Graciela Morales
email: graciela.morales@ciqa.edu.mx

Heriberto Rodríguez-Tobías

Victoria Padilla-Gainza

Karen Lozano

Daniel Grande

Harnessing

Harnessing the Potential of Fibrous Polyester Composites Meant for Bioactive Medical Devices

Keywords: Electrospinning, electrospraying, forcespinning, polyesters, bioactive composites

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Fibrous scaffolds for biomedical applications

During the past decades, scientific advances in molecular and cellular biology, as well as a progressive understanding of tissue regeneration and wound healing processes have stimulated the development of a novel and multidisciplinary field of research known as Tissue Engineering. This research field applies engineering and life science to design biodegradable and bioactive materials with specific structural properties that allow for the simulation of the extracellular matrix (ECM), with the purpose of promoting its regeneration or function [START_REF] Dlaska | Clinical Translation in Tissue Engineering-The Surgeon's View[END_REF][START_REF] Berthiaume | Tissue engineering and regenerative medicine: history, progress, and challenges[END_REF]. Most often, the ultimate goal is implantation in the body to repair an injury or replace the function of a damaged organ. Critical functions can be structural (bone, cartilage), supportive, transport (skin, blood vessels), secretory, and biochemical (liver and pancreas). The concept of scaffold in tissue engineering is to mimic the functions of native ECM [START_REF] Nair | Biodegradable polymers as biomaterials[END_REF]. Therefore, the properties of engineered scaffolds are related to the ECM functions in native tissues and are connected with their structural, biological, and mechanical features [START_REF] Chung | Fibrous Scaffolds for Tissue Engineering Applications[END_REF].

The morphological features associated with fibrous 3D materials closely mimic the natural microenvironment constituted of fibrous proteins present in native ECM [START_REF] Cao | The application of nanofibrous scaffolds in neural tissue engineering[END_REF]. In combination with their porous nature and high surface area to volume ratio, these qualities have made micro-/nano-fibrous scaffolds attractive not only from the academic point of view but also in terms of applied science to be used in tissue engineering applications. In this sense, they have been used as supports for drug delivering agents, dressings for wound healing, and porous scaffolds for the regeneration of tissues, including skin, blood vessels, nerves, tendons, bone, and cartilage [START_REF] Onuwaje | Three-dimensional culture systems in central nervous system research[END_REF][START_REF] Kumbar | Electrospun nanofiber scaffolds: engineering soft tissues[END_REF][START_REF] Kurimoto | Fibrous Materials[END_REF]. In the field of bone tissue regeneration, efforts are being made to address diseases, such as osteogenesis imperfecta, osteoarthritis, osteomyelitis, osteoporosis, traumatic injuries, and orthopedic surgeries (i.e., total joint arthroplasty, arthrodesis of the spine, fixation of implants, etc.). These efforts have produced a remarkable clinical and economic impact in the treatment of bone defects. For this reason, the demand for bone implants has been increasing exponentially, until it has become the second tissue with the highest requirement for implants [START_REF] Oryan | Bone regenerative medicine: Classic options, novel strategies, and future directions[END_REF][START_REF] Porter | Bone tissue engineering: A review in bone biomimetics and drug delivery strategies[END_REF].

Polymer matrices

A polymer matrix for medical applications has to be categorized as a biomaterial, i.e. a material able to interact with a biological system to perform a specific action of regeneration or replacement of a tissue, organ, or body function [START_REF] Williams | The Williams dictionary of biomaterials[END_REF]. A biomaterial has to be biocompatible, namely, it must have the ability to develop, with an appropriate host, a specific response without causing a cytotoxic effect. There are a wide variety of factors that affect the tissue response in contact with an implant and are mostly related to its biological and physicochemical properties, as well as to its shape and structure [START_REF] Nair | Biodegradable polymers as biomaterials[END_REF]. Some of the most important properties that should define a biodegradable material are listed below [START_REF] Lloyd | Interfacial bioengineering to enhance surface biocompatibility[END_REF]:

• Prevent a sustained inflammatory or toxic response after implantation in the body.

• Possess an acceptable duration of action, which should coincide with the healing or regeneration process. • Possess mechanical properties appropriate for the indicated application, where the variation of mechanical properties with degradation should be compatible with the healing or regeneration process. • Provide non-toxic by-products and those should be capable of being metabolized and eliminated by the body. • Present feasible processability for the intended application.

Polymeric biomaterials are currently used for biomedical applications as their mechanical and degradation properties are suitable for mimicking various tissues. Especially, scaffolds based on polyesters (poly(-caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PLG), poly(lactic-co-glycolic acid), and poly(hydroxyalcanoate)s (PHAs) among others) have gained increasing attention given their biodegradability, biocompatibility, and ease of processing [START_REF] Bhattarai | A review on properties of natural and synthetic based electrospun fibrous materials for bone tissue engineering[END_REF].

Production techniques for fibrous scaffolds

Fiber production techniques

Several methods have already been applied for generating micro-/nano-fiber, such as melt-blown [START_REF] Ellison | Melt blown nanofibers: Fiber diameter distributions and onset of fiber breakup[END_REF], three-dimensional (3D) printing [START_REF] Song | Surface-embedded stretchable electrodes by direct printing and their uses to fabricate ultrathin vibration sensors and circuits for 3D structures[END_REF][START_REF] Liu | Ultrastretchable and self-healing double-network hydrogel for 3D printing and strain sensor[END_REF], phase separation [START_REF] Zhang | Recent development of polymer nanofibers for biomedical and biotechnological applications[END_REF], template synthesis [START_REF] Dlaska | Clinical Translation in Tissue Engineering-The Surgeon's View[END_REF], and self-assembly [START_REF] Berthiaume | Tissue engineering and regenerative medicine: history, progress, and challenges[END_REF][START_REF] Chen | Electrospun polymer nanofibers decorated with noble metal nanoparticles for chemical sensing[END_REF]. However, the selection of materials that can be produced by these methods is restricted, limiting their practical application [START_REF] Park | Enhanced mechanical properties of multilayer nano-coated electrospun nylon 6 fibers via a layer-by-layer self-assembly[END_REF]. On the contrary, electrospinning [START_REF] Tiwari | An enzyme-free highly glucose-specific assay using self-assembled aminobenzene boronic acid upon polyelectrolytes electrospun nanofibers-mat[END_REF][START_REF] Villarreal-Gómez | Electrospinning as a powerful technique for biomedical applications: a critically selected survey[END_REF][START_REF] Mccullen | Morphological, electrical, and mechanical characterization of electrospun nanofiber mats containing multiwalled carbon nanotubes[END_REF] is an extensively studied and widely applied method for nanofiber production from a remarkable range of organic and inorganic materials. Compared with traditional nanofiber preparation technologies, electrospinning can produce fibers with high specific surface areas, uniform pore sizes, and high porosity, which significantly improves the performance of nanofibers. In terms of adaptability, the versatility of the electrospinning technique has allowed for producing a vast range of materials. Moreover, it enables the fiber diameter to be adjusted from nano-to micrometers [START_REF] Taepaiboon | Vitamin-loaded electrospun cellulose acetate nanofiber mats as transdermal and dermal therapeutic agents of vitamin A acid and vitamin E[END_REF].

In general, spinning technologies for the production of fibers have been based on an extrusion process, which allows for the continuous production of materials with one or more filaments. The resulting product exhibits different properties depending on the used process and selected parameters [START_REF] Deitzel | The effect of processing variables on the morphology of electrospun nanofibers and textiles[END_REF]. Polymeric fibers can be obtained from melts, solutions, and emulsions. The polymer melt process offers unique advantages as it avoids the use of solvents and possesses economic advantages given the lack of solvent recovery steps. On the other hand, using solvent-based methods possesses the advantage of increasing the selection of materials to be used while also offering lower energy consumption and the potential to develop smaller fiber diameters. Emulsion spinning is a method that is selected to produce multiphase polymer fibers with different morphologies, active component encapsulations, etc [START_REF] Wang | Microfiltration performance of electrospun nanofiber membranes with varied fiber diameters and different membrane porosities and thicknesses[END_REF][START_REF] Persano | Industrial upscaling of electrospinning and applications of polymer nanofibers: A review[END_REF].

Electrospinning typically consists of a syringe and needle through which a polymer solution is passed, and the flow is controlled by a metering pump. A power source applies several tens of kilovolts on the needle, and therefore on the polymer solution.

The high applied voltage causes a significant density of charges on the protruding polymer droplet (Taylor cone) at the needle tip, to a point where the repulsive forces of the charges overcome the surface tension and a jet of polymer is generated that goes to the grounded collector, the solvent is evaporated during the path from the needle tip to the collector. The final morphology of the materials depends not only on polymer molar mass, viscoelasticity, electrical conductivity, and surface tension [START_REF] Liu | Tunable surface morphology of electrospun PMMA fiber using binary solvent[END_REF], but also on the voltage applied during electrospinning, the distance from the tip to the collector [START_REF] Lee | Continuous bundles of aligned electrospun PAN nano-fiber using electrostatic spiral collector and converging coil[END_REF], and the feeding speed [START_REF] Tiwari | Bimodal fibrous structures for tissue engineering: Fabrication, characterization and in vitro biocompatibility[END_REF]. By adjusting these parameters and determining the appropriate values, electrospun micro/nanofibers with desirable morphologies can be obtained.

On the other hand, electrospinning and electrospraying are two electrohydrodynamic processes in which a suspension or solution can be spun or sprayed upon applying a high direct current voltage to generate fibers or particles, respectively. However, when nanostructures have to be incorporated into fibrous materials, it is difficult to uniformly disperse and distribute fillers within the electrospun fibers. In this regard, electrospraying is a flexible and effective method for fabricating nano-/micro-structures composites by spraying a solution in the form of droplets or beads. The simultaneous electrospinning and electrospraying technique is a combined strategy that has typically been used in which fibers are formed by electrospinning, while nanoparticles are deposited on the fiber surfaces through electrospraying.

Despite the versatility and effectiveness of electrospinning, there are still some challenges that need to be addressed, including the accurate and reproducible control of fiber morphology, structure, and uniformity as well as the slow collection speed, the need for a high voltage electric field, the sensitivity in the conductivity of the solution, and the difficulty in manufacturing three-dimensional (3D) structures. There are some strategies that allow for expanding the versatility of electrospinning [START_REF] Weitz | Polymer Nanofibers via Nozzle-Free Centrifugal Spinning[END_REF][START_REF] Arumuganathar | Living scaffolds (specialized and unspecialized) for regenerative and therapeutic medicine[END_REF]; however, there is still a need for techniques allowing for easy and fast generation of sub-micron polymeric fibers [START_REF] Badrossamay | Nanofiber assembly by rotary jet-spinning[END_REF].

A new process called Forcespinning® has been developed to obtain nanofibers from a wide variety of polymers, at a high production speed. This method uses centrifugal force, as opposed to the electrostatic force used in the electrospinning technique. Furthermore, through Forcespinning®, the fiber can be obtained from a polymer solution or from a molten polymer [START_REF] Sarkar | Electrospinning to Forcespinning[END_REF]. Conductivity and/or electrostatic charges are not relevant parameters for the properties of the precursor solution; therefore, the spectrum of materials that can be spun is broader. [START_REF] Sebe | Polymer structure and antimicrobial activity of polyvinylpyrrolidone-based iodine nanofibers prepared with high-speed rotary spinning technique[END_REF] One of the important features of the centrifugal spinning process is its high production speed. The average production rate is 50 g/h and meters per minute on industrial scale systems [START_REF] Sebe | Polymer structure and antimicrobial activity of polyvinylpyrrolidone-based iodine nanofibers prepared with high-speed rotary spinning technique[END_REF][START_REF] Padron | Production and characterization of hybrid BEH-PPV/PEO conjugated polymer nanofibers by Forcespinning[END_REF], which is at least two orders of magnitude higher than typical laboratory-scale electrospinning processes. This advantage makes this centrifugal spinning system a low-cost, large-scale approach to deliver practical applications of fiber-based systems [START_REF] Zhang | Centrifugal Spinning: An Alternative Approach to Fabricate Nanofibers at High Speed and Low Cost[END_REF].

During fiber formation, the polymeric fluid is placed in the spinneret which contains multiple nozzles around the side walls. When the rotation speed reaches a critical value, the centrifugal force overcomes the surface tension of the polymer fluid (polymer solution or molten polymer), causing fine streams of polymer fluid from the tips of the spin head nozzles. The centrifugal force together with the frictional force of the air elongate the liquid thread and lead to the nanofiber formation. The material is deposited on the surface of a collector, forming a non-woven mesh of nanofibers. The polymer concentration and the associated viscosity of the precursory solution, temperature, the rotational speed of the spinneret and the collection distance are parameters influencing the morphology of centrifugally spun fibers.

Design consideration of fibrous scaffolds

For a 3D scaffold construction, the mass transport is an important factor to consider.

Oxygen and nutrient delivery, waste removal, cell migration and penetration are some of the processes involved in a natural ECM environment. These processes are associated with the morphological architecture of the scaffold, which is mainly characterized by its pore size, total porosity, pore interconnectivity and surface area [START_REF] Karande | Diffusion in musculoskeletal tissue engineering scaffolds: Design issues related to porosity, permeability, architecture, and nutrient mixing[END_REF]. Pore size controls the tissue in-growth and the internal surface area available for cell attachment. If pores are too small for the cell type of interest, they could be blocked by cells preventing cellular penetration, extracellular matrix production and vascularization into the internal region of the scaffold, where diffusion limitations have been one of the mayor obstacles in the production of 3D engineered tissues [START_REF] Yang | The design of scaffolds for use in tissue engineering. Part I. traditional factors[END_REF]. There is controversial information about the optimal pore size needed for cell growth and tissue formation. It has been reported optimal sizes between 5-15 µm for fibroblast, 20-125 µm for keratinocytes and, 200-400 µm for osteoblasts [START_REF] Salgado | Bone tissue engineering: State of the art and future trends[END_REF][START_REF] Silva | The effect of anisotropic architecture on cell and tissue infiltration into tissue engineering scaffolds[END_REF][START_REF] Itälä | Pore diameter of more than 100 microm is not requisite for bone ingrowth in rabbits[END_REF]. Additionally, highly porous structures fully interconnected with a large surface-to-area volume ratio are required to allow for cell ingrowth and facilitate neovascularization. An adequate diffusion and enough surface area for cell-polymer matrix interactions have been found in porosity ratios higher than 90%. However, high porosity has a negative effect on the mechanical strength of a scaffold [START_REF] Liu | Effects of pore size on the mechanical biological properties of stereolithographic 3D printed HAp bioceramic scaffold[END_REF][START_REF] Van Tienen | Tissue ingrowth and degradation of two biodegradable porous polymers with different porosities and pore sizes[END_REF]. Therefore, the scaffold design should be optimized to get the maximum total porosity with appropriate mechanical needs based on the particular application.

Moreover, fiber diameter also plays an important role in cell behavior. Nanofiber scaffolds have resulted suitable for enhancing cell differentiation, adhesion, and proliferation [START_REF] Rampichová | Elastic three-dimensional poly (ε-caprolactone) nanofibre scaffold enhances migration, proliferation and osteogenic differentiation of mesenchymal stem cells[END_REF]. However, the small pore sizes, associated with nanoscale fibrous scaffold, limit cell migration, thus producing a cell monolayer on the scaffold surface.

On the other hand, microfiber scaffolds could be potentially advantageous due to their large pore sizes, enabling cellular infiltration and nutrient diffusion. These results suggest that a multiscale scaffold should be ideal to promote an accurate environment for tissue regeneration. Pham et al. [START_REF] Pham | Electrospun poly (ε-caprolactone) microfiber and multilayer nanofiber/microfiber scaffolds: Characterization of scaffolds and measurement of cellular infiltration[END_REF] developed a bimodal scaffold using a sequential electrospinning technique producing multiscale layers of different morphologies. They evaluated the fiber diameter effect on the cell morphology, observing a larger number of cells (mesenchymal cells) spread throughout the nanofiber membrane. Additionally, the authors obtained a significant reduction in infiltration distance of cells when the nanofiber layer increased compared with other systems. Shalumon et al. [START_REF] Shalumon | High thick layer-by-layer 3D multiscale fibrous scaffolds for enhanced cell infiltration and it's potential in tissue engineering[END_REF] produced a 3D PLA multiscale fibrous scaffold using a layer by layer method combining nanoand micro-fibers in an optimum ratio. They found cell (MG63) penetration through the macropores and a well spread by taking advantage of available nanofibers within them. Deepthi et al. [START_REF] Deepthi | Chitosan-hyaluronic acid hydrogel coated poly(caprolactone) multiscale bilayer scaffold for ligament regeneration[END_REF] designed an electrospun multiscale fibrous scaffold combining aligned and non-aligned microfibers. They used a dual electrospinning setup producing random PCL nanofibers and aligned microfibers at the same time. Their results showed improvement in cell attachment (Rabbit ligament fibroblast) and infiltration within the random microfiber systems.

In the case of composite fibrous materials, the concentration and morphology of microor nanoparticles incorporated to the polymeric matrix have to be considered as main factors affecting the morphology and final performance of the obtained composites, which will be addressed in the following sections.

Composite Fibrous scaffolds for biomedical applications

Tailoring the antimicrobial properties of fibrous polyester composites

Materials based on polymer fibers have suitable morphological characteristics that make them attractive for applications in the area of tissue engineering since they promote cell adhesion, proliferation, and migration, which are necessary mechanisms for tissue regeneration. However, their morphological characteristics could also promote the adhesion of bacteria (cells of pathogenic microorganisms), eventually leading to the formation of a biofilm.

In this context, composites materials based on polymeric matrices and metal oxide antimicrobial nanoparticles, have been extensively investigated over the last decade.

The resulting findings have evidenced the interactions between the composite materials and microorganisms, which have to be circumvented to minimize the adhesion and proliferation of the pathogenic microorganism. As a summary, a sequence of interactions is explained below:

i.Firstly, bacteria are transported near the fibrous material surface by physical forces, such as gravitational and Brownian forces, or by protein-based organelles called flagella; ii.Then, the attraction between microorganism and fiber surface takes place by physicochemical interactions (Van der Waals and hydrogen bond) or chemical reactions, which can lead to reversible and irreversible adhesion, respectively; iii.After anchoring on the material surface, the microorganism synthesizes the biofilm matrix which protects and facilitates its proliferation. iv.Finally, biofilm maturation is achieved and subsequent detachment occurs.

Considering the aforementioned composite material-microorganism interactions in conjunction with the well-known antimicrobial mechanism of metallic and metal oxide nanoparticles, it could be hypothesized that the antimicrobial activity of fibrous polymeric composites derived from different spinning techniques could be tailored by modifying the morphological features of fibers and distribution/dispersion of antimicrobial agents. For example, Shalumon et al. [START_REF] Shalumon | Sodium alginate/poly(vinyl alcohol)/nano ZnO composite nanofibers for antibacterial wound dressings[END_REF] reported ternary fibrous composites consisting of sodium alginate, poly(vinyl alcohol) (PVA), and several concentrations of ZnO nanoparticles. The ability of the mats to inhibit the growth of both S. aureus and E. coli strains was proportional to ZnO concentration, and interestingly ZnO did not cause a detrimental effect on the adhesion of fibroblast cells. These materials have proven suitable for wound dressing or cell scaffold applications. Biodegradable and/or biocompatible fibrous mats have been developed utilizing other matrices, such as chitosan (which has an inherent antibacterial activity) [START_REF] Son | Antibacterial electrospun chitosan/poly(vinyl alcohol) nanofibers containing silver nitrate and titanium dioxide[END_REF], cellulose acetate, and PCL containing ZnO nanoparticles which showed excellent antimicrobial activity against Candida albicans, E. coli, S. aureus, and Citrobacter freundii [START_REF] Anitha | Optical, bactericidal and water repellent properties of electrospun nano-composite membranes of cellulose acetate and ZnO[END_REF]. Augustine et al. [START_REF] Augustine | Electrospun polycaprolactone/ZnO nanocomposite membranes as biomaterials with antibacterial and cell adhesion properties[END_REF][START_REF] Augustine | Electrospun polycaprolactone membranes incorporated with ZnO nanoparticles as skin substitutes with enhanced fibroblast proliferation and wound healing[END_REF] found the existence of an optimal ZnO concentration to induce inflammation in animals and inhibit the growth of bacteria; furthermore, in the whole range of ZnO concentration, PCL/ZnO membranes showed an excellent fibroblast attachment, which is very important for the application as a wound healing materials.

The combination of electrohydrodynamic techniques represents a versatile approach for tailoring morphological features and consequently the antimicrobial properties of fibrous composites. For instance, Rodríguez-Tobías et al. [START_REF] Rodríguez-Tobías | Novel antibacterial electrospun mats based on poly(d,l-lactide) nanofibers and zinc oxide nanoparticles[END_REF][START_REF] Rodríguez-Tobías | Electrospinning and electrospraying techniques for designing novel antibacterial poly(3hydroxybutyrate)/zinc oxide nanofibrous composites[END_REF] investigated the influence of the electrohydrodynamic technique employed and nanoparticles concentration on the antibacterial activity and mechanical performance of biodegradable polyesters (PLA or PHB) fibers containing nano-ZnO. In the first instance, it was evidenced that increasing the ZnO concentration (from 1% to 5%) the viscosity and conductivity of polyester precursory solution remains in the same order of magnitude, thus leading to fibers with similar fiber diameter ranging from 0.7 to 0.8 microns, porosity from 40-50%, and pore sizes from 10 to 300 microns. In spite of the homogeneity in morphological features, some aggregates into the fibers and semiexposed on their surface were detected by SEM/TEM. Figure 1 gathers SEM and TEM images of the PLA electrospun fibers containing 5 wt.% ZnO nanoparticles, in which it could be observed a homogeneous fibrous morphology with a wide diameter distribution, and the ZnO aggregates near the fiber surface. Similar trends were also found in the case of the electrospinning of PHB/ZnO solutions, but the formed fibers were thinner due to the lower viscosity and higher conductivity compared with PLA solutions.

Fig. 1 SEM image of PLA/ZnO electrospun fibers (left), their fiber diameter distribution (center) and TEM image showing the inner and semi-exposed ZnO nanoparticles in one PLA fiber (right). Reprinted from Rodríguez-Tobías et al., [START_REF] Rodríguez-Tobías | Novel antibacterial electrospun mats based on poly(d,l-lactide) nanofibers and zinc oxide nanoparticles[END_REF] Copyright (2014), with permission from Elsevier.

Concerning the combination of electrohydrodynamic techniques, it was reported [START_REF] Rodríguez-Tobías | Novel antibacterial electrospun mats based on poly(d,l-lactide) nanofibers and zinc oxide nanoparticles[END_REF][START_REF] Rodríguez-Tobías | Electrospinning and electrospraying techniques for designing novel antibacterial poly(3hydroxybutyrate)/zinc oxide nanofibrous composites[END_REF][START_REF] Rodríguez-Tobías | Improvement of mechanical properties and antibacterial activity of electrospun poly(d,l-lactide)-based mats by incorporation of ZnO-graft-poly(d,l-lactide) nanoparticles[END_REF] the tandem process based on electrospinning of polyester solutions and simultaneous electrospraying of ZnO dispersion with the aim to obtain ZnO-coated fibrous materials and determine its antibacterial activity as a function of nanoparticles concentration. It was found that fiber diameter remains unchanged due to the absence of ZnO nanoparticles in the precursory solutions, and the electrospraying technique leads to a deposition system of ZnO aggregates onto the fibers surface, which ranged from several nanometers to 2-5 microns.

The evaluation of mechanical performance of fibrous composites materials is of paramount importance since they could be subjected to tensile forces not only during their handling but also once exposed to tissues by the corresponding movements. Rodríguez-Tobías et al. [START_REF] Rodríguez-Tobías | Novel antibacterial electrospun mats based on poly(d,l-lactide) nanofibers and zinc oxide nanoparticles[END_REF][START_REF] Rodríguez-Tobías | Electrospinning and electrospraying techniques for designing novel antibacterial poly(3hydroxybutyrate)/zinc oxide nanofibrous composites[END_REF][START_REF] Rodríguez-Tobías | Improvement of mechanical properties and antibacterial activity of electrospun poly(d,l-lactide)-based mats by incorporation of ZnO-graft-poly(d,l-lactide) nanoparticles[END_REF] demonstrated that the mechanical performance of PLA or PHB fibrous composites is dependent on the electrohydrodynamic technique as well as the ZnO concentration. Taking into account the ZnO concentration, both fibrous materials, i.e. electrospun and electrospun/electrosprayed polyesters, exhibited an increase in tensile strength when increasing ZnO concentration up to an optimal concentration of 3 wt.%. Higher ZnO concentrations caused a deterioration of mechanical performance probably due to the presence of a high concentration of aggregates, which eventually acts as failure points.

Regarding the main topic of this section, antimicrobial properties of the aforementioned polyester fibrous materials were evaluated against E. coli and S. aureus strains by immersion tests during 24 h. In general, antibacterial activity was dependent on the type of bacteria, ZnO concentration, chemical nature of the polyester and the electrostatic technique used. Considering the bacterium, E. coli is more resistant to the fibers containing different concentrations of ZnO nanoparticles, which has been attributed to the ability of this bacterium to metabolize low concentrations of Zn 2+ as an oligoelement in conjunction with the nature of its cell wall structure, which is more complex than that presented by S. aureus, and their components impart a partial negative charge. These findings have been reported in several research works thus demonstrating the importance to evaluate the fibrous composite materials against several microorganisms to ensure a suitable antimicrobial performance and increase the viability to scale up to medical devices.

On the other hand, the ZnO concentration has an optimal value (3 wt.%) above which no longer antibacterial activity is observed. This behavior is associated with the agglomeration trend at high ZnO concentration, thus lowering the surface area prone to attack the bacteria. As previously mentioned, the chemical nature of the polyester can influence the antimicrobial performance of the corresponding fibrous materials since the polyester chain polarity can promote the attraction or repulsion of the bacteria as a function of its cell wall composition. The effect of nanoparticles agglomeration on antimicrobial performance has also been detected for a wide range of polymers and inorganic nanoparticles, so that the research scope for these materials has been to determine the optimal concentration to lead a good balance in mechanical and antimicrobial performance.

Korina et al. [START_REF] Korina | Multifunctional Hybrid Materials From Poly(3-Hydroxybutyrate), TiO2 Nanoparticles, and Chitosan Oligomers by Combining Electrospinning/Electrospraying and Impregnation[END_REF][START_REF] Korina | Poly(3-hydroxybutyrate)-based hybrid materials with photocatalytic and magnetic properties prepared by electrospinning and electrospraying[END_REF] investigated the combination of different electrohydrodynamic techniques, thus evidencing that the use of electrospraying and electrospinning leads to the metal oxide-coated fibrous material with high surface area prone to attack more efficiently to microorganisms. In our research works, when electrospinning/electrospraying was used with at least 1 wt.% ZnO nanoparticles, values higher than 94% of growth inhibition were achieved. On the contrary, fibrous composites materials derived from mere electrospinning exhibited a moderate antibacterial activity, which could be related to the low degree of ZnO dispersion/exposition and consequently minor interactions between nanoparticles and bacteria.

Recently, Padilla-Gainza et al. [START_REF] Padilla-Gainza | Processing-structure-property relationships of biopolyester/zinc oxide fibrous scaffolds engineered by centrifugal spinning[END_REF] have taken advantage of the Forcespinning® technique to obtain polyester/ZnO fibrous materials with potential to suppress E. coli and S. aureus. The authors evaluated the antibacterial efficiency of PHB-and PLAbased fibrous composites containing ZnO. In the case of PLA, at a concentration of 5 wt.%, an inhibition of bacterial growth for both strains exceeded 97%. On the other hand, PHB showed an excellent antibacterial performance against both microorganisms, observing a slightly higher efficiency at a concentration of 1 wt.%. It is noteworthy that the presence of ZnO did not affect the osteoblasts viability, thus increasing the potential use of this mats in bone regeneration.

Tailoring the bioactive properties of fibrous polyester composites

In many cases, for the design of polymeric fiber scaffolds, it is necessary to consider the incorporation of substances that would promote cell-scaffold interactions. Scaffold bioactivity in bone tissue regeneration can be increased by incorporating ceramic biomaterials, such as laponite nanosilicates, bioactive glasses, calcium phosphates, biphasic calcium phosphate, among others [START_REF] Ibrahim | Bioactive and elastic nanocomposites with antimicrobial properties for bone tissue regeneration[END_REF][START_REF] Turnbull | 3D bioactive composite scaffolds for bone tissue engineering[END_REF]. Nevertheless, hydroxyapatite (Hap) [Ca10(PO4)6(OH)2] is the most commonly used bioactive component, since it is the main inorganic constituent of the bone matrix; specifically, around 69% of the human hard tissue bone is Hap [START_REF] Armentano | Nanocomposites Based on Biodegradable Polymers[END_REF]. Hap has a Ca/P molar ratio of 1.67 and mostly made up of a hexagonal crystal structure. The different crystalline structure of Hap allows it to have compositional variations in a biological system. In different reports [START_REF] Bhat | Functionalized Porous Hydroxyapatite Scaffolds for Tissue Engineering Applications: A Focused Review[END_REF], it has been shown that Hap contributes to important biological processes for the regeneration of bone tissue, such as osteoconduction [START_REF] Anitha | Optical, bactericidal and water repellent properties of electrospun nano-composite membranes of cellulose acetate and ZnO[END_REF] (bone growth at the superficial level), osteoinduction [START_REF] Ripamonti | Osteoinduction in porous hydroxyapatite implanted in heterotopic sites of different animal models[END_REF] (pluripotent cells are stimulated to develop bone-forming cells, process that induces osteogenesis), and osteointegration (stable anchoring of an implant, obtained by direct contact between the bone tissue and the implant) [START_REF] Albrektsson | Osteoinduction, osteoconduction and osseointegration[END_REF]. However, the understanding of how Hap stimulates the mechanisms of cell adhesion, proliferation and differentiation is a controversial issue that is still under investigation. Currently, different fibrous hybrid systems based on biopolyesters and Hap have been studied. In this context, it has been reported that these systems offer efficient support for the adhesion, growth and osteogenic differentiation of human mesenchymal stem cells (hMSCs) [START_REF] Morelli | Osteogenic and osteoclastogenic differentiation of co-cultured cells in polylactic acid-nanohydroxyapatite fiber scaffolds[END_REF][START_REF] Ramier | Biocomposite scaffolds based on electrospun poly(3-hydroxybutyrate) nanofibers and electrosprayed hydroxyapatite nanoparticles for bone tissue engineering applications[END_REF][START_REF] Guan | Attachment, proliferation and differentiation of BMSCs on gasjet/electrospun nHAP/PHB fibrous scaffolds[END_REF], osteoblasts (MG-63) [START_REF] Zhang | Amorphous calcium phosphate, hydroxyapatite and poly(d,l-lactic acid) composite nanofibers: Electrospinning preparation, mineralization and in vivo bone defect repair[END_REF], rat bone marrow cells (rBMSCs) [START_REF] Novotna | Polylactide nanofibers with hydroxyapatite as growth substrates for osteoblast-like cells[END_REF], and mouse pre-osteoblasts (MC3T3-E1) [START_REF] Sadat-Shojai | A new strategy for fabrication of bone scaffolds using electrospun nano-HAp/PHB fibers and protein hydrogels[END_REF]; properties that have been attributed mainly to the presence of Hap.

As described above, PLA and PHB have received special attention for the design of biomedical materials due their versatility to produce systems with different properties. In Table 1, hybrid fibrous scaffolds based on PLA and PHB with Hap obtained by different spinning techniques are described, with special emphasis on the fiber production technique and their biological performance.

It is interesting to observe the relationship between the fiber diameter and its production technique, even considering its dependence with precursory solution properties and operational conditions (see the section 1.2.1). Among the techniques described in Table 1, the systems with the smallest diameters were obtained with the needle/needle-less electrospinning techniques, which in turn produced narrower fiber size distributions than those obtained with Forcespinning® (see standard deviations). These results have a correlation with the scaffold porosity (space between fibers) and pore sizes. High porosity and standardized pore sizes improve the 3D material performance to be used as scaffolds for tissue regeneration.

Based on the biological performance, it is difficult to make comparison between fiber production techniques, because the results are dependent on type of cells, assay, and experimental design. However, it is clear that the Hap incorporation through electrospraying improves cell adhesion. The Hap covering on the fibers provides a highly rough surface and enables direct and efficient interactions between cells and the bioceramic compound. Therefore, the electrospinning/electrospraying approach showed improved cell performance (Figure 2) for the systems displayed in Table 1.

Derivatives of the PHA family, including PHB and poly(3-hydroxybutyric acid-co-3hydrovaleric acid) (PHBV), and the three stereochemical forms of PLA, i.e. PLLA, PDLA and PDLLA, have shown favorable results in their interactions with different types of cells. Hybrid systems including Hap concentration between 15 and 50 wt.% have been studied with mesenchymal stem and osteoblast cells. It has been demonstrated an inductive effect on the differentiation of h/BMSCs into osteoblasts and the osteogenesis. The differentiation has been confirmed by the increase in alkaline phosphatase (ALP) activity, indicating an early marker relevant in matrix mineralization [START_REF] Hessle | Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization[END_REF]. Enhanced viability has been found at 20 wt.% which was correlated with the high porosity (91%) that could facilitate the diffusive transport of nutrients improving cell viability [START_REF] Morelli | Osteogenic and osteoclastogenic differentiation of co-cultured cells in polylactic acid-nanohydroxyapatite fiber scaffolds[END_REF]. On the other hand, filopodia formation from osteoblast cells, specifically MG63, have been promoted at 11 wt.% of Hap combined with PHBV polymer matrix [START_REF] Karbowniczek | Enhanced Cells Anchoring to Electrospun Hybrid Scaffolds With PHBV and HA Particles for Bone Tissue Regeneration[END_REF]. Osteoblast differentiation have been determined by the presence of osteocalcin, obtaining a concentration significantly higher in MG63 cells grown on PLA with 15 wt.% Hap than in those grown on pristine PLA. Additionally, at this Hap concentration, it was found an increased performance in cell growth and viability. A combined effect between an adequate Hap concentration content in a 3D structure with wide distribution of fiber diameters allows for an efficient cell interaction with the scaffold at 15 wt.% system [START_REF] Novotna | Polylactide nanofibers with hydroxyapatite as growth substrates for osteoblast-like cells[END_REF].

Concerning the Forcespinning ® technique, a couple of studies are described in Table 1. Padilla et al. [START_REF] Padilla-Gainza | Centrifugally spun mats based on biopolyesters/hydroxyapatite and their potential as bone scaffolds[END_REF] reported the design and characterization of PDLLA and PHB scaffolds and their performance interacting with human osteoblast-like cells (Saos-2) to evaluate their potential in bone tissue regeneration applications. The biological performance was evaluated for both polymers at 5 wt.% of Hap. The results showed improved cellular response for PDLLA with a cell viability higher than 60%, where the PDLLA-Hap5% system promoted an increase of 10% in cell viability test by day 7 of cell interaction. This behavior could be attributed to the accessibility to the Hap nanoparticles (NPs) within the fibers because most of them were embedded in the PDLLA (Figure 3-f), avoiding the NPs-cells interactions for the first and third days of study. The fiber surface erosion (hydrolytic degradation) could produce the exposition of greater number of NPs, resulting in an increased cell metabolic activity by day 7. Additionally, the surface roughness of the final PDLLA fibers (Figure 3-b) could have played an important role in the different biological performance observed in the PHB fibers.

Padilla-Gainza et al. [START_REF] Padilla-Gainza | Development of zinc oxide/hydroxyapatite/poly(D,L-lactic acid) fibrous scaffold for tissue engineering applications[END_REF] reported an in-depth biological study of a bioactive (Hap) and antibacterial (ZnO) PDLLA scaffolds with potential applications for bone regeneration. It is important to highlight that the antibacterial evaluation, optimization process, and cell viability study [START_REF] Padilla-Gainza | Centrifugally spun mats based on biopolyesters/hydroxyapatite and their potential as bone scaffolds[END_REF] previously reported by our research team defined the appropriate ZnO and Hap concentrations used for the design of this dual (bioactive/antibacterial) hybrid scaffold. The idea to combine ZnO in the final material was to diminish the risk to promote the adhesion and growth of pathogenic microorganisms. ZnO has demonstrated a selective toxicity for bacteria but exhibits minimal effect on human cells [START_REF] Xie | Antibacterial activity and mechanism of action of zinc oxide nanoparticles against Campylobacter jejuni[END_REF]. In addition, it has been proven that it exerts a positive osteoconductive and osteoinductive effect in mesenchymal cells [START_REF] Yusa | Zinc-modified titanium surface enhances osteoblast differentiation of dental pulp stem cells in vitro[END_REF]. The results showed an increased cell viability, above 80%, over the test course of days 1, 3, 5 and 7, which could be consistent with increased cell number. From day 5, the PDLLA scaffold showed viabilities above 100% with respect to the positive control, thus suggesting that cells in the positive control were near confluence. In the case of fibrous scaffolds, due to a higher surface area and adequate pore size, cells continuously proliferated during the tested period. For day 7, mitochondria morphology and proliferation studies were further addressed. All the scaffolds promoted the growth of MC3T3-E1 cells in clusters within the nanofiber matrix. Additionally, the mitochondria morphology showed an interconnected network, representing an efficient system to deliver energy or transfer calcium between different areas of cells (Figure 4). Complementary osteoblast cells morphology was also studied by labeling actin cytoskeletal filaments (Phalloidin) and nucleus (DAPI). It is clearly observed in Figure 5, that MC3T3-E1 cells lay on the fibers and surround them, while extending in the direction of the fiber. The systems revealed normal cell morphology and no signs of necrosis/apoptosis, showing widely spread and spindle-like morphology for blank and PDLLA-ZnO 5%-Hap 5%, respectively. As it could be observed in Figure 5-b, cells were completely in contact with the fibers and some filopodia-like extensions were evidenced coming up from the cells towards the fibers (see the arrows), indicating favorable cell-fiber interactions. Regarding cell migration (Figure 6), cells were found at different depth levels of the scaffold, finding cells down to 37 μm depth from the surface. This behavior showed biocompatibility since cells were able to grow embedded within the scaffolds. These results suggest that the scaffold could promote the exchange of nutrients at different depths given the developed porosity, a feature that is desirable in biocompatible materials. This demonstrates a favorable design of the scaffold, as a result of its chemical nature, surface porosity, porosity (inter-fiber space) and fiber/pore size distribution.

Resazurin assay

Cell: Saos-2 -PDLLA systems promoted higher cellular response than those formulated with PHB. -PDLLA scaffold promoted a favorable cell response, with viabilities above 80%.

-PDLLA-ZnO 5%-Hap 5% scaffold promoted favorable cell morphology.

-Scaffold design promoted a sustained increase in cell proliferation and migration into the 3D structure.

Conclusions

In this chapter, important aspects about the design of polymeric fibrous composite materials for biological applications were addressed. Fiber size and their distribution, porosity (inter-fiber space), surface morphology, type of polymer matrix and the incorporation of agents in accurate concentration to prevent bacterial growth and improve cell interaction are crucial factors to design promising 3D fibrous structures for tissue engineering applications. Electrospinning and centrifugal spinning have been the most extensive technologies used to produce fibrous scaffolds. Particularly, PHB and PLA based fibrous scaffolds have been widely used in medical applications, and their combination with ZnO and/or Hap have produced promising antibacterial and/or bioactive alternatives for wound healing, and bone tissue regeneration.

Fig. 2

 2 Fig. 2 PHB/Hap scaffolds at 15 wt.% of Hap (a) TEM images of single fibers from blend (left side) and spray (right side) and (b) MTS assay of hMSC after 1 h of incubation on fibrous scaffolds. Bars represent mean values ± standard deviations (n = 4). Asterisks indicate significant difference obtained by t-test (p ≤ 0.05). Reprinted from Ramier et al.,[66] Copyright (2014), with permission from Elsevier.

Fig. 3

 3 Fig.3SEM images (a, b, and d), TEM (f, g), box chart of fiber diameter (c) and mapping of phosphorous element obtained through EDS of PDLLA-Hap 5% system produced at ω 7000 rpm, 𝑫 𝒇 ̅̅̅̅ and ∅ are the average fiber diameter and porosity, respectively. Reprinted from Padilla et al.,[START_REF] Padilla-Gainza | Development of zinc oxide/hydroxyapatite/poly(D,L-lactic acid) fibrous scaffold for tissue engineering applications[END_REF] Copyright (2021), with permission from Elsevier.

Fig. 4

 4 Fig. 4 (a) Resazurin-MC3T3-E1 cell viability test; Ctr.+: positive control (cells grown on glass coverslips) was taken as reference to determine the cell viability of the systems. Blank is defined by cell interacting with a PDLLA fiber without NPs. The results are presented as the mean of three experiments ± the standard deviation of the mean (*p < 0.05, **p < 0.01). (b) MC3T3-E1 Confocal micrographs (mitochondria are labeled with Mitotracker (red), while DAPI labels cell nuclei (blue)) obtained at day 7 of scaffold-cell interaction, after being subject to the cell viability test (scale bar: 20 μm). Reprinted from Padilla et al.,[74] Copyright (2021), with permission from Elsevier.

Fig. 5 Fig. 6

 56 Fig. 5 Osteoblast cells (MC3T3-E1) morphology observed in PDLLA fiber scaffolds obtained through confocal microscopy, cytoskeletal filaments (green) and nucleus (blue): (a) Cell clusters found in day 5 (PDLLA blank) and 7 (PDLLA-ZnO 5%-Hap 5%) of the scaffold-cell interaction test (scale bar: 20 μm), and (b) SEM images of the osteoblast cells interacting with the fibers from PDLLA blank and PDLLA-ZnO 5%-Hap 5%, left and right side, respectively (day 7) (scale bar: 2 μm). Reprinted from Padilla et al.,[74] Copyright (2021), with permission from Elsevier.

MTT assay, ( 3 -

 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide: it is based on reduction of the MTS tetrazolium by viable mammalian cells to generate a colored formazan dye that is insoluble in cell culture media. MTS assay, (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium): it is based on reduction of the MTS tetrazolium by viable mammalian cells to generate a colored formazan dye that is soluble in cell culture media. Resazurin assay, is based on the reduction of oxidized non-fluorescent blue resazurin to a red fluorescent dye (resorufin) by the mitochondrial respiratory chain in live cells. NR: not reported a Mercury intrusion porosimetry b ∅ = (1 -𝑚 𝑍 * 𝐴 * 𝐻 * 𝜌 )*100where m, Z, A, H, and ρ stand for the mass, thickness, width, length of the scaffold and the density of the polymer c Pore area in μm 2 , as determined by the Image J software.

Table 1

 1 Main characteristics of hybrid fibrous scaffolds based on PLLA, PDLLA, PHB or PHBV with Hap nanoparticles: technique, Hap concentration (CHap), average fiber diameter (𝑫 𝒇 ̅̅̅̅ ), pore size, porosity (Ø, inter-fiber space) and biological performance

	System	Technique	CHap	𝑫 𝒇 ̅̅̅̅ (µm)	Pore size	Ø (%)	Biological Performance	Ref
			(wt.%)		(µm)
	PHB/Hap(blend)	Electrospinning	0	950 ± 160	5-15 a	61 a	MTS assay
			15	640 ± 80	1-7	61	Cell: hMSC	[56]
							-PHB/Hap (spray) shown a higher cell adhesion after 1 h
	PHB/Hap (spray)	Electrospinning	15	950 ± 70	2-11 a	77 a	cell-scaffold interaction than PHB/Hap (blend)
		/Electrospraying
	PLLA/Hap	Electrospinning	0	770 ± 350	NR	80 ± 3 a	MTT assay and ALP activity	[55]
			20	840 ± 330		91 ± 2	Cell: hMSCs
			50	1030 ± 390		70 ± 4	-Induce osteogenic and osteoclastogenic differentiation of
							human mesenchymal stem cells.
	PHB/Hap	Gas-jet/electrospinning	10	NR	NR	NR	MTS assay	[57]
							Cell: BMSC
							-Good support for the attachment, proliferation and
							differentiation
	PLLA/Hap	Needle-less	0	160-340	NR	NR	Cell viability (live/dead viability kit) and osteogenic cell
		electrospinning	5	287-545			differentiation
			15	242-729			Cell: MG63
							-No considerable cytotoxic effect in human osteoblast-like
							MG63. 15 wt.% of Hap presented a higher potential for
							tissue engineering application.


Blandine Courbiere

Aubert Agostini

Léon Boubli

Florence Bretelle

Antoine Netter
email: antoine.netter@gmail.com

Ena El

Coiplet

Eon Boubli

Endometriosis and environmental factors: A critical review

Keywords:

teaching and research institutions in France or abroad, or from public or private research centers.

Introduction

Endometriosis is an estrogen-dependent disease characterized by the ectopic growth of endometrial tissue. In industrialized countries, this benign disease affects approximately 10% of women of childbearing age [START_REF] Sirohi | Environmental exposures to endocrine disrupting chemicals (EDCs) and their role in endometriosis: a systematic literature review[END_REF]. Its incidence reaches 50% in infertile women [START_REF] Ballester | Role of genetic and environmental factors in the development of endometriosis[END_REF]. Several circumstances may lead to the diagnosis: chronic pelvic pain, infertility workup, or incidental discovery during laparoscopy. Its pathophysiology currently remains debated but appears to be multifactorial, probably including genetic and environmental factors. Although retrograde menstruation of endometrial cells into the peritoneum is the most widely accepted theory, this phenomenon occurs in approximately 70-90% of women, whereas the prevalence of endometriosis is much lower [START_REF] Anger | The link between environmental toxicant exposure and endometriosis[END_REF]. Therefore, other factors may contribute to the pathogenesis of endometriosis, including environmental toxicants.

Recently, work has been done to examine the impact of environmental factors on the development of the disease. However, the results of these studies remain contradictory. Although the biological plausibility of the association between exposure to environmental chemicals and endometriosis is provided by several studies on primates and rodents [START_REF] Yang | Subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates the pathophysiology of endometriosis in the cynomolgus monkey[END_REF][START_REF] Rier | Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin[END_REF], several methodological obstacles limit the generalization of the results to humans: lack of statistical power; difficulty in the precise diagnosis of endometriosis; and the selection of healthy controls [START_REF] Bravi | Tobacco smoking and risk of endometriosis: a systematic review and meta-analysis[END_REF].

The objective of this work is therefore to provide a critical review of current knowledge on the relationship between various environmental factors and endometriosis.

Methods

The literature search was performed using the PubMed database. Firstly, two of the authors established a list of factors to study by searching the environmental literature in general. This list was also expanded by exploring the results of the "endometriosis environment" and "endometriosis environmental factors" searches on PubMed and can be found in Supplementary Table 1. Secondly, we successively searched each exposure factor combined with the word "endometriosis." Studies could be included if they presented data on the association between endometriosis and the environment. Only epidemiological studies involving human subjects were included. Articles published in languages other than English were not translated and were excluded. Medical treatments and hormone therapy were not considered as environmental factors and were also excluded from the review. This review does not present all the articles in an exhaustive manner; the literature was comprehensively analyzed and summarized. Depending on the factors studied, particularly when the number of studies found was important, only the most relevant and recent studies offering the best quality of evidence were retained and quoted. Conversely, for factors that had been very little studied, studies with a smaller impact or older studies could be retained to provide an understanding of the quality of the available data. Systematic reviews and meta-analyses were not excluded from our critical review. Articles could be included if they were published between January 1980 and June 2021, provided they were deemed relevant to the topic and were available on PubMed.

Results

The results of this critical review are summarized in Table 1.

Lifestyle factors

Caffeine

A 1994 case-control study of 180 infertile patients with endometriosis [START_REF] Grodstein | Relation of female infertility to consumption of caffeinated beverages[END_REF] showed that patients consuming 7 g of caffeine per month or more had an increased relative risk of presenting with endometriosis compared to low consumers (OR = 1.9 [95% CI = 1.2 -2.9], p = 0.005). In contrast, in 2014, a meta-analysis based on eight studies, including 1407 women with endometriosis, found no evidence for this association [START_REF] Chiaffarino | Coffee and caffeine intake and risk of endometriosis: a meta-analysis[END_REF]. However, in some selected studies, coffee consumption was reported without taking into account the caffeine content (variable based on the manufacturing process or the type of beverage consumed), and the estimated amounts were based on declarative data. The literature is therefore limited and does not allow any definite conclusions to be drawn regarding the relationship between coffee consumption and the risk of endometriosis.

Smoking

Tobacco exposure disrupts steroidogenesis, resulting in altered estrogen synthesis [START_REF] Sanders | Effects of nicotine and cotinine on bovine theca interna and granulosa cells[END_REF] and decreased progesterone synthesis [START_REF] Miceli | Effects of nicotine on human luteal cells in vitro: a possible role on reproductive outcome for smoking women[END_REF]. In 2014, a recent meta-analysis combining data from 38 studies found no association between smoking and the risk of endometriosis [START_REF] Bravi | Tobacco smoking and risk of endometriosis: a systematic review and meta-analysis[END_REF]. The RR was 0.96 (95% CI 0.86 to 1.08) for ever smokers, 0.95 (95% CI 0.81 to 1.11) for former smokers, 0.92 (95% CI 0.82 to 1.04) for current smokers, 0.87 (95% CI 0.70 to 1.07) for moderate smokers and 0.93 (95% CI 0.69 to 1.26) for heavy smokers. However, various biases seem to affect the results of this meta-analysis: inconsistent diagnosis of the disease between studies, self-reported information, and selection of controls among asymptomatic patients. Additional studies would therefore be necessary to further evaluate this relationship.

Alcohol

The results regarding consumption are conflicting and were reported in a recent meta-analysis based on 15 articles [START_REF] Parazzini | A metaanalysis on alcohol consumption and risk of endometriosis[END_REF]. The estimated risk for regular alcohol consumption was 1.2 (95% CI: 1.1-1.4). This relationship seems biologically plausible, as alcohol has been shown to interact with pituitary LH production and increase aromatase activity, leading to increased estrogen secretion [START_REF] Fernandez | Estrogen, alcohol consumption, and breast cancer[END_REF]. However, some confounding factors were not always considered (socioeconomic status and BMI in particular). The few studies that adjusted for age, socioeconomic status, ethnicity, gravidity, and BMI [START_REF] Hemmert | Modifiable life style factors and risk for incident endometriosis[END_REF] did not find an increased risk of endometriosis. In conclusion, although the present meta-analysis provides evidence of a positive association, it cannot be excluded that multiple mechanisms are also involved.

Dietary factors

Numerous forums, Internet blogs, and television shows address the issue of diet in endometriosis. In 2021, a review evaluated the influence of diet on endometriosis [START_REF] Helbig | Does Nutrition Affect Endometriosis?[END_REF]. Nineteen studies were selected. The different food types were then analyzed separately. In summary, the authors report that high consumption of omega-3 and omega-6 was associated with a reduction in painful symptoms [START_REF] Hopeman | Serum Polyunsaturated Fatty Acids and Endometriosis[END_REF][START_REF] Savaris | Nutrient intake, anthropometric data and correlations with the systemic antioxidant capacity of women with pelvic endometriosis[END_REF]. The consumption of red meat increased, and saturated fat was associated with a negative effect [START_REF] Parazzini | Selected food intake and risk of endometriosis[END_REF][START_REF] Yamamoto | A prospective cohort study of meat and fish consumption and endometriosis risk[END_REF]. In the prospective cohort of Yamamoto et al., including 3800 laparoscopically confirmed cases of endometriosis, the authors showed a 56% increased risk of endometriosis in women consuming red meat more than twice a day compared with those consuming it less than once a week (95% CI=1.22-1.99; p<0.0001). The evidence for fruits and vegetables, dairy products, unsaturated fats, fiber, soy, and coffee is unclear. To make more concrete recommendations, additional studies are needed (consideration of overall lifestyle, composition of each food group, comparability of foods, etc.). Therefore, the data in the literature do not allow for a clear and scientific recommendation on a specific diet. Ideally, future studies could allow the formulation of individual nutritional action plans adapted to each type of patient.

Phytoestrogens

Phytoestrogens fall into three categories: isoflavones (soy, lentils), lignans (flax, millet), and coumestans (alfalfa, red clover). Phytoestrogens act by competitively binding to estrogen receptors [START_REF] Kirichenko | Phytoestrogen-Rich Natural Preparation for Treatment of Climacteric Syndrome and Atherosclerosis Prevention in Perimenopausal Women[END_REF]. In an Iranian case-control study based on 156 infertile women undergoing laparoscopy [START_REF] Youseflu | Dietary Phytoestrogen Intake and The Risk of Endometriosis in Iranian Women: a Case-Control Study[END_REF], the authors observed inverse associations between the risk of endometriosis and total phytoestrogen (OR: 0.68; 95% CI: 0.51-0.91, p = 0.01) and isoflavone (OR: 0.38; 95% CI: 0.33-0.83; p = 0.002) consumption. In a Japanese study, higher levels of urinary isoflavones were also associated with a reduced risk of advanced endometriosis [START_REF] Tsuchiya | Effect of soy isoflavones on endometriosis: interaction with estrogen receptor 2 gene polymorphism[END_REF]. Variety, harvest location, or type of cooking may also result in variations in phytoestrogen content and should be considered when interpreting the results. Given the inflammatory and hormone-dependent nature of endometriosis, phytoestrogens may have an impact, but the evidence for this association will need to be better evaluated in future studies.

Nightshift work

Intriguing data have revealed an association between night shift work and the risk of endometriosis [START_REF] Schernhammer | Rotating nightshift work and the risk of endometriosis in premenopausal women[END_REF][START_REF] Marino | Shift work, hCLOCK T3111C polymorphism, and endometriosis risk[END_REF]. A prospective cohort study of 116,608 U.S. nurses [START_REF] Schernhammer | Rotating nightshift work and the risk of endometriosis in premenopausal women[END_REF] found an increased risk only in infertile patients who had worked on a night rotation for more than 5 years (OR 1.71; 95% confidence interval, 1.18-2.49; p = 0.005). In a case-control study based on 235 women with surgically confirmed endometriosis [START_REF] Marino | Shift work, hCLOCK T3111C polymorphism, and endometriosis risk[END_REF], night shift work was associated with a 50% increase in the risk of endometriosis (odds ratio=1.48 [95% CI =0.96-2.29]). Although it should be confirmed by other studies, these results suggest that night work may influence the development of endometriosis.

Physical activity

Biological mechanisms suggest that exercise may reduce the risk of endometriosis [START_REF] Friberg | high-sugar foods, and risk of endometrial cancer-a population-based cohort study[END_REF]. In 2016, a meta-analysis based on 9 studies including a total of 7955 cases evaluated the potential link between physical activity and endometriosis [START_REF] Ricci | Physical activity and endometriosis risk in women with infertility or pain: systematic review and meta-analysis[END_REF]. The summary OR for any activity was 0.85 (95% CI: 0.67-1.07; p = 0.08) compared with women who were never physically active. However, in these studies, controls were extracted from hospital controls [START_REF] Signorello | Epidemiologic determinants of endometriosis: a hospital-based case-control study[END_REF][START_REF] Garavaglia | Leisure and occupational physical activity at different ages and risk of endometriosis[END_REF] or infertility centers [START_REF] Cramer | The relation of endometriosis to menstrual characteristics, smoking, and exercise[END_REF]. Not all cases were surgically confirmed, and the level of physical activity was not defined consistently across studies. In a study of 473 women undergoing laparoscopy, regardless of indication [START_REF] Hemmert | Modifiable life style factors and risk for incident endometriosis[END_REF], a decreased number of daily minutes spent sitting was modestly associated with a reduced risk of endometriosis. The authors interpret it as an effect, but the result remains not statistically significant (p = 0.180). Regarding this matter, it remains difficult to differentiate the cause and the consequence: women with the highest level of pain generally practice less sport. Therefore, insufficient data are available to draw a conclusion.

Pigmentary traits and sun exposure

Intriguing data support an association between sun exposure, skin phenotype and endometriosis. In a prospective cohort of approximately 10,000 French women [START_REF] Kvaskoff | Endometriosis risk in relation to naevi, freckles and skin sensitivity to sun exposure: the French E3N cohort[END_REF], the authors reported a significant doseresponse relationship with skin sensitivity to sun exposure (p < 0.0001), number of nevi (p < 0.0001), and number of freckles (p = 0.005). A recent prospective study of 4791 laparoscopically confirmed cases of endometriosis also reported this association with sun exposure [START_REF] Farland | Recreational and residential sun exposure and risk of endometriosis: a prospective cohort study[END_REF]. The risk of endometriosis increased with the use of tanning booths (p = 0.04), the number of sunburns in adolescence Only one meta-analysis evaluated this association. The psychological stress may be both a cause and a consequence of the disease and complex to measure. We cannot therefore conclude that a relationship exists between psychological stress and endometriosis. Infection 305(9 studies) Very low

The role of the microbiome has only recently been evaluated. Some authors found more pelvic infections and alterations in the microbiome in patients with endometriosis, by causing epigenetic changes. However, interpretation of these events must be taken with caution as it is unclear whether infections are a cause or consequence of endometriosis.

Dioxines and Polychlorobiphenyls

3519(24 studies) Low Among all environmental compounds, dioxins and PCBs are the most studied in endometriosis. These persistent organic pollutants act as endocrine disruptors. In summary, some studies suggest an association between chemical toxic and endometriosis, but epidemiological evidence remains insufficient. Many methodological barriers that may explain this weak association, precise diagnosis of the pathology, valid selection of controls and choice of sampling method. This subject is still under debate and future studies should be carefully designed to address these issues. No association has been reported with lead or mercury. However, the heterogeneity of the results can be explained by the differences in the biological environments studied. Diethylstilbestrol 33(4 studies) Low Two studies showed that in utero exposure to DES was significantly associated with the risk of endometriosis, with a greater than 80% endometriosis incidence rate in women exposed.

(p = 0.03), and the percentage of time using sunscreen (p = 0.002). Given these two studies with large numbers of patients, it would be tempting to argue for an association. However, women who are highly sensitive to sun exposure or who have freckles tend to avoid sun exposure and thus have lower serum 25-dihydroxyvitamin D3 levels. Some authors have shown that vitamin D and UV independently stimulate interleukin (IL)À10 secretion, reduce the levels of the proinflammatory cytokine IL-17 and inhibit T-helper-1 immune function [START_REF] Correale | Immunomodulatory effects of Vitamin D in multiple sclerosis[END_REF]. The relationship between endometriosis and the vitamin D endocrine system

has not yet been clarified.

Psychological stress

Only one meta-analysis based on 15 studies evaluated the prevalence of psychological stress in 4619 women with endometriosis [START_REF] Brasil | Psychological stress levels in women with endometriosis: systematic review and meta-analysis of observational studies[END_REF]. The mean stress level was 41.78%. Meta-regression showed a relationship with endometriosis staging. However, this is complex to measure and may be both a cause and a consequence of the disease. We cannot therefore conclude that a relationship exists between psychological stress and endometriosis.

Infection

The role of the microbiome has only recently been evaluated. In 2019, a review examined the association between endometriosis and upper genital tract infections and pelvic infections based on 31 articles. The authors found more pelvic infections in patients with endometriosis. Alterations in the microbiome of the upper genital tract and peritoneal cavity were also found as well as an increase in mollicutes and HPV in endometriosis lesions. These infections have the potential to initiate endometriosis by causing epigenetic changes and contributing to endometriosis growth [START_REF] Koninckx | Infection as a potential cofactor in the genetic-epigenetic pathophysiology of endometriosis: a systematic review[END_REF]. However, interpretation of these events must be taken with caution as it is unclear whether infections are a cause or consequence of endometriosis due to various reasons. Further studies must be performed to understanding the interaction with the gut microbiota and confirm these findings.

Environmental factors

Dioxins and PCBs

Polyhalogenated aromatic hydrocarbons (PHAHs) are a family of organic compounds containing a variable number of halogen atoms. This family includes dioxins and dioxin-like and nondioxin-like polychlorinated biphenyls (PCBs) [START_REF] Soave | Environment and Endometriosis: a toxic relationship[END_REF]. These persistent organic pollutants act as endocrine disruptors. These substances originate from various industrial processes (waste incineration, metallurgy, iron and steel production) as well as from some natural phenomena (fires, volcanic eruptions) [START_REF] Porpora | Endometriosis and organochlorinated environmental pollutants: a case-control study on Italian women of reproductive age[END_REF]. 2,3,7,8-Tetrachlorodibenzo (TCDD) is the most toxic dioxin (also known as "Seveso dioxin" in connection with the chemical accident at the plant in 1976). Among all environmental compounds, dioxins are the most studied in endometriosis. Recent reviews [START_REF] Soave | Environment and Endometriosis: a toxic relationship[END_REF] have summarized studies on this matter. Overall, no significant correlation was observed in several case-control studies between dioxin-related and nondioxin-related PCB substances and endometriosis [START_REF] Louis | Environmental PCB exposure and risk of endometriosis[END_REF][START_REF] Pauwels | The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: a case-control study of infertile women[END_REF][START_REF] Lebel | Organochlorine exposure and the risk of endometriosis[END_REF][START_REF] Niskar | Serum dioxins, polychlorinated biphenyls, and endometriosis: a case-control study in Atlanta[END_REF]. Conversely, in a case-control study conducted in Belgium, including 50 cases and 21 controls, the authors found a statistically significant increase in the risk of deep endometriosis with exposure to dioxins and DL-PCBs [START_REF] Heilier | Increased dioxin-like compounds in the serum of women with peritoneal endometriosis and deep endometriotic (adenomyotic) nodules[END_REF]. In an Italian casecontrol study of 80 women of reproductive age, higher levels of PCBs were found in the serum of patients with endometriosis [START_REF] Porpora | Increased levels of polychlorobiphenyls in Italian women with endometriosis[END_REF]. The strength of this study was the inclusion of nulliparous women. Indeed, full-term pregnancy or breastfeeding can potentially reduce the body burden of lipophilic environmental toxins. Finally, in a more recent study of 30 patients with deep infiltrating endometriosis [START_REF] Martínez-Zamora | Increased levels of dioxin-like substances in adipose tissue in patients with deep infiltrating endometriosis[END_REF], dioxin and PCB levels were higher in adipose tissue compared with controls without endometriosis (P < 0.05). In summary, it seems that an association between chemical dioxins and endometriosis is emerging, but epidemiological evidence remains insufficient. However, there are many methodological barriers that may explain this weak association. At the present time, this subject is still under debate. Future studies should be carefully designed to address these issues, including more stringent subject selection strategies.

Parabens

Parabens are used as preservatives in cosmetics, drugs, or foods and as UV filters for sunscreens. A Spanish case-control study found higher urinary paraben levels in 35 patients with endometriosis compared with controls with no statistically significant difference [START_REF] Peinado | Cosmetic and personal care product use, urinary levels of parabens and benzophenones, and risk of endometriosis: results from the EndEA study[END_REF]. Although this study used laparoscopic confirmation to identify cases and controls, several limitations are noted, including the small sample size, single urine sample collected for each patient (preventing variability in daily exposures related to the short half-lives of these substances), and no consideration of diet and smoking. The evidence for cosmetics is therefore limited.

Phtalates

Phthalates are chemical additives, endocrine disruptors, added to plastics to make them more flexible, thus having multiple applications: medical devices (intravenous tubing), children's toys, PVC objects [START_REF] Piazza | Environmental toxins and the impact of other endocrine disrupting chemicals in women's reproductive health[END_REF]. Several studies found higher concentrations of various phthalate metabolites in human urine or plasma [START_REF] Kim | Exposure to Phthalate Esters and the Risk of Endometriosis[END_REF]. In a case-control study on 59 patients, plasma levels of DHEP (diethylhexyl phthalate) were significantly higher in cases [START_REF] Cobellis | High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis[END_REF]. Other authors used urine samples to compensate for potential contamination from intravenous tubing, finding an increase for two phthalates measured [START_REF] Louis | Bisphenol A and phthalates and endometriosis: the Endometriosis: natural History, Diagnosis and Outcomes Study[END_REF]. According to Kim et al., this association seems to involve oxidative stress, inflammatory enzymes and hormone receptors, but the pathophysiology remains unclear.

Heavy metals

The presence of heavy metals in the Earth's crust is advised by human activity (industrial, transportation, and waste management sectors) [START_REF] Rzymski | Impact of heavy metals on the female reproductive system[END_REF]. The role of cadmium (Cd) has been studied, particularly given its binding to hormone receptors [START_REF] Johnson | Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland[END_REF]. In a case-control study based on self-reported data for the diagnosis of endometriosis [START_REF] Jackson | The association between heavy metals, endometriosis and uterine myomas among premenopausal women: national Health and Nutrition Examination Survey 1999-2002[END_REF], Cd blood levels were higher in 61 patients with endometriosis. No association was reported with exposure to lead or mercury. In two other studies, where endometriosis was surgically visualized, no such association was found [START_REF] Pollack | Trace elements and endometriosis: the ENDO study[END_REF][START_REF] Heilier | Cadmium, lead and endometriosis[END_REF]. The heterogeneity of these results may be explained by the difference in the biological media studied [START_REF] Smarr | Endocrine disrupting chemicals and endometriosis[END_REF]. Blood Cd reflects recent exposures, whereas urinary Cd is representative of long-term exposure. Thus, the temporal relationship should be interpreted with caution.

Bisphenol A

Bisphenol A (BPA) is an endocrine disruptor and estrogen mimetic that binds to alpha and beta estrogen receptors. It is present in food and nonfood plastics and has the ability to migrate from its containers to the food or beverage in contact with it, thus being ingested by the body. In a case-control study with surgically confirmed endometriosis [START_REF] Upson | A population-based case-control study of urinary bisphenol A concentrations and risk of endometriosis[END_REF], urinary BPA levels were statistically associated with nonovarian pelvic endometriosis but not with ovarian endometriosis. It should be noted, however, that BPA has a very short half-life on the order of 6 h, and the authors only assessed one sample that was collected after the case was diagnosed. Therefore, these measurements may not have accurately reflected exposure during the etiologically relevant time window. In addition, controls did not undergo laparoscopy, so the possibility of asymptomatic endometriosis was not excluded. Two previous studies measuring urinary BPA levels in women with surgically visualized endometriosis reported no statistically significant association [START_REF] Louis | Bisphenol A and phthalates and endometriosis: the Endometriosis: natural History, Diagnosis and Outcomes Study[END_REF][START_REF] Itoh | Urinary bisphenol-A concentration in infertile Japanese women and its association with endometriosis: a cross-sectional study[END_REF]. Through its estrogenic properties, BPA could influence the development of endometriosis, but further research is needed, particularly studies focused on the different endometriosis subtypes.

Diethylstilbestrol

Diethylstilbestrol (DES) is a synthetic estrogen that was prescribed in France until 1977 and initially used in the prevention of preterm birth and late recurrent abortion (DES-France). In 2020, a meta-analysis evaluating data from in utero exposures on the risk of endometriosis in adulthood showed that in utero exposure to DES was significantly associated with the risk of endometriosis [START_REF] Ottolina | Early-life factors, in-utero exposures and endometriosis risk: a meta-analysis[END_REF]. Two studies supported these findings. In the prospective cohort of Missmer et al., the authors reported a greater than 80% endometriosis incidence rate in 21 women exposed to DES in utero with endometriosis confirmed by laparoscopy (95% CI À1.2 to 2.8) [START_REF] Missmer | In utero exposures and the incidence of endometriosis[END_REF]. This risk was doubled in a second case-control study comparing 9 cases of endometriosis exposed to DES in utero with 11 controls (OR 2.0, 95% CI À0.8 to 4.9) [START_REF] Upson | Early-life factors and endometriosis risk[END_REF]. Despite the very small number of patients exposed in these studies, the data suggest a potential role for DES in patients with endometriosis.

Discussion

This critical review provides an overview of current knowledge of the impact of the environment on endometriosis. To our knowledge, this is the most comprehensive review of literature on environmental factors in relation to endometriosis. Indeed, we have also taken into account lifestyle factors such as night work, exposure to sunlight, physical activity and stress."

Given the estrogen dependence of the disease, studies investigating the association between environmental pollution and endometriosis have mainly focused on endocrine disruptors, particularly PCBs, dioxins, and DES, and appear to be the strongest. Intriguing data also suggest a link with night work, red meat consumption and sun exposure. These data need to be confirmed in future studies. For most of the other risk factors studied, including lifestyle factors (coffee, soy, and alcohol consumption), smoking, physical activity, and exposure to phthalates and BPA, insufficient results are available to draw conclusions. Other exposures were studied in this analysis, including electronic cigarettes, cannabis, benzene, nanomaterials, radiation, acetaldehyde, and acrylamide, but no results were reported in the literature.

Although the biological plausibility of the association between exposure to toxic substances and endometriosis has been provided by several studies on primates and rodents [START_REF] Yang | Subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates the pathophysiology of endometriosis in the cynomolgus monkey[END_REF][START_REF] Rier | Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin[END_REF], several methodological obstacles limit the generalization of the results to humans.

First, the difficulty lies in the accurate diagnosis of this disease. The enormous variability of reported symptoms, the complexity of interpreting imaging studies, and the varied surgical presentations often make case definitions complex. Laparoscopy remains the gold standard for diagnosis. However, not all patients with endometriosis undergo laparoscopy, thus excluding potentially affected but asymptomatic patients. The type of endometriosis chosen may also affect the results [START_REF] Heilier | Increased dioxin-like compounds in the serum of women with peritoneal endometriosis and deep endometriotic (adenomyotic) nodules[END_REF]. Furthermore, the literature reports an average delay of 7 years between the onset of symptoms and diagnosis, making it difficult to establish a causal link between a given self-reported exposure and the pathology [START_REF] Nnoaham | Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries[END_REF]. To understand the results and the validity of published studies, the diagnosis of the disease, the temporal relationship, and the phenotypic variation among women with endometriosis must be clearly defined.

Second, one of the challenges of these studies is the correct and valid selection of controls. In some studies, controls also underwent laparoscopy but for other reasons (e.g., tubal ligation). However, these patients may have a different obstetrical profile from the cases (e.g., higher parity). The parity factor must be analyzed because fullterm pregnancy or breastfeeding can potentially reduce the body burden of lipophilic environmental toxins.

Finally, the choice of sampling method (serum or urine measurements) and the consideration of coexposures (often multiple, particularly for endocrine disruptors or persistent organic pollutants) require vigilance in the interpretation of published results.

It is difficult to draw clear scientific recommendations on environmental exposures from this article. However, patients affected by this disease are generally young, often ask questions and are in constant demand for information about their disease. These results could therefore provide these patients with additional advice and data to improve their overall medical care.

Conclusion

In summary, the epidemiological evidence does not support a strong, scientific link between exposure to environmental factors and endometriosis. The complexity of this disease requires advanced study designs and standardized methodology. Future studies should be carefully designed to address these issues, including the development of more rigorous subject selection strategies and the incorporation of environmental and genetic factors, to advance our understanding of the impact of the environment and its consequences on endometriosis.

Funding

There has been no financial support for this work.

Table 1

 1 Summary of the critical review. the literature do not allow for a scientific recommendation on a specific diet. However, the data seem to suggest an association with high red meat and trans fat consumption. The evidence for fruits and vegetables, dairy products, unsaturated fats, fiber, soy, and coffee remains conflicting. Ideally, future studies could allow for the formulation of individualized nutritional action plans tailored to each patient type. Phytoestrogens 789(3 studies) Very low Studies observed inverse associations between the risk of endometriosis and consumption of phytoestrogen.Variety, harvest location, or type of cooking may also result in variations in phytoestrogen content and should be considered when interpreting the results. protective role for physical activity in endometriosis. However, biases limit these data: non-surgical diagnosis, level of physical activity not homogeneously defined between studies. Regarding this matter, it remains difficult to differentiate cause and consequence: women with the highest level of pain generally practice less sport. The available data are therefore insufficient to draw a conclusion.

	Exposure Factor	Number of patients	Quality of the evidence	Comments
		with endometriosis	(grade)
		(number of studies)(studies)
	Caffeine	2635(9 studies)		In 2014, a meta-analysis found no association between coffee consumption and the risk of
				endometriosis. However, various limitations affect these findings: estimation of caffeine con-
			Very low	tent not reported in beverages, self-reported consumption, and heterogeneity in diagnosis
				and control selection between studies.
	Smoking	13 179(38 studies)		In 2014, a meta-analysis found no difference between heavy, former, current, and moderate
				smokers, and the risk of endometriosis. Various biases seem to affect the results: inconsistent
			Low	diagnosis of the disease between studies, self-reported information, and selection of controls
				among asymptomatic patients.
	Alcohol	5443(17 studies)	Very low	The estimated risk for regular alcohol consumption reported in a meta-analyses was 1.2 (95%
				CI: 1.1-1.4). Multiple mechanisms are also involved, and some confounding factors were not
				always considered in studies (socioeconomic status and BMI in particular).
	Dietary factors Current data in Nightshift work 12 725(23 studies) low 2297(2 studies) Low Intriguing data suggest that infertile women who work nights for more than 5 years may be at
				higher risk for endometriosis. The relationship between endometriosis and infertility is com-
				plex and must also be considered.
	Physical activity Data suggest a Pigmentary traits 7294(10 studies) Very low 10 674(8 studies)
	and sun exposure
	Psychological stress	4619(15 studies)	Very low

Low

Recent studies with large numbers of patients reported a significant dose-response relationship with skin sensitivity to sun exposure, number of nevi, and number of freckles. Given these data, it would be tempting to argue for an association, by interaction with vitamin D. The relationship between endometriosis and the vitamin D endocrine system has not yet been clarified.

Journal of Gynecology Obstetrics and Human Reproduction 51 (2022) 102418

Funding

None.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jogoh.2022.102418.