Transvaginal Mesh-related Complications and the Potential Role of Bacterial Colonization: An Exploratory Observational Study.

STUDY OBJECTIVE: This study aimed to investigate the potential role of transvaginal mesh bacterial colonization in the development of mesh-related complications (MRCs). DESIGN: An observational and exploratory study. SETTING: Tertiary referral center (Amsterdam UMC, location AMC, Amsterdam, The Netherlands). PATIëNTS: 49 patients indicated for mesh removal and 20 women of whom vaginal tissue was retrieved during prolapse surgery as a reference cohort. INTERVENTIONS: collection of mesh-tissue complex (patient cohort) or vaginal tissue (reference cohort) MEASUREMENTS AND MAIN RESULTS: Homogenized samples were used for quantitative microbiological culture. Inflammation and fibrosis were semiquantitatively histologically scored; Gram staining and fluorescence in situ hybridization were used to detect bacteria and bacterial biofilms. Of the 49 patients, 44 samples (90%) were culture positive, with a higher diversity of species and more Gram-negative bacteria and polymicrobial cultures in the MRC cohort than the reference cohort, with mostly staphylococci, streptococci, Actinomyces spp., Cutibacterium acnes, and Escherichia coli. Patients with clinical signs of infection or exposure had the highest bacterial counts. Histology demonstrated moderate to severe inflammation in most samples. Gram staining showed bacteria in 57% of culture-positive samples, and in selected samples, fluorescence in situ hybridization illustrated a polymicrobial biofilm. CONCLUSION: In this study, we observed distinct differences in bacterial numbers and species between patients with MRCs and a reference cohort. Bacteria were observed at the mesh-tissue interface in a biofilm. These results strongly support the potential role of bacterial mesh colonization in the development of MRCs.

Absorbable Electrospun Poly-4-hydroxybutyrate Scaffolds as a Potential Solution for Pelvic Organ Prolapse Surgery.

Women with pelvic organ prolapse (POP) have bothersome complaints that significantly affect their quality of life. While native tissue repair is associated with high recurrence rates, polypropylene knitted implants have caused specific implant-related adverse events that have detrimental, often irreversible, effects. We hypothesize that surgical outcome can be improved with a tissue-engineered solution using an absorbable implant that mimics the natural extracellular matrix (ECM) structure, releases estrogen, and activates collagen metabolism by fibroblasts as the main regulators of wound healing. To this aim, we produced electrospun poly-4-hydroxybutyrate (P4HB) scaffolds and biofunctionalized them with estradiol (E2). The cell-implant interactions relevant for POP repair were assessed by seeding primary POP vaginal fibroblasts isolated from patients on electrospun P4HB scaffolds with 1%, 2%, or 5% E2 and without E2. To test our hypothesis on whether ECM mimicking structures should improve regeneration, electrospun P4HB was compared to knitted P4HB implants. We evaluated vaginal fibroblast proliferation, ECM deposition, and metabolism by quantification of collagen, elastin, and matrix metalloproteinases and by gene expression analysis for 28 days. We established effective E2 drug loading with a steady release over time. Significantly higher cell proliferation, collagen-, and elastin deposition were observed on electrospun P4HB scaffolds as compared to knitted P4HB. For this study, physical properties of the scaffolds were more determinant on the cell response than the release of E2. These results indicate that making these electrospun P4HB scaffolds E2-releasing appears to be technically feasible. In addition, electrospun P4HB scaffolds promote the cellular response of vaginal fibroblasts and further studies are merited to assess if their use results in improved surgical outcomes in case of POP repair.

The impact of bacterial contamination on the host response towards fully absorbable poly-4-hydroxybutyrate and nonabsorbable polypropylene pelvic floor implants.

Polypropylene (PP) implants for the vaginal surgical correction of pelvic organ prolapse (POP) are known for adverse events, like vaginal or visceral exposures. It is hypothesized that this is a result of a prolonged inflammatory response. One of the triggering factors of prolonged inflammation might be bacterial contamination. A possible solution might lie in an absorbable biomaterial, which provides initial mechanical support while being gradually replaced by the host tissue. With this study we aimed to compare the host response, in a subcutaneous mouse implant infection model, to delayed absorbable poly-4-hydroxybutyrate (P4HB) and a latest generation PP implant. By comparing non-infected to Staphylococcus aureus infected mice, we assessed how bacterial contamination affects the host response and its role in the development of complications. Further, we included sham surgery as a control, mimicking the wound response in native tissue repair. Despite the higher surface area of the P4HB implants, the clearance of infection was similarly delayed in the presence of a P4HB or PP implant, as compared to sham. Further, the host response towards P4HB and PP was quite comparable, yet collagen deposition was significantly increased around infected P4HB implants at early time points. Adverse event rates were similar, though implant exposures were only seen in infected mice and more often with PP (11.1%) than P4HB implants (5.6%). Infected mice overall had significantly higher levels of infiltration of inflammatory cells and lower levels of vascularization and collagen deposition compared to non-infected mice. Thus, for both P4HB and PP, bacterial contamination negatively affected mesh integration by increased inflammation and an increased adverse event rate. Altogether, our results from this subcutaneous mouse implant infection study suggest that P4HB could be a promising degradable alternative to PP, warranting further research to study its potential as a new surgical solution for women with POP.

Animal experimental research assessing urogynecologic surgical mesh implants: Outcome measures describing the host response, a systematic review and meta-analysis.

AIM: Before the introduction of new biomaterials for prolapse surgery, animal studies on the host response are required. Unfortunately, large variation in study design hampers obtaining an overview of the safety and efficacy, and translation to clinical practice. Our aim is to systematically review the literature on all outcome measures describing the host response in animal studies assessing the biocompatibility of urogynecologic surgical mesh implants for prolapse surgery. Furthermore, by meta-analysis, we aim to assess the effect of implantation and compare this to control animals receiving sham surgery or native tissue repair. METHODS: We performed a systematic search from inception to August 2020. Since this is an explorative study we included original, controlled, and noncontrolled animal studies describing any host response to the implant. Quantitative outcome measures reported ≥10 times in ≥2 articles were eligible for meta-analysis. RESULTS: Fifty articles were included in the qualitative synthesis and 36 articles were eligible for meta-analysis. In total, 154 outcome measures were defined and classified into (1) histomorphology, (2) biomechanics and, (3) macroscopic morphology. Animals with vaginal implants demonstrated significantly increased M1 and M2 macrophages, MMP-2, neovascularization, TNF-α, and stiffness, and lower vaginal contractility compared to control animals. CONCLUSION: The host response significantly differs in animals after vaginal mesh implantation compared to control animals, both pro- and anti-inflammatory. However, we observed a paucity in the uniformity of reported outcomes. For future animal studies, we propose the development of a core outcome set, which ideally predicts the host response in women.

In Vitro Bacterial Adhesion and Biofilm Formation on Fully Absorbable Poly-4-hydroxybutyrate and Nonabsorbable Polypropylene Pelvic Floor Implants.

Knitted polypropylene (PP) implants for the correction of pelvic organ prolapse have been associated with complications such as vaginal exposure, infection, and pain. Since certain complications may be linked to bacterial contamination and persistent inflammation, there is a rationale to develop a biocompatible implant that is less prone to bacterial adhesion and biofilm formation. Delayed absorbable materials could meet these requirements and poly-4-hydroxybutyrate (P4HB) might be such a new material for future pelvic floor implants. We studied in vitro bacterial adhesion and biofilm formation on P4HB in comparison to PP. We investigated the influence of both polymers using flat films and compared P4HB and PP implants with different knitting designs. P4HB flat films were demonstrated to be hydrophilic with significantly less Staphylococcus aureus and Escherichia coli cultured from P4HB films than from hydrophobic PP films after 24 h of incubation. On the implants, a higher number of E. coli were cultured after 1 h of incubation from the knitted P4HB implant with the highest density and smallest pore size, compared to other P4HB and PP implants. No differences were observed between the implants for E. coli at later time points or for S. aureus incubation. These results show that in flat films, the polymer influences biofilm formation, demonstrated by a reduced biofilm formation on P4HB compared with PP flat films. In addition, the knitting design may affect bacterial adhesion. Despite certain design and material characteristics that give the knitted P4HB implants a higher surface area, this did not result in more bacterial adhesion and biofilm formation overall. Collectively, these results warrant further (pre)clinical investigations of P4HB pelvic floor implants.

Effects of early thyroxine treatment on development and growth at age 10.7 years: follow-up of a randomized placebo-controlled trial in children with Down's syndrome.

CONTEXT: In 2-year-old children with Down's syndrome (DS), early T4 treatment was found to result in slightly better motor development and growth. OBJECTIVES: This study sought to determine long-term effects of early T4 treatment on development and growth in children with DS with either an elevated or normal neonatal TSH concentration. DESIGN: Patients received a single follow-up visit 8.7 years after a randomized placebo-controlled trial (RCT) comparing T4 and placebo treatment during the first 2 years of life. SETTING: Dutch Academic Hospital. PARTICIPANTS: All children who completed the RCT (N = 181, of 196 randomly assigned children) were invited for the follow-up study. A total of 123 participants enrolled, at a mean age of 10.7 years. INTERVENTIONS: T4 or placebo treatment from the neonatal period until 2 years. MAIN OUTCOME MEASURES: Primary: mental and motor development. Secondary: communication skills, fine-motor coordination, height, weight, and head circumference (HC). Outcomes were compared between T4- and placebo-treated children, and between treatment groups with either a normal (<5 mIU/L), or elevated (≥ 5 mIU/L) TSH concentration at original trial entry. RESULTS: Mental or motor development, communication skills, or fine-motor coordination did not differ between T4- (N = 64) and placebo-treated children (N = 59). T4-treated children had a larger HC (50.4 vs 49.8 cm, P = .04) and tended to be taller (133.2 vs 131.1 cm, P = .06). These differences were somewhat greater in children with TSH ≥ 5 mIU/L (HC: T4, 50.5 vs placebo, 49.7 cm; P = .01; height: T4, 133.8 vs placebo, 130.8 cm; P = .02), but were not found in children with TSH <5 mIU/L (HC: T4, 50.1 vs placebo, 50.0 cm; P = .75; height: T4, 132.1 vs placebo, 131.6 cm; P = .22). CONCLUSIONS: Early T4 treatment of children with DS does not seem to benefit mental or motor development later in life. However, the positive effect on growth is still measurable, especially in children with an elevated plasma TSH concentration in the neonatal period.