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Characteristics of human hypertrophic scars and keloids. (A) Hypertrophic scar: This appears as a red, raised scar that does not extend beyond the boundaries of the original injury. They have nodular collagen deposits containing a-SMA producing myofibroblasts that are involved in scar contracture. Hypertrophic scars can regress with time. The main findings from studies on the role of TGF-b signaling and hypertrophic scarring are indicated. (B) Keloid: This appears as a shiny and smooth protuberance ranging from pink to purple in color and extends beyond the boundaries of the original wound. Unlike hypertrophic scars, keloids do not have nodular collagen deposits, a-SMA-producing myofibroblast, do not undergo scar contracture, and do not regress with time. The main findings from studies on the role of TGF-b signaling and keloid formation are indicated. Images were obtained with permission from the DermNet NZ Web site (www.dermnetnz.org). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound
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Wound healing is an intricate biological process in which the skin, or any other tissue, repairs itself after injury. Normal wound healing relies on the appropriate levels of cytokines and growth factors to ensure that cellular responses are mediated in a coordinated manner. Among the many growth factors studied in the context of wound healing, tra...
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Context 1
... scarring. Hypertrophic scarring often occurs after deep burn injury or trauma and is characterized by excessive ECM deposition. 115 HTSs appear as elevated red scar tissue that re- mains within the boundary of the original injury (Fig. 7A). 115 Although the pathophysiological mechanism(s) involved in hypertrophic scarring are not fully understood, many studies indicate that aberrant TGF-b signaling plays a key role in its etiology. For example, Scott and colleagues showed that TGF-b1 protein was present in HTSs, particularly in the deep dermis, as well as in the dermis of mature ''normal'' scars but was not de- tected in normal (non-scarred) dermis. 116 In addi- tion, Wang and colleagues showed that TGF-b1 mRNA levels are higher in HTS tissue and in cul- tured HTS fibroblasts as compared with normal skin tissue and cells, and that cultured HTS fibro- blasts secrete more TGF-b1 protein than normal ...
Context 2
... Keloids are another type of patholog- ical scar for which aberrant TGF-b signaling is thought to play a pathophysiological role. Unlike HTS, keloids often appear as shiny rounded pro- tuberances with colors ranging from pink to purple, and scarring extends beyond the boundaries of the original injury (Fig. 7B). 115 Studies using cultured keloid fibroblasts have shown that these cells pro- duce higher amounts of ''pro-scarring'' TGF-b1 and TGF-b2 as compared with normal fibroblasts. 130,131 Another study demonstrated that keloid fibro- blasts exhibit increased expression of ALK5 and TbRII as well as increased phosphorylation of Smad3 relative to normal fibroblasts. 132 Interest- ingly, increased TGF-b/Smad3 signaling has been implicated in keloid pathogenesis via epithelial- mesenchymal interactions, where keloid keratino- cytes act through a paracrine mechanism to increase ALK5 and TbRII expression and Smad3 signaling in keloid fibroblasts. 133 Genetic studies have not revealed an association between keloid disease and the occurrence of common polymor- phisms or mutations in genes encoding the three TGF-b isoforms (-b1, -b2, and -b3) in Cauca- sians 134-136 or Smads (-3, -6, and -7) in a Jamaican population. 137 However, a recent study has re- vealed an association of TGF-b1 and Smad4 vari- ants in the etiology of keloid scar in the Malay population. 138 Further genetic studies investigat- ing the potential link between keloid disease and polymorphisms/mutations in components of the TGF-b signaling pathway using larger cohorts of patients, particularly individuals with darker skin pigmentation who are more susceptible to keloid formation, are ...
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The skin graft is a surgical technique commonly used in the reconstructive surgery of the limbs, in order to repair skin loss, as well as to repair the donor area of the flaps and cover the dermal substitutes after engraftment. The unavoidable side effect of this technique consists of unaesthetic scars. In order to achieve the healing of posttrauma...
Citations
... TGF-β coordinates critical processes such as re-epithelialization, angiogenesis, fibroblast proliferation and extracellular matrix (ECM) production, leading to granulation tissue formation and wound contraction. In the remodeling phase, TGF-β influences the balance between collagen degradation by matrix metalloproteinases (MMPs) and the presence of endogenous tissue inhibitors of MMPs (TIMPs), whose expression it also regulates [11,29,30]. TGF-β is focusing in this study because the previous evidence showed TGF-β as the main factor producing chronic wounds, including diabetic ulcers [10] and pressure wounds [31]. ...
Kaab Dum, a prominent indigenous rice variety cultivated in the Pak Phanang Basin of Nakhon Si Thammarat, Thailand, is the focus of our study. We investigate the therapeutic potential of indigenous Kaab Dum rice extract in the context of chronic wounds. Our research encompasses an examination of the nutritional compositions and chemical profiles of Kaab Dum rice extract. Additionally, we assess how the extract affects chronic wounds in TGF-β-induced HaCaT cells. Our evaluation methods include the detection of cellular oxidative stress, the examination of endoplasmic reticulum (ER) stress, wound healing assays, analysis of cell cycle arrest and the study of cellular senescence through senescence-associated β-galactosidase (SA-β-gal) staining. Our research findings demonstrate that TGF-β induces oxidative stress in HaCaT cells, which subsequently triggers ER stress, confirmed by the expression of the PERK protein. This ER stress results in cell cycle arrest in HaCaT cells, characterized by an increase in p21 protein, a cyclin-dependent kinase inhibitor (CDKI). Ultimately, this leads to cellular senescence, as confirmed by SA-β-gal staining. Importantly, our study reveals the effectiveness of Kaab Dum rice extract in promoting wound healing in the chronic wound model. The extract reduces ER stress and senescent cells. These beneficial effects are potentially linked to the antioxidant and anti-inflammatory properties of the rice extract. The findings of our study have the potential to make significant contributions to the development of enhanced products for both the prevention and treatment of chronic wounds.
... Its mRNA expression is expected to increase during wound healing and can remain elevated for up to 240 h in epidermal cells and up to 72 h in fibroblasts [56]. Moreover, fibronectin can bind and sequester TGF-β, which, in turn, stimulates the synthesis of collagen type I and III [57,58]. Indeed, COL1A1 mRNA expression increased in HaCaT at 72 h after treatment with CTGF ± NPs while this was not observed in HDF cells as most of collagen type I is secreted by myofibroblasts rather than fibroblasts. ...
... Current scientific and technological advances have facilitated the development of numerous skin substitutes that enhance and modulate the wound healing process through biomodulation effects [89,90]. This includes immune cell recruitment, increased essential cytokines and growth factors, and modified molecular interactions within the wound [7,91,92]. More recently, tridimensional bioprinting has enabled the production of synthetic skin embedded with cells and bioactive molecules, resulting in increased cytokine production at the wound site. ...
Background: Skin substitutes play a crucial role in wound care by actively modulating the wound healing process, promoting angiogenesis, and protecting the integrity of the native extracellular matrix. Consequently, surgeons have increasingly recognized these resources as excellent complements to improve reconstructive outcomes. This review focuses on the author’s experience using these biomaterials in complex cases, highlighting the benefits they bring to patient care. Methods: A literature review was conducted to evaluate the regenerative properties of skin substitutes and their applicability in head and neck, upper and lower extremities, and trunk reconstruction. Results: The reviewed literature, along with the authors’ experience, supports the adjunct use of skin substitutes in various reconstructive situations. Combining them with skin grafts improves resulting skin quality and may also enhance donor site healing. They have proven to be effective in addressing chronic venous ulcers, traumatic wounds with limited donor tissues for coverage, extensive burns, diabetic foot ulcers, and oncological resections in the face and scalp. Furthermore, combining them with autologous tissue shows promising results in achieving stable closure. Conclusions: Incorporating skin substitutes in complex reconstructive scenarios offers multiple benefits. Their regenerative properties and ability to modulate the healing process contribute to enhanced outcomes and reduced overall costs.
... 12 The notably improved healing that we observed is likely related to the grafts ability to bind these endogenous growth factors, which are essential components of wound healing. 23,24 Further with the in vitro data showing that the PRBM can bind and preserve the activity of TGF-β1, bFGF, and VEGF, 12 it seems logical that the retention of these endogenous growth factors would encourage wound healing, thus leading to the early closure that we have observed. ...
As the incidence of diabetic foot ulcers (DFU) increases, better treatments that improve healing should reduce complications of these ulcers including infections and amputations. We conducted a randomized controlled trial comparing outcomes between a novel purified reconstituted bilayer membrane (PRBM) to the standard of care (SOC) in the treatment of non‐healing DFUs. This study included 105 patients who were randomized to either of two treatment groups ( n = 54 PRBM; n = 51 SOC) in the intent to treat (ITT) group and 80 who completed the study per protocol (PP) ( n = 47 PRBM; n = 33 SOC). The primary endpoint was the percentage of wounds closed after 12 weeks. Secondary outcomes included percent area reduction, time to healing, quality of life, and cost to closure. The DFUs that had been treated with PRBM healed at a higher rate than those treated with SOC (ITT: 83% vs. 45%, p = 0.00004, PP: 92% vs. 67%, p = 0.005). Wounds treated with PRBM also healed significantly faster than those treated with SOC with a mean of 42 versus 62 days for SOC ( p = 0.00074) and achieved a mean wound area reduction within 12 weeks of 94% versus 51% for SOC ( p = 0.0023). There were no adverse events or serious adverse events that were related to either the PRBM or the SOC. In comparison to the SOC, DFUs healed faster when treated with PRBM. Thus, the use of this PRBM is an effective option for the treatment of chronic DFUs.
... Fibroblasts play a pivotal role by generating disorganized collagen, predominantly comprising immature type III collagen, into the provisional matrix 13 . These fibroblasts may transform into myofibroblasts under the influence of various cytokines, culminating in heightened collagen production and eventual wound contraction 14,15 . Numerous signaling pathways, including angiotensin II and TGF-β, through both canonical and non-canonical pathways, intricately modulate the wound healing process during this phase 16,17 ...
Wound healing is a complex and dynamic process that involves a series of intricately regulated phases, each contributing to the restoration of tissue integrity. This comprehensive review dives into the fundamental aspects of wound healing, exploring the physiological mechanisms, phases, and influencing factors. The review begins with describing the significance of wound healing and navigates through sequential phases, such as hemostasis and inflammation, proliferation, remodelling, wound classification and closure techniques, thus providing insights into the diverse strategies employed in clinical settings. Much focus lies to bone healing, addressing both primary and secondary healing mechanisms, as well as the bone healing in extraction sockets. A significant segment of the review explores the factors affecting wound healing, which are categorized into local, surgical, and systemic factors encompassing ageing, diabetes mellitus, hormonal changes, immunocompromised conditions, medications, smoking, alcohol consumption, obesity, and nutrition deficiency. A synthesis of the reviewed content highlights the interplay of these factors in the 'wound healing' process. Understanding these elements is imperative for clinicians and researchers alike to develop effective therapeutic interventions tailored to individual patient needs. This review serves as a valuable resource for those seeking a comprehensive understanding of the intricate dynamics of wound healing in the human body.
... Several chronic and persistent dysfunctions are supposedly related to transmission of prolonged nociceptive signals to peripheral myofascial tissues, which sensitize the central nervous system and increase its excitability [43]. Pro-inflammatory processes [44] cause nociceptive stimuli [45] and trigger momentaneous adaptations in endogenous pain modulation [46]. At the end of 6 weeks, we observed a greater percentage increase in PPT in the EG (25.8%) than in the SG (6.5%). ...
To investigate whether myofascial reorganization ® in the trapezius muscle (MRT) improves peripheral muscle oxygenation and pain tolerance and decreases neck disability index (NDI) scores in individuals with and without nonspecific neck pain (NP) using a double-blind randomized controlled trial. Seventy-five subjects were equally and randomly assigned to three groups: the intervention groups (experimental [EG] and sham sSG]) and the control group (CG). Several inclusion criteria were applied to the intervention groups: male or female, aged 18–32 years, self-reported NP in the last 3 months without a defined cause; at least “soft” pain in session 1 of the NDI, and at least a score of 1 on the Visual Analogue Scale (VAS). The CG was required to have NDI and VAS scores of 0 at recruitment. Intervention: The EG underwent MRT for 10 min, once a week for 6 weeks. Patients with NP in the SG underwent classical massage for the same duration and frequency. Patients in the CG had no pain and underwent no intervention. Data collection was performed using the NDI Questionnaire, a pressure algometer for pain evaluation, and near-infrared spectroscopy for muscle oxygenation measurements. It was registered as NCT03882515 at ClinicalTrials.gov. The NDI score in both the EG (p<0.001) and SG (p<0.001) decreased after 6 weeks of intervention compared to the CG. The CG demonstrated a lower basal tissue saturation (TSI) index than the EG (p<0.001) and SG (p = 0.02). The EG demonstrated higher oxyhemoglobin values than the SG (p<0.001) and CG (p = 0.03). The CG had higher pain tolerance than the EG (p = 0.01) and SG (p<0.001) post-intervention. MRT increased trapezius muscle oxygenation after 6 weeks of intervention.
... [1][2][3] Similar to its alternative forms, TGF-β3 is an essential factor in the formation and restoration of extracellular matrix, as well as in the control of immune system, wound healing and embryonic development. 4 Its distinctive functions are notably recognised in palatogenesis; the embryonic development process involving the formation of the palate, implying that it has substantial ramifications for developmental biology. 5,6 TGF-β3 dysregulation has been linked to the range of pathological conditions, such as scleroderma, cancer and fibrosis; thus, it has become the central area of investigation in pursuit of therapeutic interventions. ...
Ischemic ulcers pose a multifaceted clinical dilemma for patients with atherosclerosis, frequently compounded by suboptimal wound healing mechanisms. The dual function of Transforming Growth Factor Beta 3 (TGF‐β3) in ischemic ulcer healing is not fully comprehended, despite its involvement in modulating inflammatory responses and tissue regeneration. The main aim of this investigation was to clarify the functions and mechanisms by which TGF‐β3 regulates inflammatory responses and promotes wound healing in patients with ischemic ulcers who have atherosclerosis. Between August 2022 and November 2023, this cross‐sectional investigation was conducted on 428 patients diagnosed with atherosclerotic ischemic ulcers in Haikou, China. The expression and function of TGF‐β3 were examined throughout the different stages of wound healing, including inflammation, proliferation and remodelling. In addition to documenting patient demographics and ulcer characteristics, an analysis was conducted on biopsy samples to determine the expression of TGF‐β3, pro‐inflammatory and anti‐inflammatory markers. A subset of patients were administered topical TGF‐β3 in order to evaluate its therapeutic effects. The expression pattern of TGF‐β3 was found to be stage‐dependent and significant, exhibiting increased levels during the phase of inflammation and reduced activity in subsequent phases. TGF‐β3 levels were found to be greater in ulcers that were larger and deeper, especially in inflammatory phase. TGF‐β3 applied topically induced discernible enhancement in ulcer healing parameters, such as reduction in ulcer depth and size. The therapeutic significance of TGF‐β3 was emphasised due to its twofold function of regulating the inflammatory environment and facilitating the regeneration of damaged tissues. Ischemic ulcer lesion healing is significantly influenced by TGF‐β3, which functions as an anti‐inflammatory and pro‐inflammatory mediator. Its correlation with ulcer characteristics and stages of healing suggests that it may have utility as a targeted therapeutic agent.
... Fibroblasts play a pivotal role by generating disorganized collagen, predominantly comprising immature type III collagen, into the provisional matrix 13 . These fibroblasts may transform into myofibroblasts under the influence of various cytokines, culminating in heightened collagen production and eventual wound contraction 14,15 . Numerous signaling pathways, including angiotensin II and TGF-β, through both canonical and non-canonical pathways, intricately modulate the wound healing process during this phase 16,17 ...
Wound healing is a complex and dynamic process that involves a series of intricately regulated phases, each contributing to the restoration of tissue integrity. This comprehensive review dives into the fundamental aspects of wound healing, exploring the physiological mechanisms, phases, and influencing factors. The review begins with describing the significance of wound healing and navigates through sequential phases, such as hemostasis and inflammation, proliferation, remodelling, wound classification and closure techniques, thus providing insights into the diverse strategies employed in clinical settings. Much focus lies to bone healing, addressing both primary and secondary healing mechanisms, as well as the bone healing in extraction sockets. A significant segment of the review explores the factors affecting wound healing, which are categorized into local, surgical, and systemic factors encompassing ageing, diabetes mellitus, hormonal changes, immunocompromised conditions, medications, smoking, alcohol consumption, obesity, and nutrition deficiency. A synthesis of the reviewed content highlights the interplay of these factors in the 'wound healing' process. Understanding these elements is imperative for clinicians and researchers alike to develop effective therapeutic interventions tailored to individual patient needs. This review serves as a valuable resource for those seeking a comprehensive understanding of the intricate dynamics of wound healing in the human body.
... [93][94][95] This include immune cell recruitment, increased essential cytokines and growth factors, and modified molecular interactions within the wound. [96][97][98] More recently, tridimensional bioprinting has enabled the production of synthetic skin embedded with cells and bioactive molecules, resulting in increased cytokine production at the wound site. This accelerates healing by stimulating cell proliferation, promoting macrophage differentiation, and enhancing neovascularization. ...
Background: Skin substitutes play a crucial role in wound care by actively modulating the wound healing process, promoting angiogenesis, and protecting the integrity of the native extracellular matrix. Consequently, surgeons have increasingly recognized these resources as excellent complements to improve reconstructive outcomes. This review focuses on the author's experience using these biomaterials in complex cases, highlighting the benefits they bring to patient care. Methods: A literature review was conducted to evaluate the regenerative properties of skin substitutes and their applicability in head and neck, upper and lower extremities, and trunk reconstruction. Results: The reviewed literature, along with the authors' experience, supports the adjunct use of skin substitutes in various reconstructive situations. Combining them with skin grafts improves resulting skin quality and may also enhance donor site healing. They have proven effective in addressing chronic venous ulcers, traumatic wounds with limited donor tissues for coverage, extensive burns, diabetic foot ulcers, and oncologic resections in the face and scalp. Furthermore, combining them with autologous tissue shows promising results in achieving stable closure. Conclusions: Incorporating skin substitutes in complex reconstructive scenarios offers multiple benefits. Their regenerative properties and ability to modulate the healing process contribute to enhanced outcomes and reduced overall costs.
... 8 For example, there is growing correlation between specific gene mutations and increased likelihood of developing keloid formation and hypertrophic scarring, both of which are distinguished by excessive accumulation of fibrosis. 9 On contrary, there exists correlation between diminished TGF-β activity or expression and impaired wound healing capabilities that frequently materialize as persistent non-healing ulcers. 10 Moreover, comprehending genetic factors that impact tissue repair and wound healing carry significant ramifications for advancement of therapeutic approaches. ...
Transforming Growth Factor‐Beta (TGF‐β) signalling pathway is of paramount importance in the processes of wound healing, epidermal integrity maintenance and development of skin cancer. The objective of this research endeavour was to clarify the impact of gene mutations and variations in expression within TGF‐β family on mechanisms of tissue repair, as well as to identify potential targets for therapeutic purposes in non‐melanoma skin cancer (NMSC). The methods utilized in this study involved obtaining RNA‐seq data from 224 NMSC patients and paired normal skin tissues from the PRJNA320473 and PRJEB27606 databases. The purpose of the differential gene expression analysis was to identify genes whose expression had changed significantly. In order to evaluate the effects and interrelationships of identified gene variants, structural analysis with AlphaFold and PDB data and network analysis with the STRING database were both utilized. Critical gene expression was externally validated through the utilization of the GEPIA database. Tumour tissues exhibited a notable upregulation of genes associated with the TGF‐β pathway, specifically MMP1, MMP3, MMP9, EGF, COL3A1 and COL1A2, in comparison with normal tissues. As indicated by the central node status of these genes in the network analysis, they play a crucial role in the progression of NMSCs. The results of the structural analysis suggested that mutations might cause functional disruptions. External validation of the upregulation confirmed the expression trends and emphasized the biomarker potential of the upregulated genes. In conclusion, this research offered thorough examination of molecular modifications that occur in TGF‐β family genes, which are linked to cutaneous wound healing and NMSC. The modified expression of the identified hub genes may represent innovative targets for therapeutic intervention.
