Aortic Graft Infection: Graphene Shows the Way to an Infection-Resistant Vascular Graft
Nikolaos Patelis
Dimitrios Schizas
- First Department of Surgery, Vascular Unit, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
Aortic graft infection is a potentially lethal complication of open and endovascular repair of aortic aneurysms. Graphene is the only existing two-dimensional material, and its unique structure gives graphene and its derivatives a plethora of original characteristics. Among other characteristics, graphene demonstrates bacteriostatic and bactericidal effects that could potentially resolve the problem of graft infection in the future. Data already exist in literature supporting this antibacterial effect of graphene oxide and reduced graphene oxide. Combining these materials with other substances enhances the antibacterial effect. Additionally, it looks feasible to expect antibiotic-delivering graphene-based graft materials in the future. Based on already published data, we could conclude that regarding graphene and its derivatives, the blessing of bactericidal effect comes with the curse of human cells toxicity. Therefore, it is important to find a fine balance between the desired antibacterial and the adverse cytotoxic effect before graphene is used in graft materials for humans.
Prosthetic graft infection is a grave and frequently lethal complication of both open and endovascular repair of aortic aneurysms (AA). Despite its relatively low overall incidence, the absolute numbers of graft infection are rising, as the use of synthetic grafts (Dacron, PTFE, or nylon) has become an everyday occurrence in both elective and emergency AA repair, with a reported graft infection incidence of 0.2 to as high as 6% in EVAR cases (1–4). Overall morbidity and mortality rates are high, and in cases of patients’ readmission due to aortic graft infection, in-hospital mortality can be 18% or higher (5, 6). Additionally, bacterial resistance to antibiotics is an evolving problem that could bring medicine and humanity back into the pre-antibiotic era if it remains unsolved (7).
Treatment of aortic graft infection varies from conservative treatment with long-term antibiotic administration to graft excision combined with a bypass procedure. The latter could be either extra-anatomical or follows the natural anatomic course of the aorta, but both approaches are linked to significant morbidity, mortality, and procedure-related complications. The in situ reconstruction of the aorta using either cryopreserved allografts or autologous veins is a similarly disabling method of aortic reconstruction after infected graft excision (8). As a result, our surgical attempts to resolve a case of aortic graft infection often bring our patient to worse status than before. The father of medicine, Hippocrates, stated that prevention is better than cure; therefore, the need for infection-resistant graft materials is essential in order to avoid the devastation of aortic graft infection and the patient disabling nature of existing treatment strategies.
Creating an infection-resistant material has been in the scope of biomedical engineering for a period of time, but focus has been concentrated on how an infection can be fought after it had occurred. Antibiotic-soaked and silver-containing grafts have already been used for AA repair after graft infection. Despite these grafts being a useful tool in the vascular surgery armament, the final outcomes of their use in real practice are ambiguous (9, 10). Other approaches, such as the use of bio-absorbable antibiotic-impregnated beads, have also been suggested as a potential solution to the problem of aortic graft infections (11).
Newly developed materials may cover the need for new infection-resistant graft materials. One of these futuristic super-materials that have already found its place in many health-related applications is graphene. Graphene is the only two-dimensional material, with each graphene layer being 1 atom or 0.345-nm thick (12). Graphene demonstrates a number of unique characteristics, and its promising future applications have awarded its creators, Andre Geim and Konstantin Novoselov, the 2010 Nobel Prize in Physics. Graphene is approximately more than 300-fold stronger than structural steel or Kevlar, 1,000-fold lighter than paper and almost as flexible as PTFE. These impressing characteristics are the result of the graphene’s structure as a carbon allotrope with sp2-bonded carbon atoms arranged in a sheet-like structure.
Graphene sheets are produced in a number of different methods, the most common of which are mechanical or thermal exfoliation, chemical vapor deposition (CVD), and epitaxial growth (12). Further post-processing of graphene sheets produce its derivatives, such as graphene oxide (GO) and reduced graphene oxide (rGO). Each of these methods and final products has slightly different characteristics and properties. Only graphene products of the highest quality demonstrate the abovementioned properties. These pristine graphene sheets are products of CVD, which at present renders the production expensive, but the price of graphene derivatives is constantly decreasing as production methods are optimized (13–15).
In existing literature, pristine graphene sheets have already been reported to have bacteriostatic and bactericidal properties. These two properties are of great interest for bioengineers committed to improve the graft materials of today to become less prone to bacterial infection. In a recent detailed review of graphene’s future in the grafts materials engineering, it seems that despite existing data supporting these beneficial properties of graphene, not all publications agree to the extent and efficacy of these (12). In this review, it has been reported that the surface of the graphene sheet plays a major role on the bactericidal action of this material. If the material is produced by vacuum filtration and the material particles lied flat on the surface, the bactericidal effect was minimum or none (16, 17). On the other hand, rGO with sharper particles’ edges demonstrated a significant bactericidal effect on S. aureus and E. coli bacteria (18–20). The mechanism behind this interaction of surface and bacteria is probably the bacterial membrane damage by the graphene edges and the efflux of cytoplasm. This proposed mechanism is also supported by the increased bactericidal effect of graphene on bacteria with thinner peptidoglycan membrane layer (21). At present, further mechanisms of actions on molecular level are also being considered, especially when combined materials are used (22–24).
In addition to the nature of the material surface, binding other molecules to graphene can also affect its bactericidal or bacteriostatic effect. Silver particles, platinum particles, chitosan, polyvinyl-N-carbazole, lactoferrin, diazonium salt, poly-l-lysine, and polyhexamethylene guanidine hydrochloride are a few of the substances used to increase the bactericidal and bacteriostatic effects of graphene sheets (12, 25–27). The results of these combined materials depend not only on the graphene derivative used (mainly GO or rGO) but also on the studied bacteria that show different interaction with these modified graphene surface. Endovascular materials are usually primarily contaminated and infected with S. aureus and S. epidermidis, although secondary hematogenic contamination with Gram-negative bacteria is also possible. rGO shows the strongest antibacterial effect toward both Gram-positive and Gram-negative bacteria, but in order to achieve the best possible antibacterial effect against the usual bacteria involved, further studies have to examine various combinations of graphene and other substances, although some evidence already exist (18).
Graphene has been used as a delivery agent for medication since 2008 (28). Since then graphene and its derivatives have been used in delivering a wide range of medication (29–33). In one case, graphene sheets were modified to deliver medication at a concentration controlled through electric pulses (34). Taking all these under consideration, it is not fiction to believe that in the future a graphene-based stent-graft could release antibiotics into the blood stream and/or the surrounding vessel wall when specific bacteria react with the graphene surface. This futuristic model would fight bacteria whenever that is necessary without contributing to bacteria multidrug resistance and by delivering the antibiotic directly to the affected tissues, thus minimizing systemic side effects.
Infection-resistant graphene-based graft materials could be constructed today with the already existing knowledge and technology. In the near future, these same graft materials could go a step further and evolve into infection fighting antibiotic-delivery agents. Unfortunately, before we see these steps ahead of current bioengineering, the question of biocompatibility and biotoxicity should be resolved (35). Graphene and its derivatives have been found to be toxic to certain lines of eukaryotic cells, and toxicity levels are analog to the bactericidal effect (24, 36, 37). From already published data, we could conclude that regarding graphene and its derivatives the blessing of bactericidal effect comes with the curse of human cells toxicity. Wrapping graphene particles within other structures or biofilms could resolve the problem of biotoxicity to some extent, but it would also affect its bactericidal effect (12, 38).
Graphene and its derivatives could potentially lead the way to new and truly infection-resistant or bactericidal graft materials that can be primarily used in aortic or other arterial repair in order to avoid the occurrence of graft infection, not fighting an already-occurring infection. A proper animal model and in vivo studies by a multidisciplinary team of bioengineers and vascular surgeons are necessary in order to research the potential role of graphene and its derivatives in building infection-resistant aortic grafts and provide the necessary data on patency, biotoxicity, and biocompatibility. These future materials would further reduce the incidence of graft infection that remains a lethal complication of open and endovascular aortic repair.
Author Contributions
NP—conception, data collection, literature review, manuscript writing, and critical appraisal. DS—data collection and critical appraisal. TL—conception and critical appraisal. CK—conception, manuscript writing, and critical appraisal. All the authors have accepted the final version of the manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Smeds MR, Duncan AA, Harlander-Locke MP, Lawrence PF, Lyden S, Fatima J, et al. Treatment and outcomes of aortic endograft infection. J Vasc Surg (2016) 63(2):332–40. doi: 10.1016/j.jvs.2015.08.113
2. Patelis N, Moris D, Karaolanis G, Georgopoulos S. Endovascular vs. open repair for ruptured abdominal aortic aneurysm. Med Sci Monit Basic Res (2016) 22:34–44. doi:10.12659/MSMBR.897601
3. Reis P, Oderich G. Current status of treatment of aortic endograft infection. J Vasc Endovasc Surg (2016) 1:3.
4. Kilic A, Arnaoutakis DJ, Reifsnyder T, Black JH III, Abularrage CJ, Perler BA, et al. Management of infected vascular grafts. Vasc Med (2016) 21(1):53–60. doi:10.1177/1358863X15612574
5. Vogel TR, Symons R, Flum DR. The incidence and factors associated with graft infection after aortic aneurysm repair. J Vasc Surg (2008) 47(2):264–9. doi:10.1016/j.jvs.2007.10.030
6. Batt M, Jean-Baptiste E, O’Connor S, Feugier P, Haulon S; Association Universitaire de Recherche en Chirurgie V. Contemporary management of infrarenal aortic graft infection: early and late results in 82 patients. Vascular (2012) 20(3):129–37. doi:10.1258/vasc.2011.oa0315
7. Tegou E, Magana M, Katsogridaki AE, Ioannidis A, Raptis V, Jordan S, et al. Terms of endearment: bacteria meet graphene nanosurfaces. Biomaterials (2016) 89:38–55. doi:10.1016/j.biomaterials.2016.02.030
8. Wilson WR, Bower TC, Creager MA, Amin-Hanjani S, O’Gara PT, Lockhart PB, et al. Vascular graft infections, mycotic aneurysms, and endovascular infections: a scientific statement from the American Heart Association. Circulation (2016) 134(20):e412–60. doi:10.1161/CIR.0000000000000457
9. Lew W, Moore W. Antibiotic-impregnated grafts for aortic reconstruction. Semin Vasc Surg (2011) 24(4):211–9. doi:10.1053/j.semvascsurg.2011.10.015
10. Ricco JB, Assadian O. Antimicrobial silver grafts for prevention and treatment of vascular graft infection. Semin Vasc Surg (2011) 24(4):234–41. doi:10.1053/j.semvascsurg.2011.10.006
11. Genovese EA, Avgerinos ED, Baril DT, Makaroun MS, Chaer RA. Bio-absorbable antibiotic impregnated beads for the treatment of prosthetic vascular graft infections. Vascular (2016) 24(6):590–7. doi:10.1177/1708538116630859
12. Patelis N, Moris D, Matheiken S, Klonaris C. The potential role of graphene in developing the next generation of endomaterials. Biomed Res Int (2016) 2016:3180954. doi:10.1155/2016/3180954
13. Compton OC, Nguyen ST. Graphene oxide, highly reduced graphene oxide, and graphene: versatile building blocks for carbon-based materials. Small (2010) 6(6):711–23. doi:10.1002/smll.200901934
14. Dreyer DR, Park S, Bielawski CW, Ruoff RS. The chemistry of graphene oxide. Chem Soc Rev (2010) 39(1):228–40. doi:10.1039/b917103g
15. Polat EO, Balci O, Kakenov N, Uzlu HB, Kocabas C, Dahiya R. Synthesis of large area graphene for high performance in flexible optoelectronic devices. Sci Rep (2015) 5:16744. doi:10.1038/srep16744
16. Hu W, Peng C, Luo W, Lv M, Li X, Li D, et al. Graphene-based antibacterial paper. ACS Nano (2010) 4(7):4317–23. doi:10.1021/nn101097v
17. Ruiz ON, Fernando KA, Wang B, Brown NA, Luo PG, McNamara ND, et al. Graphene oxide: a nonspecific enhancer of cellular growth. ACS Nano (2011) 5(10):8100–7. doi:10.1021/nn202699t
18. Akhavan O, Ghaderi E. Toxicity of graphene and graphene oxide nanowalls against bacteria. ACS Nano (2010) 4(10):5731–6. doi:10.1021/nn101390x
19. Novoselov KS, Geim AK, Morozov SV, Jiang D, Zhang Y, Dubonos SV, et al. Electric field effect in atomically thin carbon films. Science (2004) 306(5696):666–9. doi:10.1126/science.1102896
20. Novoselov KS, Jiang D, Schedin F, Booth TJ, Khotkevich VV, Morozov SV, et al. Two-dimensional atomic crystals. Proc Natl Acad Sci U S A (2005) 102(30):10451–3. doi:10.1073/pnas.0502848102
21. Krishnamoorthy K, Veerapandian M, Zhang L-H, Yun K, Kim SJ. Antibacterial efficiency of graphene nanosheets against pathogenic bacteria via lipid peroxidation. J Phys Chem C (2012) 116(32):17280–7. doi:10.1021/jp3047054
22. Rojas-Andrade MD, Chata G, Rouholiman D, Liu J, Saltikov C, Chen S. Antibacterial mechanisms of graphene-based composite nanomaterials. Nanoscale (2017) 9(3):994–1006. doi:10.1039/c6nr08733g
23. Zhou R, Gao H. Cytotoxicity of graphene: recent advances and future perspective. Wiley Interdiscip Rev Nanomed Nanobiotechnol (2014) 6(5):452–74. doi:10.1002/wnan.1277
24. Lukowiak A, Kedziora A, Strek W. Antimicrobial graphene family materials: progress, advances, hopes and fears. Adv Colloid Interface Sci (2016) 236:101–12. doi:10.1016/j.cis.2016.08.002
25. Li P, Gao Y, Sun Z, Chang D, Gao G, Dong A. Synthesis, characterization, and bactericidal evaluation of chitosan/guanidine functionalized graphene oxide composites. Molecules (2016) 22(1):12. doi:10.3390/molecules22010012
26. Zhang M, Zhao Y, Yan L, Peltier R, Hui W, Yao X, et al. Interfacial engineering of bimetallic Ag/Pt nanoparticles on reduced graphene oxide matrix for enhanced antimicrobial activity. ACS Appl Mater Interfaces (2016) 8(13):8834–40. doi:10.1021/acsami.6b01396
27. Xu W, Xie W, Huang X, Chen X, Huang N, Wang X, et al. The graphene oxide and chitosan biopolymer loads TiO2 for antibacterial and preservative research. Food Chem (2017) 221:267–77. doi:10.1016/j.foodchem.2016.10.054
28. Feng L, Liu Z. Graphene in biomedicine: opportunities and challenges. Nanomedicine (2011) 6(2):317–24. doi:10.2217/nnm.10.158
29. Lee DY, Khatun Z, Lee JH, Lee YK, In I. Blood compatible graphene/heparin conjugate through noncovalent chemistry. Biomacromolecules (2011) 12(2):336–41. doi:10.1021/bm101031a
30. Xue T, Peng B, Xue M, Zhong X, Chiu CY, Yang S, et al. Integration of molecular and enzymatic catalysts on graphene for biomimetic generation of antithrombotic species. Nat Commun (2014) 5:3200. doi:10.1038/ncomms4200
31. Luo Y, Cai X, Li H, Lin Y, Du D. Hyaluronic acid-modified multifunctional Q-graphene for targeted killing of drug-resistant lung cancer cells. ACS Appl Mater Interfaces (2016) 8(6):4048–55. doi:10.1021/acsami.5b11471
32. Tian J, Luo Y, Huang L, Feng Y, Ju H, Yu BY. Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring. Biosens Bioelectron (2016) 80:519–24. doi:10.1016/j.bios.2016.02.018
33. Zhou B, Huang Y, Yang F, Zheng W, Chen T. Dual-functional nanographene oxide as cancer-targeted drug-delivery system to selectively induce cancer-cell apoptosis. Chem Asian J (2016) 11(7):1008–19. doi:10.1002/asia.201501277
34. Weaver CL, LaRosa JM, Luo X, Cui XT. Electrically controlled drug delivery from graphene oxide nanocomposite films. ACS Nano (2014) 8(2):1834–43. doi:10.1021/nn406223e
35. Gurunathan S, Kim JH. Synthesis, toxicity, biocompatibility, and biomedical applications of graphene and graphene-related materials. Int J Nanomedicine (2016) 11:1927–45. doi:10.2147/IJN.S105264
36. Akhavan O, Ghaderi E, Akhavan A. Size-dependent genotoxicity of graphene nanoplatelets in human stem cells. Biomaterials (2012) 33(32):8017–25. doi:10.1016/j.biomaterials.2012.07.040
37. Kiew SF, Kiew LV, Lee HB, Imae T, Chung LY. Assessing biocompatibility of graphene oxide-based nanocarriers: a review. J Control Release (2016) 226:217–28. doi:10.1016/j.jconrel.2016.02.015
Keywords: graphene, aortic aneurysm, graft survival, infection, bacterial infections
Citation: Patelis N, Schizas D, Liakakos T and Klonaris C (2017) Aortic Graft Infection: Graphene Shows the Way to an Infection-Resistant Vascular Graft. Front. Surg. 4:25. doi: 10.3389/fsurg.2017.00025
Received: 15 February 2017; Accepted: 18 April 2017;
Published: 04 May 2017
Edited by:
Konstantinos George Tsalis, Aristotle University of Thessaloniki, GreeceReviewed by:
Efthymios Avgerinos, University of Pittsburgh Medical Center, USAPaulo Eduardo Ocke Reis, Federal Fluminense University, Brazil
Copyright: © 2017 Patelis, Schizas, Liakakos and Klonaris. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Nikolaos Patelis, patelisn@gmail.com