The most important finding of this study was that human dermal matrices implanted in both the abdominal and vaginal site in rabbits were safe. The complete histological characterization of the explants confirmed that new tissue was regenerated in the vaginal site, with maintenance of a well-organized collagen fiber structure that supported the repopulation.
The macroscopic findings of the explants showed very different behavior between the two groups, and these differences were especially relevant in the vaginal location. The control (PP) group showed a statistically significant increase in vaginal extrusion, compared to hADM. These results were expected, since vaginal extrusion of PP meshes is a known common complication. On the other hand, the hADM graft was completely integrated into the surrounding tissue in a significant percentage of cases, and in some subjects, it was impossible to identify and remove the explants, especially at the vaginal level. These results are consistent with previous publications showing 70% and 100% graft degradation in the vaginal location by Pierce et al. and Claerhout et al., respectively.19,20 The macroscopic findings in our study are therefore consistent with excellent biocompatibility of hADM grafts at the vaginal level.
The inflammatory response is a physiological process that occurs as a consequence of the immunological interaction with a foreign body. Nevertheless, the nature and intensity of this response depend on the characteristics of the implanted material. The results of this study reveal that the immune responses are different in both groups. Six months after implantation, the control (PP) group showed an inflammatory response located mainly at the epithelial level (focal response), and mainly mediated by TL; however, in the experimental group, a heterogeneous chronic rejection response with scattered invasion of inflammatory cells was observed. Our results coincide with those previously reported by Ying Yao et al. with heterogenic meshes.21
The immunological response differed depending on the implant location (vaginal or abdominal), in line with previous reports.19 Our study shows a greater immune response to foreign bodies in the vaginal location compared to the abdominal area in both groups; 9/18 animals studied presented an inflammatory response at the vaginal level and only 5 at the abdominal level. This different response depending on the location was more evident in the control group, where no subject had an inflammatory infiltrate at the abdominal level. The results of this study are thus consistent with observations in the real-world setting, where mesh complications are more common when the implant is placed at the vaginal level as compared with the abdominal location. The underlying mechanisms that explain this different behavior according to the location have yet to be determined, but could be influenced by the degree of host tissue vascularization.
The histological study provides information about the arrangement of collagen fibers, showing differences between the two groups. In the control group, collagen fibers were more compact, with a higher percentage of fibrosis both in the vaginal and abdominal locations, which results in a rejection response, as previously shown.19 Along these lines, it has been described that, in PP implants, the density of collagen increases over time, unlike the inflammatory reaction that disappears over time in the abdominal location.22 In the study group, the collagen fibers were more structured and organized, which translates into better tissue integration. This maintenance of the collagen structure was previously observed by Ying Yao et al. in heterogenic meshes.21 In terms of biomechanical properties, this study shows that stiffness of explants diminished 6 months after implantation, especially in the vaginal location, for the study group. These results are probably due to the integration and partial degradation of the explants, predominantly in the vaginal location. These findings are in agreement with previous reports.19,23−26
In summary, the excellent biocompatibility of hADM grafts suggesting a good safety profile needs to be counterbalanced by the early degradation process that challenges its efficacy profile. In terms of study limitations, the results demonstrate the safety of hADM grafts, but the animal model used does not allow us to fully evaluate graft functionality, since quadruped vs. biped standing position may affect results. Despite the animal model limitations, the findings of our work provide a putative therapeutic alternative with relevance and applicability in the field of urogynecology.
Clinical studies in women are needed to assess the functionality of the graft. The immunologic and inflammatory response to the hADM may also be different when implanted in humans, and the biocompatibility and biomechanical properties will need to be assessed.
Unlike synthetic meshes that simply act to reinforce damaged tissue, hADM acts as a natural scaffold with full integration with the surrounding soft tissue, inducing tissue regeneration. This tentative function is compatible with the hypothesis that hADM sustains biocompatibility with the recipient tissue, and is able to abrogate the complications associated with synthetic meshes that induce local inflammation. This acellular matrix seems to act as a scaffold where the host cells can migrate and proliferate and thus regenerate the tissue where it is implanted; however, biomechanical properties may need to be improved to increase host tissue support. As the previous study conducted by our group concluded, the NZW rabbit is a suitable model for assessing materials to be used as grafts for pelvic reconstructive surgery and vaginal surgery.17 This study provides further information on the biological properties of a new biomaterial — hADM — surgically implanted in the subcutaneous abdominal wall and in the vaginal submucosa layer of a NZW rabbit.