Peyronie’s disease (PD) is a debilitating pathology which is associated with penile curvature and erectile dysfunction due to the formation of fibrotic plaques in the penile tunica albuginea. In the present study, we developed a novel rabbit model of PD via subtunical injection of recombinant transforming growth factor (TGF)-β1 protein and characterized erectile function and histopathological endpoints following plaque formation. Ten adult male, New Zealand white rabbits were randomized into 3 experimental groups including nonsurgical controls (NSC, N = 3) and those receiving subtunical injections of vehicle (N = 3) or TGF-β1 protein (0.5 µg/50 µl; N = 4). Following 1 month post-op, focal fibrous plaques composed of disorganized collagen type I and III bundles as well as fragmented elastin fibers at TGF-β1 injection sites were observed in contrast to control groups. Cavernosometric and cavernosographic evaluations revealed no significant differences in maximum intracorporal pressures or substantial curvature during papaverine-induced erection in either the vehicle or TGF-β1 cohorts. Immunohistochemical and histomorphometric analyses demonstrated significant increases in elastase 2B expression in TGF-β1-induced plaques as well as significant declines in matrix metalloproteinase (MMP)-2 and -9 expression relative to control levels. Our results demonstrate that PD-like fibrotic plaques can be created in the rabbit penile tunica albuginea following TGF-β1 injection.
Esophageal pathologies such as atresia and benign strictures often require surgical reconstruction with autologous tissues to restore organ continuity. Complications such as donor site morbidity and limited tissue availability have spurred the development of acellular grafts for esophageal tissue replacement. Acellular biomaterials for esophageal repair rely on the activation of intrinsic regenerative mechanisms to mediate de novo tissue formation at implantation sites. Previous research has identified signaling cascades involved in neoepithelial formation in a rat model of onlay esophagoplasty with acellular silk fibroin grafts, including phosphoinositide 3‐kinase (PI3K), and protein kinase B (Akt) signaling. However, it is currently unknown how these mechanisms are governed by DNA methylation (DNAme) during esophageal wound healing processes. Reduced‐representation bisulfite sequencing is performed to characterize temporal DNAme dynamics in host and regenerated tissues up to 1 week postimplantation. Overall, global hypermethylation is observed at postreconstruction timepoints and an inverse correlation between promoter DNAme and the expression levels of differentially expressed proteins during regeneration. Site‐specific hypomethylation targets genes associated with immune activation, while hypermethylation occurs within gene bodies encoding PI3K‐Akt signaling components during the tissue remodeling period. The data provide insight into the epigenetic mechanisms during esophageal regeneration following surgical repair with acellular grafts.
Background: The primary strategy for urinary diversion in radical cystectomy patients involves incorporation of autologous gastrointestinal conduits into the urinary tract which leads to deleterious consequences including chronic infections and metabolic abnormalities. This report investigates the efficacy of an acellular, tubular bi-layer silk fibroin (BLSF) graft to function as an alternative urinary conduit in a porcine model of urinary diversion.Materials and methods: Unilateral urinary diversion with stented BLSF conduits was executed in five adult female, Yucatan mini-swine over a 3 month period. Longitudinal imaging analyses including ultrasonography, retrograde ureteropyelography and video-endoscopy were carried out monthly. Histological, immunohistochemical (IHC), and histomorphometric assessments were performed on neoconduits at harvest.Results: All animals survived until scheduled euthanasia and displayed moderate hydronephrosis (Grades 1–3) in reconstructed collecting systems over the course of the study period. Stented BLSF constructs supported formation of vascularized, retroperitoneal tubes capable of facilitating external urinary drainage. By 3 months post-operative, neoconduits contained α-smooth muscle actin+ and SM22α+ smooth muscle as well as uroplakin 3A+ and pan-cytokeratin + urothelium. However, the degree of tissue regeneration in neotissues was significantly lower in comparison to ureteral controls as determined by histomorphometry. In addition, neoconduit stenting was necessary to prevent stomal occlusion.Conclusion: BLSF biomaterials represent emerging platforms for urinary conduit construction and may offer a functional replacement for conventional urinary diversion techniques following further optimization of mechanical properties and regenerative responses.
Peyronie’s disease (PD) is a debilitating pathology which is associated with penile curvature and erectile dysfunction due to the formation of fibrotic plaques in the penile tunica albuginea. In the present study, we developed a novel rabbit model of PD via subtunical injection of recombinant transforming growth factor (TGF)-β1 protein and characterized erectile function and histopathological endpoints following plaque formation. Ten adult male, New Zealand white rabbits were randomized into 3 experimental groups including nonsurgical controls (NSC, N = 3) and those receiving subtunical injections of vehicle (N = 3) or TGF-β1 protein (N = 4). Following 1 month post-op, focal fibrous plaques composed of disorganized collagen type I and III bundles as well as fragmented elastin fibers at TGF-β1 injection sites were observed in contrast to control groups. Cavernosometric and cavernosographic evaluations revealed no significant differences in maximum intracorporal pressures or substantial curvature during papaverine-induced erection in either the vehicle or TGF-β1 cohorts. Immunohistochemical and histomorphometric analyses demonstrated significant increases in elastase 2B expression in TGF-β1-induced plaques as well as significant declines in matrix metalloproteinase (MMP)-2 and − 9 expression relative to control levels. Our results demonstrate that PD-like fibrotic plaques can be created in the rabbit penile tunica albuginea following TGF-β1 injection.
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