Pelvic Organ Prolapse (POP) is a disorder with a growing incidence and a concealed clinical burden. Currently, there is a scarcity of surgical grafts available to address POP repair, despite the increasing demand with the aging population. This shortage results from the commercial withdrawal of all transvaginal Meshes and, more recently, the withdrawal of all Meshes for sacrocolpopexy (abdominal correction of usually apical prolapse). In clinics, non-degradable monolayer-knitted meshes such as polypropylene (PP) have widespread applications for treating POP. However, given the adverse events, including mesh erosion and pain, non-degradable meshes have been banned from their clinical applications by the regulatory authorities in several countries, namely Australia, New Zealand, the USA and the UK. In literature, mesh-related adverse events are associated with tissue-degenerative foreign body reactions (FBR), thereby chronic inflammation [1, 2]. Human Fascia Lata (HFL) grafts have long been employed for incontinence procedures and, more recently, for sacrocolpopexy or graft-augmented vaginal repair where synthetic Mesh is contraindicated or unavailable. However, there is insufficient data investigating the FBR, an unavoidable process that occurs when any material is implanted into the body, particularly in comparison to Mesh. 
We hypothesise that human fascia Lata (HFL) can be the alternative constructs obtained from the same or different donors for their applications as autograft or allograft tissue for POP surgeries. This study harvested HFL as xenogeneic (cross-species) transplantation, aiming to directly compare the FBR to HFL and investigate patient-to-patient variability in FBR. The study used commercially available synthetic mesh to better characterise HFL's long-term implications and the mechanisms driving its integration in the body—a necessary step before widespread adoption.

HFL tissue was collected from women undergoing sacrocolpopexy or pubovaginal sling insertion (n=26). C57BL6 mice were implanted with HFL or synthetic Mesh (n=8 mice/gp/time-point) via an abdominal incision. Assessments occurred at seven and ninety-day intervals, involving gene expression analysis and spatial proteomics for immune response. Utilising spatial tissue imaging, we identified a reduced number of neutrophils around the implanted HFL seven days post-surgery compared to synthetic mesh, supported by significantly reduced E-selectin (involved in Neutrophil recruitment to the inflammatory site) gene expression. This suggests a diminished inflammatory response in the acute phase of FBR in the HFL group. Additionally, there was a significant upregulation of myeloid markers, including Mrc1, Nos2, Arg1, Nfkb1, Tlr4, Nlrp3, ninety days after HFL implantation compared to Mesh. This upregulation extended to the gene expression of leukocyte trafficking receptors, including Ccr1, Cxcr3, and Cxcr2, after ninety days in the HFL group. Simultaneously, the expression of T lymphocyte markers, cytokine receptors, and transcription factors, including Cd3, Cd4, Tbx21, Stat1, Il4r, Il13r, increased. This finding was further supported by spatial tissue imaging, revealing a higher number of dendritic cells and helper T lymphocytes around the implanted HFL ninety days after implantation. We also detected a significant difference in regulatory gene expression between the HFL and mesh groups. Two regulatory markers, Cd2seven4 and Foxp3, were upregulated in the HFL group ninety days after implantation compared to the mesh group. Spatial imaging showed an increased number of regulatory double-negative T lymphocytes in the HFL group after seven and ninety days compared to the mesh group. Furthermore, sixteen angiogenic and ECM synthesis genes were upregulated in the HFL group compared to mesh ninety days after implantation, which was supported by the increased number of CD31+ cells around the implanted HFL after ninety days.

HFL demonstrates superior performance over polypropylene mesh regarding tissue integration and durability, making it an appealing choice for surgical grafts in pelvic reconstruction. Employing advanced techniques, including Spatial Tissue Imaging and Fluidigm® 96.96 Real-Time PCR, this study revealed a significant contrast in the activation of immune cells in response to HFL compared to synthetic mesh. Furthermore, we observed an intricate interplay between the innate and adaptive immune systems following HFL implantation, leading to heightened angiogenesis and deposition of extracellular matrix ninety days post-implantation, facilitating the seamless integration of HFL into the host tissue.

The investigation into the Foreign Body Response (FBR) unveils a multifaceted immune landscape triggered by HFL and mesh implants. The upregulation of chemokine receptors (Cxcr3, Cxcr2, Ccr1) indicates a diverse array of cell trafficking patterns, potentially impacting the recruitment and activation of various immune cell types. This activation extends to myeloid cells, notably evidenced by the heightened expression of M2 macrophage markers (Arg1, Mrc1) and elevated levels of proinflammatory markers (Nos2, Tlr4, Nlrp3), showcasing the intricate balance between inflammation and tissue remodelling processes. The augmented presence of dendritic cells and macrophages surrounding HFL implants after ninety days, alongside the increased expression of T lymphocyte activation markers (Cd3, Stat1, Tbx21), suggests a close interplay between these cells and their influence on the upregulated gene expression of angiogenesis and extracellular matrix (ECM) synthesis markers. Furthermore, the enhanced expression of cell adhesion receptors (Itgb5, Vcam) within the HFL group could potentially facilitate cellular interactions within the tissue microenvironment, aiding in implant integration. Distinct patterns emerge in myeloid cell recruitment, with early prominence of dendritic cells in HFL responses and persistent neutrophil activity around mesh implants. These findings hint at unique immune trajectories elicited by biological and synthetic grafts. Notably, the increased presence of macrophages and T lymphocytes surrounding HFL implants after ninety days suggests a transition towards a resolving immune environment, potentially fostering tissue healing and integration processes. In essence, these discoveries illuminate the dynamic and complex nature of the immune response elicited by HFL and mesh implants, offering insights into their potential impact on tissue regeneration, implant integration, and the development of therapeutic strategies for biomaterial design.

The prospective meshes for POP surgeries have been unclassified (class 3) by the regulatory authorities, which indicates robust preclinical assessments centred around chronic toxicity or foreign body response (FBR). This is the first study to reveal how human fascia lata (HFL) alters the biomechanical performances and tissue response at the implant site and comments on the translational potential of these constructs as readily available tissue grafting sources for POP surgeries.

Mukherjee S et al. Biomacromolecules 2019; 20 (1):454-68
Liang R et al. BJOG. 2013 Jan;120(2):233-243