Bone tissue is a highly dynamic, complex vascularized tissue that undergoes continuous remodeling throughout life (Hoseinpour and Shariatinia, 2021). While bone tissue has a degree of self-healing ability, its ability to repair itself is limited when faced with severe injuries, such as trauma, infection, tumor removal, and joint revision (McKinley et al., 2023). These diseases are beyond the ability of humans to heal themselves, making it difficult to recover through autologous bone tissue regeneration alone. The healing time is long, and patients will suffer great pain. Bone tissue damage often leads to severe disability (Alazzam et al., 2023). Therefore, bone tissue regeneration is becoming a hot research topic, and it is vital to explore promising treatment strategies (Fu et al., 2022). Consequently, a new treatment is needed to promote bone tissue regeneration.

As the largest part of the Earth, the ocean is rich in resources containing different types of plants and animals, including seaweed. As a simple marine plant, seaweed organisms consist mainly of structural components such as extracellular matrix, cell wall, and cell plasma (Giuliani, 2019). Primary and secondary metabolites in seaweed organisms include large molecular weight biomass components (e.g., seaweed polysaccharides, proteins, and brown seaweed starch) and medium, small, and trace components, such as fucoidan polyphenols, rock seaweed polysaccharides, carotenoids, vitamins, and various mineral elements (Chudasama et al., 2022). Bioactive substances in seaweed mainly include polysaccharides, proteins, terpenoids, sterols, polyphenols, cyclic polysulfide compounds, macrolides, etc. Seaweeds mainly include red algae, green algae, brown algae, and microalgae. Red seaweed sulfated polysaccharides are mainly classified as agar and carrageenan.The polysaccharides of red algae are mainly composed of galactose with sulfate, and may contain small amounts of xylose and mannose. Ulvan is the main water-soluble polysaccharide in green algae, containing rhamnose, xylose, glucuronic acid and so on. There are three main types of fucoidan: fucoidan, fucoidan sulfate and fucoidan starch. Fucoidan in brown algae can be categorized into two main groups according to their sources: one group mainly comes from kelp, palm kelp, pine algae, branching tube algae, and cordyceps, etc.; the other group comes from the genera Vesiculoblastus and Murraya. Fucoidan has a complex structure, which not only has a variety of connection methods, but also contains monosaccharides such as fucose, a small amount of glucose, galactose, mannose, xylose and so on. Microalgae are a class of widely distributed, nutrient-rich, highly photosynthetically utilized autotrophic plants, and the products of cellular metabolism have good prospects for development in the fields of food, medicine, and genetic engineering(Barkia et al., 2019; Dolganyuk et al., 2020). Seaweed polysaccharides show superior bioactive diversity and good therapeutic potential, with antioxidant, antitumor, anti-inflammatory, antilipidemic, anticoagulant, antiviral, antibacterial, immunomodulatory, and other functional properties (Carson et al., 2018; Manlusoc et al., 2019; Cook et al., 2021). Current research has shown that the amount of specific secondary metabolites determines the potential for potent bioactivity of seaweeds also depend on the structural activity relationship of the compounds present in them, and that seaweed polysaccharides can reduce the risk of digestive disorders and chronic diseases, such as diabetes, cancer and cardiovascular disease, compared with other species of Seaweed, such as microSeaweed. Therefore, the incorporation of seaweed components into the production of novel natural medicines is one of the goals of marine medicine, a new discipline of pharmacology that has developed in recent decades. Some of these compounds have osteogenic potential, with such osteogenic compounds being dominated by the sulfated polysaccharides (SPs) of seaweed polysaccharides (Carson et al., 2018).

Regenerative medicine is an interdisciplinary discipline that has developed over the years and shown great promise in treating various diseases (Edgar et al., 2020). Studies have shown that seaweed polysaccharides can be effectively used in regenerative medicine (Chaves Filho et al., 2022), with bone tissue regeneration a popular research topic (Venkatesan et al., 2019). As research progresses, combining hydrogel, scaffold, and 3D printing technologies with seaweed polysaccharides becomes a new development trend. However, since few review articles cite the role of seaweed polysaccharides in bone tissue regeneration, this review focuses on their potential in bone regeneration. This review will introduce the main mechanisms of seaweed polysaccharides for bone regeneration and the novel preparations of seaweed polysaccharides, aiming to contribute to the regenerative medicine field.

The unique ecological environment of the ocean has led to the production of many biologically active substances with novel structures and diverse activities, the more notable being seaweed plant polysaccharides (Lomartire and Goncalves, 2022). Seaweed is one of the richest resources in the ocean, with high nutritional value, and has attracted significant attention (Chudasama et al., 2021). Polysaccharides are the main constituents of seaweeds, accounting for up to 76% of their dry weight (Xu et al., 2017). Polysaccharides are a structural component of the seaweed cell wall (de Jesus Raposo et al., 2015). Seaweed polysaccharides have good biological activity and have the advantages of being widely available, residue-free, and non-biotolerant (Echave et al., 2021). SP extracted from marine macroSeaweed can be used as a scaffolding system for the extracellular matrix of bone tissue and is usually closely associated with pharmacological activities such as anticoagulation, antioxidant, antitumor, and tissue regeneration (Saravana et al., 2018).

Seaweed SPs are a class of natural or chemically modified polysaccharides, a polysaccharide complex extracted from seaweed plants that can scavenge hydroxyl radicals and superoxide anion radicals and has the advantages of non-toxic side effects, inexpensive raw materials, easy to prepare, and easy to use (Beaumont et al., 2021). SPs have been shown to have specific biological activity in promoting bone tissue regeneration. These SPs are mainly divided into agarose and galactose, especially the 4-linked α-galactose residues of the l-series galactose called agarose and the d-series called galactose (Seedevi et al., 2017). In most seaweeds, the galactopyranosyl sulfate content is dominant, and galactopyranosyl sulfate has a linear backbone consisting of alternating 3-linked-D-galactopyranosyl units (A-unit) and 4-linked-galactopyranosyl units (B-unit) (Ciancia et al., 2020). SPs are classified as agarose and carrageenan according to their stereochemistry. Specifically, galactose with four attached α-galactose residues in the L series is called agarose, and galactose in the D series is called carrageenan. MacroSeaweed SPs have promising applications in building bone tissue repair and regeneration. For example, Kwack designed a fucoidan and polydopamine (PDA)-based composite membrane for use as a culture platform for periodontal ligament stem cells (PDLSCs) and explored the major molecular pathways induced during the osteogenic differentiation of PDLSCs by transcriptome profiling, showing that the fucoidan idan/PDA complex promotes the osteogenic potential of PDLSCs by activating key molecular pathways (Kwack et al., 2022) ( Table 1 ).

Carrageenan is mainly derived from red seaweed, accounting for about 30%–75% of the dry weight of the seaweed cell wall (Qureshi et al., 2019). It is a natural polysaccharide carbohydrate polymer consisting of alternating d-galactose and 3,6-anhydrogalactose units (Ha et al., 2022) linked by α-1,3 and β-1,4-glycosidic bonds. More than 15 carrageenans have been reported to date (Thye et al., 2022). It is abundant in the extracellular matrix of red seaweeds (Usov, 2011). Carrageenan is an anionic sulfated polygalactose consisting of repeating disaccharide units with a sulfate content of 15%–40% and an average relative molecular mass >100,000 (Prajapati et al., 2014). Carrageenan has gained much attention in biomedical engineering, drug delivery, and biosensor applications in recent years due to its special properties, such as biocompatibility, biodegradability, and gel-forming ability (Li et al., 2014). Cao et al. Conducted a study in which they experimentally showed that κ-carrageenan promotes the adhesion and spreading, metabolic activity, proliferation, and osteogenic differentiation of MC3T3-E1 preosteoblasts, suggesting that κ-carrageenan is a potential osteogenic inducer for bone regeneration that could be used for clinical applications (Cao et al., 2021).

Fucoidan is an SP usually isolated from brown seaweed (Jayawardena et al., 2022). Kylin first isolated it in 1913 (Harada and Maeda, 1998). As a linear polysaccharide with different physiological and biochemical properties according to its structure and composition, fucoidan has great application value and potential in food, medicine, and cosmetics (Mabate et al., 2021). Fucoidan is a linear multimer consisting of β-D-mannuronate and α-L-guluronate units linked by 1→4 glycosidic bonds (Etman et al., 2020). Fucoidan can have different compositions and structures from different sources, such as a high fucoidan gulono-alkylate content (M/G residue ratio <1) in Laminaria hyperborea, low fucoidan gulono-alkylate content in marine macroSeaweed (Durvillaea potatorum), and acetylation in bacteria (Li et al., 2008; van Weelden et al., 2019). Fucoidan structure is also influenced by season, growth environment, age, and site in some brown Seaweed (Fitton et al., 2019; Tran et al., 2021). Small amounts of monosaccharides, such as glucose, xylose, mannose, and galactose, are also present in the molecular structure of fucoidan (Zayed et al., 2020).Fucoidan can induce bone formation in MG-63 cells and has also been shown to induce the osteogenic differentiation of stem cells for bone tissue regeneration (Venkatesan et al., 2015; Citkowska et al., 2019). Fucoidan has the molecular formula (C₆H₈O₆)_n and is a naturally biocompatible and biodegradable polymer widely used in various biomedical applications (Guo et al., 2020). Fucoidan is a natural linear polymeric. Alginate is present in the cell wall of brown Seaweed mainly as calcium alginate and partially as magnesium alginate, potassium alginate, and sodium alginate (SA) (Guo et al., 2020). Since fucoidan has good biocompatibility and antioxidation, gelation, and other properties, it is widely used in food, biomedicine, daily chemicals, textile printing and dyeing, and wastewater treatment (Dekamin et al., 2018). In bone tissue regeneration, fucoidan has osteogenic ability and promotes stem cell proliferation, resulting in sufficient osteoblast adhesion and thus accelerating the healing of bone tissue (Sikkema et al., 2021). In cartilage tissue engineering, it provides a microenvironment for chondrocyte growth, maintains the cell phenotype and its expression, and enables faster cartilage tissue healing (Huang et al., 2012).

Ulvan is the primary water-soluble polysaccharide found in green Seaweed. Like other polysaccharides found in seaweeds, its abundance in nature, wide range of sources, and high research value in medicine have made ulvan a hot research topic (Kikionis et al., 2022; Liu D. et al., 2022; Tanaka et al., 2022). Ulvan is a complex anionic SP of the genus Ulva, and studies of its biological activities have reported anticoagulant, antioxidant, antihyperlipidemic, antibacterial, antimicrobial, antiviral, tissue regenerative, and immunomodulatory properties. Several studies have found that ulvan can be used as a biomaterial polymer with excellent chemical properties, such as the easy hydrogel formation, scaffold formation, and electrospinning of nanofibers, which could potentially be used in biomedical applications (Ibrahim et al., 2022). It has unique functional properties compared to other seaweed polysaccharides, such as carboxyl, hydroxyl, and sulfate groups (Lakshmi et al., 2020). The main component of ulvan’s chemical structure is sulfated rhamnose, which is linked to uronic acid (glucuronide and/or iduronic acid) by a 1,4-glycosidic bond (Sulastri et al., 2021). Ulvan’s biosynthesis and, therefore, its chemical structure vary by seaweed species, harvesting areas, and growing conditions (Ahmad et al., 2021). These large differences in chemical structure lead to differences in physiological functions, although the exact mechanisms of action remain unclear.

The unique ecological environment of the ocean has led to the production of many biologically active substances with novel structures and diverse activities, the more notable of which are seaweed polysaccharides. Their diverse and heterogeneous structure makes studying their structure challenging and may hinder their development as therapeutic agents. Due to their chemical and biological properties, seaweed SPs have great potential for biomedical applications, especially in bone tissue regeneration. Seaweed polysulfates have promising applications in promoting bone tissue repair and regeneration.

Bone tissue regeneration undergoes three ongoing and overlapping phases: inflammation, regeneration, and remodeling. Initial inflammation induces immune cells such as T cells or monocytes. These cells produce cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. However, infection may lead to prolonged inflammation, and systemic circulation of the remaining pro-inflammatory cytokines, such as IL-6, TNF, and IL-1, can adversely affect bone regeneration (Newman et al., 2021). Seaweed polysaccharides can induce osteogenic differentiation of stem/progenitor cells (Chaves Filho et al., 2022). It can also exert its anti-inflammatory effects by modulating a series of inflammation-related signaling pathways, including NF-κB, MAPK, JAK/STAT, PI3K/AKT, and Nrf2/HO-1, thereby regulating the production of various inflammation-related factors. Macrophages are an important target for bone repair in bone tissue engineering (Sadowska and Ginebra, 2020). Building a locally appropriate bone immune microenvironment is a novel therapeutic strategy (Schlundt et al., 2021; Healy et al., 2023). Macrophages secrete cells that regulate inflammation and control the function of osteoblasts. M1 macrophages secrete inflammatory cytokines, including TNF, IL-1β, IL-6, IL-12, and IL-23. M2 macrophages release anti-inflammatory cytokines, including IL-10, transforming growth factor (TGF)-β, and IL-1RA. One study on IL-10-deficient mice showed that IL-10 enhances osteoblast differentiation. TGF-β is an osteogenic factor upstream of the bone morphogenetic protein (BMP) signaling pathway that ultimately induces osteoblast differentiation (Lee et al., 2019). Factors such as TGF-β and IL-4 induce osteoblast migration, proliferation, or bone extracellular matrix secretion in the early stages of differentiation (Apostolova et al., 2020) ( Figure 1 ).

Alginate significantly affects the phenotype and function of macrophages (Sadowska and Ginebra, 2020; Li et al., 2023c). Alginate is the most commonly used polysaccharide and stimulates cartilage regeneration (Popa et al., 2015). Alginate is an anionic biopolymer derived from brown Seaweed with a structure similar to glycosaminoglycans in the extracellular matrix. Simulation of gelatin and alginate as collagen and glycosaminoglycan in the extracellular matrix, respectively (Valcarcel et al., 2017) creates hydrogels with excellent mechanical properties, swelling stability, biodegradability, and biocompatibility, meeting the requirements of tissue regeneration (Taghipour et al., 2020; Ahmad Raus et al., 2021). Hydrogel compounded with osteopontin significantly promoted bone regeneration when used in a critical-size bone defect rat model (Wu et al., 2023). A SA/G/MXene composite membrane was prepared by combining the sol-gel and freeze-drying methods. Adding SA/G/MXene improved the SA/G membranes’ mechanical and hydrophilic properties and cell proliferation and osteogenic differentiation (Qin et al., 2023).

Alginate can be introduced into the body through minimally invasive techniques. Because alginate gels lack the proper mechanical strength to withstand the initial stages of regeneration without fixation, studies have demonstrated that they can deliver growth factors and thus effectively promote bone regeneration (Kothale et al., 2020). The controlled release of vascular endothelial growth factor (VEGF) molecules encapsulated in alginate particles in a collagen-hydroxyapatite (HAP) scaffold promoted post-implantation scaffold angiogenesis (Quinlan et al., 2017). The researchers tested bone healing with ethyl triacetate and tributyl citrate plasticized alginate. In vivo studies have shown alginate and triacetate-modified scaffolds to have a growth-promoting effect on osteoblasts (Arslan et al., 2023). Alginate shows promise in bone tissue engineering and regenerative medicine, and it can also inform drug/growth factor delivery therapeutic strategies for diseases requiring specific drug/growth factor duration of action (Zhao et al., 2022).

Seaweed SPs have a role in promoting or enhancing osteogenesis, which is closely related to osteoblast differentiation. SP extracted from marine Seaweed can be used to construct extracellular bone tissue matrix scaffold systems. In addition, SPs have been shown to have osteoinductive properties, which are important for developing artificial bone tissue. There will also be differences in the form of polysulfate scaffold systems, such as hydrogels, composites, blends, nanoparticles, electrostatically spun fibers, and 3D printed materials (Venkatesan et al., 2019; Hakimi et al., 2023). SPs significantly affected recombinant human BMP-2-induced bone regeneration, with enhanced bone regeneration-promoting ability in both in vivo and in vitro experiments.

Fucoidan is a naturally occurring active polysaccharide rich in sulfate groups produced by brown Seaweed (Chollet et al., 2016; Li et al., 2023a). Its slow and sustained release positively affects osteogenic differentiation (Carson and Clarke, 2018; Yadav and Song, 2022). Researchers have developed an alginate-nano HAP-nano graphene oxide carrier of rockweed polysaccharide as an osteoinductive scaffold to repair and regenerate bone tissue (Devi et al., 2022; Ohmes et al., 2022). The natural rockweed polysaccharide (Fuc) extracted from brown Seaweed was coupled with gelatin (gel) to form a template to prepare a bionic scaffold. The Fuc-Gel-MTN peptide (MTNYDEAAMAIASLN)-β-tricalcium phosphate/HAP scaffold could promote bone formation and mineralization, and studies have shown that it has a very high potential for bone tissue regeneration (Pajovich and Banerjee, 2017; Nunes and Coimbra, 2019). Fucoidan and PDA were used as carriers to construct an in vitro culture system for PDLSCs. The main molecular pathways induced during PDLSC osteogenic differentiation were explored by transcriptomic profiling, and the key signaling pathways that play a critical role in PDLSC osteogenic differentiation were screened. Their complexes promote the osteogenic potential of PDLSCs by activating key molecular pathways (Kwack et al., 2022; Nielsen et al., 2022).

Bone is highly vascularized. Growth factors such as VEGF and BMP-2 are involved in angiogenesis (Liu et al., 2015). These angiogenic factors can bind directly or indirectly to polymers through covalent interactions or ligand-based adsorption, respectively. Studies have reported that VEGF gene expression and protein secretion were significantly increased with the promotion of osteogenic differentiation by rockweed polysaccharides and that VEGF/VEGF receptor inhibitors significantly inhibited VEGF’s vasculogenic effect. One study found that the medium of mesenchymal stem cell (MSC) conditioned with rockweed polysaccharide upregulated the phosphorylation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), endothelial nitric oxide synthase (eNOS) to inhibit its pro-angiogenic effect via the AKT/eNOS pathway. Animal experiments showed that rockweed polysaccharide has significant promotive effects on cranial defects and neovascularization in rabbits (Kim et al., 2018).

Kappa carrageenan (κ-CG) and ulvan have only recently been featured in some reports. Carrageenan is an SP extracted from red seaweed (Prajapati et al., 2014). It is highly hydrophilic and biocompatible and enhances the activity of the pre-osteoblastic cells required for bone regeneration (Yegappan et al., 2018; Cao et al., 2021). Researchers found that κ-CG influenced the morphology and microstructure of the octacalcium phosphate coating on titanium discs, resulting in increased preosteoblast metabolic activity, proliferation, and osteogenic differentiation (Cao et al., 2022). A series of electrospun silk fiber (SF)/κ-CG nanofiber membranes were used to mimic the structure and composition of the bone extracellular matrix to improve the biological properties of SF-based nanofibers. The results show that combining κ-CG and SF could effectively improve the biological properties of nanostructured scaffolds. κ-CG also enhanced the SF nanofibers’ osteogenic potential and bioactivity (Roshanfar et al., 2022). A potassium chloride cross-linked 3D scaffold composed of κ-CG, chitosan, and gelatin was evaluated for its mechanical and biological properties in bone tissue engineering. All materials showed good biocompatibility and a high differentiation potential with MC3T3-E1 preosteoblasts (Loukelis et al., 2022).

Ulvan, a biologically active marine SP, is of interest for its good osteoinductive properties (Tziveleka et al., 2019). Because of the lack of systematic studies on the relationship between the conformation and properties of ulvan-like compounds, their specific relevance is unclear (Tziveleka et al., 2019). Ulvan’s osteoinductive ability meant that when it was incorporated into a polycaprolactone matrix, it effectively improved cell attachment and viability, demonstrating its potential for bone tissue regeneration applications in biomedical scaffolds (Kikionis et al., 2021). The hybrid sponge-like scaffold prepared by inoculating human adipose-derived MSCs into selected ulvan/gelatin hybrid scaffolds could effectively support MSC adhesion and proliferation, making it a promising new bone tissue engineering material (Tziveleka et al., 2020 ). Ulvan’s important bioactivity and tunable physicochemical and rheological properties have made it of interest as a novel composite biomedical material ( Table 2 ).

Researchers have shown that the seaweed component SP has favorable osteogenic activity. In fact, most of the in vitro experiments have shown that SP has osteogenesis-promoting effects, but only two experiments have investigated the function of SP in vivo, so further experiments are needed to verify this. In addition, since the in vitro environment does not fully mimic the situation in living organisms, many cell types and systems are osteogenic-promoting. Therefore, the study of osteogenesis by in vivo experiments or using more complex animal models is an important part of the process.

Seaweeds are a large group of low-level photosynthetic autotrophs distributed in various seas and coastal zones worldwide. They have become a hot spot for research globally because they contain various bioactive components. Preparing new polysaccharide dosage forms with suitable carriers will help reduce adverse drug reactions, improve the therapeutic index, and enhance targeting, making exploring seaweed polysaccharide dosage forms important.

The ocean contains many compounds with a wide range of applications in biomedicine and biotechnology. It is a major renewable source of natural substances, further driving the development of new medical systems and devices (Sharma et al., 2023). In marine systems, macroSeaweed are an important source of primary and secondary metabolites of biological importance (Ren et al., 2022). Brown Seaweed contain the most compounds, followed by green and red Seaweed (Alghazeer et al., 2022). In recent years, the species and structures of seaweeds and seaweed metabolites have been intensively studied in the hope of discovering new bioactive compounds. Seaweed SPs have good potential for exploitation as bioactive substances (Ngo and Kim, 2013; Arokiarajan et al., 2022). Rockweed polysaccharides and carrageenan are two important types of seaweed SPs with a wide range of biological properties (Oliyaei et al., 2022).

Seaweed polysaccharides are considered a potential biomedical material due to their unique chemical and biological properties (Walsh et al., 2019). Carrageenan from red Seaweed, rockweed polysaccharide from brown Seaweed, and ulvan from green Seaweed show good biocompatibility. They could be used as scaffolds, nanofibers, hydrogels, or other biocompatible materials, which are expected to become a new generation of bone repair materials (Pajovich and Banerjee, 2017; Venkatesan et al., 2019). With advancements in orthopedic technology and improvements in biomaterial properties, bone tissue regeneration has been realized (Lopes et al., 2018; Ansari, 2019). Seaweed polysaccharides have promising applications in treating or constructing bone tissue repair and regeneration (Chaves Filho et al., 2018). However, few studies have explored seaweed polysaccharides such as SP in the bone tissue engineering field. In response to this situation, they should be systematically studied in the future using animal research methods with large samples (Veronesi et al., 2020). Stem cell therapy for osteoporosis is currently a hot topic, but its mechanism of action remains unclear. Combining seaweed polysaccharides with stem cells is expected to be a new biomaterial with promising applications. 3D tissue or cell cultures based on seaweed polysaccharides are also being explored, and these materials could be applied in areas such as drug evaluation, complex cell physiology, and tissue engineering (Jain et al., 2018).

Conceptualization: YJ and SL. Methodology: QY. Software: TC. Validation: YJ, DL and TC. Formal analysis: QY. Investigation: SL. Resources: YJ. Data curation: DL. Writing—original draft preparation: YJ. Writing—review and editing: TC. Visualization: QY. Supervision: SL. Project administration: YJ. Funding acquisition: DL. All authors have read and agreed to the published version of the manuscript.