May 2022, Volume 72, Issue 5

Systematic Review

Antimicrobial strategies for scaffolds aided periodontal regeneration — road so far. A systematic review

Farwa Rais  ( Army Medical College, National University of Medical Sciences, Rawalpindi , Pakistan. )
Hashmat Gul  ( Department of Dental Materials, Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan. )
Zainab Qasim  ( Army Medical College, National University of Medical Sciences, Rawalpindi , Pakistan. )
Amna Zaheer  ( Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan. )
Muhammad Kaleem  ( Department of Dental Materials, Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan. )

Abstract

Objective: To give a comprehensive understanding of the efficacy of antimicrobial-loaded scaffolds as drug delivery system for periodontal regeneration, and to review the recent advances in the field of periodontal regeneration.

 

Methods: The literature was reviewed using key words "antimicrobial releasing periodontal scaffolds" on Science Direct, PubMed and Web of Science search engines. Shortlisted articles were evaluated on the basis of specific inclusion-exclusion criteria.

 

Results: Of the 544 studies found, 34(6.25%) met the inclusion criteria. The trend indicated an increase in use of antimicrobial-loaded scaffolds that caused inhibition of periodontal pathogenic bacteria, accompanied with greater cellular interaction, and differentiation for alveolar bone healing. Contemporary treatment tactics clinically prove the ability to limit disease progression, but complete periodontal regeneration needs to be validated yet.

 

Conclusion: Emerging trends are not only improving the inhibitory effect of bacterial growth, but are also making a favourable environment for cell proliferation and differentiation, resulting in alveolar bone repair and re-growth.

 

Keywords: Periodontal scaffolds, Antimicrobials, Alveolar bone regeneration.

 

DOI:  https://doi.org/10.47391/JPMA.0505

 

Introduction

 

Periodontal disease, also acknowledged as a disease of gingiva, supporting connective tissues and alveolar bone, is an inflammatory condition initially marked by swollen and bleeding soft tissues surrounding the teeth, which, when untreated, progresses into gingival recession, leading to bone resorption and eventually tooth loss.1 The prevalence of periodontal disease differs in various demographical regions, with Asian countries having a slightly higher rate of incidence and severity. It affects around 2-20% of the adult population with 300 million people being affected worldwide, while in Pakistan a study reported about 98% prevalence rate.2

Complete regeneration of periodontal defects remains a challenge. Two major approaches for treatment include conventional approach and innovative new modalities for correcting periodontal defects like, guided tissue regeneration (GTR) and guided bone regeneration (GBR), various grafting materials and enamel matrix derivatives (EMDs). These materials aid in treating periodontitis, but in chronic conditions, these are of little help due to bacterial invasion.3

Evidence-based dentistry is attempting to use tissue engineering approach for periodontal regeneration by stem cells, growth factors and using appropriate matrix-based scaffolds. These three-dimensional (3D) biomimetic scaffolds provide an in-vivo environment that allows cell adhesion and proliferation.3 Biopolymers are preferred due to their low cost, biocompatibility, biodegradability and good mechanical properties.4

Electro-spinning (E-spinning) is a method which fabricates scaffolds with fibres of different orientations and pore sizes.4 Different pore sizes within scaffolds made possible loading drugs and controlled drug release. The antibacterial employed inhibited main periodontal pathogens, including porphyromonas (P.) gingivalis and other oral pathogens.5

The main challenge for now is to obtain both mechanical and functional bio-stability along with vascularisation of the in-vitro grown cells. This complex functionality possesses some serious hurdles in this interdisciplinary field.6 The current systematic review was planned to evaluate different studies involving antimicrobial-loaded periodontal scaffolds and its drug delivery, thereby estimating the clinical validity of the use of antimicrobials within periodontal scaffolds.

 

Methodology

 

The systematic review was done at the Army Medical College, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan, in April 2018, and comprised studies published in English language up to April 20, 2018. All titles and abstracts of articles and patents initially found were analysed. Literature was searched using key terms "Antimicrobial releasing periodontal scaffolds" primarily on Science Direct, PubMed and Web of Science search engines with a limitation to their registered published papers. Any article which was difficult to access was secondarily searched using Google Scholar search engine. Full copies of all potentially relevant articles were analysed by two reviewers. Any disagreement on eligibility of articles was resolved with mutual consensus (Figure-1).

 

 

Studies included were related to fabrication, characterisation and drug release from scaffolds used for periodontal regeneration, and those including different types of membranes and multiple drug delivery systems regarding periodontal regeneration.

Studies excluded were related to drug-releasing resins and antibacterial releasing cements as well as comparative studies, review articles and articles whose full text was not available.

 

Quality assessment

 

Quality of included studies was assessed by two individuals at different time intervals. The Cochrane statistical collaboration review guidelines were followed and results for Risk of Bias were calculated considering important aspects reported and elaborated as having low, medium and high risk for bias.1

 

Results

 

Of the 544 studies found, 34(6.25%) were selected (Figure-1). The studies were categorised into in-vitro (Table-1) group and another group comprising in-vivo and mixed studies (Table-2). Risk for bias was calculated for each study (Table-3).

 

 

 

 

 

The research trend pivoting towards use of antimicrobial-loaded scaffolds was seen to be growing since 2013 onwards (Figure-2). Employment of antimicrobials reported reduction in number of periodontal pathogens and promotion in terms of osteoblastic differentiation. Different drugs generally employed in periodontal ailments included tetracycline hydrochloride, beta tricalcium phosphate, metronidazole, doxycycline, ciprofloxacin, ampicillin, zinc phosphate, tri-calcium silicate and chitosan. Any of the selected antimicrobial agent was incorporated into the scaffold matrix by employing required fabrication methods, majorly obliging e-spinning and solvent-casting procedures. In cases where enhanced and modified properties were required, hybrid blends, composites and multiple layering of potential matrix bases were utilised for restrained drug release.

 

 

 

Discussion

 

Scaffolds: Fabrication of different type of scaffolds employs various methods. New materials are continuously being synthesised to achieve the required properties of injectability, biodegradability, low cytotoxicity, nano-scale fibres and controlled drug release. It is now a common practice to load porous matrix bases with different antimicrobial agents which render impressive results.3,7

Poly-e-caprolactone (PCL) is a hydrophobic polymer approved by the Food and Drug Administration (FDA) with good resorption rate. PCL / Gelatin (GEL) scaffold nano-fibrous composite is used successfully for bone regeneration and wound healing and its loading with anti-inflammatory and other materials. PCL / GEL hybrid fibres, when loaded with zinc oxide (ZnO) nanoparticles demonstrated different mechanical strengths in wet and dry conditions plus optimal antimicrobial activity.8

Chitosan, a natural polymer, is being used as a scaffolding material due to its good biocompatibility, antibacterial, antifungal and mechanical properties and resorption rate. Chitosan-pectin hydrogel extracellular matrix (ECM) is used for alveolar bone regeneration.9 They also inhibit P. gingivalis in periodontitis by sustained drug release.10 Hybrid of chitosan with other materials makes it one of the most commonly used scaffold material showing excellent results.11 Cell culture studies of chitosan / Alginate / polylactic-co-glycolic acid (PLGA) hybrid scaffolds are reported to promote cell adhesion, proliferation and differentiation with minimal cytotoxicity.9

Biodegradable polymers, like polylactic acid (PLA) and polyglycolic acid (PLG) hold special importance due to their bioactivity and biodegradability and are used alone or in combination.10,11 They are widely used in the form of PLGA and poly-L-lactide (PLLA). Use of electro-spun PLA scaffolds loaded with antibacterial drugs, like metronidazole and ampicillin, leads to inhibition of pathogenic bacteria in both endodontic and periodontal infections.11 PLGA scaffolds doped with drugs had favourable biocompatibility, biodegradability, cell viability, mechanical properties along with sustained drug release.12

Other scaffold biomaterials include bacterial cellulose membranes, calcium sulphate-based nano-composites, electro-spun polycarbonate urethane (PCNU), nanostructured bioglass Titanium (TI)-45S5, nano-hydroxyapatite crystals (nHA), ZnO nano-particles, different growth factors and commercial calcium acetate membranes. All of these have reported to serve as acceptable drug delivery vehicles in addition to having adequate mechanical properties, favourable degradation rates, good biocompatibility and controlled release of drugs.13,14

Effect of Antimicrobial Agent Incorporation: Scaffolds of varying composition differed in their inherent properties in the drug delivery system. One of the most routinely used antimicrobials is tetracycline (TCH), a broad-spectrum antibiotic. The inclusion of tetracycline hydrochloride (THC) into chitosan / polyvinyl alcohol (PVA) nano-fibres showed good antibacterial properties due to initial burst drug release, resulting in effective inhibition of targeted bacteria involved in periodontitis. Out of 34 studies included, 8 used THC as an antibacterial drug, depicting TCH as a promising antibiotic for periodontal use. However, due to the emergence of resistant strains against TCH, other options are more validated.15

Various promising antimicrobials, including metronidazole (MNZ) and doxycycline (DOX), upon investigation demonstrated decrease in pathogenic activity at the targeted site with minimal cytotoxicity, making them favourable for use in procedures like GTR / GBR.16 DOX showed anti-inflammatory, anti-proliferative, anti-angiogenic and osteoclast inhibitory properties as well. DOX inclusion into electro-spun nano-fibres imparted comparative antimicrobial activities with no cytotoxicity.17-19 MNZ fusion with other materials, like acetic acid, gelatin or hydroxyapatite (HA) crystals enhanced mechanical properties and increased durability of scaffolds.20 DOX, a broad-spectrum bacteriostatic, acts by inhibiting protein synthesis.21

In modern dentistry, employment of nano-particles (NPs) in different dental materials has gained popularity. Inclusion of ZnO NPs into PLGA / chitosan composite imparts antimicrobial activity and better mechanical properties.22 Chitosan fibres with nano HA (n-HA) depicted better alveolar regeneration and healing.13 Apart from antimicrobial agents, various therapeutic agents used included ciprofloxacin for rapid dissolution and drug release, tobermorite as an active glass material for periodontal regeneration, and nano-apatite crystals having adequate antibacterial activities.23-25

Antimicrobial agents in periodontal scaffolds inhibit microbial colonies and improve bone regeneration and growth. In the light of the data, it can be seen that with decrease in microbial count, increased cell adhesion, proliferation and differentiation was observed due to the inclusion of favourable agents.20 All of the therapeutic agents included into the scaffolds demonstrated compatibility with other biomaterials used, such as titanium, calcium silicate and bio-glass. Majority of these agents did not affect mechanical properties of scaffolds, but a few of them, such as tetracycline hydrochloride, chitosan and beta-tricalcium phosphate, enhanced their properties while others exhibited different results in dry and wet states.22 Although biomaterials, like autologous stem cells, bio-glass, polytetrafluoroethylene (PTFE)-based scaffolds, have been tested clinically in periodontal regenerative therapy, majority of antimicrobial-loaded scaffolds need to go through clinical trials which would confirm their action.

 

Conclusion

 

New antimicrobial-containing scaffolds are emerging rapidly with better properties and enhanced antibacterial activity. This emerging trend is not only improving the inhibitory effect of bacterial growth, but is also making a favourable environment for cell proliferation and differentiation, resulting in alveolar bone repair and re-growth. Available data demonstrated potential upsurge in the use of antimicrobial-loaded scaffolds in evidence-based dentistry for periodontal regeneration. However, more clinical trials are needed in order to make them a clinically acceptable choice and to confirm their effectiveness against dental pathogens and alveolar bone regeneration.

 

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

 

References

 

1.       Shimauchi H, Nemoto E, Ishihata H, Shimomura M. Possible functional scaffolds for periodontal regeneration. Jpn Dent Sci Rev 2013; 49: 118-30.

2.       Bokhari SAH, Suhail AM, Malik AR, Imran MF. Periodontal disease status and associated risk factors in patients attending a Dental Teaching Hospital in Rawalpindi, Pakistan. J Indian Soc Periodontol 2015; 19: 678-82.

3.       Aldana AA, Abraham GA. Current advances in electrospun gelatin-based scaffolds for tissue engineering applications. Int J Pharm 2017; 523: 441-53.

4.       Monteiro AP, Rocha CM, Oliveira MF, Gontijo SM, Agudelo RR, Sinisterra RD, et al. Nanofibers containing tetracycline/?-cyclodextrin: Physico-chemical Characterization and antimicrobial evaluation. Carbohydr Polym 2017; 156: 417-26.

5.       Karuppuswamy P, Reddy Venugopal J, Navaneethan B, Luwang Laiva A, Ramakrishna S. Polycaprolactone nanofibers for the controlled release of tetracycline hydrochloride. Mater Lett 2015; 141: 180-6.

6.       Buduneli N. Implications of Antimicrobial Usage to Prevent Bacteremia for Periodontal Therapy. Curr Oral Health Rep 2018; 5: 1-7.

7.       Gandolfi MG, Zamparini F, Degli Esposti M, Chiellini F, Aparicio C, Fava F, et al. Polylactic acid-based porous scaffolds doped with calcium silicate and dicalcium phosphate dihydrate designed for biomedical application. Mater Sci Eng C Mater Biol Appl 2018; 82: 163-81.

8.       Ramírez-Agudelo R, Scheuermann K, Gala-García A, Monteiro APF, Pinzón-García AD, Cortés ME, et al. Hybrid nanofibers based on poly-caprolactone/gelatin/hydroxyapatite nanoparticles-loaded Doxycycline: Effective anti-tumoral and antibacterial activity. Mater Sci Eng C Mater Biol Appl 2018; 83: 25-34.

9.       Duruel T, Çakmak AS, Akman A, Nohutcu RM, Gümü?derelio?lu M. Sequential IGF-1 and BMP-6 releasing chitosan/alginate/PLGA hybrid scaffolds for periodontal regeneration. Int J Bio Macromol 2017; 104: 232-41.

10.     Monteiro AP, Rocha CM, Oliveira MF, Gontijo SM, Agudelo RR, Sinisterra RD, et al. Nanofibers containing tetracycline/?-cyclodextrin: Physico-chemical characterization and antimicrobial evaluation. Carbohydr Polym 2017; 156: 417-26.

11.     Wright ME, Parrag IC, Yang M, Santerre JP. Electrospun polyurethane nanofiber scaffolds with ciprofloxacin oligomer versus free ciprofloxacin: Effect on drug release and cell attachment. J Control Release 2017; 250: 107-15.

12.     Ren K, Wang Y, Sun T, Yue W, Zhang H. Electrospun PCL/gelatin composite nanofiber structures for effective guided bone regeneration membranes. Mater Sci Eng C Mater Biol Appl 2017; 78: 324-32.

13.     Qasim SB, Najeeb S, Delaine-Smith RM, Rawlinson A, Rehman IU. Potential of electrospun chitosan fibers as a surface layer in functionally graded GTR membrane for periodontal regeneration. Dent Mater 2017; 33: 71-83.

14.     Sivashankari P, Prabaharan M. Prospects of chitosan-based scaffolds for growth factor release in tissue engineering. Int J Biol Macromol 2016; 93: 1382-9.

15.     Marycz K, Pazik R, Zawisza K, Wiglusz K, Maredziak M, Sobierajska P, et al. Multifunctional nanocrystalline calcium phosphates loaded with Tetracycline antibiotic combined with human adipose derived mesenchymal stromal stem cells (hASCs). Mater Sci Eng C Mater Biol Appl 2016; 69: 17-26.

16.     Silva MDS, Neto NL, da Costa SA, da Costa SM, Oliveira TM, de Oliveira RC, et al. Biophysical and biological characterization of intraoral multilayer membranes as potential carriers: A new drug delivery system for dentistry. Mater Sci Eng C Mater Biol Appl 2017; 71: 498-503.

17.     Shao W, Liu H, Wang S, Wu J, Huang M, Min H, et al. Controlled release and antibacterial activity of tetracycline hydrochloride-loaded bacterial cellulose composite membranes. Carbohydr Polym 2016; 145: 114-20.

18.     Bae WJ, Auh QS, Kim GT, Moon JH, Kim EC. Effects of sodium tri-and hexameta-phosphate in vitro osteoblastic differentiation in Periodontal Ligament and Osteoblasts, and in vivo bone regeneration. Differentiation 2016; 92: 257-69.

19.     Iviglia G, Cassinelli C, Torre E, Baino F, Morra M, Vitale-Brovarone C. Novel bioceramic-reinforced hydrogel for alveolar bone regeneration. Acta Biomater 2016; 44: 97-109.

20.     Lee BS, Lee CC, Lin HP, Shih WA, Hsieh WL, Lai CH, et al. A functional chitosan membrane with grafted epigallocatechin-3-gallate and lovastatin enhances periodontal tissue regeneration in dogs. Carbohydr Polym 2016; 151: 790-802.

21.     Schkarpetkin D, Reise M, Wyrwa R, Völpel A, Berg A, Schweder M, et al. Development of novel electrospun dual-drug fiber mats loaded with a combination of ampicillin and metronidazole. Dent Mater 2016; 32: 951-60.

22.     Münchow EA, Albuquerque MTP, Zero B, Kamocki K, Piva E, Gregory RL, et al. Development and characterization of novel ZnO-loaded electrospun membranes for periodontal regeneration. Dent Mater 2015; 31: 1038-51.

23.     Jurczyk K, Jaworska MM, Ratajczak M, Jurczyk MU, Niespodziana K, Nowak-Malczewska DM, et al. Antibacterial activity of nanostructured Ti-45S5 bioglass-Ag composite against Streptococcus mutans and Staphylococcus aureus. Transactions of Nonferrous Metals Society of China 2016; 26: 118-25.

24.     Ranjbar-Mohammadi M, Zamani M, Prabhakaran MP, Bahrami SH, Ramakrishna S. Electrospinning of PLGA/gum tragacanth nanofibers containing tetracycline hydrochloride for periodontal regeneration. Mater Sci Eng C Mater Biol Appl 2016; 58: 521-31.

25.     Kanimozhi K, Basha SK, Kumari VS. Processing and characterization of chitosan/PVA and methylcellulose porous scaffolds for tissue engineering. Mater Sci Eng C Mater Biol Appl 2016; 61: 484-91.

26.     He M, Xue J, Geng H, Gu H, Chen D, Shi R, et al. Fibrous guided tissue regeneration membrane loaded with anti-inflammatory agent prepared by coaxial electrospinning for the purpose of controlled release. Appl Surf Sci 2015; 335: 121-9.

27.     Farooq A, Yar M, Khan AS, Shahzadi L, Siddiqi SA, Mahmood N, et al. Synthesis of piroxicam loaded novel electrospun biodegradable nanocomposite scaffolds for periodontal regeneration. Mater Sci Eng C Mater Biol Appl 2015; 56: 104-13.

28.     Xue J, Shi R, Niu Y, Gong M, Coates P, Crawford A, et al. Fabrication of drug-loaded anti-infective guided tissue regeneration membrane with adjustable biodegradation property. Colloids Surf B Biointerfaces 2015; 135: 846-54.

29.     Qasim SB, Delaine-Smith RM, Fey T, Rawlinson A, Rehman IU. Freeze gelated porous membranes for periodontal tissue regeneration. Acta Biomater 2015; 23: 317-28.

30.     Ruggiero R, de Almeida Carvalho V, da Silva LG, de Magalhães D, Ferreira JA, de Menezes HHM, et al. Study of in vitro degradation of cellulose acetate membranes modified and incorporated with tetracycline for use as an adjuvant in periodontal reconstitution. Ind Crops Prod 2015; 72: 2-6.

31.     Gentile P, Frongia ME, Cardellach M, Miller CA, Stafford GP, Leggett GJ, et al. Functionalised nanoscale coatings using layer-by-layer assembly for imparting antibacterial properties to polylactide-co-glycolide surfaces. Acta Biomater 2015; 21: 35-43.

32.     Xiao Y, Gong T, Jiang Y, Wang Y, Wen ZT, Zhou S, et al. Fabrication and Characterization of a Glucose-sensitive antibacterial Chitosan-Polyethylene Oxide Hydrogel. Polymer (Guildf) 2016; 82: 1-10.

33.     Orellana BR, Puleo DA. Tailored sequential drug release from bilayered calcium sulfate composites. Mater Sci Eng C Mater Biol Appl 2014; 43: 243-52.

34.     Jamuna-Thevi K, Saarani NN, Abdul Kadir MR, Hermawan H. Triplelayered PLGA/nanoapatite/lauric acid graded composite membrane for periodontal guided bone regeneration. Mater Sci Eng C Mater Biol Appl 2014; 43: 253-63.

35.    Reddy NS, Sowmya S, Bumgardner JD, Chennazhi KP, Biswas R, Jayakumar R. Tetracycline nanoparticles loaded calcium sulfate composite beads for periodontal management. Biochim Biophys Acta 2014; 1840: 2080-90.

36.    Hurt AP, Getti G, Coleman NJ. Bioactivity and biocompatibility of a chitosan-tobermorite composite membrane for guided tissue regeneration. Int J Biol Macromol 2014; 64: 11-6.

37.    Shi R, Xue J, He M, Chen D, Zhang L, Tian W. Structure, physical properties, biocompatibility and in vitro/vivo degradation behavior of anti-infective polycaprolactone-based electrospun membranes for guided tissue/bone regeneration. Polymer Degradation and Stability 2014; 109: 293-306.

38.     Xue J, He M, Niu Y, Liu H, Crawford A, Coates P, et al. Preparation and in vivo efficient anti-infection property of GTR/GBR implant made by metronidazole loaded electrospun polycaprolactone nanofiber membrane. Int J Pharma 2014; 475: 566-77.

39.    Backlund C, Sergesketter AR, Offenbacher S, Schoenfisch MH. Antibacterial efficacy of exogenous nitric oxide on periodontal pathogens. J Dent Res 2014; 93: 1089-94.

40.     Hild N, Tawakoli PN, Halter JG, Sauer B, Buchalla W, Stark WJ, et al. pH-dependent antibacterial effects on oral microorganisms through pure PLGA implants and composites with nanosized bioactive glass. Acta Biomater 2013; 9: 9118-25.

Journal of the Pakistan Medical Association has agreed to receive and publish manuscripts in accordance with the principles of the following committees: