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The microvessels in hypertrophic scars, keloids and related lesions: a review.

The healing of a deep surface wound in humans begins with the formation of granulation tissue and includes a marked microvascular regeneration, initially in an inflammatory milieu. The inevitable sequel is usually a hypertrophic scar or keloid in which there is significant microvascular occlusion. The occlusion begins in the granulation tissue and is the result of an excess of endothelial cells. Several other examples of fibroses contain significant microvascular occlusion. The evidence demonstrates that hypertrophic scars and keloids are hypoxic, undoubtedly due to the microvascular occlusion. Hypoxia may stimulate excessive production of collagen, which forms the bulk of these lesions, from fibroblasts and myofibroblasts. The origin of the new fibroblast remains undetermined. The current evidence suggests it is probably not the pericyte. Resident or peripheral fibroblasts, endothelial cells or undifferentiated cells from the growing tips of microvessels are possibilities. Differential degeneration, or apoptosis, of the fibroblasts, pericytes and microvessels occurs from granulation tissue through hypertrophic scarring. Compartmentalization of fibroblasts between lateral microvascular branches probably accounts for nodule formation. Differential degeneration of the lateral microvessels may account for increases in collagen nodule growth and ultimate size. Hypertrophic scars and keloids may be resolved through light topical pressure maintained over time. Under such treatment, fibroblasts, pericytes and endothelial cells degenerate, probably at a rate greater than that which occurs normally. As degeneration or apoptosis continues the nodules and scar become more avascular and more hypoxic, prompting fibroblast death and release of lysosomal enzymes important for maturation. An alternative treatment, particularly of the granulations, would be to control excessive endothelial (microvascular) or fibroblast proliferation or collagen synthesis. To this end, determination of endothelial or fibroblast cell phenotype for possible antibody targeting may be mandatory.

Cicatrix↗

Ventilating tracheal resectoscope.

The ventilating tracheal resectoscope (Karl Storz) combines the advantages of a ventilating bronchoscope and the resecting cytoscope for removal of soft tissue from the airway. The resectoscope offers several distinct advantages over other methods of granulation tissue removal. The procedure is done under direct vision with magnification and illumination of a rod-lens optical system. Suprastomal granulation tissue is resected cleanly, without tearing or stripping adjacent mucosa. Hemorrhage is readily controlled with the coagulating mode. The resectoscope can also be used for removing benign tumors (such as recurrent respiratory papillomatosis) from the trachea and bronchi. Its use in the efficient removal of malignant tumors and subglottic soft tissue has also been described.

Child↗

Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers.

We investigated the influence of inhibition of nitric oxide (NO) synthase, using NG-nitro-L-arginine (L-NNA) or NG-mono-methyl-L-arginine (L-NMMA), and the effects of exogenous donor of NO, such as glyceryl trinitrate (GTN), on the healing of chronic gastric ulcers induced by acetic acid, on gastric blood flow around the ulcer and on the number of capillaries in the granulation tissue at the ulcer bed. The inhibition of NO synthase resulted in a delay in ulcer healing and in a reduction in blood flow at the ulcer margin and in the number of capillaries in the granulation tissue at the ulcer bed. These effects of inhibition of NO synthase were antagonized, in part, by the administration of GTN or L-arginine but not D-arginine. We conclude that endogenous NO plays an important role in the maintenance of blood flow around the ulcer, in the angiogenesis in the granulation tissue and, thus, in the healing of gastric ulcers.

Acetates↗

Effects of ultrasound delivered through a mist of saline to wounds in mice with diabetes mellitus.

OBJECTIVE: To examine the effects of ultrasound administered through a fine mist of saline on surgically placed full-thickness excisional wounds in mice with experimental diabetes mellitus. METHOD: Fifty male CD-I mice received alloxan monohydrate (100 mg/kg), a drug known to induce diabetes mellitus. The animals received five ultrasound (n = 27) or sham (n = 23) treatments for 1.5 minutes, on alternate days, for 10 days, and were then sacrificed. Following sacrifice, each animal's wound was excised and the tissues prepared for qualitative and quantitative histological analysis. RESULTS: No difference in wound-surface area was found between the groups after the treatment period. However, blinded assessment of tissue sections revealed significantly increased deposition of collagen and blood vessels in the granulation tissue of animals treated with ultrasound compared with those that received sham therapy. CONCLUSION: Ultrasound delivered through a fine mist of saline significantly altered the composition of newly formed granulation tissue in animals with experimental diabetes mellitus. Further research needs to be completed to determine other effects of this novel ultrasound therapy and to examine its clinical effectiveness.

Animals↗

Metamorphosed fibroblasts and their relation to the histogenesis of malignant fibrous histiocytoma in experimental murine model.

Malignant fibrous histiocytoma (MFH) is a clinicopathologically established entity, but its histogenesis remains to be clarified. We have reported the existence of a specific cell type, the "fibrohistiocytoid (FH) cells", in various chronic inflammatory tissues. The FH cells are the metamorphosed fibroblasts and we have revealed the morphological resemblance between FH cells and MFH cells. In the present study we carried out some experiments to ascertain whether the FH cells have a possibility of neoplastic potential for the development of MFH in mice. A total of 50 female Balb/c mice treated with a chemical carcinogen, 9,10 dimethyl-1,2-benzanthracene (DMBA), were examined histopathologically from 8 to 22 weeks after the initial treatment. It was found that 1) the chemically induced tumors in the mice resembled human pleomorphic/ storiform variant of MFH and cells from the tumor were transplantable subcutaneously in the back of another mouse, 2) the tumors were composed mainly of malignant FH cells, and there were many benign FH cells and fibroblasts in granulation tissues obtained at the initial stage of the experiment, 3) all DNA histograms obtained from MFHs were aneuploid and granulation tissues were diploid, and 4) benign FH cells in the granulation tissue appeared to have higher DNA synthesis activity than typical fibroblasts on the basis of bromodeoxyuridine (BrdU) labeling and cytofluorometric studies. From these findings, we suggest that the FH cells are not only a merely morphologically changed fibroblast, but also a biologically ominous cell which may contribute to develop MFH in mice.

9,10-Dimethyl-1,2-benzanthracene↗

[Inflammatory aortic aneurysm after vascular-prosthetic treatment. Morphological findings after years of incorporation].

Until now the causal and formal pathogenesis of the inflammatory aortic aneurysm is poorly known. This report shows the pathological- anatomical findings of surgical and autoptical preparations, on the one hand 78 months and on the other hand 82 months, after vascular-prosthetical treatment of inflammatory aneurysms in the abdominal and thoracal part of the aorta. By morphological studies it was possible to reveal, the over years existing disease, the typical picture of inflammatory aneurysm, focal destruction of the genuine aortic wall and partial substitution by inflammatory-fibrous, less qualitative granulation tissue. Even 6 1/2 years past the implantation of the Dacron-prosthesis, there is still no complete ingrown. In addition to the known findings of the transprosthetical organization with a variable development of the outer connective-tissued coat and neointima, the incorporated granulation-tissue was overlapped by a strong inflammation according to the basic disease. In several parts of the inflammatory destructed aortic wall, there is still no fixed incorporation of the prosthesis after 7 years, so that "hypermobile-prosthetic-parts" can be found as a result.

Aorta↗

Serratia marcescens infected silk suture rejected by combined acupuncture, moxibustion and low-power laser therapy from the abdominal fascia.

Upper abdominal pains lasting 12 years after cholecystectomy, were improved in an 82-year-old woman following the rejection of indigestable silk surgical sutures induced by combined therapy of acupuncture, moxibustion and low-power laser beam irradiation directed to an old post-cholecystectomy scar. An inflammatory reaction followed by granulation tissue mass was developed. Embedded in the granulation tissue were the above mentioned silk sutures which finally were expelled through the skin at the operation scar. A surgical procedure suggested to the patient, in case of acupuncture therapy failure, was obviously avoided. Serratia-marcescens infection of the expelled material was bacteriologically defined.

Abdomen↗

[Experimental studies on wound healing of the jaw bone fracture].

The author has studied on wound healing of the jaw bone fractures in 5 Malaysian monkeys aging around 2 years and weighing about 3 Kg. For the experimental studies, fractures of the jaw bone in terms of oblique osteotomies from angle to sigmoid notch of the mandible of the Malaysian monkeys were made by using #700 fissure bur and reduced and fixed them in terms of interosseous wiring. The experimental animals were sacrificed on the 1st, 2nd, 3rd, 4th and 5th week thereafter, and the fracture sites were obtained to make microscopic slides stained with Hematoxylin-Eosin, and Van Gieson method. The results obtained were as follows: 1. The blood of hematoma situated in fractured crevice are getting replaced with granulation tissue 1 week after fracture. 2. The granulation tissue occurred in fractured crevice are getting replaced with connective tissue as bone matrix 2 weeks after fracture. 3. Immature new bone formation with bony trabeculation formed 3 weeks after fracture. 4. The secondary bony callus with abundant osteoblasts and osteocytes in bone matrix formed 4 weeks after fracture. 5. The fractured wound completely healed with a new bone formation 5 weeks after fracture.

Animals↗

[Development of cholesteatoma in the middle ear ab statu nascendi].

The squamous epithelium and the granulating chronically inflamed mucosa of the middle ear are responsible for the development of a cholesteatoma. Squamous epithelium is stimulated to grow if it borders on granulation tissue, as in wound healing. Thus if granulation tissue forms in the tympanic membrane the basal membrane degenerates at circumscribed points and these matrix cells produce processes which grow in an atypical direction into the middle ear. The resulting mass of prickle cells acts as a foreign body and stimulates the growth of bone destroying soft tissue. This explains the posterior superior defect in the tympanic membrane.

Cholesteatoma↗

Growth factors in porcine full and partial thickness burn repair. Differing targets and effects of keratinocyte growth factor, platelet-derived growth factor-BB, epidermal growth factor, and neu differentiation factor.

The topical application of recombinant growth factors such as epidermal growth factor, platelet-derived growth factor-BB homodimer (rPDGF-BB), keratinocyte growth factor (rKGF), and neu differentiation factor has resulted in significant acceleration of healing in several animal models of wound repair. In this study, we established highly reproducible and quantifiable full and deep partial thickness porcine burn models in which burns were escharectomized 4 or 5 days postburn and covered with an occlusive dressing to replicate the standard treatment in human burn patients. We then applied these growth factors to assess their efficacy on several parameters of wound repair: extracellular matrix and granulation tissue production, percent reepithelialization, and new epithelial area. In full thickness burns, only rPDGF-BB and the combination of rPDGF-BB and rKGF induced significant changes in burn repair. rPDGF-BB induced marked extracellular matrix and granulation tissue production (P = 0.013) such that the burn defect was filled within several days of escharectomy, but had no effect on new epithelial area or reepithelialization. The combination of rPDGF-BB and rKGF in full thickness burns resulted in a highly significant increase in extracellular matrix and granulation tissue area (P = 0.0009) and a significant increase in new epithelial area (P = 0.007), but had no effect on reepithelialization. In deep partial thickness burns, rKGF induced the most consistent changes. Daily application of rKGF induced a highly significant increase in new epithelial area (P < 0.0001) but induced only a modest increase in reepithelialization (83.7% rKGF-treated versus 70.2% control; P = 0.016) 12 days postburn. rKGF also doubled the number of fully reepithelialized burns (P = 0.02) at 13 days postburn, at least partially because of marked stimulation of both epidermal and follicular proliferation as assessed by proliferating cell nuclear antigen expression. In situ hybridization for KGFR in porcine burns revealed strong expression of KGFR on hair follicles and basal epidermis, confirming direct rKGF action on follicular as well as epidermal keratinocytes. Although the epithelial proliferation induced by rKGF resulted in marked neoepidermal psoriasiform hyperplasia with exaggerated rete ridges and neoepidermal and follicular maturation as assessed by expression of cytokeratin 10, a marker of keratinocyte terminal differentiation was not delayed and appeared to be accelerated in some rKGF-treated burns. Recombinant epidermal growth factor induced a trend toward increased new epithelial area in deep partial thickness burns, but had no effect on reepithelialization. The recombinant neu differentiation factor-alpha 2 isoform had no significant biological effects in either full or deep partial thickness burns.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗

Influence of acid and angiogenesis on kinetics of gastric ulcer healing in rats: interaction with indomethacin.

Indomethacin delays healing of experimental gastric ulcers. We investigated whether inhibition of gastric acid secretion by omeprazole or stimulation of angiogenesis by basic fibroblast growth factor (bFGF) may reverse this delay. Rats with gastric ulcers induced by cryoprobe were treated subcutaneously with either placebo, indomethacin (2 x 0.5 mg/kg), bFGF (2 x 100 micrograms/kg), omeprazole (1 x 40 mumol/kg), indomethacin plus omeprazole, or indomethacin plus bFGF given daily for 8, 10, 15, and 22 days. Ulcer size, epithelial cell proliferation, angiogenesis, and maturation of granulation tissue were sequentially quantified. Omeprazole significantly accelerated ulcer healing in an early phase (days 3-8). In contrast, bFGF accelerated healing in a late phase (days 10-15). Indomethacin significantly delayed ulcer healing in late phase and decreased prostaglandin generation, cell proliferation, angiogenesis, and maturation of granulation tissue. Despite stimulation of angiogenesis, bFGF did not reverse indomethacin-induced delay in ulcer healing. In contrast, omeprazole reversed indomethacin-induced effects on angiogenesis, cell proliferation, maturation of granulation tissue, and ulcer healing rate.

Animals↗

Experimental pneumococcal otitis media: a histopathologic study.

An animal model for pneumococcal otitis media was studied histologically at varying intervals postinoculation. Histologic changes generally associated with acute inflammation (edema, diffuse infiltration with polymorphonuclear leukocytes, and hemorrhage) occurred early in the disease while the ears were culture positive. Changes generally associated with chronic otitis media (lymphocyte infiltration and osteoneogenesis) occurred later in the course of the disease when the ears were culture negative. Metaplasia of middle ear mucosa and middle ear granulation tissue were observed as early as five days following inoculation. Middle ear granulation tissue was identified in 82% of all cases; cholesteatoma was seen in only one ear. Tympanic membrane perforation did not occur. Labyrinthitis and endolymphatic hydrops were fairly common findings. The former was identified in 56% of ears examined, and the latter, in 45%. These two conditions coexisted in 34% of ears studied, while endolymphatic hydrops alone occurred in 11%.

Acute Disease↗

[Effect of vacuum-assisted closure on the expression of proto-oncogenes and its significance during wound healing].

OBJECTIVE: To study the effects of VAC on starting the process of wound healing and decreasing apoptosis. METHODS: To examine the variations in expression of proto-oncogenes c-myc, c-jun and Bcl-2 in pig wound model with acute full-thickness skin defect and human chronic wounds by immunohistochemistry, calculate the numbers of expressive positive cells and the labelling index (LI), and observe the process of wound healing. RESULTS: (1) In pig experiment, the wound in experimental group was very clean and without obvious exudates, many neoepiderm and granulation tissue rapidly appeared or formed after 6 days, and healed completely by the 25th day. On the contrary, in the wound of control group, more exudates and blood crust could be seen and fewer neoepiderm and granulation tissue appeared after 6 days and was healed by 30th day. Immediately after the wound was created, the expression of c-myc, c-jun and Bcl-2 was lower and mainly situated in nucleus or cytoplasma of the basilar cells. After the wound was created in control group, or after starting the VAC treatment in experimental group, their expression rapidly and obviously increased, the distribution of the positive cells also became enlarged, but the amount of expression decreased rapidly after the expressive peak have reached. In the successive 12 days following the wound was created, the expression of c-myc, c-jun and Bcl-2 in the experimental group was constantly higher than that of the control group. (2) In human chronic wounds, there wasn't obvious secretions and more healthy granulation tissue was rapidly formed after VAC treatment. The expression of c-jun was mainly located in cytoplasma of basilar cells of epithelium, dermal fibroblasts and inflammatory cells, and the positive cell and labelling index obviously decreased. The expression of c-myc and Bcl-2 was mainly in cytoplasma of basilar cells, but the amount of expression and the labelling index became obviously increased after VAC treatment. CONCLUSIONS: VAC could rapidly start the healing course of the pig' s acute skin wound and human chronic wound, decrease apoptosis of the reparative cells, so as to accelerate wound healing.

Adult↗

[Ultrastructural changes in tissues in postburn cicatricial esophageal stenosis during bougienage and prolonged intubation].

The ultrastructure of tissues in postburn esophageal strictures was studied in 24 patients varying in ages from 23 to 70 years with the postburn period ranging from 1 1/2 months to 36 years. Biopsy samples for the study were collected during fibroesophagoscopies before treatment, after bougienage and longterm intubation with the Tkachenko tube. Before treatment, pathologically altered granulation tissue forming the surface of ulcerated esophageal strictures was found to contain such mature forms of fibroblasts as collagenoblasts with moderate collagen-producing activity, myofibroblasts, and fibrocytes. Mechanical effects of bougienage and intubation of the esophagus stimulated formation of young granulation tissue in the area of ulcerated strictures, intubation of the strictures stimulating both biosynthesis and catabolism of collagen. Mature forms of fibroblasts of young granulation tissue formed in bougienage were represented by collagenoblasts with intensive collagen-producing activity, myofibroblasts, fibrocytes, and after long-term esophageal intubation also by fibroclasts.

Adult↗

Histopathologic changes in the lacrimal sac of dacryocystorhinostomy patients with and without silicone intubation.

PURPOSE: To evaluate the histopathologic impact of dacryocystorhinostomy (DCR) and silicone intubation on the lacrimal sac. METHODS: Biopsy materials were taken from the sac wall and fixed (primary biopsy) in 224 patients undergoing DCR between 1995 and 2003 in our institution. A total of 23 patients underwent a second operation as the result of restenosis, and a secondary biopsy specimen was taken from the sac wall. During the initial operation, DCR and silicone intubation were combined in 13 patients (group 1), and only DCR without silicone intubation was performed in 10% patients (group 2). The histopathologic findings of the primary and secondary biopsy specimens were compared in these 23 recurrent cases. In addition, the secondary biopsy findings in the intubation and nonintubation groups were compared to determine the possible effects of the silicone intubation on the sac mucosa. RESULTS: Endonasal examination of restenosis cases revealed macroscopic cicatrization. One of the cases with silicone intubation had pyogenic granuloma and two had polypoid granulation tissue at the site of anastomosis. Inflammatory polypoid development at the site of anastomosis was also observed in one case without intubation. The primary biopsy specimens of those 23 patients undergoing a second operation revealed the following findings: chronic inflammatory changes, mild fibrosis, focal ulceration in the epithelium, and a decrease in the number of goblet cells. In the secondary biopsy specimens, 2 patients in group 1 had polypoid granulation tissue, 1 patient had pyogenic granuloma, and 3 patients had exudate reflecting acute inflammation. In group 2, granulation tissue was observed in 1 case, and 2 patients had acute inflammation. There were no differences in the primary and secondary biopsy specimens of the two groups with respect to chronic inflammatory changes, focal ulceration, and the number of goblet cells (p = 0.31; 0.31, 0.65). A marked increase in fibrosis was observed in the secondary biopsy specimens of all cases (p < 0.0001). There were no significant differences between the intubation and the nonintubation groups in terms of secondary biopsy specimens (p > 0.05). CONCLUSIONS: The marked increase in the intensity of fibrosis observed in the secondary biopsy specimens of all cases was the result of the tissue repair reaction against surgical manipulation rather than the effect of the silicone tube.

Adolescent↗

[Salvage of exposed alloplastic materials in irradiated wounds - a case report].

BACKGROUND: Modern multimodal concepts of complex reconstructions and advanced wound management enlarge strategies for surgical oncological therapies. One of the mainstays of classical surgical therapy in case of exposed alloplastic materials in irradiated wounds was to remove the foreign body due to the risk of infection. This loss of integrity and function of the contaminated host bed was to allow wound healing and closure. METHOD: We report the management of a 56-year-old female patient who developed a lyomyosarcoma at her left shoulder girdle 8 years after radiation of the left thorax because of breast cancer. After radical tumor resection and exarticulation of her left arm in the shoulder joint a necrosis of the soft tissue envelope developed, leading to an exposed alloplastic mesh. Staged debridement and continuous application of negative pressure was performed three times. Ultimate plastic coverage was performed by means of a pectoralis myocutaneous island flap from the other breast. RESULTS: After staged debridement and repeated vacuum application excellent wound cleaning, neovascularisation, wound contraction and formation of granulation tissue within the previously irradiated tissue zone was observed. Until fourteen months postoperative wound coverage remained stable and no signs of infection were observed. DISCUSSION: By means of negative pressure therapy even in radiated wounds excellent wound cleaning and sufficient formation of granulation tissue can be achieved. In some cases negative pressure therapy together with staged debridement allows reintegration of exposed and therefore potentially contaminated alloplastic meshes into new formed granulation tissue in radiated wounds respectively radiation ulcers. Thus leading to the possibility of ultimate plastic coverage.

Breast Neoplasms↗

Matrix metalloproteases are involved in granuloma-induced cartilage degradation.

The aim of this study was to test the role of matrix metalloproteases (MMP) in the in-vivo degradation of an implanted cartilage, using the modified mouse air-pouch model. Rat femoral-head cartilages were wrapped in cotton and implanted in 6-day-old mouse air-pouches. The mice were killed and the pouches opened 4, 7, 14 and 21 days after implantation. At each time the cartilages were removed and their contents of sulfated proteoglycan and collagen were determined. The collagenolytic activity of the pouch granulation tissue was measured, using a synthetic substrate. The implanted cartilage was found to be degraded, as previously described by Bottomley et al. (1988). The disappearance of proteoglycan and collagen began at days 4 and 7 respectively and increased progressively until day 21. An EDTA-inhibited collagenolytic activity was detected in the granulation tissue, and this increased from day 4 to day 21. These results demonstrate a progressive increase in the collagenolytic activity of the mouse air-pouch granulation tissue with a parallel loss of the matrix-macromolecules content of the implanted cartilage. The characterization of the metalloproteases involved is in progress.

Animals↗

Distribution of fibronectin during wound healing in vivo.

The distribution of fibronectin during wound healing has been studied. Full thickness wounds were made in the skin on the sides of guinea pigs' trunks. Biopsy specimens were taken from the normal skin, from the 5-hr-old wound, and on days 1-18 after wounding. Unfixed frozen sections were analyzed for fibronectin distribution by indirect immunofluorescence analysis with a specific antiserum prepared in rabbits against guinea pig plasma fibronectin. Tissue samples were also embedded in methacrylate and sections cut and stained with hematoxylin and eosin for general histology or with a silver stain for reticulin. Fibronectin was prominent in the basement membranes of normal skin epidermis. It was also present in the papillary dermis and to a lesser extent in the reticular dermis. After wounding, fibronectin was part of the fibrin clot and distributed along fibrin strands. Fibronectin was also deposited along newly synthesized collagen in the granulation tissue, which was at least in part collagen type III based upon staining for reticulin. Eventually, the entire granulation tissue was transformed into aligned collagen fibrils coated with fibronectin. Throughout the period of wound healing, the level of fibronectin associated with what appeared to be type I collagen in the reticular dermis adjacent to the wound area stayed about the same. When fibrils with the histological characteristics of type I collagen were within the granulation tissue, however, they were coated with fibronectin. The results indicate that fibronectin is a major component present during wound healing.

Animals↗