Modares Mechanical Engineering

Modares Mechanical Engineering

Analytical and Experimental Investigation of Liposome Synthesis as Drug Nanocarriers via Microfluidic Method

Authors
Parniyan Javadi 1
Mohammad Passandideh-Fard 1
Seyed Ali Mousavi Shaegh 2
1 Ferdowsi University of Mashhad, Mashhad, Iran
2 Laboratory of Microfluidics and Medical Microsystems, Research Institute for Medical Sciences, Mashhad University of Medical Sciences, Mashhad, IranClinical Research Development UnitGhaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
10.48311/mme.2025.24026
Abstract
Liposomes, as a class of biological nanocarriers, play a key role in modern drug delivery, particularly in cancer therapy. However, controlling their polydispersity index (PDI), a critical parameter influencing liposome performance, remains a challenge. In this study, an analytical model was developed to predict the PDI of liposomes, offering a cost-effective and time-saving alternative to conventional experimental methods such as dynamic light scattering (DLS). The proposed model is grounded in the Gibbs free energy framework, incorporating the bending energy of phospholipid bilayers, the free edge energy, and entropic effects arising from the configurations and dispersion of phospholipid molecules in aqueous solution. Consequently, this analytical framework provides higher accuracy in calculating PDI compared to previous models that neglected entropic contributions. To validate the formulated model, a micromixer was designed and fabricated for liposome production. The synthesized liposomes were characterized using a Zetasizer and DLS technique. The model predicted PDI values of 0.182 and 0.205 for total lipid concentrations of 10 and 20 mol/m3, respectively, with relative errors of 8.91% and 10.52% compared to experimental data. Given the molecular complexities governing liposome formation and the limitations of analytically modeling all associated phenomena, these results are considered satisfactory. Overall, the presented model serves as an effective tool for predicting liposome PDI in drug delivery applications
Keywords
Liposome
analytical model
Polydispersity Index (PDI)
Micromixer
Microfluidic Systems

Subjects

1- Daraee H, Etemadi A, Kouhi M, Alimirzalu S, Akbarzadeh A. Application of liposomes in medicine and drug delivery. Artif Cells Nanomed Biotechnol. 2016;44(1):381-91.
2- Trucillo P. Drug carriers: Classification, administration, release profiles, and industrial approach. Processes. 2021;9(3):470.
3- Lombardo D, Kiselev MA. Methods of Liposomes Preparation: Formation and Control Factors of Versatile Nanocarriers for Biomedical and Nanomedicine Application. Pharmaceutics. 2022;14(3).
4- Salehi Mojarrad Mh, Hasanzadeh Ghasemi R, Keramati M. Nano-mechanical Study of a Bio Nano Actuator Under External Forces. Modares Mechanical Engineering. 2018;17(12):457-62.
5- Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol. 1965;13(1):238-52.
6- Barenholz Y. Doxil(R)--the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117-34.
7- Ernsting MJ, Murakami M, Roy A, Li S-D. Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles. Journal of controlled release. 2013;172(3):782-94.
8- Liu D, Mori A, Huang L. Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. Biochimica et Biophysica Acta (BBA)-Biomembranes. 1992;1104(1):95-101.
9- Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57.
10- van Swaay D, deMello A. Microfluidic methods for forming liposomes. Lab Chip. 2013;13(5):752-67.
11- Meure LA, Foster NR, Dehghani F. Conventional and dense gas techniques for the production of liposomes: a review. AAPS PharmSciTech. 2008;9(3):798-809.
12- Zhang H, Yang J, Sun R, Han S, Yang Z, Teng L. Microfluidics for nano-drug delivery systems: From fundamentals to industrialization. Acta Pharm Sin B. 2023;13(8):3277-99.
13- Lombardo D, Kiselev MA. Methods of liposomes preparation: formation and control factors of versatile nanocarriers for biomedical and nanomedicine application. Pharmaceutics. 2022;14(3):543.
14- Osouli-Bostanabad K, Puliga S, Serrano DR, Bucchi A, Halbert G, Lalatsa A. Microfluidic Manufacture of Lipid-Based Nanomedicines. Pharmaceutics. 2022;14(9).
15- Yu B, Lee RJ, Lee LJ. Microfluidic methods for production of liposomes. Methods in enzymology. 2009;465:129-41.
16- Bayareh M, Ashani MN, Usefian A. Active and passive micromixers: A comprehensive review. Chemical Engineering and Processing - Process Intensification. 2020;147:107771.
17- Nematollahi E, Sefid M. Numerical Study of Mixing Two-Components Non-Newtonian Fluids in Double T-Shaped Micromixers and Multiple T-Shaped with Aligned and Non-Aligned Inputs. Modares Mechanical Engineering. 2019;19(4):833-44.
18- Li Z, Zhang B, Dang D, Yang X, Yang W, Liang W. A review of microfluidic-based mixing methods. Sensors and Actuators A: Physical. 2022;344:113757.
19- Egelhaaf S, Wehrli E, Müller M, Adrian M, Schurtenberger P. Determination of the size distribution of lecithin liposomes: a comparative study using freeze fracture, cryoelectron microscopy and dynamic light scattering. Journal of Microscopy. 1996;184(3):214-28.
20- Eugster R, Orsi M, Buttitta G, Serafini N, Tiboni M, Casettari L, et al. Leveraging machine learning to streamline the development of liposomal drug delivery systems. Journal of Controlled Release. 2024;376:1025-38.
21- Yuan H, Huang C, Li J, Lykotrafitis G, Zhang S. One-particle-thick, solvent-free, coarse-grained model for biological and biomimetic fluid membranes. Physical review E. 2010;82(1):011905.
22- Weiss T, Narayanan T, Wolf C, Gradzielski M, Panine P, Finet S, et al. Dynamics of the self-assembly of unilamellar vesicles. Physical review letters. 2005;94(3):038303.
23- Huang C, Quinn D, Sadovsky Y, Suresh S, Hsia KJ. Formation and size distribution of self-assembled vesicles. Proceedings of the National Academy of Sciences. 2017;114(11):2910-5.
24- Hu M, Briguglio JJ, Deserno M. Determining the Gaussian curvature modulus of lipid membranes in simulations. Biophysical journal. 2012;102(6):1403-10.
25- Doktorova M, Harries D, Khelashvili G. Determination of bending rigidity and tilt modulus of lipid membranes from real-space fluctuation analysis of molecular dynamics simulations. Physical Chemistry Chemical Physics. 2017;19(25):16806-18.
26- Banejad A, Passandideh-Fard M, Niknam H, Hosseini MJM, Shaegh SAM. Design, fabrication and experimental characterization of whole-thermoplastic microvalves and micropumps having micromilled liquid channels of rectangular and half-elliptical cross-sections. Sensors and Actuators A: Physical. 2020;301:111713.
27- Shaegh SAM, Pourmand A, Nabavinia M, Avci H, Tamayol A, Mostafalu P, et al. Rapid prototyping of whole-thermoplastic microfluidics with built-in microvalves using laser ablation and thermal fusion bonding. Sensors and Actuators B: Chemical. 2018;255:100-9.
28- Ota A, Mochizuki A, Sou K, Takeoka S. Evaluation of a static mixer as a new microfluidic method for liposome formulation. Frontiers in Bioengineering and Biotechnology. 2023;11:1229829.
29- Kulkarni CV. Calculating the ‘chain splay’of amphiphilic molecules: Towards quantifying the molecular shapes. Chemistry and Physics of Lipids. 2019;218:16-21.
30- Raval N, Maheshwari R, Kalyane D, Youngren-Ortiz SR, Chougule MB, Tekade RK. Importance of physicochemical characterization of nanoparticles in pharmaceutical product development. Basic fundamentals of drug delivery: Elsevier; 2019. p. 369-400.
Modares Mechanical Engineering
Volume 25, Issue 4
April 2025
Pages 227-240