["179757ee585c255a30ccb9b5f3b6d1526d3caf40"]
The invisible scar
Invisible scar
fat grafting
stemmcell therapy
hypertrophic scar
atrophic scar
CELT
Diesch
Sophia
241
241
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Evidence score
06
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Wound healing and the pathological formation of scar tissue
Phases of wound healing
After an injury, the dermis triggers a healing process that results in partial regeneration of the damaged tissue and scar formation as a substitute for the original tissue. Wound healing is divided into three overlapping phases: the inflammatory phase, the proliferative phase, and the remodeling phase. During inflammation (days 1-3), disrupted blood vessels promote fibrin clot formation, creating a provisional extracellular matrix that serves as a base for cell migration, including neutrophils and macrophages involved in wound healing. Growth factors released during this phase attract additional fibroblasts and endothelial cells 1,2. Around days 4-5, the proliferative phase begins with angiogenesis, providing oxygen and nutrients to the wound. Fibroblasts produce components for the extracellular matrix, replacing the provisional one and contracting the tissue, leading to maturation of granulation tissue after 10-12 days. Epithelialization of keratinocytes also begins during this phase. The final remodeling phase occurs around 3 weeks after injury. During this phase, synthesis of the extracellular matrix decreases while remodeling of granulation tissue increases. Proteolytic enzymes replace type III collagen with normal type I collagen, and elastin is produced to restore normal skin elasticity. This process can take up to 6 months and results in a stable and elastic scar 1,2.



Pathological scar tissue formation 
The formation of pathological scar tissue is a result of disrupted wound healing, leading to a prolonged or disrupted inflammatory response. This results in an increased buildup and decreased degradation of the extracellular matrix, causing an excess accumulation of collagen. The exact molecular basis of this process is not yet fully understood. There is a direct correlation between external mechanical forces on the wound and an increase in collagen synthesis 4,5. This hypothesis is supported by the fact that fetal wound healing in early pregnancy lacks an inflammatory response, preventing scar tissue formation 6. Modulating this inflammatory response may improve tissue recovery and reduce complications. Excessive collagen accumulation can lead to hypertrophic scars or keloid formation, with differences outlined in the table below.
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Prevention of scar tissue formation
Tissue handling during surgery
As scar prevention is particularly critical during elective aesthetic surgery with long and exposed incisions, such as facelifts and browlifts, intraoperative tissue handling is of the upmost importance. At the begin of the surgery, the incision should be carefully placed parallel to the relaxed skin tension lines. The understanding of these lines is fundamental, that the tension forces after wound closure remain equal across the whole scar2,17. With incisions on the scalp, the preservation of hair follicles has to be accounted for. Incisions should be placed perpendicular to the hair follicle, to prevent postoperative alopecia.7 During surgery the wound should be treated delicately with as little external force exerted by retractors. Wound closure plays an important role in scar prevention and should follow these principles:2,17 
- Use the smallest sutures possible that overcomes wound tension
- Approximate the wound edges without excessive tension

A variety of suture techniques can be used, depending on the location, thickness of the skin, as well as angle of the incision. These techniques vary between basic intracutaneous sutures or specialized sutures like e.g. a butterfly- or corial pulley-suture. The common goal of these sutures lies in the eversion of the wound and the even distribution of tension18. The three major components of scar prevention immediately after wound closure are as follows: (1) tension relief, (2) hydration/taping/occlusion, and (3) pressure garments18.
Postoperative wound care
During the first days, correct dressing material should be used, to ensure a sufficient hydration of the wound. Wound cleaning should be done with saline water. Daily or every other day disinfection may not be needed when the wound shows no signs of infection, as alcohol and iodine might be cytotoxic. Non absorbable suture should be removed as early as possible after sufficient wound stability has been reached2. If possible, compression garments should be worn during the process of wound healing and scar formation and maturation. Silicone Scar Gels should be daily applied to prevent dehydration of the scar. 
Nutrition
Nutritional balance for optimized wound healing is critical, as the patient’s ability to synthesize proteins and collagen fibers directly influences the outcome of the scar. As vitamin supplements are increasing in popularity, the scientific basis can only offer a few studies. One study found, that patients taking proteolytic enzymes including proteases and bromelain, as well as vitamin C, calcium, bioflavonoids rutin and grapeseed extract, showed accelerated wound healing. However further studies still have to be conducted to prove a general benefit19.

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Established treamtent of scars
Optimal scarring from an aesthetic and functional point of view is crucial for patient satisfaction. Despite the high relevance of cutaneous scar treatment and the multiplicity of approaches to it, no gold standard has yet been established for the treatment of scars. The following overview encompasses established practices for scar treatment.
Noninvasive procedures 
Silicone sheets and gels 
A popular option for scar treatment, both for prophylaxis and therapeutic purposes in especially hypertrophic scars and keloids. Satisfactory results have been reported with regular daily use for a period of 2- 4 months. While the exact mechanism of action remains unclear, it is believed that the occlusive properties of silicone hinder the transepidermal water loss, thereby maintaining skin hydration of the scar which leads to fibroblast modification.20-22 Research indicates that even after wound healing, scar tissue tends to lose moisture more quickly and may take more than a year to regain its pre-injury hydration levels. Silicone-based products can aid in preventing excessive scar formation by replenishing the skin's moisture barrier through occlusion and hydration of the outermost layer of skin (stratum corneum). It's crucial to start using these silicone products as soon as the wound or suture has healed. 23
Pressure / Compression therapy
Following the identification of the clinical impact of pressure garments on hypertrophic burn scarring by Silverstein and Larson in the late 1960s, subsequent studies conducted at the Shriners Burns Institute in Galveston, Texas, were published in the early 1970s.24 This contributed to the initiation of pressure garment therapy for preventing hypertrophic scar formation in burn patients and was followed by implementing pressure/compression therapy for a variety of scar types. Pressure therapy has recently been considered an "evidence-based" modality for the treatment of scars. Despite its widespread use worldwide, the mechanism of its action remains poorly understood. Part of the effect of pressure could involve the reduction of oxygen tension in the wound through the occlusion of small blood vessels, resulting in a decrease in the proliferation of (myo)fibroblasts and collagen synthesis. Recent studies emphasize the crucial role of cellular mechanoreceptors in the high success rate of compression therapy. Mechanoreceptors are involved in cellular apoptosis and are connected to the extracellular matrix. It is conceivable that increased pressure via the matrix regulates the apoptosis of dermal fibroblasts and reduces the hypertrophic process. Furthermore, through the process of mechanotransduction, sensory nerve cells can convert mechanical pressure into intracellular biochemical and genetic expression, thus synthesizing and releasing various cytokines that may play a role in the pathophysiology of proliferative scarring. Finally, besides these causal effects, pressure therapy can also offer symptomatic treatment benefits, such as the alleviation of edema, itchiness, and pain, contributing to the patient's well-being.2,21
Oils, lotions and creams
Moisturizing creams and have proven to be effective in alleviating itching, reducing the size, and relieving pain or discomfort of scars, while also enhancing their appearance. Furthermore, they were partly able to increase patient overall satisfaction in many cases. 23
Massage therapy 
Massage therapy has emerged as a promising intervention for scar management, with several studies demonstrating its efficacy in improving scar appearance and symptoms. In a systematic review and meta-analysis of randomized controlled trials, revealing that massage therapy significantly reduced scar thickness and enhanced scar pliability in hypertrophic scars post-burn injuries.25 Shin et al observed a reduction in scar thickness and improvement in scar texture with massage therapy, suggesting its potential to mitigate scar tissue formation.26 Massage therapy is theorized to enhance circulation, promote tissue elasticity, and mitigate scar tissue adhesions. These collective findings highlight the significance of massage therapy as a valuable adjunctive approach in scar management.25,26
Psychological counseling
Scarring can have significant psychological consequences, including feelings of disfigurement, embarrassment, anxiety, and depression especially when areas like the face or neck are affected. Psychological counseling provides a supportive environment for individuals to express and process these emotions. 27
Invasive procedures
Intralesional injections
Another approach, which has been in use for over three decades, involves intralesional injections using both well-established and newer agents.
Corticosteroids
The most commonly used injectable for scar treatment are corticosteroids, in particular triamcinolone acetonide.28 Intralesional steroid injections are frequently used in the treatment of hypertrophic scars and keloids to address the suspected prolonged inflammatory reaction and as a result reduce the overproduction of immature collagen III instead of mature collagen I leading to increased tissue fibrosis.29-31 It is suggested to perform a 10 mg/ml intradermal injection and repeat it 2-3 times with an interval of 4-8 weeks between the sessions. Typically multiple treatments are required to achieve the desired outcome. However, it is important to note that this treatment method does come with potential side effects including hypopigmentation, skin atrophy and telangiectasis. 
Interferons
IFN therapy, specifically IFN-α2b has also demonstrated effectiveness in improving the appearance of keloids and hypertrophic scars, as well as reducing keloid recurrence following surgical excision. Studies have demonstrated its effectiveness in improving hypertrophic scars both systemically and intralesional, resulting in reduced scar size and improved clinical appearance. Proposed mechanisms of action include decreased collagen deposition, reduced production of TGF- β, and increased collagenase activity. Studies showed a significant increase in the rate of scar improvement with control by subcutaneous injections for 7 days with 1x106 units followed by 2x106 units for 24 weeks in 3 times per week basis. However, common adverse effects such as flu-like symptoms and injection site pain are associated with IFN treatment. Despite its costliness, IFN therapy remains a promising approach for managing excessive scars.20,21,32,33
5-Fluorouracil
5-Fluorouracil (5-FU), an antimetabolite used in cancer chemotherapy, has shown efficacy in reducing scars by increasing fibroblast apoptosis.19 Intralesional 5-FU injections have been effective in treating keloids, with studies reporting significant reduction in scar size without recurrence during follow-up. Adverse effects such as pain, ulceration, and burning sensations have been noted, but overall, intralesional 5-FU treatment appears to be both safe and effective for keloids and inflamed hypertrophic scars. 19 One study suggested the weekly intralesional injections of 5-Fluorouracil (5-FU) at a concentration of 50 mg/mL for a duration of 12 weeks. This treatment regimen has shown to effectively reduce scar size by at least 50%.34
Surgical scar correction
Traditional treatment for keloids and hypertrophic scars involves surgical excision. In contracting scars especially in joint areas the underlying consideration in scar revision surgery is choosing a surgical approach that reduces tension to the scar tissue. There are different techniques to realize that. These include among others serial excisions, z-plastics, full skin substitutes and local flaps.35 Furthermore, when approaching a surgical scar correction, it is crucial to differentiate between the hypertrophic scars and keloids before proceeding with surgery. For hypertrophic scars, timing is crucial as they often improve in the first 12 months without surgical intervention due to natural maturation processes including flattening, softening, and repigmentation without any physical manipulation. Surgical excision may not be necessary. 36However, for keloids, recurrence rates after surgery are high, ranging from 45- 100%, without adjuvant therapy like corticosteroid injections or radiation.20 Surgical intervention alone should be approached cautiously due to potential complications such as longer scars and increased risk of larger keloid formation. Nevertheless, surgical repair combined with corticosteroid injections and postoperative pressure often yields favorable cosmetic outcomes.37
Laser therapy
Advancements in laser technology have expanded its application to scar treatment. Each cutaneous laser has distinct clinical applications based on their specific wavelengths and pulse durations.38,39 The 585-nm pulsed-dye laser (PDL) stands out as particularly effective for younger hypertrophic scars and keloids. Recommended fluences range from 6.0 to 7.5 J/cm2 (7-mm spot) or 4.5 to 5.5 J/cm2 (10-mm spot), with 2 to 6 treatments typically needed for scar improvement. The mechanism involves inducing neocollagenesis and realigning collagen fibers by destroying blood vessels. Laser therapy, while offering potential benefits in scar treatment, is not without its share of reported adverse effects. These include the development of post-interventional telangiectasia, purpura, and the possibility of skin or underlying blood vessel damage.40,41 
Radiotherapy
Radiation therapy, including superficial x-rays, electron-beam therapy, and brachytherapy, has shown promising results in scar reduction protocols, often used alongside surgical removal of keloids. The effects of radiation on keloids are believed to involve inhibiting neovascular buds and proliferating fibroblasts, leading to reduced collagen production. Electron beam irradiation typically begins 24-48 h after keloid excision, with the total dose limited to 40 Gy to prevent adverse effects such as pigmentation changes and skin atrophy and teleangiectasia42. Several studies described that Post-excision keloid and hypertrophic scar recurrence can be effectively controlled by adjuvant radiation. However, due to the potential risk of carcinogenesis, particularly in sensitive areas like the breast and thyroid, caution is advised when considering radiation therapy. 43,44
Cryotherapy
Cryotherapy, either alone or combined with other treatments, has been used to address excessive scars like hypertrophic scars and keloids. Combining cryotherapy with intralesional triamcinolone acetonide (TAC) injections has shown significant improvement in scar appearance. Cryotherapy induces vascular damage, leading to tissue necrosis, with response rates ranging from 32% to 74% after multiple sessions, particularly effective for hypertrophic scars. However, its utility is limited to small scars, and common side effects include permanent changes in pigmentation, skin atrophy, blistering, and pain.20,45 Intralesional-needle cryoprobe methods have shown increased efficacy compared to contact/ spray probes. 46
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Further potential – Autologous fat grafting and CELT
Overview
In recent years, there has been remarkable progress in the field of regenerative medicine, particularly in addressing the complexities of scar tissue management. Autologous fat grafting (AFG) has emerged as a notable advancement in this regard, offering a comprehensive solution that goes beyond mere cosmetic improvement to tackle the functional limitations associated with scar tissue. Initially devised for enhancing facial aesthetics by filling in depressed scars, AFG involves the strategic transfer of adipose tissue from one area of the body to another. This approach has undergone significant refinement and is now supported by extensive scientific evidence highlighting its volumetric and regenerative properties.At the heart of AFG's effectiveness are adipose-derived stem cells (ADSCs), abundant within adipose tissue and pivotal in the wound healing process. When applied via AFG, these cells contribute not only to aesthetic enhancements but also offer therapeutic advantages, such as pain relief, reduction of itchiness, volume restoration, and improvement in functional outcomes for scarred tissues.47ADSCs play a significant role in influencing the wound healing process and scar tissue remodeling through various mechanisms:
Angiogenesis: ADSCs stimulate the formation of new blood vessels by secreting proangiogenic factors like VEGF, FGF, and HGF. These factors promote endothelial cell proliferation and migration, leading to the formation of new capillary structures crucial for tissue perfusion and oxygenation. The interplay between ADSCs and the HIF-1α/VEGF axis is pivotal in enhancing angiogenesis within scarred tissues. Additionally, S1P, secreted by ADSCs, promotes angiogenesis and stabilizes new blood vessels.
Immunomodulation: ADSCs modulate the immune response by secreting anti-inflammatory cytokines like IL-10 and TGF-β. These cytokines reduce inflammation by inhibiting pro-inflammatory cytokine synthesis and promoting the conversion of effector T cells into Tregs. Other cytokines and chemokines produced by ADSCs, such as IL-6 and IL-4, also contribute to modulating the healing environment through macrophage polarization and the JAK/STAT signaling pathway.
Cell differentiation: ADSCs can differentiate into multiple cell types, aiding in tissue repair. They regulate signaling pathways like the Wnt/β-catenin pathway for osteogenic differentiation and PPARγ activation for adipogenic differentiation, allowing them to replace damaged cells and contribute to tissue restoration.
Extracellular Matrix Remodeling: ADSCs influence the deposition and organization of collagen and other matrix components, contributing to the structural integrity and functional recovery of scarred tissue. They secrete MMPs to break down accumulated ECM proteins and regulate this breakdown through TIMPs. Additionally, ADSCs influence fibroblasts within scar tissue to modulate collagen production, promoting a more organized and less fibrotic ECM. Molecules like CTGF and Decorin, secreted by ADSCs, further regulate extracellular matrix remodeling, providing a nuanced understanding of how ADSCs influence tissue structure and function.
Given the pivotal role that adipose-derived stem cells (ADSCs) play in wound healing and scar modulation through autologous fat transfer, CELT,48 with its particularly high concentration of ADSCs, appears to be a promising approach with significant potential for the future.
Effects of AFG on scars
Scar appearance and skin characteristics
Studies utilizing the Patient and Observer Scar Assessment Scale (POSAS) have reported positive outcomes with autologous fat grafting (AFG) for scars. Significant improvements were observed in vascularity, pigmentation, thickness, relief, and pliability.49 A meta-analysis by Krastev et al. and a systematic review by Negenborn et al. both demonstrated overall improvements in scar appearance and quality, particularly in scar stiffness, color, and irregularity.50
Volume and contour
AFG not only aids in scar regeneration but also addresses volume deficiencies and contour irregularities. While studies have shown favorable outcomes in correcting volume deficiencies associated with scars, there is a challenge of volume resorption post-AFG. Efforts to enhance fat graft survival include techniques like cell-assisted lipotransfer (CAL), Cell Enriched Lipotransfer (CELT) and platelet-rich plasma (PRP) addition, aimed at promoting revascularization and improving fat graft survival.48,50,51
Fibrosis and functional impairment
AFG has shown promise in reducing fibrosis and improving functional impairment in scars, particularly in cases of radiotherapy-induced fibrosis. It releases fibrotic tissue and promotes neoangiogenesis, leading to improved skin quality. Additionally, AFG has demonstrated positive outcomes in addressing scar retraction and functional deficits, such as limited joint mobility.52
Pain
Lipofilling with AFG has been effective in reducing pain associated with scar tissue. Immediate and long-term pain relief has been reported in various types of scars, attributed to factors such as the secretion of neurotrophic factors like BDNF and the mechanical release of fibrotic adherence.
CELT as an innovative approach for scar treatment 
Given the described effects of ADSCs and their implications for scar tissue and chronic wounds, the CELT method, involving the enrichment of lipoaspirate with adipose tissue-derived stem cells, emerges as a promising future strategy for scar treatment and wound healing. Particularly, this innovative technique shows potential in addressing atrophic scars, painful scars, and underperfused scars.
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Algorithm of scar prevention and treatment for the clinical use
Algorithm for scar prevention and treatment 
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