Polypropylene Pelvic Mesh: What Went Wrong and What Will Be of the Future?

Background: Polypropylene (PP) pelvic mesh is a synthetic mesh made of PP polymer used to treat pelvic organ prolapse (POP). Its use has become highly controversial due to reports of serious complications. This research critically reviews the current management options for POP and PP mesh as a viable clinical application for the treatment of POP. The safety and suitability of PP material were rigorously studied and critically evaluated, with consideration to the mechanical and chemical properties of PP. We proposed the ideal properties of the ‘perfect’ synthetic pelvic mesh with emerging advanced materials. Methods: We performed a literature review using PubMed/Medline, Embase, Cochrane Library (Wiley) databases, and ClinicalTrials.gov databases, including the relevant keywords: pelvic organ prolapse (POP), polypropylene mesh, synthetic mesh, and mesh complications. Results: The results of this review found that although PP is nontoxic, its physical properties demonstrate a significant mismatch between its viscoelastic properties compared to the surrounding tissue, which is a likely cause of complications. In addition, a lack of integration of PP mesh into surrounding tissue over longer periods of follow up is another risk factor for irreversible complications. Conclusions: PP mesh has caused a rise in reports of complications involving chronic pain and mesh exposure. This is due to the mechanical and physicochemical properties of PP mesh. As a result, PP mesh for the treatment of POP has been banned in multiple countries, currently with no alternative available. We propose the development of a pelvic mesh using advanced materials including emerging graphene-based nanocomposite materials.


Introduction
The use of transvaginal pelvic mesh for prolapse surgery has become a highly controversial and widely discussed topic among gynaecologists in recent years. When polypropylene (PP) pelvic mesh was first introduced to the healthcare market, it was described to be a simple and permanent tool for treating pelvic organ prolapses (POP). However, there has since been a media flurry and a growing body of complaints from women reporting severe irreversible complications as a result of the procedure. This has resulted in the National Institute for Health and Care Excellence (NICE) and the Food and Drug Administration (FDA) to ban PP mesh for certain prolapse surgeries in the UK and USA, amongst other countries which have followed suit [1]. A timeline has been illustrated to highlight key dates in the regulation and investigations of PP vaginal mesh ( Figure 1). Surgical mesh consists of a flat, net-like structure ( Figure 2) that is surgically implanted to support weaknesses of soft tissue, hence its application in treating pelvic prolapses. The mesh creates tension around bodily structures and is thus useful in managing dysfunctions caused by weaknesses of muscle and soft tissue [2]. A number of materials have been used to create the mesh structure for surgical implantation. However, the most common is synthetic PP. Consequential poor patient outcomes are thought to occur either as a result of the type of material used to fabricate the mesh implant or from the procedure performed in order to insert and fixate the mesh implant. Surgical mesh consists of a flat, net-like structure ( Figure 2) that is surgically implanted to support weaknesses of soft tissue, hence its application in treating pelvic prolapses. The mesh creates tension around bodily structures and is thus useful in managing dysfunctions caused by weaknesses of muscle and soft tissue [2]. A number of materials have been used to create the mesh structure for surgical implantation. However, the most common is synthetic PP. Consequential poor patient outcomes are thought to occur either as a result of the type of material used to fabricate the mesh implant or from the procedure performed in order to insert and fixate the mesh implant. This research aimed to critically investigate the type of materials used for the fabrication of pelvic mesh, how vigorously these materials were tested prior to clinical trans-  This research aimed to critically investigate the type of materials used for the fabrication of pelvic mesh, how vigorously these materials were tested prior to clinical translation, and identify the key concerns regarding PP material and its properties. We present alternative implants currently in the animal trial stage for preclinical testing with a promising future application in POP surgery.

Pelvic Organ Prolapse
POP takes place when the pelvic muscles weaken, most often as a result of childbirth and ageing, and so the organs next to or surrounding the vagina descend into the vaginal canal, causing prolapse [3]. POP causes discomfort with symptoms including pain; the feeling of pressure or heaviness 'down below'; the sensation of a bulge or protruding mass; and a visible bulge or protruding mass coming out of the vaginal canal [4]. The symptoms of POP can have a damaging effect on mental health, social and sexual health, and wellbeing.
In the UK, 8.4% of women report the presence of a vaginal bulge. Based on examination reports, prolapse is present in up to 50% of women, according to NICE [5]. NICE also reports that one in ten women require surgical management for their prolapse and as many as 19% of these women relapse and require further surgery, thereby creating costs for the NHS. The expense to the NHS is further increased with negligence claims which, according to a UK Government House of Commons report, summates to over 800 claims against both the NHS and the companies producing PP mesh implants [6].
Surgical treatment for POP involves strengthening and supporting soft tissue weaknesses with sutures or with the use of a mesh adjunct, as discussed in this research. The clinical transvaginal surgical insertion of PP mesh for POP has been banned in the UK by NICE due to safety concerns. Transabdominal PP mesh surgery is still available and offered to patients for the management of vaginal vault prolapse and uterine prolapse, as a last resort if conservative measures have failed [7]. For both anterior and posterior wall prolapse, NICE has banned all forms of PP mesh surgery, due to the growing body of evidence that PP mesh does not improve symptomatic rates of success, including a cohort study involving nearly 19,000 women undergoing POP surgery [8].

Material of the Mesh Implants: Synthetic or Biological?
The synthetic PP mesh implant has been the most commonly used for POP surgery due to its easy availability and affordability. However other augmenting materials have also been manufactured and tried, to produce a safer and more suitable implant. The materials used for the fabrication of the mesh implant can be divided into two main categories: synthetic and biological.
Biological grafts provide an alternative to the more popular synthetic mesh and can either be autologous or heterologous. Materials used to develop biological grafts are outlined in Table 1. The cost-effectiveness of biologic grafts is questionable, as they incur greater costs than synthetic materials and studies show they lack clinical effectiveness. Current research demonstrates a high chance of symptomatic relapse and no added benefit compared to native tissue repair [9].
The production of autologous mesh grafts requires the harvesting of the patient's own tissue. The fascia lata or rectus fascia tissue is used most often due to suitability for size and strength [10]. Autologous grafts are more expensive and time-consuming since the patient must undergo two procedures: one procedure to harvest the tissue, followed immediately by the second procedure to insert the implant. Harvesting tissue from the donor site has increased risks for donor site morbidity, including postoperative infection, scarring, nerve injury, and incisional hernia [11]. The successful use of autologous fascia also relies on donor site tissue quality and is therefore not often plausible, as tissue quality worsens with age [12]. Heterologous grafts include harvested materials from allografts, cadavers, and xenografts from animal tissue [13]. The harvested material must undergo processing in order to create an acellular scaffold that integrates with the patient's tissue. Processing of the grafts is both costly and time consuming. The heterologous tissue that has been harvested using an aseptic technique first needs to be appropriately sterilised with antibiotics and screened for a number of infectious viruses. There have been no cases of viral transmission from heterologous pelvic mesh reported to date, however, the risk needs to be considered and reduced where possible [14]. Decellularisation of the scaffold is required to remove the immunogenic components of the graft and prevent host response. Decellularisation causes weakening of the biomechanical properties of the graft, however, is required, in balance, to prevent an immune response. Natural enzymatic biodegradation of the implant also occurs over time, ultimately resulting in mechanical failure and relapse of symptoms [15]. Heterologous grafts do not offer a permanent solution and are therefore rarely used to treat POP.
A landmark randomised control trial (RCT), PROSPECT, carried out in 2016, studied 1348 female patients undergoing POP surgery to compare the long-term outcomes of native tissue repair versus synthetic or biologic mesh augmentation [16]. This was the largest RCT to date, studying the outcomes of POP surgery with and without mesh. The trial found biologic graft to result in worse outcomes with more prolapse recurrence compared to standard native tissue repair. Similarly, the use of PP mesh also did not affect rates of relapse, although the same study found a complication rate of 12% in patients managed with PP mesh, at the two-year follow up.
The synthetic meshes include the well-known PP mesh, which dominated the prolapse market. However, the other meshes to note include the polyethylene terephthalate (PET) mesh, Mersilene ® , and the expanded-polytetrafluoroethylene (ePTFE) soft tissue patch, Gore-Tex ® . PET is a thermoplastic polymer of the polyester subtype considered to be more inert in vivo compared to PP [17]. Both PET and ePTFE implants are considered to have a greater risk of complications over PP [18]. Ultimately PP was favoured over both PET and PTFE due to having a superior function in triggering tissue ingrowth [19]. Over the years, synthetic mesh has been favoured over alternative biological grafts. The costs of synthetic mesh include production, often cheap, and surgical implantation, a single and quick procedure. Thus, it is considered to be the most time-and cost-effective procedure for POP treatment, whereas the other materials available incur extra costs in harvesting tissue and processing the implant, as well as having a greater risk of relapse.

Polypropylene and Its Properties Used as Mesh for Treatment of Pelvic Organ Prolapse
PP is a rigid, strong, and crystalline nonabsorbable thermoplastic produced using the propene monomer, chemical formula (C 3 H 6 ) n . It is a linear hydrocarbon resin. PP is one of the most widely used polymers for industrial applications to date, due to its low cost and ready availability. It can be used as a plastic or in the form of fibre material. It is nontoxic and thus considered appropriate for use in humans. PP is uniquely useful due to its high electrical and chemical resistance at raised temperatures. Table 2 demonstrates a summary of the mechanical and chemical properties of PP. Table 2. Summary of the mechanical and chemical properties of polypropylene material in its standard form. Note that the method of fabrication can significantly affect material properties.

Mechanical Properties Chemical Properties
Low density (0.9 g/cm 3  Hard consistency Semi-rigid structure makes it more likely to bend and flex with impact PP is a common material used in the laboratory setting for the manufacturing of plastic test tubes, carboys, and vacuum flasks. PP is also a popular material in other industries, including the manufacturing of furniture, as a result of its strength and high chemical resistance, producing plastic tables and chairs suitable for children. PP is also known to have a number of medical applications, including PP mesh for the surgical repair of hernias as well as in a number of medical devices and investigative equipment.
The development of PP mesh for surgical implantations needs consideration of the biomechanical properties of the material, mesh pore size, stiffness, elasticity, and tissue compatibility. However, in addition, patient characteristics and surgeon technique also affect clinical outcomes [20]. The ideal pelvic implant would have similar biomechanical properties to that of native surrounding tissue.
Pelvic PP mesh is a flat sheet manufactured by either knitting or weaving a PP fibre. Knitted mesh implants consist of a single filament, looped with itself to create its structure, whereas woven mesh implants consist of two different filaments crossed perpendicularly with each other (Figure 3). Knitted mesh has a higher porosity and is much more flexible than woven mesh. Hence, it is the preferred method of fabrication. Greater flexibility gives the material more resilience, so it can absorb large bursts of energy and deform elastically, providing a longer lifespan in the high-pressure environment of the pelvic cavity. Increased porosity results in a lower mesh burden and less native tissue in contact with the PP material. In turn, this dampens the immune response as less tissue is reacting to the foreign body PP mesh, reducing the risks of treatment failure and complication. The main benefit of PP, over biologic alternatives, is its resistance to enzyme degradation. the material more resilience, so it can absorb large bursts of energy and deform providing a longer lifespan in the high-pressure environment of the pelvic creased porosity results in a lower mesh burden and less native tissue in cont PP material. In turn, this dampens the immune response as less tissue is rea foreign body PP mesh, reducing the risks of treatment failure and complicatio benefit of PP, over biologic alternatives, is its resistance to enzyme degradatio PP has both a greater Young's modulus and greater ultimate tensile str pared to native pelvic tissue [21]. This means that PP is far more elastic than n tissue. Therefore, it can withstand greater force and stress without breakin Amongst other factors, the ideal mesh would need to be able to withstand the pressure in the pelvic cavity when the abdominal contents move during co sneezing.
High yield strength is important when designing the pelvic mesh implan prevent plastic deformation of the device once implanted and to maintain e supporting pelvic organs. A study of PP found that, as a material, it is unable t great strains from pressure, resulting in deformation of the implant and stretching [22]. Elastic deformation in line with surrounding pelvic tissue is a sponse to a sudden rise in stress that takes place in the pelvic cavity, as descr Therefore, elastic deformation is significant with a high upper threshold for p mation.
The soft tissue of the female pelvic anatomy has evolved to cope with hi and absorb energy while deforming elastically. Studies report that both highstiffer PP meshes negatively interfere with the contractility of the smooth m pelvic region [23]. The stiff PP mesh is thought to 'shield' the surrounding m the normal physiological forces experienced, and, in turn, accelerates tissue de This is a phenomenon known as stress shielding. It is known that when a hard in contact with a softer material, it results in the erosion of the softer materia a mismatch of properties can result in mesh erosion through native tissue. A m is softer and better matches the properties of native pelvic tissue would prev lihood of mesh erosion [24]. Ultimately the stress-shielding results in vaginal a PP has both a greater Young's modulus and greater ultimate tensile strength compared to native pelvic tissue [21]. This means that PP is far more elastic than native pelvic tissue. Therefore, it can withstand greater force and stress without breaking or failing. Amongst other factors, the ideal mesh would need to be able to withstand the changes in pressure in the pelvic cavity when the abdominal contents move during coughing and sneezing.
High yield strength is important when designing the pelvic mesh implant. This is to prevent plastic deformation of the device once implanted and to maintain efficiency in supporting pelvic organs. A study of PP found that, as a material, it is unable to cope with great strains from pressure, resulting in deformation of the implant and irreversible stretching [22]. Elastic deformation in line with surrounding pelvic tissue is a healthy response to a sudden rise in stress that takes place in the pelvic cavity, as described before. Therefore, elastic deformation is significant with a high upper threshold for plastic deformation.
The soft tissue of the female pelvic anatomy has evolved to cope with high pressure and absorb energy while deforming elastically. Studies report that both high-density and stiffer PP meshes negatively interfere with the contractility of the smooth muscle in the pelvic region [23]. The stiff PP mesh is thought to 'shield' the surrounding muscle from the normal physiological forces experienced, and, in turn, accelerates tissue degeneration. This is a phenomenon known as stress shielding. It is known that when a hard material is in contact with a softer material, it results in the erosion of the softer material. Therefore, a mismatch of properties can result in mesh erosion through native tissue. A material that is softer and better matches the properties of native pelvic tissue would prevent the likelihood of mesh erosion [24]. Ultimately the stress-shielding results in vaginal atrophy and hence degrades the quality of soft tissue of the vagina. The vaginal muscles rely on these regular forces that are experienced in order to stretch and maintain their structure and components.
There are reports of PP mesh causing an adverse immune reaction resulting in inflammation and deposits of fibrotic tissue. Large pore size is an important feature in the design of pelvic mesh. This is to reduce the risk of infection by allowing cell infiltration and integration with the mesh implant [25]. The significance of this is related to the different sizes of the smaller pathogens and larger immune cells [26]. In relevance to pore size, plastic deformation and the natural strain experienced by the mesh, in vivo, results in pore deformation and, ultimately, mesh shrinkage.
The PP pelvic mesh implant is stiffer than native vaginal tissue and, therefore, may be a cause for poor tissue integration and resultant complications. As PP does not have the same viscoelastic properties as native pelvic tissue, during movement it tends to damage the surrounding tissue and does not integrate with the site in which it has been implanted. For the surgical pelvic implant to succeed it is important for the materials to be biocompatible and for the implant itself to have similar biomechanical properties as the surrounding tissue for integration. It is important to note that the presentation of the mesh for use in surgery can also play a role in the development of complications. Transvaginal urethral tapes are usually presented and attached to the introducer and the tape is covered with plastic film, which is removed upon insertion of the tape. This minimises tape microbiome contamination, which has been associated with tape extrusion and complications [27].

Clinical Complications Arising from the Polypropylene Mesh Material
PP is a hard and heat-resistant plastic, making it well known for medical and industrial applications, as aforementioned. It is a commonly used plastic that is readily available and suitable in a number of markets. PP is ubiquitous in the developed and developing world. With its plentiful industrial applications, it will continue to be produced and manufactured at a high scale for everyday use.
PP mesh was initially authorised, with FDA, USA, and NICE, UK, approval, for use in the treatment of gastrointestinal hernia repairs, including oesophageal and hiatus hernias. With this original use of PP mesh to repair hernias, no major complications regarding the material were encountered. Therefore FDA clearance for use of the same PP mesh to treat pelvic floor dysfunction was rapid and simple to achieve. Since the PP mesh was rolled out for use to treat POP, new studies have shown long-term severe complications, see Box 1. The most prominent complication is mesh erosion, an issue negligible in the aftercare of gastrointestinal hernia repair and yet causing much controversy in pelvic dysfunction repair [28].  Testing of vaginal PP mesh, or thence the lack of it, as apparent in the literature and summary of all clinical trials, see Table 3, is described to have been minimal due to an FDA regulation waiver of the standard rigorous testing of products that are based on existing FDA-approved devices. Since PP mesh was already commonly used for hernia repair, thorough testing of the product was not required, under the FDA 510 (k) clearance rule. The FDA 510 (k) pathway provides rapid clearance to products, allowing them to bypass further clinical trials and extra safety regulation processing if they are deemed substantially equivalent to a product already approved and in use in the healthcare market. It is for these reasons that, initially, the long-term implications of pelvic PP mesh may not have been fully known. It is very important to not just evaluate the material, under GMP and GLP practice, but also the evolution of the product made and how the device adapts to the part of the body in which it is implanted.
In order to properly assess the risks and complications of PP mesh, after GMP/GLP preclinical trials, large multicentre clinical studies with long-term post-implantation followup are required. Currently, mesh erosion has been described to be the most damaging complication of mesh implant surgery, and it often takes three years or more for such symptoms to arise, hence the importance of long-term follow up in clinical trials. Clinical trials lasting more than three years are ideal as the risk of mesh erosion can be fully assessed to balance the pros and cons of the surgery. The majority of current clinical trials look at early complications and side effects from the surgery, hence why such controversy exists around this subject. It has come to light that there is a lack of clinical trials assessing mesh safety, which has been demonstrated in Table 3.
The main and most controversial complication of mesh insertion is mesh exposure and extrusion, which is caused by synthetic PP mesh, and occurs regardless of location or procedure of insertion. Mesh extrusion (Figure 4) is defined as the exposure of synthetic mesh material through the wall of the vagina and is visible on vaginal examination. Mesh extrusion affects 12% of the patients who have undergone pelvic PP mesh repair surgery in the UK, as reported by NICE in regard to a two-year follow up [29]. It is almost certain that if the follow up were extended to three years or more, the rate of this complication would rise above 12% as the risks of mesh exposure and extrusion increase with time. This is a serious complication due to the side effects it causes that impact the patient's quality of life, including, though not limited to: vaginal pain, abnormal discharge, vaginal bleeding, and dyspareunia. look at early complications and side effects from the surgery, hence why such c exists around this subject. It has come to light that there is a lack of clinical trial mesh safety, which has been demonstrated in Table 3.
The main and most controversial complication of mesh insertion is mes and extrusion, which is caused by synthetic PP mesh, and occurs regardless of procedure of insertion. Mesh extrusion (Figure 4) is defined as the exposure o mesh material through the wall of the vagina and is visible on vaginal examina extrusion affects 12% of the patients who have undergone pelvic PP mesh rep in the UK, as reported by NICE in regard to a two-year follow up [29]. It is alm that if the follow up were extended to three years or more, the rate of this co would rise above 12% as the risks of mesh exposure and extrusion increase with is a serious complication due to the side effects it causes that impact the patie of life, including, though not limited to: vaginal pain, abnormal discharge, vag ing, and dyspareunia.    86% of Pts indicated their prolapse situation to be "much better" following surgery.

[39]
Midurethral tension-free vaginal tape-macroporous PP mesh 160 with SUI Switzerland A prospective RCT comparing retropubic transvaginal tape (TVT) with the transobturator tape (outside-in TOT or inside-out TVT-O) sling operation in the treatment of female SUI or stress dominated mixed urinary incontinence.

12
Five ME complications identified. 2% TVT, 17% TOT, and 0% TVT-O Pts reported de novo sexual dysfunction, considered significant enough to halt the study.
There was no difference for Q-max between TVT, TOT and TVT-O.
Female sexual dysfunction and ME may be higher with a transobturator tape.

36
ME occurred in 13% of Pts at one-year FU, this number did not change by three-year FU.
The objective outcome was superior in the mesh group, but the use of mesh had no impact on the subjective outcome. Ultrapro ® mesh can be used in sling surgery owing to its higher success rates, and lower rates of ME and de novo urgency rates, as shown in clinical studies.

Denmark, Norway and Sweden
An RCT (without blinding) investigating the Ajust ® system vs. the current standard midurethral sling.

36
There were no major complications in either group. Minor complications of urinary tract infections were noted in both groups.
Ajust ® appears equally as safe and effective as the standard mid-urethral sling with regards to long-term FU of Pt-reported outcomes.
2012 [46] Four-arm PP TVM 160 with POP Poland An interventional clinical trial to study the safety and efficacy of performing modified anterior TVM surgery using a four-arm PP mesh adjunct for the treatment of advanced urogenital prolapse after hysterectomy.

24
Intraoperative bladder injury in 4% of Pts. 3% complained of de novo SUI. Vaginal vault prolapse recurred in 6% of cases. ME seen in 1% of Pts at six months.
Four-arm PP TVM is safe and effective and provides an alternative treatment option for vaginal vault prolapse, especially in Pts with contraindications to laparotomy and laparoscopy.
2014 [47]  Once mesh erosion occurs from the implant of PP mesh, the next mainstay of management is to excise the mesh in order to prevent further damage to adjacent soft tissue. However, the mesh tends to have already integrated with the surrounding soft tissue and so removal requires a number of complex surgeries. Surgeons performing the removal must be trained to do so and be familiar with the procedure so as to reduce the risk of further long-term damage. Mesh removal ultimately results in the recurrence of POP symptoms in around 20% of cases, meaning the patients suffer again from the same conditions with superimposed complications from the initial management [52]. Surgical procedures can vary from partial removal to the complete removal of the PP mesh, which carries high risk for postsurgical vaginal stenosis. Other therapies include more conservative methods such as the use of oestrogens, antiseptics and/or antibiotics to prevent infection and further complications of PP mesh exposure.

Future Direction
There are several materials being investigated for use in prolapse surgery with few promising candidates having reached in vivo animal trials. This section will only mention the novel devices that have reached preclinical animal trials for the application of pelvic surgery. Polycaprolactone (PCL) has the greatest volume of published research regarding application with animal studies showing promising results [53][54][55][56][57], including further experimental studies combining PCL with stem cells to augment the results [58,59]. Biodegradable PCL has also been included in experimental studies, although results found that degradation of the mesh occurred faster than tissue regeneration, hence, the higher risks of implant failure [60]. Polylactic acid was investigated, in combination with PCL and independently in the rabbit model [61]. Stem cells were also applied to a polyamide mesh in an investigation of its properties to improve integration with surrounding tissue [62].
Polycarbonate has also been investigated in a number of animal studies, including as an isolate material, processed with other chemicals, and for biodegradable purposesalthough this is a less appropriate option for long-term anatomical support if tissue regeneration is not successful [63][64][65]. Both polyvinyl plastics, polyvinyl fluoride, and polyvinylidene fluoride were studied and performed using ovine models and a porcine cadaver, respectively [66,67]. Polydimethylsiloxane, a silicone-based organic polymer, has also entered preclinical in vivo animal studies with successful outcomes compared to the standard PP mesh [68].
There remains a gap in the market for a better fitting solution than the current PP mesh with competitive alternatives currently under research. A list of properties that would produce the ideal mesh adjunct has been described, see Box 2. The unmet clinical need has resulted in a race for a novel surgical implant to enter the market of POP surgery.  We have been working on the development of vaginal mesh using a graphene-based nanocomposite copolymer [69]. Graphene is a two-dimensional (2D) honeycomb, mono-or multilayer, with sp2 hybridisation. It harbours unique electrical, chemical, optical and mechanical properties. It is 200 times stronger than steel yet at the same time it is known to be extremely elastic and very light [70,71]. We have matched the viscoelastic properties of the mesh, manufactured using Hastalex ® , to the natural viscoelasticity of pelvic tissue. Hastalex ® is unique with it has the properties of superior elasticity and great ultimate tensile strength, see Figure 5. These properties make Hastalex ® an ideal candidate for the development of a novel and innovative surgical implant for the management and cure of POP. To enhance the integration of Hastalex ® within the pelvic cavity, we have seeded the mesh with stem cells obtained from fat obtained from a surgical procedure. The material is currently undergoing preclinical testing and is under development for application in other medical devices, including a synthetic heart valve [72], muscle tendons, and in the repair and replacement of the human tympanic membrane [73]. We have been working on the development of vaginal mesh using a graphene-based nanocomposite copolymer [69]. Graphene is a two-dimensional (2D) honeycomb, monoor multilayer, with sp2 hybridisation. It harbours unique electrical, chemical, optical and mechanical properties. It is 200 times stronger than steel yet at the same time it is known to be extremely elastic and very light [70,71]. We have matched the viscoelastic properties of the mesh, manufactured using Hastalex ® , to the natural viscoelasticity of pelvic tissue. Hastalex ® is unique with it has the properties of superior elasticity and great ultimate tensile strength, see Figure 5. These properties make Hastalex ® an ideal candidate for the development of a novel and innovative surgical implant for the management and cure of POP. To enhance the integration of Hastalex ® within the pelvic cavity, we have seeded the mesh with stem cells obtained from fat obtained from a surgical procedure. The material is currently undergoing preclinical testing and is under development for application in other medical devices, including a synthetic heart valve [72], muscle tendons, and in the repair and replacement of the human tympanic membrane [73].

Conclusions
The majority of the clinical trial studies performed proved that PP mesh was biocompatible and nontoxic, though with a risk of complications, most prominently of mesh exposure. Very few studies investigated the mechanical properties of the PP mesh implant and the potential mismatch of viscoelastic properties with surrounding native tissue. The majority of clinical trials were less than three years meaning longer-term complications

Conclusions
The majority of the clinical trial studies performed proved that PP mesh was biocompatible and nontoxic, though with a risk of complications, most prominently of mesh exposure. Very few studies investigated the mechanical properties of the PP mesh implant and the potential mismatch of viscoelastic properties with surrounding native tissue. The majority of clinical trials were less than three years meaning longer-term complications may have been missed in these studies. The mismatch of viscoelastic properties and the increase in inflammatory processes can cause damage over a long-term period (more than three years) which may result in serious adverse events, hence studies over three years would be most suitable. The ideal mesh should be biocompatible, nontoxic, antibacterial, and have mechanical properties similar to the surrounding pelvic tissue, being able to withstand high pressures without breaking or failing. Currently, a number of advanced materials are under research for surgical application. Polycaprolactone has had the greatest volume of research though other materials also show positive outcomes in preclinical animal trials. Clinical translation of a novel mesh implant would overcome POP, which is currently an unmet clinical condition.  Data Availability Statement: Data sharing is not applicable. No new data were created or analysed in this study. Data sharing is not applicable to this article.

Conflicts of Interest:
The authors declare no conflict of interest.