1. Introduction
Scar is an inevitable product of the skin trauma repair process, mainly manifested as fibroblast proliferation and collagen-based extracellular matrix synthesis and deposition, resulting in scarring compare to surrounding skin tissue hardness, color changes, and increased vascular distribution. As the face is the exposed area of the body, the formation of a periorbital scar can destroy the patient’s appearance, and contracture of periorbital scar can easily lead to the abnormal function of the eyelid, so the periorbital scar can easily cause both physiological and psychological impacts on the patient, seriously disturbing the patient’s life.[1,2]There are many clinical treatments for scars, including medication, radiation, laser, cryotherapy, and surgery. Many researchers have reported that intralesional injection of Triamcinolone Acetonide (TAC) is the standard of nonsurgical treatment.[3–5] Studies have shown that TAC can inhibit the proliferation of fibroblasts in the scar, reduce collagen synthesis, and inhibit the production of inflammatory mediators to soften and flatten the scar tissue, which is particularly effective in hyperplastic keloid.[6] Jiang’s study suggests that TAC is more effective in improving scar tenderness in keloids and hyperplastic scars,[3] but after TAC treatment, scar tissue can show localized depression due to the reduction of collagen fibers and other matrices, making the scar site significantly lower than the surface of normal skin, and the patient’s scarring remains obvious.
Hyaluronic Acid (HA), is a relatively safe and most commonly used dermal filler, and is widely used in medical aesthetic treatments such as wrinkle filling, rhinoplasty, and facial contouring.[7] Lauren et al followed up on a case of keloid treatment with TAC combined with HA intrakeloid injections to recontour depressed keloid scars, with remarkable results and long-lasting efficacy over more than 2 years of follow-up.[8,9] In this study, we utilized the softening and loosening effect of TAC on scarring, combined with the local filling effect of HA, to treat periorbital scarring with injections, and investigated the efficacy and safety of this treatment protocol.
2. Materials and methods
2.1. Clinical materials
Information was retrospectively collected from 26 cases of scars (in 16 patients) that were observed between January 2018 and January 2020 at the Second Hospital of Dalian Medical University (Table 1). The mean age of the patients was 31.9 ± 11 years (18 to 55 years), the median duration of scarring was 3 months (1 to 36 months), and the Fitzpatrick skin type was type III to IV. There were 11 cases of atrophic scarring and 15 cases of hyperplastic scarring.
8 patients had 1 scar, 6 patients had 2 scars each, and 2 patients had 3 scars each. 24 cases of scarring were due to trauma, and 2 cases of scarring were due to surgery. Follow-up were performed at 1, 6, and 12 months after HA treatment and at 6-month intervals thereafter, with a mean follow-up time of 17.1 ± 4.7 months.
Scars were scored by 2 physicians according to the Vancouver scar scale (VSS)[10] (Table 2), and the mean scar tenderness score was recorded. Adhering to the randomized, single-blind and controled principle (Fig. 1).
The study was approved by the Institutional Review Board of the Second Hospital of Dalian Medical University. All patients signed an informed consent form before the trial.
2.2. Criteria for inclusion and exclusion
Inclusion Criteria: Patients with facial keloid scars, meeting the indications for facial keloid scar treatment (meeting any one or more of the following): width >2 to 3 mm; abnormal pigmentation; hyperplastic keloid; atrophic keloid; webbed keloid; linear keloid scar of more than 20 mm; misalignment with the line of skin tension and relaxation or running through the facial aesthetic unit; and causing distortion or dysfunction of the facial skin. Received treatment with TAC combined with HA intra-scar injection, with photographs taken before and after each treatment and a follow-up period of at least 12 months. Voluntarily participated in this study and signed an informed consent form.
Skin type III to IV.
Exclusion criteria: any evidence of infection or ulceration in or near the scar; pregnant women or patients preparing for pregnancy; patients who had received any intradermal injection treatment prior to receiving treatment.
2.3. Methods
2.3.1. Medicine
Trimethoprim acetate injection (TAC): Shanghai Xudong Haipu Pharmaceutical Co., Ltd. production, drug specifications 5 mL: 50 mg, i.e., each bottle of TA solution contains a total of 50 mg of TA, and its TA concentration of 10 mg/mL.
HA: Sweden Q-MedAB production of injectable sodium hyaluronate gel modification (Ruilan 2, Restylane No. 2), drug specifications for 1 mL/bottle. (No.
2), drug specifications for 1 mL/branch.
Lidocaine injection (Lidocaine hydrochloride, LH): produced by Shanghai Chaohui Pharmaceutical Co., Ltd, with drug specification of 5 mL/branch.
Compound Lidocaine Cream (Compound xylocaine cream): produced by Beijing Tsinghua Ziguang Pharmaceutical Factory, with drug specification 5 g/branch.
2.3.2. Treatment method
Pretreatment preparation: photographic, before and after each treatment in the same light conditions, angle and background, the same physician photographic record of the patient’s treatment area; surface anesthesia, all patients treatment area topical application of 5% Lidocaine cream 20 to 30 mg for about 40 to 60 minutes; 0.9% sodium chloride solution to clean the treatment area, 75% ethanol solution disinfection for 3 times, 0.9% NaCl solution was wiped once.
2.3.3. TAC injection
The total amount of TAC injected in a single session is determined by the size of the scar, usually 0.5 ml/cm², and the maximum total amount should be <80 mg/injection. TAC injection is mixed with lidocaine injection in a ratio of 2:1.
After the syringe aspirates the drug and penetrates the needle into the scar entity, make sure that it is not under the skin or on the surface of the scar, and that no blood is seen on retraction, then the injection can be injected while entering the needle until the scar is pale and swollen. Depending on the shape and size of the scar, inject every 1 cm², and try to inject the mixture into all parts of the scar, so that the medicine can fully infiltrate the scar tissue.
TAC was injected at 2-week intervals, and the scar was evaluated for VSS softness by 2 physicians before each injection until the scar softness dropped to a score of 1 or below, and then the injection was stopped.
2.3.4. HA injection
The scarred area is anesthetized with lidocaine cream and then disinfected. Using a 27G needle, the needle is inserted at multiple points from the basal part of the scar periphery, the needle is tilted to penetrate into the subcutaneous layer of the scar, and after no blood is seen on retraction, the HA is injected into the scar and into the subcutaneous layer of the scar while the needle is slowly retracted until the height of the scar is leveled off with the surrounding skin tissues. The exact amount of HA injected depends on the scar.
After injection, the injection site is massaged to distribute the HA evenly. Follow-up at 1 month, 6 months and 12 months after treatment (Fig. 1).
2.3.5. Efficacy assessment
Scars were assessed by 2 physicians using the VSS before treatment, 2 weeks after TAC treatment (when the scar VSS score was less than or equal to 1 at the end of the last TAC injection), and at 1, 6, and 12 months after HA treatment, and the scar color, vascular distribution, softness, and height scores were recorded.
Observe and record whether there are complications such as erythema, hypopigmentation, capillary dilatation, skin thinning, decreased elasticity, skin atrophy, skin ulceration, etc in the injected part and the surrounding skin during the course of TAC treatment. Observe and record whether there are complications such as allergic symptoms and vascular embolism during HA treatment. Long-term follow-up to record whether there are complications such as skin tissue necrosis or atrophy.
2.3.6. Statistical analysis
Data analysis was performed using SPSS version 27.0 (Chicago). Continuous variables (VSS scores, scar softness) were expressed as mean ± standard deviation. Paired t-tests compared: pretreatment versus 1-month post-HA VSS scores, pretreatment versus post-TAC scar softness, post-TAC versus 1-month post-HA scores, and 6-month versus 12-month post-HA VSS scores.
Adverse reactions were reported as frequencies. Statistical significance was defined as P <.05.
3. Typical clinical cases
A comparative visual representation of typical clinical scenarios is depicted in Figures 2 and 3, illustrating the pre and posttreatment clinical photographs.
4. Results
4.1. VSS scores
The mean scores of VSS scores of 26 scars at pretreatment, after TAC treatment, and 1 month, 6 months, and 12 months after HA treatment were 7.4 ± 1.7, 4.3 ± 1.2, 2.1 ± 0.7, 1.7 ± 0.4, and 1.5 ± 0.1 scores, respectively. The difference was statistically significant when comparing the scores before treatment and 1 month after HA treatment (t = 17.3, P <.01). The difference was statistically significant when comparing the scores at 6 months and 12 months after HA treatment (t = 2.74, P <.05) (Fig.
4).
4.2. Scar flexibility
The scar flexibility score of 26 cases was 3.5 ± 0.8 before treatment, and 0.6 ± 0.4 after the injection of TAC to reduce the softness to 1 and below, with a mean decrease of 3.2 ± 0.6 points. The score decreased to 0.4 ± 0.37 1 month after HA injection, and the change of scar softness before and after treatment was statistically significant (t = 18.44, P <.01) (Fig. 5).
4.3. Degree of scar depression
All scars were depressed before treatment, and 1 month after HA injection, all 26 scar depressions were corrected. After 12 months of follow-up, only 2 cases of scar indentation appeared again and the depth of indentation was <1 mm.
4.4. Adverse reactions
Erythema appeared in 2 scars during TAC treatment, and epidermal thinning was observed in 3 scars after the first TAC injection; after follow-up treatment, the erythema was reduced and the thinned epidermis returned to normal after 1 year of follow-up. After HA injection, there were no allergic symptoms, vascular embolism, skin atrophy or necrosis during the follow-up period, and only 2 cases of scar reappearance of indentation and the depth of indentation was <1 mm.
5. Discussion
Periorbital skin dermis thickness is thinner than other parts of the body, rich in blood flow, except for patients with keloid scarring, periorbital skin natural healing of the formation of scarring is mostly physiological scarring.[11]The progression of this type of scar tends to stabilize in 6 to 8 months, resulting in a scar that is similar in color to the surrounding skin, with no capillary dilatation on the surface, a softer texture, and disappearance of uncomfortable symptoms. After stabilization, the scar will atrophy, resulting in a thinning of the thickness and a reduction in volume, which may cause the scar to be lower than the surface of the skin, appearing as a groove on the surface of the skin, affecting the patient’s appearance.[12]Evaluation of scarring after treatment is an important part of clinical research, and in this study, scarring was evaluated by the VSS, which is now widely used to assess burn scars, hyperplastic keloid scars, and keloid scars. The scale is a descriptive assessment of keloid scars and is easy to administer without the use of special equipment.[13] Since VSS is highly subjective, 2 experienced physicians were arranged to assess the same scar in this study to average their scores and increase the reliability of the assessment.
TAC can improve scar flexibility by inhibiting inflammatory cell migration and inhibiting fibroblast proliferation, reducing scar volume and height, and reducing scar-related itching and pain. Since TAC injection into normal tissue may lead to atrophy or ulceration of the skin tissue surrounding the scar, the injection must be penetrated into the scar entity to confirm that it is not subcutaneous, thus complications such as atrophy of the surrounding skin and skin ulceration can be effectively avoided. Because the drug has a strong and long-lasting effect, and the higher the dose, the stronger the effect, therefore, the single injection dose should be controlled to avoid the occurrence of the above adverse reactions.[14] In this research, TAC was mixed with lidocaine at a 2:1 ratio,[15] which not only reduced the pain reaction during injection, but also diluted the TAC and reduced the dose of a single injection, which effectively reduced the occurrence of adverse reactions.
In this study, there were 2 cases of erythema in scars during TAC treatment and 3 cases of epidermal thinning after the first injection of TAC, but they all recovered in subsequent treatment and follow-up. HA was first isolated by Meyer et al in the vitreous humor of the bovine eye,[16] and it was found to be widely present in the dermis of human skin to maintain skin elasticity.
HA is a normal tissue in the human body and can be degraded on its own after injection into the body, and even if an excessive amount is injected at 1 time, it can be degraded quickly using hyaluronidase, so HA is a relatively safe dermal filler. In this study, HA was injected into the intra-scar and sub-scar skin tissues to fill in the depressions remaining after TAC treatment. HA is extremely absorbent and can take up to 1000 times its own volume of water,[17] forming an elastic matrix to fill in the keloid body.
In this study, 26 cases of scar were corrected after HA injection. And the water absorbed by HA can play a diluting role to lighten the color of the scar tissue and harmonize it with the surrounding skin. Hyaluronic acid is isovolumically degraded in tissues, i.e., after 1 molecule of HA is degraded, the remaining molecules can absorb more water to maintain the total volume unchanged.
Its maintenance effect in normal tissues is about 6 to 9 months.[7] In the present study, 26 cases of scar hyaluronic acid treatment were regularly followed up for 12 months, only 2 cases of scar with deeper depression before treatment reappeared with <1 mm of depression and the remaining scar did not show any significant depression. In the present study, the VSS scores of the 26 keloid scars at 6 and 12 months after hyaluronic acid treatment further decreased to 1.7 ± 0.4 and 1.5 ± 0.1, and the appearance of the 26 keloid scars improved compared with that before the treatment, and achieved the status of ideal keloid scars. In this study, the use of tretinoin combined with hyaluronic acid in the treatment of scar, the 2 drugs complement each other, tretinoin through the degradation of collagen fibers, reduce the role of inflammatory response, so that the scar within the tissue sparing, to achieve the purpose of softening and loosening, in order to make the injection of hyaluronic acid into the scar more smoothly.
There are some limitations to this study, as the specific amount of tretinoin and HA injected as well as the concentration failed to yield quantitative results, and the number of cases was small. In terms of scar assessment, the VSS assesses pain and cosmetic factors in a subjective and qualitative manner that lacks objectivity, and it is not sensitive enough to identify subtle changes during treatment.
6. Conclusion
Local injection of triamcinolone acetonide followed by HA is safe and effective in treating periorbital scarring and can effectively improve the appearance of patients with periorbital scarring.
Author contributions
Conceptualization: Yu Xue, Xinlei Yao.
Data curation: Yu Xue.
Formal analysis: Yu Xue, Hang Li.
Methodology: Yu Xue.
Supervision: Shuyi Liu, Don O Kikkawa, Wei Lu.
Writing – review & editing: Yu Xue.