Maya Horst

Engineering functional bladder tissues

Purpose: End stage bladder disease can seriously affect patient quality of life and often requires surgical reconstruction with bowel tissue, which is associated with numerous complications. Bioengineering of functional bladder tissue using tissue‐engineering techniques could provide new functional tissues for reconstruction. In this review, we discuss the current state of this field and address different approaches to enable physiologic voiding in engineered bladder tissues in the near future. Materials and Methods: In a collaborative effort, we gathered researchers from four institutions to discuss the current state of functional bladder engineering. A MEDLINE® and PubMed® search was conducted for articles related to tissue engineering of the bladder, with special focus on the cells and biomaterials employed as well as the microenvironment, vascularisation and innervation strategies used. Results: Over the last decade, advances in tissue engineering technology have laid the groundwork for the development of a biological substitute for bladder tissue that can support storage of urine and restore physiologic voiding. Although many researchers have been able to demonstrate the formation of engineered tissue with a structure similar to that of native bladder tissue, restoration of physiologic voiding using these constructs has never been demonstrated. The main issues hindering the development of larger contractile tissues that allow physiologic voiding include the development of correct muscle alignment, proper innervation and vascularization. Conclusion: Tissue engineering of a construct that will support the contractile properties that allow physiologic voiding is a complex process. The combination of smart scaffolds with controlled topography, the ability to deliver multiple trophic factors and an optimal cell source will allow for the engineering of functional bladder tissues in the near future. Copyright

Increased porosity of electrospun hybrid scaffolds improved bladder tissue regeneration

The object of this study was to investigate the role of scaffold porosity on tissue ingrowth using hybrid scaffolds consisting of bladder acellular matrix and electrospun poly (lactide-co-glycolide) (PLGA) microfibers that mimic the morphological characteristics of the bladder wall in vitro and in vivo. We compared single-spun (SS) PLGA scaffolds with more porous cospun (CS) scaffolds (PLGA and polyethylene glycol). Scaffolds were characterized by scanning electron microscopy. Bladder smooth muscle cells (SMCs) were seeded, and proliferation and histological assays were performed. Sixteen rats were subjected to augmentation cystoplasty with seeded SS or CS scaffolds, morphological, and histological studies were performed 2 and 4 weeks after implantation. The porosities of SS and CS scaffolds were 73.1 ± 2.9% and 80.9 ± 1.5%, respectively. The in vitro evaluation revealed significantly deeper cell migration into CS scaffolds. The in vivo evaluation showed significant shrinkage of SS scaffolds (p = 0.019). The histological analysis revealed a bladder wall-like structure with urothelial lining and SMC infiltration in both groups. The microvessel density was significantly increased in the CS scaffolds (p < 0.001). Increasing the porosity of electrospun hybrid scaffolds is an effective strategy to enhance cell proliferation and distribution in vitro and tissue ingrowth in vivo.

Determinants of Success and Failure of Seromuscular Colocystoplasty Lined With Urothelium

PURPOSE Seromuscular colocystoplasty lined with urothelium is a method of bladder augmentation that avoids incorporating intestinal mucosa into the urinary tract. Others have reported a repeat augmentation rate of 23%. We analyzed the results in 20 patients who underwent the procedure, as performed by one of us (RG), at 3 institutions. MATERIALS AND METHODS After receiving institutional review board approval we retrospectively reviewed the charts of all patients operated on since 1998. Preoperative and postoperative bladder capacity at 30 cm H(2)O, expressed as the percent of expected capacity for age using the equation, bladder capacity in ml = (age +1) x 30, as well as prior, concomitant and subsequent bladder or bladder neck procedures, continence and the need for repeat augmentation were recorded. RESULTS There were 20 patients, including 7 females, with a mean age at surgery of 9 years and a mean followup of 53 months. All patients had neurogenic bladder dysfunction. An artificial urinary sphincter was implanted at the time of seromuscular colocystoplasty in 10 patients, preoperatively in 6 and postoperatively in 1. A sling was used in 3 females. Patients were divided into 2 groups. The 15 group 1 patients underwent no concomitant procedure in the bladder and the 5 in group 2 underwent creation of a continent channel at seromuscular colocystoplasty. There were no failures of augmentation in group 1, in which bladder capacity increased from 60% of that expected for age to 100%. All patients were continent. Three of the 5 patients in group 2 required repeat augmentation. CONCLUSIONS Seromuscular colocystoplasty lined with urothelium has proved to be an effective method to augment the bladder in patients who have an artificial urinary sphincter or who undergo simultaneous artificial urinary sphincter implantation. We do not recommend constructing a continent catheterizable channel at the time of seromuscular colocystoplasty lined with urothelium.

Repeated Botulinum-A toxin injection in the treatment of neuropathic bladder dysfunction and poor bladder compliance in children with myelomeningocele.

To evaluate the efficacy of intradetrusor injection of Botulinum‐A toxin (BoNT/A) in children with neuropathic bladder dysfunction and poor bladder compliance, due to meningomyelocele.

Long-Term Followup (37 to 69 Years) in Patients With Bladder Exstrophy Treated With Ureterosigmoidostomy: Psychosocial and Psychosexual Outcomes

PURPOSE We describe the long-term psychosocial and sexual outcomes of patients born with bladder exstrophy treated with ureterosigmoidostomy at our institution. MATERIALS AND METHODS Of 42 patients born with bladder exstrophy between 1937 and 1968, 28 were located, of whom 25 agreed to participate in this study. Evaluation consisted of studying pediatric and adult medical records, medical examination, and reports of sexual and social history. RESULTS Four female and 21 male patients with a mean age of 50 years (range 39 to 67) were evaluated. Of the patients 21 (84%) were married or lived in a stable relationship, 6 (24%) had several children after normal conception and an additional 2 (8%) became parents with assisted reproductive technology. Nine patients (36%) reported no sexual activity or were unable to engage in sexual intercourse. All patients except 2 are professionally and socially successful. CONCLUSIONS The long-term followup of this study of 37 to 68 years provides valuable information on patients who live with bladder exstrophy during a long period. Most followed patients who were born with bladder exstrophy and treated with ureterosigmoidostomy were able to lead satisfactory lives socially and professionally. However, at least 36% of the patients are severely restricted in their sexual lives.

Multisystem Neuroprosthetic Training Improves Bladder Function After Severe Spinal Cord Injury

UNLABELLED Severe spinal cord injury leads to neurogenic bladder dysfunction. We recently developed a multisystem neuroprosthetic training program that promotes plastic changes capable of restoring refined locomotion in rats with severe spinal cord injury. We investigated whether multisystem neuroprosthetic training would influence the development of posttraumatic bladder dysfunction. MATERIALS AND METHODS Eight and 4 adult rats were randomly assigned to a spinal cord injury and an intact control group, respectively. Spinal cord injury consisted of 2 opposite lateral hemisections (T7 and T11), thus, interrupting all direct supraspinal input. After spinal cord injury 4 rats were subjected to a multisystem neuroprosthetic training program and 4 were not trained. At 8 weeks we performed urodynamics and evaluated kidney function using creatinine and cystatin C. Bladder investigation included morphological, histological and immunohistochemical evaluations. RESULTS Bladder capacity increased threefold in trained and sevenfold in nontrained rats compared to intact rats. During filling we found a mean ± SEM of 2.7 ± 1.1 vs 12.6 ± 5.2 nonvoiding contractions in trained vs nontrained rats. Bladder morphology was similar in trained and intact rats. Nontrained rats showed detrusor hypertrophy, characterized by increased detrusor thickness and a decreased connective tissue-to-smooth muscle ratio. As labeled with protein gene product 9.5, general nerve density was significantly increased in trained and significantly decreased in nontrained rats. The relative proportion of neurofilament 200 positive afferent nerves was significantly lower in trained than in intact and nontrained rats. Neuropeptide Y positive fibers showed significantly lower density in nontrained rats. CONCLUSIONS Multisystem neuroprosthetic training effectively counteracts the formation of neurogenic bladder dysfunction after severe spinal cord injury and might contribute to preserving bladder function and preventing long-term complications in patients with severe spinal cord injury.

Multi-system neuroprosthetic training improves bladder function after severe spinal cord injury

BACKGROUND: Severe spinal cord injury (SCI) leads to neurogenic bladder dysfunction. We recently developeda multi-system neuroprosthetic training program (MSNT) that promotes plastic changes capable of restoring refinedlocomotion in rats with severe SCI. We investigated whether MSNTinfluences the formation of posttraumatic bladder dysfunction. MATERIALS AND METHODS: Adult rats were randomly assigned to a SCI (n=8) and to a control intact (n=4) group. SCI consisted of two opposite lateral hemisections (T7, T11), thusinterrupting all direct supraspinal input. After SCI, 4 rats were subjected to MSNT, 4 rats were non-trained. After 8 weekswe performed urodynamics and evaluated kidney function (creatinine, cystatin C). Bladder investigation included morphological, histological and immunohistochemical evaluations. RESULTS: Bladder capacity increased 3-fold in trained and 7-fold in non-trained compared to intact animals. During filling,we found 2.7 ± 1.1 non-voiding contractions (NVC) in trained, compared to 12.6 ± 5.2 in non-trained rats. Bladder morphology was similar in trained and intact rats, non-trained ratsexhibited detrusor hypertrophycharacterized by increased detrusor thickness and decreased connective tissue to smooth muscle ratio. The general nerve density, labeled with PGP9.5, was significantly increased in trained and significantly decreased in non-trained rats. The relative proportion of NF200-postive afferent nerves was significantly lower in trained compared to intact and non-trained rats. NPY-positive fibers showed a significantly lower density in non-trained rats. CONCLUSIONS: MSNT effectively counteracts the formation of neurogenic bladder dysfunction after severe SCI and might contribute to preserving bladder function and preventing long-term complications in patients with severe SCI. DOI: https://doi.org/10.1016/j.juro.2012.08.200 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-64770 Accepted Version Originally published at: Horst, Maya; Heutschi, Janine; den Brand, Rubiavan; Andersson, Karl E; Gobet, Rita; Sulser, Tullio; Courtine, Grégoire; Eberli, Daniel (2013). Multi-system neuroprosthetic training improves bladder function after severe spinal cord injury. Journal of Urology, 189(2):747-753. DOI: https://doi.org/10.1016/j.juro.2012.08.200 MULTI-SYSTEM NEUROPROSTHETIC TRAINING IMPROVES BLADDER FUNCTION AFTER SEVERE SPINAL CORD INJURY Maya Horst, Janine Heutschi, Rubiavan den Brand, Karl E. Andersson, Rita Gobet, Tullio Sulser, Grégoire Courtine, Daniel Eberli Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University of Zurich, Switzerland Center for Neuroprosthetics and Brain Mind Institute, School of Life Science, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland Division of Pediatric Urology, University Children’s Hospital, Zurich, Switzerland. 4 Wake Forest Institute for Regenerative Medicine, Winston Salem, NC, USA For Submission to The Journal of Urology Corresponding Authors: Daniel Eberli MD PhD Department of Urology UniversityHospitalZurich Frauenklinikstrasse 10 CH-8091 Zurich Switzerland Daniel.eberli@usz.ch Tel: + 41 44 255 11 11 Fax + 41 44 255 96 20 GrégoireCourtine PhD School of Life Science Swiss Federal Institute of Technology Lausanne (EPFL) EPFL SV BMI station 19 CH-1019Lausanne, Switzerland gregoire.courtine@epfl.ch Tel: +41 21 693 83 43 Fax: +41 21 693 07 40 Word count: Abstract: 240, Manuscript: 2209 Runninghead neuroprosthetic training improves bladder function

Scaffold Characteristics for Functional Hollow Organ Regeneration

Many medical conditions require surgical reconstruction of hollow organs. Tissue engineering of organs and tissues is a promising new technique without harvest site morbidity. An ideal biomaterial should be biocompatible, support tissue formation and provide adequate structural support. It should degrade gradually and provide an environment allowing for cell-cell interaction, adhesion, proliferation, migration, and differentiation. Although tissue formation is feasible, functionality has never been demonstrated. Mainly the lack of proper innervation and vascularisation are hindering contractility and normal function. In this chapter we critically review the current state of engineering hollow organs with a special focus on innervation and vascularisation.

Stem Cells in Functional Bladder Engineering

Conditions impairing bladder function in children and adults, such as myelomeningocele, posterior urethral valves, bladder exstrophy or spinal cord injury, often need urinary diversion or augmentation cystoplasty as when untreated they may cause severe bladder dysfunction and kidney failure. Currently, the gold standard therapy of end-stage bladder disease refractory to conservative management is enterocystoplasty, a surgical enlargement of the bladder with intestinal tissue. Despite providing functional improvement, enterocystoplasty is associated with significant long-term complications, such as recurrent urinary tract infections, metabolic abnormalities, stone formation, and malignancies. Therefore, there is a strong clinical need for alternative therapies for these reconstructive procedures, of which stem cell-based tissue engineering (TE) is considered to be the most promising future strategy. This review is focused on the recent progress in bladder stem cell research and therapy and the challenges that remain for the development of a functional bladder wall.

Retroperitoneoscopically assisted repair of an abdominoscrotal hydrocele

We present a 2-month-old boy with a primary obstructive megaureter and a giant abdominoscrotal hydrocele (ASH) on the left side. The ASH was initially misdiagnosed as a fornix rupture with infrarenal urinoma, but clinical and radiological examination led to the right diagnosis. Retroperitoneoscopically assisted mobilization combined with the inguinal approach allowed the successful resection of this large ASH.