Elsevier

Acta Biomaterialia

Volume 85, February 2019, Pages 60-74
Acta Biomaterialia

Review article
Meshes in a mess: Mesenchymal stem cell-based therapies for soft tissue reinforcement

https://doi.org/10.1016/j.actbio.2018.11.042Get rights and content

Abstract

Surgical meshes are frequently used for the treatment of abdominal hernias, pelvic organ prolapse, and stress urinary incontinence. Though these meshes are designed for tissue reinforcement, many complications have been reported. Both differentiated cell- and mesenchymal stem cell-based therapies have become attractive tools to improve their biocompatibility and tissue integration, minimizing adverse inflammatory reactions. However, current studies are highly heterogeneous, making it difficult to establish comparisons between cell types or cell coating methodologies. Moreover, only a few studies have been performed in clinically relevant animal models, leading to contradictory results. Finally, a thorough understanding of the biological mechanisms of mesenchymal stem cells in the context of foreign body reaction is lacking. This review aims to summarize in vitro and in vivo studies involving the use of differentiated and mesenchymal stem cells in combination with surgical meshes. According to preclinical and clinical studies and considering the therapeutic potential of mesenchymal stem cells, it is expected that these cells will become valuable tools in the treatment of pathologies requiring tissue reinforcement.

Statement of Significance

The implantation of surgical meshes is the standard procedure to reinforce tissue defects such as hernias. However, an adverse inflammatory response secondary to this implantation is frequently observed, leading to a strong discomfort and chronic pain in the patients. In many cases, an additional surgical intervention is needed to remove the mesh.

Both differentiated cell- and stem cell-based therapies have become attractive tools to improve biocompatibility and tissue integration, minimizing adverse inflammatory reactions. However, current studies are incredibly heterogeneous and it is difficult to establish a comparison between cell types or cell coating methodologies. This review aims to summarize in vitro and in vivo studies where differentiated and stem cells have been combined with surgical meshes.

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.

References (111)

  • K. Su et al.

    Induction of endometrial mesenchymal stem cells into tissue-forming cells suitable for fascial repair

    Acta Biomater.

    (2014)
  • S.L. Edwards et al.

    Temporal changes in the biomechanical properties of endometrial mesenchymal stem cell seeded scaffolds in a rat model

    Acta Biomater.

    (2015)
  • J.M. Anderson et al.

    Foreign body reaction to biomaterials

    Semin. Immunol.

    (2008)
  • Y.S. Park et al.

    Improved viability and activity of neutrophils differentiated from HL-60 cells by co-culture with adipose tissue-derived mesenchymal stem cells

    Biochem. Biophys. Res. Commun.

    (2012)
  • Y. Naaldijk et al.

    Migrational changes of mesenchymal stem cells in response to cytokines, growth factors, hypoxia, and aging

    Exp. Cell Res.

    (2015)
  • N. Bertozzi et al.

    The biological and clinical basis for the use of adipose-derived stem cells in the field of wound healing

    Ann. Med. Surg.

    (2017)
  • A.C. Kirby et al.

    Indications, contraindications, and complications of mesh in the surgical treatment of urinary incontinence

    Clin. Obstet. Gynecol.

    (2013)
  • L. Rogo-Gupta

    Current trends in surgical repair of pelvic organ prolapse

    Curr. Opin. Obstet. Gynecol.

    (2013)
  • A.S. Pandit et al.

    Design of surgical meshes – an engineering perspective, Technol. Health Care Off

    J. Eur. Soc. Eng. Med.

    (2004)
  • O. Guillaume et al.

    Emerging trends in abdominal wall reinforcement: bringing bio-functionality to meshes

    Adv. Healthc. Mater.

    (2015)
  • S. Todros et al.

    Synthetic surgical meshes used in abdominal wall surgery: part I-materials and structural conformation

    J. Biomed. Mater. Res. B Appl. Biomater.

    (2017)
  • C. Brown et al.

    Which mesh for hernia repair?

    Ann. R. Coll. Surg. Engl.

    (2010)
  • M.T. Wolf et al.

    Polypropylene surgical mesh coated with extracellular matrix mitigates the host foreign body response

    J. Biomed. Mater. Res. A.

    (2014)
  • A. Coda et al.

    Classification of prosthetics used in hernia repair based on weight and biomaterial

    Hernia J. Hernias Abdom. Wall Surg.

    (2012)
  • A.F. Engelsman et al.

    In vivo evaluation of bacterial infection involving morphologically different surgical meshes

    Ann. Surg.

    (2010)
  • P.K. Amid

    Classification of biomaterials and their related complications in abdominal wall hernia surgery

    Hernia

    (1997)
  • K. Bury et al.

    Effects of macroporous monofilament mesh on infection in a contaminated field

    Langenbecks Arch. Surg.

    (2014)
  • M. Kelly et al.

    In vivo response to polypropylene following implantation in animal models: a review of biocompatibility

    Int. Urogynecol. J.

    (2017)
  • G.E. Leber et al.

    Long-term complications associated with prosthetic repair of incisional hernias

    Arch. Surg. Chic. Ill

    (1998)
  • S.L. García et al.

    Complications of polypropylene mesh for the treatment of female pelvic floor disorders

    Arch. Esp. Urol.

    (2011)
  • L. Zhang et al.

    Tension-free polypropylene mesh-related surgical repair for pelvic organ prolapse has a good anatomic success rate but a high risk of complications

    Chin. Med. J. (Engl.)

    (2015)
  • H.N. Shah et al.

    Mesh complications in female pelvic floor reconstructive surgery and their management: a systematic review

    Indian J. Urol. IJU J. Urol. Soc. India

    (2012)
  • SCENIHR (Scientific Committee on Emerging and Newly Identified Health Risks), Opinion on the safety of surgical meshes...
  • Center for Devices and Radiological Health, Urogynecologic Surgical Mesh Implants – Urogynecologic Surgical Mesh...
  • C. for D. and R. Health, Public Health Notifications (Medical Devices) – FDA Public Health Notification: Serious...
  • Center for Devices and Radiological Health, Urogynecologic Surgical Mesh: Update on the Safety and Effectiveness of...
  • Center for Devices and Radiological Health, Safety Communications – Surgical Mesh: FDA Safety Communication, (n.d.)....
  • A.G.D. of H.T.G. Administration, TGA actions after review into urogynaecological surgical mesh implants, Ther. Goods...
  • M. Śmietański et al.

    Systematic review and meta-analysis on heavy and lightweight polypropylene mesh in Lichtenstein inguinal hernioplasty

    Hernia J. Hernias Abdom. Wall Surg.

    (2012)
  • HerniaSurge Group

    International guidelines for groin hernia management

    Hernia J. Hernias Abdom. Wall Surg.

    (2018)
  • O. Mestak et al.

    Mesenchymal stem cells seeded on cross-linked and noncross-linked acellular porcine dermal scaffolds for long-term full-thickness hernia repair in a small animal model

    Artif. Organs.

    (2014)
  • L. Melman et al.

    Early biocompatibility of crosslinked and non-crosslinked biologic meshes in a porcine model of ventral hernia repair

    Hernia J. Hernias Abdom. Wall Surg.

    (2011)
  • A.H. Annor et al.

    Effect of enzymatic degradation on the mechanical properties of biological scaffold materials

    Surg. Endosc.

    (2012)
  • W.U. Hassan et al.

    Role of adipose-derived stem cells in wound healing, Wound Repair Regen

    Off. Publ. Wound Heal. Soc. Eur. Tissue Repair Soc.

    (2014)
  • S. Kariminekoo et al.

    Implications of mesenchymal stem cells in regenerative medicine

    Artif. Cells Nanomedicine Biotechnol.

    (2016)
  • V. Crisostomo et al.

    Delayed administration of allogeneic cardiac stem cell therapy for acute myocardial infarction could ameliorate adverse remodeling: experimental study in swine

    J. Transl. Med.

    (2015)
  • A.K. Berglund et al.

    Immunoprivileged no more: measuring the immunogenicity of allogeneic adult mesenchymal stem cells

    Stem Cell Res. Ther.

    (2017)
  • J.A. Ankrum et al.

    Mesenchymal stem cells: immune evasive, not immune privileged

    Nat. Biotechnol.

    (2014)
  • P. Lohan et al.

    Anti-donor immune responses elicited by allogeneic mesenchymal stem cells and their extracellular vesicles: are we still learning?

    Front. Immunol.

    (2017)
  • U. Klinge et al.

    Foreign body reaction to meshes used for the repair of abdominal wall hernias

    Eur. J. Surg. Acta Chir.

    (1999)
  • Cited by (22)

    • 3D bioprinted endometrial stem cells on melt electrospun poly ε-caprolactone mesh for pelvic floor application promote anti-inflammatory responses in mice

      2019, Acta Biomaterialia
      Citation Excerpt :

      POP is caused by the herniation of pelvic organs such as the uterus, bladder and rectum into the vaginal cavity because of the weakened vaginal wall and damage to the organ support structures. Current surgical treatment for POP had aimed at restoring the strength of vaginal wall using predominantly synthetic meshes (polypropylene (PP), prolene, polyethylene, polygalactin) and to some extent biological meshes (porcine dermis, decellularised biomaterials) [5–7]. However, several FDA warnings following post-surgical complications have escalated the vaginal mesh controversy as a growing body of evidence suggests deleterious effects with the most commonly used PP meshes.

    View all citing articles on Scopus
    1

    These authors equally contributed and should be regarded as co-first authors.

    View full text