Strategies to Minimize Surgical Scarring: Translation of Lessons Learned from Bedside to Bench and Back

Abstract

Significance:

An understanding of the physiology of wound healing and scarring is necessary to minimize surgical scar formation. By reducing tension across the healing wound, eliminating excess inflammation and infection, and encouraging perfusion to healing areas, surgeons can support healing and minimize scarring.

Recent Advances:

Preoperatively, newer techniques focused on incision placement to minimize tension, skin sterilization to minimize infection and inflammation, and control of comorbid factors to promote a healing process with minimal scarring are constantly evolving. Intraoperatively, measures like layered closure, undermining, and tissue expansion can be taken to relieve tension across the healing wound. Appropriate suture technique and selection should be considered, and finally, there are new surgical technologies available to reduce tension across the closure. Postoperatively, the healing process can be supported as proliferation and remodeling take place within the wound. A balance of moisture control, tension reduction, and infection prevention can be achieved with dressings, ointments, and silicone. Vitamins and corticosteroids can also affect the scarring process by modulating the cellular factors involved in healing.

Critical Issues:

Healing with no or minimal scarring is the ultimate goal of wound healing research. Understanding how mechanical tension, inflammation and infection, and perfusion and hypoxia impact profibrotic pathways allows for the development of therapies that can modulate cytokine response and the wound extracellular microenvironment to reduce fibrosis and scarring.

Future Directions:

New tension-off loading topical treatments, laser, and dermabrasion devices are under development, and small molecule therapeutics have demonstrated scarless wound healing in animal models, providing a promising new direction for future research aimed to minimize surgical scarring.

Swathi Balaji, PhD

SCOPE AND SIGNIFICANCE

Scar formation can cause significant physical, social, and psychological effects on a patient's quality of life. Thus, scarring-related costs have risen to become a several billion-dollar industry. However, recent advances have provided insight regarding mechanisms that lead to worsened scarring. The focus of this review is to understand the factors that affect the molecular mechanisms of wound healing and regulate surgical scar disruptions, and to discuss evidence-based strategies to minimizing surgical scarring in the pre-, intra-, and postoperative periods.

TRANSLATIONAL RELEVANCE

Recently, there have been many advances in understanding the mechanisms that influence scarring and fibrosis. Mechanical tension, such as retraction during a surgery or use of sutures, may activate fibroblasts and proinflammatory cytokines, ultimately increasing the amount of type-I collagen and matrix production. Inflammation is also a timing-dependent factor in the healing process, which is necessary in the early stages but detrimental later if it becomes chronic, through the activation of profibrotic growth factors and interleukins. Perfusion and hypoxia are also associated with poor outcomes and the development of chronic nonhealing wounds. Understanding the mechanisms of wound healing can drive therapies to modulate these factors and improve the cosmetic wound healing outcome.

CLINICAL RELEVANCE

Surgeons and patients may have a significant impact on the appearance of surgical scars. Factors including age, coexisting conditions, environmental exposure, and lifestyle habits such as smoking and medications may need to be accounted for and addressed when counseling the patient preoperatively. During the surgery, surgeons may change the placement of the incisions to mask the resulting scar, either in natural wrinkle lines or in areas that are easily covered, and may choose from many different sutures to control tension within the wound. Finally, postoperatively, there are many therapies, ointments, and devices designed to improve wound care and healing, prevent infection, reduce inflammation, and decrease tension, resulting in an improved final scar appearance.

BACKGROUND

Scars result from deposition of collagen fibrils by fibroblasts following dermal disruption. Surgical incisions are often healed by primary intention, the most expedient form of wound healing, which always results in some degree of scarring. The process of primary wound healing involves four phases: hemostasis, inflammation, proliferation of fibroblasts with extracellular matrix (ECM) deposition and new vessel formation, and remodeling, in which collagen fibers and other ECM molecules are reorganized into mature scars.¹ Imbalance or stress during any of these phases can lead to a prolonged healing process, susceptibility to infection, and increased fibrosis and scarring. Scarring may cause social and psychological effects beyond cosmesis, as studies have demonstrated a correlation between scarring and disfigurement from surgery and low satisfaction with life.² The economic impact of scar management is evident, as the market for anti-skin scarring-related medication costs an estimated $12 billion annually, and is projected to increase to $35 billion worldwide by 2023.^3,4 A wide range of techniques can be applied in the preoperative, intraoperative, and postoperative period to relieve tension, control infection, minimize inflammation, and support perfusion in the healing tissue. In this way, surgeons can optimize wound healing and minimize scar formation, with the ultimate goal to produce a thin and minimally perceptible scar, which is flat and color matched to the surrounding skin. The focus of this review was to understand the factors that affect the molecular mechanisms of wound healing and regulate surgical scar disruptions, and to discuss evidence-based strategies for minimizing surgical scarring.

Physiology of wound healing and scar formation

Wound healing in the skin occurs by one of three routes (Fig. 1). Primary intention wound healing occurs when the edges of the wound are brought together. This is the most common modality of healing after the effective closure of surgical incisions. Healing by primary intention requires less epithelialization, is least prone to infection when incision is made in a sterile environment, and produces the least amount of scarring.⁵ Secondary intention wound healing occurs when there is a large loss of tissue and the edges of the wound cannot be reapproximated, such as in the cases of large abdominal incisions. In this process, the open wound must eventually be filled with granulation tissue, which is a longer process, is more susceptible to bacterial colonization, and yields more scarring. Tertiary intention wound healing (also called delayed closure or secondary closure) occurs when closure of the wound is purposefully delayed to minimize contamination and ensure optimal tissue viability and perfusion, thus allowing definitive closure to be achieved with a higher chance of success. This route may be necessary if the surgical wound contains devitalized tissue or requires temporary drainage while an infection in the wound space is being treated.⁶ This delayed closure process is, however, at higher risk of hypertrophic scarring compared with immediate closure.⁷ Whenever feasible, a surgeon aims to execute a closure that allows for healing by primary intention.

Figure 1.

Phases of wound healing in context of primary, secondary, and tertiary intention wound healing. Created using Biorender.com. Color images are available online.

The phases of wound healing are similar regardless of whether primary, secondary, or tertiary mechanisms are used, although changes in the total length of time for wound healing and maturation vary accordingly. Immediately after injury, the hemostasis phase begins, as platelets interact with damaged endothelium and experience stasis from disrupted flow, which sets off a cascade of events leading to clumping and the formation of a fibrin clot that seals off the bleeding vessels. This phase is followed by an inflammatory phase, where neutrophils and macrophages clear wound site infection and debris over several days. Interactions of innate and adaptive immunity, orchestrated primarily by macrophages and lymphocytes in this phase, result in the secretion of growth factors that recruit cells to promote new vascularization, proliferation of fibroblasts, and ECM deposition to reconstitute the wounded dermal tissue. Proliferation first produces granulation tissue, which is rich in connective tissue and new blood vessels. Myofibroblasts contract the dermal granulation tissue, bringing in the wound margins to facilitate wound closure, whereas epidermal keratinocytes migrate and proliferate to reepithelialize the wound. After closure, the wound undergoes the maturation or remodeling phase, in which the epidermal barrier is reconstituted, and collagen fibers reorganize and restore ∼80% of the original tensile strength to the skin tissue. This process can last up to 2 years and causes the appearance of scars to change over time.¹

In comparison with uninjured skin, scar tissue lacks the elasticity of native skin and often has decreased perfusion compared with the surrounding skin.⁸ These features result in scars that distort the appearance, texture, contour, and elasticity of the skin. Intriguingly, fibrotic responses to similar surgical wounds are different among individuals, leading to a broad spectrum of response that ranges from healing with minimal fibrosis in some patients to hypertrophic scar formation, surgical adhesions, and contractures in others. Therefore, to minimize scar formation, the surgeon's primary goal is to minimize the amount of granulation tissue and subsequent scar deposition required to heal the wound. By minimizing scar tissue, the surgeon can limit changes in color, shape, elasticity, and texture caused by the scar. Efforts to minimize scarring focus on optimizing elements of wound healing in three areas: minimizing tension on wounds, limiting infection and excess inflammation, and supporting perfusion. The effects of each of these factors are discussed hereunder, along with the discussion on techniques to optimize them.

DISCUSSION

Predominant factors that influence surgical scarring

Tension on wounds

A comprehensive understanding of how tension regulates the cellular contributors of the wound repair process is imperative as most surgical methods of wound closure add nonphysiologic tension (sutures, staples, and so on) to the wound. It has been shown that exogenous tension activates fibroblasts and a cascade of profibrotic and proinflammatory cells and signaling molecules. Rolin et al. showed that the response of fibroblasts cultured as scratch-wounded monolayers and exposed to uniaxial mechanical strain (mimicking the tension sutures can exhibit) is characterized by an increase in procollagen type-I synthesis and tissue inhibitor of matrix proteases TIMP-1 along with a decrease in matrix metalloprotease 1.⁹ Type-I collagen is a main component of the ECM, a structural complex that is necessary for the healing process but can lead to excessive scarring with dysregulated deposition. Uniaxial tension on fibroblasts has also been shown to upregulate other ECM-related gene expression, including neurotrophins, that is, neural growth factors and neurotrophin-3 (NT3), which are known to stimulate fibroblast migration.¹⁰

Another study by Aarabi et al. demonstrated the importance of the mechanical tension in wounds in ECM production and pathologic fibrosis. Their studies using murine incisional wound models showed that mechanical loading of murine wounds during the proliferative phase of healing results in hypertrophic scar formation, associated with an increase in cellular density, mainly owing to stress-induced decrease in fibroblast apoptosis. Their study revealed a causal relationship between wound tension and scar hypertrophy, wherein the effects of stress-induced upregulation of Akt lead to decreased apoptosis, increased cellular accumulation, and dramatic hypertrophic scar formation.^11,12 These data correlate with previous work showing that mechanical stress acts to inhibit fibroblast apoptosis.^13,14 Recent work by Mascharak et al. places an even greater implication on tension in the pathogenesis of scarring.¹⁵ Using several murine models and fibroblast transcriptional analysis, they demonstrated that a canonical mechanotransduction pathway serves to promote yes-associated protein (YAP) expression in reticular dermal fibroblasts that activates an engrailed-1-positive lineage of fibroblasts that are singularly responsible for dermal scarring. Inhibition of this pathway using verteporfin, an FDA-approved medication used in ophthalmologic surgery, blocks YAP activation of this fibroblast lineage, effectively preventing scarring and culminating in regenerative dermal wound healing.¹⁵ Further recent work has also examined a role for mechanotransduction pathways in regulation of cellular metabolism. Park et al. demonstrated that cells integrated in a stiff matrix upregulate glycolysis as a result of actin filament reorganization.¹⁶ Fibrotic human skin has also been observed to have upregulation of glycolysis, with a fibroblast surface marker CD36 indicative of reduced glycolytic activity, upregulated fatty acid oxidation, and resultant reduction in ECM accumulation.¹⁷ The authors of this study utilized caffeic acid phenethyl ester to upregulate CD36 expression in fibroblasts, thereby shifting the cells to fatty acid oxidation that mediated fibrosis in a mouse model, highlighting the potential for translational small molecule therapeutics to modulate fibroblast metabolic activity thereby reducing scarring.

Mechanical tension also has a significant clinical role in wound healing complications, including the formation of contractures as the scar matures. Wound contraction that eventually leads to scarring and complications is known to involve tension-mediated increased fibroblast density,^18

–21 increased transforming growth factor- β (TGF-β),²² and stimulating myofibroblasts.^23
–25 Myofibroblasts, which are derived from fibroblasts and produce the contractile protein α-smooth muscle actin, are proposed to be the main drivers of scar contraction by rearranging the surrounding connective tissue,^20,26 and they have also been implicated in the contracture of hypertrophic scars.^27,28 Mechanical tension enhances both fibroblast proliferation and survival, as well as their differentiation into myofibroblasts.^24,29 Taken together, these results suggest targeted interventions to uncouple mechanical signaling or to uncouple Akt and downstream apoptotic pathways would be useful therapeutic strategies to eliminate hypertrophic scar formation. Indeed, wound healing and scarring phenotypes have been shown to be improved when tension is offloaded externally through the use of devices³⁰ or internally with surgical techniques.^31,32 Thus, to allow for optimal wound healing, two types of skin tension may be addressed in the presurgical planning period: static tension and dynamic tension.

Static tension is formed when the wound from a circular excision becomes contorted and ellipsoid owing to the underlying tension on the skin. The long axis of the ellipsoid wound contortion describes the orientation of static skin tension. Karl Langer used this principle to map the typical vectors of static skin tension (called Langer's lines or relaxed skin tension lines [RSTLs]) along the surface of the entire human body.³³ His observations of cadavers have been updated to better reflect the lines of static tension present on living human skin (Fig. 2: Langer's lines vs. Kraissl's lines). These lines correspond to the natural predominant orientation of collagen fibers in the dermis and lie perpendicular to underlying muscle fibers.^34,35 Incisions made parallel to RSTLs generally yield less tension across the wound and as a result, heal with reduced scarring.³⁶ Simon et al. studied the effects of orientation on facial laceration healing, and found that wounds oriented within 20° of Langer's lines healed with significantly superior appearance at the 2-month follow-up.³⁷ In contrast, incisions made perpendicular to Langer's lines experienced greater tension across the wound. In response, a greater amount of collagen was deposited to resist this force, resulting in more pronounced scarring.

Figure 2.

Langer's lines Versus Kraissl's lines. Color images are available online.

Dynamic tension can similarly affect wound healing. The dynamic tension forces produced by movement can disrupt wound edge alignment and affect wound healing. Kraissl's lines describe the direction of skin tension produced secondary to muscle movement. Planning incisions in parallel to Kraissl's lines allows dynamic tension to be minimized and protects wound edge alignment from disruption³⁸ (Fig. 2: Langer's lines vs. Kraissl's lines). In trials of patients undergoing forehead laceration repair, botulinum toxin was injected into the subjacent muscle to eliminate dynamic tension on the healing wound. This produced significantly enhanced healing and improved cosmetic outcomes compared with controls.³⁹ In addition, incisions parallel to these lines allow for camouflaging the wound within natural wrinkles, which can further improve esthetic outcome. In some areas, like the corner of the mouth, static and dynamic tension may exert forces in different directions, making incision planning complex. However, appropriate planning and placement of incisions may reduce tension in the resulting surgical wound, optimizing wound healing outcomes.

Infection and inflammation

Infection and inflammation contribute to suboptimal scarring through the production of factors that mediate the behavior of cells and the composition of matrices. For surgical scars, the most important infections to understand are hospital-acquired infections (Staphylococcus aureus and Pseudomonas aeruginosa). In either case, signaling by Toll-like receptors (TLRs) from altered dermal fibroblasts promotes inflammation and is also known to directly contribute to hypertrophic scarring.⁴⁰ Similarly, sterile inflammation initiated by damage-associated molecular patterns, such as cellular components, S100A8 and 9, DNA, and tenascin-C originating from tissue damage and recognized by TLRs, also activates dermal fibroblasts and culminates in scarring.^41

–44 Inflammation results from a robust immune response that increases the levels of profibrotic growth factors and cytokines in the wound microenvironment, including TGF-β and profibrotic interleukins (IL) such as IL-6, IL-4, and IL-13.^45,46 These compounds, like external tension, have end effects of increasing ECM deposition, causing a worsened appearance of the final scar. In a study carried out in mice knockdown for focal adhesion kinase (FAK) or monocyte chemoattractant protein-1 (MCP-1), Wong et al. uncovered a link between tension and inflammation. In this study, they found that mechanical tension upregulated FAK, a key regulator of cell–matrix interactions, and in FAK knockout mice, there was significantly less fibrosis and inflammation. The FAK pathway acts through MCP-1 to attract inflammatory chemokines. In MCP-1 knockout mice, there was decreased chemokine recruitment and reduced scar formation.^47

–50 By knocking out genes responsible for linking tension to inflammation, they produced mice that could heal with reduced scarring.⁴⁷ The same profibrotic mechanisms that mechanical tension is known to influence may be mediated by factors involved in inflammation such as osteopontin, which is required for myofibroblast differentiation.^51,52 These studies suggest that mounting an early inflammation response is necessary and beneficial to wound healing, whereas prolonged inflammation worsens scarring.⁵³

Perfusion

The processes involved in tissue repair and immunity are highly energy demanding, and thus, perfusion of the healing surgical wound is vital to the overall healing process.^54,55 Angiogenesis is one of the primary steps of wound healing, allowing for an influx of nutrients, oxygen, and immune cells. Excessive tension on the wound, either during the operation with retraction or during wound closure, can impair perfusion to the site. Techniques for improving perfusion to a healing wound focus both on the optimization of the local wound cytokine milieu, as well as the global circulation and patient comorbidities to influence healing systemically.

One of the most well-studied factors affecting tissue perfusion is diabetes-related impairments in vascular endothelial and endothelial progenitor cells, where chronically high levels of glucose leads to poor vascular networks, inability to vascularize a wound, and a higher likelihood of progression to a chronic, nonhealing phenotype.⁵⁶ Scars that heal with the best esthetic outcomes tend to have a network of mature vessels, whereas those with poorer outcomes have either a decreased degree of vessel formation, or a large number of immature vessels, which may result from a heightened inflammatory response.⁵⁷ Hypoxia, or low tissue oxygen levels in the wound may induce a profibrotic response mediated by hypoxia-inducible factor-1 (HIF-1) to upregulate TGF-β and other growth factors, driving deposition of type-I collagen and fibronectin.⁵⁸ Although the HIF-1-induced pathways are essential to kick off wound neovascularization, aberrations in these processes have been implicated in impaired healing and fibrosis. The hypoxia-HIF-1-TGF-β pathway has been posed as a potential target to reduce fibrosis in dermal wounds that are associated with low oxygen delivery.⁵⁹

Strategies to minimize scarring

In the following sections, best practices and evidence-based techniques for reducing wound tension, minimizing inflammation and infection, and improving perfusion will be discussed to achieve optimal esthetic closure of surgical incisions. Many classifications of scars exist, but this review will focus on optimizing the healing process of physiologic scars that result from surgical wounds. Pathological scars, including scarring from burn injuries, pressure ulcers, and keloids have different biological underpinnings and will be largely excluded from discussion.

Preoperative strategies

In the preoperative stage, a surgeon should consider three factors in preparation for creating a minimized scar closure: comorbidities affecting healing, incision placement, and preoperative skin preparation.

Assessment and mitigation of preexisting comorbid conditions

An important step in the preoperative preparation for well-healing wounds is the assessment and mitigation of comorbidities of the patient, which may affect the healing process. The process of healing involves the mobility and proliferation of many cell types in the wound space, an extracellular environment rich in nutrients, a balance of cytokines and growth factors, perfusion to the area, and profuse protein synthesis.⁶⁰ Many common chronic illnesses can affect these processes, and thus, measures should be taken to optimize modifiable conditions for wound healing within the patient preoperatively.

Diabetes is known to negatively affect wound healing through impaired growth factor production, angiogenic response, macrophage function, collagen accumulation, epithelialization, and ECM remodeling.⁶¹ Thus, blood sugar and metabolic disturbances should be well controlled before and after an operation. In trials of 183 diabetic patients, Christman et al. found that every increase in HbA1c by 1% resulted in a decrease in wound area healing rate by 0.028 cm² per day.⁶² Underwood et al. found that successful glycemic control was associated with better surgical outcomes and shorter lengths of stay for postoperative recovery.⁶³ In an outpatient setting, the goal for glycemic control before a procedure should be an HbA1c <8.0%. In an inpatient setting or in the setting of any nonelective procedure, a patient with an HbA1c >8.0% should receive regular blood glucose monitoring. For best esthetic outcome, postoperative blood glucose >140 mg/dL should receive further monitoring and correction with insulin.⁶⁴ However, a recent meta-analysis demonstrated that intensive postoperative blood glucose control (<120 or <150 mg/dL) resulted in a greater risk of hypoglycemia, although without significant effect on infection rates or mortality.⁶⁵ Thus, the American Diabetes Association (ADA) recommends maintaining postoperative glucose between 80 and 180 mg/dL.⁶⁶

Poor nutrition, especially diets lacking in vitamins A, C, E, and zinc can hinder synthesis and remodeling of collagen, production of antioxidants, and cofactors needed for polymerases that participate in the proliferation of cells involved in tissue regeneration.⁶⁰ Patients taking corticosteroids have significantly impaired healing ability, but studies have demonstrated that vitamin A supplementation can restore some healing capacity in these patients.⁶⁷ The use of perioperative vitamin A supplementation in patients taking corticosteroids (25,000 IU before and after surgery) has been shown to improve rates of healing in skin and fascia as well as increase wound tensile strength.⁶⁸ In addition, topical administration of 200,000 IU of vitamin A every 8 hours is associated with increased rates of epithelialization.⁶⁹

Tobacco use causes vasoconstriction, thrombogenesis, and aberrant cell function and should be stopped from at least 4 weeks before until 4 weeks after scar revision operations.^70
–72 Wong and Martins-Green showed that cigarette smoke produces a stress response in fibroblasts that alters their survival and migratory capabilities. In fibroblasts exposed to cigarette smoke, the increase in survival leads to a buildup of connective tissue in the wound space, whereas the inhibition of fibroblast migration contributes to the nonclosure of wounds.⁷³ For elective procedures, some surgeons refuse to operate on patients who smoke altogether; however smoking cessation, even for a short-term period, can help mitigate these risks.^74,75 Although changes in fibroblast migration caused by smoking persists for years after smoking cessation, in a review of 177 articles relevant to smoking and healing, Sørensen established that the impaired inflammatory response associated with smoking could be reversed after 4 weeks of cessation.⁷⁶ The surgeon must establish clear and realistic expectations for the patient and relevant caregivers, as this is an important part of practicing informed consent and can help the patient feel satisfied and take ownership during the postoperative wound care process. This is especially important in patients with uncontrollable variables, such as age, gender, and immunodeficiency. Although these factors may not be adjustable, they should be accounted for in surgical planning and patient counseling.⁷⁷

Planning incision placement

First, depending on the nature of the operation, the surgeon may have some freedom in defining the size, shape, location, and direction of the wound. The locations and boundaries of the incisions are chosen based on skin tension, blood supply, and the ability to camouflage the healing scar. As discussed previously, RSTLs and Kraissl's lines reveal the typical vectors of tension across the surface of the body. Using these tension maps allows for placement of incisions in parallel to forces of tension to minimize tension across the wound and thus reduce scarring. A. F. Borges described a simple technique for locating RSTLs, which can be used preoperatively to plan optimal incisions. Using this technique, the surgeon may pinch an area of skin and observe the location and orientation of furrows and ridges, which correspond to the direction of RSTLs.⁷⁸ Special consideration is given to the placement of incisions made to place tissue expanders, as the nearby skin will be under significant tension as the expander is filled. The skin tension created by expanders may not be parallel to classical RSTLs, and in such cases, the incisions are typically placed perpendicular to the direction of expansion (Fig. 3). In planning incision placement, the surgeon may also utilize existing tissue defects to minimize tension. For example, Wilson proposed a means of revising poorly healed scars by de-epithelializing the existing scar, undermining one side of the injury, then anchoring the opposite side using subcuticular sutures. This technique prevented scar widening in 34 of 35 patients who underwent scar revision.⁷⁹

Figure 3.

Change in RSTL's with tissue expander placement after a mastectomy. (A) Before tissue expander placement; (B) after tissue expander placement. Blue dashed line indicates the expander placement. RSTL, relaxed skin tension lines.

The next consideration in incision placement is the blood supply to the skin, which may be interrupted by the creation of an incision. High-resolution episcopic micrographs of human skin biopsies produced by Tinhofer et al. showed that perfusion of the skin occurs through multiple arterial units perfusing unidirectionally at different angles.⁸⁰ Thus, two incisions made in a t-, x-, or v-shape may interrupt multiple angles of perfusion and leave the edge of the intersection vulnerable to ischemia. Low oxygen tension in a wound edge may result in a slower healing, increased scarring, and more complications.

Another factor for consideration when deciding on incision placement is the potential for camouflaging the healing scar. Wrinkle and contour lines can camouflage scarring without necessarily conferring an improvement in the wound healing process.⁸¹ This powerful tool is applied regularly in facial plastic surgery in operations such as eyelid reconstruction,⁸² facelifts,⁸³ and excisions of masses on the head and neck. In a comparison of incision placements for patients undergoing upper neck mass removal, patients with retroautricular hairline incisions reported significantly higher satisfaction than those with conventional cervical incisions.⁸⁴ It is also possible, using Kraissl's lines, to plan incisions along wrinkle lines a younger patient may develop in the future. Tellioğlu described a technique to reveal placement of wrinkle lines in the younger patient by adhering a sterile, transparent plastic sheet to an area on the patient's face. Upon movement of the facial muscles, the plastic sheet deforms and wrinkle lines can be clearly observed.⁸⁵ The surgeon may also have the ability to place incisions in areas that are usually obscured, such as the hairline, behind the pinna, or areas covered by most swimsuits. The optimal placement of a surgical wound is chosen with skin tension, blood supply, and camouflage potential thoroughly considered.

Intraoperative surgical strategies

To minimize the disfiguring consequences of scar formation among all classes of coverage, the wound closure techniques described by Son et al. as the 5 A's: asepsis, absence of tension, accurate approximation, avoidance of raw surface, and atraumatic tissue handling, must be employed.⁸⁶ We summarize, hereunder, the current evidence for benefits, limitations, and applications of intraoperative techniques to improve cosmetic outcomes by minimizing scar formation.

Surgical techniques

During surgery, optimal wound healing can be fostered by successful asepsis of the wound area, the reduction of tension, accurate approximation, avoidance of raw surface, and atraumatic tissue handling.⁸⁶ Of these factors, the reduction of tension is especially important and can be achieved using a number of techniques, including layering closure, surgical undermining, and tissue expansion.

When dealing with a large wound, a layered closure may be performed. A layered closure not only eliminates dead space and mitigates the risk for infection or fluid collection, but also equilibrates tension across the deeper layers to reduce tension on the epidermis.⁸⁷ Reducing skin tension can also be performed by extensive undermining of the tissues, disrupting dermal and subdermal attachments from the epidermal layer to allow for increased elasticity to aid in closure.

Tissue expansion is a reconstructive technique that involves progressively filling a subcutaneously placed implant to allow the local tissues to slowly expand under constant pressure, so that they can be advanced in a delayed manner. This process necessarily involves a carefully limited amount of tension on the skin and subcutaneous tissue, with the goal of expanding the amount of tissue available so that a repair made in the future may heal under less tension.⁸⁸ The use of local advancement flaps ultimately results in coverage with sensate skin that looks similar in color and texture to the original tissue, but is limited by the health of adjacent skin, the condition of the wound bed, and the size of the area in need of coverage.⁸⁹

Suture selection

When closing a wound with sutures, a suture material that maximizes wound healing by reapproximating wound edges while minimizing excessive tissue damage, ischemia, and tension is considered.^90,91 There are many types of sutures commercially available: monofilament or multifilament, absorbable or nonabsorbable, as well as natural or synthetic. Many sutures today are coated in an antiseptic or metal alloy to prevent bacterial colonization.⁹² Monofilament sutures are not as strong, but they are also less likely to create sinus tracts or house bacteria as compared with multifilament sutures. Absorbable sutures lose tensile strength as they degrade, whereas nonabsorbable sutures maintain the majority of their tensile strength.^93,94 The risk of infection and cosmetic outcome have been shown to be similar for absorbable and nonabsorbable sutures, but absorbable sutures were found to decrease the risk of wound dehiscence.^95,96

Both absorbable and nonabsorbable sutures are further stratified into types composed of natural, mammalian collagen, or synthetically crafted materials. Natural absorbable sutures (chromic suture) are degraded by proteolytic enzymes, leading to a larger inflammatory reaction compared with the synthetic type, which are degraded by hydrolysis. Thus, synthetic absorbable sutures, given their method of degradation and their predictable timeline of tensile strength, may be more amenable to scar reduction in wound healing.⁹⁷ In some instances, such as wounds of the head and neck, a nonabsorbable suture may be used to avoid inflammatory reactions but removed before encapsulation to avoid fibrosis or tissue injury that may lead to undesirable cosmetic outcomes.⁹⁷ Table 1 compares the properties of commonly used suture types.^{93,98

–103}

Table 1.

Wound dressing options

Dressing	Mechanism	Indication	Precautions	Notable Example	Ref
Paper tape	Tension reduction	Removing tension from early surgical incisions	The strips are absorbent and stay soiled	Steri-Strip^™(3M)	¹⁸⁴
Silicone sheeting	Tension reduction, occlusion, moisture control	Removing tension from early surgical incisions	Limited evidence of benefit in scarring	ScarAway^® Clear Silicone Scar Sheets (Perrigo)	¹³⁶
Silicone gel	Topical moisture control	Used in combination with standard wound care techniques	Can preclude the use of adhesive dressings	ScarAway Silicone Scar Gel (Perrigo)	^131,133
Negative pressure wound therapy	Negative pressure mobilizes exudates, adhesive sheet is occlusive	Early surgical incisions	Cost, requires attachment to a vacuum	PICO™ dressing (Smith & Nephew) V.A.C.^® Therapy (KCI/3M)	¹³⁹
Bolster dressing	Stabilizes flaps with underlying wound bed	Used in flaps and grafts at risk of incorporating with wound bed, concave surfaces.	Physically bulky, may be inferior to negative pressure wound therapy		^130,185

Suture technique

Although suture selection is an important consideration in wound healing, the type of technique used is equally important. Most suturing techniques can result in appropriate wound approximation, but there are differences in suture visibility, blood flow, and number of needle passes needed to reach full approximation to minimize the distance that new blood vessels and keratinocytes participating in tissue repair will need to migrate.^104,105

Arguably, the simplest suturing technique is the simple interrupted suture, which requires one needle pass through each side of the wound before a knot is tied to bring the wound edges together with an exteriorized knot. Simple interrupted suturing is quick and reliable but results in multiple visible puncture wounds along the wound edges.¹⁰⁶ In placing the sutures, minimizing the total number of sutures needed by maximizing the distance between suture placement while adequately reapproximating the wound has been shown to decrease tissue damage and lead to more favorable scar formation among patients.¹⁰⁷ An alternate approach is the subcuticular suturing technique, which approximates wounds by piercing the dermal–epidermal junction on each side of the wound and tying a buried knot. Subcuticular suturing can be performed in an interrupted or running manner.¹⁰⁶ Whereas the number of needle passes is comparable with that required for simple interrupted suturing, subcuticular stitches do not pierce the epidermis and thus may be a better option for decreased scar formation and increased esthetic outcomes.^{106,108
–110} Subcuticular sutures have also been shown to decrease the risk of bacterial colonization^111,112 as well as wound dehiscence, as the absorbable suture retains tensile strength for a number of weeks before being degraded, whereas a nonabsorbable suture must be removed in 10–14 days.¹¹³ Unidirectional or bidirectional barbed suture may also be used in subcuticular suturing, eliminating the need for knot tying and equilibrating tension across the length of the incision while resulting in similar incidence of infection and cosmesis compared with the conventional suture.^114

–117

Although suturing may be the most common means of closure, many studies have investigated the efficacy and scar-related sequelae of each method of closure, with each method possessing its own utility and drawbacks. A comparative study by Ananda et al. aimed to identify differences in outcomes among incisions closed by suturing, stapling, or tissue adhesives after elective operations. They found that while stapling offered the quickest wound closure, tissue adhesives were superior for asepsis, cosmesis, and minimized postoperative pain.¹¹⁸ A meta-analysis conducted by Coulthard and colleagues concluded that while tissue adhesives such as Dermabond™ and Vetbond™ may offer improved cosmetic results, they require significantly more time to apply and have an increased incidence of wound dehiscence compared with sutures.¹¹⁹ When comparing sutures and stapling, other studies have shown that staples are a quick, cost-effective alternative to sutures with no statistically significant differences in rate of infection or overall cosmesis.^120

–123

Advanced technologies/therapeutics to minimize scarring postoperatively

The morphology of the healing wound has key determinants during the inflammatory and proliferative phases of healing, which occur in the first weeks after surgery, as well as the remodeling phase, which is known to last up to 1–2 years (Fig. 4).¹²⁴ Although proper surgical technique is essential to reduce scarring by optimizing the early wounding period, later interventions focused on mechanical tension and inflammation reduction extend the same principles to management at follow-up visits and for the patient at home. Current strategies to reduce scarring postoperatively ought to be explored and evaluated to provide evidence-based recommendations for the surgeon. At the postoperative stage, many methods of measuring scar severity and its effect on patients have been defined. As discussed in the background, these varied scales share commonality in their measurement of scar size, elevation, erythema, and pigmentation abnormalities. This review considers different modalities that have been effective or are worth pursuing further to reduce physiologic scarring and prevent hypertrophic scarring.

Figure 4.

Scar improvement goals by healing phase.

Strategies to off-load tension

Surgical technology is constantly evolving, and many devices have been created for offloading tension in surgical closures. One such device created specifically for tension reduction is a suture retention device known as SUTUREGUARD^® (Suturegard^® Medical, Inc., Portland, OR). SUTUREGUARD is used by placing a simple interrupted or subcutaneous suture across a wound bed and applying force to the suture. In a matter of minutes, the SUTUREGUARD system stretches collagen fibers within the dermis to increase elasticity, decrease the size of wounds, and allow for larger wounds to be closed with minimal tension. This type of device allows for the primary closure of wounds that may have previously been unable to be reapproximated while also decreasing mechanical forces on the closure itself.^125
–127

A second surgical technology is the Embrace^® device (Neodyne Biosciences, Inc., Newark, CA), a silicone elastometric dressing placed over the surgical closure to offload tension and reduce scarring. Reducing mechanotransduction pathways that trigger inflammation and poor scar outcomes is the suggested mechanism of this adjunct therapy. In a multicenter, randomized controlled trial, application of Embrace^© to abdominoplasty scars resulted in significantly improved visual analog scale (VAS) and patient and observer scar assessment scale (POSAS) scores at 12 months when applied for at least 5 weeks.¹²⁸ Of note, this study demonstrated that the most significant advantage was seen in patients who were rated as “worse scarrers” by POSAS score.¹²⁹ It has become one of the first FDA-approved mechanotherapies to improve the cosmesis of surgically placed scars. A major consideration of this device is that thus far it has only been studied in high-tension scars such as abdominoplasty, which narrows its currently recommended use.

Dressings

Dressing and splinting can be used to offload static and dynamic tension across the wound, protect from infection, provide moisture control, and even affect the flow of exudates within the wound space (Table 1). In addition, immobilization of the wound site with dressing and splinting is vital to the process of wound edge adhesion and neovascularization of the site. Bolster dressings, which are weighted dressings used commonly following full-thickness skin grafts, ensure that the graft maintains contact with the underlying wound bed while preventing seroma and hematoma formation in the space between graft and recipient site.¹³⁰

Silicone gel sheeting provides moisture and improves epithelialization while decreasing collagen deposition. In animal models, 2 weeks of application were enough to reduce scar elevation and hypertrophy by up to 80% and epidermal thickness by >30%.¹³¹ Silicone sheeting has been shown to soften and reduce the appearance of scars more than pressure dressings, and has improved scarring outcomes in some randomized controlled trials, although these trials have received criticism.^132

–135 A Cochrane review demonstrated no improvement in scar outcome by silicone gel sheeting, specifically of keloid and hypertrophic scarring, and found that many of these scar prevention studies were prone to evaluator bias.¹³⁶ Despite the mixed literature on the efficacy of silicone gel sheeting, they are a safe topical product with minimal risk profile, and for this reason, silicone sheeting has been a mainstay of postoperative scar management, especially in the first 2 weeks of scarring.

Other simple, low-cost dressings such as adhesive tape and silicone gel matrices can be used to retain moisture and decrease tension across the wound surface.¹³⁷ Another mainstay of surgical wound management is negative pressure wound therapy. Negative pressure wound therapy is a dressing technique that utilizes an enclosed foam dressing connected to a vacuum unit to decrease edema, improve perfusion, and promote wound healing by the mobilization of exudates within the wound space. A single randomized controlled study demonstrated that incisional negative pressure wound therapy resulted in clinically improved scarring among women undergoing bilateral breast reduction mammoplasty; however, a recent case-controlled study contradicted these findings by showing an increase in hypertrophic scar occurrence in patients treated with incisional negative pressure wound therapy following postbariatric brachioplasty.^138,139 Although studies have shown negative pressure wound therapy is appropriate for these purposes, and may even improve tensile strength of a closure, more studies are needed to evaluate the effect of this dressing option on scar formation after primarily closed surgical insicions.^140

–143

Paper tape has been shown to perform similarly to silicone gel and pressure dressings in preventing hypertrophic scar formation.^144,145 The most notable benefit of paper tape over silicone sheets or dressings is its significantly cheaper cost, its lack of need for routine changes, and its flexibility over joints and other surfaces with high exposure to motion. Thus, in patients with low risk of hypertrophic scarring, paper tape has been the treatment of choice.

Strategies to minimize infection

Topical agents

Maintaining moisture and reducing direct air exposure on skin wounds are known to promote faster healing of cutaneous wounds.¹⁴⁶ Mechanistically, moisture retention is thought to alter keratinocyte behavior and expression of cytokine-encoding genes as well as fibroblast collagen deposition.^147
–149 Delivery routes to maintain moisture in scars include ointments, gels, and creams. One of the simplest ointments to improve postoperative scarring is petroleum jelly. Petroleum jelly applied at least three to six times daily, or Xeroform applied daily, for 1–3 weeks has been shown to effectively maintain wound bed moisture and improve scar outcomes.^150,151 The main benefits of this approach are low cost, ease of administration, and clinical efficacy.

Despite the significant role of moisture in improving scar quality by using moisturizers and emollients, their effects are not fully explained by moisture retention. In clinical trials, there have been marked differences in the scarring outcomes from application of occlusive dressings and ointments.¹⁵² As an additional consideration, excessive moisture increases the risk of macerating the skin and thus increases the potential for infection and inflammation, which leads to worse scarring outcomes.^153,154 These concerns ought to be weighed against the benefits of moisture preservation as part of an individualized scar assessment; in addition, they highlight additional considerations in the use of topical therapies beyond moisture.

Antibiotic ointments

A significant consideration in scar minimization is avoiding infection of the scar area. Infection is known to promote inflammation-mediated fibroblast proliferation and alter collagen deposition.^155,156 At present, bacitracin ointment has been used most often in the early postoperative period during reepithelialization or in wounds located in high-risk areas such as skin creases. By preventing infection, bacitracin ointment is purported to promote faster epithelialization.¹⁵⁷ However, several studies have shown that the antibiotic component may not be necessary as petrolatum-based ointment seems to provide equivalent efficacy as combination antibiotic ointment.^157
–159 Based upon these cumulative studies, the use of antibiotic ointments over simple petroleum ointments is not recommended as part of the regular management of postoperative scars.

Antioxidants

Increased free radicals generated during inflammation induce oxidative stress that inhibits the proliferative phase of wound healing.¹⁶⁰ Antioxidants such as vitamin C and vitamin E have been long proposed as adjunct treatments for improving wound healing in nonhypertrophic scars. Although animal literature suggested that antioxidants such as vitamin E and derivatives reduced inflammation in wounds, topical vitamin E also has not been shown to be more efficacious than petroleum-based ointment to improve scar appearance.^160
–162 No evidence has demonstrated that vitamin E is effective in reducing scarring in grafting procedures.¹⁶³ A concern that vitamin E inhibits collagen synthesis, which might lead to the development of widened scars or wound dehiscence, has also been raised.^164,165

A preliminary study demonstrated that application of a hyaluronic acid sponge with zinc twice daily to surgical scar postbreast surgery (at POD 2–4) improved appearance and patient satisfaction at 12 weeks compared with hyaluronic acid with placebo application.¹⁶⁶ In contrast, the use of a hyaluronic acid sponge with vitamin C did not obtain similar benefits to scar appearance (although patient satisfaction was increased); however, this result may have been skewed by its application to scars older than 4 weeks.¹⁶⁷ Further controlled studies are required to make firm recommendations on the use of specific vitamins and minerals and matricellular compounds on scarring.

Laser therapy

Low-energy lasers (He-Ne, infrared) seem to be effective by stimulating cellular activity, resulting in improved healing and epithelialization. The use of cryogen-cooled 585-nm and 595-nm pulsed-dye lasers starting on suture removal day has been also shown to be an effective and safe method of improving outcomes in new surgical scars.^168,169 It has been shown further that three monthly sessions of 595-nm pulsed-dye laser (Vbeam; Candela Corp., Wayland, MA) starting on suture removal day (POD 7–10) can be augmented with three monthly sessions with ablative 2940-nm Er:YAG fractional laser (EYFL) sessions to provide additional improvement in VSS scores and patient satisfaction when the former was not sufficient.¹⁶⁹

Translational bench therapies

Cellular communication network factor 2

As we understand more of the specific cells, cytokines, and growth factors that are involved in the fibrosis pathway, there has been much interest in using these molecules to attenuate fibrosis. Among these is cellular communication network factor 2 (CCN2), formerly connective tissue growth factor, a growth factor that lies upstream of TGF-β and has been shown to be upregulated in hypertrophic scars. Inhibition of CCN2 reduces the number of myofibroblasts as well as the amounts of type I and III collagen.¹⁷⁰ A randomized control trial showed that injection of an antisense oligonucleotide targeting CCN2 significantly improved hypertrophic mastectomy scars.^171,172

Mesenchymal stromal cells

Another bench therapy to improve scarring outcomes uses mesenchymal stromal cells (MSCs), stem cells that retain the ability to differentiate into a variety of cells and secrete growth factors, cytokines and small extravesicular particles that are beneficial to the wound healing process. As mentioned previously, a high level of inflammation may lead to worsened scarring outcomes. MSCs have been shown to mitigate excess inflammation by altering their production of cytokines and releasing anti-inflammatory growth factors.^173,174 Many of these growth factors, including VEGF, TGF-β, and certain interleukins, enhance angiogenesis and improve the structure and organization of the ECM. Studies have shown promising results for MSCs to be able to reduce tissue scarring and improve remodeling by reducing proliferation of myofibroblasts and stimulating formation of collagen type-I.¹⁷⁵ They have also been shown to improve healing in burn injuries and diabetic ulcers.¹⁷⁶ Thus, MSCs have incredible therapeutic potential for minimizing surgical scarring, but more large-scale clinical trials are necessary and underway before their use as mainstay therapy in humans.

Adipose-derived stem cells

The application of adipose-derived stem cells (ADCs) in wound healing is a promising area of emerging research for scar minimization. By their involvement in paracrine signaling through inhibition of TGF-β action, local injections of ADCs have been shown in animal models to decrease scar size, minimize color changes, and improve scar pliability.^177,178 A number of studies using a combination of human cells injected into animal wounds have demonstrated accelerated wound closure, improved tissue strength, and improved visual appearance in the experimental group.¹⁷⁹ The ability of ADCs to mitigate scar formation throughout the healing process has yet to be thoroughly tested by in vivo human trials, which may translate into a new therapeutic strategy for scar minimization in the future.

Deferoxamine

Another therapy that has been studied in reducing fibrosis is deferoxamine, an iron-chelating compound. There have been many studies investigating the use of deferoxamine in reducing the amount of fibrosis that is associated with irradiation. Fibrosis associated with radiation presents a significant challenge for reconstructive surgery, with complication rates as high as 40%.¹⁸⁰ In murine models of irradiation, both topical and intradermal formulations of deferoxamine have improved angiogenesis and perfusion of tissue, as well as tissue pliability.^181,182 It also can mitigate the fibrosis that occurs with chronic radiation.¹⁸³ In vivo studies have shown much promise for deferoxamine as a therapeutic for improving scarring postsurgical intervention, although similar to MSC therapy, larger scale clinical trials are needed before use in humans.

CONCLUSION

In executing closure of a surgical incision, the goal of the surgeon is to restore the original appearance, texture, contour, and supple constitution to the injured tissue. The ideally healed wound is imperceptible, does not distort adjacent structures, and does not cause any restriction in movement. It has no effect on the patient's appearance, quality of life, or psychological self image. In other words, the ideal healed wound is one with the most minimized scar.

In the preoperative setting, scar minimization is best achieved through preparatory operative measures that promote a tension-free closure and help avoid inflammatory and infectious excess. Optimization and control of the patient's comorbidities and nutritional status can also help promote the ideal healing environment systemically. In the intraoperative phase, measures can be taken to reduce tension across the surgical incision to optimize the scarring process. These measures include layering closure, undermining, suture techniques, and emerging technologies. As scars form and remodel in the postoperative period, a number of treatment options, including topical ointments, steroids, biologics, and surface therapies, have been found to assist in the healing process or improve scar cosmesis.

Altogether, discussions of each of the techniques explored in this review should provide readers with a basic understanding of the underlying science and tools involved in scar minimization. We recommend the utilization of a holistic operative plan and an approach that addresses specific deficits in the anatomical, microbiological, and psychological healing process of the patient.

In the future, there is much room for new research and the development of novel technologies for scar minimization. The scarless wound healing produced in animal models using small molecule therapeutics demonstrates promising potential, although these applications have yet to be utilized in humans. New topical treatments, laser, and dermabrasion devices that arrive on the market aim at continuously improving scar minimization. Continued research on wound healing and scar minimization will be necessary so that surgeons, together with their patients, can make better decisions about scar minimization.

SUMMARY

In executing closure of a surgical incision, the goal of the surgeon is to restore the original appearance, texture, contour, and supple constitution to the injured tissue. In the preoperative setting, scar minimization is best achieved through control of the patient comorbidities and the optimization of nutritional status to promote the ideal systemic healing environment. In the intraoperative phase, measures can be taken to reduce tension across the surgical incision to optimize the scarring process. These measures include layering closure, undermining, suture techniques, and emerging technologies. As scars form and remodel in the postoperative period, many treatment options, including topical ointments, steroids, biologics, and surface therapies, have been found to assist in the healing process or improve scar cosmesis.

TAKE-HOME MESSAGES

Tension, inflammation, and perfusion are three factors that influence the wound microenvironment and negatively impact the appearance of the final scar.

Preoperatively, incision placement, skin preparation, and patient comorbidities are important to consider.

Intraoperatively, surgeons may consider various suture types and mechanisms of closure to improve the healing process.

Postoperatively, there are a variety of topical ointments, devices, and injectable therapies that are designed to take advantage of one or more of the stages of healing to decrease tension, reduce inflammation and improve perfusion, which improve the overall final appearance of the scar.

Footnotes

ACKNOWLEDGMENTS AND FUNDING SOURCES

The authors thank Miriam King, BSN, M.Ed., of the Office of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, who provided editing support for this article.

S.B. is supported by the 3M Award given by the Wound Healing Foundation, Clayton Seed Grant by the Department of Pediatric Surgery, Texas Children's Hospital and Dunn Foundation award.

AUTHORs' CONTRIBUTION

S.B., E.P.B., and A.K. conceptualized the article; U.M.P, J.M., M.J.D., A.AG, D.C., and W.D.S. synthesized data and drafted the article; U.M.P, J.M., and W.D.S. made the figures; S.B. and E.P.B., and A.K. contributed and critically edited the article; all authors discussed the results and commented on the article.

AUTHOR DISCLOSURE AND GHOSTWRITING

The authors have no financial or other competing interests to disclose. The content of this article was expressly written by the author(s) listed. No ghostwriters were used to write this article.

ABOUT THE AUTHORS

Umang M. Parikh, BA, is a medical student at Baylor College of Medicine and is currently a Medical Research Pathway fellow at Texas Children's Hospital in the Laboratory for Regenerative Tissue Repair (LRTR), where she is conducting wound healing basic science research. James Mentz, MD, Ian Collier, MD, and Daniel Colchado, MD are medical students at Baylor College of Medicine with the Department of Pediatric Surgery. Matthew J. Davis, MD, and Amjed Abu-Ghname, MD are Plastic Surgery residents at Baylor College of Medicine. Walker D. Short, MD, is a general surgery resident at Baylor College of Medicine completing his research fellowship in the LRTR. Alice King, MD, is an Assistant Professor of Surgery, Pediatrics, and Obstetrics and Gynecology at Baylor College of Medicine/Texas Children's Hospital and an attending pediatric and fetal surgeon. Edward P. Buchanan, MD, is a Melvin Spira Endowed Associate Professor and Chief of Division of Pediatric Plastic Surgery in the Department of Surgery at the Baylor College of Medicine/Texas Children's Hospital. Swathi Balaji, PhD, is an Assistant Professor in the Department of Surgery, Division of Pediatric Surgery at Baylor College of Medicine/Texas Children's Hospital and a Principal Investigator in the Laboratory for Regenerative Tissue Repair.

Abbreviations and Acronyms

References

Nguyen

, Orgill

, Murphy

. 4- The pathophysiologic basis for wound healing and cutaneous regeneration. In: Orgill

, Blanco

, eds. Biomaterials for Treating Skin Loss. Swaston, UK: Woodhead Publishing, 2009:25–57.

Kinahan

, Sharp

, Seidel

, et al. Scarring, disfigurement, and quality of life in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor study. J Clin Oncol, 2012; 30:2466.

Sen

, Gordillo

, Roy

, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen, 2009; 17:763–771.

Sen

. Human Wounds and Its Burden: An Updated Compendium of Estimates. Adv Wound Care (New Rochelle), 2019; 8:39–48.

Velnar

, Bailey

, Smrkolj

. The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res, 2009; 37:1528–1542.

Dimick

. Delayed wound closure: indications and techniques. Ann Emerg Med, 1988; 17:1303–1304.

Prasanna

, Mishra

, Thomas

. Delayed primary closure of the burn wounds. Burns, 2004; 30:169–175.

Dallon

, Sherratt

, Maini

. Mathematical modelling of extracellular matrix dynamics using discrete cells: fiber orientation and tissue regeneration. J Theor Biol, 1999; 199:449–471.

Rolin

, Binda

, Tissot

, et al. In vitro study of the impact of mechanical tension on the dermal fibroblast phenotype in the context of skin wound healing. J Biomech, 2014; 47:3555–3561.

10.

Kim

, Hong

, Nho

, Na

, Shin

. Tensile Stress Regulation of NGF and NT3 in Human Dermal Fibroblast. 13th International Conference on Biomedical Engineering. Berlin, Germany: Springer Berlin Heidelberg,, 2009:1935–1937.

11.

Vedrenne

, Coulomb

, Danigo

, Bonté

, Desmoulière

. The complex dialogue between (myo)fibroblasts and the extracellular matrix during skin repair processes and ageing. Pathol Biol, 2012; 60:20–27.

12.

Aarabi

, Bhatt

, Shi

, et al. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. FASEB J, 2007; 21:3250–3261.

13.

Linge

, Richardson

, Vigor

, Clayton

, Hardas

, Rolfe

. Hypertrophic scar cells fail to undergo a form of apoptosis specific to contractile collagen-the role of tissue transglutaminase. J Invest Dermatol, 2005; 125:72–82.

14.

Varedi

, Tredget

, Ghahary

, Scott

. Stress-relaxation and contraction of a collagen matrix induces expression of TGF-beta and triggers apoptosis in dermal fibroblasts. Biochem Cell Biol, 2000; 78:427–436.

15.

Mascharak

, desJardins-Park

, Davitt

, et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science, 2021; 372:eaba2374.

16.

Park

, Burckhardt

, Lazcano

, et al. Mechanical regulation of glycolysis via cytoskeleton architecture. Nature, 2020; 578:621–626.

17.

Zhao

, Psarianos

, Ghoraie

, et al. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nat Metab, 2019; 1:147–157.

18.

Grinnell

. Fibroblast–collagen-matrix contraction: growth-factor signalling and mechanical loading. Trends Cell Biol, 2000; 10:362–365.

19.

Kwan

, Hori

, Ding

, Tredget

. Scar and contracture: biological principles. Hand Clin, 2009; 25:511–528.

20.

Nedelec

, Ghahary

, Scott

, Tredget

. Control of wound contraction. Basic and clinical features. Hand Clin, 2000; 16:289–302.

21.

Nishiyama

, Tominaga

, Nakajima

, Hayashi

. Quantitative evaluation of the factors affecting the process of fibroblast-mediated collagen gel contraction by separating the process into three phases. Coll Relat Res, 1988; 8:259–273.

22.

Montesano

, Orci

. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci U S A, 1988; 85:4894–4897.

23.

Hinz

, Mastrangelo

, Iselin

, Chaponnier

, Gabbiani

. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol, 2001; 159:1009–1020.

24.

Junker

JPE

, Kratz

, Tollbäck

, Kratz

. Mechanical tension stimulates the transdifferentiation of fibroblasts into myofibroblasts in human burn scars. Burns, 2008; 34:942–946.

25.

Ryan

, Cliff

, Gabbiani

, et al. Myofibroblasts in human granulation tissue. Hum Pathol, 1974; 5:55–67.

26.

Hinz

, Gabbiani

. Cell-matrix and cell-cell contacts of myofibroblasts: role in connective tissue remodeling. Thromb Haemost, 2003; 90:993–1002.

27.

Garner

, Rittenberg

, Ehrlich

, et al. Hypertrophic scar fibroblasts accelerate collagen gel contraction. Wound Repair Regen, 1995; 3:185–191.

28.

Shin

, Minn

. The effect of myofibroblast on contracture of hypertrophic scar. Plast Reconstr Surg, 2004; 113:633–640.

29.

Derderian

, Bastidas

, Lerman

, et al. Mechanical strain alters gene expression in an in vitro model of hypertrophic scarring. Ann Plast Surg, 2005; 55:69–75; Discussion 75.

30.

Barnes

, Marshall

, Leavitt

, et al. Mechanical forces in cutaneous wound healing: Emerging therapies to minimize scar formation. Adv Wound Care (New Rochelle), 2018; 7:47–56.

31.

LaRoy

, White

, Jayakrishnan

, et al. Cost and morbidity analysis of chest port insertion: Interventional radiology suite versus operating room. J Am Coll Radiol, 2015; 12:563–571.

32.

Jabbour

, Awaida

, Mhawej

, Bassilios Habre

, Nasr

. Does the addition of progressive tension sutures to drains reduce seroma incidence after abdominoplasty? A systematic review and meta-analysis. Aesthet Surg J, 2017; 37:440–447.

33.

Langer

. On the anatomy and physiology of the skin: II. Skin Tension (With 1 Figure). J Plast Reconstr Aesthet Surg, 1978; 31:93–106.

34.

Cox

. The cleavage lines of the skin. Br J Surg, 1941; 29:234–240.

35.

Piérard

, Lapière

. Microanatomy of the dermis in relation to relaxed skin tension lines and Langer's lines. Am J Dermatopathol, 1987; 9:219–224.

36.

Rubin

. Langers lines and facial scars. Plast Reconstr Surg, 1948; 3:147–155.

37.

Simon

, Zempsky

, Bruns

, Sullivan

. Lacerations against Langer's lines: to glue or suture?. J Emerg Med, 1998; 16:185–189.

38.

Kraissl

. The selection of appropriate lines for elective surgical incisions. Plast Reconstr Surg, 1951; 8:1–28.

39.

Gassner

, Brissett

, Otley

, et al. Botulinum Toxin to Improve Facial Wound Healing: A Prospective, Blinded, Placebo-Controlled Study. Mayo Clin Proc, 2006; 81:1023–1028.

40.

Wang

, Hori

, Ding

, et al. Toll-like receptors expressed by dermal fibroblasts contribute to hypertrophic scarring. J Cell Physiol, 2011; 226:1265–1273.

41.

Bhattacharyya

, Midwood

, Yin

, Varga

. Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma. Adv Wound Care (New Rochelle), 2017; 6:356–369.

42.

Piccinini

, Midwood

. DAMPening inflammation by modulating TLR signalling. Mediators Inflamm, 2010; 2010:672395.

43.

Nikitorowicz-Buniak

, Shiwen

, Denton

, Abraham

, Stratton

. Abnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhanced secretion of CCN2 and S100A9. J Invest Dermatol, 2014; 134:2693–2702.

44.

Zhong

, Xu

, Zhao

, et al. S100A8 and S100A9 are induced by decreased hydration in the epidermis and promote fibroblast activation and fibrosis in the dermis. Am J Pathol, 2016; 186:109–122.

45.

Nguyen

, Austin

, Huang

, Mamalis

, Jagdeo

. The IL-4/IL-13 axis in skin fibrosis and scarring: mechanistic concepts and therapeutic targets. Arch Dermatol Res, 2020; 312:81–92.

46.

Johnson

, Stevenson

, Prele

, Fear

, Wood

. The Role of IL-6 in skin fibrosis and cutaneous wound healing. Biomedicines, 2020; 8:101.

47.

Wong

, Rustad

, Akaishi

, et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med, 2012; 18:148–152.

48.

Ferreira

, Takagawa

, Fresco

, Zhu

, Varga

, DiPietro

. Diminished induction of skin fibrosis in mice with MCP-1 deficiency. J Invest Dermatol, 2006; 126:1900–1908.

49.

Wynn

. Cellular and molecular mechanisms of fibrosis. J Pathol, 2008; 214:199–210.

50.

Wynn

. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest, 2007; 117:524–529.

51.

Lenga

, Koh

, Perera

, McCulloch

, Sodek

, Zohar

. Osteopontin expression is required for myofibroblast differentiation. Circ Res, 2008; 102:319–327.

52.

Mori

, Shaw

, Martin

. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med, 2008; 205:43–51.

53.

Rohl

, Zaharia

, Rudolph

, Murray

, et al. The role of inflammation in cutaneous repair. Wound Pract Res, 2015; 23:8.

54.

Jonsson

, Jensen

, Goodson

, 3rd, et al. Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients. Ann Surg, 1991; 214:605–613.

55.

Cohen

, Die-gelmann

, Lindblad

, Hugo

. Wound Healing: Biochemical and clinical aspects. Plast Reconstr Surg, 1992; 90:926.

56.

Okonkwo

, DiPietro

. Diabetes and wound angiogenesis. Int J Mol Sci, 2017; 18:1419.

57.

DiPietro

. Angiogenesis and wound repair: when enough is enough. J Leukoc. Biol, 2016; 100:979–984.

58.

Darby

, Hewitson

. Hypoxia in tissue repair and fibrosis. Cell Tissue Res, 2016; 365:553–562.

59.

Winocour

, Vorstenbosch

, Trzeciak

, Lessard

, Philip

. CD109, a novel TGF-β antagonist, decreases fibrotic responses in a hypoxic wound model. Exp Dermatol, 2014; 23:475–479.

60.

Guo

, Dipietro

. Factors affecting wound healing. J Dent Res, 2010; 89:219–229.

61.

Brem

, Tomic-Canic

. Cellular and molecular basis of wound healing in diabetes. J Clin Invest, 2007; 117:1219–1222.

62.

Christman

, Selvin

, Margolis

, Lazarus

, Garza

. Hemoglobin A1c predicts healing rate in diabetic wounds. J Invest Dermatol, 2011; 131:2121–2127.

63.

Underwood

, Askari

, Hurwitz

, Chamarthi

, Garg

. Response to Comment on Underwood et al. Preoperative A1C and clinical outcomes in patients with diabetes undergoing major noncardiac surgical procedures. Diabetes Care, 2014; 37:e191.

64.

Dortch

, Eck

, Ladlie

, TerKonda

. Perioperative glycemic control in plastic surgery: Review and discussion of an institutional protocol. Aesthet Surg J, 2016; 36:821–830.

65.

Buchleitner

, Martínez-Alonso

, Hernández

, Solà

, Mauricio

. Perioperative glycaemic control for diabetic patients undergoing surgery. Cochrane Database Syst Rev, 2012; 9:Cd007315.

66.

Umpierrez

, Hellman

, Korytkowski

, et al. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab, 2012; 97:16–38.

67.

Phillips

, Kim

, Fonkalsrud

, Zeng

, Dindar

. Effects of chronic corticosteroids and vitamin A on the healing of intestinal anastomoses. Am J Surg, 1992; 163:71–77.

68.

Polcz

, Barbul

. The role of vitamin A in wound healing. Nutr Clin Pract, 2019; 34:695–700.

69.

Hunt

. Vitamin A and wound healing. J Am Acad Dermatol, 1986; 15(4 Pt 2):817–821.

70.

Krueger

, Rohrich

. Clearing the smoke: the scientific rationale for tobacco abstention with plastic surgery. Plast Reconstr Surg, 2001; 108:1063–1073; Discussion 1074–1067.

71.

Rees

, Liverett

, Guy

. The effect of cigarette smoking on skin-flap survival in the face lift patient. Plast Reconstr Surg, 1984; 73:911–915.

72.

Riefkohl

, Wolfe

, Cox

, McCarty

. Association between cutaneous occlusive vascular disease, cigarette smoking, and skin slough after rhytidectomy. Plast Reconstr Surg, 1986; 77:592–595.

73.

Wong

, Martins-Green

. Firsthand cigarette smoke alters fibroblast migration and survival: implications for impaired healing. Wound Repair Regen, 2004; 12:471–484.

74.

Rohrich

, Coberly

, Krueger

, Brown

. Planning elective operations on patients who smoke: survey of North American plastic surgeons. Plast Reconstr Surg, 2002; 109:350–355; Discussion 356–357.

75.

Kean

. The effects of smoking on the wound healing process. J Wound Care, 2010; 19:5–8.

76.

Sørensen

. Wound healing and infection in surgery. Ann Surg, 2012; 255:1069–1079.

77.

Gould

, Abadir

, Brem

, et al. Chronic wound repair and healing in older adults: current status and future research. Wound Repair Regen, 2015; 23:1–13.

78.

Borges

. Relaxed skin tension lines (RSTL) versus other skin lines. Plast Reconstr Surg, 1984; 73:144–150.

79.

Wilson

. Widening of scars: foe coaxed into a friend? The Millard technique revisited. Plast Reconstr Surg, 2000; 106:1488–1493.

80.

Tinhofer

, Zaussinger

, Geyer

, et al. The dermal arteries in the cutaneous angiosome of the descending genicular artery. J Anat, 2018; 232:979–986.

81.

Wilhelmi

, Blackwell

, Phillips

. Langer's Lines: To Use or Not to Use. Plast Reconstr Surg, 1999; 104:208.

82.

Verity

, Collin

JRO

. Eyelid reconstruction: the state of the art. Curr Opin Otolaryngol Head Neck Surg, 2004; 12:344–348.

83.

Zager

, Dyer

. Minimal incision facelift. Facial Plast Surg, 2005; 21:21–27.

84.

Roh

J-L

. Retroauricular hairline incision for removal of upper neck masses. Laryngoscope, 2005; 115:2161–2166.

85.

Tellioğlu

. Determination of wrinkle lines with a transparent adhesive sheet. Plast Reconstr Surg, 2001; 108:803–804.

86.

Son

, Harijan

. Overview of surgical scar prevention and management. J Korean Med Sci, 2014; 29:751–757.

87.

Phillips

, Heggers

. Layered closure of lacerations. Postgrad Med, 1988; 83:142–148.

88.

Hudson

. Maximising the use of tissue expanded flaps. Br J Plast Surg, 2003; 56:784–790.

89.

LoGiudice

, Gosain

. Pediatric tissue expansion: indications and complications. J Craniofac Surg, 2003; 14:866–872.

90.

Moy

, Lee

, Zalka

. Commonly used suture materials in skin surgery. Am Fam Physician, 1991; 44:2123–2128.

91.

Regula

, Yag-Howard

. Suture Products and Techniques: What to Use, Where, and Why. Dermatol Surg, 2015; 41 Suppl 10:S187–S200.

92.

Hoshino

, Yoshida

, Tanimura

, Yamauchi

, Noritomi

, Yamashita

. A study of the efficacy of antibacterial sutures for surgical site infection: a retrospective controlled trial. Int Surg, 2013; 98:129–132.

93.

Byrne

, Aly

. The surgical suture. Aesthet Surg J, 2019; 39(Suppl_2):S67–S72.

94.

Edlich

, Rodeheaver

, Thacker

. Considerations in the choice of sutures for wound closure of the genitourinary tract. J Urol, 1987; 137:373–379.

95.

Sajid

, McFall

, Whitehouse

, Sains

. Systematic review of absorbable vs non-absorbable sutures used for the closure of surgical incisions. World J Gastrointest Surg, 2014; 6:241–247.

96.

, Xu

, Wang

, et al. Absorbable versus nonabsorbable sutures for skin closure: A meta-analysis of randomized controlled trials. Ann Plast Surg, 2016; 76:598–606.

97.

Erba

, Ogawa

, Vyas

, Orgill

. The reconstructive matrix: a new paradigm in reconstructive plastic surgery. Plast Reconstr Surg, 2010; 126:492–498.

98.

Dragovic

, Pejovic

, Stepic

, et al. Comparison of four different suture materials in respect to oral wound healing, microbial colonization, tissue reaction and clinical features—randomized clinical study. Clin Oral Invest, 2020; 24:1527–1541.

99.

Debus

, Geiger

, Sailer

, Ederer

, Thiede

. Physical, biological and handling characteristics of surgical suture material: a comparison of four different multifilament absorbable sutures. Eur Surg Res, 1997; 29:52–61.

100.

Najibi

, Banglmeier

, Matta

, Tannast

. Material properties of common suture materials in orthopaedic surgery. Iowa Orthop J, 2010; 30:84–88.

101.

Huang

T-W

, Cheng

P-W

, Chan

Y-H

, Wang

C-T

, Fang

K-M

, Young

T-H

. Clinical and biomechanical analyses to select a suture material for uvulopalatopharyngeal surgery. Otolaryngol Head Neck Surg, 2010; 143:655–661.

102.

Mäkelä

, Pohjonen

, Törmälä

, Waris

, Ashammakhi

. Strength retention properties of self-reinforced poly l-lactide (SR-PLLA) sutures compared with polyglyconate (MaxonR) and polydioxanone (PDS) sutures. An in vitro study. Biomaterials, 2002; 23:2587–2592.

103.

Karabulut

, Sonmez

, Turkyilmaz

, Bagbanci

, Basaklar

, Kale

. An In Vitro and In Vivo Evaluation of Tensile Strength and Durability of Seven Suture Materials in Various pH and Different Conditions: An Experimental Study in Rats. Indian J Surg, 2010; 72:386–390.

104.

Glat

, Davenport

. Current techniques for burn reconstruction: Using dehydrated human amnion/chorion membrane allografts as an adjunctive treatment along the reconstructive ladder. Ann Plast Surg, 2017; 78(2 Suppl 1):S14-S18.

105.

Shin

, Bordeaux

. How suture technique affects the cosmetic outcome of cutaneous repairs. J Drugs Dermatol, 2014; 13:967–969.

106.

. Plastic surgery made easy - simple techniques for closing skin defects and improving cosmetic results. Aust Fam Physician, 2006; 35:492–496.

107.

Stoecker

, Blattner

, Howerter

, Fancher

, Young

, Lear

. Effect of simple interrupted suture spacing on aesthetic and functional outcomes of skin closures. J Cutan Med Surg, 2019; 23:580–585.

108.

Kataria

, Ranjan

, Srivastava

. Stop suturing like cobbler. Indian J Surg, 2017; 79:472–474.

109.

Lindholt

, Möller-christensen

, Steele

. The cosmetic outcome of the scar formation after cesarean section: percutaneous or intracutaneous suture?. Acta Obstet Gynecol Scand, 1994; 73:832–835.

110.

Tanaka

, Sadahiro

, Suzuki

, Okada

, Saito

. Randomized controlled trial comparing subcuticular absorbable suture with conventional interrupted suture for wound closure at elective operation of colon cancer. Surgery, 2014; 155:486–492.

111.

Bou

, Suzuki

, Maejima

, Uchida

, Tokunaga

. Prevention of incisional surgical site infection using a subcuticular absorbable suture in elective surgery for gastrointestinal cancer. Int Surg, 2015; 100:999–1003.

112.

Polglase

, Nayman

. A comparison of the incidence of wound infection following the use of percutaneous and subcuticular sutures: an experimental study. Aust N Z J Surg, 1977; 47:423–425.

113.

Gurusamy

, Toon

, Allen

, Davidson

. Continuous versus interrupted skin sutures for non-obstetric surgery. Cochrane Database Syst Rev, 2014; 2:CD010365.

114.

Lin

, Lai

, Huang

, Du

. The efficacy and safety of knotless barbed sutures in the surgical field: A systematic review and meta-analysis of randomized controlled trials. Sci Rep, 2016; 6:23425.

115.

Faour

, Khlopas

, Elmallah

, et al. The role of barbed sutures in wound closure following knee and hip arthroplasty: A review. J Knee Surg, 2018; 31:858–865.

116.

Aliano

, Trostler

, Fromm

, Dagum

, Khan

, Bui

. A comparison of barbed sutures and standard sutures with regard to wound cosmesis in panniculectomy and reduction mammoplasty patients. Plast Surg Int, 2016; 2016:7590396.

117.

Paul

. Bidirectional barbed sutures for wound closure: evolution and applications. J Am Col Certif Wound Spec, 2009; 1:51–57.

118.

Ananda

, Vikram

, Ramesh

, Khan

. A comparative study between conventional skin sutures, staples adhesive skin glue for surgical skin closure. Int Surg J, 2019; 6:775–782.

119.

Dumville

, Coulthard

, Worthington

, et al. Tissue adhesives for closure of surgical incisions. Cochrane Database Syst Rev, 2014; 11:CD004287.

120.

Krishnan

, Crawford

, Syed

, Kim

, Rampersaud

, Martin

. Is the risk of infection lower with sutures than with staples for skin closure after orthopaedic surgery? A meta-analysis of randomized trials. Clin Orthop Relat Res, 2019; 477:922–937.

121.

Iavazzo

, Gkegkes

, Vouloumanou

, Mamais

, Peppas

, Falagas

. Sutures versus staples for the management of surgical wounds: a meta-analysis of randomized controlled trials. Am Surg, 2011; 77:1206–1221.

122.

Batra

, Bekal

, Byadgi

, Attresh

, Sambyal

, Vakade

. Comparison of skin staples and standard sutures for closing incisions after head and neck cancer surgery: A double-blind, randomized and prospective study. J Maxillofac Oral Surg, 2016; 15:243–250.

123.

Ridgway

, Mahmood

, Moore

, Bramley

, Moore

. A blinded, randomised, controlled trial of stapled versus tissue glue closure of neck surgery incisions. Ann R Coll Surg Engl, 2007; 89:242–246.

124.

desJardins-Park

, Mascharak

, Chinta

, Wan

, Longaker

. The spectrum of scarring in craniofacial wound repair. Front Physiol, 2019; 10:322.

125.

Lear

, Blattner

, Mustoe

, Kruzic

. In vivo stress relaxation of human scalp. J Mech Behav Biomed Mater, 2019; 97:85–89.

126.

Stoecker

, Howerter

, Fancher

, Lear

. A novel suture retention device for intraoperative tissue support. JAAD Case Rep, 2019; 5:454–457.

127.

Stoecker

, Howerter

, Young

, Lear

. The use of a suture retention device with punctureless technique for rapid tissue expansion in facial and lower extremity wounds. JAAD Case Rep, 2018; 4:910–914.

128.

Lim

, Weintraub

, Kaplan

, et al. The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial. Plast Reconstr Surg, 2014; 133:398–405.

129.

Longaker

, Rohrich

, Greenberg

, et al. A randomized controlled trial of the embrace advanced scar therapy device to reduce incisional scar formation. Plast Reconstr Surg, 2014; 134:536.

130.

Iacobucci

, Stevenson

. Bolster dressing to support a full-thickness skin graft. Ann Plast Surg, 1987; 18:550–551.

131.

Tandara

, Mustoe

. The role of the epidermis in the control of scarring: evidence for mechanism of action for silicone gel. J Plast Reconstr Aesthet Surg, 2008; 61:1219–1225.

132.

Gold

, Foster

, Adair

, Burlison

, Lewis

. Prevention of hypertrophic scars and keloids by the prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting. Dermatol Surg, 2001; 27:641–644.

133.

Chan

, Lau

, Adeeb

, Somasundaram

, Nasir-Zahari

. A randomized, placebo-controlled, double-blind, prospective clinical trial of silicone gel in prevention of hypertrophic scar development in median sternotomy wound. Plast Reconstr Surg, 2005; 116:1013–1020; Discussion 1021–1012.

134.

Cruz-Korchin

. Effectiveness of silicone sheets in the prevention of hypertrophic breast scars. Ann Plast Surg, 1996; 37:345–348.

135.

Niessen

. Re: Effectiveness of silicone sheets in the prevention of hypertrophic breast scars. Ann Plast Surg, 1997; 38:547.

136.

O'Brien

, Jones

. Silicone gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev, 2013; 2013:CD003826.

137.

Commander

, Chamata

, Cox

, Dickey

, Lee

. Update on Postsurgical Scar Management. Semin Plast Surg, 2016; 30:122–128.

138.

Facchin

, Pagani

, Marchica

, et al. The Role of Portable Incisional Negative Pressure Wound Therapy (piNPWT) in Reducing Local Complications of Post-bariatric Brachioplasty: A Case-Control Study. Aesthetic Plast Surg, 2021; 45:1653–1659.

139.

Tanaydin

, Beugels

, Andriessen

, Sawor

, van der Hulst

. Randomized Controlled Study Comparing Disposable Negative-Pressure Wound Therapy with Standard Care in Bilateral Breast Reduction Mammoplasty Evaluating Surgical Site Complications and Scar Quality. Aesthetic Plast Surg, 2018; 42:927–935.

140.

Suh

, Jang

, Hong

. Reply: Effects of negative-pressure wound therapy on primary closed defects after superficial circumflex iliac artery perforator flap harvest: Randomized controlled study. Plast Reconstr Surg, 2017; 140:238e.

141.

Suh

, Lee

, Park

, Hong

. Negative pressure wound therapy on closed surgical wounds with dead space: Animal study using a swine model. Ann Plast Surg, 2016; 76:717–722.

142.

Scalise

, Calamita

, Tartaglione

, et al. Improving wound healing and preventing surgical site complications of closed surgical incisions: a possible role of Incisional Negative Pressure Wound Therapy. A systematic review of the literature. Int Wound J, 2016; 13:1260–1281.

143.

Banwell

, Musgrave

. Topical negative pressure therapy: mechanisms and indications. Int Wound J, 2004; 1:95–106.

144.

Atkinson

J-AM

, McKenna

, Barnett

, McGrath

, Rudd

. A randomized, controlled trial to determine the efficacy of paper tape in preventing hypertrophic scar formation in surgical incisions that traverse langer's skin tension lines. Plast Reconstr Surg, 2005; 116:1648.

145.

Reiffel

. Prevention of hypertrophic scars by long-term paper tape application. Plast Reconstr Surg, 1995; 96:1715–1718.

146.

Hinman

, Maibach

. Effect of air exposure and occlusion on experimental human skin wounds. Nature, 1963; 200:377–378.

147.

Atiyeh

, Dibo

, Hayek

. Wound cleansing, topical antiseptics and wound healing. Int Wound J, 2009; 6:420–430.

148.

Dyson

, Young

, Len Pendle

, Webster

, Lang

. Comparison of the effects of moist and dry conditions on dermal repair. J Invest Dermatol, 1988; 91:434–439.

149.

Gallant-Behm

, Mustoe

. Occlusion regulates epidermal cytokine production and inhibits scar formation. Wound Repair Regen, 2010; 18:235–244.

150.

Regan Thomas

, Hom

. Facial Scars: Surgical Revision and Treatment. Hoboken, NJ: PMPH USA, 2019.

151.

Trookman

, Rizer

, Weber

. Treatment of minor wounds from dermatologic procedures: a comparison of three topical wound care ointments using a laser wound model. J Am Acad Dermatol, 2011; 64(3 Suppl):S8–S15.

152.

Atiyeh

, Al-Amm

, El-Musa

, Sawwaf

, Dham

. The effect of moist and moist exposed dressings on healing and barrier function restoration of partial thickness wounds. Eur J Plast Surg, 2003; 26:5–11.

153.

Atiyeh

, Ioannovich

, Al-Amm

, El-Musa

. Management of acute and chronic open wounds: the importance of moist environment in optimal wound healing. Curr Pharm Biotechnol, 2002; 3:179–195.

154.

Willis

. The effects of prolonged water exposure on human skin. J Invest Dermatol, 1973; 60:166–171.

155.

Singer

, McClain

. Persistent wound infection delays epidermal maturation and increases scarring in thermal burns. Wound Repair Regen, 2002; 10:372–377.

156.

Tenorio

, Jindrak

, Weiner

, Bella

, Enquist

. Accelerated healing in infected wounds. Surg Gynecol Obstet, 1976; 142:537–543.

157.

Smack

, Harrington

, Dunn

, et al. Infection and allergy incidence in ambulatory surgery patients using white petrolatum vs bacitracin ointment. A randomized controlled trial. JAMA, 1996; 276:972–977.

158.

Campbell

, Perlis

, Fisher

, Gloster

Jr . Gentamicin ointment versus petrolatum for management of auricular wounds. Dermatol Surg, 2005; 31:664–669.

159.

Michaels

, Del Rosso

. A comparison of postprocedural wound care treatments: do antibiotic-based ointments improve outcomes?. J Am Acad Dermatol, 2012; 2012:292–293.

160.

Soneja

, Drews

, Malinski

. Role of nitric oxide, nitroxidative and oxidative stress in wound healing. Pharmacol Rep, 2005; 57 (Suppl):108–119.

161.

Baumann

, Spencer

. The effects of topical vitamin E on the cosmetic appearance of scars. Dermatol Surg, 1999; 25:311–315.

162.

Parsa

. Vitamin E: facts and fallacies. Plast Reconstr Surg, 1988; 81:300–301.

163.

Jenkins

, Alexander

, MacMillan

, Waymack

, Kopcha

. Failure of topical steroids and vitamin E to reduce postoperative scar formation following reconstructive surgery. J Burn Care Rehabil, 1986; 7:309–312.

164.

Widgerow

, Chait

, Stals

. New innovations in scar management. Aesthetic Plast Surg, 2000; 24:227–234.

165.

Zurada

, Kriegel

, Davis

. Topical treatments for hypertrophic scars. J Am Acad Dermatol, 2006; 55:1024–1031.

166.

Mahedia

, Shah

, Amirlak

. Clinical evaluation of hyaluronic acid sponge with zinc versus placebo for scar reduction after breast surgery. Plast Reconstr Surg Glob Open, 2016; 4:e791.

167.

Amirlak

, Mahedia

, Shah

. A clinical evaluation of efficacy and safety of hyaluronan sponge with vitamin C versus placebo for scar reduction. Plast Reconstr Surg Glob Open, 2016; 4:e792.

168.

Conologue

, Norwood

. Treatment of surgical scars with the cryogen-cooled 595 nm pulsed dye laser starting on the day of suture removal. Dermatol Surg, 2006; 32:13–20.

169.

Kim

, Kim

, Lee

, Kim

, Park

. Effect of the 595-nm pulsed dye laser and ablative 2940-nm Er:YAG fractional laser on fresh surgical scars: an uncontrolled pilot study. J Cosmet Laser Ther, 2011; 13:176–179.

170.

Sisco

, Kryger

, O'Shaughnessy

, et al. Antisense inhibition of connective tissue growth factor (CTGF/CCN2) mRNA limits hypertrophic scarring without affecting wound healing in vivo. Wound Repair Regen, 2008; 16:661–673.

171.

Jensen

, Gentzkow

, Berman

, et al. Anti-CTGF Oligonucleotide Reduces Severity of Postsurgical Hypertrophic Scars in a Randomized, Double-Blind, Within-Subject, Placebo-Controlled Study. Plast Reconstr Surg, 2018; 142:192e-201e.

172.

Gale

, Jensen

, Berman

, et al. A Placebo-controlled Study of PF-06473871 (Anti-Connective Tissue Growth Factor Antisense Oligonucleotide) in reducing hypertrophic skin scarring. Plast Reconstr Surg Glob Open, 2018; 6:e1861.

173.

Jiang

X-X

, Zhang

, Liu

, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood, 2005; 105:4120–4126.

174.

Prigione

, Benvenuto

, Bocca

, Battistini

, Uccelli

, Pistoia

. Reciprocal interactions between human mesenchymal stem cells and gammadelta T cells or invariant natural killer T cells. Stem Cells, 2009; 27:693–702.

175.

, Huang

, Enhe

, et al. Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice. Int Wound J, 2014; 11:701–710.

176.

Maranda

, Rodriguez-Menocal

, Badiavas

. Role of mesenchymal stem cells in dermal repair in burns and diabetic wounds. Curr Stem Cell Res Ther, 2017; 12:61–70.

177.

, Zhang

, Gao

, et al. Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway. Stem Cell Res Ther, 2016; 7:102.

178.

Yun

, Jeon

, Lee

, et al. Effect of human adipose derived stem cells on scar formation and remodeling in a pig model: a pilot study. Dermatol Surg, 2012; 38:1678–1688.

179.

Jackson

, Nesti

, Tuan

. Mesenchymal stem cell therapy for attenuation of scar formation during wound healing. Stem Cell Res Ther, 2012; 3:20.

180.

Kronowitz

, Robb

. Radiation therapy and breast reconstruction: a critical review of the literature. Plast Reconstr Surg, 2009; 124:395–408.

181.

Dassoulas

, Mericli

, Wang

, et al. Treatment with topical deferoxamine improves cutaneous vascularity and tissue pliability in an irradiated animal model of tissue expander-based breast reconstruction. Ann Plast Surg, 2019; 82:104–109.

182.

Shen

, Borrelli

, Adem

, et al. Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis. Sci Rep, 2020; 10:12346.

183.

Flacco

, Chung

, Blackshear

, et al. Deferoxamine Preconditioning of Irradiated Tissue Improves Perfusion and Fat Graft Retention. Plast Reconstr Surg, 2018; 141:655–665.

184.

O'Reilly

, Crofton

, Brown

, Strong

, Ziviani

. Use of tape for the management of hypertrophic scar development: a comprehensive review. Scars Burn Heal, 2021; 7:20595131211029206.

185.

, Yu

, Yang

, Jin

, Lu

, Qi

. Clinical efficacy and safety of negative-pressure wound therapy on flaps: A systematic review. J Reconstr Microsurg, 2017; 33:358–366.