Wound healing represents one of the most intricate biological processes in the human body, characterized by a complex orchestration of cellular activities and molecular pathways. This remarkable process involves the coordinated actions of multiple tissues and cell lineages, requiring precise regulation of cell migration, proliferation, matrix deposition, and remodeling, alongside inflammation and angiogenesis. Current research has revealed that wound healing progresses through four distinct yet overlapping phases: hemostasis, inflammation, proliferation, and remodeling. The transition between these phases, particularly from inflammation to proliferation, is critically regulated by specific cellular interactions and molecular signals including cytokines, growth factors, and emerging regulators such as long non-coding RNAs. The dysfunction of these regulatory mechanisms can lead to impaired healing and chronic wounds, especially in conditions like diabetes mellitus, making wound healing an important area for therapeutic intervention.
The Sequential Phases of Wound Healing
Wound healing follows a highly coordinated sequence of events that can be divided into four overlapping phases. Each phase involves distinct cellular activities and molecular signals that collectively drive the repair process. Understanding these phases provides a framework for analyzing the cellular and molecular mechanisms underlying wound healing.
Hemostasis: The Initial Response to Injury
Hemostasis marks the first stage of wound healing, occurring immediately following tissue injury to establish a provisional wound matrix and prevent excessive blood loss. This phase occurs through three critical steps: vasoconstriction, primary hemostasis, and secondary hemostasis2. When skin is wounded, the immediate response to stop bleeding is vasoconstriction of the vessel walls, mediated by smooth muscle contraction in response to increased calcium ion levels7. Next, primary hemostasis initiates platelet aggregation and platelet plug formation triggered by exposure to collagen within the subendothelial matrix. Concurrently, secondary hemostasis activates the coagulation cascade where soluble fibrinogen is converted to insoluble fibrin strands that form a mesh2.
The platelet plug and fibrin mesh combine to form a thrombus, which serves several critical functions: it stops bleeding, releases complement proteins and growth factors, and provides a provisional scaffold for infiltrating cells necessary for the subsequent phases of wound healing2. During this phase, endothelial cells secrete von Willebrand factor, which facilitates platelet adhesion and activation7. The activated platelets not only contribute to clot formation but also release various growth factors from their α-granules, including platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and epidermal growth factor (EGF), which initiate and modulate subsequent healing phases6. This initial hemostatic phase typically lasts only a few minutes but establishes the foundation for all subsequent healing events7.
Inflammation: Clearing Damaged Tissue and Pathogens
The inflammatory phase of wound healing typically begins within minutes of injury and can last up to three days7. This phase is characterized by the recruitment and activation of various immune cells that clear pathogens, remove cellular debris, and release cytokines and growth factors that initiate the transition to the proliferative phase. During inflammation, mast cells promote vasodilation by secreting histamine or serotonin, facilitating the diapedesis (migration through blood vessel walls) of neutrophil granulocytes and monocytes7.
The recruitment of inflammatory cells to the wound site is orchestrated by several molecular signals. Damage-associated molecular patterns (DAMPs), hydrogen peroxide (H₂O₂), lipid mediators, and chemokines released by injured cells provide signals for neutrophil recruitment2. DAMP molecules include DNA, peptides, extracellular matrix (ECM) components, ATP, and uric acid. Research across various organisms has shown that rapid production of H₂O₂ in the wound minimizes infections, activates keratinocyte regeneration, recruits neutrophils, and promotes new vessel formation2.
Chemokines play a particularly important role in coordinating the inflammatory response. The CXC chemokines that contain an ELR motif (glutamic acid-leucine-arginine) preferentially attract neutrophils and are angiogenic, while ELR-negative chemokines primarily attract lymphocytes2. These chemokines bind to G protein-coupled receptors (GPCRs) called chemokine receptors, triggering activation of downstream pathways that lead to directional cell movement, or chemotaxis2. Among the inflammatory cytokines, interleukin-1 (IL-1), IL-2, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) facilitate leukocyte recruitment and clear dead cells during this initial inflammatory stage8.
Neutrophils are among the first immune cells to arrive at the wound site and help clean the wound by phagocytizing debris and pathogens while releasing antimicrobial compounds. Following neutrophil infiltration, monocytes enter the wound and differentiate into macrophages, which continue the process of phagocytosis and release additional cytokines and growth factors that modulate the healing response2.
Proliferation: Rebuilding Tissue
The proliferative phase of wound healing typically begins around day 3 post-injury and can last for several weeks. This phase is characterized by fibroblast proliferation, formation of granulation tissue, angiogenesis, and re-epithelialization. During this phase, resident fibroblasts proliferate and invade the clot to form contractile granulation tissue. Some fibroblasts differentiate into myofibroblasts, which contain contractile elements similar to those found in smooth muscle cells and draw the wound margins together2. The dividing fibroblasts deposit ECM components such as collagen and shift the wound microenvironment from an inflammatory to a growth state2.
The transition from the inflammatory to the proliferative phase represents a key step during wound healing, as failure of this transition leads to impaired re-epithelialization accompanied by persistent inflammation, which has been recognized as a pathological hallmark of chronic wounds4. Cellular interactions between fibroblasts and macrophages regulate this passage from the inflammatory to the proliferative phase, thus accelerating the healing process7.
Re-epithelialization is a critical aspect of the proliferative phase, involving the migration and proliferation of keratinocytes to restore the epidermal barrier. This process involves the proliferation of both unipotent epidermal stem cells from the basement membrane and de-differentiation of terminally differentiated epidermal cells2. Repair of the epidermal layer also involves reconstruction of skin appendages facilitated by tissue-resident stem cells for sebaceous glands, sweat glands, and hair follicles2. While these epidermal stem cells are mostly unipotent during homeostasis, they become highly plastic in response to injury and can give rise to other cell types to rapidly repair the epidermis during wound healing2.
Angiogenesis, the formation of new blood vessels, is essential during the proliferative phase to restore blood supply to the healing tissue. This process ensures adequate delivery of oxygen and nutrients to the wound site, supporting the metabolic demands of tissue repair13. The proliferative phase establishes the foundation of new tissue that will eventually mature during the remodeling phase.
Remodeling: Restoring Functionality
The remodeling phase represents the final stage of wound healing, beginning around 2-3 weeks post-injury and potentially lasting for months or even years. During this phase, the newly formed tissue matures and strengthens as collagen fibers are reorganized and cross-linked, increasing the tensile strength of the healed tissue. However, the strength of the scar tissue typically reaches only about 80% of the original tissue strength1.
As the wound enters the remodeling stage, macrophages in the wound regain their phagocytic phenotype and acquire a “fibrolytic” profile. These macrophages, called M2c or Mreg-like, release proteases and phagocytize excessive cells and matrix that are no longer required for wound closure2. Aberrations in macrophage function at this stage can lead to persistence of both excessive ECM and cells, resulting in skin fibrosis2.
The remodeling process involves a delicate balance between synthesis and degradation of ECM components. Matrix metalloproteinases (MMPs) play a crucial role in this phase by degrading and remodeling the provisional matrix. The balance between MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), is critical for proper remodeling and can influence the quality of the resulting scar tissue1.
Cellular Orchestrators of Wound Healing
Wound healing involves the coordinated actions of numerous cell types, each playing specific roles in different phases of the healing process. Understanding the contributions of these various cellular players is essential for developing targeted therapies to enhance healing.
Platelets: Initiating the Healing Cascade
Platelets are critical players in the hemostasis phase of wound healing and initiate the healing cascade. In the uninjured state, platelets are protected from untimely activation by the healthy endothelial cell monolayer2. When injury occurs, platelets attach to exposed collagen in the subendothelial matrix, aggregate, and form a platelet plug as part of primary hemostasis.
Beyond their role in hemostasis, platelets serve as reservoirs of growth factors and cytokines that are essential for wound healing. These bioactive molecules are stored in the α-granules of platelets and are released upon platelet activation6. Among the growth factors released by platelets are PDGF, TGF-β, EGF, and vascular endothelial growth factor (VEGF), which collectively initiate and modulate subsequent healing phases6.
The growth factors released from platelets serve multiple functions in wound healing. They are chemotactic, attracting cells to the wound site; mitogenic, stimulating cell proliferation; and angiogenic, promoting the formation of new blood vessels6. The platelet-derived growth factors also stimulate matrix formation and remodeling of the affected region, making platelets essential initiators of the entire wound healing process6.
Immune Cells: Orchestrating Inflammation and Repair
Immune cells play dynamic roles throughout the wound healing process, with different populations predominating at various stages and serving distinct functions. During the inflammatory phase, neutrophils are among the first immune cells to arrive at the wound site, attracted by chemokines and other signals released by injured cells. Neutrophils help clear the wound of pathogens and cellular debris through phagocytosis and the release of antimicrobial compounds, including reactive oxygen species and neutrophil extracellular traps (NETs)2.
Macrophages are versatile immune cells that contribute to various aspects of wound healing and undergo phenotypic changes as healing progresses. Initially, inflammatory M1 macrophages predominate, contributing to pathogen clearance and debris removal. As healing progresses, macrophages transition to an anti-inflammatory M2 phenotype, which promotes tissue repair and resolution of inflammation2.
During the proliferation stage, macrophages actively signal to dermal fibroblasts, affecting their function and phenotype. A specific CD206+/CD301b+ macrophage subset induces the fibroblast to myofibroblast transition in both mice and humans, increasing collagen and α-smooth muscle actin deposition in the wound2. Some macrophages can also transition into fibrotic cells, depositing collagen and other ECM components themselves. These cells, referred to as fibrocytes or M2a macrophages, contribute to scar formation2.
As the wound progresses into the remodeling stage, macrophages regain their phagocytic phenotype and acquire a “fibrolytic” profile (M2c or Mreg-like), releasing proteases and phagocytizing excessive cells and matrix that are no longer required for wound closure2. The proper functioning of macrophages throughout the healing process is critical, as aberrations can lead to persistent inflammation, excessive ECM deposition, and fibrosis2.
Other immune cells, including mast cells and lymphocytes, also contribute to the wound healing process. Mast cells release histamine and other mediators that promote vasodilation and increase blood vessel permeability during the inflammatory phase7. The coordinated activities of these immune cells are essential for proper progression through the phases of wound healing.
Fibroblasts and Myofibroblasts: Matrix Producers and Wound Contractors
Fibroblasts are key cells in the proliferative phase of wound healing, responsible for producing and depositing extracellular matrix components to replace the provisional fibrin matrix. They proliferate in response to growth factors and cytokines released by platelets and immune cells, migrate into the wound site, and produce collagen and other ECM proteins to form granulation tissue27.
As healing progresses, some fibroblasts differentiate into myofibroblasts, specialized cells that contain α-smooth muscle actin and exhibit contractile properties similar to smooth muscle cells. Myofibroblasts contribute to wound contraction, drawing the edges of the wound together to reduce its size2. This process, known as contracture, is crucial for the closure of larger wounds where re-epithelialization alone would be insufficient.
The interaction between fibroblasts and macrophages is particularly important for regulating the transition from the inflammatory to the proliferative phase of wound healing. This cellular cross-talk involves the exchange of various cytokines and growth factors that modulate the activities of both cell types, accelerating the healing process7.
During the remodeling phase, fibroblasts continue to produce and remodel the ECM, gradually replacing the type III collagen that predominates in granulation tissue with stronger type I collagen. The activity of fibroblasts during this phase must be carefully regulated, as excessive fibroblast activity and collagen production can lead to hypertrophic scarring and fibrosis1.
Keratinocytes and Epidermal Cells: Restoring the Skin Barrier
Keratinocytes are the primary cell type of the epidermis and play a critical role in re-epithelialization during the proliferative phase of wound healing. Following injury, keratinocytes at the wound edge become activated, lose their attachments to the basement membrane and neighboring cells, and begin to migrate across the wound bed to restore the epidermal barrier2.
Re-epithelialization involves both the migration of keratinocytes from the wound edges and the proliferation of epidermal stem cells to generate new keratinocytes. This process includes the proliferation of unipotent epidermal stem cells from the basement membrane and the de-differentiation of terminally differentiated epidermal cells, which regain proliferative capacity in response to injury2.
The repair of the epidermal layer also involves reconstruction of skin appendages, facilitated by tissue-resident stem cells for sebaceous glands, sweat glands, and hair follicles2. While these epidermal stem cells are mostly unipotent during homeostasis, they become highly plastic in response to injury and can give rise to other cell types to rapidly repair the epidermis during wound healing2.
The initiation of keratinocyte migration is among the first reparation mechanisms after skin wound creation. This process involves an increase in intracellular calcium concentration, which likely results in the upregulation of bicarbonate transporter type 2 (AE2). The increase in AE2 expression is probably involved in cell migration and contributes to wound closure5. Understanding the molecular mechanisms that regulate keratinocyte migration and proliferation is essential for developing therapies to enhance re-epithelialization, particularly in chronic wounds.
Endothelial Cells: Establishing New Blood Supply
Endothelial cells are responsible for angiogenesis, the formation of new blood vessels, which is essential for restoring blood supply to the healing tissue. During wound healing, endothelial cells proliferate and migrate in response to angiogenic factors like VEGF, which can be released by platelets, macrophages, and other cells involved in the healing process12.
Angiogenesis begins with the activation of endothelial cells in existing blood vessels near the wound. These activated endothelial cells degrade their basement membrane, proliferate, and migrate toward angiogenic stimuli in the wound bed. The migrating endothelial cells form tubular structures that eventually connect with other vessels to establish new capillary networks, restoring blood flow to the healing tissue13.
The formation of new blood vessels ensures adequate delivery of oxygen and nutrients to the healing tissue, supporting the metabolic demands of tissue repair. Impaired angiogenesis can lead to hypoxia in the wound, which can delay healing and contribute to the development of chronic wounds13. Therefore, strategies to enhance angiogenesis represent potential therapeutic approaches for promoting wound healing, particularly in conditions associated with impaired vascularization.
Molecular Regulators of Wound Healing
The complex process of wound healing is tightly regulated by a network of molecular signals that orchestrate the activities of various cell types throughout the healing process. These molecular regulators include growth factors, cytokines, signaling pathways, and emerging regulators such as long non-coding RNAs.
Growth Factors: Directing Cellular Activities
Growth factors are proteins that communicate activities to cells and play crucial roles in regulating various aspects of wound healing6. They help regulate cell migration into the wound area (chemotaxis), stimulate the growth of epithelial cells and fibroblasts (mitogenesis), initiate the formation of new blood vessels (angiogenesis), and stimulate matrix formation and remodeling of the affected region6.
Growth factors function by binding to specific receptors on target cells, activating intracellular signaling cascades that ultimately lead to changes in gene expression and cellular behavior. Their function is dependent on the receptor site they attach to, and research has shown that many growth factors may accomplish different types of responses depending on the context and target cell6.
Several growth factors have been intensively studied in the context of wound healing. Epidermal growth factor (EGF) stimulates epithelial cell proliferation and migration, promoting re-epithelialization6. Fibroblast growth factor (FGF) stimulates fibroblast proliferation, promotes angiogenesis, and supports granulation tissue formation6. Platelet-derived growth factor (PDGF) is both chemotactic and mitogenic, attracting cells to the wound site and stimulating their proliferation6. Transforming growth factor (TGF)-β plays multiple roles in wound healing, including regulating inflammation, stimulating fibroblast proliferation and ECM production, and influencing scar formation6.
Animal studies have shown that exogenously added growth factors can accelerate the normal healing process, and growth factors have been used successfully in humans to treat previously incurable wounds6. This highlights the potential of growth factor-based therapies for enhancing wound healing, particularly in challenging cases like chronic wounds.
Cytokines: Orchestrating Cellular Responses
Cytokines are proteins that act as internal cellular signals, allowing cells to communicate with one another. They range in weight from 6 to 70 kDa and can direct cellular activities even when present in small quantities6. Cytokines can regulate cellular activities and function via endocrine, paracrine, autocrine, and intracrine mechanisms6.
In order for a particular cytokine to modulate a cellular activity, the target cell must have a receptor for that cytokine. Once receptor binding takes place, a series of intracellular signals are activated, eventually resulting in a specific response6. This receptor-mediated specificity allows cytokines to precisely regulate cellular activities during wound healing.
During wound healing, different cytokines play specific roles in different phases. In the inflammatory phase, pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, and TNF-α facilitate leukocyte recruitment and clearance of dead cells8. As healing progresses, anti-inflammatory and pro-repair cytokines like TGF-β, IL-4, and IL-13 inhibit inflammation and stimulate proliferation of fibroblasts to begin extracellular matrix (ECM) deposition8.
The complex interplay of cytokines throughout the wound healing process is crucial for coordinating the activities of various cell types and ensuring proper progression through the healing phases8. Dysfunction in cytokine production can cause inflammatory non-healing wounds, highlighting the importance of proper cytokine regulation for successful wound healing8.
Signaling Pathways: Molecular Networks Governing Healing
Several signaling pathways regulate different aspects of wound healing, forming complex molecular networks that govern cellular activities throughout the healing process. These pathways integrate various signals and coordinate cellular responses to ensure proper healing.
The PI3K/AKT pathway plays an important role in cell migration, proliferation, and survival during wound healing3. This pathway is activated by various growth factors and cytokines and regulates multiple cellular processes essential for tissue repair. Targeting this pathway, through natural extracts or stem-cell-based treatments, has shown promise for enhancing wound healing3.
The Wnt/β-catenin signaling pathway enhances wound healing by upregulating the expression of genes involved in cellular proliferation, migration, angiogenesis, and other processes essential for tissue repair3. This pathway is particularly important for the proliferative phase of wound healing and has been targeted to enhance chronic wound healing in various studies3.
The TGF-β signaling pathway regulates various aspects of wound healing, including inflammation, fibroblast proliferation, ECM production, and scar formation3. TGF-β signaling plays a dual role in wound healing: while it promotes tissue repair by stimulating fibroblast proliferation and ECM production, excessive TGF-β signaling can lead to fibrosis and scarring. Therefore, balanced TGF-β signaling is essential for optimal wound healing3.
The Nrf2 signaling pathway plays a role in protecting cells from oxidative stress during wound healing. Nrf2 activation promotes the expression of antioxidant genes, reducing oxidative damage and potentially enhancing healing, particularly in chronic wounds where oxidative stress is elevated3. Studies have shown that promoting Nrf2 protein expression can help reduce oxidative stress in chronic wounds, potentially enhancing healing3.
The Notch signaling pathway contributes to various aspects of wound healing, including cell fate determination, proliferation, and differentiation3. This pathway plays roles during normal wound healing and can be dysregulated in pathological conditions like diabetic wounds and hypertrophic scars3. Understanding and targeting these signaling pathways offers potential strategies for enhancing wound healing and addressing pathological conditions like chronic wounds.
Long Non-coding RNAs: Novel Regulators of Healing
Recent research has identified long non-coding RNAs (lncRNAs) as important regulators of wound healing. A study tracking gene expression in human skin wound healing identified 20 evolutionarily conserved lncRNAs with significant roles in the healing process4.
Among these, the lncRNA SNHG26 has been identified as a pivotal regulator in keratinocyte progenitors, underpinning the transition from the inflammatory to the proliferative phase of wound healing4. Mice deficient in Snhg26 exhibit impaired wound repair characterized by delayed re-epithelialization accompanied by exacerbated inflammation, highlighting the importance of this lncRNA in the healing process4.
Mechanistically, SNHG26 interacts with and relocates the transcription factor ILF2 from inflammatory genomic loci, such as JUN, IL6, IL8, and CCL20, to the genomic locus of LAMB34. This molecular interaction facilitates the inflammatory-to-proliferative state transition of keratinocyte progenitors, a critical step in wound healing4.
These findings suggest that lncRNAs play cardinal roles in expediting tissue repair and regeneration and may constitute an invaluable reservoir of therapeutic targets in reparative medicine4. As research in this area continues to evolve, lncRNAs may emerge as important targets for novel therapeutic approaches to enhance wound healing.
Challenges and Therapeutic Approaches in Wound Healing
Despite our growing understanding of the cellular and molecular mechanisms of wound healing, significant challenges remain, particularly in the context of chronic wounds associated with conditions like diabetes mellitus, hypoxic stress, obesity, and malnutrition8. Addressing these challenges requires innovative therapeutic approaches that target specific aspects of the wound healing process.
Chronic Wounds: Understanding Pathological Healing
Chronic wounds are characterized by persistent inflammation and failure to progress through the normal healing phases. The transition from the inflammatory to the proliferative phase represents a key step during wound healing, and failure of this transition leads to impaired re-epithelialization accompanied by persistent inflammation, which has been recognized as a pathological hallmark of chronic wounds4.
Several factors can contribute to the development of chronic wounds. Dysfunction in cytokine production can cause inflammatory non-healing wounds8. Impaired angiogenesis can lead to hypoxia in the wound, delaying healing and contributing to chronicity13. Excessive oxidative stress, often present in conditions like diabetes, can damage cells and impair the healing process3.
Understanding the molecular mechanisms underlying chronic wounds is essential for developing targeted therapies. For instance, research has shown that the inflammatory-to-proliferative state transition of keratinocyte progenitors, which is regulated by lncRNAs like SNHG26, is critical for proper healing4. Dysfunction in this transition can lead to chronic wounds characterized by persistent inflammation and delayed re-epithelialization4.
Therapeutic Approaches: Targeting Molecular Mechanisms
Based on our growing understanding of the cellular and molecular mechanisms of wound healing, several therapeutic approaches have been developed or are under investigation. These approaches target specific aspects of the healing process to enhance healing, particularly in challenging cases like chronic wounds.
Growth factor therapy represents one of the most extensively studied approaches for enhancing wound healing. Animal studies have shown that exogenously added growth factors can accelerate the normal healing process, and growth factors have been used successfully in humans to treat previously incurable wounds6. PDGF, in particular, has been approved for clinical use in certain types of chronic wounds, demonstrating the potential of growth factor-based therapies6.
Cytokine modulation offers another promising approach for enhancing wound healing. By targeting specific cytokines or their receptors, it may be possible to modulate inflammation and promote the transition to the proliferative phase8. However, given the complexity of cytokine interactions and their diverse cellular targets, further research is needed to develop more specific and effective cytokine-based therapies8.
Signaling pathway modulation represents a more targeted approach to enhancing wound healing. By specifically targeting pathways like Wnt/β-catenin, TGF-β, or Nrf2 signaling, it may be possible to enhance specific aspects of the healing process or address pathological conditions like excessive inflammation or fibrosis3. For example, promoting Nrf2 protein expression has been shown to help reduce oxidative stress in chronic wounds, potentially enhancing healing3.
Newer approaches based on gasotransmitters represent an emerging area of research in wound healing therapeutics. Gasotransmitters are bioactive signaling molecules that can freely diffuse into cells and exert antioxidative effects, making them potential therapeutic targets for enhancing wound healing, particularly in conditions associated with elevated oxidative stress5.
Finally, the identification of lncRNAs like SNHG26 as regulators of key transitions in the wound healing process suggests potential for lncRNA-based therapeutic approaches4. By targeting specific lncRNAs or their interactions with transcription factors, it may be possible to modulate critical aspects of the healing process, such as the inflammatory-to-proliferative state transition4.
Conclusion
Wound healing represents a remarkable example of the body’s capacity for tissue repair and regeneration, involving intricate interactions between various cell types and molecular signals. The cellular and molecular mechanisms that drive this process are complex and finely tuned, ensuring that healing progresses through the stages of hemostasis, inflammation, proliferation, and remodeling in a coordinated manner.
Understanding these mechanisms has advanced significantly in recent years, revealing the critical roles of various cell types, including platelets, immune cells, fibroblasts, keratinocytes, and endothelial cells, in the wound healing process. Molecular regulators such as growth factors, cytokines, and signaling pathways orchestrate the activities of these cells, ensuring proper progression through the healing phases. Emerging regulators like long non-coding RNAs add another layer of complexity to this intricate process.
Despite these advances, challenges remain, particularly in the context of chronic wounds, where the normal healing process is disrupted. However, our growing understanding of the cellular and molecular mechanisms of wound healing has opened new avenues for therapeutic intervention, offering hope for improved outcomes in challenging cases.
Future research in this field should focus on further elucidating the complex interactions between different cell types and molecular signals during wound healing, particularly in pathological conditions. Additionally, the development of more targeted and effective therapeutic approaches, based on our understanding of these mechanisms, represents an important goal for improving wound care outcomes. By continuing to unravel the cellular and molecular intricacies of wound healing, we can advance toward more effective treatments for wound repair and regeneration, ultimately improving quality of life for patients with both acute and chronic wounds.
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