• absolute uterus factor infertility
• bioengineering
• decellularized scaffolds
• immune response
• infertility
• uterus transplantation

• Animals
• Female
• Tissue Engineering/methods
• Uterus/cytology
• Tissue Scaffolds
• Papio
• Humans
• Decellularized Extracellular Matrix
• Cattle
• Deoxycholic Acid
• Extracellular Matrix
• Rats
• Sheep

• 2017.0363 Knut och Alice Wallenbergs Stiftelse
• Hjalmar Svensson Research Foundation
• 2024-03487 Swedish Research Council
• 2020-09 Jane and Dan Olsson Foundation for Science
• ALFGBG-965535 ALF agreement
• Knut och Alice Wallenbergs Stiftelse
• Swedish Research Council

• evolution of birth
• feto-pelvic disproportion
• maternal mortality
• primates

• Animals
• Female
• Pregnancy
• Macaca fuscata
• Parturition/physiology
• Maternal Mortality
• Animals, Newborn
• Humans
• Head/anatomy & histology
• Skull
• Macaca
• Japan/epidemiology

• V-826 Austrian Science Fund (FWF)

• Animal model
• Biomaterials
• Graphene
• Pelvic mesh
• Polypropylene
• Preclinical trials

• Animals
• Pelvic Organ Prolapse/surgery
• Surgical Mesh
• Female
• Disease Models, Animal
• Rats
• Humans
• Sheep
• Materials Testing
• Models, Animal

• animal model
• biomaterials
• chitosan haemostatic agent
• ovine
• pelvic organ prolapse

• Sheep
• Animals
• Female
• Humans
• Chitosan
• Interleukin-10
• Interleukin-6
• Polypropylenes
• Prospective Studies
• Hemostatics
• Pelvic Organ Prolapse/surgery
• Biocompatible Materials/pharmacology
• Inflammation
• Vagina

• LIDER/21/0120/L-10/18/NCBR/2019 National Centre for Research and Development

• Animal model
• Constipation
• Pelvic organ prolapse
• Stress urinary incontinence
• Urinary retention

• Female
• Animals
• Rats
• Pelvic Organ Prolapse/complications
• Pelvic Organ Prolapse/surgery
• Urinary Incontinence
• Cervix Uteri
• Vagina
• Collagen
• Urinary Incontinence, Stress/surgery

• Absorbable scaffold
• Biomechanics
• Long-term host response
• Pelvic organ prolapse
• Poly-4-hydroxybutyrate
• Vaginal surgery

• Female
• Humans
• Pelvic Organ Prolapse/surgery
• Pelvic Organ Prolapse/metabolism
• Vagina/surgery
• Vagina/metabolism
• Collagen/metabolism
• Absorbable Implants
• Wound Healing
• Surgical Mesh/adverse effects

• Tepha Inc.

• chhaupadi
• menstratution
• nulliparous
• pelvic floor
• prolapse

• Loma Linda University
• National Health and Medical Research Council

• atrophy
• ewe
• genitourinary syndrome of menopause
• model
• ovariectomy

• Sheep
• Humans
• Female
• Animals
• Ovariectomy/adverse effects
• Menopause
• Models, Animal
• Vagina/surgery
• Iatrogenic Disease
• Glycogen

• hydrogels
• nanofibers
• pelvic organ prolapse
• tissue engineering
• uterosacral ligaments

• Female
• Animals
• Rats
• Hydrogels/pharmacology
• Uterus
• Pelvic Organ Prolapse/surgery
• Ligaments
• Treatment Outcome

• basic fibroblast growth factor
• connective tissue growth factor
• epidermal growth factor
• growth factors
• pelvic organ prolapse
• wound healing

• Animals
• Female
• Wound Healing
• Collagen/pharmacology

• aging
• animal models
• connective tissue
• pelvic floor disfunction
• pelvic organ prolapse

There are many situations where preclinical models of the human vagina would be valuable for in vitro studies into the pathophysiology of vaginally transmitted diseases, microbicide efficacy, irritability testing, and particularly, for assessing materials to be inserted in the vagina for support of the pelvic floor. The aim of this study is to develop a physiologically relevant, low cost, and ethically suitable model of the vagina using sheep vaginal tissue (SVT) to reduce the need for animal testing in gynecological research.

Tissue‐engineered (TE) vaginal models were developed by culturing primary vaginal epithelial cells and vaginal fibroblasts, isolated from the native SVTs on decellularized sheep vaginal matrices at an air–liquid interface. Morphological analyses of the models were conducted by performing hematoxylin and eosin staining and further characterization was done by immunohistofluorescence (IHF) of structural proteins and cytokeratins.

Histological analysis of the models revealed a gradual formation of a stratified epithelium on our decellularized matrices and cell metabolic activity remained high for 21 days as measured by the resazurin assay. Our models showed a dose‐dependent response to estradiol‐17β [E₂] with an increase in the vaginal epithelium thickness and cellular proliferation under higher E₂ concentrations (100–400 pg/ml). The physiological relevance of these results was confirmed by the IHF analysis of Ki67, and cytokeratins 10 and 19 expression.

In this study, we have developed an estradiol‐responsive TE vaginal model that closely mimics the structural and physiological properties of the native SVT.

• Midurethral sling
• Preclinical testing
• Sheep model
• Stress urinary incontinence

• Humans
• Female
• Animals
• Sheep
• Suburethral Slings
• Urinary Incontinence, Stress/surgery
• Vagina/surgery
• Urologic Surgical Procedures/methods
• Polypropylenes

• R21 HD095439 NICHD NIH HHS
• T32 AR007505 NIAMS NIH HHS
• TL1 DK132770 NIDDK NIH HHS

• Fibulin-3
• Fibulin-5
• Lysyl oxidase 1
• Mouse knockout model
• Pelvic organ prolapse

• Amino Acid Oxidoreductases/genetics
• Animals
• Disease Models, Animal
• Extracellular Matrix Proteins/genetics
• Female
• Mice
• Mice, Knockout
• Pelvic Floor
• Pelvic Organ Prolapse
• Pregnancy

• IK6 RX003843 RRD VA
• R21 HD095521 NICHD NIH HHS
• R21 HD095234 NICHD NIH HHS

• bacterial vaginosis
• gender diverse
• microbiome
• neovagina
• transgender
• vagina

Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes impaired collagen metabolism that affects the mechanical properties of the tissue. Ideal surgical repair, either native tissue repair or POP surgery using an implant, aims to create a functional pelvic floor that is load-bearing, activating fibroblasts to regulate collagen metabolism without creating fibrotic tissue. Fibroblast function plays a crucial role in the pathophysiology of POP by directly affecting the connective tissue quality. On the other hand, fibroblasts determine the success of the POP treatment, as the fibroblast-to-(myo)fibroblast transition is the key event during wound healing and tissue repair. In this review, we aim to resolve the question of “cause and result” for the fibroblasts in the development and treatment of POP. This review may contribute to preventing the development and progress of anatomical abnormalities involved in POP and to optimizing surgical outcomes.

• Female
• Humans
• Myofibroblasts/metabolism
• Myofibroblasts/pathology
• Pelvic Floor/pathology
• Pelvic Organ Prolapse/metabolism
• Pelvic Organ Prolapse/pathology
• Pelvic Organ Prolapse/therapy

Pelvic organ prolapse is a worldwide health problem to elderly women. Understanding its pathogenesis and an ideal animal model are crucial to developing promising treatments. The present study aimed to investigate new clinical significance and detailed mechanism of pelvic organ prolapse by comparing the structural, functional and molecular dysfunctions of pelvic organ prolapse in patient and Loxl1 deficient mice. Our results showed that human vagina tissues from prolapsed site showed disarranged collagen and elastic fibers compared with the non-prolapse tissue. A gene ontology (GO) analysis of differentially expressed genes revealed molecular changes mainly related to inflammatory response and extracellular matrix (ECM) organization. While the mice lacking Loxl1 developed stable POP phenotype and disordered ECM structure in histology. Such Loxl1 knockout mice exhibited a significantly urinary dysfunction and decreased mechanical properties of the pelvic floor tissues, implying that POP in human condition might be induced by progressively decreased mechanics of pelvic tissues following ECM catabolism. Similarly, we not only identified significant up-regulated ECM catabolism processes and down-regulated ECM synthesis processes, but also characterized high level of inflammatory response in vagina tissue of the Loxl1 deficient mice. Thus, all these pathological changes in the POP mice model was consistent with those of the clinical elderly patients. These findings provide new insight into remodeling of POP by LOXL1 regulation and be of great importance to develop combination treatments of ECM metabolism and inflammation regulation strategy.

To evaluate the host‐ and biomechanical response to a fully absorbable poly‐4‐hydroxybutyrate (P4HB) scaffold in comparison with the response to polypropylene (PP) mesh.

In vivo animal experiment.

KU Leuven Center for Surgical Technologies.

Fourteen parous female Mule sheep.

P4HB scaffolds were surgically implanted in the posterior vaginal wall of sheep. The comparative PP mesh data were obtained from an identical study protocol performed previously.

Gross necropsy, host response and biomechanical evaluation of explants, and the in vivo P4HB scaffold degradation were evaluated at 60‐ and 180‐days post‐implantation. Data are reported as mean ± standard deviation (SD) or standard error of the mean (SEM).

Gross necropsy revealed no implant‐related adverse events using P4HB scaffolds. The tensile stiffness of the P4HB explants increased at 180‐days (12.498 ± 2.66 N/mm SEM [p =0.019]) as compared to 60‐days (4.585 ± 1.57 N/mm) post‐implantation, while P4HB degraded gradually. P4HB scaffolds exhibited excellent tissue integration with dense connective tissue and a moderate initial host response. P4HB scaffolds induced a significantly higher M2/M1 ratio (1.70 ± 0.67 SD, score 0–4), as compared to PP mesh(0.99 ± 0.78 SD, score 0–4) at 180‐days.

P4HB scaffold facilitated a gradual load transfer to vaginal tissue over time. The fully absorbable P4HB scaffold, in comparison to PP mesh, has a favorable host response with comparable load‐bearing capacity. If these results are also observed at longer follow‐up in‐vivo, a clinical study using P4HB for vaginal POP surgery may be warranted to demonstrate efficacy.

Degradable vaginal P4HB implant might be a solution for treatment of POP.

Degradable vaginal P4HB implant might be a solution for treatment of POP.

• biomechanics
• degradable scaffold
• host response
• pelvic organ prolapse
• poly-4-hydroxybutyrate
• vaginal surgery

Cellular therapy is an emerging field in clinical and personalised medicine. Many adult mesenchymal stem/progenitor cells (MSC) or pluripotent derivatives are being assessed simultaneously in preclinical trials for their potential treatment applications in chronic and degenerative human diseases. Endometrial mesenchymal stem/progenitor cells (eMSC) have been identified as clonogenic cells that exist in unique perivascular niches within the uterine endometrium. Compared with MSC isolated from other tissue sources, such as bone marrow and adipose tissue, eMSC can be extracted through less invasive methods of tissue sampling, and they exhibit improvements in potency, proliferative capacity, and control of culture-induced differentiation. In this review, we summarize the potential cell therapy and tissue engineering applications of eMSC in pelvic organ prolapse (POP), emphasising their ability to exert angiogenic and strong immunomodulatory responses that improve tissue integration of novel surgical constructs for POP and promote vaginal tissue healing.

• MSC
• biomaterials
• bioscaffolds
• cell culture
• electrospinning
• endometrium
• menstrual blood
• nanofiber
• perivascular MSC
• tissue engineering

Pelvic organ prolapse (POP) decreases quality of life for many women, but its pathophysiology is poorly understood. We have previously shown that Lysyl oxidase‐like 1 knockout (Loxl1 KO) mice reliably prolapse with age and increased parity, similar to women. Both this model and clinical studies also indicate that altered elastin metabolism in pelvic floor tissues plays a role in POP manifestation, although it is unknown if this is a cause or effect. Using Loxl1 KO mice, we investigated the effects of genetic absence of Loxl1, vaginal parity, and presence of POP on the expression of genes and proteins key to the production and regulation of elastic matrix. Cultured cells isolated from vaginal explants of mice were assayed with Fastin for elastic matrix, as well as RT‐PCR and Western blot for expression of genes and proteins important for elastin homeostasis. Elastin synthesis significantly decreased with absence of LOXL1 and increased with parity (p < .001), but not with POP. Cells from prolapsed mice expressed significantly decreased MMP‐2 (p < .05) and increased TIMP‐4 (p < .05). The results suggest changes to elastin structure rather than amounts in prolapsed mice as well as poor postpartum elastin turnover, resulting in accumulation of damaged elastic fibers leading to abnormal tropoelastin deposition. POP may thus, be the result of an inability to initiate the molecular mechanisms necessary to clear and replace damaged elastic matrix in pelvic floor tissues after vaginal birth.

• cross-link
• extracellular matrix
• matrix metalloproteinase
• tissue inhibitors of matrix metalloproteinase
• tropoelastin

Uterine factor infertility was considered incurable until recently when we reported the first successful live birth after uterus transplantation. However, risky donor surgery and immunosuppressive therapy are factors that may be avoided with bioengineering. For example, transplanted recellularized constructs derived from decellularized tissue restored fertility in rodent models and mandate translational studies. In this study, we decellularized whole sheep uterus with three different protocols using 0.5% sodium dodecyl sulfate, 2% sodium deoxycholate (SDC) or 2% SDC, and 1% Triton X-100. Scaffolds were then assessed for bioactivity using the dorsal root ganglion and chorioallantoic membrane assays, and we found that all the uterus scaffolds exhibited growth factor activity that promoted neurogenesis and angiogenesis. Extensive recellularization optimization was conducted using multipotent sheep fetal stem cells and we report results from the following three in vitro conditions; (a) standard cell culturing conditions, (b) constructs cultured in transwells, and (c) scaffolds preconditioned with matrix metalloproteinase 2 and 9. The recellularization efficiency was improved short-term when transwells were used compared with standard culturing conditions. However, the recellularization efficiency in scaffolds preconditioned with matrix metalloproteinases was 200–300% better than the other strategies evaluated herein, independent of decellularization protocol. Hence, a major recellularization hurdle has been overcome with the improved recellularization strategies and in vitro platforms described herein. These results are an important milestone and should facilitate the production of large bioengineered grafts suitable for future in vivo applications in the sheep, which is an essential step before considering these principles in a clinical setting.

The aims of this study were to evaluate the feasibility of the New Zealand White (NZW) rabbit for studying implanted biomaterials in pelvic reconstructive surgery; and to compare the occurrence of graft-related complications of a commercial polypropylene (PP) mesh and new developed human dermal matrix implanted at vaginal and abdominal level. 20 white female NZW rabbits were randomized into two groups, experimental group (human acellular dermal matrices-hADM-graft) and control group (commercial PP graft). In each animal, grafts were surgically implanted subcutaneously in the abdominal wall and in the vaginal submucosa layer for 180 days. The graft segments were then removed and the surgical and clinical results were analyzed. The main surgical challenges during graft implantation were: (a) an adequate vaginal exposure while maintaining the integrity of the vaginal mucosa layer; (b) to keep aseptic conditions; (c) to locate and dissect the breast vein abdominal surgery; and (d) to withdraw blood samples from the ear artery. The most abnormal findings during the explant surgery were found in the PP group (33% of vaginal mesh extrusion) in comparison with the hADM group (0% of vaginal graft extrusion), p = 0.015. Interestingly, macroscopic observation showed that the integration of the vaginal grafts was more common in the hADM group (40%) than in the PP group, in which the vaginal mesh was identified in 100% of the animals (p = 0.014). The NZW rabbit is a good model for assessing materials to be used as grafts for pelvic reconstructive surgery and vaginal surgery. Animals are easily managed during the procedures, including surgical intervention and vaginal mucosa approach. Additionally, hADM is associated with fewer clinical complications, as well as better macroscopic tissue integration, compared to PP mesh.

Uterus tissue engineering may dismantle limitations in current uterus transplantation protocols. A uterine biomaterial populated with patient-derived cells could potentially serve as a graft to circumvent complicated surgery of live donors, immunosuppressive medication and rejection episodes. Repeated uterine bioengineering studies on rodents have shown promising results using decellularised scaffolds to restore fertility in a partially impaired uterus and now mandate experiments on larger and more human-like animal models. The aim of the presented studies was therefore to establish adequate protocols for scaffold generation and prepare for future in vivo sheep uterus bioengineering experiments. Three decellularisation protocols were developed using vascular perfusion through the uterine artery of whole sheep uteri obtained from slaughterhouse material. Decellularisation solutions used were based on 0.5% sodium dodecyl sulphate (Protocol 1) or 2% sodium deoxycholate (Protocol 2) or with a sequential perfusion of 2% sodium deoxycholate and 1% Triton X-100 (Protocol 3). The scaffolds were examined by histology, extracellular matrix quantification, evaluation of mechanical properties and the ability to support foetal sheep stem cells after recellularisation. We showed that a sheep uterus can successfully be decellularised while maintaining a high integrity of the extracellular components. Uteri perfused with sodium deoxycholate (Protocol 2) were the most favourable treatment in our study based on quantifications. However, all scaffolds supported stem cells for 2 weeks in vitro and showed no cytotoxicity signs. Cells continued to express markers for proliferation and maintained their undifferentiated phenotype. Hence, this study reports three valuable decellularisation protocols for future in vivo sheep uterus bioengineering experiments.

• bioengineering
• decellularisation
• foetal cells
• ovine
• recellularisation
• sheep
• uterus

• Animals
• Collagen Type I/metabolism
• Collagen Type III/metabolism
• Cytokines/metabolism
• Female
• Hysterectomy
• Macrophages/metabolism
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/metabolism
• Models, Animal
• Ovariectomy
• Polycarboxylate Cement
• Rats, Sprague-Dawley
• Surgical Mesh
• Urethane
• Vagina/metabolism
• Rats

• cysts
• ovariohysterectomy
• prolapse
• uterus

• Fatigue
• Histology
• Microscopic damage
• Pelvic muscle injury
• Pubovisceral muscle
• Tissue fatigue damage

• MenSC
• cell therapy
• culture expansion
• eMSC
• endometrium
• immunomodulation
• menstrual blood
• perivascular MSC

• animal models
• pelvic organ prolapse
• simulated vaginal delivery
• urinary incontinence

• biomechanics
• inflammatory response
• lightweight titanium polypropylene mesh
• polypropylene mesh
• sheep model

• midurethral sling
• pelvic organ prolapse
• pessary
• urinary incontinence
• vaginal mesh

• Minimally invasive
• Pelvic organ prolapse
• Sacrospinous ligament
• Vaginal vault suspension

An excessive foreign body response (FBR) has contributed to the adverse events associated with polypropylene mesh usage for augmenting pelvic organ prolapse surgery. Consequently, current biomaterial research considers the critical role of the FBR and now focuses on developing better biocompatible biomaterials rather than using inert implants to improve the clinical outcomes of their use. Tissue engineering approaches using mesenchymal stem cells (MSCs) have improved outcomes over traditional implants in other biological systems through their interaction with macrophages, the main cellular player in the FBR. The unique angiogenic, immunomodulatory and regenerative properties of MSCs have a direct impact on the FBR following biomaterial implantation. In this review, we focus on key aspects of the FBR to tissue-engineered MSC-based implants for supporting pelvic organs and beyond. We also discuss the immunomodulatory effects of the recently discovered endometrial MSCs on the macrophage response to new biomaterials designed for use in pelvic floor reconstructive surgery. We conclude with a focus on considerations in biomaterial design that take into account the FBR and will likely influence the development of the next generation of biomaterials for gynaecological applications.

• M1
• M2
• biomaterials
• foreign body reaction
• immunomodulation
• macrophages
• mesenchymal stem cells
• pelvic organ prolapse
• tissue engineering

• Inflammation
• Mesh
• Oxidative stress
• Platelet-rich plasma
• Rabbit
• Tissue adhesion

• Bacterial cellulose
• Biomechanics
• Histologic biocompatibility
• Polypropylene mesh
• Sheep model

• Animals
• Cellulose
• Female
• Gynecologic Surgical Procedures/instrumentation
• Pelvic Organ Prolapse/surgery
• Sheep
• Surgical Mesh
• Vagina/surgery

• 81771561 National Natural Science Foundation of China
• XDA16010102 Strategic Priority Research Program of the Chinese Academy of Sciences

• Biomechanical properties
• Genetic algorithm
• Histology
• Hyperelastic model
• Vaginal tissue

• Animal model
• Biomechanical properties
• Histological components
• Pelvic floor
• Pregnancy
• Soft tissues

• Animals
• Biomechanical Phenomena/physiology
• Cervix Uteri/anatomy & histology
• Collagen/metabolism
• Elasticity
• Elastin
• Female
• Pelvic Organ Prolapse
• Pelvis/anatomy & histology
• Pregnancy
• Pregnancy, Animal/physiology
• Rectum/anatomy & histology
• Sheep, Domestic/anatomy & histology
• Tensile Strength
• Urinary Bladder/anatomy & histology
• Vagina/anatomy & histology

• birth injury
• leak point pressure
• neurotrophin
• pudendal nerve
• urinary incontinence
• urodynamics

• Biaxial testing
• Digital image correlation
• Elasticity
• Uterosacral ligament
• Viscoelasticity

• Animals
• Cercocebus
• Female
• Monkey Diseases/pathology
• Monkey Diseases/surgery
• Parity
• Pelvic Floor Disorders/pathology
• Pelvic Floor Disorders/surgery
• Pelvic Floor Disorders/veterinary
• Postoperative Complications/pathology
• Postoperative Complications/surgery
• Postoperative Complications/veterinary
• Rectal Prolapse/pathology
• Rectal Prolapse/surgery
• Rectal Prolapse/veterinary
• Treatment Outcome

• Collagen
• Inflammation
• Platelet-Rich Plasma