ArticleLiterature Review

The Wound Healing Process: An Overview of the Cellular and Molecular Mechanisms

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Abstract

Wound healing remains a challenging clinical problem and correct, efficient wound management is essential. Much effort has been focused on wound care with an emphasis on new therapeutic approaches and the development of technologies for acute and chronic wound management. Wound healing involves multiple cell populations, the extracellular matrix and the action of soluble mediators such as growth factors and cytokines. Although the process of healing is continuous, it may be arbitrarily divided into four phases: (i) coagulation and haemostasis; (ii) inflammation; (iii) proliferation; and (iv) wound remodelling with scar tissue formation. The correct approach to wound management may effectively influence the clinical outcome. This review discusses wound classification, the physiology of the wound healing process and the methods used in wound management.

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... Chronic wounds (CWs) do not progress through the four stages of wound healing in a timely manner, and as such do not heal to a satisfactory degree or within the expected time frame as matched to a comparable acute wound [1]. They are a great cause of physical and psychological morbidity for both patients and families, and are a heavy burden on health systems' resources [2]. ...
... Moreover, total healing of CWs is often difficult or impossible, and they are often plagued with further complications such as scars, or subclinical and diagnosed infections [4], [5]. Indeed, the rate of recurrence and severe infection is high [1]. In fact, in the span of a year, the average rate of CW healing in the national health service (U.K.) between 2012/2013 and 2017/2018, was around 43 to 49% [3], [6], [7], [8]. ...
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Objectives Platelet-derived products have been shown as promising novel therapeutic agents for chronic wounds. However, their use clinically requires a greater degree of method standardisation, part of which involved more extensive cataloguing of their biochemical composition. This study aimed to quantify and compare total protein and 6 angiogenically-active growth factors in three distinct platelet products. Methods Platelet Lysate (PL, n=5), Calcium-activated Platelet Rich Plasma (Ca-PRP, n=5) and Platelet-Rich Fibrin (PRF, n=5) were prepared from pooled platelet apheresis products (n=10). Ca-PRP and PRF were prepared from the same units (n=5) by activation with 20 mmolL-1 calcium chloride. PL was prepared from the remaining (n=5) units using an established lysate. Total protein was quantified with the Bradford Assay. Sandwich enzyme-linked immunosorbent assay was used to quantify six growth factors: epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), stromal cell de-rived growth factor-1α (SDF-1α), endostatin, and transforming growth factor-β1 (TGF-β1). Results Protein retrieval differed significantly (p<0.05) between the three prod-ucts: PL (11.35±0.80 mg/mL) < Ca-PRP (20.44±8.17 mg/mL) < PRF (40.67±3.13 mg/mL). Growth factor yield was considerable in all three products and differed significantly for: VEGF (PL<PRF); EGF (Ca-PRP<PRF); HFG (PL<Ca-PRP); Endostatin (PL<Ca-PRP, PRF<Ca-PRP, PL<PRF) and TGF-β1 (Ca-PRP<PL, Ca-PRP<PRF). Conclusions Platelet apheresis products contain a substantial quantity of the in-vestigated pro- and anti-angiogenic growth factors. Their release varies depending on the manufacturing protocol used. Clinically, alternate products could thus be combined to provide a therapeutically optimal mix of growth factors.
... When a wound is a clean surgical incision or clean laceration the wound edges can be approximated by the use of sutures, tapes or tissue glue to induce healing by first intention [4]. First intention healing results in wounds that heal well through epithelial regeneration versus fibrosis due to a balance in the phases of wound healing [4,5]. Second intention wound healing can be more difficult to heal. ...
... Second intention wound healing can be more difficult to heal. This occurs in wounds that have a loss of soft tissue, as in trauma, ulcerations, severe burns and major surgery [4,5]. ...
Article
Aim Tissue engineering has historically involved research combining scaffolds, cells, and active biomolecules to treat multiple pathologies. The current research seeks to determine if the wound healing cascade can be modulated using acellular scaffolds, engineered to create an acellular electrospun dermal biomimetic. Methods The dermal biomimetic has a similar architecture to the dermis, porosity and fiber diameter, as well as physiologically relevant ratios of the primary structural dermal proteins, collagen and tropoelastin. This biomimetic wound healing device (BMWHD) was implanted into a full thickness dermal wound murine model for six days. Results WHD-treated wounds had 30% greater re-epithelialization with a thicker epidermis, new elastin fibers in the wound bed, and healed architecture that matched unwounded extracellular matrix. Conclusions Using these WHDs that closely match the native architecture and protein concentrations, accelerated the wound through the wound healing cascade and supports the hypothesis that structure alone can influence function when engineering acellular dermal biomimetic devices.
... Dermal wound healing is a dynamic process that can be triggered by thermal tissue injury. It involves complex interactions between dermal cells and the extracellular matrix (ECM) [1]- [3]. The wound healing process essentially comprises three overlapping phases: inflammatory, proliferative, and remodeling [3], [4]. ...
... It involves complex interactions between dermal cells and the extracellular matrix (ECM) [1]- [3]. The wound healing process essentially comprises three overlapping phases: inflammatory, proliferative, and remodeling [3], [4]. The characteristics of collagen constitute an index that can be used to quantify the wound healing process. ...
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Histological examination of collagen fiber organization is essential for pathologists to observe the wound healing process. A convolutional neural network (CNN) can be utilized to visually analyze collagen fibers during tissue remodeling in histology images. In this study, a universal CNN (UCNN) independent of the histological staining process is proposed to classify the histology images of burn-induced scar tissues and characterize collagen fiber organization. Normal and scar tissues obtained from an in vivo rodent model are stained using Masson’s Trichrome (MT) and Hematoxylin & Eosin (H&E). The proposed universal model is trained using both MT- and H&E-stained histological image datasets over multiple scales with color augmentation, and classification accuracies of up to 98% and 97% are achieved for the MT- and H&E-stained image datasets, respectively. Regardless of the histological staining process used, the collagen characteristics are visualized by determining the density and directional variance of the normal and scar tissues by using the features extracted with the proposed universal model. Statistical analysis results demonstrated clear differences between scar and normal tissues in terms of collagen fiber organization. The proposed UCNN model can contribute to the development of an intelligent and efficient method that pathologists can use to rapidly evaluate wound healing and tissue remodeling.
... The first stage of acute or physiological wound healing begins immediately upon injury, which disturbs the epidermal layer of the skin and traumatizes the vascular network system. The hemostasis phase is characterized by the activation of different blood clotting pathways and current platelet activation, which initiates the coagulation cascade and completes the blood clot formation [30]. Platelet aggregation creates a temporary barrier that protects the wound site from microbial contamination, controlling blood loss, providing strength, and filling the tissue gap with the blood clot. ...
... Finally, remodeling is considered a phase where the granulation tissue matures into the scar. The number of blood capillaries aggregated together by forming larger vessels, and collagen type III was replaced by type I collagen, which improves by increasing covalent cross-linking of the collagen molecule through the reorganization of collagen [30]. The sequential illustration of the stages involved in the process of wound healing as shown in Fig. 2. ...
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Purpose of Review Plant-based polyphenolic compounds are natural by-products known as plant secondary metabolites, which have significant utilities in the plant host system. Besides, plant polyphenol’s pharmaceutical and medicinal potential positively promote human health. Recent evidence suggested that humans could benefit from plant-based polyphenolic compounds through foodstuff or skin application. However, the therapeutic effects of plant-polyphenolic compounds permit them to act as an effective and alternative agent to treat various diseases and damages related to the skin as they protect and attenuate the progress of many skin disorders, including non-healing cutaneous wounds. Recent Findings The mode of polyphenol application is the reason for concern due to decreased stability and performance around the wound area. The use of natural and synthetic polymer-based biomaterials acts as a protection and carrier system for polyphenolic compounds, which improve the stability and effects on the wound area by acting as a promising agent for tissue regeneration. Polyphenols like morin, quercetin, apigenin, curcumin, gallic acid, chrysin, puerarin, and hesperidin are potent anti-oxidants and anti-inflammatory anti-bacterial, and anti-cancer agents. These compounds also have skin protective applications, curing stress, skin aging, age-related diseases, and boosting the innate immune system. Plant-based polyphenolic compounds provide anti-microbial, anti-oxidant, and anti-inflammatory properties to wound dressing, further contributing to vascularization, re-epithelization, collagen synthesis, and wound contraction. Summary The present paper reviews the recent information on the potential therapy of normal and diabetic wounds through treatment with phenolic compounds with the combination of polymer-based biomaterial that plays an essential role in the healing process.
... The lesions treated with Solosite™ during the inflammatory phase of the healing process showed greater hemorrhage than with the use of the control, possibly due to the mechanical trauma caused by cleaning the wound bed. Other authors described that necrosis, hemorrhage, hyperemia, and fibrin are common processes in the period of hemostasis, inflammation and migration of cells to the injured region, such as platelets, neutrophils, lymphocytes, endothelial cells, and, later, macrophages, aiding in angiogenesis 53,54 . While in the proliferative phase, it was verified that the lesions treated with Solosite™ continued to present greater hemorrhage than the lesions treated with the NaCl 0.9% control; it is believed that this occurred because of the injury handling during debridement and dressing changes that could have caused trauma, which is in accordance to other studies 55,56 . ...
... Thus, type III collagen begins to give way to type I collagen. This type of collagen has thicker and more resistant fibers, in which it will predominate until the end of the remodeling phase 53,54 . It is worth noticing that all products showed a greater expression of collagen fibers than the control, thus inducing the phase of replacement of type III collagen for type I collagen. ...
Article
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Purpose: To compare four commercially available hydrogel formulations in the healing of partial thickness burns experimentally induced in rats. Methods: Wistar rats were used, and after the burn wound induction they were divided into the following treatment groups: G1) NaCl 0.9%; G2) 1% silver sulfadiazine; G3) Debrigel™; G4) Safgel™; G5) Dersani™; G6) Solosite™. The animals were followed during seven, 14 and 30 days after the injury induction. Morphometric, macroscopic and microscopic evaluations were performed. Results: The treatment with Dersani™ induced better results during the inflammatory and proliferative phases of the healing process (p<0.05). The animals treated with Safgel™ presented better scaring in the remodeling phase (p<0.05), and the treatment with Dersani™ and Solosite™ induced greater wound closure (p<0.05). Conclusion: The hydrogel-based dressings presented beneficial outcomes in the healing of burn wounds experimentally induced in rats due to their ability in maintain the humidity of the wound, in removing the exudate, in promoting cell migration and collagen production during the different phases of the healing process.
... Prolonged inflammation is a major cause of chronic wounds on a cellular level. In chronic wounds, the organism is not able to resolve the physiological inflammation as part of the wound healing process, and transition to the proliferation phase is blocked [3]. Underlying mechanisms of a prolonged inflammation phase and delayed or disturbed transition into the proliferation phase in chronic wounds are still under investigation. ...
... Biopsies for mRNA expression analysis were taken on day 7 and day 16 from the outer parts of the wounds, the wound edges, whereas the histological samples were taken from the centres. We believe that the area where the biopsies were taken influenced the difference in cytokine expression and histology, since the centres of the wounds were most exposed to the resiquimod application and healed the slowest, and epithelialisation progresses from the wound edges to the wound centre [3]. Since differences in wound edge and wound base can be expected, serial biopsies from both areas need to be compared in future studies using this model of prolonged inflammation. ...
Article
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The treatment of chronic wounds still challenges modern medicine because of these wounds’ heterogenic pathophysiology. Processes such as inflammation, ischemia and bacterial infection play major roles in the progression of a chronic wound. In recent years, preclinical wound models have been used to understand the underlying processes of chronic wound formation. However, the wound models used to investigate chronic wounds often lack translatability from preclinical models to patients, and often do not take exaggerated inflammation into consideration. Therefore, we aimed to investigate prolonged inflammation in a porcine wound model by using resiquimod, a TLR7 and TLR8 agonist. Pigs received full thickness excisional wounds, where resiquimod was applied daily for 6 days, and untreated wounds served as controls. Dressing change, visual documentation and wound scoring were performed daily. Biopsies were collected for histological as well as gene expression analysis. Resiquimod application on full thickness wounds induced a visible inflammation of wounds, resulting in delayed wound healing compared to non-treated control wounds. Gene expression analysis revealed high levels of IL6, MMP1 and CD68 expression after resiquimod application, and histological analysis showed increased immune cell infiltration. By using resiquimod, we were able to show that prolonged inflammation delayed wound healing, which is often observed in chronic wounds in patients. The model we used shows the importance of inflammation in wound healing and gives an insight into the progression of chronic wounds.
... Wounds are injuries that are often experienced by every human, including actions performed by dentist. 1 Wound healing is a complex condition, includes a variety of responses to injury. 2 As a coordinated process, the process involves cellular and extracellular components that will eventually happen rearrangement injured tissue. Wound healing process starts from a series of important processes, namely hemostasis, inflammation, proliferation, and cell migration, angiogenesis, matrix synthesis, remodeling and wound contraction. 1 Inflammatory phase will involve inflammatory cells, including neutrophils, monocytes, Eosinophil, basophils, lymphocytes, and platelets. ...
... Wound healing process starts from a series of important processes, namely hemostasis, inflammation, proliferation, and cell migration, angiogenesis, matrix synthesis, remodeling and wound contraction. 1 Inflammatory phase will involve inflammatory cells, including neutrophils, monocytes, Eosinophil, basophils, lymphocytes, and platelets. Infiltration of neutrophils reached its peak of about first 24 h, then decreases with the presence of monocytes. ...
Article
In human body, biomaterials can be used to accelerate the wound healing process. Amniotic membrane-derived secretory leukocyte protease inhibitor (SLPI) is one of the biomaterials which able to accelerate the wound healing process by its several functions such as protease inhibition, leukocytes activitiy control, growth factor regulation such as transforming growth factor β (TGF-β), and its anti inflammatory, anti bacterial also anti retroviral properties. Objectives: To analyzed the SLPI effect on the TNF-α expression and the quantity of new blood vessel in the incisional wound healing. SLPI are produced from Essericea coli TOP10 as the cloning host, BL21 (DE3) strains as the expression host and pET30a plasmids were used for the expression system construction. The incison wound was made in dorsal skin area, then treated with SLPI dose 0.03 cc, 0.45 cc, 0.06 cc. After treatment, the wound covered with hypafix. The control group only covered with hypafix. In the next four days, the dorsal skin area is biopsied, then the quantity of TNF-α expression and blood vessels was analyzed with hematoyline eosin and immunohistochemistry stainining. The SLPI 0.045 cc showed the higher quantity of new blood vessel compared the SLPI 0.03 cc and control group (p < 0.05). While the TNF-α expression in the SLPI 0.045 cc is lower than SLPI 0.03 cc (p = 0.002) and control group (p = 0.000). The SLPI capable to accelerate the wound healing by decreasing the TNF-α expression and increased the new blood vessel quantity at 0.045 cc dose.
... Injuries that break and damage the body tissues or the skin traverse through a wound healing process. An ordinary wound healing process is achieved in the human body through four accurate stages: haemostasis, inflammation, proliferation, and remodelling [13]. Nevertheless, the process of wound healing can be detained by numerous systemic and local factors such as body type, age, chronic disease, hormones and infection that results in impaired tissue repair [14,15]. ...
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In recent years, there has been a surge of interest in the design, processing, and use of core-sheath fibres, especially in the production of wound healing bandages and drug delivery. In this research, a novel core-sheath pressurised gyration technique was utilised to create antibacterial fibre patches (tetracycline hydrochloride, TEHCL) using polyvinyl pyrrolidone (PVP) and polycaprolactone (PCL). Antibiotic patches showed uniform fibres with a porous surface giving rise to a biphasic delivery system, which provided an initial burst of 30–48% drug release in the first 24 hours followed by a constant rate of release throughout the course of 168 hours, suitable for wound-dressings application. The effect of operating parameters on fibre morphology, the influence of the core-sheath structure and drug loading as well as a mathematical modelling was investigated and analysed. Fourier-transform infrared spectroscopy, and differential scanning calorimetry results demonstrated successful TEHCL encapsulation as well as the presence of both polymers in the core-sheath fibres. The surface morphology of the fibres was studied using scanning electron microscopy and the core-sheath structure was verified using confocal scanning microscopy. Therefore, the core-sheath pressurised gyration method offers an exciting chance to customise fibre patches in a hybrid polymeric system. These advancements are crucial in the world of healthcare to meet demands where antibacterial dressings cannot be produced rapidly or when a personalised approach is necessary.
... Wound healing is a dynamic and complex process that involves various cell types, the extracellular matrix (ECM), and numerous regulating growth factors [1]. Re-epithelialization is an essential component of wound healing and is regulated by the proliferation and migration of keratinocytes [2,3]. ...
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Electric Cell-substrate Impedance Sensing (ECIS) is an impedance-based, real-time, and label-free measuring system for monitoring cellular activities in tissue culture. Previously, ECIS wound healing assay has been used to wound cells with high electric current and monitor the subsequent cell migration. In this study, we applied ECIS electric fence (EF) method, an alternative to electrical wounding, to assess the effects of different surface coatings on human keratinocyte (HaCaT) migration. The EF prevents inoculated cells from attaching or migrating to the fenced electrode surface while maintaining the integrity of the surface coating. After the EF is turned off, cells migrate into the cell-free area, and the increase in measured impedance is monitored. We cultured HaCaT cells on gold electrodes without coating or coated with poly-L-lysin (PLL), poly-D-lysine (PDL), or type-I collagen. We quantified migration rates according to the different slopes in the impedance time series. It was observed that either poly-L-lysine (PLL) or poly-D-lysine (PDL) limits cell adhesion and migration rates. Furthermore, the surface charge of the coated substrate in the culture condition positively correlates with the cell adhesion and migration process. Our results indicate that the EF method is useful for determining cell migration rates on specific surface coatings.
... The phase of inflammation considerably overlaps with homeostasis at the initial point and takes place during the first 72 h of tissue damage. The release of pro-inflammatory cytokines such as the tumour necrosis factor (TNF)α, interferon (IFN)-γ, and reactive oxygen species (ROS) stimulates vasodilation along with the cell adhesion factors assisting in the infiltration of neutrophils and monocytes into the wound layer (Velnar et al. 2009;Wilkinson and Hardman 2020). ...
Article
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Wound healing is a highly coordinated and dynamic process of tissue repair after injury. The global burden of disease associated with wounds, both acute and chronic, is a significantly rising health concern. Upon skin wounding, neurons have the ability to sense the disruption to mediate the release of neurotransmitters into the wound microenvironment. Serotonin that has long been recognised as a potential vasoconstrictor is now also being contemplated to play a role in re-epithelialisation of wounds. While the role of neuropeptides in stimulating diabetic wound healing is being increasingly emphasised, on the other hand, dopamine is being widely studied for its dual role in mediating both pro- and antiangiogenic effects at the site of the wounds. Similarly, epinephrine levels that are known to be elevated during stress is now recognised as a contributing factor towards delayed wound closure, thereby serving as an inhibitor of wound healing. Thus, each neurotransmitter regulates wound repair and their active regeneration in a typical way. Strengthening our understanding of the molecular pathways via which the neurotransmitter modulates the immune system to control wound healing can yield potential therapeutic measures. Further investigations regarding the safety, efficacy, and cost-effectiveness of these processes are a prerequisite for their possible translation into clinical trials.
... At around three days following injury, fibroblasts begin to proliferate at the wound site [63]. They are responsible for laying down key components of the extracellular matrix (ECM) including: hyaluronan, proeteoglycans, fibronectin [64]. ...
Thesis
People that suffer with diabetes have an elevated risk of developing diabetic foot ulcers (DFUs), a type of chronic wound associated with hyperglycaemia. Current DFU treatments vary in their effectiveness and people that suffer with DFUs have an increased risk of eventual lower limb amputation. Biological agents including vascular endothelial growth factors (VEGF) and agonists of the Wnt signalling pathway have been investigated as agents that improve wound healing, yet delivery in an active economical form remains a significant clinical challenge. In this project, we tested the hypothesis that Laponite, a synthetic smectite clay biomaterial, can be used to localise bioactive molecules to skin injury sites and can increase the rate and quality of wound healing. Growth factor (VEGF) and small molecule (BIO, a Wnt pathway agonist) were incorporated in Laponite hydrogels, and their activity tested using cell-reporter assays. Laponite hydrogels were then administered subcutaneously and applied to circular wounds made on the dorsal skin of healthy and diabetic ( db/db ) mice. Bioactivity of localised VEGF by Laponite gels and its effect on wound healing was assessed by measuring the rate of wound closure and by histological analysis of blood vessel formation, the degree of cell invasion and the rate of re-epithelisation. Human vein endothelial cell (HUVEC) tube formation was significantly increased when cultured on Laponite gels premixed with 1-5 µg /ml VEGF ( p = < 0.05-< 0.0001). Successful adsorption of BIO by Laponite from aqueous media was measured at early time points. There was substantial retention of premixed BIO by Laponite over 7 days with the only evidence of BIO release (4.76%) into aqueous media measured at 24 hours ( p = < 0.01). Laponite hydrogels were successfully retained in vivo up to 21 days (subcutaneously) and 18 days (wounds). There was a significant increase in blood vessel ingrowth into subcutaneously injected Laponite gels premixed with 10-40 µg /ml VEGF after 21 days in healthy mice ( p = < 0.05-< 0.0001). Treatment of back skin wounds of db/db mice with vehicle Laponite gels exhibited a significant increase in the rate of re-epithelisation ( p = < 0.05) and improvement to wound healing quality both visually and histologically. No further improvements to the rate of wound closure, re-epithelisation and appearance (e.g. reduced redness) was present when treated with Laponite gels containing 40 µg /ml VEGF; 1.1% alginate gel controls containing 40 µg /ml VEGF did exhibit improved wound closure suggesting that more rapid release of VEGF was more appropriate to a wound model that requires < 30 days recovery. These results show the potential of Laponite hydrogels localising biologically active molecules to skin injury sites and improving the rate and quality of wound healing. However additional in vitro analysis and a modified murine model that would better characterise impaired wound healing in human DFUs, would be required to explore these findings in greater detail.<br/
... A wound is defined as the loss of skin integrity and is usually accompanied by disruption of the structural and functional properties of the underlying tissue (Clark et al. 2007). It can be induced by intrinsic factors such as those formed as a result of chronic ulceration and microbial invasion or by extrinsic factors such as surgical incision, accidental injury, and trauma (Velnar et al. 2009). To restore the functional and structural integrity of the injured tissue, a highly organized process starts instantly after wound incidence. ...
Article
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Diabetic wounds are characterized by a delayed closure rate due to the excess inflammation and the inhibition of angiogenesis. Natural products derived from Aloe vera have shown great promise due to their healing magnificent properties. Olive oil is another natural product with anti-microbial and anti-inflammatory properties that may contribute to the healing process. In the present investigation, we tried to evaluate the efficacy of topical application of Aloe gel and/or olive oil in the enhancement of diabetic wounds using histological and immunohistochemical analysis. Excisional wounds were created on the back skin of streptozotocin-induced diabetic rats. Topical treatments of Aloe gel and/or olive oil were applied separately and in a combination (AVO) daily for experimental groups. Macroscopic and microscopic observations of the excision wounds were monitored at time intervals (3, 6, 9, 14 days) post-wounding. Macroscopic observations of the AVO group exhibited almost complete healing at day 14, while other groups were still in progress. Similarly, immunohistochemical analysis of the AVO group showed a mild expression pattern of NF-κB.. While, the cell proliferation (Ki-67), and angiogenesis (CD34) markers were upregulated. Conclusively, the obtained results showed that the AVO combination effectively improved the healing process in diabetic excisional wounds with significant differences in the healing kinetics compared to wounds that received Aloe gel or olive oil separately.
... Finally, our results showed that BA administration by both IP and TOP significantly accelerated diabetic wound healing; this suggests that treatment of diabetic wound healing should not just focus on the wound/injury itself; instead, more attention should be paid to diabetes and diabetes-mediated complications and dysfunction. This is the first time that BA has been used for the treatment of diabetic burn injury with positive results due to its anti-diabetic effect and potential protective role in diabetes-mediated dysfunction, such as oxidative stress and inflammation [55,56]. ...
Article
Background: Diabetes significantly delays wound healing through oxidative stress, inflammation and impaired re-epithelialization that lead to defective regulation of the healing process, although the related mechanism remains unclear. Here, we aim to investigate the potential role and mechanism for the beneficial effect of betulinic acid (BA) on diabetic wound healing. Methods: The molecular effect of BA on hyperglycemia-mediated gene expression, oxidative stress, inflammation and glucose uptake was evaluated in endothelial, fibroblast and muscle cells. Burn injury was introduced to streptozotocin-induced diabetic rats and BA administration through either an intraperitoneal (IP) or topical (TOP) technique was used for wound treatment. Glucose tolerance was evaluated in both muscle tissue and fibroblasts, while oxidative stress and inflammation were determined in both the circulatory system and in wound tissues. The effect of BA on the wound healing process was also evaluated. Results: BA treatment reversed hyperglycemia-induced glucose transporter type 4 (GLUT4) suppression in both muscle and fibroblast cells. This treatment also partly reversed hyperglycemia-mediated suppression of endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and nuclear factor NFκB p65 subunit (NFκB p65) activation in endothelial cells. An in vivo rat study showed that BA administration ameliorated diabetes-mediated glucose intolerance and partly attenuated diabetes-mediated oxidative stress and inflammation in both the circulatory system and wound tissues. BA administration by both IP and TOP techniques significantly accelerated diabetic wound healing, while BA administration by either IP or TOP methods alone had a significantly lower effect. Conclusions: BA treatment ameliorates hyperglycemia-mediated glucose intolerance, endothelial dysfunction, oxidative stress and inflammation. Administration of BA by both IP and TOP techniques was found to significantly accelerate diabetic wound healing, indicating that BA could be a potential therapeutic candidate for diabetic wound healing.
... Wound healing integrates various resident and migratory cells, the extracellular matrix, growth factors, and cytokines involved in inflammation, proliferation, and tissue remodeling 47 . C1q promotes the regeneration process and favors wound healing by stimulating angiogenesis in a complement-independent manner 48 . ...
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The importance of the complement component C1q has been highlighted by its involvement in autoimmunity, infection, inflammatory diseases, and tumors. The unique tulip-like structure of C1q has both a collagen-like stalk (C1q tail) and heterotrimeric globular head (gC1q), each with different binding specificities, and the binding of these components to their respective receptors leads to functional complexities in the body and bridges innate and adaptive immunity. This review describes the fundamental roles of C1q in various microenvironments and focuses on the importance of the interactions of C1q and its receptors with the inhibitory receptor LAIR-1 in maintaining homeostasis. Current therapeutic opportunities modulating LAIR-1 are also discussed. Research into the activities of the protein C1q, involved in a cascade of molecular interactions of the immune response called complement activation, is revealing new details of the protein’s role and opening up possible new therapeutic opportunities. Myoungsun Son at Feinstein Institutes for Medical Research in Manhasset, USA, reviews the involvement of C1q in infection, autoimmunity, inflammatory diseases and tumors. The interaction of C1q with a receptor protein called LAIR-1 seems to be particularly significant. LAIR-1 is present in the membrane of most blood-forming cells and is involved in maintaining the healthy balance of cellular activities referred to as homeostasis. Emerging research suggests that targeting the interactions between C1q and LAIR-1 could enable the development of new treatments for many diseases, including inflammatory diseases, the autoimmune condition lupus, a variety of cancers, and possibly Covid-19.
... A wound is defined as damage or disruption to the normal anatomical structure and function of a living tissue. 1 This ranges from a simple disruption in the epithelial integrity of the skin to deeper subcutaneous tissue involvement and also damage to other structures, like muscle and bone. 2 Wounds can arise from physical, chemical, thermal, microbial, or immunological damage to a tissue or can be the result of a disease process like diabetes mellitus. ...
Article
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Background: Brucea antidysenterica is a well-known medicinal plant that has traditionally been used to treat a variety of ailments, including wound healing. Supporting the traditional claims, wound healing, antibacterial, anti-inflammatory, and antioxidant activities of the crude extracts of different parts of the plant were reported. The aim of this study was to evaluate the wound healing and antibacterial activities of solvent fractions of the menthol leaf extract of Brucea antidysenterica. Methods: Methanol (80%) leaf extract of Brucea antidysenterica was fractionated using three solvents; water, n-butanol and chloroform. An ointment containing 2% and 4% of each fraction was formulated and applied to wounds inflicted on rats topically. The wound contraction rate, period of epithelialization, and breaking strength were analysed. In vitro antibacterial activities were tested using the agar diffusion method. The macro-tube dilution technique was used to determine the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC) was determined by sub-culturing the MIC and concentrations below the MIC. Results: The 2% and 4% aqueous fractions (AF) significantly increased wound contraction (p 0.001) compared to the negative control and increased tensile strength compared to untreated (p 0.001). Among the three fractions, the n-butanol fraction showed the highest antibacterial growth inhibition, ranging from 8 mm (E. coli) to 16 mm (S. aureus). Conclusion: Data obtained from this study collectively indicated that the aqueous fraction of 80% methanol leaf extract of B. antidysenterica possesses wound healing and antibacterial activities.
... In carrying out activities, we often experience accidents that result in injuries, both minor and serious injuries, and injuries can be preceded by trauma. Wounds are damage or loss of body tissue that occurs due to a factor that interferes with the body's protective system (Velnar et al., 2009). These factors include trauma, temperature changes, chemicals, explosions, electric shocks, or animal bites. ...
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The use of tradisional medicine in indonesia is part of the culture of the nation and much utilized by society. This study aimed to determine the effect of of the Treatment With Salve Of Topikal Tintir Castor Bark Extract (Jatropha Multifida L) on the Number of Fibroblast, Fibrin, Formation, And Density of Collagen In The Wound Healing Process of The Rat With The Acute Injury Model through excision diameter of 0.8 cm x 0.8 on the rat back. The research was conducted in the Animal laboratory of Hasanuddin University and the Education Animal Clinic(KHP), UNHAS. The method used in this research is the post-test control group design only. The sample consisted of 45 Wistar rats were divided into 3 groups: negative control (Vaseline), positive control (Oxcytetracilin 3%) and extract stem tintir distance. Data analysis using one way test anova. The study results indicated that on day 3(tree) the fibroblast showed an significant differences between groups of negative group and the tintir castro stem group of 10% (p=0.081) and there was an significant between the positive group and the tintir castro stem group of 10% (p=0.167); and on day 7(seven) and day 14, there was a difference but significant.
... Wound healing entails several biological processes, metabolic pathways, cell lineages, and chemicals, as well as highly complicated re-epithelialization mechanisms which can be grouped into the following stages: homeostasis, inflammatory response, cell proliferation, extracellular matrix formation, and maturation or remodeling. 106,312 Abrasions, lacerations, punctures, lacerations, and burns are the five most common forms of wounds, 313 and wound exudates comprise high amounts of reactive oxygen species, cytokines, and proteolytic enzymes in most of them. Exudates downregulate proteinase inhibitors and growth factors, causing tissue breakdown and disrupting the inflammatory process, as well as the entire healing cascade. ...
Article
Throughout history, natural biomaterials have benefited society. Nevertheless, in recent years, tailoring natural materials for diverse biomedical applications accompanied with sustainability has become the focus. With the progress in the field of materials science, novel approaches for the production, processing, and functionalization of biomaterials to obtain specific architectures have become achievable. This review highlights an immensely adaptable natural biomaterial, bacterial cellulose (BC). BC is an emerging sustainable biopolymer with immense potential in the biomedical field due to its unique physical properties such as flexibility, high porosity, good water holding capacity, and small size; chemical properties such as high crystallinity, foldability, high purity, high polymerization degree, and easy modification; and biological characteristics such as biodegradability, biocompatibility, excellent biological affinity, and non-biotoxicity. The structure of BC consists of glucose monomer units polymerized via cellulose synthase in β-1-4 glucan chains, creating BC nano fibrillar bundles with a uniaxial orientation. BC-based composites have been extensively investigated for diverse biomedical applications due to their similarity to the extracellular matrix structure. The recent progress in nanotechnology allows the further modification of BC, producing novel BC-based biomaterials for various applications. In this review, we strengthen the existing knowledge on the production of BC and BC composites and their unique properties, and highlight the most recent advances, focusing mainly on the delivery of active pharmaceutical compounds, tissue engineering, and wound healing. Further, we endeavor to present the challenges and prospects for BC-associated composites for their application in the biomedical field.
... A wound is defined as a disruption of the normal anatomical structure and function of a certain tissue; wounds can arise either from internal processes (inflammatory diseases) or external factors (surgical procedures or accidents). The wound healing process consists of four different phases, that succeed chronologically: (1) coagulation and hemostasis, (2) inflammation, (3) proliferation, and (4) wound remodeling, with every phase playing an essential role [1,2]. While tissue regeneration is possible in some species, in humans, wound healing generates a fibroproliferative response, including cell proliferation, migration, differentiation, and remodeling, with scar tissue formation. ...
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Wound healing is a complex process that is mediated and influenced by several cytokines, chemokines, and growth factors. Interleukin-22 (IL-22) is a cytokine that plays a critical role in tissue regeneration. Our study is a systematic review that addressed the implications of IL-22 in the healing of wounds caused by external factors. Thirteen studies were included in our review, most of them being experimental studies. Three clinical studies underlined the potential role of IL-22 in day-to-day clinical practice. IL-22 plays a central role in wound healing, stimulating the proliferation, migration, and differentiation of the cells involved in tissue repair. However, overexpression of IL-22 can cause negative effects, such as keloid scars or peritoneal adhesions. The results of the presented studies are promising, but further research that validates the roles of IL-22 in clinical practice and analyzes its potential implication in surgical healing is welcomed.
... Actomyosin is the actin-myosin complex forming the filaments responsible for muscle contraction. The contraction of the supracellular actomyosin ring around the wound is crucial for its closure, which allows the tissue to regain its structure and function (57)(58)(59). The "actomyosin" GO term was represented by gill damage-induced transcripts such as actin, alpha skeletal muscle 2-like (acta2), actin, alpha cardiac-like (actc1), myosin heavy chain, fast skeletal muscle-like (myh), and tropomyosin beta chain (tpm2). ...
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Gill damage represents a significant challenge in the teleost fish aquaculture industry globally, due to the gill’s involvement in several vital functions and direct contact with the surrounding environment. To examine the local and systemic effects accompanying gill damage (which is likely to negatively affect gill function) of Atlantic salmon, we performed a field sampling to collect gill and liver tissue after several environmental insults (e.g., harmful algal blooms). Before sampling, gills were visually inspected and gill damage was scored; gill scores were assigned from pristine [gill score 0 (GS0)] to severely damaged gills (GS3). Using a 44K salmonid microarray platform, we aimed to compare the transcriptomes of pristine and moderately damaged (i.e., GS2) gill tissue. Rank Products analysis (5% percentage of false-positives) identified 254 and 34 upregulated and downregulated probes, respectively, in GS2 compared with GS0. Differentially expressed probes represented genes associated with functions including gill remodeling, wound healing, and stress and immune responses. We performed gill and liver qPCR for all four gill damage scores using microarray-identified and other damage-associated biomarker genes. Transcripts related to wound healing (e.g., neb and klhl41b) were significantly upregulated in GS2 compared with GS0 in the gills. Also, transcripts associated with immune and stress-relevant pathways were dysregulated (e.g., downregulation of snaclec 1-like and upregulation of igkv3) in GS2 compared with GS0 gills. The livers of salmon with moderate gill damage (i.e., GS2) showed significant upregulation of transcripts related to wound healing (i.e., chtop), apoptosis (e.g., bnip3l), blood coagulation (e.g., f2 and serpind1b), transcription regulation (i.e., pparg), and stress-responses (e.g., cyp3a27) compared with livers of GS0 fish. We performed principal component analysis (PCA) using transcript levels for gill and liver separately. The gill PCA showed that PC1 significantly separated GS2 from all other gill scores. The genes contributing most to this separation were pgam2, des, neb, tnnt2, and myom1. The liver PCA showed that PC1 significantly separated GS2 from GS0; levels of hsp70, cyp3a27, pparg, chtop, and serpind1b were the highest contributors to this separation. Also, hepatic acute phase biomarkers (e.g., serpind1b and f2) were positively correlated to each other and to gill damage. Gill damage-responsive biomarker genes and associated qPCR assays arising from this study will be valuable in future research aimed at developing therapeutic diets to improve farmed salmon welfare.
... (at 1412 and 1455 cm À1 , respectively) ( Figure 1K), 50 Cellular migration is critical for wound healing. 55 However, the timeframe adopted by this study was not enough to screen bone turnover, as evidenced by the very similar findings for OCN immunolabeling, an important regulator of bone turnover, 62,63 regardless of experimental group or period. ...
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This study aims to evaluate the potential of a novel biomaterial synthesized from amorphous calcium phosphate (ACP), octacalcium phosphate (OCP), and hydroxyapatite (HA) to repair critical‐sized defects (CSD) in rabbit calvaria. In vitro analyses of cell viability, cell proliferation, formation of mineral nodules, and cell differentiation using qPCR were performed for comparing experimental calcium phosphate (ECP), deproteinized bovine bone (DBB), and beta‐tricalcium phosphate (β‐TCP). Bilateral CSDs were created in 45 rabbit calvaria. Six groups were evaluated: ECP, ECP + fibrin sealant (ECP + S), coagulum, autogenous bone, DBB, and β‐TCP. Euthanasia was performed at 2, 4, and 8 weeks, followed by micro‐computed tomography and histological and immunohistochemical analyses. Results from in vitro analyses revealed similar biocompatibility for all tested materials and a tendency for higher gene expression of some bone markers in the ECP group than in β‐TCP and DBB groups at 7 days. In contrast to that in DBB and β‐TCP groups, ECP displayed growing bone volume over total volume percentage (BV/TV%) with time in vivo. Histological analysis revealed a greater number of giant cells and reduced size of grafted particles in ECP during all periods of analysis. RUNX‐2 expression was statistically lower in ECP than DBB at 2 and 4 weeks. Despite no statistical significance, ECP presented the highest absolute values for ALP‐expression at 2, 4, and 8 weeks compared with other groups. Together, our findings indicate that a combination of the ACP, OCP, and HA phases into ECP is beneficial and promising for bone regeneration.
... The MN has a larger surface area than traditional dressings, facilitating efficient drug delivery. Angiogenesis is particularly crucial to the proliferation phase of wound healing [46,47], while endothelial cells are responsible for forming new vessels [48][49][50]. However, research on endothelial cell derived exos is scant. ...
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Clinical work and research on diabetic wound repair remain challenging globally. Although various conventional wound dressings have been continuously developed, the efficacy is unsatisfactory. The effect of drug delivery is limited by the depth of penetration. The sustained release of biomolecules from biological wound dressings is a promising treatment approach to wound healing. An assortment of cell-derived exosomes (exos) have been proved to be instrumental in tissue regeneration, and researchers are dedicated to developing biomolecules carriers with unique properties. Herein, we reported a methacrylate gelatin (GelMA) microneedles (MNs) patch to achieve transdermal and controlled release of exos and tazarotene. Our MNs patch comprising GelMA/PEGDA hydrogel has distinctive biological features that maintain the biological activity of exos and drugs in vitro. Additionally, its unique physical structure prevents it from being tightly attached to the skin of the wound, it promotes cell migration, angiogenesis by slowly releasing exos and tazarotene in the deep layer of the skin. The full-thickness cutaneous wound on a diabetic mouse model was carried out to demonstrate the therapeutic effects of GelMA/PEGDA@T + exos MNs patch. As a result, our GelMA/PEGDA@T + exos MNs patch presents a potentially valuable method for repairing diabetic wound in clinical applications. Graphic Abstract
... It is characterized by fibroblast migration and deposition of newly synthesized extracellular matrix acting as a replacement for the provisional network composed of fibrin and fibronectin. 56 The shorter epithelialization periods produced by the ointments of the crude extract and solvent fractions might be due to facilitated proliferation and migration of epithelial cells and/or increased viability of epithelial cells. Wound contraction shortens the healing time because it decreases the size of the wound and reduces the amount of extracellular matrix needed to repair the defect. ...
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Introduction: Justicia schimperiana has been used traditionally for the treatment of wound and skin burn, but there is no scientific evidence that supports the traditional claim. Objective: To evaluate the wound healing activity of 80% methanol crude extract and solvent fractions of the leaves of Justicia schimperiana in mice. Methods: Mice were used for wound healing study, while rats were used for acute dermal toxicity test. The 80% methanol crude extract and chloroform, ethyl acetate and aqueous fractions were formulated in ointments with 5% and 10% strength. Burn, excision and incision wound models were used to evaluate the effect of the crude extract, whereas the activity of the solvent fractions was evaluated using excision wound model. Parameters such as wound contraction, and period of epithelialization were studied in the excision and burn wound models, while tensile strength was measured in incision wound model. Results: Treatment of wound with 80% methanol extract of Justicia schimperiana leaves using 5% (w/w) and 10% (w/w) ointment formulation induced significant (P<0.05) improvement in wound contraction rate, epithelialization time and skin breaking strength in excision, incision and burn wound model, respectively as compared to negative control. The chloroform, ethyl acetate and aqueous fractions with 5% (w/w) and 10% (w/w) ointment formulation showed significant (p<0.001) improvement in wound contraction and epithelialization time in excision wound model as compared to the negative control group. Conclusion: This study has demonstrated that the 80% methanol crude extract and solvent fractions of Justicia schimperiana leaves possess wound healing activity.
... Smokers, older adults, and people who are overweight also have an increased risk of infection. Emergency surgeries, abdominal surgeries, and surgeries that last longer than two hours could result to a higher risk of infection (Velnar et al., 2009;Hunt et al., 2000). ...
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The serum albumin, zinc and vitamin C statuses of surgical wound patients attending General Hospital Owerri, Nigeria were investigated to determine whether or not the serum levels of these elements were normal. One hundred surgical wound patients age 20-40 years were selected. One hundred normal subjects age 20-40 years were used as control. The levels of albumin, zinc and vitamin C were significantly decreased in surgical wound patients, when compared with the control (p<0.05). The result suggests, but not conclusively, that supplementation of surgical wound patients, with food and drug containing albumin, zinc and vitamin C might be helpful, particularly for the healing f surgical wounds. Keywords albumin, zinc and vitamin C
... The process of skin wound healing can be divided into four continuous stages, namely, hemostasis, inflammation, proliferation, and remodeling, as shown in Figure 2 [28]. When injury occurs, the blood vessels in the damaged area rupture, the subcutaneous matrix in the blood vessels is exposed, and the glycoproteins on the platelet membrane bind with the collagen of the basement membrane, making the platelets adhere to and be activated [29]. Activated platelets release endogenous ADP and TXA2, which in turn promote irreversible aggregation of platelets, resulting in platelet thrombosis [30]. ...
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Skin wound healing is a continuous and complex process affected by many factors. Growth factors play an important role in the process of wound healing. Local application of growth factors can significantly promote wound healing. However, the degradation and time dependence of growth factors require appropriate delivery systems to help them play a role in wound healing. In recent years, wound dressing products with hydrogels as matrix materials or main components have shown obvious advantages in promoting wound healing. By modifying the hydrogel or combining it with other factors or materials that are beneficial to wound healing, the healing effect can be further enhanced. This review will introduce the research status of growth factors and hydrogels based on natural biological materials in skin wound repair and review the effects and research progress of the combination of growth factors and hydrogels in skin wound healing.
... The skin is the first and most crucial defense barrier in mammals; therefore, any damage to this organ must immediately be healed and repaired. Hence, seeking effective treatments with minimum treatment course and side effects would be ideal for the treatment of wounds (Broughton et al. 2006;Velnar et al. 2009). Any rupture in the integrity of skin layers or subcutaneous tissue is called a wound that might be caused by physical or chemical factors. ...
... Nowadays, the utilization of fish collagen for biomedical purposes and regenerative medicine has grown immensely. Fish collagen provides an ideal environment to proliferate the fibroblasts cells which help heal the wound [37] . Collagen helps to treat problems like inflammation, hemostasis and remodeling [38] . ...
Chapter
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With growing the population, fish wastes are increasing day by day. Fish processing industries also contain a huge amount of fish wastes. However, the discarded portion of fish contains vitamins, minerals, collagen as protein, and bioactive compounds. Fish wastes are mainly used as a byproduct. Fish collagen as a byproduct pays great attention because of its extraordinary properties such as no risk of outbreak any harmful diseases and lack of religious or ethical constraints in comparison with bovine and porcine collagen. This manuscript has detailed the extraction procedures and recent biomedical applications of fish collagen in wound healing, tissue engineering, drug delivery, and cell culture. The new development of fish collagen used in biomedical applications such as collagen-based tablets or pellets, collagen films, and collagen shields are also described. Due to the huge applications, the importance and demand of fish collagen have been increasing commercially in the fish processing industry and various biomedical sectors respectively.
... In addition, adequacy and recovery depend on available nutrient resources or reserves. 53,75 Oral feeding is recommended as soon as possible after surgery. Early oral feeding is the preferred mode of nutrition for surgical patients. ...
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Dietitians and nutritionists play a key role in optimizing the nutritional status of the patients before and after performing surgery. The importance of nutrition is often overlooked because health professionals lack knowledge about nutritional problems, structured protocols for cooperation between surgeons and clinical nutritionists do not exist, dedicated resources are lacking, and preoperative and postoperative nutrition care protocols have not been disseminated. The purpose of this review is to describe various nutrition care guidelines for use during preoperative and postoperative periods for surgical patients to enhance recovery after surgery based on a review of the literature. It should help nutritionists and surgeons to make appropriate decisions on the management during preoperative and postoperative care, as well as facilitating the understanding and application of medical nutrition therapy. Nutr Today. 2022;57(3):145-158
... Wounds are formed when the skin's epithelial continuity is broken, resulting in the disruption of function and structure of its underlying tissues [7]. Wounds can be caused by disease, or they can exhibit an intentional or accidental etiology [23]. The healing process of a wound depends on the type of wound injury and underlying disease, as well as local and systemic mediators [24]. ...
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Chronic wounds have been a global health threat over the past few decades, requiring urgent medical and research attention. The factors delaying the wound-healing process include obesity, stress, microbial infection, aging, edema, inadequate nutrition, poor oxygenation, diabetes, and implant complications. Biomaterials are being developed and fabricated to accelerate the healing of chronic wounds, including hydrogels, nanofibrous, composite, foam, spongy, bilayered, and trilayered scaffolds. Some recent advances in biomaterials development for healing both chronic and acute wounds are extensively compiled here. In addition, various properties of biomaterials for wound-healing applications and how they affect their performance are reviewed. Based on the recent literature, trilayered constructs appear to be a convincing candidate for the healing of chronic wounds and complete skin regeneration because they mimic the full thickness of skin: epidermis, dermis, and the hypodermis. This type of scaffold provides a dense superficial layer, a bioactive middle layer, and a porous lower layer to aid the wound-healing process. The hydrophilicity of scaffolds aids cell attachment, cell proliferation, and protein adhesion. Other scaffold characteristics such as porosity, biodegradability, mechanical properties, and gas permeability help with cell accommodation, proliferation, migration, differentiation, and the release of bioactive factors.
... Upon completing the task, the neutrophils are eliminated from the wound. During the late inflammatory phase, macrophages appear in the wound and continue the process of phagocytosis before progressing to the next phase of healing [23,24,[26][27][28][29][30][31]. Macrophages play an important role in the late stages of the inflammatory response, acting as key regulatory cells and storing a large amount of potent tissue growth factors [17,24,[27][28][29][30][31][32][33]. ...
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Wound healing is a complicated process, and the effective management of wounds is a major challenge. Natural herbal remedies have now become fundamental for the management of skin disorders and the treatment of skin infections due to the side effects of modern medicine and lower price for herbal products. The aim of the present study is to summarize the most recent in vitro, in vivo, and clinical studies on major herbal preparations, their phytochemical constituents, and new formulations for wound management. Research reveals that several herbal medicaments have marked activity in the management of wounds and that this activity is ascribed to flavonoids, alkaloids, saponins, and phenolic compounds. These phytochemicals can act at different stages of the process by means of various mechanisms, including anti-inflammatory, antimicrobial, antioxidant, collagen synthesis stimulating, cell proliferation, and angiogenic effects. The application of natural compounds using nanotechnology systems may provide significant improvement in the efficacy of wound treatments. Increasing the clinical use of these therapies would require safety assessment in clinical trials.
... 3,4 Wound healing is a complex process in which biocellular and biochemical activities occur continuously involving a series of complex reactions and interactions between cells and mediators, 5 which aim to restore the integrity of damaged tissue and will begin immediately after the occurrence of tissue damage by going through several stages of mechanism or phase. 6 Wound healing is characterized by an increase in the number of macrophages during inflammation phase. The function of macrophages in the wound healing process is to phagocytose and destroy necrotic tissue and foreign particles that enter the tissue. ...
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Background: The wound healing process can be optimized through the addition of a biomaterial such as recombinant secretory leukocyte protease inhibitor (rSLPI). The SLPI is a non-glycosylated proteomic material that inhibits protease enzymes and has anti-inflammatory properties, thus accelerating wound healing. This study analyzed the administration of rSLPI doses 0.04 cc and 0.06 cc in skin wound healing on the CD163 expression of macrophages and cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6) and fibroblast growth factor 2 (FGF-2). Materials and methods: rSLPI produced from Escherichia coli TOP10 as the cloning host, BL21 (DE3) strains as the expression host and pET30a plasmids were used for the expression system construction. The wound was created on Wistar rat dorsal skin, then rSLPI 0.04 cc and 0.06 cc was administered. In the next four days, the back skin was biopsied and stained by immunohistochemistry to analyze the CD163, FGF-2, IL-1 and IL-6 expression. Results: The administration of rSLPI increased CD163 and FGF-2 expression dependent on dose (p<0.05). On the other hand, administration of rSLPI decreased IL-1 and IL-6 expression depending on dose (p <0.05). Conclusion: The administration of rSLPI is able to accelerate the wound healing process by increasing the CD163 and FGF-2 expression. The cytokines such as IL-1 and IL-6 decreased depending on rSLPI doses.
Article
Background Population aging has led to an increased incidence of pressure ulcers, resulting in a social burden and economic costs. We developed a three-dimensional knitted fabric (3-DKF) with a pressure-reducing function that can be applied topically in the early stages of pressure ulcers to prevent progression. Methods We evaluated the effects of the 3-DKF in a streptozotocin-induced diabetes mellitus pressure ulcer mouse model, and the fabric was preliminarily applied to patients. Twelve-week-old male C57BL/6 mice were used for the animal experiments. In the pressure ulcer mouse model, an ischemia-reperfusion injury was created using a magnet on the dorsa of the mice. Pressure was measured with BodiTrak before and after applying the 3-DKF to 14 patients at risk of sacral pressure ulcers. Results In the 3-DKF-applied mice group, the ulcers were shallower and smaller than those in the control group. Compared with the mice in the control group, the 3-DKF group had lower platelet-derived growth factor-α and neutrophil elastase expression, as parameters related to inflammation, and increased levels of transforming growth factor (TGF)-β1, TGF-β3, proliferating cell nuclear antigen, and α-smooth muscle actin, which are related to growth factors and proliferation. Additionally, typical normal tissue staining patterns were observed in the 3-DKF group. In the preliminary clinical analysis, the average skin pressure was 26.2 mm Hg before applying the 3-DKF, but it decreased to an average of 23.4 mm Hg after 3-DKF application. Conclusion This study demonstrated that the newly developed 3-DKF was effective in preventing pressure ulcers through testing in a pressure ulcer animal model and preliminary clinical application.
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Mit jährlich circa 11 Millionen Fällen weltweit, stellen schwere Brandwunden bis heute einen großen Anteil an Verletzungen dar, die in Kliniken behandelt werden müssen. Während leichte Verbrennungen meist problemlos heilen, bedarf die Behandlung tieferer Verbrennungen medizinischer Intervention. Zellbasierte Therapeutika zeigen hier bereits große Erfolge, aufgrund der eingeschränkten Übertragbarkeit von Ergebnissen aus Tiermodellen ist jedoch sowohl die Testung neuer Produkte, als auch die Erforschung der Wundheilung bei Brandwunden noch immer schwierig. Aufgrund dessen wurden in dieser Arbeit zwei Ziele verfolgt: Die Etablierung von Methoden, um ein zellbasiertes Therapeutikum produzieren zu können und die Entwicklung eines Modells zur Untersuchung von Verbrennungswunden. Zunächst wurden hierfür die Kulturbedingungen und -protokolle zur Isolation und Expansion von Keratinozyten so angepasst, dass sie gängigen Regularien zur Produktion medizinischer Produkte entsprechen. Hier zeigten die Zellen auch in anschließenden Analysen, dass charakteristische Merkmale nicht verloren hatten. Darüber hinaus gelang es, die Zellen mithilfe verschiedener protektiver Substanzen erfolgreich einzufrieren und zu konservieren. Des Weiteren konnte ein Modell etabliert werden, das eine Verbrennung ersten Grades widerspiegelt. Über einen Zeitraum von zwei Wochen wurde seine Regeneration hinsichtlich verschiedener Aspekte, wie der Histomorphologie, dem Metabolismus und der Reepithelialisierungsrate, untersucht. Die Modelle zeigten hier viele Parallelen zur Wundheilung in vivo auf. Um die Eignung der Modelle zur Testung von Wirkstoffen zu ermitteln wurde außerdem eine Behandlung mit 5% Dexpanthenol getestet. Sie resultierte in einer verbesserten Histomorphologie und einer erhöhten Anzahl an proliferativen Zellen in den Modellen, beschleunigte jedoch die Reepithelialisierung nicht. Zusammengefasst konnten in dieser Arbeit zunächst Methoden etabliert werden, um ein medizinisches Produkt aus Keratinozyten herzustellen und zu charakterisieren. Außerdem wurde ein Modell entwickelt, anhand dessen die Wundheilung und Behandlung von Verbrennungen ersten Grades untersucht werden kann und welches als Basis zur Entwicklung von Modellen von tieferen Verbrennungen dienen kann.
Article
Extracellular vesicles are membranous particles, ranging from 30 nm to 10 µm in diameter, which are released by nearly all cell types to aid in intercellular communication. These complex vesicles carry a multitude of signaling moieties from their cell of origin, such as proteins, lipids, cell surface receptors, enzymes, cytokines, metabolites, and nucleic acids. A growing body of evidence suggests that in addition to delivering cargos into target cells to facilitate intercellular communication, extracellular vesicles may also play roles in such processes as cell differentiation and proliferation, angiogenesis, stress response, and immune signaling. As these vesicles have natural biocompatibility, stability in circulation, low toxicity, and low immunogenicity, and serve as efficient carriers of molecular cargos, these nanoparticles are ideal therapeutic candidates for regenerative medicine. Exploring and identifying the homeostatic functions of extracellular vesicles may facilitate the development of new regenerative therapies. In this review, we summarize the wound healing process, difficulties in stem cell therapies for regenerative medicine, and the applications of mesenchymal stromal cell‐derived extracellular vesicles in improving and accelerating the wound healing process.
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We performed a meta‐analysis to evaluate the effect of platelet‐rich plasma vs standard management for the treatment of diabetic foot ulcer wounds. A systematic literature search up to March 2022 was performed and 1435 subjects with diabetic foot ulcer wounds at the baseline of the studies; 723 of them were treated with platelet‐rich plasma, and 712 used control. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated to assess the effect of platelet‐rich plasma vs standard management for the treatment of diabetic foot ulcer wounds using the dichotomous method with a random or fixed‐effect model. The use of autologous platelet‐rich plasma resulted in significantly higher complete‐healed diabetic foot ulcer wounds compared with control (OR, 1.95; 95% CI, 1.49‐2.56, P < 0.001). The use of allogeneic platelet‐rich plasma resulted in significantly higher complete‐healed diabetic foot ulcer wounds compared with control (OR, 6.19; 95% CI, 2.32‐16.56, P < 0.001). The use of autologous and allogeneic platelet‐rich plasma resulted in significantly higher complete‐healed diabetic foot ulcer wounds compared with control. Though, the analysis of outcomes should be with caution because of the low number of studies in certain comparisons, for example, allogeneic platelet‐rich plasma compared with control.
Chapter
Oleoresin is a mixture of volatile and nonvolatile components available in whole extract of natural herb or spice. It principally comprises essential oils and resin. Lemongrass oleoresins come from the Cymbopogon species, which grow in the tropical and subtropical regions of the world. Oleoresin of lemongrass is a dark green-colored viscous liquid having a characteristic lemon aroma and flavor and is mostly used as a flavoring ingredient. The lemon prefix in the lemongrass specifies the characteristic lemon-like odor, which is due to the availability of citral content (mixture of two isomeric aldehydes, geranial and neral). It has been utilized in synthesizing flavors, perfumes, cosmetics, detergents, and in the food and pharmaceutical industries. Different methods are used to extract the lemongrass essential oil, but steam distillation is the most suitable method as it doesn’t alter the quality of the obtained oil. The chemical composition of lemongrass oil varies depending on its extraction methods, genetic differences, harvest period, photoperiod, plant age, farming practices, and geographical origin. Lemongrass essential oil has shown several biological activities, including antimicrobial, antifungal, antiprotozoan, antioxidant, antidiarrheal, antimutagenic, antiinflammatory, antimalarial, antinociceptive, antihepatotoxic activities, etc. Lemongrass oil is a potent food preservative because of its extraordinary antifungal and antibacterial activities.
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Wound healing and skin tissue regeneration remain the most critical challenges faced by medical professionals. Titanium(IV) oxide-based materials were proposed as components of pharmaceutical formulations for the treatment of difficult-to-heal wounds and unsightly scarring. A gallic acid-functionalized TiO2 nanomaterial (TiO2-GA) was obtained using the self-assembly technique and characterized using the following methods: scanning electron microscopy (SEM), transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy and thermogravimetry (TG). Additionally, physicochemical and biological tests (DPPH assay, Microtox® acute toxicity test, MTT assay) were performed to assess antioxidant properties as well as to determine the cytotoxicity of the novel material against eukaryotic (MRC-5 pd19 fibroblasts) and prokaryotic (Staphylococcus aureus, Escherichia coli, Candida albicans, Aliivibrio fischeri) cells. To determine the photocytotoxicity of the material, specific tests were carried out with and without exposure to visible light lamps (425 nm). Following the results, the TiO2-GA material could be considered an additive to dressings and rinsing suspensions for the treatment of difficult-to-heal wounds that are at risk of bacterial infections.
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As the first defensive line between the human body and the outside world, the skin is vulnerable to damage from the external environment. Skin wounds can be divided into acute wounds (mechanical injuries, chemical injuries and surgical wounds, etc.) and chronic wounds (burns, infections, diabetes, etc.). In order to manage skin wound, a variety of wound dressings have been developed, including gauze, films, foams, nanofibers, hydrocolloids and hydrogels. Recently, hydrogels have received much attention because of their natural extracellular matrix (ECM)‐mimik structure, tunable mechanical properties, and facile bioactive substance delivery capability. They show great potential application in skin wound repair. This paper first introduces the anatomy and function of the skin, the process of wound healing and conventional wound dressings, and then introduces the composition and construction methods of hydrogels. Next, this paper introduces the necessary properties of hydrogels in skin wound repair and the latest research progress of hydrogel dressings for skin wound repair. Finally, the future development goals of hydrogel materials in the field of wound healing are proposed. This article is protected by copyright. All rights reserved
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Advanced glycation end products (AGE) are a heterogeneous group of compounds that are physiologically synthesized in the body. Apart from this, it can be taken into the body as exogenous through nutrition and smoking. Increased levels of AGEs in the body are associated with the development of many pathologies, especially diabetes. Although many ways are suggested for the mechanism of action of AGEs on the pathophysiology of diabetes, basically two mechanisms, direct and indirect, are mentioned. In the direct mechanism, increased levels of AGEs in plasma can cause cell damage and have an effect on diabetes and its complications. Indirectly, with the increase in plasma glucose level in diabetic condition, various structural proteins glycated lose their function and free radical production is induced. As the evidence on the role of AGEs in the pathogenesis of diabetes increases, the importance of the amount of AGE taken with foods that are sources of exogenous AGEs become apparent. At this point, it is thought that restricting dietary AGE intake will be an important strategy. In this review study, it was aimed to evaluate the effects of advanced glycation end products on diabetes complications in the light of current literature
Article
Objective: The aim of the present study was to evaluate and compare the effectiveness of ozone therapy and low-level laser therapy (LLLT) on healing of oral mucosal wounds in rats through histological assessment. Methods: Thirty male Wistar rats were employed in this study. Following a 5-mm surgical wound created on the buccal mucosa, the rats were randomly distributed into 3 groups of 10: (1) ozone group (treated with topical gaseous ozone), (2) laser group (treated with LLLT), and (3) control group (received no treatment). Following the sacrifice of rats on day 21, samples were taken from rats' buccal mucosa for histological assay and scoring. The data were analyzed using Mann-Whitney test. Results: Ozone and laser groups demonstrated reduced acute inflammation scores compared to control group (p=.01), while no significant differences were observed between the ozone and laser groups (p=1.00). Similarly, ozone and laser groups showed higher histological tissue repair scores than the control group (p=.00), and no difference was found between ozone and laser groups (p=.76). On the other hand, no significant difference in expression of TNF-α (p=.33) and TGF-β1 (p=.13) was identified between ozone, laser and control samples. Conclusion: The present study demonstrated that both adjunctive ozone therapy and LLLT with a 940 nm diode laser provided significant improvement in parameters of acute inflammation and tissue repair in surgical oral mucosal wounds in rats.
Article
Impaired diabetic wound healing is a major concern for health care professionals worldwide, imposing an intense financial burden and reducing the quality of life of patients. A dysregulation of this process can be responsible for the development of intractable ulcers and the formation of excessive scars. Therefore, the identification of novel pharmacological strategies able to promote wound healing and restore the mechanical integrity of injured tissue becomes essential. In the present study, fluoxetine ecofriendly nanoemulsion (FLX-EFNE) was prepared and its potential efficacy in enhancing wound healing was tested in diabetic rats. The Box–Behnken response surface design was used to select the optimized formulation that was prepared by the high-shear homogenization-based technique. A Zetasizer was used for the characterization of the optimized formulation, providing a FLX-EFNE with a globule size of 199 nm. For the in vivo study, a wound was induced by surgical methods, and diabetic rats (streptozotocin-induced) were divided into five groups: untreated control, vehicle-treated, FLX, FLX-EFNE, and positive control receiving a commercially available formula. The treatment continued from the day of wound induction to day 21. Then, the animals were sacrificed and skin tissues were collected at the site of wounding and used for biochemical, histopathological, immunohistochemical, and mRNA expression assessments. In the FLX-EFNE treated group, the rate of wound contraction and signs of healing were significantly higher compared to all other groups. In addition, angiogenesis, proliferation, and collagen deposition were enhanced, while oxidative stress and inflammation decreased. The present data highlight the enhanced wound healing activity of the optimized FLX-EFNE formulation.
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Background: Indications for the use of negative pressure wound therapy (NPWT) are broad and include prophylaxis for surgical site infections (SSIs). Existing evidence for the effectiveness of NPWT on postoperative wounds healing by primary closure remains uncertain. Objectives: To assess the effects of NPWT for preventing SSI in wounds healing through primary closure, and to assess the cost-effectiveness of NPWT in wounds healing through primary closure. Search methods: In January 2021, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries and references of included studies, systematic reviews and health technology reports. There were no restrictions on language, publication date or study setting. Selection criteria: We included trials if they allocated participants to treatment randomly and compared NPWT with any other type of wound dressing, or compared one type of NPWT with another. Data collection and analysis: At least two review authors independently assessed trials using predetermined inclusion criteria. We carried out data extraction, assessment using the Cochrane risk of bias tool, and quality assessment according to Grading of Recommendations, Assessment, Development and Evaluations methodology. Our primary outcomes were SSI, mortality, and wound dehiscence. Main results: In this fourth update, we added 18 new randomised controlled trials (RCTs) and one new economic study, resulting in a total of 62 RCTs (13,340 included participants) and six economic studies. Studies evaluated NPWT in a wide range of surgeries, including orthopaedic, obstetric, vascular and general procedures. All studies compared NPWT with standard dressings. Most studies had unclear or high risk of bias for at least one key domain. Primary outcomes Eleven studies (6384 participants) which reported mortality were pooled. There is low-certainty evidence showing there may be a reduced risk of death after surgery for people treated with NPWT (0.84%) compared with standard dressings (1.17%) but there is uncertainty around this as confidence intervals include risk of benefits and harm; risk ratio (RR) 0.78 (95% CI 0.47 to 1.30; I2 = 0%). Fifty-four studies reported SSI; 44 studies (11,403 participants) were pooled. There is moderate-certainty evidence that NPWT probably results in fewer SSIs (8.7% of participants) than treatment with standard dressings (11.75%) after surgery; RR 0.73 (95% CI 0.63 to 0.85; I2 = 29%). Thirty studies reported wound dehiscence; 23 studies (8724 participants) were pooled. There is moderate-certainty evidence that there is probably little or no difference in dehiscence between people treated with NPWT (6.62%) and those treated with standard dressing (6.97%), although there is imprecision around the estimate that includes risk of benefit and harms; RR 0.97 (95% CI 0.82 to 1.16; I2 = 4%). Evidence was downgraded for imprecision, risk of bias, or a combination of these. Secondary outcomes There is low-certainty evidence for the outcomes of reoperation and seroma; in each case, confidence intervals included both benefit and harm. There may be a reduced risk of reoperation favouring the standard dressing arm, but this was imprecise: RR 1.13 (95% CI 0.91 to 1.41; I2 = 2%; 18 trials; 6272 participants). There may be a reduced risk of seroma for people treated with NPWT but this is imprecise: the RR was 0.82 (95% CI 0.65 to 1.05; I2 = 0%; 15 trials; 5436 participants). For skin blisters, there is low-certainty evidence that people treated with NPWT may be more likely to develop skin blisters compared with those treated with standard dressing (RR 3.55; 95% CI 1.43 to 8.77; I2 = 74%; 11 trials; 5015 participants). The effect of NPWT on haematoma is uncertain (RR 0.79; 95 % CI 0.48 to 1.30; I2 = 0%; 17 trials; 5909 participants; very low-certainty evidence). There is low-certainty evidence of little to no difference in reported pain between groups. Pain was measured in different ways and most studies could not be pooled; this GRADE assessment is based on all fourteen trials reporting pain; the pooled RR for the proportion of participants who experienced pain was 1.52 (95% CI 0.20, 11.31; I2 = 34%; two studies; 632 participants). Cost-effectiveness Six economic studies, based wholly or partially on trials in our review, assessed the cost-effectiveness of NPWT compared with standard care. They considered NPWT in five indications: caesarean sections in obese women; surgery for lower limb fracture; knee/hip arthroplasty; coronary artery bypass grafts; and vascular surgery with inguinal incisions. They calculated quality-adjusted life-years or an equivalent, and produced estimates of the treatments' relative cost-effectiveness. The reporting quality was good but the evidence certainty varied from moderate to very low. There is moderate-certainty evidence that NPWT in surgery for lower limb fracture was not cost-effective at any threshold of willingness-to-pay and that NPWT is probably cost-effective in obese women undergoing caesarean section. Other studies found low or very low-certainty evidence indicating that NPWT may be cost-effective for the indications assessed. Authors' conclusions: People with primary closure of their surgical wound and treated prophylactically with NPWT following surgery probably experience fewer SSIs than people treated with standard dressings but there is probably no difference in wound dehiscence (moderate-certainty evidence). There may be a reduced risk of death after surgery for people treated with NPWT compared with standard dressings but there is uncertainty around this as confidence intervals include risk of benefit and harm (low-certainty evidence). People treated with NPWT may experience more instances of skin blistering compared with standard dressing treatment (low-certainty evidence). There are no clear differences in other secondary outcomes where most evidence is low or very low-certainty. Assessments of cost-effectiveness of NPWT produced differing results in different indications. There is a large number of ongoing studies, the results of which may change the findings of this review. Decisions about use of NPWT should take into account surgical indication and setting and consider evidence for all outcomes.
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As burn injuries are often followed by a derailed immune response and excessive inflammation, a thorough understanding of the occurring reactions is key to prevent secondary complications. This systematic review, that includes 247 animal studies, shows the post-burn response of 14 different immune cell types involved in immediate and long-term effects, in both wound tissue and circulation. Peripheral blood neutrophil and monocyte numbers increased directly after burns, whereas thrombocyte numbers increased near the end of the first week. Lymphocyte numbers, however, were decreased for at least two weeks. In burn wound tissue, neutrophil and macrophage numbers accumulated during the first three weeks. Burns also altered cellular functions as we found increased migratory potential of leukocytes, impaired antibacterial activity of neutrophils and enhanced inflammatory mediator production by macrophages. Neutrophil surges were positively associated with burn size and were highest in rats. Altogether, this comprehensive overview of the temporal immune cell dynamics shows that unlike normal wound healing, burn injury induces a long-lasting inflammatory response. It provides a fundamental research basis to improve experimental set-ups, burn care and outcome.
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Commiphora gileadensis (CG) is a small tree distributed throughout the Middle East. It was traditionally used in perfumes in countries in this area. In Saudi Arabia, it was used to treat wounds burns and as an antidote to scorpion stings. This study aimed to evaluate the antimicrobial activity and cutaneous wound healing efficiency of the CG extracts using microbiological tests, rate of wound contraction and histopathological changes. CG pants were extracted using the methanol extraction technique; then, the methanolic extract was characterized using liquid chromatography coupled with mass spectrometry (LC–MS). Afterwards, a six-millimetre (mm) excision wound was induced in 60 male Balb/c mice. Mice were classified into two classes; each class consisted of three groups of 10 mice. In the non-infected wound class, the group I was assigned as control and received normal saline. Group II received gentamicin treatment, and group III treated with CG-methanolic extract. In the Staphylococcus aureus-infected class, group IV received normal saline, and groups V and VI were treated with gentamicin and CG-methanolic extract, respectively. The colonization of infected wounds was determined using colony-forming units (CFUs), and the percentage of wound contraction was measured in all groups. Finally, the histopathologic semi-quantitative determination of wound healing was evaluated by inflammatory cell infiltration, the presence of collagen fibres and granulation tissue, and the grade of re-epithelization. Composition analysis of the methanolic extract confirmed the presence of a high amount of ceramide (69%) and, to a lesser extent, hexosylceramide (18%) and phosphatidylethanolamine (7%) of the total amount. Additionally, there was a statistically significant difference between the percentage of wound contraction in the CG-treated and control groups in both Staphylococcus aureus-infected and non-infected wounds (p < 0.01). The colonization of the infected wounds was lower in the group treated with CG than in the control group (p < 0.01). In both non-infected and infected wounds, the CG-treated group showed significant statistical differences in inflammatory cell infiltration, collagen fibres, re-epithelization and granulation tissue formation compared with the control group (p < 0.01). The CG extract possesses antibacterial and anti-inflammatory properties that induce wound healing.
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The healing of a burn wound is a complex process that includes the re-formation of injured tissues and the control of infection to minimize discomfort, scarring, and inconvenience. The current investigation’s objective was to develop and optimize a geranium oil–based self-nanoemulsifying drug delivery system loaded with pravastatin (Gr-PV-NE). The geranium oil and pravastatin were both used due to their valuable anti-inflammatory and antibacterial activities. The Box–Behnken design was chosen for the development and optimization of the Gr-PV-NE. The fabricated formulations were assessed for their droplet size and their effects on the burn wound diameter in experimental animals. Further, the optimal formulation was examined for its wound healing properties, antimicrobial activities, and ex-vivo permeation characteristics. The produced nanoemulsion had a droplet size of 61 to 138 nm. The experimental design affirmed the important synergistic influence of the geranium oil and pravastatin for the healing of burn wounds; it showed enhanced wound closure and improved anti-inflammatory and antimicrobial actions. The optimal formulation led to a 4-fold decrease in the mean burn wound diameter, a 3.81-fold lowering of the interleukin-6 serum level compared to negative control, a 4-fold increase in the inhibition zone against Staphylococcus aureus compared to NE with Gr oil, and a 7.6-fold increase in the skin permeation of pravastatin compared to PV dispersion. Therefore, the devised nanoemulsions containing the combination of geranium oil and pravastatin could be considered a fruitful paradigm for the treatment of severe burn wounds.
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The response of human endothelial cell migration to various extracellular matrix components and growth factors has been assessed. Human endothelial cells demonstrate increased chemotaxis and chemokinesis when placed in a modified Boyden chamber with endothelial cell growth factor (ECGF) used at a concentration of 10(-9) M. Anti-ECGF antibody inhibits the chemotactic response. Heparin (10(-8) to 10(-10) M) was also chemotactic and was shown to potentiate the chemotactic activity of ECGF. Although laminin, fibronectin, the polypeptide (epidermal, fibroblast, and nerve) growth factors, and collagen types I, II, III, IV, and V demonstrate a chemotactic response, these activities were one third to one half less than observed with ECGF. These data suggest that ECGF and heparin may play a significant role as response modifiers of human endothelial cell migration which may be relevant to tumor metastasis, wound healing, and atherogenesis.
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When reconstructing facial gunshot wounds, the best results are obtained when the soft and hard tissue reconstruction are addressed concomitantly. Current techniques make it possible, in most cases, to reconstruct the osseous injuries without compromising the end result.
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The human response to injury involves the coordinated interplay of a variety of physiologic processes that result in a healed wound. In a highly reproducible manner, hemostasis is achieved, inflammation is induced, mesenchymal cells migrate into the wounded area and proliferate, revascularization occurs, epithelial continuity is re-established, collagen and other matrix components are synthesized, wound contraction occurs, and the wound remodels itself. These various functions involved in the healing process are all orchestrated by cytokines and other mediators of cellular function.
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Background: Cutaneous wound healing is a normal physiologic function, observed and described for centuries by those afflicted with wounds and by those caring for them. Recently, tremendous progress has been made in discovering the cellular and molecular mechanisms responsible for wound healing. Counseling patients appropriately and planning future therapeutic interventions in delayed or abnormal wound healing may be improved by a thorough understanding of the relationship between clinical, cellular, and subcellular events occurring during the normal healing process. materials and methods: A review of the wound healing literature from the past several decades, with a focus on the past 5 to 10 years in particular, along with illustrative case examples from our clinical practice over the past decade. Results: Traditional clinical stages of wounding healing are still relevant, but more overlap between stages is likely a more accurate depiction of events. The role of cells such as platelets, macrophages, leukocytes, fibroblasts, endothelial cells, and keratinocytes is much better known, particularly during the inflammatory and proliferation stages of healing. Molecules such as interferon, integrins, proteoglycans and glycosaminoglycans, matrix metalloproteinases, and other regulatory cytokines play a critical role in the regulation of healing mechanisms. Conclusion: Cutaneous wound healing in normal hosts follows an orderly clinical process. The scientific underpinnings for healing are better understood than ever, although much remains to be discovered. Eventually, such improved understanding of cellular and subcellular physiology may lead to new or better forms of therapy for patients with acute, chronic, and surgical skin wounds.
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Background: Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. Observation: This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and wound healing end points. Conclusions: The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.
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Background: Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. Observation: This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and wound healing end points. Conclusions: The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.(Arch Dermatol. 1994;130:489-493)
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The response of human endothelial cell migration to various extracellular matrix components and growth factors has been assessed. Human endothelial cells demonstrate increased chemotaxis and chemokinesis when placed in a modified Boyden chamber with endothelial cell growth factor (ECGF) used at a concentration of 10(-9) M. Anti-ECGF antibody inhibits the chemotactic response. Heparin (10(-8) to 10(-10) M) was also chemotactic and was shown to potentiate the chemotactic activity of ECGF. Although laminin, fibronectin, the polypeptide (epidermal, fibroblast, and nerve) growth factors, and collagen types I, II, III, IV, and V demonstrate a chemotactic response, these activities were one third to one half less than observed with ECGF. These data suggest that ECGF and heparin may play a significant role as response modifiers of human endothelial cell migration which may be relevant to tumor metastasis, wound healing, and atherogenesis.
Angiogenesis, the formation of new blood vessels, is an important component of restoration of hematopoiesis after BMT, but the mediators involved in hematopoietic angiogenesis have not been identified. We examined the influence of the lipid growth factors, phosphatidic acid (PA), lysophos- phatidic acid (LPA), and sphingosine 1-phosphate (S1P), on several angiogenic properties of en- dothelial cells, including migration and stabilization of vascular barrier integrity. In a previous study, PA was found to disrupt the permeability of established endothelial monolayers, an early event in the angiogenic response that liberates cells for subsequent mobilization. In the present study, both PA and LPA weakly induced the chemotactic migration of endothelial cells from an established monolayer. The chemotactic response induced by PA and LPA was similar in intensity to that ob- served with optimal levels of the known protein endothelial cell chemoattractants, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). A markedly greater chemo- tactic response was effected by nanomolar concentrations of S1P, indicating that this platelet-de- rived factor plays an important role in a key aspect of angiogenesis, chemotactic migration of en- dothelial cells. The chemotactic response to S1P was completely inhibited by preincubation of endothelial cells with antisense oligonucleotides to the high-affinity S1P receptor, Edg-1. In addi- tion, chemotaxis of endothelial cells to S1P was inhibited by preincubation of cells with specific in- hibitors of tryosine kinases, but inhibitors of phosphatidylinositol 3 9 kinase had little effect. Finally, LPA effectively stabilized endothelial monolayer barrier function, a late event in angiogenesis. Thus, the phospholipid growth factors, PA, S1P, and LPA, display divergent and potent effects on angio- genic properties of endothelial cells and giogenic differentiation of endothelial cells potentially act in tandem to effectively induce neovascularization. These mediators may thus exert important roles in restoration of hematopoiesis, as they facilitate blood vessel formation at sites of transplanted stem cells, allowing the progeny of engrafted progenitors to move from marrow sinusoids to the periph- eral vasculature.
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Epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) stimulate keratinocyte migration on collagen by up-regulating the α2 subunit of the collagen integrin, α2β1. Interleukin-1 (IL-1) is an autocrine factor, produced by keratinocytes them- selves, that is modulated by ultraviolet light and increases the proliferative potential of keratinocytes in culture. The autocrine nature of keradnocyte- derived IL-1α is emphasized by the fact that it induces tile keratinocyte to synthesize IL-1α and TGF-α, a cytokine known to induce keratinocyte motility. Further, topical application of IL-1α has been shown to promote wound healing in animals. In this study, we used a well-defined keratinocyte migration assay to assess the effect of IL-1α on keratinocyte motility and to examine whether the IL-1α TGFα pathway is involved, The addition of recombinant human IL-1α to keratinocytes produced a statistically significant and concentration-dependent increase in migration on matrices of collagen types I and IV, but not on laminin, Maximal levels of keratinocyte migration obtained on these matrices with IL-1α were comparable to those obtained with stimulation by EGF and TGF-α. The effects of TGF-α and IL-1α on keratinocyte migration are additive; however, the maximal level of migration achieved by using IL-1α and TGF-α in combination never exceeds the maximal level of migration found by using either cytokine alone. The time course of keratinocyte migration induced by IL-1α is delayed (onset of migration 9-12 h after addition) as compared with that induced by TGF-α (onset of migration 6-9 h after addition) even if the cells are preincubated in IL-1α. Flow cytometry analysis demonstrated no change in surface expression of integrin subunits, specifically that of integrin subunit α2, previously shown to be up-regulated by EGF/TGF-α. These results suggest that IL-1α stimulates keratinocyte migration on collagen via a mechanism distinct from that of EGF/TGF-α.
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Background: Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. Observation: This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and wound healing end points. Conclusions: The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.
Article
Das Debridement ist definiert als Entfernung von nicht-vitalem Gewebe aus einer Wunde. In chronischen Wunden wird mit dem Debridement die Elimination von Nekrosen, aber auch die Abtragung von Verbandresten, Fremdkörpern oder anderen avitalen Bestandteilen bezeichnet. Das sachgerechte Debridement stellt eine grundlegende Voraussetzung für den Ablauf eines nicht verzögerten Wundheilungsprozesses dar. Eingebunden in Überlegungen zur Therapie der zugrunde liegenden Ursachen einer verzögerten Wundheilung sollte das Debridement den ersten Schritt in einer adäquaten Phasen-adaptierten Wundgrund-Konditionierung chronischer Wunden darstellen.
Article
Defekt. Während die Wundinfektion immer eine Komplikation darstellt, kann die Defektwunde ihre Ursache entweder in einer traumatischen oder postinfektiösen Genese haben oder aber nach ausgedehnten Resektionen wie z.B. onkologischen Eingriffen entstanden sein. Insofern ist die infizierte die eigentlich “komplizierte Wunde”, da sie alle vorausgegangenen therapeutischen Bemühungen zunichte macht und sogar zur vitalen Gefährdung für den betroffenen Patienten werden kann. Jede Wunde, gleich welcher Genese, ist unabhängig von ihrer Lokalisation, ihrer Größe und ihres zeitlichen Auftretens kontaminiert. Ob es zu einer Infektion kommt, hängt sowohl von der Menge, Art und Virulenz der Erreger ab, wie auch der Abwehrlage des Patienten und der lokalen Durchblutung. Für das Erkennen von Wundinfektionen sind die von Celsus beschriebenen klassischen Merkmale Rubor, Calor, Dolor, Tumor und Functio laesa immer noch gültig. Sie können in ihrer Ausprägung jedoch stark variieren. Die Häufigkeit von Wundinfektionen ist abhängig von der Art und dem Ort der Operation. Je nach Kontaminationsgrad des OP-Gebietes unterscheiden wir nach allgemein akzeptierten Richtlinien der Krankenhaushygiene folgende drei Kategorien: Operationen der Gruppe A: ASEPTISCH. (z.B. Gelenk- und Knochenoperationen, einschließlich Arthroskopie) Operationen der Gruppe B: KONTAMINIERT. (z.B. abdominal- und lungenchirurgische Operationen) Operationen der Gruppe C: SEPTISCH. (z.B. Abzesse, Fistel, Empyeme und Osteitiden)
Article
Wound healing can no longer be thought of as a generic term. Wounds heal by various processes such as coagulation, inflammation, matrix synthesis and deposition, angiogenesis, fibroplasia, epithelialization, contraction, and remodeling.27 The Wound Healing Society has stated that when wounds proceed through these processes in an orderly and timely manner and achieve sustained anatomic and functional integrity, they are considered acute wounds.19 When they either do not proceed in an orderly and timely fashion or do so without achieving sustained anatomic and functional integrity, they are considered chronic. Tarnuzzer and Schultz44 have suggested that repeated trauma, ischemia, and infection are leading causes of the pathobiology leading to wound chronicity.
Article
Engineering of fetal tissue has a high potential for the treatment of acute and chronic wounds of the skin in humans as these cells have high expansion capacity under simple culture conditions and one organ donation can produce Master Cell Banks which can fabricate over 900 million biological bandages (9 × 12 cm). In a Phase 1 clinical safety study, cases are presented for the treatment of therapy resistant leg ulcers. All eight patients, representing 13 ulcers, tolerated multiple treatments with fetal biological bandages showing no negative secondary effects and repair processes similar to that seen in 3rd degree burns. Differential gene profiling using Affymetrix gene chips (analyzing 12,500 genes) were accomplished on these banked fetal dermal skin cells compared to banked dermal skin cells of an aged donor in order to point to potential indicators of wound healing. Families of genes involved in cell adhesion and extracellular matrix, cell cycle, cellular signaling, development and immune response show significant differences in regulation between banked fetal and those from banked old skin cells: with approximately 47.0% of genes over-expressed in fetal fibroblasts. It is perhaps these differences which contribute to efficient tissue repair seen in the clinic with fetal cell therapy.
Article
SummaryThe capacity of vascular endothelial cells to modulate their phenotype in response to changes in environmental conditions is one of the most important characteristics of this cell type. Since different growth factors may play an important signalling role in this adaptive process we have investigated the effect of endothelial cell growth factor (ECGF) on morphological, physiological and molecular characteristics of cerebral endothelial cells (CECs). CECs grown in the presence of ECGF and its cofactor heparin exhibit an epithelial-like morphology (type I CECs). Upon removal of growth factors, CECs develop an elongated spindle-like shape (type II CECs) which is accompanied by the reorganization of actin filaments and the induction of α-actin expression. Since one of the most important functions of CECs is the creation of a selective diffusion barrier between the blood and the central nervous system (CNS), we have studied the expression of junction-related proteins in both cell types. We have found that removal of growth factors from endothelial cultures leads to the downregulation of cadherin and occludin protein levels. The loss of junctional proteins was accompanied by a significant increase in the migratory activity and an altered protease activity profile of the cells. TGF-β1 suppressed endothelial migration in all experiments. Our data provide evidence to suggest that particular endothelial functions are largely controlled by the presence of growth factors. The differences in adhesiveness and migration may play a role in important physiological and pathological processes of endothelial cells such as vasculogenesis or tumor progression.
Article
Wound healing is a complex interchange, orchestrated between cellular components that play their respective parts signaled by and mediated by different cellular instruments of healing. When healing is performed well, the final product is a thing of beauty. When healing is delayed, interrupted, or excessive, then unsightly scars of chronic painful wounds that are frustrating to the patient and physician occur.
Article
To characterise the magnitude and distribution of fibroblast growth factor-2 (FGF-2) following topical application in hypromellose gel and film formulations or a solution in an animal wound model, in order to assess the potential of this route for treatment of chronic wounds. Topical formulations of FGF-2 were applied to punch biopsy wounds, and FGF-2 levels within the wound measured. Each 12 mm diameter wound received 0.3 microg FGF-2 in solution, a 7% (w/w) hypromellose gel, a dried hypromellose film on Melolin-backing or a saline control. After 2, 5 or 8 h the wounds were horizontally dissected into four sections (surface granulation, subcutaneous fat, superficial muscle and deep muscle) which were then analysed for FGF-2 concentration using ELISA. Confocal microscopy was used to evaluate the distribution of FGF-2 within the wound. There were significant differences in the mean FGF-2 levels with respect to formulation and time following application (P < 0.05). FGF-2 penetrated faster into tissue when formulated as a solution than as a gel or a film. There did not appear to be a significant difference between the gel and the film with respect to total concentrations achieved in the tissue, although confocal microscopy showed differences in FGF-2 distribution within the wound. Delivery of FGF-2 to wounds in a solution gave the greatest increase in tissue FGF-2 concentration when measured by ELISA and visualised using confocal microscopy. Gel and film formulations prolonged the release of FGF-2 into the wound, although FGF-2 levels were not significantly different from controls when measured by ELISA. Confocal microscopy highlighted the differences in the penetration and distribution of the FGF-2 within the wound when released from different formulations.
Article
A review of the normal hemostatic mechanism is presented. The controversy surrounding the complicated nomenclature for the coagulation system is discussed as well as the complex chain reaction or multiplier effect involving the extrinsic and intrinsic systems. Attention is also given to the role of thrombin and the role of the liver in the clotting mechanisms.
Article
The use of the term "prophylactic antibiotics" is probably not appropriate because we are in fact treating contaminated wounds. Only broad spectrum antibiotics that can be expected to be effective against coagulase-positive Staphylococcus aureus should be selected for antibiotic therapy in open fractures. We have found cephalothin-cephalexin therapy to be effective in significantly reducing the infection rate. However, the final selection of antibiotic treatment should be determined by the previous experience of organisms isolated and sensitivity studies done from open fracture wounds in each institution. These organisms will vary from hospital to hospital.
Article
During the years 1985 to 1989, 82 patients were included in the soft tissue sarcoma protocol. Preoperative irradiation (50-54 Gy) was performed in all patients before tumor extirpation. Microwave hyperthermia was performed in conjunction with radiation in patients who had gross tumor remaining after initial biopsy. Primary closure with vascularized tissue (flaps) in lieu of conventional wound closure by skin approximation led to less complications (19% versus 51%), fewer secondary procedures for wound closure (10% versus 35%), shorter average hospitalization (15 versus 48 days) and greater limb salvage rate (97% versus 91%). The authors conclude that vascularized tissue (flaps) for primary wound closure in irradiated tissue leads to improved wound healing, and should be considered the procedure of choice for heavily irradiated soft tissue sarcoma defects.
Article
The advent of modern wound care management constitutes one of the most innovative applications of medical device technology. The foundation for wound care recent advances has been built upon the developments achieved in polymer technology over the last three decades. New and unique materials have been engineered to provide properties with significant technical and clinical benefits. These new wound care products were made possible by the convergence of three interrelated disciplines: (1) more complete understanding of the underlying principles of dermal wound healing processes, (2) new elastomeric polymers capable of being fabricated into protective dressings, and (3) advances in breathable adhesive technology. The following discussion provides a critical review of the current status of technology and the worldwide opportunities for improved wound management products. Particular attention is focused on the clinical applications of the newer, breathable dressing products, which approximate a temporary synthetic artificial skin.
Article
The primary goal in reconstructing a gunshot wound to the face is identical to that for a major injury of the hand or lower extremity: primary healing of the soft tissue. This prevents the cascade of soft-tissue infection, further delay in healing, bone graft infection, and soft-tissue contracture. Current craniofacial techniques and methods of fixation allow for concomitant bony reconstruction without compromising primary healing of the soft tissues. The result is not only that the soft tissue is healed but also that the original contour, stretch, and pliability are maintained. Once the soft tissue collapses around inadequate bony reconstruction, it is difficult to restore the original situation. Despite the techniques outlined, there is no substitute for sound surgical judgment. Inevitably, cases will arise when the ideal reconstruction cannot be performed because of other injuries, inappropriate initial management at referring institutions, or medical complications. Compromises are then required in the interest of the patient's overall care, with the knowledge that the best chance to restore the anatomy of the hard and soft tissue is in the first few days after the injury.
Angiogenesis, the formation of new blood vessels, plays a central role in a variety of physiological and pathological processes such as embryonic development, wound healing and tumor growth. It is a complex, multi-step process that involves the migration and proliferation of capillary endothelial cells. Several factors that stimulate the proliferation of endothelial cells in vitro have been shown to induce angiogenesis in vivo. Among these angiogenic growth factors are wide-spectrum multifunctional mitogens (e.g. the fibroblast growth factors) and the recently identified factors with distinct specificity for vascular endothelial cells (e.g. the platelet-derived endothelial cell growth factor). Another group of factors apparently induce angiogenesis indirectly (e.g. transforming growth factor-beta) by stimulating target cells to release angiogenic factors or by other mechanisms. The differential expression, release and activation of these factors might regulate angiogenesis under various physiological and pathological conditions.
Article
Angiogenesis, i.e. the generation of new blood capillaries, occurs in utero (during embryonal and fetal development) and in both physiological and pathological situations during extrauterine life. Several angiogenic factors have now been isolated, including angiogenin, acidic and basic fibroblast growth factors, and alpha and beta transforming growth factors. Their amino acid sequences have been determined and their genes cloned. Other factors await complete characterisation. An account is given of techniques used in the investigation of angiogenesis, both in vivo (transparent chambers; corneal micropockets; implantation on chick chorioallantoic membrane; employment of polymers for the sustained release of angiogenesis factors) and in vitro (cloning and long-term culture of capillary endothelial cells). The angiogenesis induced by solid tumours differs from other forms in that it is not self-limited and continues indefinitely until eradication of the tumour or death of the host. Anti-angiogenic factors have also been identified, particularly a new class of nonglucocorticoid steroids. Their employment in tumour therapy is a possibility, since neoplastic expansion is essentially dependent on angiogenesis.
Article
Sixty thousand to 118,000 lower extremity amputations are performed each year in the United States. The combination of peripheral vascular disease and diabetes mellitus accounts for most cases, with diabetic patients representing 45% to 70% of all nontraumatic, lower extremity amputations. The 3-year survival rate after amputation is only 50%. As podiatric physicians, we are directly involved in limb preservation. Progress has occurred in both the diagnosis and treatment of lower extremity, chronic, nonhealing ulcers. An aggressive, comprehensive amputation intervention program is critical to those patients with refractory wounds to prevent the emotional, functional, and economic costs of limb loss. Recent developments in recombinant growth factors are making it possible to decrease the morbidity and mortality associated with defective angiogenesis, fibroblastic proliferation, collagen remodeling, and epithelial regeneration. Widespread use of growth factors will first occur in topical applications. Absorbable sutures, as well as impregnated bandages, are a likely method of delivering the growth factors to the wound site. Biotechnology companies are developing a stable formulation for bFGF topical application. Clinical trials have begun at various teaching hospitals across the United States for treatment of venous stasis ulcers. U.S. and European firms are collaborating to conduct the clinical studies required to obtain regulatory approvals leading to the sale of topical recombinant bFGF. Although U.S. approval is pending, European use of EFG in the healing of corneal incisions began several years ago. In the future, use of recombinant EGF topically with burn patients may permit earlier reharvesting of healed donor sites as well as coverage of larger graft areas. As some growth factors affect specific processes of healing and cell types, it may be necessary to combine growth factors for complex wounds. PDGF application in combination with other growth factors to incisional wounds may decrease postoperative complications with wound dehiscence while mediating inflammation and repair. In vivo experimental findings suggest that combinations of PDGF and insulin applied topically to wounds may increase the rate of wound repair in diabetics. It is also possible that even the normal healing process may be accelerated, thereby shortening postsurgical convalescence. Approval for internal administration of growth factors will require additional research and thorough clinical trials. The ability of TGF-beta to promote collagen formation may also relate to a metabolic condition such as osteoporosis, in which inadequate formation of collagen or other components of the bone matrix may contribute to pathogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Soft-tissue infections are best prevented by proper initial management of the wound. When they do occur, they produce certain characteristic physical signs, the appearance of which mandates prompt operative intervention. The extent of debridement is determined by the intraoperative findings. Diagnostic categorization of the infection is performed postoperatively on the basis of the level of soft-tissue involvement and the results of bacterial cultures.
Article
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.
Article
Within the past 2 years, several angiogenic factors have been fully purified, their amino acid sequences determined, and their genes cloned. These polypeptides include acidic and basic fibroblast growth factor, angiogenin, and transforming growth factors alpha and beta. Other less well characterized angiogenesis factors have also been isolated, some of which are lipids. This article traces the discovery of the angiogenic factors and describes their possible significance in understanding growth regulation of the vascular system. When evaluated according to their putative targets, they appear to fall into two groups: those that act directly on vascular endothelial cells to stimulate locomotion or mitosis, and those that act indirectly by mobilizing host cells (for example, macrophages) to release endothelial growth factors. In addition to their presence in tumors undergoing neovascularization, the same angiogenic peptides are found in many normal tissues where neovascularization is not occurring. This suggests that physiological expression of angiogenic factors is tightly regulated. In addition to the persistent angiogenesis induced by tumors, it now appears that a variety of nonneoplastic diseases, previously thought to be unrelated, can be considered as "angiogenic diseases" because they are dominated by the pathologic growth of capillary blood vessels.