Collagen, an extracellular protein, covers the entire human body and has several important biological functions in normal physiology. Recently, collagen from non-human sources has attracted attention for therapeutic management and biomedical applications. In this regard, both land-based animals such as cow, pig, chicken, camel, and sheep, and marine-based resources such as fish, octopus, starfish, sea-cucumber, and jellyfish are widely used for collagen extraction. The extracted collagen is transformed into collagen peptides, hydrolysates, films, hydrogels, scaffolds, sponges and 3D matrix for food and biomedical applications. In addition, many strategic ideas are continuously emerging to develop innovative advanced collagen biomaterials. For this purpose, it is important to understand the fundamental perception of how collagen communicates with receptors of biological cells to trigger cell signaling pathways. Therefore, this review discloses the molecular interaction of collagen with cell receptor molecules to carry out cellular signaling in biological pathways. By understanding the actual mechanism, this review opens up several new concepts to carry out next level research in collagen biomaterials.

The development of biomaterials with the potential to accelerate wound healing is a great challenge in biomedicine. In this study, four types of samples including pepsin soluble collagen sponge (PCS), acid soluble collagen sponge (ACS), bovine collagen electrospun I (BCE I) and bovine collagen electrospun II (BCE II) were used as wound dressing materials. We showed that the PCS, ACS, BCE I and BCE II treated rats increased the percentage of wound contraction, reduced the inflammatory infiltration, and accelerated the epithelization and healing. PCS, ACS, BCE I, and BCE II significantly enhanced the total protein and hydroxyproline level in rats. ACS could induce more fibroblasts proliferation and differentiation than PCS, however, both PCS and ACS had a lower effect than BCE I and BCE II. PCS, ACS, BCE I, and BCE II could regulate deposition of collagen, which led to excellent alignment in the wound healing process. There were similar effects on inducing the level of cytokines including EGF, FGF, and vascular endothelial marker CD31 among these four groups. Accordingly, this study disclosed that collagens (PCS and ACS) from tilapia skin and bovine collagen electrospun (BCE I and BCE II) have significant bioactivity and could accelerate wound healing rapidly and effectively in rat model.

Type II acid soluble collagen (CIIA), pepsin soluble collagen (CIIP) and type II gelatin (GII) were isolated from silvertip shark (Carcharhinus albimarginatus) cartilage and examined for their physicochemical and antioxidant properties. GII had a higher hydroxyproline content (173 mg/g) than the collagens and cartilage. CIIA, CIIP and GII were composed of two identical α₁ and β chains and were characterized as type II. Amino acid analysis of CIIA, CIIP and GII indicated imino acid contents of 150, 156 and 153 amino acid residues per 1000 residues, respectively. Differing Fourier transform infrared (FTIR) spectra of CIIA, CIIP and GII were observed, which suggested that the isolation process affected the secondary structure and molecular order of collagen, particularly the triple-helical structure. The denaturation temperature of GII (32.5 °C) was higher than that of CIIA and CIIP. The antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl radicals and the reducing power of CIIP was greater than that of CIIA and GII. SEM microstructure of the collagens depicted a porous, fibrillary and multi-layered structure. Accordingly, the physicochemical and antioxidant properties of type II collagens (CIIA, CIIP) and GII isolated from shark cartilage were found to be suitable for biomedical applications.

Collagen is the most abundant extracellular fibrous protein that has been widely used for biomedical applications due to its excellent biochemical and biocompatibility features. It is believed that the smaller molecular weight collagen, i.e., collagen peptide (CP), has more potent activity than native collagen. However, the preparation of CP from fish bone collagen is a complex and time-consuming process. Additionally, the osteogenic effect of CP depends on its molecular weight and amino acid composition. Considering the above concept, the present work was undertaken to extract the CP directly from Mahi mahi fish (Coryphaena hippurus) bones and test its osteogenic potential using bone marrow mesenchymal stem (BMMS) cells. The hydrolyzed collagen contained triple alpha chains (110 kDa) and a peptide (~1 kDa) and the peptide was successfully separated from hydrolyzed collagen using molecular weight cut-off membrane. CP treatment was up-regulated BMMS cells proliferation and differentiation. Interestingly, CP accrued the mineral deposition in differentiated BMMS cells. Protein and mRNA expression revealed that the osteogenic biomarkers such as collagen, alkaline phosphatase, and osteocalcin levels were significantly increased by CP treatment in differentiated BMMS cells and also further elucidated the hypothesis that CP was upregulated osteogenesis through activating Runx2 via p38MAPK signaling pathway. The above results concluded that the CP from Mahi mahi bones with excellent osteogenic properties could be the suitable biomaterial for bone therapeutic application.

Collagen from a marine resource is believed to have more potential activity in bone tissue engineering and their bioactivity depends on biochemical and structural properties. Considering the above concept, pepsin soluble collagen (PSC) and acid soluble collagen (ASC) from blue shark (Prionace glauca) skin were extracted and its biochemical and osteogenic properties were investigated. The hydroxyproline content was higher in PSC than ASC and the purified collagens contained three distinct bands α₁, α_2, and β dimer. The purity of collagen was confirmed by the RP-HPLC profile and the thermogravimetric data showed a two-step thermal degradation pattern. ASC had a sharp decline in viscosity at 20–30 °C. Scanning electron microscope (SEM) images revealed the fibrillar network structure of collagens. Proliferation rates of the differentiated mouse bone marrow-mesenchymal stem (dMBMS) and differentiated osteoblastic (dMC3T3E1) cells were increased in collagen treated groups rather than the controls and the effect was dose-dependent, which was further supported by higher osteogenic protein and mRNA expression in collagen treated bone cells. Among two collagens, PSC had significantly increased dMBMS cell proliferation and this was materialized through increasing RUNX2 and collagen-I expression in bone cells. Accordingly, the collagens from blue shark skin with excellent biochemical and osteogenic properties could be a suitable biomaterial for therapeutic application.

Recent studies have identified the regulatory mechanism of collagen in bone ossification and resorption. Due to its excellent bio-mimicry property, collagen is used for the treatment of several bone and joint disease such as arthritis, osteoporosis, and osteopenia. In bone, the biological action of collagen is highly influenced by the interactions of other bone materials such as glycosaminoglycan and minerals. In view of the above perceptions, collagen was crosslinked with chitosan, hydroxyapatite (H), and chondroitin sulfate (Cs), to produce a natural bone-like 3D structure and to evaluate its effect on bone homeostasis using bone marrow mesenchymal stem cells, osteoblast, and bone marrow macrophages. The XRD and micro-CT data confirmed the arrangement of H crystallites in the chitosan-collagen-H-Cs (CCHCs) three-dimensional (3D)-matrix and the three-dimensional structure of the matrix. The stimulatory osteoblastogenic and exploitive osteoclastogenic activity of 3D-matrices were identified using differentiated osteoblasts and osteoclasts, respectively. Besides, osteogenic progenitor’s paracrine cues for osteoclastogenesis showed that the differentiated osteoblast secreted higher levels of RANKL to support osteoclastogenesis, and the effect was downregulated by the CCHCs 3D-matrix. From that, it was hypothesized that the morphology of the CCHCs 3D-matrix resembles trabecular bone, which enhances bone growth, limits bone resorption, and could be a novel biomaterial for bone tissue engineering.