Introduction
A diabetic foot ulcer (DFU) is an open sore or wound that most likely occurs at the
bottom of the foot or toes where repetitive trauma and pressure are encountered. It
is the major complication of uncontrolled diabetes mellitus associated with a high
degree of morbidity and mortality [1]. DFU
can be caused by inadequate glycemic control, peripheral vascular disease, or poor
foot care and is also one of the most common causes of osteomyelitis and amputations
of the lower extremities [2]. The
occurrence of DFU can be identified by several common symptoms and signs, including
drainage on the person's socks, redness, and swelling. Occasionally, an odor
may occur if the ulcer has progressed significantly [3].
The battling issues faced by these ulcers are impaired or delayed wound healing.
Wound healing is an innate mechanism of action that works reliably most of the time.
During the healing process, damaged wound tissue is restored to its original state
by a series of biomolecular and cellular processes. Cell
migration/proliferation, inflammation, and remodeling are the fundamental
biological processes involved in wound healing [4]. In wound healing, stepwise repair of the extracellular matrix (ECM)
is vital to the overall healing process. These diseases can cause impairment of
biochemical signaling, ECM deposition, and cell migration, which can ultimately lead
to DFU progression [3].
DFUs have a multifactorial etiology. Low blood sugar levels, calluses, foot
deformities, excessively tight footwear, underlying peripheral neuropathy, poor
circulation, dry skin, etc. are all potential contributing factors. About
60% of diabetics develop neuropathy, which eventually results in foot
ulcers. In people with a flat foot, the risk of developing a foot ulcer increases
since they have disproportionate stress across the foot, resulting in tissue
inflammation in high-risk areas [5].
Global Epidemiology of DFU
DFU has become a major global epidemic and has shown an increasing trend over
previous years. The annual incidence of DFUs worldwide is between 9.1 to 26.1
million. Around 15 to 25% of patients with diabetes mellitus (DM) will
develop a DFU during their lifetime [2]. As the number of newly diagnosed diabetics is increasing yearly,
the incidence of a DFU is also bound to increase. DFUs can occur at any age but
are most prevalent in patients with diabetes mellitus ages 45 and over [3]. Approximately 405.6 million adults
worldwide are affected with type 2 diabetes and are predicted to reach more than
510.8 million by 2030 [1]. Overall,
the rate of lower limb amputation in patients with DM is 15 times higher than in
patients without diabetes [4]. About
19–34% of patients with diabetes are expected to be affected
with DFUs while the occurrence of DFUs is expected to be more frequent in aged
patients [5]. Approximately 405.6
million adults are affected with type 2 diabetes around the world and are
predicted to reach more than 510.8 million by 2030 [6]. About 15–25% of
diabetic patients can develop foot ulcers which eventually lead to amputation
[7]. Epidemiological studies show
that the number of patients with DM increased from about 30 million cases in
1985, 177 million in 2000, 285 million in 2010, and is estimated that with the
current rate, more than 360 million people by 2030 will have DM [8]
[9]. In total it is estimated that 15% of patients with
diabetes will suffer from DFU during their lifetime. While it is difficult to
obtain accurate figures for the prevalence of DFU, still the prevalence of this
complication ranges from 4–27%. Early effective management of
DFU can reduce the severity of complications such as preventable amputations and
possible mortality, and also can improve the overall quality of life as per the
strategies of the National Institute for Health and Clinical Excellence [10]. [Fig. 1] illustrates the DFUs incidence
in the diabetic population and respective overall life expectancies according to
DFU treatment (amputation vs. no amputation).
Fig. 1 Incidence of diabetic foot ulcers (DFUs) in diabetic
population and respective overall life expectancies according to DFU
treatment (amputation vs. no amputation) [9]
[10].
Pathophysiology of DFU
DFUs are one of the most frequent complications of diabetes, resulting from a
complex interaction of factors, namely ischemia, and neuropathy. Neuropathy,
which is characterized by modifications insensitive and autonomic functions,
causes ulceration due to trauma or excessive pressure in a deformed foot without
protective sensibility [3]. Autonomic
neuropathy causes dryness of the skin by decreasing the sweating, and therefore
increasing the vulnerability of the skin to break down. Once the protective
layer of skin is damaged, deep tissues are exposed to bacterial colonization
[11]. Diabetes-associated ischemia
is caused by peripheral arterial disease. Poor arterial inflow decreases blood
supply to the ulcer area and is associated with reduced oxygenation, nutrition,
and ulcer healing [4]. These ulcers
are frequently colonized by pathogenic bacteria and infection is facilitated by
immunological deficits related to diabetes, rapidly progressing to deeper
tissues, increasing the presence of necrotic tissue, rendering amputation
inevitable [2]. Diabetic patients
frequently require minor or major amputations of the lower limbs
(15–27%), which not only contribute dramatically to high
morbidity among diabetic patients but is also associated with severe clinical
depression and increased mortality rates [12].
Risk factors
The major risk factors concerned in the development of DFUs include loss of
protective sensation due to diabetic peripheral neuropathy where feet become
numb and injury goes unnoticed and peripheral artery disease (PAD) which is
associated with the development of DFUs [13]. Foot deformity and calluses can result in high plantar pressure,
which may result in additional risk [11]. While other risk factors such as older aging, infections, poor
glycemic control, diabetic neuropathy, cigarette smoking habit, peripheral
vascular diseases, ischemia, previous foot ulceration, amputation, and reduced
personal care have also been demonstrated to play roles in the pathogenesis and
progression of diabetic foot ulceration [14]. DFUs may follow bacterial invasion resulting in infection and
decay, in any part of the body especially in the distal part of the lower leg,
and lead to lower limb amputation.
Biofilm and antimicrobial resistance in DFU
Biofilm formation is an important pathophysiological stage in DFU. It has a
primary role in the disease progression and chronicity of the lesion, the
development of antibiotic resistance, making it difficult to treat the wound
[15]. Biofilms, by definition, are
the ubiquitous and natural phenotype of bacteria. They typically consist of
polymicrobial populations of cells, which are attached to a surface and encase
themselves in hydrated extracellular polymeric substances. The main problem in
DFU is the difficulty in distinguishing between infection and colonization [16]. The bacteria present in DFU are
organized into functionally equivalent pathogroups that allow for close
interactions between the bacteria within the biofilm. Consequently, some
bacterial species that alone would be considered non-pathogenic, or incapable of
maintaining a chronic infection, could co-aggregate symbiotically in a
pathogenic biofilm and act synergistically to cause a chronic infection [17]
[18]. Wound infection, faulty wound healing, and ischemia are the most
common precursors to diabetes-related amputations. Indeed, 80% of
lower-limb amputations in diabetic patients are preceded by biofilm-infected
foot ulceration. Infected wounds result in an increased risk of death within 18
months [19]. The host-microorganism
interface plays a major role in DFU development. In DFU, bacteria are
classically organized into functionally equivalent pathogroups, where pathogenic
and commensal bacteria co-aggregate symbiotically in a pathogenic biofilm to
maintain a chronic infection [20].
This polymicrobial biofilm has been observed both in pre-clinical studies using
animal models and in clinical research on DFU. It represents the main cause of
delayed healing. Bacteria that reside within mature biofilms are highly
resistant to many traditional therapies. Currently, one of the most successful
strategies for the management of biofilm-related conditions is the physical
removal of the biofilm, such as frequent debridement of DFUs [21].
Nanotherapeutic Modalities in the Management of Diabetic Foot Ulcers
Mild and acute clinical cases can be managed with conventional or standard therapies
alone but the chronic wounds and those appearing as secondary complications of
metabolic disorders require intensive pharmaceutical care and pharmacotherapy [25]. The complications with chronic
ulcerations and the failure of other conventional treatments paved the way for the
emergence of nanotechnology-based therapeutic agents to tackle the complexity of
diabetic wound healing [26]. In the past
few years, several nanoformulations have emerged in the market that offer promising
results for such patients. The development of nanotechnology has created a means of
prolonging the bioavailability of target molecules at the wound site, intending to
accelerate the healing process, avoide secondary complications, and improve patient
compliance. Conceptually, the use of nanoformulations in cutaneous wound healing has
major advantages [27].
Nanotechnology-based wound healing methods offer several advantages such as cell
specificity, suitability for topical drug delivery, and sustainable and controlled
release of encapsulated drugs for a required period until the wound heals. In the
case of wound healing, nanoparticles are ideal for topical delivery, supporting
better interactions with the biological target and increased penetration at the
wound sites [24]. Nanoparticles have
emerged as an emerging scientific and technological revolution in the management of
DFUs. They have made major contributions to pharmaceutical applications and have
been proved beneficial in the treatment of DFU [28]
[29]. A combination of
antibacterial nanoparticles like silver nanoparticles (AgNPs), gold nanoparticles
(AuNPs), copper nanoparticles (CuNPs), etc. with polymeric matrix could efficiently
inhibit bacterial growth and at the same time speeds up the wound healing process.
The present review aimed to discuss the most modern astonishing potential of
polymeric nanoparticles, metallic nanoparticles, inorganic nanoparticles, lipid
nanoparticles, siRNA-based nanoparticles, and nanofibrous structures in the
management of DFU.
Studies on the use of nanotherapeutics for the treatment of diabetic foot
ulcers: Preclinical status
Polymeric nanoparticles
Polymeric nanoparticles, specifically naturally occurring polymers like
chitosan nanoparticles, have been studied for their antibacterial activity
and pro-wound-healing properties. Polymeric nanomaterial therapy involves
the use of polymeric materials as dressings or as delivery vehicles. There
have been numerous conventional wound dressings that were employed for the
management of DFUs; however, there is a lack of absolute and versatile
choice, therefore polymer-based dressings are used for the treatment of
DFUs. Due to the hydrophilic nature of polymers, they are generally employed
in wound dressing or as drug-delivering systems. The wound healing
properties of polymers are because of their moisture absorption capacity and
water vapor transmission that allow the maintenance of the moist environment
in the wound along with the collection of wound exudates. Both natural and
synthetic polymers, as well as their combination, have been investigated for
wound healing and antimicrobial mechanisms which may include
Poly-lactic-co-glycolic acid (PLGA) nanoparticles, polycaprolactone (PCL),
and polyethylene glycol (PEG). A very versatile range of
naturally-originated polymers including chitosan (CS), hyaluronic acid (HA),
cellulose, alginate, dextran, collagen, gelatin, elastin, fibrin, and silk
fibroin which has been utilized for the treatment of DFUs [25]
[26].
In the case of polymeric nanoparticles, chitosan, a natural polymer is used,
due to its biocompatibility and antimicrobial activity. It is possible to
encapsulate a wide range of natural components such as aloe vera, vitamin E,
and curcumin, which have potentially beneficial effects on skin wound
healing. PLGA, PCL, poly (lactic acid) (PLA), and PEG are synthetic polymers
approved by the Food and Drug Administration (FDA). Among these polymers,
PLGA is considered the most appropriate biodegradable polymer due to its
ability to release lactate, a degradation byproduct. PLGA nanoparticles have
been reported to stimulate cell proliferation and shorten the duration of
wound healing in diabetic rats and despite moderate drug use, loading may be
a promising delivery system for growth factors. Nanoparticles and
biomolecules can be incorporated in hydrogels and thus, have opened the door
to more advanced topical drug delivery with unique benefits such as improved
tissue localization, minimized burst release, and controlled sequential drug
release, by preserving the structural integrity of nanoparticles [25]
[27]
[28].
Hydrogels with high water content, tunable viscoelasticity, and
biocompatibility have been intensively explored to enable topical delivery
of bioactive molecules. Hydrogels are widely used for wound healing
applications due to their similarity to the native ECM and ability to
provide a moist environment. These multifunctional hydrogels can be
fabricated with a wide range of functions and properties, including
antibacterial, antioxidant, bioadhesive, and appropriate mechanical
properties [29]. In a study,
Bairagi et al. developed ferulic acid (FA) nanoparticles and studied their
hypoglycemic wound healing activities. FA-loaded polymeric nanoparticles
dispersion (oral administration) and FA-loaded polymeric nanoparticles-based
hydrogel (topical administration) treated wounds were found to epithelize
faster as compared with the diabetic wound control group. The hydroxyproline
content increased significantly when compared with diabetic wound control.
Results showed that FA significantly promotes wound healing in diabetic rats
[30].
Metallic nanoparticles
Metallic nanocarriers have been extensively evaluated as suitable cargoes for
biomedical applications. They have attained an exceptional position in the
field of diagnosis, and drug delivery owing to their inimitable properties
such as small size, very high surface area, capability for surface
modification, and high reactivity towards living cells. Metallic
nanoparticles such as AgNPs, AuNPs, and copper-based nanoparticles are
widely used as therapeutic agents, primarily for their anti-infective and
anti-inflammatory effects [21].
Silver nanoparticles
There is an unmet need for a novel antibiofilm approach and effective
antimicrobial compounds, and silver nanotechnology-based therapeutics
have captured the attention of health care providers for enhancing
patient health care. AgNPs are used in clinical practice for a wide
range of treatments such as burns, chronic ulcers, and diabetic wounds
that have developed antibiotic resistance and hospital-acquired
bacterial infection. In addition to anti-inflammatory effects, AgNPs
treated wounds have shown abundant collagen deposition that could
accelerate wound healing [23]
[25]. AgNPs are
the maximum studied nanoparticles in wound care management because of
their known antibacterial effects [31]. The antibacterial effects of Ag are facilitated by the
interaction of Ag+ with three main constituents of the bacterial
cell viz. (i) peptidoglycan composed cell wall, (ii) bacterial DNA, and
(iii) proteins and enzymes involved in essential cellular processes such
as electron transport chain (ETC). It also shows anti-inflammatory
activity which promotes wound healing by reducing the release of
cytokine, thereby, decreasing the infiltration of lymphocyte and mast
cells.
In an investigation, Tsang et al. developed nanocrystalline silver (nAg)
dressing which is on increase popularity-wise for treating DFU. Herein,
it is shown that nAg alginate is potentially superior to MH and
conventional dressing in healing DFUs in terms of ulcer size reduction
rate [32]. In another
research, Singla et al. prepared silver nanoparticles in the matrix of
bamboo and examined cellulose nanocrystals for their ability to reduce
inflammatory cytokines, oxidative stress and hasten the progress of
healing events in the streptozotocin-induced diabetic mice model. These
nano bio-composites showcased the potential to serve as highly effective
and biocompatible DFU patients [33]. Later on, Almonaci Hernández et al., formulated
AgNPs with antimicrobial properties. Daily topical administration of
AgNPs solution with a metallic silver concentration of
1.8 mg/mL showed that such administration causes an
improvement of the wound healing on average in less than 25 days of
treatment [34]. Furthermore,
Appapalam et al. formulated a phytofabricated nano-structured silver
nanoparticle. They found that minimum bactericidal concentration (MBC)
of AL-AgNPs (20 µg/mL) was highly effective
against the studied multi antibiotic-resistant DFU isolates. The
short-term exposures of DFU bacterial isolates with AL-AgNPs have
displayed a remarkable growth inhibition, preformed biofilm disruption,
enhanced intracellular ROS accumulation, increased membrane leakage,
altered membrane integrity, and drastically ruptured membrane [35]. Thus, herein it is seen
that phytofabricated nano-structured silver could serve as the best
antimicrobial agent for the eradication of infections in the diabetic
wound. In a recent investigation, Li et al. developed a new
Ag–ZnO loaded carboxymethyl
cellulose/K-carrageenan/graphene oxide/konjac
glucomannan (Ag–ZnOCGK) hydrogel clinical applications as
wound-recuperating materials. The Ag–ZnO@CGK hydrogel indicated
incredible swelling assimilation and impressive mechanical properties.
Also, Ag–ZnO@CGK hydrogel exhibited great bactericidal movement
against test microorganisms. In vitro viability testing
demonstrated that fibroblast cells could endure well within the sight of
Ag@CGK hydrogel, showing that Ag–ZnO@CGK hydrogel has great
viability. In vivo animal models demonstrated that the
Ag–ZnO@CGK hydrogel adequately quickened wound recuperation and
histological examinations demonstrated advanced fibroblast development
and quickened epithelialization. The test results demonstrated that
Ag–ZnO@CGK hydrogel has incredible potential in advanced wound
healing [36].
Gold nanoparticle
AuNPs have been widely studied for medical applications. Biocompatible
AuNPs are biologically active materials that have potential medical
applications in tissue regeneration, wound healing, and drug delivery.
They inhibit lipid peroxidation and prevent reactive oxygen species and
hence can reinstate the antioxidant imbalances [26]. The wound healing
efficiency of AuNPs is operated at the phase of hemostasis and
inflammation which is highly beneficial to DFUs. Several studies have
reported the anti-oxidative and anti-hyperglycemic potential of AuNPs
[28]. In a study, Yu et
al., synthesized nerolidol functionalized gold nanoparticles (N-AuNPs)
by the reduction of chloroauric acid. Their results-based N-AuNPs have
delivered a novel therapeutic route for wound dressings in diabetic
patients. AuNPs were found to be crystalline in nature, spherical in
shape, and size in the range of 50–70 nm. The developed
N-AuNPs based ointment showed an enhanced effect in the treatment of DFU
[37]. In another study,
Hernández Martínez et al. investigated gold
nanocomposite functionalized with calreticulin that was found to promote
clonogenicity of fibroblasts, keratinocytes, and accelerates the
migration of fibroblasts [38].
Copper-based nanoparticles
CuNPs have also gained special attention in managing DFU infections. They
are extremely small and have a high surface-to-volume ratio that can
also serve as antifungal/antibacterial agents. These
nanoparticles can promote wound healing by enhancing angiogenesis,
re-epithelialization, matrix remodeling, and stabilization of collagen
content [39]. In a research
investigation, Goerne et al. prepared
Cu/TiO2-SiO2 nanoparticles gel as an
evident improvement in DFU cases. The prepared
Cu/TiO2-SiO2 showed fabulous
advantages in the healing of ulcers which indicates that it can be used
as a primary apposite to stimulate the autolytic debridement on injures
[40]. In another study,
Xiao et al. prepared copper-based metal-organic framework nanoparticles
incorporated with folic acid have been shown to induce angiogenesis,
collagen deposition, and increased wound closure in diabetic mice [41]. In another study,
López-Goerne et al. synthesized
Cu/TiO2–SiO2 nanoparticles and
embedded them in a polymeric gel matrix. The
Cu/TiO2–SiO2 nanogel was used as conservative therapy
for a chronic non-healing DFU on a 62-year-old female with several
comorbidities and chronic complications of diabetes. Wound debridement
was performed before nanogel administration. The nanogel was applied
over the ulcer on alternate days initially for 2 weeks and then
continued for 10 months. Significant improvement was observed in the
wound healing process since the first application. The infection was
limited and tissue regeneration was enhanced until the ulcer was
completely healed. Cu/TiO2–SiO2 nanogel therapy enhanced
reepithelialization and healing of the DFU. The successful outcome
allowed to avoid the amputation that was proposed for the patient [39].
Inorganic Nanoparticles
Recent advances have shifted our focus to inorganic nanoparticles for
specific targeting and control of their cellular actions. Being inorganic,
they remain stable for long periods [42].
Inorganic NPs such as ZnO, TiO2, CeO2, and
Y2O3 are a few most attractive options for DFU as
they are comprised of essential mineral elements for the human body. ZnO
nanoparticles (ZnO NPs) have exhibited therapeutic activities against
melanoma, diabetes, bacterial infection, and inflammation, and have shown
potential for wound healing applications. ZnO NPs have strong antibacterial
properties and can stay at the wound site for a longer period, thus, are
effectively used for wound healing. Zn reduces blood sugar levels by
inhibiting glucose absorption and raising glucose absorption by skeletal
muscles and adipose tissues [27]
[28]
[42].
Increased incidence of multi-drug resistance in microorganisms has become the
greatest challenge in the treatment of DFU and urges the need for a new
antimicrobial agent. In a study, Steffy et al. determined the bactericidal
effects of ZnO NPs green synthesized from Aristolochia indica against
Multi-drug Resistant Organisms (MDROs) isolated from pus samples of DFU
patients attending a tertiary care hospital in South India. Minimum
inhibitory concentration (MIC)/MBC assays were performed to
determine bactericidal or bacteriostatic effects. Protein leakage and flow
cytometric analysis confirmed bacterial cell death due to ZnO NPs [43]. In another research, Liu et
al. synthesized zinc oxide nanoparticles (ZnO-NPs) using radish root
(Raphanus sativus) extract. The produced ZnO-NPs display
exceptional antibacterial activity towards microbes isolated from DFUs like
P. aeruginosa ATCC 27853, MDR–Escherichia coli,
Staphylococcus aureus ATCC 29213, MDR–MRSA, E.
coli ATCC 25922, Enterococcus faecalis ATCC 29212,
MDR–Pseudomonas aeruginosa, and MDR Acinetobacter
baumannii. These antibacterial ZnO-NPs further established the
opportunity of developing wound dressing material for DFUs in nursing care
[44].
Ceramic nanoparticles containing inorganic components have the fundamental
therapeutic ability and can transport drugs to injury sites. CeO2
is considered one of the most important options to be utilized for the
treatment of DFU. Instead of bacteriostatic activity, they have antioxidant
and auto regenerative abilities along with non-toxicity to neutrophils and
macrophages [26]. CeO2
NPs can scavenge free radicals and rescue cells from oxidative
stress-induced cell death, and thus, be exploited in the healing of DFUs.
CeO2 NPs when conjugated with microRNA-146a enhanced the
diabetic wound healing without impairing the biomechanical properties of the
skin post healing [45]. Kobyliak
et al. reported successful topical treatment of neuropathic DFUs with a
novel gel containing CNPs. They investigated the ability of topical
application of cerium (Ce) dioxide nanoparticles (CNPs) to accelerate wound
healing in an animal model and provide a rationale to develop this
technology for use in humans affected by traumatic injury, diabetes, and
burns. The CNPs have bacteriostatic activity, anti-inflammatory properties,
can penetrate the wound tissue and reduce oxidative damage, therefore,
protecting regenerative tissue, and suggesting its therapeutic potential for
topical treatment of DFUs [46].
Short interference RNA (siRNA)-based nanoparticles
SiRNAs are artificially synthesized 19–23 nucleotide long
double-stranded RNA molecules. RNA interference therapy permits the
silencing of gene expression by targeting selective molecules in chronic
wounds. Nanoparticle-based technology emerged as a strategy to protect the
delivery of siRNA from degradation by intracellular RNases. Yan et al.
developed collagen/GAG (Col/GAG) scaffolds activated by
matrix metalloproteinase-9 (MMP-9)-targeting siRNA (siMMP-9) because the
downregulation of the MMP-9 level in situ and the regeneration of
impaired tissue are critical for improved DFU healing. Mixing the RALA
cell-penetrating peptide with siMMP-9 led to the successful formation of the
siMMP-9 complexes. The complexes were formulated at N: P ratios of
6–15, with a diameter of approximately 100–110 nm,
and a positive zeta potential of about 40 mV, making them ideal for
cellular uptake. The MMP-9 gene and protein level of M1 macrophages
decreased by around 50% and 30% respectively in the
scaffolds. The prepared formulation downregulated the MMP-9 gene and protein
levels of human M1 macrophages by about 50-30% respectively [47]. In another research, Kim and
Yoo fabricated an MMP-2siRNA-incorporated linear polyethylenimine (LPEI)
complex onto a nano-fibrous mesh in response to a high concentration of MMPs
which accelerates the ulcers [48].
Lipid-based nanoparticles
In dermatology, lipid nanoparticles (LNPs) have received great attention from
researchers due to their significant functionalities, greater adhesion to
the skin, and film formation, enabling the hydration and maintenance of skin
integrity, as well as more effective penetration through the skin barrier
[49]. Lipid-based carriers are
generally constituted from physiological lipids. Therefore, they are
considered to be safe and free from toxicity. They liberate non-toxic moiety
upon degradation and are well accepted for therapeutic purposes. Lipid-based
nanocarriers are beneficial in many aspects such as controlled drug release,
enhanced stability, biodegradability, drug targeting, increased drug load,
and cost-effectiveness. In addition to being safe, are extensively used to
deliver both hydrophilic and hydrophobic drugs.
Recent attention to nanostructured lipid carrier (NLC) research has proven
their potential for the effective management of DFU [50]. Motawea et al. investigated
the impact of topical phenytoin-loaded nanostructured lipid carriers in
improving wound healing in patients with neuropathic DFUs. Twenty-seven
patients with neuropathic DFUs were enrolled in this study. Patients were
comparable in terms of size, grading of ulcer, and control of diabetes with
no major deformity. All patients were managed by weekly sharp debridement if
indicated and offloaded with cast shoes. They were equally categorized into
three groups: phenytoin (PHT)-NLC-hydrogel (0.5%w/v),
phenytoin hydrogel (0.5%w/v), and blank hydrogel groups.
Changes in wound area were monitored over 2 months. Ulcers treated with
PHT-NLC hydrogel showed smaller wound areas compared to control groups
(ρ<0.05). PHT-NLC hydrogel speeds up the healing process of
the DFU without adverse effects when compared to the positive and negative
control hydrogels [51].
Inefficient diabetic ulcer healing and scar formation remain a challenge
worldwide, owing to a series of disordered and dynamic biological events
that occur during the process of healing. A functional wound dressing that
is capable of promoting ordered diabetic wound recovery is eagerly
anticipated. Natarajan et al. developed a pio-nanostructured lipid carrier
(Pio-NLC)-loaded collagen/chitosan (COL-CS) scaffold and evaluated
it for its healing ability in diabetic wounds. The in vitro studies
revealed that the Pio-NLC-COL-CS scaffold was biocompatible and enhanced
cell growth compared with control and NLC-COL-CS. Using the
streptozotocin-induced diabetic wound model, significantly
(p+<+0.001) higher rates of wound contraction
in the Pio-NLC-COL-CS scaffold-treated group were observed in comparison
with that in the control and NLC-COL-CS-treated group. Later on, Sun et al.,
designed a silicone elastomer with embedded 20(S)-protopanaxadiol-loaded
nanostructured lipid carriers (PPD-NS) to achieve ordered recovery in
scarless diabetic ulcer healing. The PPD-NS showed excellent in vitro
anti-inflammatory and proangiogenic activity. Moreover, in diabetic mice
with full-thickness skin excision wounds, treatment with PPD-NS
significantly promoted in vivo scarless wound healing by suppressing
inflammatory infiltration in the inflammatory phase, promoting angiogenesis
during the proliferation phase, and regulating collagen deposition in the
remodeling phase [52].
Nanofibers
Nanofibers have received much attention because of their structural
similarity, which closely mimics the native ECM environment. Nanofibers
promote wound healing by providing characteristics of high surface area to
volume ratio, tunable mechanical properties, increased porosity, and ability
to encapsulate nanoparticles and bioactive compounds for controlled release,
which can support the cells to actively interact with the matrix during
functionalization and remodeling [53]. Nanofibers could be a wonderful candidate for the DFU
treatment with so many benefits. Huge porosity, excellent humidity
absorption, a better oxygen exchange rate, and some antibacterial activities
make it a suitable dosage form for the treatment of DFU [53].
Nanofibrous scaffolds are promising platforms for wound healing, especially
due to their similarity to the extracellular matrix (ECM) and their
capability to promote cell adhesion and proliferation and to restore skin
integrity when grafted into the wound site [54]. Assi et al. hypothesized that
delivery of mesenchymal stem cells (MSCs) in a biomimetic collagen scaffold
improves diabetic ulcers. Rolled scaffolds were hypoxic, inducing MSC
synthesis and secretion of vascular endothelial growth factor (VEGF).
Diabetic mice with wounds treated with rolled scaffolds containing MSCs
showed increased healing compared to those in controls. Increased cellular
proliferation, increased VEGF expression and capillary density, and
increased numbers of macrophages, fibroblasts, and smooth muscle cells were
observed during histologic examination. With the addition of laminin to the
collagen scaffold, the aforesaid effects were enhanced [55]. Later on. Goonoo and
Bhaw-Luximon observed polymeric nanofibrous translational chronic wound
healing. Research showed that the three-dimensional (3D) scaffold more
closely mimics the biochemical-mechanical milieu of wounds and advancing
knowledge of cell biology had led to the next generation of engineered
biopolymeric nano scaffolds; this has paved the way towards personalized
wound care as they can address multiple requirements of skin physiology
[53].
Furthermore, Zheng et al. prepared collagen-based dressings for the delivery
of neurotensin (NT), a neuropeptide that acts as an inflammatory modulator
in wound healing. The performance of NT alone and NT-loaded collagen
matrices to treat wounds in STZ diabetic induced mice was evaluated. Results
showed that the prepared dressings were not-cytotoxic up to 72 h
after contact with macrophages (Raw 264.7) and human keratinocyte (HaCaT)
cell lines. Moreover, those cells were shown to adhere to the collagen
matrices without a noticeable change in their morphology [56]. Liu et al. developed
electrospun nanofibers as a wound dressing for treating DFUs by
electrospinning with huge porosity, excellent humidity absorption, a better
oxygen exchange rate, and some antibacterial activities. They laid much
emphasis on the present techniques which are applied in the fabrication of
nanofibrous dressing that utilizes a variety of materials and active agents
to offer better health care for the patients suffering from DFU [57].
Moreover, Samadian et al. prepared functional wound dressing for DFU
management and treatment of DFU. Cellulose Acetate/Gelatin
(CA/Gel) electrospun mat loaded with berberine (Beri) was fabricated
as the DFU-specific wound dressing. The wound healing efficacy of the
fabricated dressings was evaluated in streptozotocin-induced diabetic rats.
The antibacterial evaluations demonstrated that the dressings exhibited
potent antibacterial activity. The collagen density and the angiogenesis
score obtained in the animal studies indicated proper wound healing. These
findings implied that the incorporation of berberine did not compromise the
physical properties of dressing while improving the biological activities
[58]. Li et al. developed
bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with
high angiogenesis for promoting diabetic wound healing and skin repair. The
study displayed prominent multifunctional properties and angiogenic capacity
of PABC hydrogel scaffolds which enable their promising applications in
angiogenesis-related regenerative medicine [59]. In a subsequent study, Roy et
al. developed a flexible screenprinted wound dressing employing a
nanocomposite hybrid for the selective detection and quantification of S.
aureus target DNA which is responsible for slow or non-healing DFUs
[60].
Near-infrared (NIR)-responsive black phosphorus (BP)-based gel
Current therapeutic approaches for diabetic ulcers primarily focus on injury
debridement, reducing microbial infiltration, weight control, and patient
training. These medicines can offer some relief from discomfort and may
assist with forestalling contamination. Nevertheless, their impact on
speeding up injury mending is minor. The therapy of diabetic ulcers remains
a significant clinical challenge because of the intricate injury
recuperating milieu that highlights constant injuries, hindered
angiogenesis, relentless torment, bacterial diseases, and exacerbated
irritation. An exceptional technique was created by Ouyang et al., 2020 that
successfully focuses on this multitude of issues. The examination discusses
a BP-based gel with the qualities of fast arrangement and NIR responsiveness
to resolve these issues. The in situ showered BP-based gel could go
about as a brief, biomimetic "skin" to briefly protect the
tissue from the external climate and speed up constant injury recuperation
by advancing the expansion of endothelial cells, vascularization, and
angiogenesis and a medication "repository" to store helpful
BP and agony diminishing lidocaine hydrochloride (Lid). With a few minutes
of NIR laser illumination, the BP-based gel produces local heat to speed up
the microcirculatory bloodstream, intercede the arrival of stacked Lid for
"on request" help with discomfort, dispose of microscopic
organisms, and reduce irritation. This original methodology not just
presents an idea of in situ sprayed, NIR-responsive discomfort
relieving gel focusing on the difficult injury recuperating milieu in
diabetes but additionally gives a proof-of-idea utilization of BP-based
materials in DU treatment [61].
Clinical outcomes
Preclinical studies have shown promising results in improving wound
healing using a variety of agents for promoting tissue healing,
including growth factors, small molecules, and siRNA-based therapies.
Despite recent technological advances, challenges in retaining and
extending their therapeutic effect in the harsh wound environment have
limited the pace for clinical implementation [62]. To overcome this
limitation, nanoparticle formulations, nanofiber scaffolds, and
hydrogel-related treatments are being developed [21]
[22]. Many clinical trials have
been conducted on the use of AgNPs for wound healing, particularly burns
and chronic wounds (diabetic wounds). Currently, some dressings
available in the market contain AgNPs [63]. The most successful
polymer for fabricating polymeric nanoparticles is PLGA, which is
approved for clinical use in humans as a DDS by the FDA [64]. Clinical trials have shown
that recombinant human-platelet-derived growth factor, the only
FDA-approved growth factor available for clinical use, increases the
likelihood of wound closure and decreases the time to heal the wound
completely [65]. As of now,
the only siRNA delivery depot waiting for approval is the siG12D LODER
therapeutic to combat non-resectable pancreatic dual adenocarcinoma
[66]. Several wound
bandage materials that are effective in promoting skin regeneration have
been introduced to the market. Inorganic-based Au, copper, ZnO, cerium
oxide, and silica nanoparticles are still under clinical investigation
[67].
