Hybrid microneedle arrays for antibiotic and near-IR photothermal synergistic antimicrobial effect against Methicillin-Resistant Staphylococcus aureus.

The rise of antibiotic-resistant skin and soft tissue infections (SSTIs) necessitates the development of novel treatments to improve the efficiency and delivery of antibiotics. The incorporation of photothermal agents such as plasmonic nanoparticles (NPs) improves the antibacterial efficiency of antibiotics through synergism with elevated temperatures. Hybrid microneedle (MN) arrays are promising local delivery platforms that enable co-therapy with therapeutic and photothermal agents. However, to-date, the majority of hybrid MNs have focused on the potential treatment of skin cancers, while suffering from the shortcoming of the intradermal release of photothermal agents. Here, we developed hybrid, two-layered MN arrays consisting of an outer water-soluble layer loaded with vancomycin (VAN) and an inner water-insoluble near-IR photothermal core. The photothermal core consists of flame-made plasmonic Au/SiO2 nanoaggregates and polymethylmethacrylate (PMMA). We analyzed the effect of the outer layer polymer, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), on MN morphology and performance. Hybrid MNs produced with 30 wt% PVA contain a highly drug-loaded outer shell allowing for the incorporation of VAN concentrations up to 100 mg g-1 and temperature increases up to 60 °C under near-IR irradiation while showing sufficient mechanical strength for skin insertion. Furthermore, we studied the combinatorial effect of VAN and heat on the growth inhibition of methicillin-resistant Staphylococcus aureus (MRSA) showing synergistic inhibition between VAN and heat above 55 °C for 10 min. Finally, we show that treatment with hybrid MN arrays can inhibit the growth of MRSA due to the synergistic interaction of heat with VAN reducing the bacterial survival by up to 80%. This proof-of-concept study demonstrates the potential of hybrid, two-layered MN arrays as a novel treatment option for MRSA-associated skin infections.

Customizable Fabrication of Photothermal Microneedles with Plasmonic Nanoparticles Using Low-Cost Stereolithography Three-Dimensional Printing.

Photothermal microneedle (MN) arrays have the potential to improve the treatment of various skin conditions such as bacterial skin infections. However, the fabrication of photothermal MN arrays relies on time-consuming and potentially expensive microfabrication and molding techniques, which limits their size and translation to clinical application. Furthermore, the traditional mold-and-casting method is often limited in terms of the size customizability of the photothermal array. To overcome these challenges, we fabricated photothermal MN arrays directly via 3D-printing using plasmonic Ag/SiO2 (2 wt % SiO2) nanoaggregates dispersed in ultraviolet photocurable resin on a commercial low-cost liquid crystal display stereolithography printer. We successfully printed MN arrays in a single print with a translucent, nanoparticle-free support layer and photothermal MNs incorporating plasmonic nanoaggregates in a selective fashion. The photothermal MN arrays showed sufficient mechanical strength and heating efficiency to increase the intradermal temperature to clinically relevant temperatures. Finally, we explored the potential of photothermal MN arrays to improve antibacterial therapy by killing two bacterial species commonly found in skin infections. To the best of our knowledge, this is the first time describing the printing of photothermal MNs in a single step. The process introduced here allows for the translatable fabrication of photothermal MN arrays with customizable dimensions that can be applied to the treatment of various skin conditions such as bacterial infections.

Highly Efficient Near-IR Photothermal Microneedles with Flame-Made Plasmonic Nanoaggregates for Reduced Intradermal Nanoparticle Deposition.

Near-infrared (NIR) photothermal therapy by microneedles (MNs) exhibits high potential against skin diseases. However, high costs, photobleaching of organic agents, low long-term stability, and potential nanotoxicity limit the clinical translation of photothermal MNs. Here, photothermal MNs are developed by utilizing Au nanoaggregates made by flame aerosol technology and incorporated in water-insoluble polymer matrix to reduce intradermal nanoparticle (NP) deposition. The individual Au interparticle distance and plasmonic coupling within the nanoaggregates are controlled by the addition of a spacer during their synthesis rendering the Au nanoaggregates highly efficient NIR photothermal agents. In situ aerosol deposition of Au nanoaggregates on MN molds results in the fabrication of photothermal MNs with thin plasmonic layers. The photothermal performance of these MN arrays is compared to ones made by three methods utilizing NP dispersions, and it is found that similar temperatures are reached with 28-fold lower Au mass due to reduced light scattering losses of the thin layers. Finally, all developed photothermal MN arrays here cause clinically relevant hyperthermia at benign laser intensities while reducing intradermal NP deposition 127-fold compared to conventional MNs made with water-soluble polymers. Such rational design of photothermal MNs requiring low laser intensities and minimal NP intradermal accumulation sets the basis for their safe clinical translation.

Laser-Induced Forward Transfer Printing on Microneedles for Transdermal Delivery of Gemcitabine.

Cancer treatment with chemotherapeutic drugs remains to be challenging to the physician due to limitations associated with lack of efficacy or high toxicities. Typically, chemotherapeutic drugs are administered intravenously, leading to high drug concentrations that drive efficacy but also lead to known side effects. Delivery of drugs through transdermal microneedles (MNs) has become an important alternative treatment approach. Such delivery options are well suited for chemotherapeutic drugs in which sustained levels would be desirable. In the context of developing a novel approach, laser-induced forward transfer (LIFT) was applied for bioprinting of gemcitabine (Gem) to coat polymethylmethacrylate MNs. Gem, a chemotherapeutic agent used to treat various types of cancer, is a good candidate for MN-assisted transdermal delivery to improve the pharmacokinetics of Gem while reducing efficiency limitations. LIFT bioprinting of Gem for coating of MNs with different drug amounts and successful transdermal delivery in mice is presented in this study. Our approach produced reproducible, accurate, and uniform coatings of the drug on MN arrays, and on in vivo transdermal application of the coated MNs in mice, dose-proportional concentrations of Gem in the plasma of mice was achieved. The developed approach may be extended to several chemotherapeutics and provide advantages for metronomic drug dosing.

Tailored Biocompatible Polyurethane-Poly(ethylene glycol) Hydrogels as a Versatile Nonfouling Biomaterial.

Polyurethane-based hydrogels are relatively inexpensive and mechanically robust biomaterials with ideal properties for various applications, including drug delivery, prosthetics, implant coatings, soft robotics, and tissue engineering. In this report, a simple method is presented for synthesizing and casting biocompatible polyurethane-poly(ethylene glycol) (PU-PEG) hydrogels with tunable mechanical properties, nonfouling characteristics, and sustained tolerability as an implantable material or coating. The hydrogels are synthesized via a simple one-pot method using commercially available precursors and low toxicity solvents and reagents, yielding a consistent and biocompatible gel platform primed for long-term biomaterial applications. The mechanical and physical properties of the gels are easily controlled by varying the curing concentration, producing networks with complex shear moduli of 0.82-190 kPa, similar to a range of human soft tissues. When evaluated against a mechanically matched poly(dimethylsiloxane) (PDMS) formulation, the PU-PEG hydrogels demonstrated favorable nonfouling characteristics, including comparable adsorption of plasma proteins (albumin and fibrinogen) and significantly reduced cellular adhesion. Moreover, preliminary murine implant studies reveal a mild foreign body response after 41 days. Due to the tunable mechanical properties, excellent biocompatibility, and sustained in vivo tolerability of these hydrogels, it is proposed that this method offers a simplified platform for fabricating soft PU-based biomaterials for a variety of applications.

Vancomycin-Loaded Microneedle Arrays against Methicillin-Resistant Staphylococcus Aureus Skin Infections.

Skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare burden, often treated with intravenous injection of the glycopeptide antibiotic vancomycin (VAN). However, low local drug concentration in the skin limits its treatment efficiency, while systemic exposure promotes the development of resistant bacterial strains. Topical administration of VAN on skin is ineffective as its high molecular weight prohibits transdermal penetration. In order to implement a local VAN delivery, microneedle (MN) arrays with a water-insoluble support layer for the controlled administration of VAN into the skin are developed. The utilization of such a support layer results in water-insoluble needle shafts surrounded by drug-loaded water-soluble tips with high drug encapsulation. The developed MN arrays can penetrate the dermal barriers of both porcine and fresh human skin. Permeation studies on porcine skin reveal that the majority of the delivered VAN is retained within the skin. It is shown that the VAN-MN array reduces MRSA growth both in vitro and ex vivo on skin. The developed VAN-MN arrays may be extended to several drugs and may facilitate localized treatment of MRSA-caused skin infections while minimizing adverse systemic effects.