The goal of this prospective randomized controlled clinical study is to evaluate the effectiveness and safety of intracavernosal injections of umbilical cord-derived mesenchymal stem cells (MSCs) and umbilical cord-derived MSC-derived exosomes in men aged 25 to 75 years with diabetic erectile dysfunction (ED) who have not responded adequately to conventional medical treatments such as phosphodiesterase type-5 (PDE-5) inhibitors.

Diabetes mellitus is a major risk factor for erectile dysfunction and is associated with endothelial dysfunction, impaired smooth muscle relaxation, neuropathy, and increased fibrosis within penile tissue. Although many patients respond to standard pharmacological treatments, diabetic patients often demonstrate reduced responsiveness to these therapies. Regenerative medicine approaches, including stem cell therapy and stem cell-derived exosomes, have emerged as potential therapeutic strategies due to their regenerative, angiogenic, neuroprotective, and anti-fibrotic effects.

The main questions this study aims to answer are:

• Whether intracavernosal administration of mesenchymal stem cells or MSC-derived exosomes improves erectile function, as measured by changes in the International Index of Erectile Function-5 (IIEF-5) and Erectile Hardness Score (EHS).
• Whether penile hemodynamics improve following treatment, as assessed by penile Doppler ultrasonography parameters including peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI).

Participants will be randomly assigned to one of three groups:

• Intracavernosal placebo injection
• Intracavernosal injection of umbilical cord-derived mesenchymal stem cells (5×10⁶ cells)
• Intracavernosal injection of umbilical cord-derived mesenchymal stem cell-derived exosomes (75 μg) All interventions will be administered as a single intracavernosal injection under controlled clinical conditions.

Participants will undergo baseline evaluation including medical history, physical examination, erectile function assessment using the IIEF-5 questionnaire, and penile Doppler ultrasonography. Follow-up evaluations will be conducted at 1, 3, 6, and 12 months after treatment to assess changes in erectile function, penile vascular parameters, and treatment-related adverse events.

The study will also monitor potential side effects such as pain, bruising, hematoma, edema, or other complications related to the intracavernosal injection procedure.

Participants will be recruited from patients presenting to the urology outpatient clinic with diabetic erectile dysfunction. Eligible participants must have a diagnosis of erectile dysfunction for at least six months, a history of diabetes mellitus for at least five years, and insufficient response to standard medical therapy. Patients with penile anatomical deformities, active infections, malignancy, unstable cardiovascular disease, autoimmune disease, or other contraindications to intracavernosal treatment will be excluded.

Detailed Description This prospective randomized controlled clinical study is designed to evaluate the safety and efficacy of intracavernosal injections of umbilical cord-derived mesenchymal stem cells (MSCs) and MSC-derived exosomes in men with diabetic erectile dysfunction (ED) who have not responded adequately to conventional medical treatments such as phosphodiesterase type-5 (PDE-5) inhibitors. The study will compare these regenerative therapies with placebo in order to determine their therapeutic effectiveness.

The primary focus of the study will be the improvement in erectile function as assessed by changes in the International Index of Erectile Function-5 (IIEF-5) and Erectile Hardness Score (EHS). In addition, penile hemodynamics will be evaluated using penile Doppler ultrasonography parameters including peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI). Safety outcomes and treatment-related adverse events will also be closely monitored throughout the study period.

________________________________________ Background and Rationale Erectile dysfunction is a common condition that significantly affects quality of life in men and their partners. Diabetes mellitus is one of the most important risk factors for erectile dysfunction and is associated with endothelial dysfunction, neuropathy, reduced smooth muscle content, oxidative stress, and cavernosal fibrosis. These pathophysiological changes impair penile vascular and neural mechanisms necessary for normal erectile function.

Although phosphodiesterase type-5 inhibitors are considered first-line therapy for erectile dysfunction, patients with diabetes often demonstrate reduced responsiveness to these medications. As a result, alternative therapeutic approaches are needed for patients with treatment-resistant diabetic erectile dysfunction.

Regenerative medicine has emerged as a promising field for the treatment of erectile dysfunction. Mesenchymal stem cells have been shown in preclinical studies to promote angiogenesis, improve endothelial function, enhance neuronal regeneration, and reduce fibrosis within penile tissue. In addition to stem cells themselves, stem cell-derived exosomes have gained increasing attention as a cell-free regenerative therapy. Exosomes contain various bioactive molecules including proteins, microRNAs, and signaling factors that can stimulate tissue repair and cellular communication.

Preclinical studies have demonstrated that both mesenchymal stem cells and stem cell-derived exosomes can improve erectile function in diabetic models by enhancing vascularization, restoring nitric oxide signaling, and protecting neural structures. Early clinical studies investigating stem cell therapy in erectile dysfunction have also reported improvements in erectile function scores with acceptable safety profiles.

Based on these findings, the present study aims to evaluate the therapeutic potential of umbilical cord-derived mesenchymal stem cells and MSC-derived exosomes in patients with diabetic erectile dysfunction.

________________________________________ Primary Objective The primary objective of this study is to evaluate the efficacy of intracavernosal mesenchymal stem cell and MSC-derived exosome injections in improving erectile function in men with diabetic erectile dysfunction, as measured by changes in the International Index of Erectile Function-5 (IIEF-5) and Erectile Hardness Score (EHS) from baseline to follow-up visits.

________________________________________ Secondary Objectives Penile Hemodynamics Changes in penile vascular parameters including peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) will be evaluated using penile Doppler ultrasonography.

Safety and Adverse Events All adverse events related to the intracavernosal injection procedure, including pain, bruising, hematoma, edema, infection, or other complications, will be documented and monitored throughout the study.

Clinical and Physical Examination Findings Changes in physical examination findings such as penile deformity, Peyronie plaque formation, and other genital examination findings will be evaluated during follow-up.

Long-Term Treatment Effects Patients will be followed at 1, 3, 6, and 12 months after treatment in order to assess the durability of treatment effects and long-term safety outcomes.

________________________________________ Study Design This study is designed as a prospective, randomized, placebo-controlled, single-blinded clinical trial.

Participants will be randomly assigned to one of three treatment groups using a closed-envelope randomization method:

• Placebo group receiving intracavernosal saline injection
• Umbilical cord-derived mesenchymal stem cell group (5×10⁶ cells)
• Umbilical cord-derived mesenchymal stem cell-derived exosome group (75 μg) All treatments will be administered via intracavernosal injection under sterile clinical conditions. A penile clamp will be applied at the base of the penis prior to injection and removed approximately 10 minutes after the procedure to limit systemic dispersion.

Study Population The study will enroll 90 male participants aged 25 to 75 years who have a diagnosis of diabetic erectile dysfunction for at least six months and have had diabetes mellitus for at least five years. Eligible participants must have demonstrated inadequate response to standard medical therapies such as PDE-5 inhibitors or intracavernosal pharmacotherapy.

Participants will be recruited from patients presenting to the urology outpatient clinic at Ankara Bilkent City Hospital.

Carefully defined inclusion and exclusion criteria will be applied to ensure patient safety and select appropriate participants for regenerative therapy.

________________________________________ Study Procedures Informed Consent All participants will receive detailed information about the study procedures, potential risks, and expected benefits before providing written informed consent.

Baseline Evaluation Participants will undergo baseline clinical evaluation including medical history, physical examination, laboratory tests, erectile function assessment using the IIEF-5 questionnaire, and penile Doppler ultrasonography.

Randomization and Treatment Eligible participants will be randomized into three groups. Intracavernosal injection of placebo, mesenchymal stem cells, or umbilical cord-derived MSC-derived exosomes will be administered under sterile clinical conditions.

Post-treatment Monitoring Patients will be monitored for immediate post-injection complications and observed for 24 hours for potential adverse events.

Follow-Up Assessments Participants will be evaluated at 1, 3, 6, and 12 months following treatment. These visits will include erectile function assessment using the IIEF-5 questionnaire, physical examination, and adverse event monitoring. Penile Doppler ultrasonography will be performed at 3 and 12 months.

________________________________________ Data Collection and Analysis Clinical data will be collected prospectively throughout the study period. Changes in IIEF-5 and EHS scores will be used to evaluate treatment efficacy. Penile Doppler parameters will provide objective measurements of penile vascular function.

Statistical analyses will compare treatment groups to determine whether mesenchymal stem cell or exosome therapy results in significant improvements compared with placebo.

________________________________________ Ethical Considerations Ethical Considerations This study will be conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and the Good Clinical Practice (GCP) guidelines.

The study protocol titled "Effectiveness of Mesenchymal Stem Cell and Exosome Therapy in the Treatment of Diabetic Erectile Dysfunction" (Protocol Code: SEK-ED001) has been reviewed and approved by the Clinical Research Ethics Committee of Ankara Bilkent City Hospital (Decision No: E-Kurul-E2-25-13291, Approval Date: 24 December 2025).

In addition, the project has been evaluated by the Scientific Advisory Commission for Stem Cell Applications of the General Directorate of Health Services, Ministry of Health of the Republic of Türkiye, and has been deemed appropriate for implementation.

All participants will be informed about the purpose, procedures, potential risks, and benefits of the study before enrollment. Written informed consent will be obtained from each participant prior to participation.

Participant confidentiality will be strictly protected, and all personal data will be coded and stored securely. Participants will have the right to withdraw from the study at any time without affecting their standard medical care.

________________________________________ Expected Outcomes This study aims to provide clinical evidence regarding the safety and therapeutic efficacy of mesenchymal stem cell and MSC-derived exosome therapy in patients with diabetic erectile dysfunction. It is expected that regenerative treatment approaches may lead to improvements in erectile function and penile hemodynamics with minimal adverse effects.

The results of this study may contribute to the development of novel regenerative treatment strategies for patients with treatment-resistant diabetic erectile dysfunction and support the design of future large-scale clinical trials.

Official Title Safety and Efficacy of Mesenchymal Stem Cell and Exosome Therapy for Diabetic Erectile Dysfunction: A Randomized Placebo-Controlled Clinical Trial

Inclusion Criteria:

• Male patients aged 25 to 75 years
• Diagnosis of erectile dysfunction for at least 6 months
• Type 1 or Type 2 diabetes mellitus for at least 5 years
• Inadequate response to medical treatment, including phosphodiesterase type-5 (PDE-5) inhibitors and/or intracavernosal prostaglandin E1 therapy
• Candidates for penile prosthesis implantation due to treatment-resistant erectile dysfunction
• Ability and willingness to provide written informed consent

Exclusion Criteria:

• Penile anatomical deformities
• Active infection or skin lesion on the penis
• Bleeding disorders or coagulation abnormalities
• Previous penile prosthesis implantation, penile vascular surgery, or pelvic surgery
• Untreated hypogonadism
• Unstable cardiovascular disease
• History of malignancy
• Autoimmune disease
• Use of immunosuppressive therapy
• Presence of systemic or local infection
• Uncontrolled diabetes mellitus

Participants must be biologically male because erectile dysfunction is a male-specific condition that affects penile erectile function.

Demographic Information De-identified demographic characteristics of participants, including age and relevant medical history.

Baseline Assessments Baseline erectile function assessments including the International Index of Erectile Function-5 (IIEF-5) score and Erectile Hardness Score (EHS), as well as penile Doppler ultrasonography parameters such as peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI).

Treatment Data Information regarding treatment allocation and intervention details, including intracavernosal administration of placebo, umbilical cord-derived mesenchymal stem cells (5×10⁶ cells), or mesenchymal stem cell-derived exosomes (75 μg).

Follow-Up Data Outcome data collected during follow-up visits at 1, 3, 6, and 12 months, including changes in IIEF-5 scores, EHS scores, and penile Doppler ultrasonography measurements.

Data will become available after publication of the study results and will remain available for up to 3 years following publication.

Eligible Users Access to individual participant data (IPD) will be granted to qualified researchers, academic institutions, and regulatory authorities with a legitimate scientific interest in the study data, particularly those conducting research related to erectile dysfunction, regenerative medicine, mesenchymal stem cell therapy, or exosome-based therapies.