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Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, 22, 911-926
911
REVIEW ARTICLE
Advancement in Nanoformulations for the Management of Diabetic Wound
Healing
Shailendra Singh Bhadauria1 and Rishabha Malviya1,*
1
Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh,
India
ARTICLE HISTORY
Received: July 6, 2021
Revised: December 1, 2021
Accepted: January 7, 2022
DOI:
10.2174/1871530322666220304214106
Abstract: People with diabetes have a very slow tendency for wound healing. Wound healing is a
vast process where several factors inhibit the sequence of healing. Nano-formulations play a major
role in acute and chronic wound healing. The present manuscript aims to discuss the role of nanoformulations for diabetic wound healing treatment. Diabetes is a common disease that has harmful
consequences which over the time lead to serious damage to many of the body's systems, especially
the nerves and blood vessels. During the literature survey, it was observed that nanotechnology has
significant advantages in the treatment of diabetic wound healing. The present manuscript summarized the role of nanomaterials in wound healing, challenges in diabetic wound healing, physiology
of wound healing, limitations that come during wound repair, and treatments available for wound
healing. After a comprehensive literature survey, it can be concluded that health worker needs more
focus on the area of wound healing in diabetic patients. Medical practitioners, pharmaceutical, and
biomedical researchers need more attention towards the utilization of nano-formulations for the
treatment of wound healing, specifically in the case of diabetes.
Keywords: Nano-formulation, diabetic wound healing, nanomaterial, diabetes, patient care, drug delivery.
1. INTRODUCTION
Diabetes is usually associated with diet and the gastrointestinal system. This disease causes consequences during
wound healing with significant clinical problems when left
untreated. Diabetic wounds are characterized by excessive inflammation, which damages healthy tissue and prevents effective immune response as well as a healing process [1]. Patients
suffering from diabetes are also much more vulnerable to an
open wound in their lower extremities due to peripheral neuropathy associated with type II diabetes [2]. There are currently 35 million patients with type II diabetes in the United
States, which is expected to rise to 55 million by 2030 [3].
IDF DIABETES ATLAS 9th issue 2019 provides contemporary information about diabetes. Diabetes affects nearly 463
million people (20-79 years old) worldwide, and this figure is
expected to rise to 700 million by 2045. 79% of people with
diabetes live in lower and middle-income countries. One out
of five patients over 65 years of age suffer from diabetes. 1 or
2 out of 232 million patients with diabetes have not been diagnosed. 4.2 million deaths have been reported due to diabetes. The minimum amount spent for the treatment of diabetes
in 2019 was 760 billion USD, 10 % of the total expenditure
*Address correspondence to this author at the Department of Pharmacy,
School of Medical and Allied Sciences, Galgotias University, Plot No. 2, Sector 17A, Greater Noida, Uttar Pradesh, India; Tel: +91-9450352185;
E-mails: [email protected],
[email protected]
1871-5303/22 $65.00+.00
for adults. Upwards of 1.1 million children and young adults
have type 1 diabetes, over 20 million natively (1 in 6 natively)
are affected by diabetes during pregnancy, with 374 million
patients at higher risk for developing type II diabetes [4].
Diabetic wounds are also linked to increased complications, gangrene, and amputation, including higher rates of infection [5, 6]. Throughout diabetic conditions, impaired
wound healing has also been attributed to the deterioration of
several physiological processes, including keratinocyte and fibroblast migration and proliferation, angiogenesis, collagen
accumulation, growth factor production, epidermal barrier
function, and extracellular matrix (ECM) production and remodeling imbalances [7]. The dysfunctional reaction by macrophages, the main initiators, and arbitrators of wound healing, are also linked to the impaired progression of wounds in
the diabetic state [8]. Fig. (1) represents a comparison between
normal wound healing and diabetic wound healing.
2. NANOMATERIALS USE FOR WOUND HEALING
As the researcher explained, wound healing had a serpentine 4-stage process that involved hemostasis, inflammation,
proliferation, and remodeling. The rationality of any substance was relevant to the process as well as the duration of its
therapeutic effect, dose, and mechanism of action. Various
nano-based perspectives examine the application for wound
healing. Researchers have made an effort to develop products
that come up with humid circumstances and have antibacterial
activity. Diversification with natural or synthetic materials or
© 2022 Bentham Science Publishers
912 Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9
Bhadauria et al.
Fig. (1). Comparison between normal and diabetic wound. (A higher resolution/colour version of this figure is available in the electronic copy
of the article).
their amalgamation has also been put together for specific
pathways of wound healing. Herein, natural polymers have
been applied generalship due to their important biological
functions and innumerable wound healing. Collagen is considered as a visionary healing scaffold with a superlative condition and moderately strong mechanical properties, a fundamental clot that reduces bleeding like silk fibroin was used
due to its structural strength. Keratin is another example that
is widely used to treat wounds with nanomaterials. The nanomaterials are used due to their potential to encourage a selfhealing framework that may imitate reincarnation. However,
the variety of wounded tissues requires a thorough understanding of the mechanics influencing these nanomaterials
and their cell cascade for different wound-healing applications. Nanoparticles can be used efficiently in this field of research because of their superior surface-to-volume ratio.
Metal nanoparticles such as gold, silver, and zinc possess excellent movables, along with wound healing activation and antibacterial activity trying to make them ideal for assimilation
into wound dressings [9]. Table 1 describes the multiple types
of nano-formulations used in wound healing and their properties. Fig. (2) represents various types of nanomaterials used in
diabetic wound healing.
Fig. (2). Various nanomaterials used for the wound healing. (A
higher resolution/colour version of this figure is available in the
electronic copy of the article).
Table 1. Multiple types of nano-formulations with their properties are summarized.
Nano-Formulation
Properties
Nano-scaffolds
Mimic the properties of extracellular matrix
(fibrous nature and nanoscales features)
Nanofibers
Create favorable conditions for cell attachment and cell drug interaction by replacing
artificial dermal analogs
Other Lipid particles
Controlled drug release and versatility of administration
Liposomes
Provide sustained drug release and a moist
environment on the wound surface.
Polymeric particles
Prevent drug release and ensure controlled
release against wound protease degeneration.
Inorganic nanoparticles
Its intrinsic property displays similar benefits
and strong antibacterial effects in wound
healing treatment.
Silver nanoparticles can regulate the release of anti-inflammatory cytokines and encourage fast injury closure without increasing scarring. The propagation of keratinocytes can
also stimulate epidermal reepithelization [10]. Gold nanoparticles (AuNPs) have the ability to promote cures and inhibit
microbial colonization. However, at lower AuNP concentrations, they can stimulate keratinocyte growth and differentiation [11]. Zinc oxide nanoparticles (ZnONPs) are effective
anti-bacterial agents modulating the perforation of the bacterial cell membrane in hydrogel-based wound dressings. [12].
Overall, time is increased and keratinocyte migration is endorsed and re-epithelialization is therefore improved [10].
Throughout the relationship, even the delivery of the wound
dressing vectors has potent antimicrobial and epithelial properties for polymeric nanoparticles (for example, hyaluronic
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Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9 913
ácid, Chitosan, Cellulose, Alginate). Alginate absorbs water
and produces moist alginate easily. Wound conditions also
limit wound identification [13]. Due to its hygroscopic nature,
Hyaluronic acid controls cell adhesion or adhesion during
wound healing [14]. An interpretation of the vascular endothelial growth factors has been significantly enhanced by endothelial cell proliferation, motility, and angiogenesis [15].
Cellulose triggers the closure of the wound by several growth
factors, including the epidermal growth factor or the local release of the fundamental fibroblast growth factor [10]. The
postulant is also completely comprehensive in polyurethane,
PLGA, PCL PEG, and PLA. Eventually, there may be another
alternative to produce wound scaffolds that imitate the qualities of the extracellular matrix. Nanofiber polymers can also
focus on the improvement of fibroblast adhesion on wounds
with their development [12]. Different types of nanoparticles
are described below.
2.1. Organic Nanomaterials
2.1.1. Micelles
In a hydrophobic inner core, micelles have been circumambient by an aqueous hydrophilic shell, creating respectively hydrophilic or hydrophobic agents. Contemporary polymer micelles have ideal colloidal stability, high load capacity, biocompatibility, toxicity, and controlled drug release
[16]. Curcumin-loaded hydrogel related to PEG-PCL hydrogel exists in both linear and full-thickness wound models with
blank (13.3 ± 2.9 mg-1) and control (11.3 ± 1.8 mg -1) administered in mice. They show significantly higher granulation
(4.17 ± 0.41) and wound strength of character in mice with the
linked PEG-PCL hydrogel (22.4 ± 2.2 μg−1) than the curcumin-loaded (Cur-M) (16.9 ± 2.3 μg mg−1) and control (11.3 ±
1.9 mg−1) [17]. The encapsulation of silver sulfadiazine in chitosan oleate micelles was also a copy. The connection demonstrated throughout the personification that not only drug levels
surface-to-volume ratios and dispersions were enhanced,
while the drug concentrations were also increased. It is also
intended to prevent the cytotoxic effects of the drug by coating
human cells without affecting its antimicrobials properties.
Researchers proved that silver sulfadiazine micelles augmented the antimicrobial activity against Staphylococcus aureus and Escherichia coli strains (with MIC values of 50 μg
mL−1 and 25.8 50 μg mL−1, respectively) compared to the control suspension (150 50 μg mL−1 for S. aureus and 37.5 for S.
aureus) 50 μg mL−1 E. coli [18]. Curcumin-loaded anti-diabetes and injury therapeutic properties of chitosan-based mixed
polymeric micelles, alginate-maltodextrin, pluronic F127,
P123, and Tween-80 were also reviewed recently through
studies in diabetic rats. These have come to an end that perhaps formulations prosper with the highest curcumin levels
(over 48, 74 ppm) can stimulate wound healing response,
demonstrating significant improvements in wound closure on
the 14th day, lowering aerial blood glucose or lipid profile,
clearly demonstrates its potential as a diabetes-controlling and
wound healing agent [19]. Another auspicious example is PluroGel R focusing mostly on technology, including its micelle
matrix, made up of a cell-friendly surfactant, and claims to
maintain humid content of the wound which control the loss
of fluids, that helps in the protection of the wound injury and
allowing slighter painful removal [16].
2.1.2. Polymeric Nanoparticles
Polymeric nanoparticles also consists of biodegradable
polymers and copolymers, to which drug can dissolve, trap,
encapsulate or attach. The polymers are composed of natural,
synthetic, and semi-synthesized polymers such as gelatine, albumin, alginate, chitosan, poly (glycolic acid), and their copolymers (PLGA). It provides the advantage of controlled and
sustainable release, high encapsulation levels, increased bioavailability, and biocompatibility of cells and tissue [16]. So
many interpretations of polymeric NPs in wound healing are
given in the literature. For example, in the thickness of the
excisional model, granulation tissue (LL37 activates epidermal cellulose), re-epithelial composition (IL-6), augmented
angiogenesis (triggered by the production of VEGFα via upregulation with IL-6) (LL37) and lactate encapsulated with
PLGA NPs exhibited greater wound healing property in the
mice treated with host protective peptide. In addition, PLGALL37 NPs encoded the inflammatory reaction in the macrophages of the mouse, using the down-regulation aspect of
TNF5-007 [20].
Amphotericin B was implemented in the silane-hydrogel
nanoparticle vehicle which helps in slaying the effectiveness
against Candida. The untreated control and traditional formulation groups were reduced by 72.4-91.1%. Furthermore,
wounds treated with amphotericin B nanoparticles significantly decrease the metabolic activity of the fungal biofilm
from 80 to 95% [21].
2.1.3. Dendrimers
Dendrimers were synthesized from a radially derived
branch of monomers from the central core [22]. The effectiveness of VEGF-coding minicircle plasmid DNA was assessed
for wounds on diabetic mice in combination with arginine
(Arg)-grafted cationic dendrimer [23]. This results in the polycomplex injection which has managed to heal wounds faster
in rapidly sprouting basal cells and abundant deposition of
collagen compared to the bare plasmid VEGF. Polyamidoamine (PAMAM) gelatin skin (PAMAM) has also shown relatively high gelatin levels, increased cell adhesion, keratinocyte proliferation, and fibroblasts with increased fibroblast
type I gene expression which was correlated with native collagen type. Furthermore, interpretation for angiogenesis modulators such as HIF1 alfa and VEGF was higher in the PAMAM blended gelatin matrix [24].
2.1.4. Nanoemulsions
Nanoemulsions are colloidal type system that consists of
emulsified oil and water systems that holds poorly water-soluble drugs dispersed within them. Nanoemulsions are now
widely used in cosmetic applications [16]. As drug delivery
carriers, they have a high ability to load drugs, also have the
capability for improving drug solubility and bioavailability.
The main benefits of nanoemulsions as drug suppliers are that
they are comparatively simple in preparation and escalation;
they also regulate the release of drugs and provide safety from
enzyme degradation [16].
In a study, Barroso et al. discussed that after 36 hr of phenytoin-charged alkyd nanoemulsions administration producing
25 and 50 mg of phenytoin mL−1, there had been improvement
914 Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9
in closure activity by creating a 75-82 % "scratch zone" related to phenytoin-concentration solutions [9]. Concentrationup released property help in the maintenance of the optimal
level of phenytoin for keratinocyte cell growth [25].
In another study, wound healing outcomes of Eucalyptus
Essential Oil (EEO) nanoemulsion formulations were compared to pure EEO and regular gentamycin. Comparable findings were seen during the treatment with the normal gentamycin-optimized formulations. But the quality of the collagen
was greatly increased as compared to pure EEO. The EEO
nanoemulsion increased the injury contraction substantially
from day 12 to 24 to control (P<0.05) [26].
2.1.5. Liposomes
Liposomes are nano-sized vehicles that embrace an inner
aqueous compartment enclosed by bilayer phospholipids. Liposomes are healthy, biodegradable, non-toxic, biocompatible,
and capable of encapsulating water-soluble as well as lipophilic substance. The most common disadvantages of liposomes are their low stability due to oxidation, hydrolysis of
phospholipids, as well as leakage and fusion of embossed drug
molecules [27]. Fibroin hydrogel core-based BFGFloaded liposome showed improvement in the strength and acceleration of the BFGF in wound fluid by facilitating the formation of granulation tissue, collagen deposition, angiogenesis, re-epithelialize [28].
In a study, Barroso et al. discussed the advantages of topical application compared to the drug itself and curcuminloaded liposomes [9]. In a study on rats, liposomes containing
curcumin improved wound closure on the 14 th day after the
lesion was opened (93.67 ± 3.56%), (P ± 0.05) [29]. The recent evidence suggests that the synergistic effect of dual liposomal ointment contains retinoic acid (RAD) and cationic deformable EGF liposomes which help in cell proliferation, migration, stimulated wound closures, enhanced appendix skin
formation, and increased collagen development. They also
demonstrate the synergistic effect of TRA, which is caused by
increasing the expression of EGF and HB-EGF recipients
[30]. The use of composite liposome scaffold systems to treat
wounds has recently been studied depending on the therapeutic value of liposomes and the mechanical strength of scaffolds [31].
2.1.6. Other Lipid-Based Nanoparticles
Nanostructured lipid carriers (NLCs) and solid lipid NPs
were developed as possible alternatives [32]. The preparation
of NLCs with phenytoin was described in a previous study.
This study aimed at increasing the effectiveness of drug trapping and the continuous release of drugs in the treatment of
Diabetic Foot Ulcers (DFU) [33]. Results demonstrate that after administration of phenytoin hydrogel NLC (0.26 ± 0.22
cm2) the wound surface was lowered as compared to the PHThydrogel (0.25 ± 0.89 cm2) and blank (7.24 ± 3.65 cm2). The
medicinal potential of topical essential rosemary oil (REO)
was started in another study. The infected wound was treated
by NLCs. The REO-NLC shows their antibacterial activity
against the epidermis of S. aureus, monocytogenes steria. The
MIC values for E. coli, Pseudomonas aeruginosa ranged from
5.34 ± 1.7 to 10.13 to 1.67 mg mL−1. In addition, IL-3, IL-10,
Bhadauria et al.
and VEGF (P < 0.001), neovascularization (P < 0.05), infiltration by fibroblast, collagens deposition and re-epithelization
were increased simultaneously [34]. Similarly, assessments of
the curcumin and ampicillin SLN semi-solid formulations as
burn wound healing agents were performed in in vitro and in
vivo studies. Semi-solid formulations simultaneously increased the wound treatment rate with the use of the synergistic effects of ampicillin and provided better antibacterial effects [35].
Diabetic wound mice played an important role in the assessment of abnormal and regulated healing processes,
whereas overproduction of TNF-α can reduce chronic inflammation and promote wound closure. Researchers also examined the siRNA-loaded lipids for wound healing purposes.
The topical application of TNF-α causes gene silencing of approximately 50%, nearly approaching traditional baseline levels of normal glycemic mice, resulting in a reduced wound
area and a quicker closure within 13 days [36].
2.2. Inorganic Nanomaterials
2.2.1. Magnetic Nanoparticles
Magnetic NPs such as magnetite (Fe3O4) were used due to
their distinctive characteristics i.e. magnetic field susceptibility [37]. Surface modifications of magnetic NPs have been
thoroughly examined in the medical field [38]. To analyze the
effect on Candida albicans, colonization rates and biofilm development of nano-coated wound dressings containing magnetite NPs were studied and the results showed that it strongly
inhibits fungal adherence [39]. Smililarly, the timber-based
Fe3O4 NPs dressing inhibition efficacy has been also demonstrated [40].
2.2.2. Silica Nanoparticles
Studies revealed the controlled oxidation rate of silica nanoparticles which occurs due to its vital component, in addition to its antimicrobial, in inflame, cell proliferation, ECM
deposition, geosynthetics, and reshaping of matrix properties
[12]. The higher antimicrobial effect against P. aeruginosa
and E. coli was shown by NO-releasing silica (SiO2) NPs
(with ~5 killing logs for both Gram-negative species) while
optimal efficiency to discourage C. Albicans (3 biofilm destroying logs) and biofilm showed the lowered efficacy
against gram-positive bacteria such as S. aureus, and S. epidermidis (2 biofilm bacteria logs) [41]. Further research has
revealed the effects of silica NPs as sources of silica acid on
the proliferation and migration of fibroblasts. According to the
researchers, fibroblasts are easily internalized in silica NPs
(charged positively), resulting in the silica-acid intracellular
release. Molecules also stimulate the migration of cells and
gradually help in wound healing [42]. The efficacy of hydrophilic chitosan-silica hybrid sponge not only promotes proliferation, migration, endothelial cell proliferation but also helps
in secretion. Growth factors like TGF-β in a porcine model
show improved deposition in collagen and angiogenesis [43].
With the murine model, nanostructured PVP (polyvinylpyrrolidone) gel SiO2 resulted in increased cell proliferation and
cell migration (due to moisture), advanced 9-day reepithelization (652.9 ± 142.6 vessels/mm2 vs. 489.3 ± 207 vessels/mm3).
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Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9 915
3. THE WOUND HEALING PROCESS AND WOUND
CATEGORIES
skin [61, 62]. Figs. (3 and 4) represent various factors involved in acute and chronic wound healing factors, respectively.
3.1 Wound Categories
The skin break or abnormalities caused by injuries or by
any physiological/medical conditions are known as wounds.
Damage of the skin and loss of it’s physiological functions
often occur under these circumstances. In general, the wounds
come under two categories: acute wounds and chronic
wounds; acute wounds are caused by mechanical injuries or
exposure to intense warmth, irradiation, electric shock, chemical agents. These wounds recover in a very short period if
adequate wound care is utilized [32, 44, 45]. Chronic wounds
usually cause complications for certain particular illnesses,
such as diabetes, which are well-known for the horrific occurrence of ulcers. These injuries need a longer time for healing
and may become critical if not treated properly [45]. Wounds
can be divided into three different wound depths: surface
wounds (with only a portion of the epidermis), partial thick
wounds (with epidermis and deeper skin layers), and subcutaneous wounds (with epidermis) (subcutaneous fat and deeper
tissue are disrupted) [46].
4. CHALLENGES IN DIABETIC WOUND HEALING
Despite significant progress in the last 25 years, extreme
assessment of diabetic foot ulcers (DFUs) will be performed
in the future. The mean time in the healing of a diabetic wound
3.2. Wound Healing Process
Wound cure involves various cells, mediators, extracellular (ECM) elements, development factors, and proteinases. It's
a physiological complex and dynamic process [47]. In particular, the disease can be divided into three interlaced phases:
inflammation, proliferation, re-epithelial/remodeling [48, 49].
The inflammatory cycle usually lasts for 2-5 days after skin
injury. If there is an accident, intravascular platelets cause the
hemostasis to form coagulation and minimizing bleeding immediately [50]. Platelet thrombin is also triggered to release
several growth factor factors, including EPD, IG F-1, PDGF,
Fibroblast growth factor (FGF), TgF-α, and TGF-β (TGF). In
addition, activation of the platelet activates the thrombin and
leads to the release of several growth factors [51, 52]. Growth
factors were dispersed into the injured tissue and it is also
served as biological signals to attract, further, mediate inflammation and protect the skin from infection. [53, 54]. In proliferation, it generally takes 3 to 2 days to complete cell proliferation and migration [55]. Approaching new blood vessels or
capillaries gradually, proangiogenic factors such as PDGF released by platelets encourages the inflammatory cells in the
wound region [56]. Stimulation of PDGF and FGF causes the
relocation of fibroblasts from inflammatory cells to granulated tissue concurrently with angiogenesis [57, 58]. With fibroblast accumulation and proliferation new ECMs consisting
of collagen, proteoglycans and elastin are produced. So many
fibroblasts become a myofibroblast and play an important role
in the contraction of the injury area [59]. Additionally, activate the keratinocytes to fully re-epithelialize and relocate into
wounded areas [60].
The re-epithelialization and restructure post-injury process
ranges between three weeks to one year. In the newly synthesized ECM, collagen III is slowly replaced by collagen I. The
newly produced collagen fibers become more orderly structured in the grid and increase the tensile strength in the cured
Fig. (3). Factors involved in the acute healing process. (A higher resolution/colour version of this figure is available in the electronic
copy of the article).
Fig. (4). Factors involved in the chronic healing process. (A higher
resolution/colour version of this figure is available in the electronic
copy of the article).
916 Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9
without treatment is approximately 12 weeks, and the risk of
amputation is high [63, 64]. After a new DFU, the five-year
survival rate is 50%-60% worse than many common cancers
[64, 65]. Although there is data showing cardiovascular risk
reduction [65], the latest statistics from a Veteran healthcare
administration show that only 81%, 69%, and 29 % of the population lived for 1 to 2 and 5 years, respectively. Mortality was
larger than any macrovascular disease in the correlation between DFU [66, 67]. Iversen et al. found that even 10 years
later, the incidence of a DFU was just an independent mortality indicator [67]. There are still huge prices for wound healing charged by hospitals. Till 2015, diabetes damage management is projected to up to $1.3 billion globally [68]. And up
to one-third of expenses on diabetes have also been diagnosed
in the United States for lower limb-related problems [69]. The
most up-to-date statistics from the UK estimate that the gross
annual management costs in respect of DFUs surpass 1 billion
pounds (1.32 billion dollars) [70].
5. TREATMENT STRATEGIES FOR DIABETIC FOOT
ULCERS
5.1. Main Preventive Measures-Elimination of Recent
DFUs
The occurrence of ulcers is quite small in the population.
Selected populations of patients suffering from diabetes in the
United States, the total incidence is recorded i.e. 5.8 and 6.0%
[71-73]. While fewer chosen populations in Europe have been
recorded the incidences of Type 2 diabetes are solitary i.e.
2.1% and 2.2 % [74, 75]. The effects of early diabetes screening are unknown, but a shorter decline in early diabetes from
total local diabetes populations can be expected. However, the
number of DFUs will continue to fall, which will grow in line
with the global type 2 diabetes epidemics without causing any
significant changes to ulcer prevention. The several risk factors for the development of ulceration have been well recognized [76], there is no consensus on which to prevail, and no
studies report currently justifies the adoption of any particular
primary prevention for the population selection strategy. In
this study, however, the achievement of various measurement
systems has been compared [77]. Although the incidence of
new skulls may be minimized through the possibility and anticipation of foot care education, the evidence for the use of
any elementary education measures is weak, there were just a
limited number of RCTs reported, while high-quality benefits
were not reported in randomized controlled trials [78, 79].
The cumulative incidence of primary preventive trials with
diabetes in unselected populations with new foot ulcers is relatively low [80].
5.2. DFU Inability to Cure Promptly the First Expert Assessment State of DFU
The severe ulceration has a poor prognosis and this is the
basis of existing assessment schemes [63, 80, 81]. There is
also a statistically significant correlation between recent data
[82, 83].
5.3. The Connection between DFU and Renal Failure
There is a similar temporal association between foot ulceration and the beginning of dialysis for renal end-stage disease
Bhadauria et al.
[84, 85]. While ulceration can be believed in such cases that it
has resulted from the degradation of renal function, the final
decline in renal function is equally and potentially more likely
to be caused by ulceration inflammations [86]. After major
amputation, the mortality rate was also 290% higher for dialysis patients. These observations were more commonly observed by nephrologists [87].
5.4. Recent Ulceration after the Healing Process
The ulceration treatments rate is high, with 40% of patients
developing new ulcers (on or on the same site) during 12
months. This is an important characteristic of diabetic foot
disease as foot disorders should not be considered cured but
treated in remission if the ulcer recovers [69]. In this respect,
the diabetic foot is directly linked to malignancy. Therefore,
the person whose foot is in remission should follow the same
structure as everyone who is in remission after cancer therapy.
This long-lasting need for expert monitoring should undoubtedly be given more attention from all DFU management
fields. The recent DFU surveys may decrease the need for
RCTs relatively, but with the highest possible short-term incidence of persistent ulcers, the long-term benefit for both patients and the health professional may be very high.
5.5. Strategies that Reduced Diabetic Foot Ulcer Recurrence
Apart from the availability of suitable footwear, a focused
target is considered an integral part of secondary prevention
for patients with (particularly) plantar ulceration. However,
there is conclusive evidence of its effectiveness [88]. In comparison, a single group recorded three studies to show how the
foot skin temperature was tracked every day while no other
organizations have verified the approaches yet [89].
6. THE PROBLEM OF WOUND HEALING AND ITS
PHENOMENON IN DIABETES
The result of the pathophysiological interaction of diabetic
impairment includes vascular, neuropathic, immune, and biochemical [90]. Blood vessels and microvascular dysfunction
reduces tissue oxygenation, which is associated with hyperglycemia [91]. Diabetic vessel alterations also result in minimization of the relocation of leucocyte to the wound, which is
more susceptible to infections that can affect leucocyte function. Peripheral neuropathy can also cause area numbness
which results in chronic wounds. This is not detected immediately and lower limbs are treated, particularly the foot,
which is more exposed and chronically vulnerable to minor
lesions. Modifications to the motor and sympathetic functions
also cause a deformation of the physical foot, increased plantar pressure, and unnoticed skin dryness [90].
The chance of diabetic foot ulcers is 15-25% across their
lives; 40-80% of people are affected so badly that it involves
the bones [92]. Worldwide epidemiological studies show that
North America is more dominant in the disease [93]. A large
number of incidents of foot ulceration require hospitalization
and surgical procedure to separate the concerned body part.
Furthermore, after 3 years from the first episode, the recovery
rate of a foot ulcer is more than 50% [94]. That is why DM-
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Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9 917
impaired wound cure is the main health issue and a major economic burden [95, 96].
Wound healing is a physiological process where the integrity
of the skin is removed and the barrier function of the skin is
affected as well. This can occur very frequently because the
skin is exposed to external offenses and a fast defense system
is needed to prevent systemic infections [97]. The normal state
of the skin is completely recoverable by physiological healing,
it only achieves up to 70% of the previous strength of the tensile [62]. The process proceeds in several subsequent phases.
Inflammatory, proliferative, and remodeling phases are usually recognized by three successive phases.
6.1. Inflammatory Response
The inflammatory stage is preceded by a coagulation
stage, which is the first response of the injured skin by activating the coagulation cascade with the recruitment and formation of a fibrin plug [56]. Weathering is also important for
the treatment. Additional clot platelets form a basis for the recruitment of inflammatory cells, which are attracted by various cytokines, including PDGF (platelet-based growing factor) and TGF, and attract different types of cells (transforming
factor of growth). Neutrophils and monocytes are present and
supported by simultaneous vasodilatation. Later, macrophages occur at a very early stage and through the release of
growth factors and cytokines, they are considered major contributors to this inflammatory stage. There is a migration of
keratinocytes in the injured region which causes a rise in local
fibroblasts [98]. These events occur soon, after a few hours of
the wound occurrence, and are rapidly help in the formation
of the tissue within 48-72 hr, including all types of recruited
early granulation tissue [99].
6.2. Proliferation and Remodeling
These steps are intended to assist in the healing of wounds.
In this respect, granulated tissue and keratinocyte migration,
extracellular matrix formation (ECM) protein formation, as
well as myofibroblasts' appearance led to contractedness as
one of the primary wound closure events. The main cell type
in this phase is fibroblasts, which begin to reconstruct the injured region by releasing collagen. Hypoxia is an instrument
that helps in encouraging cell type migration, proliferation,
and the release of growth factors that characterizes the former
wound healing phases [99]. Hypoxia leads to Hypoxia-inductive factor (HIF)-1α activation and VEGF-A stimulation,
which is one of the main target genes in HIF-1α [100]. Endothelial cells, therefore, proliferate actively and are essential to
support neo-angiogenesis-based formed tissue. VEGF-A increases the density of the wound and restores the flow of blood
that promotes wound healing [101]. Some vessels become durable and mature followed by the recruitment of pericytes,
which release vascular and anti-angiogenic factors. The formation of chaotic, abundant vessels characterizes this initial
period [102]. For the first time healing is developed by remodeling collagens of type III, to type I (as normal non-injured
tissue observed) [103]. The new skin contains neovascularisation [104] and the wound repair method is restored the physiological skin texture [48]. A chronic wound appears when the
physiological repair process fails, or an excessive repair occurs through a hypertrophic scar or a keloid. The presence of
hypertrophic scars usually implies patient predisposition and
occurs temporarily usually within 6 months. Keloids, is a coverage area that extends far beyond original skin damage, is
present in patients with genetic disorders, and is permanent.
Ulcers also occur in ischemic conditions, which causes a delay
in the disease treatment [97].
7 WHAT ARE THE LIMITATIONS IN DIABETES
DURING WOUND REPAIRING?
The diabetes healing procedure is usually inflammatory
and the antigenic process is disrupted. The number of endothelial progenitors in cells has decreased and the extracellular
matrix prescription has become imbalanced. Furthermore,
chemical chemokines containing neutrophils and macrophages help in physiological wound repair, which quickly enters the lesion area. The factor of tumor necrosis α (T NFFα)
for which the levels will not be increased during the initial
inflammation phase of acute repair but will remain at higher
concentrations in an injured area over a longer-term [105].
The production of many growth factors in diabetes is affected
during the treatment. In injured tissue, insulin levels such as
IGF-1 (growth factor-1) and β-Growth (TGFβ) were decreased in both diabetic animals and humans. IGF-1 involves
in cell granulation and wound reepithelization [106]. In TGF,
angiogenesis and ECM formation are also involved which
helps in immune cells, keratinocytes, fibroblasts, and vascular
cell formation [107]. However, the equilibrium between the
formation and maturation of new vessels is troubled in diabetes. In high-glucose endothelial cells, angiogenesis is dysfunctional and the capillary wound area is insufficient. HIF-1α target genes such as VEGF are being suppressed for their stability and activity [108]. In diabetes animal models, the primary
source for VEGF macrophages shows phagocytic activity
with disability of the modified phenotype, which leads to failure in tissue repair [8]. As a result, DB/DB mice are compared
with the control mice in which the VEGF-A mRNA and protein levels have fallen sharply [109]. An early leaky, misformed vasculature and large local edema is the characteristic
of the accelerated closeup of the injury and VEGF-A treatment, which was very obvious until the VEGF-A treatment
stopped [110]. The decreasing population of endothelial parent cells in bone marrow results due to dysregulation production in both the proangiogenic and the vascular maturation
factors found in diabetes [111]. This causes alterations in angiogenic germs and finally vascular aberrant architecture in
diabetic wounds [112, 29]. Diabetes also aids in the healing of
the wound's ripening phase. Factors contributing to mature
vascular phenotype (for example, Angiopoietin (ANG) 1 and
2 and PDGF) are developed in line with competition [113, 30].
In streptozotocin-induced diabetic mouse table model and
DB/DB mouse, the topical application of ANG 1 and PDGF
improved wound healing, respectively [113, 114]. Finally, diabetes interferes with ECM regulation, which is developed by
metalloproteinase (MMP) and metalloproteinase tissue inhibitors (TIMPs). In diabetic wounds, higher MMP levels were
detected, possibly due to the high glycolysis caused by developing MMP and reducing TIMP, which can interfere with the
918 Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9
Bhadauria et al.
healing process [115]. In a range of wound treatment phases,
MMPs are involved in cell migration through degraded ECM,
leukocyte invasion, and multiple cytokines processing to ensure no distortion of the scaffolding structure necessary for
correct wound healing, equilibriums between MMPs and
TIMPs [116]. Table 2 represents the physiology of insulin in
normal patient and diabetic patient [117].
a healthy tissue that helps in the exposure to repair the
wounded area [48]. There are many forms of debriding including enzymes based on auto-activation of mechanical or operational fibrin enzymes. This is the most effective way of eliminating and preventing necrotic tissue from spreading.
Table 2. Physiology of insulin in the normal population and diabetic patient.
The process of dressing the wound in diabetic patient is an
important factor represented a Fig. (5).
8.1. Dressings
Insulin
Phases
Physiology of Normal
Physiology of
Population
Diabetic Population
Coagulation -> fibrin plug
TGF-β, PDGF-> recruitment
Inflammatory
phase
of neutrophils and macrophages
Chronic inflammation->
Higher IL-1 β and TNFα
Inflammation-> IL-1β growth
factors
Dysfunction macrophages
Migration of fibroblast and
keratinocytes
Hypoxia-> HIFα-> VEGF->
Neoangiogeneses
Proliferative
phase
Extracellular matrix deposition
Decreased angiogenesis
Disequilibrium between
MMPs and TIMPs -> altered ECM
Granulation tissues formation
Vascular maturation
Decreased pericyte
Fig. (5). Schematic representation of dressing in the treatment of diabetic wound healing. (A higher resolution/colour version of this figure is available in the electronic copy of the article).
8.2. Antidiabetic Drugs
Treatment of diabetes, especially in a patient suffering
from a wound, is a critical step and requires medical supervision (Fig 6).
function
Collagen remodeling
Remodeling
phase
Reduced vascular
Wound edge concentration
maturation
Migration of fibroblasts and
keratinocytes
Decreased wound
strengthening
8. TREATMENT AVAILABLE FOR WOUND HEALING
The normal wound healing procedure involves controlling
infection, removal of strain, and preservation of moist wound
beds. Infections can also be controlled by debridement. The
primary objective is always to prevent infection and clean the
area of non-viable tissue in the treatment of chronic wounds.
Infections can easily occur as a consequence of loss of inborn
blockage in the skin, which can also impair the healing process by pathogens in the area of damaged tissue or debridements, which also allows the cell to migrate and proliferate in
Fig. (6). Steps involved in the use of antidiabetic drug use for the
treatment of diabetic wound healing. (A higher resolution/colour version of this figure is available in the electronic copy of the article).
Advancement in Nanoformulations
Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9 919
8.3. Growth Factors
Diabetic wound healing can be treated by using growth
factors. Fig (7) represents the role and application of growth
factors in the treatment of diabetic wound healing.
9.3. Drug
Phenytoin.
9.3.1. Effect on Wound Healing
Phenytoin has antibacterial activity, proliferation of the fibroblast, granulating tissue enhanced liberating VEGF and angiogenesis activities.
9.3.2. Evidence from Human Studies
Enhanced cure for a range of wounds. There are several
randomized but methodologically poor clinical trials are
available.
9.3.3. Administration
The topical administration of Phenytoin [121].
9.4. Drug
Statins.
9.4.1. Effect on Wound Healing
Statins have anti-inflammatory, angiogenesis properties.
9.4.2. Evidence from Human Studies
Fig. (7). Schematic representation of the role of growth factors used
for the treatment of diabetic wound healing. (A higher resolution/colour version of this figure is available in the electronic copy of the
article).
Mevastatin reverses various changed molecular pathways
in ex vivo specimens that are derived from diabetic foot ulcers
on the non-healing rim.
9.4.3. Administration
Statins were administered topically [122,123].
9. THE DRUG WHICH HAS A REPARATIVE EFFECT
IN IMPAIRED WOUND HEALING
9.5. Drug- β-Blockers
9.1. Drug- DPP-4 Inhibitors
9.5.1. Effect on Wound Healing
9.1.1. Effect on Wound Healing
DPP-4 inhibitors have proliferation, angiogenesis,
keratinocyte migration wound realigning properties and also
possess anti-inflammatory, anti-oxidant, endothelial cell precursor's propagation activity.
9.1.2. Evidence from Human Studies
In diabetic patients, it improves wound cure and chronic
foot ulcers activity.
9.1.3. Administration
Systemic administration of DPP-4 inhibitors [118,119].
9.2. Drug- Metformin
9.2.1. Effect on Wound Healing
β-blockers have proliferation characteristics.
9.5.2. Evidence from Human Studies
Data is provided based on the animal study.
9.5.3. Administration
β-blockers were administered topically.
9.6. Drug
ACE-inhibitors.
9.6.1. Effect on Wound Healing
ACE-inhibitors have anti-oxidative properties.
9.6.2. Evidence from Human Studies
Data provided based on the animal study.
Metformin possesses anti-inflammatory, anti-oxidant,
proliferation, ECM organization angiogenesis collagen deposition, and endothelial cell precursor activity.
9.6.3. Administration-
9.2.2. Evidence from Human Studies
9.7. Drug
Improved healing in traumatic wounds and ulcers.
ACE-inhibitors were administered topically.
Estrogen.
9.2.3. Administration
9.7.1. Effect on Wound Healing
Metformin was administered topically [120].
Estrogen has angiogenesis and proliferation of keratinocytes properties.
920 Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9
9.7.2. Evidence from Human Studies
Data provided based on the animal study.
9.7.3. Administration
Estrogen was administered through topical/systemic route.
10. THE APPROACH OF NANOTECHNOLOGY IN
WOUND HEALING AND MANAGEMENT
10.1. Nanosensors
There are some contemporary gaps in glucose monitoring
that how glucose monitoring is implemented. The patient is
selected for a separate time point and insulin is administered
as necessary within the open-end system to measure the blood
glucose concentration. The obstacle is that glucose levels constantly fluctuate in the blood and discreet samples do not have
the data needed for the productive treatment of these fluctuating levels. This challenge has been explained by biosensors
using Glucose Oxidase (GOx) for the quantification of glucose response in the blood to glucose acid and H2O2 by an
electrode in the vicinity [124]. This idea is enhanced by a few
different strategies through nanotechnology. To increase the
efficiency of electrodes, nanotubes or nanopaths are used
[125]. Nanoparticles use electron conductors which are the
most popular electron transport strategy between GOx and
electrode. The popular choice in this application is carbon
nanotubes (CNT), due to their unique surfaces and their ability
to conduct electrics. In particular, nanoparticles and biological
molecules such as GOx have been used with a variety of other
nanomaterials. A major disadvantage of immobilized GOx
systems is biodegradability. The sensors can provide excellent
longevity and stability. In addition to this, chitosan stability in
the GOX-coated film showed 80% activity which is maintained after 20 days at less than 60oC temperature [126]. However, a silent sensor should be replaced. It is also possible to
respond to electrochemical changes in the blood because of
pharmaceuticals like acetaminophen and diets. Thus it is used
to synthesize hollow nanoparticles, which are work at electrochemical potential [127].
10.2. Nanoparticles
For patients to improve their quality of life, the emergence
of drug delivery systems through nanoparticles mediate a significantly improved supply of small molecular drugs. The
nanotechnologies are more assured than conventional forms
of dosage, as they represent chronic diseases with several
more comorbidities by providing a site-specific supply of
drugs with a higher bioavailability and reduced dose regimes.
Intensive research was carried out for the oral administration
of nanoparticles with peptides such as glucagon. The nanoparticles also allow changes in encapsulation of microparticles,
glycol (PEG)-PEGyulation, and actively targeted ligands. In
addition to the provision of medicinal products, it is directly
relevant to diabetics; nanoparticles could also be used to diagnose other co-morbid conditions such as non-healing wounds.
Oligonucleotide-function lipid nanoparticles are used topically [128] at lipid-target cells [129]. The FDA have announced that these nanoparticles are used in the treatment of
diabetic injuries.
Bhadauria et al.
Nanoparticles have the shape and size that allows high surface areas on which reactions with the particle surface and
functional biomolecules can occur. Mostly they have antibacterial characteristics associated with antibacterial molecules to
mitigate infection and heal injuries quickly. It can spread into
the 3-D medium to eliminate harmful biofilms synthesized by
a certain pathogenic bacteria survival mechanism [41]. A multitude of coatings or groups were used in conjunction with nanoparticles to enhance the treatment of injury or chronic injury. For example, nanoparticles in gold epigallocatechin
(EGCG) and a-lipoic acid combined antioxidant in which gold
stimulates angiogenesis and reduces macrophage activity
[130]. Poly nanoparticles (LACGA) were coated with VEGF,
curcumin, and antibiotic molecules [131-133]. The adaptability of nanoparticles as a delivery vehicle is therefore marvelously demonstrated. In combination with other nanomaterials
such as nanofibers, nanoparticles have been used to produce a
range of nanocomposite wound dressings that promote the
correct healing process and prevent infections [134, 135].
Various manufacturing strategies are based on the composition of the nanoparticles. Nanoparticles based on polymers often use self-build processes like desolation [136, 137]. Desolation dissolves the material in a solvent and adds an anti-solvent to nanoparticles (miscible in the solvent but unable to
dissolve the nanoparticle material). This anti-solvent generates and precipitates the nanoparticles. Emulsion-based methods provide another way for the self-build polymers and lipids
[138, 139]. Due to hydrophobic interactions of nanoparticles
material to the aqueous solution, emulsion results in the selfbuild of nanoparticles. The nanoparticle size can be controlled by how much energy is added to a solution by homogenization or sonication during preparation. The resultant nanoparticles are solid or shell-based and being prepared by single or double emulsions [140, 141].
10.3. Nanofibers
Nanofibers are attractive wound healing technology for
both weather and cellular regeneration [142]. Nanofibers have
the core concept of developing injury clothing that imitates
ECM functioning. Nanofibers are commonly found as molecules that occur within the ECM of the skin. Examples include
collagen, gelatin, fibrin, hyaluronic acid, silk fibroin, chitosan, cellulose, and many more [143, 144]. In addition, a
study on other popular nonbiological nanomaterials including
polylactic acid, polycaprolactone, polyurethane, polyvinyl alcohol, polyethylene oxide, glycol, and PLGA has been conducted [145, 146]. Nanofibers have advantages in terms of
their permeability and they also have the capability of 3-D
dressings which act as a local medicine supply system [147,
148]. In addition to nanofibres, nanomats, and nanogels, the
weather potential is matched to the technology that has been
adapted for the treatment of several wound types which is associated with diseases by loading the network with development factors [149]. The solution could even include several
nano-fiber polymers for core-shell preparation with drugs
[150, 151].
CONCLUSION
Inflammation, proliferation, and remodeling are three
stages in the wound healing process. Internal and external
Advancement in Nanoformulations
Endocrine, Metabolic & Immune Disorders-Drug Targets, 2022, Vol. 22, No. 9 921
causes include altered cellular and cytokine responses, poor
vascularization, microorganism infection and it also interrupts
the physiology of the healing process in DFU. This review focuses on nanoparticle-based therapeutics that deliver peptides,
nucleic acids, antibiotics, and antioxidants through polymeric
and natural nanostructures, hydrogels, and nanofibers which
have shown impressive outcomes in chronic diabetic wound
re-epithelialization, collagen fibers deposition, tissue regeneration, and ultimately a faster rate of wound closure. The use
of nanoparticles and biopolymers in the form of a nanocomposite has a great impact on tissue repairing and the wound
healing process. While nanomaterials have been extensively
studied for wound healing, further research is needed in this
field. Overall, nanoparticles have appeared as a promising
agent in diabetic wound healing.
[9]
[10]
[11]
[12]
[13]
CONSENT OF PUBLICATION
Not applicable.
[14]
FUNDING
None.
CONFLICT OF INTEREST
[15]
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENT
[16]
Authors are highly thankful to the Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, India, for providing a library facility
for the literature survey.
[17]
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