The Ontogeny of Canine Small Intestinal Submucosa Regenerated Bladder

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Abstract
Small intestinal submucosa has previously been shown to promote regeneration of transitional epithelium, smooth muscle and peripheral nerves in rat and dog bladders. The origin of these regenerated components is presently unknown. This study attempts to define the origin of vascular, smooth muscle and peripheral nerve regeneration. A total of 22 adult male dogs weighing 25 to 30 kg. underwent partial cystectomy and immediate augmentation with a small intestinal submucosa patch graft. The small intestinal submucosa graft-native bladder interface was marked with permanent marking sutures for future reference. Small intestinal submucosa regenerated bladders were harvested at 2, 3, 4, 6, 8 and 10 weeks after augmentation. The tissue was then studied with routine histology and immunohistochemistry using factor VIII, smooth muscle specific actin (1A4) and neurofilament staining. Results demonstrated that epithelialization of the graft surface was complete by 3 to 4 weeks with normal transitional histology. In the early periods neovascularization was prominent throughout the entire graft, as shown by factor VIII staining. Later more mature vessels were noted. Early in muscle formation sheets of elongated spindle cells extended into the graft from the incised native bladder at both surgical margins and ran parallel to the mucosal surface. At 4 weeks this spindle cell proliferation completely traversed the graft. Trichrome stained sections of the 4-week-old grafts showed no evidence of muscle differentiation and the spindle cells appeared to be fibroblasts. However, these cells stained positive for smooth muscle specific actin (1A4), indicating myogenic potential. Between weeks 4 and 6 the spindle cells became more haphazardly arranged and were separated by loose interstitium. By weeks 8 to 10 there was distinct smooth muscle bundle formation within these areas of proliferating myocytes. Neural regeneration appeared to coincide with smooth muscle development. Early neurofilament positive cells were noted predominantly at the graft-native bladder interface. At 4 weeks neurofilament positive cells were present throughout the graft and by 10 weeks nerve trunks composed of several nerve fibers were identified in association with newly formed smooth muscle bundles. Small intestinal submucosa serves as a platform for bladder regeneration. Neovascularization smooth muscle and neural regeneration appear to occur through pannus ingrowth from the graft-native bladder interface. Smooth muscle regeneration seems to begin with the maturation of myofibroblasts, which migrate into the graft as early as 2 weeks after augmentation, and it progresses to the formation of distinct smooth muscle bundles by 10 weeks.