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Developed on the basis of what was "high tech" only a few years ago, when the discovery of biochemical pathways and quantification of metabolic rates opened new vistas.
It has been shown that Oxy-Mist Treatments with Amino-Plex® may help improve oxidative metabolism and enhance repair of injured tissue. Such actions are of potential value for a wide variety of clinical conditions ranging from physical injuries to the consequences of chronic vascular occlusion.
Amino-Plex® is essential for cellular re-birth. Amino-Plex®, a revolutionary cosmeceutical ingredient is exclusive to biO2 Cosmeceuticals International, Inc. Our unique combination of these ingredients is why our formulation works. It is made up of:
• natural amino acids (building blocks of the body)
• trace minerals (essential in assimilation and utilization of vitamins
and nutrients within cells)
• electrolytes (conduct electricity within the cells)
• nucleotides & nucleosides (building blocks of RNA & DNA) |
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To respond to physical injury by regenerating the destroyed structure. Mammals can only replace epithelium, liver and bone with new tissue of the same kind. The main components of response to injury in other tissues in mammals are connective tissue repair and reepithelization. Any tissue injury which causes the death of cells initiates a complex repair process. That is only partly understood at the present time.
Thus wound healing in man is a nonspecific process during which newly formed fibrous tissue restores continuity and strength, always leaving a scar, except where injury is limited to the epithelium or mucosa. It is a dynamic catabolic and anabolic process involving physiological, biochemical and morphological alternations in a highly integrated orderly plan,
Healing may be impaired by an abnormal inflammatory response impaired fibroplasia and collagen formation. Prolonged acute inflammatory responses occur when there is much necrotic tissue to remove, when wound infection ensues and when foreign bodies are present in the wound. The inflammatory phase is also protracted in patients with defective inflammatory responses, such as diabetics, in cases of polymorphonuclear granulocyte- or macrophage deficiencies, and iatrogenically following treatment with highly anti-inflammatory steroids or immunosuppressants.
Metabolic deficiencies in the wound may impede repair by delaying fibroplasia. They can be caused by local disturbances of circulation or by nutritional metabolic deficiencies. Collagen synthesis in the wound depends to a considerable degree upon the vascularity and blood circulation in the tissue. For instance, the chronic changes in tissue following radiation exposure and in patients given steroids is associated with poor vascular regeneration.
Connective tissue undergoing repair, even where healing is not impeded, consumes more nutrients and oxygen than doe’s normal connective tissue. Since circulation at a wound margin is always impaired nutritional demands are greatest when the local circulation is less able to respond. Several investigators have reported that hypoxia impedes repair, tissue removed from healing wound under hypoxic conditions have a lower capacity for oxygen- and glucose utilization and contain lower concentrations of ATP .
Experimental evidence has shown that a multitude of factors are involved in the process of wound healing and a wide variety of specific, metabolic, nutritional and other deficiencies can interfere with wound healing. Normal healing is impaired in a variety of ways when hypoxia plays a principle aetiological role. These include lowered cellular energy metabolism, diminished cell migratory activity and reduced cell proliferation. The multifactorial nature of the healing process and multifactorial deficiencies interfering with normal healing dictate the need for multifactorial therapeutic approaches to the problem, particularly when specific single mechanism disturbances cannot be identified. |
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During the process of evolution, animal species have progressively lost their ability to respond to physical injury by regenerating the destroyed tissue. Mammals can only replace epithelium, liver and bone with new tissue of the same kind, and the main components of response to injury in mammals are thus connective tissue repair and reepithelization. Any tissue injury which causes the death of cells initiates a repair process, but the factors involved are only partially understood at the present time Wound healing in man is a nonspecific process during which newly formed fibrous tissue restores continuity and strength. The healing process thus always leaves a scar, except where injury is limited to the epithelium or mucosa.
Wound healing is a dynamic process involving physiological, biochemical and morphological alternations. These events are highly integrated and follow an orderly plan, Nevertheless, they can still be influenced dramatically by metabolic and nutritional factors and can therefore be enhanced if appropriate measures are taken.
Based on histological, histochemical and electron microscopic investigations, recognized three overlapping phases of tissue repair - Inflammation, proliferation and remodeling and this classification is useful for practical purposes. Granulation tissue Is formed during the first two stages, and the wound tissue 'is reorganized during the third stage.
During the first five days following injury, the number of fibroblasts in the wound rises and collagen synthesis begins. Of all the proteins, collagen alone contains high levels of hydroxyproline and hydroxylysine. These two substances first enter the amino acid chain as proline and lysine, and are then enzymatically hydroxylated, using molecular or dissolved oxygen as substrate, ferrous iron and alpha-ketoglutarate as co-factors and reducing agents such as ascorbic acid. A deficiency of any of these substances impairs hydroxylation and probably prevents collagen extrusion from fibroblasts
Newly formed collagen can be found in the wound as early as 24 hours after injury. In primary wound healing, the highest rate of synthesis seems to occur between about the fifth and seventh days. Collagen synthesis persists at a higher rate than normal for several months, even up to a year, after injury. Parallel to this, collagen lysis also occurs, and the interplay of these two processes is the basis of wound tissue remodeling.
Synthesis and lysis proceed at different rates, and there may be net collagen loss at certain times during healing. The amount of collagen per unit volume of wound tissue drops steeply once the defect has been closed. Ordinary proteases do not break down native collagen, and specific collagenases are necessary. These enzymes are synthesized by inflammatory cells such as PMN granulocytes and macrophages. Provided that the wound is supplied with adequate levels of nutrients and oxygen, then collagen synthesis and lysis are in equilibrium. Since hydroxyproline is found only in collagen, the conversion of labeled proline to hydroxyproline allow the rate of collagen synthesis to be measured, and the specific activity of the label in hydroxyproline may be used to monitor collagen breakdown.
The proteoglycans of the tissue matrix are large complexes of protein and polysaccharide, otherwise called acid mucopolysaccharides or glycosaminoglycans. Seven different types of polysaccharide or glycosaminoglycan fractions of the molecule are recognized: chondroitin, condroitin-4-sulphate, chondroitin-6-sulphate, dermatan sulphate, heparan sulphate, keratan sulphate and hyaluronic acid. The proteoglycans are synthesized by fibroblasts, so they appear only after fibroplasia has become well established. The exact function of these molecules in connective tissue remains unclear, but it is thought that they are involved in the extracellular production of collagen fibrils and in collagen maturation. There is also evidence that proteoglycans are responsible for the formation of elastin fibrils in vitro, but the physiological significance of this is uncertain . The role played by proteoglycans in the tissue matrix is complicated further by their interactions with fibronectin, a glycoprotein which is responsible for adhesions between cells and between cells and the substratum . The pattern of proteoglycan synthesis in wounds differ according to the individual glycosaminoglycans involved and varies from tissue to tissue. In experimental skin wounds, hyaluronic acid is initially present at high concentrations, but levels fall after the fifth day; in the case of chondroitin-4-sulphate and dermatan sulphate, on the other hand, concentrations increase after the fifth day.
Cells do not bind directly to collagen, but interact via glycoproteins called attachment factors . These are large glycoproteins with specific sites for collagen, proteoglycan and cell surface receptors. So far, three different factors have been described: fibronectin, which is the best characterized, chondroitin and laminin.
Fibronectin occurs in many tissues and in plasma (CIG, cold-insoluble glycoprotein). It serves as an attachment protein for smooth muscle cells and fibroblasts to collagen types I and 111. Fibronectin may be involved in several of the wound healing processes, including: 1) maintenance of the clot bound to the wound margins, 2) chemoattractant action for fibroblasts, and 3) possible role in the attachment of macrophages to collagen and to debris during phagocytosis. Fibronectin is synthesized by a variety of different cell types, including fibroblasts , endothelial cells and epithelial cells . Studies on the nature of the cell surface receptors for fibronectin have shown that gangliosides compete with cells for binding with fibronectin molecules anchored to the collagen substratum . Gangliosides do not bind directly to cells or to collagen. It is thought that the cell surface ganglioside may be part of the fibronectin binding site, and that the carbohydrate portion could be involved. The fibronectin receptor may thus resemble the cell surface receptor for thyrotropic hormone and some other glycoprotein hormones with both glycoprotein and glycolipid components.
Laminin mediates the attachment of epithelial and endothelial cells to the collagen of the basement membrane. It is produced by epithelial cells and by both striated and smooth muscle cells. Following injury, laminin is probably synthesized initially by myofibroblasts, the first connective tissue cells to migrate into the wound area. Laminin generated by these cells may enhance the attachment of endothelial cells, thus supporting the ingrowth of new blood vessels.
The connective tissue of repair consumes more nutrients and oxygen than does normal connective tissue. The circulation at the wound margin is always impaired, so nutritional demands are greatest when the local circulation is least able to respond. If the local circulation is inadequate, then diffusion from vascularized areas is the only way of supplying the nutrients required. In large wounds, the distances between capillaries are too great; cells near to the blood supply consume the nutrients and oxygen before they can reach the central parts of the wound area. This may lead to delayed healing, or even non-union, if the Neovascularization process is inadequate. We do not yet know what processes are responsible for stimulating new blood vessel formation (angiogenesis), as the factors regulating the growth of endothelial cells are less well understood than those governing connective tissue cells. The angiogenic response is dependent upon the migration and proliferation of endothelial cells. It is not yet clear whether endothelial cell growth is regulated by a series of factors similar to those acting upon connective tissue. Soon after the arrival of fibroblasts, new capillaries and other blood vessels start growing into the wound area. 'Angiogenetic factors’ extracted from normal tissue and from tumor cell-conditioned media have been shown to induce vascularization in vivo.According to our present concept neovascularization is based on two main facts: "1. new vessels always originate from existing vessels, and 2. whatever their ultimate size or function, all new vessels begin as capillary buds. In general, angiogenesis takes three forms: 1. Generation of a whole new vascular network where a large defect has to be filled, 2. the joining with an unused circulation as when host bed provides circulation to a skin graft, and 3. joining and rejoining of vessels across a primarily healing wound".In primary repair, circulation bridges the wound by the second or third day. We do not yet fully understand how larger vessels are reconstructed . However, as most blood vessel endothelia contain fibrinolysin, thrombosed vessels may be reopened by some thrombolytic mechanism. In large tissue defects, where a whole new vascular network must be constructed sprouts of vascular cells from the vessels nearest the wound start growing into the wound area. They unite with similar sprouts from other venular or arteriolar branches to form a functioning capillary loop.
Epithelization and wound contraction are parallel but independent processes. Contraction involves the active drawing in of the normal skin surrounding the wound to reduce the size of the defect. Contraction is affected by myofibroblasts, an intermediate cell form combining the characteristics of fibroblasts and smooth muscle cells. Collagen is not essential for wound contraction.
Epidermis is a 'labile' tissue which is constantly being replaced and which can thus be regenerated without scar formation. Epithelia have their own style of repair; usually, the cells multiply at the wound edge, spread across the wound and mature to form a virtually normal epithelium consisting of one or two cell layers. If epidermis is damaged, there is a lag phase lasting about 12 hours before cells in the stratum germinativum start undergoing mitosis. Several environmental factors affect epidermal cell migration into and across the wound; the most important of these seem to be the degree of tissue hydration and oxygen availability. Epidermal cells can only migrate across or through well-hydrated tissues. In practice, they migrate across open wounds only if the lesion is kept moist and covered by an occlusive dressing or some other means of preventing evaporation. Epidermal cells can survive without oxygen, but the division and migration rates are P02-dependent, so regeneration cannot proceed under conditions of anoxia. The higher the level of oxygen in the cellular environment, the greater the potential for oxidative energy production and the higher the rate of migration. As epidermis does not have its own blood vessels, epidermal cells must migrate into the underlying tissue by moving under the wound debris, blood clot or eschar. As they advance they release collagenases, destroying the collagen connecting the viable and nonviable tissue.Superficial injuries such as second degree burns epithelize not only from the wound margin but also from hair follicles and other deep dermal structures that extrude living squamous cells onto the surface of the wound. Third degree burns, on the other hand, can heal only from the edges of the lesion.Where lesions fail to heal and form ulcers, a number of factors may be involved which inhibit epithelial cell mitosis, migration and/or adhesion to the wound surface. An inadequate energy supply (anoxia) may impair either mitosis or migration, and epithelial adherence to the wound surface depends in some unknown way on certain adhesive factors such as fibronectin, and possibly also on the type of collagen underlying the migrating epithelial cells. Squamous repair is thus dependent on the underlying tissue, the two influencing each other by mesenchymal-epithelial interaction .As granulation tissue becomes covered with epithelium, it loses its blood vessels and shrinks, and its collagen matures. The fully developed epithelial scar is thin and flat and has no dermal papillae; its surface is wrinkled as a result of shrinkage and contraction.
Healing may be delayed for one of two reasons; the inflammatory response may be abnormal, or fibroplasia and collagen formation may be impaired. Prolonged acute inflammatory responses occur when there is a lot of necrotic tissue to remove, when infection ensues and when foreign bodies are present in the wound. The inflammatory phase is also protracted in patients with defective inflammatory responses, such as diabetics, in cases of PMN granulocyte or macrophage deficiencies, and iatrogenically following treatment with highly anti-inflammatory steroids or immunosuppressants. Metabolic deficiencies in the wound may delay fibroplasia. They can be caused by local disturbances of circulation or by systemic deficiencies. Vascular regeneration is a delicate process, and it may be interrupted by histamine depletion or by numerous cytoplasmic toxins in use as chemotherapeutic agents. Vascular regeneration is poor in tissue showing chronic changes following radiation exposure and in patients given steroids. The collagen synthesis in a wound depends to a considerable ' degree upon the vascularity and blood circulation in the tissue. In healthy patients, proline hydroxylation is usually the limiting factor in-collagen synthesis, and it has been shown experimentally that deficiencies of prolylhydroxylase co-factors can delay healing; hypoxia and scurvy both reduce collagen synthesis. In adequately nourished patients, the limiting factor in collagen synthesis is thus the rate at which oxygen can be supplied to cells involved in the repair process.More oxygen and nutrients are consumed by regenerating connective tissue than by normal tissue. The delivery of nutrients to cells is related to the condition of the microcirculation and to the quantity and nature of nutrients present in the blood. The supply of the various nutrients is thus determined by their availability and diffusion constants, by capillary permeability and by the distance they have to diffuse to reach the cells. In the case of rapidly utilized nutrients such as oxygen, the utilization rate also plays a role.Several research groups, investigating a variety of wound types, have shown that hypoxia impedes repair while an elevated ambient oxygen tension improves the healing process . Tissues removed from wound healing under hypoxic conditions have been tested in vitro and shown to have a lowered capacity for oxygen and glucose utilization. Hyperoxia improves healing by accelerating the accumulation Of Collagen and enhancing repair cell differentiation, measurable as a rise in the RNA:DNA ratio Hyperoxia shifts metabolism in the wound away from anaerobic-toward aerobic glycolysis, and it activates the Krebs Cycle. The ATP concentration in the wound tissue, reduced in hypoxic animals, was shown to be higher in animals exposed to an elevated oxygen tension.
The collagen content of the tissue and the tensile strength of the wound are frequently used to evaluate the healing process, but a relatively long time elapses before the original tensile strength of the tissue has been regained. The limiting factor for collagen synthesis in adequate nourished patients is the rate of oxygen delivery to the repair cells. Moreover, hypoxia impairs the migration of these cells, slows proliferation and reduces the differentiation potential. This is a crucial factor in healing wounds, since the rate of fibroblast and endothelial cell migration into the wound area determines the rate of repair. Wound healing is impaired in a variety of conditions where hypoxia plays a principle aetiological role, i.e. in conditions characterized by lowered cellular energy metabolism, diminished cell migratory activity and reduced cell proliferation. Under such conditions, the repair process can therefore be enhanced by utilizing factors which stimulate energy metabolism, migration and proliferation, particularly where support can be provided for connective tissue cells damaged, but not irreversibly destroyed, by the injury.It has also been reported that daily local hyperalimentation of experimental wounds, i.e. the injection of a mixture containing electrolytes, glucose, amino acids and vitamins into the dead space, can accelerate collagen accumulation in the repair tissue .In summary, then, it can be stated that healing in wounds subjected to chronic hypoxia and low nutrient levels can be improved if the supply of oxygen and other nutritive substances is increased.
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Which offer a challenge to the treating physician Oxy-Mist Treatments with Amino-Plex may represent a valuable aid in the treatment of various difficult to treat conditions such as a varity of chronic and intractable ulcers thermal injuries and irradiation lesions.
Decubitus ulcers present a great problem of prolonged bed occupancy and expensive and protracted nursing care . The average time per patient increases by 50% in cases with decubitus ulcers when compared with equally ill patients with no such lesions . Once a decubitus ulcer develops, and unless the principle cause of pressure is totally eliminated, it increases in size and depth and may result in serious medical complications. While early detection of ulcer formation and relief of the pressure are basic ingredients of ulcer management the repair process is still extremely slow. It is therefore desirable to accelerate healing, shorten bed occupancy and thus prevent unnecessary complications. Oxy-Mist Treatments with Amino-Plex have shown to help reduce the recovery time in patients.
By accelerating the course of wound healing and shortening bed occupancy. Most of the considerable morbidity and mortality which attend major burn injury is the result, directly or indirectly, of infections, disorders of thermoregulation and inhalation injury. Similarly, morbidity in patients with lesser burns is also related to infection. To prevent wound sepsis and septicemia, it is essential to combat infection effectively, to speed up the course of wound healing and to shorten the duration of hospital stay.
With regard to the local treatment of the burns, two different points of view prevail. The proponents of aggressive surgery advocate early excisional procedures and wound closure. The advocates of 'guided wound management', however, favor eschar elimination by means of proteolytic enzymes and enhancement of healing by the use of wound healing products and antimicrobials, with closure of extensive full-thickness burns being undertaken 3-4 weeks post-injury. Favorring the latter point of view,
Oxy-Mist Treatments with Amino-Plex may help enhances granulation tissue formation and epithelization, favor cosmetically excellent scar development, shortens the duration of hospital stay and thus reduces the risks of wound sepsis and septicemia which account for a major part of morbidity and mortality in burn injury.
To endothelial cells, speeds up the return of reversibly damaged differentiating cells to their normal state and encourages angiogenesis and the re-flow phenomenon in irradiated (ischemic) tissue.
Radiation therapy, particularly through its long term effects, presents a difficult obstacle to repair . Radiation inhibits the multiplication and differentiation of endothelial endothelial cells into proliferating vascular buds, and the concomitant intimal proliferation slowly closes blood and lymph vessels. The typical long-term effects of irradiation then develop once the tissues loses its microvasculature. The skin hardens, becomes shiny and pigmented, and teleangiectasia appear as a sign of abnormal vessel formation.
Open ulcers, in tissues severely damaged by radiation, repair poorly and remain resistant to all modes of treatment - even surgery. Debridements of irradiation ulcers are followed by surface necrosis and more debridements, unless proper measures to break the vicious circle are undertaken. To achieve this goal, the risk of hypoxic trauma to endothelial cells should be reduced, reversibly-damaged, proliferating and differentiating cells brought back to their normal state, and a properly functioning microvascular network re-established. Oxy-Mist Treatments with Amino-Plex® may help achieve this goal.
Following mechanical, thermal, immunologic or ischaemic injury, the damaged tissue transmits a number of signals; these are received by cells which ordinarily perform other functions, inducing them to act in a reparative mode when they enter the damaged tissue. The first signals arise from complement activation. In their wake come a number of chemotactic factors generated by blood clotting reactions Chemoattractant peptides released by fibrinpolymerization and lysis attract mononuclear cells. The' inflammatory response is established within about 12 hours of injury, i.e. an inflammatory exudate rich in mononuclear ' ear cells has accumulated, and this exudate transmits additional signals (,X). The cells involved include blood cells such as leucocytes, and platelets, as well as fibroblasts, smooth muscle cells, endothelial cells and, in the case of internal organs, parenchymal cells. These cells alter the surrounding milieu, withdrawing certain substances while adding others; local pH and pC02 fall, pC02 rises, glucose is rapidly utilized and lactate accumulates.
Phagocytic cells (leucocytes and macrophages) are the first to accumulate in the wound, with polymorphonuclear (PMN) granulocytes and lymphocytes predominating during the first few days. They act to inhibit and kill contaminating bacteria. Leucoattractants are released immediately following injury, and the highly motile PMN leucocytes arrive at the scene first. They are attracted by the same factors as macrophages, which appear 24 hours later. These include bacterial products and platelet factors 4 do and C5a
Macrophages predominate by about the fifth day and take over the direction of repair at this stage. They secrete substances which induce fibroblast replication (MDGF=macrophagederived growth factor) and attract blood vessels to the wound (WAF @ wound angiogenesis factor) (4). Macrophages also ingest debris, process macromolecules to useful amino acids and sugars and attract other macrophages. They secrete lactate, and this stimulates collagen synthesis by fibroblasts. The macrophage is the key element in the inflammatory response to injury.
Fibroblasts are not seen in normal tissue, but they begin to appear in the actively healing wound on the third or fourth day after injury, along with smooth muscle cells. We are just starting to understand the nature of the chemical substances which cause a sudden burst of fibroblast replication near the area of injury. Thrombin-activated platelets release 'plateletderived growth factor' (PDGF) almost immediately after injury, and PDGF present in a-granules is liberated following platelet aggregation. PDGF attracts connective tissue cells (fibroblasts and smooth muscle cells) and acts together with other factors present in the plasma, such as somatomedins and insulin, to induce them to undergo DNA synthesis and cell division. PDGF can only be found in damaged tissue and not in plasma.
The great majority of fibroblasts is actually formed within the wound (perivascular cells). In-vitro tests have shown that fibroblasts are attracted by collagen, collagen a-chains and collagenous peptides, as well as by fibronectin (9), fibronectin fragments and PDGF . The fibroblast synthesizes collagen, proteoglycans, elastin and fibronectin.
The extra cellular matrix consists of collagen, glycoproteins and proteoglycans. These molecules interact with each other and with the cells present in the tissue. During normal repair, it is the type and quantity of the newly formed matrix which determine the integrity of the repair tissue.
The major structural component of repair tissue is the fibrous protein collagen. Together with mucopolysaccharides, it fills the gap left by injury. It also attracts fibroblasts. The collagenous matrix produces a network of interlacing fibers which bind the edges of the wound together; the collagen-mucopolysaccharide matrix forms a wound bed which is penetrated by new blood vessels and over which new and migrating epithelium can grow. The collagen matrix gives the healing wound its mechanical strength, with a strong correlation during the first two or three weeks after injury between collagen content and tensile strength.
The synthesis of collagen follows much the same course as for other proteins, but there are some peculiarities which are of significance in wound healing.
The main stages of collagen biosynthesis are:
1. Fibroblast proliferation
2. Amino acid chain production
3. Hydroxylation
4. Glycosylation
5. Collagen extrusion from fibroblasts
6. Telopeptide removal
7. Aldehyde cross-linking
8. Arrangement along lines of stress
9. Binding to glycosaminoglycans
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