PubMed Health⌕ Search

Biomedical subjects

T A Mustoe

Publications and source records attributed to T A Mustoe.

At least 55 records · Page 3Linked to original sources
PubMed1994

Role of hypoxia in growth factor responses: differential effects of basic fibroblast growth factor and platelet-derived growth factor in an ischemic wound model.

Both recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer are potent inducers of new tissue generation in models of normal dermal repair. However, their therapeutic targets include chronic wounds, which are frequently characterized by local tissue hypoxia. To explore the potential of recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer to stimulate more clinically relevant repair, we created an ischemic dermal wound on the rabbit ear by ligating two of the arteries which feed the ear. Both recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer stimulated marked neovascularization of the wound (p < 0.0001), but only recombinant platelet-derived growth factor-BB homodimer accelerated and augmented granulation tissue formation (p = 0.01) and reepithelialization. This study is the first demonstration of a direct angiogenic effect of recombinant platelet-derived growth factor-BB homodimer in vivo. India ink perfusion coupled with endothelial cell-specific histochemistry showed that nearly all the neovessels in all wounds were functional, indicating rapid capillary morphogenesis. In the nonischemic (normal) rabbit ear, recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer accelerated healing comparably, as expected. Higher doses of recombinant basic fibroblast growth factor also failed to elicit stimulatory effects in ischemic wounds. These results indicate that differential responsiveness to growth factors is related to local tissue hypoxia, angiogenesis alone is an insufficient stimulus for repair. These data also suggest new therapeutic approaches for the treatment of chronic wounds.

Journal Article↗
PubMed1994

Platelet-derived growth factor-BB accelerates wound closure in a new mesentery culture model without macrophages.

Platelet-derived growth factor-BB has multiple effects in vitro and has been demonstrated to accelerate wound healing in several animal models, but its precise mechanisms of action in vivo have not been fully explained. A rat mesentery culture model was developed, and platelet-derived growth factor-BB (100 ng/ml) was added to the medium containing 2% fetal calf serum for examining its closure effects. The mesentery specimens were stained by routine hematoxylin and eosin and immunohistochemical staining for macrophages. A significant improvement in closure rate and complete closure rate was seen when platelet-derived growth factor-BB was added to the medium compared with the controls (p < 0.05). There are significantly fewer macrophages in the in vitro specimen than in the in vivo specimen. In conclusion, platelet-derived growth factor-BB can contribute to wound closure of a mesenteric defect even without macrophages, suggesting a second mechanism in which it can act directly on mesenchymal cells during wound healing. This tissue-culture model is useful for gaining further insights into growth factor interactions and wound healing.

Animals↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor: differential action on incisional wound healing.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) specifically stimulates granulocyte, macrophage, and eosinophil colonies; granulocyte colony-stimulating factor (G-CSF) acts directly on neutrophil-restricted progenitor cells in their proliferation. Those cells have been implicated in the process of wound healing. METHODS: Paired 6 cm incisions were made on rats; GM-CSF or G-CSF was given systemically (100 micrograms/kg/dose) or locally (30 micrograms/wound). The controls received vehicle alone. Impaired healing was induced by injection of methylprednisolone (30 mg/kg). White blood cells (WBC) were counted at day 2 after treatment. Tissue strips were evaluated for tensiometry and histologic features at days 7 and 14 after wounding. RESULTS: For local GM-CSF treated incisions, the breaking strength was 25% stronger than controls at day 7 (p = 0.004), 36% at day 14 (p < 0.0001), and 42% at day 7 (p = 0.012) in impaired animals. Local G-CSF and systemic GM-CSF and G-CSF increased circulating WBC (p < 0.05), but they had no effects on healing. Histologic studies revealed an increase of wound cellulity at day 7 and day 14 in topical GM-CSF treated wounds. CONCLUSIONS: These results suggest GM-CSF is an activator of tissue macrophages and that increasing circulating WBC did not affect wound healing.

Animals↗
PubMed1994

Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB.

Cellular and molecular mechanisms responsible for the observed vulnerary effects of recombinant human platelet-derived growth factor BB (rP-DGF-BB) in man have not been elucidated. In a double-blinded trial, patients having chronic pressure ulcers were treated topically with either rPDGF-BB or placebo for 28 days. To explore how rPDGF-BB may induce chronic wounds to heal, biopsies were taken from the ulcers of a cohort of 20 patients from the trial and evaluated in a blinded fashion by light microscopy for 1), fibroblast content, 2) neovessel formation, and 3), collagen deposition. Electron microscopy also was used to assess fibroblast activation and collagen deposition. Before initiation of therapy most wounds had few fibroblasts and most of those present were not activated. When mean scores for the total active treatment phase (days 8, 15, and 29) for rPDGF-BB-treated ulcers were compared with the scores for placebo-treated ulcers, fibroblast content was significantly higher for the rPDGF-BB-treated ulcers (P = 0.03, Kruskal-Wallis test). More significant differences in fibroblast and neovessel content were observed when six nonhealing wounds were eliminated from the analysis (three placebo, three treatment). Thus, in all healing wounds, rPDGF-BB therapy significantly increased fibroblast (P = 0.0007) and neovessel (P = 0.02) content. These results were correlated with increased collagen fibrillogenesis by fibroblasts from healing rPDGF-BB-treated wounds, as assessed by intracellular procollagen type I immunostaining, and by electron microscopy, and were concordant with clinical measurements (eg, area of ulcer opening and ulcer volume) which showed greater healing in rPDGF-BB-treated wounds. These results suggest induction of fibroblast proliferation and differentiation is one mechanism by which rPDGF-BB can accelerate wound healing and that rPDGF-BB can augment healing responses within a majority of, but not all, nonhealing chronic pressure ulcers in man.

Antibodies↗
PubMed1993

Enhancement of wound healing by the alkaloid taspine defining mechanism of action.

Taspine (mol wt 369,000) is an alkaloid extracted from trees of Croton (family Euphorbiaceae) of the western Amazon region that has been used by natives and others as a vulnerary agent. Taspine was purified from tree sap to test its healing properties using different topical concentrations in the paired rat surgical incision model. Wound tensile strength and histology were evaluated. Samples treated with 250 micrograms, but not those treated with 50 micrograms or 10 micrograms, had significant higher values for MBS than paired controls (26%, P < 0.005, and 30%, P < 0.001, by Days 5 and 7, respectively). Taspine did not modify MBS at Day 12. Sample treated with 250 micrograms had significantly greater mononuclear cellular infiltration at Days 5 and 7 but not at Day 12. To better understand the effect of taspine as an enhancer of wound healing, we conducted in vitro studies in cell cultures. Taspine stimulated chemotaxis for fibroblasts. Taspine did not have an effect on specific assays for macrophage chemotaxis, neutrophil activation, fibroblast proliferation, or matrix assembly. Taken together, the data suggest that taspine promotes early phases of wound healing in a dose-dependent manner with no substantial modification thereafter. Its mechanism of action is probably related to its chemotactic properties on fibroblasts and is not mediated by changes in extracellular matrix.

Alkaloids↗
PubMed1993

Modulation of wound healing response in chronic irradiated tissues.

Radiation wounds represent some of the most difficult wounds to treat. Historically, there have been few nonsurgical options. Recent research suggests future potential of a therapeutic role for growth factors. Hyperbaric oxygen is currently widely used, but its addition to growth factors may give much greater benefits in the future.

Animals↗
PubMed1993

Acceleration of tissue repair by transforming growth factor beta 1: identification of in vivo mechanism of action with radiotherapy-induced specific healing deficits.

BACKGROUND: Transforming growth factor beta 1 (TGF-beta 1) is an effective accelerator of soft tissue repair in both normal and impaired healing models; however, its in vivo mechanism of action remains unclear. Modern radiation techniques can create unique healing deficits, allowing for a more specific definition of tissue response to growth factor therapy. In the rat linear skin incision model, cobalt 60 photon beam total body irradiation (TBI), 800 rads, causes a marked depression of circulating monocytes and largely spares the skin tissue. Megavoltage electron beam surface irradiation (SI), 2500 rads, markedly impairs surface healing while sparing the bone marrow. With these models of selective healing deficits, the ability of TGF-beta 1 to accelerate tissue repair directly in the absence of circulating macrophage precursors (TBI) or in the presence of damaged dermal fibroblasts (SI) was evaluated. METHODS: Adult male Sprague-Dawley rats were randomly assigned to groups of TBI, SI, or nonirradiated sham controls and received radiation 2 days before wounding. Paired linear full-thickness skin incisions were created and a single dose of TGF-beta 1 (2 micrograms/wound) or vehicle control was applied to each wound. RESULTS: Both radiation techniques produced a marked healing deficit when assessed on postwounding days 7 and 12. TBI treatment was characterized by severe monocytopenia, confirmed by a tissue macrophage-specific immunohistochemical technique. On days 7 and 12 after wounding, TGF-beta 1 significantly accelerated soft tissue repair and wound-breaking strength in the TBI-treated rats, demonstrating an ability to directly promote the induction of collagen synthesis in the absence of monocytes/macrophages. In contrast, TGF-beta 1 was unable to reverse the SI-induced healing deficit characterized by impaired function of dermal fibroblasts. CONCLUSIONS: These in vivo observations provide further evidence for a direct mechanism of action by TGF-beta 1 on collagen synthesis by wound fibroblasts during soft tissue repair.

Animals↗
PubMed1992

Acceleration of soft tissue repair by a thrombin-derived oligopeptide.

Augmentation of thrombin-modulated chemotaxis and mitogenic activity within the early phase of soft tissue repair is now possible. Identification of high-affinity thrombin receptor binding domains within thrombin has enabled the synthesis of a family of peptides which interact with thrombin receptors and enhance in vitro mitogenesis. A single (5.0 micrograms/wound) application of the thrombin receptor-activating peptide (P517-30) significantly increased wound breaking strength from Day 5 (31% over controls) to Day 12. Two models of impaired healing created by radiotherapy (RT) were used to elucidate possible mechanisms of P517-30 action. Although P517-30 did not completely overcome the RT-induced healing impairments, it increased breaking strength under conditions of penetrating whole body RT-induced pancytopenia by 22% and of nonpenetrating surface RT-induced dermal cell damage by 42%. This suggests that P517-30 directly stimulates resident endothelial cells, fibroblasts, or other cells to overcome dermal and circulating monocytic deficits. These results suggest a method to accelerate wound healing with potential clinical applications and emphasize the activity of thrombin as a growth factor.

Amino Acid Sequence↗
PubMed1992

Essential fatty acids are not required for wound healing.

Rats with essential fatty acid deficiency (EFAD) exhibit mild body growth retardation, diminished leukocyte influx in certain models of inflammation, and skin lesions characterized by ulceration, thinning and decreased pigmentation. In the present study we examined the role of EFAD in cutaneous wound healing, a process in which the inflammatory response and the macrophage play a central role. We reproduced the EFAD condition in Lewis rats (n = 35), and examined its effects in wound healing using the paired rat surgical incision model. Rats were compared with weight-matched controls, receiving standard chow diet. Skin samples harvested at days 5, 7, 14 and 21 post-wounding were evaluated for tensiometry and histology. EFAD rats exhibited all the characteristics of this condition, and the typical alteration of liver lipids. Skin samples harvested at different days post-wounding did not show difference in maximal breaking strength when compared to weight-matched controls. Histological evaluation of skin samples showed no difference in the cellular inflammatory infiltration in either EFAD rats or in weight-matched controls. Immunohistochemical studies revealed no difference in the influx of macrophages in the different groups of rats. Fatty acid supplementation of EFAD rats (n = 7), successfully reversed the EFAD state as assessed by the macroscopic skin and liver changes and liver fatty acid content, without modifying either tensile strength or cellular inflammatory infiltration. Our results suggest that EFAD does not alter the normal course of the cutaneous wound repair in rats, despite all the cutaneous alterations produced by this condition. We conclude that essential fatty acids (EFAs) are not essential for cutaneous wound repair.

Animals↗
PubMed1992

A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers.

Chronic wounds such as venous stasis ulcers have become a socioeconomic problem. Even with successful initial management, the recurrence rate approaches 70%. With the advent of new wound healing agents, nonoperative attempts to heal these wounds appear indicated. This study reports a prospective randomized evaluator-blinded trial comparing two potential wound healing agents to an inert vehicle placebo. Eighty-six evaluable patients completed the trial. Silver sulfadiazine 1% in a cream proved to statistically reduce the ulcer size compared with a biologically active tripeptide copper complex 0.4% cream formulation or the placebo. There was no difference between the latter two treatments. Silver sulfadiazine has been shown to allow keratinocyte replication and to have antiinflammatory properties. In this trial its antibacterial action was not used since all ulcers had comparable bacterial levels (less than or equal to 10(5)/gm of tissue) before treatment. These results suggest that the silver sulfadiazine cream used in this study may facilitate healing in wounds healing largely by the process of epithelialization.

Adult↗
PubMed1992

Continuous versus intraoperative expansion in the pig model.

Continuous tissue expansion utilizing a continuous infusion device that maintains a constant expander pressure was previously demonstrated to be feasible and successful in obtaining rapid tissue expansion in a canine model. Intraoperative tissue expansion has been described and has gained some clinical acceptance as a method to gain rapid expansion. We compared the efficacy of continuous tissue expansion versus intraoperative tissue expansion in a piglet model. After completing a pilot study, continuous tissue expansion was performed in six pigs (14.5 to 20 kg) on one flank over a 3-day period utilizing an improved prototype device; at the termination of continuous tissue expansion, intraoperative tissue expansion was performed on the opposite flank. There were no complications or continuous tissue expansion device malfunctions. Intraoperative tissue expansion gave a true gain in area of 7.4 percent, while continuous tissue expansion produced a 22 percent gain (p < 0.02). When the effects of both recruitment and expansion were added, continuous tissue expansion gave a dividend of 286 percent versus 192 percent for intraoperative tissue expansion (p < 0.01). Biomechanically, intraoperative tissue expansion skin showed few differences from unexpanded skin, while continuous tissue expansion skin showed a significant increase in stress relaxation (47.78 versus 38.74) and decrease in breaking strength. Histologic analysis revealed some epidermal hyperplasia and inflammation surrounding the continuous tissue expansion expander and some vascular congestion over the intraoperative tissue expansion expander. We conclude that continuous tissue expansion is superior to intraoperative tissue expansion and that the prototype device may be useful clinically.

Animals↗
PubMed1992

Enhanced healing of cutaneous wounds in rats using beads with positively charged surfaces.

The efficacy of electrical fields in soft-tissue repair is unclear. Materials with a charged surface provide a localized charged environment. We examined the effects of surface-charged particles in wound healing in rats with paired dorsal incisions with one side serving as a control. Tensiometry demonstrated that after 10 days, wounds with positively charged particles were 53 percent stronger (p less than 0.001) than controls (10 rats, 30 wound strips), whereas differences with negatively charged (6 rats, 15 strips) or uncharged beads (11 rats, 33 strips) were insignificant. Histologically, wounds with positively charged particles were characterized by large quantities of collagen-rich connective tissue and by prominent bead-associated giant cells. At 94 days, no differences in wound strength were noted. This method of creating charged local environments has potential clinical implications and may add insights into the behavior of cells in response to charged stimuli.

Analysis of Variance↗
PubMed1992

Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair.

Recombinant platelet-derived growth factor (BB homodimer, rPDGF-BB), transforming growth factor beta 1 (rTGF-beta 1), and basic fibroblast growth factor (rbFGF) can accelerate healing of soft tissues. However, little information is available characterizing the components of wound matrix induced by these growth factors and the molecular mechanisms underlying accelerated repair and wound maturation. In this study, the composition, quantity, and rate of extracellular matrix deposition within growth factor-treated lapine ear excisional wounds were analyzed at different stages of healing using specific histochemical and immunohistochemical stains, coupled with image analysis techniques. Single application of optimal concentrations of each growth factor accelerated normal healing by 30% (P less than 0.0003); rPDGF-BB markedly augmented early glycosaminoglycan (GAG) and fibronectin deposition, but induced significantly greater levels of collagen later in the repair process, compared with untreated wounds rTGF-beta 1 treatment led to rapidly enhanced collagen synthesis and maturation, without increased GAG deposition. In contrast, rbFGF treatment induced a predominantly angiogenic response in wounds, with a marked increase in endothelia and neovessels (P less than 0.0001), and increased wound collagenolytic activity (P less than 0.03). rbFGF-treated wounds did not evolve into collagen-containing scars and continued to accumulate only provisional matrix well past wound closure. These results provide new evidence that growth factors influence wound repair via different mechanisms: 1) rPDGF-BB accelerates deposition of provisional wound matrix; 2) rTGF-beta 1 accelerates deposition and maturation of collagen; and 3) rbFGF induces a profound monocellular angiogenic response which may lead to a marked delay in wound maturation, and the possible loss of the normal signal(s) required to stop repair. These results suggest that specific growth factors may selectively regulate components of the repair response by differing mechanisms, offering the potential for targeted therapeutic intervention.

Animals↗
PubMed1992

Platelet-activating factor: improvement in wound healing by a chemotactic factor.

Platelet-activating factor (PAF) is chemotactic for inflammatory cells and activates macrophages but, unlike growth factors, which have been demonstrated to accelerate healing, it has no effects on cell proliferation. The possible role of PAF in wound healing has not been explored previously. We examined the effect of different topical concentrations of PAF on the paired rat surgical incision model. Samples harvested on different days after wounding were evaluated for tensiometry and histology. Samples treated with 1 microgram, but not with 0.1 or 10 micrograms, showed an increase in maximal breaking strength (33.2%, 25.6%, and 4.9% by days 5, 7, and 12, respectively), reaching significance on days 5 and 7. Samples treated with 1 microgram PAF demonstrated a greater cellular infiltration (fibroblasts and monocytes) on day 7. Further histochemical studies revealed an increase of macrophages by day 7. Treatment with PAF receptor antagonist blocked the response to PAF but had no effect on normal wound healing, suggesting that, although PAF can accelerate healing, its endogenous production does not play a key role in normal wound repair. Our results demonstrate promotion of wound healing by PAF, a phospholipid chemotactic factor not previously shown to have wound-healing properties. This study gives new insights into how cytokines act to promote healing and suggests a strategy for improving wound repair with a monocyte chemotactic factor.

Animals↗
PubMed1991

Topical silicone gel for the prevention and treatment of hypertrophic scar.

We studied the effects of a silicone gel bandage that was worn for at least 12 hours daily on the resolution of hypertrophic burn scar. In a second cohort, the prevention of hypertrophic scar formation in fresh surgical incisions by this bandage was also evaluated. In 19 patients with hypertrophic burn scars, elasticity of the scars was quantitated serially with the use of an elastometer. An adjacent or mirror-image hypertrophic burn scar served as a control. Scar elasticity was increased after both 1 and 2 months compared with that in controls. There was corresponding improvement clinically that persisted for at least 6 months. In the other cohort, scar volume changes in 21 surgical incisions were measured before and after 1 and 2 months. Gel-treated incisions gained less volume than control incisions after both intervals. Clinical assessment corroborated this quantitative demonstration of a decrement in scar volume. We concluded that topical silicone gel is efficacious, both in the prevention and in the treatment of hypertrophic scar.

Administration, Topical↗
PubMed1991

The frontonasal flap: utility for lateral nasal defects and technical refinements.

This report details the experience with 27 patients over a 5-year period who had nasal reconstruction using a frontonasal flap. The frontonasal flap procedure is a useful method for the repair of relatively large post-Mohs micrographic surgery defects of the lower, upper, lateral and central nose. Our modified method has been extended (1) to resurface lateral as well as central defects of the caudal one-third of the nose; (2) the scar can be shortened so it does not extend into the forehead; (3) the flap can be combined with the island nasalis flap, or nasolabial flaps to resurface large (3-4 cm) defects; (4) early dermabrasion has improved the scars in sebaceous skin.

Adult↗
PubMed1991

Lymph node metastasis in spindle cell carcinoma arising in odontogenic cyst. Report of a case.

The majority of primary intraosseous carcinomas of the jaws develop in preexisting odontogenic cysts. These tumors are usually well-differentiated keratinizing carcinomas with relatively good prognosis. Only two of 41 previously reported acceptable cases of primary intraosseous carcinomas from ex-odontogenic cysts were associated with cervical lymph node metastasis. Spindle cell carcinoma is an anaplastic dimorphic neoplasm with poor prognosis. It has a special predilection for the upper aerodigestive tract. This is to our knowledge the first report of spindle cell carcinoma developing in an odontogenic cyst. Cervical lymph node metastasis showing typical histologic features of spindle cell carcinoma was detected 8 months postoperatively. The prognostic implications of this finding are discussed in light of previously reported cases of intraosseous carcinoma arising in odontogenic cysts and of spindle cell carcinoma of the oral cavity.

Carcinoma↗