cells Review Revisiting the Regenerative Therapeutic Advances Towards Erectile Dysfunction Ming-Che Liu 1,2,3,4, Meng-Lin Chang 5,6,7, Ya-Chun Wang 8, Wei-Hung Chen 8, Chien-Chih Wu 1,9 and Shauh-Der Yeh 10,11,* 1 Department of Urology, Taipei Medical University Hospital, Taipei 11031, Taiwan; [email protected] (M.-C.L.); [email protected] (C.-C.W.) 2 Clinical Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan 3 Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan 4 School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan 5 Department of Urology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 242, Taiwan; [email protected] 6 School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan 7 Graduate Institute of Applied Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan 8 TCM Biotech International Corp., New Taipei City 22175, Taiwan; [email protected] (Y.-C.W.); [email protected] (W.-H.C.) 9 Department of Education and Humanities in Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan 10 Department of Urology and Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan 11 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan * Correspondence: [email protected] Received: 24 March 2020; Accepted: 15 May 2020; Published: 19 May 2020 Abstract: Erectile dysfunction (ED) is an inability to attain or maintain adequate penile erection for successful vaginal intercourse, leading to sexual and relationship dissatisfaction. To combat ED, various surgical and non-surgical approaches have been developed in the past to restore erectile functions. These therapeutic interventions exhibit significant impact in providing relief to patients; however, due to their associated adverse effects and lack of long-term efficacy, newer modalities such as regenerative therapeutics have gained attention due to their safe and prolonged efficacy. Stem cells and platelet-derived biomaterials contained in platelet-rich plasma (PRP) are thriving as some of the major therapeutic regenerative agents. In recent years, various preclinical and clinical studies have evaluated the individual, as well as combined of stem cells and PRP to restore erectile function. Being rich in growth factors, chemokines, and angiogenic factors, both stem cells and PRP play a crucial role in regenerating nerve cells, myelination of axons, homing and migration of progenitor cells, and anti-fibrosis and anti-apoptosis of damaged cavernous nerve in corporal tissues. Further, platelet-derived biomaterials have been proven to be a biological supplement for enhancing the proliferative and differentiation potential of stem cells towards neurogenic fate. Therefore, this article comprehensively analyzes the progresses of these regenerative therapies for ED. Keywords: erectile dysfunction (ED); platelet-rich plasma (PRP); platelet-derived biomaterials; stem cells; regenerative therapy; intracavernosal injection; intracavernosal pressure (ICP) Cells 2020, 9, 1250; doi:10.3390/cells9051250 www.mdpi.com/journal/cells Cells 2020, 9, 1250 2 of 21 Cells 2020, 9, x FOR PEER REVIEW 2 of 21 1.1. IntroductionIntroduction ErectileErectile dysfunctiondysfunction (ED) (ED) severely severely impacts impacts the the personal, personal, social, social, and and sexual sexual life life of patients of patients [1,2 ][1,2] and isand found is found be more be more frequent frequent among among the middle the middle aged andaged aging and aging population population [3]. In [3]. the In context the context of sexual of health,sexual health, ED affects ED affects all domains all domains such assuch desire, as desire, arousal, arousal, erectile erectile function, function, and and ejaculation ejaculation/orgasm/orgasm [4]. Therefore,[4]. Therefore, its earlyits early diagnosis diagnosis and and management management are are highly highly imperative. imperative. TheThe etiologyetiology of ED may may includeinclude aging,aging, psychological psychological disorders, disorders, spinal spinal injury in/jury/nervousnervous disorders, disorders, diabetes, diabetes, sleep apnea,sleep chronicapnea, obstructivechronic obstructive pulmonary pulmonary disease, disease, renal insu renalfficiency, insufficiency, cavernous cavernous fibrosis, fibrosis, Peyronie’s Peyronie’s disease, disease, and the adverseand the eadverseffect of drugseffect of (Figure drugs1 (Figure)[ 3]. In 1) addition, [3]. In addition, excessive excessive use of drugs use of and drugs over and stress over also stress lead also to progressivelead to progressive ED. The ED. progression The progression of diabetes, of diabetes cardiovascular, cardiovascular disorders, disorders, and hypertension and hypertension also pose also a highpose riska high of EDrisk and of ED hence and decreased hence decreased libido. libido. Figure 1. Pathophysiology of erectile dysfunction (ED). Aging, psychogenic issues, drugs, nerve injury, andFigure diabetes 1. Pathophysiology represent major of etiologicalerectile dysfunction factors leading (ED). Aging, to physiological psychogenic changes issues, such drugs, as excessnerve collageninjury, and deposition, diabetes endothelialrepresent major dysfunction, etiological cavernous factors leading fibrosis, to arterialphysiological insuffi ciencychanges in such penile as corpusexcess cavernosum,collagen deposition, and loss ofendothelial erectile function. dysfunction, cavernous fibrosis, arterial insufficiency in penile corpus cavernosum, and loss of erectile function. To address therapeutic alternatives, both traditional and current pharmacologic approaches haveTo been address explored. therapeutic The traditional alternatives, measures both including traditional use and of animal, current insect, pharmacologic arthropod, approaches and herbal products,have been exercise, explored. and The acupuncture traditional measures mainly addresses including the use balance of animal, between insect, physical arthropod, and and emotional herbal responseproducts, along exercise, with and hormone acupuncture regulation mainly [5,6]. addres The slowses the recovery balance through between lifestyle physical changes and emotional as the first stepresponse to overcome along with ED has hormone prompted regulation the scientific [5,6]. communityThe slow recovery to explore through other treatmentlifestyle changes measures as such the asfirst available step to overcome surgical/non-surgical ED has prompted intervention the scient (drugs)ific community for rapid to recovery explore other [3]. Phosphodiesterase treatment measures 5 (PDE5)such as inhibitorsavailable surgical/non-surgical such as sildenafil citrate, intervention vardenafil, (drugs) and for tadalafil rapid recovery are the most [3]. Phosphodiesterase popular choice of drugs5 (PDE5) [7]. inhibitors Moreover, such the useas sildenafil of PDE5 drugscitrate, may vardenafil, cause headache, and tadalafil nasal are congestion, the most popular and dyspepsia choice [of8]. Besides,drugs [7]. the Moreover, sublingual the apomorphineuse of PDE5 drugs is another may cause recently headache, developed nasal alternative congestion, drug and fordyspepsia ED [8]. In[8]. the Besides, case of the no sublingual response apomorphine to these oral medications,is another recently the intracavernous developed alternative injections drug of alprostadil,for ED [8]. papaverine,In the case of and no phentolamine response to these have oral proven medicati to beons, successful the intracavernous alternatives. However,injections of owing alprostadil, to their short-termpapaverine, eff andect, thesephentolamine interventions have doproven not fully to be cure successful ED. The alternatives. use of vacuum However, constriction owing and to penile their prosthesesshort-term iseffect, considered these interventions as a last resort do mostly not fully in cu there case ED. ofThe older use patientsof vacuum with constriction much less and frequency penile ofprostheses sexual encounters is considered [7]. Theas a highlast resort cost, invasiveness, mostly in the and case irreversibility of older patients are limiting with much factors less for frequency surgical interventionof sexual encounters for ED. [7]. The high cost, invasiveness, and irreversibility are limiting factors for surgicalHowever, intervention the recent for ED. development in regenerative medicine has directed the route to develop cell-basedHowever, therapy the for recent the feasibilitydevelopment of long-term in regenerative treatment medicine of ED. Stemhas directed cells and the platelet-rich route to develop plasma (PRP)cell-based are widely therapy studied for the candidates feasibility forof long-term regenerative treatment therapies of ED. for variousStem cells disorders and platelet-rich [9]. Based plasma on this fact,(PRP) we are discuss widely below studied the candidates various basic for research regenerati andve clinicaltherapies studies for various on the therapeuticdisorders [9]. potential Based on of stemthis fact, cells, we PRP, discuss and theirbelow combination the various withbasic stimulatoryresearch and agents clinical for studies regenerating on the therapeutic damaged cavernous potential nerveof stem in penilecells, corporalPRP, and tissues. their combination with stimulatory