Cellular Infiltration in an Injectable Sulfated Cellulose Nanocrystal Hydrogel and Efficient Angiogenesis by VEGF Loading

Overview

Journal Biomater Res

Specialty Biomedical Engineering

Date 2023 Apr 10

PMID 37038209

Authors

Kiyoon Min

Giyoong Tae

Affiliations

Soon will be listed here.

Abstract

Background: Cellular infiltration and angiogenesis into implanted biomaterial scaffolds are crucial for successful host tissue integration and tissue regeneration. Cellulose nanocrystal (CNC) is a nano-sized cellulose derivative, which can form an injectable physical gel with salts. Sulfate groups of sulfated CNC (CNC-S) can act as a binding domain to various growth factors and cytokines with a heparin-binding domain for sustained release of them. Vascular endothelial growth factor (VEGF) can promote the proliferation of endothelial cells and angiogenesis. In this study, VEGF-loaded CNC-S hydrogel was evaluated as an injectable scaffold that can induce cellular infiltration and angiogenesis.

Methods: CNC-S was hydrolyzed to get desulfated CNC (CNC-DS), which was used as a negative control group against CNC-S. Both CNC-S and CNC-DS hydrogels were prepared and compared in terms of biocompatibility and VEGF release. The hydrogels with or without VEGF loading were subcutaneously injected into mice to evaluate the biocompatibility, cellular infiltration, and angiogenesis induction of the hydrogels.

Results: Both hydrogels possessed similar stability and shear-thinning behavior to be applicable as injectable hydrogels. However, CNC-S hydrogel showed sustained release (until 8 weeks) of VEGF whereas CNC-DS showed a very fast release of VEGF with a large burst. Subcutaneously injected CNC-S hydrogel showed much enhanced cellular infiltration as well as better biocompatibility with milder foreign body response than CNC-DS hydrogel. Furthermore, VEGF-loaded CNC-S hydrogel induced significant angiogenesis inside the hydrogel whereas VEGF-loaded CNC-DS did not.

Conclusion: CNC-S possesses good properties as a biomaterial including injectability, biocompatibility, and allowing cellular infiltration and sustained release of growth factors. VEGF-loaded CNC-S hydrogel exhibited efficient angiogenesis inside the hydrogel. The sulfate group of CNC-S was a key for good biocompatibility and the biological activities of VEGF-loaded CNC hydrogel.

Citing Articles

Advancements and Applications of Injectable Hydrogel Composites in Biomedical Research and Therapy.

Omidian H, Chowdhury S Gels. 2023; 9(7).

PMID: 37504412 PMC: 10379998. DOI: 10.3390/gels9070533.

References

Mariia K, Arif M, Shi J, Song F, Chi Z, Liu C . Novel chitosan-ulvan hydrogel reinforcement by cellulose nanocrystals with epidermal growth factor for enhanced wound healing: In vitro and in vivo analysis. Int J Biol Macromol. 2021; 183:435-446. DOI: 10.1016/j.ijbiomac.2021.04.156. View

Mohammadi S, Ramakrishna S, Laurent S, Shokrgozar M, Semnani D, Sadeghi D . Fabrication of Nanofibrous PVA/Alginate-Sulfate Substrates for Growth Factor Delivery. J Biomed Mater Res A. 2018; 107(2):403-413. DOI: 10.1002/jbm.a.36552. View

Rivet C, Zhou K, Gilbert R, Finkelstein D, Forsythe J . Cell infiltration into a 3D electrospun fiber and hydrogel hybrid scaffold implanted in the brain. Biomatter. 2015; 5:e1005527. PMC: 4581123. DOI: 10.1080/21592535.2015.1005527. View

Griveau L, Lafont M, le Goff H, Drouglazet C, Robbiani B, Berthier A . Design and characterization of an in vivo injectable hydrogel with effervescently generated porosity for regenerative medicine applications. Acta Biomater. 2021; 140:324-337. DOI: 10.1016/j.actbio.2021.11.036. View

Goh M, Hwang Y, Tae G . Epidermal growth factor loaded heparin-based hydrogel sheet for skin wound healing. Carbohydr Polym. 2016; 147:251-260. DOI: 10.1016/j.carbpol.2016.03.072. View

Jansen L, Amer L, Chen E, Nguyen T, Saleh L, Emrick T . Zwitterionic PEG-PC Hydrogels Modulate the Foreign Body Response in a Modulus-Dependent Manner. Biomacromolecules. 2018; 19(7):2880-2888. PMC: 6190668. DOI: 10.1021/acs.biomac.8b00444. View

Wang K, Nune K, Misra R . The functional response of alginate-gelatin-nanocrystalline cellulose injectable hydrogels toward delivery of cells and bioactive molecules. Acta Biomater. 2016; 36:143-51. DOI: 10.1016/j.actbio.2016.03.016. View

Choi W, Sahu A, Vilos C, Kamaly N, Jo S, Lee J . Bioinspired Heparin Nanosponge Prepared by Photo-crosslinking for Controlled Release of Growth Factors. Sci Rep. 2017; 7(1):14351. PMC: 5662564. DOI: 10.1038/s41598-017-14040-5. View

Wang Q, Xu W, Koppolu R, van Bochove B, Seppala J, Hupa L . Injectable thiol-ene hydrogel of galactoglucomannan and cellulose nanocrystals in delivery of therapeutic inorganic ions with embedded bioactive glass nanoparticles. Carbohydr Polym. 2021; 276:118780. DOI: 10.1016/j.carbpol.2021.118780. View

10.

Guo R, Lan Y, Xue W, Cheng B, Zhang Y, Wang C . Collagen-cellulose nanocrystal scaffolds containing curcumin-loaded microspheres on infected full-thickness burns repair. J Tissue Eng Regen Med. 2017; 11(12):3544-3555. DOI: 10.1002/term.2272. View

11.

Whitelock J, Iozzo R . Heparan sulfate: a complex polymer charged with biological activity. Chem Rev. 2005; 105(7):2745-64. DOI: 10.1021/cr010213m. View

12.

Liu J, Zheng H, Poh P, Machens H, Schilling A . Hydrogels for Engineering of Perfusable Vascular Networks. Int J Mol Sci. 2015; 16(7):15997-6016. PMC: 4519935. DOI: 10.3390/ijms160715997. View

13.

Chen G, Lv Y . Matrix elasticity-modified scaffold loaded with SDF-1α improves the in situ regeneration of segmental bone defect in rabbit radius. Sci Rep. 2017; 7(1):1672. PMC: 5432001. DOI: 10.1038/s41598-017-01938-3. View

14.

Du W, Deng A, Guo J, Chen J, Li H, Gao Y . An injectable self-healing hydrogel-cellulose nanocrystals conjugate with excellent mechanical strength and good biocompatibility. Carbohydr Polym. 2019; 223:115084. DOI: 10.1016/j.carbpol.2019.115084. View

15.

Garcia J, Clark A, Garcia A . Integrin-specific hydrogels functionalized with VEGF for vascularization and bone regeneration of critical-size bone defects. J Biomed Mater Res A. 2015; 104(4):889-900. PMC: 5106804. DOI: 10.1002/jbm.a.35626. View

16.

Pandey A, Derakhshandeh M, Kedzior S, Pilapil B, Shomrat N, Segal-Peretz T . Role of interparticle interactions on microstructural and rheological properties of cellulose nanocrystal stabilized emulsions. J Colloid Interface Sci. 2018; 532:808-818. DOI: 10.1016/j.jcis.2018.08.044. View

17.

Modo M, Ghuman H, Azar R, Krafty R, Badylak S, Hitchens T . Mapping the acute time course of immune cell infiltration into an ECM hydrogel in a rat model of stroke using F MRI. Biomaterials. 2022; 282:121386. DOI: 10.1016/j.biomaterials.2022.121386. View

18.

Mendes B, Gomez-Florit M, Osorio H, Vilaca A, Domingues R, Reis R . Cellulose nanocrystals of variable sulfation degrees can sequester specific platelet lysate-derived biomolecules to modulate stem cell response. Chem Commun (Camb). 2020; 56(50):6882-6885. DOI: 10.1039/d0cc01850c. View

19.

Chamberlain M, Gupta R, Sefton M . Bone marrow-derived mesenchymal stromal cells enhance chimeric vessel development driven by endothelial cell-coated microtissues. Tissue Eng Part A. 2011; 18(3-4):285-94. PMC: 3267971. DOI: 10.1089/ten.TEA.2011.0393. View

20.

Yin A, Xu J, Yang C, Hsu S . Antiviral and Antibacterial Sulfated Polysaccharide-Chitosan Nanocomposite Particles as a Drug Carrier. Molecules. 2023; 28(5). PMC: 10003885. DOI: 10.3390/molecules28052105. View