Clinical outcomes after lip injection procedures—Comparison of two hyaluronic acid gel fillers with different product properties

Abstract

Background

Transient swelling is common after lip injections with hyaluronic acid (HA) based fillers. Swelling and other injection‐site reactions may relate to the injection procedure itself, or to gel properties, which differ between fillers due to differences in manufacturing methods.

Objectives

To evaluate safety and effectiveness of lip injections with two HA fillers manufactured using different gel technologies.

Methods

In a study sample of 40 subjects, treatment with two soft tissue filler product (HA_RK or HA_JUS) was randomly assigned. Subjects were injected with 0.5 cc per upper and lower lip using a standardized injection procedure. Early‐onset adverse events (AEs) were assessed by evaluation up to Day 14. Aesthetic improvement, subject satisfaction, and AEs post‐Day 14 were assessed up to 24 weeks.

Results

In subjects treated with HA_RK, the intensity of early onset swelling, erythema, and pain/tenderness was lower than in subjects treated with HA_JUS. Aesthetic improvement was achieved in both groups, and most subjects were satisfied with the appearance of their lips. Treatment‐related AEs post‐Day 14 mostly related to the implant site; most were mild‐to‐moderate, and none were serious.

Conclusions

The intensity of early‐onset swelling, and other injection‐site reactions was lower in subjects treated with HA_RK than in subjects treated with HA_JUS. Since both the injection volume and injection procedure were standardized, the difference in local tolerability between the two HA fillers may relate to differences in gel properties. Aesthetic improvement, subject satisfaction, and AE profiles post‐Day 14, however, were similar between filler groups.

INTRODUCTION

Aesthetic interventions are increasing in popularity with lip augmentation procedures utilizing soft tissue fillers being of special interest. Lip enhancement procedures may be separated depending on desired outcome into contouring versus volumizing; generally, contouring procedures are more frequently performed in younger patients, whereas contouring and volumizing procedures are being performed more frequently in patients of more advanced age.

Lip contouring procedures involve placement of soft tissue fillers along the vermilion border superficial to the orbicularis oris muscle in a subdermal plane. Previous studies have shown that this plane is safer to avoid injecting the labial arteries located deeper in the submucosal plane. The superficial injection plane, however, may allow product visibility and more prominent swelling. Swelling is thus an expected sequela of the trauma caused by the injection itself. Although the swelling is usually mild, transient, and not requiring any further intervention, it may still impact patients' satisfaction with the procedure.

Various manufacturing methods produce hyaluronic acid (HA) based soft tissue fillers that differ in gel characteristics such as HA concentration, crosslinking degree, and particle size, which determine in vivo gel behavior. Differences in gel properties influence aesthetic treatment outcome, and occurrence of adverse events (AEs) such as edema formation. However, the gel properties are tested in a laboratory setting and it is unclear to what extent the parameters assessed translate into a clinical setting.

The objective of the present study was to investigate in a clinical setting whether lip injection with products with different gel properties in general and can result in a distinct clinical outcome. To test this hypothesis, two different soft tissue filler products were utilized with a standardized lip injection procedures and their clinical outcome was investigated related to AEs, aesthetic improvement, and subject satisfaction.

MATERIALS AND METHODS

Study subjects

Key inclusion criteria were non-pregnant, non-breastfeeding women aged 18–65 years who were treatment-naive for lip augmentation procedures of the vermilion zone. Subjects were not included if they had undergone permanent procedures of the peri-oral region, or non-permanent procedures within the previous 12 months. Other exclusion criteria included active inflammation or infection near the treatment area and hypersensitivity to HA or lidocaine.

Study design

The study was designed as an interventional 24-week-follow-up, randomized, subject- and evaluator-blinded, comparative, parallel-group, single-center study (NCT01745250). Treatment was randomly assigned (1:1) to either HA_RK containing 20 mg/ml HA or HA_JUS containing 24 mg/ml HA by central randomization.

Injection procedure

The injection procedure focused on contouring the vermillion border and was executed independent of the treatment group, that is, independent of the product utilized, by the same injector (S.H.). A 30 G ½ needle was used for the injection of 0.5 cc of product into each of the upper and lower lip resulting in a total administration of 1.0 cc per subject. The injection technique relied on a superficial retrograde linear threading technique which positioned the product in the subdermal plane (Figure ). As the injection volume, technique, and procedure were strictly standardized, treatment groups were not adjusted or stratified by lip fullness, and there were no requirements to attain at least one-grade improvement in lip fullness. Additional anesthesia, post-treatment topical cooling, or touch-up was not permitted.

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Products utilized

One treatment group was injected with HA_RK, whereas the other treatment group was injected with HA_JUS. Both products are HA-based fillers with 3 mg/cc of lidocaine; the HA content is 20 mg/cc in HA_RK and 24 mg/ml in HA_JUS.

HA_RK is a flexible gel manufactured with the OBT/XpresHAn Technology™ and is indicated for restoration or augmentation of lip volume in the EU and many other countries world-wide, and for lip augmentation and correction of upper perioral rhytids in the USA.

HA_JUS is manufactured with the Hylacross™ technology and specifically developed for lip injection, with gel properties similar to those of Juvéderm® Ultra 3 and Juvéderm® Ultra Plus XC (Allergan).

Clinical outcome measures

Occurrence and intensity of early-onset AEs (edema/swelling, erythema, and bruising) was assessed live by an independent (not in the treatment process involved) evaluator at Days 0, 1, 3, 7, and 14. Intensity of pain/tenderness and pruritus was assessed by subject questioning. The intensity of AEs was graded on a 4-point scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. The independent evaluator also assessed if product feel was as expected (i.e., injected product of uniform density without lumpiness). AEs post-Day 14 were monitored by the treating physician.

Aesthetic improvement was rated independently by subjects and by an independent evaluator using the Global Aesthetic Improvement Scale (GAIS; Table ) on Day 14 and at Weeks 4, 12, and 24. Baseline photographs of the subjects' lips were compared with photographs taken at each visit. Aesthetic improvement was defined as subjects with both lips assessed as somewhat improved, much improved, or very much improved on the GAIS.

TABLE 1 Scoring options for the GAIS

Subject assessment	Blinded evaluator assessment
Very much improved	Optimal cosmetic result for the filler in this subject
Much improved	Marked improvement in appearance from the original condition, but not completely optimal for this subject
Somewhat improved	Obvious improvements in appearance from the original condition
No change	The appearance is essentially the same as the original condition
Worse	The appearance is worse than the original condition

Lip fullness was assessed by an independent evaluator using the validated 5-point Lip Fullness Grading Scale (LFGS) on Days 0 and 14, and at Weeks 4, 12, and 24.

Subject satisfaction was assessed using subject satisfaction questionnaires at the screening visit, on Days 0 and 14, and at Weeks 4, 12, and 24.

Statistical analysis

As no primary objective was defined for the study, the sample size (20 subjects per treatment group) was not based on a statistical calculation but was considered sufficient for an initial evaluation of any differences in performance between HA_RK and HA_JUS.

The intensity grade distribution of each local tolerability symptom was compared between treatment groups using exact Wilcoxon rank-sum tests. Tests were performed for each assessment occasion separately and over the whole evaluation period comparing group mean values from subjects' maximum grade of upper and lower lip symptoms.

RESULTS

Study participants follow-up

Twenty subjects in each treatment group (i.e., 40 subjects in total) participated in the study and were included in the intention-to-treat population. One subject in the HA_RK group was lost to follow-up after Day 7; thus, 39 subjects completed all study visits. Demographics and baseline characteristics were similar between groups (Table ).

TABLE 2 Subject demographics and baseline characteristics

Characteristic	HARK (n = 20)	HAJUS (n = 20)
Ethnic origin, white	17 (85.0)	16 (80.0)
Mediterranean Caucasian	3 (15.0)	4 (20.0)
Age, years	39.3 (23–65)	40.8 (23–63)
Smokers	10 (50.0)	11 (55.0)
Previous facial procedures	12 (60.0)	10 (50.0)
Fitzpatrick Classification
1: White, very fair	2 (10.0)	1 (5.0)
2: White, fair	2 (10.0)	4 (20.0)
3: Cream white	12 (60.0)	11 (55.0)
4: Brown	4 (20.0)	4 (20.0)
Glogau classification
1: Mild	6 (30.0)	6 (30.0)
2: Moderate	8 (40.0)	6 (30.0)
3: Advanced	5 (25.0)	7 (35.0)
4: Severe	1 (5.0)	1 (5.0)
LFGS upper lip /lower lip
0: Very thin	5 (25.0) / 0 (0.0)	4 (20.0) / 3 (15.0)
1: Thin	8 (40.0) / 10 (50.0)	13 (65.0) / 6 (30.0)
2: Moderately thick	7 (35.0) / 6 (30.0)	2 (10.0) / 9 (45.0)
3: Thick	0 (0.0) / 3 (15.0)	1 (5.0) / 2 (10.0)
4: Full	0 (0.0) / 1 (5.0)	0 (0.0) / 0 (0.0)

Early-onset adverse events (blinded evaluation Days 0, 1, 3, 7, and 14)

Comparison of the highest edema/swelling intensity per subject during the whole evaluation period showed that HA_RK treatment was associated with lower edema/swelling intensity than HA_JUS treatment (p < 0.001; Table ). For subjects receiving HA_RK, the intensity was assessed as none or mild in 80% of subjects, in contrast to for 15% of HA_JUS subjects. The mean values of edema/swelling intensity were also significantly lower in the HA_RK group at Days 0, 1, 3, and 7 (p < 0.001; Figure ). In addition, edema/swelling resolved faster in HA_RK subjects as 25% were affected at Day 3, whereas 100% of HA_JUS subjects were still affected at that time-point.

TABLE 3 Summary of early-onset adverse events up to Day 14

n (%)		0: None	1: Mild	2: Moderate	3: Severe	p-Value
Edema/swelling	HARK	1 (5.0)	15 (75.0)	4 (20.0)	0	<0.001
HAJUS	0	3 (15.0)	15 (75.0)	2 (10.0)
Erythema	HARK	13 (65.0)	7 (35.0)	0	0	0.013
HAJUS	5 (25.0)	13 (65.0)	2 (10.0)	0
Bruising	HARK	2 (10.0)	17 (85.0)	1 (5.0)	0	0.820
HAJUS	3 (15.0)	14 (70.0)	2 (10.0)	1 (5.0)
Pain/tenderness	HARK	6 (30.0)	12 (60.0)	2 (10.0)	0	0.011
HAJUS	3 (15.0)	7 (35.0)	8 (40.0)	2 (10.0)
Pruritus	HARK	19 (95.0)	1 (5.0)	0	0	0.182
HAJUS	15 (75.0)	5 (25.0)	0	0

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Live assessments showed that subjects in the HA_RK group experienced significantly lower intensity of lip erythema than subjects in the HA_JUS group over the whole evaluation period (p < 0.05; Table ) and at Days 0 and 3 (p < 0.05; Figure ). In total, 65% of HA_RK subjects and 25% of HA_JUS subjects did not experience erythema.

There was no significant difference in the intensity of bruising between treatment groups over the whole evaluation period (Table ).

Pain/tenderness intensity ratings were significantly lower with HA_RK treatment than with HA_JUS (p < 0.05; Table ; Figure ) and resolved earlier in the HA_RK group compared with the HA_JUS group. During the whole evaluation period, 10% of HA_RK subjects experienced pain/tenderness of moderate intensity, in contrast to in the HA_JUS group, where 40% experienced pain/tenderness of moderate intensity and 10% experienced pain of severe intensity. In addition, the proportion of subjects not experiencing any pain was twice as large in the HA_RK group (30%) compared with the HA_JUS group (15%).

Over 90% of subjects in both treatment groups had normal lip palpability. On Day 14, two subjects in each treatment group were assessed as having palpable product between 1 and 3 mm in diameter. The median duration was 21 days for the palpable product to resolve for the two subjects in the HA_RK group, while the duration was 53 days for one of the two affected subjects in the HA_JUS group; the other subject in the HA_JUS group still had palpable product at the final 24-week visit.

Adverse events reported to Week 24

No serious AEs were reported in either study group, and the number of reported AEs was similar between groups (Table ). Treatment-related AEs in both groups mainly related to the implant site and included pain, papules, and swelling, except for two HA_JUS subjects reporting herpes simplex. All AEs were mild or moderate, except for one case of severe implant-site swelling in the HA_JUS group.

TABLE 4 Treatment-related adverse events post Day 14

	HARK (n = 20)	HAJUS (n = 20)	Total (n = 40)
Subjects	Events	Subjects	Events	Subjects	Events
n (%)	n	n (%)	n	n (%)	n
System organ class and preferred term
General disorders and administration site conditions
Implant site pain	2 (10.0)	4	3 (15.0)	4	5 (12.5)	8
Implant site papules	3 (15.0)	4	2 (10.0)	2	5 (12.5)	6
Implant site swelling	2 (10.0)	3	5 (25.0)	7	7 (17.5)	10
Infections and infestations
Herpes simplex	0 (0.0)	0	2 (10.0)	1	2 (5.0)	2
Total	5 (25.0)	11	7 (35.0)	15	12 (30.0)	26

Global Aesthetic Improvement Scale

The blinded evaluator recorded aesthetic improvements of both lips on the GAIS for all HA_RK subjects and for ≥95% of subjects treated with HA_JUS up to Week 12. Improvements were maintained for 90% of subjects in the HA_RK group and for 85% of subjects in the HA_JUS group at Week 24 (Figure ).

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With respect to subject-evaluated GAIS scores up to Week 12, ≥95% of subjects treated with HA_RK and ≥ 84% of subjects treated with HA_JUS assessed that both lips were improved. At Week 24, GAIS scores were similar between treatment groups, with ≥74% of subjects reporting improvements in both lips (Figure ).

Lip Fullness Grading Scale

Mean LFGS scores increased from baseline (see Table ) to 2.0 for HA_RK and 2.1 for HA_JUS in the upper lip, and 2.4 for both groups in the lower lip at Day 14. Mean upper lip LFGS scores at Week 24 were 1.7 for HA_RK and 1.8 for HA_JUS, and lower lip scores 2.2 for HA_RK and 2.0 for HA_JUS.

Subject satisfaction questionnaire

At baseline, 20% of subjects were very or somewhat satisfied with the appearance of their lips. This proportion increased to Day 14 in both groups (100% in the HA_RK group; 90% in the HA_JUS group) and was maintained at Week 12 (95% in the HA_RK group; 90% in the HA_JUS group). At Week 24, 79% of subjects in the HA_RK group and 70% of subjects in the HA_JUS group were still very or somewhat satisfied with the appearance of their lips.

The subject satisfaction questionnaires also included assessment of pain and discomfort during treatment. Most subjects reported that they experienced mild to moderate pain and discomfort during treatment (HA_RK: 95%; HA_JUS: 75%), whereas four subjects (20%) in the HA_JUS group experienced severe pain.

At Day 14, all subjects in the HA_RK group and 79% of subjects in the HA_JUS group agreed that the time to recovery after treatment was acceptable (Table ). Most subjects in both groups felt more attractive at Week 4. At Week 24, the majority of subjects agreed that their lips had a natural look and responded that they would repeat the treatment and recommend it to a friend.

TABLE 5 Subject satisfaction questionnaire results

Time	Parameter	HARK n (%)	HAJUS n (%)
How satisfied are you today with the appearance of your lips?
Baseline	Very/somewhat satisfied	4 (20.0)	4 (20.0)
Neither satisfied nor dissatisfied	6 (30.0)	4 (20.0)
Somewhat/very dissatisfied	10 (50.0)	12 (60.0)
Week 24	Very/somewhat satisfied	15 (78.9)	14 (70.0)
Neither satisfied nor dissatisfied	2 (10.5)	4 (20.0)
Somewhat/very dissatisfied	2 (10.5)	2 (10.0)
The time to recover after treatment was acceptable
Day 14	Fully/somewhat agree	19 (100.0)	15 (78.9)
Neither agree nor disagree	0 (0.0)	1 (5.3)
Somewhat/completely disagree	0 (0.0)	3 (15.8)
I feel more attractive after the treatment
Week 4	Fully/somewhat agree	17 (89.5)	17 (85.0)
Neither agree nor disagree	2 (10.5)	2 (10.0)
Somewhat/completely disagree	0	1 (5.0)
My lips have a natural look after treatment
Week 24	Fully/somewhat agree	17 (89.5)	16 (80.0)
Neither agree nor disagree	1 (5.3)	3 (15.0)
Somewhat/completely disagree	1 (5.3)	1 (5.0)
Would you recommend the treatment to a friend?
Week 24	Yes	18 (94.7)	19 (95.0)
No	1 (5.3)	1 (5.0)
Would you do the treatment again?
Week 24	Yes	17 (89.5)	19 (95.0)
No	2 (10.5)	1 (5.0)

DISCUSSION

This study compared the clinical outcome of lip contouring procedures performed in 40 women with two products manufactured with different gel technologies: OBT/XpresHAn Technology (HA_RK) or Hylacross (HA_JUS). To allow direct comparisons between products, a standardized injection volume of 0.5 cc per upper and lower lip was used. The injection procedure was also standardized to minimize bias relating to the investigator's injection technique on the occurrence of AEs. The results revealed that no statistically significant difference was observed in the occurrence and intensity of bruising or pruritus between the two treatment groups (p = 0.182). However, the intensity of edema/swelling within 14 days after the procedure was significantly higher in the HA_JUS group as compared with the HA_RK group (p < 0.001). Additionally, the intensity of erythema and pain/tenderness was also higher in the HA_JUS group (p = 0.013). Due to the standardization of injection technique, this can be interpreted as a potential result of differences in gel properties between products due to differences in manufacturing methods. However, as the sample size was relatively small, individual susceptibility to swelling may also have contributed to the higher intensity of early-onset edema/swelling, erythema, and pain/tenderness seen with HA_JUS.

The anatomic location of the injection procedures performed corresponds to the boundary between the red and the cutaneous part of the lip (both upper and lower lip). This boundary is termed the vermilion border or the white roll and contains a multitude of loose connective tissue. In contrast to the vermillion border, the red portion of the lip contains a dense subdermal arterial and venous plexus and the terminal part of the orbicularis oris muscle. Furthermore, the structure of the cutaneous part of the lip differs from that of both the vermillion border and the red portion of the lip. The cutaneous part of the lip contains a dense network of muscular and connective tissue fibers that connect to the dermal underside and form a strong and stable meshwork. The difference in structure between these anatomic locations could provide some insights into the ability of tissue to swell visibly, for example, after lip contouring injections in the vermillion border.

Further to the relatively small sample size, additional study limitations include the subjective nature of the clinical assessments made by subjects, treating investigator, or the independent evaluator.

Despite the difference in gel properties between the tested products, the GAIS assessments showed comparable results between the two treatment groups, with most subjects showing aesthetic improvements at all time-points. The slight decrease in GAIS at Week 24 may be due to the natural degradation of HA and subsequent reduced clinical effect. The discrepancies between subject and the independent evaluator GAIS assessments may be due to subjects' expectations and subjectivity versus the professional judgment of the evaluators and are not unexpected given the small sample size.

GAIS assessments were matched by high overall subject satisfaction. Almost all subjects considered their lips to have a natural look after treatment and that the treatment made them feel more attractive. In addition, the majority of subjects said they would have the treatment again and that they would recommend the treatment to a friend.

As a standardized injection volume was used, the study was not designed to achieve optimal aesthetic results, or to achieve a one or more grade increase in lip fullness on a validated scale. LFGS scores thus increased moderately, which was predicted due to the small volume injected. Nevertheless, the injected volume was sufficient to achieve GAIS improvements and appreciation of lip appearance, and the time to recovery was considered acceptable in all subjects receiving HA_RK.

It has to be noted that using a needle poses a certain degree of risk if the superficial plane is not precisely targeted. Previous studies have revealed that both the superior and the inferior labial arteries travel in the majority of the cases (approximately 80%) in the deep plane, that is, deep to orbicularis oris muscle and oral mucosa. Injecting into the red portion of the lips without respecting the superficial plane might increase the risk for intra-vascular product application with the respective consequences of soft tissue loss and injection related visual compromise. Avoiding the deep plane and staying superficial is therefore paramount for safe lip procedures.

A limitation of the study is the absence of objective outcome measurements such as ultrasound imaging or volumetric 3-dimensional analyses. Such objective assessment tools might allow for an evaluator-independent outcome rating. However, such tools are associated with financial investments and with technologic knowledge to operate appropriately (f.i. ultrasound). It is hoped that future aesthetic studies will utilize such objective outcome measurement tools to allow for independent and neutral evaluations especially when evaluating lip swelling.

CONCLUSION

In subjects treated with HA_RK, the intensity of early-onset swelling and other injection-site reactions was lower than in subjects treated with HA_JUS as assessed by blinded evaluation. Since both the injection volume and injection procedure were standardized, the difference in local tolerability between the two HA fillers may relate to differences in gel properties. Aesthetic improvement, subject satisfaction, and AE profiles post-Day 14, however, were similar between filler groups.

AUTHOR CONTRIBUTIONS

Dr. Hilton is a consultant for Allergan, Almirall, and Galderma. Prof. Dr. Cotofana, Dr. Frank, and Mr. Alfertshofer declare to have no commercial associations or financial disclosures that might pose or create a conflict of interest with the methods applied or the results presented in this article.

ACKNOWLEDGEMENTS

We would like to thank Lucy Bee, PhD, of Fishawack Communications Ltd and Carolina Edwartz, PhD, of Galderma for support during medical writing, and Dr. Jeremy Green for assistance with proof reading.

FUNDING INFORMATION

The conception and the execution of the study was funded by Galderma, Uppsala, Sweden.

ETHICS STATEMENT

The study was approved by the Ethical Review Board of the Medical Association in North Rhine, Germany on December 12, 2012 (approval/serial number 2012403) and conformed with the Declaration of Helsinki of 2008 and Good Clinical Practice. Written informed consent was obtained from each subject prior to study participation.

DATA AVAILABILITY STATEMENT

Research data are not shared.

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