Safety and efficacy evaluation of botulinum toxin an injection by FITTER® microneedle to treat medial lower eyelid wrinkles

Treatment for medial lower eyelid wrinkles is in great demand now. However, conventional injection of botulinum toxin A (BTX‐A) often leads to serious complications.


| INTRODUC TI ON
The utilization of BTX-A treatment for facial rejuvenation has gained widespread acceptance in over 50 countries and currently holds the distinction of being the most administered nonsurgical cosmetic procedure in the United States.As of 2014, the annual number of procedures performed exceeded 3.5 million. 1Periocular skin laxity is the primary surface feature of facial aging, 2 which commonly manifests as canthal and lower eyelid wrinkles.Facial rejuvenation and the reduction of periocular wrinkles are among the first indications for botulinum toxin A (BTX-A) injection, which has revolutionized cosmetology with very reliable clinical outcome. 3However, when targeting the lower eyelid, especially the dynamic wrinkles close to the medial canthus, one needs to be cautious with BTX-A therapy. 4Lower eyelid skin and soft tissues are relatively thin.With conventional BTX-A injection method and dosage, the tone of musculus orbicularis oculi of the lower eyelid is weakened, and the direction of muscular traction may change.
This often causes the formation of false dermatochalasis by fat prolapse, and the separation of the eyelid from the globe due to eyelid rim laxity; in more serious cases diplopia may occur. 1 We also note that injection into different depth and uncontrolled diffusion is some of the reasons for ocular complications, as the incidence rate of complications is highest with inexperienced doctors.
Although these complications can ease or resolve spontaneously in 4-6 weeks, such a long recovery period is unacceptable to most patients presenting for cosmetic therapy.
In this paper, we devised a simple method to help clinicians reduce or even avoid complications by more accurate injection into the desired eyelid layers with microneedle.With the method, BTX-A is injected into the dermis or the interface between the dermis and the superficial layer of the facial muscles, which can weaken the superficial muscle fibers inserted into the lower layer of the skin, the main causes of fine lines and wrinkles.We conducted a prospective single-arm clinical trial to evaluate the safety and efficacy of this method.

| MATERIAL S AND ME THODS
We collected clinical data of 16 patients who received botulinum toxin A injection by microneedle at the Department of Plastic Surgery, Xijing Hospital between January 2021 and December 2021 to treat dynamic wrinkles on the medial aspect of the lower eyelid.Compound lidocaine cream (prilocaine and lidocaine, Tongfang Pharmaceutical Group Co., Ltd.; ~2 g) was applied to the injection site of the lower eyelid, sealed with membrane for 40 min, and then cleansed with water.After routine sterilization, BTX-A (Botox, 100 units/vial, Allergan Pharmaceuticals, Ireland; diluted in 5 mL saline) was injected into the treatment sites using a microneedle (FITTER® microneedle, 34G4A, Yangzhou Chengmei Medical Device Co., Ltd.).The microneedle has four 34G needles with 1.2 mm long (Figure 1).The injection site was in the rugae zone of the medial aspect of the lower eyelid, 2 mm away from the palpebral margin.The dose was 2-3 units per side.Four to eight points were selected for intradermal injection based on the degree of wrinkles and the size of the affected area, with an interval of 3-4 mm between each point (Figure 2).While patient was instructed to smile and wink, the physician injected the solution into the dynamic wrinkle area.The skin mound could be seen immediately after the injection, which usually resolved in 1-2 h.Postoperative care included the application of an ice pack.Patients could wash their faces with water 12 h after treatment and resume usual skincare after 24 h.Safety was evaluated by adverse events recorded at each stage.
Efficacy was evaluated by VISIA analysis and subjective assessment of the patient and the physician before treatment and at 1 month and 3 months after treatment.
The data were analyzed using SPSS 21.0, and quantitative data is represented as (x ± s), while qualitative data is represented as (%).VISIA was used to assess the wrinkle severity by measuring the average roughness Ra, 5 using a roughness plane correction option.
Roughness is quantified by the vertical deviations of a real surface from its ideal form.Ra decreases with shallower wrinkles.The improvement in wrinkles did not show significance at 1 month after treatment (p > 0.05), but was significant at 3 month (p < 0.05)based on VISIA wrinkle quantification (Figure 3).
The severity of wrinkles was rated according to the optical photographs and VISIA 3D images (Figure 4) before and after treatment (Level 1 indicates no wrinkles, Level 2 for slight wrinkles, Level 3 for superficial wrinkles, Level 4 for moderate wrinkles, and Level 5 for severe wrinkles). 6The subjective score was evaluated by three physicians (twice each) and self-rated twice by the patient.The accuracy of the subjective score was determined by the consistency of the two assessments and the consistency between evaluators, using the kappa statistic.Kappa >0.6 indicates high consistency, 0.4-0.6 for medium consistency, and <0.4 for weak consistency.The average kappa values of the three evaluators and of the patients were both greater than 0.6, suggesting that the subjective evaluation is reliable.The subjective score by the patient was 3.6 ± 0.94 before treatment and 1.6 ± 0.68 after treatment (p < 0.01).The subjective score of physicians was 3.95 ± 0.88 before treatment and 1.30 ± 0.57 after treatment (p < 0.01).

| DISCUSS ION
The periocular skin is thinner than other parts of the face, so it is more prone to aging and deformation.In addition, there are abundant expressive muscles around the eyes.Among them, the orbicularis oculi muscle may cause the orbital skin to form small horizontal wrinkles.
There are surgical and non-surgical treatments to improve lower eyelid wrinkles.Surgery is traumatic and needs a long recovery time.Non-surgical treatments include hyaluronic acid filling, RF laser, radio frequency skin treatment, exfoliative wrinkle removal, pulsed light, and so on, each with its own advantages and specific indications, but their disadvantages include adverse reactions such as tissue necrosis, pain, scar, and pigment change. 1 In general, these methods are not effective in treating dynamic wrinkles.BTX-A has been extensively used in full-face wrinkle removal since it was first approved for dynamic wrinkles between the eyebrows in 2002. 6There are many reports of its use in wrinkle removal around the eyes. 1,3,6When BTX-A is injected to improve lower eyelid wrinkles, it can easily lead to complications such as F I G U R E 2 Distribution of typical injection points and the FITTER® microneedle.

F I G U R E 3
The improvement assessed by roughness Ra of VISIA after one-month and three-month treatment.lower eyelid skin laxity, pouch protrusion, lower eyelid orbicularis muscle dysfunction, and even diplopia. 4In one study, 7 3 of 11 patients injected with 4-U of BTX-A in the lower eyelid had mild dry eye.One patient had to reduce the use of contact lens because of dry eye symptoms.Three of the 8 patients injected with 8-U BTX-A had temporary lower eyelid edema, two of them had photophobia in bright sunlight, and another two had sphincter dysfunction in their eyes.Skorochod 8 reviewed 25 articles and reported 49 ophthalmic adverse events after BTX-A injection.The most common adverse reactions are diplopia (64%), followed by blepharoptosis (14%) and impaired or lost vision (8%).
The epidermis around the eye is 0.2 mm thick, and the dermis is 0.7-1.2mm thick according to the histological analysis.And a recent living human ultrasonography analyses shown the depth of the orbicularis oculi muscle from the skin surface at the midpoint of the frontal process is 2.0 ± 0.4 mm. 9 The depth of this point is almost Even without the adverse effects, conventional treatment often leads to the disappearance of "Jelly rolls" due to weakened contraction of the pretarsal orbicularis oculi in the lower eyelid, which makes the eye not soft-looking during dynamic facial expressions.Chinese patients want not only to eliminate wrinkles but also to maintain as natural an expression as possible.The BTX-A dosage reported in the literature is still too high. 10This new injection method targets the superficial muscle fibers of the lower eyelid, so that it has less impact on the volume and strength of the muscle.The treatment reduces dynamic wrinkles with minimal impact on the appearance of the lower eyelid (Figure 5), which makes facial expression softer (Figure 6).
Cosmetic medicine is very subjective.Hence a variety of metrics are needed to evaluate the outcome of the treatment.This is the first paper to analyze the effectiveness of lower eyelid wrinkle treatment with a microneedle by instrument and objective evaluations.We combined non-contact image analysis, doctors' blinded evaluation of the results, and patients' self-assessment score, and performed quantitative analysis to determine the effectiveness of this method, to ensure the accuracy of the results.
The VAS pain score recorded immediately after injection in our study was 1.15 ± 0.33.Compared with the VAS score of 4.2 reported by Horovitz, 11 our method substantially decreased the pain and discomfort during treatment.
The effect of our intradermal injection lasts shorter than that of intramuscular injection, consistent with other report. 12The reason may be that out method uses lower doses and lower concentration of the drug.However, most patients find that the shorter maintenance time is acceptable.Patients' satisfaction peaked 90 days after treatment and started to decline after 120 days.Thus, retreatment may be considered based on the patient's preference to maintain the treatment effect.
This study has a small sample (16 patients).Given the high satisfaction rate of doctors and patients, further research is warranted.
We need to find the optimal doses for different degrees of eyelid wrinkles, and the optimal concentration to achieve long lasting effects.Such efforts will provide clinical support for the safety and standardization of this treatment.

FU N D I N G I N FO R M ATI O N
The authors have no financial interest to declare in relation to the content of this article.NSFC: 81572676; NSFSX: 2022SF-493; 2021JM-239.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author.The data are not publicly available due to privacy or ethical restrictions.

E TH I C S S TATEM ENT
Not required.

R E FE R E N C E S
F I G U R E 6 Comparison of the patient with smile before (A) and after treatment (B).
The 16 patients of both sexes, aged 18-60 years (37.4 ± 6.7), were included in the study with the following criteria: (1) diagnosis of dynamic wrinkles or mild non-dynamic wrinkles on the medial aspect of the lower eyelid; (2) BTX-A injection into the lateral musculus orbicularis oculi and nasal dorsum proven ineffective in alleviating wrinkles.Exclusion criteria included: (1) patients with an obvious eye-bag or who had previously undergone eye-bag surgery; (2) allergy to BTX-A; (3) those who had received BTX-A injection in the treatment region within 6 months prior to the trial; (4) other common contraindications to BTX-A injection; and 5) those who were known or reasonably suspected to have poor compliance, such as patients with alcoholism, drug dependence, or mental illnesses.Informed consent was obtained from each patient before trial started.
Between group comparisons are conducted using t-tests and Chisquared tests.p < 0.05 indicates statistical significance.F I G U R E 1 The specifications of FITTER® microneedle.

3 | RE SULTS 3 . 1 |
All 16 patients completed 3 months of postoperative follow-up.The following adverse events were observed.Wheals were seen immediately after injection, which resolved spontaneously 1-2 h after treatment.Three patients (18.75%) had lower eyelid bruising immediately after injection, with spontaneous regression within 1 week.Four patients (25%) developed lower eyelid swelling 2 days after injection, which resolved spontaneously within 5 days.No patients had eye-bag, lower palpebral margin laxity, diplopia, or dry eye.

F I G U R E 4 5
Before treatment (A, C) and 3 months after treatment (B, D), VISIA screenshot of local folds in the lower eyelid and the 3D images of the same site.Comparison of "Jelly rolls" contraction under dynamic expression before (A) and after treatment (B). the thinnest around the eye.As a result, the FITTER® microneedle we used in this study has four microneedle (1.2 mm long) for precise intradermal, but not orbicularis, injection.With this method, the attenuated dilution of BTX-A decreased the drug's effect, so it could reduce the adverse reactions.Compared with previous reports, our method is safer: only three to four patients had temporary bruising and edema, and no patient had serious complications.