Nanocelluloses (NCs), with their remarkable characteristics, have proven to be one of the most promising “green” materials of our times and have received special attention from researchers in nanomaterials. A diversity of new functional materials with a wide range of biomedical applications has been designed based on the most desirable properties of NCs, such as biocompatibility, biodegradability, and their special physicochemical properties.
NCs Type |
Drug Delivery System |
Cellulose Source Drug |
Toxicological Experiment Drug-Release Conditions |
Cells Lines Drug Release Mechanism |
Toxicological Results Ref. |
---|---|---|---|---|---|
Material |
Cellulose Source |
Toxicological Experiment |
Cells Lines |
Toxicological Results Results and Possible Application |
Results and Possible Application |
Ref. |
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CNC |
cCNC/SA double-membrane hydrogels |
CH, EGF |
PBS, pH 7.4, 37 °C; t90% = 3 days (CH); t90% = 4 to 8 days (EGF). |
Swelling/erosion |
[89] |
|
TEMPO-oxidized CNC/CSos |
PrHy, IMI |
Breast cancer PBS, pH 7.4, room temp.; t40% = 12 min (PrHy); t80% = 2 h (IMI). |
- |
[50] [90] |
||
CNC-HDQ complex |
HDQ |
dH2O, room temp., in the dark; t40% = 1 h; t80% = 4 h. |
- |
[91] |
||
CS/CNC nanocomposite hydrogels |
C |
SGF, pH 1.2, 37 °C; 120 min: 65% (0.5% CS/CNC); 50% (2.5% CS/CNC). |
Ritger–Peppas model; n = 0.61–0.66; Non-Fickian diffusion. |
[92] |
||
QC/cCNC/β-GP nanocomposite hydrogels |
DOX | |||||
[ | ||||||
] | ||||||
BNC | ||||||
Ear cartilage TE | ||||||
[ | ] |
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BNC/Alg bilayer composite |
Neocartilage formation |
[133] |
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BNC/CS composites |
Cartilage tissue regeneration |
[134] |
Abbreviations: CS—Chitosan; PVA—Poly(vinyl) alcohol; Gel—Gelatin; ApA—Phosphonate; HA—Hyaluronic acid; Col—Collagen; GMs—Gelatin microspheres; PEG—Poly(ethylene glycol); PAAm—Polyacrylamide; a-CNC—Anionic CNC; HAp—Hydroxyapatite; Alg—Alginate; PMS—Paraffin microspheres; DBC—Dialdehyde bacterial cellulose; Col-p—Collagen peptide; PA—Procyanidin; Ap—Carbonate apatite; OGP—Osteogenic growth peptide; CNTs—Carbon nanotubes.
Material |
Cellulose Source |
Toxicological Experiment |
Cells Lines |
Toxicological Results |
Results and Possible Application |
Ref. |
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---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ref. | |||||||||||||||||
CNC |
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BNC |
CNC |
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BNC scaffolds Cotton (Whatman 1 filter paper) |
MTS assay; |
G. xylinus |
CCk-8 assayATP assay. |
BEAS 2B hMDMs |
HUVECs, SMCs, Fibroblasts Cytotoxicity at 100 mg/mL; No micronuclei induction after exposure to 2.5–100 mg/mL; No induction of proinflammatory cytokines in hMDMs. |
BC tubes have no toxic or side effects on vessel-related cells cultured on their surface; Toxicity impact on lungs or bone marrow |
the surface of BC tubes was beneficial for cell attachment, proliferation, and ingrowth. [135] |
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CNF | Vascular TE |
Double crosslinking 3D-printed CNF hydrogels |
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[ | ] |
CNC CNC- carboxyl Skin TE |
groups | ||||||||||||||
[ | [ | ] |
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CNC |
Wheat bran |
MTT assay |
Caco-2 |
Dose-dependent decrease in cell viability, but only with significant results above 1000 μg/mL; The cell viability decreased significantly upon contact with CNC90 (88.09%) at 2000 μg/mL, although CNC30 (92.81%) and CNC60 (93.11%) did not significantly decrease the cell viability. |
Biocompatible nanocomposites |
[140] |
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Bleached dissolving pulp Norway spruce (Picea bies) |
MTT assay [3H]-thymidine uptake assay |
L929; Thymocytes PBMNCs |
CNFs were not cytotoxic; CNC has non-inflammatory and on-immunogenic properties. |
Implantable biomaterials TE |
[151] |
Octenidine-loaded BNC Softwood cellulose pulp 111] |
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MTS assay |
K. xylinus CaCO-2, HeLa, MDCK, J774 |
CNC not exhibit any significant cytotoxicity; can exert stress on cells if they possess a high charge density; Charge-dependent decrease in mitochondrial activity (charge contents > 3.9 mmol/g). |
Drug delivery |
[136] |
ATP assay |
HaCaT |
Pure BNC has no influence on HaCaT viability; OCT/BNC extracts exhibited time and concentration-dependent toxicity; cell-damaging effects were observed at extract conc >10% and longer incubation times (24 and 48 h). |
Active wound dressing |
[167] |
CNF/PVA bilayer scaffold |
Skin TE |
[115] |
|||||
c-CNCs t-CNCs |
Cotton Tunicate from Stuela clava |
LDH assay |
A549 MDM | ||||||||||||||
BNC |
Sugar cane molasses |
LDH activity MDDC |
HepG2/C3A The aspect ratio in combination with CNCs dose influences the uptake by the 3D co-culture system of the human epithelial airway barrier system. |
Toxicity impact on lungs |
BC is not cytotoxic (conc. < 170 μg/mL); BNC has a protective effect against CP-induced myelotoxicity and enotoxicity. [137] |
Biomaterial TE |
CNF/Gel/ApA |
Bone TE |
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[ | ] |
CNC PBS, pH 7.4, 37 [°C; 116]t |
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Wood pulp |
TB assay 90% = 4 days (0% cCNC); t90% = 7 days (1% cCNC); t90% = 17 days (2.5% cCNC). |
Swelling/erosion |
A549 [93] |
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CNC were nontoxic to A549 cells; | Toxicity impacts on dermal, lung, and macrophage cells | ||||||||||||||||
Vaccarin- loaded BNC |
G. xylinus | CNC induced a robust inflammatory response; CNC particles induced a more robust inflammatory response compared to NCF. |
MTT assay |
L929 |
BNC-Vac has lower toxicity and better biocompatibility than BNC; Comparable toxicity of CNC with CNF |
RGR for both BNC and BNC-Vac was above 74%. [ |
Wound dressing 138] |
[153] |
|||||||||
[ | ] |
Gel/CNC nanocomposite hydrogels |
CNC | TPh |
CNF CNC/PVA nanocomposites SGF, pH 1.2, 37 °C; |
Skin TE |
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CNCgel CNCdry |
Wood pulp |
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Gentamycin-loaded BNC Bleached Eucalyptus Globulus kraft pulp |
24 h: 90% (5% CNC); 85% (10% CNC); 60% (25% CNC). |
- |
[117 |
K. xylinus MTT assay] [94] |
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LDH assay |
NR assay MH-S |
A549 THP-1 |
U2-OS Low conc. (1.5 and 5 μg/cm2) induce no cytotoxicity; A high dose of CNCdry induced a decrease in cell viability; CNC exposure further altered the secretion of cytokines. |
Cytotoxic effect at the highest dose tested; |
No cytotoxicity on osteoblast culture after 24 h;Genotoxic effects in A549 cells in the co-cultures; gentamycin released from G-BNC after 8 h (400 mg/L) and 16 h (600 mg/L) is enough to eliminate S. aureusNo oxidative DNA damages. Toxicity impact on lungs |
and P. aeruginosa biofilms. TE |
Bone regeneration TE [154] |
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[ | ] | m-CNC/Alg hydrogels |
Gel/HA/CNC hydrogels Ibu |
CNFSkin wound repair PBS, pH 7.4, 37 °C; t = 0–30 min; 45%–60% burst release; t = 30–330 min; sustained release. |
[118] Fickian diffusion |
[95] |
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CNF |
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Col/CNC/GMs |
K-CNC PDA/TEMPO-CNF composite hydrogels |
R-CNC Blood vessel TCH | |||||||||||||||
Curcumin- Curauá fibers (Ananas erectifolius L. B. Smith) |
loaded BNC Cytotoxicity assays ISO 10993-5 |
Vero |
K. xylinus |
MTS assay CNF shows no cytotoxicity and suitable biocompatibility; |
HNDF The morphology and basic functions of the cells are not affected by the direct contact with the tested materials. |
The cytotoxic effect on the cells depended on the conc. of curcumin; at 0.5 mg/mL C, a strong cytotoxicity for BNC-C and BNC-DC180; BNC-DC300 suitable cytotoxicity, even at higher extract conc. Scaffold TE |
Wound dressing [155] |
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[ | ] |
Rubberwood fiber Kenaf-bast fiber [119 PBS; “On-off” drug release under NIR irradiation; 120 min: 60% (pH 5.0); 30% (pH 7.4); 15 h: 70% (pH 5.0); 55% (pH 7.4). |
] Korsmeyer–Peppas model; |
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MTT assay |
RAW 264.7 HaCaT |
Cytotoxicity of K-CNC and R-CNC is not significant up to 700 μg/mL;Non-Fickian diffusion. |
[96] |
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K-CNC and R-CNC induced the formation of ROS in RAW264.7 macrophages. |
CNF |
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BNC-GTMAC Softwood bleached kraft fiber |
BNC-GHDE LDH | Biocompatible nanocomposites |
G. xylinus assay |
AB assay Caco-2, HT-29MTX Raji B [ |
HaCaT Minimal or no cytotoxicity in a cellular model of the intestinal epithelium (for CNC-25 at 0.75% and 1.5% w/w, as well as for CNF-50 at 0.75% w/w). |
No cytotoxicity; Suitable wound closure rates in the presence of the samples, with complete coverage of the scratched area after 5 days. Biocompatible material |
Wound dressing 141] |
[156] |
CNF/HPMC nanocomposites |
KT |
PBS, pH 7.4; 8 h: 95% (5% CNF), 62% (0.5% CNF), 56% (0.75% CNF), |
PEG-grafted CNC nanocomposites |
|||||
CNC CNC-FL CNC-HM Bone TE | 37% (1% CNF). |
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[ |
[ |
Cellulose pulp120] Non-Fickian diffusion; n = 0.52–0.61. |
[97] |
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] |
MTT assay |
ATCC PCS201012, A375 |
No cytotoxicity in direct and indirect contact assays. |
Drug delivery |
[142] |
CNF |
Banana peel bran |
MTT assay |
Caco-2 |
CNF conc. < 500 mg/mL are not cytotoxic to Caco-2 cells; Viability of Caco-2 decreased with increasing CNF conc. |
Biocompatible material |
[157] |
CNF/Alg hydrogels |
MH |
|||
BNC in nanocomposites |
CNC/PVA hybrid hydrogels |
U-NFC A-NFC Soft TE | |||||||||||||||
CNC in nanocomposites | C-NFC P-NFC S-NFC SGF, pH 1.2; SIF, pH 7.4, 37 °C; T40% = 90 min (CNF/Alg-50/50, SGF) t80% = 145 min (CNF/Alg-50/50, SIF). |
[121 Fickian diffusion mechanism |
] [98] |
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Never-dried bleached sulfite softwood dissolving pulp |
BNC |
BNC-SA hybrid hydrogels |
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Ibu |
CNC/PAAm composite hydrogels |
TE PBS, pH 1.5, 7.0 and 11.8; 37 °C; 24 h: 90% (pH 11.8); 80% (pH 7.0); and 60% (pH 1.5); PBS, pH 7.4; 0.15 V, 0.3 V, 0.5 V; 24 h: 95% (0.5 V); 85% (0.3 V and 0.15 V); 80% (0 V). |
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Collagen/CNCs/ GMs scaffolds |
MCC[122] Korsmeyer–Peppas model; Non-Fickian diffusion; pH; |
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MTT assay | n |
HUVECs = 0.498–0.772; |
No cytotoxicity; Excellent biocompatibility. |
Vascular TE |
[143] |
a-CNC/Gel hydrogels composite |
Breast cancer |
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CNC CNC-AEM CNC-AEMA |
[ |
Softwood pulp123] |
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ATP assay |
J774 A.1 PBMNC |
One cationic CNC induced secretion of proinflammatory cytokine IL-1b associated with increase mitochondrial-derived ROS and extracellular ATP levels. |
Drug and DNA delivery systems |
[144] |
TEMPO-CNC reinforced PVA hydrogels |
Corneal implant |
[124] |
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PLA/CNCg-PEG nanocomposites |
Southern pine |
Live/dead assays |
hMSCs |
Suitable biocompatibility; Nontoxic effect on hMSCs proliferation. |
Bone TE |
[145] |
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CNF |
Pinus radiata pulp |
LDH assay MTT assay |
HEK NHDF |
No toxic effect for keratinocytes and fibroblasts; Non-immunotoxic. |
Wound dressings |
[152] |
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CNF CNC |
Wood pulp |
TB assay |
A549 |
CNF caused a significant decrease in cell viability, at 72 h; Decrease in GSH levels after exposure to CNF. |
CNC toxicity |
[138] |
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U-NFC A-NFC C-NFC |
Never-dried bleached sulfite softwood dissolving pulp |
AB assay LDH assays |
HDF MRC-5 THP-1 |
No cytotoxicity for treated NFC; HDF and MRC-5 cells: the metabolic activity of the treated cells was comparable to that of the negative control; THP-1 cells: a higher metabolic activity of the NFC-treated; U-CNF has an inflammatory response, which was suppressed when surface charges were introduced on the CNFs. |
E-field; n = 0.700–0.491. |
[99] |
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TCH-loaded BNC composites |
TCH |
HEPES buffers, pH 7, 37 °C; 3 h: ~100% (free TCH); 90% (0.5% TCH); 60% (0.3% TCH); 20% (0.1% TCH); 10% (0.05% TCH); |
- |
[100] |
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OCT-loaded BNC |
OCT |
PBS, pH 7.4, 32 °C; 8 h: 82.7% ± 2.6% in first; 24 h 91.8% ± 2.0% after |
Ritger–Peppas model; n = 0.51–0.55; Non-Fickian diffusion. |
[101] |
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PI-loaded BNC |
PI |
PI buffer, 32 °C; t84% = 48 h. |
Ritger–Peppas model; n = 0.608–0.612 |
[102] |
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PHMB-loaded BNC |
PHMB |
PHMB buffer, 32 °C; t87% = 48 h. |
Ritger–Peppas model; n = 0.863–0.871 |
[102] |
Abbreviations: cCNC—Cationic cellulose nanocrystals; SA—Sodium alginate; CH—Ceftazidime hydrate; EGF—Epidermal growth factor human; PBS—Phosphate-buffered saline; CSos—Chitosan oligosaccharide; PrHy—Procaine hydrochloride; IMI—Imipramine hydrochloride; HDQ—Hydroquinone; C—Curcumin; CS—Chitosan; QC—Quaternized cellulose; β-GP—β-glycerophosphate; DOX—Doxorubicin; Gel—Gelatin; TPh—Theophylline; m-CNC—Magnetic cellulose nanocrystals; NIR—Near-infrared spectroscopy; PDA—Polydopamine; HPMC—Hydroxypropylmethyl cellulose; KT—Ketorolac tromethamine; Alg—Alginate; MH—Metformin hydrochloride; SGF—Simulated gastric fluid; SIF—Simulated intestinal fluid; HEPES—(4-(2-hydroxyethyl)-1-piperazine- ethanesulfonic acid); TCH—Tetracycline hydrochloride; AM—Acrylamide; Ibu—Ibupofren; OCT—Octenidine; PI—Povidone-iodine; PHMB—Polihexanide; dH2O—Distilled water.
NCs Type |
TE Systems |
Applications |
References |
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---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CNF |
CNF/CS nanocomposites |
Artificial skin |
[30] |
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CNF-based thixotropic gels | ||||||||||||||
Resazurin Assay | ||||||||||||||
Caco-2 | ||||||||||||||
BNC/ALG bilayer composites |
G. xylinus | None of the NFCs inducing cytotoxic effects in the intestinal cells; The differences in physics-chemical properties of the studied NFCs were not reflected in the Caco-2 response in terms of metabolic activity and cell membrane integrity. |
Drug release in gastrointestinal tract (GIT) |
[ |
ISO10993-5:2009 |
hNCs hMNC |
The composites were found to be noncytotoxic, with a cell viability of 98% and a uniform distribution of cells on the entire porous layer. |
Neocartilage TE ] |
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[ | ] |
U-NFC C-NFC H-NFC P-NFC S-NFC |
Never-dried bleached sulfite softwood dissolving pulp |
MTS Assay |
BEAS-2B |
No cytotoxicity for the highest tested dose (500 μg/mL) for any of the NFCs; None of the NFCs induced genotoxic effects; | ||||||||
BNC-COL-Ap composites |
G. xylinus |
MTT assay |
Osteoblastic cells All samples were able to increase intracellular formation of ROS. |
The composites did not exhibit cytotoxicity effects. In vitro toxicity of NFCs |
[159] |
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Bone regeneration TE | [174] |
c-CNF cys-CNF |
Never-dried bleached sulfite softwood dissolving pulp |
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ALG/BCN/COL |
PB assay |
composite hDF |
A. xylinum |
CCk-8 assay |
MC3T3-E1 hAMS cys-CNF did not induce toxic effects on hDF when tested at a concentration up to 0.5 mg/mL, nor did the starting material c-NF cys-CNF presented a dual action in vitro: inhibition of metalloproteinase and radical scavenging activity. |
MC3T3-E1 and hams cells were viable and proliferate well, after 2 and 5 days of incubation—suitable cytocompatibility. Wound dressing |
TE [160] |
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[ | ] |
CNF in nanocomposites |
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BC-PHEMA composites |
A. xylinum |
AB assay |
rMSCs |
BC-PHEMA composites are nontoxic and biocompatible; did not influence the morphology and proliferation of the rMSCs. |
Wound dressing |
[176] |
BNC |
TEMPO-CNC reinforced PVA hydrogels |
CNF L-CNF CNC BNC/Fibrin composites |
L-CNC MCC |
Dissolving pulp |
|||
BC/COL composites |
New blood vessel |
[78] |
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G. xylinus |
AB assay |
AB assay |
Live/ Dead assay HCE-2cells |
A549 THP-1 Nontoxicity; Excellent biocompatibility; |
UCBMSCs The HCE-2 cells viability above the 70%. |
Cytotoxic and inflammatory responses were dependent on type, size, and hydrophobicity Low or inexistent toxicity of all CNMs in A549 cells Dose-dependent cytotoxic and inflammatory responses in THP-1 cells. |
No cytotoxicity; Provide advanced microenvironment for UCB-MSCs viability and in vitro proliferation; Significantly elevated proteins and calcium deposition. Ophthalmic applications |
TE [146] |
[ |
Bone regeneration161] |
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TE | [ |
BNC-Gel/HAp nanocomposites |
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] |
PVA/CNC nanocomposites |
CNF /GEL/ApA |
||||||||||||
GEL/BNC nanocomposite Bleached birch pulp |
Bone TE |
[125] |
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Sugarcane bagasse |
A. xylinum MTT assay |
L929 |
MTT assay Noncytotoxic effect; Strong attachment and proliferation of human fibroblast skin cells on the scaffold. |
MTT assay MSCs TE scaffolds |
HEK293 CNFs and CNF-COOHs have no cytotoxicity; CNF-COOH-ApA cells expressed a low level of stress, visible through lower cell density and the cell inclusions. [ |
Bone TE |
[ |
BNG showed negligible cytotoxicity. ] |
Wound dressing ] |
Alg/BNC/Col composite |
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[ | ] |
GA-HA-CNC hydrogels TE |
MCC [126] |
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NFC hydrogels crosslinked with Ca2+ |
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BNC-GEL Bleached sulfite softwood pulp |
nanocomposite CCK-8 assay |
AB assay |
- |
MTS NIH-3T3 |
assay hDF Cell viability, at 1, 4, and 7 days, higher than 70% limit; No foreign body response. |
MRC-5 Cell viability about 78% indicates no toxic effects. |
The samples have no cytotoxicity, and the cells retained their morphology in direct contact with the membrane,No inflammatory response of blood-derived mononuclear cells was observed in relation to the cytokines secretion. Skin TE |
[ |
The cells attaching to the GEL porous site, while not attaching to the GEL thin-coated BC side. Wound healing |
Bone regeneration TE ] |
[163] |
|||
[ | ] |
3D BNC/PMS scaffolds |
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CS/Gel/NCC/CP nanocomposites TE; soft tissues regeneration |
TEMPO-CNF hydrogel Soft wood cellulose fibers [127] |
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Bleached birch kraft pulp MTT assay |
MTT assay Fibroblast cell |
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Chitosan-BNC |
K. xylinus hDF Lack of cytotoxicity after 3 days of increasing the cells’ viability. |
MTT assay Nontoxicity effect and great hDF cells viability. Wound healing |
[ |
Wound healing 149] |
[164] |
DBC/Col-p |
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CNC/PVA TE; tissues regeneration | ||||||||||||||
GM07492 |
No cytotoxicity for the BC group and BC-Chi-Cip group; Ciprofloxacin-loaded BC-Chi samples exhibited a significant but slight decrease in the metabolic activity of cells (moderate cytotoxicity). |
Wound dressing |
[180] |
NFC/QCRs nanocomposites MCC [128] |
||||||||||
GO/n-HAp/BNC/b-glucan biocomposite Brown algae |
AB assay |
MTT assay HCE-2 |
L929 Nontoxic and cytocompatible profile of the CNC-PVA hydrogel; Suitable biocompatibility toward HCE-2. |
Ophthalmic applications |
[150] |
BNC/PA/Gel/HAp |
Bone repair |
[129] |
||||||
(BNC-Col)-Ap/OGP peptides |
Bone TE |
[130] |
||||||||||||
BNC-CNTs composites |
Bone regeneration |
Abbreviations: BEAS 2B—Human bronchial epithelial cells; hMDMs—Monocyte-derived macrophages; Caco-2—Human colon carcinoma cells; HeLa—Human cervix; MDCK—Dog kidney; J774—Mouse macrophages; A549—Epithelial cells; MDM—Human blood monocyte-derived macrophages; MDDC—Dendritic cells; MH-S—Murine alveolar macrophages; RAW 264.7—Macrophages; ATCC PCS201012—Primary human fibroblasts; A375—Malignant melanoma cells; J774A.1—Mouse monocyte/macrophage; PBMNC—Peripheral blood mononuclear cells; hMSCs—Human mesenchymal stem cells; L929—Mouse fibroblast; NIH-3T3—Fibroblast; HCE-2—Human corneal epithelial cells; LDH assay—Lactate dehydrogenase cytotoxicity assay; MTT assay—(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay; TB assay—Trypan blue exclusion staining cell viability assay; MTS assay—CellTiter-Glo luminescent cell viability assay; MCC—Microcrystalline cellulose.
Material | ||||||
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CNF | ||||||
- | ||||||
NR | ||||||
assay | ||||||
MC3T3-E1 | ||||||
Cells viability is higher than 80% (for 5 to 1000 μg/mL CNFs/QCRs), indicating that there is no cytotoxicity. |
All samples had suitable potential for cell adhesion and proliferation with very low cytotoxicity The order of the cell viability: BgC-1.4 (93%) > BgC-1.3 (79.8%) > BgC-1.2 (71.4%) > BgC-1.1 (68.9%). |
Wound healing |
Bone regeneration [165] |
TE |
[ |
] |
Abbreviations: HUVECs—Human umbilical vein endothelial cells; SMCs—Smooth muscle cells; HaCaT—Human keratinocytes cells; HepG2/C3A—Human C3A hepatoma cells; L929—Mouse skin fibroblast cells; U2-OS—Osteoblast cell; HNDF—Human neonatal dermal fibroblasts; MC3T3-E1—Mouse osteoblastic cells; rMSCs—Mouse mesenchymal stem cells; UCBMSCs—Human umbilical cord blood-derived mesenchymal stem cells; MRC-5—Normal lung tissues cells; GM07492—Human fibroblast cells; CCk-8 assay—Cholecystokinin-octopeptide proliferation assay; ATP assay—Adenosine triphosphate assay; LDH assay—Lactate dehydrogenase assay; NR assay—Neutral red assay; MTS assay—CellTiter 96® Aqueous Non-Radioactive Cell Proliferation assay; AB assay—Alamar blue assay; G. xylinus—Gluconacetobacter xylinus; K. xylinus—Komagataeibacter xylinus; A. xylinum—Acetobacter xylinum; BNC- GTMAC—BNC functionalized with glycidyl trime-thylammonium chloride (GTMAC); BNC-GHDE—BNC functionalized with glycidyl hexadecyl ether (GHDE).