3D-Printed Concentration-Controlled Microfluidic Chip with Diffusion Mixing Pattern for the Synthesis of Alginate Drug Delivery Microgels.

Shixuan Cai,Qilu Xue,Bo Hu,Lei Zhao,Fu Wang,Hongyan Shi,Guoqian Li

doi:10.3390/nano9101451

Abstract

Alginate as a good drug delivery vehicle has excellent biocompatibility and biodegradability. In the ionic gelation process between alginate and Ca2+, the violent reaction is the absence of a well-controlled strategy in the synthesizing calcium alginate (CaA) microgels. In this study, a concentration-controlled microfluidic chip with central buffer flow was designed and 3D-printed to well-control the synthesis process of CaA microgels by the diffusion mixing pattern. The diffusion mixing pattern in the microfluidic chip can slow down the ionic gelation process in the central stream. The particle size can be influenced by channel length and flow rate ratio, which can be regulated to 448 nm in length and 235 nm in diameter. The delivery ratio of Doxorubicin (Dox) in CaA microgels are up to 90% based on the central stream strategy. CaA@Dox microgels with pH-dependent release property significantly enhances the cell killing rate against human breast cancer cells (MCF-7). The diffusion mixing pattern gives rise to well-controlled synthesis of CaA microgels, serving as a continuous and controllable production process for advanced drug delivery systems.

Highlights

IntroductionAlginate microgels have a wide variety of pharmaceutical and biomedical applications, such as delivery vehicles of natural medicine [1,2], liquid metal droplets [3], protein [4,5], hydrophilic and hydrophobic drugs [6], MR imaging [7], cell encapsulation [8,9] and biocatalyst [10], due to its advantageous features of biocompatibility, low toxicity [11], low cost, magnetic property, controlled release [12] and stimuli-response [13,14]
The microfluidic chip consists of three inlets, three outlets, and one straight channel (Figure 1a,b)
calcium alginate (CaA) microgels are prepared through controlled diffusion and mixing between one water stream in the middle inlet channel and two reagent streams in the side inlet channels

Summary

Introduction

Alginate microgels have a wide variety of pharmaceutical and biomedical applications, such as delivery vehicles of natural medicine [1,2], liquid metal droplets [3], protein [4,5], hydrophilic and hydrophobic drugs [6], MR imaging [7], cell encapsulation [8,9] and biocatalyst [10], due to its advantageous features of biocompatibility, low toxicity [11], low cost, magnetic property, controlled release [12] and stimuli-response [13,14]. High solubility of calcium ions in aqueous solution will lead to a poorly controlled preparation of alginate hydrogels. When the reactivity of ionic cross-linkers (Ca2+) is reduced, the cross-linking process becomes slower, and the properties of hydrogels are much better [16]. The buffer containing phosphate (e.g., sodium hexametaphosphate), insoluble divalent salts (e.g., CaCO3, CaSO4) and reaction temperature, have been used to control the gelation process [17]. These methods will introduce new impurities, leading to additional purification processes. There is growing need for the development of a controlled synthesis method of alginate microgels

Methods

Results

Conclusion