Marine collagen for regenerative medicine: Structure–function advantages, limitations, and translational pathways

Abstract

Marine collagen is emerging as a transformative natural-derived material in regenerative medicine. Unlike traditional mammalian collagen, it has unique structural properties (e.g., a distinct amino acid profile) that confer high biocompatibility and low immunogenicity, along with excellent antibacterial activity and a sustainable supply chain that eliminates zoonotic disease risks. This review establishes the foundational rationale for this shift by conducting a comprehensive analysis of the structure-function relationships underpinning the regenerative superiority of marine collagen. We critically evaluate how advanced manufacturing technologies (e.g., 3D bioprinting, electrospinning) leverage these intrinsic properties to deliver transformative therapeutic outcomes, exemplified by biomechanically optimized cartilage scaffolds and immunomodulatory wound matrices. Our review also delineates actionable pathways for clinical translation, addressing challenges in scalability, regulatory compliance, and long-term stability. This review uniquely integrates structure-function relationships with green industrialization pathways, offering an actionable framework for clinical translation of marine collagen, which repositions marine collagen from a mere alternative to an indispensable platform material, poised to drive the next generation of regenerative therapies.

Graphical abstract

Highlights

• •Marine collagen's unique bioactivity and structure drive regenerative medicine.
• •This review covers marine collagen's unique properties: low immunogenicity, low denaturation temperature, low hydroxyproline content, etc.
• •This review discusses characterization, applications, advanced technologies, and solutions to challenges.

1. Introduction

Collagen is the most abundant extracellular matrix (ECM) protein in the human body, accounting for approximately 25-30% of total protein content. It is widely distributed across various tissues and organs, including the skin, bones, tendons, ligaments, and blood vessels [[1], [2], [3]]. Its unique triple-helix structure provides a solid foundation for its biological functions, enabling it to perform critical physiological roles [4]. Currently, 28 collagen subtypes have been identified, with types I, II, and III being the most abundant and widely distributed, collectively constituting 80-90% of total body collagen [5]. Collagen is also prevalent in the skin, bones, and muscles of animals, and even the simplest multicellular organisms, such as sponges, express at least two types of procollagen genes. Collagen derived from different species exhibits variations in amino acid composition, structural characteristics, and applications. Bovine collagen is primarily extracted from cowhide, bones, and tendons, accounts for approximately one-third of the global collagen [6]. While bovine collagen exhibits favorable biocompatibility, it may trigger immune responses in humans owing to disparities in amino acid sequences between bovine and human collagen [7]. Swine collagen is mainly sourced from swine skin, and since swine foot-and-mouth disease does not affect humans, the product is generally considered safe [8]. However, potential food safety concerns remain. Murine collagen is primarily extracted from rat tails, rendering it a costly option [9]. Compared to collagen derived from commonly used mammals such as bovine and swine, collagen from marine organisms presents several significant advantages. First, the molecular weight of collagen from marine organisms is typically lower than that of mammalian collagen, facilitating more efficient absorption by human tissues and organs such as the skin and bones. Second, marine collagen exhibits lower immunogenicity, rendering it suitable for individuals with allergic reactions to bovine or swine collagen, thus enhancing its safety profile and expanding its application scope. Third, marine organisms carry a lower risk of environmental contamination compared to mammals, particularly collagen derived from deep-water sources, which contains fewer heavy metals, presents lower pathogen risks, and is more suitable for health products and skincare formulations. Fourth, collagen from marine organisms is typically sourced from by-products such as fish scales and skins, making full use of marine fisheries’ secondary products, reducing resource waste, and aligning with environmental protection and sustainability trends. Finally, collagen from marine sources is free from religious or ethnic restrictions, further broadening its application [10].

The source of collagen plays a crucial role in determining its physical and biological properties. Recently, collagen derived from marine organisms has attracted increasing attention [11]. The ocean covers over 70% of the Earth's surface and hosts half of global species diversity. Collagen can be extracted from marine invertebrates (such as sponges [12], jellyfish [13], sea urchins [14], squids [15], cuttlefish [16], sea anemones [17], shrimp [18], and starfish [19]), marine vertebrates (such as fish and marine mammals). Other marine sources, such as algae-derived polysaccharides, are often combined with marine collagen to enhance material properties. Marine organisms like fish and shellfish generate significant amounts of waste during processing, including fish skin, scales, bones, internal organs, and fins, all of which are rich in collagen [20,21]. Extracting collagen from marine waste promotes resource recycling and environmental protection and holds substantial economic and social value due to its unique biological properties and broad potential for application [22,23]. The collagen extracted from these wastes is often processed into scaffolds, hydrogels, fibers and microspheres through 3D printing and electrospinning or other methods, which are commonly used in drug delivery, tissue engineering, wound dressings, some hydrolyzed products of fish collagen are also used in the cosmetics and food industries [24] (Fig. 1). For marine organisms, there are significant variations in the collagen content, the denaturation temperature, hydroxyproline content, and functional motifs across different species and growth environments of fish [25,26]. Deep-water fish inhabit high-pressure, low-temperature, and high-salinity environments, resulting in minimal pollution exposure. Consequently, deep-water fish collagen has a high content of pure collagen with minimal pollutants and exhibits good biocompatibility and bioactivity [27]. Collagen content in shallow-water fish is generally lower than in deep-water fish, which may be related to growth rates, food sources, and environmental factors [28]. Within shallow-water fish, collagen content varies by species, with some freshwater fish, such as the bighead carp [29], silver carp [30], and grass carp [31], having collagen content in their skin that can exceed 80% of the total protein content. Collagen content in marine organisms also varies by species, with sea cucumbers and jellyfish containing exceptionally high levels of collagen, exceeding 70% of their protein content, and possessing unique physiological functions and application potential. The hydroxyl group of hydroxyproline in collagen can form hydrogen bonds with amino acids in other chains, thus enhancing the stability of the collagen triple helix [32]. As a result, the hydroxyproline content can indirectly indicate the denaturation temperature of collagen. Denaturation temperature of marine collagen is generally lower than that of mammalian collagen, and marine organisms tend to have lower hydroxyproline content than mammals. The denaturation temperature of fish collagen (e.g., Tilapia has around 7-8.6% hydroxyproline (Hyp) and a denaturation temperature of 34.4-36.1 °C) is generally slightly lower than that of terrestrial mammals (e.g., calf has around 9.4% Hyp and a denaturation temperature of 38.2 °C) [33,34], which is closely linked to its physiology, evolutionary background, and ecological niche. Mammals maintain a body temperature of approximately 37 °C, whereas fish body temperature aligns with their environment. Among fish, deep-water species have lower Hyp content (e.g., Antarctic Ice-fish has around 4.5% Hyp and a denaturation temperature of just 6 °C) [35], compared to Shallow-water fish species (e.g., Tilapia has around 7-8.6% Hyp and a denaturation temperature of 34.4-36.1 °C) [33], which corresponds to the higher denaturation temperature of Shallow-water fish collagen (Table 1). Furthermore, previous studies have reported that rearing in higher water temperatures can enhance the thermal stability of collagen in ectothermic animals.

Fig. 1.

Schematic drawing of marine collagen sources and potential sources from marine ecosystems, application forms, and scenarios. Fig. 1 shows the diversity of collagen sources by marine animal classes (fishes, invertebrates, etc.) and functions. Created with Biorender.com.

Table 1.

Physical properties and application fields of collagen from different marine sources.

	Species	Application	Source	Hyp Content (%)	Denaturation temperature (°C)	Recommended application scenarios	Ref.
Mammal	Porcine	Drug delivery, Bone tissue engineering	Skin	10	36.3	Heart valves, tendon/ligament repair, absorbable sutures, dental guided tissue regeneration membranes	[36]
	Calf	Drug delivery, Bone tissue engineering	Skin, tendon	9.4	38.2		[34]
Amphibia	Bullfrog	Drug delivery	Skin	5.4	30.3	Cartilage tissue engineering, Skin tissue engineering	[37]
Shallow-water fish	Tilapia	Bone tissue engineering	Skin, scale	7-8.6	34.4-36.1	Skin tissue engineering, Drug delivery, Food industry	[38,39]
	Silver carp	Bone tissue engineering	Skin, scale, internal organ	7.6-8	28		[40]
	Mrigal	Wound dressing	Scale	8	35		[41,42]
Deep-water fish	Jellyfish	Cartilage tissue engineering	Bell, oral arm	2.9	30.8	Health supplements, Wound dressings, Skin care products	[43,44]
	Shark	Bone tissue engineering	Skin	8-9.8	28.3-29.8		[45]
	Salmon	Wound dressing	Skin, scale	7.71	19		[46,47]
	Cod	Healthcare industries	Skin	3.96	18.25		[48]
	Eel	Drug delivery	Skin	9.4	35-38.5		[49]
	Antarctic Ice-fish	-	Skin	4.5	6		[35]

Note: Due to the different denaturation temperatures of different species, their aggregation temperatures under neutral conditions may also be different.

Marine collagen is subjected to processing steps such as cleaning and degreasing to remove impurities. Targeted extraction of collagen can be achieved through enzymatic hydrolysis or membrane separation technology. Finally, according to the final requirements, multifunctional materials can be generated via composite modification technology. Centered on turning waste into wealth and converting low-value marine waste into high-value materials, this model constitutes a green industrial chain integrating resource recovery, high-value transformation, and precise application. As a novel source of collagen, the in-depth development and application of marine collagen in the field of biomedical materials is of great necessity.

Marine collagen is emerging as a transformative natural-derived material in regenerative medicine. Due to evolutionary conservation, the structure and function of marine collagen are relatively similar to those of mammalian collagen, thus holding great promise as an alternative to traditional collagen. (1) Marine collagen exhibits good similarity to mammalian collagen in terms of amino acid composition, quaternary structure, and other aspects. Glycine residues account for approximately one-third of marine-derived collagen, which possesses a complete natural triple-helical structure. It exists in marine animal tissues in the form of collagen fibers, displaying typical structural characteristics of collagen. The structure and properties of certain marine collagens can even be nearly identical to those of mammalian collagen. (2) Structure determines function, and this structural similarity endows marine collagen with functional similarities to mammalian collagen. As a natural component of the extracellular matrix, marine collagen exhibits excellent biocompatibility, biosafety, and biodegradability. (3) Similarity in source distribution: Traditional collagen is mostly derived from the skin and bone tissues of pigs and cattle, while marine collagen is also classified into two major categories: skin collagen and bone collagen. (4) The preparation processes of marine collagen and mammalian collagen are similar, mainly including acid method, alkali method, and enzymatic method. However, compared with traditional mammalian-derived collagen, it exhibits distinct differences: (1) Most marine collagens have a lower amino acid content than traditional collagen, resulting in slightly lower thermal stability and more pronounced thermal shrinkage at human physiological temperature. (2) The structure of marine collagen is relatively loose, with mechanical properties slightly inferior to those of mammalian collagen. (3) Marine collagen exhibits significantly reduced immunogenicity—TNF-α expression is reduced by more than 30% compared with bovine collagen [50]. The main epitopes of mammalian collagen are concentrated in the telopeptide region (a non-triple-helical structure), whereas the telopeptide of marine collagen is shorter, containing only 10-15 residues (compared to 20-30 residues in mammalian collagen). This shortened telopeptide sequence reduces the recognition of epitopes, endowing marine collagen with lower immunogenicity [51]. (4) Sustainable sources, avoiding the risks of zoonoses and religious restrictions. (5) Marine collagen peptides exhibit excellent antibacterial activity. After marine collagen peptides bind to lipopolysaccharides on the bacterial cell membrane, the outer cell membrane is partially disrupted. Meanwhile, their basic side chains can interact with the cytoplasmic membrane to exert a synergistic and enhanced antibacterial effect [52]. But it cannot be denied that mammalian collagen still has undeniable advantages, such as a higher denaturation temperature, more stable physical and chemical properties, superior mechanical performance, a higher level of maturity in industrial production and applications, and more substantial evidence for clinical use.

This review was conducted using PubMed and Web of Science databases, covering references from 2000 to 2025 to ensure comprehensiveness.

2. Synthesis and assembly of collagen

Collagen is a protein with a unique quaternary structure, and its hierarchical structure is pivotal to its biological function and mechanical properties (Supplementary Note 1). Collagen is a protein family encompassing various subtypes, with types I, II, and III being the most extensively studied. Type I collagen is primarily found in the skin, bones, and tendons, accounting for over 90% of the collagen in the human body. It is the main component responsible for the elasticity and strength of the skin. Type II collagen is predominantly present in cartilage and the eye's vitreous body, and it plays a crucial role in maintaining the structure and function of cartilage. Type III collagen is mainly localized in blood vessels, internal organs, muscles, and skin, and it plays a vital role in wound healing and tissue repair. The biosynthesis and assembly of collagen is a complex, multi-stage process involving numerous steps inside and outside the cell (Fig. 2).

Fig. 2.

The assembly process of collagen and the hierarchical structure of collagen. A. In vivo. Reproduced with permission [53]. Copyright 2014, Springer Nature. B. In vitro. (a) Collagen extracted from animal tissues. (b) Collagen extracted from the deposits of cells cultured in vitro or from the culture medium. (c) Recombinant collagen produced using genetically modified microorganisms. (d) Synthetic collagen from peptide synthesizer. Created with Biorender.com.

In vivo, the synthesis of collagen initiates with the transcription of genetic information in the cell nucleus (Fig. 2A): Genes encoding collagen peptide chains are transcribed into mRNA in the nucleus, and upon entering the cytoplasm. The mRNA is translated into three pro-α chains containing amino acid residues on the ribosomes of the endoplasmic reticulum, followed by hydroxylation and glycosylation modifications. Subsequently, the three pro-α chains are linked via disulfide bonds in their terminal peptides and assemble from the C-terminus to the N-terminus to form a triple helical structure with propeptides (i.e., procollagen), which is then secreted extracellularly. The extracellular space constitutes a critical stage for the maturation of collagen fibers: The amino-terminal or carboxy-terminal of procollagen are specifically cleaved by amino- or carboxy-procollagen peptidases, respectively, to form collagen microfibrils. Under neutral pH and 37 °C conditions (may vary for marine collagens due to lower denaturation temperatures), these molecules from human and mammalians spontaneously aggregate into collagen microfibrils due to the intermolecular attraction of regions with different charges. Subsequent formation of cross-linked structures via interchain aldolamine condensation reactions leads to the generation of mature and stable fiber bundles, which significantly enhance the tensile strength and toughness of collagen microfibrils while reducing their solubility [54,55].

In vitro, collagen can be obtained from four different sources (Fig. 2B). (a) It can be extracted from animal tissues. Using dilute acids [56], enzymes [57], or alkalis [58,59], collagen can be extracted and purified from various tissues. (b) It can be extracted from the deposits of cells cultured in vitro or from the culture medium [60]. Collagen is synthesized by specialized cells, and the necessary molecules are produced by the cultured cells, which are collected from the culture medium or the deposited cell layer. (c) Recombinant collagen can be produced using genetically modified microorganisms. For example, yeast [61] and Escherichia coli [62] can produce large amounts through recombinant expression. (d) It can be directly synthesized using peptide synthesizers. The trimeric structure of the Gly-X-Y repeating sequence is synthesized, as its length is less than 10 nm, far shorter than the 300 nm length of type I collagen, and thus is called a collagen mimic sequence or collagen-like peptide [63]. There are still many drawbacks to collagen assembly in vitro compared to the in vivo assembly process (Supplementary Note 2).

3. Modification of collagen

Marine collagen presents several primary application challenges compared with conventional collagen sources, such as poor thermal stability and inadequate mechanical performance. Its low denaturation temperature severely limits its applicability under typical sterilization, storage, and transportation conditions, as the material is highly prone to denaturation, which negatively impacts product integrity. In addition, the fibrous structure of marine collagen is relatively weak and prone to fracture under external forces. This makes it susceptible to losing its original shape and functionality when subjected to significant mechanical loads, failing to meet the mechanical and environmental requirements necessary for in vivo tissues and organs [55]. Specifically, its inherently low tensile strength and Young's modulus are generally insufficient to satisfy the mechanical requirements of load-bearing or high-stress tissue engineering constructs. To address these inherent drawbacks, researchers have explored modification strategies including enhancing intra- and intermolecular crosslinking, constructing composite systems with various materials, and optimizing processing parameters. These efforts have endowed marine collagen with substantial potential in high-performance biomanufacturing. However, marine-derived collagen still requires further enhancement to be suitable for application under mammalian physiological conditions.

To address these challenges, various crosslinking methods have been explored to stabilize collagen (Table 2). Physical modifications are also used to improve mechanical strength, such as ion treatment, UV irradiation, gamma irradiation, and dehydrothermal treatment. These physical methods alter the molecular structure and alignment of collagen, thereby enhancing its mechanical properties. Although physical crosslinking has a lower toxicity and retains the biological active sites, its crosslinking strength is relatively weak and its rate is slow. Another approach is through chemical crosslinking, which involves introducing crosslinking agents such as methacrylation agents, glutaraldehyde, genipin, EDC/NHS, bioorthogonal reagents and Schiff base reactants. These agents facilitate the formation of chemical crosslinks between collagen molecules, significantly enhancing the mechanical strength of collagen hydrogels in a short time, and the crosslinking sites can be controlled. However, it may have potential toxicity, and excessive crosslinking can mask the biological active sites. Additionally, certain enzymes are employed to catalyze the crosslinking of collagen, such as glutaminase transaminase, tyrosinase oxidative, which can interact with glutamine and lysine residues on the collagen scaffold. Enzymatic crosslinking offers high specificity and can be completed within minutes to hours, though reaction times remain relatively long. Enzyme crosslinking has precise reaction sites and good biocompatibility, but there is potential immunogenicity.

Table 2.

Advantages and disadvantages of different crosslinking strategies for collagen.

Methods	Strategies	Advantages	Disadvantages	Impact on biological activity	Ref.
Physical	1.Ion crosslinking 2.Hydrogen bonding 3.UV crosslinking 4.Thermal treatment	1.Low cytotoxicity 2.Low cost	1.Weak crosslinking strength 2.A slow rate of crosslinking process	1.Retain the biologically active sites	[[64], [65], [66]]
Chemical	1.Methacrylation 2.Glutaraldehyde 3.EDC/NHS 4.Genipin 5.Bioorthogonal reaction 6.Schiff base reaction	1.Fast crosslinking speed 2.Controllable crosslinking sites 3.High crosslinking strength	1.Potential cytotoxicity 2.Disruption of the bioactive sites of collagen	1.Excessive crosslinking will mask the cell binding sites	[[67], [68], [69], [70], [71], [72], [73]]
Enzymatic	1.Glutaminase transaminase 2.Tyrosinase oxidative	1.Accurate crosslinking sites 2.Good biocompatibility	1.Potential immune responses 2.Slow reaction rates	1.Excessive crosslinking can lead to pathological fibrosis	[[74], [75], [76], [77]]

4. Fabrication methods and applications

4.1. Fabrication methods of marine collagen

The versatile applications of collagen are closely related to its various fabrication forms (Table 3). In recent years, several methods have been proposed to process collagen into products with different structures and properties, including 3D bioprinting [[78], [79], [80], [81]], electrospinning [82,83] et al. (Fig. 3). These techniques aim to produce collagen-based products that can aid in tissue regeneration for various types of tissues, facilitate drug delivery, serve as wound dressings, and utilize hydrolyzed collagen derivatives in other industries such as cosmetics [84,85], food [86], etc.

Table 3.

Advantages and disadvantages of marine collagen in different processing methods.

		Advantages	Disadvantages	Ref.
Processing method	3D Extrusion-based Printing	1.Simple and easy-to-operate 2.Equipment for precise cell control 3.Reproducibility	1.High requirements for ink 2.Slow printing speed 3.Low printing accuracy	[78,79,87,88]
	Coaxial Printing and Volumetric Printing	1.Reproducibility 2.High printing accuracy	1.Fast printing speed	[89,90]
	Electrospinning	1.Easy to operate 2.Make nanofibers	1.Toxic solvents 2.High electric fields affect cell viability	[82,83,91,92,93]
Application form	Scaffold	1.Provides structural support for cells	1.Insufficient mechanical strength 2.Rapid degradation	[[94], [95], [96], [97]]
	Microsphere	1.Large specific surface area 2.Good cell adhesion	1.Possible residual crosslinking agents 2.Difficult to regulate degradation rate 3.Insufficient mechanical strength	[98]
	Fiber	1.Large specific surface area and porosity 2.Good cell adhesion 3.Promotes cell deposition	1.Insufficient mechanical strength 2.Potential cytotoxicity	[99,100]
	Hydrogel	1.Simulate ECM environment 2.Good for cell adhesion and proliferation	1.Insufficient mechanical strength 2.Rapid degradation rate	[44,101]

Fig. 3.

The means of processing marine collagen. A. Schematic representation of blue shark collagen processing into 3D cell-laden printable inks and its osteogenic potential. Reproduced with permission [87]. Copyright 2022, Elsevier. B. Cell distribution throughout the 3D printed hydrogels, (a) Projected and (b) Cross-sectional views. Fluorescence microscopy image illustrating 3D printed mineralized collagen: alginate scaffold at 21 days of culture for hASCs DAPI (nucleus) image. A color coding was employed to identify a range from 0 to 350 μm of depth to identify the specific position of cells. Blue indicates more superficial cells, while red represents cells that colonized the scaffolds' interior. (c) Immunodetection of osteogenic-related markers, Runx2 and osteopontin. Scale bar: 20 μm. Reproduced with permission [87]. Copyright 2022, Elsevier. C. Schematic diagram of the electrospinning manufacturing process for FC/CS membranes and HAp-FC/CS membranes. Reproduced with permission [91]. Copyright 2022, American Chemical Society. D. Effect of HAp-FC/CS fibrous membrane on periodontal alveolar bone regeneration in vivo. Representative micro-CT images of 3D reconstruction and sectioned periodontal defects in rats of the natural healing (NC) and HAp-FC/CS groups. Reproduced with permission [91]. Copyright 2022, American Chemical Society. E. Representative images of HE staining and Masson trichrome staining of the NC group, FC/CS membrane group, and HAp-FC/CS membrane group. The black dashed box indicates NAB. NAB: newly formed alveolar bone. Scale bar: 600 μm. Reproduced with permission [91]. Copyright 2024, American Chemical Society.

4.1.1. Marine collagen in 3D bioprinting

Marine-derived collagen has been successfully applied in various tissue engineering fields, including skin, bone, and neural tissue engineering. It has been reported that marine collagen exhibits excellent biocompatibility and can support the survival of fibroblasts and keratinocytes, which are key cells of the skin, rendering it a suitable biomaterial for skin tissue engineering. For example, a bioink for extrusion printing of a bilayer skin model was developed using collagen from Basa fish skin. This bioink demonstrated excellent printability and biocompatibility, supporting the survival of fibroblasts and keratinocytes, making it suitable for skin model printing [78]. In addition, marine collagen also has good antimicrobial activity, 3D bioprinted marine collagen is also used to make wound dressings. Chen et al. extracted collagen from carp scales and combined it with plant extracts to prepare a novel biomaterial for 3D bioprinting of wound dressings. Fish collagen promotes the activation of platelets and the coagulation system, acting as a film-forming agent, making it suitable for hemostatic applications. The plant extracts serve as crosslinking agents, enhancing the biocompatibility of collagen and modifying its properties [102]. Many studies have explored the printability of marine collagen from different sources. Collagen extracted from discarded eel skin was first reported to be mixed with alginate to create extrudable 3D bioprinting materials, producing scaffolds that, compared to alginate scaffolds without collagen, showed enhanced metabolic activity and cell proliferation, demonstrating significant potential for tissue engineering applications [103]. A hybrid solution of hydroxyapatite-mineralized blue shark skin collagen and sodium alginate was proposed for cell-loaded 3D bioprinting (Fig. 3A). Bioinks with a higher collagen content showed promising results in short-term 3D culture of mouse fibroblasts. The immune detection for Runx2 and osteopontin 21 days after printing, suggests the potential of the ink for bone purposes (Fig. 3B) [87]. Subsequently, the study also investigated the effect of cell culture density on the viability of human adipose-derived stem cells, showing expression of osteogenic-related markers (Runx2 and osteopontin) after 21 days of culture, indicating its potential as a bioactive bioink for bone tissue regeneration [87]. Therefore, marine collagen exhibits favorable printability after mixed with other materials and have a wide range of applications in tissue engineering and wound dressings. Unmodified collagen is usually unstable in triple helix structure and prone to unfolding at 37 °C, so in addition to physical doping, it is also chemically cross-linked to modify the MA group to improve its stability. The development of ColMA overcomes the shortcomings of traditional collagen as a bioink that is susceptible to change at high temperatures and neutral pH, while retaining the biological activity of collagen and improving mechanical strength. A study has verified the high cytocompatibility of ColMA by UV crosslinking during the 3D bioprinting process, and the high cytocompatibility has been verified by encapsulating L929 cells, and the Young's modulus in the range of 0.1-30 kPa can be customized according to specific application scenarios, which can be applied to soft tissue regeneration (such as nerve regeneration: 0.1-1 kPa) and muscle tissue engineering (∼10 kPa) and bone tissue engineering (∼30 kPa), which has great application potential [104]. In addition to conventional 3D extrusion printing, marine collagen has been used in coaxial printing, as reported in previous studies. For example, collagen was extracted from red snapper skin, and the conditions for neural cell seeding and encapsulation were optimized using unmodified collagen, thermally crosslinked collagen, and UV-induced crosslinked ColMA. The study explored 3D coaxial printing of neural and skeletal muscle cell cultures to create a model for neuromuscular junction formation. This model provides a low-cost, customizable, scalable, and rapid-printing platform for drug screening and the study of neuromuscular junction physiology and pathogenesis [105]. The MA modification retains the activity of collagen and improves the mechanical properties of the material, but at the same time, it has some drawbacks. First, a degree of modification of ColMA that is too high will lead to an unstable collagen structure and easy denaturation. Second, there are batch-to-batch differences and inconsistencies in mechanical properties and biological activity caused by inconsistent modification degrees between different batches, resulting in the inability to be popularized in large quantities. Third, ColMA is not very friendly to some light-sensitive cells, which can cause damage to cells and affect their function during UV light crosslinking.

At present, marine collagen remains in the early research stage in the field of 3D bioprinting, but it demonstrates great application potential due to its unique biological properties. In the future, 3D bioprinting will need to address technical challenges such as the risk of collapse during high-precision structure printing and compatibility with high-precision platforms through methods like crosslinking and support baths.

4.1.2. Marine collagen in electrospinning

Electrospinning is one of the most established techniques for producing nanofiber materials for tissue engineering. The network structure formed by electrospun fibers can effectively promote the integration of new tissue and its recruitment into the fiber scaffold, thereby accelerating tissue growth. The primary function of nanofiber scaffolds is to provide cells with an appropriate 3D environment that supports cell attachment and proliferation. Recently, research has led to improvements in electrospinning equipment. Wang and colleagues developed a series of tools to manufacture cell-scale fiber scaffolds and stack cell-scaffold complexes into 3D structures [106]. These electrospun scaffolds with aligned fiber orientation can guide cell morphology and induce cell function, which is crucial for directing the alignment of cells within tissues/organs that are essential for cell morphology, differentiation, and function in vivo, such as skeletal muscle [105], heart [106], tendon [107], and cartilage [108]. Collagen and its derived peptides can be transformed into nanofiber materials using electrospinning, which possess porous micro- and nano-structures, good mechanical properties, and excellent biocompatibility. However, there are some limitations that cannot be ignored, such as the organic solvents used in electrospinning and the high-voltage electric field may damage the triple helix structure of collagen, resulting in its denaturation. Compared with mammal-derived collagen, marine collagen is structurally more unstable and more susceptible to damage from the external environment, so there is still a long way to go in developing benign solvents that are friendly to marine collagen.

Marine collagen electrospun materials have found widespread applications in tissue engineering, including artificial skin, artificial blood vessels, cartilage repair, drug delivery, wound dressings, periodontal repair, and biofilms. For example, Shue et al. prepared low-immunogenicity fish collagen and bioactive nHA-enhanced PLGA nanofiber membranes using electrospinning, and the viability of BMSCs cultured on PFC5 (the weight proportion of FC to PLGA ratio at 5:100) and PFC5H15 (the weight proportion of FC to nHA to PLGA ratio at 5:15:100) membranes was slightly higher compared to the pure PLGA group, suggesting that the incorporation of FC and nHA promoted cell adhesion and growth. Collagen provides the necessary elasticity to the cell, which enhances cell migration to form ECM and collagen secretion. In addition, the tensile strength (1.5 ± 0.11 MPa) and elastic modulus (31.7 ± 4.4 MPa) of pure PLGA membranes are poor, while the strain rate is as high as 232.6 ± 10.9%. PFC5 and PFC5H15 achieve four and three times the maximum tensile strength of PLGA, suggesting that the addition of FC greatly improves the mechanical strength of the membrane and can be used to guide bone regeneration (Fig. 4C–c-e) [109]. Due to the characteristics of high porosity, small pore size, large surface area and fine microstructure, marine collagen fiber membrane has good bioadhesion and hygroscopicity, which can be used to prepare dressings and grafts to keep wounds moist and prevent bacterial infection. Chandika et al. fabricated a novel bilayer nanofiber scaffold composed of fish collagen and PCL using electrospinning with average pore size is 150 ± 50 μm, and covalently crosslinked with chitosan oligosaccharides via carbodiimide chemistry. The nanofiber scaffold exhibited functional activity for NHDF-neo and HaCaT keratinocytes, leading to the creation of a highly effective tissue-engineering implant for full-thickness wound healing applications. This scaffold shows significant potential as a tissue-engineered skin implant for rapid skin regeneration [92]. Marine collagen peptides demonstrate significant antimicrobial properties. Gomez et al. investigated the antibacterial activity of peptides derived from tuna and squid skin against 18 bacterial strains. The results demonstrated that both types of peptides exhibited substantial inhibitory effects on Lactobacillus acidophilus, Bifidobacterium animalis, and other tested strains [52]. To make up for the lack of low mechanical strength and improve antimicrobial activity of fish collagen, some bioactive ingredients can be added to make fish collagen more suitable for therapeutic use, such as preventing infection of exposed wounds, and can also effectively induce skin regeneration. Zhou et al. developed a biomimetic electrospun tilapia skin collagen/BG (Col/BG) nanofiber (Fig. 5B). It was found that compared with pure fish collagen nanofibers, the tensile strength of Col/BG nanofibers was increased to 21.87 ± 0.21 MPa, which had certain antibacterial activity against Staphylococcus aureus (One of the main bacteria during skin infections). It also promotes adhesion, proliferation, and migration of human keratinocytes. Col/BG nanofibers induce the secretion of type I collagen and VEGF by human dermal fibroblasts, further stimulating the proliferation of human vascular endothelial cells. Animal experiments have shown that Col/BG nanofibers can accelerate the healing of skin wounds in rats. The possibility of use as a functional skin wound dressing is provided [110]. Periodontal restoration materials not only need certain mechanical strength and good biodegradability, but also periodontal restoration materials are needed to prevent ECs and connective tissue from growing into the defect area, so as to create space for the co-migration and proliferation of periodontal ligament cells. Li et al. developed an enhanced biomimetic mineralized HAp-FC/CS nanofiber membrane extracted from grass carp scales, and the enhanced biomimetic mineralized hydroxyapatite coating provides active calcium and phosphate sites to promote stem cell recruitment (Fig. 3C). In the rat model of periodontal defects, the fibrous membrane not only prevents connective tissue from growing into bone lesions, but also promotes collagen matrix regeneration and bone formation (Fig. 3D) [91]. Moreover, it is of great significance to develop materials capable of inducing periodontal tissue regeneration, have certain antimicrobial activity, and can prevent infection and postoperative peri-implantitis. Researchers compounded with bioactive glass (BG) and chitosan (CS) to enhance the antimicrobial properties of the membrane by electrospinning for improved repair of periodontal tissue defects (Fig. 5C). Streptococcus mutans was seeded with nanofibers, and it was found that the Streptococcus mutans cultured on Col/BG/CS membranes were significantly more dispersed than those in the control group. In the dog class II bifurcation defect model, the Col/BG/CS membrane group (new bone formation: 69.31%) formed more bone and denser connective tissue and fewer inflammatory cells than the control group (new bone formation: 44.63%). In addition, HE staining also revealed the presence of bone matrix proteins in the newly formed bone. The results showed that compared with the control group, the Col/BG/CS membrane group could prevent the growth of gingival connective tissue without causing a significant inflammatory response, and also increased bone formation and mineralization, providing great potential for clinical application [111]. The collagen fiber membrane prepared by electrospinning has good biological activity for SMC and EC, which is very suitable for the production of vascular grafts. A novel tubular scaffold composed of jellyfish collagen and PLGA fibers, with an average pore size of approximately 150 μm, was fabricated using freeze-drying and electrospinning techniques for use in vascular grafts. The addition of PLGA enhanced the mechanical strength of the scaffold, and under pulsatile perfusion, SMC and EC were seeded onto the vascular scaffold. Co-culture induced cellular alignment, vascular EC development, and retention of differentiated cell phenotypes [83]. Therefore, marine collagen has certain application in tissues as good biocompatibility.

Fig. 4.

Application forms of marine collagen. A. Scaffold. (a) Physical image of scaffolds. (b) SEM images of 3D jellyfish collagen scaffolds. (c) SEM (d) Immunofluorescence staining image of cartilage-stimulated hMSCs cultured on jellyfish collagen scaffolds for 21 days. The cytoskeleton of the cells was stained using phalloidin (green) and nuclei with DAPI (blue). Cells of spherical shape (indicated by arrows) were discovered which resemble the chondrogenic phenotype. Reproduced with permission [112]. Copyright 2014, Elsevier. B. Microsphere. (a) Physical image and (b) SEM image of lyophilized fish collagen-MA microspheres. (c) HE staining and (d) Masson's trichrome staining of fish collagen-MA microspheres at 6 weeks after implantation in a rat model of osteomyelitis. Reproduced with permission [98]. Copyright 2023, Frontiers. C. Nanofiber. (a) SEM images of 2% EPS and cross-linked cotton collagen nanofiber spinning. (b) Partially zoomed in on the image, the fibers can be seen. Reproduced with permission [93]. Copyright 2024, Elsevier. Fluorescence staining of BMSCs on (c) PLGA, (d) PFC5 and (e) PFC5H15 membranes after incubating 4 days. The cytoskeleton of the cells was stained using F-actin (red), nuclei with DAPI (blue) and mitochondria (green). Reproduced with permission [109]. Copyright 2019, American Chemical Society. D. Hydrogel. jCOL/CHT/FUC in (a) Physical image and (b) SEM image. Reproduced with permission [44]. Copyright 2022, Elsevier. (c) Physical image of NCs grown within MCh for 14 days, stained with Alcian blue. Reproduced with permission [113]. Copyright 2020, MDPI. (d) Chondrocytes were recovered after hydrogel digestion and seeded on plates under 2D conditions. Reproduced with permission [113]. Copyright 2020, MDPI.

Fig. 5.

Evaluation of the efficacy of marine collagen. A. Nasolabial wrinkle analysis at baseline and 12 weeks in participants supplemented with VWC or placebo. Reproduced with permission [85]. Copyright 2020, Wiley-JCD. B. Multifunctional biomimetic Col/BG nanofibers induce skin regeneration. (a) Immunostaining (CD31) of wound sections treated with the Col/BG nanofibers at days 4 and 7 promoted the formation of early angiogenesis. (early angiogenesis were indicated by arrows) (b) Representative images of skin wounds after treatment 0 day and 14 days with Col/BG nanofibers. Untreated wounds are used as controls. Reproduced with permission [110]. Copyright 2017, Taylor & Francis. C. The antimicrobial activity of Col/BG/CS. (a) SEM image and (b) physical image of Streptococcus mutans inoculated on Col/BG/CS membranes for 1 day. (c) HE staining of dog class II furcation defects at 60 days postoperatively. The control group was not covered with a membrane. NB: newbone. The Col/BG/CS membrane covering group. Reproduced with permission [114]. Copyright 2017, IOP Publishing. D. CRECs cultured for 48 h on the FC/PCL nanofibrous scaffolds induced the upregulated expression of major thymopoietic molecules (IL-7, GM-CSF, and ICAM-1). (a) RT-PCR analysis for the measurement of mRNA levels of IL-7, GM-CSF, and ICAM-1 expressed in CRECs grown on the PCL and FC/PCL (0.4:9.6 and 1:9) nanofibrous scaffolds. (b) Confocal microscopy for staining of ICAM-1 (green) and DAPI (blue) in the FC/PCL 0.4:9.6 nanofibrous scaffolds. Scale bar: 30 μm. Reproduced with permission [115]. Copyright 2015, Elsevier. E. Lymphangiography to check for lymphatic reconnection. (a) Schematic diagram of the placement of 5% BDE-Methyl-Col on the dissected lymphatic vessels. (b) Immunofluorescent staining of BVs (CD31), LVs (CD31 and LYVE-1), and SMA on a 5% BDE-Methyl-Col patch. (c) Fluorescence images show lectin-FITC flow through newly formed and reconnected LVs in the 5% BDE-Methyl-Col patch, with LV resection alone (sham control) resulting in blockage of lectin-FITC flow. White arrows represent the flow direction of Lectin-FITC, green arrow pointing to the newly formed and reconnected LVs, yellow dashed box outlines the area occupied by the implanted 5 wt% BDE-crosslinked methylated collagen patch. Reproduced with permission [116]. Copyright 2017, Elsevier.

In conclusion, the nanofibers prepared by marine collagen under electrospinning technology have a 3D porous structure and certain mechanical strength, which can mimic the microstructure of ECM, and have many applications in tissue engineering, wound dressings, artificial blood vessels and other fields. However, there are still problems of low spinning efficiency and poor reproducibility, so a lot of efforts are still needed in the design of spinnerets, the optimization of collection devices and the delivery of solutions, so that marine collagen nanofibers can play a more important role in biomedicine [[117], [118], [119]]. For marine collagen, there is still the problem of poor processability in electrospinning, which may be related to the viscosity and surface tension of the solution. In this scenario, developing benign, eco-friendly solvents for reproducible micro/nanofiber fabrication represents a solution, in the meanwhile, modulating collagen characteristics to fully adapt to the electrospinning procedure might ensure the bioactivity of collagen before and after processing.

4.2. Applications of marine collagen

The translational potential of marine collagen in regenerative medicine is intrinsically linked to clinical urgency gradients across tissue types. Acute skin wounds demand immediate barrier restoration to prevent infection and fluid loss, positioning dermal repair as the most time-sensitive application. Subsequently, bone defects requiring structural and functional reconstruction follow in urgency due to their impact on mobility. Finally, cartilage and nerve regeneration, characterized by intricate structural hierarchies and slow innate healing, represent the highest complexity tier. Therefore, we structure applications by escalating clinical demands from urgent barrier repair to functionally integrated reconstruction, highlighting how marine collagen's tunable properties address each tier. The versatility in its preparation allows marine collagen to be processed into different forms using various techniques, catering to the needs of different applications. These forms include hydrogels, microspheres, freeze-dried scaffolds, and fibers, among others. These forms can be utilized in a wide range of fields, including dietary supplements, cosmetics [117,118], and medical products [119]. The availability of these different forms allows marine collagen to be more widely integrated into daily life, providing support for health and beauty.

4.2.1. Marine collagen hydrogel

In recent years, hydrogels have gained significant attention due to their ability to encapsulate and deliver drugs, growth factors, or other bioactive compounds and high-water content (Fig. 4D–a-b), making them highly relevant in fields such as drug delivery [[120], [121], [122], [123]], biosensors [124,125], tissue engineering [122], soft robotics [[126], [127], [128]], and cosmetics [129]. Jellyfish-derived collagen hydrogels possess elasticity similar to human cartilage, which is vital for withstanding repeated compressive forces, making them ideal for cartilage tissue engineering. Carvalho et al. formulated hydrogels using varying concentrations and ratios of jellyfish collagen, blue shark skin collagen, squid-derived chitosan, and fucoidan. Rheological analysis showed the hydrogels to have good structural stability and high mechanical properties, with only an 18% weight loss observed in degradation tests over 30 days [44]. Research has demonstrated that jellyfish collagen hydrogels not only support chondrocyte proliferation but also maintain their phenotype, promoting the synthesis of ECM components necessary for cartilage repair [130]. Researchers produced an injectable marine collagen-based hydrogel by blending the natural collagen of jellyfish nodules with marine gelatin functionalized with hydroxyphenylpropionic acid (HPA). NCs grown in MCh were able to deposit GAG-rich matrices, and Alixin blue staining of MCh also showed GAG production by chondrocytes within MCh (Fig. 4D–c-d). Thus, GAGs accumulate in hydrogels, reflecting the feasibility of using MCh to maintain viable chondrocytes [113]. Therefore, jellyfish collagen is very suitable for the treatment of articular cartilage. In addition, it has also been found that collagen from Bester sturgeon can quickly form macrofibril bundles and good mechanical properties under certain conditions. This property makes it have great potential for application in tissues that require high mechanical properties, such as bone tissue engineering. Researchers extracted type I collagen from sturgeon swim bladder and prepared a double-network hydrogel with PDMAAm. Since fish maw collagen has an extremely fast fibrogenesis capacity, anisotropic hydrogels can be obtained by a simple injection method. The loosely cross-linked PDMAAm network improves the toughness of the collagen network without disrupting anisotropy. In vivo experiments showed that the gel had good biomechanical properties (Young's modulus 0.15 ± 0.04 MPa) and excellent osseobinding ability, and there was no obvious degradation (Young's modulus 0.10 ± 0.03 MPa) after 4 weeks of implantation of rabbit knee cartilage. This tough anisotropic double-network hydrogel based on sturgeon collagen has the potential to be the next generation of artificial weight-bearing implants [131]. Therefore, marine collagen can provide sufficient mechanical strength and suitable structure and microenvironment, and has a wide range of application potential in bone and cartilage tissue engineering.

The development of advanced and effective wound dressings is a key area of modern regenerative medicine research, especially for some wounds that are difficult to heal, such as extensive burns, diabetic foot ulcers, etc. These dressings not only need to cover and protect the wound, but also have a controlled and sustained release effect, which in turn improves the therapeutic effect and reduces side effects. Because these wounds are not just simple wounds, they also have vascular damage that reduces the supply of oxygen and nutrients, and diabetic wounds are in a high-sugar environment, which can easily breed bacteria, increase the risk of infection, lead to tissue damage and trigger further inflammation. Therefore, in this type of wound dressing, special attention should be paid to antibacterial and anti-inflammatory. Marine collagen has been shown to have an antimicrobial effect that inhibits the growth of a wide range of bacteria, making it ideal for these hard-to-recover wounds [132]. As a result, there is a focus on finding better treatments. Due to its water retention and breathability, marine collagen hydrogel materials have been extensively studied in the field of wound dressings. Li et al. prepared an injectable hydrogel for wound healing using collagen peptides derived from cod skin, which can rapidly achieve hemostasis, accelerate cell migration, and promote effective wound healing. In addition, it is highly biocompatible and biodegradable, showing great potential as a wound dressing [133]. Marine collagen products can also be used as wound dressings and drug carriers at the same time. Anguchamy et al. isolated type I collagen from eels at a denaturation temperature of 38.5 °C, which is close to the denaturation temperature of mammalian collagen. The extracted collagen was tested on human pathogenic microorganisms as a drug carrier, which was confirmed by the inhibitory zone of drug production, and standard commercially available drugs such as ampicillin and tetracycline were successfully delivered through collagen gels, with the potential capacity for drug delivery [49]. It has also been reported in the literature that oral marine collagen products can significantly improve the healing of diabetes-related wounds. Zhu et al. investigated the role of marine salmon skin oligopeptides in regulating high-fat diet and low-dose streptozotocin-induced hyperglycemia and β cell apoptosis in rats with T2DM and its therapeutic mechanism [134]. The results showed that salmon oligopeptide treatment significantly reduced the apoptosis of FBG and T2DM-associated islet cells in diabetic rats, and in addition, oligopeptide treatment significantly inhibited inflammation by reducing serum pro-inflammatory TNFα and IFNγ levels and downregulating the expression of Fas. This trial provides a basis for further design of new therapies for T2DM. Next, they explored the effect of marine collagen peptides on metabolic nuclear receptor markers in patients with T2DM who did not have hypertension. It was found that patients treated with marine collagen peptides showed significant improvements, with significant reductions in levels of free fatty acids, hs-CRP, resistin, prostacyclin, and significantly higher levels of adiponectin and bradykinin. This may be due to the underlying mechanism in the regulation of metabolic nuclear receptors by marine collagen peptides, which is very helpful for the further development of new drugs for marine bioactive peptides [135]. In conclusion, marine collagen can reduce inflammatory responses, wound contraction and collagen deposition, and promote angiogenesis, which playing an important role in hard-to-heal wound models.

4.2.2. Marine collagen microsphere

Microspheres, as a physical form of marine collagen, have been extensively studied in the context of carrying and controlled-release drug delivery systems, due to their biodegradability. Collagen microspheres have a large specific surface area, which is conducive to cell adhesion and proliferation. The preparation of microspheres involves precise control and manipulation at the micro- and nanoscale using microfluidic technology, allowing for the production of monodisperse, uniform hydrogel microspheres. These microspheres can be chemically cross-linked to facilitate sustained drug release. Hu et al. chemically modified fish collagen and utilized microfluidic technology to fabricate vancomycin-loaded hydrogel microspheres for the treatment of osteomyelitis (Fig. 4B). The microspheres gradually release the antibacterial vancomycin at the site of infection, and the degraded fish collagen also synergistically promotes bone repair. Bacterial coating plate assays demonstrated that the composite hydrogel microspheres exhibited excellent antibacterial effects, with an antibacterial rate of 99.8%. Immunofluorescence staining and X-ray results indicated that the microspheres were highly effective in promoting bone repair, providing clinical significance for the subsequent treatment of osteomyelitis [98]. However, there is not much research on the use of marine collagen in the form of microspheres, which may be due to the fact that the production of microspheres requires specific technologies and processes, and has high requirements for equipment and operating conditions. But with the advancement of technology and the increase in market demand, there may be more research and application development in the future.

4.2.3. Marine collagen scaffold

Collagen scaffold is transplantable (Fig. 4A). Pure collagen scaffolds have poor mechanical properties and degrade quickly, so they are often chemically cross-linked and combined with various bioactive molecules to enhance their functionality. An ideal tissue engineering scaffold needs to provide an appropriate environment for cell growth to enable the regeneration of damaged tissues. The combination of different materials can improve the mechanical properties, providing a better environment, but the type of crosslinking method and agents used can affect the porosity of scaffold, mechanical properties, and bioactivity. Li et al. extracted type I collagen from bass skin and prepared it into scaffold forms using lyophilization. They investigated the effects of different crosslinking methods on scaffold porosity and mechanical performance. In a rabbit dura mater defect model, the scaffold reduced inflammation, promoted fibroblast growth, and enhanced tissue regeneration and healing, showing potential as a dura mater substitute in tissue engineering applications [136]. The source species of collagen also influences the outcomes in tissue engineering. Collagen extracted from blue shark skin was combined with HAp derived from blue shark teeth to create 3D composite scaffolds via freeze-drying. Compared to bovine collagen enhanced with synthetic hydroxyapatite, the blue shark collagen scaffolds exhibited higher porosity, better mechanical properties, and slower degradation rates. Bone tissue regeneration was evaluated in a femoral condyle defect in New Zealand rabbits. Histological analysis showed that the blue shark collagen scaffolds resulted in significantly higher tissue formation (17.9 ± 6.9%) compared to bovine collagen scaffolds (12.9 ± 7.6%) [97]. This suggests that marine-derived collagen may have greater potential in bone tissue engineering. Other studies have shown that even collagen from the same marine species can yield different results in bone tissue engineering. The collagen in sponge has species-specific and batch-to-batch variations, which directly affect the physical and chemical properties as well as the biological functions of the material. Therefore, in the application of biological materials, strict species selection, batch tracking, and quality control must be carried out to ensure the safety and effectiveness of the products. Two different sponge-derived collagens were extracted and compared, revealing different degradation properties and distinct osteogenic potential in a rat bone defect model [137]. The proportion of components also affects stent performance. The interest in developing various component multi-component chitosan/fish collagen/glycerol 3D porous scaffolds is to achieve a perfect composition that mimics the native ECM to promote cell infiltration, adhesion, proliferation, and support the development of new tissues. The average pore size of the stent was in the range of 100.73 ± 27.62 - 116.01 ± 52.06 μm, the porosity was 71.72 ± 3.46 - 91.17 ± 2.42%, the tensile modulus was 0.32 ± 0.03 - 0.14 ± 0.04 MPa in a humid environment, and the biodegradation rate (at day 30) was 60.38 ± 0.70 - 83.48 ± 0.28%. In vitro cultures of human fibroblasts and keratinocytes have shown that the multi-component 3D scaffolds of various compositions have good cytocompatibility, however, the scaffolds contain a large amount of fish collagen, which promotes cell proliferation and adhesion well. The various ingredient chitosan/fish collagen/glycerol 3D porous scaffolds developed in this study can be effectively used for skin tissue engineering and regeneration [138]. Collagen scaffolds are also used in tissue engineering for drug delivery of bioactive factors. Photo-biomodulation, through the interaction of light with tissues, induces a series of metabolic changes in cells, regulates the inflammatory process post-injury, stimulates the secretion of angiogenesis factors, and accelerates soft and hard tissue healing. Researchers developed sponge collagen scaffolds to promote bone healing in a cranial defect model, and observed that the treated animals showed a significant increase in connective tissue and newly formed bone in the defect area at 45 days post-surgery [139]. It can be seen that the crosslinking method and the source of collagen have an important impact on the mechanical properties and degradability of collagen scaffolds. Through reasonable crosslinking, the marine collagen scaffold prepared by optimizing the ratio of collagen to other materials has important application value in bone tissue engineering.

Collagen scaffolds are also promising alternatives in skin grafts for wound healing. Due to the lack of dermal tissue, stent grafts are more suitable for full-thickness injury notches larger than 1 cm in diameter [140]. The 3D collagen scaffold provides a platform for cell migration, adhesion, and differentiation and prevents the contraction of the wound bed during the initial stages of wound healing [141]. The 3D scaffold covers the wound, retains moisture, and absorbs wound bed exudate [142]. In addition, open porous and interconnected networks promote cell migration and proliferation, accelerating nutrient and waste exchange, thereby enhancing angiogenesis and the formation of new tissues [143]. Collagen is the main component of the dermal ECM and plays a vital role in the wound healing process, which has led to extensive research on collagen in dermal substitute materials [144]. For example, researchers developed a bi-layered skin-like scaffold based on collagen derived from the marine invertebrate sea urchin for skin injury treatment. The upper layer, a thin and dense 2D collagen membrane, reduces water evaporation and protein diffusion, serving as a barrier to bacterial infiltration, thus functionally mimicking the epidermal layer. The thick, sponge-like 3D collagen scaffold effectively supports fibroblast infiltration; it maintains mechanical stability under physiological conditions while structurally and functionally mimicking the dermal layer [96]. Pallabi et al. extracted type I collagen from mrigal fish, prepared highly porous collagen scaffolds by freeze-drying, developed an in vitro skin model by co-culturing fibroblasts and keratinocytes to reconstitute the epidermal layer of the skin, and the 18-day degradation time provided sufficient time for it to function, thus becoming a promising dermal alternative [41]. In addition to the common scaffold forms that can be implanted with cells, collagen scaffolds are also used for subcutaneous implantation as patches made of cold pressing. Wang et al. lyophilized type I collagen derived from Snakehead scales and cold-pressed it with a heat press for 10 min to make collagen patches (Fig. 5E). After implantation in the hind limbs of rat, no adverse immune response was observed. Efficient wound care requires processes that involve acute inflammation and the anagen phase, including angiogenesis, tissue migration, and remodeling. Therefore, they evaluate the growth of blood vessels and lymphatic vessels after implantation. After 21 days of implantation, cross-sections of collagen-implanted skin were imaged using CD31 (BVs) and LYVE-1 (LVs), and the presence of collagen patches significantly promoted the growth of BV and LV. The efficacy of the collagen patch in promoting hind limb lymphatic vessel regeneration and religation was further explored, and co-staining of LYVE-1, CD31, SMA showed the presence of initial lymphatic vessels (without SMA staining) and collecting lymphatic vessels (positive SMA staining) on 5 wt% BDE cross-linked collagen patches. Overall, the presence of collagen patches promotes spontaneous lymphatic rejunction and the restoration of lymphatic blood flow, and collagen patches may be used to treat inflammation-related diseases [116]. Therefore, the ideal material for wound care should have features that allow cell attachment, tissue regeneration, and angiogenesis without causing long-term foreign body reactions. Collagen scaffolds, due to their transplantability and antibacterial properties, have been extensively studied in bone tissue fillers and skin substitutes.

5. Clinical trials and products of marine collagen in regenerative medicine

Currently, there is active progress in advancing the clinical applications of marine collagen products. Several universities and companies have recently conducted clinical trials on collagen products (Table S1). In 2017, China promulgated the updated Catalogue of Medical Device Classification, which basically classifies all collagen-based products into Class III medical devices for regulatory purposes. In accordance with the requirements of GB/T 16886.1 or ISO 10993 standards, biocompatibility evaluations including intradermal irritation, sensitization, local implantation, subchronic toxicity, and genotoxicity are conducted for these products. To date, numerous studies have verified that marine collagen exhibits excellent long-term biocompatibility. Additionally, ISO/TS 10993-20:2006, an international standard, provides guidelines for immunotoxicity assessment covering five key aspects: validation, immunosuppression, immunostimulation, hypersensitivity, and autoimmunity. Multiple studies have demonstrated that marine collagen possesses low immunogenicity. However, future research should focus on enhancing the understanding of immune responses in specific patient populations (e.g., seafood-allergic individuals). Furthermore, batch-to-batch variability may lead to inconsistent immune responses and thus heterogeneous clinical outcomes. Therefore, although marine collagen generally demonstrates superior long-term in vivo safety compared to mammalian collagen, with its low immunogenicity and favorable biocompatibility laying a solid foundation for long-term implantation, batch-to-batch variability and immune responses in specific patient populations remain critical challenges for clinical translation.

Marine collagen has become increasingly mature in the fields of cosmetics, food, health food, etc. (Table S2), but the development and application of its medical products in the field is still in its infancy in the world, and has not yet formed a market scale (Table 4). Shandong Haida Beierxin Biotechnology Co., Ltd. developd the wound dressing product “Beierxin hemostatic healing sponge” approved by the CFDA as a class III medical device-using fish bladder collagen and chitin composites. it is suitable for surgery, obstetrics and gynecology, plastic surgery, stomatology and other surgeries. EUCARE company mainly develops fish collagen series products, and its products have clinical indications including wound care, hemostasis, burn healing and oral materials, etc. The KolSpon®Plug product developed by EUCARE based on type I fish collagen is used for socket filling, which can effectively prevent gingival absorption, promote wound healing, and reduce infection. In addition, the products used for periodontal restoration include KolSpon®Cubes, Periocol-GTR®. EUCARE uses type I collagen as a drug carrier to develop Periocol-TC® product with tetracycline hydrochloride, with a drug load of 2 mg, for the treatment of inflammation or infection of periodontium, reduce gingival recession, and promote periodontal tissue repair. In addition, Periocol-CG® is a drug-loaded film prepared by combining type I collagen with 2.5 mg chlorhexidine gluconate, which can also be used for the treatment of periodontal tissue inflammation or infection. BioFil®/Helisorb® Particles product is a granular wound dressing containing type I collagen developed by EUCARE Company for chronic wounds and diabetic foot ulcers. In 2013, the U.S. FDA approved the world's first acellular matrix fish collagen-like medical product, Kerecis™ Omega3, which is mainly used for wound dressings, hernia patches, etc. In addition, Body Organ Biomedical Corporation uses the decellularized fish scale biological cornea BioCornea® developed by using sea bream scales, which is structurally similar to the human cornea, with a regular layered structure and transparency, and has been approved by the German Federal Institute for Medicines and Medical Devices under the German Federal Ministry of Health in 2015 for human experiments. The product has completed the initial clinical trials and is currently in the stage of international multi-center validation. It is expected to obtain the marketing approval in Europe and the United States within the next 2-3 years and will officially enter clinical application.

Table 4.

Already available products with marine collagen and derivatives.

Brand	Products	Ingredients	Applications	Listed countries
Kerecis	Kerecis™ Omega3	Fish skin decellularized matrix	Wound dressing, Dura mater patch, Hernia patch	America
Shandong Haida Beierxin Biotechnology Co., Ltd.	Beierxin Absorbable Hemostatic Sponge	Chitin + Fish Scales Derived Collagen	Wound dressing	China
EUCARE	Periocol®-GTR	Fish collagen	Periodontal soft tissue regeneration surgery, to repair gum atrophy	India, European Union
	KolSpon® Plug	Fish collagen	Socket filling and promote periodontal tissue repair	India, European Union
	KolSpon® Cubes	Fish collagen	Induce periodontal tissue, tooth tissue regeneration	India, European Union
	Periocol®-TC	Fish collagen + Tetracycline	Slow-release antibiotics for treating periodontal infections	India
	KolSpon® Tape	Fish collagen	Promote wound healing	India, European Union
	Kollagen®-D/Helisorb® Sheet	Fish collagen + nylon mesh	Various burns and wounds	India, European Union
	BioFil®/Helisorb® Particles	Fish collagen	Acute and chronic ulcers, diabetic foot ulcer	India, European Union
	DonorDres®	Fish collagen + polyurethane	Coverage care of the donor site during autologous transplantation surgery	India
	Helisorb® Sponge Powder	Fish collagen	Hemostasis	European Union

6. Challenges and future perspectives

Despite the significant progress made in the application of marine collagen, there are still some technical and market challenges to address. Firstly, the stiffness of marine collagen is relatively low, which may not meet the requirements of high-strength tissues, such as bone tissue. Therefore, there is an urgent need to develop more stable marine collagen materials with high mechanical performance or to enhance their mechanical properties and structural stability by combining them with other materials. Secondly, marine collagen has a fast degradation rate. While this characteristic can promote tissue regeneration in specific applications, an overly rapid degradation may lead to premature material failure, preventing it from providing sufficient support and repair. Therefore, controlling the degradation rate is a significant challenge limiting marine collagen application. Thirdly, in regenerative medicine, the quality and performance of materials must be highly consistent to ensure the efficacy and safety of clinical treatments. Thus, establishing stringent production standards is crucial for the clinical application of collagen. Fourthly, although marine collagen has shown good biocompatibility in in vitro experiments, its long-term safety and toxicity still lack sufficient clinical data. Different patient populations may respond differently to marine collagen, particularly in cases of prolonged intake or use, where immune reactions or other adverse effects may occur. To ensure its clinical safety, extensive clinical trials are necessary. Personalized treatment plans may involve selecting suitable marine collagen types, regulating its degradation rate, and functionalizing its surface, which will increase the complexity of material development and production. Fifthly, as the application of marine collagen as a biomaterial is relatively new, there may be differences in regulatory requirements and approval procedures in different countries and regions. In some countries, marine collagen-based medical products may be classified as “biologics” or “medical devices”, requiring rigorous regulatory review and approval. The lack of equipment standardization has led to a difference between batches, and a joint ISO/ICH standard needs to be established. With the ongoing development of regenerative medicine technologies, related regulations may be adjusted and improved, but currently, the registration and clinical application of marine collagen products still face certain challenges.

The global collagen standard system presents a structure “based on international standards, framed by national regulations, and supplemented by industry standards”. The application of marine collagen in biomedical materials and medical devices is still in its infancy, with no established industry standards to date (Table 5). Currently, there is no unified national quality standard for medical marine collagen in China. The national industry standard YY/T 1453-2016 “Tissue engineering medical device products - Methods for determination of type I collagen” specifies quality control indicators and recommended testing methods for land animal-derived medical collagen, while the industry standard YY 0954-2015 “Nonactive surgical implants - Type I collagen implants - Specific requirements” elaborates on various quality control requirements for implantable collagen. Internationally, collagen-related standards are also limited. Among them, ASTM F2212 developed by ASTM International (American Society for Testing and Materials) is a commonly referenced standard for medical collagen, and Germany's DIN 58924 provides a standardized testing method for collagen-based adhesive hemostatic agents. However, there is a lack of universal standards governing general requirements for medical collagen products. Countries such as France, Japan, and Romania have also formulated collagen-related industry standards or specifications, but these primarily focus on fields such as food and pharmaceutical gelatin. For the in-depth development of marine collagen products and their application as alternatives to land animal-derived collagen in the medical field, the establishment of universal industry standards is an imperative challenge. This requires the joint efforts of regulatory authorities, the scientific research community, industry, and the medical profession.

Table 5.

Relevant international standards for collagen.

Standard number	Standard name	Notes
ISO 13485:2016	Medical devices - Quality management systems - Requirements for regulatory purposes	The International Organization for Standardization
ISO 14971:2019	Medical devices - Application of risk management to medical devices	The International Organization for Standardization
ISO 10993-1:2025	Biological evaluation of medical devices	The International Organization for Standardization
YY/T 0954-2015	Nonactive surgical implants - Type I collagen implants - Specific requirements	Pharmaceutical and Medical Device Industry Standard of the People's Republic of China (PRC)
YY/T 1453-2016	Tissue engineering medical device products - Methods for determination of type I collagen	Pharmaceutical and Medical Device Industry Standard of the People's Republic of China (PRC)
ASTM F2212-2009	Standard Guide for Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates for Tissue Engineered Medical Products (TEMPs)	American Society for Testing and Materials
ASTM F2212-2011	Standard Guide for Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates for Tissue Engineered Medical Products (TEMPs)	American Society for Testing and Materials
DIN 58924-2009	Haemostaseology - Reference method for the determination of the collagen binding activity of the VWF	German Institute for Standardization
NF V59-201-1988	Collagen. Determination of hydroxyproline content	French Association for Standardization
NF V59-202-1988	Collagen. Determination of nitrogen content	French Association for Standardization

The research on marine biomedical materials in China has a history of nearly 30 years, but its industrialization process lags significantly behind the basic research, and the analysis of the reasons mainly includes the following problems. First, the control of raw materials. As the first threshold of biomedical devices, the safety and stability of raw materials are directly related to and even determine the quality of the final product, which is a basic and key issue in the process of industrialization and engineering. Second, the formulation of standards is not only difficult to keep up with the needs of product improvement in terms of time, but also difficult to effectively cover all product categories in terms of quantity and scope. Third, the supporting issues of engineering and large-scale production. Most of the enterprises have backward supporting facilities, outdated facilities low efficiency, and low-quality system perfection, which not only affects the industrialization process but also seriously restricts the level of large-scale production. Fourth, the supporting technical issues of engineering. At present, most foreign biomedical material manufacturers have poor technology update capabilities, and they are in a state of in-situ, which makes it difficult to meet the engineering requirements. Marine biomedical materials are the Chinese sunrise industry, has initially realized the “scientific research units-production enterprises-clinical application” combined with each other and formed a strategic alliance, during the formation of some independent products and technologies with international advanced technology level, and a large number of follow-up work has been carried out in an orderly manner, forming a prototype of sustainable development. In the future, the design of collagen sequences will need to be driven by AI [145,146]. AI-designed collagen sequences enable flexible adjustment of G-X-Y repeat numbers and amino acid compositions, as well as precise control over hydrophilic-hydrophobic properties, charge distribution, and other key parameters. This facilitates the creation of collagen molecules that do not exist in nature but exhibit superior functionalities, breaking through natural evolutionary constraints to achieve “on-demand customization”. This technology has brought unprecedented innovation freedom to the collagen field, holding great promise for addressing the fundamental issues of limited sources and single functionality associated with traditional collagen. It is poised to inject new momentum into the healthcare and cosmeceutical industries. AI has great potential in the field of collagen design, but bridging the gap from “computational to clinical” still requires in-depth collaboration in three aspects: fundamental theoretical innovation (such as modeling of supramolecular force fields), technology tool development (specialized algorithms and verification platforms), and industrial ecosystem construction (data sharing, regulatory adaptation). Integrating multimodal learning, developing tools for collagen design, and establishing a shared database will promote the standardization of data on the functions, structures, and processing of marine collagen [147].

7. Conclusion

Most existing studies have focused on the material properties or basic applications of marine collagen, whereas the industrial stability during clinical translation constitutes its core bottleneck. This review presents two transformative frameworks. Firstly, we dissect the tripartite relationship of “structure-function-application”, exploring the hierarchical organizational mode from the stability of the triple-helical structure to fiber arrangement and further to the determination of regenerative outcomes. Secondly, when analyzing the bottlenecks in scale expansion, we focus on green industrialization pathways, identifying extraction costs (accounting for 60% of production costs) and regulatory fragmentation as key obstacles, and proposing artificial intelligence (AI)-based sequence design and a global regulatory alliance as solutions [145,148]. By linking molecular characteristics to clinical outcomes, we position marine collagen as an indispensable platform for next-generation regenerative strategies rather than a mere substitute. This review follows the logical sequence of “regenerative medicine needs → structural advantages of marine collagen → modification strategies → adaptation of processing technologies → clinical applications” (Fig. 6). For the first time, it systematically analyzes the bottleneck issues in the transformation process of marine collagen-based regenerative medicine products from the perspective of the “full industrial chain”, breaking the limitation of existing reviews that focus on basic research while neglecting industrialization, and puts forward schemes to accelerate the industrialization of marine collagen products. In conclusion, marine collagen, as a high-value product derived from aquatic processing waste, has established an integrated value chain spanning from raw material recovery to clinical translation. Sourced from the green recycling of marine waste, it is now a key force reshaping the biomedical and health industries. Future research must focus on elucidating the structure-activity relationships of specific marine collagens—particularly their cell adhesion, angiogenic, and immunomodulatory properties. Due to its low immunogenicity and high flexibility, marine collagen is expected to be fabricated into nerve conduits, scaffolds, and hydrogels for bridging peripheral nerve defects, filling spinal cord injury sites, assisting brain injury repair and fine nerve regeneration, guiding axon growth, and inhibiting scar hyperplasia. Integrating molecular simulation with high-throughput screening will enable the precise prediction and targeted optimization of their biological functions. These breakthroughs will propel marine collagen to evolve from an “alternative material” to an “intelligent life programming platform”, ultimately realizing a next-generation regenerative medical system capable of on-demand tissue regeneration and precise immune modulation. This progression will ultimately establish a sustainable “Resource-to-Therapy” closed-loop paradigm, cementing the role of the blue bioeconomy in shaping the future of healthcare.

Fig. 6.

Graphical diagram of marine collagen extraction, processing, and application. Created with Biorender.com.

CRediT authorship contribution statement

Rui Yuan: Writing – review & editing, Writing – original draft, Conceptualization. Wenhui Huang: Writing – review & editing, Writing – original draft. Heng Liu: Writing – review & editing, Writing – original draft. Juan Wu: Writing – review & editing, Visualization. Hui Yu: Writing – review & editing, Writing – original draft. Xiyuan Zhao: Visualization, Validation. Shen Ji: Visualization, Validation. Xinhuan Wang: Visualization, Validation. Qi Gu: Project administration, Conceptualization.

Ethics approval and consent to participate

This review article does not involve any ethical applications or approvals.

Funding statement

The authors acknowledge the funding support from the National Natural Science Foundation of China (T2222029, U23A20453, 62127811, U21A20396, 82402502), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB1030000, XDB1150000, XDC0200000), the National Key Research and Development Program of China (2022YFA1104701, 2024YFB4607800, 2024YFA1108404), and the Initiative Scientific Research Program of the Institute of Zoology (2023IOZ0101).

Declaration of competing interest statement

Qi Gu is an early career editorial board member for Bioactive Materials and was not involved in the editorial review or the decision to publish this paper. All authors declare that there are no competing interests.

Abbreviations

2D

two-dimensional

3D

three-dimensional

BDE

1,4-butanediol diglycidyl ether

BG

bioactive glass

BMSC

bone mesenchymal stem cell

BV

blood vessel

ColMA

methacryloylated collagen

CREC

cortical epithelial reticular cell

CS

chitosan

EC

endothelial cell

ECM

extracellular matrix

EDC

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

EPS

exopolysaccharide

ER

endoplasmic reticulum

FBG

fasting blood glucose

FC

fish collagen

FUC

fucoidan

GAG

glycosaminoglycan

hASC

human adipose stem cell

HAp

hydroxyapatite

hMSC

human Mesenchymal stem cell

HPA

hydroxyphenylpropionic acid

hs-CRP

hypersensitive C-reactive protein

HE

hematoxylin and eosin

Hyp

hydroxyproline

IFNγ

interferon-gamma

jCOL

jellyfish collagen

LAB

laser-assisted bioprinting

LV

lymphatic vessel

LYVE-1

lymphatic vessel endothelial hyaluronic acid receptor-1

MA

methacrylic anhydride

MC

marine collagen

MC3T3-E1

mouse embryo osteoblast precursor cell

MCh

marine collagen hydrogel

NC

nasal chondrocyte

nHA

nanohydroxyapatite

NHDF

normal human dermal fibroblast

NHS

N-hydroxy succinimide

PCL

polycaprolactone

PDMAAm

poly (N, N-dimethacrylamide)

PLLA

poly (L-lactic acid)

PLGA

poly (lactic-co-glycolic acid)

SMC

smooth muscle cell

SEM

scanning electron microscopy

T2DM

type 2 diabetes mellitus

TNFα

tumor necrosis factor-alpha

UV

ultraviolet

VEGF

vascular endothelial growth factor

Appendix A. Supplementary data

The following is the Supplementary data to this article: