Biomedical subjects

M C Robson

Publications and source records attributed to M C Robson.

At least 37 records · Page 2Linked to original sources

PubMed1999

TGF-beta2 activates proliferative scar fibroblasts.

BACKGROUND: Cytokines, such as the transforming growth factor beta (TGF-beta) isoforms, have been linked to the formation of proliferative scars. This study examines the stimulating effects of exogenous TGF-beta2 on cultured keloid, burn hypertrophic scar, and normal skin fibroblasts and whether such effects can be suppressed with TGF-beta2 antibody. METHODS: In vitro, the fibroblast-populated collagen lattice (FPCL) is used in the evaluation of fibroblast activation by measuring contraction of the lattice over time. Primary cultures of fibroblasts were grown from keloids, burn hypertrophic scars, and normal skin using standard cell culture techniques. TGF-beta2 (10 ng/ml) was added to each of the three types of cell cultures and placed on prefabricated FPCLs. Each was tested against their normal control counterparts. TGF-beta2 antibody (100 ng/ml) was then placed on the TGF-beta2-treated FPCLs. All lattices were allowed to contract and areas were measured for 5 days. RESULTS: Compared to controls, keloid fibroblasts were most affected by the addition of exogenous TGF-beta2. Normal skin fibroblasts did not show a significant increase in contraction early on, yet a significant difference was seen as time progressed. The addition of TGF-beta2 antibody inhibited the function of keloid and burn hypertrophic scar fibroblasts. It also reversed the increased contraction of the TFG-beta2-treated proliferative scar fibroblasts. CONCLUSION: By utilizing an in vitro model, we have demonstrated that TGF-beta2 antibody reverses the increased contraction of FPCLs by proliferative scar fibroblasts treated with TGF-beta2. This points to a possible treatment modality in patients afflicted with this disfiguring problem.

Antibodies↗

PubMed1999

Exogenous transforming growth factor beta(2) modulates collagen I and collagen III synthesis in proliferative scar xenografts in nude rats.

BACKGROUND: Keloid and hypertrophic scars are fibrous dermal tumors characterized by overabundant collagen deposition. Previous studies demonstrated that exogenous transforming growth factor beta (TGF-beta) might increase collagen production in incisional wound models and in vitro. Using an in vivo model of human scar xenografts maintained in congenitally athymic, asplenic "nude" rats, we examined endogenous TGF-beta(2), collagen I, and collagen III levels in keloids and burn hypertrophic scars treated with TGF-beta(2) and TGF-beta(2) antibody. METHODS: Fresh keloid and burn hypertrophic scar specimens excised from human subjects were explanted to pedicled flaps based on the superficial inferior epigastric vessels in athymic "nude" rats. These flaps were allowed to mature for 3 weeks, after which the scar explants were directly perfused with 200 ng of TGF-beta(2) or 250 microg of TGF-beta(2) antibody daily for 5 consecutive days, then again on Days 10, 15, and 20. Biopsies were taken 30 and 120 days following the initiation of treatment. Immunohistochemical staining was then performed for TGF-beta(2), collagen I, and collagen III. The intensity of staining was quantified. RESULTS: Our results demonstrated that treatment of human proliferative scars with exogenous TGF-beta(2) results in a significant increase in endogenous TGF-beta(2), collagen I, and collagen III production. By contrast, exogenous addition of anti-TGF-beta(2) antibody significantly decreased endogenous TGF-beta(2), collagen I, and collagen III production. CONCLUSION: This study supports a causative role for TGF-beta(2) in the formation of proliferative scars and suggests that TGF-beta(2) antibody may be a new potential antiscarring agent.

Animals↗

PubMed1999

Maintenance of wound bacterial balance.

BACKGROUND: There is a critical number of bacteria above which tissue responds with infection. This balance of 10(5) or fewer bacteria/g tissue is also required for wound healing to proceed normally. This study evaluated whether a chronic wound once in bacterial balance can maintain that balance over time. METHODS: Serial biopsies for bacterial analyses were obtained weekly during a blinded, placebo-controlled cytokine clinical trial of pressure ulcers. To enter the trial ulcers had to be debrided and have a bacterial count of 10(5) or fewer bacteria/g tissue with no beta-hemolytic streptococci. RESULTS: In all, 96% of cultures (350/363) remained at <10(2) bacteria/g tissue over the 5-week trial; 3% had 10(2) to 10(5), and only 1% had >10(5) bacteria/g tissue. CONCLUSION: Chronic pressure ulcers, once debrided and brought into bacterial balance, will remain in bacterial balance if cared for and kept free of necrotic tissue.

Biopsy↗

PubMed1999

The effect of denervation on leukocyte function in soft tissue infection.

BACKGROUND: The present study was undertaken to investigate the effect of denervation on leukocyte function in soft-tissue infection in an isolated in vivo ovine flap model. METHODS: Fifteen adult ewes were divided into three groups. An island pedicle flap was raised on the right buttock. In group I (no denervation), the cutaneous nerve remained intact, whereas in group II (acute denervation) the nerve was divided acutely. In group III (prolonged denervation) the nerve was divided 7 days before flap elevation. All flaps received intradermal inoculation of 10(7) Staphylococcus aureus, and the animals were observed for 96 hours. RESULTS: In both groups II and III, the leukocyte chemiluminescence and chemotaxis were significantly decreased when compared with group I. Furthermore, there was profound impairment of leukocyte functions in group III compared with group II. Group III also had significantly higher bacterial counts, larger septic foci, lower viable leukocyte ratios, and decreased bacterial killing compared with group I. CONCLUSIONS: Denervation, particularly over a period of time, results in increased bacterial growth of soft-tissue septic foci. This appears to be due to decreased leukocyte function resulting in diminished bacterial killing.

Animals↗

PubMed1999

The efficacy of 5% Sulfamylon solution for the treatment of contaminated explanted human meshed skin grafts.

Large TBSA burns have a deficiency of skin graft donor sites necessitating meshed skin autografts, cultured epithelial autografts or biosynthetic skin substitutes. Because these do not effect immediate complete biological closure of the wound, the burn victim remains at risk for life-threatening infection. Topical antimicrobials can protect colonization of these grafts from becoming invasive sepsis. However, many of these agents are cytotoxic to new partially keratinized epithelial cells. This study using a model of epithelialization kinetics of human meshed skin grafts explanted to athymic 'nude' rats evaluated: (1) the effect of bacterial colonization on the rate of closure of meshed graft interstices; (2) the efficacy of 5% Sulfamylon solution for bacterial control and (3) the effect on interstitial closure rates caused by control of bacterial proliferation. Results showed the rate of interstitial closure was progressive over 7 days in noncontaminated grafts treated with moistened saline dressings. Areas of total closure of a 1:1.5 meshed graft were seen as early as 5 days. When grafts were inoculated with 10(2) or 10(3) Pseudomonas aeruginosa organisms and treated with saline moistened dressings, the resultant bacterial load rose to 10(6) organisms, less than 3% of the interstices closed and grafts were destroyed. With the same organism level of contamination, bacterial levels were eradicated with topical 5% Sulfamylon solution, interstitial closure rates returned to normal and areas of total meshed graft closure were seen by day 4. These data demonstrate the efficacy of 5% Sulfamylon solution on epithelialization kinetics of contaminated meshed skin grafts.

Animals↗

PubMed1999

A model for the assessment of sensory recovery of experimental skin grafts.

The return of sensation to skin grafts is often suboptimal. Although the reinnervation of skin grafts has been examined by a number of authors during the past century, studies in humans have left a number of unanswered issues, whereas animal studies have been largely confined to histological work and a few electrophysiological studies. Based on knowledge that rats exhibit a reflexive flick of the back skin in response to stimulation, the authors hypothesized that it should be possible to develop a noninvasive model for assessing return of sensation in experimental skin grafts. Full-thickness skin grafts were created, one per animal, on the dorsa of male Sprague-Dawley rats. Sensory testing was performed using a hand-held pinprick device designed to deliver a stimulus of reproducible force. A positive response was observed as a flick of the dorsal skin--a very reliable reflex involving the cutaneus trunci muscle. The stimulus was delivered to each of 25 sectors of the graft on days 9, 13, 16, 20, 40, 60, and 110 postoperatively. Results were analyzed regarding the percentage of grafts responding at each time point as well as the topographical pattern of sensory return. Evidence of sensation was first detected at day 13 at the margins of the skin grafts and then progressed centrally until homogenous reinnervation (94% of the graft surface) was observed at day 40 and was maintained through the end of the study. Growth Associated Protein (GAP)-43 immunostaining was used to document reinnervation of the skin grafts histologically.

Animals↗

PubMed1999

Effect of TGF-beta2 on proliferative scar fibroblast cell kinetics.

Keloids, hypertrophic scars, and burn hypertrophic scars are all forms of proliferative scarring characterized by overabundant matrix formation. Recently these dermal proliferative disorders have been linked clinically to the cytokine transforming growth factor beta (TGF-beta), and in vitro tests have shown it to be responsible for the activation of fibroblasts and their production and deposition of collagen. Using an established in vivo animal model of proliferative scarring, the effects of this cytokine, specifically the isoform TGF-beta2, on these scars were examined. Proliferative scar specimens were implanted into athymic, asplenic nude rats and isolated in sandwich island flaps based on the superficial inferior epigastric pedicle. After establishment of the transferred flap, the scars were injected with varying doses of TGF-beta2 or vehicle for 5 consecutive days and then again on days 10, 15, and 20. The specimens were measured weekly during the period of dosing, and a biopsy was acquired on days 30 and 60. Fibroblasts from the explanted biopsies and the original scars were grown in cell culture, and cell proliferation studies were performed and the results compared. There was a dose response to TGF-beta2, with 200 ng showing the greatest effect. From the original scar specimens, keloid scars demonstrated the greatest cell proliferation kinetics--significantly faster than nonburn and burn hypertrophic scars. After treatment with TGF-beta2, both keloids and burn hypertrophic scars showed an increase in their cell proliferation kinetics compared with vehicle alone. This was not demonstrated with the nonburn hypertrophic scars. Elevated levels of TGF-beta2 are a major contributing factor to the process of proliferative scars, but because nonburn hypertrophic scars do not result in an equally increased response to this cytokine, a truly causative role for this cytokine cannot be promulgated. Rather, it is the combination of the proliferative scar fibroblasts' abnormal response to TGF-beta2 stimulation and elevated levels of this cytokine that controls more accurately the process of keloid and burn hypertrophic scar formation.

Animals↗

PubMed1998

Differential production of apoptosis-modulating proteins in patients with hypertrophic burn scar.

BACKGROUND: The biochemical and cellular pathways resulting in the production of proliferative scar in the thermally injured patient remain incompletely elucidated. A promising area of investigation is the phenomenon of programmed cell death and its modulation. The following study was designed to quantify differential levels of the bcl-2 protooncogene and the Fas cell surface receptor, two apoptosis-modulating proteins, in the peripheral blood mononuclear cell (PBMC) fractions of burn patients with hypertrophic scar versus those considered to have healed normally. The study also encompassed an immunohistochemical examination of fibroblasts in vitro, to identify differential levels of Fas, bcl-2, and interleukin converting enzyme (ICE). METHODS: PBMC fractions were isolated from two matched burn patient cohorts of 10 patients each, the experimental group carrying the clinical and histopathologic diagnosis of hypertrophic burn scar. The supernatant from each mitogenically stimulated specimen was halved and subjected to the Fas/APO-1 enzyme-linked immunosorbent assay (ELISA) and the bcl-2 ELISA. Results for each assay were compared between groups by unpaired t tests. Further biopsy specimens of isolated proliferative scar were used in vitro to analyze the role of these apoptosis-modulating proteins and ICE. This immunoperoxidase technique was analyzed qualitatively. RESULTS: The expression of the bcl-2 protein in the PBMC fractions of the burn patients with hypertrophic scar is significantly elevated in comparison to the control cohort (307.72 +/- 72.29 u/ml vs 31.55 +/- 6.73 u/ml; P = 0.0042). The quantitative levels of the Fas receptor did not differ significantly between the groups, respectively (0.3988 +/- 0.179 u/ml vs 0.2899 +/- 0.066 u/ml; P = 0.5787). Immunoperoxidase staining of proliferative scar fibroblasts and those from surrounding skin revealed relatively decreased levels of membrane-bound Fas and ICE. bcl-2 was not detectable in these specimens. CONCLUSIONS: Differential expression of the bcl-2 protooncogene and the Fas cell surface receptor in the PBMC fraction of patients with burn injuries may suggest a disequilibrium in a complex biochemical signaling mechanism mediating programmed cell death. The increased levels of bcl-2 could be responsible for delayed fibroblast apoptosis, resulting in the disruption of normal healing and subsequent hypertrophic scarring. This is confirmed by an in vitro examination of wound fibroblasts versus those from surrounding uninjured skin. This immunoperoxidase technique reveals a localized relative decrease in Fas and ICE, two apoptosis-inducing proteins, at the level of the fibroblast in the proliferative scar specimen.

Adult↗

PubMed1998

An in vivo model of human proliferative scar.

BACKGROUND: Many aspects related to the biology and the effective therapy of proliferative scars have remained undefined, in part due to a lack of an accurate and reproducible animal model with which to systematically study them. This report describes a new model for investigating the pathophysiology and manipulation of human proliferative scars. MATERIALS AND METHODS: Human proliferative scars (n = 86) were explanted into flaps based on isolated vascular pedicles in congenitally athymic rats. Serial analysis of the structural and functional integrity of the explanted scars was performed by microscopy and by measurement of human procollagen type III peptide (PIIIP) production, human factor VIII immunostaining, and in vitro cellular proliferation. RESULTS: By these methods, both fibroblastic and epithelial components of explanted scar specimens retained the histologic characteristics of original human scar specimens, for up to 12 months. Over the same duration, scar explants continued to have high levels of human PIIIP, comparable to those found in original surgical specimens. The microvasculature of scar explants demonstrated a double basement membrane, with no staining of human factor VIII in the inner capillary endothelial layer, suggesting that host vessels were growing into ghost vessels of the human donor scar. Human factor VIII staining decreased over time. Fibroblasts cultured from explanted scar demonstrated less aggressive growth characteristics than those from original surgical specimens. CONCLUSIONS: This new model is the first to allow such long-term maintenance and serial evaluation of human proliferative scar on an accessible, isolated vasculature. It may prove useful in further defining the biology and therapy of this widespread pathologic process.

Animals↗

PubMed1998

Aprotinin in ischemia-reperfusion injury: flap survival and neutrophil response in a rat skin flap model.

Multiple drugs have been used in experimental skin flap models to reduce the effects of reperfusion ischemia. The effects of antiproteases, however, have not been studied. A skin flap ischemia reperfusion model was developed in the rat to study the effects that aprotinin, a broad-spectrum antiserine protease, would have on skin flap viability. Thirty-two male rats underwent elevation of a ventral pedicled skin flap based on the superficial inferior epigastric artery. The flaps were subjected to 10 hr of warm ischemia by clamping the neurovascular pedicle followed by reperfusion. Aprotinin or saline (control) was administered systemically via the contralateral femoral vein either before or after the ischemic insult. Full-thickness skin biopsies were obtained at 1, 8, and 24 hr into reperfusion. Biopsies were evaluated for neutrophil concentration (using a myeloperoxidase [MPO] assay) and thromboxane B2 [TxB2] content. Flap survival was calculated at 1 week using standardized photography and computer-assisted digital imaging. Aprotinin given before an ischemic insult significantly improved flap survival compared to saline controls (52.3% alive vs. 29.6%, P = 0.0132, unpaired t-test). Aprotinin given after ischemia did not significantly influence flap survival (28.8% vs. 34.4% in saline controls, P = 0.708). MPO levels in the aprotinin preischemia treatment group were significantly less at 1 and 8 hr into reperfusion, indicating decreased neutrophil numbers. No statistical difference in TxB2 levels was noted in either group at any time after reperfusion. Aprotinin significantly improves skin flap survival when given prior to but not after an ischemic insult. Aprotinin appears to lower the concentration of neutrophils in skin flaps pretreated with the drug. Reperfused skin flap levels of thromboxane B2 are unaffected by the pre- or postischemic administration of aprotinin.

Analysis of Variance↗

PubMed1998

The future of recombinant growth factors in wound healing.

For more than a decade, clinical trials have been conducted of the application of topical exogenous recombinant growth factors in attempts to accelerate the healing of chronic wounds. Although the results of some of these trials have been encouraging, overall the results have been somewhat discouraging. Much of the difficulty lies in the paucity of carefully controlled clinical trials of wound healing. Since wound healing is a complex process that can be influenced, both positively and negatively, by many factors, designing these trials has proved difficult. To date, only a single recombinant growth factor-recombinant human platelet-derived growth factor-BB (rhPDGF-BB)- has been approved by the US Food and Drug Administration; and that only for use in diabetic foot ulcers. It is unlikely, however, that a single growth factor will be able to resolve all issues of repair or strengthen all vulnerabilities of chronic wounds. Our expectation, therefore, is that growth factors, cytokines, and other biologic agents will be used more specifically in the future, for example, by targeting growth factor therapy at those specific components or processes that a given wound uses to heal.

Anticoagulants↗

PubMed1997

Wound infection. A failure of wound healing caused by an imbalance of bacteria.

Infection in a wound, like infection elsewhere in the body, is a manifestation of a disturbed host-bacteria equilibrium in favor of the bacteria. This not only elicits a systemic septic response but actually inhibits the multiple processes involved in the wound healing scheme. Each process involved in healing is affected when bacteria proliferate in a wound. Wound infection, whether in an intentional operative incision, an acute traumatic laceration, or a chronic pressure ulcer, results when bacteria indigenous to the patient or exogenous to the wound achieve dominance over the systemic and local factors of host resistance. To be able to prevent and manage wound infections requires an understanding of how each prophylactic or therapeutic maneuver works to maintain or re-establish the bacteria-host balance. Only when this equilibrium is in balance can the normal processes of wound healing proceed to give a satisfactory healing trajectory.

Chronic Disease↗

PubMed1997

Minoxidil and wound contraction.

Minoxidil has been proposed as a potential topical inhibitor of wound contraction and proliferative scarring. Suggestions for this application are derived from in vitro investigations demonstrating inhibition of various fibroblastic functions. The purpose of this study was to attempt to establish in vivo support of these effects using an established animal model of wound contraction. Standardized cutaneous wounds were created on the dorsum of Sprague-Dawley rats, which were divided equally into six treatment groups. Wounds were treated daily after tracing their unhealed areas. On complete closure of the wounds, analyses of the contraction rates and tensile strength were performed for comparison among groups. Minoxidil did not demonstrate significant inhibition of wound contraction rates relative to either an inert vehicle, an active vehicle, or no treatment. Contrarily, as previously demonstrated in this animal model, silver sulfadiazine did demonstrate significant inhibition of wound contraction rates relative to both vehicles. No significant difference in tensile strength was demonstrated among groups. These observations do not support the proposed use of minoxidil as an "antifibrotic" agent.

Animals↗

PubMed1996

Beneficial effect of Aloe on wound healing in an excisional wound model.

Recent evidence from in vitro and in vivo experiments suggests that topical antimicrobials may be toxic to fibroblasts and keratinocytes and retard wound healing. The purpose of this study was to determine the effects of Aloe, a potential wound-healing agent, on wound contraction in excisional wounds treated with topical antimicrobials. Sprague-Dawley rats were prepared with four 1.5 cm2 dorsal defects through the skin and panniculus. The animals were divided into five groups (n = 10 per group): (1) Aloe, (2) NaOCl solution (0.025%), (3) mafenide acetate, (4) mafenide acetate + Aloe, and (5) control. Wounds were treated topically for 14 days 3 times a day. Serial standard photographs and serial wound planimetry were performed weekly. Following healing, the breaking strength of each resultant scar was determined using an Instron tensiometer. Kruskal-Wallis, ANOVA, and multiple comparison methods were used for data analysis. Aloe and NaOCl solution significantly accelerated wound contraction (p < 0.05). In the mafenide acetate + Aloe group, contraction was similar to the control, whereas the mafenide acetate alone retarded wound healing. The addition of Aloe in combination and alone in wounds increased the breaking energy when compared to controls (p < 0.05). Aloe appears to expedite wound contraction and neutralize the wound retardant effect seen with the topical mafenide acetate alone. This effect appears to be due to an increased collagen activity, which is enhanced by a lectin, consequently improving the collagen matrix and enhancing the breaking strength.

Aloe↗

PubMed1996

Fluconazole increases bactericidal activity of neutrophils.

BACKGROUND: Candida infections after injury are associated with significant mortality. Death often results from gram negative sepsis. Because antifungal therapy lowers mortality seen with Candida infections, this study was undertaken to determine whether fluconazole (FCZ) augments host response against bacteria, specifically, the bactericidal activity of polymorphonuclear neutrophils (PMN). METHODS: PMN from 23 volunteers were incubated with phosphate-buffered saline or FCZ (20 micrograms/mL or 40 micrograms/mL). Bactericidal activity of these PMN, as well as FCZ alone, was determined using Escherichia coli and a colony forming unit protocol. RESULTS: PMN possess potent bactericidal activity while FCZ possesses minimal inherent bactericidal activity. PMN bactericidal activity is significantly augmented by preincubation with FCZ. This enhanced bactericidal state is greater than the combined individual bactericidal properties of either FCZ concentration and PMN. CONCLUSIONS: FCZ augments PMN bactericidal activity. This augmentation may help to explain the improved survival of critically injured patients receiving FCZ.

Antifungal Agents↗

PubMed1996

Fluconazole increases bactericidal activity of neutrophils through non--cytokine-mediated pathway.

BACKGROUND: Polymorphonuclear neutrophils (PMNs) preincubated with fluconazole (FCZ) demonstrate enhanced bactericidal activity in vitro. OBJECTIVE: This study was undertaken to determine the role of cytokines in FCZ-induced augmentation of PMN function. METHODS: PMNs were preincubated with PBS or FCZ and exposed to Escherichia coli. Cell culture supernatants and mRNA were isolated after preincubation and again after exposure to E. coli. Tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-8 protein and mRNA levels were determined using enzyme-linked immunosorbent assay and polymerase chain reaction, respectively. Results were compared using the Student's t test. RESULTS: Preincubation of PMNs with FCZ resulted in enhanced killing but no difference in cytokine protein or mRNA levels when compared to control. After exposure to E. coli, PMNs significantly up-regulate IL-8 and tumor necrosis factor-alpha independent of the solution with which they were preincubated. CONCLUSIONS: Up-regulation of the cytokine cascade plays a minor role, at most, in the mechanism through which FCZ augments the bactericidal activity of PMNs.

Antifungal Agents↗

PubMed1995

An in vivo model for epithelialization kinetics in human skin.

Epithelialization of wounds has been difficult to measure objectively due to the lack of an adequate model. This paper presents a model for the investigation of epithelialization kinetics in human skin using athymic (nude) rats as an in vivo vehicle. Nude rats are T-cell depleted and as such tolerate xenografts. This technique allows an epithelialization rate for a graft to be calculated by plotting the percentage of its designated analysis area to be closed by neoepithelium over time. This model provides a tool whereby the effect of various agents on the epithelialization kinetics of human skin can be objectively and reproducibly examined. This information may be usefully applied to the clinical management of wounds.

Animals↗

PubMed1995

Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds.

Some human chronic dermal wounds treated with recombinant platelet-derived growth factor-BB (rPDGF-BB) show increased healing coupled with fibroblast activation and granulation tissue formation. To determine whether endogenous PDGF is associated with healing and nonhealing dermal ulcer phenotypes, we developed monoclonal antibodies capable of recognizing the three isoforms of PDGF, AA, AB, and BB dimers, and capable of discriminating between two alternatively spliced A chain transcripts. We detected little PDGF isoform expression in normal skin and in nonhealing dermal ulcers. In contrast, in surgically created acute wounds and chronic ulcers treated with rPDGF-BB, markedly upregulated levels of PDGF-AA (long form) were found. In both types of wounds, increased PDGF-AA was detected primarily in capillaries and fibroblasts, although in rPDGF-BB-treated chronic wounds, widespread expression of PDGF-AA was somewhat delayed. With continued treatment, the long form of PDGF-AA, which can preferentially bind extracellular matrix, was expressed only in capillaries, while fibroblasts began synthesizing the short form of PDGF-AA. Within capillaries, all endothelial cells and varying numbers of pericytes and smooth muscle cells contained PDGF-AA. In all wounds, macrophages and keratinocytes were not a major contributor. While PDGF-BB and PDGF-AB were present in a minority of healing wounds, they were usually present at lower levels than PDGF-AA. PDGF-beta receptors, which bind only PDGF-BB and not other isoforms, were found in normal skin and granulation tissue, providing a molecular basis for treating human chronic wounds with exogenous rPDGF-BB.

Adult↗