3D printing combined with pH-induced 4D printed iron(III)-oxidized starch gels for controlled iron delivery and enhanced iron supplementation

Abstract

Iron deficiency anemia (IDA) necessitates effective iron supplementation with high bioavailability and controlled release. This study developed 4D-printed ferric-oxidized starch gels (4D-FeOMS) as a stimulus-responsive platform for targeted iron delivery. By combining hot-extrusion 3D printing with pH-triggered 4D transformation, Fe³⁺ was effectively coordinated within oxidized starch networks via ionic crosslinking. Rheological analysis revealed Fe³⁺ hydrolysis disrupted starch molecular hydrogen bonding and reducing molecular weight, leading to diminished gel network uniformity and density. Compared to 3D-printed samples (3D-FeOMS), 4D-FeOMS exhibited red-shifted CO FTIR peaks, lower Fe 2p XPS binding energies, and reduced correlation length (ξ), indicating improved molecular entanglement and network uniformity. In vitro digestion demonstrated gastric resistance (<30 % Fe³⁺ release) and rapid iron release (>85 %) in the proximal small intestine. In vivo evaluation in IDA mice showed that 4D-FeOMS significantly restored biochemical and hematological parameters, increased organ iron stores (restored >94.6 %), and enhanced antioxidant enzyme activity, outperforming iron salts and 3D-FeOMS. Mechanistically, 4D-FeOMS optimized hepcidin expression and regulated ferritin/transferrin levels, facilitating systemic iron transport. Notably, 4D-FeOMS-10 % demonstrated iron supplementation efficacy performance due to the appropriate iron addition and optimal Fe³⁺ complexation. These findings highlighted the potential of 4D-printed starch-based platforms as intelligent mineral delivery systems for treating micronutrient deficiencies.

Introduction

Iron deficiency anemia (IDA) is a general health condition caused by insufficient iron intake or absorption disorders, resulting in reduced hemoglobin levels with decreased oxygen transport and various adverse physiological effects (Camaschella, 2017; Lynch, 1997). Conventional iron supplements, such as ferrous salts, are often hindered by poor bioavailability, gastrointestinal irritation, and patient non-compliance (Sun et al., 2020). These challenges require the development of advanced iron conveying systems to improve iron absorption and utilization while minimizing adverse impacts (Shingles et al., 2001). Among the emerging alternatives, polysaccharide‑iron complexes have attracted attention due to their biocompatibility and biodegradability properties (Ji, Guo, et al., 2022; Liu et al., 2018; Zhang et al., 2019). Polysaccharides could interact with iron ions via electrostatic or coordination mechanisms to form stable complexes that prevent iron dissolution in the gastrointestinal tract (Li et al., 2022), thereby improving the solubility and bioavailability of iron and reducing the side effects of traditional iron supplements (Krupnik et al., 2024). Iron from these complexes could be efficiently absorbed in the duodenum and jejunum, where it binds to transferrin for systemic transport and storage (Wang et al., 2020; Zhang et al., 2012).

In this context, starch, a widely available and cost-effective polysaccharide (Li et al., 2011), offers an attractive alternative to polysaccharide‑iron complexes (Shi et al., 2024). Research has demonstrated that starch can form coordination complexes with iron ions (Somsook et al., 2005). Its molecular structure can be chemically modified to introduce functional groups, such as carboxyl groups, improving its binding affinity for Fe3+ ions and enabling controlled release. However, unmodified starch‑iron complexes often exhibit instability in gastric conditions, necessitating structural modifications to maintain iron coordination and regulate its release under physiological conditions (Komulainen et al., 2013). Starch-based hydrogels, with their high swelling and water retention capacity, serve as an effective matrix for the encapsulation and controlled release of ions (Zheng et al., 2023). These three-dimensional crosslinked networks can regulate iron release through gel degradation or concentration gradient diffusion (du Poset et al., 2018; Kazemi-Taskooh & Varidi, 2021). However, the stability of Fe(III)-oxidized starch gels is determined not only by the presence of carboxyl and hydroxyl groups but also by the microstructure of the gel network (Qiu et al., 2022). Therefore, improving the structural integrity and iron-binding capacity of the gels is crucial for optimizing its therapeutic performance (Ji, Xu, et al., 2022; Zhao et al., 2022).

To address these challenges, 4D printing technology offers a novel approach to developing intelligent, stimulus-responsive iron delivery systems (Gladman et al., 2016; Paccione et al., 2024). Unlike conventional 3D printing, 4D printing introduces dynamic, self-assembling capabilities that allow materials to respond to external stimuli such as temperature, humidity, or pH changes (Li, Yang, Wu, et al., 2023). This adaptability is particularly valuable for designing controlled-release drug and nutrient delivery systems (Li, Yang, Chen, et al., 2023), where the rate and location of iron release can be precisely tuned. By leveraging hot extrusion-based 4D printing, starch-based hydrogels with tailored network structures, enhancing iron retention and enabling targeted release in the small intestine could be engineered.

In this study, a novel approach was proposed for the development of Fe(III)-oxidized starch (OMS) gels by starch oxidation with 4D printing technology to construct an intelligent, responsive iron delivery system oxidative modification. By incorporating carboxyl groups into starch molecules through oxidative modification, Fe3+ can be effectively complexed while simultaneously reducing starch molecular weight. We hypothesized that the resulting Fe3+-oxidized starch (FeOMS) gels, fabricated through hot extrusion-based 4D printing, allow for precise control over gel network structure and ionic crosslinking interactions, ensuring stable iron coordination and controlled release. The acid-resistant of 4D-FeOMS gels inhibited the premature iron release from the stomach, while their pH responsive degradation resulted in rapid iron release from the proximal small intestine after amylase hydrolysis. This mechanism improved the iron absorption efficiency and provided a cost-effective and scalable substitute for small molecular polysaccharides in mineral supplements. This study also investigated the functional properties of 4D-printed FeOMS gels in an IDA mouse model, evaluating the impact of varying iron concentrations on hematological parameters, iron metabolism, and physiological responses. By elucidating the relationship between 4D-printed FeOMS structure and iron bioavailability, this research provided new insights into the design of starch-based mineral supplements (Scheme 1).

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Zhipeng Qiu, Qiyong Guo, Jiayu Lv, Ling Chen, 3D printing combined with pH-induced 4D printed iron(III)-oxidized starch gels for controlled iron delivery and enhanced iron supplementation, Carbohydrate Polymers, Volume 366, 2025, 123933, ISSN 0144-8617, https://doi.org/10.1016/j.carbpol.2025.123933.