Tolerability and Efficacy of Newly Developed Penile Injection of Cross

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ORIGINAL ARTICLE Tolerability and efﬁcacy of newly developed penile injection of cross-linked dextran and polymethylmethacrylate mixture on penile enhancement: 6 months follow-up

DY Yang1,WKLee1 and SC Kim2

Cross-linked dextran and polymethylmethacrylate mixture (Lipen-10) is newly developed tissue filler. The purpose of this study was to evaluate tolerability and efficacy of Lipen-10 on penile enhancement. Twenty adult males were included in this study. Lipen-10 was injected into the subcutaneous tissue of the penile shaft. The penile girth and length were measured in the flaccid state, before and 1, 3 and 6 months after the injection. The circumference increased by 3.7±1.2 cm (50.8%, Po0.0001) at penile base, 4.2±0.9 cm (59.0%, Po0.001) at mid-shaft, and 3.8±1.0 cm (53.2%, Po0.0001) at distal shaft and the length increased by 2.3±1.4 cm (63.2%, Po0.001). There was, however, no significant difference between 3 and 6 months post-treatment in girth and length (P-values: 0.796, 0.498, 0.600 and 0.084 for penile base, mid- and distal-shaft and length, respectively). The complications were only one mild asymmetry of penile shape and one 5-mm-sized nodule in the injected site. There were no clinically significant adverse events in all subjects. Penile injection of Lipen-10 led to a significant increase in penile size, showed a good durability and was well-tolerated, without serious adverse events. These results suggest that penile injection of Lipen-10 may be a new effective method for penile enhancement.

International Journal of Impotence Research (2012) 25, 99–103; doi:10.1038/ijir.2012.41; published online 22 November 2012 Keywords: cross-linked dextran; ﬁller; penile enhancement; polymethylmethacrylate

INTRODUCTION neocollagenetic properties, and are replaced by the body’s own 3,6 Penis size has been a source of anxiety for men throughout tissue after dermal injection. Cross-linked dextran and PMMA history, and men often feel the need to enlarge their penises in are easy to mix and do not affect each other physicochemically. order either to improve their self-esteem or to satisfy and impress In this study, we evaluated the efficacy and tolerability of cross- their partners.1 A variety of cross-cultural references to penile linked dextran and PMMA mixture on penile enhancement during enhancement exist. However, there have been reported various a follow-up period of 6-months after injection. adverse events such as re-contracture and shortening after suspensory ligament dissection and graft tissue necrosis, as well as donor site scar after dermal fat graft.2 MATERIALS AND METHODS Currently, as the need for safer, effective and less invasive Subjects procedures are increasing, penile enhancement procedures using Adult male subjects aged 20–70 (mean age; 44.4 years), who wanted penile injectable products are in high demand. There are several types of enhancement, were recruited in this study. Before procedure, all subjects injection materials for penile enhancement. However, most of were evaluated on history and physical examination, especially on them are not approved yet by the professional societies, and are anatomical features of the genitalia and on psychological details. The performed in private settings, leading to medico-legal implications subjects signed an informed consent form, after the study design and and paucity of scientific data.2 possible complications of the penile injection were explained. Men with the following conditions were excluded from the study: psychological/ Dextran is a complex with branched glucan, and is generally 3 psychiatric history, including major depression; congenital or acquired used as antithrombotic agent or volume expander. It has been malformation of the penis; previous penile plastic surgery; phimosis; and recently used as bulking material for the treatment of any chronic major systemic disease, such as cancer or diabetes. vesicoureteral reflux.4 Polymethylmethacrylate (PMMA) consists Finally, 20 subjects were recruited to this study in two medical of 32–120-mm-sized microspheres with smooth surface. The institutions, each of them having 10 subjects. Approvals for the study injected PMMA is not absorbable, and its esthetic effects have were obtained from the respective Institutional Review Boards of the two endured for 410 years.5,6 In 2006, it was approved for the institutions (No. 09-113). treatment of nasolabial folds in USA,5 and has been widely used to 6 fill lines and wrinkles in the face. Injection material Cross-linked dextran and PMMA mixture (Lipen-10; Chungwha The filler (Lipen-10) is newly developed dermal filler for soft-tissue Medipower Corporation, Seoul, Korea) is newly developed dermal augmentation, and is a commercially available product approved by the filler for soft-tissue augmentation. Both of these substances have Korean Food and Drug Administration in 2010.

1Department of Urology, College of Medicine, Hallym University, Kangdong Sacred Heart Hospital, Seoul, Korea and 2Chung-Ang University, Seoul, Korea. Correspondence: Professor SC Kim, Department of Urology, College of Medicine, Chung-Ang University, Chung-Ang University Hospital, 224-1, Heukseok-dong, Seoul, Korea. E-mail: [email protected] Received 9 September 2011; revised 26 July 2012; accepted 16 October 2012; published online 22 November 2012 Filler injection for penile enhancement D Yul Yang et al 100 Lipen-10 consisted of cross-linked dextran in 75% and PMMA in 15%. other P-values were two-sided. A Po0.005 was considered as statistically Cross-linked dextran and PMMA are microspheres with diameters of significant for all analyses. 45–120 mm and 32–120 mm, respectively. These microspheres (90% by volume) are suspended in hypromellose solution (10% by volume), therefore, there is no physical or chemical interaction between them. RESULTS Once injected, the smooth, electrically uncharged PMMA microspheres become encapsulated by endogenously derived connective tissue, which Out of 20 subjects who finished baseline evaluation and injection, prevents migration of the microspheres. The PMMA microspheres resist one subject dropped out of the study because of the withdrawal phagocytosis and are not degraded by enzymatic digestion.6 Cross-linked of consent. Finally, a total of 19 subjects were analyzed. dextran, another component of the mixture, is derived from dextran used The fillers were uniformly distributed in appearance at 6 months as volume expander. The positive surface charges of dextran apparently post-treatment and did not migrate from the injected surface attract macrophages. In turn, the macrophages release TGF-b and (Figure 1). On magnetic resonance imaging, the fillers were well- interleukins, which stimulate fibroblasts to produce collagen fibers. After 7 circumscribed between Buck’s fascia and dartos fascia (Figure 2). extensive resorption, dextran is replaced by the body’s own tissue. The penile girth at 6 months post-treatment increased by 2 cm or more in all subjects (100%). The mean circumferences of penile Injection method base, mid-shaft and distal shaft before treatment and at 6 months A single surgeon performed the procedure at each institute. The post-treatment were 7.2±0.8 and 10.9±1.1 cm with a mean procedures were carried out in an office setting with the patient in the increase of 3.7±1.2 cm (50.8%, Po0.0001), 7.1±0.8 and supine position. The penile skin was cleansed with povidone-iodine topical 11.3±0.9 cm with a mean increase of 4.2±0.9 cm (59.0%, antiseptics, and a penile block was induced by injecting 2 ml 0.2% Po0.0001) and 7.1±0.8 and 10.8±1.1 cm with a mean increase lidocaine into the penis root. of 3.8±1.0 cm (53.2%, P 0.0001), respectively (Figure 3). There After the anesthesia had taken effect, the filler was injected into the o subcutaneous tissue of the penile shaft, between dartos fascia and Buck’s were no significant differences in the girth between 3 and 6 fascia by the fanning technique using a syringe with 20-gauge needle. The months post-treatment (P-value for comparison at penile needle was directed posteriorly and laterally, parallel or tangential to the base ¼ 0.796, mid-shaft ¼ 0.498 and distal shaft ¼ 0.600, Figure 4). corpus cavernosum, distributing the material as uniformly as possible from With regard to the penile lengthening, 16 subjects (84.2%) the penile root to the distal shaft, by a continuous back and forth showed increases of 1 cm or more at 6 months after the penile movement, while constantly pressing the syringe plunger. Injected injection. The mean penile length before treatment and at 6 material did not cover ventral part of the penis, to avoid urethral injury months post-treatment was 3.6±1.8 and 5.8±1.5 cm with a mean or compression. During the procedure, the penis was maintained in the increase of 2.3±1.4 cm (63.2%, Po0.0001, Figure 3). When stretched state. Mean injected volume was 23.73 ml (range 17–30 ml), and comparing between 3 and 6 months post-treatment, there was 4–6 needle punctures were performed during the procedure. The injected surface was thoroughly massaged in order to redistribute the filler as no significant difference (P-value ¼ 0.084, Figure 4). uniformly as possible, without leaving palpable nodules. All subjects experienced mild and transient penile edema after After injection, an elastic penile support bandage was applied, to the bandage was unwrapped. However, in almost all subjects, the support uniform fixation of the injected material and to avoid penile penile edema spontaneously subsided within 2 weeks, and there edema. The patients were instructed to construct bandage by himself not was no case of penile edema lasting for 4 weeks. At follow-up of to compress too tightly, to avoid squeezing the injected material out of the 1 month after the penile injection, one subject presented mild injected place or voiding difficulty. asymmetry of penile shape that was corrected by an additional injection. At 6 months post-treatment, one subject showed a Evaluation nodule of about 5 mm on the injected site. This nodule was Before injection of the filler, penile girth and length were measured for all caused in separately injected site not by a cyst or granuloma. Both subjects. With the penis in the flaccid state, the penile girth was measured cases were mild, and resulted from technical mistakes, rather than without tension, with a caliper at the base, mid-shaft and distal shaft. The drug-induced side effects. There were no abnormal texture, penile length was measured from the pubic-penile skin junction to the firmness or feeling of the penis in all subjects. Any subjects did coronal sulcus of the penis, and did not include the penile glans, while not complain about problems associated with the penile erection penis was perpendicular to the body without stretching. The prepubic fat state, such as distortion, loss of length, or restriction of erect penis, pad was pushed to the bone at the maximum. All measurements were during the study period. performed in supine position at stable environment. These measurements There were no statistical differences in the results between the were repeated at 1, 3 and 6 months after penile injection. The primary end-point of this study was increase in penile girth by 2 cm two institutes (P-values for penile base, 0.518; mid-shaft, 0.887; or more in the flaccid state at 6 months post-treatment. Another end point distal shaft, 0.821; and penile length, 0.435). was increase in flaccid penile length by 1 cm or more. Mathematically, if we consider that the penis as a cylinder and that injected materials are not absorbed or migrated, the increase in girth is 1.97 cm after injection of DISCUSSION 18 ml of filling materials. The lengthening effect of penile injection is Many different types of penile enhancement surgery are difficult to calculate mathematically, owing to physiologic contraction and relaxation of penis. Therefore, on the basis of previous results from performed all over the world, although there are medicolegal methods using the same principle, such as autologous fat transplantation, the cutoff point for increase of penile length was decided.2 Changes in the penile girth and length were analyzed at 1, 3 and 6 months post-treatment. The adverse events, defined as an undesirable medical condition that was not observed before penile injection, were evaluated. Differences in the results between institutes were also analyzed for all parameters.

Statistics The changes in the penile girth and length were analyzed at 1, 3 and 6 months post-treatment, using the Student’s t-test and paired t-test. Adverse events were analyzed with McNemar test. Statistical Package for the Social Science version 19.0 (SPSS, Chicago, IL, USA) was used for all Figure 1. Representative ﬁgure of injection for penile enhancement. statistical assessments. The P-values for changes of penile girth and length Grossly, materials were uniformly distributed, and the penis at before and 6 months after penile injection were one-sided, whereas the 6 months after injection (right) was more larger than before (left).

International Journal of Impotence Research (2012), 99 – 103 & 2012 Macmillan Publishers Limited Filler injection for penile enhancement D Yul Yang et al 101

Figure 4. Changes of penile size between, before and 6 months after penile injection. There were no signiﬁcant differences between penile sizes at 3 months after penile injection and that at 6 months (all P-vlaues40.05). Circumf, circumference.

Results for autologous fat injections are considered unpredictable, because of the lack of adequate blood supply to the injected fat and because the plane into which the adipocytes are injected has not been determined.11 Small amount (up to 0.75 ml) of silicone injection has been commonly used for cosmetic purposes, with satisfactory results and relative safety, mainly in cases of soft- tissue augmentation and restoration of damaged skin. However, in order to achieve penile enhancement, larger volumes of silicone, ranging from 100–150 ml, are required. Therefore, the silicone injection has not been recommended, because of the develop- ment of severe complications. Some of the complications were related to the large volumes injected, and others were due to Figure 2. Coronal view of penis on magnetic resonance imaging at 6 drifting and distant migration, swelling, penile distortion and months after penile injection. Materials were well-circumscribed idiosyncratic and late granulomatous reactions.2,13 In addition, between Buck’s fascia and dartos fascia, and not migrated. Injected injection of silicone into the penis increases the likelihood of materials were shown inside of dotted line. damaging blood vessels and nerves, thereby causing loss of sensation and erectile dysfunction.14,15 The collagen products were the first injectable fillers used for esthetic improvement, because endogenous collagen functions as the structural base for the skin, providing strength and support.6 However, the collagen caused rapid degradation, required frequent reinjection and produced infrequent but significant hypersensitivity reactions.16 Unlike the aforementioned products, cross-linked dextran and PMMA mixture was well-tolerated, did not cause serious adverse events and provided a significant penile enhancement in this study. All of 19 subjects (100%) fulfilled the criteria for primary end point of penile girth enhancement. Interestingly, 16 of 19 subjects (84.2%) fulfilled the criteria for primary end point of penile length enhancement, and the mean increase of flaccid penile length after 6 months was 2.3±1.4 cm (63.2%). There are only few studies showing an increase in penile length after penile injection using any materials One of the hypotheses is the splint effect of cross- linked dextran and PMMA mixture. As the mixture of cross-linked Figure 3. Mean Penile sizes before (black color) and 6 months after dextran and PMMA is evenly distributed between Buck’s fascia penile injection (gray color). All P-values were o0.001. Circumf, and dartos fascia, it prevents the physiologic contraction of the circumference. penis and leads to the lengthening effect. From the viewpoint of adverse events, cross-linked dextran and PMMA mixture was issues and paucity of scientific data.2 Currently, as the need for superior to the aforementioned products. There were only a few safer, effective and less-invasive procedures are increasing, penile mild adverse reactions, possibly caused by technical mistakes enhancement procedures using injectable products are in high during injection, rather than drug-induced side effects. demand. Injectable soft-tissue substitutes provide an affordable, Lipen-10, cross-linked dextran and PMMA mixture, is newly nonsurgical alternative for correcting contour defects and soft- developed dermal filler for soft-tissue augmentation, and is a tissue augmentation. Several penile injection materials have been commercially available product approved by the Korean Food and used for penile enhancement, including autologous fat, silicone, Drug Administration in 2010. PMMA-based dermal filler was collagen and hyaluronic acid (HA).6,8–11 approved in USA in 2006 for the treatment of nasolabial folds.5 The injection of autologous fat was initially thought to be a Once injected, the smooth, electrically uncharged PMMA promising technique. However, during the injection process, a microspheres are encapsulated by endogenously derived con- significant number of adipocytes are ruptured or reabsorbed, and nective tissue, preventing migration of the microspheres. The probably the final result leaves only 10% of the fat cells intact.12 PMMA microspheres resist phagocytosis and are not degraded by

& 2012 Macmillan Publishers Limited International Journal of Impotence Research (2012), 99 – 103 Filler injection for penile enhancement D Yul Yang et al 102 enzymatic digestion.6 Histological studies indicate that each volume of cross-linked dextran and PMMA mixture was microsphere is encapsulated by a thin layer of collagen, maintained sufficiently. macrophages and fibroblasts by as early as 1 month.17 Cross- There were a few limitations to this study. First, the duration of linked dextran, the other component of mixture, is derived from follow-up was not enough to confirm the long-term effect of dextran used as a volume expander, and consists of microspheres cross-linked dextran and PMMA mixture. A longer term follow-up similar to PMMA. The positive surface charges of dextran over a year is needed for the clinical use. Also, there was no apparently attract macrophages. In turn, the macrophages control group in this study. Lastly, evaluation of patient release TGF-b and interleukins, which stimulate fibroblasts to satisfaction and partner’s response should be followed. produce collagen fibers. After being extensively reabsorbed, In conclusion, penile injection of cross-linked dextran and dextran is replaced by the body’s own tissue.7 PMMA mixture showed a significant enhancement of penile girth, Jang et al.18 studied both the bio-safety and the volume-related good durability at 6 months post-treatment, and was well-tolerated, effect of Lipen-10, as soft tissue filler in the rat model for 13 weeks. without serious adverse events. Penile injection of cross-linked During the experimental period, there were no dead rats and dextran and PMMA mixture may be a new effective tool for penile scratching behavior which is a most common symptom when enhancement. Long-term follow-up for tolerability and efficacy rejecting foreign body was observed. The volume of injected should be needed to confirm its value in penile enhancement. mixture was maintained sufficiently. Complete blood count finding indicated that there were no significant differences in the number of inflammatory cells between control and experi- CONFLICT OF INTEREST mental group. In addition, the parameters of hepatic toxicity The authors declare no conflict of interest. (aspartate aminotransferase, alanine transaminase, alkaline phos- phatase, g-glutamyl transpeptidase, lactate dehydrogenase), renal toxicity (creatinine, blood urea nitrogen, cholesterol, albumin, ACKNOWLEDGEMENTS phosphorus), and other organ toxicity (calcium, triglyceride, Authors were investigators on clinical trial sponsored by Chungwha Medipower and creatine phosphokinase) using serum biochemical Corporation. analysis did not show the significant differences between the control and experimental group, suggesting that systemic toxicity was not found. 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