Review of extended-release drug delivery systems for non-surgical treatment of inflammatory periodontal diseases

Relevance. The onset of periodontal pathogen resistance to systemic antibiotics revealed a new direction in periodontics. The characteristics of local drug delivery systems allow for a prolonged impact on periodontal pocket microbiota.
Materials and methods. The non-interventional study was carried out by an analytical review of Russian and international scientific publications of independent clinical and laboratory research databases PubMed, ResearchGate, ScienceDirect, and eLIBRARY.RU for the last decade. The search was performed using the keywords: "periochip", "periodontal treatment", "the matrix", "tissue engineering", and "bioactive cryogels". The review included randomized controlled studies, controlled clinical trials, prospective and retrospective comparative cohort studies of drug delivery systems and systematic reviews.
Results. In contrast to systemic drug administration, biodegradable local drug delivery systems provide long-lasting and effective treatment at the lesion site at much lower doses and in a shorter period of time. The prolonged drug activity time combined with non-surgical treatment of inflammatory periodontal diseases results in faster soft tissue regeneration. Gels, foams, fibres, bioactive cryogels, micro- and nanoparticles, and chips may be biodegradable matrices for the extended-release drug delivery system. The basic polymer for all these forms can be of natural origin (proteins, collagen), semi-synthetic (cellulose derivatives) or synthetic.
Conclusion. Films, chips and bioactive cryogel are nowadays more common forms. Due to its unique structure, the bioactive drug cryogel can serve as a controlled and multifunctional system for drug delivery to the periodontal tissues, which determines its importance in periodontics and high interest f or further research.

1. Atrushkevich VG, Orekhova LYu, Yanushevich OO, Sokolova EYu, Loboda ES. Optimization of the terms of supportive periodontal therapy using photoactivated disinfection. Parodontologiya. 2019;24(2):121-126 (In Russ.) doi:10.33925/1683-3759-2019-24-2-121-126

2. Orekhova LYu, Atrushkevich VG, Mikhalchenko DV, Gorbacheva IA, Lapina NV. Dental health and polymorbidity: analysis of modern approaches to the treatment of dental diseases. Parodontologiya. 2017;22(3):15-17 (In Russ.). Available from: https://www.elibrary.ru/download/elibrary_30060550_12935769.pdf

3. Orekhova LYu, Kudryavtseva TV, Burlakova YuS. Drugs local delivery system in periodontology. Parodontologiya. 2016;21(1):34-39 (In Russ.). Available from: https://www.parodont.ru/jour/article/view/226/226

4. Orekhova LYu, Musaeva RS, Loboda ES, Grinenko EV, Chuprinina AV, Ryazantseva ES. Analysis of antiinflammatory toothpastes efficiency among patients with diabetes mellitus and chronic generalized periodontitis. Parodontologiya. 2020;25(1):47-53 (In Russ.). doi: 10.33925/1683-3759-2020-25-1-47-53

5. Samoilenko AV, Orishchenko VYu, Klimovich LA, editors. Medicines used in periodontology. Dnepropetrovsk. 2015. 172 p. (In Russ.). Available from: https://repo.dma.dp.ua/5805/1/%D0%9B%D0%B5%D0%BA%D0%B0%D1%80%D1%81%D1%82%D0%B2%D0%B5%D0%BD%D0%BD%D1%8B%D0%B5%20%D1%81%D1%80%D0%B5%D0%B4%D1%81%D1%82%D0%B2%D0%B0%2C%20%D0%BF%D1%80%D0%B8%D0%BC%D0%B5%D0%BD%D1%8F%D0%B5%D0%BC%D1%8B%D0%B5%20%D0%B2%20%D0%BF%D0%B0%D1%80%D0%BE%D0%B4%D0%BE%D0%BD%D1%82%D0%BE%D0%BB%D0%BE%D0%B3%D0%B8%D0%B8.-%202017.pdf

6. Neyzberg DM, Orekhova LYu, Loboda ES, Silina ES. Candida spp. and Actinomyces spp. infections as a probable reason for resistance to periodontal therapy. Parodontologiya. 2022;27(1):61-73 (In Russ.). doi: 10.33925/1683-3759-2022-27-1-61-73

7. Romanova RO, Zyulkina LA, Ivanov PV, Kuryaev II, Kashlevskaya ME. Modern aspects of etiopathogenesis inflammatory periodontal diseases (review). Medical newsletter of Vyatka. 2022;1(73):96-102 (In Russ.). doi: 10.24412/2220-7880-2022-1-96-102

8. Yarov YuYu. Microbial associations of toothgingival junction and periodontal pocket in patients with various periodontal tissues’ states. Stomatologist. 2013;2(9):41-46 (In Russ). Available from: file:///C:/Users/irakn/Downloads/2_2013.pdf

9. Kaplish V, Manpreet Kaur Walia, Hari Kumar SL. Local drug delivery systems in the treatment of periodontitis: a review. Pharmacophore. 2013;4(2):39–49. Available from: file:///C:/Users/irakn/Downloads/local-drug-deliverysystems-in-the-treatment-of-periodontitis-a-review.pdf

10. Herrera D, Matesanz P, Martín C, Oud V, Feres M, Teughels W. Adjunctive effect of locally delivered antimicrobials in periodontitis therapy: A systematic review and meta-analysis. Journal of clinincal periodontology. 2020;22:239-256. doi: 10.1111/jcpe.13230

11. Soskolne WA. Subgingival delivery of therapeutic agents in the treatment of periodontal diseases. Critical reviews in oral biology and medicine: an official publication of the American Association of Oral Biologists. 1997;8(2):164-174. doi: 10.1177/10454411970080020501

12. Elango J, Selvaganapathy PR, Lazzari G, Bao B, Wenhui W. Biomimetic collagen-sodium alginate-titanium oxide (TiO2) 3D matrix supports differentiated periodontal ligament fibroblasts growth for periodontal tissue regeneration. International journal of biological macromolecules. 2020;163:9-18. doi: 10.1016/j.ijbiomac.2020.06.173

13. Sheng-Jie Cui, Yu Fu, Min Yu, Lei Zhang, Wen-Yan Zhao, Ting Zhang, et al. Functional periodontal regeneration using biomineralized extracellular matrix/ stem cell microspheroids. Chemical Engineering Journal. 2022;431(3):133220. doi: 10.1016/j.cej.2021.133220

14. Yuan Z, Yuan X, Zhao Y, Cai Q, Wang Y, Luo R, et al. Injectable GelMA Cryogel Microspheres for Modularized Cell Delivery and Potential Vascularized Bone Regeneration. Small. 2021;17(11):e2006596. doi: 10.1002/smll.202006596

15. Mendes BB, Gómez-Florit M, Araújo AC, Prada J, Babo PS, Domingues RMA, et al. Intrinsically Bioactive Cryogels Based on Platelet Lysate Nanocomposites for Hemostasis Applications. Biomacromolecules. 2020;21(9):3678-3692. doi: 10.1021/acs.biomac.0c00787

16. Bakhshpour M, Idil N, Perçin I, Denizli A. Biomedical Applications of Polymeric Cryogels. Applied Sciences. 2019;9(3):553. doi: 10.3390/app9030553

17. Eigel D, Werner C, Newland B. Cryogel biomaterials for neuroscience applications. Neurochemistry international. 2021;147:105012. doi: 10.1016/j.neuint.2021.105012

18. He Y, Wang C, Wang C, Xiao Y, Lin W. An Overview on Collagen and Gelatin-Based Cryogels: Fabrication, Classification, Properties and Biomedical Applications. Polymers. 2021;13(14):1-26. doi: 10.3390%2Fpolym13142299

19. Osman B, Sagdilek E, Gümrükçü M, Göçenoğlu Sarıkaya A. Molecularly imprinted composite cryogel for extracorporeal removal of uric acid. Colloids and surfaces B: Biointerfaces. 2019;183:110456. doi: 10.1016/j.colsurfb.2019.110456

20. Savina IN, Zoughaib M, Yergeshov AA. Design and Assessment of Biodegradable Macroporous Cryogels as Advanced Tissue Engineering and Drug Carrying Materials. Gels. 2021;7(3):79. doi: 10.3390/gels7030079

21. Konorev MR, editor. Clinical pharmacology in dentistry. Vitebsk: VSMU. 2018. 196 p. (In Russ.). Available from: https://www.elib.vsmu.by/bitstream/123/17772/1/Klinicheskaia_farmakologiia_v_stomatologii_Konorev-MR_2018.pdf

22. Aimetti M. Nonsurgical periodontal treatment. The international journal of esthetic dentistry. 2014;9(2):251-267. PMID: 24765632. Available from: https://pubmed.ncbi.nlm.nih.gov/24765632/

23. Graziani F, Karapetsa D, Alonso B, Herrera D. Nonsurgical and surgical treatment of periodontitis: how many options for one disease? Periodontology 2000. 2017;75(1):152-188. doi: 10.1111/prd.12201

24. Chackartchi T, Hamzani Y, Shapira L, Polak D. Effect of Subgingival Mechanical Debridement and Local Delivery of Chlorhexidine Gluconate Chip or Minocycline Hydrochloride Microspheres in Patients Enrolled in Supportive Periodontal Therapy: a Retrospective Analysis. Oral health & preventive dentistry. 2019;17(2):167-171. doi: 10.3290/j.ohpd.a42375

25. Henke CJ, Villa KF, Aichelmann-Reidy ME, Armitage GC, Eber RM, Genco RJ, et al. An economic evaluation of a chlorhexidine chip for treating chronic periodontitis: the CHIP (chlorhexidine in periodontitis) study. The Journal of the American Dental Association. 2001;132(11):1557-1569. doi: 10.14219/jada.archive.2001.0091

26. Jagadish Pai BS, Rajan SA, Srinivas M, Padma R, Suragimath G, Walvekar A, et al. Comparison of the efficacy of chlorhexidine varnish and chip in the treatment of chronic periodontitis. Contemporary clinical dentistry. 2013;4(2):156-161. doi: 10.4103/0976-237X.114848

27. Gupta R, Singh P, Dev Y, Sardana S, Rathee K, Sethi M. Effectiveness of Controlled Release Chlorhexidine Chip as an Adjunctive to Scaling and Root Planning for the Treatment of Chronic Periodontitis. The journal of contemporary dental practice. 2019;20(12):1402-1405. PMID: 32381840 Available from: https://pubmed.ncbi.nlm.nih.gov/32381840/

28. Tyagi P, Dodwad V, Kukreja BJ, Kukreja P. A comparison of the efficacy of scaling and root planning with application of pomegranate chip, pomegranate gel, and scaling and root planing in sufferers with adult periodontitis – A prospective study. Journal of Indian Society of Periodontology. 2021;25(1):41-46. doi: 10.4103/jisp.jisp_243_20

29. Vennila K, Elanchezhiyan S, Ilavarasu S. Efficacy of 10% whole Azadirachtaindica (neem) chip as an adjunct to scaling and root planning in chronic periodontitis: A clinical and microbiological study. Indian journal of dental research: official publication of Indian Society for Dental Research. 2016;27(1):15-21. doi: 10.4103/0970-9290.179808

30. Rosa CDDRD, Gomes JML, Moraes SLD, Lemos CAA, da Fonte TP, Limirio JPJO, et al. Use of chlorhexidine chip after scaling and root planning on periodontal disease: A systematic review and meta-analysis. The Saudi dental journal. 2021;33(1):1-10. doi: 10.1016/j.sdentj.2020.11.002

31. Wacharanad S, Thatree P, Yiemwattana P, Paoprajak P, Ngamsangiam P, Valyanont M, et al. Antimicrobial Activity of Roselle-capped Silver Nanochip on Aggregatibacter actinomycetemcomitans. European journal of dentistry. 2021;15(3):574-578. doi: 10.1055/s-0041-1725574

32. Tyagi P, Dodwad VW, Vaish S, Chowdhery T, Gupta N, Kukreja JB. Clinical Efficacy of Subgingivally Delivered Punica Granatum Chip and Gel in Management of Chronic Periodontitis Patients. Kathmandu University medical journal (KUMJ). 2020;18(71):279-283. Available from: https://pubmed.ncbi.nlm.nih.gov/34158437/

33. Kumar AJ, Ramesh Reddy BV, Chava VK. Effect of chlorhexidine chip in the treatment of chronic periodontitis. Journal of natural science, biology, and medicine. 2014;5(2):268-72. doi: 10.4103/0976-9668.136159

34. Medaiah S, Srinivas M, Melath A, Girish S, Polepalle T, Dasari AB. Chlorhexidine chip in the treatment of chronic periodontitis - a clinical study. Journal of clinical and diagnostic research: JCDR. 2014;8(6):ZC22-25. doi: 10.7860/JCDR/2014/8808.4477

35. Jhinger N, Kapoor D, Jain R. Comparison of Periochip (chlorhexidine gluconate 2.5 mg) and Arestin (Minocycline hydrochloride 1 mg) in the management of chronic periodontitis. Indian journal of dentistry. Jan-Mar 2015;6(1):20-26. doi: 10.4103/0975-962X.151697

36. Puri K, Dodwad V, Bhat K, Puri N. Effect of controlled-release Periochip™ on clinical and microbiological parameters in patients of chronic periodontitis. Journal of Indian Society of Periodontology. 2013;17(5):605-611. doi: 10.4103/0972-124X.119299

37. Lyubchenko OV, Velihoria IE, Polyakova SV, Ivanov OE, Tzyhanova NB, Pushkar LY, et al. Microbiological aspects of conservative treatment of periodontal disease using gel-based preparations. Polski merkuri usz lekarski: organ Polskiego Towarzystwa Lekarskiego. 2021;49(290):125-128. Available from: https://pubmed.ncbi.nlm.nih.gov/33895758/

38. Ranch KM, Maulvi FA, Koli AR, Desai DT, Parikh RK, Shah DO. Tailored Doxycycline Hyclate Loaded In Situ Gel for the Treatment of Periodontitis: Optimization, In Vitro Characterization, and Antimicrobial Studies. AAPS PharmSciTech. 2021;22(3):77. doi: 10.1208/s12249-021-01950-x

39. Hasan F, Ikram R, Adel A, Abbas A, Ain Bukhari QU, Asadullah K. Treatment of periodontal diseases by the local drug delivery system using 1% chlorhexidine gel: A randomized clinical trial. Pakistan journal of pharmaceutical sciences. 2021;34(1):41-45. Available from: https://www.pjps.pk/wp-content/uploads/pdfs/34/1/Paper-6.pdf

40. Katherine R. Hixon, Marissa N. Carletta, Sydney M. Neal, Muhamed Talovic, Andrew J. Dunn, Koyal Garg, et al. Mineralization and antibacterial potential of bioactive cryogel scaffolds in vitro. International Journal of Polymeric Materials and Polymeric Biomaterials. 2018;68(15):1-14. doi: 10.1080/00914037.2018.1522504

41. Saylan Y, Denizli A. Supermacroporous Composite Cryogels in Biomedical Applications. Gels. 2019;5(2):1-20. doi: 10.3390%2Fgels5020020

42. Gun'ko VM, Savina IN, Mikhalovsky SV. Cryogels: morphological, structural and adsorption characterization. Advances in colloid and interface science. 2013;187-188:1-46. doi: 10.1016/j.cis.2012.11.001

43. Suner SS, Demirci S, Yetiskin B, Fakhrullin R, Naumenko E, Okay O, et al. Cryogel composites based on hyaluronic acid and halloysite nanotubes as scaffold for tissue engineering. International journal of biological macromolecules. 2019;130:627-635. doi: 10.1016/j.ijbiomac.2019.03.025

44. Wartenberg A, Weisser J, Schnabelrauch M. Glycosaminoglycan-Based Cryogels as Scaffolds for Cell Cultivation and Tissue Regeneration. Molecules: a journal of synthetic chemistry and natural product chemistry. 2021;26(18):1-21. doi: 10.3390%2Fmolecules26185597