3D Microfabrication of Fully-Embedded Transdermal Microneedles for Single-Administration Vaccines

Specific medication schedules need to be strictly followed to make treatments effective. Repeated bolus injections are associated with higher costs and poor compliance and can hinder the implementation of global immunization campaigns. The concept of a single-injection vaccine has been investigated for many years. Furthermore, injection-based systems continue to raise substantial concerns regarding biohazards and the risk of disease transmission from the billions of needles/syringes that are disposed of every year. As a result, there is a critical need to develop a new drug and vaccine delivery approach that is injection free and requires only a one-time administration. Here, we present a high-throughput and scalable 3D-manufacturing approach to create a biodegradable core-shell-microneedle system that can be fully embedded in the skin and that requires only a one-time insertion for the delayed burst release of vaccine antigens at different programmable time points, ranging from days to months.<br/>The microneedles have a core–shell microstructure that is generated using a 3D manufacturing process that assembles together three different components of the microneedles, including a microneedle shell, a microneedle cap and a dried drug or vaccine core. The drug or vaccine core is encapsulated by the cap and base layer, which are made from the same biodegradable polymer, that is, poly(d,l-lactide-co-glycolide) (PLGA). By tailoring the degradation of the PLGA shell, we can precisely control when the drug is released.<br/>The release studies, <i>in vitro</i> and <i>in vivo,</i> confirm that the core–shell microneedles have a high level of control over the drug-release time. Core–shell microneedles from different biodegradable polymers of PLGA with varying molecular masses and ratios of lactic versus glycolic components were fabricated. The microneedles made from PLGA with higher molecular masses or longer degradation times provided longer lag times (for example, up to 48 d when using the PLGA 6 (PLGA 75:25 acid-terminated,85 kDa)). Furthermore, microneedles made by blending two PLGAs together offered lag times in-between those given by microneedles that were made purely of each PLGA separately. These results confirm that the core–shell microneedles have a high level of control over the drug-release time, which can be fine-tuned by tailoring the encapsulating PLGA compositions. In mechanical testing, the average failure force of the softest core–shell microneedles that were made from the lowest-molecular-mass PLGA was measured at 0.33 N per needle, which would be sufficient to facilitate insertion into human skin without breaking. In rats, microneedles loaded with a clinically available vaccine (Prevnar-13) against the bacterium <i>Streptococcus pneumoniae </i>induced immune responses that were similar to immune responses observed after multiple subcutaneous bolus injections, and led to immune protection against a lethal bacterial dose. The animals that were vaccinated with Prevnar-13 microneedles exhibited no substantial weight loss and limited clinical signs of illness. The mortality curves of the Prevnar-13 microneedles and s.c. injection groups were not significantly different, although the Prevnar-13 microneedle group had a higher percentage of survival (100%) compared with the s.c. injection (80%). Irritation assessment has shown that PLGA microstructures are highly biocompatible for skin implantation without much local immune reaction.<br/>We report the development and preclinical testing of patches of transdermal core–shell microneedles—which were fabricated by the micromoulding and alignment of vaccine cores and shells made from PLGA with varying degradability kinetics—for the preprogrammed burst release of vaccine payloads over a period of a few days to more than a month from a single administration. Microneedle patches delivering preprogrammed doses may offer an alternative strategy to prophylactic and therapeutic protocols that require multiple injections<b>.</b>