Introduction

Peyronie disease (PD), or induratio penis plastica, is an ailment that occurs due to the development of fibrosis in the tunica albuginea (TA) layer of penis. This disease can cause progressive penile curvature and pain and/or erectile dysfunction (ED) in around 20% of patients [1]. In the absence of any treatment, the curvature may disappear in about 12% of patients [2].

While the cause is unknown, it appears to be a result of poor wound healing following penile damage in genetically susceptible individuals, with the most commonly accepted concept being exposure of the TA to repeated microvascular stress [3]. The frequency in the male population ranges from 0.4 to 9% [4,5,6,7,8]. PD results in curvatures, shortening, hourglass, or hinge deformities, and symptoms that can range from pain with erections and impossibility of sexual intercourse to ED [9]. All these symptoms lead to discomfort in the sexual activity of patients, often with psychological repercussions and marital difficulties that could influence their quality of life [4, 10,11,12,13,14].

Several oral treatments have been examined, but with inconsistent evidence of effectiveness and low levels of evidence [15]. Intraplaque injections of pharmacological substances have emerged as a treatment option for curvature, aiming to counteract TA fibrosis, which is the final product of the pathological process of PD, before the deposit of calcifications [16]. These injectables include verapamil, which requires numerous injections [17], Interferon-α2b [18], which remains off label, the debated use of hyaluronic acid (HA) [19], collagenase Clostridium histolyticum (CCH), which is expensive and not readily available the European Union [20], and botulinum toxin which is still under study [21]. The interesting improvement rates observed with these treatments are challenged by their side effects such as corporeal ruptures for CCH [22], flu-like symptoms for Interferon-α2b [23], or dizziness and nausea for verapamil [24]. Despite the fact that several drugs have been used for therapy, a consensus on the appropriate treatment is yet to be found.

To this day, surgery remains the first-line treatment to correct the deformity of this disease [25,26,27]. Although definitive resolution of PD often requires surgery, there are non-surgical alternatives that may achieve significant improvements, avoiding potential complications or sequelae such as ED and loss of penile length [28]. Among these alternatives, oral, topical or shockwave therapy treatments have yet to demonstrate clear efficacy [15].

New therapeutic strategies have recently emerged, aiming to repair tissue damage of the penis caused by PD. One of these strategies is the promising Platelet-rich Plasma (PRP) injections [29]. Although the use of PRP in urology is still in its infancy, it made its debut in other fields of medicine such as orthopedics and plastic surgery back in 1987 [14]. Studies have been conducted in these fields, discussing the safety and efficacy of PRP. However, despite more than 30 years of use, its physiological properties and effects remain poorly understood and controversial when it comes to autologous injections [14]. According to recommendations from the American Urological Association and Sexual Medicine Society of North America, PRP shows promising potential that still needs to be proven [14].

A better understanding of this emerging controversial modality is essential in guiding physicians dealing with patients suffering from PD. Administering this autologous biological product directly into the fibrotic plaque of the corpora cavernosa within the TA has the potential to alleviate fibrosis and effectively treat the disease. To this day, little to no information is known about the use of pure PRP in PD. PRP, along with its containing growth factors, is involved in many aspects of natural wound healing, such as chemotaxis, cell proliferation and differentiation, regulation of mitogenesis, angiogenesis, and metabolism [30, 31]. They also control and conduct synthesis, modification, and degeneration of extracellular matrix proteins. The coordination of these cellular and molecular processes is integral to proper wound healing and tissue regeneration [30, 31].

The aim of this study is to test the safety and feasibility of percutaneous needle tunneling (PNT) of the TA plaque with subsequent administration of PRP injections in the outpatient department. This combination henceforth termed PNT/PRP with vacuum therapy could lead to a more cost-effective treatment.

Subjects and methods

This prospective, non-randomized, cohort and preliminary study was conducted after obtaining approval from the Ethics Committee of Turin Hospital (Approval number: CT2022-74). The study adhered to the Helsinki protocols, and patients provided written, informed consent. This article was composed in accordance with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines for reporting cohort studies [32]. This study was intended to observe and analyze PNT joined with PRP injections of the plaque of PD in terms of safety, feasibility, and outcome.

We included all male consecutive patients of any age who complained of a penile curvature condition with difficulties during coitus related to the presence of a palpable TA plaque; indicative of PD. The exclusion criteria included patients receiving curative doses of any anticoagulation medication, patients with unstable plaques, curvatures that had no impact on sexual performance, and patients with ED not responding to treatment. The study was performed in our urology outpatient department and the study was completed in 21 months (from November 2020 to July 2022).

All patients were instructed to take personal penile photos in a fully erect state, capturing dorsal and lateral views, using their own personal devices. These photos served as a baseline for measuring the penile curvature angle, which was determined using a goniometer (Considered the gold standard).

The treatment protocol consisted of accomplishing 6 PNT/PRP, with each session scheduled 4 weeks apart. Penile vacuum therapy was initiated on day 14 after each session. The patient was positioned on a medical table in a supine decubitus position. The penis was disinfected using disinfection a chlorohexidine 0.5% solution. Local anesthesia (Lidocaine 2% [20 mg/mL], 5 mL) was administered using a 25 G × 5/8 (0.5 ×16 mm) subcutaneous needle, targeting the penile tissue layers before reaching the plaque zone.

PRP was prepared with RegenKit BCT-3 (Regen Lab, Le Mont sur Lausanne, Switzerland). This dedicated medical device consists of evacuated sterile tubes that are designed to isolate PRP from the other blood components by a single centrifugation, using a chemically inert thixotropic separator gel, that acts as a mechanical barrier between blood components, and a sodium citrate solution, that allows fully reversible anticoagulation of the biological sample. This system is automated and works in closed circuit. In brief, venipuncture is performed at the antecubital fossa with a blood collection set. A preset volume of 10 ml of blood is automatically collected into the tube that is labeled. The tube is then centrifuged for 5 min at a relative centrifugal force of 1500 × g, corresponding to speed of 3500 rounds per minute in a centrifuged equipped with 45° fixed angle rotor. During the centrifugation, the blood components are separated according to their relative density, whereas the separator gel becomes fluid, migrates upward, and inserts itself precisely between the blood components, thanks to its thixotropic ability and its specific density. When the centrifugation stops, the separator gel regains its original consistency and forms a physical barrier that isolates the platelets and the plasma in the upper part of the tube, while the red and white blood cells are entrapped in the lower part of the tube (Fig. 1). After gentle agitations of the tube, to put the platelets, that have sedimented on the surface of the separator gel, back in suspension in the plasma, the PRP is ready to use. This proprietary technology allows the preparation of 5–6 ml of a standardized leukocyte poor PRP, with a platelet concentration factor of 1.5–1.6 times the baseline value in blood and a very low contamination with red blood cells and pro-inflammatory white blood cells. This PRP is classified as P2-Bβ according to Delong PAW classification [33].

Fig. 1: Artwork that simplifies the process and production of Platelet-Rich Plasma (PRP).
figure 1

Withdraw of venous blood (Phlebotomy) is obtained using the butterfly needle system directly into a tube with negative pressure already containing an anticoagulant and a separator gel. The tubes are then labeled and centrifuged for 5 min at a speed of 3500 rounds per minute. The end result as shown is the PRP in yellow separated by the separator gel in white from the rest of the blood components (White and red blood cells) in red. Only the yellow part is used and transferred to a syringe.

Full size image

The main procedure involved initiating PNT [34, 35]. This was accomplished by creating multiple pits and channels along the entire longitudinal axis of the plaque using a 25 G × 5/8 (0.5 × 16 mm) subcutaneous needle. The needle was connected to a syringe filled with PRP, and mini-doses of PRP were injected into the plaque until the syringe was empty (Fig. 2). PRP administration was completed in less than 5 min from its preparation for all patients.

Fig. 2: Artwork of percutaneous needle tunneling technique.
figure 2

The idea is to create multiple crevasses and tunnels along the entire longitudinal axis of the plaque using a 25 Gauge × 5/8 inches (0.5 × 16 mm) subcutaneous needle. An injection of a total of 5–6 ml of PRP into the plaque.

Full size image

Vacuum therapy was standardized; all patients were prescribed and educated on the use of a vacuum erectile devices (VED) (VACURECT™, Pretoria, South Africa) for daily use, 30 min each day, starting 14 days after the PNT/PRP session and continuing until the next session. After the procedure, a semi-compressive dressing was applied, and patients were instructed to remove it after 2 h. Sexual intercourse was prohibited for 24 h.

Patients were instructed to take the same photos as before the protocol for follow-up at day 28 after the sixth session. To minimize bias, all injections were administered by the same expert urologist. Pain levels were assessed during the PNT/PRP procedure, as well as at 2 and 24 h after the procedure, using a 10-point visual analog scale (VAS).

Statistical analysis was performed using the software SPSS for Windows version 18.0 (IBM, Armonk, New York, USA) and p-value of < 0.05 was considered statistically significant. Categorical variables were expressed as numbers and percentages, while quantitative variables were expressed by measures of central tendency, dispersion and spread. The changes in penile curvature angle within the group were compared using a one-sample paired Student’s t-test.

Results

Data was collected from 54 patients who were enrolled into our protocol. All patients completed the protocol and were compliant with penile vacuum therapy. Their median age in years was 47.50 interquartile range 40–55. The median duration of PD was 18 months (12–31.50). The penile curvature was stabilized in 47/54 (87.04%) patients upon consultation. Patients’ demographics, past history and past ineffective treatment history are shown in Table 1. Blood thinners were taken by 9/54 (16.67%) patients; 7/54 (12.96%) were receiving a daily dose of 75 mg of acetylsalicylic acid and 2/54 (3.70%) were receiving a daily dose of 75 mg of clopidogrel. None of the patients stopped their blood thinners before PNT/PRP. Loss of penile length was observed in 40/54 (74.07%) with a median loss of 1.25 cm [1,2,3].

Table 1 Patients’ demographics, past history and past ineffective treatment history.
Full size table

Plaque locations were as follows; dorsal distal third in 10/54 (18.52%), dorsal middle third in 9/54 (16.67%), dorsal proximal third in 3/54 (5.56%), right dorsolateral distal third in 4/54 (7.41%), right dorsolateral middle third in 3/54 (5.56%), right dorsolateral proximal third in 6/54 (11.11%), left dorsolateral distal third in 5/54 (9.26%), left dorsolateral middle third in 4/54 (7.41%), left dorsolateral proximal third in 4/54 (7.41%), right lateral middle third 1/54 (1.85%), left lateral distal third 1/54 (1.85%), left lateral middle third 2/54 (3.70%), left lateral proximal third 1/54 (1.85%), left ventrolateral proximal 1/54 (1.85%).

The median VAS score was 3 (0–4.25). 9/54 (16.67%) patients reported a pain of 6 or more. Two hours after PNT/PRP, pain was described in 11/54 (20.37%) but none required any pain medication and pain disappeared within 24 h in all patients. 41/54 patients (75.93%) reported penile ecchymosis and half the patients 27/54 reported a minor hematoma that disappeared spontaneously without further complications. A single patient (1.85%) reported an injection site skin infection which was cured with the help of oral antibiotics. No urinary symptoms were reported as a cause of PNT/PRP.

Penile curvature data is shown in Table 2. Comparing pre- and post-PNT/PRP with VED we found a significant improvement in curvature [p-value = 0.001, 95% CI (−29.76 to (−18.02)), paired Student’s t-test].

Table 2 Data of patients’ penile curvature.
Full size table

Discussion

Our protocol has demonstrated a significant correction of penile curvature angle deformity with minor complications, which is safe and feasible in the outpatient setting. Based on our results, this significance is both clinical and statistical.

Surfing through the English and French literature, a study done by Virag et al. showed similar results; they evaluated the feasibility and efficacy of intralesional injections of autologous PRP combined with HA. Thirteen patients with deformity due to PD were included. The therapeutic protocol consisted of an intralesional injection every 15 days for 2 months under ultrasound guidance. The treatment was prepared from 2 tubes of 4 mL of whole blood previously containing HA. The mean follow-up was 9.3 months. In total, 10 of the 13 patients showed an average reduction of 30% in their initial curvature associated with a reduction in plaque size in 53% of cases. One hematoma was reported [29].

The withdrawal of CCH from the European Union [36] which obtained a Food and Drug Administration approval [20] as the only non-surgical treatment for PD motivated us to find an alternative in PRP. Approved by the European Medicines Agency in 2015, intralesional injection of CCH has demonstrated an improvement in curvature in selected patients, sparing many of them from surgery [20, 37, 38]. Following its approval, several changes to the original drug-use protocol have been proposed, such as adding vacuum erectile devices (VED), decreasing the duration of the protocol, or increasing the amount of CCH for each injection, in order to improve treatment results and lower costs [39, 40].

In our case, the patients were instructed to use VED only after 14 days of the PNT/PRP session It was only fair to add VED therapy to our protocol to acquire better results synergistically, which is the number of days where PRP rests active in the lesions. Using VED might displace the PRP due to their suction effect which is absent in penile traction therapy [41,42,43,44,45,46].

Leriche described a technique in 2002, later named PNT, where plaque perforations using an 18-gauge needle as an alternative percutaneous treatment for PD that could improve the curvature itself [47]. We implemented the same technique in our protocol but with a finer needle while simultaneously injecting PRP. Although the exact effect of PNT on the plaque at the structural level is unidentified, we do not expect any histopathological changes other than a simple mechanical action that would enhance drug diffusion while creating microcracks that allow the plaque to be more malleable, so that traction therapy can achieve better results. Using a finer needle, in our opinion, will reduce iatrogenic trauma and post-interventional inflammation. PRP will counteract the harmful inflammatory processes and also signal an enhanced restorative response stabilizing the damaged plaque [48].

PRP is an autologous plasma with a supraphysiological platelet concentration in unit volume. It is produced from the centrifugation of whole blood that contains a 3 to 7 times higher platelet concentration compared to whole blood. It also contains growth factors related to wound healing and tissue repair such as platelet-derived growth factor, transforming growth factor, insulin-like growth factor, and epidermal growth factor, and plasma proteins enabling hemostasis and adhesion such as fibrin, fibronectin, and vitronectin [49,50,51]. PRP leads to the migration of macrophages, monocytes, and neutrophils as well as inhibiting the release of pro-inflammatory cytokines by suppressing the release of interleukin-1 from the macrophages [52, 53]. These therapies are being increasingly exploited in numerous medical settings, including dermatology, ophthalmology, cardiology, colorectal surgery, and plastic surgery [54]. PRP has been frequently used for orthopedic conditions such as bone and soft tissue trauma, inflammatory conditions, and chronic pain syndromes [54,55,56]. PRP has been employed as a primary therapeutic technique as well as a complement to other therapies in the hopes of enhancing wound healing, tissue regeneration, and angiogenesis. Despite the fact that most research on PRP injections have been limited and heterogeneous, they all show safety and effectiveness [48]. Additionally, the concept of autologous therapy may be particularly attractive to some patients [57]. Autologous treatment eliminates the necessity for immunosuppression and the fear of rejection. There are several circumstances in urology, as in many other specialties, where tissue regeneration is desirable [48]. Regenerative medicine is now a hot topic in medicine that could help stop the process and restore function. Stem cell therapy for PD has become a wide subject of research in animal studies with rising hopes for future treatments with adipose derived stem cells [29].

Limitation of our current research is the lack of a placebo group and the fact that we cannot exclude if the results are due to PNT or vacuum rather than PRP. Additionally, taking comparable photos by the patients is the most important criterion in evaluating curvature improvement which is also reliant on the quality of the erection. Also, self-photographs of the penis are not reliable in assessing penile curvature so the results may be affected by how they were taken. Despite these favorable results, the sample size was small and should be augmented and dispersed in many medical centers to test reproducibility more efficiently. The strengths of the study include the fact that all injections were done by the same urologist, an expert in PD injections (CCH, verapamil, etc.). Moreover, we used the same tube brand from the Regen Lab SA, Geneva, Switzerland for all the patients to keep the same efficiency and safety. In conclusion, we believe PNT/PRP followed by VED is conceivably an effective, safe, and feasible treatment for penile deformity in PD that can be performed comfortably in the outpatient department.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.