The Challenge of Stress Incontinence and Pelvic Organ Prolapse

Revisiting Biologic Mesh Materials

William D'Angelo; Jenna Dziki; Stephen F. Badylak

Disclosures

Curr Opin Urol. 2019;29(4):437-442. 

In This Article

Modifying Surgical Meshes to Improve Clinical Outcomes

Attempts to develop improved strategies for the surgical repair of POP/SUI have focused upon addressing mesh-related complications, primarily through modification or functionalization of mesh materials. The continued determination of the mechanism by which mesh materials promote tissue remodeling has highlighted the importance of modifying the host response. Specifically, the early host macrophage response has been shown to be an important determinant of mesh-mediated tissue remodeling at later outcomes. Attempts to modify mesh materials to promote a better host response has been the central focus of the biomaterials field, and has broad implications for the field of POP/SUI repair.

For example, a comparison between a composite mesh composed of polypropylene sutured to a sheet of UBM versus polypropylene (Gynemesh PS, Ethicon) alone or UBM (MatriStem RS, ACell) alone in a rhesus macaque model of POP showed that the addition of UBM attenuated the early proinflammatory immune response to the polypropylene in the composite mesh. However, the UBM mesh alone performed better than polypropylene or the composite mesh in terms of biomechanical, histomorphologic, and biochemical endpoints at 12 weeks postsurgery.[29] Coating polypropylene mesh with a platelet-rich plasma (PRP) gel compared with uncoated polypropylene mesh in a rabbit model showed that the PRP-coated mesh reduced inflammatory cell infiltrate at 30 days and promoted increased collagen production between the vaginal epithelium and the rectovaginal facia at 90 days after implantation.[30] Similarly, Darzi et al. evaluated whether collagen coatings could improve the host response to polypropylene. A comparison between uncoated polypropylene (Avaulta Solo, Bard) and chemically crosslinked porcine collagen-coated polypropylene (Avaulta Plus, Bard) or solubilized atelocollagen-coated polypropylene (PP-sCOL, Sofradim International; Trevoux, France) meshes at 60 and 180 days after implantation in an ovine model of POP showed improved biocompatibility (i.e. an improved macrophage response) compared to uncoated polypropylene with atelocollagen-coated polypropylene. Conversely, crosslinked collagen coating delayed the pro-inflammatory (M1-like) to pro-remodeling (M2-like) macrophage phenotype transition compared with the atelocollagen coating. However, by 180 days, similar amounts of mature and immature collagen fibers were found with all mesh types.[31]

The use of alternative synthetic polymers to promote a favorable host response has also been widely investigated. For example, polyvinylidene fluoride (PVDF) has been reported to have improved biocompatibility compared with polypropylene in preclinical animal models[32,33] and has been used in multiple clinical trials for incisional hernia repair.[34,35] Barski et al. evaluated a PVDF transvaginal mesh (DynaMesh-PR4, FEG Textiltechnik; Aachen, Germany) for POP repair in 34 women. At follow-up (mean 19 months), 14% of patients experienced complications including recurrent prolapse, urinary incontinence, and mesh exposure, and 8.8% required reoperation.[36] Jango et al. used rat abdominal wall partial thickness defect model to evaluate the host response to a synthetic biodegradable scaffold composed of methoxypolyethylene glycol polylactic-co-glycolic acid (MPEG-PLGA; ASEED, Coloplast). Meshes were implanted with or without autologous muscle fiber fragments (MFF) seeded between the mesh and the muscle defect. The muscle fiber fragments contributed to increased muscle growth on the scaffold 8 weeks after implantation, and uniaxial biomechanical testing showed significantly higher strength with MFF seeding.[37] Though this method showed promising preclinical results, the use of autologous muscle transfer may prohibit expedited clinical translation of such approaches.

In addition to biochemical properties of mesh materials, physical microstructure is also an important consideration when attempting to modify the host response to any biomaterial. Electrospinning is a fabrication technique that uses an electric charge to deposit nano-scale polymer fibrils in a random pattern to produce a microarchitecture, which mimics natural ECM. The intent of this deposited fibril coating is to facilitate cell attachment and growth.[38] Lai et al. used a rabbit model to test mechanical strength and biocompatibility of an electrospun polypropylene sub-urethral support mesh (Regensling, Medprin Biotech GmbH; Frankfurt, Germany) after 4, 12, and 26 weeks postimplantation in a rabbit model. Compared with conventional knitted polypropylene mesh (Gynecare TVT-O, Ethicon), histological analysis of the electrospun mesh showed less immune cell infiltrate in the mesh area, and explants had significantly higher tensile strength.[39] Wang et al. compared adipose-derived stem cell (ADSC) growth on electrospun poly-lactic acid (PLA) and poly(L-lactide)-trimethylene carbonate-gycolide (PLTG) for 1 and 2 weeks. Measured outcomes included proliferation, morphology, ECM protein expression, and uniaxial tensile strength, and results suggested that cells proliferated well and deposited ECM, which significantly increased the tensile strength of the material after 2 weeks.[40] Mangir et al. engineered an oestradiol-releasing electrospun PLA mesh on which they cultured ADSCs and measured proliferation and ECM production. They also evaluated the ability of this mesh to stimulate angiogenesis using the chorioallantoic membrane assay.[41] This group similarly developed and tested an oestradiol-releasing electrospun polyurethane scaffold, and showed that the addition of oestradiol resulted in significantly increased ECM deposition, angiogenesis, and tensile strength.[42]

Biologic materials have been modified in an attempt to improve their ability to promote new matrix deposition. For example, Li et al. evaluated a porcine UBM scaffold with crosslinked Sca-1 antibody and bFGF, which was designed to recruit host stem cells and promote their differentiation to smooth muscle cells. Seven days after implantation into the mouse vaginal wall, explanted scaffolds were found to be enriched for Sca-1+ cells, and production of the smooth muscle marker fibulin-5 was increased.[43] The use of a polydopamine adhesive to coat a porcine UBM scaffold with the basement membrane proteins laminin and nidogen to enhance host cell attachment and proliferation has also been explored. Scaffolds crosslinked with EDC/NHS in an attempt to reduce the degradation rate and implanted in a rat vaginal mucosa defect for 6 weeks showed an increase in CD31+ cells and had higher Th2:Th1 and M2:M1 ratios compared with uncoated UBM, suggesting room for improvement in modifying the host response with ECM-based biomaterials.[44] Simões et al.[45] decellularized whole porcine urethras and demonstrated their recellularization in vitro with skeletal muscle myoblasts, muscle progenitor cells, and adipose-derived stromal vascular fraction as a step toward urethra replacement and tissue engineering applications. Finally, Good et al. [46] applied a fibulin-5-releasing hydrogel to inhibit the function of matrix metalloprotease-9 and promote ECM synthesis in mouse vaginal fibroblasts in vitroand in the mouse vaginal wall in vivo, suggesting an innovative strategy for POP/SUI treatment that could be used alone or in combination with other materials.

Although the results of such preclinical studies hold promise for the use of alternative synthetic polymer mesh materials, novel manufacturing methods to control their physical properties, and composite materials that incorporate biologic components, hurdles remain to their clinical translation. Beyond the economic consequences of utilizing stem-cell-based or autologous tissue, batch-to-batch variability and their anticipated clinical outcomes remains an unaddressed concern. Combinatorial approaches using drug-coatings and other biologics to augment both synthetic and biologic meshes not only introduces heightened economic burdens, but also introduces further regulatory considerations. Moreover, the inability to closely model POP/SUI in preclinical animal studies likely has significant implications on the disparity between preclinical and clinical success in the use of surgical mesh augmentation to primary repair. A parallel investment in an increased understanding of the pathogenesis of POP/SUI injury, better preclinical animal models, and the determination of the impact of both composition and structure of mesh materials upon mechanisms of constructive and timely tissue repair will be crucial to improving patient outcomes.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....