Increased Wound Tensile Strength Research Articles

Sulfaphenazole reduces thermal and pressure injury severity through rapid restoration of tissue perfusion

Pressure injuries, also known as pressure ulcers, are regions of localized damage to the skin and/or underlying tissue. Repeated rounds of ischemia–reperfusion (I/R) have a major causative role for tissue damage in pressure injury. Ischemia prevents oxygen/nutrient supply, and restoration of blood flow induces a burst of reactive oxygen species that damages blood vessels, surrounding tissues and can halt blood flow return. Minimizing the consequences of repeated I/R is expected to provide a protective effect against pressure injury. Sulfaphenazole (SP), an off patent sulfonamide antibiotic, is a potent CYP 2C6 and CYP 2C9 inhibitor, functioning to decrease post-ischemic vascular dysfunction and increase blood flow. The therapeutic effect of SP on pressure injury was therefore investigated in apolipoprotein E knockout mice, a model of aging susceptible to ischemic injury, which were subjected to repeated rounds of I/R-induced skin injury. SP reduced overall severity, improved wound closure and increased wound tensile strength compared to vehicle-treated controls. Saliently, SP restored tissue perfusion in and around the wound rapidly to pre-injury levels, decreased tissue hypoxia, and reduced both inflammation and fibrosis. SP also demonstrated bactericidal activity through enhanced M1 macrophage activity. The efficacy of SP in reducing thermal injury severity was also demonstrated. SP is therefore a potential therapeutic option for pressure injury and other ischemic skin injuries.

Aesculus hippocastanum L. Extract Does Not Induce Fibroblast to Myofibroblast Conversion but Increases Extracellular Matrix Production In Vitro Leading to Increased Wound Tensile Strength in Rats.

The ability of horse chestnut extract (HCE) to induce contraction force in fibroblasts, a process with remarkable significance in skin repair, motivated us to evaluate its wound healing potential in a series of experiments. In the in vitro study of the ability of human dermal fibroblasts to form myofibroblast-like cells was evaluated at the protein level (Western blot and immunofluorescence). The in vivo study was conducted on male Sprague-Dawley rats with inflicted wounds (one open circular and one sutured incision) on their backs. Rats were topically treated with two tested HCE concentrations (0.1% and 1%) or sterile water. The control group remained untreated. The incisions were processed for wound tensile strength (TS) measurement whereas the open wounds were subjected to histological examination. On the in vitro level the HCE extract induced fibronectin-rich extracellular matrix formation, but did not induced α-smooth muscle actin (SMA) expression in dermal fibroblasts. The animal study revealed that HCE increased wound TS and improved collagen organization. In conclusion, the direct comparison of both basic wound models demonstrated that the healing was significantly increased following HCE, thus this extract may be found useful to improve healing of acute wounds. Nevertheless, the use of an experimental rat model warrants a direct extrapolation to the human clinical situation.

Topical small molecule\xa0granzyme B\xa0inhibitor improves remodeling in a\xa0murine model of impaired burn wound healing

Granzyme B (GzmB) is a serine protease that has long been thought to function exclusively in lymphocyte-mediated apoptosis. In recent years, this paradigm has been revisited due to the recognition that GzmB accumulates in the extracellular milieu in many autoimmune and chronic inflammatory disorders, and contributes to impaired tissue remodeling due to the cleavage of extracellular matrix proteins. Knockout studies suggest that GzmB-mediated cleavage of decorin (DCN) contributes to impaired collagen fibrillogenesis and remodeling. As DCN is anti-fibrotic and contributes to reduced hypertrophic scarring, GzmB-induced DCN cleavage could play a role in wound healing following burn injury. In the present study, a novel, gel-formulated, first-in-class small-molecule inhibitor of GzmB, VTI-1002, was assessed in a murine model of impaired, diabetic burn wound healing. VTI-1002 exhibited high specificity, potency, and target selectivity. Gel-formulated VTI-1002 was able to penetrate the stratum corneum and was retained in the skin with minimal systemic absorption. Daily topical administration of VTI-1002 gel for 30 days following thermal injury showed significantly accelerated wound closure, increased DCN protein levels, and collagen organization that was translated into significantly increased wound tensile strength compared to controls. Overall, VTI-1002 gel was well-tolerated in vivo and no adverse events were observed. Topical application of VTI-1002 represents a novel therapeutic approach for the treatment of cutaneous burn wounds.

Comparative assessment of dermal wound healing potentials of various Trifolium L. extracts and determination of their isoflavone contents as potential active ingredients

Ethnopharmacological relevanceTrifolium species are used in Turkish folk medicine as a wound healing agent, expectorant, antiseptic, sedative and to alleviate pain in rheumatism. In the present study, the aqueous methanolic extracts (80%) of 13 Trifolium species (Trifolium ambigum, Trifolium arvense var. arvense, Trifolium campestre, Trifolium canescens, Trifolium hybridum var. anatolicum, Trifolium hybridum var. hybridum, Trifolium pannonicum, Trifolium pratense var. pratense, Trifolium purpureum var. purpureum, Trifolium repens var. repens, Trifolium resupinatum var. microcephalum, Trifolium spadiceum and Trifolium trichocephalum) collected from different regions of Anatolia were evaluated for their in vivo wound healing effects. Materials and methodsIn vivo wound healing activities of the plant aqueous methanolic extracts were evaluated by linear incision and circular excision wound models subsequent to histopathological analysis. Active constituents were determined by a validated high performance liquid chromatographic method. Precision of the method was performed by the evaluation of intra-day and inter-day variations of the each standard at limits of quantification (LOQ) levels. ResultsThe aqueous methanolic extracts of Trifolium canescens and Trifolium pretense var. pratense possessed better wound healing activity compared to the other extracts and control groups. The animal groups treated with the Trifolium canescens extract demonstrated increased contraction (48.96%) on excision and a significant increase in wound tensile strength (35.6%) on incision models. The main compounds were detected as genistein and biochanin A for Trifolium canescens. ConclusionThe results of the present study revealed the wound healing potential of Trifolium canescens. This might be due to the combined effect of the isoflavones genistein, formononetin, daidzein, and biochanin A present in the extract.

Wound Repair Potential ofOlea europaeaL. Leaf Extracts Revealed byIn VivoExperimental Models and Comparative Evaluation of the Extracts' Antioxidant Activity

Leaves and fruits of Olea europaea L. (olive) have been used externally as an emollient for skin ulcers and for healing of inflammatory wounds. n-Hexane and aqueous extracts, prepared from the dried leaves of olive, were evaluated for their wound healing activity by using in vivo wound models of linear incision and circular excision in comparison with the reference ointment Madecassol® (Bayer, Istanbul, Turkey). The group of animals treated with the aqueous extract demonstrated increased contraction (87.1%) on excision and a significant increase in wound tensile strength (34.8%) on incision models compared to the other groups. Moreover, the antioxidant activity assay showed that aqueous extract has higher scavenging ability than the n-hexane extract. According to the experimental data, the aqueous extract of O. europaea leaves displayed wound healing activity. Secoiridoid oleuropein (4.6059%) was identified as the major active compound according to high-performance liquid chromatography analysis of the aqueous extract.

Pulsed Magnetic Fields Accelerate Cutaneous Wound Healing in Rats

Previous studies of pulsed magnetic fields have reported enhanced fracture and chronic wound healing, endothelial cell growth, and angiogenesis. This study characterizes the biomechanical changes that occur when standard cutaneous wounds are exposed to radiofrequency pulsed magnetic fields with specific dosage parameters, in an attempt to determine whether return to functional tensile strength could be accelerated in wound healing. There were two study phases and a total of 100 rats. In phase 1, wounds were exposed to a 1.0-G pulsed magnetic field signal in clinical use for wound repair for 30 minutes twice daily for 21 or 60 days. Phase 2 was a prospective, placebo-controlled, double-blind trial in which rats were treated for 30 minutes twice daily with three different low-amplitude signals (0.02 to 0.05 G), configured assuming a Ca binding transduction pathway, for 21 days. A midline, 8-cm, linear skin incision was made on the rat dorsum. Tensile strength was determined by measuring the point of rupture of the wound on a standard tensiometer loaded at 0.45 mm/second. The mean tensile strength of treated groups in phase 1 was 48 percent (p < 0.001) greater than that of controls at 21 days; there was no significant difference at 60 days. In phase 2, the treated groups showed 18 percent (not significant), 44 percent, and 59 percent (p < 0.001) increases in tensile strength over controls at 21 days. The authors successfully demonstrated that exposing wounds to pulsed magnetic fields of very specific configurations accelerated early wound healing in this animal model, as evidenced by significantly increased wound tensile strength at 21 days after wounding.

003 α1‐Antichymotrypsin – A Human Serpin with the Potential to Heal Diabetic Ulcers

α1‐Antichymotrypsin (α1‐ACT) is a secreted serine proteinase inhibitor of the serpin family. It is strongly upregulated during the inflammatory phase of wound repair to control the undesirable destructive side effects of cathepsin G which is released from infiltrating neutrophils. We have shown that α1‐ACT and its mouse homologue spi2 exhibit a classic acute phase response after cutaneous injury in murine and human skin. The induction of spi2 gene expression following wounding is significantly less pronounced in diabetic mice. Transient overexpression of spi2 or α1‐ACT significantly increased wound tensile strength in two independent diabetic models: in genetically diabetic mice, gene gun mediated delivery of spi2 or α1‐ACT cDNA increased the average wound strength by 42%(P = 0.001) and 21%(P = 0.013) at d5 post‐wounding respectively. In a STZ induced diabetic rat model the breaking strength of adenovirally spi2‐ or α1‐ACT‐infected wounds increased by 20%(P = 0.049) and 23%(P = 0.004) at d7 after injection respectively. Moreover, the topical application of human α1‐ACT protein to wounds of diabetic mice had a significant and dose dependent effect on tensile strength at d5 post‐wounding (21% increase, P = 0.003). Histological analyses of these wounds indicated less infiltration of neutrophils in the treated wounds. α1‐ACT appears to be a key mediator between proteolysis and cytokine agonism and antagonism. Our data indicate that this balance is disturbed in diabetic wounds and that α1‐ACT might act as a switch to initiate wound healing in diabetic ulcers.

Effect of sodium diphenylhydantoin on skin wound healing in rats.

This study evaluated the effect of phenytoin (sodium diphenylhydantoin) on skin wound healing in a rat model. The study was divided into two parts. In part I, 20 mul of phenytoin (10 mg/ml) was subcutaneously injected into the 3-cm dorsal full-thickness incisional wounds of 14 rats on postoperative days 0, 3, and 6. Twelve rats that received saline injections were used as the controls. The skin samples were harvested and tested for tensile strength and histology. An additional 12 rats with the same incisional wounds were tested for chemokine gene expressions. In part II, 20 mul of phenytoin (10 mg/ml) was applied topically once a day on a 4 x 4 cm area of the open dorsal wounds of 10 rats. Saline was applied to the wounds of the 10 control group rats. The wounds were measured weekly. The results showed that the average tensile strength of the phenytoin-treated wound was 0.49 +/- 0.08 MPa compared with the control group at 0.02 +/- 0.01 MPa (p < 0.05). The density ratio of chemokine monocyte chemotactic protein (MCP-1) to beta-actin in the phenytoin-treated group was also significantly higher than in the control group (p < 0.05). Histologic analysis of the phenytoin group showed a large amount of fibroblast proliferation, collagen synthesis, and neovascularization. Phenytoin-treated wounds were also smaller at 1 to 6 weeks postoperatively than the control group wounds. The authors conclude that the administration of phenytoin can promote wound healing and significantly increase MCP-1 expression. Phenytoin-treated wounds showed significant increase in collagen deposition and neovascularization, which resulted in an increased wound tensile strength and accelerated healing of both open and closed wounds.

Laser tissue soldering: applications in the genitourinary system.

Within the past 25 years, lasers have transitioned from merely destructive or ablative tools to those with reconstructive uses. It has been shown that the application of laser thermal energy to tissue will result in welding of the approximated areas. Furthermore, the addition of protein solder and chromophores (tissue soldering) has increased wound tensile strength while decreasing peripheral tissue damage. Laboratory studies have demonstrated application of laser tissue soldering to virtually all components of the genitourinary system. Increasing human experience in recent years has reinforced the success of this technique.

An investigation on skin wound healing in mice with a taurine-chitosan gel formulation.

The process of wound healing begins immediately following surface lesions or just after exposure to radiation, chemical agents or extreme temperatures. Taurine (2-aminoethane sulfonic acid), an amino acid containing sulfur, is found in almost all tissues in mammals, playing various important physio-logical roles in each organ. Taurine exhibits an antioxidant effect and is also known to have effects on cell proliferation, inflammation and collagenogenesis. Many antioxidants have been used to eliminate the negative effects of oxygen free radicals on wound healing. The objective of the present study was to examine the wound healing effect in mice of taurine-chitosan gel, which releases taurine slowly over a long time period. Fifty mM of taurine in 1.5% chitosan polymer (TAU-GEL) and 1.5% chitosan polymer (CHI-GEL) were applied to full thickness skin wounds of mice once a day for seven days. After seven days of treatment, lipid peroxide formation-malondialdehyde (MDA) and hydroxyproline (HPX) levels and the tensile strength of wound tissues were measured. All results were compared with those of the untreated control group (CONT). The structural alterations in the skin layers were also histologically investigated. It was found that locally administered TAU-GEL form significantly increased wound tensile strength by decreasing the MDA and increasing HPX levels. These results were supported by histological findings. All observations suggest that taurine gel may be effective in wound healing.

Particle-Mediated Gene Transfer of PDGF Isoforms Promotes Wound Repair

Several techniques for cutaneous gene transfer have been investigated for either in vitro or in vivo applications. In the present study, we investigated whether the direct delivery of platelet-derived growth factor cDNA into skin results in improvement in tissue repair. Cutaneous transfections were carried out in rats using a particle-bombardment device (Accell). As revealed by reverse transcriptase-polymerase chain reaction, transgene expression in vivo was transient, with low level expression by day 5. When compared with wounds transfected with a control cytomegalovirus-luciferase plasmid, wounds transfected with platelet-derived growth factor A or B in the MFG vector showed a significant increase in wound tensile strength 7 and 14 d after transfection. At both time points platelet-derived growth factor A transfected wounds exhibited the highest increase in tensile strength over controls, resulting in a 3.5-fold increase at day 7 and a 1.5-fold increase at day 14. The degree of stimulation was not remarkably different between wounds transfected with platelet-derived growth factor B, which is predominantly cell associated, or a truncation mutant, platelet-derived growth factor B211, which is predominantly secreted. These findings demonstrate that in vivo gene transfer by particle bombardment can be used to improve the tissue repair response. This approach provides a robust tool to assess the biologic activity of various proteins and will aid in the development of therapeutic cutaneous gene delivery.

Wound Healing: Tensile Strength vs Healing Time for Wounds Closed Under Tension

To measure tensile strength of wounds closed with and without tension in rats, delineating the postoperative time interval when tensile strength is equal. To study patterns of growth in tensile strength. Transverse incisions on the backs of control rats were closed with minimal tension. In experimental animals, after excision of skin from the back, wounds were closed with closing tensions in excess of 70 g. Animals were killed at designated healing intervals for tensile-strength testing of wounds. One hundred Sprague-Dawley rats were divided into 5 groups days 5, 7, 10, 14, and 21, with equal numbers of control and experimental animals in each group. Wounds from 94 animals were available for breakload testing. Closing tensions were measured for transverse incisions on the backs of control animals before closure and after removal of 50 to 60 mm of skin from the backs of experimental animals. Tensile strength was not significantly different on day 5. However, wounds closed under tension showed significantly higher tensile strength on 7, 10, 14, 21. Polynomial regression suggests a cubic relationship between healing time and tensile strength. Results suggest that tensile strength of wounds closed under tension exceeds that of tensionless wounds as early as day 7 following surgery. This study also illustrates the 2 periods of rapid increase in wound tensile strength that probably coincide with specific stages of wound healing.

Effect of taurine on wound healing

Taurine which has antioxidant effects is also known to have effects on cell proliferation, inflammation and collagenogenesis. The aim of this study was to investigate the effect of taurine on incisional skin wounds.The mice incised on the dorsal area were divided into control and experimental groups. Saline was injected intraperitoneally to half of the animals in the control group and locally applied to the other half. Fifty mM taurine solution was given intraperitoneally to the first half of the experimental animals and locally to the second half of the experimental group.After four days of treatment, malondialdehyde (MDA) and histamine levels as well as the tensile strength of the wound tissue were measured. Structural alterations in epidermis and dermis were histologically evaluated.The locally administreated taurine significantly increased wound tensile strength by decreasing the MDA and histamine levels and prevented the degranulation of the mast cells. These observations suggest that taurine may be useful on wound healing.

Acidic fibroblast growth factor accelerates dermal wound healing.

Acidic fibroblast growth factor (aFGF) is a potent mitogen in vitro for many cells of ectodermal and mesodermal embryonic origin including skin-derived epidermal keratinocytes, dermal fibroblasts and vascular endothelial cells. Based on the mitogenic activity for these skin-derived cells, we tested the ability of topically applied aFGF to promote healing of full-thickness dermal wounds in healthy rodents. Low doses of aFGF can produce almost a two-fold maximum acceleration in the rate of closure of full-thickness dermal punch biopsy wounds in young healthy mice and rats. The mitogen also produces a 3 to 4 day acceleration in the time to complete closure in rats. Quantitative histomorphometric analysis of wound tissue shows that aFGF induces a marked stimulation of angiogenesis, granulation tissue formation and the growth of new epithelium, but does not promote dermal contraction. Application of aFGF to linear incisions in rat skin produces a transient increase in wound tensile strength accompanied by enhanced cellularity and deposition of collagen. Therefore, aFGF functions as a pharmacological agent that can accelerate dermal wound healing in rodents and could act therapeutically to promote dermal tissue repair in humans.

Chronic administration of growth hormone-releasing factor increases wound strength and collagen maturation in granulation tissue

The effects of chronic administration of growth hormone-releasing factor (GRF) on wound healing were studied in rats. Cutaneous wound strength was measured by tensometry at 5, 10, and 14 days postwounding in rats implanted with a slow-release pellet which contained a compressed mixture of a fatty acid and [desamino Tyr 1, d-Ala 2, Ala 15]hGRF(1–29)NH 2 or the fatty acid alone. There was a significant increase in wound tensile strength in GRF-treated rats compared to controls at each measurement: Day 5, 130 ± 12 vs 97 ± 14 g; Day 10, 402 ± 18 vs 280 ± 11 g; Day 14, 830 ± 17 vs 614 ± 14 g ( P < 0.01 for each value). Granulation tissue obtained from subcutaneously implanted polyvinyl alcohol sponges encased in silicone tubing was also studied. The amount of collagen deposited in the granulation tissue was estimated by measuring the hydroxyproline (Hyp) content of sponges retrieved 5, 10, and 14 days postinsertion from GRF-treated and control rats. Hyp content (nmole/mg sponge) was similar in both treated and control animals at each measurement: Day 5, 1.7 ± 0.2 vs 2.2 ± 0.2; Day 10, 31.9 ± 4.1 vs 26.7 + 0.4; and Day 14, 41.6 ± 7.3 vs 38.5 ± 4.4. Hyp/proline, Hyp/glycine, and glycine/total amino acid ratios, evaluated after 10 days, were also similar in both groups. Collagen from the granulation tissue of sponges retrieved after 14 days from treated and control rats was studied by electron microscopy (magnifications, 7,100 and 22,720). The intercellular spaces in the sponges of the control rats were sparsely covered by collagen fibrils, in contrast to the intercellular spaces in the sponges of the treated rats, which were completely filled with collagen fibrils. These results demonstrate that chronic administration of GRF for 14 days increases wound strength during the early stage of healing in rats. In addition, GRF does not stimulate collagen deposition in granulation tissue, but accelerates collagen maturation instead. We postulate, therefore, that this effect is responsible for the enhanced cutaneous wound strength seen at 10 and 14 days postwounding in GRF-treated rats.

Effects of fibroblasts and basic fibroblast growth factor on facilitation of dermal wound healing by type I collagen matrices

Healing of large open dermal wounds is associated with decreased values of the tensile strength even up to 6 months post-wounding. Results of previous studies have shown that healing is facilitated in the presence of a type I collagen sponge by promoting deposition of newly synthesized large-diameter collagen fibers parallel to the fibers of the sponge. In this study healing is evaluated in dermal wounds treated with a collagen sponge seeded with fibroblasts or coated with basic fibroblast growth factor (bFGF). Experimental results indicate that the presence of a collagen sponge results in increased wound tensile strength and increased collagen fiber diameters in the upper dermis 15 days post-wounding in an excisional guinea pig dermal wound model. In comparison, dermal wounds treated with collagen sponges seeded with fibroblasts or coated with bFGF showed increased tensile strengths 15 days postimplantation and increased degree of reepithelialization. These results indicate that fibroblast seeding and bFGF coating in conjunction with a type I collagen sponge matrix facilitate early dermal and epidermal wound healing.

Acceleration of tensile strength of incisions treated with EGF and TGF-beta.

The ability of surgeons to accelerate wound healing through pharmacologic intervention is limited. The effects of locally applied, biosynthetic human epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) on tensile strength of experimental incisions were investigated. A single dose of EGF in saline failed to increase tensile strength over controls. Thus, EGF was incorporated into multilamellar liposomes, which prolonged the exposure of incisions to EGF (p less than 0.001). A single dose of EGF in multilamellar liposomes produced a 200% increase in wound tensile strength over controls between 7 and 14 days (p less than 0.05). Light and electron microscopy of the wounds revealed increased collagen formation and fibroblast proliferation. A single dose of TGB-beta in a collagen vehicle stimulated a 51% increase in wound tensile strength at 9 days (p less than 0.01). We conclude that addition of EGF and TGF-beta in appropriate vehicles stimulates early transient increases in wound tensile strength in normal rats.

Tensile strength of skin wounds in rats after treatment with corticosteroids.

ABSTRACT The tensile strength of skin wounds has been studied in rats at different times after operation. Cortisol acetate (5 or 50 mg/kg) or prednisolone acetate (1 or 10 mg/kg) were injected daily subcutaneously. According to the dose and potency of the corticosteroid given, the wound tensile strength was found to be decreased between the 3rd and 9th day. This effect was most pronounced on the 6th day. On the 12th day and even more distinctly on the 20th day after operation, a reversal of this effect could be observed. Low doses of glucocorticoids resulted in an increase in wound tensile strength, whereas high doses, already toxic after prolonged administration, still caused a decrease. If treatment was started at the end of the collagen phase (11th day), only an increase in wound tensile strength was seen, regardless of the dose of glucocorticoid administered. Short-term treatment during the scar phase (day 19 to 20) resulted in an increase in wound tensile strength which correlated with the dose and potency of the glucocorticoid given. It is therefore concluded that scar tissue of wounded skin reacts like normal connective tissue as far as the increase in tensile strength induced by glucocorticoids is concerned.

An evaluation of the effects of cartilage powder on wound healing.

THE acceleration of wound healing by the application of cartilage powder has been advocated by Prudden,^1-3and his observation of increased wound tensile strength has been substantiated by San Miguel and Enquist.⁴Using methods found to be highly reproducible in our laboratory, a series of experiments were undertaken to further evaluate the effects of cartilage on wound healing. Increases in tensile strength were recorded, and these were maximal if the cartilage was injected into the wound site one week prior to surgery. A disturbing finding, however, was that the cartilage appeared to be antigenic and that animals who had prior exposure to the powder and were then treated a second time showed actual impairment of wound healing. <h3>Methods</h3> Male Holtzman rats, weighing 300 to 400 gm were used throughout the study. All rats were housed in individual cages and were given a balanced diet with water ad lib.

Thermographic studies of wound healing

1.1 A series of preoperative and postoperative patients have been studied with newly developed techniques of long wave infra-red sensing and recording instrumentation.2.2 Observation and control values of normal abdominal surface infra-red emission have been outlined for further evaluation.3.3 The variations of temperature and thermogram patterns in different surgical wounds have been described and compared to previous modalities studied (i.e., the classical phases of wound healing, changes in tensile strength, and biochemical sequences).4.4 It has been suggested that the thermographic pattern may be a useful tool in predicting the early evidence of increase in wound tensile strength. It may also note initial evidence of complications or factors prolonging the healing of a surgical wound.