These authors contributed equally to this work.
Tissue Engineering Penoplasty With Biodegradable Scaffold Maxpol-T Cografted Autologous Fibroblasts for Small Penis Syndrome
Article first published online: 2 JAN 2013
2011 American Society of Andrology
Journal of Andrology
Volume 32, Issue 5, pages 491–495, September-October 2011
How to Cite
Jin, Z., Wu, Y.-G., Yuan, Y.-M., Peng, J., Gong, Y.-Q., Li, G.-Y., Song, W.-D., Cui, W.-S., He, X.-Y. and Xin, Z.-C. (2011), Tissue Engineering Penoplasty With Biodegradable Scaffold Maxpol-T Cografted Autologous Fibroblasts for Small Penis Syndrome. Journal of Andrology, 32: 491–495. doi: 10.2164/jandrol.110.011247
- Issue published online: 2 JAN 2013
- Article first published online: 2 JAN 2013
- Received for Publication July 12, 2010; Accepted for Publication December 7, 2010
- PLGA scaffold;
- small penis;
- autologous fibroblasts;
ABSTRACT: In this study, we investigated the safety and efficacy of a poly acid-co-glycolide biodegradable scaffold (Maxpol-T) coated by autologous fibroblasts (AF) for penile girth enlargement in small penis syndrome (SPS). Eighty patients with SPS were enrolled in a clinical study at 2 medical centers; 69 patients completed the study protocol. Scrotal skin was harvested under local anesthesia, and AFs were cultured and seeded on a Maxpol-T scaffold; the cografted scaffold was implanted under the Buck's fascia of penile shaft via a circumcising incision. Patients were followed up at 1, 3, and 6 months to evaluate penile girth changes. Patient satisfaction was assessed via Visual Analogue Scale and scored on the International Index of Erectile Function-5 (IIEF-5). Mean preoperative penile girth in the flaccid and erect state was 8.18 ± 0.83 cm and 10.26 ± 1.22 cm, respectively. At the 6-month postoperative follow-up, mean penile girth in the flaccid and erect state was increased to 12.19 ± 1.27 cm and 13.18 ± 1.31 cm, respectively (P < .001 for change in both flaccid and erect state). Sixty-five patients (94.2%) reported satisfaction with the procedure. Among them, 4 cases (5.8%) were dissatisfied, 7 cases (10.1%) were satisfied, 26 cases (37.7%) were very satisfied, and 32 cases (46.4%) were extremely satisfied. All men maintained IIEF-5 scores of more than 22. Complications included prolonged subcutaneous edema in 3 patients (4.3%) and pinpoint erosion at the suture area in 3 patients (4.3%). Implantation of autologous fibroblasts seeded on a Maxpol-T collagen scaffold holds promise as a safe and novel technique for penile girth enhancement in patients with SPS.
The average flaccid penile length and girth in Chinese males has been reported to be 8.03 cm and 8.08 cm, respectively (Wu et al, 2007b). The clinical diagnosis of microphallus is reserved for those men whose penile size is more than two and a half standard deviations below the mean and is commonly associated with severe hypogonadism, androgen insensitivity, or, rarely, traumatic etiology. Although true microphallus is a rare clinical entity, a substantial proportion of men (up to one-third in some series) express dissatisfaction with their penis size because of a perception that the penis is abnormally small; this may lead to substantial psychological anguish with implications for the man's self-esteem and sexual relationships. Some authors have advocated labeling this condition “small penis syndrome” (SPS; Wylie and Eardleyt, 2007; Xin, 2007).
Endocrine therapy has some utility in cases of true microphallus but is not clearly indicated in cases of SPS. Although patient education may be sufficient to reassure some patients about the normality of their penile size, surgical correction with penoplasty may be contemplated for some patients with severe distress related to SPS. Autologous fat injection may be performed as an outpatient procedure, but transplanted adipose tissue is typically reabsorbed and can form a painful tuberculum (Ersek, 1991; Reed, 1994). Rotational flaps from the groin and latissimus dorsi have also been reported (Ranno et al, 2007) but the extensibility of these flaps and the substantial risk of donor site deformity tend to limit the utility of these approaches. Implantation of nonautologous acellular dermis matrix has many advantages, such as low antigenicity, no donor site morbidity, and easy tissue molding; however, the degree of penis enlargement with this technique is generally low, and the high price of these materials limit their clinical usefulness (Austoni et al, 1999; Zhang et al, 2004).
Maxpol-T is a high–interval-porosity sponge material composed of Poly acid-co-glycolide in a 75:25 ratio of lactide to glycolide (PLGA). Our previous study demonstrated that fibroblasts grow well after seeding in Maxpol T in vitro and that implantation of autologous fibroblast–coated Maxpol-T enlarged rabbit penile girth without severe side effects (Wu et al, 2007a). Although no length enhancement was reported in this animal study, the enhancement of penile girth is of greater general interest because of existing reports that heterosexual females are generally more interested in penile girth than length (Eisenman, 2001; Francken et al, 2002).
In this paper, we report the first human clinical trial to evaluate the clinical safety and efficacy of a PLGA biodegradable scaffold impregnated with autologous fibroblasts for penile girth enhancement.
Materials and Methods
The patients in this clinical trial complained of dissatisfied penis size, were clinically diagnosed with SPS, and agreed to participate with written informed consent. All procedures were approved by the institutional review board of Peking University First Hospital, Peking University.
Inclusion criteria included 1) complaints of dissatisfied penis size and a clinical diagnosis of SPS; 2) age ranging from 18 to 60 years old; and 3) knowledge of the trial procedures and agreement by written consent.
Exclusion criteria included 1) no previous surgical penis extension operations; 2) no penis urethra abnormalities and no blood creatinine abnormalities (eg, high or low alanine transaminase or aspartate transaminase levels), spirit disease, excessive sex vanity, homosexuality, or sex pouring wrong disease; 3) allergic history to PLGA, alcohol abuse, cancer, diabetes, or erectile dysfunction; 4) any ethical or other reason according to the researchers that might influence the experimental results.
Patients who dropped out of the clinical trial, regardless of reason, were not included in the analysis. Reasons to drop out included 1) an allergic reaction to the medical treatment; 2) incompliance; 3) the patient or patient's guardian decided on withdrawal; 4) the tracking investigator dropped out (eg, switched to another hospital); 5) the patient acquired a sexual disease; 6) a researcher judged that the patient was unsuitable, or some other serious reaction occurred.
All subjects underwent standard history and physical examination, including assessment of age, tobacco and alcohol use, baseline erectile function, and frequency of sexual intercourse. Psychological morbidity was assessed with the Zung Self-Rated Depression Scale (Akashiba et al, 2002). Penis size was measured for penis girth by a single investigator with a tape measure in the flaccid state and after induction of erection by intracavernosm injection therapy using prostaglandin E1 (10 mg). All clinical procedures were approved by the Institutional Patient Care and Use Committee of the Peking University.
Isolation and Culture of Human Fibroblasts
An elliptical-shaped skin incision was made, and 0.5 by 1.0 cm of scrotal dermal tissue was harvested. Biopsied dermal tissue was washed to remove red blood cells in serum-free Dulbecco's modified eagle medium (DMEM) and minced into pieces of less than 1 mm in size. The tissues were treated with collagenase type IV (2 mg/mL) and incubated at 37°C with 5% CO2 for 16 hours. The collagenase was removed, and the remaining fibroblasts were suspended in DMEM growth media (DMEM + 5% AB-type human serum + 1% antibiotics) and grown in culture until total cell numbers reached at least 2 × 107, which required about 2 weeks. The presence of fibroblasts was confirmed by staining for vimentin expression. Preparation of Fibroblast-Seeded Maxpol-T Cograft—The Maxpol-T sample (T-61273) was provided by Maxgen Co Ltd, Mianyang, China. The inner diameter was 26 mm, exterior diameter was 32 mm, and length was 50 mm. The dry Maxpol-T was hydrated by complete immersion into 75% ethanol solution in aseptic conditions and kept in a refrigerator at 4°C overnight. The ethanol solution was removed completely by repeated washing with sterile, pyrogen-free cold water, phosphate-buffered saline solution, and serum-free culture medium. Pretreated scaffolds were then coated with approximately 2 × 106 autologous fibroblasts (AF) and incubated in a sterile container at 37°C for 2 hours before operation. The AF-coated Maxpol-T cograft was then sent to the operating room in a sterile chamber.
The Penis Enlargement Operation
After preparation of the skin with a potadine aqua solution, local anesthesia of the penis was induced with 2% lidocaine. A circumcising incision was made, and the skin of the penis was degloved to the penile base to expose the tunica albuginea. The Maxpol-T graft was shaped according the penile size. The AF-coated Maxpol-T cograft was implanted into the space between the side fascia and tunica albuginea, followed by fixation in optimal position so as to prevent urethral compression. The Buck's fascia and penile skin were closed in the standard fashion with absorbable suture, and a slightly compressive dressing was applied (Figure 1). The patients were treated with antibiotics for 1 week and were advised to avoid sexual activity until 6 weeks after the operation. Patients were followed up for a mean of 9.1 ± 5.5 months.
Efficacy and Safety Evaluation
Girth enhancement of greater than 2 cm above baseline at 6-month follow-up was our primary outcome of interest. Secondary endpoints included subjective satisfaction with the procedure, assessed with the use of a Visual Analogue Scale (VAS) from 0 to 10, with higher numbers corresponding to greater satisfaction. For the purposes of analysis, 0 to 2 was classified as dissatisfied, 3 to 5 satisfied, 6 to 8 very satisfied, and 9 to 10 extremely satisfied. The erection functions were evaluated with the International Index of Erectile Function (IIEF-5). Laboratory checks included routine blood and urine analysis, blood biochemical check, IIEF-5, and physical examination for adverse events.
Analysis of pairwise covariances was considered statistically significant at P ≤ .05 (SPSS 15.0 for Windows; SPSS Inc, Chicago, Illinois). The patients' self-assessed VAS was evaluated by the Wilcoxon signed rank test to determine whether changes in satisfaction were statistically significant. Increase in penis girth and VAS self-satisfaction ranking were evaluated with the Wilcoxon signed rank correlation test to measure the validity of the objective and subjective indicators. The original study design divided patients into intention to treatment and per-protocol categories. The sign of the Wilcoxon test was used to determine whether the level of satisfaction covaried by treatment category.
Enlargement of Penile Girth
A total of 80 patients with SPS were invited to participate in the clinical trial. Sixty-nine patients (82.7%) completed the clinical trial. The mean age of participants was 33.0 ± 9.14 (range, 19–52 years old), including 8 cases with hypogonadism (total testosterone < 300 ng/dL; all patients evaluated were more than 18 years old). Eleven patients (18.3%) dropped out voluntarily or because of venereal disease and skin disease at the time of screening (4 cases voluntarily choose not to participate, 5 cases because of venereal disease, and 2 cases because of skin disease).
Average preoperative penile girth was 8.18 ± 0.83 cm (range, 5.50–11.00 cm) and 10.26 ± 1.22 cm (range, 8.62–13.48 cm) in the flaccid and erect states, respectively. The mean flaccid penis girth at 1, 3, and 6 months postoperative was 11.79 ± 1.18 cm (12.20 ± 1.24 cm and 12.19 ± 1.27 cm, respectively). The mean erect penile girth at 1, 3, and 6 months postoperative were 14.29 ± 1.19 cm, 14.75 ± 1.30 cm, and 14.28 ± 1.23 cm, respectively. Penile girth at flaccid state and erect state were significantly increased postoperation (P < .001; Figure 2). On the basis of our primary endpoint, an increase of at least 2 cm in penile girth was noted in 95% of subjects.
However, the penis length changes in flaccid state and erected state showed no significant changes at 1, 3, and 6 months postoperation (P > .05).
Satisfaction With Surgical Results
Patient satisfaction according to VAS results at the end of 6 months postoperation was dissatisfied (4 cases, 5.8%), satisfied (7 cases, 10.1%), very satisfied (26 cases, 37.7%), and extremely satisfied (32 cases, 46.4%), which was significantly different when compared with the preoperation results (P < .001; Figure 3).
The patients' self evaluation of girth enlargement after this surgery at the 6-month follow-up was 95.45%, and penile length showed no difference with preoperation length.
No postoperative laboratory abnormalities were noted with respect to hematologic, electrolyte, and liver function assays. The IIEF-5 evaluation of erection function for all patients, preoperation and postoperation, did not vary. All men had normal erectile function (IIEF-5 score >22) in the inclusion criteria, and all men maintained IIEF-5 scores >22 pre- and postoperation. Three patients (4.3%) experienced prolonged, subcutaneous edema for about 12 weeks. In 3 other patients (4.3%), pinpoint erosion at the suture area was noted; these cases were treated by local medication. Among them, in 2 patients, penile subcutaneous fluid was absorbed after taking levofloxacin (0.2 g, twice a day, orally, 10 days), whereas one other patient was given oral azithromycin tablets for 7 days to control his infection, then healed after debridement in 10 days. These men reported the unsatisfied results.
The Maxpol-T cytoskeleton is mainly made of PLGA and is very similar to human dermis. The mesh material structure of each ca 125–200-μm bore provides a generous surface to which cells may attach and procure nutrients from adjacent tissues (Wu et al, 2007a). PLGA has been used for bone fixation, heart valve replacement, and development of cartilage cells. Formed of lactic acid and glycolic acid, PLGA material has been approved by the US Food and Drug Administration for clinical use (Kiely et al, 2006; Pataro et al, 2007).
The safety and stability of AF for implantation is an important topic for clinical research. To conduct a safety assessment of the established human skin fibroblast line to conform to the safety and stability of the fibroblast, a series of tests, such as cell morphology, chromosome karyotyping, soft agar test, nude mice carcinogenic test, endotoxin test, mycoplasma determination, detection of viral agent, bacteria, fungi sterile test, and abnormal toxicity test, was conducted. No abnormal changes were observed (Chen, 2002). Previous study on the efficacy and safety of Maxpol-T–coated autologous fibroblast cells in an animal model demonstrated that it is effective and safe for penis girth enhancement (Wu et al, 2007a); meanwhile, the adipose-derived stromal cells seeded to the Maxpol-T cograft might be a future research direction (Vermette et al, 2007).
Perovic et al (2006) have previously used PLGA matrix clinically for penile girth enhancement in 84 patients. Among these, 70.24% presented with penile dysmorphic disorder, and 25 patients (29.76%) had a history of previously failed penile girth enlargement. They were referred to their institutions as patients with penile dysmorphic disorder. Postoperative complications occurred as infection in 3, penile skin pressure necrosis in 2, and seroma formation in 5 patients, and all were treated conservatively. Overall, the mean value of self-scored genital appraisal in this study was “very good,” and roughly two-thirds of patients were satisfied with penile girth in the flaccid and erect state (63.09% and 69.09%, respectively). The mean size of flaccid and erect girth gained was 3.15 ± 0.42 (range, 1.9–4.1 cm) and 2.47 ± 0.49 (range, 1.8–3.0), respectively. Surgical intervention was appraised by patients on a scale of 1 to 5, wherein best (5) was given by 44.05%, very good (4) by 36.90%, and good (3) by 19.05%; only 1 patient judged general penile appearance as dissatisfactory (2). In our current study, 65 (94.2%) patients reported satisfaction with at least 2 cm improvement in penile girth. There was no de novo sexual dysfunction according to IIEF-5 scoring. In our group, 3 cases of postoperative penis local infection with blood leukocytosis and surgical site pain was seen, however without body fever, and a large area of skin redness above the implant surface was found, perhaps from bacterial infection. No patients experienced itching or increased blood eosinophils, so an allergic response to Maxpol-T can be ruled out. Surgical infection will lead directly to reduced patient satisfaction scores; if a serious infection because of the implant is found, the Maxpol-T will have to be removed. Fortunately, no implant was removed in our group. We noted that no rejection occurred when the Maxpol-T was transplanted in this clinical trial. Erectile function and penile sensitivity did not change after surgery. This new treatment approach for penile girth enhancement appears to be very safe with low morbidity and a low incidence of complications.
Implantation of an autologous fibroblast–coated Maxpol-T on the penile shaft could be a novel and effective method for penile girth enlargement in patients with SPS. Further study is recommended.
We thank Dr Alan Shindel (University of California, San Diego) for English editing.
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This work was supported by Beijing Municipal Science and Technology Commission Fund (Z08050703320000).