Marine organisms harbor numerous bioactive substances that can be utilized in the pharmaceutical and cosmetic industries. Scientific research on various applications of collagen extracted from these organisms has become increasingly prevalent. Marine collagen can be used as a biomaterial because it is water soluble, metabolically compatible, and highly accessible. Upon review of the literature, it is evident that marine collagen is a versatile compound capable of healing skin injuries of varying severity, as well as delaying the natural human aging process. From in vitro to in vivo experiments, collagen has demonstrated its ability to invoke keratinocyte and fibroblast migration as well as vascularization of the skin. Additionally, marine collagen and derivatives have proven beneficial and useful for both osteoporosis and osteoarthritis prevention and treatment. Other bone-related diseases may also be targeted by collagen, as it is capable of increasing bone mineral density, mineral deposition, and importantly, osteoblast maturation and proliferation. In this review, we demonstrate the advantages of marine collagen over land animal sources and the biomedical applications of marine collagen related to bone and skin damage. Finally, some limitations of marine collagen are briefly discussed.
Keywords: marine collagen, wound healing, bone regeneration, collagen peptides, antiaging, osteoporosis, osteoarthritis, fish collagen, marine sponge
The extracellular matrix (ECM) plays important roles in the physical integrity of cells, where it is involved in cell proliferation, differentiation, migration, and adhesion [1,2,3,4,5,6]. Collagen is the main structural protein in the ECM and connective tissue of animals. In mammals, collagen protein is highly abundant and mainly localized in the ECM of fibrous connective tissues, such as the tendon and skin [7,8,9,10]. It plays key structural roles by supporting the formation, tensile strength, and flexibility of joints [11,12,13,14,15]. Collagen types I, II, III, V, and XI are able to form fibrils that are necessary for structural support and resistance to mechanical stress in connective tissues [16,17]. Type I collagen is the most abundant form and is mainly present in the tendons and skin [18,19,20].
Collagen has numerous biomedical applications ranging from wound healing, bone and tissue regeneration, and drug delivery (Figure 1) [21,22]. Its accessibility, flexibility, and biocompatibility make it a useful biomaterial in several fields [22,23,24]. Collagen is a trimeric molecule made up of three polypeptide alpha-chains, forming highly organized three-dimensional structures capable of resisting mechanical stress and supporting the growth of cells [25,26].
The marine sources of collagen and its main biomedical applications that are discussed in this paper. (Created with BioRender.com accessed on 7 December ).
Marine organisms such as fish, jellyfish, sponges, and other invertebrates harbor a significant source of collagen and are highly advantageous over other sources, as they are metabolically compatible, lack religious constraints and are free of animal pathogens [27,28,29,30]. In fact, fish skins are commonly used for type I collagen extraction, as they are not only immensely abundant but also do not have religious restrictions and are not a risk of disease transmission [31,32,33]. Land animals possess many transmittable diseases, which makes them less favorable for use in industries. For example, cattle, although a large source of collagen, pose risks for bovine spongiform encephalopathy (BSE) as well as transmissible spongiform encephalopathy (TSE) [29,34,35]. These progressive neurological disorders affect cattle and can result in life-threatening infections in humans [29]. In addition, some religious constraints on the use of bovines for the pharmaceutical and cosmetic industries are up for debate [35]. These factors make marine sources of collagen a much safer, easier, and promising alternative.
Skin wounds may take a long time to heal and often do not heal completely. Marine collagen isolated from organisms like fish, jellyfish, and sponges has been implicated in several studies on its potential for increasing wound healing rates [36,37,38,39,40,41]. The processes involve increased fibroblast and keratinocyte migration as well as vascularization and epidermal growth [42,43,44]. In addition to accelerating wound healing, marine collagen has also been shown to have anti-aging properties by slowing the aging process in mice [45,46,47,48]. Studies on humans have also shown that marine collagen can reduce wrinkles, improve skin elasticity, and enhance the overall structure and appearance of skin. Furthermore, collagen&#;s ability to regenerate bone has been shown to be successful in rat models of menopausal osteoporosis [49]. Marine collagen is able to increase bone mineral density and osteoblastic activity, serving protective effects against bone degeneration [49,50,51,52,53]. Collagen has also been shown to induce chondrogenic differentiation and prevent the development of osteoarthritis (OA) [54,55].
Here, we review the potential application of marine collagen in facilitating wound healing and highlight that marine collagen can enhance skin elasticity and thus, reduce the aging process of the skin. Furthermore, we describe the suitability of marine collagen for bone tissue engineering and cartilage formation due to its high biocompatibility. Although some limitations associated with the use of marine collagen exist, it is evident that the advantageous and efficacious potential of marine collagen significantly outweighs its drawbacks.
Marine collagen sources serve not only as a promising avenue for healing skin injuries but also for bone-related trauma and regeneration. Bone fracture repair and healing is a form of tissue regeneration and is a complex process involving bone formation and breakdown [90,91]. Often, patients present with conditions that require reconstruction of large bones as a result of genetic abnormalities, trauma, infection, and tumors [92]. There is an increasing demand to improve methods of bone repair and regeneration, such as functional bone grafts [93].
Marine collagen bioactive peptides are known to aid in the absorption of calcium and zinc, which are important components of bone and are beneficial for osteoporosis prevention [94,95]. A study performed by Xu et al found that marine collagen peptides isolated and derived by hydrolysis from chum salmon increased serum osteocalcin in treated rats compared to controls. Osteocalcin is a protein hormone secreted by osteoblasts and plays a role in bone maintenance and regeneration through interaction with calcium. The study also found that bone organic matrix, density, femoral length, and femur mineral ions were significantly higher in the collagen-treated group than in the controls [94]. It was hypothesized that the increase in bone mineral density was likely due to increased osteoblast activity, as seen by the increase in bone size and serum osteocalcin [94]. These results shed light on the potential collagen peptides involved in mineral deposition, bone matrix development and an increase in osteoblastic activity, which strongly suggests that collagen is a promising biomaterial for the prevention and treatment of osteoporosis [94]. Osteoporosis and net bone loss are prevalent among aging women going through menopause resulting from estrogen deficiency [49]. Nomura et al. demonstrated that 20 mg of collagen isolated from shark gelatin also increased the bone mineral density of the spongy bone in rat models of menopausal osteoporosis [49].
Furthermore, the biological effect of marine collagen on rat-derived bone marrow stem cells has also been demonstrated. Liu et al. showed that 0.2 mg/mL collagen isolated from fish promoted cell survival and upregulated the expression of several osteogenic and endothelial markers [50]. As shown in Figure 7, there was a significant increase in cell viability at 0.2 and 0.02 mg/mL in the collagen-treated groups [50]. Interestingly, the 2 mg/mL-treated group showed no significant differences due to the high dose resulting in a complex negative feedback mechanism that suppressed cell proliferation [50].
Figure shows the cell viability of rat-derived bone marrow mesenchymal stem cells in the control and marine collagen-treated groups [50]. The results show a significant increase in cell viability at 0.2 and 0.02 mg/mL in the collagen-treated groups (marked with *). The 2 mg/mL-treated group revealed no significant differences due to the high dose resulting in a complex negative feedback mechanism that suppressed cell proliferation.
In addition, osteogenic markers, such as alkaline phosphatase (which enhances the differentiation of cells into osteoblast/bone-forming cells), were significantly upregulated in the collagen-treated groups at 3 and 10 days post-treatment [50]. Similar to this study, Elango et al. found that collagen-treated bone marrow stem cells and mature osteoblastic cells depicted dose-dependent increased proliferation compared to controls [52]. Additionally, osteogenic marker mRNA and protein expression significantly increased in the treated groups compared to controls [52]. These results suggest that collagen is able to promote stem cell differentiation and osteoblastic activity. Yamada et al. also showed that marine collagen peptides extracted from both bone and skin of fish were able to increase osteoblastic cell proliferation, expression of osteogenic markers and mineral deposition [96].
In addition to the use of hydrolyzed collagen peptides, collagen scaffold structures have been shown to be beneficial with regards to bone regeneration. Diogo et al. found that collagen-calcium phosphate scaffold structures crosslinked with EDC/NHS supported the attachment and production of bone-building cells [97]. A more recent study found that within the jellyfish collagen scaffolds, there was greater de novo bone formation and increased macrophage recruitment compared to control groups [98]. Inflammatory cells, such as macrophages, are known to promote tissue repair, regulate inflammation and homeostasis, which is promising for bone tissue regeneration [98]. Similar to the above studies, Rachmawati et al. found that collagen scaffolds isolated from the Aurelia aurita jellyfish helped regenerate alveolar bone [99]. When treated with the collagen scaffold, there was increased osteoblasts and decreased osteoclasts compared to the control group suggesting a potential for alveolar bone regeneration. STRO-1, a biomarker for mesenchymal stem cells and osteocalcin, a protein hormone synthesized by osteoblasts were also increased in the collagen treated groups. These results suggest promising bone regeneration properties [99].
Marine sponges, also known as poriferans, serve as an important source of collagen and have a structure that resembles the cancellous architecture of bone tissue. Lin et al. conducted an in vitro assay using fibrinous collagen isolated from the Callyspongiidae marine sponge [100]. The study observed osteoblasts were able to anchor onto the surface of sponge fibers, proliferate, and grow on the cell-sponge constructs. The study also assessed the osteoconductive potential of the sponge collagen scaffold constructs and found that after 7 days the gene expression of two osteogenic markers, osteocalcin, and osteopontin, significantly increased [100]. On day 14, alkaline phosphatase gene expression, an indicator of osteoblastic differentiation, also significantly increased [100]. Similarly, Green et al. also utilized a marine sponge skeleton scaffold to assess whether collagen could induce osteogenesis [101]. The study found that human osteoprogenitor cells were able to attach to the scaffold within 16 h, and by 21 days, osteoprogenitor cells secreted an extracellular matrix. Furthermore, at 9 and 14 days, alkaline phosphatase activity significantly increased compared to controls [101]. All together, these results indicate that collagen fibers in the marine sponge skeleton provide a scaffold framework for osteoblast attachment, proliferation, and migration, which suggest a promising potential for use in bone tissue engineering [100,101].
The biomedical applications of marine collagen are not limited to skin and bone but also encompass cartilage regeneration. Osteoarthritis (OA) is characterized by a disturbance in cartilage homeostasis, which lacks self-repair and regenerative potential [102,103]. In OA, degradation of the cartilage occurs, which results in exposure of the subchondral bone, and this negatively impacts ones quality of life due to painful and stiff joints [103]. Promisingly, marine collagen has been shown to induce chondrogenic differentiation, paving the pathway for potential cartilage regeneration. Raabe et al. found that hydrolyzed fish collagen as well as the growth factor TGFB1 induced proteoglycan and collagen fiber synthesis [104]. Fish collagen also induced chondrogenic differentiation [104]. Similarly, Bourdon et al. investigated the effects of three collagen hydrolysates from fish skin and cartilage on the breakdown of chondrocytes [55]. The study found that 0.5, 50 and 100 µg/mL collagen hydrolysates elevated the level of collagen type I and II collagen. In addition, collagen-treated cells had decreased expression of protease markers known to be involved in OA development, Htra1, Mmp103, Adamts5 and Cox2 [55]. Ohnishi et al. also found that rabbits administered a combination of fish collagen peptides and glucosamine were protected from induced cartilage degradation (OA), whereas control groups developed OA [105]. It was found that fish collagen peptide and glucosamine, which are present in large amounts in connective tissue, and help maintain cartilage structure and integrity, had some protective effects alone, but their combined effects provided the most protection against OA [105].
In a histological experiment by Ahmed et al., the effect of collagen from jellyfish sponge scaffolds on the chondrogenicity of bovine cartilage was observed [106]. Chondrogenicity is a complex process involving the proliferation and differentiation of chondroprogenitors and deposition of the extracellular matrix (ECM) [106]. In this experiment, chondrocytes derived from bovine cartilage tissue were seeded on jellyfish scaffolds to evaluate the amount of collagen deposition, and picrosirius red dye was applied to observe the content and orientation of collagen fibers (Figure 8) [106]. They used three different culture media: native tissue (bovine-derived immature cartilage) and bovine cartilage tissue containing chondroprogenitor cells in the presence and absence of transforming growth factor-β1 (TGFβ1) [106]. TGFβ1 has been shown to be an effective growth factor in cartilage formation and is present at high levels in healthy cartilage, but its level is greatly reduced in the cartilage of OA patients [106]. Staining results showed that in native bovine tissue, collagen fibers are mainly located on the tissue surface, but in chondrogenic culture, both at the tissue surface and in deeper areas, deposition of collagen fibers is more visible. Moreover, the addition of TGFβ1 to the culture medium further contributed to increasing the deposition of collagen fibers [106]. Taken together, the present data support the application of marine collagen in cartilage regeneration.
Histologic results show the amount and orientation of collagen fibers in native bovine tissue (containing immature chondrocytes) and chondrogenic tissue derived from bovine cartilage in the presence and absence of TGFβ1. Tissues are seeded on jellyfish collagen scaffolds. Collagen fibers were identified by picrosirius red staining. (a) Surface (b) center of scaffolds. Scale bars: 0.1 mm [106].
Marine resources of collagen have many advantages over land animals and other sources. Not only are they available in abundance, have no religious constraints and are easily accessible, there have been few reported toxic effects at effective doses [32,33]. This is significant as a major source of collagen is from cattle, which have a risk of transmitting highly dangerous BSE and TSE [29,35]. In addition to its promising safety profile, the use of marine collagen is environmentally friendly. Fish skin, bones, and scales are vast sources of collagen, yet they are often discarded by seafood processing industries [30]. By using marine collagen, useful waste is reduced, and no further organisms are harmed in the isolation of collagen. Furthermore, collagen has a variety of applications in many fields, such as drug delivery, wound healing, skin aging, and tissue regeneration. Marine collagen was also shown to be as effective as sham collagen. In the example mentioned above, marine collagen was as effective as the currently administered antioxidant BHT [89]. In addition, other comparisons of sponge collagen membrane versus polyurethane membrane on healing of grant donor sites depicted that collagen use significantly increased wound healing quality and reduced healing time [107]. Marine collagens are also hydrolyzed more easily than mammalian collagen, which makes them more suited for further processing into peptide derivatives [108]. Furthermore, collagen has both structural and functional properties that make it a natural substrate for cell attachment, growth, and differentiation [109]. It is important to note, however, that although minor, some limitations do exist. It has been shown that marine collagen is less thermally stable than collagen from bovines, as they have fewer proline and hydroxyproline residues [110]. Additionally, most studies have investigated marine collagen&#;s efficacy in vitro or in animal models; however, more studies are needed that investigate the efficacy and potential adverse effects of marine collagen on human skin. Overall, the few limitations of marine collagen are strongly outweighed by their wide variety of benefits.
The present review highlights the biomedical applications of marine collagen in wound healing, skin antiaging, and bone and cartilage regeneration. It is evident that marine collagen sources are significantly more advantageous than land animal sources. The ability of marine collagen to promote skin re-epithelization, vascularization, fibroblast migration, and overall faster wound healing rates has been demonstrated. Furthermore, the antiaging effects of marine collagen related to greater skin elasticity and wrinkle reduction are highly promising for the cosmetic industry. Furthermore, the significant impact on osteoporosis prevention and treatment by increasing bone density and mineral deposition is also evident. Bone-related diseases such as osteoporosis and OA can negatively impact one&#;s quality of life. Marine collagen and its derivatives were shown to delay and protect against OA and, thus, reduce mortality outcomes. Therefore, there should be continued investigation and discoveries of marine collagen sources, as they have thus far proven extremely beneficial.
Conceptualization, A.R.; validation, A.R.; resources, A.R., S.G., P.B.; writing&#;original draft preparation, A.R., S.G., P.B.; writing&#;review and editing, A.R.; visualization, A.R. and S.G; supervision, A.R.; project administration, A.R.; funding acquisition, A.R. All authors have read and agreed to the published version of the manuscript.
This research received no external funding.
The authors declare no conflict of interest.
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&#;Collagen is one of the major building blocks in skin, bones, tendons, ligaments, muscles, and blood vessels,&#; explains Taylor Wallace, PhD, a food scientist and adjunct professor in the department of nutrition and food studies at George Mason University in Fairfax, Virginia. There are 28 types of collagen in the body. Research shows that we lose collagen naturally due to aging and other factors, so the idea that we could replace that lost collagen with external sources sounds plausible.
&#;Because collagen is part of the supporting structures in skin, a lack of it can contribute to wrinkles and sagging skin,&#; says Melina Jampolis, MD, a physician, nutrition specialist, and author of Spice Up, Live Long.
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While collagen treatments got their start in skin care, the protein is not well suited for topical applications because it is too large to penetrate the skin, says Joshua Zeichner, MD, director of cosmetic and clinical research in dermatology at Mount Sinai Hospital in New York City. This is why some formulations use collagen peptides, or hydrolyzed collagen, which has been partially broken down.
This is similar to what happens when you eat collagen. The protein is broken down into amino acids that circulate in your blood, and some experts theorize that these circulating byproducts of collagen may signal skin to rev up new collagen production, says Dr. Zeichner. Whether this is accurate, and how effective it is, is still unclear.
One review found that collagen peptides act as antioxidants to quelch damaging free radicals and inflammation (both of which are associated with chronic diseases and aging) in skin cells. In another small study, 50 women ages 45 to 60 took 10 grams (g) of a marine collagen powder supplement for 12 weeks and had a 35 percent reduction in wrinkles compared with a group who took a placebo powder, according to a randomized, triple-blind, parallel study from . Measures of skin elasticity, hydration, and firmness also improved.
In a double-blind, randomized, clinical trial, 120 people took a supplement containing hydrolyzed fish collagen, vitamins, antioxidants, and compounds like glucosamine and had an increase in skin elasticity by 40 percent compared with a placebo, as well as a self-reported 43 percent reduction in joint pain and 39 percent better joint mobility. It&#;s difficult to know whether fish collagen alone was responsible for these results. Currently, there is a lack of human trials analyzing the potential benefits of marine collagen on joint health or arthritis.
The collagen you hear about packaged in collagen powders and supplements is traditionally made from bovine (cow) sources, while marine collagen comes from fish. &#;Many people are trying to move away from animal products like red meat, and they know fish is healthier, so it seems like a better source of collagen to the consumer compared with cow or pig skin and bones,&#; says Dr. Jampolis.
Whether marine collagen is actually any healthier is still a source of debate. At a chemical level, there&#;s little difference between the two. &#;Collagen molecules themselves are structurally similar, regardless of the source they are derived from,&#; says Zeichner.
There is some evidence that different sources of ingestible collagen may act upon different types of collagen in the body (remember, there are 28 kinds). Bovine collagen has been found to increase collagen types 1 and 3, the primary kinds that make up skin, says Dr. Wallace. Marine collagen increases types 1 and 2, the kinds found in cartilage, in the structures of your eyes, and within vertebral discs, according to one review.
Because marine collagen supplements are a newer product type than bovine ones, there is less research on them and a need for longer-term clinical studies. &#;I&#;d like to see a head-to-head comparison of marine versus bovine collagen to specifically recommend one over the other,&#; says Jampolis.
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Marine collagen does have some other known advantages, however. Notably, it is a far more sustainable source of protein than other kinds. A previously mentioned review noted, &#;Marine organisms and their wastes can be a sustainable, eco-friendly source of collagen.&#;
The paper also points out that marine collagen may appeal to people who restrict meat from their diets for religious, cultural, or moral reasons. Several major religions restrict consumption of pork and beef, for instance, and people who follow vegetarian diets may not wish to consume animal products but are okay with eating fish.
Additionally, the same review points out that some people avoid animal-derived collagen out of fear that it may potentially transmit diseases, such as bovine spongiform encephalopathy, also known as mad cow disease.
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If you are allergic to fish, you should absolutely not take marine collagen. Also, since collagen is a protein, you should consider this a protein supplement. One form of marine collagen powder from Vital Proteins contains 11 g of protein per two scoops. If you have severe kidney disease and your doctor has recommended limiting protein, then you&#;ll need to count the grams of protein consumed from marine collagen powders or capsules, says Jampolis.
It&#;s natural to want to see the benefits of any supplement or diet change right away, but you&#;ll have to wait some time. With regular consumption, Jampolis says that you may see skin benefits in 8 to 12 weeks, enough time for skin to repair and turn over.
If you want to try marine collagen, follow the instructions on the label for the dosage. Also, it&#;s always best to talk to your doctor first before taking any supplement to make sure that it&#;s safe for your individual health concerns. Look for trusted brands that use wild-caught fish and are third-party verified, which can help ensure that what you&#;re taking is free from contaminants and contains the ingredients that are listed.
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No. Two scoops &#; 12 g or a half ounce &#; are 45 calories, per Vital Proteins. While excess intake of anything can make you gain weight, it&#;s unlikely that adding marine collagen in normally consumed amounts will cause weight gain, says Jampolis.
Marine collagen supplements differ from eating fresh fish. You&#;ll find collagen in fish skin, bones, heads, scales, fins, and entrails, as well as fish cartilage, notes one review. These are parts you&#;re typically not consuming unless you eat small, whole fish (such as sardines, anchovies, or mackerel). In that instance, you&#;ll consume higher amounts of collagen compared with eating a regular fish fillet, says Wallace.
Overall, consuming a varied diet filled with whole foods is the best way to take in a range of nutrients that will support healthy skin and joints. &#;It&#;s unclear whether collagen supplements are superior to eating a well-balanced diet with adequate protein,&#; says Zeichner.
If you&#;re looking to maximize your intake of collagen and cost is not a factor &#; these supplements can be pricey &#; consider adding marine collagen to your existing diet. Supplements can offer a higher dose. They are available as a powder that you mix into liquid, like a smoothie or coffee, or as capsules. Ensure that you&#;re choosing hydrolyzed collagen peptides, which are already broken down, making them easily digested by the body, says Jampolis. And compare the amount of collagen peptides in a serving of capsules versus powder, as they may differ.
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