Review Article

Najmeh Ahangari1
Curcumin in tissue engineering: A Saeid Kargozar1
traditional remedy for modern medicine Majid Ghayour-Mobarhan1,2,3
Francesco Baino4
Alireza Pasdar1,5
Amirhossein Sahebkar6,7
Gordon A. A. Ferns8
Hae-Won Kim9,10,11
Masoud Mozafari 12,13,14*

1
Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2
Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3
Cardiovascular Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
4
Institute of Materials Physics and Engineering, Applied Science and Technology Department, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129,
Torino, Italy
5
Division of Applied Medicine, Medical School, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
6
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
7
Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical
Sciences, Mashhad, Iran
8
Brighton and Sussex Medical School, Division of Medical Education, Rm 342, Mayfield House, University of Brighton, Brighton, UK
9
Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, South Korea
10
Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan, South Korea
11
Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine Research Center, Dankook University,
Cheonan, South Korea
12
Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran, Iran
13
Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
14
Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

Abstract
Curcumin is the principal polyphenolic compound present in the potential to facilitate tissue healing, including anti-inflamma-
turmeric with broad applications in tissue engineering and regen- tory, anti-oxidant, and antibacterial activities. Therefore, curcumin
erative medicine. It has some important inherent properties with has been used for the treatment of various damaged tissues,

Abbreviation: ALP, alkaline phosphatase; α-SMA, alpha-smooth muscle actin; ANG, angiogenin; BMSCs, bone marrow mesenchymal stem cell; BMP-2,
bone morphogenetic protein 2; CaP, calcium phosphate; CS, calcium silicate; CMCS, carboxymethyl chitosan; CNCs, cellulose nanocrystals; Ce, cerium;
Cur, curcumin; DNA, deoxyribonucleic acid; EISA, evaporation-induced self-assembly; ECM, extracellular matrix; FDA, Food and Drug Administration; Ga,
gallium; GRAS, generally recognized as safe; GT, gum tragacanth; H&E, hematoxylin and eosin staining; HO-1, heme oxygenase 1; HFF-1, human foreskin
fibroblast cells; HA, hyaluronic acid; OH−, hydroxyl radicals; HIF-1, hypoxia-inducible factor-1; IFNγ, interferon gamma; IL-6, interleukin-6; MDA, malondialde-
hyde; mTOR, mammalian target of rapamycin; MMP-9, matrix metallopeptidase 9; MBGs, mesoporous bioactive glasses; MesoCS, mesoporous calcium sil-
icate; MRSA, methicillin-resistant Staphylococcus aureus; MAOA, monoamine oxidase A; n-GO, Nanographene oxide; NIPAAM, N-isopropylacrylamide; NO,
Nitric oxide; NSAID, nonsteroidal anti-inflammatory drug; VP, N-vinyl-2-pyrrolidone; ROO, peroxyl radicals; NOO, peroxynitrite; pDNA, plasmid DNA; PEG-A,
poly (ethyleneglycol) monoacrylate; PEG, poly(ethylene glycol); PCL, poly(ε-caprolactone); PCL-PEG-PCL, PCEC, Poly(ε-caprolactone)-poly(ethylene glycol)-
poly(ε-caprolactone); PLGA, poly(lactic-co-glycolic acid); PEI, polyethylenimine; ROS, reactive oxygen species; RANKL, receptor activator of nuclear factor
kappa-B ligand; RPE, Retinal pigment epithelium cells; RUNX2, Runt-related transcription factor 2; O−, Scavenging superoxide anion; SD, Sprague Dawley;
SD, Sprague–Dawley rat model; SDF1, stromal cell-derived factor 1; ESBL, the enzyme extended-spectrum beta-lactimases; TGF-β1, transforming growth
factor beta 1; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; WHO, World Health Organization; Zn, Zinc
© 2018 International Union of Biochemistry and Molecular Biology
Volume 00, Number 00, 2018, Pages 1–17
*Address for correspondence: Masoud Mozafari, PhD, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
E-mail: mozafari.masoud@gmail.com
Received 6 September 2018; accepted 12 October 2018
DOI 10.1002/biof.1474
Published online 00 Month 2018 in Wiley Online Library
(wileyonlinelibrary.com)

BioFactors 1

especially wound injuries. There are different forms of curcumin,
among which nano-formulations are of a great importance in
regenerative medicine. It is also important to design sophisti-
cated delivery systems for controlled/localized delivery of curcu-
min to the target tissues and organs. Although there are many
Keywords: curcumin; anti-inflammation; anti-oxidant; antibacterial;
wound healing; scaffold; tissue repair; tissue engineering
1. Introduction
Research over the past four decades has described the various
pharmacological effects of curcumin [1]. Curcumin has been
applied to chemoprevention as well as in eliciting a potential
therapeutic effect in several chronic diseases [2,3]. Hence, the
extraction and synthesis of curcumin and new synthetic deriva-
tives of curcumin is a major focus of research [4].
Curcumin is the principal curcuminoid of the turmeric rhi-
zome (Curcuma longa). Curcuminoids comprise curcumin I
(77%), curcumin II (17%), curcumin III (3%), and cyclocurcumin,
and were originally isolated by Vogel and Pelletier in 1815 [5].
The chemical structure and chemical synthesis of curcumin were
reported by Lampe and Miłobędzka in 1913 [6]. Curcumin can be
extracted as a yellow-orange dye from the powdered root of Cur-
cuma longa, and has been widely used in Ayurveda, Siddha, and
traditional Chinese medicine for centuries, as it has several ther-
apeutic properties, including: analgesic, anti-inflammatory, anti-
oxidant, antiseptic, and anti-carcinogenic properties [7,8]. It has
been shown that a dose of up to 12 g/day is safe for human con-
sumption over short periods in clinical trials [9].
There has been increasing attention on the use of curcumin
for regenerative medicine applications. Most studies on curcu-
min have focused on the wound healing process [10]. However,
there has been a gradually broadening of applications to recon-
struct other tissues like tendon and bone [11,12]. Based on the
literature, the use of curcumin with appropriate biomaterials
scaffolds (e.g., polymeric matrices) has been strongly suggested
for tissue engineering applications.
In this review article, we aim to introduce the potential of cur-
cumin as a promising biomaterial in the repair and regeneration of
soft and hard tissues such as skin, tendon, bone, and cartilage.
Moreover, we highlight research gaps for the broader use of curcu-
min for tissue engineering and regenerative medicine applications.
2. Extraction of curcumin
Curcuma longa L (turmeric) is cultivated in tropical and sub-
tropical regions. India is the main producer of turmeric, and
curcumin has been used as a home remedy for several ailments
for many centuries [13,14].
The word “curcuminoid” denotes a group of compounds includ-
ing curcumin, demethoxycurcumin, bis-demethoxycurcumin, and
cyclic curcumin. Curcumin has been identified as the major
2 Curcumin in tissue engineering
BioFactors
reports on the advantages of this compound, further research is
required to fully explore its clinical usage. The review describes
the physicochemical and biological properties of curcumin and
the current state of the evidence on its applications in tissue engi-
neering. © 2018 BioFactors, 00(00):1–17, 2018
component. As the most commonly used approach, solvent extrac-
tion followed by column chromatography is reported for purifying
curcumin from turmeric. However, other polar and non-polar
organic solvents are also applied including hexane, ethylacetate,
acetone, and methanol [15]. Whilst chlorinated solvents extract cur-
cumin very efficiently, they are not commonly employed due to their
non-acceptability in the food industry. Other approaches including
soxhlet extraction, ultrasonic extraction, microwave, zone-refining,
and dipping methods have also been tried. In general, the soxhlet,
ultrasonic, and microwave extractions are the most widely used
methods for curcumin extraction [16,17].
3. Nanoformulation of curcumin
Nanotechnology-based delivery systems have gained wide-
spread use because of their promising potential and advantages
over the conventional approaches. These advantages include:
(1) limiting biodegradation of the encapsulated cargo [18];
(2) facilitation of the controlled/sustained release of the encap-
sulated drugs; (3) enhancement of dissolution and tissue perme-
ability of the poorly water-soluble drugs [19]; (4) enhancement
of cellular uptake for effective targeting of bioactive molecules;
(5) and optimization of target-specific delivery of drugs and
superior drug retention into the target tissues [20,21]. Accord-
ingly, recent studies have applied nano-technology-based
approaches for the formulation of curcumin to increase its bio-
availability. These approaches include encapsulation of curcu-
min in liposomes [22], chitosan [23], biodegradable
microspheres [24], silk microspheres [25], complexed with
phospholipids [26] and polymerizing N-isopropylacrylamide
(NIPAAM) with N-vinyl-2-pyrrolidone (VP) and poly (ethylene-
glycol) monoacrylate (PEG-A) (see Fig. 1) [27].
4. Physico-chemical properties of
curcumin
4.1. Hydrophobicity
Curcumin is practically insoluble in water at either acidic or
neutral pH. The compound is, however, soluble in alkaline
media. The pKa values for the dissociation of the three acid
protons in curcumin have previously been determined to be
7.8, 8.5, and 9.0, respectively [28]. It has been shown that this
substance can interacts with several biomolecules via non-
covalent and covalent binding. The aromatic and tautomeric
structure as well as the flexibility of the linker group of curcu-
min offers its hydrogen bonding and hydrophobicity that is
responsible for the non-covalent interactions.
4.2. Stability
The use of curcumin was previously limited due to low water
solubility under acidic or neutral conditions, high decomposi-
tion rate in alkaline media and photo-degradation in organic
solvents. Attempts to prepare water-soluble curcumin by com-
plex formation or interaction with various macromolecules
(e.g., gelatin, polysaccharides) have been reported [29,30]. The
rapid degradation of curcumin clearly complicates the process.
It is therefore of interest to study the possibility of forming a
water-soluble curcumin complex at a pH where hydrolysis is at
a minimum and to investigate the stability of curcumin in such
a complex [31]. Several recent studies reported different
methods to stabilize curcumin in biologic conditions as a thera-
peutic agent [31,32]. Microencapsulation of curcumin within
hybrid structures, consisting of curcumin-loaded liposomes
within a protein matrix, significantly increased its bioaccessibil-
ity (
1.seven-fold) compared to the free compound, and could
successfully stabilize it against degradation in PBS (pH = 7.4).
The proposed approach thus proved to be a promising alterna-
tive to produce powder-like functional ingredients [33].
5. Biological characteristics
5.1. Antioxidant effects
Several studies have shown that curcumin has antioxidant
properties [34]. The antioxidant activity of curcumin, dimethox-
ycurcumin, and bisdemthoxycurcumin have been often studied
with in vitro model systems. For example, curcumin has been
Different formulations suggested for preparing nanoscale curcumin can increase its therapeutic effects. With permission from
FIG 1 Ref [10].
ahangari et al.
shown to be an effective scavenger of reactive oxygen species
(ROS) and to exert cytoprotective effects against H2O2-induced
oxidative stress in cultured retinal pigment epithelium (RPE)
cells [35]. Curcumin exerts an antioxidant effect by affecting
reactive species; scavenging superoxide anion (O−), peroxyni-
trite (NOO), nitric oxide (NO), peroxyl radicals (ROO), and
hydroxyl (OH−) radicals and inducing an up-regulation of anti-
oxidant proteins [36]. Curcumin has been reported to reverse
liver, brain and kidney damage, hyperglycemia, lipid oxidation,
inflammation, and oxidative stress [37].
5.2. Anti-inflammatory functions
The roles of curcumin as an inhibitor of inflammatory cytokines
have been extensively studied [38–40]. Several mechanisms by
which curcumin can exert anti-inflammatory activity have been
suggested. It was proposed that curcumin relieves oxidative
stress and inflammation in chronic diseases by its effects on the
Nrf2-keap1 signaling pathway. Moreover, curcumin can sup-
press pro-inflammatory pathways associated with most chronic
conditions and block both the production of tumor necrosis fac-
tor (TNF) and the cell signaling mediated through TNF in differ-
ent cell types [41–43]. Because of the chemical structure of
curcumin, it may act as a natural-free radical scavenger which
can reduce the release of various interleukins over NF-κB. Cur-
cumin may mimic the stress response that induces some com-
ponents of the protein homeostasis network [44].
5.3. Antibacterial activity
The antibacterial effect of curcumin has been well documented
and the relevant mechanism involves the interaction with the
essential cell division initiating protein FtsZ [45]. The FtsZ pro-
tein is involved in bacterial cell division and is the first protein
to appear at the impending site of division. FtsZ is present in
almost all prokaryotic species and is also essential for the
3

division of chloroplasts and mitochondria in some eukaryotes.
Immunolocalization experiments have shown that, in bacteria,
the FtsZ protein undergoes polymerization, forming a ring
structure known as the Z-ring at the site of imminent cell divi-
sion. The ring structure indicates that FtsZ is a cytoskeletal pro-
tein, exhibiting functional homology with tubulin, a eukaryotic
cytoskeleton protein. However, the structures of bacterial cyto-
skeleton proteins are markedly different from their eukaryotic
homologs, making it possible to develop specific inhibitors for
bacterial proteins [46,47]. Experimental data suggest that the
methoxy and hydroxyl groups of curcumin are directly involved
in the antimicrobial activity [48,49]. As an illustration, curcu-
min could strongly prohibit the formation of the cytokinetic Z-
ring in Bacillus subtilis 168 without affecting the segregation
and organization of the molecule. The authors of this study con-
cluded that curcumin hinders bacterial cell division by prevent-
ing the assembly dynamics of FtsZ in the Z-ring [47].
5.4. Anti-apoptotic effects
It is commonly assumed that curcumin exerts its action through
antioxidant and anti-apoptotic effects [50]. However, it has also
been shown that pre-treatment with curcumin is able to reduce
the levels of apoptosis in intestinal epithelial cells exposed to
interferon gamma (IFNγ) [51]. However, it is not clear how cur-
cumin acts on IFNγ-induced apoptosis and cytokine secretion.
One of the known actions of curcumin regards iron chelation
and reduction [52,53]. Other studies showed the anti-apoptotic
effect of curcumin in other conditions such as drug-induced
liver injury [54] and cadmium-induced apoptosis in rat testes
[55]. Based on the available literature, it seems likely that cur-
cumin may impart global protection in vivo by opposing several
crucial events that are instrumental to both apoptosis and
necrosis.
5.5. Stimulatory and inhibitory effects on angiogenesis
It has been demonstrated that a curcumin can inhibit invasion
of cancer-associated fibroblast-driven prostate cancer cells by
regulating MAOA/mTOR/HIF-1α signaling [56]. Thus, curcumin
appears to regulate tumor progression through multiple biolog-
ical pathways [57]. Studies on curcumin have shown its antian-
giogenic potential by suppressing the expression or synthesis of
HIF-1α and vascular endothelial growth factor (VEGF) in pitui-
tary adenomas, fibrotic liver, and diabetic kidneys [58,59]. On
the other hand, curcumin promotes healing of indomethacin-
induced gastric ulceration by stimulation of angiogenesis via
upregulation of VEGF and TGF-β1 [60] and accelerated healing
in dexamethasone impaired wound via enhanced expression of
TGF-β1 and its receptors [61]. It has also been reported that
curcumin stimulates the neovascularization at the diabetic
wound site directly, by the increased expression of antigenic
factors such as VEGF, TGF-β1, and other factors such as HIF-
1α, SDF1a, and HO-1, as well as indirectly, by anti-
inflammatory and antioxidant action [62].
4 Curcumin in tissue engineering
BioFactors
5.6. Toxicity and limitations
Despite the potentially beneficial roles of curcumin, a few stud-
ies have suggested that high concentrations of curcumin trigger
nuclear DNA fragmentation in mammalian cell lines [63]. Balaji
and Chempakam evaluated the toxicity of 200 chemical com-
pounds from turmeric. To cross-validate the results, the
authors selected curcumin. The results indicated that, in con-
trast to curcumin and its derivatives, there are few other com-
pounds in turmeric that are non-mutagenic, non-carcinogenic,
non-hepatotoxic, and without side-effects [64]. Ganiger
et al. [65] examined the reproductive toxicity of curcumin and
reported no adverse effect over two generations of rats. How-
ever, these results were then reviewed by a committee of the
World Health Organization (WHO) and the risk of curcumin-
induced reproductive toxicity could not be completely excluded.
The potential use of curcumin in chemopreventive or thera-
peutic settings has raised the obvious issues of toxicity and tol-
erance [66]. Multiple studies have been done so far to establish
the safe dose of curcumin. It has been stated that an oral
administration of 400 mg/kg of curcumin is required to obtain
detectable tissue levels in rats [67]. Moreover, oral administra-
tion of curcumin was safe in humans at doses between 36 and
180 mg/day even if taken for up to 4 months [68]. Phase I clini-
cal trials suggest that curcumin is well tolerated in human sub-
jects when taken at doses as high as 12,000 mg/day [69,70].
These results were confirmed by Lao and coworkers [71]. The
available experimental evidence clearly showed that, although
the acceptable daily intake of curcumin as an additive had been
defined by the WHO as 0–3 mg/kg body weight, it was well tol-
erated in human subjects at a dose about 50 times higher [72].
It is worth underlining that turmeric is currently listed as “gen-
erally recognized as safe” (GRAS) as a coloring and flavoring
agent in food by the US Food and Drug Administration
(FDA) [73].
6. Curcumin in TE strategies
As mentioned in the literature, it is possible to use curcumin by
the topical administration [72]. This provides the feasibility of
preparing and fabricating a broad range of curcumin-loaded
constructs, like nanofibrous scaffolds for reconstruction strate-
gies. Therefore, a large number of scaffolds with different
applications from hard to soft tissue repair and regeneration
are being developed. These are summarized below.
6.1. Wound healing
Among various natural candidates, curcumin has been exten-
sively used for wound healing applications [74]. Yen et al. have
recently shown that curcumin can accelerate cutaneous wound
healing via the regulation of a series of molecules such as TNF-
α, MMP-9, α-SMA, and collagen [75]. The authors prepared
Pluronic F127 gels containing 0.2 mg/mL of curcumin and used
them by topical administration for treating wounds in mice for
3, 5, 7, 9, and 12 days. The obtained results from histology and
immunohistochemistry analyses revealed the fast wound
closure and well-formed granulation tissue in the mice treated
with the curcumin-containing gels. They reported an increase
in the expression levels of collagen and α-SMA in the samples
treated with curcumin-containing gels. Moreover, the expres-
sion of mRNA and protein of TNF-α and MMP-9 significantly
decreased in the experimental group as compared to the con-
trol, confirming the positive effect on the acceleration of wound
healing. Mohanty et al. showed that curcumin improves healing
in a Sprague–Dawley (SD) excisional full-thickness wound
model via the down-regulation of the NF-kB pathway that con-
tributes to the depletion of inflammation and lipid peroxidation
[76]. Taken together, these results provide evidence that curcu-
min accelerates wound healing by reducing inflammation,
increasing cell proliferation and improving collagen deposition
in the injured sites.
Different topical formulations of curcumin have been used
for wound healing including films, fibers, hydrogels, emulsion,
and nano-sized formats (nanoparticles, nanovesicles, micelles,
and nanofibers) (see Fig. 2). Curcumin is mainly used as an
additive in these natural (e.g., chitin, chitosan and alginate) or
synthetic (e.g., PLGA and PCL) polymeric formulations for
wound dressing to manage various wound complications
including burns, diabetics ulcers, and full-thickness excision
(see Table 1).
Burns. The therapeutic effects of the topical administration of
curcumin on burn wounds have been previously evaluated by
Kulac et al. [78]. The authors produced second-degree burn
wound (2.5 cm in diameter) on the back of the Wistar-albino
rats using aluminum branding irons. The experimental groups
received topical curcumin at a concentration of 100 mg/kg body
weight, once daily for 12 days. The results of histopathological
and biochemical analyses showed faster wound healing in the
rats treated with curcumin. The improved rates of inflamma-
tory cell migration, collagen deposition, angiogenesis, granula-
tion tissue formation, and epithelialization were observed in the
curcumin-treated injuries in comparison to the controls. It has
been proposed that curcumin could reduce burn injury-
associated pain and wounds as an alternative to opioids,
Various topical formulations of curcumin for wound
FIG 2 healing strategies. With permission from Ref [77].
ahangari et al.
nonsteroidal anti-inflammatory drugs (NSAIDs), antidepres-
sants, and anticonvulsants [79–81]. According to the previously
published reports, the analgesic effect of curcumin is related to
its anti-inflammatory properties [82].
There is a need to improve the delivery systems for curcu-
min because of its relatively low bioavailability. Two nano-
based approaches have been developed to overcome this prob-
lem. Krausz et al. prepared curcumin-encapsulated nanoparti-
cles as an innovative antimicrobial and wound healing agent
for managing burns. Nanoformulation of curcumin improves its
poor aqueous solubility and rapid degradation profile as well as
enables its extended topical delivery [83]. The authors of this
study examined the efficacy of this system on the burn injuries
created by heat (160  C for 10 s) on the back of Balb/c mice.
The experiment included different groups: untreated control,
silver sulfadiazine, control nanoparticle, curcumin, and curcu-
min nanoparticle. The mice treated with the sol–gel-prepared
curcumin nanoparticles benefitted from a significant improve-
ment in the treatment of the burns with reduced bacterial load
and enhanced wound healing (Fig. 3).
Mo et al. [84] prepared electrospun nanofibres containing
curcumin and angiogenin (ANG) with controlled dual delivery
capacity that can accelerate skin regeneration. They fabricated a
novel drug and plasmid DNA (pDNA) dual delivery system by
electro-spinning the dispersion composed of PEI-CMCS/pDNA-
ANG nanoparticles, curcumin, PLGA, and cellulose nanocrystals
(CNCs). In vitro cell experiments confirmed the bioactivity of cur-
cumin and ANG in the nanofibers. Moreover, the release profile
showed 90% release of the curcumin for 6 days. In order to dem-
onstrate the in vivo angiogenesis and anti-infection properties,
the authors transplanted the PLGA/CNCs/Curcumin/pDNA-ANG
composite nanofibres into infected full-thickness burn wounds in
mice. Based on a set of analyses including histology, immunohis-
tochemistry, immunofluorescence, real-time quantitative PCR (rt-
qPCR), and western blotting the PLGA/CNCs/Curcumin/pDNA-ANG
nanofibres were proven to prevent local infection as well as to
promote skin regeneration.
Diabetic ulcers. Curcumin has anti-oxidant and anti-
inflammatory properties and these have been used in tissue-
engineered constructs suitable for healing these chronic
wounds. Merrell et al. [85] examined the therapeutic effects of
curcumin-loaded poly(ε-caprolactone) (PCL) nanofibers for
treatment of a streptozotocin-induced diabetic mouse model.
They showed the feasibility and potential of PCL nanofibres as a
delivery system for controlled release of curcumin in wound
healing. The in vitro experiments revealed that this system had
no adverse effects on the human foreskin fibroblast cells (HFF-
1) and showed a good anti-oxidant effect while maintaining the
viability of the cells under conditions of oxidative stress. More-
over, the construct could reduce inflammation as demonstrated
by reduced levels of interleukin-6 (IL-6) release from mouse
monocyte-macrophages seeded onto the nanofibres following
stimulation by E-coli-derived lipopolysaccharide. The in vivo
results in mice confirmed the efficacy of curcumin loaded-PCL
5

Some of the most important studies on the use of curcumin for wound healing
TABLE 1
Composition
Curcumin (100 mg/kg, topically)
Curcumin nanoparticles (curc-np)
Electrospun nanofibers composed of
PEI-CMCS/pDNA-ANG nanoparticles,
curcumin, poly (D, L-lactic-co-glycolic
acid) (PLGA) and cellulose nanocrystals
(CNCs)
Collagen-cellulose nanocrystal scaffolds
containing curcumin-loaded
microspheres
Curcumin-loaded poly (ε-caprolactone)
nanofibers
Curcumin (0.3%) in Pluronic F-127 gel
6 Curcumin in tissue engineering
BioFactors
Therapeutic Target Remarks Ref (s)
Burns - Accelerating wound healing in Wistar– [78]
Albino rats through improving the rates
of inflammatory cells, collagen
deposition, angiogenesis, granulation
tissue formation, and epithelialization
Burns - Inhibiting in vitro growth of [83]
methicillin-resistant Staphylococcus
aureus (MRSA) and Pseudomonas
aeruginosa in a dose-dependent fashion
- Improving the wound healing in an
in vivo murine wound model
Burns - Releasing nearly 90% of curcumin during [84]
the first 6 days
- Releasing nearly 90% of ANG during the
first 20 days
- Exhibiting the excellent biocompatibility
- Preventing the local infection in the
injured site
- Promoting skin regeneration
Burns - Along and sustained curcumin release [95]
profile
- Exhibiting a significant antibacterial
activity
- Preventing local inflammation in vivo
- Accelerating dermis regeneration in
Male SD rats
Diabetics - Showing a sustained release of curcumin [85]
for 72 h
- Lack of cytotoxicity
- Exhibiting antioxidant,
anti-inflammation, and antibacterial
activities
- Increasing the rate of wound closure in a
diabetic mice model
Diabetics - Improving the wound contraction [96]
- Decreased the expressions of
inflammatory cytokines/enzymes such
as TNF-α, IL-1β, and MMP-9
- Increasing the levels of
anti-inflammatory cytokine of IL-10
- Increasing the antioxidant enzymes of
superoxide dismutase, catalase, and
glutathione peroxidase
- Better granulation tissue dominated by
marked fibroblast proliferation and
collagen deposition, and wounds were
covered by a thick regenerated epithelial
layer
 (Continued)
TABLE 1
Composition
Curcumin-loaded gum tragacanth/poly
(ε-caprolactone) electrospun nanofibers
Curcumin conjugated to hyaluronic acid
(HA)
Curcumin loaded chitosan nanoparticles
impregnated into collagen-alginate
scaffolds
Curcumin-loaded
poly(e-caprolactone)-poly(ethylene
glycol)-poly(e-caprolactone) fibrous
mats
Curcumin containing polymeric micelles
(Cur-M) loaded thermosensitive
hydrogels
Curcumin loaded nanographene oxide
(n-GO) reinforced fish scale collagen
ahangari et al.
Therapeutic Target Remarks Ref (s)
Diabetics - Exhibiting antibacterial effects against [87]
the MRSA
- Improving wound healing as a result of
better wound closure with well-formed
granulation tissue dominated by
fibroblast proliferation, collagen
deposition, complete early regenerated
epithelial layer and formation of sweat
glands and hair follicles
Diabetics - Enhancing the cell proliferation [88]
- Decreasing oxidative damage
- Improving the migration of cells in
scratch wound model in vitro
- Exhibiting antibacterial activity against
MRSA
- Better wound closure in rats received
25 mM of curcumin conjugated to
210 mg/ml of HA, topically
- Fewer inflammatory cells and increased
deposition of dermal layers in the
damaged site
- Formation of well-formed granulation
tissue rich in fibroblast, collagen, and
re-epithelialization
Diabetics - Showing good in vitro characteristics in [97]
terms of better water uptake,
biocompatibility, and sustained drug
availability
- Improving wound contraction
- Formation of complete epithelialization
with thick granulation tissue formation
Excisional full-thickness - Exhibiting significant anti-oxidant [93]
efficacy and low cytotoxicity
- Sustained release of curcumin
- Regenerating wound defects of Wistar
rats to its normal condition after 21 days
Excisional full-thickness - Exhibiting well tissue adhesiveness [92]
- Releasing curcumin in an extended
period
- higher tensile strength and thicker
epidermis in the injured site
- Better wound closure
- Higher collagen content, better
granulation, and higher wound maturity
- Decreasing superoxide dismutase, and
slight increasing in catalase
Excisional full-thickness - Showing antibacterial activity against [98]
both positive and negative strains
7

(Continued)
TABLE 1
Composition Therapeutic Target
Curcumin-Loaded Chitosan/Gelatin Excisional full-thickness
Composite Sponge
Curcumin incorporatedcollagen films Excisional full-thickness
nanofibers improving wound closure in diabetic ulcers. In
accordance to what already pointed out elsewhere, these
authors concluded that the biological activity of curcumin is
highly dependent on concentration, and the long-term release
of curcumin from nanofibres and its subsequent biological
activity should deserve further evaluation.
Angiogenesis, a vital process for wound healing, gets com-
promised in diabetes resulting in a delay in wound healing pro-
cess. Previously published reports showed that curcumin can
either stimulate or inhibit the angiogenesis process [62,86].
Kant et al. [62] attempted to exploit the angiogenic potential of
curcumin for accelerating wound healing in diabetic rats. They
treated open excisional diabetic wounds on the back of adult
male Wistar rats by topical administration of Pluronic gel (25%)
and curcumin (0.3%) for 19 days. The data obtained from dif-
ferent analyses including histology, immunohistochemistry (for
CD31 marker), real-time PCR (for VEGF, TGF-β1, HIF-1α, SDF-
1α, and HO-1), and western blotting (for VEGF and TGF-β1)
confirmed the positive effect of curcumin in the treatment of
diabetics’ wounds. Rapid wound closure with well-formed gran-
ulation tissue dominated by fibroblast proliferation, collagen
deposition, and complete early regenerated epithelial layer was
observed in rats treated with curcumin. Furthermore, the
expression of the angiogenic markers was significantly higher
in the groups receiving curcumin as a therapeutic agent. In
brief, the authors concluded that curcumin can enhance the
angiogenesis and thereby accelerate the wound healing in dia-
betic rats through up-regulation of different angiogenic factors.
In 2016, Ranjbar et al. [87] assessed the potential of
curcumin-loaded gum tragacanth/poly(ε-caprolactone) (Cur/PCL/
GT) electrospun nanofibers for antibacterial performance and
in vivo diabetic wound healing. In fact, the antibacterial PCL/GT/
Cur membranes were proposed for sustainably delivering
8 Curcumin in tissue engineering
BioFactors
Remarks Ref (s)
- Faster wound healing efficiency of
curcumin-loaded constructs
- Improving water uptake ability and [99]
antibacterial activity
- A greater wound closure in wounds
treated with curcumin-loaded constructs
- Showing an excellent anti-oxidant [91]
activity
- Increased wound reduction, enhancing
cell proliferation, and efficient free
radical scavenging
- Higher shrinkage temperature of the
curcumin containing films and thereby
increasing hydrothermal stability as
compared to normal collagen films
curcumin to repair diabetic wounds. The in vitro results showed
that the nanofibrous membranes release curcumin for about
20 days. The antibacterial effects of the curcumin-containing scaf-
folds were analyzed against methicillin-resistant Staphylococcus
aureus (MRSA) and the enzyme extended-spectrum beta-
lactimases (ESBL) bacteria revealed that PCL/GT/Cur nanofibers
were 99.9% antibacterial against MRSA and 85.14% against ESBL.
Moreover, the authors showed that the implantation of these scaf-
folds with umbilical cord-derived mesenchymal stem cells in male
Wistar rats results in a fast wound closure with well-formed gran-
ulation tissue dominated by fibroblast proliferation, collagen depo-
sition, complete early regenerated epithelial layer, and formation
of sweat glands and hair follicles in the injured sites.
More recently, Sharma et al. examined wound healing
activity of curcumin-conjugated to hyaluronic acid (HA) in dia-
betic mice [88]. They used this system to overcome the hydro-
phobicity and lack of stability of curcumin. The in vitro data
revealed that HA-conjugated curcumin treatment leads to
improved cell proliferation, decreased oxidative damage, and
enhanced cell migration in the 2D scratch assay as compared
to the treatment with native curcumin. According to the in vivo
results, the authors reported a better wound healing in dia-
betics’ rats treated with HA-conjugated curcumin in compari-
son to HA-free curcumin and HA alone. They suggested this
formulation as a promising candidate for enhancing wound
healing in diabetic ulcers.
Full-thickness excisional wounds. Full-thickness excisional
wound models are commonly used for evaluating a plenty of
wound healing situations in vivo [89]. Curcumin has been previ-
ously proposed as a therapeutic agent for the treatment of this
type of skin injuries [90]. In a pioneering study, Gopinath
et al. [91] took benefit from the antioxidant effects of curcumin
 Effects of curcumin on burn wounds. Curcumin nanoparticle is able to enhance the formation of granulation tissue, collagen deposi-
FIG 3 tion, and neoangiogenesis. Hematoxylin and eosin (H&E) and Masson’s trichrome staining of wounds treated with different mate-
rials. Untreated: control, SS: silver sulfadiazine, np: wounds treated with nanoparticles, curcumin: wounds treated with curcumin,
and curcumin nanoparticle: wounds treated with curcumin nanoparticle. On H&E images, the magnification is 4×, bar = 500 μm;
10×, bar = 100 μm and on trichrome images, the magnification is 40×, bar = 100 μm. With permission from Ref [83].

embedded in collagen films to improve wound healing in a full-
thickness model of male Wistar rats. Spectroscopic studies con-
firmed the correct bonding of curcumin to the collagen films
without affecting its triple helicity. Also, an anti-oxidant assay
using 2, 20 -azobisisobutyronitrile proved the in vitro antioxidant
activity of the constructs. The authors then implanted the
curcumin-containing films into the animals and evaluated the
results by histological analysis. The obtained results showed a
substantial increase in neutrophils along with proliferating
fibroblasts and macrophages in the rats treated with curcumin-
doped collagen, while only a moderate increase in the animals
treated with collagen films and control group was observed on
day 7 of wound healing.
Various porous polymeric scaffolds containing curcumin
have been fabricated to use in the management of full-thickness
wounds. For instance, Gong et al. [92] prepared biodegradable
hydrogels containing curcumin encapsulated in micelles for
improving cutaneous wound healing. They aimed to take
advantage of the anti-oxidant and anti-inflammation properties
of curcumin in the hydrogels. In order to overcome curcumin’s
high hydrophobicity, the authors encapsulated it in polymeric
micelles (Cur-M) with high drug loading and encapsulation
capability. Then, the Cur-M-loaded thermosensitive hydrogels
(Cur-M-H) was prepared and used as wound dressing. The
in vitro results showed the good tissue adhesiveness of Cur-M-H
as well as the sustained release of curcumin from the con-
structs. The in vivo data revealed the higher tensile strength
and thicker epidermis in the excisional injure treated with Cur-
M-H as compared to other groups. Moreover, better wound clo-
sure and granulation, as well as higher collagen content and

ahangari et al. 9
 BioFactors

The schematic illustration of the study performed by Yang et al. regarding the efficacy of curcumin for wound healing process.
FIG 4 As shown, the authors firstly implanted the BMSC sheets into the skin wounds of the recipient mice. Then they added curcumin
to the wound site for inducing the secretion of various chemokines such as stromal cell-derived factor 1 (Sdf1) and subsequent
improved wound healing. With permission from Ref [94].

wound maturity, were observed in the groups treated with the
Cur-M-H.
Drug-loaded electrospun polymer mats are being used as
wound dressings for wound healing due to their similarity to
the three-dimensional porous structure of native ECM of skin.
In this regard, Fu et al. [93] successfully prepared curcumin
containing poly(ε-caprolactone)-poly(ethylene glycol)-poly
(ε-caprolactone) (PCL-PEG-PCL, PCEC) copolymer using co-
electrospinning technology. They evaluated the potential of the
scaffolds regarding skin regeneration in full-thickness exci-
sional defects of Wistar rats. After confirming the incorporation
and subsequent sustained release of curcumin from the mats,
the authors showed the antioxidant activity of these membranes
(with the curcumin content of 20 wt %) on primary mouse skin
fibroblast cells. The analysis of results of in vivo examination
showed a significant skin regeneration (93.3  6.6%) in the
groups treated with the curcumin-loaded PCEC mats. The
imbalanced immune response is one of the main problems in
adult full-thickness cutaneous wound repair, which may result
in non-functional reconstructed tissue and fibrosis. For addres-
sing this issue, Yang et al. recently investigated curcumin-
mediated bone marrow mesenchymal stem cell (BMSCs) sheets
as an immune microenvironment for adult full-thickness cuta-
neous wound healing (see Fig. 4) [94]. They found that curcu-
min can promote the proliferation rate of BMSCs in vitro and
modify the characteristics of produced ECM (secreted by
BMSCs), especially the contents of ECM structural proteins like
fibronectin and collagens I and III. The results obtained from

10 Curcumin in tissue engineering

the in vivo study revealed that the group of curcumin-induced
BMSCs provided a favorable immune microenvironment with
abundant amounts of SDF1, facilitating a mass migration of leu-
kocytes. In conclusion, the authors stated that the curcumin-
induced BMSCs group has better engraftment; meanwhile, cur-
cumin can improve the delivery and efficacy of BMSCs to pro-
mote its pro-healing functions.
6.2. Musculoskeletal regeneration
Anti-inflammatory and antineoplastic effects are two key
properties of curcumin regarding its application in the repair
and regeneration of musculoskeletal disorders [100,101]. It
has been well-documented that curcumin can improve multi-
ple aspects of bone health in subjects with osteoporosis
through affecting mechanisms involved in the activation and
differentiation of osteoclasts. These mechanisms include the
inhibition of NF-κB, RANKL, NO production, ROS generation,
and inflammatory cytokine synthesis [102–109]. By affecting
these mechanisms, curcumin decreases the number of osteo-
clasts as well as their differentiation and activation, leading to
shifting the balance between osteoblast and osteoclast activity
in favor of osteoblasts. Moon et al. [110] showed the effective-
ness of curcumin on other bone-related disorders by using
intraperitoneal injection of curcumin in a mice model of oste-
oarthritis for 2 weeks. There was a proliferation of splenic T
cells, the expression of tumor TNF-α, and IL-1β in the ankle
joint as well as down-regulation of the serum immunoglobulin
concentrations [110].
The role of curcumin in the treatment of other specific mus-
culoskeletal disorders has not been well documented. There
are few reports focused on bone/cartilage tissue engineering as
well as tendon repair and regeneration; in the following sec-
tions, we present the studies conducted on the reconstruction of
these tissues.
Bone and cartilage regeneration. In a pioneering study,
Shruti et al. evaluated the potential of cerium-, gallium-, and
zinc-substituted mesoporous bioactive glasses for the loading
and delivery of curcumin [111]. The authors firstly synthesized
the MBGs based on 80%SiO2–15%CaO–5%P2O5 (mol%) formula-
tion using the evaporation-induced self-assembly (EISA)
method. Then, they applied the impregnation method for incor-
porating curcumin into MBGs. The in vitro results revealed that
gallium- and cerium-containing MBGs-loaded curcumin more
than un-substituted glasses as a result of the high affinity of
curcumin toward hard Lewis acids. However, all the prepared
samples (high, low, and un-substituted MBGs) showed a release
profile of curcumin that is able to exert pharmacological activi-
ties. The authors concluded that MBGs doped with low amounts
of Ce, Ga, and Zn (1%, 1%, and 2%, respectively) can be consid-
ered as proper drug release formulation for curcumin since
these glasses showed the higher release of curcumin with quick
in vitro bioactivity and the added values of the substituents.
Jain et al. [112] examined the effects of curcumin-loaded
PCL electrospun nanofibers on osteogenesis via phytochemical
based bone tissue engineering. The authors loaded curcumin in
ahangari et al.
the nanofibers at 1 and 5 wt% (CU1 and CU5, respectively), and
observed the sustained release of curcumin from the fibrous
scaffolds, with a higher release of drug release from CU5. As an
important note, the curcumin-releasing scaffolds reduced cell
proliferation as compared with controls. However, the results
of gene and protein expression of osteogenic markers (RUNX2
and BMP-2) as well as quantification of mineral deposition (ALP
production and bone nodule formation) revealed a significant
improvement regarding bone regeneration for the group CU1,
but not CU5.
Calcium silicate (CS) cements are widely used for bone tis-
sue engineering, especially for dental applications due to their
excellent bioactivity and ability to induce the bone-like apatite
formation [113]. However, there is a problem with the use of
these materials, that is, their degradability and the subse-
quent condition that can cause the inflammatory response at
the early post-implantation stage [114]. Regarding this issue,
Chen et al. [115] prepared and evaluated the anti-
inflammatory effects of curcumin-loaded mesoporous calcium
silicate (MesoCS/Cur). They synthesized the MesoCS nanopar-
ticles via a template method and add curcumin to this formu-
lation at a concentration of 2, 5 mg/mL, and 10 mM (named as
C0, C2, C5, and C10, respectively). The results showed good
biocompatibility of MesoCS/Cur samples without any adverse
effects on their apatite-formation ability. Moreover, these sys-
tems could reduce the expression of inflammatory molecules
including TNF-α and IL-1, confirming its anti-inflammatory
ability.
More recently, Sedghi et al. developed biocompatible
zinc/curcumin-loaded coaxial nanofibers for bone tissue
engineering application [116]. They showed that the
curcumin-containing scaffolds are cytocompatible and can
promote osteogenesis in vitro. Also, the scaffolds showed an
excellent antibacterial activity against E. coli and S. aureus
strains. In another study, Bose et al. evaluated the effects of
different polymeric matrices (PCL, PEG, and PLGA) on cur-
cumin release from calcium phosphate matrix for in vitro
and in vivo bone regeneration [12]. The main object of this
study was the local delivery of curcumin via the polymers
for an effectual treatment regarding improving its bioavail-
ability and providing a higher release. The in vitro results
revealed enhanced cell viability in the group of curcumin +
PCL-PEG coated scaffolds in comparison to control samples.
Moreover, the authors developed 3D printed curcumin-
coated TCP scaffolds for non-load-bearing tissue engineer-
ing applications (see Fig. 5). The presence of curcumin in
the scaffolds resulted in an increased bone formation after
6 weeks as compared to pure TCP scaffolds (control). The
authors also suggested that local release of curcumin could
be exploited in load-bearing implants with the aid of
strengthening polymeric coatings deposited on the brittle
TCP structure.
Cartilage reconstruction. The use of curcumin has also been
proposed for cartilage repair and regeneration. In this regard,
11

Schematic illustration of experiments conducted by Bose et al. for preparing a curcumin-PCL/PEG-coated 3D printed CaP scaf-
FIG 5 folds, which implanted in the femoral defect of rats. With permission from Ref [12].
Kim et al. fabricated porous composite curcumin/silk scaffolds
to find an appropriate clinical replacement for defected carti-
lage [117]. For this purpose, the authors fabricated silk-based
scaffolds with different concentrations of curcumin (0.5–-
2 mg/ml). The obtained data revealed higher cell viability rate
and ECM formation for 1 mg/ml curcumin-containing silk
scaffolds as compared with the other groups. After implanta-
tion in the subcutaneous region of nude athymic mice, the his-
tological evaluations confirmed the biocompatibility and
formation of a cartilaginous matrix in the chondrocytes
(1 × 104 cells/scaffold) loaded curcumin/silk scaffolds groups
(see Fig. 6). Therefore, curcumin-containing silk scaffolds
show promise in providing clinical support for the patients
with different cartilage disorders.
Tendon healing. Inflammation is one of the main processes
playing a role in the pathogenesis of tendon-related disorders
such as tendinitis and tendinopathy [118,119]. This inflamma-
tion is controlled by several pro-inflammatory cytokines like
IL-1 and TNF-α. So, the use of materials that have anti-
inflammation activity has been proposed as a potential way to
manage these diseases. Buhrmann et al. [120] showed that
curcumin can modulate NF-κB-mediated inflammation in
human tenocytes in vitro. They also evaluated the mechanism
of curcumin action on IL-1-mediated inflammatory signaling.
Their results revealed that curcumin at concentrations of
12
BioFactors
5–20 μM can inhibit the inflammation process induced by IL-1
in human tenocytes. Moreover, curcumin suppressed IL-
1-induced NF-κB activation via inhibiting phosphorylation and
degradation of inhibitor of κBα, inhibition of inhibitor of κB
kinase activity, and inhibition of nuclear translocation of NF-
κB. This study was the first report on the potential of curcu-
min in treating tendon inflammation through modulation of
NF-κB signaling.
Jiang et al. evaluated the therapeutic potential of curcumin
regarding tendon healing in SD rats [11]. For this aim, they cre-
ated a patellar tendon window defect in the animals and
administered curcumin (100 mg/kg) via an oral gavage. The
results of histological and biochemical evaluations showed that
curcumin could improve the healing process through stimulat-
ing collagen deposition with well-organized structure in the
damaged sites and decreasing malondialdehyde (MDA) level,
respectively. Moreover, the biomechanical parameters
(e.g., tensile strength of tendon) were improved in the rats trea-
ted with curcumin. Based on the results, the authors stated that
the use of curcumin could be an additional therapeutic agent
for the management of damaged tendon tissue.
Cui et al. showed that the controlled release of curcumin
can prevent peritendinous adhesion during Achilles tendon heal-
ing in rats [121]. The authors loaded curcumin in nanomicelles
(gold nanorods [GNRs]-1/curcumin in polymeric nanomicelles
[curc@PMs]) and then injected these nano-structures into the
Curcumin in tissue engineering
 The results of histological evaluations (H&E, safranin-O, and alcian blue staining) of curcumin-containing silk scaffolds implanted
FIG 6 in the subcutaneous region of nude mice for 2 and 4 weeks. With permission from Ref [117].

surgical site (0.44 mg curcumin/kg) at weeks 1, 2, and 3, for
three times 10 s each. In the same manner, the control groups
received 0.44 mg curcumin/kg and 0.1 mL of saline, respectively.
The data obtained from biomechanical and histological evalua-
tions revealed the lowest grade of peritendinous adhesions in the
animals treated with NRs-1/curc@PMs group in comparison to
the other groups. The authors claimed that curcumin-loaded
nanoparticles possess the great potential for preventing adhe-
sion in clinical patients.
In vitro and in vivo anti-inflammatory and tendon-healing
effects of an extended curcumin delivery with porous
microspheres in Achilles tendinopathy has been recently evalu-
ated by Kim et al. [122]. They prepared curcumin-loaded porous
PLGA microspheres (Cur/PMSs) by a fluidic device. The cell cul-
ture study showed that the Cur/PMSs have anti-inflammatory
effects on LPS-treated tenocytes in a dose-dependent manner.
This effect was proven through significant down-regulation of
pro-inflammatory markers including MMP-3 and MMP-13, COX-
2, ADAMTS-5, IL-6, and TNF-α. The in vivo results revealed the
effectiveness of the local injection of Cur/PMSs in terms of ten-
don tissue healing of rats with collagenase-induced Achilles ten-
dinopathy (Fig. 7). Similar to the above-mentioned studies, an

The schematic illustration of curcumin loaded porous microspheres (Cur/PMSs) injected in the damaged Achilles (tendinitis) of
FIG 7 rats with the aim of reducing the inflammation and improving the healing process. With permission from Ref [122].

ahangari et al. 13

improvement in the biomechanical properties, that is, the incre-
ment of the tensile strength of tendon tissue, was observed in
the animals receiving Cur/PMSs in a dose-dependent manner.
7. Conclusions and outlook
The literature clearly supports the application of curcumin in
modern regenerative medicine. However, the insolubility in
water and poor bioavailability of unmodified curcumin has lim-
ited its therapeutic applications. The advent of new delivery
strategies and biocompatible carriers, curcumin has now been
employed in drug therapies based on implantable biomaterials
rather than simple oral ingestion. The anti-inflammatory, anti-
oxidant, and angiogenetic properties of curcumin have been
shown very helpfully in accelerating the regeneration of bone
tissue, cartilage, and injured tendon as well as in promoting the
healing of chronic wounds.
Looking at the future, new applications of curcumin to treat
other damaged tissues/organs and diseases deserve investiga-
tion, also considering that its use is considered clinically safe
and, thus there appear to be limited barriers to testing and
experimentation from a regulatory viewpoint.
Cardio-protective effects of curcumin are particularly
attractive, as cardiovascular diseases are estimated by the
WHO to be the first cause of death globally [123]. These benefi-
cial effects have recently been reviewed by Wongcharoen and
Phrommintikul [124]. The antioxidant effects of curcumin have
been shown to attenuate adriamycin-induced cardiotoxicity and
to prevent cardiovascular complications caused by diabetes. Its
anti-thrombotic, antiproliferative, and anti-inflammatory effects
along its ability to decrease the serum cholesterol level may
protect against the pathological changes associated with ath-
erosclerosis. Curcumin is also known to reduce the fatty acid
deposits on the walls of blood vessels. The inhibitory effect of
curcumin on p300-HAT has been demonstrated to reduce the
development of cardiac hypertrophy and heart failure in animal
models. The modulatory effect of curcumin on calcium homeo-
stasis may also play a role in the prevention of ventricular
arrhythmias.
Curcumin’s ability to inhibit several factors like NF-κB,
which modulates some pro-inflammatory and profibrotic cyto-
kines, provide a rational molecular basis for its use in hepatic
disorders [125]. Curcumin can attenuate liver injury induced by
alcohol abuse, iron overdose, cholestasis and acute CCl4 intoxi-
cation. Interestingly, curcumin can even reverse CCl4-induced
liver cirrhosis to some extent. The relatively limited number of
studies in this area should be dramatically expanded in the next
few years as hepatic diseases are one of the main causes of dis-
ability and mortality worldwide.
Belcacemi et al. [126], has suggested that curcumin could
also play a role in the treatment of Alzheimer disease; one of
the most important societal and medical challenges in the
next few years [127]. In fact, in vitro and in vivo studies have
revealed that curcumin can target biomolecular pathways
involved in this type of dementia, such as β-amyloid cascade,
14
BioFactors
tau phosphorylation and, more generally, neuroinflammation
or oxidative stress. In the field of neurosurgery, curcumin was
also shown to be able to promote peripheral nerve regenera-
tion in rats under both normal [128] and diabetic condi-
tions [129].
Potential applications of curcumin in the field of lung can-
cer treatment have been suggested through further biomolecu-
lar and preclinical studies should be carried out to elucidate its
effectiveness. In fact, if on one hand curcumin was reported to
inhibit the migratory and invasive ability of A549 lung cancer
cells in human patients by blocking the adiponectin receptor
1 [130], on the other hand a negative effect was observed in
smokers and ex-smokers, where curcumin was reported to
stimulate ROSs production and, thus, have a potential carcino-
genic effect [131].
In summary, there should be further studies testing the
effects of curcumin in the regeneration of complex tissues and
organs such as nerve, liver, heart, and lung. For this purpose,
reliable animal models should be used that take account the
best way for curcumin administration in the specific clinical
case considered. Local delivery instead of oral ingestion could
be indeed preferred to maximize the efficacy and minimize any
possible side effect. The selection of compatible biomaterials to
use as carrier/scaffold for curcumin (e.g., soft polymeric matri-
ces with tunable porosity degradation rates) will be the key to
the success of these new therapeutic approaches.
Conflict of interest
The authors declare that there are no conflicts of interest
regarding the publication of this paper.
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