On-demand radiofrequency-controlled drug release from microcapsule depot in ex vivo tissue model

Abstract

Passive antibiotic release from implanted depot systems often leads to sub-therapeutic dosing, which in some cases may increase the risk of bacterial resistance. Addressing this limitation requires precise, controllable dosing strategies that do not rely on additional surgical interventions. To this end, this work presents a core–shell depot microcapsule system that enables externally controlled, on-demand antibiotic release using radiofrequency (RF) heating. The microcapsules (d ≈ 500 µm) consist of a norfloxacin-loaded wax solid core and a dually crosslinked methacrylated alginate shell containing superparamagnetic iron oxide nanoparticles (SPIONs). RF-induced heating of the SPIONs triggers the melting of the wax core, initiating drug release only when required, enabling precise repeated delivery up to 10 times. The dual-crosslinked shell ensures structural integrity, maintaining prolonged stability under physiological conditions. Mathematical and experimental models confirm the thermal safety of the process. Furthermore, antibacterial efficacy was validated on Escherichia coli-coated agar plates and in ex vivo animal tissue model, showing significant bactericidal effects in vitro. The findings highlight a promising approach for targeted, responsive antibacterial treatment while minimizing the risks of resistance development.

Introduction

The growing need for more precise, responsive, and patient-tailored therapies has driven intense research efforts toward advanced drug delivery strategies capable of adapting to disease-specific biochemical and biological signals. In this broader context, concepts emerging from smart closed-loop drug delivery—where therapeutic action is informed by real-time physiological or pathological cues—have underscored the importance of spatiotemporal control over drug release, particularly in conditions characterized by localized and evolving disease states. (Paci et al., 2025, Mendez et al., 2024, Pelkey et al., 2023) Parallel advances in stimuli-responsive biomaterials and implantable delivery platforms have laid the groundwork for next–generation therapeutic depots with unprecedented levels of control. (Sun et al., 2024, Zheng et al., 2021, Lu et al., 2023).

Despite significant advances in implantable therapeutic and diagnostic platforms, many existing systems are fabricated from non-biodegradable materials and therefore require surgical removal once their functional lifetime has elapsed. (Kluin et al., 2013) Such secondary interventions are inherently undesirable, as they increase the risk of infection, impose additional physical and psychological burden on patients, and contribute to higher healthcare costs. (Xi et al., 2021) In parallel with efforts aimed at improving control over drug release, substantial attention has also been directed toward the development of transient and bioresorbable implantable materials, with the aim of reducing long-term material retention and the need for device retrieval. (Li et al., 2018, Brenckle et al., 2015).

One particularly compelling example where such advanced material concepts could offer substantial benefits is local antibiotic drug depots. By enabling localized delivery directly at the site of infection, antibiotic depots can achieve high local drug concentrations while reducing systemic exposure. (Gao et al., 2018) Importantly, depots designed to provide controlled, temporally defined antibiotic release offer a promising route toward administering antibiotics only when needed, while minimizing unintended exposure outside defined treatment windows.

Local antibiotic depots are already widely employed in clinical practice, particularly in post-surgical settings such as orthopedic interventions, dental surgery, and the management of implant-associated infections, where the risk of local bacterial contamination is high. These depots are typically designed to provide sustained, localized antibiotic release directly at the surgical site, with the aim of preventing infection and reducing the need for repeated systemic administration. (Shah and Hong, 2022, Li et al., 2022, Pandya et al., 2023, Wassif et al., 2021, Fuglsang-Madsen et al., 2024).

Most clinically used depot formulations—such as drug-loaded polymer beads, antibiotic bone cements, and injectable in situ-forming depots—rely on passive diffusion- or erosion-controlled release, resulting in continuous, predefined release profiles with limited control over the timing and rate of antibiotic delivery, which can promote prolonged exposure to sub-therapeutic drug concentrations, particularly at later stages of depot depletion. (Saklani et al., 2022, Butreddy et al., 2021, Xiong et al., 2024, Wassif et al., 2021, Ter Boo et al., 2016) Such exposure profiles are widely recognized to impose selective pressure on bacterial populations, thereby promoting bacterial adaptation and the emergence of antibiotic resistance. (Yarahmadi et al., 2025, Andersson and Hughes, 2014) This concern is especially pronounced in post–surgical and implant-associated infections, where bacteria are exposed to sustained local antibiotic levels over extended periods and where biofilm formation and impaired drug penetration further exacerbate resistance development. (Wassif et al., 2021, Liu et al., 2024, Turner et al., 2019) The World Health Organization estimates that antibiotic-resistant bacteria are responsible for around 700,000 deaths annually, with this number potentially escalating to 10 million by 2050. (Naghavi et al., 2024, Tang et al., 2023).

Among externally triggered drug delivery systems, radiofrequency (RF)-induced heating has attracted considerable interest due to its ability to achieve non-invasive, localized activation in deep tissues. (Mahmoudi et al., 2018, Fan et al., 2025) RF-responsive systems typically incorporate magnetic nanoparticles that convert electromagnetic energy into heat, enabling on-demand drug release from thermally sensitive carriers. (Liu et al., 2019) Such approaches have been explored in applications ranging from magnetic hyperthermia for glioblastoma treatment to controlled drug delivery. (Rivera et al., 2025, Ozel et al., 2025) Although RF-triggered systems require external activation and careful control of thermal safety, they offer precise temporal control over dosing and repeated activation of implanted depots, making them particularly attractive for localized therapies requiring intermittent drug administration. (Sun et al., 2020).

The ability to trigger drug release on demand is particularly attractive for local antibiotic therapy. An ideal local antibiotic depot would be capable of delivering high, bactericidal drug concentrations within clearly defined treatment windows, while minimizing or completely avoiding antibiotic exposure outside the required periods. Such temporal control over antibiotic availability would reduce unintended selective pressure on bacterial populations and align drug delivery more closely with the actual therapeutic demand at the infection site.

In this work, we present a local antibiotic depot that enables externally controlled, on–off antibiotic delivery using RF heating. The system is based on a core–shell depot architecture (Fig. 1a, b) in which localized RF-induced heating triggers antibiotic release only at defined time points, thereby decoupling drug delivery from continuous passive diffusion and allowing bactericidal concentrations to be generated when required while avoiding unintended low-dose exposure between treatment \windows. To demonstrate the practical functionality of this approach beyond simplified in vitro models, the depot performance is evaluated in a complex biological matrix, providing an important intermediate validation step prior to future in vivo studies of externally triggered antibiotic delivery systems.

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Chemcials

Kanamycin was obtained from Carl Roth GmbH, Germany. Ammonium hydroxide solution was purchased from Honeywell. Calcium chloride (anhydrous) was obtained from Lach-Ner. Acetonitrile, ascorbic acid, hydrochloric acid 35%, sodium chloride, yeast extract, and tryptone for bacterial cultivation were obtained from Penta. Rubitherm RT 42 paraffin wax was obtained from Rubitherm Technologies GmbH, Germany. Agar and dextran from Leuconostoc spp., and 1,10 phenanthroline, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-aminoethyl methacrylate, 2-hydroxy-2-methylpropiophenone (Irgacure 1173), ammonium acetate, ammonium phosphate monobasic, atenolol, HEPES, hydroxylamine, iron (II) chloride tetrahydrate, iron (III) chloride hexahydrate, MES buffer, N-hydroxysuccinimide, norfloxacin, phosphate-buffered saline (tablets), resazurin sodium salt, sodium alginate, sodium borohydride, and sorbitan monooleate (SPAN 80) were obtained from Sigma-Aldrich. Frozen chicken breasts were purchased from Vodňanská drůbež, a.s. Deionised water (deH2O) (conductivity < 1 µS/cm) was produced by the Aqual 25 ionex device (Aqual, Czech Republic).

Karolína Slonková, Ondřej Navrátil, Rostislav Huňa, Bohumil Dolenský, Denisa Lizoňová, František Štěpánek, On-demand radiofrequency-controlled drug release from microcapsule depot in ex vivo tissue model, International Journal of Pharmaceutics, Volume 701, 2026, 127115, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127115.

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