**7. Tissue engineering approaches to design novel materials to be used in pelvic floor repair**

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 directly by constructing a cell-tissue construct for implantation.

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

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 and configurations. With respect to choice of materials for POP we have suggested a biodegradable material, poly-L-lactic acid (PLA). This is a polymer of lactic acid which is among the most commonly used polymers in biomedical applications [68]. For a biomaterial to treat stress urinary incontinence (SUI) we have selected a nondegradable polymer of polyurethane Z3-as this is not the subject of this chapter this will not be discussed further in this review.

A major limitation here is the relative infancy of the field of urogynecology and our current inability to characterize the biomechanical features of the pelvic floor. Despite this there are now a small number of academic groups (and a very few number of commercial manufacturers) worldwide engaged in understanding the biomechanical challenges of the pelvic floor, the host response to implanted materials and how to develop biomaterials which will be designed specifically for use in the pelvic floor to be introduced on their own or with patient derived cells. Although it is too soon for any of these approaches to have translated into clinical trials there are now alternative materials which have been rigorously evaluated *in vitro* for mechanical properties and these are starting to be evaluated in appropriate models (the sheep in Europe and monkeys in the US) which can discriminate between materials which will fail mechanically or provoke sustained inflammation and those which do not. There is now reason for optimism that better materials can and will be developed which can translate into more effective surgical support for patients without causing the unacceptably high level of severe side-

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

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

47

We thank The Urology Foundation and the Rosetrees Trust for supporting Naside Mangir.

1 Department of Material Science and Engineering, Kroto Research Institute, University of

[1] Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. International Urogynecology Journal [Internet]. Jan 25, 2010;**21**(1):5-26. Available from: http://www.

[2] Durnea CM, Khashan AS, Kenny LC, Durnea UA, Smyth MM, O'Reilly BA. Prevalence, etiology and risk factors of pelvic organ prolapse in premenopausal primiparous women. International Urogynecology Journal [Internet]. Nov 16, 2014;**25**(11):1463-1470. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24737300 [Accessed: Mar 18,

and Sheila MacNeil<sup>1</sup>

\*

effects which patients are currently suffering with PPL mesh.

**Acknowledgements**

Naşide Mangir1,2, Christopher R. Chapple2

\*Address all correspondence to: s.macneil@sheffield.ac.uk

2 Department of Urology, Royal Hallamshire Hospital, Sheffield, UK

ncbi.nlm.nih.gov/pubmed/19937315 [Accessed: Mar 18, 2018]

**Author details**

Sheffield, UK

**References**

2018]

PLA is highly biocompatible and as a degradable polymer it is commonly used as a drug delivery material [69]. In one of our first studies with a biodegradable PLA scaffold produced using the electrospinning technique we showed that the material was extensively infiltrated by host cells together with new collagen deposition and new blood vessel formation after 7 days of implantation into the rat abdomen [70]. We than tried to mimic the organization of the natural extracellular matrix by spinning transversely, obliquely and irregularly aligned PLA electrospun fibers. Here we sought to achieve the viscoelastic mechanical properties of native fascia. We confirmed that MSC cells would grow on these fibers and produce new extracellular matrix. This allowed us to report in 2016 that electrospun scaffolds with several layers of different polymers to achieve the desired biomechanical properties of native fascia [71] maintained good mechanical integrity, compared to PPL meshes, over 90 days following implantation using a rabbit model [50]. The host response to these multi-layered PLA scaffolds was characterized as a predominantly M2 (remodeling) type 30 and 90 days after implantation onto the abdomen of the rabbit.

Another crucial requirement to achieve a rapid integration into host issues is related to vascular supply in and around the biomaterial. This can be particularly concerning in cases where the wound bed is already poorly vascularized, such as pelvic floor tissues of postmenopausal women with SUI and POP [72]. The growth of new blood vessels into a tissue engineered substitute is crucial to improve its' tissue integration and to obtain a successful long term clinical outcome. It has been estimated that a distance of less than 200 μM from the supplying capillary is the critical distance for diffusion of oxygen and nutrients to any new tissue introduced into the body. Because of this, the survival of any three-dimensional tissue graft relies on rapid development of new blood vessels to supply not only the center but also the margins of the graft [73].

Accordingly we have explored the introduction of clinically acceptable agents (specifically ascorbic acid and estradiol) that would stimulate neovascularisation and new extra cellular matrix production by the patient's endogenous cells. To this end we have demonstrated effective pharmacological functionalization of electrospun PLA scaffolds by incorporating ascorbic acid into them to stimulate ECM production without compromising mechanical properties [74]. We have also recently described an estradiol releasing, biocompatible mesh of electrospun PLA which doubled the number of blood vessels in and around the mesh when tested *in vivo* [75].
