Controlled drug delivery from chitosan-coated heparin-loaded nanopores anodically grown on nitinol shape-memory alloy

Nitinol (NiTi shape-memory alloy) is an interesting candidate in various medical applications like dental, orthopedic, and cardiovascular devices, owing to its unique mechanical behaviors and proper biocompatibility. The aim of this work is the local controlled delivery of a cardiovascular drug, heparin, loaded onto nitinol treated by electrochemical anodizing and chitosan coating. In this regard, the structure, wettability, drug release kinetics, and cell cytocompatibility of the specimens were analyzed in vitro. The two-stage anodizing process successfully developed a regular nanoporous layer of Ni-Ti-O on nitinol, which considerably decreased the sessile water contact angle and induced hydrophilicity. The application of the chitosan coatings controlled the release of heparin mainly by a diffusional mechanism, where the drug release mechanisms were evaluated by the Higuchi, first-order, zero-order, and Korsmeyer-Pepass models. Human umbilical cord endothelial cells (HUVECs) viability assay also showed the non-cytotoxicity of the samples, so that the best performance was found for the chitosan-coated samples. It is concluded that the designed drug delivery systems are promising for cardiovascular, particularly stent applications.

💡 Research Summary

This paper presents a novel drug‑delivery platform based on nitinol (NiTi) shape‑memory alloy that combines a two‑step electrochemical anodizing process with a chitosan coating to achieve controlled release of the anticoagulant heparin. First, NiTi discs were polished, electrically connected, and anodized in a 95 % ethylene glycol/5 % water electrolyte containing 0.3 M NaCl. The anodization was performed at 10 V for a total of 60 minutes, split into a 30‑minute static stage followed by a 30‑minute dynamic (stirred) stage. This protocol generated a regular nanoporous Ni‑Ti‑O oxide layer approximately 10 µm thick with an average pore diameter of about 45 nm, as confirmed by field‑emission scanning electron microscopy (FE‑SEM) and image‑analysis. Energy‑dispersive X‑ray spectroscopy verified the presence of Ni, Ti, O, Cl, and a trace of Si (from the silicone adhesive used during processing).

Heparin (5 mg · mL⁻¹) was loaded into the nanopores by a vacuum‑assisted infiltration method: the samples were placed in a sealed balloon, evacuated for 15 minutes, then the heparin solution was introduced and left for 24 hours, followed by air drying. To modulate release kinetics, two chitosan solutions (0.1 wt% and 0.2 wt% in 0.2 % acetic acid) were applied by brief immersion (10 s) and subsequent drying at 50 °C, yielding thin polymeric caps of differing thickness.

Wettability tests showed that anodization dramatically reduced the water contact angle, indicating a transition to a highly hydrophilic surface. The additional chitosan layer further increased hydrophilicity and introduced a positive surface charge, which favors electrostatic interaction with the negatively charged heparin molecules.

In vitro release studies were conducted in phosphate‑buffered saline (PBS) at 37 °C. Samples were removed at predetermined intervals up to 168 hours, and the amount of heparin released was quantified using a Toluidine Blue O assay (absorbance at 631 nm). The uncoated nanoporous sample (NP‑Hep) displayed a pronounced burst release, delivering more than 60 % of the loaded drug within the first 24 hours. Both chitosan‑coated variants exhibited markedly attenuated burst release; the 0.1 wt% chitosan coating reduced the initial release to roughly 30 % and extended drug delivery over the full week, while the 0.2 wt% coating provided the most gradual release profile, albeit with a lower total amount released.

Kinetic modeling of the release data demonstrated that the Higuchi model (which describes diffusion‑controlled release proportional to the square root of time) provided the best fit (R² > 0.98) for all samples. The Korsmeyer‑Peppas model also yielded high correlation coefficients with diffusion exponents (n) between 0.45 and 0.55, confirming a Fickian diffusion mechanism. Zero‑order and first‑order models were less representative of the overall behavior, though they captured certain later‑stage trends.

Biocompatibility was assessed using human umbilical vein endothelial cells (HUVECs). After sterilization, the samples were seeded with 1 × 10⁴ cells per well in a 48‑well plate and cultured for 1 and 3 days. Cell viability, measured by the CCK‑8 assay (optical density at 450 nm), remained above 70 % for all groups, with no statistically significant differences (p > 0.05). Notably, the chitosan‑coated specimens supported slightly higher cell attachment and proliferation, likely due to their enhanced hydrophilicity and positive surface charge, which are known to promote endothelial cell adhesion.

The authors conclude that the two‑step anodizing technique enables the formation of relatively thick (≈10 µm) nanoporous oxide layers on nitinol, providing a high‑capacity reservoir for heparin. The subsequent chitosan coating effectively tempers the initial burst and yields a diffusion‑controlled, sustained release profile while preserving, and even improving, endothelial cell compatibility. These findings suggest that such a system could be directly translated into drug‑eluting cardiovascular stents, offering a safer alternative to conventional polymer‑based drug‑eluting stents by minimizing early thrombogenic risk and supporting rapid re‑endothelialization. Future work is recommended to validate the platform in dynamic flow conditions, assess long‑term corrosion resistance, and explore multi‑drug loading strategies for broader therapeutic applications.