The skin is the largest organ of the human body by weight and surface area [1,2], composed primarily of the epidermis, an outer epithelial layer, and the dermis, a deep layer consisting mainly of connective tissue [3]. Below the dermis lies the hypodermis, a subcutaneous tissue composed mostly of adipose tissue pads [4]. Skin flaps (or cutaneous flaps) are skin segments transferred from a donor site to a recipient site, maintaining their necessary blood supply through a pedicle to ensure the flap's survival [5,6]. This procedure is frequently used in plastic and reconstructive surgery [7,8]. However, complications can occur during the transfer of these flaps, notably a lack of blood perfusion and subsequent ischemia, which characterizes an ischemic skin flap (ISF). The failure to effectively manage this inflammatory process can result in tissue necrosis [8,9]. Therefore, maintaining blood supply is an essential factor for ensuring the viability and survival of ISFs [5]. To address the challenge of ISF necrosis, various therapeutic strategies have been explored to enhance flap viability. These include pharmacological interventions such as vasodilators (e.g., nitroglycerin) to improve perfusion [68,69], anticoagulants to prevent microthrombosis [70], and antioxidants or reactive oxygen species (ROS) scavengers to counteract ischemia-reperfusion injury [71]. Additionally, approaches aimed at promoting angiogenesis, including cell-based therapies and modulation of pathways involving nitric oxide (NO), have been investigated [72]. Despite extensive existing research, new biocompatible approaches are still needed [5,10].

In response to this demand, the use of biomaterials has emerged as a promising alternative, defined as engineered substances designed to interact with living systems to direct therapeutic or diagnostic procedures [11]. Its diverse applications include drug and protein delivery systems, as well as aid in wound healing [12,13]. An example of such a biomaterial is the extract of Rhizophora mangle (R. mangle, or red mangrove), a subtropical and tropical plant that is the most abundant vegetation in Brazilian mangroves [14,15]. R. mangle has been widely used in folk medicine for its pharmacological properties, which are attributed to its constituent compounds, including tannins and flavonoids—two types of polyphenols which belong to distinct structural classes [16]. Tannins are larger, non-flavonoid polyphenols, generally subdivided into hydrolyzable and non-hydrolyzable types based on their core structure and linkages [[73], [74], [75]]. Flavonoids, in contrast, are water-soluble compounds featuring a specific two-benzene-ring structure [73,76]. Together, these compounds provide R. mangle with anti-inflammatory, antioxidant, antimicrobial, and antibacterial properties [17,18], and also regulate tissue regeneration through angiogenesis and increased fibroblast proliferation [8,19]. Among the plant's polyphenolic compounds, tannic acid (TA) is the hydrolysable tannin with the simplest structure [18,20]. TA is known to possess beneficial chemical properties and functional capabilities, including biocompatibility [21], antioxidant, antimicrobial, and antiviral activity [59], and the ability to modulate growth factors and inflammatory cytokines, among others [19,22].

In parallel, hydrogels have gained prominence in biomedical applications. They consist of three-dimensional polymeric networks (either natural or synthetic) and are flexible, cross-linked, hydrophilic or amphiphilic materials capable of retaining large amounts of water or biological fluids [12,23], being remarkably versatile and are frequently studied and used, especially as controlled release systems [24,25]. Alginate (ALG) is an example of a linear anionic biopolymer commonly used in hydrogel form (ALGgel) [6], and widely analyzed in the literature for possessing relevant properties such as biodegradability, biocompatibility, low toxicity, and moldability [26]. Other prominent controlled release systems include Metal-Organic Frameworks (MOFs), which are porous materials with a hybrid three-dimensional crystalline structure formed by metal ions as connectors and organic molecules as linkers [27,28]. Zeolitic Imidazolate Frameworks (ZIFs) are a subcategory of MOFs composed of zinc ions and imidazolates [29,30]. One such MOF is ZIF-8 (Zeolitic Imidazolate Framework-8), widely considered for biomedical applications as a drug carrier [31,32].

The materials R. mangle, TA, ALGgel, and ZIF-8 exhibit properties that may contribute to preventing necrosis in ISFs by promoting antioxidant, angiogenic, anti-inflammatory, and controlled drug release effects. Recent advancements suggest that combining hydrogels with MOFs like ZIF-8 can create delivery systems with synergistic advantages, which could potentially enhance compound stability and provide controlled release kinetics [[64], [65], [66], [67]]. In the present study’s approach, the alginate forms the primary matrix while the incorporated ZIF-8 is intended to function as a drug delivery system (DDS), leveraging the distinct effects of both R. mangle and TA for optimized local delivery. Thus, this study aimed to evaluate the potential of novel alginate-ZIF-8 hydrogel systems, enriched with either R. mangle extract or TA, to prevent tissue necrosis in a rat model.