**6. Designing synthetic materials to be used in pelvic floor reconstruction**

The PPL vaginal meshes in current clinical use were never designed or tested specifically for use in pelvic floor. Instead they were cleared in regulatory terms based on their biocompatibility and the similarity of their textile properties to the existing abdominal hernia products via a 510(k) loophole. In other words, PPL mesh was used in pelvic floor based on an assumption that if it worked well in the abdomen to reinforce hernia repairs it would work equally well to support vaginal prolapse repairs. It is now being recognized that this approach was inherently flawed as the microbial flora, pH, vascular supply and physiological mechanical requirements of the pelvic floor are different from that of the abdomen.

Novel synthetic materials that are mechanically compatible with the requirements of the pelvic floor and that can effectively integrate into host tissues after implantation can be designed by using biomaterials and tissue engineering techniques. This requires an in depth understanding of the mechanical and biochemical properties of the pelvic floor. This section will review the available evidence on the biomechanics of the pelvic floor with a view to defining the design requirements for pelvic floor tissue engineering.

#### **6.1. Basic definitions in biomechanics**

The pelvic floor is the hammock-like structure made up of skeletal and smooth muscles surrounded by connective tissues and attached to pelvic bones. Its' main function is to counteract the forces generated by gravity and intra-abdominal pressure. When studying bioengineering of the pelvic floor we need to consider its biological constitution in relation to the mechanical forces acting on it. Namely, any material used to support the pelvic floor needs to have defined characteristics of material deformation and load bearing as well as how it contributes to tissue remodeling once it is implanted in to the body. It is important that clinicians/surgeons have a basic understanding of biomechanical principles so that they can define the biomechanics of the tissue to be replaced and select the best material to meet the specific needs.

Briefly, when a force is applied to a material it cause a change in size or shape of the material (deformation). This is most commonly expressed in a stress-strain curve from a uniaxial tensile test (**Figure 2**). This test gives an idea about the maximum forces needed to break the material (ultimate tensile strength) and the point where plastic deformation starts (yield strength). These parameters need to be considered together with the requirements of the site of implantation when designing an implant material.

#### **6.2. Defining the mechanical characteristics of the native human pelvic floor**

postoperative outcomes. Surgeons' experience is another potentially important factor in the mesh implant procedures. Several recent consensus reports on how to control vaginal mesh related complications are now emphasizing that only surgeons/centers with subspecialist experience on implantation and postoperative management of patients with stress urinary incontinence and pelvic organ prolapse should undertake these procedures. Also the implementation of national mesh registries, thus not relying solely on the manufacturers to report mesh related adverse event

**6. Designing synthetic materials to be used in pelvic floor reconstruction**

The PPL vaginal meshes in current clinical use were never designed or tested specifically for use in pelvic floor. Instead they were cleared in regulatory terms based on their biocompatibility and the similarity of their textile properties to the existing abdominal hernia products via a 510(k) loophole. In other words, PPL mesh was used in pelvic floor based on an assumption that if it worked well in the abdomen to reinforce hernia repairs it would work equally well to support vaginal prolapse repairs. It is now being recognized that this approach was inherently flawed as the microbial flora, pH, vascular supply and physiological mechanical

Novel synthetic materials that are mechanically compatible with the requirements of the pelvic floor and that can effectively integrate into host tissues after implantation can be designed by using biomaterials and tissue engineering techniques. This requires an in depth understanding of the mechanical and biochemical properties of the pelvic floor. This section will review the available evidence on the biomechanics of the pelvic floor with a view to defining

The pelvic floor is the hammock-like structure made up of skeletal and smooth muscles surrounded by connective tissues and attached to pelvic bones. Its' main function is to counteract the forces generated by gravity and intra-abdominal pressure. When studying bioengineering of the pelvic floor we need to consider its biological constitution in relation to the mechanical forces acting on it. Namely, any material used to support the pelvic floor needs to have defined characteristics of material deformation and load bearing as well as how it contributes to tissue remodeling once it is implanted in to the body. It is important that clinicians/surgeons have a basic understanding of biomechanical principles so that they can define the biomechanics of the tissue to be replaced and select the best material to meet the specific needs. Briefly, when a force is applied to a material it cause a change in size or shape of the material (deformation). This is most commonly expressed in a stress-strain curve from a uniaxial tensile test (**Figure 2**). This test gives an idea about the maximum forces needed to break the material (ultimate tensile strength) and the point where plastic deformation starts (yield strength). These parameters need to be considered together with the requirements of the site

and mandatory post-implantation surveillance systems are recommended.

requirements of the pelvic floor are different from that of the abdomen.

the design requirements for pelvic floor tissue engineering.

of implantation when designing an implant material.

**6.1. Basic definitions in biomechanics**

42 Pelvic Floor Disorders

Our knowledge on the mechanical properties of the female pelvic floor mainly comes from mechanical testing of samples from the pelvic floor from human and animal samples. The availability of human samples for mechanical testing is often limited due to challenges and ethical concerns related to obtaining large tissue samples. Whole pelvic floor samples of animals that contain all the muscles and the connective tissues of the pelvic floor (e.g. 'vaginal supportive tissue complex') have been obtained from rats demonstrating that the ultimate failure in the testing protocol was due to a failure of paravaginal attachments [52]. Samples that only contain the connective tissues (e.g. fascia) have also been tested [53]. Disruption in the fascial structures is thought to be the main mechanism by which pelvic organ prolapse occurs [52].

Another factor limiting our ability to have robust definitions of mechanical properties of pelvic floor structures is the lack of standardized mechanical testing protocols for biological tissue samples. To obtain reproducible results when mechanically testing biological samples their unique organization, composition and *in vivo* functions need to be adopted to the mechanical testing protocols. Currently mechanical testing of samples from animal or human pelvic floor can mainly be tested by uniaxial and biaxial tensile testing. In uniaxial testing, the tissue to be tested is placed between two clamps (clamp-to-clamp testing) and a load is applied to the sample in one direction while observing for elongation/strain. Uniaxial testing is most commonly performed in these studies and it gives more reproducible results.

From a biomechanical point of view, the pelvic floor is a complex structure composed of active (e.g. muscles) and passive soft tissue (e.g. fascia) components attached to the pelvic bones all

**Figure 2.** Defining the basic mechanical properties of a material by uniaxial mechanical testing. The 'maximum load' is the maximum amount of stress that a material can bear before it fails. The 'maximum elongation' is the maximum strain a material can achieve before it fails. The 'yield strength' is where irreversible deformation to the material starts.

contributing to the mechanical strength [54]. Computational models have the potential to mathematically combine all the complex anatomical, mechanical and biochemical data pertinent to pelvic floor to create computational models predicting the biomechanical behavior of the female pelvic floor in health and disease. Anatomical models demonstrating detailed 3D anatomy of the pelvic floor can now be reliably produced thanks to magnetic resonance imaging [55]. The remaining considerable challenge seems to be integrating the functionality of the muscles and other soft tissues into these models. The hope they offer is that once an accurate biomechanical model is created, population based data can be applied to these models before they are used clinically to predict individual patient/disease outcomes.

It is now widely accepted that the failure of PPL in pelvic floor is due to its mechanical incompatibility and the unfavorable mesh-tissue interaction leading to poor tissue integration. Essentially the PPL mesh is too strong and not elastic enough to be used in the pelvic floor [62, 63]. Additionally, animal studies have confirmed that the host response to the PPL initiated by macrophages in the mesh-tissue interface is mainly an M1 (proinflammatory) response, instead of an M2 (remodeling) response, characterized by secretion of matrix metalloproteinases and pro-inflammatory cytokines leading to a vigorous and persistent foreign body reaction [50]. Thus PPL is biologically and mechanically not the best material for pelvic floor repair. A recent European consensus report acknowledged the need for more research into

Synthetic Materials Used in the Surgical Treatment of Pelvic Organ Prolapse: Problems…

http://dx.doi.org/10.5772/intechopen.76671

45

In conclusion when designing a material for use in the pelvic floor, the design characteristics should be optimized to consider its biodegradation and immunological response to it. When defining degradability of a material *in vivo* degradation characteristics and degradation products need to be defined. In case of non-degradable materials the chemical and mechanical changes to the material over many years need to be considered. Irrespective of this the host response to the material needs to be investigated in terms of both the acute and the longer term immunological response to the material. Finally its resistance to infection needs to be

considered-this is often a combination of the material and its method of implantation.

**7. Tissue engineering approaches to design novel materials to be** 

directly by constructing a cell-tissue construct for implantation.

tion and increase neovascularization in a rat model in 2013 [67].

Tissue engineering and regenerative medicine can meet the clinical need in this area by either constructing biodegradable scaffolds that the host cells and tissues can use to remodel or

Compared to tissue engineering of other organs, such as bone and blood vessels, the area of pelvic floor tissue engineering is newly developing necessitating a better understanding of pelvic floor anatomy, physiology and mechanics. The first tissue engineered approach to construct an autologous fascia equivalent for POP repair was reported in 2010. In this study human vaginal fibroblasts were seeded on a PLGA knitted mesh before implantation into nude mice for 12 weeks and a well-organized new fascia with a high collagen I/III ratio was demonstrated [64]. A stronger tissue engineered material was also constructed from knitted silk mesh seeded with adipose derived MSCs in 2013 [65]. In 2013 comparative studies evaluated novel synthetic materials such as polyetheretherketone and polyamide as alternative materials to the PPL [66]. A gelatin-coated polyamide knit mesh seeded with endometrial MSCs that was designed for POP repair was also shown to reduce inflammatory cell infiltra-

Our own group in Sheffield has also been developing biomaterials and tissue engineered substitutes to be used in pelvic floor repair over the last 6years. To produce the materials we have selected the technique of electrospinning. Electrospinning is a widely used technique in tissue engineering that allows fabrication of scaffolds with micro/nano sized fibers with different compositions

more acceptable materials for use in the pelvic floor [12].

**used in pelvic floor repair**

#### **6.3. Biological requirements of pelvic floor**

Early materials implanted into the human body were designed to have appropriate physical properties to match tissues at the site of implantation and to be made of materials which would have minimal toxicity. These materials were biologically 'inert' which ensured a minimal immune response to the foreign material. Although the consideration of the predicted immune response to an implanted material is still conceptually valid, there is a shift of paradigm about the inertness of a biomaterial. The next generation of biomaterials were purposefully designed to be bioactive to achieve a desired reaction post-implantation (e.g. antibiotic or extracellular matrix coated materials). Additionally the degradation times of the materials started to be finely tuned with advancements in resorbable biomaterials. The main advantage of using a degradable material would be that the foreign material would eventually be degraded after guiding the host to achieve a desired tissue regeneration (e.g. absorbable sutures commonly used in surgery).

The polypropylene material commonly used is traditionally considered 'inert'. Although PPL completely degrades over many years, its' inertness is now questioned after repeated demonstrations of surface degradation on the PPL fibers [56, 57]. The most common complication of surgical implantation of the mesh is spontaneous pain, occurring in 32.5% patients (pain during sexual intercourse 14.7%) [58]. The mechanisms leading to this pain are complex, probably involving infection, nerve and muscle injury and mesh contraction [59]. It has been demonstrated in mesh samples explanted from patients that PPL can actually degrade *in vivo* as early as 18 months after implantation [56]. This PPL polymer can breakdown in response to high temperature, UV light and oxidation [57].

Another important point to consider is the tissue specific immune response to the implanted biomaterial. The host immune system, mainly affected by tissue macrophages, initiate a cascade of events as soon as the material is implanted in the body. These reactions mainly take place at the material-tissue interface meaning that the surface structure and chemistry can potentially influence the initial macrophage response to the implanted material. Modifications of the surface properties of materials have been investigated as a potential strategy to shift the macrophage polarization towards a constructive remodeling type (M2) of reaction instead of a proinflammatory (M1) type. A well described pathway leading to biomaterial failure in the long term is development of a foreign body reaction leading to encapsulation of the material isolating it from the surrounding tissues. A foreign body reaction is a result of chronic M1 predominated inflammatory reaction. It has been demonstrated that synthetic materials when designed with a highly porous structure elicit less chronic inflammation leading to encapsulation [60, 61].

It is now widely accepted that the failure of PPL in pelvic floor is due to its mechanical incompatibility and the unfavorable mesh-tissue interaction leading to poor tissue integration. Essentially the PPL mesh is too strong and not elastic enough to be used in the pelvic floor [62, 63]. Additionally, animal studies have confirmed that the host response to the PPL initiated by macrophages in the mesh-tissue interface is mainly an M1 (proinflammatory) response, instead of an M2 (remodeling) response, characterized by secretion of matrix metalloproteinases and pro-inflammatory cytokines leading to a vigorous and persistent foreign body reaction [50]. Thus PPL is biologically and mechanically not the best material for pelvic floor repair. A recent European consensus report acknowledged the need for more research into more acceptable materials for use in the pelvic floor [12].

contributing to the mechanical strength [54]. Computational models have the potential to mathematically combine all the complex anatomical, mechanical and biochemical data pertinent to pelvic floor to create computational models predicting the biomechanical behavior of the female pelvic floor in health and disease. Anatomical models demonstrating detailed 3D anatomy of the pelvic floor can now be reliably produced thanks to magnetic resonance imaging [55]. The remaining considerable challenge seems to be integrating the functionality of the muscles and other soft tissues into these models. The hope they offer is that once an accurate biomechanical model is created, population based data can be applied to these models before

Early materials implanted into the human body were designed to have appropriate physical properties to match tissues at the site of implantation and to be made of materials which would have minimal toxicity. These materials were biologically 'inert' which ensured a minimal immune response to the foreign material. Although the consideration of the predicted immune response to an implanted material is still conceptually valid, there is a shift of paradigm about the inertness of a biomaterial. The next generation of biomaterials were purposefully designed to be bioactive to achieve a desired reaction post-implantation (e.g. antibiotic or extracellular matrix coated materials). Additionally the degradation times of the materials started to be finely tuned with advancements in resorbable biomaterials. The main advantage of using a degradable material would be that the foreign material would eventually be degraded after guiding the host to achieve a desired tissue regeneration (e.g. absorbable sutures commonly used in surgery).

The polypropylene material commonly used is traditionally considered 'inert'. Although PPL completely degrades over many years, its' inertness is now questioned after repeated demonstrations of surface degradation on the PPL fibers [56, 57]. The most common complication of surgical implantation of the mesh is spontaneous pain, occurring in 32.5% patients (pain during sexual intercourse 14.7%) [58]. The mechanisms leading to this pain are complex, probably involving infection, nerve and muscle injury and mesh contraction [59]. It has been demonstrated in mesh samples explanted from patients that PPL can actually degrade *in vivo* as early as 18 months after implantation [56]. This PPL polymer can breakdown in response to high temperature, UV light and oxidation [57].

Another important point to consider is the tissue specific immune response to the implanted biomaterial. The host immune system, mainly affected by tissue macrophages, initiate a cascade of events as soon as the material is implanted in the body. These reactions mainly take place at the material-tissue interface meaning that the surface structure and chemistry can potentially influence the initial macrophage response to the implanted material. Modifications of the surface properties of materials have been investigated as a potential strategy to shift the macrophage polarization towards a constructive remodeling type (M2) of reaction instead of a proinflammatory (M1) type. A well described pathway leading to biomaterial failure in the long term is development of a foreign body reaction leading to encapsulation of the material isolating it from the surrounding tissues. A foreign body reaction is a result of chronic M1 predominated inflammatory reaction. It has been demonstrated that synthetic materials when designed with a highly porous structure elicit less chronic inflammation leading to encapsulation [60, 61].

they are used clinically to predict individual patient/disease outcomes.

**6.3. Biological requirements of pelvic floor**

44 Pelvic Floor Disorders

In conclusion when designing a material for use in the pelvic floor, the design characteristics should be optimized to consider its biodegradation and immunological response to it. When defining degradability of a material *in vivo* degradation characteristics and degradation products need to be defined. In case of non-degradable materials the chemical and mechanical changes to the material over many years need to be considered. Irrespective of this the host response to the material needs to be investigated in terms of both the acute and the longer term immunological response to the material. Finally its resistance to infection needs to be considered-this is often a combination of the material and its method of implantation.
