Review 审查

Biomedical Applications and Nutritional Value of Specific Food-Derived Polysaccharide-Based Hydrogels
特定食品源多糖水凝胶的生物医学应用和营养价值

Natural food-derived polysaccharides are ubiquitous in living organisms, including animals, plants, and microorganisms. Animal-derived polysaccharides are widely distributed and present in almost all animal tissues and organs, renowned for their abundant biological activity, complex structure, and potential for hydrogel formation. Polysaccharides of animal origin predominantly localize in the interstitial spaces of cells and encompass a broad range of compounds, such as glycogen, chitin, heparin, chondroitin sulfate, hyaluronic acid, keratin sulfate, acid mucopolysaccharides, and glycosaminoglycans. These polysaccharides, including chondroitin sulfate, hyaluronic acid, and keratin sulfate, are all glycosaminoglycans, a class of amino-containing polysaccharides that serve as the sugar chain component of proteoglycans.
天然食品来源的多糖普遍存在于生物体中，包括动物、植物和微生物。动物源多糖分布广泛，几乎存在于所有动物组织和器官中，以其丰富的生物活性、复杂的结构和形成水凝胶的潜力而闻名。动物源性多糖主要存在于细胞间质空间中，包括多种化合物，如糖原、几丁质、肝素、硫酸软骨素、透明质酸、硫酸角蛋白、酸性粘多糖和糖胺聚糖。这些多糖，包括硫酸软骨素、透明质酸和硫酸角蛋白，都是糖胺聚糖，是一类含氨基的多糖，作为蛋白聚糖的糖链成分。

Plant polysaccharides can be categorized as either terrestrial or marine. The cell walls of terrestrial plants, especially certain “Chinese herbs that can be added as food to the daily diet,” such as Lycium chinense Miller, Ziziphus jujuba Mill, Citrus reticulata Blanco peel, Cornu Cervi pantotrichum, etc., consist of various prebiotic polysaccharides, including cellulose, hemicelluloses, lignin, inulin, starch, pectin, and guar gum [8]. Polysaccharides found in most plants (except starch) are indigestible by the human body and serve as prebiotics to promote gastrointestinal health by curbing pathogens and stimulating the immune system.
植物多糖可分为陆地植物多糖和海洋植物多糖。陆生植物，特别是某些“可食的中药材”，如枸杞、大枣、陈皮、鹿茸等，其细胞壁中含有多种益生元。多糖，包括纤维素、半纤维素、木质素、菊粉、淀粉、果胶和瓜尔胶[ 8 ]。大多数植物中发现的多糖（淀粉除外）不能被人体消化，可作为益生元，通过抑制病原体和刺激免疫系统来促进胃肠道健康。

Microbial sources of polysaccharides, which include bacteria, fungi, and prokaryotes, are classified into extracellular, cell wall, and intracellular varieties. Extracellular polysaccharides primarily consist of Gellan, xanthan, curdlan, pullulan, bacterial cellulose, welan gum, and hyaluronic acid. Cell wall polysaccharides primarily comprise lipopolysaccharides, lipopolysaccharides in bacteria, glucan, chitosaccharides, and their complexes in fungi. Intracellular polysaccharides are predominantly unique to microorganisms themselves, such as edible fungal polysaccharides (e.g., Flammulina velatum, Dictyophora, and Cordyceps Link) and bacterial (e.g., Aspergillus flavus and Lactobacillus) polysaccharides for fermentation.
多糖的微生物来源包括细菌、真菌和原核生物，分为细胞外多糖、细胞壁多糖和细胞内多糖。胞外多糖主要由结冷胶、黄原胶、凝乳多糖、支链淀粉、细菌纤维素、韦兰胶和透明质酸组成。细胞壁多糖主要包括脂多糖、细菌中的脂多糖、真菌中的葡聚糖、壳聚糖及其复合物。胞内多糖主要是微生物本身所特有的，如食用真菌多糖（如金针菇、竹荪和冬虫夏草）和用于发酵的细菌（如黄曲霉和乳酸菌）多糖。

The utilization of naturally occurring polysaccharides directly from food sources for hydrogel production has been comparatively underexplored, particularly with regard to animal- and microbial-derived polysaccharides. Polysaccharide materials present a challenge and complexity in overcoming their production limitations, unearthing their additional biological activities, and integrating these findings with hydrogel production research.
利用直接来自食物来源的天然多糖来生产水凝胶的研究相对较少，特别是在动物和微生物衍生的多糖方面。多糖材料在克服其生产限制、挖掘其额外的生物活性以及将这些发现与水凝胶生产研究相结合方面提出了挑战和复杂性。

Thirty studies [[9], [10], [11], [12], [13], [14],[16], [17], [18], [19], [20], [21],[23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40]] used plant polysaccharides, which were derived from Zingiber officinale, Astragalus species, Bletilla striata, the flower bud of Lonicera japonica Thunb, the aerial parts of Mentha haplocalyx Briq, Tamarind Kernel, Aloe barbadenis, Strychnos potatorum Linn (SPL) seeds, Ulva armoricana, Porphyridium sp., konjac, Egyptian Avena sativa L., Abelmoschus esculentus pods, and Fucus vesiculosus (or Undaria pinnatifida, Laminaria saccharina, Cladosiphon okamuranus). Two studies [15,22] used polysaccharides from microbial sources, the fungus Flammulina velutipes, and single-celled eukaryotes Euglena. Ten [9,12,17,19,23,27,29,33,39,40] of the studies used Bletilla striata to extract Bletilla striata polysaccharides (BSP) as one of the raw materials for making FBPHs. BSP shows low toxicity, good biocompatibility, good biodegradability, non-immunogenicity, and ample availability, playing a repairing role in skin, bones, joints, and other tissues. Six [31,32,[34], [35], [36], [37]] of the studies used fucoidan (FU) from Fucus vesiculosus, Undaria pinnatifida, Laminaria saccharina, or Cladosiphon okamuranus to manufacture FBPHs. FU performs anticancer, antioxidant, immunoregulatory, antiviral, antithrombic, and anti-inflammatory properties. Three studies [10,11,14] have used Tamarind Kernel polysaccharides (TKP) to produce FBPHs that can play a beneficial role in wound healing and promote osteogenic differentiation. The demonstration of good biocompatibility and low toxicity enables TKP to exhibit anti-inflammatory, antioxidant, anti-tumor, and immunomodulatory functions to varying degrees.
三十项研究 [ [9] , [10] , [11] , [12] , [13] , [14] , [16] , [17] , [18] , [19] , [20] , [21] 、 [23] 、 [24] 、 [25] 、 [26] 、 [27] 、 [28] 、 [29] 、 [30] 、 [31] 、 [32] 、 [33] 、 [34 ]、[ 35] 、 [36] 、[ 37 ]、 [38] 、 [39] 、 [40] ]使用植物多糖，其中源自姜， 黄芪、白芨、金银花的花蕾、薄荷的地上部分、罗望子仁、库拉索芦荟、马钱子 (SPL) 种子、石莼、紫球藻、魔芋、埃及燕麦。 , 黄秋葵豆荚和墨角藻（或裙带菜、糖海带、 Cladosiphon okamuranus ）。两项研究 [ 15 , 22 ] 使用了微生物来源的多糖，即金针菇真菌和单细胞真核生物眼虫。十项研究[ 9,12,17,19,23,27,29,33,39,40 ]利用白及提取白及多糖( BSP)作为制备FBPHs的原料之一。 BSP具有低毒性、良好的生物相容性、良好的生物降解性、非免疫原性和充足的利用性，对皮肤、骨骼、关节等组织起到修复作用。 六项研究 [ 31 , 32 , [34] , [35] , [36] , [37] ] 使用来自墨角藻、裙带菜、糖海带或冈村枝管藻的岩藻依聚糖 (FU) 来制造 FBPH。 FU 具有抗癌、抗氧化、免疫调节、抗病毒、抗血栓和抗炎特性。三项研究 [10,11,14 ]使用罗望子仁多糖 (TKP) 生产 FBPH，可以在伤口愈合和促进成骨分化中发挥有益作用。良好的生物相容性和低毒性使得TKP能够不同程度地表现出抗炎、抗氧化、抗肿瘤和免疫调节功能。

The inherent properties of polysaccharides derived from diverse sources dictate their distinct biological activities, thereby facilitating the development of hydrogels fabricated from these polysaccharides for therapeutic applications in various clinical settings. This warrants attention and represents a promising avenue for exploration in the tissue engineering field.

The application efficacy of FPBHs in biomedicine is determined by their attributes and characteristics, which are commonly evaluated based on physical properties (such as form, structure, and shape), chemical properties (including composition, content, and chemical structure), and functional properties (such as rheology, water absorption, and stability).

FPBHs have various physical properties, among which form, structure, and shape are the most important. The FPBHs is a gel-like substance in terms of its form, capable of exhibiting rheological properties under the influence of external forces (like gravity, pressure, etc.) and transitioning into a soft gel state. This gel state can be regulated by adjusting the concentration of polysaccharide molecules, temperature, pH value, and other factors to achieve the needs of different application scenarios. FmocFF/PSP hydrogel made by Halperin-Sternfeld et al. [18], as depicted in Figure 4B (i-v), exhibited distinct gel states with varying textures and proportions.

In addition, FPBHs possess both viscosity and plasticity, enabling them to adapt to the application requirements of diverse morphologies and structures. Regarding structure, the architecture and morphology of FPBHs can be regulated through various preparation methods and conditions. This allows for the formation of different structural forms such as nanoparticles [24], microspheres [46], fibers [47], and films [48]. These distinct forms exhibit varied physical and chemical properties that can be utilized in the fabrication of diverse functional materials. For instance, nanoparticles and microspheres are suitable for drug delivery systems although fibers and films are ideal for medical dressings and tissue repair materials [49]. Concerning shape, FPBHs can be tailored into various configurations including sheets, spheres, rods, etc., based on specific needs. Different shaped FPBHs possess unique application characteristics that make them suitable for preparing a wide range of medical dressings and repair materials. For example, flake-shaped FPBHs can be employed to locally wrap wounds whereas globular FPBHs are well-suited for cavity filling and repair [49].

The physical properties of FPBHs are diverse and adjustable, which can be regulated and optimized by adjusting preparation conditions and structural morphology, providing a wide range of possibilities for their application in the medical and food health field.

The chemical properties of FPBHs primarily encompass their composition, content, and chemical structure. The polysaccharide component of FPBHs plays a pivotal role in exerting their bioactivity. Polysaccharides are composed of monosaccharide molecules combined in varying proportions, making it crucial to analyze the monosaccharide composition within polysaccharide molecules. All studies except for 2 [15,24] analyzed or described the monosaccharide composition of the polysaccharides used, as presented in Table 1. In terms of composition, the polysaccharide content of FPBHs serves as a crucial indicator of their chemical properties. The polysaccharide content typically refers to the mass fraction of polysaccharide molecules within the FPBHs and can be determined through chemical analysis methods.

Additionally, the molecular weight of polysaccharides is also an important parameter (Table 1). The variation in polysaccharide content can influence the physical and chemical properties, as well as application effects of FPBHs. For instance, high-content FPBHs exhibit increased viscosity and strength; however, they may also display compromised rheological properties. Regarding chemical structure, it encompasses the monomer composition of polysaccharide molecules, the bonding mode between monomers, and their spatial arrangement. Distinct polysaccharide molecules possess diverse chemical structures that contribute to disparities in the properties and application effects of FPBHs.

The chemical properties of FPBHs are determined by multiple factors including their composition, content, and chemical structure. A comprehensive understanding of these chemical properties facilitates a better comprehension of their physical, chemical, and biological characteristics although offering novel possibilities for applications in medical and health domains.

The functional characteristics of FPBHs encompass rheological properties, water absorption, and stability. FPBHs exhibit favorable rheological properties and can undergo stress-induced rheological changes to form a soft gel state, which is attributed to their physical properties. This rheological property can be modulated by adjusting factors such as polysaccharide molecule concentration, temperature, and pH value to meet diverse application requirements. For instance, in the preparation of medical dressings, the rheological properties of FPBHs can be tailored for enhanced adherence to wound surfaces and improved promotion of wound healing [50].

Moreover, FPBHs possess excellent water absorption capabilities that enable rapid swelling and formation of stable gel states. This water absorption property renders FPBHs highly versatile in applications within the medical and health fields including drug-containing hydrogel formulation and medical dressing development. For instance, in the formulation of drug release systems, the water absorption capacity of FPBHs can be harnessed to encapsulate drugs within hydrogels and achieve controlled drug release effects [51]. FPBHs exhibit excellent stability, maintaining their gel state and chemical properties unaltered for a specific duration. This inherent stability ensures the reliability and safety of FPBHs in medical material preparation. For example, FPBHs can be employed in fabricating medical dressings, with their stability guaranteeing no rupture or drug leakage during usage [50].

The functional attributes encompass rheological properties, water absorption capability, and stability; collectively rendering FPBHs highly promising for diverse applications within the realm of medicine and healthcare.

The biocompatibility of FPBHs serves as a crucial foundation for their application in the fields of medicine and biological sciences. Biomaterials exhibiting excellent biocompatibility can be readily accepted by human tissues without eliciting noticeable immune rejection or toxic reactions, although also possessing the potential to interact with surrounding tissues, thereby facilitating tissue repair and regeneration. Twenty seven studies [[9], [10], [11], [12],[14], [15], [16], [17], [18], [19], [20],23,[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40]] utilized cell models as research subjects to investigate the biocompatibility of FPBHs. The cell lines employed included macrophages THP-1 [9], RAW264.7 [10,11,15,16,20,22,23], hepatocytes HepG2 [26], fibroblasts L929 [9,19,27,52,[29], [30], [31],33,35,[38], [39], [40]] and NIH/3T3 [14, 16, 17, 23, 30], human umbilical vein endothelial cells (HUVECs) [10,38], human embryonic kidney M293T [12], and mouse forestomach carcinoma cells (MFCs) [28], human keratinocyte cell HaCat [14], mouse neuroblastoma F11 [10,11,14], Saos-2 cells [10, 11], human mesenchymal stem cells (MSCs) [9,37], mouse MSCs [10, 11], mouse and rat bone-marrow derived preosteoclasts (BMMs) [10,11], and rat calvarial osteoblasts (RCOs) [10], MC3T3-E1 osteoblasts line [18], nasopharyngeal carcinoma cells (NPCs) [32], primary rabbit articular chondrocytes [34], mouse islet β cells (MIN6) [36].

Ten studies [11,12,14,15,19,23,26,28,29,32,34] suggested that FPBHs could enhance cell growth and proliferation. In 10 studies [12,17,19,27,29,31,33,[37], [38], [39]], fresh animal blood was employed to assess the hemolysis rate on hydrogels, revealing a hemolysis rate of <5%, thereby demonstrating favorable blood compatibility of FBPHs. The results indicated that FPBHs exhibited favorable biocompatibility with these cells without causing significant toxicity. The biocompatibility of FBPHs in animals was investigated in 1 study [14]. Choudhury et al. [14] developed a hydrogel composed of TKP and AA, which was applied in an acute dermal skin erosion model in SD rats, demonstrating no exacerbation of wound damage; additionally, subcutaneous injection of FPBHs in BALB/c mice did not exhibit any toxic effects.

It can be seen that research on biocompatibility should explore the interplay between materials and organisms rather than solely observing the presence or absence of toxicity in interventions. Such research would have greater theoretical significance. FPBHs have potential value in tissue engineering. These studies serve as a foundation for the development of FPBHs for clinical use.

The anti-tumor efficacy of FPBHs was demonstrated in vitro using mouse melanoma cell line B16-F10 [21, 31], human HeLa cells [25], and mouse 3T3-L1 cells [25] in vitro. Kang et al. [21] embedded Apatinib in hydrogels made of Astragalus and HA and found that it effectively suppressed the growth and reproduction of Mouse melanoma cell B16-F10 cell line; then, they injected B16-F10 cells subcutaneously into C57BL/6 mice, and used FPBHs for intervention. It was found that FPBHs could effectively inhibit vasculogenic mimicry formation and melanoma growth in a mouse tumor transplantation model. The CMC/OF/AuNPs@TA hydrogel was synthesized by Chang et al. [31] using oxidized FU, tannic acid (TA) modified gold nanoparticles and CMC. The ACMC/OF/AuNPs@TA hydrogel demonstrated significant inhibition of tumor B16-F10 cell growth and proliferation in vitro, and when injected around the tumor of KM mice injected with B16-F10 cells on their back, effectively suppressed tumor expansion. Nagaraja et al. [25] reported the development of functionalized SPL seeds polysaccharide-based hydrogels, which serve as an effective carrier for targeted delivery of 5-Fluorouracil (5-FU) and exhibit potent inhibitory effects on the growth and proliferation of human HeLa and mouse 3T3-L1 cells, although also showing increased DPPH scavenging activity. The dose-dependent cytotoxicity of various hydrogels against HeLa and 3T3-L1 cells. The results unequivocally demonstrate the anticancer efficacy of the 5-FU-loaded hydrogel, exhibiting a reduction in activity by a factor of 2.5 and two-fold compared to pure 5-FU. It is anticipated that the release of 5-FU from the hydrogel networks is delayed.

The presence of FPBHs exerts a significant impact on the oxygen and nutrient supply in the vicinity of tumor cells, thereby creating an unfavorable milieu for tumor cell proliferation, consequently modulating the tumor microenvironment and impeding both tumor growth and metastasis. The Fucoidan-Manganese Dioxide Nanoparticles developed by Sung-Won et al. [53] exhibit the potential to downregulate the expression of phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2) and CD31 in tumors, thereby demonstrating their ability to inhibit tumor angiogenesis. The inhibitory effect can be ascribed to the biological activity of fucoidan incorporated within the materials. The immunobiological activity of the polysaccharide is also the foundation of the anti-tumor ability of the hydrogel. By promoting T cell activation and proliferation, polysaccharide can enhance immune surveillance and improve the clearance of tumors, such as Codium fragile [54] and Angelica dahurica [55] polysaccharides, so they can be made into hydrogels to achieve the same or better effect. FPBHs have the ability to activate multiple apoptotic pathways, including the mitochondrial and death receptor pathways, leading to the induction of tumor cell apoptosis and exhibiting anti-tumor properties [56,57]. However, hydrogels exhibiting such characteristics may pose challenges in terms of biocompatibility and potential induction of apoptosis in normal cells.

A pivotal breakthrough in this domain lies in the ability to precisely target specific tumors although demonstrating tailored anti-tumor functionalities, necessitating further advancements in hydrogel design to enhance specificity and biocompatibility.

Polysaccharide molecules has a good osteogenic function, which can promote the proliferation and differentiation of bone cells, as well as the formation and growth of new bone tissue [58]. The hydrogels composed of polysaccharide molecules with this capability can serve as both scaffolds in bone tissue engineering and therapeutic agents for bone injury repair. The treatment of fractures and osteoporosis involves the injection of hydrogels into the targeted site, wherein the active factors within stimulate preosteoblasts to differentiate into osteoblasts, thereby enhancing bone trabecular density for therapeutic purposes (Figure 5B).

Six studies [[9], [10], [11],18,34, 37] have found that FPBHs could promote the expression of osteogenic genes in different cells, and may have some benefits in repairing bone damage. Two studies [10,11] demonstrated that the surface of the Tamarind kernel powder olephan-acid (TKP-AA) hydrogel increased mouse and rat BMMs and mouse MSCs in the absence of osteogenic inducers, although also enhancing the expression of osteogenic genes in Saos-2 cells; it suggested a potential benefit for promoting osteogenic differentiation of cells. Halperin-Sternfeld et al. [18] found that MC3T3-E1 osteoblasts had increased calcium deposition on red marine microalga Porphyridium sp. Polysaccharide complex hydrogel, and had certain osteogenic ability. MC3T3-E1 preosteoblasts exhibited higher cell viability on the hydrogel compared to the control group, indicating favorable biological activity of FmocFF/PS hydrogel. Furthermore, significant calcium deposition on FmocFF/PS hydrogels suggests excellent osteogenic potential. The Nap-FFGRGD/FU hydrogel was synthesized by Zhao et al. [34] through the cross-linking of FU and Nap-FFGRGD peptide via a simple physical mixing method. This hydrogel can serve as a culture substrate to effectively enhance the osteogenic differentiation of primary rabbit articular chondrocytes. Similarly, Egle et al.’s hydrogels made from FU and chitosan also promote osteogenic differentiation of human MSCs derived from bone marrow [37].

Two animal studies utilized C57BL/6 mice as a model, where human MSCs coated hydrogel was subcutaneously injected [9], and the hydrogel was externally applied to full-layer bone defect wounds in New Zealand rabbits [34]. Niu et al. [9] reported that acBSP, a hydrogel prepared by BSP, could promote The expression of pro-osteogenic/-angiogenic in humans monocyte THP-1 cell line genes. The acBSP not only facilitates a tightly integrated surface with an ample number of tissue cells but also establishes a porous polysaccharide network that effectively enhances the proliferation of host tissue cells on days 14 and 28. Moreover, subcutaneous injection of acBSP-loaded human or mouse mesenchymal stem cells into the dorsal region of mice demonstrated that hydrogels functioned as effective scaffolds for tissue integration by inducing macrophage activation and enhancing bone differentiation in vivo. The Nap-FFGRGD/FU hydrogel, when applied to the bone defect, exhibited remarkable efficacy in promoting cartilage regeneration in rabbits with full-layer cartilage injury by augmenting oxidative stress (SOD, CCL4, CCL20) and mitochondrial function through activation of the Nrf2 pathway [34].

Polysaccharide molecules within the hydrogel can activate cellular signal transduction pathways by binding to cell surface receptors, thereby promoting bone cell proliferation and differentiation, as well as accelerating bone tissue repair and regeneration [58]. Furthermore, these polysaccharide molecules can interact with the extracellular matrix to form a scaffold structure that provides support and protection for newly generated bone cells, facilitating bone tissue growth and repair. Additionally, polysaccharides are capable of regulating the expression and release of growth factors and immune factors, further promoting bone tissue growth and repair [58]. Polysaccharides have the ability to bind and stabilize growth factors, thereby extending their half-life, augmenting their biological activity, facilitating the proliferation and differentiation of bone cells, as well as promoting the formation and growth of new bone tissue [59].

Therefore, FPBHs exhibits extensive potential in the realm of bone tissue engineering and repair, rendering it an exceptional biomaterial for addressing bone defects, promoting bone healing post-osteotomy, facilitating bone transplantation, and other related applications.

FPBHs, possessing remarkable bioactivity and histocompatibility, exhibit promising potential as a material for facilitating wound healing. Polysaccharide molecules in the hydrogel can bind to receptors on the surface of cells, promote cell proliferation, differentiation, and migration, thereby forming new tissue and repairing damaged tissue [60]. FPBHs can contribute to the skin regeneration of both common and infected wounds by exerting bacteriostatic, immunomodulatory, and hemostatic effects (Figure 5C).

Fourteen studies [12,13,16,17,19,22,23,28,30,31,33,35,38,39] have reported that FPBHs could accelerate the healing of animal wounds through external application on the basis of their biocompatibility. The BSP/carboxymethyl chitosan/Carbomer940 (BSP/CMC/CBM₉₄₀) hydrogel developed by Huang et al. [12] demonstrated accelerated wound healing in a Kunming mouse full-thickness wound model, with a diameter of ∼10mm, compared to the control group without FPBHs. the oxidized plant-polysaccharides-chitosan hydrogel (OPHs), as demonstrated by Xue et al. [28], exhibited the potential to enhance skin wound healing in a BALB/C mouse full-thickness skin wound model (6 mm deep and 2 mm diameter) through augmentation of collagen cell recovery ability. Jakfar et al. [19] also used BSP to make methylcellulose/ BSP (MB) hydrogels, apply it to the model, and found that it can recover the wound faster and reconstruct the skin tissue more completely.

In another study [22], 2 models were created using SD rats, namely an acute wound model (representing full-skin defects on the rat back) and a chronic wound model (representing third-degree scalds on the rat back). By evaluating the topical application of FPBHs in these models, researchers observed that paramylon hydrogel facilitated recovery of both acute and chronic wounds by promoting vascular regeneration through HIF-1α-VEGF signaling although reducing local inflammatory reactions. Similarly, Zhu et al. [16] utilized P-OK hydrogel (an injectable hydrogel by mixing the adipic acid dihydrazide modified γ-polyglutamic acid with oxidized Konjac glucomannan) in a full-thickness defect model with 8 mm diameter on the back of SD rats and observed that P-OK as a wound dressing effectively shortened the inflammatory period of wounds and promoted wound repair. El Hosary et al. [13] employed carrageenan-induced foot edema model and rat full-thickness wound model (1.5×1.5 m²) to validate the efficacy of polyvinyl alcohol / Avena sativa L. polysaccharides (PVA/ASP) hydrogel in promoting wound healing.

FPBHs exhibits favorable moisturizing and permeability properties, thereby effectively preventing wound desiccation and bacterial infection although facilitating wound repair and healing [61]. Furthermore, the regulation of growth factor expression and release by FPBHs can promote wound healing. The incorporation of polysaccharide molecules within the hydrogel enables binding and stabilization of growth factors, leading to prolonged half-life and enhanced biological activity. Consequently, this promotes cellular proliferation, differentiation, migration, as well as expedites wound healing and repair processes [61].

Anti-inflammatory effect of FPBHs through immune response

Polysaccharide molecules in the hydrogel might bind to receptors on the surface of immune cells, activate the function of immune cells, thereby regulating the function of the immune system and inhibiting the occurrence of inflammatory reactions [62,63]. Taking skin wounds as an example (Figure 5C), FPBHs can facilitate tissue repair by stimulating immune cells such as macrophages and neutrophils, although also regulating the expression of inflammatory factors like IL-6, IL-7, and TNF-α.

Six articles [15,22,23,30,31,35] indicated that FPBHs exhibit significant efficacy in reducing inflammation Three studies [15,22,23] demonstrated the impact of FPBHs on immune response in RAW264.7 cells, although another study, one study [30] revealed their potential to mitigate inflammation by modulating the expression of immune factors in infected wounds in rats. Liu et al. [23] fabricated a composite material consisting of BSP, gelatin, and methyl acrylate using ultraviolet light cross-linking technique to prepare PHBs, which was found to effectively induce the polarization of RAW264.7 macrophages toward an anti-inflammatory phenotype. The CMC/OF/AuNPs@TA hydrogel, prepared by Chang et al. [31], was applied to the surgical wound following melanoma resection in mice; remarkably, this hydrogel not only failed to accelerate tumor growth but also effectively mitigated the inflammatory response of the wound, thereby promoting wound healing. The CA/FU hydrogel loaded with Lactobacillus rhamnosus, as prepared by Dou et al. [35], was applied to treat traumatic ulcers of wounds ∼5 mm in diameter on the cheek of SD rats. This intervention effectively mitigated neutrophil adhesion-mediated inflammatory responses.

In 2 other studies, Soy protein isolate -Flammulina velutipes polysaccharide (SPI-FVP) hydrogel is able to isolate the protein by promoting the expression of IL-6, IL-10 and TNF-α for inhibiting the pro-inflammatory effects of RAW264.7 cells [15], although Paramylon hydrogel inhibited the inflammatory response of LPD-induced macrophages by reducing the levels of TNF-α and IL-7 [22]. In immunohistochemical experiments, Zhang et al. [30] found that AP (Aloe barbadenis polysaccharide) / Honey @ PVA hydrogels can significantly reduce the expression of IL-6 and TNF-α in rat infected wounds, promote the expression of VEGF and CD31, thus regulating inflammatory response and collagen deposition.

The anti-inflammatory activity of FPBHs may be related to the anti-inflammatory activity of polysaccharide molecules in hydrogels. Among them, the activation of T cells by polysaccharide molecules is the most prominent. Polysaccharide molecules in the hydrogel can bind to receptors on the surface of T cells, thereby activating their functions [64]. This activation effect includes increasing the proliferation of T cells, promoting the differentiation of T cells, and regulating the immune activity of T cells, thereby enhancing the immune system [65]. Polysaccharide molecules can also activate the functions of macrophages and dendritic cells [66]. Macrophages and dendritic cells are important immune cells in the immune system.PBHs can interact with these immune cells, thereby stimulating them to release various cytokines and signaling molecules, enhancing their immune function, and thus enhancing the clearance ability of the entire immune system [67]. Polysaccharide molecules can not only regulate immune cells, but also bind to inflammatory mediators to neutralize the effect of inflammatory mediators and reduce the severity of inflammatory response [68]. Besides, polysaccharide molecules also exert anti-inflammatory effects by regulating the occurrence of oxidative stress reactions [69]. They can inhibit the occurrence of oxidative stress reactions, reduce the production of oxygen free radicals, thereby reducing the severity of inflammatory reactions.

Therefore, FPBHs has broad application prospects in the treatment of inflammatory diseases, promotion of wound healing, immune therapy and other aspects, and can be used as an ideal biomedical material.

FPBHs has a strong antibacterial effect, which can effectively inhibit the growth and reproduction of various bacteria and fungi [70]. Six studies [13,16,24,30,31,35], have found that FPBHs can inhibit the growth and reproduction of microorganisms in vitro, thereby playing a certain prevention and control of infection. Zhang et al. [30] found that AP/Honey@PVA hydrogel showed significant growth inchibition against Staphyloccus aureus (S. aureus), Escherichia coli (E. coli), and fungus Candida albicans (C. albicans). The AGNPS Colloids hydrogel produced by Massironi et al. [24] has inhibitory effects on Gram-negative (E. coli and Pseudomonas aeruginosa) and Gram -positive (S. aureus) bacteria. Similarly, the P-OK hydrogel made by Zhu et al. [16] and the CMC/OF/AuNPs@TA hydrogel made by Chang et al. [31] indicated their inhibitory action for S. aureus and E. coli; and El Hosary et al. produced PVA-AP Hydrogel to effectively control bacterial reproduction, including gram-positive (S. aureus and Micrococcus Leutus) and gram-negative (E. coli and Pseudomonas Aeruginosa) [13]. The CA/FU hydrogel loaded with Lactobacillus rhamnosus prepared by Dou et al. [35] had inhibitory effects on S. aureus and fungus C. albicans. However, the mechanism of hydrogels inhibiting microbial growth has not been deeply explored in these studies.

The inhibitory effect of FPBHs is primarily attributed to the interaction between polysaccharide molecules in the hydrogel and bacterial and fungal structures, including the cell wall, cell membrane, and other components. This interaction disrupts their normal metabolism and physiological functions, thereby impeding their growth and reproduction [70]. At present, the research on FPBHs antibacterial ability is mainly verified by in vitro experiments. In vivo, FPBHs enhance its antibacterial effect by regulating the function of the immune system. Polysaccharide molecules in the hydrogel bind to receptors on the surface of immune cells, activate the function of immune cells, enhance the clearance ability of the immune system, and strengthen the attack and clearance of bacteria, achieving the antibacterial effect [71]. Experiments conducted within living organisms predominantly rely on indirect indicators such as inflammation levels or infection markers; direct observation of microorganism proliferation is limited. Furthermore, research on fungi and viruses remains scarce.

Therefore, FPBHs hold significant potential for diverse applications in medical care settings where various antibacterial materials can be developed (e.g., mouthwash solutions or surgical supplies).

The hydrogel's polysaccharide molecules may elicit the activation of clotting factors within the bloodstream, thereby inducing local vasoconstriction or expediting platelet aggregation, thus exerting a role in hemostasis. Five studies [23,27,29,33,38] employed murine or rodent liver bleeding models, although 2 studies [27, 33] utilized the mouse tail amputation model to investigate the hemostatic properties of hydrogels.

The XG/OP hydrogel, prepared by Liu et al. [38], was injected into the liver wound of liver hemorrhage mice model, resulting in a significantly reduced bleeding volume (22.6±6.8 mg) compared to the normal control group (45.7±9.6 mg); this observation suggests that the hydrogel not only adhered to the wound site and facilitated physical hemostasis but also triggered platelet activation. The BG hydrogel prepared by Zhang et al. [33] exhibits a pronounced hemostatic effect in both rat bleeding liver and mouse bleeding amputation models. in rats model, the BG hydrogel group achieved rapid hemostasis within 32.2±1.8 s, although in the mouse model, it achieved rapid hemostasis within 325.6±53 s following amputation. The remarkable hemostatic efficacy of the BG hydrogel could be attributed to its microporous structure, which facilitates increased surface area for red blood cell adhesion and platelet aggregation. Furthermore, the presence of cationic gelatin with abundant positively charged amine groups contributes to its antihemorrhagic properties by promoting clot formation.

FPBHs has a significant hemostatic effect, which can quickly form clots and effectively control bleeding. Polysaccharide molecules in the hydrogel can bind to fibrinogen in the blood, promote fibrinogen aggregation and coagulation, and form fibrin clots, thereby achieving hemostasis. PBHs can also exert hemostatic effects by regulating platelet aggregation and activation. Polysaccharide molecules in the hydrogel can bind to receptors on the surface of platelets, promote platelet aggregation and activation, thereby enhancing the hemostatic effect. In addition, PBHs has good biocompatibility and biodegradability, which can be safely used in humans body without adverse effects.

FPBHs has broad application prospects in the fields of surgery, trauma, etc., and can be used to prepare various hemostatic dressings, hemostatic sponges, and other hemostatic materials, providing safer and more effective hemostatic measures for clinical medicine.

Given their excellent biocompatibility, FPBHs can serve as a favorable substrate for cellular growth and activity. Leveraging the unique biological properties of polysaccharide molecules, FPBHs have the potential to enhance the secretion of specific neuroendocrine cells. However, limited research has been conducted in this area, with only one study [36] reporting on the impact of hydrogel on mouse islet beta cell secretion.

Amin et al. [36] fabricated the PVA-FU-MA hydrogel through photocrosslinking, encapsulated MIN6 cell aggregates within the hydrogel, then conducted ATP detection to assess cell metabolic activity and glucose-stimulated insulin secretion (GSIS). The findings demonstrated that the intracellular ATP levels in the PVA-FU-MA hydrogel remained consistently elevated, although the GSIS test exhibited enhanced insulin secretion. Therefore, it can be concluded that the PVA-FU-MA hydrogel effectively promoted insulin secretion of MIN6 cells and serves as an excellent carrier for cell encapsulation. The secretory capacity of food-derived polysaccharides may be attributed to their biological activity, although further investigation is required to elucidate the specific underlying mechanism. If this unique characteristic of food-derived polysaccharides can be harnessed for hydrogel development, it holds immense potential in the realm of hormone secretion.

In addition to their role in the biomedical field mentioned above, FPBHs may also hold potential applications in ophthalmology, as well as in the management of reproductive and metabolic chronic diseases.

Customizable hydrogels loaded with specific food-derived polysaccharides can exhibit tailored physical, chemical, and biological properties suitable for drug delivery carriers, tissue scaffolds, sealants, and injections. Injectable hydrogels utilizing the porous structure and biocompatibility have been investigated for corneal injury repair and regeneration of diseased corneal tissue in ophthalmology. Notably, a study demonstrated that a clear gelatin-based hydrogel containing hepatocyte growth factor significantly increased the thickness of regenerated epithelial cells on the gel after 5 days of culture using optical coherence tomography imaging assessment [72]. Furthermore, hydrogels hold great potential for treating other eye diseases such as glaucoma, retinopathy, eyelid abnormalities, and uveal melanoma. However, there is limited literature on specific applications of specific food-derived polysaccharides in ophthalmology despite their promising prospects.

The application of FPBHs in the field of reproduction is also applicable to female reproductive diseases, where hydrogels are expected to play a reparative role in endometrial injury, injured harem adhesion, follicle dysplasia, and low blastocyst formation rate. Particularly in the current focus on frozen eggs research, a study has demonstrated that FU can effectively mitigate ice crystal formation during cell freezing process, reduce mechanical damage to cells, and enhance cell survival rate and functional recovery post-thawing [73]. This component may hold potential value in embryo cryopreservation; however, further research is warranted for confirmation. In male reproductive diseases, hydrogels are anticipated to safeguard testicular tissue and stimulate testosterone production. The application potential of photo-crosslinked gelatin, alginate, and dextritol hydroxymethacrylate hydrogel was discussed for testicular tissue culture in vitro. Findings revealed that testicular tissue cultured on alginate methacrylate exhibited the highest tubule integrity rate at day 32 (0.835 ± 0.021), a high density of spermatocytes (2107.627 ± 232.082 /mm²), as well as a substantial proportion of SOX9-positive and well-preserved tubules at day 32 (0.473 ± 0.047) [74].

Due to the need for further verification of biomaterial safety, FPBHs have not been reported in clinical studies. Particularly for chronic metabolic diseases such as diabetes and its complications, metabolic fatty liver disease, atherosclerosis, and metabolic bone disease, long-term injection or oral intake of hydrogels would be required with higher safety requirements. However, although limited research has been conducted on FPBHs in chronic metabolic diseases, numerous studies have reported the beneficial effects of specific food-derived polysaccharides through oral treatment. For instance, Tibetan brassica polysaccharide alleviates hyperlipidemia in rodents [75] although Morchella polysaccharide reduces weight gain and colon inflammation caused by a high-fat diet in mice [76]. These examples demonstrate that FPBHs also hold potential for addressing chronic metabolic diseases. By customizing suitable material forms, biological activity-containing polysaccharide molecules can be delivered to target organs although improving the nutritional value of the polysaccharides themselves

Although FPBHs have wide application prospects in the medical and nutritional health field, there are still some difficulties in the research. First of all, the preparation and performance control of FPBHs still face certain challenges. Many factors should be considered in the preparation process of FPBHs, such as polysaccharide type, crosslinking degree, pH value, ion concentration, etc. These factors interact with each other in a complex way, which requires in-depth study to obtain high-quality FPBHs. In addition, the regulation of FPBHs also needs to be studied to meet different medical and nutritional needs. Second, the biological activity and biosafety of FPBHs still need to be further studied. At present, the metabolism, toxicity, and immunological effects of FPBHs in vivo are not enough, and further studies are needed. Finally, the large-scale production and application of FPBHs face certain challenges. The preparation of FPBHs requires the support of production technology and equipment. Besides, the application scenarios of FPBHs need to be further expanded and deepened to meet different medical and nutritional needs.

Despite the above research difficulties, FPBHs still have a broad application prospect in the medical and health fields. In the future, with the continuous progress of science and technology and in-depth research, it is believed that the application prospect of FPBHs will be more extensive and far-reaching. However, it is worth noting that although specific food-derived polysaccharides offer a promising avenue for the synthesis of FPBHs, research in this area is still in its infancy. The use of specific food-derived polysaccharide as a raw material for FPBHs has not yet been widely explored, and there is currently a lack of clinical data or retrospective studies summarizing the basic experiments conducted with these hydrogels. Therefore, further research is needed to explore the nutritional potential of natural polysaccharides in the synthesis of FPBHs, and to determine their effectiveness and safety for clinical applications.
尽管存在上述研究困难，FPBHs在医疗卫生领域仍然具有广阔的应用前景。未来，随着科学技术的不断进步和研究的深入，相信FPBH的应用前景将更加广泛和深远。然而，值得注意的是，尽管特定的食品多糖为 FPBH 的合成提供了有前景的途径，但该领域的研究仍处于起步阶段。使用特定的食品源多糖作为 FPBH 的原料尚未得到广泛探索，目前缺乏总结这些水凝胶进行的基础实验的临床数据或回顾性研究。因此，需要进一步研究探索天然多糖在 FPBH 合成中的营养潜力，并确定其临床应用的有效性和安全性。