Analysis of the efficacy of blunt separation combined with uncrosslinked sodium hyaluronate composite solution for the treatment of tear trough deformity in Asians

Filling therapy is becoming increasingly popular for correcting tear trough deformities (TTD). However, its therapeutic effect and retention time are limited.


| INTRODUC TI ON
The eyes play an essential role in the beauty of the face, and the periorbital skin belongs to the thinner and earlier aging part of the body skin. 1 Tear trough deformity (TTD) is the most common problem of periorbital aging, which can make the face look unhealthy and tired or even aged. 2The causes of TTD are complex, and mainly include volume loss, tissue aging, and underdevelopment of the infraorbital malar complex. 3Recently, there has been an increasing demand for treating TTD.The traditional treatments for TTD include surgery, fat transplantation, and hyaluronic acid (HA) fillers.
Nevertheless, surgical trauma is significant, postoperative recovery time is long, and patients often experience fear.For patients who undergo orbital septal liposuction, the TTD will be more evident following fat removal. 4To improve the problem of TTD caused by traditional surgery, researchers have attempted treatment using the fat collected from the prolapsed fat pad or other parts and by transplanting it into the area of TTD to improve the tear trough (TT). 5However, studies have found that fat transplantation to the periosteum's upper plane results in more bruising, swelling, and abnormal contours. 6th the emergence and application of HA fillers, more patients can accept HA fillers to improve their TTD.HA fillers require an easy operation and are comfortable and inexpensive.However, they do not have a permanent effect. 7If the injection level is too shallow, it can quickly produce skin irregularities; in patients with larger fat pads, filler treatment can only moderately improve appearance, and for patients with periorbital melanosis, appearance may be improved after treatment; however, the improvement of skin color in the lesion area is not guaranteed. 3 recent years, to better apply HA to tissue and mucosal filling, many experts composite HA with collagen and vitamins and derive a series of sodium hyaluronate composite products that can promote collagen regeneration, maintain cell redox metabolism, and improve pigmentation, benefiting the skin for a long time after metabolism. 8Traditional injection methods mainly include local, spot, and linear injections to improve TTD through the support of HA fillers; however, a short maintenance time will be required, and Tyndall phenomenon and other complications may occur. 9To prolong the treatment effect and reduce complications after treatment, TTD can be treated by using a blunt separation technique to repair tissue trauma.After the tissue structure is released and destroyed by blunt separation technology, many cytokines can be produced in the repair process, improving facial skin problems and achieving good results. 10This paper describes our research team's injection method of the improved blunt separation technique combined with an uncrosslinked sodium hyaluronate composite solution to fill the deep dermis through the principles of wound repair, filling, and stimulating collagen regeneration to treat TTD.

| Ethics statement
The study was approved by the relevant ethics committee and was performed in accordance with the ethical standards stipulated in the 1964 Declaration of Helsinki.Written informed consent was obtained from all patients.

| Participants
This study included 26 patients with TTD at our department from September 2021 to December 2021, including 21 women and 5 men, with a mean age of 34.54 ± 9.21 (range, 20-56) years.
TTD severity was evaluated and scored according to the tear trough rating scale (TTRS) created by Sadick et al. (Table 1). 11mprehensive pre-treatment evaluation was conducted according to the filling suggestions put forward by Anido et al. 12 Pretreatment evaluation of the 26 patients mentioned above using TTRS showed a score less than 8 points, which is considered suitable for the treatment of TTD filling.
The patients' scores were obtained by adding the points obtained in each column.(1) A patient with a TTRS score less than 2 points is an ideal candidate for HA treatment.(2) Patients with TTD with a TTRS score between 2 and 8 points can be treated with HA and should be assessed individually.(3) Treatment is not recommended for patients with TTRS scores greater than 8 points; surgery should be considered for such patients. 12e eligibility criteria were: TTRS score between 2 and 8 points, good health, no chronic disease, obvious TTD, willingness to improve TTD, provision of informed consent, and voluntary participation in this trial.The exclusion criteria were as follows: severe underlying diseases, scar physique, local infection at the injection site, hypersensitivity to any component of the filling (detailed in the packaging leaflet of the recommended product) or allergic disease, 13 past injections of unknown filling materials into the TT area and local palpation not completely degraded, abnormal blood coagulation and daily use of oral anticoagulants, pregnancy and lactation, minors, and mental illness.

| Instrument
An iPhone 11 Pro (Apple, California, USA) was used to take the twodimensional photographs.The same physician injected each patient with a sodium hyaluronate composite solution (

| Procedures
The treatment method was explained to the patients, who signed an informed consent form.After cleaning the patient's face, photographs were taken to evaluate the TT.After evaluation, the face was disinfected with an iodophor (up to the hairline and down to the edge of the mandible).The patient sat with a 30°tilt of the head using a pillow to raise the head slightly to highlight the TTD and fully expose the lower eyelid fat pad.The needle entry point was determined by determining the intersection of the projection of the nasojugal fold and the perpendicular projection of the outer canthus of the eye. 13First, local infiltration anesthesia with lidocaine hydrochloride injection was used at the injection point.After the anesthesia, the skin was punctured with a 22G needle tilted horizontally 15° upward.After the skin was punctured, a 23G cannula was used to puncture the triangular area formed by the palpebromalar, nasojugal, and zygomatic grooves, and the deep dermis was extensively blunted, resulting in artificial damage to the subcutaneous space.
After extensive stripping, linear retrograde fanning was performed to inject the filler slowly into the TTD.According to the degree of TTD, the average unilateral injection volume was 0.51 ± 0.16 mL, and slight pressing was performed after injection to promote even product distribution in the TT area.After treatment, the skin was cleaned again, a cold compress was applied to the treatment area for 20 min to reduce bruising, and images were taken immediately.Patients were recommended to avoid local heat or wearing devices in the treatment area within 1-2 weeks to reduce or prevent trauma and avoid strenuous exercise and alcohol consumption within 1 week. 14

| Outcomes
The criteria for judging the curative effect were as follows.Evaluation of therapeutic effect: Before treatment, immediately after treatment, and 1, 3, 6, and 12 months after treatment, the severity of TTD was scored and compared using the TTRS.Because of the difference in bilateral TTD in the same patient, the bilateral TTRS scores were compared separately.
Patient satisfaction score was assessed as follows: Immediately after treatment, and 1, 3, 6, and 12 months after treatment, a satisfaction score scale was for assessing individual subjective satisfaction with the treatment effect, including responses of "very satisfied," "satisfied," "average," "dissatisfied," and "very dissatisfied." This was assessed on a 1-5 scale, and the satisfaction rate was calculated as follows: satisfaction rate = (very satisfied cases + satisfied cases)/total cases × 100%.

| Safety evaluation
All patients were followed up for 12 months.Adverse reactions included swelling, bruising, pain, allergic reactions, infection, Tyndall phenomenon, nodule and cord eminence, granulomatous reaction, and vascular embolism.The recurrence rate was evaluated in all patients 12 months postoperatively, and it was calculated as follows:

| Statistical analysis
The Statistical Package for Social Science version 25.0 and GraphPad Prism 8.0 were used for statistical analysis.Normally distributed data were expressed as mean ± standard deviation, and the paired t-test was used for within group comparisons.A p-value < 0.05 was deemed statistically significant.

Recurrence rate
= number of cases of recurrence∕treatment − effective cases × 100%.

| RE SULTS
All 26 patients who received treatment completed the patient satisfaction survey and follow-up evaluation.According to the clinical photographs, TTD improved after blunt exfoliation with a cannula alone, which was significantly improved after injection and filling compared with that before treatment, including alleviation of wrinkles and depressions, flattening of the periorbital skin, and improvement of eyelid ptosis (Figure 1).The optimal therapeutic effect was maintained 3-6 months after injection, and all patients showed varying degrees of therapeutic effect after 12 months (Figures 2-4).

| Analysis of treatment effectiveness
Clinical efficacy evaluation: TTRS scores: Before treatment, the TTRS scores of all patients were 5.78 ± 1. Twelve months after treatment, the TTRS score for the left side was 4.65 ± 1.26 points, and that for the right side was 4.23 ± 1.21 points, demonstrating a statistically significant difference (p < 0.05; Figures 5 and 6).
Patient satisfaction score: The satisfaction score and satisfaction rate at various time points were as follows: immediately after treatment, the patient satisfaction rate was as high as 96.2%;One month after treatment, the patient satisfaction rate remained high, still as high as 92.8%; 3-6 months after treatment, the patient satisfaction rate decreased in varying degrees, but still maintained the best therapeutic effect; 12 months after treatment, the patient satisfaction rate remained as high as 73.1% (Table 2).Traditional methods for the clinical treatment of TTD include surgery, fat transplantation, and HA filling.Traditional surgery can lead to obvious TTD and relative depressions at the middle confluence of the medial orbit and the middle junction of the lower eyelid. 17Fat transplantation lasts for a long time, and the local skin quality is improved.However, the skin and soft tissue covering the TT area is so thin that the inaccurate placement of fat can lead to significant contour abnormalities, and it is impossible to accurately quantify how much fat is injected into the TT and zygomatic region.

| Safety and patient satisfaction
Furthermore, its physical properties make it difficult to assess its survival percentage. 5HA filling is a simple, safe, and reversible nonoperative method.HA is a polyanionic polymer that naturally exists in the extracellular matrix of many human tissues, and its content decreases with age.Because of their unique rheological properties and good biocompatibility, HA fillers are used in skin cosmetology to maintain the volume and elasticity of the skin. 18Under physiological pH conditions, HA is widely combined with water to fill the tissue.A high level of crosslinking degree and larger particle size is positively correlated with the persistence of fillers; however, it can also increase water absorption, leading to an increase in the frequency of other adverse reactions, such as swelling, irregular contours, and Tyndall phenomenon. 19In the Glycine, proline, and alanine contained in the sodium hyaluronate complex solution are the main components that form the original collagen structure and promote collagen synthesis. 21L-sarcosine can enhance cells' antioxidant capacity and reduce cell glycosylation. 22Vitamin B2 can maintain the cells' redox metabolism and improve TT's pigmentation. 8The combination of the aforementioned ingredients can effectively improve the quality of the skin around the orbit, improve TTD, and benefit the skin for a long time.
Different TTD injection methods have varying effects.There are abundant blood vessels around the orbit, the most important of which are the infraorbital artery, which has been considered a highrisk injection area, including HA fillers. 23The infraorbital artery is a branch of the maxillary artery, which emerges from the orbit at the infraorbital foramen.If a needle is injected into the periosteal layer during infraorbital depression TT correction, there may be a risk of retrograde thrombosis. 24Second, HA fillers are injected perpendicular to the periosteum to fill the depth of the depression in an attempt to fill the depression of the TT.This is a very effective treatment for patients with thick skin of the lower eyelid, apparent subcutaneous emptiness, and negligible fat prolapse. 7However, it does not solve the problem of adhesion between the skin under the TT and subcutaneous layer, which interferes with the realization of a smoother lid-cheek, especially in the presence of fat bumps. 25Using a cannula can reduce the risk of vascular injury and improve its safety.Mustak

TA B L E 1
The patient score is obtained by adding the points obtained in each column: ① The patient with values less than 2 is the ideal candidate for hyaluronic acid treatment.② A tear trough deformity with a score between 2 and 8 could be treated with hyaluronic acid and should be assessed individually.③ We do not recommend treatment if the score is greater than 8 (assess surgery). 12a According to the Glogau scale.10(1) Mild-Little wrinkles, no keratosis, requires little or no makeup for coverge; (2) Moderate-Early wrinkling, sallow complexion with early actinic keratosis, requires little makeup; (3) Advanced-Persistent wrinkling, discoloration of the skin with telangiectasias and actinic keratosis, always wears makeup; (4) Severe-Severe wrinkling, photoaging, gravitational and dynamic forces affecting skin, actinic keratosis with or without cancer, wears makeup with poor coverage.Tear trough deformity clinical evaluation scale (TTRS).
28 and 5.42 ± 1.14 points for the left and right side, respectively, which dropped to 2.27 ± 0.78 and 2.04 ± 0.82 points for the left and right side, respectively, immediately after treatment, demonstrating a significant difference (p < 0.05).The TTRS scores at 1 month after treatment for the left and right side were 2.42 ± 0.50 and 2.34 ± 0.49 points, demonstrating a significant difference (p < 0.05).Three months after treatment, the TTRS scores for the left and right side were 2.92 ± 0.56 and 2.81 ± 0.81 points, respectively, demonstrating a significant F I G U R E 1 The pre-therapy and posttreatment (sodium hyaluronate compound solution treatment) images of tear trough deformity (twodimensional photograph).(A) At baseline; (B) mark the needle opening; (C) local infiltration anesthesia is used, and after the anesthesia takes effect, and the subcutaneous tissue is bluntly dissected with a 23G cannula; (D) a comparison of immediate effects through blunt dissection on the right side, and the contralateral side was not treated; (E) both sides were treated with blunt dissection combined with sodium hyaluronate compound solution injection immediately-bruising appeared on the left side during blunt dissection and subsided after 6 days.difference (p < 0.05).Six months after treatment, the TTRS score for the left side was 3.19 ± 0.57 points, and that for the right side was 3.04 ± 0.60 points, demonstrating a significant difference (p < 0.05).
Patients experienced mild pain during treatment; the average Visual Analog Scale score was 2.31 ± 0.55 points.Three patients experienced adverse reactions associated with the injection, characterized by postinjection bruising lasting 6-7 days and later subsided.No other adverse reactions or recurrences were observed during follow-up.4| DISCUSS IONWith the continuous improvement of living standards, popularization of aesthetic concepts, and improvement of aesthetic levels, the number of people pursuing beauty with a youthful face is gradually increasing.Periorbital aging occurs first during the overall process F I G U R E 2 Pre-therapy and posttreatment (sodium hyaluronate compound solution treatment) images of tear trough deformity (twodimensional photograph).(A) At baseline; (B) immediately after treatment; (C) 1 month after treatment; (D) 3 months after treatment; (E) 6 months after treatment; (F) 12 months after treatment. of facial aging, and the appearance of TT is an early clinical manifestation.Therefore, scholars have conducted extensive clinical research on periorbital aging.In 1969, Flowers et al. identified a deep groove at the junction of the lower eyelid and cheek, first named TTD, because tears often flow from the upper and medial sides of the groove. 15Thereafter, Stutman and Codner et al. summarized a large body of literature and redefined TTD: The medial depressionextending obturately from the inner canthus to the pupillary midline is called TT, whereas the lateral depression is known as the palpebromalar groove.16The leading causes of TTD are as follows:11 (1) volume reduction: atrophy of bone, orbital septum fat, and deep medial cheek fat compartment; (2) skin changes: loss of skin collagen; (3) relaxation of supporting ligaments of orbicularis oculi muscle and orbicutaris retaining ligaments; (4) zygomatic retraction caused by reduction of anterior zygomatic fat, aggravation of orbital septum fat, aggravation of eye bags, and obvious deepening of TT and palpebromalar groove.

F I G U R E 3
Pre-therapy and posttreatment (sodium hyaluronate compound solution treatment) images of tear trough deformity (twodimensional photograph).(A) At baseline; (B) immediately after treatment; (C) 1 month after treatment; (D) 3 months after treatment; (E) 6 months after treatment; (F) 12 months after treatment.
treatment of TTD, to reduce the complications caused by HA, Berguiga et al. chose semi-crosslinked HA fillers to treat TTD, and the symptoms of early transitional edema were significantly reduced. 20With the increasing demand for fillers, a series of sodium hyaluronate composite products have been derived in recent years.The sodium hyaluronate composite solution used in this study was uncrosslinked HA.Compared with traditional fillers, they have smaller particle sizes and lower viscosities.It is suitable for intradermal and dermal injections and can be administered quickly.

F I G U R E 4
Pre-therapy and posttreatment (sodium hyaluronate compound solution treatment) images of tear trough deformity (twodimensional photograph).(A) At baseline; (B) immediately after treatment; (C) 1 month after treatment; (D) 3 months after treatment; (E) 6 months after treatment; (F) 12 months after treatment.

TA B L E 2
et al. used linear retrograde fanning technology for more than 1000 periorbital injections without serious complications.19After blunt tissue separation, tissue repair promotes the proliferation and differentiation of fibroblasts and produces collagen, resulting in the formation of endothelial cells and neovascularization.9The anatomy of TTD originates from the tear trough ligament (TTL), which firmly attaches the dermis to the periosteum.Extensive peeling off of the subcutaneous tissue and TTL with a cannula can break the adhesion site of the periorbital subcutaneous tissue, artificially cause local lacuna damage in the suborbital tissue, and promote blood infiltration containing inflammatory cells and various growth factors, improving blood circulation and nourishing the periorbital tissue.It plays a positive role in tissue regeneration and improving skin pigmentation.26Huang et al. used a cannula for TTL, which was repeatedly punctured and loosened and injected with autologous fate into TTD, achieving very satisfactory results.27In this study, we combined the blunt separation and filling techniques to maximize tissue coverage and create conditions for wound repair.As shown in Figure1, after we used the cannula for blunt separation, an immediate improvement was observed, and we used the uncrosslinked sodium hyaluronate compound solution for injection to achieve temporary filling.Immediately after treatment, the TTD of all patients significantly improved.Three to 6 months after treatment, the TTRS scores increased to varying degrees but maintained the best therapeutic effect.In the process of TT repair, many fibroblasts proliferate and differentiate to produce collagen, endothelial cells, and granulation tissue formed by neovascularization, filling the depression in the early stage and achieving long-term filling through cell proliferation and matrix deposition in the later stage.28According to Deglesne et al., an uncrosslinked sodium hyaluronate complex solution can promote the activity of human skin fibroblasts and increase the expression of type 1 collagen and elastin genes by nearly 10 times.29This synergism maximizes volume recovery, especially for Asian TTD characterized by suborbital fat loss and skin aging.We believe that the filling of TTD with blunt separation combined with uncrosslinked sodium hyaluronate can overcome the disadvantage of the traditional filling and injection method, which cannot maintain long-term effects, maximize the time and degree of skin benefits, and improve regeneration and repair.Moreover, because of the thin skin tissue around the orbit, HA is easily injected into the subcutaneous or subcutaneous fat to overlap and accumulate.The dose of each injection is relatively small; if the injection F I G U R E 5 Comparison of the tear trough rating scale scores at each stage pre-and post-operatively.This figure demonstrates the improvement of the tear trough deformity on the left side.*p < 0.05, **p < 0.01; A score of 0 points indicates no symptoms and 8 points indicate severe symptoms.F I G U R E 6 Comparison of the tear trough rating scale scores at each stage pre-and postoperatively.This figure demonstrates the improvement of the tear trough deformity on the right side.*p < 0.05; **p < 0.01.Subject satisfaction (n = 26).