Katrina Knight

Vaginal degeneration following implantation of synthetic mesh with increased stiffness

To compare the impact of the prototype prolapse mesh Gynemesh PS with that of two new‐generation lower stiffness meshes, UltraPro and SmartMesh, on vaginal morphology and structural composition.

Impact of parity on ewe vaginal mechanical properties relative to the nonhuman primate and rodent.

Introduction and hypothesisParity is the leading risk factor for the development of pelvic organ prolapse. To assess the impact of pregnancy and delivery on vaginal tissue, researchers commonly use nonhuman primate (NHP) and rodent models. The purpose of this study was to evaluate the ewe as an alternative model by investigating the impact of parity on the ewe vaginal mechanical properties and collagen structure.MethodsMechanical properties of 15 nulliparous and parous ewe vaginas were determined via uniaxial tensile tests. Collagen content was determined by hydroxyproline assay and collagen fiber thickness was analyzed using picrosirius red staining. Outcome measures were compared using Independent samples t or Mann–Whitney U tests. ANOVA (Gabriel’s pairwise post-hoc test) or the Welch Alternative for the F-ratio (Games Howell post-hoc test) was used to compare data with previously published NHP and rodent data.ResultsVaginal tissue from the nulliparous ewe had a higher tangent modulus and tensile strength compared with the parous ewe (p < 0.025). The parous ewe vagina elongated 42 % more than the nulliparous ewe vagina (p = 0.015). No significant differences were observed in collagen structure among ewe vaginas. The tangent modulus of the nulliparous ewe vagina was not different from that of the NHP or rodent (p = 0.290). Additionally, the tangent moduli of the parous ewe and NHP vaginas did not differ (p = 0.773).ConclusionsParity has a negative impact on the mechanical properties of the ewe vagina, as also observed in the NHP. The ewe may serve as an alternative model for studying parity and ultimately prolapse development.

Differential effects of selective estrogen receptor modulators on the vagina and its supportive tissues.

Objective:Some selective estrogen receptor modulators (SERMs) have been associated with increased incidence of urinary incontinence and pelvic organ prolapse. This study explored the effects of five SERMs on the function and matrix components of the vagina and its supportive tissues. Methods:Fifty-six rats were administered SERMs by oral gavage for 8 weeks (n = 8 for each SERM): raloxifene, tamoxifen, idoxifene, bazedoxifene at three different doses, and bazedoxifene with conjugated estrogens. Thirty-two rats were used as controls (n = 8 per group): sham operation (no ovariectomy), ovariectomy only, ovariectomy with vehicle gavage, and 17&bgr;-estradiol (subcutaneous). Vaginal supportive tissue complex was tested by uniaxial tensile testing. Total collagen content (hydroxyproline) and glycosaminoglycan content (Blyscan) were measured. Results:Ovariectomy significantly decreased the mechanical integrity of the vagina and its supportive tissue complex, with a decrease in ultimate load and stiffness (all P < 0.05). Although 17&bgr;-estradiol supplementation maintained these properties similarly to sham operation, none of the SERMs was as effective—particularly idoxifene, bazedoxifene at higher doses, and bazedoxifene with conjugated estrogens (all P < 0.05). In addition, idoxifene and bazedoxifene induced increased total collagen content compared with sham or 17&bgr;-estradiol treatment (all P < 0.05). Glycosaminoglycan content did not change significantly. Conclusions:Unlike 17&bgr;-estradiol, SERM supplementation does not fully prevent ovariectomy-induced deterioration in the biomechanical properties of the vagina and its supportive tissues, with the effects of idoxifene and bazedoxifene being the least. The paradoxically increased collagen content in these two groups may be related to increased formation of nonfunctional collagen.

Exploring the basic science of prolapse meshes.

Purpose of review Polypropylene mesh has been widely used in the surgical repair of pelvic organ prolapse. However, low but persistent rates of complications related to mesh, most commonly mesh exposure and pain, have hampered its use. Complications are higher following transvaginal implantation prompting the Food and Drug Administration to release two public health notifications warning of complications associated with transvaginal mesh use (PHN 2008 and 2011) and to upclassify transvaginal prolapse meshes from Class II to Class III devices. Although there have been numerous studies to determine the incidence and management of mesh complications as well as impact on quality of life, few studies have focused on mechanisms. Recent findings In this review, we summarize the current understanding of how mesh textile properties and mechanical behavior impact vaginal structure and function, as well as the local immune response. We also discuss how mesh properties change in response to loading. Summary We highlight a few areas of current and future research to emphasize collaborative strategies that incorporate basic science research to improve patient outcomes.

Towards rebuilding vaginal support utilizing an extracellular matrix bioscaffold

As an alternative to polypropylene mesh, we explored an extracellular matrix (ECM) bioscaffold derived from urinary bladder matrix (MatriStem™) in the repair of vaginal prolapse. We aimed to restore disrupted vaginal support simulating application via transvaginal and transabdominal approaches in a macaque model focusing on the impact on vaginal structure, function, and the host immune response. In 16 macaques, after laparotomy, the uterosacral ligaments and paravaginal attachments to pelvic side wall were completely transected (IACUC# 13081928). 6-ply MatriStem was cut into posterior and anterior templates with a portion covering the vagina and arms simulating uterosacral ligaments and paravaginal attachments, respectively. After surgically exposing the correct anatomical sites, in 8 animals, a vaginal incision was made on the anterior and posterior vagina and the respective scaffolds were passed into the vagina via these incisions (transvaginal insertion) prior to placement. The remaining 8 animals underwent the same surgery without vaginal incisions (transabdominal insertion). Three months post implantation, firm tissue bands extending from vagina to pelvic side wall appeared in both MatriStem groups. Experimental endpoints examining impact of MatriStem on the vagina demonstrated that vaginal biochemical and biomechanical parameters, smooth muscle thickness and contractility, and immune responses were similar in the MatriStem no incision group and sham-operated controls. In the MatriStem incision group, a 41% decrease in vaginal stiffness (P=0.042), a 22% decrease in collagen content (P=0.008) and a 25% increase in collagen subtypes III/I was observed vs. Sham. Active MMP2 was increased in both Matristem groups vs. Sham (both P=0.002). This study presents a novel application of ECM bioscaffolds as a first step towards the rebuilding of vaginal support. STATEMENT OF SIGNIFICANCE Pelvic organ prolapse is a common condition related to failure of the supportive soft tissues of the vagina; particularly at the apex and mid-vagina. Few studies have investigated methods to regenerate these failed structures. The overall goal of the study was to determine the feasibility of utilizing a regenerative bioscaffold in prolapse applications to restore apical (level I) and lateral (level II) support to the vagina without negatively impacting vaginal structure and function. The significance of our findings is two fold: 1. Implantation of properly constructed extracellular matrix grafts promoted rebuilding of level I and level II support to the vagina and did not negatively impact the overall functional, morphological and biochemical properties of the vagina. 2. The presence of vaginal incisions in the transvaginal insertion of bioscaffolds may compromise vaginal structural integrity in the short term.

Basic Science of Vaginal Mesh

The use of mesh to treat gynecologic disorders of pelvic organ prolapse and stress urinary incontinence is widespread. While mesh has provided many women relief of their symptoms and relatively good anatomical outcomes, surgeries employing mesh have had significant complications, resulting in the release of public health notifications, the up-classification of these devices, the discontinuation of mesh products by vendors, and multi-district litigation. To date the precise etiology of mesh complications is unknown; however, basic science research investigating the pathogenesis of mesh complications has increased over the past 10–15 years, and potential mechanisms have been identified. The purpose of this chapter is to provide an overview of the ex vivo and in vivo studies that have shed light on our understanding of the factors that contribute to mesh complications. Specifically, the impact of mesh textiles properties and mechanics on the host response will be explored. Additionally, this chapter will summarize the pertinent in vivo animal and human studies that have investigated the host response to polypropylene-based mesh. Although biological meshes have also been used in the treatment of gynecologic disorders, polypropylene urogynecologic meshes will be the main focus of this text. Lastly, the chapter will conclude with a future perspective of basic science research on urogynecologic meshes.

Deformation of Transvaginal Mesh in Response to Multiaxial Loading

Synthetic mesh for pelvic organ prolapse (POP) repair is associated with high complication rates. While current devices incorporate large pores (>1 mm), recent studies have shown that uniaxial loading of mesh reduces pore size, raising the risk for complications. However, it is difficult to translate uniaxial results to transvaginal meshes, as in vivo loading is multidirectional. Thus, the aim of this study was to (1) experimentally characterize deformation of pore diameters in a transvaginal mesh in response to clinically relevant multidirectional loading and (2) develop a computational model to simulate mesh behavior in response to in vivo loading conditions. Tension (2.5 N) was applied to each of mesh arm to simulate surgical implantation. Two loading conditions were assessed where the angle of the applied tension was altered and image analysis was used to quantify changes in pore dimensions. A computational model was developed and used to simulate pore behavior in response to these same loading conditions and the results were compared to experimental findings. For both conditions, between 26.4% and 56.6% of all pores were found to have diameters <1 mm. Significant reductions in pore diameter were noted in the inferior arms and between the two superior arms. The computational model identified the same regions, though the model generally underestimated pore deformation. This study demonstrates that multiaxial loading applied clinically has the potential to locally reduce porosity in transvaginal mesh, increasing the risk for complications. Computational simulations show potential of predicting this behavior for more complex loading conditions.

Preventing Mesh Pore Collapse by Designing Mesh Pores With Auxetic Geometries: A Comprehensive Evaluation Via Computational Modeling

Pelvic organ prolapse (POP) meshes are exposed to predominately tensile loading conditions in vivo that can lead to pore collapse by 70-90%, decreasing overall porosity and providing a plausible mechanism for the contraction/shrinkage of mesh observed following implantation. To prevent pore collapse, we proposed to design synthetic meshes with a macrostructure that results in auxetic behavior, the pores expand laterally, instead of contracting when loaded. Such behavior can be achieved with a range of auxetic structures/geometries. This study utilized finite element analysis (FEA) to assess the behavior of mesh models with eight auxetic pore geometries subjected to uniaxial loading to evaluate their potential to allow for pore expansion while simultaneously providing resistance to tensile loading. Overall, substituting auxetic geometries for standard pore geometries yielded more pore expansion, but often at the expense of increased model elongation, with two of the eight auxetics not able to maintain pore expansion at higher levels of tension. Meshes with stable pore geometries that remain open with loading will afford the ingrowth of host tissue into the pores and improved integration of the mesh. Given the demonstrated ability of auxetic geometries to allow for pore size maintenance (and pore expansion), auxetically designed meshes have the potential to significantly impact surgical outcomes and decrease the likelihood of major mesh-related complications.

Parity Negatively Impacts the Uniaxial Mechanical Properties of the Vagina in the Ewe

Pelvic organ prolapse (POP) is a common disorder with a profoundly negative impact on the physical and psychological health of women worldwide; however, the exact etiology is currently unknown. Parity, defined as the number of births, is commonly identified as one of the leading risk factors for the development of POP. The objective of this study was to examine the impact of parity on the uniaxial mechanical properties of the sheep vagina along the longitudinal direction. The findings of this study revealed that parity negatively impacts the tangent modulus (54% decrease), tensile strength (54% decrease), and strain-energy density (47% decrease) of the vagina in the ewe (female sheep). Based on similar findings in primate, these data suggest that the ewe may serve as a cheaper alternative for studying the pathogenesis of POP moving forward.Copyright