Hybrid antibacterial microneedle patches against skin infections

Abstract: Skin and soft tissue infections (SSTIs) are a major healthcare burden that has increased in incidence since the beginning of the 21st century resulting in an annual spending of approximately 15 b$ in 2012 in the United States (US).1 Treatment of SSTIs is complex and typically involves the administration of antibiotics. However, the antibiotic therapy of SSTIs has multiple obstacles interfering with an efficient treatment outcome such as (i) limited local antibiotic penetration into the skin and (ii) rising antibiotic resistant SSTIs. The limitation of local drug penetration is associated with the route of administration. On the one hand, antibiotics can be given topically; however, the protective function of the skin limits the types of drugs that can efficiently be given via this route. On the other hand, systemic administration of the antibiotic parenterally or intravenously (IV) shows low local skin absorption while suffering from side effects associated with the systemic exposure of the body to the antibiotic. Furthermore, the rise in antibiotic resistance urgently calls for the development of novel antibacterial treatment options to optimize the antibacterial effect of current antibiotics and reduce further resistance development. A potential to improve the antibacterial effect of antibiotics is through multimodal therapies and as such the incorporation of heat from photothermal therapy (PTT) has been reported as a promising avenue to improve antibiotic efficiency. In the scope of this thesis, microneedle (MN) arrays were developed to address the problems faced in the treatment of bacterial SSTIs. In the first part of this thesis, dissolvable MN arrays loaded with the antibiotic vancomycin (VAN) were developed and tested in ex vivo porcine infection models of methicillin-resistant Staphylococcus aureus (MRSA), a strain commonly found in SSTIs. The MN arrays allowed the delivery of high concentrations of VAN locally in the skin where it remained active to inhibit the growth of MRSA after only two applications for 10 minutes. The second part of this thesis describes the development of photothermal MN arrays with plasmonic Au/SiO2 and Ag/SiO2 nanoaggregates. Four different fabrication methods following traditional mold-and-casting methods using Au/SiO2 revealed that the rational selection of the fabrication method allows for a control over the MN morphology, photothermal effect, and a reduction of nanoparticle (NP) deposition into the skin. Additionally, Ag/SiO2 nanoaggregates were employed in nanocomposites of ultraviolet (UV)-curable resin to be used for the 3D printing of photothermal MN arrays. Such 3Dprinted photothermal MN arrays allowed for the in vitro killing of the SSTI-associated bacterial species S. aureus and Pseudomonas aeruginosa by heat. However, final temperature of the planktonic samples reached >60 ºC limiting the clinical potential of such photothermal MNs as monotherapies since such high temperatures may cause damage to healthy cells. Therefore, hybrid MN arrays were developed that incorporate both VAN and photothermal nanoaggregates to reduce the needed antibiotic and temperature dose through synergistic interactions. Such hybrid MNs were fabricated employing an outer, dissolvable, drug-loaded layer and an inner, non-dissolvable, photothermal core aiming to combine the advantages of (i) high local VAN delivery and (ii) intradermal PTT. We showed the successful synergistic growth inhibition of MRSA in vitro of such hybrid MN arrays. Overall, the work in this thesis introduces a potential novel treatment option for bacterial SSTIs.