Review articleMeshes in a mess: Mesenchymal stem cell-based therapies for soft tissue reinforcement
Graphical abstract
Introduction
Surgical meshes are medical devices designed to reinforce and stabilize weakened tissue, frequently used for the treatment of incisional hernia, pelvic organ prolapse, and stress urinary incontinence [1], [2], [3]. The implantation of surgical meshes by open surgery or laparoscopy is a common procedure. According to bioengineering parameters, the “ideal mesh” should be inert, resistant to infections, and flexible, with long-term tensile strength and rapid mesh-tissue integration [4]. It is important to note that the concept of “ideal mesh” is closely related to the pathology to be treated. In this sense, urogynecologic meshes (for stress urinary incontinence and pelvic organ prolapse) are implanted in tissues which are mechanically, anatomically, and biologically different from abdominal or inguinal hernias. Currently, non-absorbable meshes are the most widely-used implants for tissue reinforcement in hernia-related complications; their successful integration involves histopathological and immunological changes providing long-term strength, stability, and durability [5].
The majority of non-absorbable surgical meshes are made of polypropylene, polyester, expanded polytetrafluoroethylene (ePTFE), or polyvinylidene fluoride (PVDF). Out of these materials, polypropylene is the most commonly used due to its versatility, mechanical stability, strength, lower risk of bacterial infections, and resistance to biological degradation [6]. These synthetic meshes have been combined with a wide range of compounds to improve their biological properties [7], [8]. Several studies have demonstrated that the physical-mechanical properties of implanted meshes are closely related to the pore size, weight, and elasticity of the mesh. They can also be divided into ultralight, light, standard, or heavy categories [9] and classified in terms of tensile strength (N/cm2, MPa). Animal models have demonstrated that multifilament hydrophobic meshes exhibit an increased bacterial persistence when compared to monofilament polypropylene [10]; furthermore the risk of infection is inversely correlated with the pore size of surgical meshes [11], [12], [13].
It is important to note that these non-absorbable meshes can lead to pathological changes such as adherence to visceral organs, hardening, shrinking, fibrosis, calcification, thrombosis, and infections, all of which are related to clinical symptoms such as chronic pain and discomfort [14], [15], [16]. These adverse effects are frequently reported in patients with urogynecological disorders where tissue erosion at the implantation site is particularly common [17], [18], [19]. At present, the unacceptable failure rate of surgical interventions is a matter of debate in the FDA (Food and Drug Administration) and EMA (European Medicines Agency) [20], [21]. In October 2008, after a review of adverse events, the FDA supplied a Public Health Notification about the safety and effectiveness concerns over the use of surgical meshes for the transvaginal repair of pelvic organ prolapse [22]. Given the high number of reports of injury, death, and malfunction, in 2011 the FDA issued an Update on the Safety and Effectiveness of Transvaginal Placement for Pelvic Organ Prolapse [23] as well as a Safety Communication [24] to inform patients and health care providers about the risks associated with urogynecologic meshes. In light of these warnings, many devices were removed from urogynecological use [25].
In hernia-related disorders, several complications are possible after mesh implantation [26]; however compared to pelvic organ prolapse or stress urinary incontinence, the failure rates are significantly lower [27].
Apart from non-absorbable meshes, both absorbable and biological meshes are being used to decrease post-operative complications. Absorbable meshes are gradually absorbed over time to minimize the amount of foreign material remaining. In theory, these meshes should be capable of reducing the intense foreign body reaction and immune response encountered with non-absorbable meshes [5]. Biological meshes are composed of decellularized tissue with a dense network of collagen and biological factors which positively influence wound healing. In comparison to synthetic materials, biological meshes increase the safety of mesh implantation in contaminated areas [5]. They can be crosslinked to delay degradation and increase their stability; however, crosslinking seems to decrease the biocompatibility of the material as well as the strength of incorporation into host tissue [28], [29]. It is important to note that also patient-specific factors may differently influence the wound-healing response to the same biological mesh, modifying the implantation environment and mesh degradation [30].
In the last decade, cell-based therapies have become attractive tools for improving host tissue infiltration and integration of surgical meshes. In the case of mesenchymal stem cell (MSC) based therapies, these cells have been found to exhibit an anti-inflammatory effect and a pro-regenerative potential thus enhancing wound healing and tissue repair [31], [32]. An autologous approach to MSC therapy (i.e., using cells from the patient's own body) may be safer in that it avoids unwanted immune responses, yet it presents obvious drawbacks in the time frame for treatments and clinical costs. Allogeneic therapies offer the possibility of administering cells as an “off-the-shelf” product that can be subjected to more stringent quality control than autologous products [33]. Recent studies demonstrate that allogeneic MSCs are not immunoprivileged, exhibiting both cell- and humoral-mediated immune responses to major histocompatibility complex (MHC)-mismatched MSCs [34], [35], [36]. In any case, under the authors’ point of view, both autologous and allogeneic MSCs may provide safe and clinically applicable therapies in the field of surgical meshes. Therefore, the purpose of this review is as follows: (I) to provide an overview of in vitro and in vivo studies where differentiated cells have been combined with surgical meshes; (II) to summarize current research on surgical meshes and mesenchymal stem cell-based therapies; and (III) to describe and classify the sequential mechanisms that occur after surgical-mesh implantation and the role of MSCs in these mechanisms.
Section snippets
Fibroblast-based therapy
One of the main disadvantages of non-absorbable materials is the induction of adverse foreign body reactions [37]. To ameliorate this problem, various studies have been conducted attempting to enhance the biocompatibility of these materials. As shown in Table 1, autologous differentiated cells have been combined with biomaterials and in vitro and in vivo assays have been performed to assess tissue regeneration.
A number of in vitro studies have been conducted to assess the feasibility of
Mesenchymal stem cell-based applications for surgical mesh implantation
The use of MSCs with surgical meshes represents a new option in the field of abdominal wall repair when soft tissue reinforcement is necessary. Their differentiation, immunomodulatory effect, and anti-inflammatory properties can be combined with the physical-mechanical support provided by the surgical mesh itself. However, few studies have thoroughly investigated the optimal source of MSCs and their participation in tissue remodeling and inflammation.
Based on a bibliographic search, it can be
Foreign body reaction and MSC activity during surgical mesh implantation
Foreign body reaction is the host response to implanted biomaterials which, after inflammation and wound healing, leads to fibrous encapsulation of the implant. In this fibrous capsule, macrophages and giant cells surrounded by lymphocytes and plasma cells are accumulated around the biomaterial. In this section, we summarize the different phases of this sequential process together with the biological mechanisms in which the MSCs may simultaneously participate during tissue integration of
Future perspectives for mesenchymal stem cell-based therapies in surgical meshes
According to the preclinical studies described above and the therapeutic potential of MSCs, it is expected that these cells will become a valuable tool in the treatment of diseases requiring tissue reinforcement. From a surgical point of view, future studies should be conducted to develop medical devices and surgical procedures to optimize MSC delivery at the implantation site. In the field of stem cell biology, such studies should focus on determining the optimal source for MSC-based therapies
Acknowledgement
Special thanks to Nuria Gónzalez Trejo for graphical abstract design and to Beatriz Macías for reviewing the manuscript.
Funding
This work was supported in part by ISCIII (CP17/00021), co-funded by ERDF/ESF, “Investing in Your Future,” a grant from Junta de Extremadura (Ayuda a grupos catalogados de la Junta de Extremadura, GR15175), a grant from Junta de Extremadura to JGC (IB16168) co-funded by ERDF/ESF, a grant from MAFRESA S.L. to FM and grants to MVB as Researcher at the National Council for Science and Technological Development – CNPq, Brazil (308019/2015-6 and 200346/2017-2).
Disclosure
The authors declare that they have no competing interests.
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These authors equally contributed and should be regarded as co-first authors.