title: Sonic hedgehog delivery from self-assembled nanofiber hydrogels reduces the fibrotic response in models of erectile dysfunction.
abstract: Erectile dysfunction (ED) is a serious medical condition in which current treatments are ineffective in prostatectomy and diabetic patients, due to injury to the cavernous nerve (CN), which causes irreversible remodeling of the penis (decreased smooth muscle and increased collagen), through a largely undefined mechanism. We propose that sonic hedgehog (SHH) and neural innervation, are indispensable regulators of collagen in the penis, with decreased SHH protein being an integral component of the fibrotic response to loss of innervation. We examined collagen abundance and morphology in control (Peyronie's), prostatectomy and diabetic patients, and in rat models of penile development, CN injury, SHH inhibition and under regenerative conditions, utilizing self-assembling peptide amphiphile (PA) nanofiber hydrogels for SHH delivery. Collagen abundance increased in penis of ED patients. In rats, collagen increased with CN injury in a defined time frame independent of injury severity. An inverse relationship between SHH and collagen abundance was identified; SHH inhibition increased and SHH treatment decreased penile collagen. SHH signaling in the pelvic ganglia (PG)/CN is important to maintain CN integrity and when inhibited, downstream collagen induction occurs. Collagen increased throughout penile development and with age, which is important when considering how to treat fibrosis clinically. These studies show that SHH PA treatment reduces collagen under regenerative post-prostatectomy conditions, indicating broad application for ED prevention in prostatectomy, diabetic and aging patients and in other peripheral nerve injuries. The PA nanofiber protein vehicle may be widely applicable as an in vivo delivery tool.
  
  
  CONCLUSIONS
  We use self-assembling peptide amphiphiles (PA) as biological delivery vehicles to prevent cavernous nerve (CN) injury induced erectile dysfunction (ED). These versatile hydrogels were molecularly pre-programmed for sonic hedgehog (SHH) protein delivery, either from an injectable solution with fast, in situ assembly into a soft hydrogel, or by highly aligned monodomain nanofiber bundles. We used PAs to examine a novel neuronal component to collagen regulation and the role of SHH in the fibrotic response to CN injury. SHH perturbation in the penis or the CN, selectively impacts collagen, with SHH inhibition increasing and SHH treatment suppressing collagen. These results suggest that SHH treatment by PA has translational potential to suppress collagen induction and remodelling, an irreversible component of ED development.
authors.affiliation: Department of Urology, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Shawn
authors.initials: S
authors.lastname: Choe
authors.affiliation: Department of Urology, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Dorina
authors.initials: D
authors.lastname: Veliceasa
authors.affiliation: Department of Allergy/Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, United States.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Bond
authors.affiliation: Department of Biosciences, Rice University, Houston, TX 77005, United States.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Harrington
authors.affiliation: Simpson-Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, United States.; Department of Chemistry, Northwestern University, Chicago, IL 60611, United States; Department of Materials Science and Engineering, Northwestern University, Chicago, IL 60611, United States; Department of Biomedical Engineering, Northwestern University, Chicago, IL 60611, United States.
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
authors.affiliation: Division of Urology, Southern Illinois University School of Medicine, Springfield, IL 62794, United States.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: McVary
authors.affiliation: Department of Urology, University of Illinois at Chicago, Chicago, IL 60612, United States; Department of Physiology and Bioengineering, University of Illinois at Chicago, Chicago, IL 60612, United States. Electronic address: cap325@uic.edu.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Podlasek
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D003920:Diabetes Mellitus / Q000503:physiopathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D005355:Fibrosis; D005724:Ganglia / Q000187:drug effects; D053823:Hedgehog Proteins / Q000008:administration & dosage* / Q000627:therapeutic use*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D057139:Nanofibers / Q000737:chemistry*; D010413:Penis / Q000187:drug effects / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology; D011468:Prostatectomy; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D013997:Time Factors
chemical_list: D053823:Hedgehog Proteins; D020100:Hydrogels; D010455:Peptides; D003094:Collagen; D006909:Hydroxyproline
keywords: Cavernous nerve injury; Collagen; Penis; Self-assembling peptide amphiphile nanofiber hydrogels; Sonic hedgehog