Proliferative Phase Of Healing Research Articles

Diabetic Foot Ulcers Healing Promoted by Novel Glibenclamide-loaded Micelle Wound Dressing

Diabetic foot ulcers (DFU) are chronic wounds, which do not respond to traditional wound treatments. In this work, wound dressings of glibenclamide (GB) incorporated into a novel mixed matrix were fabricated in the aim of accelerating the healing process of diabetic wounds. GB was loaded into different weight ratios of Soluplus® (SP) and polyvinylpyrrolidone (PVP). The developed dressings were characterized İn vitro and in vivo, for their ability to promote diabetic wound healing. The particle size was
 between (1.4-2) µm. The morphology abided by the SP/PVP ratio in the formulated microparticles. Cup/bowl shape, semispherical with corrugated surface, apple shape with smooth surface, concave/star shape, and Irregular corrugated morphology were denoted for GB-SP/PVP1-0, GB-SP/PVP1-1, GB-SP/PVP0-1, GB-SP/PVP1-2, and GB-SP/PVP2-1 formulations, respectively. Glibenclamide was in amorphous form and hydrogen-bonded with the matrix polymers. The GB-SP/PVP0-1 wound dressings showed a burst drug release in about 1 hour due to the hydrophilic nature of PVP. The other GB-SP/PVP formulated polymeric micelles were of sustained release, where GB-SP/PVP2-1 extended the drug release for 48 hours. The MTT assay showed that all GB-SP/PVP dressings have good cytocompatibility, and in consequence, they can be used in further investigations on biomedical applications. In vivo tests on a rat model of a full-thickness wound showed rapid closure, indicating the success of the wound dressings in decreasing inflammation and promoting wound healing without scar formation. Therefore, topical administration of GB-SP/PVP1-0 and GB-SP/PVP2-1 wound dressings has a high potential for the treatment of diabetic wounds in inflammatory and proliferative phases of healing with high bioavailability and fewer systemic adverse effects.

Liver is a primary source of insulin-like growth factor-1 in skin wound healing.

Insulin-like growth factor (IGF)-1 plays important role in tissue repair through its ability to stimulate wound cell activity. While IGF-1 is expressed locally by wound cells, liver-derived IGF-1 is also present at high levels in the circulation, and the contributions of local vs circulating IGF-1 to wound levels remain undefined. The hypothesis of this study was that liver is a primary source of IGF-1 during skin wound healing. To test this hypothesis, we utilized a model that allows inducible ablation of IGF-1 specifically in liver of adult mice. We demonstrate that ablation of liver IGF-1 leads to >85% loss of circulating IGF-1 and ~60% decrease in wound IGF-1 during the proliferative phase of healing in both male and female mice. This reduction of liver-derived IGF-1 did not alter local mRNA expression of Igf1 in wounds. Knockdown of liver IGF-1 significantly delayed wound re-epithelialization and reduced granulation tissue formation and collagen deposition. Knockdown of liver IGF-1 also significantly reduced angiogenesis and resulted in persistent macrophage accumulation. In summary, liver is a primary source of IGF-1 in skin wounds and contributes to many aspects of both epithelial and dermal healing.

Ex vivo tolerization and M2 polarization of macrophages dampens both pro- and anti-inflammatory cytokine production in response to diabetic wound fluid stimulation

Monocytes/macrophages play a prominent role in cutaneous wound healing. Persistent inflammation in diabetic wounds is associated with the inability of monocytic cells to switch from a phagocytic M1 (classically activated) to an anti-inflammatory, pro-regenerative M2 (alternatively activated) phenotype and as consequence, the proliferative phase of healing does not commence. A targeted cell therapy approach could potentially restore the pathological wound microenvironment through paracrine signalling to enable healing. This study investigated whether in vitro pre-treatment of monocytic (J774.1 A) cells - using a combination of endotoxin-induced immune tolerance (Pam3CSK4) and M2 polarization (IL-4) - could make these cells impervious to the pathological wound microenvironment and enhance the release of anti-inflammatory cytokines/growth factors. The effect of Pam3CSK4-induced tolerance and IL-4-associated polarization was assessed independently and in combination, on the expression of intracellular (flow cytometry) and secreted (ELISA) cytokines (TNF-ɑ, IL-6, IL-10, TGF-β) with and without re-stimulation to define the optimal pre-treatment conditions. Successive pre-treatment approach consisting of endotoxin tolerance followed by IL-4 priming, dampened TNF-ɑ release and induced intracellular TGF-β production upon re-stimulation. To mimic a chronic wound microenvironment, the J774A.1 monocytes were differentiated into macrophages using GM-CSF prior to pre-treatment (optimal condition) and subsequently exposed to diabetic wound fluid. The data demonstrated that in the presence of wound fluid, the successive pre-treatment, promoted M2 polarization (CD206) of monocytic cells and significantly dampened the intracellular production of both pro-inflammatory (TNF-ɑ, IL-6) and anti-inflammatory (IL-10, TGF-β) cytokines.

Hyaluronan in skin wound healing: therapeutic applications.

Hyaluronan is a vital constituent in effective skin wound healing. This polysaccharide is ubiquitous throughout the human body and has functional significance for tissue repair and remodelling. The importance of hyaluronan in the proliferative phase of healing is diverse, impacting on cell migration, proliferation, modification of the inflammatory response and on angiogenesis. As such, it holds therapeutic potential for a variety of clinical applications that range from facilitating effective wound healing to burns management and scarring. This overview of the multifaceted roles of hyaluronan considers its current applications to clinical practice in plastic surgery as well as the latest advances in research.

Topical administration of hydroethanolic extract of Trifolium pratense (red clover) accelerates wound healing by apoptosis and re-epithelialization

ABSTRACT We investigated the wound healing effects of an ointment prepared from a hydroethanolic extract of Trifolium pratense (red clover) in Wistar rats. An animal model was prepared by making 314 mm2 full thickness skin excisions in all animals. Rats were divided into four experimental groups. Group 1 was a non-intervention control. Groups 2, 3 and 4 were treated topically with ointments containing 1.5, 3.0 and 6% (w/v) T. pretense extract, respectively. We evaluated the effects of these ointments by histological analysis of collagen production, epidermis thickness, fibroblast distribution and wound contraction ratio, and also by estimating expression of Bax, Bcl-2 and p53. Collagen production, epidermis thickness, fibroblast distribution and wound contraction ratio were significantly increased in groups 2 − 4 compared to group 1. Groups 2 − 4 also exhibited significantly increased levels of Bcl-2 mRNA and reduced mRNA levels of Bax and p53 compared to group 1. Groups 2 − 4 exhibited accelerated healing by up-regulating Bcl-2 expression, reducing p53 and Bax levels, and by promoting the proliferative phase of healing. We suggest that a hydroethanolic extract of T. pratense in commercial ointments may be useful for promoting wound healing.

604-P: Deficiency of Dedicator of Cytokinesis 5 Impairs Epidermal Wound Healing

Wound healing is impaired under diabetes, and the proliferative phase of healing, mainly the charge of epidermal keratinocytes, is essential for tissue repair. Failure to maintain this process contributes to the dysfunction of tissue homeostasis and global burden; however, the factors that mediate this process are not fully understood. Here, we identified dedicator of cytokinesis 5 (Dock5) as a critical regulator of cutaneous wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte migration and proliferation and influences the functions of angiogenesis and extracellular matrix (ECM) deposition by binding with integrin α3 (Itgα3). Genetic ablation of Dock5 in mice leads to attenuated re-epithelialization and granulation tissue formation, while Itgα3 overexpression improves the repressive effects on skin repair seen in Dock5 KO mice. Moreover, in patients and animal models of diabetes, Dock5 expression at the skin edge is reduced, further suggesting a direct correlation between its abundance and healing capability. Rescuing Dock5 expression in diabetic mice causes a significant improvement in re-epithelialization, angiogenesis, collagen deposit, ECM production and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes. Disclosure Y. Zheng: None. H. Qu: None. Funding Army Medical University (2017R013, 2019XQYYYJ003-2)

Evaluation of burst release and sustained release of pioglitazone-loaded fibrous mats on diabetic wound healing: an in vitro and in vivo comparison study.

In order to provide more effective treatment strategies for the rapid healing of diabetic wounds, novel therapeutic approaches need to be developed. The therapeutic potential of peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone hydrochloride (PHR) in two different release kinetic scenarios, burst release and sustained release, was investigated and compared with in vitro and in vivo tests as potential wound healing dressings. PHR-loaded fibrous mats were successfully fabricated using polyvinyl-pyrrolidone and polycaprolactone by scalable pressurized gyration. The results indicated that PHR-loaded fibrous mats expedited diabetic wound healing in type-1 diabetic rats and did not show any cytotoxic effect on NIH/3T3 (mouse embryo fibroblast) cells, albeit with different release kinetics and efficacies. The wound healing effects of fibrous mats are presented with histological and biochemical evaluations. PHR-loaded fibrous mats improved neutrophil infiltration, oedema, and inflammation and increased epidermal regeneration and fibroblast proliferation, but the formation of hair follicles and completely improved oedema were observed only in the sustained release form. Thus, topical administration of PPAR-γ agonist in sustained release form has high potential for the treatment of diabetic wounds in inflammatory and proliferative phases of healing with high bioavailability and fewer systemic side effects.

Glycyrrhizinate Dipotassium (DPG) Effects over Skin Wound Healing

Skin wound healing is a complex process involving cellular, and molecular events: inflammatory, proliferative, and remodeling phases. Infectious disease, pre‐existing diseases, medications, and aging can negatively interfere in healing. Research on leptin, collagenase, and tretinoin have been done attempting to promote healing. Glycyrrhizinate Dipotassium (DPG), derived from licorice, has anti‐allergic, antibiotic, and anti‐inflammatory effects, besides promoting the skeletal muscle regeneration by activating quiescent satellite cells, leading myoblasts and myotubes differentiation, and forming new muscle fibers. Considering these aspects, we purpose to verify the 2% DPG pharmacological effect on secondary intention wound healing in adult and aged animals. Twenty male Wistar rats were used. Two skins' excisions (2 cm diameter) of normal skin were made in the animal dorsal region (Naïve group). Topical application of 2% DPG was done on the distal wound daily for 7 days (Treated group). The proximal wound was not treated (Control group). After 14 or 21 days (n = 5 each) of wound creation, the samples were excised, fixed in 10% formol, and processed for paraffin inclusion. Slides were stained with hematoxylin and eosin (H&E), and Masson's trichrome (MT) for histological analysis. Wound healing areas, epidermal and dermal measurements were performed. Statistical analysis adopted a 5% coefficient for null hypothesis rejection. Histological analysis revealed intact skins for Naïve group. Control and Treated groups presented skin with epidermis and dermis reshaped: all epidermal layers (basale, spinosum, granulosum, lucidum, and corneum stratum), as papillary and reticular dermis. In aged rats, the wound was smaller in treated than in untreated animals, resulting in a larger scar compared with the adult rats. However, when treated wounds were compared, no differences were found between the wound areas in adult and aged rats. After 14 days the epidermis thickness of adult and aged animals treated with DPG was thicker than untreated animals. However, after 21 days, the adult epidermis thickness of animals treated with DPG was thinner than untreated animals. The dermis thickness of adult and aged animals treated or non‐treated with 2% DPG did not differ. On the 21st day, adult and aged complete reepithelialization were found in treated animals. Results indicate that 2% DPG significantly reverses wounds process to a skin normal state, even for aged animals, by reepithelization, probably acting during inflammatory and proliferative phases of healing. Such results point DPG as a promissory agent to promote skin healing.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

500 Vibrotactile Stimulation and Pain Modulated Range of Motion Gains in Burn Scars

With an increase in survivability from burn injuries over the past couple of decades comes the challenge of managing post-burn scars. When scar tissue impairs joint function, range of motion (ROM) may be limited. Management of post-burn scar tissue offers many challenges for burn therapists including tolerance to ROM, particularly during the proliferative phase when the scar tissue is vascular, contracting, and the patient may be experiencing dysesthesia. When managing scars during this phase of healing, we investigated an alternative modality that may reduce pain and can be applied in conjunction with ROM to facilitate tissue elongation. We conducted trial runs of two outpatient post-burn survivors, both with right axilla involvement. Patient 1 had been discharged from the burn center for 94 days and patient 2 for 28 days. Both patients spent time at inpatient care facilities upon discharge. Patients were given protocol-based standardized treatments for ROM and measurements taken at conclusion of same, with patient reporting pain at maximal ROM attained. At that point, ROM was resumed with application of vibration for a dosage of 2–3 minutes per square inch of scar with use of skin lubricant. ROM was then measured and pain assessed at maximal ROM attained, and differences compared within each session. The handheld corded vibratory massager used during these trials produces 120 V / 60 Hz of power with adjustable intensity through a three pinpoint triad head. Intensity was adjusted to patient tolerance. The total contact area of the head was 2 cm2. Patient 1 was treated 3 times per week for 19 weeks and was 5 months post-burn at time of first session. Patient 2 was treated 3 times per week for 19 weeks and was 2 months post-burn at time of first session. At the completion of 4 weeks of treatment, patient 1 increased right shoulder flexion by 25 degrees (18.51%) and right shoulder abduction by 18 degrees (12.86%). Patient 2 increased right shoulder flexion by 18 degrees (12.86%), R shoulder abduction by 28 degrees (19.72%), and right shoulder extension by 17 degrees (34%). Both patients 1 and 2 reported less pain with use of vibration, with averages of 5/10 -> 0/10 and 4/10 -> 2/10, respectively. Preliminary data suggests that using a targeted vibratory stimulus during passive ROM may enhance analgesia and ROM gains in the outpatient setting. Reported pain during ROM was found to decrease for both patients. A prospective randomized trial is needed. This study could offer practitioners an alternate modality to use in conjunction with ROM to promote ROM gains while providing vibratory analgesia during the proliferative phase of healing. A prospective, randomized trial is needed.

Inflammation and wound diabetic

Generally, the wound healing proccess undergoes four phase, which are coagulation (hemostasis), inflammation, proliferation and remodelling. The coagulation phase is the first stage of the wound healing proccess which involves platelet cells.1 The inflammation phase starts a few minutes after injury and then continues for several days. During this phase, antiinflammatory cells adhere into the site of injury and actively perform a mobilization with leukocytes (polimorfonuclerleukocytes or neutrophil). If there is no interaction and contamination in the inflammatory phase, it will develope to the proliferative phase of healing. The proliferative phase is characterized by the formation of granulation tissue in the wound and contraction. This phase will be the end if dermis epithelial and collagen layer resurface the wound, the wound begins to contract and a number of growth factors which is produced by macrofag and platelet will accelerate this contraction.1 The remodelling phase starts approximately the third week after wounding and usually lasts about 12 months. The collagen synthesis which started in the beginning of the proliferative phase will continue in the maturation phase. The gelatinous collagen which is secreted in the proliferative phase will realign to mature collagen tissue which are stronger and better than gelatinous collagen.1

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

During dermal wound repair, hypoxia-driven proliferation results in dense but highly permeable, disorganized microvascular networks, similar to those in solid tumors. Concurrently, activated dermal fibroblasts generate an angiopermissive, provisional extracellular matrix (ECM). Unlike cancers, wounds naturally resolve via blood vessel regression and ECM maturation, which are essential for reestablishing tissue homeostasis. Mechanisms guiding wound resolution are poorly understood; one candidate regulator is pigment epithelium-derived factor (PEDF), a secreted glycoprotein. PEDF is a potent antiangiogenic in models of pathological angiogenesis and a promising cancer and cardiovascular disease therapeutic, but little is known about its physiological function. To examine the roles of PEDF in physiological wound repair, we used a reproducible model of excisional skin wound healing in BALB/c mice. We show that PEDF is abundant in unwounded and healing skin, is produced primarily by dermal fibroblasts, binds to resident microvascular endothelial cells, and accumulates in dermal ECM and epidermis. PEDF transcript and protein levels were low during the inflammatory and proliferative phases of healing but increased in quantity and colocalization with microvasculature during wound resolution. Local antibody inhibition of endogenous PEDF delayed vessel regression and collagen maturation during the remodeling phase. Treatment of wounds with intradermal injections of exogenous, recombinant PEDF inhibited nascent angiogenesis by repressing endothelial proliferation, promoted vascular integrity and function, and increased collagen maturity. These results demonstrate that PEDF contributes to the resolution of healing wounds by causing regression of immature blood vessels and stimulating maturation of the vascular microenvironment, thus promoting a return to tissue homeostasis after injury.

The effects of social isolation on wound healing mechanisms in female mice

Various stressors impair wound healing in humans and rodents. For example, social isolation delays wound closure in rodents, but the healing mechanisms that underlie this delay have yet to be identified. Here, the effects of three weeks of social isolation on hypothalamic–pituitary–adrenal axis responses and healing factors involved in the inflammatory and proliferative phases of wound healing were assessed in adult female hairless mice. Social isolation reduced basal circulating corticosterone concentrations and increased body and thymus weights compared with group-housed controls. Isolation impaired dermal wound closure by up to 30% and reduced initial total wound bacterial load relative to controls. Inflammatory gene expression in the wounds was not affected by the observed differences in wound bacterial load. However, isolation reduced wound gene expression of keratinocyte growth factor and vascular endothelial growth factor, which are involved in keratinocyte proliferation/migration and angiogenesis during the proliferative phase of healing. These data indicate that social isolation induces healing impairments that may be attributed to reductions in growth factors necessary for proper skin cell proliferation and blood vessel growth during healing. This healing impairment occurred in the absence of both high wound bacterial load and elevated circulating glucocorticoids, which have previously been hypothesized to be required for stress-impaired healing in mice.

Effects of Autologous Conditioned Plasma® (ACP) on the healing of surgically induced core lesions in equine superficial digital flexor tendon

Tendon pathologies are among the most common musculoskeletal disorders in horses. After damage the tendon repairs by forming disorganized scar tissue that is of inferior functional quality than normal tendon, leading to high re-injury rates. Many of the currently available treatment modalities cannot significantly reduce this high recurrence rate. Autologous Conditioned Plasma (ACP, Arthrex Inc., USA) has been described in the literature as a leukocyte-reduced platelet concentrate. This blood product has been used in equine and human medicine for the treatment of tendon and ligament injuries. However, the effect of this therapeutical approach on tendon healing is unknown. Core lesions were surgically induced in the Superficial Digital Flexor Tendons (SDFT) of both fore- and hind limbs in eight healthy horses. At days 7 and 15 after lesion induction one randomly assigned fore- and hindlimb was treated with ACP and the contralateral one with saline. This study used data from the forelimbs SDFTs only. Gray-scale and color Doppler ultrasonographic parameters monitored throughout the study did not differ significantly at any time point. 22 weeks after the last treatment, the ACP treated tendons presented a significantly lower concentration of sulphated glycosaminoglycans (GAGs) (p≤0.05) when compared to saline. Other compositional, biomechanical and histological parameters presented no significant differences. Our study indicates that 2 intra-tendinous ACP treatments (without anticoagulant) during the proliferative phase of healing in surgically induced tendon core lesions have a limited effect on tendon healing when comparing ultrasonographic, biochemical, biomechanical and histological parameters with the control treatment. Long-term placebo controlled clinical trials with more horses are warranted to determine if this effect is clinically significant.

Cellular and Molecular Factors in Flexor Tendon Repair and Adhesions: A Histological and Gene Expression Analysis

Flexor tendon healing is mediated by cell proliferation, migration, and extracellular matrix synthesis that contribute to the formation of scar tissue and adhesion. The biological mechanisms of flexor tendon adhesion formation have been linked to transforming growth factor β (TGF-β). To elucidate the cellular and molecular events in this pathology, we implanted live flexor digitorum longus grafts from the reporter mouse Rosa26LacZ/+ in wild-type recipients, and used histological β-galactosidase (β-gal) staining to evaluate the intrinsic versus extrinsic cellular origins of scar, and reverse transcription-polymerase chain reaction to measure gene expression of TGF-β and its receptors, extracellular matrix proteins, and matrix metalloproteinases (MMPs) and their regulators. Over the course of healing, graft cellularity and β-gal activity progressively increased, and β-gal-positive cells migrated out of the Rosa26LacZ/+ graft. In addition, there was an evidence of influx of host cells (β-gal-negative) into the gliding space and the graft, suggesting that both graft and host cells contribute to adhesions. Interestingly, we observed a biphasic pattern in which Tgfb1 expression was the highest in the early phases of healing and gradually decreased thereafter, whereas Tgfb3 increased and remained upregulated later. The expression of TGF-β receptors was also upregulated throughout the healing phases. In addition, type III collagen and fibronectin were upregulated during the proliferative phase of healing, confirming that murine flexor tendon heals by scar tissue. Furthermore, gene expression of MMPs showed a differential pattern in which inflammatory MMPs were the highest early and matrix MMPs increased over time. These findings offer important insights into the complex cellular and molecular factors during flexor tendon healing.

Electroacupuncture Increases the Concentration and Organization of Collagen in a Tendon Healing Model in Rats

The aim of this study was to investigate the effect of electroacupuncture (EA) on the composition and organization of the extracellular matrix of the rat Achilles tendon after a partial transection during the proliferative phase of healing. Wistar rats were divided into three groups: rats that were not tenotomized (G1), tenotomized rats (G2), and rats that were tenotomized and submitted to EA (G3). EA was applied 15 days after injury at the ST36 and BL57 acupoints for 20 min, three times per week on alternate days for a total of six sessions. Biochemical analyses were performed using non-collagenous proteins, glycosaminoglycans, and hydroxyproline quantifications. An analysis of metalloproteinase-2 was carried out by zymography. The general organization of the extracellular matrix and the metachromasy of the tendons were analyzed under light microscopy. The organization of the bundles of collagen fibers was analyzed by birefringence analysis. The results showed that EA did not alter the concentration of non-collagenous proteins or glycosaminoglycans or the enzymatic activity of metalloproteinase-2 in the transected tendons. However, the concentration of hydroxyproline was significantly increased when these tendons were treated by EA. The analysis of birefringence showed a higher organization of collagen fibers in the group treated by EA. These results indicate, for the first time, that EA may offer therapeutic benefits for the treatment of tendon injuries by increasing the concentration of collagen and by inducing a better molecular organization of the collagen fibers, which may improve the mechanical strength of the tendon after injury.

Selective release of cytokines, chemokines, and growth factors by minced skin in vitro supports the effectiveness of autologous minced micrografts technique for chronic ulcer repair

A new effective surgical procedure to repair chronic ulcers called minced micrografts technique has been recently reported. The technique consists in spreading a finely minced skin sample upon the wound bed. In this study, we investigate the in vitro release of cytokines (interleukin-6, tumor necrosis factor-α, interleukin-1α, and granulocyte-colony stimulating factor), chemokines (monocyte chemoattractant protein-1 and growth-related oncogene-α), and growth factors (platelet-derived growth factor, basic fibroblast growth factor, vascular endothelial growth factor, hepatocyte growth factor, and nerve growth factor) by minced (referred to as the minced sample) vs. not minced (referred to as the whole sample) human skin biopsy samples from the same donor. Factor release in the culture medium at different time points was detected using a multiplexed protein assay. The minced sample, which could behave like the skin fragments used in vivo in the autologous minced micrografts technique, expressed higher levels of tumor necrosis factor-α, interleukin-1α, platelet-derived growth factor, and basic fibroblast growth factor, and lower levels of interleukin-6, monocyte chemoattractant protein-1, growth related oncogene-α, and vascular endothelial growth factor compared with the whole sample. In conclusion, mincing of healthy skin may allow appropriate regulation of the inflammatory phase of wound healing and could induce overexpression of some growth factors, which facilitates the proliferative phase of healing.

Calidad de vida de persona con heridas complejas en Cartagena, Colombia

Estimating the health-related quality of life (HRQOL) of people suffering complex wounds who were receiving care in an extramural health service provider institution in Cartagena during May-June 2010.This was a quantitative, descriptive study where the population/sample consisted of 93 adults receiving care in an extramural health service provider institution's complex wounds program in the city of Cartagena. A questionnaire regarding socio-demographic characteristics, an observational guide on the characteristics of injuries and the Multicultural Quality of Life Index were used. SPSS 12.0 software was used for the statistical analysis.Mean age was 59.3 years, females predominated (61.3%), 43.0% were married, 38.7% were housewives, 38.7% had finished primary education, 68.8% came from socioeconomic levels 2 and 3 and 93.5% of the participants had health social security affiliation. Complex wounds were characterised by a greater percentage being in the proliferative phase of healing (80.6%), measuring six to ten inches (63.4%) no infection being reported (85%), no amputation (90.3%) or wound-related pain (52.7%) and presenting physical limitations related to the wound (66.7%).People perceived their HRQOL as poor, their low scores highlighting low personal fulfillment, occupational functioning and physical and psychological wellbeing.

Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing

β-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate β-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating β-catenin and found an increase in β-catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3β-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased β-catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of β-catenin signaling. Because fibronectin is a transcriptional target of β-catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.

Overcoming Lower-Extremity Wound Defects Using Hydrocolloid Framing

This article describes an innovative tool to address wound depth defects. A hydrocolloid frame is applied only to the wound periphery and, using regular compression dressings, lowers it to the level of the base, greatly speeding the proliferative phase of healing. The technique is described and supplemented with photographs.

The influence of interleukin-4 on ligament healing

Despite a complex cascade of cellular events to reconstruct the damaged extracellular matrix, ligament healing results in a mechanically inferior scarred ligament. During normal healing, granulation tissue expands into any residual normal ligamentous tissue (creeping substitution), resulting in a larger region of healing, greater mechanical compromise and an inefficient repair process. To control creeping substitution and possibly enhance the repair process, the antiinflammatory cytokine, interleukin-4 (IL-4), was administered to rats before and after rupture of their medial collateral ligaments. In vitro experiments showed a time-dependent effect on fibroblast proliferation after IL-4 treatment. In vivo treatments with IL-4 (100 ng/mL IV) for 5 days resulted in decreased wound size and type III collagen and increased type I procollagen, indicating a more regenerative early healing in response to the IL-4 treatment. However, continued treatment of IL-4 to day 11 antagonized this early benefit and slowed healing. Together, these results suggest that IL-4 not only influences the macrophages and T lymphocytes but also stimulates fibroblasts associated with the proliferative phase of healing in a dose-, cell-, and time-dependent manner. Although treatment significantly influenced healing in the first week after injury, IL-4 alone was unable to maintain this early regenerative response.