J.ophthalmol.(Ukraine).2020;3:53-60.

http://doi.org/10.31288/oftalmolzh202035360

Received: 26 February 2020; Published on-line: 24 June 2020


Dynamics of depositing and diffusion of drugs (chlorhexidine, 5-fluorouracil and doxorubicin) in hydrogel implants with different hydrogel crosslinking densities

Iu.M. Samchenko1, A.P. Maletskiy2, N.M. Bigun3, G.A. Dolynskyy1, L.O. Kernosenko1, N.O. Pasmurtseva1; T.P.  Poltoratska1; I.Ie. Mamyshev1

1 Ovcharenko Institute of Biocolloid Chemistry, NAS of Ukraine; Kyiv (Ukraine)

2 SI “The Filatov Institute of Eye Diseases and Tissue Therapy of the National Academy of Medical Sciences of Ukraine”; Odesa (Ukraine)

3 Lviv Regional Clinical Hospital; Lviv (Ukraine)

E-mail:  maletskiy@filatov.com.ua

TO CITE THIS ARTICLE: Samchenko Iu.M., Maletskiy A.P., Bigun N.M., Dolynskyy G.A., Kernosenko L.O., Pasmurtseva N.O., Poltoratska T.P., Mamyshev I.Ie. Dynamics of depositing and diffusion of drugs (chlorhexidine, 5-fluorouracil and doxorubicin) in hydrogel implants with different hydrogel crosslinking densities. J.ophthalmol.(Ukraine).2020;3:53-60. http://doi.org/10.31288/oftalmolzh202035360


Background: Due to increasing prevalence of ocular trauma, more and more patients need to have their affected orbit, orbital adnexa, and periorbital area restored, which results in an increasing demand for implant materials. It is important for these materials to contain antimicrobial and antitumor drugs in order to prevent inflammation and recurrent inflammation around the implant before and after tumor removal.

Purpose: To study the dynamics of depositing and diffusion of drugs (chlorhexidine, 5-fluorouracil and doxorubicin) in hydrogel implants with different hydrogel crosslinking densities.

Material and Methods: Pharmaceuticals: 2.0% chlorhexidine digluconate; 5-fluorouracil (Ebewe Pharma, Unterach, Austria) infusion solution concentrate, 50 mg/ml; and doxorubicin (Ebewe), 2 mg/ml.

Results: The time required for the drug concentration to reach the minimum therapeutic level was as small as several minutes for the low-density cross-linked hydrogel, whereas the diffusion lag time for the high-density cross-linked hydrogel was as large as several hours. The latter hydrogel was found to have a higher capacity for deposition of chlorhexidine digluconate and 5-fluorouracil, and is reasonable to be utilized in implants with a prolonged antibacterial effect, whereas the former hydrogel is reasonable to be utilized for a fast-release bolus antiseptic delivery. In in vitro experiments, the low-density cross-linked hydrogel hydrogel provided a 3-4-fold greater drug concentration in the environment, and allowed for a smoother and more prolonged drug release profile compared to the high-density cross-linked hydrogel hydrogel.

Conclusion: Such a capacity for prolonged drug release will promote application of hybrid hydrogel implants for depositing anti-cancer drugs and maintaining effective concentrations of the latter at pathology focus.

Keywords: hybrid hydrogel, endoprosthesis, drug deposition and diffusion, degree of hydrogel crosslinking, reconstructive surgery


References

1.O.V. Grusha, Ia.O. Grusha. [Five hundred of orbital plastic repairs: analysis of complications]. Vestn Oftalmol. Jan-Feb 2006;122(1):22-4. Russian.

2.Gundorova RA, Neroev VV, Kashnikov VV, editors. [Ocular injuries]. Moscow: GEOTAR-Media; 2009. Russian.

3.Krasnovid TA. [Ocular trauma under present conditions. Providing urgent care in Ukraine]. Proceedings of the Conference of Ophthalmologists of Chernihiv, Kyiv, and other regions. Chernihiv; 2013. pp. 40-4. Russian.

4.Tselomudryi OI, Venger GE, Rizvaniuk AV, Pogorelyi DN, Putienko VA. [Current system of stage-by-stage treatment for combat-related eye injuries in the area of ATO]. In: [Proceedings of the Conference commemorating the 80th anniversary of the Filatov Institute and 14th Congress of the Black Sea Ophthalmological Society]. Odesa, 2016. Russian.

5.Maletskiy AP, Samchenko Iu.M, Vit VV, Bigun NM, Kernosenko LO. [Response of orbital and auricular soft tissues to the developed hydrogel implant in rabbits]. Arkhiv oftalmologii Ukrainy. 2018;6(2):20-7. Ukrainian. 

6.Chai Q, Jiao Y, Yu X. Hydrogels for biomedical applications: Their characteristics and the mechanisms behind them. Gels. 2017;3(1):6.

Crossref   PubMed

7.Wichterle O, Lim D. Hydrophilic gels for biological use. Nature. 1960; 185: 117–8.

Crossref  

8.Hoare TR, Kohane DS. Hydrogels in drug delivery: Progress and challenges. Polymer. 2008;49: 1993–2007.

Crossref  

9.Jeong CG, Zhang H, Hollister SJ. Three-dimensional poly (1,8-octanediol–co-citrate) scaffold pore shape and permeability effects on sub-cutaneous in vivo chondrogenesis using primary chondrocytes. Acta Biomater. 2011 Feb;7(2):505-14.

Crossref   PubMed

10.Murray RZ, West ZE, Cowin AJ, Farrugia BL. Development and use of biomaterials as wound healing therapies. Burns Trauma. 2019;7:2.

Crossref   PubMed

11.Overstreet DJ, McLemore RY, Doan BD, Farag A, Vernon BL. Temperature-responsive graft copolymer hydrogels for controlled swelling and drug delivery. Soft Matter. 2013; 11: 294–304. Crossref  

12.Yu X, Jiao Y, Chai Q. Applications of gold nanoparticles in biosensors. Nano LIFE. 2016; 6: 1642001.

Crossref   

13.Sugak OA, Panasenko OI, Knysh YG, Kamyshny OM. [Antimicrobial and antifungal activity of derivatives of 3- (alkylthio) -4-R-5- (thiophen-2-ylmethyl) - 4H-1,2,4-triazoles]. Aktualni pytannia farmacevtychnoi i medychnoi nauky ta praktyky. 2015;3(19):67–70. Ukrainian.

14.Shapiro JM, Oyen ML. Hydrogel composite materials for tissue engineering scaffolds. JOM. 2013; 65: 505-16.

Crossref 

15.Kryklia SO, Samchenko Iu.M, Konovalova VV, Poltoratska TP, Pasmurtseva NO, Ulberg ZR. [Hybrid Ph- and thermosensitive hydrogels based on polyvinylalcohol and acrylic monomers]. Magisterium. 2016;63:20-8. Ukrainian.

16.Brünler R, Aibibu D, Wöltje M, Anthofer AM, Cherif C. In silico modeling of structural and porosity properties of additive manufactured implants for regenerative medicine. Mater Sci Eng C Mater Biol Appl. 2017; 76: 810–817.

Crossref   PubMed

17.Abureesh MA, Oladipo AA, Gazi M. Facile synthesis of glucose-sensitive chitosan-poly(vinyl alcohol) hydrogel: drug release optimization and swelling properties. Int J Biol Macromol. 2016 Sep;90:75-80.

Crossref   PubMed

18.Van Tienen TG, Heijkants RG, Buma P, de Groot JH, Pennings AJ, Veth RP. Tissue ingrowth and degradation of two biodegradable porous polymers with different porosities and pore sizes. Biomaterials. 2002 Apr;23(8):1731-8.

Crossref  

19.Yang S, Leong KF, Du Z, Chua CK. The design of scaffolds for use in tissue engineering. Part I. Traditional factors. Tissue Eng. 2001 Dec;7(6):679-89.Crossref   PubMed 

20.Zeltinger J, Sherwood JK, Graham DA, Müeller R, Griffith LG. Effect of pore size and void fraction on cellular adhesion, proliferation, and matrix deposition. Tissue Eng. 2001 Oct;7(5):557-72.

Crossref   PubMed

21.Oh SH, Park IK, Kim JM, Lee JH. In vitro and in vivo characteristics of PCL scaffolds with pore size gradient fabricated by a centrifugation method. Biomaterials. 2007 Mar;28(9):1664-71.

Crossref   PubMed

22.Murphy CM, Haugh MG, O’Brien FJ. The effect of mean pore size on cell attachment, proliferation and migration in collagen–glycosaminoglycan scaffolds for bone tissue engineering. Biomaterials. 2010 Jan;31(3):461-6.

Crossref   PubMed

23.Bulysheva AA, Bowlin GL, Klingelhutz AJ, Yeudall WA. J. Low-temperature electrospun silk scaffold for in vitro mucosal modeling. Biomed Mater Res. Part A. 2012; 100: 757–67.

Crossref   PubMed

24.Rnjak-Kovacina J, Wise SG, Li Z, Maitz PK, Young CJ, Wang Y, Weiss AS. Tailoring the porosity and pore size of electrospun synthetic human elastin scaffolds for dermal tissue engineering. Biomaterials. 2011 Oct;32(28):6729-36.

Crossref   PubMed

25.Somo SI, Akar B, Bayrak ES, Larson JC, Appel AA, Mehdizadeh H, Cinar A, Brey EM. Pore interconnectivity influences growth factor mediated vascularization in sphere-templated hydrogels. Tissue Eng Part C Methods. 2015 Aug;21(8):773-85.

Crossref   PubMed

26.Khare A, Peppas NA. Swelling/deswelling of anionic copolymer gels. Biomaterials. 1995 May;16(7):559-67.

Crossref  

27.Gamelin EC, Danquechin-Dorval EM, Dumesnil YF, et al. Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU. Cancer. 1996 Feb 1;77(3):441-51.

Crossref  

28.Parker WB, Cheng YC. Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther. 1990;48(3):381-95.

Crossref 

29.Wang LL, Huang S, Guo HH, Han YX, Zheng WS, Jiang JD. In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer. Drug Des Devel Ther. 2016 Sep 8;10:2855-2867.

Crossref   PubMed 

30.Miyake M, Anai S, Fujimoto K, Ohnishi S, Kuwada M, Nakai Y, et al. 5 fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma. Oncol Let. 2012 Jun;3(6):1195-1202.

Crossref   PubMed

31.Ma Y, Wang Y, Xu Z, Wang Y, Fallon JK, Liu F. Extreme low dose of 5-fluorouracil reverses MDR in cancer by sensitizing cancer associated fibroblasts and down-regulating P-gp. PLoS One. 2017 Jun 29;12(6):e0180023.

Crossref   PubMed

32.Yang LQ, Lan YQ, Guo H, Cheng LZ, Fan JZ, Cai X, et al. Ophthalmic drug-loaded N,O-carboxymethyl chitosan hydrogels: synthesis, in vitro and in vivo evaluation. Acta Pharmacologica Sinica. 2010; 31: 1625–34;

Crossref   PubMed

 

The authors certify that they have no conflicts of interest in the subject matter or materials discussed in this manuscript.