PI David Vorp, PhD
Co-PIs Michael Chancellor, MD; Douglas Chew, BS; Johnny Huard, PhD; Naoki Yoshimura, MD, PhD
Title Bioengineered Urethral Augmentation
Summary Urethral dysfunction is a common complication of diabetes mellitus, spinal cord injury and pelvic trauma. Stress urinary incontinence (SUI) – the involuntary loss of urine secondary to a damaged urethral sphincter mechanism – is particularly common in women and can result from vaginal childbirth. There are currently several approaches to treat SUI, all of which are limited by ineffectiveness or subsequent complications. Regenerative medicine approaches, including cell therapy and tissue engineering, could potentially address these limitations. We believe that utilization of a functional tissue engineered urethral wrap (TEUW) will allow the native urethra to remain intact, while providing enhanced mechanical stability and functional reinforcement through designed regenerative repair mechanisms.
We will explore the use of progenitor cells as the functional component of a TEUW. Specifically, we will explore the following two hypotheses:
a living, functional, smooth muscle-populated tubular construct can be fabricated in-vitro by appropriately stimulating bone marrow derived progenitor cells (BMPCs) within a natural biological matrix; and
a tissue engineered urethral wrap (TEUW) derived from these constructs can be successfully implanted and will reverse the short-term changes in mechanical and functional properties of the urethra found in a rat model of SUI. We propose two specific aims to explore these hypotheses.
AIM 1 is to fabricate a living, functional smooth muscle populated tubular construct from BMPCs and a natural biological matrix that is suitable for implantation as a TEUW. This will be determined by determining the in-vitro stimulation regimen, chosen from a cadre of combinations of mechanical strain and biochemicals that yield optimal histological, functional, biomechanical and immunological properties.
AIM 2 is to assess a TEUW composed of the BMPC-derived SMC-populated constructs from specific aim 1. Assessments will include both in vitro and in vivo analyses, using histological, functional, biomechanical, and immunological endpoints. Results will be compared with normal and diseased native urethra, as well as a TEUW constructed using isolated native urethral SMCs. Successful development a TEUW for an insufficient urethral continence mechanism would potentially provide relief from SUI and other urethral disorders.
Source NIH-R21
Term 2 Years