Navigating the challenges in fucoidan industrialization: factors affecting biological activity and strategies for application of functional material

Abstract

Fucoidan, a sulfated polysaccharide from brown seaweed, exhibits diverse biological activities such as anti-inflammatory, antiviral, anticoagulant, and anticancer effects. However, its structural attributes, influenced by seaweed species, environment, and extraction methods, pose challenges for standardization and industrial application. Issues such as composition variability, regulatory concerns, and high production costs further hinder commercialization. We aimed to provide an integrated analysis of fucoidan, spanning its structural characterization, biological activities, and challenges in industrial applications, while proposing strategies to enhance its utilization. In this review, we synthesized the literature on advanced extraction, purification, and bioavailability enhancement techniques to address key challenges in fucoidan research and industrialization. Critical factors influencing fucoidan’s structure and bioactivity were identified. Advanced methods improved extraction yields and reduced contaminants, addressing industrial barriers. This review offers valuable insights into the current state of fucoidan research and its prospects in the functional materials of dietary supplements, pharmaceuticals, nutraceuticals, and cosmetics.

Graphical abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s10068-025-01937-5.

Introduction

Fucoidan, a sulfated polysaccharide predominantly found in brown seaweeds, has garnered significant scientific interest due to its diverse and potent biological activities. Its unique structural features, including sulfate content, molecular weight, and monosaccharide composition, are critical determinants of its biological efficacy (Li et al., 2008). However, these attributes are influenced by various factors, such as seaweed species, environmental conditions, and extraction methods (Hahn et al., 2012). Understanding these factors is essential for optimizing fucoidan’s biological activities, including its anti-inflammatory, antiviral, anticoagulant, and anticancer properties (Luthuli et al., 2019). These properties position fucoidan as a promising candidate in functional materials, pharmaceuticals, nutraceuticals, and cosmetics.

Despite its potential, industrial applications of fucoidan face significant challenges, including composition variability, material standardization challenges, and regulatory hurdles such as heavy metal contamination. Additionally, high production costs, largely due to low extraction yields, complicate its commercialization (Zayed and Ulber, 2019). Addressing these limitations requires innovative strategies and technological advancements.

In this review, we comprehensively analyzed fucoidan to evaluate its structural characterization, biological activities, and challenges in its industrial applications. We further explored advanced extraction and purification techniques and strategies to enhance fucoidan’s bioavailability. Unlike previous studies that focused on specific aspects of fucoidan, we attempt to fill a critical knowledge gap by offering an integrated perspective that spans from basic structural characterization to industrial application. This perspective enhances our understanding of fucoidan and provides a roadmap for overcoming existing challenges and seizing opportunities associated with its industrial utilization.

Furthermore, we aimed to accelerate the use of fucoidan in various fields, including dietary supplements, pharmaceuticals, and cosmetics, by offering valuable insights into the current state of fucoidan research and strategies for its industrialization.

Definition of fucoidan and its biological activities

Fucoidan is a complex sulfated polysaccharide primarily found in brown seaweeds, comprising 5–20% of their dry weight. It is a key component of the intercellular matrix in these seaweeds. Fucoidans mainly consist of sulfated L-fucose and sulfate ester groups, with less than 10% of other monosaccharides (Liyanage et al., 2023c). The compound was first isolated from marine brown algae by Kylin in 1913 and named “fucoidan.” However, in accordance with IUPAC rules, it is now referred to as “fucoidan,” though alternative names such as fucan, fucosan, or sulfated fucan are still occasionally used (Li et al., 2008). Fucoidans are nontoxic, rarely cause irritation, and exhibit numerous biological activities, making them highly promising for therapeutic applications, as shown in Table 1. With the growing interest in natural marine products, fucoidans have become a research hotspot. Current investigations focus on their separation, purification, preparation, structural analysis, and bioactivity, reflecting their significant potential in various fields.

Table 1.

Major biological activities of fucoidan

Category	Biological activity	Description	References
Classical activities	Antitumor effects	Induces apoptosis in cancer cells, inhibits tumor growth and metastasis	(van Weelden et al., 2019)
	Antioxidant activity	Strong antioxidant effects, often surpassing synthetic antioxidants	(Lim et al., 2014)
	Anticoagulant and antithrombotic effects	Influences both intrinsic and common coagulation pathways	(Wang et al., 2010)
	Immunoregulatory activity	Activates immune cells, promotes cytokine and chemokine release	(Jayawardena et al., 2022)
	Antiviral activity	Effective against various viruses	(Nagahawatta et al., 2024)
	Anti-inflammatory effects	Inhibits inflammatory mediators	(Liyanage et al., 2023a)
Emerging activities	Metabolic syndrome alleviation	Helps alleviate symptoms of metabolic syndrome	(Shang et al., 2017)
	Gastrointestinal protection	Protective effects on the gastrointestinal tract, including ulcer treatment	(Liyanage et al., 2022)
	Angiogenesis and bone health	Potential benefits for blood vessel formation and bone health	(Hwang et al., 2016; Wen et al., 2023)
	Hepatoprotective effects	Protects liver cells	(Chale-Dzul et al., 2014)
	Neuroprotective effects	Protects nerve cells	(Gao et al., 2012)
	Lipolytic and anti-adipogenic activity	Potential in managing obesity through effects on fat metabolism	(Zhang et al., 2022)
	Antibacterial activity	Demonstrates antibacterial properties	(Kumar and Marudhupandi, 2013)
	Cosmeceutical applications	Explored for cosmetic and dermatological uses	(Kang et al., 2024)

Factors affecting the biological activities of fucoidan

Seaweed species and habitat

The structure and biological activity of fucoidans are heavily influenced by their habitats and sources. The composition and structure of fucoidans vary considerably across species and even within the same species due to environmental factors (Britton et al., 2020; Marinho-Soriano et al., 2006). This variability impacts the biological activities of fucoidans (Peng et al., 2024; Zhou et al., 2024), underscoring the importance of understanding the relationship between source, habitat, and the resulting fucoidan structural and biological characteristics. Fucoidans are predominantly derived from brown seaweed species such as Fucus vesiculosus, U. pinnatifida, Laminaria japonica, and Sargassum spp., each exhibiting distinct and variable fucoidan levels. Geographical location also plays a vital role, as environmental factors such as temperature, light exposure, and water salinity vary across regions (Ptak et al., 2021a).

Extraction and purification methods further influence the yield, fucoidan content, sulfate levels, and monosaccharide composition (Ale et al., 2011b). For example, crude Fucus vesiculosus extract from Wilhelmshaven, Germany, using pH-maintained extraction with a maleic acid buffer, exhibited a fucose content of 92.43% (Zayed et al., 2016). By contrast, crude U. pinnatifida extract from Trinity Bay, Japan, using HCl extraction, contained 53% fucose (Vishchuk et al., 2011). Fucoidan purified from U. pinnatifida in Wando, Korea, via DEAE-cellulose anion-exchange chromatography, contained 72.3% fucose (Kim et al., 2007). In terms of sulfate content, fucoidan from U. pinnatifida in Gijang, Korea, contained a high sulfate content of 32.45% (Gu, 1994). The crude extract of Saccharina japonica in Rongcheng, Shandong, China, using HCl extraction, included a sulfate content of 51.09% (Jin et al., 2013). Similarly, purified Saccharina japonica extract from Quangang, Fujian Province, China, via Q Sepharose chromatography, exhibited 36.94% sulfate (Ye et al., 2020).

Fucose content also varies: fucoidan purified from U. pinnatifida in Xiapu, Fujian Province, China, using DEAE ion-exchange chromatography, contained 79.49% fucose (Ni et al., 2020). Purified fucoidan from Hizikia fusiforme (H. fusiforme) in Yonabaru, Okinawa, Japan, via DEAE anion-exchange chromatography, contained 80.0% fucose and 38% sulfate (Shiroma et al., 2008). Crude Sargassum horneri extract from Wando, Korea, via hot water extraction exhibited 277.1 mg/g fucose content (Park et al., 2023), while the crude extract of the same species from Pontevedra, Spain, using hot water extraction, included 23.7% sulfate content (González-Ballesteros et al., 2021). These variations were strongly influenced by geographic location and habitat (Table 2).

Table 2.

Changes in fucoidan, sulfate, and fucose content by brown algae species and habitat differences

Species	Collection location/country	Extraction and purification methods	Key elements	References
Fucus vesiculosus	Barents Sea	Ultrasound-assisted extraction	Fucose 102 ~ 116.6 mg/g	(Obluchinskaya et al., 2022)
	Edondela, pontevedra, Spain	HCl, KOH extraction	Yields 3.4%, uronic acid 52.8%, sulfate 11.5%, fucose 39.1%	(Ruperez et al., 2002)
	Zelenetskaya Bay of the Barents Sea	Ultrasound-assisted extraction	Sulfate 27.6%, uronic acid 9.2%, fucose 28.7%	(Ayrapetyan et al., 2021)
		Water extraction, CaCl2 precipitation, dialyzed with a 3.5 kDa pore dialysis membrane	Sulfate 18.3%, uronic acid 5.1%, fucose 38.6%, neutral sugar-fucose 43.1%
	Tasmania, Australia	Raw material	Fucose 84.2 mol%	(Amin et al., 2024)
	Wilhelmshave , Germany	Acidic (pH 1.0) extraction, EtOH precipitation, CaCl₂ precipitation	Fucose 88.59%	(Zayed et al., 2016)
		Acidic (pH 6.0) extraction, EtOH precipitation, CaCl₂ precipitation	Fucose 86.85%
		pH-maintained extraction method for fucoidan using maleic acid buffer	Fucose 92.43%
U. pinnatifida	Trinity Bay, Japan	HCl extraction	Yields 3.4%, fucose 53%	(Vishchuk et al., 2011)
		Anion-exchange chromatography on DEAE-cellulose	Yields 1.8%, fucose 51.0%
	Wando, Korea	Anion-exchange chromatography on DEAE-cellulose	Uronic acid 26.2%, sulfate 7.4%, fucose 72.3%	(Kim et al., 2007)
	Weihai, Shandong Province, China	Anion-exchange chromatography on DEAE-cellulose	Sulfate 1.34%, fucose 0.942 mol%	(Song et al., 2024)
	Auckland, New Zealand	Purified (Purified high-molecular-weight fraction of this fucoidan with MWCO of 300 kDa)	Sulfate 20.01%, uronic acid 4.55%	(Koh et al., 2019)
Blade of U. pinnatifida	Gijang, Korea	HCl extraction	Crude fucoidan (% of brown seaweed) yield 1.73%	(Gu, 1994)
		Anion-exchange chromatography on DEAE-cellulose	Partially purified fucoidan (% of brown seaweed) yield 0.40%, partially purified fucoidan (% of crude fucoidan) yield 23.19%, uronic acid 7.21%, sulfate 32.45%, fucose 57.11%
Sporophylls of U. pinnatifida	Gijang, Korea	HCl extraction	Crude fucoidan (% of brown seaweed) yield 12.75%	(Gu, 1994)
		Anion-exchange chromatography on DEAE-cellulose	Partially purified fucoidan (% of brown seaweed) yield 6.65%, partially purified fucoidan (% of crude fucoidan) yield 52.16%
Saccharina japonica	Trinity Bay, Japan	HCl extract	Yields 9.7%, fucose 47%	(Vishchuk et al., 2011)
		Anion-exchange chromatography on DEAE-cellulose	Yields 3.0%, fucose 57.0%
	Quangang, Fujian Province, China	Q sepharose	Sulfate 36.94%, fucose 24.15%	(Ye et al., 2020)
	Xiapu, Fujian Province, China	Water extraction, EtOH precipitation, CaCl2 precipitation	-	(Ni et al., 2020)
		Anion-exchange chromatography on DEAE-cellulose	Total sugar 56.55%, sulfate 30.72%, fucose 79.49%
	Rongcheng, Shandong, China	HCl extraction	Fucose 66.1%, sulfate 25.8%	(Geng et al., 2018)
	Rongcheng, Shandong, China	HCl extraction	Fucose 43.46%, uronic acid 0.03%, sulfate 51.09%, fucose 1 mol%	(Jin et al., 2013)
	Russian far east	Anion-exchange chromatography on DEAE-cellulose	Fucose 62%	(Vishchuk et al., 2012)
			Fucose 58%
	Wando, Korea	Supercritical water extraction	Conventional method-fucose 4.89 mol%	(Saravana et al., 2016)
			Water based-fucose 5.78 mol%
			0.1% sodium hydroxide-fucose 6.39 mol%
			0.1% formic acid-fucose 6.24 mol%
			70% ethanol-fucose 3.17 mol%
			50% ethanol-fucose 4.65 mol%
			25% ethanol-fucose 5.67 mol%
H. fusiforme	Zhejiang Province, China	Water extraction, EtOH precipitation, CaCl2 precipitation, anion-exchange chromatography on DEAE-cellulose	Fucose 20.1%, uronic acid 29.3%, sulfate 11.6%, fucose 38.2%	(Li et al., 2006)
		Water extraction, EtOH precipitation, CaCl2 precipitation, purified (Sepharose CL-6B)	Fucose 31.2%, uronic acid 13.4%, sulfate 23.9%
	Yonabaru, Okinawa, Japan	HCl extraction, cetylpyridinium chloride (CPC) precipitation, anion-exchange chromatography on DEAE-cellulose	Yield 31.9%, fucose 80.0%	(Shiroma et al., 2008)
	Jeju, Korea	Enzyme-assisted extraction, anion-exchange chromatography on DEAE-cellulose	Sulfate 27.22%, fucose 79.20%	(Wang et al., 2020a, b)
	Busan, Korea	HCl extraction	Crude fucoidan (% of brown seaweed) yield 4.85%	(Gu, 1994)
		Anion-exchange chromatography on DEAE-cellulose	partially purified fucoidan (% of brown seaweed) yield 2.51%, partially purified fucoidan (% of crude fucoidan) yield 52.29%, uronic acid 12.27%, sulfate 25.44%, fucose 74.68%
Sargassum horneri	Jeju, Korea	Enzyme assisted extraction	Enzyme extract-polysaccharide 57.94%	(Sanjeewa et al., 2019)
		Enzyme-assisted extraction, EtOH precipitation	Crude polysaccharide-sulfate 12.5%, fucose 36.86%
		Enzyme-assisted extraction, EtOH precipitation, anion-exchange chromatography on DEAE-cellulose	Purified fucoidan-sulfate 22.05%, fucose 48.69%
	Wando, Korea	Hot water extraction	Fucose 277.1 mg/g	(Park et al., 2023)
	Shandong Province, China	Water extraction, EtOH precipitation, CaCl2 precipitation, anion-exchange chromatography on DEAE-cellulose	Sulfate 12.96%, fucose 63.29%	(Fan et al., 2024)
	Keelung, Taiwan	Hot water extraction, EtOH precipitation, CaCl2 precipitation	Sulfate 12.30%, fucose 8.11%	(Wang and Chen, 2016)
	Taiwan	Hot water extraction	Fucose 57.8%	(Lee et al., 2020)
	India	HCl extraction, EtOH precipitation, CaCl2 precipitation, Anion-exchange chromatography on DEAE-cellulose	Yield 44.8%, sulfate 24.5%, fucose 58.5%	(Dinesh et al., 2016)
	Pontevedra, Spain	Hot water extraction	Sulfate 23.7%, fucose 22.3%	(González-Ballesteros et al., 2021)
Sargassum horneri (Processing residue)	Japan	Hot water extraction	Uronic acid 4.02%, sulfate 0.33%	(Jang et al., 2011)

Seasonal variation

Fucoidan composition varies considerably with the season, with production increasing up to five-fold from April to July in the Northern Hemisphere (Zhao et al., 2018). Fletcher et al. (2016) reported seasonal variations in fucoidan content from brown seaweeds, including Fucus serratus, Fucus vesiculosus, and Ascophyllum nodosum (Fletcher et al., 2017). The fucoidan content is lowest in spring, characterized by a lower molecular weight and higher sulfate content. It increases during summer as the molecular weight rises, reaching its peak in autumn with the highest molecular weight and lower sulfate content. In winter, the fucoidan content and molecular weight both decrease (Fletcher et al., 2017).

Seasonal variations in fucoidan yield, as well as sulfate and fucose contents, from different brown seaweed species harvested at various times, highlight how these factors change throughout the year (Fletcher et al., 2017). For example, Fucus vesiculosus harvested between April 2010 and March 2011 displayed fucoidan content ranging from 7 to 12 wt%, with fucose content from 20 to 28%, and sulfate content from 9 to 35%, highlighting substantial seasonal variability (Fletcher et al., 2017). In U. pinnatifida sporophylls collected from November 2015 to March 2016, fucoidan content ranged from 13 to 20%, with fucose levels of 45–55% and sulfate content from 13 to 26%, suggesting the influence of late-autumn to early-spring harvesting on polysaccharide composition (Arijón et al., 2021). Similarly, Saccharina japonica harvested between January 2009 and October 2009 showed lower fucoidan contents (0.87–4.26%, dry weight basis) (Skriptsova, 2016). Additionally, S. japonica collected from February 2007 to July 2007 had a carbohydrate content of 61–68% and lower fucose content (2–3%), reflecting seasonal fluctuations in carbohydrate and fucoidan composition within this species (Hwang et al., 2014).

Geological and environmental variation

Fucoidans extracted from the same species grown in different locations exhibit structural and compositional variations (Ponce and Stortz, 2020). These differences are attributed to environmental conditions unique to each geographic region. Key environmental factors, including light, temperature, and salinity, influence the physiology of seaweeds and consequently affect fucoidan structure and content (Bruhn et al., 2017). In some species, fucoidan composition also varies between vegetative and reproductive structures (Ponce and Stortz, 2020). Fucoidans play a protective role in preventing desiccation, with sulfate groups associated with magnesium ions aiding in water retention within the fronds. This suggests that fucoidan structure may adapt to environmental challenges specific to seaweed habitats (Hentati et al., 2020). Furthermore, environmental factors also highly affected the nutritional levels and fucoidan contents in brown seaweeds. Higher salinity generally correlates with increased fucoidan content (Ptak et al., 2021b). Seaweed in shallow, exposed areas tends to have higher fucoidan content, and latitude in northern distribution limits may have altered fucoidan composition (Rani et al., 2017). Rocky shores or shallow coastal areas can influence the fucoidan yield (Rani et al., 2015). Nutrient availability also affected the variation in nutrient levels between locations can affect fucoidan content (Manns et al., 2017). The significant variability in fucoidan structure and composition across species, habitats, and seasons presents both challenges and opportunities for industrial-scale production and application. While this diversity contributes to a broad spectrum of biological activities, it complicates the standardization and quality control processes essential for commercial production. As demand for fucoidan grows in dietary supplements and pharmaceutical applications, addressing the challenges of large-scale extraction, purification, and characterization becomes imperative. The subsequent sections outline the major obstacles to fucoidan industrialization and propose strategies for sustainable and efficient production of this valuable marine polysaccharide.

Structural diversity of fucoidan

The structural diversity of fucoidan, including variations in sulfate content, molecular weight, monosaccharide composition, and branching patterns, is crucial for its biological activity, as shown in Table 1 (Li et al., 2008). These structural features influence its interactions with biological molecules and pathways, directly affecting its therapeutic applications (Li et al., 2008).

Backbone of fucoidan

The backbone structure of fucoidan plays a critical role in its biological activity and potential applications. Composed primarily of α-L-fucopyranose units, the backbone varies considerably depending on the seaweed species and extraction methods. These linkages determine the polysaccharide’s primary structure, conformation, and flexibility. For example, fucoidans from Fucus vesiculosus and Ascophyllum nodosum typically feature alternating (1 → 3) and (1 → 4) linkages, whereas fucoidans from U. pinnatifida predominantly exhibit α(1 → 3) linkages (Zayed et al., 2023).

Other than that, Fucoidans are classified into types such as U, F, and G primarily based on their backbone structure, which varies depending on the seaweed species from which they are extracted. Fucoidan has a backbone of alternating α-(1 → 3)- and α-(1 → 4)-linked L-fucopyranose residues. Sulfation occurs mainly at C-2 and C-4 positions of the fucose units (Li et al., 2008; Wang et al., 2020a, b). This structure was elucidated through methylation and alkali treatment studies (Wang et al., 2020c). The backbone structure of (1 → 3)- and (1 → 4)-linked-α-L-fucopyranosyl residues is substituted at C-2 and C-3 (Li et al., 2008). U fucoidan is classified as a sulfated galactofucan, containing both fucose and galactose in its backbone. The monosaccharide composition includes fucose, xylose, galactose, glucose, rhamnose, and mannose. The ratio of fucose to galactose is approximately 1.1:1.03 (Zhao et al., 2018). U fucoidan's backbone includes various linkages such as 1–3 linked fucose, 1–3, 1–4, and 1–6 linked galactose. Sulfation occurs mainly at 2- or 4-positions of fucose residues and 3- or 6-positions of galactose residues (Zhao et al., 2018). G fucoidan typically has a backbone of primarily α-(1 → 3)-linked L-fucopyranose residues (Li et al., 2008). While specific structural details for G fucoidan are limited, fucoidans from the Laminariales order generally have more complex structures with potential branching (Li et al., 2008). The composition includes fucose as the main sugar, along with galactose, mannose, and xylose (Lee et al., 2006).

Fucoidans with alternating α(1 → 3) and α(1 → 4) linkages, such as those from F. vesiculosus and A. nodosum, often demonstrate strong anticoagulant properties due to their flexible backbone, which enhances interactions with coagulation factors (Wang et al., 2020c). Additionally, Kumashi et al. (2007) reported that 2-O-α-D-glucuronopyranosyl branches in the linear (1 → 3)-linked poly-α-fucopyranoside chain are critical for anticoagulant activity (Cumashi et al., 2007).

The backbone structure also affects fucoidan’s antitumor and anti-inflammatory properties (Lee et al., 2022; Liyanage et al., 2023a). Fucoidans with a higher proportion of α (1 → 3) linkages, such as those from U. pinnatifida, exhibit potent antitumor activities, as reported by Li et al. (2008) and Wang et al. (2020a, b). Anti-inflammatory effects are often linked to highly branched structures, which enhance interactions with immune system components (Jayawardena et al., 2020b; Li et al., 2008). Moreover, fucoidans classified as galactofucans, containing galactose branches, have been shown to stimulate immune responses, further highlighting the connection between backbone structure and immunomodulatory properties (Wang et al., 2020c).

Monosaccharide composition

The backbone composition is another critical factor influencing the biological activity of fucoidan. According to Zhao et al. (2018), the backbone of U. pinnatifida fucoidan primarily consists of two monosaccharides: fucose and galactose, linked through α(1 → 3) or alternating α(1 → 3) and α(1 → 4) glycosidic bonds (Li et al., 2008). These sugars form the main chain in an approximate ratio of 1.1:1.0 (fucose: galactose) (Zhao et al., 2018), a distinguishing feature compared to fucoidans from other brown seaweed species, which predominantly contain sulfated fucose chains. While fucose and galactose are the main components, U. pinnatifida fucoidan also includes other monosaccharides such as mannose, xylose, glucose, and rhamnose, adding to its structural complexity (Zhao et al., 2018). Fucose, the primary monosaccharide in most fucoidans, considerably influences biological activity, with higher fucose content often linked to stronger anticoagulant, anti-inflammatory, and anti-viral effects (Lee et al., 2023; Liyanage et al., 2023b; Luthuli et al., 2019; Nagahawatta et al., 2022).

The presence of galactose in fucoidan, particularly in galactofucans like those from U. pinnatifida, considerably influences its biological properties. For instance, one study reported that U. pinnatifida fucoidan inhibited the growth of human lung cancer cells more effectively than fucoidans from other sources (Zhao et al., 2018). Additionally, galactose within the fucoidan structure may enhance interactions with immune system components, potentially amplifying immunomodulatory effects (Jayawardena et al., 2022). Other monosaccharides, such as mannose, xylose, and uronic acid, also contribute to the biological activities of fucoidan. For example, fucoidan from Sargassum horneri, which contains glucuronic acid, has demonstrated strong antioxidant effects (Luthuli et al., 2019). Similarly, the presence of mannose in S. horneri fucoidan has been linked to substantial anti-inflammatory effects in skin keratinocytes (Jayawardena et al., 2022).

Sulfate

Sulfate groups are commonly attached to the fucose units in fucoidans, and their positions and densities can vary. Sulfation typically occurs at the C-2 and C-4 positions of fucose residues. The degree and pattern of sulfation are critical determinants of fucoidan’s biological activity. These groups contribute to the polysaccharide’s negative charge, enabling interactions with positively charged biological molecules such as proteins and cell receptors (Nagahawatta et al., 2023).

Higher sulfation levels are often associated with enhanced anticoagulant and antiviral activities (Nagahawatta et al., 2023; Zayed et al., 2023). While high sulfation generally boosts biological activity, it can also increase viscosity and reduce solubility, complicating its use in certain applications. Excessive sulfation may lower bioavailability, as highly sulfated molecules are more prone to aggregation or precipitation (Zayed et al., 2020).

Molecular weight

The molecular weight of fucoidans is a crucial factor that considerably influences their biological activity and potential applications. Fucoidans exhibit a wide range of molecular weights, typically from 10 to over 500 kDa, with some studies reporting even higher molecular weights. For example, fucoidan from U. pinnatifida collected in Wando, South Korea, has an average molecular weight of 2,100 kDa (Kim et al., 2007). This variability can be attributed to factors such as seaweed species, geographical location, harvesting conditions, and extraction methods. Most studies have shown that lower-molecular-weight fucoidans exhibit higher biological activities. For instance, fucoidans isolated from Sargassum swarzii, Ecklonia maxima, Padina commersonii, and Chnoospora minima demonstrated enhanced biological activity (Asanka Sanjeewa et al., 2019; Fernando et al., 2017; Jayawardena et al., 2020a, 2020b; Nagahawatta et al., 2022). However, a few studies have confirmed that higher-molecular-weight fucoidans also possess significant biological activity. Yoo et al. (2019) reported the immunomodulatory effects of a high-molecular-weight fucoidan from U. pinnatifida (Yoo et al., 2019). Similarly, Shimazu et al. (2005) observed that fucoidan from Cladosiphon okamuranus, with a higher molecular weight, promoted murine cytotoxic T cells (Shimizu et al., 2005).

Polydispersity, or molecular weight distribution within a sample, is another important characteristic of fucoidans. According to Choi et al. (2014), higher-molecular-weight fucoidan tend to exhibit greater polydispersity. As molecular weight decreased through degradation by gamma irradiation, polydispersity also declined (Choi et al., 2014). A more uniform molecular weight distribution may produce consistent and predictable biological effects. Furthermore, lower polydispersity can improve the experimental reproducibility and the consistency of potential therapeutic applications. However, different biological activities may be optimized at varying molecular weight ranges and polydispersity levels.

Extraction methods of fucoidan

The extraction of fucoidan from brown seaweed is a critical process that substantially influences its yield, purity, and structural integrity (Jayawardena et al., 2022). This structure–activity relationship is crucial for understanding and optimizing fucoidan’s potential applications. For example, higher temperatures and longer extraction times can degrade the fucoidan structure, whereas mild conditions (lower temperatures and shorter times) help preserve its native structure, maintaining the integrity of the sulfate groups and fucose content (Jayawardena et al., 2022). Various extraction methods have been developed to optimize fucoidan recovery while preserving its biological activity. Traditional methods such as hot water extraction are widely used for simplicity, cost-effectiveness, and environmental friendliness. This method is generally safe for workers and suitable for food and pharmaceutical applications because it avoids introducing harmful chemical residues. It also helps preserve the native structure of fucoidan to some extent. However, hot water extraction has notable drawbacks, including lower yields, longer processing times, and high water and energy consumption. Extended exposure to high temperatures may also risk the thermal degradation of fucoidan. Additionally, it can co-extract other water-soluble compounds, necessitating further purification steps and reducing selectivity for fucoidan, potentially complicating downstream processing. Despite these limitations, hot water extraction remains popular due to its simplicity and safety, though researchers often explore advanced techniques or combinations to optimize fucoidan extraction. (Hahn et al., 2012).

As shown in Table 1, traditional methods can involve harsh conditions that degrade fucoidan and reduce its bioactivity (Ummat et al., 2024). Solvent choice also affects the polysaccharide composition. For instance, acid extraction may alter the structural features, whereas gentler water-based methods typically yield purer fucoidans with fewer contaminants, enhancing specific biological activities. Optimizing extraction techniques to preserve desired structural features can improve bioactivity. Combined methods, such as mild acid extraction followed by ultrasound-assisted depolymerization, have shown promise for improving yield and activity. Overall, careful balancing of the extraction parameters is vital for maximizing fucoidans’ therapeutic potential in various applications (Hahn et al., 2012).

Enzymatic extraction has emerged as a promising alternative. This method utilizes specific enzymes to break down seaweed cell walls, releasing fucoidans under mild conditions that preserve their structural integrity and biological function (Nguyen et al., 2020). Advanced techniques such as ultrasonic-assisted extraction (Suprunchuk, 2021) and microwave-assisted extraction (Rodriguez-Jasso et al., 2011) have been developed to enhance extraction efficiency and reduce processing time. These methods influence the physical forces that disrupt the cell walls and facilitate fucoidan release while minimizing degradation (Rodriguez-Jasso et al., 2011). Other modern techniques include pressurized liquid extraction and pulsed electric field (PEF) extraction (Hsieh et al., 2019). Pressurized liquid extraction uses high pressure and temperature to improve fucoidan solubility and diffusion into the extraction solvent, while PEF applies short bursts of high voltage to disrupt cell membranes and release fucoidan (Hsieh et al., 2019). These innovative methods offer significant advantages in efficiency and scalability, rendering them suitable for industrial applications (Hahn et al., 2012). The different extraction methods and their utilization, advantages, and limitations are summarized in Table 3.

Table 3.

Overview of extraction methods for fucoidan

Extraction method	Factors	Properties	Yield%	Effects on fucoidan	Advantages	Limitations	References
Hot water extraction	Based on fucoidan's solubility in hot water and insolubility in ethanol	Low cost Simple operation Time-consuming Large solvent volumes	~ 12.9	Preserves natural bioactivity Maintains structure Gentle on molecular weight	Eco-friendly Preserves native structure Suitable for large-scale production	Time-consuming Large water consumption Lower yield compared to some methods	(Zhao et al., 2018)
Dilute acid extraction	Uses fucoidan's solubility in dilute HCl solution	Can damage structure Affects bioactivity Not high extraction rate	~ 3.9	Potential structural damage May reduce molecular weight Can affect bioactivity negatively	Effective for some species Can increase yield for certain algae	Potential degradation of fucoidan Environmental concerns with acid use May alter bioactivity	(Kim et al., 2007)
Microwave-assisted extraction	Uses microwave radiation to improve extraction efficiency	More selective Quicker Better yields Less energy and solvent use	Up to 18.2	Can be optimized to reduce structural damage May affect molecular weight Potentially higher purity	Rapid extraction Energy-efficient Higher yields than conventional methods	Potential for localized overheating Initial equipment cost May require optimization for each species	(Rodriguez-Jasso et al., 2011)
Ultrasound-assisted extraction	Uses cavitation to disrupt cell walls	Higher yields Lower structural damage than conventional methods	Up to 33	Better preservation of the structure Maintains bioactivity Efficient extraction of high molecular weight fractions	High yield Preserves structure and bioactivity Reduced extraction time	Potential for free radical formation Equipment cost May require a cooling system	(Song et al., 2015)
Enzyme-assisted extraction	Uses enzymes to break down cell walls	Effective extraction Maintains structure and bioactivity	~ 7.76	Preserves structural integrity Maintains bioactivity Potential for selective extraction	Highly selective Mild conditions preserve the structure Environmentally friendly	High enzyme costs Requires optimization of the enzyme mixture May need additional purification steps	(Nguyen et al., 2020)
Pressurized liquid extraction	Uses high pressure to maintain solvents in liquid state at elevated temperatures	High efficiency Shorter extraction times Lower solvent consumption	10.22–11.7	Can affect molecular weight depending on temperature May increase extraction of other compound	Rapid extraction Environmentally friendly Potential for selective extraction	High initial equipment cost May require the optimization of parameters Potential thermal degradation at high temperatures	(Dobrincic et al., 2020)
Pulsed electric field (PEF) extraction	Uses short electric pulses to create pores in cell membranes	Non-thermal process Preserves heat-sensitive compounds Can be combined with other methods	Varies (can enhance yields of other methods)	Minimal effect on molecular structure Can improve extraction efficiency when combined with other methods	Gentle extraction Preserves bioactive compounds Can enhance other extraction methods	Requires specialized equipment May need to be combined with other extraction methods for optimal results Limited data on fucoidan-specific extraction	(Dobrincic et al., 2020)
Ultra-filtration membrane extraction	Uses enzymes to disrupt cell walls and membrane filtration to separate	Extract fucoidan effectively while maintaining structure and bioactivity	7.76	Preserves structural integrity and bioactivity	Effective extraction, maintains structure, shorter extraction time	Requires specialized equipment, may need optimization	(Zhao et al., 2018)

Dilute acid extraction is an alternative approach, particularly effective for certain seaweed species. Using hydrochloric acid (HCl) solutions, this method breaks down cell walls more effectively than water alone. While it offers some advantages in terms of yield and extraction efficiency for specific algal types, it has significant drawbacks, including potential structural damage to fucoidans, reduced molecular weight, and negative effects on bioactivity. Additionally, acid use raises environmental concerns and necessitates complex neutralization processes. With a yield of approximately 3.9%, this method is less attractive for large-scale production, especially given the potential degradation of valuable fucoidan molecules (Kim et al., 2007). Microwave-assisted extraction is a modern and technologically advanced approach that dramatically reduces extraction time through rapid volumetric heating, yielding up to 18.2%. Its energy efficiency and low solvent consumption make it environmentally friendly. This technique allows for precise control over the extraction parameters and shows potential for automation. However, this method has some challenges. A non-uniform microwave distribution can create problematic hotspots, increasing the localized degradation of fucoidan. Additionally, the initial equipment investment is substantial, and optimization requires careful tuning of parameters for different seaweed species (Rodriguez-Jasso et al., 2011).

Ultrasound-assisted extraction is a highly promising technique with impressive yields up to 33%. This method utilizes cavitation effects to enhance cell wall disruption, enabling lower operating temperatures that preserve heat-sensitive compounds. The reduced extraction time and ability to maintain fucoidan’s structural integrity make it particularly attractive. This process offers efficient extraction of high-molecular-weight fractions while maintaining bioactivity. However, challenges include potential free radical formation, high equipment costs, and the need for effective cooling system management (Song et al., 2015). Enzyme-assisted extraction offers a gentle and highly selective method for fucoidan isolation. It uses specific enzymes to break down cell walls, preserving fucoidan’s structural integrity and bioactivity. This environmentally friendly approach is advantageous for selective extraction but faces limitations such as high enzyme costs, complex optimization requirements, and relatively lower yields of around 7.76%. Additional purification steps and variability in enzyme effectiveness across different seaweed species add to the challenges (Nguyen et al., 2020).

Pressurized liquid extraction is a sophisticated technique that combines high efficiency with environmental considerations. By enabling extraction at temperatures above the solvent’s boiling point, it can increase yield and selectivity. With yields ranging from 10.22% to 11.7%, it offers a balance between efficiency and preservation of fucoidan properties. The closed system prevents the loss of volatile compounds and reduces environmental exposure. However, high equipment costs, complex optimization processes, and risks of thermal degradation at high temperatures limit its broader adoption (Dobrincic et al., 2020). PEF extraction is a unique non-thermal approach for fucoidan isolation. By creating temporary pores in cell membranes, this method enhances extraction efficiency while minimizing structural damage. The gentle extraction process preserves heat-sensitive compounds and maintains their molecular integrity. However, this technique requires specialized equipment, often in combination with other methods, and is limited by a lack of extensive research specific to fucoidan extraction (Dobrincic et al., 2020).

Ultrafiltration membrane extraction combines enzymatic cell wall disruption with sophisticated membrane separation techniques. This method effectively extracts fucoidan while maintaining its structure and bioactivity, with yields around 7.76%. This approach allows for potential fractionation based on molecular weight and offers a continuous processing option. However, it requires specialized equipment and complex optimization and faces challenges with membrane fouling and potential loss of smaller molecular fractions (Zhao et al., 2018). Each extraction method has unique advantages and limitations, reflecting the complexity of fucoidan isolation. The optimal approach depends on specific research or industrial requirements, balancing factors such as yield, purity, preservation of biological activity, cost, and scalability. As research progresses, hybrid approaches and continued technological innovations hold promise for enhancing fucoidan extraction techniques, making them more efficient and accessible for diverse applications. The efficiency of each extraction method in industrial perspective was summarized in Supplementary Table 1.

Purification of fucoidans

Purification of fucoidans is a critical step in producing high-quality bioactive polysaccharides for industrial applications. Crude fucoidan extracts typically contain impurities such as proteins, alginates, polyphenols, and other low-molecular-weight compounds, which can interfere with their biological activities (sinurat et al., 2016). The purification process aims to remove these impurities while preserving the structural integrity and bioactivity of fucoidan. Various methods, including ethanol precipitation, ion exchange chromatography, ultrafiltration, and enzymatic treatment, have been developed for this purpose (Flórez-Fernández et al., 2020a, b). The choice of purification method considerably influences the yield, purity, and biological activity of the resulting fucoidan products. A summary of these methods is presented in Table 4.

Table 4.

Fucoidan purification methods

Purification Method	Advantages	Limitations	Ref
Ethanol precipitation	Simple and cost-effective Removes some contaminants Can be repeated for higher purity	May not remove all impurities Can co-precipitate other polysaccharides	(Lim and Wan Aida, 2017)
Ion-exchange chromatography	Highly effective for sulfated fucoidans Removes less charged contaminants Can be scaled up	Requires specialized equipment May need optimization for different fucoidan sources	(Sichert et al., 2021)
Chelating agent treatment	Effective at removing metal contaminants Can improve fucoidan purity	May affect fucoidan structure Additional steps needed to remove chelating agents	(Imbs et al., 2015)
Calcium chloride precipitation	Effective at removing alginate contaminants Relatively simple procedure	May not remove all types of contaminants Can affect fucoidan yield	(Sichert et al., 2021)
Ultrafiltration	Can effectively remove low molecular weight contaminants Preserves fucoidan structure	May not remove contaminants of similar size to fucoidan Can be time-consuming	(Rajauria et al., 2023)
Dialysis	Effective at removing salts and small molecules Gentle on fucoidan structure	Time-consuming May not remove larger contaminants
Enzyme-assisted purification	Can be highly selective Preserves fucoidan structure	Expensive Requires optimization for each fucoidan source	(Sichert et al., 2021)

Major barriers in the industrial application of fucoidans

Quality control of raw seaweeds

Standardization is crucial for the successful industrialization of fucoidan, ensuring consistent production quality across applications. However, brown seaweed-derived fucoidan and other marine bioresources face significant challenges due to variability in supply and composition, which are influenced by environmental factors and seasonal harvesting (Fletcher et al., 2017). This variability complicates efforts to produce fucoidan-based products of uniform quality. The standardization of fucoidan from brown seaweed is particularly challenging because of variations in its composition, structure, and sulfation patterns (Manns et al., 2017). These variations complicate its industrial applications. Additionally, environmental and processing factors such as harvest timing, drying, and storage considerably impact fucoidan quality, requiring careful management to ensure consistent quality.

High production cost due to low fucoidan content in seaweeds

The fucoidan content of most brown seaweeds generally ranges from 5 to 20% (Liyanage et al., 2023c). Despite advancements in extraction and purification methods, fucoidan recovery remains inherently limited due to its low natural abundance in the source material. Fucoidan is typically isolated and purified using its ionic charge characteristics, employing techniques such as anion-exchange chromatography. This method facilitates the isolation of high-purity fucoidan through its negative charges, but yields remain low despite high purity.

Studies have quantified fucoidan yields obtained from various brown algae using HCl extraction followed by anion-exchange chromatography. Gu et al. (1994) reported a 1.73% yield from U. pinnatifida blades via HCl extraction, with further purification yielding only 0.4%. In contrast, U. pinnatifida sporophylls showed a 12.75% yield through HCl extraction and a 6.65% yield after purification. Similarly, Vishchuk et al. (2011) reported a 9.7% yield from Saccharina japonica using HCl extraction, but only 3.0% after purification. These low yields, combined with the absence of cost-effective purification techniques, contribute to high production costs. Consequently, industrial-scale production of fucoidan is economically challenging, as the expenses required to achieve high purity do not offset the low yield.

Arsenic

Algae are primary accumulators of arsenic in marine environments (Almela et al., 2006). Algal cell walls, which function as hydrocolloids, bioaccumulate elements from seawater through active and/or passive mechanisms, often resulting in higher concentrations than those found in the surrounding environment (Díaz et al., 2012). The abundance of elements in algal tissues depends on seawater concentrations, species-specific metabolic processes, algal age, and environmental factors such as temperature, light, pH, and nitrogen availability (Sánchez-Rodrıguez et al., 2001).

The International Agency for Research on Cancer classifies arsenic and its compounds as Group 1 carcinogens, causally linked to human cancers (McCarty et al., 2011). The toxicity of arsenic compounds varies depending on their form (Koch et al., 2007), with the toxicity order being AsH₃ (sine) > As (III, arsenite) > As (V, arsenate) > MMA (monomethylarsonic acid) > DMA (dimethylarsinic acid). Inorganic As, particularly As(III) and As(V), is highly toxic and linked to health issues such as skin lesions, cardiovascular disease, and cancer (McCarty et al., 2011). The inorganic forms of As, including As(III) and As(V), are carcinogenic (Díaz et al., 2012). Organic arsenic compounds are the most prevalent type of arsenic in algae (Koch et al., 2007). Organic forms such as arsenobetaine, arsenocholine, and arsenosugars are substantially less toxic than inorganic forms of arsenic MMA(III) and DMA(III) (Ichikawa et al., 2010; McCarty et al., 2011) (Andrewes et al., 2004). Arsenosugars, where arsenic is bonded to sugar molecules, are the primary arsenical constituents in marine algae, typically ranging from 2 to 50 mg arsenic/kg dry mass (Francesconi et al., 2002; Niegel and Matysik, 2010).

Díaz et al. (2012) reported that inorganic arsenic levels in 14 algal species ranged from 0.8% to 13% of the total arsenic concentration, indicating that most arsenic in these algae is organic arsenic. Brown algae exhibited the highest total arsenic concentrations among the studied samples; however, algal species intended for direct human consumption were deemed not to pose a health risk. One study (Ichikawa et al., 2010) found that within three days of administering cooked or dried Hizikia fusiforme to mice, 66–92% of the administered arsenic was excreted, with only about 5% accumulating in the body. In general, the As levels in fish and seafood are considered to have minimal impact on human health (Ichikawa et al., 2010). However, Hijiki seaweed is an exception, with inorganic arsenic concentrations reaching up to 135 mg/kg dry weight, accounting for 50–80% of its total arsenic content. These elevated levels have raised toxicological concerns among consumers (Wondimu et al., 2007), (Yokoi and Konomi, 2012).

At present, countries like Australia and New Zealand enforce a maximum inorganic arsenic concentration limit of 1 mg kg − 1, while France and the USA have set their limit at 3 mg kg − 1 (Díaz et al., 2012; Almela et al., 2006). In Korea, the Ministry of Food and Drug Safety (MFDS) mandates that processed foods containing H. fusiforme and Sargassum fulvellum must contain less than 1 mg kg − 1 of inorganic arsenic content. The As content in various seaweed species has been studied and reported in the scientific literature. Fucus vesiculosus contains a total arsenic content of 13.5 mg/kg, with inorganic arsenic levels of 0.34 mg/kg (Balina et al., 2016). U. pinnatifida has a higher total arsenic content of 30 mg/kg but a lower inorganic arsenic level of 0.15 mg/kg (Salomone and Riera, 2020). Laminaria japonica has an even higher total As content of 47 mg/kg, with inorganic As at 0.297 mg/kg (Almela et al., 2002).

In contrast, H. fusiforme had considerably elevated As levels, with a total As content of 141 mg/kg and an inorganic As concentration of 77.44 mg/kg (Ma et al., 2018). Lastly, Sargassum species exhibit a wide range of arsenic content, with total arsenic varying from 19 to 255 mg/kg and inorganic arsenic ranging from 3.7 to 105 mg/ kg (Ortega-Flores et al., 2023).

Iodine

Seaweeds are well-known as a rich source of iodine, an essential mineral nutrient required for thyroid function and metabolic health when consumed in appropriate amounts (Nitschke and Stengel, 2015). Edible brown seaweeds such as wakame, kombu, and kelp (Laminaria) are particularly abundant in iodine. While iodine is beneficial, its presence can pose challenges for industrial-scale manufacturing (González et al., 2020). The recommended daily intake of iodine is about 2 µg/kg of body weight, i.e., about 140 µg for an adult weighing 70 kg (Mouritsen et al., 2019). Insufficient dietary iodine can disrupt hormone levels and result in hypothyroidism; therefore, it is considered an essential daily nutrient for maintaining a healthy balanced diet. However, excessive iodine intake may lead to hyperthyroidism, necessitating caution regarding the regular consumption of seaweed in the human diet (Mouritsen et al., 2019).

Iodine accumulates in brown seaweeds in various chemical forms, primarily as inorganic iodide (I⁻) (Blikra et al., 2022), which is highly accessible and readily absorbed from saltwater. Trace amounts of iodate (IO₃⁻) and organo-iodine compounds, including iodinated proteins, amino acids, thyroid hormone precursors, iodinated lipids, and fatty acids, are also present (Al-Adilah et al., 2022; Leblanc et al., 2006). Furthermore, seaweeds release molecular iodine (I₂) as a volatile component or it develops under specific oxidative circumstances, which contributes to atmospheric iodine and marine aerosols (Nitschke et al., 2013). In marine macroalgae, inorganic iodide is the predominant form, constituting 9–99% of water-soluble iodine, depending on species, with higher levels observed in Chlorophyta and Laminariales (61–93%) (Krook et al., 2024). While brown seaweeds are a valuable dietary supplement for iodine-deficient populations, excessive consumption can lead to thyroid-related health issues (Kumar and Sharma, 2021). The iodine content in seaweeds varies greatly according to the species, environment, growth patterns throughout the year, and processing techniques. The iodine content in various seaweed species has been reported in scientific literature, with measurements typically expressed in micrograms per gram of dry weight (µg/g dw). Iodine concentrations in brown seaweeds can range from 2000 to 8000 µg/g dw, which is significantly greater than in green or red seaweeds (Al-Adilah et al., 2022). Fucus vesiculosus contains iodine levels of 226 and 260 µg/g dw (Biancarosa et al., 2018; Phaneuf et al., 1999), respectively. U. pinnatifida has lower iodine content, with reported values of 32 and 41 µg/g dw (Teas et al., 2007). Laminaria japonica shows a wide range of iodine content, ranging from 241 to 4921 µg/g dw and 2110 µg/g dw, respectively (Ownsworth et al., 2019; van Netten et al., 2000). H. fusiforme contains iodine levels of 262 and 436 µg/g dw (Dawczynski et al., 2007; van Netten et al., 2000). Saccharina latissima has iodine contents of 238 and 380 µg/g dw (Yeh et al., 2014). Lastly, Laminaria digitata exhibits particularly high iodine levels, with reported values of 1997 and 5762 µg/g dw (Teas et al., 2007).

Therefore, consuming iodine in moderation is crucial, especially in populations with a limited tolerance for excessive intake. The World Health Organization recommends the following daily iodine levels to avoid deficiencies and maintain normal thyroid function. Iodine intake levels should be 90 µg/day for infants ages 0–5, 120 µg for children ages 6–12, and 150 µg for adults and adolescents ages 12–18. It is recommended that women who are pregnant or nursing take 250 µg/day (Zimmermann, 2009). These guidelines aim to balance iodine intake, as both deficiency and excess can adversely affect thyroid health.

Standardization of manufacturing process

The industrial application of fucoidan faces challenges due to its variability and the lack of a universally accepted definition for its quantification. Additionally, the absence of high-purity standard reference materials complicates the establishment of standardized protocols for its production (Mensah et al., 2023). Conventional methods for fucoidan extraction have been reported, but achieving high-purity fucoidan requires techniques such as DEAE and anion exchange chromatography, which are costly (Flórez-Fernández et al., 2018). Furthermore, many fucoidan extracts described in the literature may contain impurities, including heavy metals or iodine, as these are often not adequately reported (Du et al., 2022). Current extraction and purification protocols do not fully address issues related to optimizing fucoidan yield while removing harmful compounds. This lack of robust, standardized procedures poses a significant barrier to industrializing fucoidan production. Advanced research to optimize large-scale production processes, considering challenges such as cost, safety, and quality control, would enhance the industrial applicability of fucoidan and expand its potential across diverse fields.

Strategies of fucoidan industrialization

To utilize fucoidans in industry, several factors must be considered, including the availability and cost of raw materials, the production costs of fucoidans, and the simplicity of implementing the manufacturing protocol. The selection of seaweed species for fucoidan production should be based on biological properties, sustainable resources for a reliable supply, and the harvesting season, which can affect bioactive components. Additionally, the extraction and purification processes must be optimized to remove unnecessary impurities from the final fucoidan extract. After production, measuring the fucose and sulfate contents as functional bioactive components is necessary. Evaluating purity by measuring the polysaccharide, protein, polyphenol, uronic acid, and ash contents of the final fucoidan is recommended, as purity can affect biological activity. For industrial applications, confirming the levels of inorganic arsenic and iodine in the final fucoidans is particularly important for addressing potential safety concerns.

Removing alginates

Alginate, a major polysaccharide found in brown algae, is a valuable compound with wide-ranging applications in the food, pharmaceutical, and biomedical industries. However, in the context of fucoidan extraction, alginate is considered a contaminant that can interfere with the properties and biological activities of fucoidan (Hahn et al., 2012). The structural similarities between fucoidan and alginate, which are both anionic polysaccharides, make their separation a crucial step in obtaining high-purity fucoidan. Alginate removal increases the purity of the fucoidan extract, which is crucial for both research and commercial applications (Beata Łabowska et al., 2019). The alginate-free fucoidan exhibited more consistent characteristics, allowing for more reliable experimental results and improved product quality. Furthermore, the presence of alginate can potentially mask or alter the biological activities of fucoidans, making its removal necessary for an accurate assessment of fucoidan properties (Fernando et al., 2019). Optimizing alginate removal techniques is crucial for researchers and manufacturers working with fucoidan, as they directly influence the final product’s quality and efficacy.

Various methods have been developed to effectively separate alginate from fucoidan during extraction (Beata Łabowska et al., 2019). These methods exploit differences in physicochemical properties, such as solubility, ion reactivity, and susceptibility to enzymatic degradation. Effectiveness can vary depending on seaweed species and extraction conditions (Fernando et al., 2019). The most common approach is calcium precipitation, where a calcium chloride solution is added to the crude extract, causing alginate to form insoluble calcium alginate, which is removed by centrifugation or filtration. Residual calcium ions may remain in the extract and require further purification. One of the main disadvantages of this method is the incomplete removal of alginate, which potentially leaves residual contaminants in the fucoidan extract (Hahn et al., 2015). A risk of fucoidan loss or coprecipitation with alginate exists, which reduces the overall yield. Further, improperly controlled conditions can degrade or alter fucoidan’s bioactive components (Hahn et al., 2015). This can be time-consuming, particularly at larger scales, and may not be compatible with all extraction techniques, such as enzyme-assisted or microwave-assisted methods (Flórez‐Fernández et al., 2020).

Owing to these limitations, researchers often combine the calcium chloride method with other purification techniques such as ethanol precipitation (Liyanage et al., 2023a), ion-exchange chromatography, or sequential extraction processes to obtain high-purity fucoidan while preserving its bioactivity. Sugiono et al. (2019) reported a sequential extraction method that involves alginate removal from seaweed samples using sodium carbonate before extracting fucoidan (Sugiono and Ferdiansyah, 2019). Brown algae were treated with Na₂CO₃ solution (1–5% concentration) at a solvent ratio of 1:20 (w/v) and then extracted at temperatures ranging between 30 and 90 °C for 60–180 min. This step selectively extracted alginate from seaweed biomass. The remaining residues, mostly free of alginate, were used for fucoidan extraction (Sugiono and Ferdiansyah, 2019). Acid or alcohol precipitation is another method for alginate removal. Acid precipitation involves adjusting the pH of the alginate-fucoidan solution to acidic conditions (pH 2–3) using HCl or H₂SO₄. This led to the precipitation of alginic acid, while fucoidan remained in the solution. During alcohol precipitation, ethanol is added to the alginate-fucoidan solution (typically in a 1:2 ratio of solution to ethanol) (Bojorges et al., 2023), causing alginate to precipitate while fucoidan remains soluble. Enzymatic degradation is another method, employing alginate lyase to selectively degrade alginate, while fucoidan remains intact in solution. The degraded alginate fragments are removed by ultrafiltration. Additional methods, such as ion-exchange chromatography and ultrafiltration, can also remove alginate, though they may not be suitable for industrial-scale processes.

A combination of conventional and novel methods is often most effective for removing alginate from fucoidans. Dodero et al. (2020) demonstrated alginate degradation via ultrasonication with saline (Dodero et al., 2020), which can be combined with other methods to remove alginate residues. Rhein-Knudsen et al. (2023) reported producing pure fucoidans using a commercial cellulase blend (Cellic® CTec2) combined with endo- and exo-acting thermophilic alginate lyases. This method produced fucoidan with high fucose and sulfate content and minimal contaminants, including cellulose, laminarin, and alginate (Rhein-Knudsen et al., 2023). Microwave-assisted alginate extraction is another novel technique that overcomes the limitations of conventional methods, such as temperature and solvent type. The major advantages of this method are high processing speed and low solvent consumption (Silva et al., 2015). Selecting or establishing an efficient alginate removal protocol is a critical step in the industrialization of fucoidans.

Removal of arsenic

H. fusiforme generally has the highest levels of inorganic As among the three types, which has led to consumption advisories in some countries (Su et al., 2021). Industries must ensure that the heavy metal content of fucoidan extracts meets national safety standards. In Korea, the MFDS recommends that pretreatment procedures, such as soaking for 30 min and heating for 30 min, be performed before the main processing of these brown algae to effectively eliminate arsenic compounds. The detailed reduction methods for arsenic are presented in Table 5.

Table 5.

Reduction methods of arsenic on the dietary safety reported in previous studies

Method	Description	References
Dilution and washing	Dried Hijiki water soaking (30 min), cooking at 90 °C for 20 min (reduction range of 75.0–81.4% of Arsenic)	(Ichikawa et al., 2006)
	Rising washing temperatures from 0 to 60 °C with 500 cm3 water reduce arsenic levels in commercial and natural hijiki	(Hanaoka et al., 2001)
Treatment with acids	Hot water treatment at 60 °C for 120 min, followed by 0.6% citric acid, and acidic extraction at pH 4 and 50 °C for 8 h achieves 95.9–96.6% arsenic removal	(Wang et al., 2022), (Zheng et al., 2013)
	15 min hot water treatment at 90 °C or heat treatment with citric acid for 2 h at 60 °C have reduced arsenic from 89.0 to 10.1 mg/kg	(Cisneros-Ramos et al., 2024)
	Soaking dried Hhijiki in 4% sodium hydrogen carbonate or acetic acid, followed by rinsing in pure water, effectively reduces arsenic levels. Briefly, boiling akamoku in a sodium chloride solution also achieves arsenic reduction	(Masayuki et al., 2015)
Activated carbon treatment	Activated carbon has shown an 83.4.0% reduction efficiency in streamed Hijiki Sargassum fusiform	(Kang et al., 2021)
Biological methods	Fermentation of the citric acid processed seaweed extract using Lactobacillus rhamnosus (5%) for 48 h	(Wang et al., 2022)

Removal of iodine

As discussed in Sect. 3.3, iodine concentrations in brown seaweeds can range from 2000 to 8000 µg/g DW, which is considerably greater than in green or red seaweeds (Al-Adilah et al., 2022). During fucoidan extraction, iodine present in seaweeds may be released. Therefore, after quantifying iodine in the final fucoidan extracts, processes to reduce iodine should be implemented, especially when excessive iodine poses safety concerns. Several methods, such as food processing and nutritional research, have been studied or developed for iodine removal from brown seaweed. These techniques to lower the iodine concentration, including fermentation, boiling, blanching at temperatures between 30 and 80 °C, and rehydration, are reported (Krook et al., 2024).

Confirmation of standardized fucoidan

Measuring of fucose content

Fucose, an important monosaccharide in fucoidan, plays a crucial role in its structural and functional properties. Fucose-rich sulfated polysaccharides have attracted considerable attention for their antioxidant (Wang et al., 2020a, b), anticancer (P et al., 2019) anti-inflammatory and anticoagulant (Cumashi et al., 2007) properties. As the core sugar component or backbone of fucoidans, fucose is often used as an indicator of their presence (Ale et al., 2011b). The fucose content in fucoidan varies based on the source and extraction methods, as shown in Table 2 of Sect. 3.2.1, and in studies such as those by Li et al., 2008 (Bilan and Usov, 2008; Li et al., 2008). Monosaccharide content, including fucose, can be assessed using high-performance liquid chromatography.

Measuring of sulfate content

The sulfate groups of fucoidan are responsible for its bioactive properties. These groups enhance interactions between fucoidan and proteins, influencing cellular signaling and biological responses (Kusaykin et al., 2008; Pomin and Mourão, 2008; Tissot et al., 2003). Fucoidans with a higher sulfate content are known to exhibit strong antioxidant, antiviral, anticoagulant, and immunomodulatory activities. These effects may arise from structural similarities to heparin sulfate found in mammalian mucosa (Berteau and Mulloy, 2003) (Rhein-Knudsen et al., 2023).

Sulfate content is linked to the ability of fucoidans to modulate the immune system, and fucoidans with a higher sulfate content can enhance immune responses and exhibit immunomodulatory effects (Ale et al., 2011a; Yang et al., 2008). The degree of sulfation influences the absorption, distribution, metabolism, and excretion of fucoidans in biological systems (Qiu et al., 2006);(Mensah et al., 2023). Sulfate content can vary depending on the seaweed species, harvesting conditions, and extract methods (Ale et al., 2011b; Bilan et al., 2002; Yu et al., 2021). The sulfate content of fucoidans has been reported to have various ranges, as shown in Table 2 of Sect. 3.2.1.

Purity of fucoidan extract

High-purity fucoidans exhibit enhanced biological activities, making it crucial to achieve greater purity and eliminate adulteration in crude fucoidan extracts. To ensure the quality of fucoidans for health-related applications, determining impurity levels of proteins, polyphenols, alginates, ash, and lipids present in the final extract is crucial. Additionally, the polysaccharide content should also be assessed to accurately estimate the purity of the fucoidan, ensuring its effectiveness in functional materials.

Polysaccharides

Brown algae primarily consist of three polysaccharides: fucoidans, alginate, and laminarin, which constitute 50–60% of the dry weight (DW) (Flores-Contreras et al., 2023). Olson et al. (2020) reported that carbohydrate content varies between 237 and 557 g kg⁻¹ DW, making it the largest constituent in most species studied (Olsson et al., 2020). The polysaccharide content and chemical composition differ based on factors such as geographical location, harvest season, water temperature, seaweed species, and even variations within the same species (Deniaud-Bouët et al., 2017; Ehrig and Alban, 2014).

Alginates

Alginate, a major structural component of brown algae, is found in the cell wall and intracellular matrix, constituting approximately 40% of the algae’s dry weight (Flores-Contreras et al., 2023). Its d-mannuronic acid and l-guluronic acid contents can be analyzed using high-performance liquid chromatography (Honda et al., 1989), while the Uronic acid content of fucoidan samples is typically determined by absorbance spectroscopy (Liu et al., 2017; Yu et al., 2021).

Proteins

Brown algae have relatively low protein content, typically ranging from 5 to 15% of DW (Forbord et al., 2020; Schiener et al., 2015). Protein content varies considerably among seaweed types, with green seaweed containing 90–184 g/kg DW, red seaweed containing 103–201 g/kg DW, and brown seaweed containing 59–120 g/kg DW (Olsson et al., 2020). Protein levels are influenced by inorganic and organic nitrogen content, which fluctuate based on growth location and season (Marinho et al., 2016). Since some seaweeds accumulate nitrate, accurate protein determination using nitrogen-to-protein conversion factors is challenging (Young et al., 2007). A universal conversion factor of 5 has been adopted for seaweeds as an average across seasons, species, and localities (Angell et al., 2016).

Ash

The high ash content in seaweed arises from its marine environment and its capacity for mineral uptake, including calcium, magnesium, iron, iodine, copper, manganese, and selenium (Cabrita et al., 2016), and heavy metals, such as arsenic (Hurd et al., 2014). Ash content varies depending on seaweed type, extraction method, and growth conditions (Ale et al., 2011b; Fitton, 2011; Rioux et al., 2007). Ash levels range from 118 and 419 g kg⁻¹ DW and represent a significant constituent in marine seaweed species (Olsson et al., 2020).

Polyphenols

Seaweeds are a rich source of polyphenols such as phlorotannins, bromophenols, flavonoids, and phenolic terpenoids (Cotas et al., 2020). These compounds are located in the seaweed cell wall, and certain brown seaweeds are known to contain up to 30% polyphenols (Stiger-Pouvreau et al., 2014). Fucoidan, a water-soluble polysaccharide typically extracted in aqueous solutions, generally yields low polyphenol levels. Consequently, polyphenols are considered to have minimal impact on the purity of the final fucoidan product (Ichikawa et al., 2006).

Confirmation of heavy metals and iodine contents

When utilizing seaweeds for certain applications, high concentrations of several unwanted metals, such as arsenic, aluminum, copper, chromium, and nickel, should be considered for processing or human consumption (Olsson et al., 2020). The Korean MFDS mandates that each functional material submitted for approval must include arsenic, cadmium, mercury, and lead content data. Some brown seaweed species can absorb and store high levels of iodine from their habitats, with certain species known to accumulate iodine concentrations over 30,000 times higher than those found in seawater (Küpper et al., 1998). Given the potential health risks associated with excessive iodine intake, avoiding individuals with elevated iodine levels is crucial, regardless of their biological activity. During the manufacturing and standardization process before industrial use, the iodine and heavy metals levels, such as inorganic arsenic and cadmium, in the final fucoidan extracts or compounds should be carefully tested to ensure safety.

Other considerations for standardization

To understand the individual molecular structure and composition of fucoidan extracts, analytical techniques such as Fourier transform infrared spectroscopy with attenuated total reflectance are commonly used (Flórez-Fernández et al., 2021). Additionally, the molecular weight distribution of fucoidan molecules can be analyzed using techniques such as GPC to ensure the consistency and quality of the fucoidan. However, if the final fucoidan sample has not been purified, accurately measuring its molecular weight with GPC may be challenging (Zayed et al., 2020).

Microbiological evaluation and stability

Due to their high moisture content, seaweeds are natural substrates for microbial growth, which can pose risks for safe consumption. Monitoring the contamination status of seaweed extracts is essential to ensure their safety for use (Cotas et al., 2024). Seaweed aquaculture farmers should adopt effective post-harvest techniques to minimize the risk of pathogenic microorganisms and preserve seaweed biomass (Healy et al., 2023). Typical post-harvest treatments for seaweed involve cleaning, soaking, blanching, and drying/dehydration. (Zhu et al., 2021). The MFDS, Korea, regulates that in the case of functional ingredients used in health functional foods, coliforms should be negative, and for liquid samples only, the general bacterial count should be < 100 CFU/g according to the Health Functional Foods Act published by the MFDS. Estimating the shelf life of fucoidan extracts by monitoring their biological activity under various conditions such as temperature, light, humidity, and storage period is crucial.

The safety assessment of fucoidan

Although fucoidan is widely recognized for its beneficial effects, some studies have reported potential toxic effects under certain conditions. Research on fucoidans derived from various brown seaweeds has explored their toxicity profiles in in vivo models. For instance, a study using the spontaneously hypertensive rat model found that administering U. pinnatifida fucoidan at a dose of 2,000 mg/kg body weight per day for 28 days did not result in hepatotoxicity or mutagenicity (Chung et al., 2010). Similarly, in vivo testing in a mouse model demonstrated that U. pinnatifida fucoidan at a treatment concentration of 5 mg/mL did not exhibit genotoxic effects (Kim et al., 2010). However, other findings indicate potential risks. For example, in vivo studies in rats demonstrated that administering fucoidan from U. pinnatifida at a dosage of 1,350 mg/kg body weight per day for four weeks caused an increase in serum urea nitrogen levels, suggesting potential renal toxicity (Kim et al., 2010). The toxicity profiles of fucoidans from brown seaweeds are presented in Table 6, highlighting the importance of dosage considerations and further investigation into their safety for different applications.

Table 6.

Toxicity of fucoidan from brown seaweeds

Species	Type	Chemical compositions	Concentration and Exposure Time	Toxic effect	References
U. pinnatifida	Crude fucoidan (hot water extract)	–	250, 500, 1000, 2000 mg/kg/day	No sign of hepatotoxicity, mutagenicity	(Chung et al., 2010)
U. pinnatifida	–	–	1.25, 2.5, 5 mg/mL	No sign of genotoxicity	(Kim et al., 2010)
U. pinnatifida (Sporophyll)	Crude fucoidan, Haewon biotech	Total carbohydrate 61.3 ± 1.82%, fucose 64.4 ± 6.0%, galactose 31.9 ± 4.7%, mannose 3.6 ± 1.3%	1350 mg/kg body weight/day, four weeks	Serum urea nitrogen increase	(Kim et al., 2010)

Clinical study of fucoidan

Although extensive studies and data on fucoidans exist in relation to in vitro and in vivo experiments, relatively few clinical trials have been conducted on fucoidans derived from brown seaweeds. This lack of clinical data poses a significant barrier to the industrialization of fucoidan, as it complicates the verification of its safety and efficacy as a health supplement (Brown et al., 2014). Validating fucoidan’s efficacy through clinical trials is essential for its successful application in various industries, including food, functional health foods, and pharmaceuticals (Hsu and Hwang, 2019; Myers et al., 2016; Zhao et al., 2018). Clinical studies have explored the potential of fucoidans derived from candidate brown algae species, including Fucus vesiculosus, Saccharina japonica, and Sargassum horneri (Table 7). These trials have demonstrated promising benefits, such as reducing joint pain and improving mobility in osteoarthritis patients, enhancing glycemic control in individuals with type 2 diabetes mellitus (T2DM), and stabilizing blood sugar levels to manage dysglycemic conditions (Derosa et al., 2019; Geurts et al., 2024; Myers et al., 2016). Saccharina japonica extracts have shown potential cognitive-enhancing effects, with participants exhibiting significant improvements in memory performance, particularly in recall and recognition tasks (Jung Park et al., 2019). Sargassum horneri extracts have been investigated for managing T2DM, with findings indicating significant reductions in fasting and postprandial blood glucose levels (Geurts et al., 2024).

Table 7.

Clinical study on the fucoidan from brown seaweeds

Species	Age range and number of subjects	Administration dosage	Types of clinical studies	References
Fucus vesiculosus	Ages 25–65 years, mild-to-moderate OA, 122 participants	F. vesiculosus extract (85% fucoidan) at a dose of 300 mg/day for 12 weeks	Osteoarthritis (no difference between the placebo and fucoidan treatment group)	(Myers et al., 2016)
Fucus vesiculosus	Adult patients (> 18 years old) with T2DM, 37 participants	Fucus vesiculosus extract 5 g/day for 5 weeks	T2DM (decrease of average blood glucose level of fucoidan treatment, from 10.1 ± 3.3 to 9.2 ± 0.7 mmol/L)	(Geurts et al., 2024)
Saccharina japonica	Ages 18–65 years, 69 participants (control group (n = 36) and treatment group (n = 33)	Participants were asked to take either 2 capsules, once a day for 4 weeks of lactobacillus fermented Saccharina japonica (FSJ)	Memory enhancing effect (left and right brain activity related to space perception, improved by fucoidan treatment)	(Jung Park et al., 2019)
H. fusiforme	adult patients (> 18 years old) with T2DM, 37 participants	H. fusiforme extract 5 g/d for 5 weeks	T2DM (decrease of postprandial glucose level in fucoidan group, 9.7 to 8.5 mmol/L)	(Geurts et al., 2024)

Overall, these clinical studies highlight the therapeutic potential of fucoidan derived from brown seaweeds, supporting its use in dietary supplements for osteoarthritis, type 2 diabetes, and cognitive enhancement. However, further research is necessary to fully validate its applications and unlock its potential in the dietary supplement industry.

While the above clinical studies suggest promising therapeutic effects of fucoidan in humans, several limitations should be acknowledged to provide a balanced perspective. A significant constraint across current clinical trials is the small sample size (Tsai et al., 2017), which limits statistical power and the generalizability of findings. Additionally, there is a lack of standardization in the preparation and characterization of fucoidan extracts used in different studies (Li et al., 2023; Tsai et al., 2017). Variability in molecular weight, sulfate content, and extraction methods makes it difficult to compare outcomes across trials or establish consistent dosing guidelines (Tsai et al., 2017).

Furthermore, many studies do not employ rigorous clinical trial methodologies, such as double-blinding or placebo control, and often involve short follow-up periods. These factors reduce the strength of the clinical evidence and call for cautious interpretation of the results (Tay et al., 2022).

It is also important to clearly distinguish the effects observed in human trials from those reported in in vitro and in vivo studies. While preclinical data have robustly demonstrated anti-inflammatory, anti-oxidative, and glucose-regulating properties of fucoidan, these mechanistic insights may not directly translate to clinical outcomes without further substantiation (Li et al., 2023; Tsai et al., 2023). Thus, although existing human trials indicate therapeutic potential, larger, well-controlled, and standardized clinical studies are essential to validate the efficacy and safety of fucoidan in diverse populations.

Suggestion

This review outlines the key factors that influence the physicochemical characteristics and biological activities of fucoidans, with a focus on the challenges and strategic considerations for their industrial production. Fucoidan composition varies widely depending on seaweed species, as well as geographical origin, seasonal harvest time, and the extraction and purification methods used. These variables not only impact yield and purity, but also significantly affect functional properties such as antioxidant and immunomodulatory activity etc. To support large-scale application, the review emphasizes the importance of developing cost-effective and scalable extraction and purification protocols that maximize yield while maintaining or enhancing bioactivity. Methods must also address critical safety concerns, especially the removal of arsenic and iodine, which are commonly found in seaweed-derived materials. Furthermore, the standardization of fucoidan is essential for reproducible quality and regulatory approval. Key quality biomarkers including fucose and sulfate content, product purity, and heavy metal levels should be routinely assessed across production batches. Establishing consistent quality control will help ensure that final products are safe, effective, and compliant with relevant health regulations. The review also highlights the need for continued research and innovation to improve fucoidan bioavailability and extraction efficiency. Emerging technologies, such as biotechnological and nanotechnological approaches, hold promise for enhancing the functionality and commercial potential of fucoidan-based products. By integrating these strategies, the industrial utilization of fucoidan can be accelerated, expanding its application in health, nutrition, and pharmaceutical sectors.

Supplementary Information

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Declarations

Conflict of interest

The authors declare that they have no competing interests.