Theoretical and experimental evaluation of implant materials used in pelvic organ prolapse repair

Rather than investigating the indications for mesh in prolapse surgery, the focus of this study was on searching the ideal mesh. When starting from the design table, manufacturers would ask the end-users for the physical properties the textile pelvic floor enforcement or substitute would need to have. One of the first tools in such an endeavor would be to calculate what range of forces, or estimate what deformation potential such implant would need to have. Such theoretical mathematical model, which can be used to calculate the effect of manipulation of each of the contributing variables, could help understand both the mechanism leading to prolapse, as well as helping in designing more appropriate mesh materials from a biomechanical viewpoint. We herein propose a mathematical model for that purpose, as was done previously for abdominal wall reconstruction following either hernia or evisceration. We estimated with our model a range of membrane tensions at the urogenital hiatus and mid-pelvis. We did so for patients with and without prolapse, and based ourselves on actual geometric variables and abdominal pressure values measured at rest and valsalva. We calculated a membrane tension at the urogenital hiatus at rest at around 0.35 N/cm. Surprisingly the calculated membrane tensions are much lower than what is reported for the abdominal cavity (16 N/cm). One of the reason for these larger values is that the abdominal pressures used for calculation of the membrane tension in that study, where higher (2 N/cm) than what we, as well as others have measured (0.27 N/cm). Conversely lower pressures would yield membrane tensions in the abdominal wall closer to what we calculated. But apart from that the factor abdominal pressure, lower tensions are also logic in the pelvis as opposed to higher in the abdomen, certainly when considering the law of Laplace. Larger dimensions inherently result in larger membrane tensions. The body copes with these larger forces higher up in the abdomen, by a thicker abdominal wall. Based on Laplace s law, on valsalva, membrane tensions increased (in non-prolapse patients) to 0.85 N/cm (factor 2.5). In prolapse the factor by which it increases is 3.6. The difference between POP- and POP+ can be explained largely by an increased anatomical dimension in case of prolapse, which does not answer the question whether this is the cause or effect of the prolapse. For prolapse patients, this effect becomes even more important when taking the specific orientation of the structures. We did show that due to alterations in the presumed orientation of the tissues during valsalva, the adjusted membrane tensions were up to five times higher. The above mathematically modeled membrane tensions are much lower than what current implant materials have. For instance, Gynemesh M (Ethicon), which was used throughout several experiments in this thesis 127,128, has a membrane tension of 630 N/cm ex vivo, which exceeds by far the forces it is exposed to. This would suggest that there might is lots of room for constructing a more ideal mesh material. Other frequently used pelvic floor meshes (which are typically heavier) have even larger tensions. In other words, the currently available implants are still over-engineered. Biomechanical testing may be even more important in post implantation research. Biomechanical studies provide quantitative information on the generation of and response to physical forces present within implants or tissues. The base line tests are destructive in nature and subject implants or explants to an increasing force, while the consecutive displacement is measured. In uni-axial experiments a rectangular sample is subjected to forces pulling along the axis of the sample. This generates a plot which can for biological tissues typically is divided in 3 regions: an initial linear region of low stress and strain, followed by a transition to a linear region at higher stress and strain, until final failure. When un-implanted textiles are subject to such uniaxial tensiometry such plot actually provides information about the properties of the structure. Most multi-axial testing subjects the implant to forces perpendicular to the test sample and information about the behaviour of the fibers or filaments of the implant, rather than their interaction as a structure. We were interested in measuring both within the framework of a single experiment. During the research period, a custom build inflation device became available. The device exposes the tested im- or explant to pressures generated by compressed fluid, while the displacement is being optically measured. We demonstrated that for a given material, which was stiffer on uni-axial measurement, that material was also stiffer when subjected to multi-axial testing. Though at first glance multiaxial testing would seem to substitute other biomechanics tests, we experimentally and mathematically demonstrated that both test generated different hence more comprehensive complementary information. Ideally future experiments should provide results from both tests. Another observation was that, irrespective of the testing method, explants maintained a supra-physiologic or stiffer profile. Our research was not only methodological, but also (pre)clinical. We used the uni-axial experimental set up to look at biomechanical changes following host tissue ingrowth. We did so for a stiff, heavier mesh (SPMM, Covidien) as well as a lighter mesh (Gynemesh M, Johnson&Johnson Medical, Norderstedt, Germany). Interestingly, though prior to implantation there were significant differences between these dry implants, in-growth of host tissues made those differences disappear (uniaxial at 120 days). At first glance, it would thus seem that prior manipulation of the textile properties of the implant are in vain, as they disappear after incorporation into the host. In another (again uni-axial) experiment however, we demonstrated that this is not always so. Anisotropic fabrics, such as Gynemesh M, apparently keep their anisotropic properties following implantation, though the differential properties attenuate over time. Again, as before, also in that experiment, the ultimate compliance of the implant remained less than that of normal, native tissues. This lead again to the conclusion that from this perspective available meshes remain still far from ideal. This observation was a constant throughout all further experiments. This opens doors for further innovation and improvement. Speculating that structure of the textiles determines the ultimate biomechanical (hence functional) properties, one might improve the mesh biomechanics (prior to implantation), as well as to decrease the host response, for instance by using progressively lighter materials. This can be achieved by structural changes (increasing pore size) and/or less and smaller diameter polymers, or use different polymer materials. We experimentally investigated shrinkage and biomechanical properties of implants with a residual weight of residual non-resorbable fibers (PP or PVDF) at or below 32 g/m². PP-32 actually turned out to be more compliant than PP-8, at least with a structure as we tested it. Following incorporation that difference disappeared. The reason for that remains unclear; we have not yet documented the ultrastructural features of the host response. Also, very light materials were shrinking, which we did not observe when using 32 g/m² implants. In conclusion, though manufacturers, through changing the polymers and/or the structure may change the dry biomechanical properties, not all of these persist after implantation. Again in these experiments we keep on demonstrating that explants by no means have the properties of native tissues. Therefore, there is still a role for innovation and manufacturers may start drawing novel products. Perhaps they should start sketching on their design tables starting from the biomechanical properties of healthy native tissues, rather than incremental small modifications of existing products, which eventually remain far too strong and not as compliant. In the latter study we also made a clinically relevant observation. Dry materials may become structurally so elastic, that they become materials which are difficult if not impossible to handle from a surgical viewpoint. One solution is to enforce the structure by adding resorbable fibers (or sheets), so that handling properties increase. We demonstrated that polyglecaprone fibers did not compromise the biomechanical properties following in growth, whereas sheets did not allow this to happen. In the same experiment on different light weight meshes (≤32 g/m²),we fully documented the non-linear stress-strain relationship of the different biological tissues. We adapted the bilinear model, as initially described by Jones et al. for implant materials in dry conditions. We defined the low stress zone or comfort zone as that zone, where physiologic forces and displacements are expected, and perhaps of more functional relevance. We believe this differentiation is also relevant to textile design. It intuitively seems logic that designers should concentrate on the biomechanical properties of future explants in that range of forces. Meanwhile the concept was picked up in the hernia literature as well. Our research addressed another factor which may be important for the ultimate biomechanics of implants following incorporation into the host. The above studies, as well as the bulk of our and other groups research evaluate implants following their use for reconstructing the abdominal wall. The environmental factors in the vagina differ much from that in the abdominal wall and might result in different host response, fibrosis and biomechanical properties of the implanted material. For that reason, one cannot extrapolate such findings to vaginal mesh insertion and it might be better to study vaginal meshes in purpose designed models.We and others embarked into the study of implants following vaginal implantation. Having experience with rabbits, and given earlier studies on this being a model for vaginal surgery, we also did set up experiments in rabbits. Unfortunately, the vaginal extrusion rate was as high as 50%, which is far from what is observed clinically. Exposure is a common observation in rabbit vaginal implant studies. Though the exact cause of it may not be determined with certainty, we speculated that both mesh size and its suturing were not appropriate. Additionally, the relative thin vaginal epithelium and its limited vascularization following dissection may predispose to wound healing problems. Further, contraction was that frequent, that actual biomechanical measurements were not possible, if not, unreliable. In view of the relevance we think biomechanical studies have, we feel that, at least in our hands, small animal vaginal models are less appropriate. In essence, appropriate biomechanical testing requires sufficiently large specimens, for which we now are using a sheep model. Lastly one might comment on the animal models and techniques used in this work. Our initial work started off with determining the ultimate strength of implanted materials in a rat model. Alponat designed this model for experiments relating to repair of abdominal wall defects, but we successfully applied in previous experiments. As we initially did the experiments, this yielded explants of limited dimensions. For more extensive biomechanical testing, one would require larger samples and therefore larger implants. The rabbit model, which was also used as an abdominal hernia model, is very much in line with the rat model. We speculated that not only its size, but probably also we thought the larger bowel system would induce more important forces, which together would make the rabbit more appropriate. Next to that rabbits can be used for longer term studies. The possible disadvantages of an altered collagen metabolism and a higher susceptibility to infections as well as the costly housing and breeding of the animals are potential limitations. With larger explants for uniaxial testing, we also expanded the outcome parameters of our biomechanical evaluations so that the experiments are more comprehensive. Several limitations of our setup however have to be pointed out. These include clamping influences, axial coupling and inadequate strain measurement. These factors might lead to important scatter in results, as in the experiments comparing Ultrapro with SPMM after implantation. On the other hand, our set-up did allow to distinguish between the directional differences within one material (Ultrapro). We feel comfortable with these methods, which essentially those commonly used in urogynecological or hernia experiments. Exploring other techniques, such as multi-axial measurement, however may yield unanticipated outcomes. Therefore, further methodologic study is required, and actually ongoing with us as with others. Future research directions The mathematical model describes how membrane tensions are higher, and increase more in patients with prolapse. Though it cannot be determined whether this is cause or consequence, we would complement these observations by calculating membrane tensions following repair. Actually this should be done in patients undergoing successful repair, as well as in a longitudinal study with patients who fail ultimately. Such studies could demonstrate that the latter patients have increased membrane tension, as compared to those who remain without prolapse.Nevertheless such mathematical model remains an approximation of the true physiological conditions. One could therefore embark on a series of finite element models to unravel this problem. Although the authors truly believe in such an approach, different problems occur when using these models, which are not easily overcome. One would have to model each component, each fiber and each muscle separately, i.e. one needs to know its exact location and dimensions anatomically, its origin and its attachments and most importantly, its response to physiological conditions. This then comes down on a series of translational experiments, involving medical imaging, finite element modeling and in vitro experiments. When one would finally succeed in such a piece of art, its findings would still have to be validated. Our group has meanwhile decided to further investigate the potential of non invasive in vivo biomechanical measurements. This will allow for longitudinal follow up of experimental animals, as well as clinical subjects, and correlate those findings with functional outcomes. We also conclude that there was stillroom for making lighter, more compliant, or in other words less strong products. None of the tested implant materials ever yielded biomechanical properties of native tissues, where at the same time none of them was actually the weakest element in the chain. Reducing weight of materials apparently introduces new problems, such as inappropriate handling properties, folding or shrinking. Therefore manufacturers may focus rather on structural changes of the fabrics, rather than only reducing the amount of material, or move away from textiles towards other manufacturing methods.nrpages: 176status: publishe