Progress in Applied Research of Marine Biological Calcium

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       Calcium is an essential mineral that plays an important role in human health, especially bone health. Marine biocalcium is a recognized rich resource with a complex active structure. This article reviews progress in research on calcium sources in marine organisms, the use of calcium supplements, calcium bioavailability, and new applications of marine calcium. The potential for future development and use of marine biocalcium products in biomedical research and in the pharmaceutical, medical and food industries is also addressed. The purpose of this review is to provide comprehensive documentation on the use of marine living resources and product development.
       Calcium is an essential micronutrient that is widely known to influence bone health and metabolism in the body. Calcium deficiency can lead to diseases such as osteoporosis, rickets, epilepsy and anemia. Calcium enters the circulation through food or calcium supplements, maintaining a dynamic balance between blood and bone calcium1. The main source of calcium is dairy products, including milk and milk by-products such as cheese and condensed milk, followed by other sources such as cereals and tofu2. However, poor diet can reduce the bioavailability of calcium. For example, phytic acid, present in grains, and oxalic acid, present in green leafy vegetables, cause calcium to precipitate as phytate and calcium oxalate, which are insoluble compounds3. In the United States, one study found that about 38% of adults who relied solely on foods containing minerals and vitamins had insufficient calcium levels, and about 93% of adults had insufficient levels of vitamin D, which plays a lesser role in calcium absorption. , bones and bone health. Homeostasis and bone repair4,5. Calcium deficiency can lead to progressive weakness with age6. Chronic calcium deficiency has led to an epidemic of osteoporosis7. More and more people continue to experience calcium deficiency and calcium deficiency diseases8,9,10. Therefore, more and more people are increasing their calcium intake through supplementation based on recommendations from doctors or the media11.
       Sources of calcium for these supplements include calcium carbonate ores, calcium-rich animal bones, sea shells and crustaceans12. However, natural calcium carbonate ore may contain harmful elements such as heavy metals13. Animal bones may pose a risk of prion transmission14,15. In recent years, marine calcium supplements have attracted attention due to their abundant supply, high safety, and high biological activity16,17. Through the development and use of marine resources, more than 50% of aquatic products such as fish bones, fins, heads and offal discarded every year can be recycled. Marine mineral supplements may increase bone turnover and help prevent injury and repair damaged bones in humans18. Utilization of marine biological calcium as a rich source of calcium is an important way to improve the utilization rate of biological resources. This article comprehensively evaluates marine calcium sources, calcium supplement formulation technology, and the biological activity and bioavailability of marine calcium to provide a basis for the effective development of marine calcium supplements.
       The ocean contains rich biological resources, and calcium is an important mineral component of marine life. The main sources of calcium for humans from the ocean are fish bones, shells of mollusks and crustaceans, corals and seaweed (Fig. 1).
       Fish bones are a general term for the axes, appendages and bones of a fish, which constitute approximately 10% to 15% of the total weight of a fish19. Fish bone tissue mainly consists of an organic extracellular matrix coated with hydroxyapatite [Ca5(PO4)3OH. Compared to eight different fish species, salmon have the lowest calcium content, ranging from 135 to 147 g/kg. Fat-free solids 20. Shark cartilage is another excellent source of calcium. For example, calcium in the soft cartilage of a shark's jaw is primarily present in the form of calcium hydroxyphosphate crystals [Ca10(PO4)6(OH)2]. Its calcium phosphate content is the highest, with a core value of 67% on a dry weight basis. in the range from 124 to 258 g/kg21. Fish bones from large fish must be treated with chemical and biological methods to break down organic matter or bind to collagen to increase the rate of calcium dissolution, since the hydroxyapatite form of calcium is not suitable for human absorption22. Small fish with cartilaginous heads, such as anchovies and lizardfish, can be processed into prepared meals and eaten with bones23. The production of calcium from fish bones is usually carried out by cooking, alkali treatment, treatment with organic solvents or enzymatic hydrolysis to remove protein and fat, and then ultrafine grinding to obtain fish bone powder.
       Shells make up about 60% of the mass of mollusks, and the calcium carbonate content in the shells can reach 95%. The shells are a rich source of high-quality marine calcium. Shellfish farming provides people with an environmentally friendly source of protein24. In 2016, global aquaculture production of shellfish reached 17.139 million tons, accounting for 21.42% of total aquaculture production25. In addition, since the proportion of calcium in shells is higher than in fish bones, the yield of shells is higher26,27. The effect of adding calcium in the form of Ezo scallop shell powder and fossil shell powder was studied. The results showed that calcium in these natural calcium sources had good solubility and bioavailability28; Shell calcium supplements have been sold in many countries around the world, but the utilization rate of shell resources is still low, and the comprehensive utilization and development of shell calcium needs further support;
       People can directly absorb calcium by eating small shrimp or crabs. Processing and consumption of crustaceans results in the generation of 30-40% of marine waste29. Crustacean shells mainly contain calcium carbonate (CaCO3), chitin and protein30. Research on shrimp and crab shells mainly focuses on the utilization of chitin and protein resources, while calcium is sometimes processed as by-products such as calcium hydrogen phosphate, calcium lactate and calcium 31 .
       Coral calcium is formed from the exoskeletons of living organisms of many species32. Coral calcium is a natural source of marine calcium containing 24% calcium, 12% magnesium and over 70 minerals. In recent years, it has become a new trend in international calcium supplements. Coral calcium is often used as a calcium supplement to treat bone metabolism disorders, osteoporosis, and other bone diseases33,34.
       Seaweed, especially green algae, is rich in minerals such as calcium35. For example, Aquamin is a typical calcium-rich supplement obtained from the calcified skeletal remains of the red seaweed Lithotamnion, which has a calcium concentration of up to 31% by weight36. Previous research has shown that seaweed is a better source of calcium for horses than calcium carbonate supplements (37). Calcium extracted from seaweed has also been found to have beneficial anabolic effects on bone calcification in animal models of osteoporosis38. Algal calcium, derived from oyster shell and seaweed powder, has higher bioavailability than calcium carbonate39.
       The most common direct calcium supplements are shrimp, shell powder, small fish, etc. Some marine calcium supplements, such as oyster shell and coral calcium, have been marketed in various countries. However, the main ingredients of these marine sources are calcium carbonate and polyhydroxyphosphate, which are difficult to digest and increase stress on the stomach40. To increase calcium absorption, marine sources are often first crushed or vacuum heated41,42. Research has shown that marine sources of calcium have certain advantages over calcium carbonate supplements or other calcium-rich foods. For example, Aquamin has better bioavailability and ability to slow bone loss compared to calcium carbonate36. Hake bone (HBF) is a good source of calcium and is as effective as lithotham (L), a calcium supplement derived from Lithothamnion Calcareum. Fish bone meal (foscalim) and radial cartilage hydrolysate (glycollagen) are comparable to milk in terms of short-term calcium absorption and bone resorption 16. Calcium tablets prepared from haddock bones are sufficient to replenish calcium stores and prevent osteoporosis43. The current international recommended daily allowance for calcium for the general population is 700–1200 mg/day. However, adolescents (9–18 years) require approximately 1300 mg calcium per day, and pregnant women with low dietary calcium intake require 1500–2000 mg calcium per day44,45. Research has shown that more than 50% of people with calcium deficiency are men and women over 70 years of age, women aged 51–70 years, boys and girls aged 9–13 years, and girls aged 14–18 years 46 . Conscious supplementation of marine calcium is very effective in preventing calcium deficiency. Obtaining calcium directly from the marine environment is ideal for daily calcium supplementation, however it is not sufficient to treat diseases caused by calcium deficiency; Treatment of conditions such as calcium deficiency also requires higher doses of calcium supplements or medications 5.
       Organic calcium acids such as calcium citrate, calcium L-lactate, calcium gluconate, calcium acetate, calcium formate and calcium propionate have high bioavailability, solubility and absorption rate regardless of gastric contents because they are less sensitive to gastric pH than calcium carbonate . 11,40,47. It is mainly obtained by neutralizing or fermenting calcium compounds (Fig. 2). As a calcium dietary supplement, calcium formate has been found to show significant advantages over calcium carbonate and calcium citrate48. Calcium glucoenanthate exhibits higher relative calcium bioavailability and is better tolerated in humans than calcium carbonate49. However, calcium gluconate and calcium lactate are less concentrated forms of calcium, making them impractical as oral supplements. Calcium acetate and calcium propionate are also not widely used50. By themselves, organic calcium acids are poorly absorbed because they are combined with oxalic acid or phytic acid in food. Calcium combines two or more organic acids, such as calcium citrate malate (CCM)10, which combines bovine collagen peptides with calcium citrate51,52. The combined use of polysaccharides and calcium lactate gluconate53,54 has been found to have a beneficial synergistic effect compared with the use of calcium organic acid alone.
       Marine sources of organic calcium acid are mainly fish bones, shrimp, crab shells and other shells3. To promote calcium absorption, appropriate processes such as calcination, enzymatic hydrolysis and fermentation methods should be selected based on nutrient content and appropriate processing characteristics55,56. Citric acid, gluconic acid, lactic acid, acetic acid and/or propionic acid are then added to produce calcium organic acid. The solubility and bioavailability of natural shellfish calcium containing citrate and lactate increased after decompression therapy26. Fish bones can be fermented by Leuconostoc mesenteroides to produce large amounts of soluble calcium, which contains free calcium, calcium amino acid, calcium acetate, small calcium peptide, calcium lactate, etc. Fermentation of grass carp bones can improve the bioavailability of calcium, and also help avoid calcium loss from fish bones and water protein57.
       Calcium chelates refer to metal complexes that form stable bonds between amino acids or peptides and calcium metal ions, including two main products: calcium amino acid chelates and calcium peptides 58, 59, 60. It is mainly produced by chelation of polypeptides or oligopeptides with calcium ions or chelation of individual or complex amino acids with calcium ions (Fig. 3). Amino acid calcium is independent of vitamin D3 and can be absorbed by the body through amino acid metabolism. For example, calcium lysate, a new calcium supplement, may have better absorption, making it a better calcium supplement than calcium carbonate and CCM61. However, peptide-chelated calcium has advantages over other calcium supplements 62,63,64. An increasing number of chelating peptides have been identified that promote and increase the bioavailability of minerals65,66. Calcium peptide chelates prepared by combining fish bone calcium and calcium-binding collagen peptides through enzymatic hydrolysis have shown increased calcium bioavailability67,68,69. Algal peptide-based calcium chelating complexes and calcium alginate nanoparticles can be used as calcium supplements to improve bone health70,71,72. However, the production cost of calcium peptide chelate is high and the yield is low. With the development of new production technology, peptide chelate calcium is likely to become a good calcium supplement.
       Marine biocalcium performs biological functions and also improves calcium homeostasis and bone health. For example, coral calcium has been shown to regulate blood pressure and prevent metastasis of colon cancer 30,73,74. Spirulina Calcium is derived from Spirulina Platensis (Spirulina Platensis), a filamentous blue-green microalgae from rivers and lakes that has been shown to actively inhibit herpes simplex virus type 1 and possibly other herpes virus infections75. Coral calcium hydroxide acts as an antioxidant to slow aging and prevent liver steatosis in mice76,77,78. Calcium oxide derived from scallop shells has been shown to inhibit Pseudomonas aeruginosa, an egg-spoilage bacterium that is highly resistant to chemical agents such as disinfectants and disinfectants79. Calcium in oysters has shown good efficacy in inhibiting the formation and proliferation of oral squamous cell carcinoma80.
       Ocean calcium can serve as raw material for the production of high-value-added compounds that can be used in biomedical research, as well as in the pharmaceutical, medical and food industries81. Previous studies have found great potential for the production of porous scaffolds from oyster shells, clam shells, cuttlefish bones and salmon bones82,83,84,85. The structural features of these scaffolds have been found to be beneficial in improving biological activity, including mechanical properties, bone growth and vascularization 86 . The production of natural hydroxyapatite (nHAP) from salmon and rainbow trout bones has great potential as a replacement bone implant material in bone tissue engineering87. Marine biocalcium can also be used to prepare adsorbent materials, demonstrating its potentially wide range of applications in water treatment. For example, calcium-rich biochar prepared from crab shells can be used to remove dyes and phosphorus from wastewater88,89. Acid-insoluble calcium silicate hydrate synthesized from oyster shells can also be used to remove organic pollutants and heavy metal ions90. Single-phase hydroxyapatite (HA) and dual-phase calcium phosphate (HA/β-TCP) derived from Atlantic cod bones have no known cytotoxic effects and exhibit good biological activity in simulated body fluids91. Thus, calcium phosphate derived from marine organisms holds great promise in the production of bone substitutes that are resistant to bacterial infections or in the treatment of bone defects. HA (Ca10(PO4)6(OH)2, HAp), extracted from cod bones, is a calcium phosphate that is a safer option in sunscreen formulations, indicating its potential for widespread use in nutraceuticals and cosmetics92.
       Biocalcium from marine waste can still be used in the food industry. For example, fish bones can be added to fish surimi to improve the gelling properties of the product93. Oyster shell calcium powder can improve the chewiness and elasticity of reconstituted ham94. The calcium-rich shells of shrimp and crabs can also be used to make food flocculants95. There are many calcium supplements available, such as calcium carbonate, calcium silicate, calcium sulfate, calcium lactate, etc. Calcium supplements derived from marine organisms may be safer due to their natural origin.
       Marine waste is often considered useless, but it is an abundant and cheap source of calcium. One study found that 55 brands of calcium supplements were divided into seven categories based on their main ingredients, three or more of which were derived from marine organisms, most notably oysters/clam shells, algae, shark cartilage, and chelated calcium products (Table 1). 10. In addition, calcium from marine organisms has good bioavailability and biological functions. Reusing marine life by-products can increase the added value of calcium and reduce the risk of environmental pollution. When developing calcium supplements, future work should focus on the integrated utilization of nutrients such as protein, collagen, chitin, and calcium in marine organisms, as well as the use of specific active ingredients to improve calcium bioavailability. Among other applications, research may have to focus on converting marine calcium into nutraceuticals, new materials or food additives for scaling up to commercial scale.
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