Biodegradable Therapeutic Microneedle Patch for Rapid Antihypertensive Treatment.

A hypertensive emergency causes severe cardiovascular diseases accompanied by acute target organ damage, requiring rapid and smooth blood pressure (BP) reduction. Current medicines for treating hypertensive emergencies, such as sodium nitroprusside (SNP), require careful dose control to avoid side effects (e.g., cyanide poisoning). The clinical administration of SNP using intravenous injection or drip further restrict its usage for first aid or self-aid in emergencies. Here, we developed an antihypertensive microneedle (aH-MN) technique to transdermally deliver SNP in combination with sodium thiosulfate (ST) as a cyanide antidote in a painless way. Dissolvable microneedles loaded with SNP and ST were fabricated via the centrifugation casting method, where the SNPs were stably packaged in microneedles and would be immediately released into the systemic circulation via subcutaneous capillaries when aH-MNs penetrated the skin. The antihypertensive effects were demonstrated on spontaneously hypertensive rat models. Rapid and potent BP reduction was achieved via aH-MN treatment, fulfilling clinical BP-control requirements for hypertensive emergencies. The side effects including skin irritation and target organ damage of aH-MN therapies were evaluated; the combinative delivery of ST effectively suppressed these side effects induced by the consecutive intake of SNP. This study introduces an efficient and patient-friendly antihypertensive therapy with a favorable side-effect profile, particularly a controllable and self-administrable approach to treat hypertensive emergencies.

Functionalized Spiky Particles for Intracellular Biomolecular Delivery.

The intracellular delivery of biomolecules is of significant importance yet challenging. In addition to the conventional delivery of nanomaterials that rely on biochemical pathways, vertical nanowires have been recently proposed to physically penetrate the cell membrane, thus enabling the direct release of biomolecules into the cytoplasm circumventing endosomal routes. However, due to the inherent attachment of the nanowires to a planar 2D substrate, nanowire cell penetrations are restricted to in vitro applications, and they are incapable of providing solution-based delivery. To overcome this structural limitation, we created polyethylenimine-functionalized microparticles covered with nanospikes, namely, "spiky particles", to deliver biomolecules by utilizing the nanospikes to penetrate the cell membrane. The nanospikes might penetrate the cell membrane during particle engulfment, and this enables the bound biomolecules to be released directly into the cytosol. TiO2 spiky particles were fabricated through hydrothermal routes, and they were demonstrated to be biocompatible with HeLa cells, macrophage-like RAW cells, and fibroblast-like 3T3-L1 cells. The polyethylenimine-functionalized spiky particles provided direct delivery of fluorescent siRNA into cell cytosol and functional siRNA for gene knockdown as well as successful DNA plasmid transfection which were difficult to achieve by using microparticles without nanospikes. The spiky particles presented a unique direct cell membrane penetrant vehicle to introduce biomolecules into cell cytosol, where the biomolecules might bypass conventional endocytic degradation routes.

Protection of Nanostructures-Integrated Microneedle Biosensor Using Dissolvable Polymer Coating.

Real-time transdermal biosensing provides a direct route to quantify biomarkers or physiological signals of local tissues. Although microneedles (MNs) present a mini-invasive transdermal technique, integration of MNs with advanced nanostructures to enhance sensing functionalities has rarely been achieved. This is largely due to the fact that nanostructures present on MNs surface could be easily destructed due to friction during skin insertion. In this work, we reported a dissolvable polymer-coating technique to protect nanostructures-integrated MNs from mechanical destruction during MNs insertion. After penetration into the skin, the polymer could readily dissolve by interstitial fluids so that the superficial nanostructures on MNs could be re-exposed for sensing purpose. To demonstrate this technique, metallic and resin MNs decorated with vertical ZnO nanowires (vNWs) were employed as an example. Dissolvable poly(vinyl pyrrolidone) was spray-coated on the vNW-MNs surface as a protective layer, which effectively protected the superficial ZnO NWs when MNs penetrated the skin. Transdermal biosensing of H2O2 biomarker in skin tissue using the polymer-protecting MNs sensor was demonstrated both ex vivo and in vivo. The results indicated that polymer coating successfully preserved the sensing functionalities of the MNs sensor after inserting into the skin, whereas the sensitivity of the MN sensor without a coating protection was significantly compromised by 3-folds. This work provided unique opportunities of protecting functional nanomodulus on MNs surface for minimally invasive transdermal biosensing.

Microneedle-Mediated Delivery of Lipid-Coated Cisplatin Nanoparticles for Efficient and Safe Cancer Therapy.

Cisplatin is the first-line chemotherapeutic agent, but its systemic toxicity and side effects severely limit its clinical use. We report a microneedle technique to mediate the transdermal delivery of lipid-coated cisplatin nanoparticles (LCC-NPs) for efficient and safe cancer therapy. Cisplatin was encapsulated by tumor-targeting pH-responsive lipid nanoparticles with a high loading rate of 80%, and the encapsulation substantially increased the solubility of cisplatin and enhanced its antitumor efficiency in vitro. The LCC-NPs were embedded in dissolvable microneedles, and released from the microneedles after inserting into the skin. This enabled the nanoparticles to pass the stratum corneum for safe local delivery. An in vivo study with a xenograft tumor animal model demonstrated that microneedle arrays loaded with cisplatin nanoparticles significantly increased cytotoxicity and apoptosis in cancer cells with an apoptotic index of 58.6%, resulting in significantly reduced tumor volume and weight. Moreover, serum platinum, pulmonary toxicity, hepatotoxicity, and nephrotoxicity were not detected in vivo, indicating that this technique is biosafe. The cisplatin-nanoparticle microneedle system developed in this study may offer promising opportunities in cancer therapy for enhancing antitumor effects and reducing systemic toxicity and side effects.

Nanospikes-mediated Anomalous Dispersities of Hydropobic Micro-objects and their Application for Oil Emulsion Cleaning.

Many fields of applications require dispersion of hydrophobic particles in water, which is traditionally achieved by using surfactants or amphiphilic molecules to modify particle surfaces. However, surfactants or amphiphilic molecules may disturb the native solution or particles' surface hydrophobicity, limiting extended applications such as oil emulsion cleaning. Recently one example of 2 µm-size polystyrene microparticles covered with ZnO nanospikes has been shown to exhibit excellent dispersity in water in spite of surface hydrophobicity. Whether this anomalous dispersion phenomenon was applicable to other hydrophobic microparticle systems was still unclear and its application scope was limited. Here the anomalous dispersities of different hydrophobic spiky micro-objects were systematically explored. The results show that the anomalous dispersion phenomenon was universally observed on different hydrophobic spiky micro-objects including different hydrophobic coating, particle sizes, material compositions and core particle morphologies. In addition, the spiky micro-objects displayed anomalous dispersity in water without compromising surface hydrophobicity, and their applications for oil spills absorption and oil emulsion cleaning were demonstrated. This work offers unique insight on the nanospikes-mediated anomalous dispersion phenomenon of hydrophobic micro-object and potentially extends its applicability and application scopes.

Nanospikes functionalization as a universal strategy to disperse hydrophilic particles in non-polar media.

Dispersion of hydrophilic particles in non-polar media has many important applications yet remains difficult. Surfactant or amphiphilic functionalization was conventionally applied to disperse particles but is highly dependent on the particle/solvent system and may induce unfavorable effects and impact particle hydrophilic nature. Recently 2 µm size polystyrene microbeads coated with ZnO nanospikes have been reported to display anomalous dispersity in phobic media without using surfactant or amphiphilic functionalization. However, due to the lack of understanding whether this phenomenon was applicable to a wider range of conditions, little application has been derived from it. Here the anomalous dispersity phenomenons of hydrophilic microparticles covered with nanospikes were systematically assessed at various conditions including different particle sizes, material compositions, particle morphologies, solvent hydrophobicities, and surface polar groups. Microparticles were functionalized with nanospikes through hydrothermal route, followed by dispersity test in hydrophobic media. The results suggest nanospikes consistently prevent particle aggregation in various particle or solvent conditions, indicating the universal applicability of the anomalous dispersion phenomenons. This work provides insight on the anomalous dispersity of hydrophilic particles in various systems and offers potential application to use this method for surfactant-free dispersions.

Anomalous dispersion of magnetic spiky particles for enhanced oil emulsions/water separation.

In situ effective separation of oil pollutants including oil spills and oil emulsions from water is an emerging technology yet remains challenging. Hydrophobic micro- or nano-materials with ferromagnetism have been explored for oil removal, yet the separation efficiency of an oil emulsion was compromised due to the limited dispersion of hydrophobic materials in water. A surfactant coating on microparticles prevented particle aggregation, but reduced oil absorption and emulsion cleaning ability. Recently, polystyrene microbeads covered with nanospikes have been reported to display anomalous dispersion in phobic media without surfactants. Inspired by this phenomenon, here magnetic microparticles attached with nanospikes were fabricated for enhanced separation of oil emulsions from water. In this design, the particle surfaces were functionalized to be superhydrophobic/superoleophilic for oil absorption, while the surface of the nanospikes prevented particle aggregation in water without compromising surface hydrophobicity. The magnetic spiky particles effectively absorbed oil spills on the water surface, and readily dispersed in water and offered facile cleaning of the oil emulsion. In contrast, hydrophobic microparticles without nanospikes aggregated in water limiting the particle-oil contact, while surfactant coating severely reduced particle hydrophobicity and oil absorption ability. Our work provides a unique application scope for the anomalous dispersity of microparticles and their potential opportunities in effective oil-water separation.

Transdermal Delivery of Living and Biofunctional Probiotics through Dissolvable Microneedle Patches.

Bioactive functional probiotics play an important role in many health applications such as maintaining skin health and the immunity of the human host. Artificial supplementation of probiotics would enhance immune functions as well as regulate skin health. However, simple and effective methods to deliver probiotics into the dermis to regulate local dermal tissue are still lacking. Furthermore, microneedles have been used for transdermal drug delivery in a pain-free manner, yet there were few reported methods to deliver living microbes via microneedles. In this work, we developed a technique to deliver bioactive functional probiotics, using lactobacillus as the model probiotic, into local dermis by dissolvable microneedles. The transdermal delivery of probiotics might enhance local skin regulation and immunity, and dissolvable microneedles served as a safe and pain-free tool for dermal microbial delivery. Lactobacillus was encapsulated in dissolvable microneedles with high viability by a centrifugation casting method. The microneedles rapidly dissolved after skin penetration, releasing the lactobacillus into the subcutaneous space, without causing local tissue irritation. The lactobacillus was functionally bioactive following transdermal delivery, actively synthesizing lactic acid both ex vivo and in vivo. Our technique provided a safe, effective, and convenient approach for the transdermal delivery of probiotics into local skin, with the potential to improve skin health and immunity.