Lignin: Drug/Gene Delivery and Tissue Engineering Applications

Abstract

Lignin is an abundant renewable natural biopolymer. Moreover, a significant development in lignin pretreatment and processing technologies has opened a new window to explore lignin and lignin-based bionanomaterials. In the last decade, lignin has been widely explored in different applications such as drug and gene delivery, tissue engineering, food science, water purification, biofuels, environmental, pharmaceuticals, nutraceutical, catalysis, and other interesting low-value-added energy applications. The complex nature and antioxidant, antimicrobial, and biocompatibility of lignin attracted its use in various biomedical applications because of ease of functionalization, availability of diverse functional sites, tunable physicochemical and mechanical properties. In addition to it, its diverse properties such as reactivity towards oxygen radical, metal chelation, renewable nature, biodegradability, favorable interaction with cells, nature to mimic the extracellular environment, and ease of nanoparticles preparation make it a very interesting material for biomedical use. Tremendous progress has been made in drug delivery and tissue engineering in recent years. However, still, it remains challenging to identify an ideal and compatible nanomaterial for biomedical applications. In this review, recent progress of lignin towards biomedical applications especially in drug delivery and in tissue engineering along with challenges, future possibilities have been comprehensively reviewed.

Keywords: biomedical engineering; biopolymer; drug delivery; lignin; nano-biosystem; nanomedicine; tissue engineering.

Figure 1

Progress of research articles about lignin (A) and its application in different fields (B). Reprinted from Sustain Chem Pharm, 18, Domínguez-Robles J, Cárcamo Martínez Á, Stewart SA, Donnelly RF, Larrañeta E, Borrega M. Lignin for pharmaceutical and biomedical applications – could this become a reality? 100320, Copyright (2020), with permission from Elsevier.

Figure 2

Systemic of lignocellulosic biomass structure and major components. Reprinted from Trends Chem. 2(5), Bertella S, Luterbacher JS. Lignin functionalization for the production of novel materials, 440–453, Copyright (2020), with permission from Elsevier .

Figure 3

Lignin, cellulose, and hemicellulose units in biomass. Reprinted from Renew Sustain Energy Rev, 107, Chio C, Sain M, Qin W. Lignin utilization: a review of lignin depolymerization from various aspects, 232–249, Copyright (2019), with permission from Elsevier.

Figure 4

Chemical transformation of lignin to introduce diverse functional group. Reproduced from Ganewatta MS, Lokupitiya HN, Tang C. Lignin biopolymers in the age of controlled polymerization. Polymers (Basel). 2019;11(7):1176. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.

Figure 5

Widely used strategies for formulation of different drug delivery systems-based lignin. (A) nanoparticles of lignin and drug mixture, (B) drug loaded lignin nanoparticles stabilized emulsion, and (C) lignin wraps drug into nanoparticles. Reproduced from Liu R, Dai L, Xu C, Wang K, Zheng C, Si C. Lignin‐based micro‐ and nanomaterials and their composites in biomedical applications. ChemSusChem. 2020;13(17):4266–4283. © 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 6

(A) lignin based micro initiator and graft copolymer LnPDMAEMA synthesis through ATRP. Graft copolymer transfection efficiency in different cell lines Cos-7 (B), MDA-MB-231 (C), and HeLa (D) cells. Reprinted from Colloids Surf B Biointerfaces, 125, Liu X, Yin H, Zhang Z, Diao B, Li J. Functionalization of lignin through ATRP grafting of poly(2‐dimethylaminoethyl methacrylate) for gene delivery, :230–237, Copyright 2015, with permission from Elsevier.

Figure 7

Widely used strategies to formulate lignin hydrogel. (A) lignin-polymer blend hydrogel, (B) lignin-polymer crosslinking hydrogel, (C) nanoparticles of lignin and polymer blend hydrogel, and (D) lignin nanoparticles polymer crosslinking hydrogel. Reproduced with permission from Liu R, Dai L, Xu C, Wang K, Zheng C, Si C. Lignin‐based micro‐ and nanomaterials and their composites in biomedical applications. ChemSusChem. 2020;13(17):4266–4283. © 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.ref.

Figure 8

(A) Chitosan, alkali lignin, and formulate hydrogel viability against mesenchymal stem cells; (Data are expressed as means ± SD. ***Indicated the significance between two groups, ***P<0.001, n = 3); (B) SEM images (yellow dotted circles showing the cell adhesion on chitosan-alkali lignin hydrogel) and (C) FDA stain and (D) DAPI stained fluorescence images of cell adhesion on chitosan-alkali lignin hydrogel (Inset: Fluorescence micrographs showing the cell adhesion on chitosan). Reproduced from Mater Sci Eng C, 102, Ravishankar K, Venkatesan M, Desingh RP, et al. Biocompatible hydrogels of chitosan-alkali lignin for potential wound healing applications. Mater Sci Eng C, 447–457, Copyright 2019, with permission from Elsevier.

Figure 9

Strategies used for fabrication of nanoscale scaffolds for tissue engineering. Reproduced from Witzler M, Alzagameem A, Bergs M, et al. Lignin-derived biomaterials for drug release and tissue engineering. Molecules. 2018;23(8):1885. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.

Figure 10

SEM images of crosslinked nanofibers of PVA (A and B), PVA-PGS (C and D), PVA-PGS/lignin (1%wt) (E and F), PVA-PGS/lignin (3%wt) (G and H), and PVA-PGS/lignin (5%wt) (I and J) fibers. Reprinted from Mater Sci Eng C, 104, Saudi A, Amini S, Amirpour N, et al. Promoting neural cell proliferation and differentiation by incorporating lignin into electrospun poly(vinyl alcohol) and poly(glycerol sebacate) fibers, 110005, Copyright 2019, with permission from Elsevier.

Figure 11

Electrospun polycaprolactone nanofibers embedding lignin nanoparticles as nerve conduit. (A–D) different views of nerve conduit, (E) intraoperative view in the left sciatic nerve, and (F) P10L, (G) P15L Implantation and (H) 90 days of post-surgery at a 10 mm nerve gap. Reprinted from Int J Biol Macromol, 159, Amini S, Saudi A, Amirpour N, et al. Application of electrospun polycaprolactone fibers embedding lignin nanoparticle for peripheral nerve regeneration: in vitro and in vivo study. 154–173, Copyright 2020, with permission from Elsevier.

Figure 12

Systemic presentation of biomineralization of bone Hap induced by lignin. Reprinted with permission from Wang D, Jang J, Kim K, Kim J, Park CB. “Tree to bone”: lignin/polycaprolactone nanofibers for hydroxyapatite biomineralization. Biomacromolecules. 2019;20(7):2684–2693. Copyright (2019) American Chemical Society.

Figure 13

(A) lignin-PCL copolymer and (B) PCL/lignin-PCL nanofibers inhibition efficiency towards free radicals and proliferation of (C) BMSCs and (D) Schwann cells against nanofibers after H₂O₂ treatment. (Data are expressed as means ± SD. *Indicated the significance between two groups, *p < 0.05, n = 3). Reprinted from Colloids Surf B Biointerfaces, 169, Wang J, Tian L, Luo B, et al. Engineering PCL/lignin nanofibers as an antioxidant scaffold for the growth of neuron and schwann cell. Colloids Surf B Biointerfaces, 356–365, Copyright 2018, with permission from Elsevier.

Figure 14

Macroscopic images display wounds treated with different formulation on different time points. Reprinted by permission from Springer Nature, Drug Deliv Transl Res, Reesi F, Minaiyan M, Taheri A. A novel lignin-based nanofibrous dressing containing arginine for wound-healing applications, 8(1):111–122, Copyright (2018).

Figure 15

(A) PAM/LNP hydrogel fabrication procedure, (B) reaction of hydrogel formation; (C) hydrogel, (D) compressing, (E) bending, and (F) knotting images of hydrogels. Reprinted fromInt J Biol Macromol, 128, Chen Y, Zheng K, Niu L, et al. Highly mechanical properties nanocomposite hydrogels with biorenewable lignin nanoparticles, 414–420, Copyright (2019), with permission from Elsevier.