Effects of Senescence in Wound Healing

With the advent of aging society, the effects of aging on all aspects of the body are attracting more and more attention. Among them, the increasing incidence of chronic wounds in the elderly not only affects the quality of the elderly’s life significantly, but also brings a heavy medical burden on society. Delayed and poor wound healing increases the possibility of severe infections. To find out a solution for infection and chronic wounds, it is necessary to clarify the specific mechanisms of wound healing and possible intervention targets. Wound healing is a complex physiological process in the human body, which involves the coordinated activation of multiple cell types and signaling pathways. The role of senescent cells in wound healing is causing growing attention in recent years. It was thought that wound healing needs to take a longer time in elder people. In recent years, it has been found that senescent cells promote wound healing. So far, the effects of senescent cells on the efficiency and quality of wound healing and its specific mechanism have not been fully clarified. What is certain is that different types of senescent cells and even different subtypes of the same senescent cells play different roles in fast and chronic wound healing. It is not only the heterogeneity of the senescent cell itself, but also the difference in the surrounding microenvironment that determines the effect of senescent cells on wound healing. The study of its mechanism is helpful to find a way to promote the healing of wounds. It is worth noting that senescent cells themselves may also induce poor wound prognosis, such as chronic wounds, inflammation and decreased anti-infection ability. Therefore, the ideal treatment strategy to apply senescent cells will be a comprehensive plan that maximizes the efficiency and quality of wound healing, while minimizing the risk of senescent cells itself becoming an inducement for chronic wounds.     

Clinical trials of amniotic membranes in burn wound care

Four test conditions of increasing complexity were used to evaluate the clinical efficacy of amniotic membranes as biologic dressings on donor sites and burn wounds in children. These were the clean-skin donor-site wound, the uncontaminated shallow partial-thickness burn wound, the bed of freshly excised full-thickness wounds, and the granulating surface of colonized burn wounds. The rate of epithelialization under amniotic membranes was the same as that under 5% scarlet red ointment or 0.5% silver nitrate solution dressings. Preservation of a healthy excised wound bed and maintenance of a low bacterial count in contaminated wounds paralleled the experience with human allograft dressings despite technical difficulties and the absence of vascularization of amniotic membrane and its fragile structure. Tentative conclusions are drawn as to the mechanisms by which biologic dressings exert their beneficial effects.     

Removing radionuclides from wound fluids using chemical speciation and chelation lavage

Abstract

The relative efficacy of a range of chelating agents for dissolving plutonium(IV) hydroxide precipitated in wounds is assessed by computing the chemical speciation prevailing in the wound fluid and wound lavage solution. The most promising ligand for mobilisation is DTPA when used under mildly acid (approx. pH 6.4) conditions. If the Pu(IV) oxide has been formed, none of the ligands are effective.     

Connexins in wound healing; perspectives in diabetic patients

Skin lesions are common events and we have evolved to rapidly heal them in order to maintain homeostasis and prevent infection and sepsis. Most acute wounds heal without issue, but as we get older our bodies become compromised by poor blood circulation and conditions such as diabetes, leading to slower healing. This can result in stalled or hard-to-heal chronic wounds. Currently about 2% of the Western population develop a chronic wound and this figure will rise as the population ages and diabetes becomes more prevalent [1]. Patient morbidity and quality of life are profoundly altered by chronic wounds [2]. Unfortunately a significant proportion of these chronic wounds fail to respond to conventional treatment and can result in amputation of the lower limb. Life quality and expectancy following amputation is severely reduced. These hard to heal wounds also represent a growing economic burden on Western society with published estimates of costs to healthcare services in the region of $25B annually [3]. There exists a growing need for specific and effective therapeutic agents to improve healing in these wounds. In recent years the gap junction protein Cx43 has been shown to play a pivotal role early on in the acute wound healing process at a number of different levels [4-7]. Conversely, abnormal expression of Cx43 in wound edge keratinocytes was shown to underlie the poor rate of healing in diabetic rats, and targeting its expression with an antisense gel restored normal healing rates [8]. The presence of Cx43 in the wound edge keratinocytes of human chronic wounds has also been reported [9]. Abnormal Cx43 biology may underlie the poor healing of human chronic wounds and be amenable therapeutic intervention [7]. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.     

Effects of CD100 promote wound healing in diabetic mice

Diabetes is a condition that causes delayed wound healing and results in chronic wounds. CD100 has been reported to promote and induce potent and obvious angiogenesis both in vivo and in vitro studies, the absence of which are a main cause of the diabetic chronic wound. In the present study, we investigated the effects of application of soluble CD100 on wound healing in diabetic mice. Four 5-mm full-thickness dermal wounds were made on each male db/db mouse. 12 mice from CD100 group were subcutaneously injected with 250 ng of CD100 (50 µl) per wound, in addition, 12 mice were injected with the same volume phosphate-balanced solution as the control. The animals were treated every other day until the wounds healed completely. Images were obtained to calculate the area ratio of the original area. HE and Masson’s trichrome staining were used for histological examination. Collagen remodeling, angiogenesis and wound bed inflammation were evaluated by immunohistochemical staining and western blot. We demonstrated that CD100 had distinct functions during the wound healing process. Histological and western blotting analysis showed a more organized epithelium and dermis, more collagen fibers, higher angiogenesis and lower inflammation in the CD100 group than in the PBS group. These findings suggest that CD100 may accelerate wound healing in diabetic mice by promoting angiogenesis in the wound and by reducing the inflammatory response.     

Circulating fibrocyte mobilization in negative pressure wound therapy

Non‐healing diabetic wounds are difficult to treat. They also create heavy financial burdens for both patients and society. Negative pressure wound therapy (NPWT) has been adopted to treat intractable wounds and has proved to be effective. However, the mechanisms that underlie the effects of this treatment are not entirely understood. Circulating fibrocytes are unique haematopoietic‐derived stem cells that have been reported to play a pivotal role in wound healing. Here, we have investigated the effect of NPWT on fibrocyte mobilization and the role of fibrocyte mobilization in the healing of diabetic wounds during NPWT. We show that the NPWT group exhibited 2.6‐fold to 12.1‐fold greater numbers of tail vein‐injected PKH‐26‐labelled fibrocytes in the diabetic wound sites compared with the control group. We also demonstrate that the full‐thickness skin wounds treated with NPWT exhibit significantly reduced mRNA and protein expression, blood vessel density and proliferating cells when exogenous fibrocyte mobilization is inhibited. We speculate that systemic mobilization of fibrocytes during NPWT may be a mechanism for healing intractable wounds in a diabetic rat model experiment and that enhancement of cell mobilization may represent a potential treatment idea for intractable wound healing across all fields of surgery.     

Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice.

The rise of multiply antibiotic resistant bacteria has led to searches for novel antimicrobial therapies to treat infections. Photodynamic therapy (PDT) is a potential candidate; it uses the combination of a photosensitizer with visible light to produce reactive oxygen species that lead to cell death. We used PDT mediated by meso-mono-phenyl-tri(N-methyl-4-pyridyl)-porphyrin (PTMPP) to treat burn wounds in mice with established Staphylococcus aureus infections The third degree burn wounds were infected with bioluminescent S. aureus. PDT was applied after one day of bacterial growth by adding a 25% DMSO/500 microM PTMPP solution to the wound followed by illumination with red light and periodic imaging of the mice using a sensitive camera to detect the bioluminescence. More than 98% of the bacteria were eradicated after a light dose of 210 J cm(-2) in the presence of PTMPP. However, bacterial re-growth was observed. Light alone or PDT both delayed the wound healing. These data suggest that PDT has the potential to rapidly reduce the bacterial load in infected burns. The treatment needs to be optimized to reduce wound damage and prevent recurrence.     

Role of platelet-derived growth factor in wound healing

Platelet-derived growth factor (PDGF) is a potent activator for cells of mesenchymal origin. PDGF stimulates chemotaxis, proliferation, and new gene expression in monocytes-macrophages and fibroblasts in vitro, cell types considered essential for tissue repair. Therefore, we analyzed the influence of exogenously administered recombinant B chain homodimers of PDGF (PDGF-BB) on two experimental tissue repair paradigms, incisional and excisional wounds. In both types of wounds, as little as 20-200 picomoles applied a single time to wounds significantly augmented the time dependent influx of inflammatory cells and fibroblasts and accelerated provisional extracellular matrix deposition and subsequent collagen formation. In incisional wounds, PDGF-BB augmented wound breaking strength 50-70% over the first 3 weeks; in excisional wounds, PDGF-BB accelerated time to closure by 30%. PDGF-BB exaggerated, but did not alter, the normal course of soft tissue repair, resulting in a significant acceleration of healing. Long term observations established no apparent differences between PDGF-BB treated and non-treated wounds. Thus, the vulnerary effects of PDGF-BB were transient and fully reversible in both wound healing models. Furthermore, analysis of PDGF-treated and non-treated wounds has provided important insights into mechanisms of normal and deficient tissue repair processes. PDGF appears to transduce its signal through wound macrophages and may trigger the induction of positive autocrine feedback loops and synthesis of endogenous wound PDGF and other growth factors, thereby enhancing the cascade of tissue repair processes required for a fully-healed wound. Thus, PDGF and other wound produced polypeptide growth factors may be the critical regulators of extracellular matrix deposition within healing wounds.     

The Effects of Sericin Cream on Wound Healing in Rats

Sericin has good hydrophilic properties, compatibility, and biodegradation, it can be used as a wound-healing agent. We evaluated the effects of sericin on wound healing and wound size reduction using rats by generating two full-thickness skin wounds on the dorsum. Group 1 animals were treated with Betadine^® on left-side (control) wounds and, with 8% sericin cream on right-side (treated) wounds. Group 2, cream base (formula control) and 8% sericin cream (treated) were topically applied to left-, and right-side wounds respectively. Sericin-treated wounds had much smaller inflammatory reactions, and wound-size reduction was much greater than in the control throughout the inspection period. Mean time in days for 90% healing from sericin-treated wounds was also much less than for cream base-treated wounds. Histological examination after 15 d of treatment with 8% sericin cream revealed complete healing, no ulceration, and an increase in collagen as compared to cream base-treated wounds, which showed some ulceration and acute inflammatory exudative materials.     

Mitogenic whey extract stimulates wound repair activity in vitro and promotes healing of rat incisional wounds

The ability of single growth factors to promote healing of normal and compromised wounds has been well described, but wound healing is a process requiring the coordinated action of multiple growth factors. Only the synergistic effect on wound healing of combinations containing at most two individual growth factors has been reported. We sought to assess the ability of a novel milk-derived growth factor-enriched preparation ?mitogenic bovine whey extract (MBWE), which contains six known growth factors, to promote repair processes in organotypic in vitro models and incisional wounds in vivo. MBWE stimulated the contraction of fibroblast-populated collagen lattices in a dose-dependent fashion and promoted the closure of excisional wounds in embryonic day 17 fetal rat skin. Application of MBWE increased incisional wound strength in normal animals on days 3, 5, 7, and 10 and reversed the decrease in wound strength observed following steroid treatment. Wound histology showed increased fibroblast numbers in wounds from normal and steroid-compromised animals. These data suggest the mixture of factors present in bovine milk exerts a direct action on the cells of cutaneous wound repair to enhance both normal and compromised healing.     

The effects of sericin cream on wound healing in rats

Sericin has good hydrophilic properties, compatibility, and biodegradation, it can be used as a wound-healing agent. We evaluated the effects of sericin on wound healing and wound size reduction using rats by generating two full-thickness skin wounds on the dorsum. Group 1 animals were treated with Betadine on left-side (control) wounds and, with 8% sericin cream on right-side (treated) wounds. Group 2, cream base (formula control) and 8% sericin cream (treated) were topically applied to left-, and right-side wounds respectively. Sericin-treated wounds had much smaller inflammatory reactions, and wound-size reduction was much greater than in the control throughout the inspection period. Mean time in days for 90% healing from sericin-treated wounds was also much less than for cream base-treated wounds. Histological examination after 15 d of treatment with 8% sericin cream revealed complete healing, no ulceration, and an increase in collagen as compared to cream base-treated wounds, which showed some ulceration and acute inflammatory exudative materials.     

Validation of a model for the study of multiple wounds in the diabetic mouse (db/db)

The genetically diabetic db/db mouse exhibits symptoms that resemble human type 2 diabetes mellitus, demonstrates delayed wound healing, and has been used extensively as a model to study the role of therapeutic topical reagents in wound healing. The purpose of the authors' study was to validate an excisional wound model using a 6-mm biopsy punch to create four full-thickness dorsal wounds on a single db/db mouse. Factors considered in developing the db/db wound model include reproducibility of size and shape of wounds, the effect of semiocclusive dressings, comparison with littermate controls (db/-), clinical versus histologic evidence of wound closure, and cross-contamination of wounds with topically applied reagents. The size of wounds was larger, with less variation in the db/db mice (31.11 +/- 3.76 mm2) versus db/- mice (23.64 +/- 4.78 mm2). Wounds on db/db mice that were covered with a semiocclusive dressing healed significantly more slowly (mean, 27.75 days) than wounds not covered with the dressing (mean, 13 days; p < 0.001), suggesting the dressings may splint the wounds open. As expected, wounds healed more slowly on db/db mice than db/- mice (covered wounds, 27.75 days versus 11.86 days, p < 0.001; wounds not covered, 13 days versus 11.75 days, p = 0.39). Covered wounds, thought to be closed by clinical examination, were confirmed closed by histology only 62 percent of the time in the db/db and 100 percent of the time in the db/- mice. Topical application of blue histologic dye or soluble biotinylated laminin 5 to one of the four wounds did not spread locally and contaminate adjacent wounds. Multiple, uniform, 6-mm wounds in db/db mice heal in a relatively short time, decrease the number of animals needed for each study, and allow each animal to serve as its own control. The db/db diabetic mouse appears to be an excellent model of delayed wound healing, particularly for studying factors related to epithelial migration.     

全身放射损伤对皮肤伤口成纤维细胞参与组织修复能力的影响

合并全身放射损伤的创伤（放创复合伤）是一种重要而有代表性的难愈性创伤,其难愈机制尚未完全阐明,成纤维细胞是最为重要的组织修复细胞,其辐射敏感性较低,为了明确放创复合伤时合并的放射损伤是否对伤口成纤维细胞有直接损伤作用,以及这些损伤作用对创伤愈合的影响,实验检测了分离,培养的放创复合伤和单纯创伤大鼠皮肤伤口成纤维细胞的增殖,凋亡及其他反映其参与组织修复能力的指标变化,结果发现,在去除全身因素和局部因素,特别是创伤局部细胞因子和细胞外基质对成纤维细胞的反馈作用后,放创复合伤组伤口成纤维细胞增殖力,贴壁力和粘附力均显著弱于单纯创伤组,而成纤维细胞的凋亡率则显著增加,这些细胞表明,全身放射损伤对伤口成纤维细胞有直接损伤作用,使其参与组织修复能力显著受抑,这是合并全身放射损伤时创伤难愈的重要原因。     

Nanocrystalline silver dressings in wound management: a review

This paper describes the properties of nanocrystalline silver products (Acticoat) and their applications and examines available evidence supporting their use in wound management. Acticoat utilizes nanotechnology to release nanocrystalline silver crystals. Acticoat releases 30 times less silver cations than silversulfadiazine cream or 0.5% silver nitrate solution but more of the silver released (by Acticoat). Silver-impregnated slow-release dressings release minute concentrations of silver which are quickly bound up by the chloride in the wound exudate. While extrapolations from in vitro and animal studies are cautious, evidence from these studies suggests Acticoat is: effective against most common strains of wound pathogens; can be used as a protective covering over skin grafts; has a broader antibiotic spectrum activity; and is toxic to keratinocytes and fibroblasts. Animal studies suggest a role for nanocrystalline silver in altering wound inflammatory events and facilitation of the early phase of wound healing. Quality human clinical trials into nanocrystalline silver are few. However, evidence suggests using Acticoat in wound management is cost effective, reduces wound infection, decreases the frequency of dressing changes and pain levels, decreases matrix metalloproteinase activity, wound exudate and bioburden levels, and promotes wound healing in chronic wounds. Although there is no in vivo evidence to suggest nanocrystalline silver is toxic to human keratinocytes and fibroblasts, there is in vitro evidence to suggest so; thus these dressings should be used cautiously over epithelializing and proliferating wounds. Future clinical research, preferably randomized controlled trials into nanocrystalline silver technology, may provide clinicians a better understanding of its applications in wound management.     

Intrinsic electric fields promote epithelization of wounds in the newt, Notophthalmus viridescens

The lateral electric fields (LFs) in the vicinity of small wounds made in hindlimb digit tip skin of Notophthalmus viridescens have been measured and manipulated. Healing of these wounds was assessed by crystal violet staining and by histology. Paired experiments were conducted on the animals: the healing of one digit's wound was compared with healing of the contralateral digit's wound whose LF was changed from that of its contralateral wound. When currents were passed through the animal (into one wound and out of the contralateral wound) so that the LF of one wound was zero while the contralateral wound had an enhanced LF, the wounds with the enhanced LF healed more rapidly than the wounds with the zero LF. When digits on one side were treated with 30 microM benzamil in an artificial pond water so that their wound LFs were reduced to approximately zero, and the contralateral wounds were kept in artificial pond water without benzamil so that they had normal wound LFs, there was significantly less epithelization of the benzamil-treated wounds than of the control wounds. This effect on wound healing was reversed by adding currents that restored the normal wound LFs, but not by adding currents that reversed the wound LFs to the opposite polarity. When currents were added to reverse the wound LFs on one side of the animal, leaving the contralateral wounds free of added currents, the wounds with the reversed LFs healed more poorly than the contralateral wounds with normal LFs. These results are consistent with the hypothesis that the intrinsic LFs in the vicinity of wounds promote epithelization of these wounds.     

Preparation and evaluation of a nonproprietary bilayer skin substitute.

Cross-linked, allogeneic, telopeptide-depleted dermal grafts were lyophilized and laminated with silicone rubber elastomer. Resultant bilayers were studied for incorporation into the wound site and capacity to inhibit cutaneous wound contraction in experimental animals. Bilateral full-thickness skin wounds were made in 20 male New Zealand white rabbits. One side was grafted with the processed graft, while the contralateral side remained ungrafted as a control wound. Over 63 days, wound sites were analyzed at intervals on the basis of the extent and rate of wound contraction and by histologic examination. Cutaneous wounds successfully incorporated graft matrix and were significantly inhibited in their rate and extent of wound contraction. Notably, by day 63, grafted wounds retained 71 percent of their original area, whereas ungrafted control wounds retained only 16 percent of their original area. There were no graft rejections, and the bilayer graft's dermal analogue appeared to function as a biodegradable template that physically conformed neodermis to a preestablished pattern while counteracting contractile forces. This investigation suggests that, in experimental animals, the success of bilayer dermal grafts is less dependent on highly specialized and complex preparative techniques than typically has been presumed and that relatively simple, previously published, nonproprietary techniques, when adapted to a bilayer format, yield acceptable results as defined in terms of biocompatibility, capacity for graft incorporation, and inhibition of wound contraction.     

Wet wound healing

Wound treatment in a flexible transparent chamber attached to the perimeter of the wound and containing a liquid has been extensively tested in preclinical experiments in pigs and found to offer several advantages. It protects the wound; the liquid medium or saline in the chamber provides in vivo tissue culture-like conditions; and antibiotics, analgesics, and various molecules can be delivered to the wound through the chamber. The wound chamber causes no injury to the wound itself or to the surrounding intact skin. Topical delivery of, for instance, antibiotics can provide very high concentrations at the wound site and with a favorable direction of the concentration gradient. A series of 28 wounds in 20 patients were treated with a wound chamber containing saline and antibiotics. Most patients had significant comorbidity and had not responded to conservative or surgical management with débridement and delayed primary closure or skin grafts. Six wounds had foreign bodies present; four of these were joint prostheses. Seven patients were on corticosteroids for rheumatoid arthritis, lupus, or chronic obstructive pulmonary disease, and four patients had diabetes. Most patients were treated with the wound chamber in preparation for a delayed skin graft or flap procedure, but one was treated with a wound chamber until the wound healed. Twenty-five of the wounds (89 percent) healed, and five wounds (18 percent) required additional conservative management after the initial chamber treatment and grafting procedure. Of the three wounds that did not heal, one healed after additional chamber treatment, one had a skin graft that did not take, and one required reamputation at a higher level. Antibiotic delivery was less than one intravenous dose daily, which avoided the potential for systemic absorption to toxic levels. Antibiotics such as vancomycin and gentamicin could be used in concentrations of up to 10,000 times the minimal inhibitory concentration. Forty-eight hours after application, 20 percent or more of the original antibiotic concentration was present in the wound chamber fluid. In conclusion, the wound chamber provides a safe, powerful tool in the treatment of difficult infected wounds.     

Radiation crosslinking polymerization of sterculia polysaccharide-PVA-PVP for making hydrogel wound dressings

The present study deals with the modification of sterculia gum by PVA-PVP through radiation crosslinking, to develop the hydrogels meant for the delivery of antimicrobial agent to the wounds. The hydrogels were characterized by SEM, FTIR, TGA and swelling studies. For the evaluation of swelling and drug release mechanism, the swelling kinetics and in vitro release dynamics of model drug from this matrix have been studied respectively in the solution of different pHs and simulated wound fluid. After 24h swelling per gram of the hydrogel has taken (17.03±0.19)g of simulated wound fluid and has released (0.230±0.01)mg of drug in the simulated fluid. The release of drug in simulated fluids occurred through non-Fickian diffusion mechanism.     

Application of wound closure Molndal technique after laparoscopic cholecystectomy--initial comparative study

Because of a possible delayed wound healing, critical colonization and infection of wounds present a problem for surgeons. Colonized and infected wounds are a potential source for cross-infection. Molndal technique of wound dressing has proven to be effective in prevention of infection. Also the wound heal better and faster. In our study we wanted to describe the benefits of the Molndal technique wound dressing after laparoscopic cholecistectomy compared to traditional wound dressing technique. Molndal technique consisted of wound dressing with Aquacel Ag--Hydrofiber (ConvaTec, Dublin, Ireland). Traditional technique was performed using gauze compresses and hypoallergic adhesives. We analyzed the results of 100 patients after laparoscopic cholecystectomy. 50 patients were treated by Molndal technique and 50 patients by the traditional technique of wound dressing. In the group treated by Molndal technique only 1 (2%) patient has revealed a wound infection, proven by positive microbiological examination and suppuration, mostly in the subumbilical incision. In the traditional technique group 7 (14%) patients developed wound infection also predominantly in the subumbilical incision. The difference was statistically significant (p < 0.01). Our results are clearly showing that Molndal technique is effective in preventing the infection of subumbilical incision wound and is to by recommend for regular use at designated site after laparoscopic cholecistectomy.     

Scarless fetal wound healing: a basic science review

SUMMARY: Scar formation is a major medical problem that can have devastating consequences for patients. The adverse physiological and psychological effects of scars are broad, and there are currently no reliable treatments to prevent scarring. In contrast to adult wounds, early gestation fetal skin wounds repair rapidly and in the absence of scar formation. Despite extensive investigation, the exact mechanisms of scarless fetal wound healing remain largely unknown. For some time, it has been known that significant differences exist among the extracellular matrix, inflammatory response, cellular mediators, and gene expression profiles of fetal and postnatal wounds. These differences may have important implications in scarless wound repair.