Søren Gräs

Tissue engineering as a potential alternative or adjunct to surgical reconstruction in treating pelvic organ prolapse

Introduction and hypothesisCell-based tissue engineering strategies could potentially provide attractive alternatives to surgical reconstruction of native tissue or the use of surgical implants in treating pelvic organ prolapse (POP).MethodsBased on a search in PubMed, this review focuses on candidate cell types, scaffolds, and trophic factors used in studies examining cell-based tissue engineering strategies to treat POP, stress urinary incontinence (SUI), and the closely related field of hernias.ResultsIn contrast to the field of SUI, the use of cell-based tissue engineering strategies to treat POP are very sparsely explored, and only preclinical studies exist.ConclusionThe available evidence suggests that the use of autologous muscle-derived cells, fibroblasts, or mesenchymal stem cells seeded on biocompatible, degradable, and potentially growth-promoting scaffolds could be an alternative to surgical reconstruction of native tissue or the use of conventional implants in treating POP. However, the vagina is a complex organ with great demands of functionality, and the perfect match of scaffold, cell, and trophic factor has yet to be found and tested in preclinical studies. Important issues such as safety and economy must also be addressed before this approach is ready for clinical studies.

The clinical relevance of cell-based therapy for the treatment of stress urinary incontinence.

Stress urinary incontinence is a common disorder affecting the quality of life for millions of women worldwide. Effective surgical procedures involving synthetic permanent meshes exist, but significant short‐ and long‐term complications occur. Cell‐based therapy using autologous stem cells or progenitor cells presents an alternative approach, which aims at repairing the anatomical components of the urethral continence mechanism. In vitro expanded progenitor cells isolated from muscle biopsies have been most intensely investigated, and both preclinical trials and a few clinical trials have provided proof of concept for the idea. An initial enthusiasm caused by positive results from early clinical trials has been dampened by the recognition of scientific irregularities. At the same time, the safety issue for cell‐based therapy has been highlighted by the appearance of new and comprehensive regulatory demands. The influence on the cost effectiveness, the clinical relevance and the future perspectives of the present clinical approach are discussed.

Fresh muscle fiber fragments on a scaffold in rats–a new concept in urogynecology?

OBJECTIVE To investigate if a synthetic, biodegradable scaffold with either autologous in vitro cultured muscle-derived cells or autologous fresh muscle fiber fragments could be used for tissue repair. STUDY DESIGN Twenty scaffolds with muscle-derived cells and 20 scaffolds with muscle fiber fragments were implanted subcutaneously on the abdomen of rats, 2 in each rat, and examined after 3 weeks (10 of each preparation) and 8 weeks (10 of each preparation). Immonohistochemistry and histopathology was undertaken for assessment of growth pattern and biocompatibility, respectively. RESULTS At 3 weeks, both muscle-derived cells and muscle fiber fragments could be identified. At 8 weeks, the muscle fiber fragments generated fragmented, striated muscle tissue in 6 of 10 explants, whereas the muscle-derived cells and all scaffolds had vanished. CONCLUSION Autologous fresh muscle fiber fragments on a biodegradable scaffold seem useful for tissue repair. This study introduces a promising new concept with possible implications for the surgical reconstruction of pelvic organ prolapse.

Examinations of a new long-term degradable electrospun polycaprolactone scaffold in three rat abdominal wall models:

Alternative approaches to reinforce native tissue in reconstructive surgery for pelvic organ prolapse are warranted. Tissue engineering combines the use of a scaffold with the regenerative potential of stem cells and is a promising new concept in urogynecology. Our objective was to evaluate whether a newly developed long-term degradable polycaprolactone scaffold could provide biomechanical reinforcement and function as a scaffold for autologous muscle fiber fragments. We performed a study with three different rat abdominal wall models where the scaffold with or without muscle fiber fragments was placed (1) subcutaneously (minimal load), (2) in a partial defect (partial load), and (3) in a full-thickness defect (heavy load). After 8 weeks, no animals had developed hernia, and the scaffold provided biomechanical reinforcement, even in the models where it was subjected to heavy load. The scaffold was not yet degraded but showed increased thickness in all groups. Histologically, we found a massive foreign body response with numerous large giant cells intermingled with the fibers of the scaffold. Cells from added muscle fiber fragments could not be traced by PKH26 fluorescence or desmin staining. Taken together, the long-term degradable polycaprolactone scaffold provided biomechanical reinforcement by inducing a marked foreign-body response and attracting numerous inflammatory cells to form a strong neo-tissue construct. However, cells from the muscle fiber fragments did not survive in this milieu. Properties of the new neo-tissue construct must be evaluated at the time of full degradation of the scaffold before its possible clinical value in pelvic organ prolapse surgery can be evaluated.

Tissue engineering as a potential alternative or adjunct to surgical reconstruction in treating pelvic organ prolapse: reply to Osman et al.

Dear Editor, We thank Dr. Osman and collaborators for their positive interest in our recent review on the potential use of tissue engineering techniques for pelvic organ prolapse repair [1]. We agree with their general comments on the use of biocompatible and biodegradable implant materials in combination with cells or tissue to avoid the complications we face today. Numerous tissue engineering strategies have been employed in this and other medical fields and we acknowledge that a synthetic or biological implant made of electrospun polylactic acid or porcine small intestine submucosa in combination with autologous buccal mucosa fibroblasts or lipoaspirate stem cells are potentially interesting combinations although the ideal implant material and cell type or tissue have yet to be established. Generally speaking, we believe that a synthetic biocompatible and biodegradable material is more attractive than a biological material because it can be manufactured under controlled circumstances and at a low cost and potentially can be engineered to mimic the normal biomechanics of the pelvic floor. Autologous lipoaspirate stem cells indeed are interesting candidate cells. They are able to differentiate into several cell lineages of relevance to pelvic floor repair. The abundance of potential donor tissue and the relatively easy isolation procedure also allow for a strategy using freshly isolated cells instead of cultured cells. Such a strategy would be simple and cost-effective and consequently increase the clinical relevance of the procedure.

Tissue engineering: creation of an autogenic collagenous neoligament for cure of urinary stress incontinence. Reply to Petros

Dear Editor, We thank Dr. Petros [1] for his interest in our recent review about tissue engineering as a potential alternative or adjunct to surgical reconstruction in treating POP [2]. Regenerative medicine is a new interdisciplinary biomedical field that is aimed at replacing or regenerating human cells, tissues or organs to restore or establish normal function [3]. Avariety of biomedical approaches have been explored and traditionally, the term tissue engineering has been confined to strategies involving ex vivo creation of replacement tissue using cells and scaffolds with the intention of subsequent in vivo implantation [4]. For clarity, our review focused on such strategies. Petros et al. implantedMersilene tape in dogs and observed formation of collagenous tissue around the tape; following surgical removal of the tape, the collagenous tissue persisted for at least 6 weeks [5]. We acknowledge that the idea of attempting to create a ligament with a removable implant is innovative and that the procedure in a broader sense of the term may be called tissue engineering. It remains to be seen if the newly formed collagenous tissue is in fact a neo-ligament, as claimed by the authors, and not just transient scar tissue. The disappointing results from the subsequent clinical trial reported by Dr. Petros may point to the latter. Dr. Petros states that the tissue fixation system (TFS) evolved from this experiment and that it has been successfully applied to the cure of POP. However, the minislings and anchors of the TFS are permanent implants, which to us make a great difference. Furthermore, we are not aware of any studies that demonstrate that TFS is better and/or safer than native repair or the use of other implants for the treatment of POP. Two relevant questions concerning a future application of tissue engineering strategies to treat POP are raised by Dr. Petros: where and how do we place the cells? The TFS uses permanent minislings with permanent tissue anchors in an attempt to repair and reinforce pelvic floor ligaments. Perhaps a similar or better effect and fewer complications can be achieved with a TFS-like procedure using slings and anchors made of a degradable material loaded with autologous fibroblasts and trophic factors.