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PubMed1995

[The bone-implant-interface: an experimental study on the effects of micro-motion].

Aseptic loosening of a prosthesis is a hazardous problem after total joint replacement. In revision surgery, fibrous granulation tissue is always seen between the prosthesis and the bone or between the bone cement and the bone. We refer to this granulation tissue as the "bone-implant-interface" and it invades into the bone, resulting in osteolysis around the prosthesis. In order to investigate the histology of this granulation tissue and the mechanism of bone resorption, we produced an experimental model of the loosening of implants (alumina ceramic, PMMA, HDP) in the distal femoral condyles of rabbit. Each implant was inserted into the distal femoral condyle and connected with a Kirschner wire which was wired down to the tibia and fixed tightly to the tibial cortex. The implants could then be mobilized when the rabbits moved their knees. We called this a "micro-motion model". Besides doing this, we also developed a similar model in rabbit with ferritin-induced arthritis to investigate whether or not arthritis exacerbated the loosening of a prosthesis. The histological examinations of the bone-implant-interface in the micro-motion model in normal rabbit revealed three layers: a surface layer containing small round cells such as synovial lining cells, a middle layer containing many fibroblasts, macrophages and giant cells which phagocytize wear debris, and a deep layer adjacent to the bone containing many osteoclasts. In the models with ferritin-induced arthritis, more synovial lining cells were seen in the surface layer and more osteoclasts were seen in the deep layer. Also more osteolysis occurred around the implant in the arthritis model. In summary, the results suggested that the mechanical stress of motion stimulated the growth of synovial lining cells and macrophages in the bone-implant-interface, resulting in increased numbers of osteoclasts and in subsequent osteolysis.

Animals↗
PubMed2006

Recruitment of a prostaglandin E receptor subtype, EP3-expressing bone marrow cells is crucial in wound-induced angiogenesis.

E-type prostaglandins have been reported to be proangiogenic in vivo. Thus, we examined prostaglandin receptor signaling relevant to wound-induced angiogenesis. Full-thickness skin wounds were created on the backs of mice, and angiogenesis in wound granulation tissues was estimated. Wound closure and re-epithelization in EP3 receptor knockout mice (EP3-/-) were significantly delayed compared with their wild-type (WT) mice, whereas those in EP1-/-, EP2-/-, and EP4-/- were not delayed. Wound-induced angiogenesis estimated with CD31 immunohistochemistry in EP3-/- mice was significantly inhibited compared with that in WT mice. Immunoreactive vascular endothelial growth factor (VEGF) in wound granulation tissues in EP3-/- mice was markedly less than that in WT mice. Wound closure in WT mice was delayed significantly by VEGF neutralizing antibody compared with control IgG. Wound-induced angiogenesis and wound closure were significantly suppressed in EP3-/- bone marrow transplantation mice compared with those in WT bone marrow transplantation mice. These were accompanied with the reductions in accumulation of VEGF-expressing cells in wound granulation tissues and in mobilization of VEGF receptor 1-expressing leukocytes in peripheral circulation. These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF.

Animals↗
PubMed1990

Chronic inflammatory disease of the middle ear cavities: Gd-DTPA-enhanced MR imaging.

Twenty-seven patients with chronic middle ear infection were prospectively studied with pre- and post-contrast magnetic resonance (MR) images to assess the role of MR imaging in the recognition of middle ear tissue abnormalities. The findings were correlated with computed tomographic (CT) scans and surgical and pathologic data. Granulation tissue constantly appeared enhanced on studies done with gadolinium diethylenetriaminepentaacetic acid (DTPA), unlike cholesteatoma, cholesterol granuloma, or brain herniation into the middle ear cavities. Evaluation of extension and thickness of the inflammatory tissue with MR imaging was in accordance with surgical findings. In six cases, isolated granulation tissue misdiagnosed as either a cholesteatoma or herniated brain on CT scans was accurately evaluated on postcontrast MR images. When granulation tissue was associated with other soft-tissue masses, Gd-DTPA-enhanced MR images allowed accurate definition of the site and the extension of each lesion. Furthermore, abnormal meningeal enhancement was precisely depicted by MR images in two cases.

Adolescent↗
PubMed2002

The advantages of delayed nasal full-thickness skin grafting after Mohs micrographic surgery.

BACKGROUND: Full-thickness skin grafting following Mohs micrographic surgery (MMS) of the nasal tip and ala provides easy postoperative wound care and avoids functional impairment caused by wound contraction of the nasal ala free margins. Direct comparison of immediate and delayed skin grafting determined which offers greater success and defined factors contributing to success. OBJECTIVE: To determine if delayed or immediate full-thickness skin grafting results in better graft survival with improved function and appearance, and to identify the recipient bed characteristics, including the size of the wound, the proportion of the wound base having perichondrium, denuded cartilage, and granulation tissue, and graft survival for each technique. METHODS: We used a prospective study comparing 200 patients with wounds having a 3-5 cm2 surface area repaired immediately with a full-thickness skin graft (FTSG) to 200 patients with a delayed FTSG. The depth and diameter of the wound of the nasal ala and tip, and characteristics of recipient bed including size (cm2), location, proportion of wound base with perichondrium present, denuded cartilage, granulation tissue, and proportion of graft loss were the main outcomes measured. RESULTS: Partial graft loss occurred in 11% of those having delayed skin grafts and 30% of those with immediate repair. Delayed grafting was associated with a larger wound surface area (P <.0001), more denuded cartilage (P =.017), greater exposed perichondrium (P <.0001), and less partial graft loss (P <.001). When partial graft loss occurred, the area of loss was smaller with delayed FTSG (P =.036). Contraction of the wound and subsequent nasal valve impairment occurred less often with delayed FTSG (P <.0001). Graft depression was significantly less with delayed FTSG of the ala (P <.0001) and also improved on the nasal tip (P =.47). CONCLUSION: This prospective clinical trial of immediate and delayed FTSGs of the nasal tip and ala with denuded cartilage showed improved graft survival in cases where grafting was delayed for 12-14 days. During this period, substantial granulation tissue formed in the wound base. Assessment of the wound base and the presence of granulation tissue are key factors in the success of full-thickness skin grafting.

Aged↗
PubMed2000

Expression and function of keratinocyte growth factor and activin in skin morphogenesis and cutaneous wound repair.

Reepithelialization and granulation tissue formation during cutaneous wound repair are mediated by a wide variety of growth and differentiation factors. Recent studies from our laboratory provided evidence for an important role of keratinocyte growth factor (KGF) in the repair of the injured epithelium and for a novel function of the transforming growth factor-beta superfamily member activin in granulation tissue formation. KGF is weakly expressed in human skin, but is strongly upregulated in dermal fibroblasts after skin injury. Its binding to a transmembrane receptor on keratinocytes induces proliferation and migration of these cells. Furthermore, KGF has been shown to protect epithelial cells from the toxic effects of reactive oxygen species. We have identified a series of KGF-regulated genes that are likely to play a role in these processes. In addition to KGF, activin seems to be a novel player in wound healing. Activin expression is hardly detectable in nonwounded skin, but this factor is highly expressed in redifferentiating keratinocytes of the hyperproliferative wound epithelium as well as in cells of the granulation tissue. To gain insight into the role of activin in wound repair, we generated transgenic mice that overexpress activin in basal keratinocytes of the epidermis. These mice were characterized by a hyperthickened epidermis and by dermal fibrosis. Most importantly, overexpression of activin strongly enhanced the process of granulation tissue formation, demonstrating a novel and important role of activin in cutaneous wound repair.

Activins↗
PubMed1991

Transforming growth factor-beta stimulates wound healing and modulates extracellular matrix gene expression in pig skin: incisional wound model.

Enhanced wound healing is elicited by exogenous administration of transforming growth factor- beta 1 (TGF- beta 1) in split-thickness, excisional wounds in the pig (Quaglino, Lab Invest 63:307-319, 1990). A study was designed to investigate if the selective and localized effects of TGF-beta 1 found in the previous model were dependent upon the type of wound or could be considered a more general effect of the cytokine. Transdermal, sutured incisions in the pig were evaluated by conventional histology and by in situ hybridization to reveal locally affected gene expression of collagen, elastin, fibronectin, stromelysin, TGF- beta 1, and basic fibroblast growth factor. Granulation tissue formation was markedly enhanced at 6 d by a single injection of recombinant human TGF beta 1 at the time of wound closure. Although granulation tissue was confined within the margins of the incisional wound, prominent differences in hybridization signals were observed between control and treated wounds. The stimulatory effect of TGF- beta 1 on granulation tissue formation was accompanied by a distinct enhancement in cells expressing mRNA for several different extracellular matrix proteins including collagens type I and III and elastin, whereas a single injection of human recombinant TGF beta 1 (4 micrograms) at the wound site diminished the expression of the neutral metalloprotease, stromelysin, and enhanced the frequency and intensity of cells expressing TGF- beta 1. The data reinforce the concept that TGF- beta 1 can act as a potent, auto-inductive modulator of connective tissue remodeling during the repair process.

Animals↗
PubMed1997

Tumor necrosis factor mediates impaired wound healing in chronic abdominal sepsis.

BACKGROUND: The role of systemic tumor necrosis factor (TNF) as a mediator of impaired wound healing in sepsis is unclear. The purpose of this study was to examine the effects of a specific TNF antagonist (TNFbp) on wound healing during chronic abdominal sepsis. METHODS: Male Sprague-Dawley rats were divided into four groups: control, control + TNFbp, sepsis, and sepsis + TNFbp. Saline (1.0 mL) or TNFbp (1 mg/kg, 1.0 mL) was injected subcutaneously daily, polyvinylalcohol (PVA) sponge implants were placed in subcutaneous pockets, and sepsis was induced by creation of a chronic, intra-abdominal abscess. Sponge implants were removed on day 5 and examined histologically. Granulation tissue infiltration and quality (connective tissue, cellularity, vascularity) were scored on a scale from 1 to 4 in a blinded fashion. RESULTS: Septic mortality (19 vs. 25%) was not influenced by TNFbp. Granulation tissue penetration and quality were decreased in septic animals. The administration of TNFbp significantly attenuated the effects of sepsis on granulation tissue histology, but not to control levels. CONCLUSIONS: These studies provide evidence that TNF contributes to the impaired wound healing observed in this model of chronic abdominal sepsis.

Abdomen↗
PubMed1999

The theory of the trigger, the bridge and the transmigration in the pathogenesis of acquired cholesteatoma.

The purpose of the study was to evaluate factors in the otitis media process that could play a role in the pathogenesis of acquired cholesteatoma. The study was divided in two parts: firstly the temporal bones of 75 cats and 15 chinchillas with induced otitis media, and 78 human bones with otitis media were evaluated. Special emphasis was placed on epithelial breaks. These breaks were commonly observed, leaving areas of connective tissue of the mucoperiostium in direct contact with the middle ear effusion. As these changes progressed, the effusion became organized, serving as a bridge for granulation tissue. In later stages these areas became totally or partially covered with epithelium. Areas of epithelial breaks became connected to each other through the organized effusion. Cholesteatomas in humans seem to spread using the connective tissue as scaffolding. Secondly, we reviewed 15 chinchillas in which a chemically modified membrane was placed leading from the external auditory canal to the promontory, through a tympanic membrane perforation. Squamous epithelial migration with cholesteatoma formation occurred through the tympanic membrane perforation, collagen membrane, organized effusion and granulation tissue in 53.5% of the experimental animals. The authors propose the theory that for transmigration of squamous epithelium to occur, a trigger (inflammatory process) and a bridge (granulation tissue and organized effusion) are needed in a predisposed subject.

Animals↗
PubMed2000

Role of myofibroblasts during normal tissue repair and excessive scarring: interest of their assessment in nephropathies.

Following injury, tissue repair process takes place involving inflammation, granulation tissue formation and scar constitution. Granulation tissue develops from the connective tissue surrounding the damaged area and contains vessels, inflammatory cells, fibroblasts and myofibroblasts. Myofibroblasts play an important role in many tissue injuries and fibrocontractive diseases. The process of normal wound repair after tissue injury follows a closely regulated sequence including the activation and the proliferation of fibroblastic cells. In pathological situations, the normal resolution stages are abrogated and the proliferation of myofibroblasts continues, inducing excessive accumulation of extracellular matrix. The differentiation of fibroblastic cells into myofibroblasts is an early event in the development of tissue fibrosis. Myofibroblastic cells express smooth muscle cytoskeletal markers (alpha-smooth muscle actin in particular) and participate actively in the production of extracellular matrix. The evaluation of myofibroblast differentiation in renal biopsies would be useful for histopathologists to appreciate the intensity of tissue injury and particularly to predict the long term outcome of some nephropathies. Immunohistochemical studies for alpha-smooth muscle actin should be made systematically in renal tissue biopsies. Myofibroblastic differentiation appears to play a significant role in the progression of renal failure and seems to be a useful marker of progressive disease.

Animals↗
PubMed2000

Pulsed lavage: promoting comfort and healing in home care.

The purpose of this study was to determine if hydrodebridement with pulsed lavage facilitates the removal of necrotic tissue, promotes healing, and increases comfort in the homebound patient. Home healthcare provides cost-effective care in the setting that is most conducive to healing. People want to be at home, yet many illnesses require services that cannot be obtained at home. Wound care sometimes falls into this category. Pulsed lavage has expanded treatment options for the homebound patient. Hydrodebridement with pulsed lavage is site specific, avoids cross contamination, and is less expensive than whirlpool therapy. It also may facilitate the removal of necrotic tissue and promote the formation of healthy granulation tissue. The authors performed a retrospective audit to gather data on 28 patients who received pulsed lavage treatments at home. A descriptive analysis of five variables that affect healing was undertaken including mobility/activity, nutritional status, cardiovascular/respiratory status, continence, and sensory perception. All of the clients in the sample achieved a clean, warm, moist wound bed, free of signs and symptoms of infection, absence of necrotic tissue, and the presence of granulation tissue to meet the definition of "ready for healing" as presented in the literature. The majority of clients experienced no pain. Although comorbid conditions required rehospitalization for 35.7% of the sample, the conditions did not interfere with healing. Hydrodebridement with pulsed lavage is a viable nontraumatic, noninvasive, site-specific treatment alternative for patients receiving care in the home.

Aged↗
PubMed1980

Treatment of chronic ulceration of the legs with human amnion.

Chronic leg ulcers in fifteen patients were prepared for autografting with a dressing of cultured human amnion. In thirteen vascular responses filled the ulcer beds with granulation tissue. Four patients initially received more traditional therapy and their lesions altered little in gross appearance and were not regarded clinically to have produced a granulation-tissue response. Fourteen patients received autografts after 5 days of amnion application and eight of these grafts have remained intact for 2-10 months. The appearance of healthy granulation tissue after amnion application was associated with successful autografting.

Adult↗
PubMed1984

Histochemical studies of cholesteatoma.

Frozen sections of cholesteatomas were compared with postauricular and auditory canal skin and studied using histochemical methods. Several dehydrogenases, lysosomal enzymes and proteolytic activity were studied. Lactate and malate dehydrogenase activity was very strong in the epithelium and subepithelial tissue of cholesteatomas; no succinate dehydrogenase activity was observed. Esterase and acid phosphatase activity was prominent in cells of granulation tissue. Considerable proteolytic activity was observed in these cells and one specimen showed possible extracellular activity. Strong evidence of fat was found in the granulation tissue, particularly at the interface of granulation tissue and bone. In postauricular and auditory canal skin, enzyme activity was generally weaker; no evidence of fat was found. The findings are discussed in the light of other investigations on the importance of enzyme activity in bone destruction associated with cholesteatoma.

Acid Phosphatase↗
PubMed1981

Collagen synthesis in cultured mesothelial cells. Response to silica.

Mesothelial cells were isolated from the peritoneal surface of rats using trypsinization. The cells were polygonal-shaped and proliferated rapidly forming confluent cultures. Application of colloidal silica to mesothelial cell cultures in doses known to induce peritoneal adhesion disease was injurious to the cells and reduced their synthesis of total proteins and collagen. This effect was dose dependent. Media from silica-treated mesothelial cells and granulation tissue fibroblasts were applied to similar but non-treated mesothelial cell and granulation tissue fibroblast cultures. Media from SiO2-treated mesothelial cells increased collagen synthesis markedly both in the mesothelial cell and fibroblast cultures compared with the control cultures as estimated from the incorporation of radioactive proline into hydroxy-proline-containing proteins. However, no stimulation of collagen synthesis was induced by media from the SiO2-treated granulation tissue fibroblasts. Similar effects are known to be induced in fibroblast cultured by media from silica-treated peritoneal macrophage cultures. The alkaline ribonuclease activities of the media were decreased in silica-treated mesothelial cell and macrophage cultures but not in the media of fibroblast cultures. These results suggest that mesothelial cells, like macrophages, can interfere with the protein synthesis of fibroblasts and thus contribute to the regeneration of mesothelium after injury and to the formation of adhesions.

Animals↗
PubMed1989

[Fibronectin and fibrinogen/fibrin at the focus of an experimental myocardial infarct].

The content of fibrinogen/fibrin, plasma and cellular fibronectin, the 1st type collagen, laminin and skeletal muscle myosin in the zone of experimental myocardial infarction was studied by the immunofluorescent method. The infiltration of the necrotized cardiomyocytes with fibrinogen/fibrin and plasma fibronectin was observed 3 hours and later after coronary artery ligation. Fibrinogen/fibrin and plasma fibronectin form a "primary matrix" of the granulation tissue in which the fibers of the 1st type collagen are being formed. Cellular fibronectin starts to be synthesized 3 days after the infarct development and its content in the extracellular matrix (ECM) of the granulation tissue increases 7-15 days after the infarction. The amount of the fibronectin in ECM of the scar tissue decreases 30 days after the infarct. Fibrinogen/fibrin is always found in the granulation tissue replacing the myocardial infarction but its content in ECM decreases during the scar formation.

Animals↗
PubMed1984

The inflammatory reaction in healing wounds: the role of polymorphonuclear leucocytes.

The inflammatory process in granulation tissue in full-thickness skin wounds was studied and the role of polymorphonuclear leucocytes (PMNLs) in this process evaluated in an experimental model in the rat. The number of PMNLs in the wound, assessed by determination of the PMNL-specific enzyme myeloperoxidase (MPO) activity in wound exudate, increased from 0.45 U/ml on day 1 after wounding to 0.8 U/ml on day 2, and then remained constant throughout the five days of observation. The concentration of prostaglandin E2 (PGE2) in wound exudate increased progressively from 70 ng/ml on day 1 to 290 ng/ml on day 5. The lack of correlation between these two variables indicated that PMNLs were not the major source of PGE2. Blood flow and albumin extravasation in the granulation tissue were measured, and the relation between these two variables and PMNL accumulation was studied. Rats were rendered neutropenic with an antineutrophil serum, resulting in an 83% decrease in circulating PMNLs and a 61% decrease in granulation tissue MPO activity on day 5, as compared with rats treated with normal rabbit serum. These reductions did not, however, affect either blood flow or albumin extravasation, and no correlation was observed; but when inter-individual variations in the absolute levels of the variables measured were eliminated by calculating in each rat a left-to-right wound ratio, PMNL accumulation correlated well to both blood flow (R = 0.81) and albumin extravasation (R = 0.65). It is suggested that blood flow and albumin extravasation in the granulation tissue are influenced by local PMNL accumulation and, further, that the inflammatory response varies considerably between one animal and another.

Animals↗
PubMed2002

A role for endogenous glucocorticoids in wound repair.

Exogenous glucocorticoids are known to inhibit wound repair, but the roles and mechanisms of action of endogenous glucocorticoids during the healing process are as yet unknown. Therefore, we wounded mice expressing a DNA-binding-defective mutant version of the glucocorticoid receptor (GR(dim) mice) and also analysed fibroblasts from these animals in vitro. We found a remarkably enlarged granulation tissue with a high fibroblast density in GR(dim) mice. This difference is likely to result from an increased migratory and proliferative capacity of GR(dim) fibroblasts and from elevated expression levels of soluble factors involved in granulation tissue formation in wounds of GR(dim) mice. In spite of the larger granulation tissue seen in early wounds, late wounds appeared normal, most likely due to an enhanced ability of GR(dim) fibroblasts to contract collagen. These results demonstrate an as yet unidentified role of endogenous glucocorticoids in the regulation of wound repair.

Animals↗
PubMed1991

Quality of gastric ulcer healing: a new, emerging concept.

Assessment of gastric ulcer healing is usually based on a visual examination (by endoscopy in patients, or the evaluation of ulcer size in experimental studies), and not on histologic and ultrastructural assessment of subepithelial mucosal healing. This approach has led to the assumption that the mucosa of grossly "healed" gastric and/or duodenal ulcers returns to normal, either spontaneously or following treatment. However, the re-epithelialized mucosa of grossly "healed" experimental gastric ulcer has recently been found to have prominent histologic and ultrastructural abnormalities, including reduced height, marked dilation of gastric glands, poor differentiation and/or degenerative changes in glandular cells, increased connective tissue, and disorganized microvascular network. It has been postulated that these residual abnormalities might interfere with mucosal defense and may be the basis of ulcer recurrence. In the present article, the ulcer healing process and the role of luminal factors, transitional zone at the ulcer margin, and granulation tissue are discussed. The healing of an ulcer is accomplished by filling of the mucosal defect with epithelial cells and connective tissue to reconstruct mucosal architecture. Under influence of growth factors [predominantly epidermal growth factor (EGF) and transforming growth factor (TGF alpha)], the epithelial cells at the ulcer margin dedifferentiate and proliferate, supplying cells for re-epithelialization of the mucosal scar surface and reconstruction of glandular structures. Granulation tissue at the ulcer base supplies connective tissue cells to restore the lamina propria and endothelial cells and microvessels for mucosal microvasculature reconstruction. The final outcome of healing reflects a dynamic interaction between an "epithelial" component from the ulcer margin and a connective tissue component including microvessels originating from granulation tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Microvasculature in hypertrophic scars and the effects of pressure.

The fine structure of the microvasculature was compared among eight samples of normal skin, 79 granulation tissues, 48 hypertrophic scars, 11 hypertrophic scars treated with mechanical pressure, and 13 mature scars. Increased synthesis activity is suggested in endothelial cells from granulation tissues, is less in hypertrophic scars, and low in mature scars. In hypertrophic scars most of the microvessels appear partially or completely occluded. Endothelial cell nuclei are crenated, many villous projections from the endothelial cell membranes exist on the blood side, and endothelial cell junctions are often complex, although no large gaps are observed. In all the granulation tissues studied fibrin polymer is present, occurring intraluminally and interstitially, which may be related to endothelial cell proliferation. Therapeutic mechanical pressure over 1 to 3 months effects striking changes in endothelial and perivascular satellite cells. Rented areas appear in endothelial cell cytoplasm. A few such areas were found in cases of nontreated hypertrophic scars but in no other group. Pressure-treated scars also demonstrate degenerating perivascular satellite cells, which also are observed in a few cases of mature scars but in no other group. A previously published theory that hypoxia is related to generation of the hypertrophic scar, and that pressure probably increases hypoxia, resulting in long-term focal degeneration of selective cells, appears further supported by the present findings.

Blood Vessels↗