3D-Printed Multifunctional Multicompartment Polymer-Based Capsules for Tunable and Spatially Controlled Drug Release

Abstract

The development of polymer-based systems is central to the design of next-generation drug delivery carriers, as polymers enable versatile tuning of physicochemical properties and responsiveness. In this work, we introduce a 3D printing-based strategy for the fabrication of multicompartment capsules that integrate multiple polymers within a unique one-step process. This approach allows precise spatial organization and structural complexity, yielding capsules with customizable features such as compartmentalization, polymer-specific responsiveness, and localized release control. In particular, pH-triggered release can be programmed across distinct polymeric regions of the capsules, enabling site-specific delivery along different intestinal segments, including the small intestine and colon. The use of 3D printing thus provides a scalable and adaptable platform to generate multifunctional polymer-based carriers with finely tunable drug release profiles, paving the way for new directions in polymer-enabled controlled delivery technologies.

Introduction

3D-printed capsules for enteric drug delivery represent an emerging technology with significant potential to transform oral therapeutics by enabling patient-specific dosing, precise control of release kinetics, and the creation of complex, multicompartmental structures that enhance targeting within the gastrointestinal tract [1,2,3]. Through additive manufacturing, these systems can integrate enteric coatings or compartmentalized drug loading to protect active ingredients from gastric acidity and ensure site-specific intestinal release [4,5]. Despite these advantages, clinical and commercial translation is hindered by critical challenges, including the limited availability of pharmaceutical-grade printable polymers with proven biocompatibility and mechanical strength, the risk of structural fragility in low-density designs, slower production rates compared to conventional capsule manufacturing, and regulatory frameworks that are not yet adapted to additive manufacturing [3,6,7].

Recent studies have reported several strategies to overcome these limitations [8,9,10,11]. Extrusion-based printing has enabled the fabrication of single- or dual-layer capsules with enteric protection, but such approaches often lack the ability to finely modulate release profiles beyond a binary “on–off” behavior [12,13,14]. Other works have exploited polymer blends or functional coatings to impart responsiveness to pH, temperature, or enzymatic activity; however, these methods typically require sequential processing steps and are less effective at generating complex architectures with distinct functional domains. Moreover, post-processing or coating stages introduce variability and increase the risk of inter-batch inconsistency, which remains a barrier to reproducibility and scalability [15,16,17,18,19,20].

In contrast, our approach introduces a fully integrated 3D-printed process in which compartment filling and sealing occur in one continuous automated workflow. Each capsule can be produced in less than 2 min (excluding the Eudragit drying phase), with a 98% reproducibility rate for shell fabrication and >90% reproducibility for inner-compartment formation. The platform is inherently scalable, and production time per capsule is expected to decrease further in high-throughput settings, where the dead time associated with cartridge changes is minimized. By combining different polymers in spatially organized compartments, this approach allows for the direct integration of polymer-specific responsiveness within the capsule structure, eliminating the need for additional coating or processing stages. Compared with conventional extrusion or coating-based systems, our method offers several advantages: (i) enhanced structural complexity through programmable spatial patterning, (ii) tailored release kinetics enabled by compartmentalized polymer domains and polymer crosslinking, and (iii) improved design versatility that can be adapted to specific therapeutic needs, including site-targeted release along different intestinal segments. Importantly, the multicompartmental design not only enables multi-drug loading with independent release triggers but also allows the physical separation of compounds that would otherwise be incompatible in a single formulation—for instance, preventing direct contact between probiotics and lipids (e.g., essential oils), thereby preserving their stability and efficacy [21,22,23].

In the system developed, each compartment is engineered with a specific polymeric material serving a defined function (Figure 1): Eudragit L100, deposited on the capsule lid, provides gastroresistance and acts as a pH-sensitive trigger for intestinal release; BioFlex polymer forms the capsule shell, combining mechanical robustness with flexibility to facilitate swallowing and promote content release under peristaltic pressure [24]; xanthan gum enables incorporation of essential oils into a stable microemulsion; alginate blended with xanthan gum creates a viscous gel matrix that mediates sustained essential oil release; and gelatin forms the upper layer potentially encapsulating probiotics and ensuring their earlier release compared to the essential oil. Notably, gelatin also displays a favorable sol–gel transition, remaining solid at room temperature but becoming more viscous under physiological conditions, thereby promoting controlled release. Beyond their functional roles, the selected materials—xanthan gum, alginate, and gelatin—are already available at an industrial scale for commercial applications and are widely recognized as edible, biocompatible, and pharmacologically inert, minimizing risks of undesired interactions with co-administered drugs.

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Chemicals and Materials

2.1. Chemicals and Materials

BioFlex® (FILOALFA, Turin, Italy) was used to print the capsule shell. Sodium alginate (CAS No. 9005-38-3), xanthan gum from Xanthomonas campestris (CAS No. 11138-66-2), gelatin from porcine skin (CAS No. 9000-70-8), triethyl citrate (CAS No. 77-93-0), phosphate-buffered saline (pH 7.4), and Rhodamine B (CAS No. 81-88-9) were purchased from Sigma-Aldrich (St. Louis, USA). Rosemary essential oil was purchased from a local shop. Eudragit® L100 was purchased from Evonik Operations GmbH and was selected for its pH-dependent solubility that allows dissolution at pH ≥ 6.0, ensuring selective release in the small intestine.

2.2. Bioink and Polymer Preparation

Sodium alginate at 3% w/v concentration and xanthan gum at 1.5% w/v were dissolved in sterile water under vigorous stirring at 80 °C. After 2 h, rosemary essential oil was added in the ratio of 1:3 (v/v). The mixture was stirred overnight at room temperature. Rhodamine B was added to a 10% gelatin at a concentration of 175 nM; the blend was pre-warmed at 37 °C during the printing step. Eudragit L100 was dissolved in 90% ethanol in the ratio 1:10 w/w under vigorous stirring at room temperature overnight. Triethyl citrate at 15% w/w was added to the Eudragit blend as a plasticizer. Biopolymers were kept at 4 °C in dark conditions until use.

Minopoli, A.; Perini, G.; Evangelista, D.; Marras, M.; Augello, A.; Palmieri, V.; De Spirito, M.; Papi, M. 3D-Printed Multifunctional Multicompartment Polymer-Based Capsules for Tunable and Spatially Controlled Drug Release. J. Funct. Biomater. 2025, 16, 456. https://doi.org/10.3390/jfb16120456