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What is Collagen?

Collagen derives its name from the Greek word “kolla” meaning glue. Consequently, it serves as a glue, connecting all structures and the word “gen” means “the one which produces”. In simpler terms, collagen means a structure which produces a glue like substance responsible for adherence. Collagenis the main structural protein present in the extracellular matrix found in the body’s various connective tissues. As the main component of connective tissue and the most abundant protein making up from 25% to 35% of the whole-body protein content of human body. Collagen consists of amino acids bound together to form a triple helix of elongated fibril known as a collagen helix. Collagen is mostly found in connective tissue such as cartilages, bones, tendons, ligaments and skin. Depending upon the degree of mineralization, collagen tissues may be rigid (bone) or compliant (tendon) or have a gradient from rigid to compliant (cartilage). The fibroblast is the most common cell that creates collagen. Collagen synthesis occurs both intracellularly and extracellularly. Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed. Collagen forms a scaffold that provides strength and structure within the body. Along with elastin and soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. As we age, we produce less collagen in our skin every year hence, the tendency toward wrinkles and thinning skin we see the older we get. The collagen molecule contains 45 aspartic acids, 72 glutamic acids, and 37 lysine and 45 arginine residues. These residues are polar in nature and, on dissociation, the carboxyl groups are negatively charged. In the isoelectric state and in equilibrium with water in the pH range from 5.5 to 9.5, these polar groups are completely ionized. Collagen is an amphoteric ionic structure attaining the highest degree of charge, both positive in the isoelectric pH range, i.e. around 7.0 for collagen.

There are close to 30 different types of collagen that have been identified so far. The most abundant type of collagen present in the human body is that of Type I (over 90% of the collagen in the body being type I) with significant amounts of Type II, III and IV also accounted for. The type V  occurs main in the nail and hair.

• Collagen I – found in bones, tendons, organs.
• Collagen II – found mainly in cartilage
• Collagen III – found mainly in reticular fibres (fine fibrous connective tissue occurring in networks to make up the supporting tissue of many organs).
• Collagen IV– found in the basement membrane of cell membranes (a thin noncellular layer located between epithelial cells and the connective tissue that underlies them, composed of collagen and other proteins and having a variety of functions including support and filtration).
• Collagen V– found in hair and nails.

2.Once outside the cell peptide chains are cleaved and tropocollagen is formed. These tropocollagen molecules gather to form collagen fibrils, via covalent cross-linking. Multiple collagen fibrils form into collagen fibers.

Each fiber of collagen contains thousands of individual collagen molecules that are bound together by cross-linking and staggered covalent bonds (the strongest bonds that exist between protein molecules). The collagen molecules themselves are made from a triple helix—three polypeptides or strings of amino acids chains twisting around each other.

• There are 1,050 amino acids in each of the three chains that make up collagen. And they’re held together with hydrogens—the smallest atom.
• Glycine is amino acid that takes up the middle of the triple helix structure because it’s the only one that can fit. Glycine is an amino acid that has a single hydrogen atom as its side chain. It is the simplest amino acid.
• These long fibers don’t just exist as single protein ropes. Collagen can come together to form striated horizontal sheets.

Role of Collagen in burns and deep wound healing

            Collagens are the most abundant protein found throughout the body. In the healing wound, these collagens are synthesized by cells such as fibroblasts and modified into complex morphologies. The type, amount and organization of collagen changes in the healing wound and determines the tensile strength of the healed skin. Collagen III is the first to be synthesized in the early stages of wound healing and is replaced by collagen I, the dominant skin collagen. The initial random deposition of collagen during the granulation tissue formation is further enhanced by lysyl oxidase enzyme-induced covalent cross-linking. This process matures the collagen into complex structures that are reoriented for tensile strength restoration. Collagen remodeling continues for months after wound closure and the tensile strength of the repaired tissue increases to about 80–85% of normal tissue if all processes proceed without any perturbations.

In the skin, the fibrillar collagens types I, III and V are the most common, followed by fibril-associated collagens type XII, XIV, XVI, and VI. The non-fibrillar collagens type IV, XVIII are found in the basement membrane of the skin.Collagen contributes to the mechanical strength and elasticity of tissues and acts as a natural substrate for cellular attachment, proliferation, and differentiation. Biofilm-mediated upregulation of MMP-2 via microRNAs creates a collagenolytic environment in the wound, sharply decreasing the collagen I/collagen III ratio and compromising the biomechanical properties of the repaired skin, possibly making the repaired skin vulnerable to wound recurrence. A recent mapping study of collagen structure and function suggested that in normal, injured tissue the collagen fibril is in a closed conformation that upon exposure to blood following injury exposes cell- and ligand-binding sites that could promote the wound healing process. Several recent reviews detail roles of collagen in the skin and wounds.

In GYOGY, Collagen is available in sheets and particles and their prime functions are as follows,

1. Collagen in wound healing is to attract fibroblasts and encourage deposition of new collagen to the wound bed. Collagen helps stimulate new tissue growth, while encouraging autolytic debridement, angiogenesis, and re-epithelialization.
2. Collagen bind and inactivate excessive MMPs found within the extracellular matrix (ECM).
3. Collagen absorb exudate while providing an optimal moist environment to enhance healing.

Role of Collagen in Inflammation

The inflammatory phase of wound healing includes hemostasis and inflammation. Collagen exposure due to injury activates the clotting cascade, resulting in a fibrin clot that stops the initial bleeding. Collagen I and IV fragments can be mediators of inflammation by acting as potent chemo attractants for neutrophils, enhancing phagocytosis and immune responses and modulating gene expression. Inflammation is a critical step in the normal process of wound healing and drives the proliferation of fibroblasts which synthesize collagen and ECM. The resolution of inflammation in a timely manner is equally important in normal wound healing. Resolution of inflammation is an active process that is driven by balanced pro and anti-inflammatory responses. A study using a stabilized collagen matrix showed that collagen mounts a robust and sharp inflammatory response that is transient and resolves rapidly to make way for wound healing to advance. Furthermore, an important role for collagen in promoting an anti-inflammatory, pro-angiogenic wound macrophage phenotype via microRNA signaling has also been demonstrated.

Role of Collagen in Angiogenesis

Angiogenesis, a critical component of physiological (development, wound healing) and pathological (cancer) processes, is tightly regulated by the balanced activity of stimulators and inhibitors. ECM remodeling provides critical support for vascular development and collagens play an important role in this process. Depending on the type of collagen, the role might be as a promoter or inhibitor of angiogenesis. A live analysis via multiphoton microscopy of neovessel formation in vitro identified a dynamic modulation of collagen I that showed early stage remodeling of collagen fibrils progressing to collagen condensation in later stages of development. Collagen I is known to potently stimulate angiogenesis in vitro and in vivo through engagement of specific integrin receptors. Specifically, the C-propeptide fragment of collagen I recruits endothelial cells, potentially triggering angiogenesis in the healing wound. By contrast, proteolytic collagen fragments of collagen IV and XVIII (e.g., endostatin, arresten, canstatin, tumstatin) show anti-angiogenic properties. Studies have shown a role for these fragments in inhibiting proliferation and migration of endothelial cells and inducing endothelial cell apoptosis. These fragments are of interest in curbing angiogenesis in several pathological conditions.

Role of Collagen in ECM Remodeling

Collagens are a structural component of the ECM that contribute to skin flexibility in addition to stabilizing growth factors and regulating cell adhesion and signaling between cells and ECM. In the process of wound healing, as the wound tissue undergoes remodeling over years, the adult wound heals with the formation of a ‘normal’ scar. The scar tissue regains anywhere from 50–80% of the original tensile strength of normal skin but may be functionally deficient. The main difference between the scar and unwounded skin appears to be the density, fiber size and orientation of the collagen fibrils.

Abnormalities in the ECM reconstitution during wound healing result in hypertrophic and keloid scars. Scarring is a consequence of altered levels of the same molecules that typically make up the ECM^, i.e., collagen I and III, fibronectin and laminin are abnormally high in scar tissue. Collagen fiber orientation in scars (normotrophic, hypertrophic and keloid) are parallel to the epithelial surface unlike that of normal skin where the fibers form a three-dimensional basketweave-like network. There are structural and compositional differences between these types of scars. Keloid scars are characterized by abnormally thick bundles of collagen that are poorly organized with fewer cross-links that are found in the deep dermis compared to superficial dermic. Hypertrophic scars have thinner collagen bundles than keloid or normotrophic scars. The ratio of collagen I to III is higher in keloids than normotrophic scars. Even within the keloid scar, there is a heterogeneity to the collagen I/III ratio.

From the above discussed significant patronage of collagen in wound healing procedure, it was identified as equitablycoherent and constructive methodology to promote products proficient of augmenting the wound healing process in order to warrant ease to the patients who are already in a great grieve. Hence GYOGY has sternly unambiguous to promote collagen based product at an economical cost just to bring back smile in the faces of the patients.

Stages of wound healing:

            The wound healing process comprises of four important phases, they are as discussed below-

1. Hemostasis Phase, It is the process of the wound being closed by clotting.

• Happens very quickly.
• It starts when bloodleaks out of the body, then blood vessels constrict to restrict the flow.
• The platelets aggregate and adhere to the sub-endothelium surface within seconds of the rupture of a blood vessel’s epithelial wall.
• After that, the first fibrin strands begin to adhere in about sixty seconds.
• As the fibrin mesh begins, the blood is transformed from liquid to gel through pro-coagulants and the release of prothrombin.
• The formation of a thrombus/clot keeps the platelets and blood cells trapped in the wound.
• The thrombus is generally important in the stages of wound healing but becomes a problem if it detaches from the vessel wall and goes through the circulatory system, possibly causing a stroke, pulmonary embolismor heart attack.

2. Inflammatory Phase, begins right after the injury when the injured blood vessels leak transudate (made of water, salt, and protein) causing localized swelling.

• Inflammation both controls bleeding and prevents infection.
• The fluid engorgement allows healing and repair cells to move to the site of the wound.
• During the inflammatory phase, damaged cells, pathogens, and bacteriaare removed.
• The white blood cells, growth factors, nutrients and enzymes create the swelling, heat, pain and redness commonly seen during this stage of wound healing.
• Inflammation is a natural part of the wound healing process and is only problematic if prolonged or excessive.

3. Proliferative Phase commences when the wound is rebuilt with new tissue made up of collagen and extracellular matrix.

• The wound contracts as new tissues are built.
• A new network of blood vessels must be constructed so that the granulation tissue can be healthy and receive sufficient oxygen and nutrients.
• Myofibroblasts cause the wound to contract by gripping the wound edges and pulling them together using a mechanism similar to that of smooth muscle cells.
• In healthy stages of wound healing, granulation tissue is pink or red and uneven in texture. Healthy granulation tissue does not bleed easily.
• Dark granulation tissue can be a sign of infection, ischemia, or poor perfusion.
• Finally epithelial cells resurface the injury.
• Epithelialization happens faster when wounds are kept moist and hydrated.
• Generally, when occlusive or semi-occlusive dressings are applied within 48 hours after injury, they will maintain correct tissue humidity to optimize epithelialization.

4. Maturation Phase re models the collagen from type III to type I and the wound fully closes.

• The cells that had been used to repair the wound but which are no longer needed are removed by apoptosis, or programmed cell death.
• The collagen laid down during the proliferative phase is disorganized and the wound is thick.
• Collagen is remodeled into a more organized structure along lines of stress, thereby increasing the tensile strength of the healing tissues. Fibroblasts secrete matrix metalloproteinases. The enzymes facilitate remodeling of type III collagen to type I collagen.
• Generally, remodeling begins about 21 days after an injury and can continue for a year or more. Even with cross-linking, healed wound areas continue to be weaker than uninjured skin, generally only having 80% of the tensile strength of unwounded skin.