What is Collagen?

Introduction

Collagen in the Body

Understanding Proteins

Collagen's Shape and Structure

Collagen in Human Use Products

Traditional uses of collagen in the health care field have been

Collagen's Role in Healing Skin Tissue: The Nature of Collagen makes it a Key Player in Healing

Collagen Fragmentation

Collagen and the Phases of Wound Healing

Essential Balance

The CellerateRX® Approach

Intact Collagen vs. Activated Collagen

Types of Collagen



Introduction

Collagen is a rich and powerful protein that serves multiple purposes and performs a variety of tasks in the body. Historically, collagen has been used medicinally since the Egyptian times and modern medicine has documented the use of collagen since the 1900's as suturing material. With the advent of new techniques and advances in molecular biology, researchers continue to discover new properties about this very well documented protein. Collagen can no longer be thought of as just a passive molecule that provides strength to tissue but rather as an active compound that can regulate other cells' functions.


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Collagen in the Body

Collagen is one of the most abundant proteins found in the body (30%) and in the skin (75%). Collagen has traditionally been classified as a structural protein but hormonal- and enzymatic-like properties can be attributed to it blurring the appropriate classification. This makes one question its classification as a 'structural' protein.


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Understanding Proteins


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Collagen's Shape and Structure

Collagen molecules are composed of three long strands of amino acids averaging 1,050 amino acids per strand. Amino acids can be likened to the gas that drives the engine of the car. The amino acids' chemical properties, delineated by which amino acid is in the protein, determine the function of the protein, for example, hydroxyproline is only found in type I collagen. Proteins not only catalyze most of the biological activity in living cells, they control virtually all cellular process.


The shape of the collagen molecule is uniformly a triple helix. Type I collagen is composed of three collagen fibrils wrapped around each other from a left to right direction forming the helix. In this shape the helix is called a fiber. Collagen fibers wrap around each other from a right to left direction and the resulting unit is called a bundle. Bundles and fibers continue to bind together to form the mass that is needed to fill in the defects of the wounds. The primary function of collagen is determined by its structure. If the molecule is intact, the collagen functions in the well documented traditional role of providing a foundation for cells to adhere to and providing tensile strength to tissue. If the structure of the collagen molecule is fragmented, research has shown that the predominant function is chemotactically stimulating fibroblast and macrophages.


For the intact collagen molecule, the structure gives Type I collagen its strength and maintains the integrity of the molecule in the presence of harsh environments in the body. The links that bind amino acids are positioned inward and away from the enzymes and proteases that are able to break them down due to the twisting and folding of the triple-helix shape. Collagenase is the only enzyme that is able to dissolve the links that holds the collagen in its triple-helix shape. The triple helix shape can be likened to the metal braces of a car that protects the occupants therefore; the structure of the intact collagen molecule protects the molecule from degradation.


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Collagen in Human Use Products

Collagen is available today in thousands of different products from skin creams to synthetic skin substitutes. It has been used safely and economically for many years in the health care field and is relatively easy to obtain today. The predominant type of collagen in the health care arena is sourced from bovine because of the presence of key amino acids and the sequence of the amino acids are similar to human collagen. Other sources of collagen are available such as aviary and porcine but these types of collagen are lacking key amino acids. The amino acids that distinguish human Type I collagen from other types of collagen are hydroxyproline and proline. These two amino acids provide the strength of the molecule and specifically provide the strength to the bends that shapes the form of the triple-helix.


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Traditional uses of collagen in the health care field have been


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Collagen's Role in Healing Skin Tissue: The Nature of Collagen makes it a Key Player in Healing

Introduction of collagen's role structurally, and the importance of the amino acids that comprise collagen. High level introduction of each of the types of roles that collagen will play throughout healing.


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Collagen Fragmentation

Collagen fragments are produced when damage has occurred to the binding links. The damage can be from physical trauma or from enzymatic erosion. Failed links allows the molecule to unravel and break apart exposing the amino acids. The amino acids can be absorbed by the underlying tissue and are nutritive in nature. Collagen's primary role of providing strength and structure is shifted more to a reparative role when the collagen looses its intact structure. Studies indicate that collagen fragments are Chemotactic for several key cells required for wound repair. Monocytes, when activated, turn into macrophages which are the conductors for the inflammatory phase of wound healing. The macrophage has a well documented list of functions, and just like collagen, that function list continues to grow with the advances in molecular biology. The macrophage's initial role is to break down the damaged tissue and debride and phagocytized the debris in the wound. The macrophage then turns its attention to orchestrating the simultaneous processes that move the wound from the inflammatory phase to the proliferative phase of wound healing by releasing and or stimulating the release of growth factors, helping the production of new blood vessels, regulating the building of the extracellular matrix and transitioning the wound from the inflammatory phase over to the proliferative phase.


The fibroblast is instrumental in the goal of dermal rebuilding and closure of the wound in the proliferative phase of wound healing. One of the primary functions of the fibroblast is to produce collagen to fill in the defect from the wound. The fibroblast also orchestrates the multitude of reparative processes occurring at this juncture by stimulating growth factor production, stimulating angiogenesis and releasing proteases that will allow remodeling to occur. The two types of collagen that are instrumental in wound repair are Types I and Type III with Type I predominating at a volume of 80% and Type III with a volume of 20%. During the early stages of wound healing, this ratio is initially reversed and then reverts back to Type I at 80% and type III at 20%.


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Collagen and the Phases of Wound Healing

The phases of wound healing are a dance of nature that is perfectly balanced between the production and destruction of collagen in a manner that is timely and well orchestrated. Collagen plays a key role in all three phases of the wound healing process. During the inflammatory phase, injury has occurred causing the intact skin to be punctured, underlying tissue to be damaged and blood vessels to be broken and bleed. The body builds a clot immediately to stop the bleeding from fibrin that adheres to collagen in the tissue. The clot is called a provisional matrix and will be replaced by the transitional matrix duringthe proliferative phase. Collagen fragments caused from the injury call in monocytes and fibroblasts. The monocytes adhere to the collagen and differentiate into macrophages. The macrophage and nuetrophils start the debridement of the devitalized tissue in the wound. Macrophages produce enzymes that break down the damaged collagen into smaller pieces to be used by the wound to chemotactically call in more macrophages and fibroblasts. Once the wound is cleared of devitalized tissue and debris, the macrophages are instrumental in transitioning the wound to the next phase of healing which is the proliferative phase by stimulating and secreting growth factors.


During the proliferative phase, the wound defect will be filled in with granulation tissue, new blood vessels will be stimulated to grow to support the cells that are producing the granulation tissue and an epithelial cover will be produced to close the wound. The fibroblast is the key cell that orchestrates and stimulates the above steps in the wound healing process. The granulation tissue laid down during this phase is temporary, composed of a higher percentage of Type III collagen than normal and is generally called the extracellular matrix or the transitional matrix. When the fibroblast comes in contact with mature collagen, the collagen signals the fibroblast to stop synthesis of further collagen. During the production and deposition of granulation tissue, epithelial cells from the wound edges are slowly advancing across the blood rich granulation tissue covering the granulation tissue with a thin film of epidermis. The wound is now considered closed and transition to the maturation phase of wound healing.


The fibroblasts and collagen are the instrumental cells during the maturation phase. The goal of this phase is to remove the transitional matrix, ECM composed mainly of collagen, synthesize new Type I collagen and deposit the newly synthesized collagen in an organized pattern. The fibroblasts send out enzymes that degrade the collagen in the transitional matrix and synthesize new collagen. Type III collagen covers the Type I collagen to add bulk and strength to the Type I collagen. The maturation phase can last up to twelve months for the complete removal of the ECM and deposition of Type I collagen. The wound will slowly increase in strength as more Type I collagen is deposited but will only gain back 80% of the strength of the original undamaged tissue.


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Essential Balance

The way the body repairs itself is a well documented sequence of events with specific cells and factors timed to perform their function in an efficient manner. Modern medicine has attempted to accelerate the sequence by identifying a specific growth factor and adding it arbitrarily to the wound. The success rate has been dismal because the balance in the wound chemistry was altered in a way that was not efficient or appropriate with the other cells' function at that time. One factor that is universal across the wound healing phases is the use of collagen, especially collagen fragments, by the body to orchestrate the timely sequence. Collagen fragments stimulate the two most important cells in wound healing, the macrophage and the fibroblast. The body uses these two cells to orchestrate the three phases of wound healing to achieve closure of the wound. If one is to manipulate the wound, it makes sense to manipulate it in a way that is beneficial and allow the body to follow its sequence of events that lead to wound closure and not to manipulate it in a manner that disrupts the balance of the finely honed events.


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The CellerateRX® Approach

As outlined throughout this discussion of wound healing, the body is able to achieve healing and wound closure through a delicate balance of many different cells, growth factors, and other key elements that result in healing. Introducing any single factor to the wound site can produce an imbalance that may result in not only the futile use of an expensive therapy, but inadvertently lead to the stagnation of a wound in a particular wound phase. There is strong body of evidence in the literature to support the role of collagen as a key signaling agent throughout the phases of wound healing. This signaling or chemotaxis calls in essential cells and elements to create balance in the wound bed. For this reason, CellerateRX®RX contains no synthetic elements, and provides hydrolyzed collagen to the body in an optimum form.


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Intact Collagen vs. Activated Collagen

The collagen found in CellerateRX®RX is Activated Collagen™, a patented molecular form of collagen called CRXα™. This Activated Collagen™ is actually collagen fragments at an average size which is approximatly 1/100th of native intact collagen. Fragmentation of collagen to form CRXα™ is achieved through a highly controlled hydrolysis process to achieve the ideal average size. The size of CRXα™, combined with the properties of its Type I, bovine source, provide the wound site with a form of collagen that is ready to be immediately used by the body. Other forms of collagen in commercially available products require time for the body to prepare collagen for use in its own processes, this is the CellerateRX®RX advantage.


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Types of Collagen

Currently, there are over 22 different types of collagen identified, Type I to Type XXV, distributed in every organ and tissue of the body. The functional versatility of collagen is well documented from structural scaffolding for new tissue growth to possessing chemotactic properties that regulate cellular functions. There are seven collagen molecules that have recently been discovered but their function is still a mystery.


Key characteristics of the five most documented collagen types:

Type

Location

Function

I

Extracellular; skin, tendon, bone, teeth, scar tissue. Thick fibrils and fibers

Strength and integrity of tissue, chemotactic for macrophage and fibroblast, adhesive properties, hydrophillic

II

Extracellular; cartilage and vitreous humor. Thin fibrils

Joint mobility and shock absorption

III

Extracellular; skin, muscle, blood vessels, lungs, granulation tissue Intermediate-sized fibrils

Allows for distendibility and provides strength and integrity to tissue

IV

Intracellular; basement membrane and lamina

Component forming network Mesh-like scaffold for filtration

V

Extracellular; found in all tissue and around cells as a cytoskeleton

Similar to Type III collagen


The composition of collagen is similar across the different types yet each type has unique characteristic. The types are grouped according to their physical structure, for example, Type I collagen is long and linear while Type IV collagen is in a mesh-like form. Type I collagen is used to build new tissue so needs be in a form that can be bundled together to build mass and fill in skin defects of wounds. Type IV can be found in the basement membrane of the dermis and needs to allow filtration of nutrients through it to nourish the dermis layer of the skin.


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