At the cellular level ED is thought

At the cellular level, ED is thought to be caused by neuro-vascular or hormonal dysfunction resulting in impaired vasodilatation of penile diprenorphine (Salonia et al., 2012; Weyne and Albersen, 2014). When the natural nocturnal erection is lost, the penis tissue enters a chronic hypoxic state leading to vascular dysfunction (Mulhall et al., 2010). Adipose-derived regenerative cells (ADRCs, also referred to as stromal vascular fraction, SVF) are able to differentiate into vascular cells and neurons in vitro (Gimble et al., 2013; Lin et al., 2008; Zuk, 2010), and a large body of preclinical work shows a surprisingly good effect of ADRC injection into the corpora cavernosa (Lin et al., 2012). One human study reported improved erectile function using umbilical cord blood cells in 7 diabetic ED patients (Bahk et al., 2010). This latter study demonstrates proof of concept for the use of cell therapy in clinical ED treatment, even if the etiology of ED in diabetics may reflect less nerve injury as compared to patients after radical prostatectomy (RP) (Schauer et al., 2015). The safety of applying freshly isolated autologous ADRCs for non-homologous use in intracavernous injections has not previously been explored.
Methods
Results We included 17 men (Fig. 1) aged between 46 and 69years (63 (9), median (IQR)) years with ED after prostatectomy to intracavernosal injection with their own ADRCs freshly isolated after a liposuction. All patients had high IIEF-5 scores (23 (3), median (IQR)) and EHS scores (4 (1), median (IQR)), and reported an active sex life before RP. Eleven men were continent while 6 were incontinent at the time of inclusion, but baseline characteristics including age, BMI, smoking, alcohol intake, physical activity, degree of co-morbidities and medication were similar for the two groups (Table 1). Time between RP and ADRC treatment 10.1 (5.7) (median (IQR) months with no difference (p=0.2450, Mann–Whitney test) between continent and incontinent men is shown in Supplemental Fig. S1. The characteristics of ADRCs isolated by the automated Celution® system (Table 2) were comparable to those previously reported for other ADRCs/SVF (Domenis et al., 2015) including yield (ADRCs/g fat tissue, 1.4×105, 3.7×104; mean, SD), cell size (10.7, 0.2; mean, SD), viability (84.7, 3.0; mean, SD) and, percentage of fibroblastoid colony forming units (%CFU-F, 1.5, 0.8; mean, SD). The number of ADRCs obtained per patient was strongly correlated to the amount of lipoaspirate (Fig. 2A), while we observed no relationship between age and yield per gram fat tissue (Fig. 2B). A large proportion of the freshly isolated ADRCs expressed the surface markers CD34 (67.3, 11.0%; mean, SD) and CD90 (71.3, 7.4%; mean, SD), whereas CD31 and CD73 each defined smaller subpopulations (14.8%, 6.4% and 24.2%, 12.1%, respectively; mean, SD) (Fig. 2C). The fraction of stromal stem cells as defined phenotypically by the markers CD235a-CD45-CD31-CD34+, encompassed approximately 26% of the parent ADRCs (Fig. 2D), which is similar to what has been shown by others (Domenis et al., 2015; Aronowitz and Ellenhorn, 2013). The men received between 8.4–37.2 million ADRCs immediately after cell isolation and were discharged from hospital the same day. No serious adverse events were reported. Five patients reported minor events related to the liposuction and ADRC injection at the one-month evaluation time point. Two men had experienced transient redness and swelling at the injection sites. One had a scrotal and penile hematoma that resolved within 14days. This patient had taken large doses of NSAID medicine for back pain in the days before the treatment. Finally, 2 patients reported abdominal pain and tenderness for 2–6days after the liposuction. All events resolved without intervention and at the 3- and 6-month evaluations, no patients reported any side- or adverse events. During the study period, eight out of 17 participants recovered erectile function after ADRC injection with the ability to complete intercourse (Fig. 3A). Post-hoc stratification according to urine continence at inclusion revealed an apparent strong conditional association to the regain of function. Preliminary efficacy was solely demonstrated in the patients that were continent at inclusion (Fig. 3). In the continent group, the IIEF-5 score was unchanged 7 (Shabsigh et al., 2005) (median (IQR) (mean 0.92 (95% CI 0.78–1.1), p=0.3859, RM one-way ANOVA with Sidak\'s multiple comparisons test) 1month after the treatment, but significantly increased to 11 (Gimble et al., 2013) (0.66, (0.44–0.98), p=0.0414) after 3months and to 17 (Gimble et al., 2013) (0.57 (0.38–0.85), p=0.0069) after 6months (Fig. 3B). The EHS scores supported these data although with slight differences. The EHS data were significantly increased at 6months (3(1) (p=0.0314, Friedman\'s with Dunn\'s multiple comparisons test) as compared to inclusion (1(1)), while no change was observed after 1month and 3months (Fig. 3D). In the group of incontinent men, the IIEF-5 scores were similar after 1, 3 and 6months and did not differ from the score at the time of inclusion (5 (1)(median (IQR) (mean 1 (95% CI 0·85–1.18), p>0.9999, RM one-way ANOVA with Sidak\'s multiple comparisons test), Fig. 3C). Likewise, EHS data for this group were unchanged throughout the study period (fig. 3E). There were no differences in ADRC characteristics between the groups of continent versus incontinent men (table 2). To estimate the rate of spontaneous reversion of ED post RP in our department, we reviewed the medical records for 2010–2013. These included records of 165 prostatectomized men with information about their sexual status and urine continence. There were 135 urine continent men and 30 incontinent men. In these groups, 40 and 4 men, respectively, reported having adequate sexual function, and were able to complete intercourse with or without medication 6 and 12months after operation (Fig. 3F).