Healing

Last updated
Diagram featuring stages of tissue healing 417 Tissue Repair.jpg
Diagram featuring stages of tissue healing

With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area and replace it with new living tissue. The replacement can happen in two ways: by regeneration in which the necrotic cells are replaced by new cells that form "like" tissue as was originally there; or by repair in which injured tissue is replaced with scar tissue. Most organs will heal using a mixture of both mechanisms.[ citation needed ]

Contents

Within surgery, healing is more often referred to as recovery, and postoperative recovery has historically been viewed simply as restitution of function and readiness for discharge. More recently, it has been described as an energy‐requiring process to decrease physical symptoms, reach a level of emotional well‐being, regain functions, and re‐establish activities [1]

Healing is also referred to in the context of the grieving process. [ citation needed ]

In psychiatry and psychology, healing is the process by which neuroses and psychoses are resolved to the degree that the client is able to lead a normal or fulfilling existence without being overwhelmed by psychopathological phenomena. This process may involve psychotherapy, pharmaceutical treatment or alternative approaches such as traditional spiritual healing.[ citation needed ]

Regeneration

In order for an injury to be healed by regeneration, the cell type that was destroyed must be able to replicate. Cells also need a collagen framework along which to grow. Alongside most cells there is either a basement membrane or a collagenous network made by fibroblasts that will guide the cells' growth. Since ischaemia and most toxins do not destroy collagen, it will continue to exist even when the cells around it are dead.[ citation needed ]

Example

Acute tubular necrosis (ATN) in the kidney is a case in which cells heal completely by regeneration. ATN occurs when the epithelial cells that line the kidney are destroyed by either a lack of oxygen (such as in hypovolemic shock, when blood supply to the kidneys is dramatically reduced), or by toxins (such as some antibiotics, heavy metals or carbon tetrachloride).[ citation needed ]

Although many of these epithelial cells are dead, there is typically patchy necrosis, meaning that there are patches of epithelial cells still alive. In addition, the collagen framework of the tubules remains completely intact.[ citation needed ]

The existing epithelial cells can replicate, and, using the basement membrane as a guide, eventually bring the kidney back to normal. After regeneration is complete, the damage is undetectable, even microscopically.[ citation needed ]

Healing must happen by repair in the case of injury to cells that are unable to regenerate (e.g. neurons). Also, damage to the collagen network (e.g. by enzymes or physical destruction), or its total collapse (as can happen in an infarct) cause healing to take place by repair.[ citation needed ]

Genetics

Many genes play a role in healing. [2] For instance, in wound healing, P21 has been found to allow mammals to heal spontaneously. It even allows some mammals (like mice) to heal wounds without scars. [3] [4] The LIN28 gene also plays a role in wound healing. It is dormant in most mammals. [5] Also, the proteins MG53 and TGF beta 1 play important roles in wound healing. [6]

Wound healing

Wounded patients at the Red Cross Hospital in Tampere, Finland during the 1918 Finnish Civil War Haavoittuneita Punaisen ristin sairaalassa Tampereella (26901645371).jpg
Wounded patients at the Red Cross Hospital in Tampere, Finland during the 1918 Finnish Civil War

In response to an incision or wound, a wound healing cascade is unleashed. This cascade takes place in four phases: clot formation, inflammation, proliferation, and maturation.

Clotting phase

Healing of a wound begins with clot formation to stop bleeding and to reduce infection by bacteria, viruses and fungi. Clotting is followed by neutrophil invasion three to 24 hours after the wound has been incurred, with mitoses beginning in epithelial cells after 24 to 48 hours.[ citation needed ]

Inflammation phase

In the inflammatory phase, macrophages and other phagocytic cells kill bacteria, debride damaged tissue and release chemical factors such as growth hormones that encourage fibroblasts, epithelial cells and endothelial cells which make new capillaries to migrate to the area and divide.[ citation needed ]

Proliferative phase

In the proliferative phase, immature granulation tissue containing plump, active fibroblasts forms. Fibroblasts quickly produce abundant type III collagen, which fills the defect left by an open wound. Granulation tissue moves, as a wave, from the border of the injury towards the center.[ citation needed ]

As granulation tissue matures, the fibroblasts produce less collagen and become more spindly in appearance. They begin to produce the much stronger type I collagen. Some of the fibroblasts mature into myofibroblasts which contain the same type of actin found in smooth muscle, which enables them to contract and reduce the size of the wound.[ citation needed ]

Maturation phase

During the maturation phase of wound healing, unnecessary vessels formed in granulation tissue are removed by apoptosis, and type III collagen is largely replaced by type I. Collagen which was originally disorganized is cross-linked and aligned along tension lines. This phase can last a year or longer. Ultimately a scar made of collagen, containing a small number of fibroblasts is left.[ citation needed ]

Tissue damaged by inflammation

After inflammation has damaged tissue (when combatting bacterial infection for example) and pro-inflammatory eicosanoids have completed their function, healing proceeds in 4 phases. [7]

Recall phase

In the recall phase the adrenal glands increase production of cortisol which shuts down eicosanoid production and inflammation.[ citation needed ]

Resolution phase

In the Resolution phase, pathogens and damaged tissue are removed by macrophages (white blood cells). Red blood cells are also removed from the damaged tissue by macrophages. Failure to remove all of the damaged cells and pathogens may retrigger inflammation. The two subsets of macrophage M1 & M2 plays a crucial role in this phase, M1 macrophage being a pro inflammatory while as M2 is a regenerative and the plasticity between the two subsets determine the tissue inflammation or repair.[ citation needed ]

Regeneration phase

In the Regeneration phase, blood vessels are repaired and new cells form in the damaged site similar to the cells that were damaged and removed. Some cells such as neurons and muscle cells (especially in the heart) are slow to recover.[ citation needed ]

Repair phase

In the Repair phase, new tissue is generated which requires a balance of anti-inflammatory and pro-inflammatory eicosanoids. Anti-inflammatory eicosanoids include lipoxins, epi-lipoxins, and resolvins, which cause release of growth hormones.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Fibroblast</span> Animal connective tissue cell

A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals.

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

<span class="mw-page-title-main">Scar</span> Area of fibrous tissue that replaces normal skin after an injury

A scar is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in some degree of scarring. An exception to this are animals with complete regeneration, which regrow tissue without scar formation.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

<span class="mw-page-title-main">Bone healing</span> Healing from bone injury

Bone healing, or fracture healing, is a proliferative physiological process in which the body facilitates the repair of a bone fracture.

<span class="mw-page-title-main">Wound healing</span> Series of events that restore integrity to damaged tissue after an injury

Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.

<span class="mw-page-title-main">Fibrosis</span> Excess connective tissue in healing

Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue.

<span class="mw-page-title-main">Lipoxin</span> Acronym for lipoxygenase interaction product

A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size. Examples of granulation tissue can be seen in pyogenic granulomas and pulp polyps. Its histological appearance is characterized by proliferation of fibroblasts and thin-walled, delicate capillaries (angiogenesis), and infiltrated inflammatory cells in a loose extracellular matrix.

<span class="mw-page-title-main">Bowed tendon</span>

Tendinitis/tendonitis is inflammation of a tendon, often involving torn collagen fibers. A bowed tendon is a horseman's term for a tendon after a horse has sustained an injury that causes swelling in one or more tendons creating a "bowed" appearance.

Protection from mechanical injury, chemical hazards, and bacterial invasion is provided by the skin because the epidermis is relatively thick and covered with keratin. Secretions from sebaceous glands and sweat glands also benefit this protective barrier. In the event of an injury that damages the skin's protective barrier, the body triggers a response called wound healing. After hemostasis, inflammation white blood cells, including phagocytic macrophages arrive at the injury site. Once the invading microorganisms have been brought under control, the skin proceeds to heal itself. The ability of the skin to heal even after considerable damage has occurred is due to the presence of stem cells in the dermis and cells in the stratum basale of the epidermis, all of which can generate new tissue.

<span class="mw-page-title-main">Myofibroblast</span>

A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.

The dermal equivalent, also known as dermal replacement or neodermis, is an in vitro model of the dermal layer of skin. There is no specific way of forming a dermal equivalent, however the first dermal equivalent was constructed by seeding dermal fibroblasts into a collagen gel. This gel may then be allowed to contract as a model of wound contraction. This collagen gel contraction assay may be used to screen for treatments which promote or inhibit contraction and thus affect the development of a scar. Other cell types may be incorporated into the dermal equivalent to increase the complexity of the model. For example, keratinocytes may be seeded on the surface to create a skin equivalent, or macrophages may be incorporated to model the inflammatory phase of wound healing.

Dermal fibroblasts are cells within the dermis layer of skin which are responsible for generating connective tissue and allowing the skin to recover from injury. Using organelles, dermal fibroblasts generate and maintain the connective tissue which unites separate cell layers. Furthermore, these dermal fibroblasts produce the protein molecules including laminin and fibronectin which comprise the extracellular matrix. By creating the extracellular matrix between the dermis and epidermis, fibroblasts allow the epithelial cells of the epidermis to affix the matrix, thereby allowing the epidermal cells to effectively join together to form the top layer of the skin.

<span class="mw-page-title-main">Diabetic foot ulcer</span> Medical condition

Diabetic foot ulcer is a breakdown of the skin and sometimes deeper tissues of the foot that leads to sore formation. It may occur due to a variety of mechanisms. It is thought to occur due to abnormal pressure or mechanical stress chronically applied to the foot, usually with concomitant predisposing conditions such as peripheral sensory neuropathy, peripheral motor neuropathy, autonomic neuropathy or peripheral arterial disease. It is a major complication of diabetes mellitus, and it is a type of diabetic foot disease. Secondary complications to the ulcer, such as infection of the skin or subcutaneous tissue, bone infection, gangrene or sepsis are possible, often leading to amputation.

Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, or partial regeneration, which involves closing up the injury site with some gradation of scar tissue. Some tissues such as skin, the vas deferens, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury.

Scar free healing is the process by which significant injuries can heal without permanent damage to the tissue the injury has affected. In most healing, scars form due to the fibrosis and wound contraction, however in scar free healing, tissue is completely regenerated. During the 1990s, published research on the subject increased; it is a relatively recent term in the literature. Scar free healing occurs in foetal life but the ability progressively diminishes into adulthood. In other animals such as amphibians, however, tissue regeneration occurs, for example as skin regeneration in the adult axolotl.

<span class="mw-page-title-main">Dermal macrophage</span> Skin macrophages used for wound repair and hair growth

Dermal macrophages are macrophages in the skin that facilitate skin homeostasis by mediating wound repair, hair growth, and salt balance. Their functional role in these processes is the mediator of inflammation. They can acquire an M1 or M2 phenotype to promote or suppress an inflammatory response, thereby influencing other cells' activity via the production of pro-inflammatory or anti-inflammatory cytokines. Dermal macrophages' ability to acquire pro-inflammatory properties also potentiates them in cancer defence. M1 macrophages can suppress tumour growth in the skin by their pro-inflammatory properties. However, M2 macrophages support tumour growth and invasion by the production of Th2 cytokines such as TGFβ and IL-10. Thus, the exact contribution of each phenotype to cancer defence and the skin's homeostasis is still unclear.

Immune system contribution to regeneration of tissues generally involves specific cellular components, transcription of a wide variety of genes, morphogenesis, epithelia renewal and proliferation of damaged cell types. However, current knowledge reveals more and more studies about immune system influence that cannot be omitted. As the immune system exhibits inhibitory or inflammatory functions during regeneration, the therapies are focused on either stopping these processes or control the immune cells setting in a regenerative way, suggesting that interplay between damaged tissue and immune system response must be well-balanced. Recent studies provide evidence that immune components are required not only after body injury but also in homeostasis or senescent cells replacement.

References

  1. Allvin, Renée; Berg, Katarina; Idvall, Ewa; Nilsson, Ulrica (March 2007). "Postoperative recovery: a concept analysis". Journal of Advanced Nursing. 57 (5): 552–558. doi:10.1111/j.1365-2648.2006.04156.x. ISSN   0309-2402. PMID   17284272.
  2. McBrearty BA, Clark LD, Zhang XM, Blankenhorn EP, Heber-Katz E (1998). "Genetic analysis of a mammalian wound-healing trait". Proc Natl Acad Sci U S A. 95 (20): 11792–7. Bibcode:1998PNAS...9511792M. doi: 10.1073/pnas.95.20.11792 . PMC   21719 . PMID   9751744.
  3. "Genetic discovery promises healing without scars". the Guardian. March 15, 2010.
  4. Bedelbaeva, Khamilia; Snyder, Andrew; Gourevitch, Dmitri; Clark, Lise; Zhang, Xiang-Ming; Leferovich, John; Cheverud, James M.; Lieberman, Paul; Heber-Katz, Ellen (March 30, 2010). "Lack of p21 expression links cell cycle control and appendage regeneration in mice". Proceedings of the National Academy of Sciences. 107 (13): 5845–5850. Bibcode:2010PNAS..107.5845B. doi: 10.1073/pnas.1000830107 . PMC   2851923 . PMID   20231440.
  5. Maron, Dina Fine. "New Limb Regeneration Insight Surprises Scientists". Scientific American.
  6. "Gene identified that helps wound healing: New research on gene that regulates healing and may control scarring". ScienceDaily.
  7. The Anti-Inflammation Zone, Barry Sears, pages 230-233, 2005.