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, down stream 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.

Self-assembling peptide-based building blocks in medical applications

“…Lastly, bioactive peptides for epitope-specific biological interactions can also be incorporated; for example, cell adhesion molecules are often incorporated to mimic native extracellular matrices (Figure 8). In recent years, the majority of in vivo applications using cylindrical PA-based scaffolds include regeneration for, bone [198], nerves [199–202], and reproductive organs [203]. …”

“…The scaffolds supported Schwann cell growth in vitro , and in a critical sized, sciatic nerve defect in rats, PLGA conduits filled with aligned PAs demonstrated motor and sensory recovery, with increased axonal and Schwann cell regeneration within the nerve gap after 12 weeks via histology. In addition, the ability of PA nanofiber hydrogels to regenerative collagen in response to cavernous nerve injury within prostatectomy and diabetic patients have also been reported, providing another promising use for PA use in regenerating tissues [203]. …”

Role of Nanotechnology in Erectile Dysfunction Treatment

“…These studies concluded that PA technology was effective in delivering SHH protein in vivo to the penis and in suppressing the apoptotic index after CN resection. In a follow up study utilizing the same PA methodology, SHH was shown to also suppress collagen induction in response to CN injury [21]. Thus SHH delivered by PA has translational potential to suppress penile remodeling in response to CN injury (prostatectomy model).…”

“…The rats utilized for experimentation were 70 days old at the beginning of the study. At this age the penis continues to grow and add collagen until adulthood is reached (P115–120) [21]. It would be interesting to examine if findings are similar in an adult animal, which is not actively undergoing growth of the penile tissue.…”

Peptide amphiphile nanofiber hydrogel delivery of sonic hedgehog protein to the cavernous nerve to promote regeneration and prevent erectile dysfunction

“…Only a small portion (36%) of prostatectomy patients recover erectile function without intervention [6], and PDE5 inhibitors are ineffective in the majority (69%) of prostatectomy patients [7], thus improved treatments are needed. In response to CN injury, the down stream target of innervation, the corpora cavernosa of the penis, undergoes extensive remodeling, with abundant smooth muscle apoptosis [8] and increased collagen deposition [9–10]. This irreversible process makes the corpora cavernosal tissue unresponsive to normal signaling pathways, even when the CN undergoes limited regeneration.…”