Biomaterials for microfluidic technology

doi: 10.1088/2752-5724/ac39ff

Zehao Chen^{1, 2},
Zhendong Lv³,
Zhen Zhang¹,
Yuhui Zhang^{1, 3
,},
Wenguo Cui^2
,

1.
School of Mechatronic Engineering and Automation, Shanghai University, Nanchen Road 333, Shanghai 200444, People’s Republic of China
2.
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, People’s Republic of China
3.
Department of Spine Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, 160 Pujian Road, Shanghai 200127, People’s Republic of China

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Corresponding author: E-mail: zhangyuhui2019@gmail.com; E-mail: wgcui80@hotmail.com

摘要

Abstract: Micro/nanomaterial-based drug and cell delivery systems play an important role in biomedical fields for their injectability and targeting. Microfluidics is a rapidly developing technology and has become a robust tool for preparing biomaterial micro/nanocarriers with precise structural control and high reproducibility. By flexibly designing microfluidic channels and manipulating fluid behavior, various forms of biomaterial carriers can be fabricated using microfluidics, including microspheres, nanoparticles and microfibers. In this review, recent advances in biomaterials for designing functional microfluidic vehicles are summarized. We introduce the application of natural materials such as polysaccharides and proteins as well as synthetic polymers in the production of microfluidic carriers. How the material properties determine the manufacture of carriers and the type of cargoes to be encapsulated is highlighted. Furthermore, the current limitations of microfluidic biomaterial carriers and perspectives on its future developments are presented.
- microfluidics /
- drug delivery /
- cell delivery /
- hydrogel microspheres /
- nanomaterials
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Scheme 1. Schematic diagram of microfluidic carriers made of various materials.

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Figure 1. (A) Basic droplet generator junctions for microsphere production. (i) Flow-focusing. (ii) T-junction. (iii) Co-flow. (B) Microfluidic geometries for nanoparticle production. (i) Flow-focusing. (ii) Y-junction. (iii) Spiral mixer. (iv) Tesla mixer. (C) Schematic of solidification methods for microfluidic fiber fabrication. (i) Flow- focusing. (ii) Co-flow. (iii) Gland-like shape. (iv) Co-flow for helical fibers.

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Figure 2. Microfluidics carriers made of hyaluronic acid and alginate. (A) Construction of PDA-modified liposome-HAMA microsphere. [43] John Wiley & Sons. (© 2021 Wiley-VCH GmbH). (B) Schematic diagram of oil droplet-encapsulated alginate fibers. The shape of the oil droplets and inter-droplet distance could be changed by varying the flow rates. Reprinted from [60], Copyright (2017), with permission from Elsevier.

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Figure 3. Microfluidics carriers made of chitosan and dextran. (A) (i) Schematic illustration of gas microfluidic CMC/CS capsules. (ii) Single-layer capsule. (iii) Bilayer capsule. (iv) Multi-layer capsule. Reprinted from [74], Copyright (2017), with permission from Elsevier. (B) (i) Off-center encapsulated cells in hydrogel microspheres. (ii) Cell focusing via delayed enzymatically crosslinked. [80] John Wiley & Sons. [© 2017 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim].

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Figure 4. Microfluidics carriers made of SF and collagen. (A) Single (i), (ii) and double (iii) SF fibers generated by flow-focusing co-extrusion. The diameter and structure of the fiber can be adjusted by varying the shear pressure and flow rate. [58] John Wiley & Sons. [© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH]. (B) (i) Schematic diagram of the fabrication of hepatic-lobule-like microtissue collagen spheroids using a precursor cartridge. (ii) Fluorescence image of the fabricated collagen microspheres with or without lobule-like microstructure. (iii) Shadowgraphic microscopy image of microspheres. [112] John Wiley & Sons. [© 2021 The Authors. Advanced Materials published by Wiley-VCH GmbH].

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Figure 5. Preparation of microfluidic GelMA-BP microspheres capturing Mg²⁺ for cancellous bone regeneration. Reprinted with permission from [121]. Copyright (2021) American Chemical Society.

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Figure 6. Microfluidics carriers made of PEGDA and PLGA. (A) The fabrication of microfluidic PEGDA fiber and its longitudinal SEM image. Reprinted with permission from [134]. Copyright (2019) American Chemical Society. (B) (i) SEM images of PLGA microspheres and their cross section. (ii) The distribution of radiolabeled PLGA microspheres in vivo. Reprinted with permission from [142]. Copyright (2020) American Chemical Society.

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Figure 7. (A) Schematic illustration of fabrication and alkaline hydrolysis of microfluidic PLLA microspheres. (B) SEM images of porous PLLA microspheres. (C) SEM images of BSA-PLLA microspheres. [153] John Wiley & Sons. [© 2020 Wiley-VCH GmbH].

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Table 1. The application of polysaccharide in preparing microfluidic carriers.

Classification of polysaccharide	Carrier material	Carrier type	Solidification method	Cargo	Cargo type
Hyaluronic acid	HA-DA [42]	Microsphere	Oxidation crosslinking
	HAMA [43]	Microsphere	Photo-crosslinking	Gallic acid	Hydrophilic drug
	HAMA [45]	Microsphere	Photo-crosslinking	Progesterone	Hydrophobic drug
	VS-HA [46]	Microsphere	Photo-crosslinking	NSCs	Cell
	HAMA [49]	Microfiber	Photo-crosslinking	hTDCs	Cell
	HA-EDA-C₁₈ [50]	Microfiber	Physical assembly	Dexamethasone	Hydrophobic drug
Alginate	Na-alginate [53]	Microsphere	Ion crosslinking
	RGD peptide-modified sodium alginate [55]	Microsphere	Ion crosslinking	MSCs	Cell
	Alginate [56]	Microsphere	Ion crosslinking	-TC6 cell	Cell
	Alginate [59]	Microfiber	Ion crosslinking	MSCs	Cell
	Oxidized AlgMA [62]	Microsphere	Photo-crosslinking	Chondrocytes	Cell
	AlgMA [63]	Microfiber	Photo-crosslinking	HUVECs	Cell
Chitosan	Chitosan [68]	Nanoparticle	Ion crosslinking	Insulin	Hydrophilic drug
	Chitosan [74]	Microcapsule	Ion crosslinking	Sodium salicylate and bovine hemoglobin	Hydrophilic drug and protein
	Chitosan [75]	Microsphere	Ion and chemical crosslinking	5-fluorouracil	Hydrophilic drug
	Chitosan [76]	Microcapsule	Chemical crosslinking	Tea tree oil	Hydrophobic drug
Dextran	Dex-TA [80]	Microsphere	Enzymatic crosslinking	MSCs	Cell
	AcDex [81]	Microsphere	Solvent evaporation
Heparin	HAMA and HepMA [83]	Microsphere	Photo-crosslinking	PDGF-BB and TGF-3	Hydrophilic drug
	StarPEG-Heparin [84]	Microsphere	Chemical crosslinking	HUVECs	Cells
Other plant polysaccharides	Pectin [86]	Microsphere	Ion crosslinking
	KGM [88]	Microfiber	Physical aggregation	Ofloxacin	Hydrophobic drug
	EPS [90]	Microsphere	Ion crosslinking	TGF-1	Hydrophilic drug

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Table 2. The application of proteins in preparing microfluidic carriers.

Classification of proteins	Carrier material	Carrier type	Solidification method	Cargo	Cargo type
SF	SF [95]	Nanoparticle	Physical assembly
	SF [97]	Microsphere	Physical assembly	HRP	Hydrophilic drug
	RSF [104]	Microfiber	Physical assembly
	SF [58]	Microfiber	Physical assembly
Collagen	Collagen [111]	Microsphere	Physical assembly	BMSCs	Cell
	Collagen [112]	Microsphere	Physical assembly	HepG2/C3A and EA.hy926	Cell
	Collagen [113]	Microfiber	Physical assembly	PC12 cells	Cell
	Collagen [114]	Microfiber	Chemical crosslinking
Gelatin	Gelatin [116]	Microsphere	Physical crosslinking
	Gelatin [117]	Microsphere	Enzymatic crosslinking
	Gel-SH [119]	Microsphere	Chemical crosslinking	BMSCs	Cell
	BP-grafted GelMA [121]	Microsphere	Photo-crosslinking
	GelMA [122]	Microsphere	Photo-crosslinking	DS	Hydrophobic drug
	GelMA [128]	Microsphere	Photo-crosslinking	BMSCs	Cell

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Table 3. The application of synthetic polymers in preparing microfluidic carriers.

Carrier material	Carrier type	Solidification method	Cargo	Cargo type
PEGDA	Microsphere and microfiber [134]	Photo-crosslinking
	Microcapsule [136]	Photo-crosslinking	VEGF and PDGF	Hydrophilic drug
	Microcapsule [137]	Photo-crosslinking	Fibrinogen and mineral oil	Hydrophilic and hydrophobic drug
PLGA	Nanoparticle [141]	Physical assembly	PFC	Hydrophobic drug
	Microsphere [142]	Solvent evaporation	Levofloxacin	Hydrophobic drug
	Microsphere [145]	Solvent evaporation	SDF-1 and kartogenin	Hydrophilic and hydrophobic drug
PCL	Microfiber [147]	Solvent extraction
PLA	Microsphere [150]	Solvent evaporation	Ibuprofen	Hydrophobic drug
PLA	Microcapsule [151]	Solvent evaporation	Yeast cells	Cell
PLLA	Microsphere [153]	Solvent evaporation	rhsTNFRII	Hydrophilic drug

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