Although metal ions, such as silver and gold, have been shown to have strong antimicrobial properties, their potential to have toxic effects on human and environmental health has gained interest with an improved understanding of their mechanisms to promote oxidative stress. Redox control is a major focus of many drug delivery systems and often incorporates an antioxidant as the active pharmaceutical ingredient (API) to neutralize overproduced reactive oxygen species (ROS). Nevertheless, there are still limitations with bioavailability and extended redox control with regard to antioxidant drug delivery. Herein, this study develops a colloidal antioxidant crystal system that dissolves sustainably through polymer stabilization using sodium hyaluronate conjugated with dopamine (HA-dopa). We explore the role of dopamine incorporation into crystal-stabilizing polymers and quantify the balance between drug–polymer interactions and competing polymer–polymer interactions. We propose that this type of analysis is useful in the engineering of and provides insight into the release behavior of polymer–crystal complexes. In developing our crystal complex, N-acetylcysteine (NAC) was used as the model antioxidant to protect against silver ion toxicity. We found that our optimized HA-dopa-stabilized NAC crystals prolong the release time of NAC 5-fold compared to a polymer-free NAC crystal. Therefore, following sublethal exposure to AgNO3, the extended lifetime of NAC was able to maintain normal intracellular ROS levels, modulate metabolic function, mitigate fluctuations in ATP levels and ATP synthase activity, and preserve contraction frequency in engineered cardiac muscle tissue. Furthermore, the protective effects of the HA-dopa-stabilized NAC crystals were extended to a Daphnia magna model where silver-ion-induced change to both cell-level biochemistry and organ function was alleviated. As such, we propose that the packaging of hydrophilic antioxidants as colloidal crystals drastically extends the lifetime of the API, better maintains ROS homeostasis post metal ion exposure, and therefore preserves both intracellular biochemistry and tissue functionality.

Crystallization engineering is crucial for the preparation of drug delivery systems with precise release behavior and improved stability. Although evaporation has been commonly used to prepare pharmaceutical film formulations, controlled evaporative crystallization to achieve uniform crystal size and shape has rarely been investigated. In this study, ordered submicrometer composite structures of acetaminophen (ACM) and polymers were prepared via directional evaporative crystallization controlled by a temperature gradient. The ACM crystals had submicrometer sizes while retaining the original crystal polymorph and were aligned along the direction of the temperature gradient, resulting in line structures having branches with uniform and oriented crystal structures. Although the use of a polymer did not affect conventional oven-crystallized films, it significantly decreased the melting point and heat of fusion of directionally crystallized films. The formation of ordered submicrometer composite structures must rely more on kinetic parameters than thermodynamic parameters since no significant intrinsic molecular interactions were discovered. A wide range of sustained-release characteristics could be obtained depending on the polymer types. This unique fast directional crystallization method could offer a new opportunity for future film delivery systems.

Smart surfaces containing thermo-responsive hydrogels have been investigated for several decades, but the development of mechanically durable and versatile surfaces that can undergo distinct property changes remains a challenging task. Herein, we prepare smart surfaces showing reversible changes in micro-scale roughness, which are attachable to various polymeric substrates. The hydrogel microphase located between silicone phases responsively rise and descend (volcanic-terrain-mimetic transition); as a result, the surface properties reversibly swing from those of the hydrophobic silicone-like ones to those of the wet hydrogel ones. The durability of these surfaces resembles that of silicone, while their fast water release characteristics allow the utilization of the studied materials in self-aligning and artificial sweating applications. The release of the drug molecules loaded into the hydrogel phase is controlled by varying the temperature and composite structure. Thus, the fabricated versatile surfaces utilizing the volume transition of thermo-responsive hydrogels can meet the requirements of various future applications.

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