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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5604_Библиотеки_им_академика_М_И_Перельмана.pdf
Tabl e 1 (continued)
Sl.
CS/Carbon
No.
Nanomaterial
Based Drug Delivery
Vehi c l e
7 MWCNTs/
gelatin-chitosan
8 FA-C MCS /AGO Doxorubicin FTIR, SEM,
9 CS/CMC/Ca2+/GO 5-fluorouracil FTIR, FESEM,
10 CS/TPP/GO Sumatriptan
Drug Model Characterization Stimuli
Ciprofloxacin SEM, FTIR,
succinate
ATR-IR, TGA,
UV–Vis, EDX
HRTEM, Raman,
AFM, DLS, Zeta
potential, UV–Vis
UV–Vis
SEM, TEM, AFM,
TGA, XRD, FTIR,
EDS, DLS
Responsiveness
pH 7.4 90 min 98 Targeted drug
pH 5.3 48 h 86.0 Anticancer drug
pH 1.2 580
pH 1.2 – More
Drug Release Applications References
pH Time %
delivery agent in
nanomedicine,
targeted thermal
tumor ablation
and magnetic
field targeting of
tumors
7.4 48 h –
min
5.5 580
min
7.4 580
min
7.4
26 pH-controlled
51
68
substantial
release at 7.4
delivery
cancer drug
delivery
Drug delivery and
migraine
treatment
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 425
[94]
[95]
[96]
[97]
426 A. M. Mahmoud et al.
Fig. 4 a Fabrication procedure of CS/GO nanocomposite hydrogel and drug accommodation and
b obtained findings of drug release study of CS/GO nanocomposite hydrogel in pH 1.2 and 7.4.
Reproduced with permission from Elsevier [96]
3 Chitosan/Carbon Nanocomposites in CVDs
3.1 Chitosan-Based Scaffolds
Scaffolds are defined as 3D porous material with high biocompatibility that could be
injected or implanted for tissue engineering. The scaffolds are employed to deliver
pharmaceutical drugs, cells, proteins, and genes [98]. The high porosity of the scaffold allows cell growth, differentiation, proliferation, and nutrient transportation [99].
Scaffolds should achieve 50–90% permeability to allow oxygen, nutrients, and fluids
diffusion [100]. If scaffolds aren’t fulfilling these requirements, it could lead to cytocompatibility. One necessary criterion of the scaffold is that it must exhibit similar
mechanical properties as the native tissue and the extent of its degradation ability
should equal the rate of tissue regeneration. The scaffolds should be non-toxic and
deliver the therapeutic entities to the proper tissue without inducing the immune
response [98, 101]. For the conventional therapeutic approach, repeated doses of
the drugs might lead to high variance in the drug concentration during the course
of curing time and the concentration of the drug sometimes increases above the
safe levels that subject the patients to immense toxic effects. Economically, usage
of the drugs with high concentrations causes a huge loss of the drug materials.
Therefore, tremendous attempts have been made to fabricate scaffold and novel drug
delivery systems that encapsulated the therapeutic drugs to achieve controllable and
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 427
Fig. 5 Biological impacts essential for myocardial regeneration induced by polymeric biomaterials.
Reproduced with permission from MDPI [100]
sustainable drug release [102]. Besides, these scaffolds should be biodegradable and
achieve safe elimination from the patients’ bodies [99]. The polymer biomaterialbased scaffolds for cardiac regeneration must have adequate capability to biomimetic
cell adhesion, proliferation, angiogenesis and cell differentiation and have the potential to synchronize with cardiac rhythm. Furthermore, scaffold topology should be
similar to cell alignment, and it should comprise of electro-conductive components.
All of the above-mentioned characteristics are the required biological effects for
myocardial regeneration (Fig. 5)[100].
One of the best known polymer biomaterials for cardiac regeneration is CS [100].
CS has displayed potential for applications in cardiac tissue engineering owing to its
structural similarities with ECM in the heart, hydrophilicity, and controllable pore
size. CS can be fabricated into films, fiber, gels, and beads [103, 104]. Controlled
rate freezing and lyophilization technique (CRFLT) is the most effective strategy
to modify the size of CS scaffold pores. CS has high solubility in acidic aqueous
solutions, and therefore different freezing rates of the solution into ice will introduce
different phase changes. Then, lyophilization is used to remove the solid ice during
the vapor phase at low pressure. No melting occurs during the CRFLT process, and
the formed CS scaffold is left with pores. The pore size is vital to regulate mechanical
properties of the CS scaffold. Manipulation of the pore size can enhance the nutrient
and fluids flow, biodegradability, and cell growth. Also, various bioactive materials
like drugs, cells, and genes could be incorporated during the manufacturing process
since CRFLT is conducted at low temperatures. For example, different GAG analogs
were incorporated into CS scaffolds to replicate the ECM of the cardiac tissue [105].
Further, CS scaffolds could be costumed in different 3D structures by freezing the
428 A. M. Mahmoud et al.
polymer solutions into specific molds. However, enzymatic and cellular rejection
restricts the practical application of CS scaffolds and hydrogels. If CS is subjected to
lysozyme degradation to non-toxic D-glucosamine [106]. Therefore, cross-linking
with various materials such as carbon nanofibers and aliphatic polyesters has the
potential to improve the mechanical characteristics indistinguishable from the native
tissue and enhance the biological response to CS [107, 108].
CS-based materials have a viscoelastic behavior that can store and relax the stress
to mimic the biological tissues [109]. However, there are several factors that determine the stress-relaxation behavior such as the molecular weight, concentration, and
the fabrication conditions of the scaffold. CS with a molecular weight higher than
310 kDa exhibited stress-carrying capacity without deformation as compared to CS
with 50–190 kDa [110]. Ratakonda et al. concluded that CS and CS-gelatin have the
same stress-relaxation properties, but CS-gelatin withstands higher stresses, making
CS stronger [111]. Mombini et al. developed a CS-PVE-CNT nanofiber scaffold
composed of CS, polyvinyl alcohol (PVA) and CNT.The nanofiber scaffold displayed
mechanical durability of approximately 130 ± 3.605 MPa, with cell viability and
water uptake ability greater than 80%. Interestingly, the nanofiber scaffold showed
promising cardiac differentiation properties. The addition of the nanofiber scaffold to
the cultured undifferentiated mesenchymal stem cells upregulated the gene expression of the cardiac markers β–MHC, troponin I, and Nkx 2.5 which are accountable
for the differentiation and electrical stimulation in the cardiovascular tissue [112]. Xie
et al. engineered CS/poly(lactide-co-glycolide) (PLGA) composite as a potent electrospun scaffold for tissue engineering. Since CS is highly hydrophilic and PLGA is
relatively hydrophobic, this 3D copolymer enhances cell proliferation and adhesion,
representing a promising substrate for cell culture [113]. Therefore, reinforcement
of CS scaffold with CS fiber is a key to fabricate a mechanically viable engineered
heart valve construct. CS fibers incorporation significantly improved the mechanical
characteristics of CS scaffold and broadened its applicability [114].
The cardiac tissue has electroactive properties that can transfer the electrical
signal across the heart muscle. Therefore, the materials used for scaffold fabrications should have electrical behavior to imitate the microenvironment of cardiac
tissue. Although CS is not a conductive polymer that can transfer the electric signals
between cardiomyocytes, the integration of other conductive materials such as carbon
nanofiber and CNTs improves the electrical potential [107]. Carbon nanofiber has
better electrical conductivity than CNTs due to the presence of more sites on the outer
wall that enable electron mobility of the analytes. Further, it is noticeable that CS/
carbon scaffolds had similar elasticity to rat myocardium (28.1 ± 3.3 kPa) and an
electrical conductivity of 0.25 ± 0.09 S/m [107, 115]. Therefore, in this context CSPVA-CNT nanofiber scaffold prepared by Mombini et al. which not only helped in
enhancing the mechanical properties of CS but also exhibited the electrical conduc-
–6
tivity value of 3.4 × 10
S/Cm [112]. Pok et al. demonstrated that the introduction of
SWCNTs into CS-gelatin hydrogel achieved a native myocardial tissue conduction
velocity (22 ± 9 cm/s) and enhanced the beating and cardiomyocytes [116].
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 429
3.2 Chitosan in Cardiac Tissue Engineering
A propitious method for heart regeneration is cardiac tissue engineering. Human
stem cells may now be produced in large quantities and can differentiate into various
categories of cell types. The ability to construct cardiac tissues with excellent functional and molecular features has been made possible by advancements in the area
of materials science and bioreactor design. Engineered cardiac tissues are better at
recreating the intricate structure of the heart, achieving adequate vascularization,
and reducing the danger of arrhythmias. Researchers are currently using a variety
of techniques to regenerate injured heart tissues [117]. When compared to cells,
employing biomaterials for cell delivery has the advantage of acting as a medium
similar to the ECM, which serves as the necessary binding location for the cells as
well as aiding in their long-term retention in the intended region. Additionally, these
biomaterials offer suitable application sites for the controlled or sustainable release
of growth factors and immune-modulatory substances in the case of their delivery.
These substances give stability and guard against the compounds’ quick biodegradation inside the body [118, 119]. Polymeric biomaterials are popular options for
cardiac regeneration because they have mechanical properties that are comparable to
those of heart tissues. These biomaterials are most frequently employed as hydrogels,
cardiac scaffolds, microspheres, and nanoparticles [118, 120].
Recent research in the field of cardiac tissue engineering focuses on developing
tissue constructs that can reinforce, replace, repair, improve, and restore the functionality of damaged or ill myocardial tissue. Direct injection of relevant and required
cells into the infarcted myocardial tissue was the initial goal of cardiac tissue engineering, but this approach has poor cell survival and retention rates. Incorporating
a biomaterial within the heart wall in close touch with the cardiac cells is an alternate and promising approach to vanquish these limitations. This method involves
injecting natural or synthetic components into a mixture of different biomaterials
or cells [121]. CS is an appropriate biomaterial for use in tissue regenerative activities and has the properties of being biocompatible and biodegradable and possesses
antimicrobial activity and facilitates wound healing. Its antibacterial properties have
been extensively s tudied and proved in several investigations. These properties have
been demonstrated to improve cell engraftment and survival, which aids in cardiac
repair [121, 122].
In the event of progressive heart failure following MI, injectable scaffolds represent a viable treatment option for cardiac tissue regeneration. Because CS contains
positively charged amino acid groups, it has mucoadhesive, cell-binding and hemostatic properties. It can also create scaffolds with sufficient porosity and connections
to maintain cell viability with the constant supplementation of oxygen and nutrients [123]. Controlled delivery of the drugs and growth factors put on a CS-based
scaffold is an important component. They are the best choice for cardiac tissue regeneration and tissue engineering. CS serves as an ECM where immobilized angiogenic
advancement factors might trigger cellular reactions that could encourage endothelial cell migration and proliferation, ultimately facilitating the creation of a modern
430 A. M. Mahmoud et al.
vascularized network [124]. Studies have revealed that CS and genipin are used to
cross-link the porcine ECM. This makes it easier to maintain the biological makeup
of the ECM and also strengthens the injectable scaffolds mechanically. Before using
non-medicinal ECM as a substrate for tissue engineering, the immunogenicity impact
was reduced by decellularizing it.
The in vitro creation of three-dimensional (3D) myocardial tissue-like constructs
using cells, biomolecules and biomaterials is another intriguing approach for heart
tissue regeneration. The complication with this technique is preserving the functional
properties of cardiomyocytes throughout an extended period of culture and therapy.
The electrospinning method has been successfully used to create bioactive 3D CS
nanofiber scaffolds and assess the persistent heart function in the 3D co-culture
structure. The confinement of fibronectin onto the CS nanofibers by adsorption was
reported to improve cellular adhesion with the fibers and infiltration into the interfibrous gaps [125]. An electro-conductive scaffold for cardiac tissue engineering has
been prepared by Abedi et al. The scaffold was synthesized from CS, MWCNT and
PVA and it possessed improve functionality for cardiac tissue. Preparation of CS/
PVA/MWCNTs and different steps of tissue engineering process through the developed material are schematically represented in Fig. 6 [126]. Kroustalli et al. investi-
gated the characteristics of MWCNT/CS nanocomposite film for tissue engineering
applications. It was shown that there is an enhancement in cell proliferation and cell
viability after the addition of MWCNT within the CS matrix. Further, MWCNT/
CS is not toxic towards vascular myofibroblasts and endothelial cells and also does
not cause apoptosis. Due to the above-mentioned suitability, MWCNT/CS can be
implemented in cardiovascular tissue engineering applications [127].
3.3 Chitosan-Based Cell Therapy
Recently, stem cell therapy for the treatment of damaged cardiac tissue as a result of
MI attracted the attention of researchers. Stem cells are undifferentiated cells that can
be divided into different cell types with a high capacity for self-renew and are accountable for regeneration, maturation, and development of all tissue types. Various types
of stem cells that are used widely in cardiac therapy applications include embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem
cells (iPSCs), hematopoietic stem cells (HSCs), bone marrow stem cells (BMCs),
and cardiac progenitor cells (CPCs) [128–131]. Previous studies have shown the
abilities of these cells to differentiate into beating cardiomyocytes, regenerate the
injured cardiac tissue and enhance heart function [132]. However, there are a lot of
variables that assess the success rate of cell therapy, including the ability of the cell
to survive in the damaged tissue which is regarded as a challenging environment for
cell viability, immune compatiblity, and electrophysiological compatibility with the
cardiac muscle of the host body [133]. To overcome these obstacles, biocompatible
polymeric-based materials are used to deliver cells to the ischemic region [118, 119].
CS is a promising natural polymer that provides the delivered cell with an ECM-like
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 431
Fig. 6 Preparation of CS/PVA/MWCNTs and different steps of tissue engineering process.
Reproduced with permission from Elsevier [126]
microenvironment and enhances its viability and retention. It could be fabricated into
different forms for cell delivery therapy, including hydrogel [134], scaffold [112],
coating [135], and 3D-printed structure [136]. MSCs are multipotent stem cells that
have the potential to differentiate into different lineages, including ectoderm, mesoderm, and endoderm. Also, they secrete soluble molecules with immunomodulatory
and anti-inflammatory properties that aid in improving cell therapy for tissue regeneration [137]. CS-based hydrogel serves as an injectable scaffold that is employed
for administration of MSCs into the infracted myocardium of rats. This scaffold
enhanced the cell retention and graft size in the ischemic heart and enhanced cardiac
function and neovasculature formation [138]. Brown adipose-derived stem cells
(BADSCs) are a new source for cardiomyocytes used for regeneration of the infracted
heart. CS-based hydrogel was used to carry and deliver BADSCs and improved
the heart function and increased angiogenesis. CS helps in enhancement of the
differentiation of BADSCs into cardiomyocytes through collage synthesis promotion [139]. Hua et al. demonstrated that CS/dextran/β-glycerophosphate hydrogel
accommodated with hMSCs can enhance acute myocardial infractions. This hydrogel
improved the survival rate and increased the expression of pro-inflammatory and
pro-angiogenic [140].
432 A. M. Mahmoud et al.
3.4 Chitosan-Based Gene Delivery
Gene therapy has attracted attention in the last decade to treat severe heart failure,
peripheral ischemia, and dyslipidaemias. Despite the enormous potential and positive
preclinical results of CVD gene therapy, there are several limitations that restrict the
clinical translation. These obstacles include poor gene delivery and limited time of
transgene expression. Therefore, CS represents a safe and promising natural alternativefor viral vector systems that showed unfavorable toxic and immunogenetic effects
[49]. Yu et al. fabricated a low molecular weight CS-polyethyleneimine-eprosartan
composite to deliver a vascular endothelial growth factor (VEGF) plasmid in myocardial ischemia rat model. Eprosartan is a specific antagonist for angiotensin II type
1 receptor (AT1R) of cardiomyocytes which is used to strengthen and enhance the
composite capacity for VEGF delivery. This novel copolymer achieved high and
effective delivery of VEGF plasmid and showed strong therapeutic effects against
myocardial ischemia [141]. Recently, galactose-modified trimethyl CS nanoparticles
(GTANPs) were conjugated with atorvastatin. These GTANPs were used to encapsulate Baf60a siRNA (siBaf60a) and anti-miR-33 pDNA (pAnti-miR-33) to assess the
antiatherosclerosis efficiency of the codelivery statin and nucleic acid. Interestingly,
intravenously injected GTANPs/siBaf60a significantly reduced plasma cholesterol
and LDL-C levels. In addition, surprisingly, oral administration of GTANPs/pAntimiR-33 increased HDL-C and anti-inflammatory cytokines that resulted in inhibition of plaques formation. The oral route of administration is the effortless technique
for chronic diseases such as atherosclerosis [142]. Also, CS nanoparticles successfully delivered miRNA (miR-33) to macrophages that reduced cholesterol efflux to
apolipoprotein A1 through inhibition of ABCA1 expression. ABCA1 is the main
regulator of cholesterol efflux from macrophages [143].
3.5 Chitosan-Protein Interaction
CS can be crosslinked with different therapeutic proteins to promote their biological
activities. Modified CS nanoparticles with cyclic Arg-Gly-Asp-Phe-Lys peptide (cRGD) are used to load Lumbrokinase (LK) which has strong thrombolytic activities
but it is exposed to inactivation and has a short half-life. c-RGD peptide showed
high specific binding with platelet membrane GPIIb/IIIa receptors which enable
targeted delivery of LK to the thrombus. CS nanoparticles prolong the activity and
increase the cumulative release of LK and exhibited superior thrombolysis activity
in Sprague–Dawley rats carotid artery thrombus model as compared to free LK and
non-modified CS nanoparticles loaded with LK [144]. In addition, CS hydrogel is
photo-crosslinked with fibroblast growth factor-2 (FGF-2) to control the release of
FGF-2 molecules that induced angiogenesis and improved regional blood flow in the
ischemic myocardium rabbit model [145]. Reactive oxygen species (ROS) generation
is one of the major obstacles that face tissue transplantation which prevents successful
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 433
tissue repair. CS-glutathione (GSH) hydrogel was efficiently fabricated to combine
the bioactive properties of CS and the antioxidant properties of GSH in one system.
Injectable CS-GSH hydrogel showed high antioxidant activity that can scavenge the
excessive intracellular ROS and protect cardiomyocytes against oxidative damage
[125]. Moreover, CS interacts with fibrin which is a fibrous protein that plays an
essential role in the coagulation procedure. The CS-fibrin gel serves as a supportive
matrix that promotes the formation of cardiac muscle [146]. CS is blended with silk
fibroin to enhance angiogenesis and support stem cell differentiation into cardiomyocytes [147]. Silk fibroin is procured from the fibers of silkworms, scorpions, and
spiders and is used widely in wound healing applications [148]. Furthermore, CS
interacts with fibronectin which is a glycoprotein of ECM and can bind efficiently
with ECM components for coculture of cardiac myocytes and fibroblasts [125].
4 Challenges and Future Perspective
CS/carbon nanocomposite exhibits various magnificent properties such as mucoadhesive,hemostatic, cell-binding ability and protectective effect against cardiac infarction. Even after possessing the above-mentioned advantageous properties, more
attention needs to be provided on the designing of electroactive and biodegradable CS/carbon nanocomposite-based scaffold for CVDs treatment and therapeutic
administration. In addition, the employment of this efficacious combination in clinical trials is restricted since its in vivo investigation and the modification ability of CS
have not been enormously explored yet. Therefore, creation of CS/carbon nanocomposites with required characteristics for CVDs’ treatment and drug delivery application during future research advancement is the absolute desideratum to overcome
challenging procedures that come on the path of development.
5 Concluding Remarks
CS is a natural cationic polymer that is used for drug, gene, and therapeutic proteins
delivery. It is used for tissue engineering purposes through the fabrication of scaffolds
and hydrogels. The positive charge of CS facilitates the interaction with negatively
charged biomolecules such as nucleic acid and membranes. In addition, CS increases
the bioavailability of drugs and achieves controllable drug release and increases the
half-life of the drug which represents huge progress in the pharmaceutical industry for
developing drug delivery carriers to treat chronic diseases. The targetability of CS is
enhanced through a modification with peptides and proteins that interact specifically
with cell receptors to enable the safe delivery of the drugs. The safety and biocompatibility of CS are favorable requirements for biomaterials that are used in tissue engineering applications. Further, CS-based scaffold exhibited a great enhancement in
tissue engineering due to its interaction with ECM components that improve survival
434 A. M. Mahmoud et al.
and cell viability. However, several obstacles limit the clinical usage of CS in general
and particularly in cardiac tissue engineering. Therefore, several modifications were
performed to enhance the electrical properties of CS-based scaffolds. Being a highly
immaculate, less toxic, greatly reactive, biodegradable and biocompatible component and with the ability to functionalized CS, carbonaceous nanomaterials have been
reconnoitered and employed in the preparation procedure of CS/carbon nanocomposite. Moreover, it can be concluded that CS/carbon nanocomposites have shown
immense applicability in CVDs treatment and drug delivery applications.
Acknowledgements The authors acknowledge UGC India for awarding SJSGC Doctoral Fellowship to Krishna Manjari Sahu.
Conflict of Interest The authors declare that there is no conflict of interest in publishing this
article.
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