Since the early 1980s, when bovine collagen products were first introduced as dermal fillers, various formulations have been developed and utilized in the clinical setting [1]. Such dermal fillers have been used with increasing frequency because they have fewer adverse effects than surgical cosmetic procedures, are less invasive, are less expensive, and result in satisfactory patient outcomes [2]. However, despite these advantages, bovine collagen products trigger hypersensitivity reactions in 3% of patients, which warrants the inconvenience of an allergen test prior to the procedure [3]. Moreover, since collagenand hyaluronic acid-based dermal fillers are naturally absorbed by the body within a short period of time, the further inconvenience of regular procedures is required [45]. Therefore, long-lasting products such as calcium hydroxyapatite, injectable poly-L-lactic acid, and polymethyl methacrylate (PMMA) fillers have been developed, but each filler has distinct advantages and disadvantages.

A recently developed dermal filler consisting of PMMA and cross-linked dextran (Lipen-10; Chungwha Medipower Corporation, Seoul, Korea) is known not to cause allergic reactions. Furthermore, PMMA microspheres are not subjected to phagocytosis due to their large molecular size, while some are encapsulated by connective tissue consisting of fibroblasts, which inhibit their migration to other tissues and subsequent volume loss. Dextran also stimulates fibroblasts after being absorbed by macrophages, and is therefore replaced by internal tissue, resulting in no loss of volume [26]. In a previous study, we established the tolerability and short-term efficacy of a mixture of PMMA and cross-linked dextran for penile augmentation [7]. In this study, we report full efficacy and safety data over 18 months of follow-up.

A total of 20 patients completed the baseline evaluation and underwent penile augmentation using Lipen-10®. Follow-up was conducted in a total of 17 patients for one year (two patients withdrew their consent and one was lost to follow-up). At 18 months, two more patients had been lost to follow-up; therefore, a total of 15 patients completed the full extent of follow-up.

At 12 and 18 months of follow-up after the procedure, the increases in circumference observed six months after the procedure were maintained without change (Fig. 1). In the flaccid state 18 months after the procedure, the base, mid-shaft, and distal shaft circumference measurements were 10.4±0.9 cm, 11.0±0.8 cm, and 10.6±1.4 cm, respectively, which were significant increases compared to the baseline values (Fig. 2; all p<0.001). The 18-month measurements were not significantly different from those obtained six and 12 months after the procedure. The average length of the flaccid penis increased between before the procedure (3.6±1.8 cm) and 12 months after the procedure (6.6±1.6 cm). The increased length was maintained at 6.6±1.2 cm at 18 months, with no statistically significant differences compared to the six-month or 12-month values (p=0.103, p=0.897, respectively).

At 12 months of follow-up after the procedure, no local symptoms, such as penile edema, that were observed immediately after the procedure remained present. At 12 and 18 months of follow-up, no abnormal findings were observed, even in a patient who required an additional procedure to correct mild penile shape asymmetry observed one month after the initial procedure. In one patient, a 5-mm nodule that was observed at the injection site in the six-month follow-up examination was still visible at 12 and 18 months of follow-up, with no changes, but the patient did not complain of pain or discomfort during sexual intercourse. On a pelvic MRI conducted during the 18-month follow-up visit, no traces were observed of the injected filler having migrated to the scrotum or the abdominal wall, and the volume appeared well maintained, based on a comparison with pelvic MRI findings immediately and six months after the procedure (Fig. 3).

Man's desire for a larger penis has persisted over time [8], despite the range of objections that have been articulated against penile augmentation. Doctors who are against penile augmentation have expressed concerns that patients may be negatively affected by unforeseen complications, such as penile deformity, paradoxical penile shortening, unpleasant scarring, granuloma formation, migration of the injected material, and sexual dysfunction. However, the use of penile decorations throughout history, including piercings and the intentional biting of the glans of the penis by poisonous snakes, highlights man's continual desire for penile augmentation [9].

Patients seek out penile augmentation to boost their self-esteem and satisfy their partners [10]. Interestingly, most patients consider the size of their penis in the flaccid state more important than its size when erect [1112]. This may be due to the castration complex, in which a young boy compares his penis with that of his healthy father during the course of normal psychological development [13]. It may also be due to a persistent feeling of inferiority regarding penis size based on comparisons with friends of the same age whose secondary sexual characteristics developed earlier, given that the timing of the development of secondary sexual characteristics during puberty varies among individuals [14].

A study of penis size and self-esteem of Korean males in their twenties found that the average penis length of Korean males was 6.1±1.3 cm, and that most subjects who considered their penis unusually small or large were within the range of one standard deviation, indicating that they had incorrect views regarding their penis size [12]. The penis length data of that study and those of the present study on Korean men in their forties could not be directly compared due to differences in the measurement methods. However, the average circumference at the mid-shaft of the penis, where similar measurement methods were used, was 8.9±0.8 cm for men in their twenties, which was approximately 1 cm larger than observed in men in their forties (7.3±0.9 cm). However, 18 months after penile augmentation, the mean penile circumference of the men in their forties was 11.0±0.8 cm, showing an average increase to 2 cm more than that of men in their twenties. Despite the fact that this involved an indirect comparison between different numbers and groups of patients, this finding suggests that the augmentation effect of Lipen-10® was stable.

In this study, a mean 3-cm increase in the length of the flaccid penis was observed after penile augmentation using Lipen-10®. This penile length enhancement effect was consistently observed over 18 months of follow-up, and was likely due to the splint effect, which inhibits physiological contraction of the penis once the Lipen-10® becomes stably fixed after its injection into the site between Buck's fascia and the dartos fascia [7]. This result is significant, since it shows that the injection material alone enabled long-term penile lengthening.

Although dermal filler injections are minimally invasive compared to surgical cosmetic procedures, their safety issues have been the subject of significant debate. Autologous fat injection has been reported to have only a 10% survival rate, while a number of complications have been reported to be related to ischemia due to an insufficient blood supply to the injected fat [15]. A volume of over 100 mL of silicone is required for penile augmentation, and the injected silicone migrates with gravity, causing penile distortion and a granulomatous reaction [1617]. The collagen products that were first used as dermal fillers also exhibited problems related to rapid degradation and hypersensitivity [18]. Hyaluronic acid is a natural component within the human body and has no issues with biocompatibility and immune reaction, but it does have the disadvantage of requiring regular injections every three to six months [25]. In contrast, Lipen-10®, which is a mixture of cross-linked dextran and PMMA, did not show volume changes over 18 months of follow-up and no adverse effects were observed, with the exception of a tiny nodule that resulted from a technical mistake during the injection.

Although Artefill® (Artes Medical, San Diego, CA, USA), a PMMA-based dermal filler, was approved by the United States Food and Drug Administration [19], it remains unclear whether PMMA, which is composed of non-degradable microspheres, subcutaneously grafted to the penis can migrate to a site distant from the graft site due to the physical impact generated during sexual intercourse. In fact, for materials such as polyacrylamide that cannot produce their own collagen, migration due to external impacts is possible and related adverse effects have been reported [2021]. Our results over 18 months of follow-up demonstrate that Lipen-10® maintained its volume and location despite normal sexual activity. This is likely due to the neocollagenesis characteristic of PMMA, which has been conclusively observed in histological analyses in animal experiments using rats. After one year, most of the cross-linked dextran disappears after degradation and the site becomes filled with a large amount of self-produced collagen, which encapsulates the PMMA and allows it to withstand physical impacts [6].

Of the dermal fillers that are currently in use, autologous fat, collagen, and hyaluronic acid are non-permanent options that are retained for a maximal duration of three to twelve months [221]. Hence, studies with 18 months of follow-up are rare. Even with the development of permanent fillers such as PMMA and polyacrylamide, long-term follow-up of injections of these materials has not been reported to date. Long-term follow-up is especially important for permanent fillers, since fatal adverse effects can occur, as with silicone. In this study, Lipen-10® successfully maintained its volume and location for 18 months, and no significant adverse effects were observed.

Despite its prospective design, this study has several limitations. First, due to the nature of the clinical experiment, no control group was included. As such, further comparative experiments with other novel dermal fillers might be beneficial. Second, no data were collected regarding patients' subjective satisfaction. Since penile augmentation is performed for personal reasons, patients' subjective satisfaction might be more important than objectively measured data.

Penile injections of a mixture of cross-linked dextran and PMMA demonstrated significant efficacy in enhancing penile girth, showed good durability, and were welltolerated, without serious adverse events over 18 months of follow-up.