Introduction: A surgically efficient and cost-effective tissue engineered implant to reconstruct the urethra has not yet replaced current surgical practice of autologous tissue grafts. Cell based approaches have shown progress. However, these have been associated with high costs and logistical challenges. An acellular, off-the-shelf implant with good regenerative potential is more likely to be used in clinical practice than a cellular implant. Methods: Collagen implants were developed over a period of 8 years all using bovine collagen as base material. 69 male New Zealand rabbits were utilized to refine the final design. The various implant generations underwent in vitro testing, mechanical analyses, and bench testing by surgeons. The final prototype was implanted in 9 rabbits and 6 dogs. Rabbits were evaluated at 1, 3, and 6 months using visual examination and contrast voiding cysto-urethrography. Biopsies of repaired sites from euthanized rabbits were subjected to histology and immunohistochemistry. The dogs were examined by clinical patency assessment and histology up to 16 months. Approval was given from the Medical Research Ethics Committee at University of Malaya Medical Centre (UMMC),Malaysia, for a 5 patient first in man study to evaluate the implants for substitution urethroplasty of distal urethral strictures of 3cm. The first patients were operated in August 2022 using the acellular collagen implant and the standard surgical technique. Results: Rabbit urethra: 2cm defect Sacrifice time (months) 1 3 6 Number of animals 1 4 4 Micturition & Patency Normal micturition and patent urethra Dog urethra: 4cm defect Sacrifice time (months) 1 5 and 10 12 and 16 Number of animals 2 2 2 Micturition & Patency Normal micturition and patent urethra Spontaneous urothelial coverage of the implants and smooth muscle cell migration into the implanted area was demonstrated by standard histology and immunohistochemistry in the different time points in the in vivo studies. 2 patients have been implanted with the final prototype bridging urethral defects of less than 3 cm. A peri-ureterogram was done 3 weeks post-surgery and showed no leak and both patients have no voiding complications to date. Conclusions: The acellular implant may have the potential to be an off the shelf product rendering substitution urethroplasty less harmful. Its mechanical properties allow surgeons to easily recreate a physical conduit while its material properties favour tissue regeneration. A large-scale clinical trial is required to further confirm safety, performance and cost effectiveness. SOURCE OF Funding: Swiss and Malaysian Grants
