Introduction

Scars are the endpoint of cutaneous wound healing. In particular, facial scars may have negative effects on wellbeing, quality of life and function [1]. Scars can be classified into atrophic, hypertrophic and keloidal scars. In hypertrophic and keloidal scars high-mobility group box protein-1 (HMGB-1) exerts profibrotoic actions. Matrix metalloproteinases (MMPs) degrade the extracellular matrix. MMP-1 is decreased in keloids and hypertrophic scars. MMP-2 has been found to be increased and are thought to possibly contribute to keloid expansion through peripheral extracellular matrix catabolism [2]. Reactive oxygen specimen, oxidative stress and regulation of myofibroblasts all contribute to fibrosis [3]. In atrophic scars there is an imbalance of MMP’s and their inhibitors and a deficiency of collagen production [4]. Numerous treatment options are available for scar revision, surgical, laser-assisted, topical ointments or dressings. Atrophic scars can be corrected by fillers or autologous fat transfer [5-7].

Hyaluronidase is approved as an adjuvant for local anesthesia causing a spreading effect for the anesthetic drugs. When used in wound models, hyaluronidase had no negative effects on wound healing [8, 9].

Hyaluronidase injections have been used to treat skin injuries in the neonatal intensive care unit with success [10]. We report on the use of intralesional injections of hyaluronidase to improve facial scars.

Patients

Seven patients with facial scars after tumor surgery (5), laser surgery (1) and accidental trauma (1) have been treated with hyaluronidase. The site of scars was on nose (2), upper lip (1), ear lobe (1), mandibula and cheek (2), and inner canthus (1). Six patients were female, six Caucasians and one Asian. The age range was 46 to 78 years. Fitzpatrick skin type was II (6) or 3 (1).

Treatment

Bovine hyaluronidase (Hylase® “Dessau” 150 IU, Riemser Pharma, Greifswald – Insel Riems; Germany) has been reconstituted in 0.9 % sodium chloride solution according to the product leaflet and injected intralesional 0.1 ml per injection site. Injection sites were 0.5 cm apart. Injection was performed according to the individual needs of patients and their scars eow. When stored in a refrigerator the product is stable for 12 months.

Scars were scored using the Vancouver Scar Scale (VSS) (Table 1) [11]. Photographic documentation was used for follow-up.

Fig. 1: 78-year-olf female with asymmetric lip contour due to a scar after tumor surgery. Before (left) and after 3 treatment sessions (right).

Fig. 2: 60-year-old female with ultraviolet light induced cutaneous changes. Scar with cicatrical pull on nose and inner canthus after tumor surgery. (Before (left) and after two treatment sessions (right).

Results

Hyaluronidase injection was realized with 0.1 to 0.5 ml per session according to the size of scars. Treatment was performed once (2) or repeated two times (1) and 3 times (4), respectively. The median VAS was 5.9±1.6 before and 2.2±1.5 at the end of treatment. Treatment was well tolerated. No inflammation or allergic reaction was noted. The only adverse effect was moderate pain during injection of small volumes. No other adjuvant treatment was used. No treatment failure was observed.

Fig. 3: 46-year-old female with scars on the mandibular arch resulting from an accident. Before (left) and after two treatment sessions (right).

Fig. 4: 50-year-olf female with an impressed scar on the nostril. Before (left) and after a single treatment (right).

Discussion

Scars are the usual end-stage of wound healing. Scarless healing is only possible in fetal stage. The quality of the final scar is an important outcome measure of wound healing for patients and doctors. Hyaluronic acid (HA) is a major component of the extracellular matrix. Tumor necrosis factor-stimulated gene-6 (TSG-6) catalyzes the covalent transfer of heavy chains 1 and 2 from inter-alpha-inhibitor to HA. The resulting complexes of HA with heavy chains are involved in tissue remodeling ad wound healing. In keloid scars TSG-6 is down-regulated what results in an abnormal HA pattern [12]. In addition, HA is diminished due to a decreased expression of HA synthase and hyaluronidase [13]. Scar fibroblasts express increased amounts of CD44, the principle HA receptor. In these cells, CD44 expression is not down-regulated by presence of extracellular HA [14]. An increased inflammatory response does further contribute to abnormal scarring and increases also CD44 expression [15].

Hyaluronidase is an endoglycosidase. Due to its HA cleaving activity it increases membrane permeability, has spreading activity for fluids and drugs injected into tissues [16]. Hyaluronidase produces low-molecular weight HA segments. HA molecules stimulate proliferation of mesenchymal stem cells (MSC) [17, 18]. MSC have been experimentally employed for attenuation of scar formation [19]. They are capable of homing to and engrafting on sites of tissue damage where they regulated the function of immune cells and inflammation. They reduce radical oxygen species and produce a number of anti-fibrotic factors including interleukin-10 or adrenomedullin. Furthermore, SC can differentiate into dermal cells. Low-molecular weight HA stimulated angiogenesis [20].

We suppose that the injection of hyaluronidase into scars does not only soften scar tissue but may also activate MSC, which can improve blood vessel supply and volumized connective tissue in case of impressed scars [21]. In case of flap edema the spreading activity seems to be responsible for the clinical effects in analogy to the improvement of lid edema after filler injection [22].