Healing Of Chronic Skin Ulcers Research Articles

The effect of autologous plasminogen on the rate of healing of chronic skin ulcers in patients with diabetes mellitus and the level of proteins - markers of hypoxia and angiogenesis

chronic diabetic wounds are a complication of diabetes mellitus that develop as a result of the toxic effects of hyperglycemia, which leads to metabolic disorders with the development of immunosuppression, angiopathy, and neuropathy. A considerable amount of experimental data has been accumulated, which indicates that the participation of the plasminogen-plasmin system in wound healing is not only to clear wounds of fibrin clots, but also to fine-tune the activity of cells that ensure an adequate course of all stages of healing. This study was conducted to investigate the effect of autologous plasminogen on the rate of chronic wound healing in patients with diabetic foot syndrome. The study involved 45 patients with purulent necrotic form of diabetic foot. The efficacy of topical application of standard medications was compared with the application of autologous plasminogen. The wound area was measured once every two days until complete healing. To study the molecular mechanisms of plasminogen effect on wound healing, the level of marker proteins of key physiological processes associated with healing, namely hypoxia and angiogenesis, was determined. The levels of protein regulators of angiogenesis (vascular endothelial cell growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α) and angiostatins) in the skin tissue of wounds at the beginning and end of treatment with autologous plasminogen in patients with chronic diabetic wounds with neuropathic diabetic foot were evaluated. The levels of VEGF, HIF-1α and angiostatins were determined by Western blotting. We have found that wound tissue in patients with chronic diabetic wounds before treatment is characterized by a reduced level of VEGF, which represents the inability of these wounds to regenerate. At the same time, an increased level of HIF-1α and angiostatins is detected. After treatment with autologous plasminogen applications, a significant increase in VEGF expression was observed against the background of a progressive decrease in HIF-1α and angiostatin activity. The results indicate that increased production of angiogenic inhibitors may counteract angiogenesis and contribute to the failure of chronic wound healing. The use of plasminogen applications reduces the level of angiostatins in wound biopsies, which allowed to increase the level of proangiogenic factors. Treatment with plasminogen demonstrated an improvement in the condition of the wound surface and the transition of healing to the proliferative phase due to the initiation of the inflammatory process in wounds. The results of planimetric measurement of the wound area indicate a 5-fold reduction in the time required for complete wound healing in the group receiving plasminogen applications compared to this parameter in the comparison group.

VAP-PLGA microspheres (VAP-PLGA) promote adipose-derived stem cells (ADSCs)-induced wound healing in chronic skin ulcers in mice via PI3K/Akt/HIF-1α pathway

ABSTRACT Chronic skin ulcers are a primary global health problem. Velvet antler polypeptide (VAP) regulates endothelial cell migration and angiogenic sprout. Adipose-derived stem cells (ADSCs) are reported to make pivotal impacts upon wound healing. This study aimed to explore the role of VAP combined with ADSCs in wound healing of chronic skin ulcers. The effect of VAP on phenotypes of ADSCs, and VAP (PLGA microspheres) combining with ADSCs on wound healing of chronic skin ulcers in vivo was evaluated. VAP generally promoted the proliferation, migration and invasion of ADSCs, and ADSC-induced angiogenesis in human umbilical vein endothelial cells (HUVECs) through PI3K/Akt/HIF-1α pathway. VAP-PLGA (PLGA microspheres) enhanced the promoting effect of ADSCs on wound healing, pathological changes, and angiogenesis in chronic skin ulcers in vivo. VAP-PLGA intensified the effect of ADSCs on up-regulating the levels of p-PI3K/PI3K, p-Akt/Akt, HIF-1α, vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), C-X-C motif chemokine receptor 4 (CXCR4), angiopoietin-4 (Ang-4), VEGF receptor (VEGFR), and transforming growth factor-β1 (TGF-β1), and down-regulating the levels of interleukin-1 β (IL-1β), IL-18 and IL-6 in wound tissues in chronic skin ulcers in vivo. Collectively, VAP promoted the growth, migration, invasion, and angiogenesis of ADSCs through activating PI3K/Akt/HIF-1α pathway, and VAP-PLGA enhanced the function of ADSCs in promoting wound healing in vivo, which was associated with angiogenesis, inflammation inhibition, and dermal collagen synthesis.

New strategies for treatment of onychomycosis

Objective: The objective of this study was to study the antimicrobial activity of topical photodynamic therapy (PDT) on chronic skin ulcers infected with Pseudomonas aeruginosa (PA). Methods: Patients with chronic skin ulcers in lower limbs infectedwith PAwere enrolled. The surface areas of the ulcerswere treatedwith either a combination of aminolevulinic acid (ALA) and red light (ALA PDT) or red light alone, both once aweek for 2weeks. Results: At 24h post treatment, although the bacteria levels in two groups were similar (p<0.05), the reduction in ALA PDT group was more significant (p<0.01). At seven days post treatment, the mean ulcer area in the red light group was reduced 45%, that of the PDT group 73% (p<0.01). Conclusion:ALA PDT is a potentialmodality to control PA infection and promote healing of chronic skin ulcers in lower limbs.

A clinical study of photodynamic therapy for chronic skin ulcers in lower limbs infected with Pseudomonas aeruginosa.

The objective of this study is to evaluate the antimicrobial activity and healing-promoting effect of topical photodynamic therapy (ALA-PDT) on chronic skin ulcers infected with Pseudomonas aeruginosa (PA). A total of 26 patients with chronic skin ulcers in lower limbs infected with PA were enrolled. The surface areas of the ulcers were treated with either δ-aminolevulinic acid (ALA)-mediated PDT (20% ALA solution, 1.5 h incubation, 630 nm red light, 80 J/cm(2)) or red light alone, both once a week for two weeks. Before treatment, the wound areas and the bacteria levels in these two groups were comparable (p > 0.05). Results indicated that the bacteria levels in the skin ulcers of the light only group of 24 h post-treatment (3.4 × 10(7) ± 7.1 × 10(7) CFU/cm(2)) and pre-treatment (5.5 × 10(7) ± 1.6 × 10(8) CFU/cm(2)) were not significantly different. In contrast, the bacteria levels on the surfaces of the ulcers in the PDT group of 24 h post-treatment (6.3 × 10(5) ± 1.7 × 10(6) CFU/cm(2)) and pre-treatment (8.9 × 10(7) ± 1.7 × 10(8) CFU/cm(2)) were significantly different (p < 0.01). At seven days post treatment, the mean ulcer area in the red light group was reduced from 11.85 ± 6.83 to 7.8 ± 4.9 cm(2) (p < 0.01), that of PDT group from 12.72 ± 8.58 to 3.4 ± 3.4 cm(2) (p < 0.01). Better healing was seen in PDT group (p < 0.01). In conclusion, ALA-PDT is a potential modality to control PA infection and promote healing of chronic skin ulcers in lower limbs.

Effects and action mechanisms of Buyang Huanwu Decoction in wound healing of chronic skin ulcers of rats

To explore the effects and action mechanisms of Buyang Huanwu Decoction, a compound traditional Chinese herbal medicine, in wound healing of chronic skin ulcers of rats. A total of 54 male SD rats with back full-thickness skin lesion were used in this study. Except for the normal control group, the rats were injected with hydrocortisone for inducing chronic skin ulcers, and were randomly divided into untreated group and Buyang Huanwu Decoction group. The rate and the time of wound healing were observed. Immunohistochemical method and image analytical method were used to test the expression of vascular endothelial growth factor (VEGF) and microvessel count (MVC) in granulation tissue of chronic skin ulcers in the rats. The rate of wound healing was significantly lowered in the untreated group as compared with the normal control group (P<0.01, P<0.05), and the time of wound healing was obviously longer too (P<0.01). In the Buyang Huanwu Decoction group, the rate of wound healing was significantly higher than that in the untreated group (P<0.01), and the time of wound healing was obviously shorter than the latter's (P<0.01). In the untreated group, the expression of VEGF and MVC were significantly lower than those in the normal control group (P<0.01); the expression of VEGF and MVC were obviously increased in the Buyang Huanwu Decoction group as compared with those in the untreated group (P<0.01). Buyang Huanwu Decoction has the effect to promote the wound healing for chronic skin ulcers of rats by regulating the expression of VEGF in granulation tissue of chronic skin ulcers.

Application of Periodontal Tissue Engineering Using Enamel Matrix Derivative and a Human Fibroblast‐Derived Dermal Substitute to Stimulate Periodontal Wound Healing in Class III Furcation Defects

Enamel matrix derivative (EMD) has been shown to promote several aspects of periodontal regeneration in vitro and in vivo. Recently, a bioengineered tissue (DG) was developed to promote wound healing of chronic skin ulcers. This pilot study sought to assess the effects of EMD and DG, alone or in combination, on periodontal wound healing in surgically created Class III furcation defects. Six female baboons received bilateral ostectomy of approximately 10 mm around the first and second mandibular molars to achieve Class III, subclass C furcation defects. Wire ligatures and cotton pellets were left in place for 2 months to maintain the depth of the defects and promote plaque accumulation. Each furcally involved molar was then assigned to one of four treatments: open flap debridement (OFD), OFD plus EMD, OFD plus DG, or OFD plus DG and EMD. This resulted in six total sites per treatment group. Seven months after defect creation and 5 months after treatment, and after no oral hygiene, tissue blocks of the mandible were taken for blinded histometric analysis to assess parameters of periodontal regeneration adjacent to furcal root surfaces and from the mid-furcal aspect (i.e., new bone, new connective tissue attachment, new epithelial attachment, and new cementum formation). Histometric analysis demonstrated differential regenerative responses with respect to treatment within each animal. However, statistically significant differences between treatments from all six animals were not observed (P >0.20, mixed-model analysis of variance). EMD-treated sites presented mildly positive regenerative results and no negative responses. Both DG only and combination therapy demonstrated similar or less than positive responses relative to OFD controls. The descriptive analysis may suggest a positive effect of enamel matrix proteins and a negative effect of DG used alone or in combination with enamel matrix proteins on the regeneration of Class III furcation defects in baboons.

Comments, opinions, and brief case reports: biosurgical debridement facilitates healing of chronic skin ulcers.

Comments, opinions, and brief case reports: biosurgical debridement facilitates healing of chronic skin ulcers.

Ectopic localization of matrix metalloproteinase-9 in chronic cutaneous wounds

It has been hypothesized that excessive activity of matrix metalloproteinases (MMPs), in particular the gelatinases MMP-9 and MMP-2, contributes to poor healing of chronic skin ulcers. We compared MMP-9 and MMP-2 in wound margin biopsies of standardized acute partial-thickness wounds in healthy volunteers (n = 6) and in venous leg ulcer patients (n = 12) with those of chronic wounds of different etiologies (n = 34) by a combination of specific analyses of activity and protein localization. We also studied MMP-14 by immunohistochemistry and in situ hybridization in parallel. Neither MMP-9 (P =.814) nor MMP-2 (P =.742) endogenous activities differed significantly between acute and chronic wound tissues. Acute wound healing was characterized by induction of MMP-9 in the advancing epithelium. In chronic wounds, prominent MMP-9 immunostaining was seen in neutrophils and macrophages in the ulcer bed, but virtually no MMP-9 was detected in wound edge keratinocytes. MMP-2 was increased and activated with acute wound age. MMP-2 was found abundantly in dermal fibroblasts and endothelial cells beneath, but not in new epithelium of acute and chronic wounds. MMP-14 mRNA or protein was detected solely in the stroma of both acute and chronic wounds. In conclusion, the overall activity of gelatinases MMP-9 and MMP-2 was not increased in chronic wounds compared to normally healing wound tissues. Chronic nonhealing wounds may not be caused by excessive gelatinase activity, but are distinguished from healing wounds by an unfavorable distribution and persistance of MMP-9. HUM PATHOL 33:355-364. Copyright 2002, Elsevier Science (USA). All rights reserved.

Preclinical promise of becaplermin (rhPDGF-BB) in wound healing

Advances in molecular biology have made possible the production of highly purified recombinant human proteins, and recombinant human growth factors have emerged as potential therapeutic wound healing agents. Becaplermin (recombinant human platelet-derived growth factor-BB [rhPDGF-BB]) quickly emerged as one of the leading candidates for clinical trials. Before the expected therapeutic potential of rhPDGF-BB and other growth factors could be realized, a number of concerns had to be addressed (eg, would growth factors show effects in normal animals, what parameters of wound healing would be affected, and would quality of healed wounds be normal?). In animal models, rhPDGF-BB demonstrated wound healing activity, predominantly by enhancing the formation of granulation tissue, but it was not known whether this effect on granulation tissue would translate into enhanced healing of chronic skin ulcers in humans. The objective of this article is to review how the study of rhPDGF-BB in animal wound healing models has assisted in addressing the potential clinical utility of rhPDGF-BB. Results of animal studies are summarized, and the advantages and limitations of the animal models are discussed.

Role of growth factors in cutaneous wound healing: a review.

The well-orchestrated, complex series of events resulting in the repair of cutaneous wounds are, at least in part, regulated by polypeptide growth factors. This review provides a detailed overview of the known functions, interactions, and mechanisms of action of growth factors in the context of the overall repair process in cutaneous wounds. An overview of the cellular and molecular events involved in soft tissue repair is initially presented, followed by a review of widely studied growth factors and a discussion of commonly utilized preclinical animal models. The article concludes with a summary of the preliminary results from human clinical trials evaluating the effects of growth factors in the healing of chronic skin ulcers. Throughout, the interactions among the growth factors in the wound-healing process are emphasized.

Ontogenesis of the Basement Membrane Zone After Grafting Cultured Human Epithelium: A Morphologic and Immunoelectron Microscopic Study

Sheets of cultured epithelial cells have been successfully used as autografts for the permanent coverage of patients with full-thickness burns and as allografts to stimulate the healing of chronic skin ulcers. The basement membrane zone (BMZ), composed of lamina lucida, lamina densa, and anchoring fibrils, plays a pivotal role in the firm adherence of the epidermis to the dermis. The present study describes the ultrastructural development during various stages of wound healing after resurfacing different wound areas by cultured epithelial grafts. For this purpose, biopsies were obtained from five patients 5 d to 4.5 years after resurfacing full-thickness burns with cultured autografts, and from five patients at various stages after treatment of excised tattoos and chronic skin ulcers with cultured allografts. One biopsy was taken from a spontaneously healed burn wound 30 years post-injury. Ultrathin sections were prepared for transmission and immunoelectron microscopy, using monoclonal antibodies against type IV and VII collagen. Findings were compared to controls of age- and site-matched normal skin. Eleven days after grafting, the first BMZ features had regenerated, including lamina lucida, a discontinuous lamina densa, hemidesmosomes, and sparse anchoring fibrils. The process of de novo synthesis of BMZ components had begun, and within 4 to 5 weeks complete reformation of BMZ was observed, including normal distribution of anchoring fibrils. Immunolabeling of type VII collagen was first observed upon the lower part of lamina densa at day 11 and steadily increased, reaching normal values 5 weeks after grafting. In contrast, gold deposition of type IV collagen upon lamina densa was strongly increased at day 19 compared to normal. This high expression reduced a little at 5 weeks, but remained high up to 30 years after injury. Long-term burn scars exhibited pseudopodia-like extensions of all basal cells, abundant anchoring fibrils, and an increased amount of arching anchoring fibrils. These features might compensate for the lack of proper rete ridges.

The effect of topical nitroglycerin on transcutaneous oxygen

The use of topical nitroglycerin has been reported to aid the healing of chronic skin ulcers. In this study, the effect of 2% nitroglycerin ointment on transcutaneous oxygen pressure (TcPO2) was investigated in skin adjacent to the area of ointment application. Topical nitroglycerin caused a two-fivefold decrease in TcPO2 in skin next to or up to 9 cm away from the site of application of the ointment.

Collagenous Materials Enhance Healing of Chronic Skin Ulcers

AbstractType I collagen in a porous sponge form attracts fibroblasts in culture and accelerates repair of animal wounds. This study examines the effect of type I collagen sponge and flakes on healing of chronic skin ulcers. Patients included in this study had skin ulcers.Patients included in this study had skin ulcers characterized by loss of dermis and epidermis without exposure of muscle, tendon or bone. Patients showing evidence of systemic infection or patients with ulcers that decreased in area during an initial three week observation period were excluded.Three out of seven patients treated with a collagen sponge and twelve out of fourteen patients treated with collagen flakes showed a 40% decrease in wound area after six weeks of treatment. In comparison, eighteen control patients showed no change in wound area over the same time interval. These results suggest that collagen flakes are effective in initiating healing of chronic skin ulcers.