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OBSTRACT: interpreting the abstraction of tissue regeneration and re-engineering of female pelvic floor disorders in clinical practice

Discussion meeting

Location

The Royal Society, London, 6-9 Carlton House Terrace, London, SW1Y 5AG

Overview

Scientific discussion meeting organised by Dr Sohier Elneil, Professor Sheila MacNeil, Professor Margot Damaser and Dr Gloria Esegbona.

An abstraction of a regenerating pelvic tissue, produced by Dr Gloria Esegbor.

This novel interdisciplinary meeting will bring together scientists and clinicians to review our current understanding of the pathophysiology of female pelvic floor disorders (PFD). Through an analysis of the molecular, cellular, biomechanical and neurological constituents that govern the trauma and subsequent healing process, and correlating this with the ambiguities plaguing the prognosis of surgical repairs. Investigate how our current technologies of regenerative medicine and tissue engineering may offer restorative properties of existing pelvic floor tissue. In addition, explore how these treatment methods can be used in a cost-effective, personalized and scientific approach to care.

The schedule of talks and speaker biographies will be available shortly. Recorded audio of the presentations will be available on this page after the meeting has taken place. 

Attending this event

This meeting is intended for researchers in relevant fields: 

  • Free to attend 
  • Limited places, advanced registration is essential
  • An optional lunch can be purchased during registration

Enquiries: Contact the Scientific Programmes team.


Event organisers

Select an organiser for more information

Schedule of talks

16 October

09:00-12:30

SESSION 1: Regenerating repair

7 talks Show detail Hide detail

Chairs

Professor Margot Damaser, Cleveland Clinic Foundation

09:00-09:20 Why regenerative medicine for female PFD: rising incidence and challenges with current management

Dr Sohier Elneil, University College Hospital

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09:20-09:40 Signalling away from scarring to regeneration

Dr Gloria Esegbona, King's College London

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09:40-10:15 Why regenerate? Morphological adaptations in pelvic tissue architecture, and extracellular matrix (ECM) during birth

Professor Marianna Alperin, UC San Diego Health

Abstract

Pelvic floor muscles (PFMs) are integral for the proper function of the female pelvic floor. Epidemiological studies identify vaginal childbirth as a key risk factor for PFM injury and consequent dysfunction, which are critical for the development of pelvic floor disorders. Despite this, preventative strategies for maternal birth trauma continue to be non-existent and the available treatments offer marginal promise at best. Significant constraints, associated with directly probing PFMs in women, hinder the progress. We used an animal model, validated through a comparative analysis of the human and rat PFM architecture, to answer the following fundamental questions: (1) what are the effects of pregnancy on the contractile and extracellular matrix (ECM) muscle components? and (2) what are the mechanisms of pelvic muscles’ birth injury and subsequent dysfunction? 

Using rat model, we discovered a number of antepartum changes in the pelvic floor muscles, including fiber elongation via serial addition of sarcomeres, or sarcomerogenesis, and changes in ECM content and muscle stiffness. The results of our direct muscle properties’ measures of the PFMs, subjected to simulated birth injury in the absence and presence of pregnancy-induced adaptations will be discussed. Our findings provide a scientific rationale for the development of novel strategies, aimed at maximizing protective adaptations and regeneration of PFMs following birth injury.

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10:15-10:40 Scientific translation discussion

11:00-11:35 What are we regenerating? On the functional anatomy of the female pelvic floor

Professor James Ashton-Miller, University of Michigan

Abstract

The goal of this presentation is to survey what is known and, more importantly, what is not known about how the pelvic floor works because knowledge gaps can hinder the selection of the most appropriate targets for tissue engineering to restore pelvic floor function.  For example, the urethral sphincter is comprised of the urethral lumen, vascular plexus, longitudinal smooth muscle, circular smooth muscle, and circumferentially-oriented striated muscle.  It is presently thought that the vascular plexus, smooth muscle, and striated muscle each contribute one-third of the urethral closure pressure required to maintain continence.  But this dogma is based on one small study - hardly the quality of evidence upon which to decide which urethral layer needs to be regenerated in order to restore continence in an incontinent patient. Another example of a knowledge gap pertains to pelvic organ prolapse.  Older dogma was that prolapse is caused by a defective vaginal wall.  But newer research points instead to defects in apical and paravaginal tissues (which can be surgically corrected), as well as torn pubovisceral muscle.  However a knowledge gap persists in the causes of prolapse in the absence of such defects; indications are that the re-innervation and regeneration of denervated muscle may be required.

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11:35-12:10 Corpus intrapelvinum with intrapelvic urogenitodigestive diaphragm as the stabilising organ in functional pelvis anatomy and decisive factor in reconstructive pelvis surgery in the female

Dr Kees Waaldijk, Babbar Ruga National Obstetric Fistula Centre

Abstract

During extensive obstetric trauma surgery, many of the operation techniques have nothing to do with reconstructive pelvis surgery but more with financial profit to the medical industry. Other concepts are needed in order to understand the functional pelvis anatomy in the female, to identify the underlying defects and then to reconstruct the pelvis anatomy correctly using available autologous structures ensuring normal physiology and functioning. The different pelvis organs with their vascular supply and innervation are embedded into, protected by, and encapsulated or ensheathened by a complex connective tissue body/organ of pelvis as corpus intrapelvinum as part of the tela urogenitalis securing/ stabilising the organs in their variable anatomic position. This ensures their physiologic functioning independently or combined. 

The corpus intrapelvinum forms a 3-dimensional functional dymamic organ consisting of a cohesive mixture of collagen for strength, elastin for passive elasticity and plasticity and smooth muscle fibers for dynamic action in a loose, dense or condensed form all under control by the autonomic nervous system. One of its highly specialised structures is the intrapelvic urogenitodigestive diaphragm which supports the continence mechanisms and if intact prevents the high-pressure organs of the urinary tract, genital tract and digestive tract to prolapse into the zero-pressure vagina and then if not corrected further thru the vagina to the outside. Only by further research into the corpus intrapelvinum as a whole and into its highly specialised structures will it be possible to develop real reconstructive operation techniques ensuring normal physiology.


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12:10-12:30 Scientific translation discussion

13:30-17:00

SESSION 2: Repairing regeneration

6 talks Show detail Hide detail

Chairs

Dr Sohier Elneil, University College Hospital

13:30-14:05 A regenerative medicine approach to pelvic floor reconstruction: the host response as a primary determinant of success

Professor Stephen F. Badylak, University of Pittsburgh

Abstract

Regenerative medicine approaches to soft tissue repair and reconstruction, including pelvic floor repair, typically involve the use of cells, scaffold materials, and/or bioactive molecules. Cell-based therapies, including the use of stem/progenitor cells, have largely failed to achieve successful clinical translation. However, biomaterial-based approaches, especially those that consist of naturally occurring materials, have had a significant positive influence upon the reconstruction of soft tissue structures such as the abdominal wall and skeletal muscle.

The outcomes for any given clinical application depend upon several factors including biomaterial design, anatomic location, patient-specific factors, and surgical technique, among others. All implantable biomaterials elicit a host response, the nature of which logically influences the clinical outcome. Recent findings have shown that naturally occurring biomaterials can stimulate a constructive, immunomodulatory microenvironment and promote the recruitment, proliferation, and differentiation of stem cells into site-appropriate functional tissue. The relationship between the host response to biomaterials and clinical outcomes will be discussed, including the use of inductive immunomodulatory biomaterials for reconstruction of pelvic floor soft tissues.

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14:05-14:40 Biomaterials and tissue engineering for pelvic floor regeneration

Dr Sheila MacNeil, University of Sheffield

Abstract

Age is unkind to women - childbearing and vaginal childbirth often lead to weakened pelvic floors and stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP).  20% of healthy women will require surgery for POP by the age of 80. Non-degradable polypropylene (PP) meshes which have been used to support the pelvic organs for the last decade are  now known to cause unacceptable side-effects in around  5% of woman when used as small tapes to support the urethra for SUI, and around  20% of woman when used as larger areas to support the pelvic organs in POP. Our team of scientists and clinicians are engaged in developing alternative next-generation biomaterials and tissue engineering approaches to provide solutions specifically designed for the dynamic pelvic floor.

For SUI we have developed a fascia mimetic nondegradable mesh of polyurethane which has strength and elasticity much closer to the patient,s native tissue than the inflexible PP meshes currently used. This is currently being evaluated in a sheep vagina model developed by Professor Jan Deprest in Leuven.

For POP we are developing a slow degrading mesh of polylactic acid (PLA) designed to be introduced with lipoaspirate derived MSc. The latter cells are capable of producing new tissue and the challenge here will be to develop a methodology for accessing MSc in a minimally invasive procedure in theatre and combining them with the PLA membrane for surgical implantation. We have also developed materials which release oestradiol to encourage neovascularisation and good tissue integration.

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14:40-15:10 Clinical translational discussion

15:30-16:05 Towards rebuilding vaginal support utilising extracellular matrix bioscaffolds

Professor Pamela Moalli

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16:05-16:40 Biomechanics of female pelvic cavity: lessons for regeneration from computational models

Professor Renato Jorge, University of Porto

Abstract

Female pelvic floor dysfunction can result from weakening or damage of the pelvic floor muscles or connective tissue. It is studied in the clinical setting, and computational biomechanical analysis has contributed along the years, in a translational research basis.

Computational frameworks to study the childbirth influence in the mechanical behavior of the pelvic floor will be presented. Besides the experience in characterizing and modeling the mechanical properties of soft tissues, there is a lack of tools to predict the requirements for implementation of regenerative solutions to the pelvic tissues. It has been observed that macro-scale biomechanical evidences of damage in tissue may be detected earlier at a micro and nano-scale of the extracellular matrix structure. Pelvic supportive tissues have high demands on functionality, however their material properties vary significantly interpersonally. The balance between synthesis and degradation of collagen on the ECM maintain the tissue integrity and tensile strength. Any deviation from the normal conditions will change the mechanotransduction processes and produce damage into the tissue. 

In the context of a mechanical approach to cell biology, there is a close relationship between cellular function and mechanical properties. Given the importance of the actin contraction on the physiological functions, the establishment of a constitutive model to describe how the filamentous network controls its mechanics actively is crucial. Assuming an enthalpic deformation of isotropic cross-linked network as the dominant contribution to elasticity, the development of a suitable constitutive model will be discussed.

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16:40-17:00 Clinical translational discussion

17 October

09:00-12:30

SESSION 3: Engineering repair

6 talks Show detail Hide detail

09:00-09:35 Potential for biomaterials and bioactive signal expression in engineered materials for pelvic floor disorders

Professor Karl-Dievert Sievert, University Clinic of Rostock

Abstract

Thousands of surgical procedures are performed every day. Tissue is removed or damaged for different reasons. In the past these wounds healed with scar tissue.  This scar tissue is a natural part of the healing process, however, it does not have the same flexibility and elasticity as healthy/original muscle. 

The field of tissue engineering (TE) aims to regenerate damaged tissues by combining cells, signaling pathways from the body with engineered material, which act as temporary templates for the tissue to promote functional regeneration and  ‘guide’ the growth of new tissue.  One of our challenges have been to develop TE tissue as close as possible to the previously damaged or removed tissue.

In the past extracellular tissue was the biomaterial closest to the original removed/injured tissue. New technologies have given us the capability to manufacture biomaterials with the capability to propagate the most similar extracellular tissue, which can function in its environment - the pelvic floor.  The aim of these scaffolds is to mimic certain advantageous characteristics of the natural/ original extracellular matrix.  With enhanced understanding of the micro-environment in regeneration vs. the healing after injury/tissue damage, new opportunities can be pioneered to attain the aim of restoring original functionality.

Modern synthetic biomaterials can be designed with integrated bioactive ligands or other factors necessary for the accurate signal expression. This way the cells respond and assimilate with and within the biomaterial.  The cultivated understanding of the role of growth factors and cytokines and their interactions with components of the extracellular matrix and novel biomaterials that help to mimic natural regeneration of tissues will result in increased efficacy in applications of tissue repair and regeneration. 

This presentation will summarise the current research results that will define new healing treatments but also address improvements to optimise outcomes for those patients with pelvic floor disorders. 

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09:35-10:05 Characteristics of vaginal fibroblasts, their attachment to biomaterials and potential application of cell-based therapy for treatment of female Pelvic Floor Disorders

Assistant Professor Oksana Shynlova, University of Toronto

Abstract

Currently Pelvic Floor Disorders (PFDs) affect almost half of post-menopausal women. The frequency and severity of symptoms increase after menopause, which may be due to loss of protective effects of ovarian hormones leading to faster deterioration of the pelvic floor extracellular matrix. Thus, we studied fundamental molecular mechanisms underlying the development of Pelvic Organ Prolapse (POP) in pre- and post-menopausal women using molecular biological, biochemical, and immunohistochemical approaches. Our focus was on in vivo expression of genes and proteins participating in elastogenesis and collagenogenesis, as well as major proteolytic enzymes and their tissue inhibitors. The effect of Local Estrogen Therapy was assessed in vaginal biopsies of post-menopausal women with severe POP. We observed an increase in the expression of structural proteins (collagen/elastin) and local activation of the immune system, which supports a beneficial role of Estrogen in the remediation of pelvic floor tissue in POP patients.
We used an integration-free episomal system to generate induced Pluripotent Stem Cells (iPSCs) from urine specimens of female patients with Stress Urinary Incontinence. The reprogramming success was independent of patients’ age or menopause status. After passaging, urine iPSCs were free of the reprogramming vector and therefore safe for potential application in humans. iPSC lines can be maintained undifferentiated in stem cell conditions for more than 30 passages, then reconstituted from cryopreservation and differentiated to fibroblasts and muscle cells.  Generating autologous patient-specific muscle cells and fibroblasts from urine-derived somatic cells can potentially revolutionize modern urogynecological treatment of PFDs.

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10:05-10:40 Implantation strategy discussion

11:00-11:35 Tissue engineering approaches for treating Pelvic Organ Prolapse (POP) using a novel source of mesenchymal stem/stromal cells and new materials

Associate Professor Caroline Gargett, Hudson Institute of Medical Research

Abstract

We are using a tissue engineering approach to address problems associated with using vaginal mesh for treating POP. We propose to use autologous endometrial mesenchymal stem cells (eMSC) delivered on polyamide/gelatin composite meshes (eMSC/PA+G) to improve mesh biocompatibility and regenerate vaginal tissue damaged from childbirth injury. 

eMSC are purified from biopsies obtained from premenopausal and short-term estrogen-treated post-menopausal women using SUSD2 magnetic-bead sorting. eMSC are culture-expanded in serum-free medium under hypoxia with a small molecule TGFβ-receptor inhibitor, A83-01, generating 90-95% SUSD2+ eMSC. ATACseq and RNAseq revealed that A83-01 maintains eMSC stemness by opening chromatin loci enriched for transcription factor binding sites and upregulating gene networks involved in developmental and stem cell signalling pathways. 

A rat model treated with human eMSC/PA+G constructs showed that eMSC increased vascularisation, reduced chronic inflammation, promoted deposition of crimped collagen, generating a biomechanically less stiff mesh/tissue complex compared to PA+G. The eMSC had a paracrine mechanism of action in improving biocompatibility of PA+G mesh. 

We are using an autologous preclinical ovine model of vaginal surgical repair in multiparous ewes. POP is assessed using a modified POP-Q and our novel fibre-optic pressure sensor device. Ovine eMSC are isolated from hysterectomies by FACS sorting CD271+CD49f  cells, culture-expanded and labelled with IODEX-FITC paramagnetic nanoparticles for cell tracking before seeding on PA+G mesh and implanting transvaginally using urogynaecological surgical procedures. 
Our tissue engineering approach using autologous eMSC delivered on polyamide/gelatin scaffolds addresses some problems associated with the use of vaginal mesh and may improve surgical outcomes for treating POP.

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11:35-12:10 Modulating the regeneration response: regulation of cellular microenvironments and novel solutions to translational hurdles

Professor Alicia El Haj, Keele University

Abstract

Engineering complex tissues creates major challenges for tissue engineering and regenerative medicine strategies. Complex form and function in tissues such as the pelvic floor comprise multiple musculoskeletal tissues with cross-tissue integration and junctions. Our lab has been involved in understanding the ways we can engineer a stem cell niche which can go on to regenerate multiple tissues. Our aim is to deliver donor progenitor cells which can build and define replacement tissues in vivo. The challenge lies in engineering control solutions for stem cells which have clinical relevance. We have developed multiple control systems which can be aligned with cell based therapies and have gone some way towards translating these approaches towards first in man. In this presentation I will describe our novel stem cell bandage which can be used for enhancing and maintaining stem cell communities in bone. I will present our work in nanomedicine with remote magnetic nanoparticle control strategies for stem cell activation and optimised differentiation which is now in preclinical trial.  Finally I will align these strategies to potential treatments for pelvic floor disorders and consider how we can translate these approaches towards a clinical solution for patients

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12:10-12:30 Implantation strategy discussion

13:30-17:00

SESSION 4: Engineering regeneration

7 talks Show detail Hide detail

Chairs

Dr Sheila MacNeil, University of Sheffield

13:30-14:00 Non-cellular regenerative medicine techniques for prevention of female pelvic floor disorders

Professor Margot Damaser, Cleveland Clinic Foundation

Abstract

One of the greatest risk factors for development of pelvic floor disorders is vaginal delivery of children, which can damage the nerves and muscles responsible for continence in addition to the connective tissues responsible for the position of pelvic organs. Without complete nerve regeneration, the muscles can atrophy. Pelvic floor connective tissue can fail to restore the vascularisation necessary for full regeneration. Current treatments, such as an implanted mesh or sling, can have a high rate of complications and a high revision rate. Regenerative interventions done soon after delivery of children, prior to muscle atrophy, has the potential to have an increased success rate and to prevent pelvic floor disorders.

Regenerative medicine usually involves local treatment with autologous stem or progenitor cells. This approach has had mixed results in clinical trials with women with stress incontinence. The mechanism of action of these cells is likely via their secretions. Therefore, a non-cellular approach with fewer risks could be to give the secretions of stem cells rather than inject the cells themselves. This approach also holds the promise of providing an off-the-shelf treatment. 

This talk will summarise our preclinical studies which demonstrate that treatment with secretions of cells provide a strong regenerative effect, even when given systemically. In addition, Professor Damaser will present preclinical data demonstrating that electrical stimulation could also promote neuro-regeneration and facilitate repair. Non-cellular therapies, such as these, given soon after childbirth in women at greatest risk of development of pelvic floor disorders hold great potential to improve the lives of many women.

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14:00-14:30 Preclinical animal models for pelvic organ prolapse

Professor Jan Deprest, UZ Leuven

Abstract

The cause of pelvic organ prolapse (POP) is multifactorial yet includes a complex interplay between genetic factors, vaginal birth-induced trauma, aging and lifestyle. Currently, surgery is the mainstay of therapy and the life-time risk is 19% by the age of 802. Given the relevance of the condition and the failure of current strategies a better understanding of the genesis of POP and the potential for its prevention or improving current therapies appropriate animal models are required. Finding an optimal model is challenging, since humans are bipedal, have no tail, and the foetal head is relatively large compared to the pelvic dimensions, making vaginal delivery more traumatic when compared to other species. This talk will discuss both pelvic organ prolapse and birth induced injuries in animal models

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14:30-15:00 Discussion

15:20-15:45 Implantable tibial neuromodulation therapy for over active bladder

Dr Guri Oron, BlueWind Medical

Abstract

Overactive bladder (OAB) affects millions of people worldwide with neuromodulation offering treatment option for refractory patients. A novel peripheral implantable neurostimulator device for the treatment of OAB was developed (RENOVA iStim™ system), which electrically stimulates the tibial nerve at the site just proximally of the medial malleolus. The implant is wirelessly powered by a wearable unit that controls the therapeutic parameters and is worn by the patient during treatment at home. A Clinician Programmer is used to remotely set individual stimulation parameters. Herewith, the safety and performance of the RENOVA iStim™ system is being observed for the treatment of OAB. Short term; 6-mos results, and long term; 24-mos partial results, will be presented.

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15:45-16:10 Mechanical and etiological aspects of female pelvic floor disorders.

Dr Pedro Martins, University of Porto

Abstract

It is commonly accepted that Pelvic floor disorders (PFD) have many risk factors. However, there is no consensus on their scope and importance. Some are specific for an individual (number of pregnancies) others common to a group or population. A complete and coherent map of prolapse etiology remains an open question.
The complexity of PFD led to different, often complementary, research efforts. The mechanical behaviour of pelvic tissues, is intimately linked with their ‘normal’ and ‘diseased’ status; also influenced by individual characteristics (age, hormonal status, etc.). This led to studies on the changes in the morphology and biomechanics of pelvic tissues using animal models, since it is not feasible (materially, ethically, etc.) to conduct some research on humans. These studies are designed to clarify the scope of each PFD risk factor.

A new and promising frontier lies on the fusion of statistical/epidemiologic information with individual-level knowledge. The estimation of tissue’s mechanical behaviour based on patient specific data, may in turn, feed epidemiologic models with predictive capabilities. Such models bring an array of possibilities and implications - improved clinical diagnostics, PFD risk assessment, improved surgical outcome estimation, etc. To build such tool(s) will require a multidisciplinary effort, between medical doctors, engineers, and mathematicians. 


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16:10-16:40 Tissue engineering and regeneration: regulatory routes to the clinic

Ms Alison Wilson, CellData Services

Abstract

Developing a new medical product requires an understanding of the regulatory environment: how the law views the product and which agencies must be involved in the process. This talk will highlight the different ways in which regenerative medicine products can be regulated in the UK/EU, which in turn dictates how they can be brought into clinical use. Authorisation for clinical trials, processes and supporting data requirements are all entirely dependent upon how a TE/RM product is regulated: as a medical device, a human tissue product or a medicinal product / ATMP. Although perhaps not as exciting as the scientific and clinical challenges involved, an appreciation of the regulatory position early in the process can only increase your chances of successfully developing a safe, effective product that reaches patients in a timely way.

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16:40-17:00 Discussion

OBSTRACT: interpreting the abstraction of tissue regeneration and re-engineering of female pelvic floor disorders in clinical practice The Royal Society, London 6-9 Carlton House Terrace London SW1Y 5AG UK