeng ACS biomaterials science & engineering Dissolvable microneedle (MN) patches have been widely investigated for transdermal drug delivery. The dissolution rate of MN controls the status of drug release from the MN, which in turn determines drug absorption through skin. However, no systematic approaches have been reported to tune the dissolution profile of dissolvable MN matrices. This is the first study to show polyvinylpyrrolidone (PVP)-based dissolvable MN patches with varying dissolution profiles when PVP is copolymerized with cellulose materials. The MN patches were fabricated through thermal curing and photolithography in tandem. The various grades of pharmaceutical cellulose, such as hydroxypropyl methylcellulose and methyl cellulose, have been investigated as dissolution modifier incorporated in the MN patches. The resultant MN patches had dissolution profiles ranging from 45 min to 48 h. The dissolution rates varied with the grades of cellulose materials. Besides dissolution examination, the MN patches were characterized for their mechanical strength, moisture absorption, and skin penetration efficiency. All of the MN patches were able to penetrate the human skin in vitro. Overall, the PVP MN patches have great potential for skin applications as drug carriers with tunable dissolution profiles. 10.1021/acsbiomaterials.0c00759
Self-Assembly Nanomicelle Microneedles for Enhanced Photoimmunotherapy Autophagy Regulation Strategy. Chen Minglong,Yang Dan,Sun Ying,Liu Ting,Wang Wenhao,Fu Jintao,Wang Qingqing,Bai Xuequn,Quan Guilan,Pan Xin,Wu Chuanbin ACS nano Although certain therapeutic agents with immunogenic properties may enhance antitumor immunity, cancer cells can eliminate harmful cytoplasmic entities and escape immunosurveillance by orchestrating autophagy. Here, an ingenious self-assembled nanomicelle dissolving microneedle (DMN) patch was designed for intralesional delivery of immunogenic cell death-inducer (IR780) and autophagy inhibitor (chloroquine, CQ) coencapsulated micelles (C/I-Mil) for efficient antitumor therapy. Upon insertion into skin, the self-assembled C/I-Mil was generated, followed by electrostatic binding of hyaluronic acid, the matrix material of DMNs, accompanied by the dissolution of DMNs. Subsequently, photothermal-mediated size-tunable C/I-Mil could effectively penetrate into deep tumor tissue and be massively internalized CD44 receptor-mediated endocytosis, precisely ablate tumors with the help of autophagy inhibition, and promote the release of damage-associated molecular patterns. Moreover, CQ could also act as an immune modulator to remodel tumor-associated macrophages toward the M1 phenotype activating NF-κB. results showed that the localized photoimmunotherapy in synergy with autophagy inhibition could effectively eliminate primary and distant tumors, followed by a relapse-free survival of more than 40 days remodeling the tumor immunosuppressive microenvironment. Our work provides a versatile, generalizable framework for employing self-assembled DMN-mediated autophagy inhibition integrated with photoimmunotherapy to sensitize superficial tumors and initiate optimal antitumor immunity. 10.1021/acsnano.0c10396
Balloon-based drug coating delivery to the artery wall is dictated by coating micro-morphology and angioplasty pressure gradients. Tzafriri Abraham R,Muraj Benny,Garcia-Polite Fernando,Salazar-Martín Antonio G,Markham Peter,Zani Brett,Spognardi Anna,Albaghdadi Mazen,Alston Steve,Edelman Elazer R Biomaterials Paclitaxel coated balloon catheters (PCB) were developed as a polymer-free non-implantable alternative to drug eluting stents, delivering similar drug payloads in a matter of minutes. While PCB have shown efficacy in treating peripheral arterial disease in certain patient groups, restenosis rates remain high and there is no class effect. To help further optimize these devices, we developed a scanning electron microscopy (SEM) imaging technique and computational modeling approach that provide insights into the coating micromorphology dependence of in vivo drug transfer and retention. PCBs coated with amorphous/flaky or microneedle coatings were inflated for 60 sec in porcine femoral arteries. Animals were euthanized at 0.5, 24 and 72 h and treated arteries processed for SEM to image endoluminal coating distribution followed by paclitaxel quantification by mass spectrometry (MS). Endoluminal surfaces exhibited sparse coating patches at 0.5 h, predominantly protruding (13.71 vs 0.59%, P < 0.001), with similar micro-morphologies to nominal PCB surfaces. Microneedle coating covered a 1.5-fold endoluminal area (16.1 vs 10.7%, P = 0.0035) owing to higher proximal and distal delivery, and achieved 1.5-fold tissue concentrations by MS (1933 vs 1298 μg/g, P = 0.1745) compared to amorphous/flaky coating. Acute longitudinal coating distribution tracked computationally predicted microindentation pressure gradients (r = 0.9, P < 0.001), with superior transfer of the microneedle coatings attributed to their amplification of angioplasty contact pressures. By 24 h, paclitaxel concentration and coated tissue areas both declined by >93% even as nonprotruding coating levels were stable between 0.5 and 72 h, and 2.7-fold higher for microneedle vs flaky coating (0.64 vs 0.24%, P = 0.0195). Tissue retained paclitaxel concentrations at 24-72 h trended 1.7-fold higher post treatment with microneedle coating compared to the amorphous/flaky coating (69.9 vs 39.9 μg/g, P = 0.066). Thus, balloon based drug delivery is critically dependent on coating micromorphologies, with superior performance exhibited by micromorphologies that amplify angioplasty pressures. 10.1016/j.biomaterials.2020.120337
A Double-Layered Microneedle Platform Fabricated through Frozen Spray-Coating. Ning Xiaoyu,Wiraja Christian,Lio Daniel Chin Shiuan,Xu Chenjie Advanced healthcare materials This work reports a frozen spray-coating method for the fabrication of double-layered microneedles (MNs). Taking swellable methacrylated hyaluronic acid (MeHA)-derived MNs as the model, both hydrophobic molecules (Nile red, Cy5) and hydrophilic ones (FITC, FITC-Dextran, Insulin) can be homogeneously coated without impacting the mechanical properties of the original MeHA MNs. The prepared double-layered MNs can execute multiple roles. It is demonstrated that insulin-coated MeHA double-layered MNs allow the effective delivery of the insulin into circulation of mice for controlling the blood glucose level while they also permit the extraction of skin interstitial fluid for the timely analysis of the biomarker (glucose). 10.1002/adhm.202000147
Bacterial nanocellulose-hyaluronic acid microneedle patches for skin applications: In vitro and in vivo evaluation. Fonseca Daniela F S,Vilela Carla,Pinto Ricardo J B,Bastos Verónica,Oliveira Helena,Catarino José,Faísca Pedro,Rosado Catarina,Silvestre Armando J D,Freire Carmen S R Materials science & engineering. C, Materials for biological applications The aim of the present study was to develop innovative patches for dermo-cosmetic applications based on dissolvable hyaluronic acid (HA) microneedles (MNs) combined with bacterial nanocellulose (BC) as the back layer. HA was employed as an active biomacromolecule, with hydrating and regenerative properties and volumizing effect, whereas BC was used as support for the incorporation of an additional bioactive molecule. Rutin, a natural antioxidant, was selected as the model bioactive compound to demonstrate the effectiveness of the system. The obtained HA-MNs arrays present homogenous and regular needles, with 200 μm in base width, 450 μm in height and 500 μm tip-to-tip distance, and with sufficient mechanical force to withstand skin insertion with a failure force higher than 0.15 N per needle. The antioxidant activity of rutin was neither affected by its incorporation in the MNs system nor by their storage at room temperature for 6 months. Preliminary in vivo studies in human volunteers unveiled their safety and cutaneous compatibility, as no significant changes in barrier function, stratum corneum hydration nor redness were detected. These results confirm the potentiality of this novel system for skin applications, e.g. cosmetics, taking advantage of the recognized properties of HA and the capacity of BC to control the release of bioactive molecules. 10.1016/j.msec.2020.111350
Fabrication of Tip-Hollow and Tip-Dissolvable Microneedle Arrays for Transdermal Drug Delivery. Ye Rui,Yang Jingbo,Li Yanjun,Zheng Ying,Yang Jian,Li Yuanyuan,Liu Bin,Jiang Lelun ACS biomaterials science & engineering We developed a modified micromolding method for the mass production of a novel tip-hollow microneedle array (MA). The tip-hollow MA was fabricated by tuning of the vacuum degree at -80 kPa for 60 s during the micromolding process. Subsequently, a tip-dissolvable MA encapsulated with drugs in the microcraters was fabricated from tip-hollow MA using repeated dipping and the freeze-drying process. Both the tip-hollow and tip-dissolvable MAs could easily penetrate in the rabbit skin without breakage, while the tip-hollow MA can just create a shallow loop hole in the skin. The drug-loaded tip-dissolvable MA can rapidly dissolve, releasing and diffusing the drug in the skin. The tip-dissolvable MA exhibited the best drug permeation ability in that the corresponding flux through the punctured skin using tip-dissolvable MA loaded with Rhodamine B is about 1.7- and 5.8-fold of that through the punctured skin using solid MA and the intact skin, respectively. The tip-dissolvable MA loaded with 5 IU insulin was fabricated to treat the type 1 diabetic SD rats. The tip-dissolvable MA had a good hypoglycemic effect and exhibited longer normoglycemic period in comparison with subcutaneous injection (5 IU). Therefore, our tip-dissolve MA is a promising medical device for transdermal drug delivery. 10.1021/acsbiomaterials.0c00120
Directly Compressed Tablets: A Novel Drug-Containing Reservoir Combined with Hydrogel-Forming Microneedle Arrays for Transdermal Drug Delivery. McAlister Emma,Dutton Bridie,Vora Lalitkumar K,Zhao Li,Ripolin Anastasia,Zahari Dk Siti Zawanah Binti Pg Hj,Quinn Helen L,Tekko Ismaiel A,Courtenay Aaron J,Kelly Stephen A,Rodgers Aoife M,Steiner Lilach,Levin Galit,Levy-Nissenbaum Etgar,Shterman Nava,McCarthy Helen O,Donnelly Ryan F Advanced healthcare materials Microneedle (MN) patches consist of a hydrogel-forming MN array and a drug-containing reservoir. Drug-containing reservoirs documented in the literature include polymeric films and lyophilized wafers. While effective, both reservoir formulations are aqueous based, and so degradation can occur during formulation and drying for drugs inherently unstable in aqueous media. The preparation and characterization of novel, nonaqueous-based, directly compressed tablets (DCTs) for use in combination with hydrogel-forming MN arrays are described for the first time. In this work, a range of drug molecules are investigated. Precipitation of amoxicillin (AMX) and primaquine (PQ) in conventional hydrogel-forming MN arrays leads to use of poly(vinyl alcohol)-based MN arrays. Following in vitro permeation studies, in vivo pharmacokinetic studies are conducted in rats with MN patches containing AMX, levodopa/carbidopa (LD/CD), and levofloxacin (LVX). Therapeutically relevant concentrations of AMX (≥2 µg mL ), LD (≥0.5 µg mL ), and LVX (≥0.2 µg mL ) are successfully achieved at 1, 2, and 1 h, respectively. Thus, the use of DCTs offers promise to expand the range of drug molecules that can be delivered transdermally using MN patches. 10.1002/adhm.202001256