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The Wound Healing Process: An Overview of the Cellular and Molecular Mechanisms
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.
... By 2024, the global market for wound therapy is expected to reach a value of approximately USD 15-22 billion [9]. [10]. Acute wounds Acute wounds are defined as those that heal spontaneously, follow a prompt, organised healing pathway, and ultimately result in both functional and anatomical restoration. ...
... Acute wounds can arise from surgery or from trauma-related tissue loss. The healing process typically takes from 5 to 10 days or within 30 days [10,11]. These might be full-thickness skin damage where the subcutaneous layer is affected, or they can be superficial injuries affecting only the epidermis and superficial dermis. ...
... These elements include of exudation, necrosis, tissue hypoxia, infection, and elevated inflammatory cytokine levels. Numerous conditions, such as naturopathy, hypertension, burns, venous and arterial insufficiency, and vasculitis, can produce chronic wounds [10]. Chronic wounds can lead to major consequences and are more difficult to manage due to their unusual healing progress, poor healing period, and persistence. ...
The body's initial line of defence, the skin protects the inside organs from heat, chemical, and mechanical harm. It has a highly developed immune system that protects the body from harmful illnesses. The body's natural response to tissue damage is wound healing. But wound healing is a complicated process that involves a wide range of cell types, cytokines, mediators, and the vascular system interacting with one another. It is a complex, strictly controlled process that is essential to retaining all other skin functions in addition to the skin's barrier function. Numerous factors, both modifiable and non-modifiable, can impact this process. In order to successfully restore the damaged tissue, wound healing is a dynamic process supported by a variety of cellular processes, including as homeostasis, inflammation, proliferation, and remodelling. These activities must be properly integrated with one another. When there is damage to the skin, bacteria can swiftly infiltrate the tissues behind the skin, leading to life-threatening infections and chronic wounds. Natural phytomedicines with significant pharmacological qualities have been used extensively and successfully to treat wounds and prevent infections. Phytotherapy has been used for millennia to effectively cure skin wounds and delay the formation of infections. This study focuses on cutaneous wound healing and highlights the classical wound healing phases because wound healing occurs in many regions of the human body. Changes in any one of these stages may encourage the development of chronic wounds and hinder their healing. Numerous plants have been shown to aid in wound healing through a variety of processes.
... The healing process occurs through four stages: haemostasis, inflammation, proliferation, and remodelling. When just one of these stages does not progress as usual, it can lead to a chronic open wound [1][2][3][4] . In the inflammatory phase, mainly involving the activation of the innate immune system, neutrophils and monocytes rapidly migrate into damaged skin. ...
... In response, neutrophils are recruited from the circulation to the wound site in the early inflammatory stage, or they perform phagocytosis to remove pathogens and cellular debris. About 3 days after injury, monocytes are recruited to the injury site, where they differentiate into macrophages and promote healing [2][3] . Pathological figures such as diabetes mellitus, chronic conditions, and peripheral vascular diseases can lead to wounds. ...
... The cyclophosphamide-induced neutropenia test was performed in three phases. The first phase was done on day zero with a blood sample to count leukocytes and platelets that are known to be miles stone in the wound healing process [1,2] . The second phase of our assay consisted of counting of leukocytes 10 days post treatment. ...
... The healing process occurs through four stages: haemostasis, inflammation, proliferation, and remodelling. When just one of these stages does not progress as usual, it can lead to a chronic open wound [1][2][3][4] . In the inflammatory phase, mainly involving the activation of the innate immune system, neutrophils and monocytes rapidly migrate into damaged skin. ...
... In response, neutrophils are recruited from the circulation to the wound site in the early inflammatory stage, or they perform phagocytosis to remove pathogens and cellular debris. About 3 days after injury, monocytes are recruited to the injury site, where they differentiate into macrophages and promote healing [2][3] . Pathological figures such as diabetes mellitus, chronic conditions, and peripheral vascular diseases can lead to wounds. ...
... The cyclophosphamide-induced neutropenia test was performed in three phases. The first phase was done on day zero with a blood sample to count leukocytes and platelets that are known to be miles stone in the wound healing process [1,2] . The second phase of our assay consisted of counting of leukocytes 10 days post treatment. ...
... These cytokines include interleukins (IL) -IL-1, IL-6, IL-8growth factors TGF-α, TGF-β, PDGF, FGF, VEGF, heparin-binding epidermal growth factor (HB-EGF), chemokines. They stimulate cell migration, angiogenesis, collagen accumulation as well as epithelization [4,9,16,17]. Released cytokines (mainly TGF-β) react to vascular endothelial cells, which results in increased expression of adhesion molecules, e.g. ...
... Cytokines such as TGF-β, tumor necrosis factor α (TNF-α), and IL-1, released by the macrophages, regulate leukocyte protease activity [9,18]. About 72 hours after tissue damage (in the final course of the inflammation phase), the last cells participating in this healing phase, i.e. lymphocytes, flow into the wound [17,19]. They are attracted to IL-1, complement components, and immunoglobulin G (IgG) breakdown products; IL-1 affects the action of collagenase, which in later stages determines the remodeling of collagen, which is a component of the ECM. ...
... In this way, the damaged tissue is prepared to enter the next phase of the healing processthe proliferative phase. Its purpose is to close the wound and then create new tissue that will be resistant to infection [5,9,17]. ...
Gojenie się ran to proces dynamiczny, którego celem jest przywrócenie homeostazy oraz funkcjonalności uszkodzonej tkanki. To wysoce złożony, wieloetapowy proces, którego zaburzenie prowadzi do powikłań i problemów zdrowotnych osoby poszkodowanej. Omawiany proces przebiega w ustroju ludzkim dwiema drogami. Pierwszą z nich jest ziarninowanie, drugą rychłozrost. Niezależnie od sposobu gojenia się rany, poszczególne fazy tego procesu wzajemnie nachodzą na siebie, gdzie przed zakończeniem fazy poprzedniej rozpoczyna się następna. Rozgraniczenie poszczególnych faz ma charakter czysto praktyczny. Wyróżnia się cztery fazy gojenia: fazę hemostazy, fazę zapalenia, fazę proliferacyjną – inaczej fazę replikacji i syntezy – oraz fazę remodelingu. Proces gojenia się ran jest procesem naturalnie zachodzącym w organizmie, długotrwałym i złożonym, który zachodzi w przypadku zranienia. Nieprawidłowy przebieg gojenia może skutkować wystąpieniem ran przewlekłych, martwic czy nadmiernego bliznowacenia. Wspomaganiem tego naturalnie zachodzącego w organizmie procesu jest leczenie ran. W przypadkach wymagających takiego wsparcia stosuje się opatrunki, które są elementem niezbędnym, mającym zastosowanie w ochronie zdrowia. Idealny opatrunek powinien: tworzyć barierę przed czynnikami zewnętrznymi, utrzymywać odpowiednie środowisko w łożysku rany (odpowiednia temperatura, wysoka wilgotność, lekko kwaśne pH, umożliwienie wymiany gazowej), absorbować nadmiar krwi oraz wysięku, utrzymywać ranę w czystości – oczyszczać z tkanki martwiczej i toksyn – nie przywierać do rany, aby uniknąć jej uszkodzenia w trakcie wymiany opatrunku, nie wykazywać działania uczulającego, a także drażniącego.
... Various studies show the ever-increasing expense in healthcare due to wounds [1,2]. The natural wound healing mechanism of the skin is a structured and timely process that starts from the time of wounding and may persist for a period of time, which depends on the type of wound [3]. This orderly process might get disrupted due to various underlying comorbidities [4,5]. ...
... Any injury or disorder in the natural anatomy of the skin ranging from a break in the epithelial structure of the skin up to damage in deep subcutaneous tissues and organs is defined as a wound [6,7] (Fig. 1). In response to wounding, the body initiates a series of physiological mechanisms to isolate, disinfect, regrow, and heal the affected tissue within an expected course of time, known as wound healing [3]. Time frame is an important factor Associate Editor Joel Stitzel oversaw the review of this article. ...
... A timeline of 4 to 6 weeks is generally observed for the healing process [8]. Wounds that heal in an orderly manner within this expected timeline resulting in an anatomically balanced and functional tissue are known as Acute wounds [3,7]. While some wounds fail to heal either within the expected time frame or in the expected manner, such wounds are defined as chronic wounds [7,9]. ...
Electrical stimulation as a mode of external enhancement factor in wound healing has been explored widely. It has proven to have multidimensional effects in wound healing including antibacterial, galvanotaxis, growth factor secretion, proliferation , transdifferentiation, angiogenesis, etc. Despite such vast exploration, this modality has not yet been established as an accepted method for treatment. This article reviews and analyzes the approaches of using electrical stimulation to modulate wound healing and discusses the incoherence in approaches towards reporting the effect of stimulation on the healing process. The analysis starts by discussing various processes adapted in in vitro, in vivo, and clinical practices. Later it is focused on in vitro approaches directed to various stages of wound healing. Based on the analysis, a protocol is put forward for reporting in vitro works in such a way that the outcomes of the experiment are replicable and scalable in other setups. This work proposes a ground of unification for all the in vitro approaches in a more sensible manner, which can be further explored for translating in vitro approaches to complex tissue stimulation to establish electrical stimulation as a controlled clinical method for modulating wound healing.
... When the healing stages are disturbed in one of the healing phases, the wound becomes chronic and the healing rate is lower and lasts more than 12 weeks [14]. Normal wound healing is a dynamic and complex process that begins at the time of injury and involves all resident cells as well as migratory cell populations, the extracellular matrix, and the action of soluble mediators [15]. The optimal wound healing involves the following events: (1) rapid hemostasis; (2) appropriate inflammation; (3) mesenchymal cell differentiation, proliferation, and migration to the wound site; (4) suitable angiogenesis; (5) prompt reepithelialization (regrowth of epithelial tissue over the wound surface); and (6) proper synthesis, cross-linking, and alignment of collagen to provide strength to the healing tissue [16]. ...
... Pharmaceutics 2023,15, 2692 ...
Essential oils are valuable alternatives to synthetic antibiotics that have the potential to avoid the pathogen resistance side effects generated by leather. Helichrysum italicum and Lavandula latifolia essential oils combined with fish scale gelatin were electrospun using a coaxial technique to design new bioactive materials for skin wound dressings fabrication. Fish scale gelatins were extracted from carp fish scales using two variants of the same method, with and without ethylenediaminetetraacetic acid (EDTA). Both variants showed very good electrospinning properties when dissolved in acetic acid solvent. Fish scale gelatin nanofibers with Helichrysum italicum and Lavandula latifolia essential oil emulsions ensured low microbial load (under 100 CFU/g of total number of aerobic microorganisms and total number of yeasts and filamentous fungi) and the absence of Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 10536, and Candida albicans ATCC 1023 as compared to fish scale gelatin without essential oils, which recommends them for pharmaceutical or topical applications. A scratch-test performed on human dermal fibroblasts proved that the biomaterials contributing to the wound healing process included fish scale gelatin nanofibers without EDTA (0.5% and 1%), fish scale gelatin nanofibers without EDTA and Lavandula latifolia essential oil emulsion (1%), fish scale gelatin nanofibers with EDTA (0.6%), and fish scale gelatin nanofibers with EDTA with Helichrysum italicum essential oil emulsion (1% and 2%).
... Damage to the skin requires a long healing process of at least 5 to 10 days (Velnar et al, 2009). During the healing period, these wounds can cause new problems such as infection due to the growth of fungi, bacteria, and parasites. ...
... Cuts (Vulnus scissum), are wounds characterized by the surface of the wound edges in the form of straight and regular lines (Orsted et al, 2010). The process of wound healing in the human body can take place naturally but this process requires a long term, usually ranging from 5 to 10 days (Velnar et al, 2009 These secondary metabolites have antiinflammatory (Banno, et al, 2005), antibacterial and anti-allergic effects (Tan et al, 2017), which can reduce the time of inflammation in the wound, thereby accelerating wound healing. ...
Botto'-botto' plant (Chromolaena odorata L.) is a native Indonesian plant that belongs to the Asteraceae family and is known to have a high flavonoid content and antioxidant activity that can slow down the oxidation process to prevent infection while accelerating wound healing. botto'-botto' is designed as a patch to make it easier to use and provide the most effective treatment. The purpose of this study was to make a patch preparation and to investigate its effects on wound healing. The patch was formulated and then tested for physical properties (organoleptic, superficial pH, moisture loss, thickness, weight uniformity, and folding endurance test) and their activity against wounds experimentally using rabbits as an animal test with 4 (four) treatment groups, namely the control group, botto'-botto’ patch 10%, 20%, and 30%. Wounds were made with an area of 2 cm and 0.1 cm deep. The wound was plastered with a patch and observed for 18 days. Data were analyzed statistically using ANOVA. The results showed that the patch formulation of leaves extract botto'-botto’ affects for wound healing in rabbits significantly, with p<0.05. Furthermore, the patch formulation of ethanol extract botto’-botto’ with a concentration of 30% had the best and fastest healing effect among all formulas. KEYWORDS: Botto’-botto’, wound healing, transdermal patch
... The last step involves the collagen type III substitution by collagen type I and the reordered of both type of fibers to improve the mechanical proprieties. Injures remain as a clinical problem due early and late complications, otherwise the incidence of chronic wounds has rapidly increased due to the rising prevalence of type 2 diabetes, peripheral vascular disease, and metabolic syndrome [1][2][3] . ...
... Even though, fast and optimal wound closure are the main aims for wound care, no topically effective medication has been developed to accelerate the wound healing process and/or to prevent abnormal wound healing 4 . 2 Wound healing effects of phenolic compounds such as flavonoids, secoriridoids, phenolic acids, phenolic alcohols and lignans have been studied, due their antioxidant, antimicrobial, and/or biostimulatory properties related to tissue regeneration 5 . ...
Gold nanoparticles (AuNPs) have been used in a broad range of applications conferring to bio-molecules diverse proprieties such as deliver, stabilization and reduction of adverse effects of drugs or plant ex-tracts. Polyphenolic compounds from Bacopa procumbens (BP) are able to modulate proliferation, adhesion, migration and cell differentiation, reducing artificial scratch area in fibroblast cultures and promoting wound healing in in vivo model. Here, chemically synthetized AuNPs conjugated with BP (AuNP-BP) were characterized by Uv-Vis, ATR-FTIR, DLS and zeta-potential. Results showed over-lapping FTIR spectra of polyphenolic compounds from B. procumbens capping the AuNPs, stable size by the DLS and zeta potential, AuNP-BP was 44.58 nm, the zeta-potential of AuNPs was -36.3±12.3 mV after conjugation with the BP; - (AuNP-BP), the zeta-potential was reduced to -18-2±7.02 mV. Enhancement of wound healing effect were evaluated by morphometric, histochemical and FTIR changes in rat wound excision model. Results showed that the nanoconjugation process reduced 100 folds BP concentrations to have the same wound healing effect of BP alone. Besides histological and FTIR spec-troscopy analyses, demonstrated that AuNP-BP treatment displayed better macroscopical performance; the reduction on inflammatory cells, and the increased synthesis and better organization of collagen fibers.
... The skin is the largest organ of the human body, having multiple roles such as maintaining the hydration levels, regulating the temperature and protecting the body from external factors [1]. A disruption of the skin due to a wound can influence its structure and function, negatively affecting the human body [2]. Wound healing is a non-linear dynamic process, that takes place during four overlapping phases: coagulation/hemostasis, inflammation, proliferation and remodeling [2][3][4]. ...
... A disruption of the skin due to a wound can influence its structure and function, negatively affecting the human body [2]. Wound healing is a non-linear dynamic process, that takes place during four overlapping phases: coagulation/hemostasis, inflammation, proliferation and remodeling [2][3][4]. Enhancing the wound healing process has been a challenge for many years, with numerous treatments being developed, such as using stem cells, wound dressings, tape removal, electrical stimulation or exposure to laser [5][6][7]. ...
This study aims to investigate the effectiveness of low power red light (661 nm) in accelerating the wound healing process of an in vitro scratch assay model of keratinocytes. Furthermore, the study aims to clarify the role of light irradiation parameters, optimize them and gain additional insight into the mechanisms of wound closure as a result of photobiomodulation. Wound healing was studied using scratch assay model of NCTC 2544 keratinocytes. Cells were irradiated with a laser at various power densities and times. Images were acquired at 0, 24, 48 and 72 h following the laser treatment. Cellular proliferation was studied by MTT. ROS were studied at 0 and 24 h by fluorescence microscopy. Image analysis was used to determine the wound closure rates and quantify ROS. The energy range of 0.18–7.2 J/cm ² was not phototoxic, increased cell viability and promoted wound healing. Power and irradiation time proved to be more important than energy. The results indicated the existence of two thresholds in both power and irradiation time that need to be overcome to improve wound healing. An increase in ROS production was observed at 0 h only in the group with the lowest healing rate. This early response seemed to block proliferation and finally wound healing. Low level laser light at 661 nm enhanced both proliferation and migration in keratinocytes, providing evidence that it could possibly stimulate wound healing in vivo. The observed results are dependent on irradiance and irradiation time rather than energy dose in total.
... Trauma (such as burns or injuries), a subsequent disease condition (such as leg ulcers), or a mix of both can result in acute skin lesions [17]. These wounds heal on their own using a prompt and systematic healing process that returns the skin's structural and functional integrity [18]. In contrast to chronic wounds, which take months to fully recuperate, acute wounds take just a few weeks. ...
... Coagulation and haemostasis occur immediately after injury to prevent bleeding [18,19]. These mechanisms necessitate a series of interconnected procedures to secure blood vessels and establish matrixes for cell influx required in the latter stages of the healing process [20,21]. ...
... Large phagocytosis cells produce transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) in high concentration in the lesion for 2-3 days after injury. The above-mentioned growth factors control the inflammatory response, angiogenesis stimulation, and the formation of granulation tissue (Eming et al., 2007;Reinke & Sorg, 2012;Velnar et al., 2009). (c) Proliferation or granulation: The proliferative phase, which lasts 4 to 21 days, includes the production of extracellular matrix (ECM), epithelization, and angiogenesis. ...
... Within a few hours, epithelial cells begin to migrate from the wound margins following skin damage, forming a single layer of cells over the defect at first, followed by a significant increase in epithelial cell mitotic activity near the wound edges. When two migrating epithelial cells come into contact, migration stops, and basement membrane development begins (Beldon, 2010;Childs & Murthy, 2017;Singh et al., 2017;Velnar et al., 2009). (d) Remodeling or maturation: Remodeling or maturation is the final stage of the healing process, which begins 2 to 3 weeks after the lesion appears and can persist for up to a year. ...
Nanotechnological Aspects for Next-generation Wound Management provides detailed, up-to-date literature on nanotechnology's role in wound management and its applications using nanoparticles, nanocomposites, carbon-based nanostructures and nanomaterials. Scaffolds, three-dimensional approaches, skin tissue engineering, and polymer-based films are discussed to treat wounds. This one-of-a-kind reference is ideal for health practitioners, clinicians and researchers who will find the book to be excellent reference material for updates on recent trends in nanotechnology for wound management.
... Large phagocytosis cells produce transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) in high concentration in the lesion for 2-3 days after injury. The above-mentioned growth factors control the inflammatory response, angiogenesis stimulation, and the formation of granulation tissue (Eming et al., 2007;Reinke & Sorg, 2012;Velnar et al., 2009). (c) Proliferation or granulation: The proliferative phase, which lasts 4 to 21 days, includes the production of extracellular matrix (ECM), epithelization, and angiogenesis. ...
... Within a few hours, epithelial cells begin to migrate from the wound margins following skin damage, forming a single layer of cells over the defect at first, followed by a significant increase in epithelial cell mitotic activity near the wound edges. When two migrating epithelial cells come into contact, migration stops, and basement membrane development begins (Beldon, 2010;Childs & Murthy, 2017;Singh et al., 2017;Velnar et al., 2009). (d) Remodeling or maturation: Remodeling or maturation is the final stage of the healing process, which begins 2 to 3 weeks after the lesion appears and can persist for up to a year. ...
Every individual encounters wound at some point in their lives, whether they are acute or chronic. Recently, antibiotic resistance has become a big issue for humans, with acute wounds becoming chronic due to a lack of proper dressing, healing, and care. To deal with antibiotic resistance microbes, traditional wound healing and wound treatment are complex and insufficient. Several limitations can be overcome by utilizing carbon-based nanomaterials that are very selective and sensitive. Nanotechnology has recently developed highly biocompatible, low-toxic, carbon-based nanostructured materials for wound healing management, including carbon quantum dots, graphene quantum dots, fullerene, graphene oxide, and nanodiamonds. Different forms of carbon-based nanomaterials are thoroughly explored in this chapter. Their prospects are also a significant focus of this work.
... The occurrence of infection compromises the natural wound healing process, a sequence of events through which the skin recovers its anatomical and physiological integrity [2,3]. When it fails to achieve a persistent structural and functional restoration within a 5 to 10 days timeframe (although it can take as long as 30 days), the wound is termed chronic [1,4]. Chronic, non-healing wounds have a huge impact on the health and quality of life of patients and their families. ...
... Care was taken so that the time spent inside the autoclave after the end of the autoclaving cycle was always the same whenever samples were autoclaved. In a variation of this drug 4 loading/sterilization method, the discs remained in the PHMB solution for 24 h at 34 °C after autoclaving. ...
Wound infection is a common complication of chronic wounds. It can impair healing, which may not occur without external help. Antimicrobial dressings (AMDs) are a type of external help to infected chronic wounds. In this study, highly porous membranes made of only chitosan and containing the antiseptic polyhexanide (poly(hexamethylene biguanide); PHMB) were prepared by cryogelation, aiming to be used in AMDs. These membranes exhibited high water swelling capacity, fast water absorption and high water vapor transmission. The best drug loading method involved simultaneous loading by soaking in a PHMB solution and sterilization by autoclaving, resulting in sterilized, drug-loaded membranes. The drug release kinetics was comparable to that of a commercial PHMB-releasing AMD assayed under the same conditions. These membranes exhibited high antibacterial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, which are bacterial species commonly found in infected wounds, and blood clotting activity. The obtained results suggest that these membranes may be suitable for use in the development of AMDs.
... The wound healing process is a dynamic and complex process. During the inflammatory phase of wound healing CUR could regulate inflammation via regulating main signaling pathways and reducing concentration target molecules like TNF-and IL-1 and fibroblast recruiting, releasing protease and removing the rate of reactive oxygen species (ROS) as well [28]. In the proliferation stage, CUR also has a critical role in the differentiation of fibroblast and collagen synthesis, decreasing the level of the number of membrane matrix metallo-proteinases (MMPs) [29]. ...
Due to their outstanding structures and properties, three-dimensional (3D) hydrogels and nanoparticles have been widely studied and indicated a very high potential for medical, therapeutic, and diagnostic applications. However, hydrogels and nanoparticles systems have particular drawbacks that limit their widespread applications. In recent years, the incorporation of nanostructured systems into hydrogel has been developed as a novel way for the formation of new biomaterials with various functions to solve biomedical challenges. In this study, alginate-loaded Zinc- laponite—curcumin (Zn/La/Cur) nanocomposites were fabricated via ionic cross-linking. The prepared nanocomposite hydrogels were characterized via FTIR and FE-SEM. Moreover, energy dispersive x-ray spectroscopy (EDX) was used to study the elements of the Zn/La/Cur nanocomposite. The NIH3T3 fibroblast cell line was utilized for the MTT assay to determine the cell viability of the fabricated alginate-loaded Zn/La/Cur nanocomposites. MTT results demonstrated that there was no evidence of toxicity in the samples. These outcomes suggest that applying Al/Zn/La/Cur nanocomposite as a biological agent could be a novel tissue engineering strategy for treating soft tissue disorders.
Graphical Abstract
... In wound healing, the inflammatory phase dominates the first 3 days after surgery, followed by the proliferative phase, which starts about 3 days after surgery and continues for 2-4 weeks, whereafter the remodeling phase takes over. 18 This finding in our study is similar to that found in a study about the postoperative appearance of enterectomy, where the maximal wall thickness occurred between day 3 and 6, postoperatively. 6 A resolution of free fluid and pneumoperitoneum was seen over a 4−15-day period. ...
Pyometra is a prevalent disease in intact bitches and the standard treatment is ovariohysterectomy (OHE). Published descriptions of normal sonographic findings after OHE are currently lacking. The aims of this prospective observational study were to describe and compare postoperative abdominal sonographic features for three timepoints following OHE in a group of dogs with pyometra and an uneventful recovery. A total of 22 dogs had sequential focused abdominal ultrasound examinations on days 1, 4–6, and 10–15 postsurgery. Recorded sonographic features for each examination time point and characteristics of the cervical stump and the mesovarium, size, and echogenicity of medial iliac lymph nodes (MILNs), presence of free peritoneal fluid, and pneumoperitoneum. The cervical stump appeared as a heterogenous area with a hypoechoic center surrounded by hyperechogenic tissue in all dogs. The cervical stump transverse‐sectional area was larger on day 4–6 compared with day 1 and day 10–15 ( P = .0009). Mesovarium ligature reactions were identified as heterogeneous and hyperechoic areas with central and/or edge shadowing in all dogs. The size and echogenicity of MILNs and the mesovarium reactions did not significantly differ among time points. Free peritoneal fluid was detected in 45%, 41%, and 9% and pneumoperitoneum in 95%, 82%, and 14% of dogs at sequential time points. Findings from this sample of dogs with an uneventful recovery following OHE due to pyometra can be used to assist veterinarians in interpreting postoperative abdominal ultrasonographic characteristics in future dogs treated surgically for pyometra.
... These fibroblasts migrate into the wound, stimulated by factors such as TGF-β and PDGF released by inflammatory cells and platelets. Fibroblasts then synthesize the extracellular matrix (ECM), which serves as a medium for cell migration (Velnar et al., 2009). In addition to fibroblasts, neutrophil cells and macrophages also produce PDGF, TGF-β, FGF, and VEGF, which function as the central cytokines capable of stimulating the formation of granulation tissue prior to the work of fibroblast cells. ...
High levels of free radicals in diabetic wounds often cause chronic inflammation. Nigella sativa and Trigonella foenum-graecum seed extracts are rich in antioxidants and have anti-inflammatory effects. Trigonella foenum-graecum seed extracts can also accelerate the reepithelialization process in wound healing. This study aimed to determine the combination of ethanol extract of Nigella sativa and Trigonella foenum-graecum seeds on wound length and the number of neutrophils, macrophages, fibroblasts, and collagen density in the incision wound of diabetic mice induced by streptozotocin. T. This study used three types of controls, namely Normal (Normal mice, HPMC 3%), DM (Diabetic mice, HPMC 3%), and Iodine (Diabetic mice, Povidone Iodine 10%). Topical treatment with 70% ethanol extract ointment combined with Nigella sativa and Trigonella foenum-graecum in various variations, namely N (20%:0%), T (0%:10%), NT (10%:5%), Observations of the wound healing process were carried out on 3rd, 7th and 14th day. Data were analyzed using the One Way ANOVA and Duncan Multiple Range Test. The study's results by observing the morphology of the wound length on day 7th day showed that the combination treatment of extracts of Nigella sativa and Trigonella foenum-graecum resulted in the shortest wound, which was significantly different from the wound in untreated diabetic mice. In addition, diabetic wounds without treatment showed infection, and on the contrary, the infection did not occur in wounds treated with a combination of extracts of Nigella sativa and Trigonella foenum-graecum. The results of wound histology observations showed that the combination treatment of extracts of Nigella sativa and Trigonella foenum-graecum showed a decrease in inflammation which was indicated by a significant decrease in the number of neutrophil cells, macrophages, and accelerated reepithelialization of wound healing as indicated by a significant increase in the number of fibroblasts and collagen density since the third day of treatment.
... Inflammation is a body's preventive response that produces redness, heat, edema, pain, and loss of function as a result of infectious, chemical, and physical agents. 1 Hemostasis, inflammation, proliferation, and remodeling or maturation are four distinct and highly planned processes by which tissues in the body can heal, either through regeneration or repair mechanisms. 2 Serious inflammatory conditions that can worsen if inflammation is left untreated include reperfusion injury, hypersensitivities, rhinitis, atherosclerosis, rheumatoid arthritis, asthma, autoimmune disease, chronic inflammation, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, and glomerulonephritis. They are considered the major clinical, social, and economic problems in most communities around the world. ...
Background
Even though it is a protective reaction, inflammation continues to be one of the most challenging medical disorders. The current conventional anti-inflammatory drugs have many undesirable health effects and are in need of newer drugs. The purpose of this study was to evaluate the anti-inflammatory effects of an aqueous methanol crude extract of Premna schimperi leaves.
Methods
Premna schimperi leaf was extracted with 80% methanol and concentrated; the concentrated extract was used to evaluate the acute toxicity and anti-inflammatory effects. For the acute toxicity study, a single dose of Premna schimperi extract at a dose of 2000 mg/kg was administered and observed for 14 days. Acute, sub-acute, and chronic anti-inflammatory models were employed to evaluate the anti-inflammatory effect of the extract compared to the standard drug. Data were analyzed with SPSS V. 27, and the significance was established with a one-way ANOVA followed by a post hoc Tukey’s test.
Results
Acute oral toxicity testing at a dose of 2000 mg/kg did not show any sign of toxicity. According to the phytochemical study, the plants contained flavonoids, terpenoids, tannins, cardiac glycosides, steroids, phenolics, and anthraquinones. The extract doses of 200 mg/kg, 400 mg/kg, and 800 mg/kg of extracts effectively (p<0.001) reduced paw edema in the acute and sub-acute models of inflammation. When compared to the negative control group, all tested doses in the chronic model significantly (p<0.05) decreased the production of exudates and the amount of granuloma tissue.
Conclusion
Premna schimperi displayed significant anti-inflammatory activity. The tested doses inhibit the formation of edema, granulomas, and exudates.
... The occurrence of infection compromises the natural wound healing process, a sequence of events through which the skin recovers its anatomical and physiological integrity [2,3]. When it fails to achieve a persistent structural and functional restoration within a 5 to 10 days timeframe (although it can take as long as 30 days), the wound is termed chronic [1,4]. Chronic, non-healing wounds have a huge impact on the health and quality of life of patients and their families. ...
Wound infection is a common complication of chronic wounds. It can impair healing, which may not occur without external help. Antimicrobial dressings (AMDs) are a type of external help to infected chronic wounds. In this study, highly porous membranes made of only chitosan and containing the antiseptic polyhexanide (poly(hexamethylene biguanide); PHMB) were prepared by cryogelation, aiming to be used in AMDs. These membranes exhibited a water swelling capacity of 748%, a water drop penetration time of 11 s in a dry membrane and a water vapor transmission rate of 34,400 g H2O/m2/24 h when in contact with water. The best drug loading method involved simultaneous loading by soaking in a PHMB solution and sterilization by autoclaving, resulting in sterilized, drug-loaded membranes. When these membranes and a commercial PHMB-releasing AMD were assayed under the same conditions, albeit far from the in vivo conditions, their drug release kinetics were comparable, releasing PHMB for ca. 6 and 4 h, respectively. These membranes exhibited high antibacterial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, which are bacterial species commonly found in infected wounds and blood clotting activity. The obtained results suggest that these membranes may have potential for use in the development of AMDs.
... Fifty percent of ridge width will be loss. [4,13] Excessive amounts of bone loss will complicate prosthodontic treatment with the result that clinicians must invest considerable effort in preserving the alveolar bone. Socket preservation can be undertaken using bone graft to maintain bone dimension and avoid future invasive bone augmentation. ...
Aim : This study was undertaken to comprehend the effect of a combination of bovine bone graft (BBG) and propolis extract on the receptor activator of nuclear κB ligand (RANKL) and osteoprotegerin (OPG) expressions in post-extraction tooth sockets.
Materials and methods : Fifty-six male Cavia Cobayas were divided into eight groups each containing seven subjects. The lower left incisor of each subject was removed prior to four different materials - polyethylene glycol (PEG), propolis extract+PEG, BBG+PEG, and propolis extract+BBG+PEG (combination) being applied to the post-extraction sockets. The laboratory animals were sacrificed at three and seven days. An immunohistochemical examination was subsequently performed to observe the expression of RANKL and OPG using a light microscope at 1000× magnification.
Results : The mean expression of RANKL on the third and seventh days was the lowest in the combination group, while the mean OPG expression on those days was the highest in the combination group. The one-way ANOVA tests conducted on each group produced a p value <0.05 indicating that significant differences existed between certain groups. A Pearson’s correlation test conducted on both observation day groups highlighted the opposite correlation of RANKL and OPG.
Conclusions : A combination of propolis extract and BBG effectively upregulates OPG expression and downregulates RANKL expression in the preserved post-extraction socket.
... Villagomez et al. [11] conducted a similar experimental study in rats that compared cyanoacrylate and traditional poliglecaprone sutures in surgical wound closure, and found no significant difference between the two groups, indicating that both methods may be effective for treating surgical wounds. The process of healing involves several steps, including haemostasis, inflammation, proliferation, and remodelling [12] . Sutures or adhesives are used to accurately approximate incisional wound margins in order to reduce strain and facilitate healing [13] . ...
Background
The skin closure procedure should be technically simple, acceptable, quick, and cost-effective. Sutures remain the technique’s mainstay, however tissue adhesive is becoming more used in clinical practice. Collagen ratios of types I and III play a significant role as postoperative wound healing parameters. Here, the authors aim to examine the collagen I/III ratio of tissue adhesive vs. non-absorbable sutures for abdominal skin closure in Wistar albino rats.
Material and methods
The authors allocated 20 rats into four experimental groups. Wounds in groups 1 and 3 were sealed with tissue adhesive (cyanoacrylate), while those in groups 2 and 4 were closed using suture material (monofilament non-absorbable nylon). Groups 1 and 2 were sacrificed on postoperative day (POD) 4, while those in groups 3 and 4 were euthanized on POD 7. Skin samples (1×0.5 cm) were collected for analysis, and the collagen I/III ratios were determined using immunohistochemistry staining techniques.
Results
The levels of collagen I and III expression did not exhibit statistically significant differences between tissue adhesive and nylon suture groups at either POD 4 ( P =0.052, P =0.513) or POD 7 ( P =0.125, P =0.80). Similarly, the collagen I/III ratio did not significantly differ between the two groups at POD 4 (1.23±2.26 vs. 0.70±0.24; P =0.47) or POD 7 (0.68±0.96 vs. 0.77±1.22; P =0.857).
Conclusions
There were no statistical significance difference in collagen I/III ratio between the tissue adhesive and suture material groups, suggesting that the choice of wound closure material may not influence the abdominal skin closure.
... However, there are no drugs that meet all the necessary criteria for the ideal treatment of chronic injuries 11,12 . Therefore, popular medicinal culture has been used as source of plant derived medicines 13 . ...
Purpose
The angiogenic, osteogenic and anti-inflammatory activity of latex of Hancornia speciosa has been evidenced and indicates pharmacological potential with great applicability in the health area, especially in the wound healing process. The present work aimed to compare the effects of the H. speciosa macroporous latex biomembrane with saline on wound healing.
Methods
Forty-three Wistar rats were submitted to excisional wound induction procedure and divided into groups according to treatment: saline (G1), and macroporous biomembrane (G2). The animals were euthanized at three, seven, 14, and 21 days after injury induction (DAI), and three animals were used for the debridement test. Morphometric, macroscopic, and microscopic analyses of general pathological processes were performed.
Results
The macroporous biomembrane minimized necrosis and inflammation during the inflammatory and proliferative phases of the healing process, confirmed by the lower intensity of the crust and the debridement effect. In addition, the wounds treated with the macroporous biomembrane presented greater contraction rates in all the experimental periods analyzed.
Conclusions
The macroporous biomembrane presents angiogenic, anti-inflammatory and debridement effects, contributing to the healing process, and can be considered a potentially promising new biomaterial to be used as a dressing.
Key words
Biocompatible Materials; Wound Healing; Anti-Inflammatory Agents; Debridement
... The normal continuous wound healing process can be divided into four phases: (i) coagulation and haemostasis, (ii) inflammation, (iii) proliferation, and (iv) wound remodeling with scar tissue formation [6]. The periodontal wound healing follows the general principles of wound healing, but possesses the own characteristics. ...
Purpose
Reconstructive periodontal surgery, which has received more and more interest in modern periodontology, can help save severely compromised teeth and solve aesthetic problems caused by the destruction of periodontal tissues in periodontal diseases. Unfortunately, there is few literatures reviewing the use of suspensory suture techniques in reconstructive periodontal surgeries.
Methods
An electronic search of the PubMed and Web of Science was performed. Full-text articles were obtained from the records after screening in the title and abstracts.
Results
Effective suture is of central importance to a successful treatment outcome of periodontal surgeries, especially incremental soft or hard tissue surgeries. Limitations in suture techniques may negatively affect the intimate contact of the affected tissues, wound closure and stabilization, and successful wound healing. Suitable anchors can be selected to help achieve this objective. Suspensory sutures may be more precise suture techniques, due to the use of relatively immobile anchors.
Conclusion
This review aims to provide key points of successful wound healing and summarize the current state of the suspensory suture techniques for reconstructive periodontal surgeries in daily practice, including their treatment application, detailed steps, advantages, and disadvantages.
... Mammals are capable of scar-free injury repair in the embryonic stage; however, after birth, they display increasingly limited capacity to regenerate injured tissues 1 . The characteristic stages of wound healing in adult mammals -(1) hemostasis, (2) inflammation, (3) proliferation, and (4) wound remodeling 2 -result in tissues that may be functional but do not completely recapitulate the gross morphology and microscopic patterning of the unwounded tissue. In contrast, tetrapods, such as axolotls (Ambystoma mexicanum), are able to regenerate entire complex-tissue limb structures throughout their life-spans 3,4 . ...
Adult mammals are generally believed to have limited ability to regenerate complex tissues and instead, repair wounds by forming scars. In humans and across mammalian species, the tympanic membrane (TM) rapidly repairs perforations without intervention. Using mouse models, we demonstrate that the TM repairs itself through a process that bears many hallmarks of epimorphic regeneration rather than typical wound healing. Following injury, the TM forms a wound epidermis characterized by EGFR ligand expression and signaling. After the expansion of the wound epidermis that emerges from known stem cell regions of the TM, a multi-lineage blastema-like cellular mass is recruited. After two weeks, the tissue architecture of the TM is largely restored, but with disorganized collagen. In the months that follow, the organized and patterned collagen framework of the TM is restored resulting in scar-free repair. Finally, we demonstrate that deletion of Egfr in the epidermis results in failure to expand the wound epidermis, recruit the blastema-like cells, and regenerate normal TM structure. This work establishes the TM as a model of mammalian complex tissue regeneration.
... Thus, following inflammation, cell migration is the central step that enables tissue repair. In this sense, understanding the processes and mechanisms involved in cell migration of fibroblasts, as the most abundant cell type of connective tissue, as well as their interactions with the extracellular matrix, are crucial aspects to understand how homeostasis of damaged tissue is achieved [3]. All these considerations underline the need to deepen the knowledge of the movement of these cells in fish in order to search for new strategies to improve wound healing in these animals. ...
... type I collagen) to regenerate the skin structure and initiate the process of wound healing. Several factors are involved in the wound healing process such as epithelial cells, cytokines including antimicrobial peptides 4,26 . Recent studies have demonstrated that antimicrobial peptides not only eliminate microorganisms but also stimulate different cell types 4 . ...
Human neutrophil peptides (HNPs) can induce cell proliferation and activation so their growth promoting activities may have potential clinical benefit. This study investigated the effects of HNPs on human dermal fibroblasts. Differential gene expression in HNP-treated cells and genes involved in regulating intracellular pathways were explored. Dermal fibroblasts were isolated from healthy neonatal foreskin and treated with HNPs in 2D and 3D cell culture systems. The expression of cell proliferation ( Ki-67 ) gene and cell activation ( COL1A1 ) gene plus their proteins was measured. Differential gene expression was determined using RNA-seq, and upregulated and downregulated genes were mapped onto intracellular pathways by KEGG analysis and Gene Ontology databases. HNPs significantly increased cell proliferation without cytotoxicity whilst HNP1 enhanced expression of COL1A1 and type I collagen production in 2D cells and 3D spheroids. RNA-sequencing analysis showed gene clustering with clear separation between HNP1-treated and control groups. A heatmap of top 50 differentially expressed genes was consistent among HNP1-treated samples. Most upregulated genes were associated with cell proliferation and activation as mapped into intracellular pathways whilst most downregulated genes belonged to steroid/arachidonic acid metabolism and inflammatory signaling pathways. HNP1 increased cell proliferation and activation but reduced lipid metabolism and inflammation.
... After four to five weeks of active net collagen formation, type III collagen is replaced by type I collagen during the course of the next year [14]. According to Velnar et al. [15], matrix metalloproteinases, or zincdependent endopeptidases, which are released by epidermal cells, are crucial for tissue remodeling. Hemostasis, inflammation, proliferation, and remodeling are all crucial for the wound healing process to be successful [16]. ...
Background
Usually, wounds recover in four to six weeks. Wounds that take longer time than this to heal are referred to as chronic wounds. Impaired healing can be caused by several circumstances like hypoxia, microbial colonization, deficiency of blood flow, reperfusion damage, abnormal cellular reaction and deficiencies in collagen production. Treatment of wounds can be enhanced through systemic injection of the antibacterial drugs and/or other topical applications of medications. However, there are a number of disadvantages to these techniques, including the limited or insufficient medication penetration into the underlying skin tissue and the development of bacterial resistance with repeated antibiotic treatment. One of the more recent treatment options may involve using nanotherapeutics in combination with naturally occurring biological components, such as snail extracts (SE). In this investigation, chitosan nanoparticles (CS NPs) were loaded with an Eobania vermiculata whole-body muscle extract. The safety of the synthesized NPs was investigated in vitro to determine if these NPs might be utilized to treat full-skin induced wounds in vivo.
Results
SEM and TEM images showed uniformly distributed, spherical, smooth prepared CS NPs and snail extract-loaded chitosan nanoparticles (SE-CS NPs) with size ranges of 76–81 and 91–95 nm, respectively. The zeta potential of the synthesized SE-CS NPs was − 24.5 mV, while that of the CS NPs was 25 mV. SE-CS NPs showed a remarkable, in vitro, antioxidant, anti-inflammatory and antimicrobial activities. Successfully, SE-CS NPs (50 mg/kg) reduced the oxidative stress marker (malondialdehyde), reduced inflammation, increased the levels of the antioxidant enzymes (superoxide dismutase and glutathione), and assisted the healing of induced wounds. SE-CS NPs (50 mg/kg) can be recommended to treat induced wounds safely. SE was composed of a collection of several wound healing bioactive components [fatty acids, amino acids, minerals and vitamins) that were loaded on CS NPs.
Conclusions
The nanostructure enabled bioactive SE components to pass through cell membranes and exhibit their antioxidant and anti-inflammatory actions, accelerating the healing process of wounds. Finally, it is advised to treat rats’ wounds with SE-CS NPs.
Graphical abstract
... Numerous cytokines and growth factors, including as insulin-like, platelet-derived, transforming, and epidermal growth factors, are found in abundance in platelets. The wound healing cascade [9] begins with the activation and attraction of neutrophils, which in turn attracts macrophages, endothelial cells, and fibroblasts as repair agents. Following the coagulation phase comes the inflammatory phase, which begins with the early inflammatory reaction and lasts until the early postcoagulation phase. ...
The skin protects the internal organs from mechanical, chemical, and thermal injury and is thus the body's first line of defence. It has an advanced immune response that protects the body from harmful microbes. Healing a wound is a dynamic process supported by a plethora of cellular processes such as homoeostasis, inflammation, proliferation, and remodelling, all of which must work in tandem to restore the health of the injured tissue. Following cutaneous injury, germs may rapidly invade subcutaneous tissues, leading to painful chronic sores and even death. Wound therapy and infection prevention have both benefited greatly from the use of natural phytomedicines, which have been used extensively due to their potent pharmacological effects. Phytotherapy has been used effectively to heal cutaneous wounds, delay the emergence of infections, and limit the use of antibiotics that contribute to dangerously widespread antibiotic resistance since ancient times. Achiella millefolium, Aloe vera, Althaea officinalis, Calendula officinalis, Matricaria chamomilla, Curcuma longa, Eucalyptus, Jojoba, plantain, pine, green tea, pomegranate, and Inula are only a few of the many commonly used botanicals in the Northern Hemisphere for wound healing. This article discusses the most popular medicinal plants of the Northern Hemisphere used for wound healing, and it also offers suggestions for effective natural alternatives.
... Immediately after burn injury, pro-inflammatory neutrophils and macrophages accumulate at the wound site (5)(6)(7). These phagocytic cells play a critical role in eliminating cell debris and pathogens from the injured area (8). ...
Introduction
Thermal injury often leads to prolonged and excessive inflammation, which hinders the recovery of patients. There is a notable absence of suitable animal-free models for investigating the inflammatory processes following burn injuries, thereby impeding the development of more effective therapies to improve burn wound healing in patients.
Methods
In this study, we established a human full skin equivalent (FSE) burn wound model and incorporated human peripheral blood-derived monocytes and T cells.
Results
Upon infiltration into the FSEs, the monocytes differentiated into macrophages within a span of 7 days. Burn-injured FSEs exhibited macrophages with increased expression of HLA-DR ⁺ and elevated production of IL-8 (CXCL8), in comparison to uninjured FSEs. Among the T cells that actively migrated into the FSEs, the majority were CD4 ⁺ and CD25 ⁺ . These T cells demonstrated augmented expression of markers associated with regulatory T cell, Th1, or Th17 activity, which coincided with significant heightened cytokine production, including IFN-γ, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IP-10 (CXCL10), and TGF-β1. Burn injury did not impact the studied effector T cell subsets or cytokine levels.
Discussion
Collectively, this study represents a significant advancement in the development of an immunocompetent human skin model, specifically tailored for investigating burn-induced innate or adaptive immune reactions at the site of burn injury.
... Thus, the surrounding ECM becomes stiffer, and the prestressed matrix transforms fibroblasts into pro-to-myofibroblasts containing actin stress fibers. Prestressed matrices require stronger traction forces to ensure wound closure (30)(31)(32)(33). ...
Primary fibroblast cultures obtained from Wistar rats were investigated with a focus on two vital physiological mechanisms: inflammatory processes and oxidative stress balance. These are believed to be affected by mud and sulfurous natural mineral waters, forming the fundamental biological basis for understanding the therapeutic effects of these substances. Existing scientific research highlights that various cell types, including fibroblasts, are recruited during inflammation. These cells respond to a wide array of intercellular and microenvironmental signals, leading to a regulated production of both pro- and anti-inflammatory mediators. Examples include cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, as well as chemokines and enzymes like cyclooxygenase (COX)-2. Together, these play vital roles in modulating the inflammatory response.
... Early wound healing significantly impacts the course and outcomes of future skin regeneration and the likelihood of pathologic scarring [33]. According to a recent study, the first phases of repair are when the benefits of PDT are most felt [34]. ...
Microbial skin infections, antibiotic resistance, and poor wound healing are major problems, and new treatments are needed. Our study targeted solving this problem with Nigella sativa (NS) oil and photodynamic therapy based on methylene blue (MB-PDT). Antibacterial activity and minimum inhibitory concentration (MIC) were determined via agar well diffusion assay and broth microdilution, respectively. Transmission electron microscopy (TEM) proved deformations in Staphylococcus aureus ATCC 6538. Gas chromatography–mass spectrometry identified useful compounds that were suggested to be responsible for the potency of the oil. NS oil was tested as an antivirus against low pathogenic coronavirus (229E). Therapies examined, MB-PDT, NS, and MB-PDT + NS oil, to accelerate wound healing. The antibacterial efficacy against S. aureus was promising, with a MIC of 12.5% and TEM showing injured cells treated with NS oil. This oil inhibited 229E virus up to 42.85% and 32.14%. All tested therapies were successful in accelerating wound healing. The most successful was combined therapy (MB-PDT + NS oil), with a faster healing time. The combined therapy (MB-PDT + NS oil) reduced bacterial counts, which may be a key factor in accelerating wound healing. Skin wound histology was investigated; blood hematology and biochemical analysis did not change significantly after the safe combination treatment. A combination treatment could facilitate healing in a simple and inexpensive way in the future. Based on the results of the in vitro and in vivo studies, it was determined that NS oil had antibacterial and anti-corona virus activity when used in conjunction with photodynamic treatment based on methylene blue to treat wound infections.
... The wound healing process is highly intricate, requiring the coordination of multiple cell types and stages, including hemostasis, inflammation, proliferation, and remodeling [1]. Wound healing is a dynamic and ongoing process that necessitates the collaboration of various cell populations, extracellular matrix, and mediators such as growth factors [2]. Effective wound healing is crucial for minimizing infection risk, promoting tissue regeneration, and preventing complications like scarring. ...
Hydrogels have gained significant attention as wound dressings due to their potential for rapid healing. Researchers have actively explored a range of techniques for antimicrobial applications, including incorporating drug payloads, utilizing inorganic nanometals, and harnessing the properties of natural cationic polymers. In terms of hemostasis and coagulation promotion, techniques such as drug delivery, adhesive physical hemostasis, and adhesive functional groups have been studied. To control inflammation, researchers have investigated the application of natural antioxidants and antioxidant functional groups, which have demonstrated anti-inflammatory effects. Furthermore, the smart responsiveness of hydrogel wound dressings to pH, temperature, and light has been explored. This review presents a summary of the research progress and application prospects in these areas and offers an outlook on the future development direction of hydrogel wound dressings.
Diabetes is one of the most significant causes of death all over the world. This illness, due to abnormal blood glucose levels, leads to impaired wound healing and, as a result, foot ulcers. These ulcers cannot heal quickly in diabetic patients and may finally result in amputation. In recent years, different research has been conducted to heal diabetic foot ulcers: one of them is using cold atmospheric pressure plasma. Nowadays, cold atmospheric pressure plasma is highly regarded in medicine because of its positive effects and lack of side effects. These conditions have caused plasma to be considered a promising technology in medicine and especially diabetic wound healing because studies show that it can heal chronic wounds that are resistant to standard treatments. The positive effects of plasma are due to different reactive species, UV radiation, and electromagnetic fields. This work reviews ongoing cold atmospheric pressure plasma improvements in diabetic wound healing. It shows that plasma can be a promising tool in treating chronic wounds, including ones resulting from diabetes.
Background and Objectives The use of stem cells for skin wound healing is still facing serious challenges. This study aims to determine the effectiveness of human adipose tissue-derived stem cells (ADSCs) spray in histologically improving skin wounds in male diabetic rats. Subjects and Methods In this experimental study, mesenchymal stem cells were isolated from adipose tissue and cultured and characterized by evaluating the expression of specific CD markers. Microbial contamination in samples was assessed before treatment. Then, 18 male Wistar rats were divided into control and treatment groups. Diabetes was induced by a single injection of streptozotocin. Then, wounds with a diameter of 0.8 cm were created in the back of the rats. The ADSCs were sprayed on the wound area in the treatment group. Wound healing was assessed on days 7, 14, and 21 after treatment using visual observation and histopathological examination. The data were analyzed using ANOVA. Results Wound closure was accelerated on days 7, 14 and 21 in the treatment group compared to the control group. Histological examination showed that the skin thickness, angiogenesis, and epithelialization were higher in the treatment group on days 7, 14, and 21 compared to the control group. Conclusion The spray of ADSCs on the wound area can accelerate the healing process and can be used for skin wound repair.
The study's objective is to clarify the probable mechanisms underlying the wound‐healing properties of Helianthemum canum L. (Cistaceae), a traditional anti‐inflammatory and wound‐healing medicine. LC/MS‐MS was used to perform phytochemical analyses on a 70% methanol extract of the plant's aerial parts. In vivo linear incision and circular excision models were used to evaluate the wound healing activity. For anti‐inflammatory effect, in vivo acetic acid capillary permeability assay and in vitro Interleukin 1, Interleukin 6, and Interferon Ɣ levels in LPS‐induced FR skin fibroblast cell line were also evaluated. The extract significantly improved wound healing in experimental models, with tensile strength values of 27.8% and a contraction value of 35.09%. Histopathological examinations, hydroxyproline estimation, hyaluronidase, collagenase, and elastase enzyme inhibitory assays confirmed wound healing potential. Inflammatory cytokines were significantly inhibited in the LPS‐induced FR cell line, with the highest effect seen on IL‐6 (34.5±2.12 pg/mL). This study offered the first concrete proof that H. canum can be used to treat wounds by suggesting that the myricetin and quinic acid content identified by LCMS‐MS analysis may be accountable for the effect of H. canum on wound contraction and hydroxyproline production.
The prolonged hypoxic conditions hinder chronic wounds from healing and lead to severe conditions such as delayed re‐epithelialization and enhanced risk of infection. Multifunctional wound dressings are highly required to address the challenges of chronic wounds. Herein, we report polyurethane‐coated sodium per carbonate‐loaded chitosan hydrogel (CSPUO2) as a multifunctional dressing. The hydrogels (Control, CSPU, and CSPUO2) were prepared by freeze gelation method and the developed hydrogels showed high porosity, good absorption capacity, and adequate biodegradability. The release of oxygen from the CSPUO2 hydrogel was confirmed by the increase in pH and a sustained oxygen release was observed over the period of 21 days, due to polyurethane (CSPU) coating. The CSPUO2 hydrogel exhibited around 2‐fold increased angiogenic potential in CAM assay when compared with Control and CSPU dressing. CSPUO2 also showed good level of antibacterial efficacy against E. coli and S. aureus. In a full‐thickness rat wound model, CSPUO2 hydrogel considerably accelerated wound healing with exceptional re‐epithelialization granulation tissue formation less inflammatory cells and improved skin architecture highlighting the tremendous therapeutic potential of this hydrogel when compared with control and CSPU to treat chronic diabetic and burn wounds.
The regulation of proinflammatory mediators has been explored to promote natural healing without abnormal inflammation or autoimmune response induced by their overproduction. However, most efforts to control these mediators have relied on pharmacological substances that are directly engaged in biological cycles. We believe that functional porous materials removing target mediators provide a new way to promote healing process using their adsorption mechanisms. In this study, the Zr‐based MOF‐808 (Zr 6 O 4 (OH) 4 (BTC) 2 (HCOO) 6 ) crystals were found to be effective at removing proinflammatory mediators, such as nitric oxide (NO), cytokines, and reactive oxygen species (ROS) in vitro and in vivo, because of their porous structure and surface affinity. The MOF‐808 crystals were applied to in vivo skin wound model as a hydrogel dispersion. The hydrogel containing 0.2 wt% MOF‐808 crystals showed significant improvement in terms of wound healing efficacy and quality over the corresponding control. It was also proven that the mode of action is the removal of the proinflammatory mediators in vivo. Moreover, the application of MOF‐808‐containing hydrogels promoted cell activation and proliferation, and inhibited chronic inflammation, leading to increased wound healing quality. These findings suggest that Zr‐based MOFs may be a promising drug‐free solution for skin problems related to proinflammatory mediators.
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Objective
To evaluate the local effect of a slow oxygen-release gel on the healing of standardised skin wounds caused in rats.
Method
Skin wounds were created on the backs of male rats (Rattus norvegicus, Wistar) that were randomly allocated into two groups. In the treated (T) and control (C) groups, oxygen gel and distilled water, respectively, were applied to the wounds on alternate days for 28 days. Postoperatively, euthanasia was performed at 5, 10, 14, 21 and 28 days, followed by clinical, histological (Masson's trichrome) and immunohistochemical analysis. Data were subjected to analysis of variance (ANOVA) and Bonferroni's test.
Results
The cohort comprised 50 rats. On clinical and histological analysis, groups C and T showed similar characteristics 5 days post-operation. Subsequently, group T showed better healing at 14, 21 and 28 days and presented more intense inflammatory infiltrate up to 10 days. At days 14, 21 and 28, group T exhibited a reduction in oedema and increased angiogenesis, granulation tissue formation, and deposition of collagen fibres than group C. Immunohistochemical analysis showed the presence of tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) in both the groups, but the levels were significantly higher in group T (p<0.05).
Conclusion
The local application of slow oxygen-release gel accelerated the healing of standardised skin wounds created surgically in rats, with increased angiogenesis and better collagen fibre formation.
A wound is a disruption of the cellular and anatomic continuity of a tissue, with or without microbial infection. The perennial plant Kalanchoe pinnata (Bryophyllum) is a member of the Crassulaceae family. The present study was based on the quality standardisation and comparative study of leaf and root of Kalanchoe pinnata in the treatment of wound healing on albino rats. The plant was gathered in Uttarakhand, Dehradun, India. The plant leaves were used after being thoroughly rinsed in water. Additionally, the root was scrubbed and allowed to dry at room temperature in the shade and/or away from the sun. The plant was identified and authenticated by Dr Sunita Garg (Reference No. NIScPR/RHMD/Consult/2023/4486-87). The leaves and roots of Kalanchoe pinnata were extracted using methanol solvent. Physicochemical and phytochemical screening was done for both the extracts. The Methanolic extract of Kalanchoe pinnata root and leaf (5% Ointment Topical Application for 15 days) was assessed and compared for its wound healing activity on excisional wound healing animal using Albino rats. GC-MS analysis of the MEKP spectral spectrum showed, the presence of eight essential ingredients was shown as flavone with a retention time of 16.08 and a peak area of 11.9%, palmitic acid with a retention time of 16.73 and a peak area of 8.4%, and phytol with a retention time of 17.82 and a peak area of 39.8%. etc. It was found that MEKP Leaf (5% Ointment) showed superior contraction of wound and faster epithelialization compared to MEKP Root (5% Ointment). Our findings support the possibility of using this plant therapeutically in routine medical care. By following these recommendations, we can drive the development of safe, effective, and accessible phytoconstituent-based wound healing agents.
Wound healing is a complex process involving many cells consisting of four phases namely hemostasis, inflammation, proliferation, and remodeling. The usage of natural resources that have pharmacological features can hasten the wound's physiological healing procedure. The example of natural resources is virgin coconut oil (VCO) and ethanol extract of Artocarpus lakoocha Roxb. leaves (EEAL) which have the potential for wound healing. This study aimed to examine the combination of VCO and EEAL in an ointment formulation for wound healing in male Wistar rats. The ointment was divided into five formulas with different concentrations of VCO and EEAL and underwent stability and homogeneity evaluation. In vivo animal testing was divided into five groups according to the number of formulas. The wound healing activity was evaluated by using white male rats in the aspect of wound healing percentage and epithelial diameter from a histopathology study. The results showed that all formulas are stable and F3 by using the ratio of 3:1 (VCO: EEAL) has the best wound healing activity in the aspect of wound healing percentage and epithelial diameter compared to the other groups. In conclusion, our findings suggest that the VCO and EEAL in ointment preparation have great potential for wound healing activity.
Objective
The current study was carried out to assess the humoral immune responses according to age at different stages of wound healing in Black Bengal goats (BBG).
Materials and Methods
Apparently, healthy BBGs (n = 20) were collected and divided into five groups based on their age: Group A (control, 3 years), Group B (3 to 5 years), Group C (2 to <3 years), Group D (1 to <2 years), and Group E (<1 year). Except for control, all BBGs were allowed to have artificial surgical wounds, and follow-up data were collected from day 0 to 21. The humoral immune responses [immunoglobulins (Igs) and interleukin-6 (IL-6)] were determined by ELISA using commercial goat ELISA kits. Statistical Product and Service Solutions (Version 20) was used to analyze the data.
Results
The normal range of immune cells in control BBGs was immunoglobulin G (IgG) (20.21 ± 0.13 mg/ml), immunoglobulin M (IgM) (2.87 ± 0.0.05 mg/ml), immunoglobulin A (IgA) (0.33 ± 0.01 mg/ml), and IL-6 (1.6 ± 0.05 pg/ml). In this experiment, higher concentrations of IgG (21.11 ± 0.20 mg/ml), IgM (2.92 ± 0.04 mg/ml), IgA (0.35 ± 0.02 mg/ml), and IL-6 (1.62 ± 0.05 pg/ml) were found in Group B BBGs, whereas the lower levels of IgG, IgM, IgA, and IL-6 were found at 17.16 ± 0.18 mg/ml, 2.12 ± 0.01 mg/ml, 0.29 ± 0.03 mg/ml, and 1.55 ± 0.05 pg/ml, respectively, in the Group E BBGs. Rapid wound healing was observed in the older groups compared to the younger groups of BBGs. The concentrations of Igs (IgG, IgM, and IgA) and IL-6 were gradually increased in all groups from day 3 (early inflammatory stage) and day 7 (late inflammatory stage), and then they decreased gradually from day 14 (proliferative stage) to reach the final stage of day 21 (remodeling stage), where the concentrations were found to be at a level comparable to their per-incisional period. No gender-related differences were detected.
Conclusion
Adult BBGs (3 to 5 years old) showed faster wound repair and stronger immune responses. This finding may assist veterinarians and researchers in considering age-related immune responses for the recovery and rapid cure of surgical wounds.
Importance
Obstetrics and gynecology (OB/GYN) accounts for at least half of all open abdominal surgeries performed. Rates of surgical wound complications after open procedures in OB/GYN range from 5% to 35%. Therefore, optimizing management of surgical wound complications has the potential to significantly reduce cost and morbidity. However, guidelines addressing best practices for wound care in OB/GYN are limited.
Objective
The objectives of this review are to describe the fundamentals of wound healing and to evaluate available evidence addressing surgical wound care. Based on these data, we provide recommendations for management of extrafascial surgical wound dehiscence after OB/GYN procedures.
Evidence Acquisition
Literature search was performed in PubMed, Medline, OVID, and the Cochrane database. Relevant guidelines, systematic reviews, and original research articles investigating mechanisms of wound healing, types of wound closure, and management of surgical wound complications were reviewed.
Results
Surgical wound complications in OB/GYN are associated with significant cost and morbidity. One of the most common complications is extrafascial dehiscence, which may occur in the setting of hematomas, seromas, or infection. Management includes early debridement and treatment of any underlying infection until healthy granulation tissue is present. For wounds healing by secondary intention, advanced moisture retentive dressings reduce time to healing and are cost-effective when compared with conventional wet-to-dry gauze dressings. Negative pressure wound therapy can be applied to deeper wounds healing by secondary intention. Review of published evidence also supports the use of delayed reclosure to expedite wound healing for select patients.
Conclusions
Optimizing surgical wound care has the potential to reduce the cost and morbidity associated with surgical wound complications in OB/GYN. Advanced moisture retentive dressings should be considered for wounds healing by secondary intention. Data support delayed reclosure for select patients, although further studies are needed.
Target Audience
Obstetricians and gynecologists, family physicians.
Learning Objectives
After reading this article, the provider will be better able to explain the clinical significance of surgical wound complications, particularly in OB/GYN; identify the stages of wound healing and types of wound closure; discuss the TIME framework for wound care; and describe a recommended approach for the management of extrafascial wound dehiscence.
Diabetic wounds have imposed a significant burden on both patients and society with prolonged healing processes hindered by dysfunctional skin repair cells. Small extracellular vesicles (sEVs), as the important media for intercellular communications, show promising therapeutic potential in treating diabetic wounds by restoring cellular functions. However, low yields and limited bio‐function of sEVs greatly challenge their large‐scale clinical use. Here, we briefly overview the biogenesis and cellular uptake of sEVs, emphasize current advances in improving the yields of sEVs and optimizing the function of sEVs with engineering approaches, and summarize the applications of engineered sEVs in diabetic wound treatment. Furthermore, the undissolved issues during the clinical transformation of engineered sEVs are also discussed. This critical review aims to provide meaningful guidance for future applications of engineered sEVs in the management of diabetic wounds.
Wound care and treatment can be critical from a clinical standpoint. While different strategies for the management and treatment of skin wounds have been developed, the limitations inherent in the current approaches necessitate the development of more effective alternative strategies. Advances in tissue engineering have resulted in the development of novel promising approaches for accelerating wound healing. The use of various biomaterials capable of accelerating the regeneration of damaged tissue is critical in tissue engineering. In this regard, cerium oxide nanoparticles (CeO2 NPs) have recently received much attention because of their excellent biological properties, such as antibacterial, anti-inflammatory, antioxidant, and angiogenic features. The incorporation of CeO2 NPs into various polymer-based scaffolds developed for wound healing applications has led to accelerated wound healing due to the presence of CeO2 NPs. This paper discusses the structure and functions of the skin, the wound healing process, different methods for the synthesis of CeO2 NPs, the biological properties of CeO2 NPs, the role of CeO2 NPs in wound healing, the use of scaffolds containing CeO2 NPs for wound healing applications, and the potential toxicity of CeO2 NPs.
The advancement of tissue engineering for regenerating injured tissues and organs has progressed significantly in recent years. Various techniques have been used to modify the cells' microenvironments in the targeted tissue via their extracellular environment for achieving these aims. The 3D structured scaffolds alone or combined with bioactive molecules or genes and cells hold great promise for the development of functional engineered tissues. As an emerging and state-of-the-art technology in this field, integrating tissue engineering and gene therapy, known as gene-activated matrix (GAM), has gained immense attention as a promising approach for restoring damaged or dysfunctional tissues' function and structure. Nonetheless, fabricating GAMs with low cytotoxicity, high transfection efficiency, and long-term gene delivery efficiency is still challenging. Here we provide a complete overview of different tissue engineering approaches and their ongoing preclinical research trials. Moreover, the GAM strategy with a focus on gene-activated matrix development, faithful application, and future prospects as a tissue repair and regeneration replacement is assayed. The challenges and future research prospects in regenerative medicine are also presented. Eventually, we propose that GAMs offer a basic mechanistic infrastructure for “tissue engineering” to pave the way for clinical translation and achieve personalized regenerative medicine.
Electric fields are generated in vivo in a variety of physiologic and pathologic settings, including penetrating injury to epithelial barriers. An applied electric field with strength within the physiologic range can induce directional cell migration (i.e., electrotaxis) of epithelial cells, endothelial cells, fibroblasts, and neutrophils suggesting a potential role in cell positioning during wound healing. In the present study, we investigated the ability of lymphocytes to respond to applied direct current (DC) electric fields. Using a modified Transwell assay and a simple microfluidic device, we show that human PBLs migrate toward the cathode in physiologically relevant DC electric fields. Additionally, electrical stimulation activates intracellular kinase signaling pathways shared with chemotactic stimuli. Finally, video microscopic tracing of GFP-tagged immunocytes in the skin of mouse ears reveals that motile cutaneous T cells actively migrate toward the cathode of an applied DC electric field. Lymphocyte positioning within tissues can thus be manipulated by externally applied electric fields, and may be influenced by endogenous electrical potential gradients as well.
Recombinant platelet-derived growth factor (PDGF) and transforming growth factor beta 1 (TGF-beta 1) influence the rate of extracellular matrix formed in treated incisional wounds. Because incisional healing processes are difficult to quantify, a full-thickness excisional wound model in the rabbit ear was developed to permit detailed analyses of growth-factor-mediated tissue repair. In the present studies, quantitative and qualitative differences in acute inflammatory cell influx, glycosaminoglycan (GAG) deposition, collagen formation, and myofibroblast generation in PDGF-BB (BB homodimer)- and TGF-beta 1-treated wounds were detected when analyzed histochemically and ultrastructurally. Although both growth factors significantly augmented extracellular matrix formation and healing in 10-day wounds compared with controls (P less than 0.002). PDGF-BB markedly increased macrophage influx and GAG deposition, whereas TGF-beta 1 selectively induced significantly more mature collagen bundles at the leading edge of new granulation tissue (P = 0.007). Transforming growth factor-beta 1-treated wound fibroblasts demonstrated active collagen fibrillogenesis and accretion of subfibrils at the ultrastructural level. Myofibroblasts, phenotypically modified fibroblasts considered responsible for wound contraction, were observed in control, but were absent in early growth-factor-treated granulating wounds. These results provide important insights into the mechanisms of soft tissue repair and indicate that 1) PDGF-BB induces an inflammatory response and provisional matrix synthesis within wounds that is qualitatively similar but quantitatively increased compared with normal wounds; 2) TGF-beta 1 preferentially triggers synthesis and more rapid maturation of collagen within early wounds; and 3) both growth factors inhibit the differentiation of fibroblasts into myofibroblasts, perhaps because wound contraction is not required, due to increased extracellular matrix synthesis.
We utilized fluorescence microscopy and affinity-purified antibodies to probe the form and function of cytoplasmic actin in endothelial cells (EC) recovering from injury and grown on extracellular matrices in vitro. Bovine aortic EC were seeded onto glass microscope coverslips that had been coated with either BSA, fibronectin, type I and III (interstitial) collagens, type IV (basement membrane) collagen or gelatin. After EC that had been grown on glass, glass-BSA or extracellular matrix-coated coverslips reached confluence, a 300-400 micron zone of cells was mechanically removed to stimulate EC migration and proliferation. Post-injury EC movements were monitored with time-lapse, phase-contrast videomicrography before fixation for actin localization with fluorescence microscopy using affinity-purified antibodies. We found that the number of stress fibres within EC was inversely proportional to the rate of movement; and, the rates of movement for EC grown on glass or glass-BSA were approximately eight times faster than EC grown on gelatin or type IV collagen (X velocity = 0.5 micron/min versus 0.06 micron/min). EC movements on fibronectin and interstitial collagens were similar (X velocity = 0.2 micron/min). These results suggest that extracellular matrix molecules modulate EC stress fibre expression, thereby producing alterations in the cytoskeleton and the resultant EC movements that follow injury in vitro. Moreover, the induction of stress fibres in the presence of basement membrane (type IV) collagen may explain the failure of aortic EC to migrate and repopulate wounded regions of intima during atherogenesis in vivo.
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.
It has been suggested that fibrinogen (fg) or its physiological derivatives influence the motility and growth of endothelial cells (ECs), but direct support for this concept is still lacking. In the present study, the capacity of fg to interact with ECs and induce the migration of ECs was examined. The capacity of fg to induce EC migration was studied by means of a modification of the Boyden chamber technique. fg in the lower compartment of the chamber caused a time- and concentration-dependent migration of ECs across filters. fg present in equal concentrations above and below the filter increased EC migration, but the maximal effect invariably occurred in the presence of a gradient between the lower and the upper compartments. Trypsin or plasmin digestion of fg and preincubation of fg with Fab fragments from specific antibody completely abolished fg-induced EC migration. Dialysis of fg to eliminate small peptides that might contaminate the preparation did not modify fg-induced migration. Plasma obtained from healthy donors induced EC migration, but plasma from an afibrinogenemic patient was completely ineffective. The addition of purified fg to afibrinogenemic plasma restored plasma-induced EC migration. Plasmin degradation fragments D and E, of 100,000 and 50,000 mol wt, respectively, did not induce EC migration. However, fragment E caused dose-related inhibition of fg-induced EC migration Direct interaction of highly purified radioiodinated human fg with cultured human and bovine Ecs was observed. The binding was time dependent and plateaued at 10 min. Nonlabeled fg in a large molar excess inhibited the interaction, but unrelated proteins, including fibronectin, ovalbumin, and myoglobin, did not. Monospecific Fab fragments directed to fg inhibited binding by 38% at a 50 to 1 molar ratio whereas nonimmune Fab caused only 2% inhibition at a similar concentration. The binding of 125I-fg with ECs was saturable, and an apparent dissociation constant of 0.23 x 10(-6) M was estimated from binding isotherms. After 30 min of incubation the interaction between 125I-fg and the cells was completely reversible and displaceable by a large molar excess of unlabeled fg. Autoradiography of the display of EC-bound 125I on polyacrylamide gel showed the constitutive B beta- and gamma-chains of the fg molecule, with a partial loss of the A alpha-chain. Purified fragment E and E were tested for their capacity to inhibit fg binding. At a 1 to 400 125I-fg-to-fragment molar ratio, fragment E, which also inhibited migration, competed for binding by 44%, but fragment D was completely ineffective. These data show that fg may specifically associate with ECs and induce migration of these cells; it also appears that the structural requirement of this activity is located in the N-terminal part of the molecule.
Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.
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.
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.
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.
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.
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)
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.
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.
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.
Zusammenfassung
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.
Dieser Beitrag soll eine Übersicht über die unterschiedlichen Optionen der Durchführung eines Debridements in der Therapie chronischer Wunden bieten. Für die Durchführung eines Debridements chronischer Wunden eignen sich als therapeutische Maßnahmen Chirurgie, Biochirurgie, Laser, Ultraschall, Hydrotherapien, Naß‐zu‐trocken‐Methode, Autolyse, proteolytische Enzyme, osmotisches‐ oder chemisches‐Debridement.
Das einzig richtige Debridement gibt es nicht! So individuell die Patienten und die Ursachen der zugrunde liegenden Wundheilungsstörungen sind, so unterschiedlich sinnvoll kann auch der Einsatz der verschiedenen Methoden der Durchführung eines Debridements sein. Für welche therapeutische Option man sich entscheidet, wird durch eine Vielzahl von Faktoren bestimmt. Darüber hinaus kann auch die sukzessive Verwendung unterschiedlicher Methoden je nach Zusammensetzung des Wundmilieus sinnvoll sein.
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)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
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.
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.
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.
We report here that epidermal growth factor (EGF) isolated from male mouse salivary glands is active as a potent chemoattractant for a rat heart vascular endothelial cell line (RHEC). Human EGF and transforming growth factor-alpha (TGF-alpha) produced in Escherichia coli are also active as chemoattractants for these cells. The chemotactic response of the cells is induced by concentrations of murine EGF that ranged from 0.01 to 1.0 nM with similar specific activities for both the human EGF and TGF-alpha. Other growth factors such as fibroblast growth factor (FGF), TGF-beta, platelet-derived growth factor (PDGF), insulin, or IGF were not active as chemoattractants for these cells. The chemotactic response exhibited similar kinetics to those reported for connective tissue cells responding to PDGF (2-6 h) and required both RNA and protein synthesis. However, in contrast to NIH/3T3 cells responding to PDGF, the proliferating cultures of RHEC respond as well as growth-arrested cultures in the chemotaxis assay. In in vivo studies of connective tissue regeneration it appears that EGF-like factors are present in wound fluid collected from rats. Acid extracts of wound fluid contained a RHEC chemotactic activity that was neutralized with anti-EGF antisera. These studies indicate that EGF-like factors may function in vivo to control in part the angiogenic events that occur during tissue repair.
Many of the biochemical events of wound healing are prisoners of the victim's physiologic state. Although the initial local events of inflammation occur normally in any viable tissue, the subsequent reparative capacities of macrophages, fibroblasts, and endothelial cells are seriously impaired by any compromise of local perfusion and oxygenation. In particular, the bacteriocidal capacities of granulocytes are heavily dependent on local oxygenation/perfusion, nutrition, and endocrine status. This article depicts the local mechanisms of repair with special attention to the means by which physiologic and nutritional support at the clinical level influence repair, even to a point at which wound healing may exceed contemporary expectations. Without appropriate physiologic, nutritional, and endocrine support, wound healing often fails totally. It is now possible, although not always easy, to achieve optimal physiologic support.