Marine-Originated Materials and Their Potential Use in Biomedicine

: Aquatic habitats cover almost 70% of the Earth, containing several species contributing to marine biodiversity. Marine and aquatic organisms are rich in chemical compounds that can be widely used in biomedicine (dentistry, pharmacy, cosmetology, etc.) as alternative raw biomaterials or in food supplements. Their structural characteristics make them promising candidates for tissue engineering approaches in regenerative medicine. Thus, seaweeds, marine sponges, arthropods, cnidaria, mollusks, and the biomaterials provided by them, such as alginate, vitamins, laminarin, collagen, chitin, chitosan, gelatin, hydroxyapatite, biosilica, etc., are going to be discussed focusing on the biomedical applications of these marine-originated biomaterials. The ultimate goal is to highlight the sustainability of the use of these biomaterials instead of conventional ones, mainly due to the antimicrobial, anti-inﬂammatory, anti-aging and anticancer effect.


Introduction
Almost 70% of the Earth is covered by aquatic habitats, hosting a great biodiversity of flora and fauna [1]. Several of these marine and aquatic organisms play a crucial role in the ecosystem, provide raw materials and filters, and are capable of being consumed as seafood [2]. Nematodes, sponges, algae, bryozoans, fishes, cuttlefishes, and many others are among the aquatic organisms (invertebrates and vertebrates) that either produce toxins and chemical compounds, mainly for defense reasons, which can be used in pharmacy, or provide themselves with alternative raw biomaterials [3]. Chitin and chitosan, for instance, are biopolymers with antimicrobial potential [4], and hydrophobic luffa sponges have been proven efficient for oil removal from water [5]. Bryostatin is also a characteristic example of a very promising marine-originated pharmaceutical against melanoma, cell sarcoma, and other cancer types [6].

Seaweed-Originated Components
Seaweeds are marine organisms that contribute to the vast biodiversity of the sea. Seaweeds are multicellular organisms (macroalgae) that differ from Earth plants due to the lack of roots, leaves, and stems [21]. Brown, red, and green algae are the main categories of seaweed, as has been mentioned [7]. Among various other renewable resources living in the marine environment, seaweeds can be used in environmental, paper and textile, food, cosmetics, and pharmaceutical applications [22][23][24]. Seaweeds are a major source of raw material for agar production due to the fact that they are rich in hydrophilic colloids (phycocolloids) [25]. Thus, mainly in Asia, seaweeds are consumed as gelling agents in the dietary and food industries [26]. Other seaweeds, such as Sargassum wightii (brown algae), are commonly used as food ingredients in soy sauce, in soups, and in other traditional Asian dishes due to their high food value.

Biomedical and Food Applications of Seaweed-Originated Components
Seaweeds have been thoroughly studied for their nutritional composition. Based on the rich bioactive compounds that are found in seaweeds, the wide use of them has been linked to a healthy and beneficial diet. Several analyses have shown that the levels of proteins, proline, lipids, polyphenols, chlorophyll contents, dietary fibers, and carbohydrates that are included in seaweeds are high [27]. Apart from proline, essential amino acids, such as methionine, lysine, valine, and phenyl alanine, are found in significant levels in seaweed's composition [28]. Furthermore, linolenic acid and α-linolenic acid, which are fatty acids with high nutritional value, and vitamins (mainly vitamin C) are among the main ingredients of seaweeds [29]. Thus, it is reasonable that seaweeds might be used as nutritional supplements. Many studies have thoroughly analyzed the composition of seaweeds, indicating that they are rich in essential minerals, such as iron, magnesium, calcium, potassium, zinc, selenium, copper, iodine, phosphorus, and fluoride [30]. Other studies have focused on the vitamins that are found in seaweeds, such as A, B1, B2, B9, B12, C, D, E, K, riboflavin, folic acid, and pantothenic acid. In particular, Porphyra umbilicalis, Himanthalia elongata, and Crassiphycus changii are among the species that are rich in vitamin C [8]. Syad et al., analyzing the nutritional composition of G. acerosa and S. wightii, proposed their use as potential food supplements [24]. Thus, the common point of these studies is that they propose seaweeds as low-caloric, nutritive foods [23].
Marine pharmaceuticals is a quite modern branch of pharmacology. The possible use of seaweed compounds for the development of natural drugs is among the scopes of this scientific field. Seaweeds have been used in biomedicine, mainly in Asian countries, since ancient times [7]. According to Arokiarajan et al., marine organisms, like algae, are a source of various bioactive compounds, such as sulfated polysaccharides, and although they are a defensive barrier against any infective organism, protecting algae, they might also be used in biomedicine, due to their anti-inflammatory, antitumor, antiviral, and antimicrobial potentials, which are mainly used in tissue engineering or in drug delivery system development [31]. Furthermore, various studies have indicated that seaweeds provide antioxidant and enzyme inhibitory effects [32]. Moreover, alkaloids, terpenoids, and steroids have been detected in brown algae (genus Cystoseira) in the Mediterranean Sea, and Amico et al. have focused on their pharmaceutical potential [33].
Also, laminarin and alginate are found in brown seaweeds. Laminarin is a linear polysaccharide that is mainly used in biomedicine. It has immunostimulatory activity, activating macrophages possessing antitumor and auto-healing properties [39]. It is worth mentioning that, upon irradiation with gamma rays, laminarin's antioxidant behavior is enhanced [40]. Alginate is a biopolymer, with very good stabilizing properties. It is used in food products and in medicine [41]. Particularly, it is widely used in dentistry for mold making, in the whitening process, and for artificial dental implants [42] and is also used as a bio-ink in 3-D bioprinting [43].
Terpenoids and terpens are found in algae. Numerous studies have indicated that they might be used as anticancer agents and have focused on the possible therapeutic effect of them on lung, breast, prostate, colon, and pancreatic cancer cells [44]. Other studies have shown that seaweed phytosterols, e.g., fucosterol, can reduce cholesterol levels presenting several beneficial properties, such as anti-diabetic, anti-obesity, anti-aging, and anticancer effects [45].
Cosmeceuticals is considered a cosmetology field focusing on the use of bioactive ingredients [21]. Recently, macroalgae extracts have gained interest due to their benefits for the treatment of skin disorders and their anti-inflammatory and anti-aging properties [46]. Table 1 summarizes the biomedical and food applications of seaweed-originated components.

Marine Sponge-Originated Components
Marine sponges, a Porifera species, can offer numerous biomaterials that are part of their chemical composition [49]. Their structure allows them to be used in environmental, anti-pollutant agents. Also, commercial sponges derived from natural sponges (commercial sponges can be synthetic or natural if they can be collected from dead natural sponges, dried, and used for commercial purposes) can be utilized particularly against water pollutants and oil spills [50]. Natural sponges have significant advantages over synthetic ones. They are long-lasting, more absorbent, and odor repellent with a soft texture [12]. Actually, sponges play an important role in ecology since they act as indicators of ocean pollution. Also, the biomedical applications of marine sponges are mainly related to chitin, biosilica, and polyphosphate, which are found to be abundant in them, and are associated with their ability to biomineralize, forming bioglass [51].

Biomedical Applications of Marine Sponge-Originated Components
Marine sponges are rich in secondary metabolites of pharmaceutical significance. Most of them are microbial origins, which symbiotically exist due to sponges [52]. Terpenes, alkaloids, and peptides are among the main metabolites produced by marine sponges. de Silva et al. have isolated manoalide from sponge L. variabilis in Palau [53]. This compound exhibited antibacterial activity against Streptomyces pyogenes and S. aureus. Manoalide, according to Ortiz et al., could inhibit the activity of the phospholipase A2 (PLA2) enzyme that provides a substrate of pro-inflammatory mediators [54]. Isomalabaricanes are triterpenes found in marine sponges. They can be classified into stelletins, stelliferins, and globostellatic acids [12]. Su et al. have indicated that stelletins from J. stellifera and Stelleta tenuis are cytotoxic to murine leukemia P388 cells [55]. Manzamine A, an alkaloid isolated from Haliclona sp., has shown cytotoxic, anti-malarial, and antibacterial activity [56]. Discodermin A, a peptide detected in Discodermia kiiensis (and in discodermins B, C, and D) has exhibited antibacterial potential, inhibiting PLA2 [57].
Zhou et al. isolated from Aspergillus sp. Misszrtine A, an alkaloid with anticancer effects on HL-60 and LNCap cells [62]. Also, gracilosulfates A, B, C, D, E, F, and G, which are steroids found in Haliclona gracilis, has shown anti-tumor activity in human prostate cancer [63]. Monacolin X, a polyketide isolated from Monascus sp., showed a significant anti-proliferative and anti-migratory effect on human breast cancer cells [64].
Silicon dioxide (SiO 2 ) or silica can be synthesized by marine sponges to form their skeletal elements. Thus, this type of silica is widely known as biosilica (biogenously formed polymeric silica) [65]. Biosilica has numerous areas of application, such as in sensoring, coating, and the development of hybrid materials and drug delivery systems [66]. Also, it can be used with positive effects on cartilage and bone healing; thus, it can be used in tissue engineering to form scaffolds [67].
Polyphosphates are inorganic compounds that are produced from various animals and are also present in the skeletons of marine sponges. According to various studies, this substance has an osteogenic role. Lowe et al. have shown that polyphosphates enhanced the mineralization of osteoblast-like SaOS-2 cells [68]. Skaggs et al. indicated that polyphosphates upregulated collagen type I and II levels in osteogenic and chondrogenic cells [69]. Thus, polyphosphates should be used in regenerative medicine, and mainly in bone repair and bone therapies, due to biomimetic behavior.
Collagen-like protein (spongin) can be extracted from marine sponges, such as Axinella cannabina and Suberites carnosus [70]. Spongin has ideal properties, regarding porosity, thermostability, and mechanical strength, and, hence, it can be used in tissue engineering [71]. Spongin-based scaffolds have been isolated from Demosponge Hippospongia communis and used as a template for the hydrothermal deposition of crystalline titanium dioxide, with potential use in biomedicine [72].
Chitin is a very famous biopolymer present in many organisms, including marine sponges and arthropods [73]. Thermostability, biocompatibility, and biodegradation, in parallel with good mechanical properties, are the major advantages of chitin to be used in applications, such as drug delivery system development and tissue engineering (wound healing, scaffolds, etc.) [74]. Chitin can also be used in biosensing and as a water filter since it can be stable even in high-temperature and high-pressure conditions [75]. Table 2 presents some of the most significant biomedical applications of marine-sponge-originated components.  To sum up, marine-based materials have shown promising properties, and the main applications of them are schematically presented in Figure 1.

Arthropod-Originated Components and Their Biomedical Applications
Arthropods and particularly crustacea such as crabs, shrimps, and lobsters are a gre source of calcium carbonate, silk, chitin, and chitosan [14,15,76]. Most of them have a outer skeleton, consisting of chitin-protein fibers and precipitated calcium carbona within the chitin matrix for protection [77].
Applications of chitin derived from marine organisms, such as sponges, have bee already mentioned. Chitosan is a polysaccharide that is obtained by the deacetylation chitin and is available in crustaceans shells. In biomedicine, chitosan is used due to i high solubility and its active sites [73]. The wide use of chitosan in drug delivery system and in tissue engineering are quite well known, but it is also worth mentioning the app cations of chitosan in dentistry (wound healing, tissue engineering, and antimicrobial a tivity) [78].
Calcium carbonate is naturally available in the shells of crustaceans such as crabs an shrimps. The source of calcium is the water itself. In ocean water, the concentration calcium is high. Thus, crustacea store calcium using a biomineralization process. Calciu carbonate in their exoskeletons, acting as a biomineral, can be used in regenerative med cine to form scaffolds or 3D templates for bone repair [79].
Silk is another promising biomaterial that is found in crustacea [80,81]. Silk is a pr tein-based biomaterial produced by arthropods, among other animals [81]. It has a gre variety of applications, including in the textile industry and optoelectronics, due to i

Arthropod-Originated Components and Their Biomedical Applications
Arthropods and particularly crustacea such as crabs, shrimps, and lobsters are a great source of calcium carbonate, silk, chitin, and chitosan [14,15,76]. Most of them have an outer skeleton, consisting of chitin-protein fibers and precipitated calcium carbonate within the chitin matrix for protection [77].
Applications of chitin derived from marine organisms, such as sponges, have been already mentioned. Chitosan is a polysaccharide that is obtained by the deacetylation of chitin and is available in crustaceans shells. In biomedicine, chitosan is used due to its high solubility and its active sites [73]. The wide use of chitosan in drug delivery systems and in tissue engineering are quite well known, but it is also worth mentioning the applications of chitosan in dentistry (wound healing, tissue engineering, and antimicrobial activity) [78].
Calcium carbonate is naturally available in the shells of crustaceans such as crabs and shrimps. The source of calcium is the water itself. In ocean water, the concentration of calcium is high. Thus, crustacea store calcium using a biomineralization process. Calcium carbonate in their exoskeletons, acting as a biomineral, can be used in regenerative medicine to form scaffolds or 3D templates for bone repair [79].
Silk is another promising biomaterial that is found in crustacea [80,81]. Silk is a protein-based biomaterial produced by arthropods, among other animals [81]. It has a great variety of applications, including in the textile industry and optoelectronics, due to its physicochemical and mechanical properties. The biocompatibility of silk allows its use in tissue engineering, regenerative medicine, and cosmetics. The sustainability and biodegradability of silk-based biomaterials make them desirable [76]. Silk can be used to enhance composite materials. Kim et al. created a PEG-silk hydrogel mimicking the structure of cartilage [82]. Silk fibers and hyaluronic acid were used by Yu et al. to develop a scaffold for biomedical use, supporting the cellular proliferation of bone marrow mesenchymal stem cells [83]. A vascular graft made of elastin-silk fibroins was implanted into the aorta of rats with stability and few side effects [84]. Silk can also be used in combination with hydroxyapatite for coating to improve its performance in bone tissue engineering [85]. These studies have focused on silk sericin and fibroin, particularly obtained from silk cocoons. However, the similarities between cocoon-derived silk and that obtained by crustacea allow us to think about several biomedical applications of marineoriginated silk. Kakui et al. have shown that shrimp-like ocean crustaceans, known as tanaids, produce silk for shelter and safety, anchoring to rocks. Thus, this new type of silk could be used in environmentally friendly, water-resistant materials for fabrics; medical uniforms; and numerous other biomedical applications [86]. Table 3 presents the main biomedical applications of arthropod-originated components.  [73] chitin marine crab shells biomedicine (tissue engineering, drug delivery systems, biosensoring, and water filter): several biomedical applications of chitin due to its good properties [74,75] chitosan crabs biomedicine (dentistry, wound healing, antimicrobial activity) [78] calcium carbonate crabs and shrimps biomedicine (regenerative medicine): scaffolds or 3D templates for bone repair [79] silk arthropods biomedicine (regenerative medicine, tissue engineering, cosmetics): biocompatibility [76] silk in combination with hydroxyapatite Silk cocoons and mollusks biomedicine (tissue engineering, bone repair): coating in bone tissue engineering [85] silk shrimp-like ocean crustaceans biomedicine and environment (tissue engineering, bone repair): environmentally friendly water-resistant materials for fabrics and medical uniforms [86] In summary, arthropod-derived biomaterials are mainly used in regenerative medicine, drug delivery systems, and dentistry, possessing also antimicrobial properties.

Mollusk-Originated Components and Their Biomedical Applications
Mollusks such as cuttlefishes, octopuses, squids, oysters, and mussels are great sources of aragonite and, consequently, of hydroxyapatite [17]. Hydroxyapatite is a widely used bioceramic due to its ideal properties. Actually, it is a calcium phosphate (Ca 10 (PO 4 ) 6 (OH) 2 ) ( Figure 2) that is used in environmental and biomedical applications. silk arthropods ics): biocompatibility [76] silk in combination with hydroxyapatite Silk cocoons and mollusks biomedicine (tissue engineering, bone repair): coating in bone tissue engineering [85] silk shrimp-like ocean crustaceans biomedicine and environment (tissue engineering, bone repair): environmentally friendly water-resistant materials for fabrics and medical uniforms [86]

Mollusk-Originated Components and Their Biomedical Applications
Mollusks such as cuttlefishes, octopuses, squids, oysters, and mussels are great sources of aragonite and, consequently, of hydroxyapatite [17]. Hydroxyapatite is a widely used bioceramic due to its ideal properties. Actually, it is a calcium phosphate (Ca10(PO4)6(OH)2) (Figure 2) that is used in environmental and biomedical applications. Hydroxyapatite artificial implants are very popular in applications of hard tissue replacements. This material allows the acceleration of bone growth assisting the implant to be incorporated [87]. Corals and mollusks can provide hydroxyapatite, and its microstructure is similar to the inorganic mineralized structure of natural bones [88]. Thus, various studies have focused on the possible use of marine-derived hydroxyapatite obtained from cuttlefish bone from Sepia officinalis via hydrothermal transformation because it can help Hydroxyapatite artificial implants are very popular in applications of hard tissue replacements. This material allows the acceleration of bone growth assisting the implant to be incorporated [87]. Corals and mollusks can provide hydroxyapatite, and its microstructure is similar to the inorganic mineralized structure of natural bones [88]. Thus, various studies have focused on the possible use of marine-derived hydroxyapatite obtained from cuttlefish bone from Sepia officinalis via hydrothermal transformation because it can help make procedures low-cost and eco-friendly. Also, the porosity and bioactivity of this material allows its use in scaffold development [17].
Hydroxyapatite also has a close analogy to the inorganic portion of human teeth. The enamel, which is the external layer of a human tooth, consists of~97% inorganic compounds, and the dentine consists of~70% inorganic material, with hydroxyapatite being the main part of this inorganic phase. Thus, it is used as a biomaterial in dentistry for implants [89]. Table 4 gathers some biomedical applications of marine-originated hydroxyapatite.

Cnidaria-Originated Components and Their Biomedical Applications
Jellyfishes and corals are members of the phylum cnidaria. Corals are rich in hydroxyapatite, and the main applications of it have already been mentioned. Jellyfishes are a source of gelatin, which is also obtained from other species, such as mammalians [90].
Gelatin is commonly obtained by the hydrolysis of collagen. Type A gelatin can be produced from jellyfish and is widely used for food applications. Due to its emulsifying and foaming properties, it can also be used in pharmacy (tablets coating, carriers, etc.); cosmetics (emulsion stabilizers, etc.); and biomedicine, particularly in wound healing and tissue engineering [91].
More specifically, gelatin can be applied in numerous cosmetic products, including body lotions, face creams, hair sprays, sunscreens, shampoos, etc. [92]. Their antioxidant, antimicrobial, and anticancer potentials have also been studied. Hydrolyzed gelatin has shown an anticancer effect against MCF-7 breast cancer cells and U87 glioma cells [93]. Furthermore, antihypertensive peptides from gelatin have been shown by Lv et al. [94]. Thus, there is a great variety of applications of gelatin due to its structural and physicochemical properties. Table 5 gathers some of the most significant biomedical applications of cnidaria-originated components. Table 5. Biomedical applications of cnidaria-originated components.

Cnidaria-Originated
Component Source Application Ref.

Conclusions
Since the sources of raw materials are non-renewable, and the conventional chemical methods are not always eco-friendly, it is important to find alternative solutions to obtain biomaterials. Thus, aquatic habitats are a great solution due to the diversity, availability, and sustainability of marine organisms. Marine organisms are rich in a great variety of chemical compounds with potential biomedical applications. Their physicochemical and mechanical properties allow the wide use of these materials in tissue engineering, pharmacy, food industry, cosmetics, etc.
Biomaterials such as chitin, chitosan, alginate, gelatin, hydroxyapatite, biosilica, etc., can be isolated from marine organisms (e.g., seaweeds, marine sponges, arthropods, cnidaria, and mollusks), and their properties are comparable to those obtained from different sources. Thus, it is of crucial importance to gradually exploit the potential of marine organisms to develop advanced biomaterials.

Conflicts of Interest:
The authors declare no conflict of interest.