Scars can be caused by physical trauma, surgical incisions, burn injuries and even acne. Deep cutaneous injuries induce pathological scars. Other factors, such as mechanical loading, bacterial colonization are potential factors thought to underlie human hypertrophic and keloid scar formation or contractures. The effect may include functional impairment and aesthetic disadvantages.

Various non-invasive mechanical interventions of physical scar management (e.g. extracorporeal shock wave therapy or ESWT) could have a beneficial influence on wound healing and prevention of hypertrophic scars. ESWT considerably improves the appearance and symptoms of hypertrophic scars. However, the mechanism underlying the observed beneficial effects is not well understood. The objective of the first part of the study is to elucidate the mechanism underlying changes in cellular mechanosensitive pathways that are induced by ESWT. This review will introduce the histopathological effects on ESWT during wound healing and scar development.

The main objective of this study is to determine how much mechanical loading on dermal scars will lead to normal scar healing. The optimal duration, the frequency and the intensity of the applied forces in ESWT to generate a beneficiary effect during different phases of wound healing remains unclear.

In this study, biopsies from abdomionplasty postsurgical scars will be examined. Thereby it is possible to evaluate the outcomes on a cellular level through assessing the histology of human biopsies under controlled condition. In the second part, the underlying mechanism of ESWT on postsurgical scars will be explored, in different stages of wound healing. Furthermore, the investigators will investigate if changes in physical characteristics (redness, thickness and pliability) in postsurgical scars are associated with changes in reactivity of mechanosensitive pathways. This study will close the gap between the fundamental knowledge on cellular mechanotransduction and the clinical application of mechanotherapy during physical scar management (ESWT).

1. State of the art Every year 80 million scars develop in the world and 40-70% of these will develop into hypertrophic or problematic scars. Moreover, fibrosis and scar formation of the skin pose a substantial physiological and psychological burden on patients. Scars can be caused by physical trauma, surgical incisions, burn injuries and even acne. Most superficial injuries, that do not reach the dermis, do not leave significant scars. However, deep cutaneous injuries can induce pathological scars. Such scars often result in pain, itching, functional impairment, aesthetic disadvantages, anxiety, depression and poor quality of life of the affected person. All these aspects may cause poor functioning during ADL (4). Other aspects, such as uncontrolled mechanical loading, prolonged inflammation, overactive proliferation, bacterial colonization, and foreign-body reaction are potential factors thought to underlie human hypertrophic and keloid scar formation or contractures.

   Recent studies have identified that under influence of mechanical load scar proliferation will be prolonged and will even prohibit full maturation of the scar within the foreseen timeframe of two years of wound healing. Mechanical loading can be regarded as any mechanical stress applied to a healing wound, for example imposed forces during physical therapy or tensile forces during activities of daily living. It has been proven that specific sites that are frequently subjected to mechanical load during daily activities have more risk to develop into hypertrophic scars.

   Interestingly, mechanical loading cannot only be regarded as a negative predictive factor in scar formation. Under controlled conditions, mechanical load can activate a process called 'mechanotransduction'. Once activated inflammation, proliferation and thereby fibrosis and hypertrophic scarring can be regulated/controlled. Thus, mechanotransduction can be defined as the intracellular conversion of mechanical stimuli into internal chemical signals resulting in gene transcription. This has an effect on the cytoskeleton and the ECM. Signaling pathways are activated or modulated resulting in modification of the affected (scar) tissue.

   Various non-invasive mechanical interventions of physical scar management (e.g. extracorporeal shock wave therapy or ESWT, pressure therapy, vacuum massage,..) apply mechanical load and thereby initiate mechanotransduction. Controlled physical scar management can have a beneficial influence on wound healing and prevention of pathological scars. Therefore, this study will focus on the application of mechanical forces in the form of ESWT application. ESWT considerably improves the appearance and symptoms of hypertrophic scars. However, the mechanisms underlying the observed beneficial effects in scar management is not well understood.

   To date, there is no consensus concerning the optimal standard of care in scar treatment. Therefore, there is a need to study the underlying mechanism of scarring and the related influence of controlled mechanical forces.

2. Rationale of the study The heterogeneity in causes of scars, the complicated histology of scarring and the numerous intervention possibilities make late-stage clinical research in this field a search for a needle in a haystack. Moreover, it is always difficult to control variables such as location, demographics and genetics in studies.

First, proper identification of the cause and scar type is necessary to understand the complicated pathophysiology of excessive scarring. In this study, human dermal scar biopsies from patients who had undergone an abdominoplasty will be examined. By focusing on one specific region and one type of surgery, the influence of localization in wound healing will be controlled and a more homogenous scar formation process can be expected.

Abdominoplasty is one of the most frequently performed procedures in aesthetic surgery making that subjects can be more readily recruited and tested. An abdominoplasty is performed for various reasons: bariatric patients after weight loss with residual excess skin, post pregnancy patients to restore their previous appearance and the aging population who wants to maintain their youth belly. It's general aim is to remove the excess skin and fat, as well as to tighten the abdominal muscle. A surgeon will try to perform this procedure with the smallest possible incision. To ensure the best possible postsurgical scar outcome, preoperative incision planning, wound tension during closure, and postsurgical management (e.g. postsurgical dressing) are all critical. After an abdominoplasty, patients get the advice to use a scar cream, silicone tape and scar massage. However, as mentioned earlier surgical scars could result in contracting scars from a hypertrophic scar.

Currently, animal models (mice, pig and rabbit ear) are mostly used to unravel the pathophysiology of scarring and to develop new therapies. Underlying mechanisms in fibrosis research is heavily reliant on in vivo animal models, due to ethical and logistical limitations. Because of ethical concerns most human studies on the underlying mechanism of scars, have been limited to observational studies.

Unfortunately, animal models aren't able to reproduce the normal process of hypertrophic scar development as occurs in humans. For example, in murine models, the resting tension of the skin is lower in human skin. In addition, laboratory animals have a fibromuscular layer under the dermis, which is considered to be the main pathological difference to humans.

Skin biopsies provide valuable information on cellular and molecular level of a human dermal scar. Because of the accessibility of the skin and application of local anaesthesia, skin biopsies can be performed quite easy. By assessing the histopathology of human dermal skin biopsies the investigators will be able to study the mechanism under controlled conditions and evaluate the outcome on a cellular and molecular level. In addition, the overall cosmetic result of a punch biopsy is well-accepted and has a low complication and infection risk. Furthermore, patients after an abdominoplasty have an incision that is approximately 75 cm long making it possible to obtain a biopsy for our study.

There are some preliminary studies that took a biopsy in human dermal scars to examine the cellular and molecular changes. In vivo patient scarring research, by examining human dermal skin biopsies, enables us to study scar pathogenesis and thereby effect of therapeutic scar treatment. This kind of research is, to the best of our knowledge, the most representative model for the underlying mechanism of human wound healing and scarring.

In this study, the investigators will investigate one intervention, namely ESWT. ESWT meets all the requirements for the ideal scar treatment. ESWT is a non-invasive scar treatment, well tolerated by patients, easy to apply and it has a precise control of load intensity and frequency. In addition, it has low complication rates and is easy to use in outpatient settings. ESWT is also cost-effective and can already be applied during wound healing and early scar formation and thus can be used as a preventive therapy for pathological scars.

Only a few studies have examined the effects of ESWT in combination with surgical techniques. Preliminary results showed that ESWT diminishes the adverse effects of the surgical procedure and wound healing can be improved. An increased perfusion and angiogenesis in the wound due to increased systemic growth factor expression are thought to be responsible this effect. Finally, the application of ESWT, post-surgery, has also beneficial clinical results for the patients. Studies demonstrate that all relevant physical and physiological scar parameters such as height, pliability, vascularity and pigmentation, improve after ESWT. These changes will ameliorate function, which is, among others, demonstrated on retracting hand scars by an increase of passive ROM. From this previous research the investigators can conclude that it is safe to apply ESWT after surgery. Only one study was found on ESWT by abdominoplasty. This pilot study examined the effect of preoperative ESWT on the postoperative scar formation. Patients who had undergone and abdominoplasty were conducted and were preoperatively allocated to low energy ESWT or placebo. Scar formation was evaluated by 19 different scar parameters. This study showed that ESWT reduces scar formation and postoperative symptoms after abdominoplasty surgery. The largest differences were observed in thickness and overall impression of the scar (Vancouver scar scale). Together with other ESWT research the investigators therefore hypothesize: that postoperative ESWT have beneficial effects after abdominoplasty surgery. As it is already proven preoperative, ESWT application after surgery presumably have advantages on quality of life and reduce pain.

This study will close the gap between the fundamental knowledge on mechanotransduction and the clinical application of mechanotherapy during physical scar management (especially ESWT) by:

1. examining the association of the cellular and molecular changes with the changes in physical characteristics of scars
2. using different treatment modalities in ESWT
3. during different wound healing phases

Although some studies have been performed on ESWT for prevention of hypertrophic and keloid scars, the exact mechanism remains largely unclear. Based upon current clinical research the optimal duration, the frequency and the energy levels of the applied forces in ESWT to generate a beneficiary effect on scar formation remain unclear. Furthermore, it has not yet been proven that there is an association between these mechanosignaling pathways and physical and physiological changes during different phases in scar formation. This study will be the stepping stone towards future late stage clinical research in non-invasive scar management.

Novelty in this study:

• standardizable: 1 type and location of surgery scar: scar after abdominoplasty

• controllable load application: extracorporeal shock wave therapy or ESWT

• evaluation of the outcome on different levels:

  1. cellular and molecular through assessing the histopathology and molecular mechanosignaling pathways.
  2. scar level through physical non-invasive scar assessments (thickness, elasticity, and colour of the scar).

  3. Research objectives In this study the investigators will elucidate the mechanisms underlying changes in cellular and molecular mechanosensitive pathways that are induced by ESWT. More specifically, in this study, changes in amount of ∝-SMA, myofibroblast, macrophages, TGF-β, collagen, TLR3, collagen orientation and the angiogenetic process will be examined. Furthermore, the investigators want to determine how much mechanical loading on dermal scars will lead to normal scar healing. In addition, physical outcomes will be measured by subjective and objective assessments.

The underlying mechanism of the application of ESWT on postsurgical scars will be explored, in different stages of wound healing by taking a biopsy before and after treatment and at a fixed time during scar formation. A control group (without ESWT treatment) will be compared with an intervention group (with ESWT treatment). In the intervention group different ESWT modalities will be applied, during different stages scar formation (especially during the proliferation and maturation phase). Besides, the investigators will investigate if changes in physical characteristics (pain, colour, thickness, pliability and quality of life) in postsurgical scars are associated with changes in reactivity of mechanosensitive pathways in the different control or intervention group during different stages of scar formation.

Inclusion criteria

• Eligible patients aged between 18 and 80 years
• Dutch or English speaking
• Patients who had undergone an abdominoplasty resulting in a dermal scar
• Informed consent (approved by the ethics committee) will be provided before the surgical intervention Exclusion criteria
• All type of skin diseases or dermatological problems
• Previous surgery or ESWT intervention at the current scar site
• Age under 18 years or above 80 years
• Inability to provide informed consent
• Expected problems in therapy compliance or follow up
• Pregnancy

Datasets will be made available upon request.