Tissue Repair

K. Krafts , in Encyclopedia of Toxicology (Tertiary Edition), 2022

Abstract

Tissue repair is defined every bit the restoration of tissue architecture and function following an injury. In toxicant-induced injury, tissue repair plays a principal office in determining whether the patient volition recover from injury, or whether the injury will progress and lead to decease. This article describes the process of tissue repair with particular emphasis on features unique to chemical-induced injury. The main steps in repair, along with important molecular signaling mechanisms, are reviewed. Factors determining the extent of repair following toxic injury are discussed. Features of tissue repair unique to the lung, liver, and kidney are considered. Finally, the importance of tissue repair in the development of treatment strategies following toxic exposure is discussed.

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Role of Tissue Repair and Death Proteins in Liver Injury

Harihara 1000. Mehendale , in Drug-Induced Liver Disease (Third Edition), 2022

Conclusions

Tissue repair is a dynamic restorative cell proliferation and tissue regeneration response stimulated in order to overcome acute toxicity and recover organ/tissue construction and function. Extensive evidence in rodent models using structurally and mechanistically diverse hepatotoxicants such as acetaminophen, allyl booze, CCl 4, CHCliii, dichlorobenzene, TCE, and thioacetamide has demonstrated that tissue repair plays a critical function in determining the final outcome of toxicity, i.e., recovery from injury and survival, or progression of injury leading to liver failure and death. Tissue repair is a complex process governed past intricate cellular signaling involving a number of chemokines, cytokines, growth factors, and nuclear receptors leading to promitogenic gene expression and cell division. Tissue repair also encompasses regeneration of the hepatic extracellular matrix and angiogenesis, processes that are necessary to completely restore the structure and function of liver tissue lost to toxicant-induced initiation of injury followed by progression of that injury mediated by lytic enzymes. The lytic enzymes, such as calpain and sPLA2, that spill out of cells necrosing equally a consequence of the initiated injury destroy both perinecrotic partially afflicted and unaffected cells past degrading their plasma membrane upon activation by Caii+ in the Ca2+-rich (1.3   mM) extracellular milieu.

New insights take emerged since the 1960s, indicating that tissue repair follows a dose response. Tissue repair increases with the toxicant dose until a threshold dose is reached, across which information technology is delayed and impaired due to inhibition of cellular signaling, resulting in runaway secondary events that crusade tissue destruction, organ failure, and decease [ninety]. A prompt and adequately stimulated tissue repair response to toxic injury is critical to stopping decease protein-mediated expansion of liver injury for recovery from toxic injury. Tissue repair is modulated by a variety of factors, including historic period, disease, nutrition, species, and strain, which cause marked changes in susceptibility and toxic outcome. This chapter has focused on the properties of tissue repair and the unlike factors affecting tissue repair. The mechanisms that govern tissue repair and progression of injury are initiated past toxicants. It as well highlighted the significance of tissue repair equally a target for drug development strategies and as an important consideration in the assessment of risk from exposure to toxicants. Furthermore, the new findings on the mechanisms of injury expansion also suggest valuable therapeutic approaches to arresting the expansion of liver injury by targeting the death proteins such as calpain and sPLA2 [52,53,89,92].

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Liver

J.Due east. Kester , in Encyclopedia of Toxicology (Third Edition), 2022

Stage II: Repair or Progression

Tissue repair is a dynamic procedure, modified by species, strain, age, and other private characteristics, that opposes progression of injury from developing into organ failure and death. Tissue repair has been observed to increase in a dose-dependent manner up until a threshold dose is exceeded. Depression to moderate doses stimulate tissue repair, but its onset is increasingly delayed equally the dose rises. Thus, at doses beyond a certain threshold, the tissue repair response is too picayune and too late to arrest the progression of injury.

While much is known near the Phase I injury processes, the mechanisms responsible for Stage Two events are less well understood. Three mechanisms appear to be involved in progression of injury: (ane) activation of inflammatory cells, (ii) production of free radicals and oxidative stress, with subsequent lipid peroxidation, and (3) leakage of degradative enzymes from the dying and injured cells.

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New Strategies to Enhance Stem Cell Homing for Tissue Repair

Leslie W. Miller , in Stalk Cell and Gene Therapy for Cardiovascular Affliction, 2022

Tissue repair is an essential mechanism to maintain the integrity and part of the body in response to a variety of both acute and chronic injuries and illness states. I of the major challenges to achieve clinically meaningful tissue regeneration and repair is a better understanding of the mechanisms involved in both native or endogenous, as well equally exogenous stem cell homing of transplanted cells. Both approaches involve a complex network of factors and sequence of events that drive the trafficking and homing of stem cells to the area of injury to optimize repair. This affiliate volition review the major factors that orchestrate stem cell homing, and discuss a number of new jail cell and tissue-based strategies to improve the homing, engraftment, and efficacy of cell therapy.

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Neurogenesis in Cerebrovascular Disease

D.A. Greenberg , in Primer on Cerebrovascular Diseases (Second Edition), 2022

Introduction

Tissue repair is as old as tissues themselves, as it can be observed in the well-nigh primitive multicellular organisms. Still, evolution confers tissue complexity and cellular specialization at a price, which includes less effective repair capacity. As the most circuitous and nearly specialized tissue, brain is as well the most difficult to regenerate after injury, such every bit that associated with cerebrovascular disease. Nevertheless, mechanisms for brain regeneration and repair exist. 1 such mechanism involves the manufacture of new cognitive neurons, or neurogenesis, which occurs at select sites in the brain and may contribute to functional recovery from stroke.

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Hypoxia and Hypoxia Signaling in Tissue Repair and Fibrosis

Zerina Lokmic , ... Ian A. Darby , in International Review of Cell and Molecular Biology, 2022

1 Introduction

Tissue repair and wound healing is a highly orchestrated sequence of complex overlapping events that are precisely timed to repair damage, prevent infection, and restore office of tissue after injury or insult. The procedure used by the organism to repair tissue is broadly like in many tissues, so that wound healing in the skin can be used as a model of tissue repair that in many respects resembles the repair process carried out elsewhere in the body. In the example of peel wound repair, these events are classically divided into inflammatory, proliferation, and remodeling phases ( Clark, 1996; Fig. 3.1). Invasion by inflammatory cells debrides the wound of damaged tissue and prevents infection, while releasing soluble factors that stimulate chemotaxis of fibroblasts and endothelial cells to grade the granulation tissue (Singer and Clark, 1999). Simultaneously, rapid migration of keratinocytes covers and seals the wound from the external environs to forestall infection. In postnatal total-thickness wound repair regardless of the type of injury be information technology burns, pathological damage, toxin related, autoimmune, or physical trauma, the inevitable event is scarring and in the example of chronic organ damage, subsequent loss of tissue role (Darby and Hewitson, 2007).

Figure 3.i. Schematic overview of the wound healing phases over time and the peak of different cells during these phases. This dynamic process is classically divided into 3 overlapping phases: inflammation (astute or chronic), proliferation (fibrogenesis and angiogenesis), and remodeling (acute or chronic). During tissue repair, cells migrate speedily into the wound site and eventually form the granulation tissue. Eventually, wounds contract and cellularity is later reduced via apoptosis. Matrix is degraded by MMPs. The scars of resulting mature wounds are relatively acellular and avascular.

 Adopted from Greenhalgh (1998).

Wound healing inherently involves a complex series of interactions between cells, chemic signals, extracellular matrix proteins, and microenvironments collectively termed "dynamic reciprocity" (Singer and Clark, 1999). Alteration to the precise nature of these events leads to lacking wound healing and/or abnormal scar formation (Clark, 1996). A cardinal determinant of this microenvironment is tissue oxygenation. Blood vessels office as conduits for the delivery of oxygen and nutrients in all physiological and pathological states. Following injury, vessel office is compromised leading to acute tissue hypoxia and the hypoxic state is sustained farther due to rapid influx of inflammatory and mesenchymal cells with a high metabolic demand for oxygen (Remensnyder and Majno, 1968). Local relative hypoxia has been observed in wounds past direct measurement of local oxygen pressure and its necessity in maintaining practiced angiogenesis during wound healing has been well defined (Knighton et al., 1981). In this review, the general mechanics of wound healing are reviewed with accent on the office of hypoxia and its signaling pathways on the wound healing procedure. A detailed exam of skin wound healing and kidney disease is used as illustrative examples of repair and pathological fibrosis in full general.

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Tissue Engineering Craniofacial Os Products

Darja Marolt , in Stem Cell Biological science and Tissue Technology in Dental Sciences, 2022

40.iv.iii.3 Aastrom Biosciences Os Marrow-Derived Prison cell Transplants (Tissue Repair Cells)

Tissue repair cells are a proprietary product derived from autologous bone marrow. Mononuclear cells are expanded in civilisation in a unmarried-step 12-day culture procedure with a ramped medium perfusion schedule, using proprietary bioreactor technology (Aastrom Replicell Organisation, ARS), to generate a cell population containing high doses of stem and progenitor cells (run across Department 40.3.four) [73,100]. Tissue repair prison cell-based products take been used to treat over 240 patients in several clinical trials for bone regeneration, including: osteonecrosis of the femoral caput (Phase 2, completed; ClinicalTrials.gov identifier: NCT00505219); non-wedlock fractures (Phase 1/Phase 2, completed; ClinicalTrials.gov identifier: NCT00424567); posterior lumbar spine fusion (Phase ane/Phase 2, completed; ClinicalTrials.gov identifier: NCT00797550); alveolar bone defects (Phase 1/Phase ii, status unknown; ClinicalTrials.gov identifier: NCT00755911); and sinus flooring bone augmentation (Phase ane/Stage 2, ongoing, not recruiting; ClinicalTrials.gov identifier: NCT00980278) (www.clinicaltrials.gov, www.aastrom.com). Aastrom has reported positive interim clinical trial results for TRCs, suggesting both the clinical rubber and the ability of TRCs to promote healing [100].

Kaigler and colleagues characterized the os repair cells produced with Aastrom technology, and used them to repair a localized craniofacial defect after molar extraction [101]. The patient received cultured cells absorbed onto a gelatin sponge (Gelfoam, Pfizer, USA), followed by dental implant placement afterwards 6 weeks. Tissue biopsy at the fourth dimension of implant placement showed highly vascularized, mineralized os tissue formation through entire length of the cadre [101].

Mendonca and Juiz-Lopez used tissue repair cells for facial reconstruction of final stage osteoradionecrosis and other advanced craniofacial diseases in three patients [102]. The cells were mixed with platelet-rich and platelet-poor plasma and beta-tricalcium phosphate/hydroxyapatite to form a TE bone substitute. In all cases, implants were inserted in grafted and non-grafted areas after iv months. Results in the first patient with maxillary and mandibular radionecrosis with pathologic fracture showed early osteogenesis, and full recovery from alveolar nerve anesthesia, facial nerve reinnervation, and skin regeneration. Some other patient with nonhealed fracture, os loss, and bilateral paresthesia demonstrated callus formation, os regeneration, and nerve recovery. Finally, the third patient showed maxillary bone regeneration after massive deficiency. Restoration of oral functional with implants and stock-still prosthesis was accomplished in all cases [102].

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Wound Healing

Patricia J. Provost , in Equine Surgery (Quaternary Edition), 2022

Nutritional Condition

Tissue repair is an anabolic procedure, and data suggest that healing may be improved with diets containing adequate protein. 98,99 Malnutrition preceding surgery or at the fourth dimension of trauma can greatly influence result. In animal studies, poly peptide deficiency directly delayed the charge per unit of wound healing through the suppression of fibroblast proliferation, angiogenesis, collagen synthesis, and remodeling. 100 In a big study involving war veterans, low preoperative serum albumin level was identified as the most significant variable for predicting surgical complications, including wound infection and acute wound failure. 101 Although comparable studies do not exist for the horse, information technology seems reasonable to expect similar results. Vitamins and micronutrients are as well known to impact healing when either deficient or in excess. 4,102 Vitamin A is essential for normal cell differentiation, and deficiencies can outcome in impaired collagen synthesis and cross-linking and in delays in epithelialization. 103 Vitamin C and the B vitamins (thiamine, pyridoxine, and riboflavin) are of import cofactors in collagen cantankerous-linking reactions, whereas vitamin E stabilizes cell membranes. Iron not only is necessary for blood-red blood cell production but also is required as a cofactor in collagen synthesis. Zinc is a cofactor in many enzymatic reactions including DNA and protein synthesis. All of these mechanisms are necessary steps in the healing procedure.

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Myogenesis

Antonio L. Serrano , ... Pura Muñoz-Cánoves , in Current Topics in Developmental Biological science, 2022

2 Muscle Tissue Regeneration: To Repair or Pathologically Scar

Tissue repair normally occurs very quickly subsequently mechanical trauma, exposure to toxins or infections which cause tissue injury. However, rapid resolution of tissue injury requires a sequential and well-orchestrated series of events. Perturbation of whatsoever of these stages tin upshot in unsuccessful muscle regeneration, typically characterized by persistent myofiber degeneration, inflammation, and pathological scarring or fibrosis, which is essentially an excessive aggregating of ECM components (reviewed in Grounds et al., 2005; Kaariainen et al., 2000; Wynn, 2008). The cardinal events leading to normal and defective/fibrotic musculus repair are detailed in Fig. 7.2 and as follows.

Figure 7.2. Cellular and soluble effectors of fibrosis in skeletal muscle repair. Replacement of damaged musculus fibers is mediated by tissue-resident stem cells, the satellite cells, which are usually quiescent and located under the basal lamina of muscle fibers (acme right). Acute and chronic injury leads to activation, proliferation, and differentiation of these cells, withal, their concluding ability to mediate repair is modified by the extent and type of injury and consequently their interaction with diverse cellular and soluble mediators. Tissue-resident and extravasating peripheral macrophages play an of import early role, with classically activated M1 macrophages interim kickoff to clear the damage and alternatively activated M2 macrophages (left) acting at later stages in tissue repair and fibrosis. M1 and M2 macrophages release a range of pro- and anti-inflammatory cytokines, respectively, that deed on both myogenic cells and fibroblasts (center). Activated fibroblasts (termed myofibroblasts) respond to damage and growth factor/cytokine signals by releasing a host of agents that attune extracellular matrix (ECM) formation, including TGFβ, metalloproteinases (MMPs) and their inhibitors, the TIMPs, dissimilar types of collagen and other molecules. Aberrations in the intensity, the kinetics, or the interaction of these various factors, such as in aging and the muscular dystrophies, leads to excessive ECM accumulation and replacement of muscle with fibrotic tissue (lesser right). (See Color Insert.)

Immediately afterwards skeletal muscle injury, cytokines and growth factors are released from both the injured blood vessels and infiltrating inflammatory cells (reviewed by Chazaud et al., 2009; Tidball and Villalta, 2010). These factors stimulate migration of inflammatory cells to and at the site of injury, also as mediating proliferation and cell survival, whereas invading inflammatory cells are also responsible for phagocytosing prison cell debris. The specific role of many impairment signals, growth factors, and inflammatory molecules on satellite cell behavior is still being investigated (Greenish et al., 2009; Tidball and Villalta, 2010), but the next critical stage of repair is the formation of new musculus fibers via these cells. This begins with their activation since satellite cells normally lie beneath the muscle basal lamina of musculus fibers in a quiescent state. Extensive proliferation follows activation, with some cells undergoing self-renewal to replenish the satellite cell pool whereas most undergo commitment and subsequent differentiation, whereby myoblasts fuse either to themselves, or to the damaged myofibers to supplant the lost muscle.

In add-on to inflammatory and satellite cells, efficient muscle repair also requires the migration and proliferation of fibroblasts to produce new and temporary ECM components, such as collagen type I, collagen type Iii, fibronectin, elastin, proteoglycans, and laminin, in order to stabilize the tissue and serve as a scaffold for new fibers. In addition to new ECM components, satellite cells likewise utilize the basement membranes of preexisting necrotic fibers to maintain a similar myofiber position. Basement membranes and temporary ECM components are also critical for guiding the formation of neuromuscular junctions (NMJs; Lluri et al., 2006). Germination and degradation of the ECM is performed by several proteases and their specific inhibitors which are expressed during tissue repair. ECM degradation also leads to the generation of protein fragments that provide important biological activities needed to facilitate normal tissue repair at an injury site (Chen and Li, 2009). Aberrant or dysregulated ECM accumulation during repair is thus the classical definition of fibrosis. Finally, in improver to ECM remodeling, angiogenesis facilitates development of a new vascular network at the site of injury while newly formed muscle fibers undergo growth and maturation.

Although this summary underscores the process in skeletal muscle, similar processes are known to occur in other organs and tissues. Overall information technology emphasizes that fibrosis-associated pathology is a complicated sequence of mechanisms whose cardinal is the sustained interaction between activated immune and structural cells with both soluble and cell-associated factors that are able to requite rising to pronounced harm of tissue or organ function and even death. As in other fibrotic conditions, sustained or aberrant activation of the wound-healing process is the most common and relevant mechanism for inducing fibrosis. In skeletal muscle and particularly in DMD, this may exist further divers by the post-obit cardinal features: (i) persistence of muscle tissue harm in conjunction with different degrees of necrosis and apoptosis; (ii) the recruitment and persistence of inflammatory cells which release profibrotic growth factors and cytokines; (three) recruitment and activation of ECM-producing cells; and (iv) qualitative and quantitative changes in the ECM which limit the capacity for repair in the presence of persistent degeneration. In this review, nosotros volition overview these key points and discuss how the persistence of muscle damage-driven inflammation is a dominant promoter of fibrosis in skeletal muscle. Indeed, damage to tissues, and to muscle tissue in particular, tin outcome from a variety of astute or chronic stimuli, but pathogenic fibrosis typically results from chronic inflammatory reactions.

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Regenerative Medicine and Tissue Engineering

Frank P. Luyten , ... Francesco Dell'Accio , in Kelley and Firestein's Textbook of Rheumatology (10th Edition), 2022

Because tissue repair mimics the cellular and molecular cascade of embryonic tissue formation, investigating the role of developmental pathways in articulation and skeletal disorders/diseases could identify novel therapeutic targets.

Tissue repair and regeneration are partially determined by genetic factors.

Tissue engineering has adopted the concept of biomimetics of in vivo tissue evolution. Developmental engineering is the term used to describe novel methodology for the rational and accurate design of robust, well-controlled manufacturing processes of "biological spare parts."

Cellular therapeutics and their combination products are complex with regard to their machinery of action and manufacturing and accept evolved into avant-garde therapy medicinal products with a specific regulatory path.

Recent advances in regenerative medicine and tissue engineering relevant to rheumatology have entered clinical practice and include the biologic repair of joint surface defects and bone healing.

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