Journal of Clinical & Translational Endocrinology 37 (2024) 100366

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Journal of Clinical & Translational Endocrinology

journal homepage: www.elsevier.com/locate/jcte

Advances in nucleic acid delivery strategies for diabetic wound therapy

Soniya Sarthi , Harish Bhardwaj , Rajendra Kumar Jangde *
University Institute of Pharmacy, Pt. Ravishankar Shukla University Raipur, Chhattisgarh 492010, India

A R T I C L E I N F O A B S T R A C T

Keywords: In recent years, the prevalence of diabetic wounds has significantly increased, posing a substantial medical
Diabetic wound healing challenge due to their propensity for infection and delayed healing. These wounds not only increase mortality
Nanotechnology rates but also lead to amputations and severe mobility issues. To address this, advancements in bioactive mol­
Targeted gene therapies
ecules such as genes, growth factors, proteins, peptides, stem cells, and exosomes into targeted gene therapies
Nucleic acid
have emerged as a preferred strategy among researchers. Additionally, the integration of photothermal therapy
(PTT), nucleic acid, and gene therapy, along with 3D printing technology and the layer-by-layer (LBL) self-
assembly approach, shows promise in diabetic wound treatment. Effective delivery of small interfering RNA
(siRNA) relies on gene vectors. This review provides an in-depth exploration of the pathophysiological charac­
teristics observed in diabetic wounds, encompassing diminished angiogenesis, heightened levels of reactive
oxygen species, and impaired immune function. It further examines advancements in nucleic acid delivery,
targeted gene therapy, advanced drug delivery systems, layer-by-layer (LBL) techniques, negative pressure
wound therapy (NPWT), 3D printing, hyperbaric oxygen therapy, and ongoing clinical trials. Through the
integration of recent research insights, this review presents innovative strategies aimed at augmenting the
multifaceted management of diabetic wounds, thus paving the way for enhanced therapeutic outcomes in the
future.

Introduction of signaling molecules including VEGF and protein kinase B, sometimes

referred to as Akt, indicates that this hormone can promote cellular
One of the main health issues for people with diabetes mellitus (DM) differentiation and proliferation. A thick epidermal layer developed in
is impaired wound healing. Neuropathy and vascular injuries are two of diabetic rats after topical insulin therapy shortened the time required for
the causes that contribute to this illness [1]. Additionally, a chronic wound epithelialization. According to in vivo-secreted inflammatory
hyperglycemic condition is caused by insufficient insulin synthesis or by mediators, this quicker wound healing may be linked to macrophage
the inability of insulin to interact with cells [2], the prevalence of dia­ infiltration [4].
betes in the population aged 18 to 99 is predicted to increase from 8.4 % Diabetes has a complex pathophysiology that includes metabolic,
in 2017 to 9.9 % in 2045. Wound healing in diabetic people is a chal­ vascular, immunological, and neuropathic elements that impair healing.
lenging and dangerous health issue. Biochemical mechanisms such as Reduced tissue oxygenation is a result of slower circulation and micro­
homeostasis, inflammation, proliferation, and tissue remodeling are vascular dysfunction, both of which are associated with larger blood
triggered during the healing process in non-diabetic individuals, ac­ vessels in hyperglycemia. Reduced leukocyte migration into the wound,
cording to Baltzis et al. However, the metabolic impairment of these which increases sensitivities to infection, is also explained by diabetic
processes is delayed in individuals with diabetes mellitus (DM), which individuals’ blood vessel abnormalities [5]. The hyperglycemic sur­
might cause persistent wounds to form. Opportunistic infections can roundings themselves may impair leucocyte activity. Furthermore, if
infect them if they are not appropriately treated, which frequently re­ wounds are not properly recognized and treated, peripheral neuropathy
sults in the amputation of the affected limbs [3]. can lead to numbness and a decreased perception of pain. The aspects
Based on the kind of tissue, insulin operates by boosting the insulin that have been outlined are especially important for the lower limbs,
receptors found in vertebrates, which facilitate the repair process’ especially the foot, which is more vulnerable to chronicization because
metabolic route. The repairing metabolic pathways’ enhanced synthesis of its increased exposure to even small lesions. Moreover, changes in

* Corresponding author.
E-mail address: [email protected] (R. Kumar Jangde).

https://doi.org/10.1016/j.jcte.2024.100366
Received 15 March 2024; Received in revised form 13 August 2024; Accepted 22 August 2024
Available online 30 August 2024
2214-6237/© 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
S. Sarthi et al. Journal of Clinical & Translational Endocrinology 37 (2024) 100366

Fig. 1. Phase of wound healing.

motor and sympathetic nervous system function result in plantar pres­ phase, is when the injured skin starts the clotting cascade by drawing
sure and physical deformity of the foot. Excessive skin dryness can also platelets and creating a fibrin plug. In addition to dressing and shielding
exacerbate fissures and minor lesions that go untreated [6]. wounds, hemostasis depends on it. The clot’s aggregated platelets act as
Diabetic foot ulcers can occur in 15–25 % of patients during their a basis for the inflammatory cells’ recruitment. By producing a range of
lifetime, of which 40–80 % proceed to osteomyelitis due to severe cytokines and growth factors, including platelet-derived growth factor
infection that affects the bone [7]. North America may have a greater (PDGF) and transforming growth factor (TGF), they also attract different
incidence, according to global epidemiological research. A substantial types of cells. Monocytes and neutrophils are among them; concomitant
percentage of foot ulcer patients require hospitalization and surgical vasodilation facilitates their passage. The latter soon change into mac­
intervention, including amputation of the afflicted body part. Addi­ rophages, which are believed to be the main cellular actors during this
tionally, three years from the initial incident, the recurrence risk of a phase of inflammation since they again release cytokines and growth
foot ulcer is higher than 50 % [8]. Consequently, poor wound healing in factors [16]. Furthermore, keratinocytes go to the site of injury, where
diabetes mellitus poses a substantial clinical challenge and financial local fibroblasts start to multiply. Within 48 to 72 h following the injury,
burden [9,10]. Notably, Diabetic foot ulcer therapy is more costly than these processes begin and quicken, helping to create the early granula­
normal diabetes care due to the higher incidence and prevalence of the tion tissue [17].
disease [11–13].
Proliferation and remodeling
The physiology of wound healing
These phases are designed to encourage the closure of wounds. One
The physiological phenomenon known as wound healing is intricate of the first stages of wound closure is contraction, which is triggered by
and arises when the skin’s barrier function is compromised due to a loss the formation of myofibroblasts, granulation tissue, keratinocyte
of integrity. Due to the skin’s high level of exposure to external irritants migration, and extracellular matrix (ECM) protein synthesis. Fibro­
& the requirement to prevent internal infections, a quick defense blasts, the major cell type in this phase, release collagen to start the
mechanismmay be triggered often [14]. When tensile strength is typi­ process of repairing the wounded area. The early phases of wound
cally only obtained to a maximum of 70 % of its earlier value, the skin healing are characterized by hypoxia, which promotes the release of
can fully return to its natural state during physiologic repair [15]. This growth factors and the migration and proliferation of all cell types. In
process proceeds in several levels, and four distinct phases are often actuality, hypoxia triggers the activation of HIF-1 and the stimulation of
identified: the stages of hemostasis, inflammation, proliferation, and VEGF-A, one of HIF-1′s primary target genes [18]. Consequently, Active
remodeling shown in Fig. 1. proliferation of endothelial cells is the cornerstone of neo-angiogenesis
and is crucial for supplying the growing tissue with the support it
Hemostasis needs. Wound healing is aided by VEGF-A’s enhanced capillary density
and restored blood flow. Following the initial proliferative phase is
Hemostasis, the process of clotting blood to stop bleeding, can be characterized by the growth of many, chaotic vessels. Following this,
hampered in diabetic wounds by several conditions, including reduced there is a maturation phase in which certain vessels mature and become
immunological function, neuropathy, inadequate blood flow, and durable by the recruitment of pericytes that generate antiangiogenic
platelet dysfunction. It could need extra measures to achieve hemostasis chemicals and vascular maturation factors [19]. Consequently, healing
in diabetic wounds, like regulating blood sugar levels, enhancing cir­ progresses toward a modelling step where collagen type I (which is
culation, applying cutting-edge wound dressings, and keeping a close typically seen in normal, non-injured tissue) replaces type III collagen,
eye out for infections. which first accumulates [20], the process of wound healing proceeds to
restore the skin’s physiologic structure while neovascularization is
Inflammatory response contained and returns to normal [21].
A chronic wound problem occurs as an ulcer or, in the opposite case,
The inflammatory phase, which is preceded by the coagulation as an excessive healing event that, when the physiologic reparative

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Fig. 2. Mechanisms underlying activation of diabetic wounds.

process is interfered with, produces a hypertrophic scar or keloid. Hy­ applied in a variety of methods. While the majority of the examples in
pertrophic scars are usually transitory, appearing in association with the this review focus on accelerating the healing of diabetic ulcers, we also
patient’s susceptibility and often regressing within six months. On the provide some examples of how TNAs can be used to treat other types of
other hand, keloids form in people who are genetically predisposed, chronic wounds, such as burns, pressure ulcers, venous ulcers, and
cover a larger area than the initial skin damage, and are permanent [22]. myocardial infarction, each of which has specific requirements.
On the other hand, ulcers are common in diabetes individuals and
frequently arise under ischemia situations. They are one of the main Nucleic acid delivery strategies
delayed effects of the illness.
Gene therapy and nanotechnology are combined in nucleic acid-
Mechanism of wound healing encapsulatedparticles to effectively suppress or express a particular
gene for the treatment of chronic wounds [29]. Chronic wound healing
Multiple cell types, cytokines and growth factor interact in a complex can be sped up by expressing certain proteins, which is supported by
network to facilitate wound healing. Three overlapping stages have gene transfer to the site of damage. For example, the use of viral vectors
traditionally been used to categorize the course of wound healing: has transfectedpatients with diabeteswith VEGF to induce angiogenesis
remodeling, proliferation & inflammation. The inflammatorystage in chronic wounds, and the effect on wound healing has been reported.
function is to control damage and get rid of infections. Although it might However, given that viral vectors might cause an immunological reac­
linger up to two weeks, inflammation usually passes after a few days tion and should always be handled carefully, it is preferable to employ
[23]. Increased vascular permeability and the release of several che­ non-viral carriers of nucleic acid, such as nanoparticles [30,31]. SiRNA
moattractant facilitate the inflow of neutrophils and monocytes into a specifically targets matrix metalloproteinase (MMP), ganglioside-mono
wound caused by the release of substance P, a neuropeptide, from the sialic acid 3 synthase (GM3S), and TNF-are among the genes that are
peripheral nerves [24]. Mature monocytes develop into macrophages overexpressed in chronic wounds. Allowing for the decrease of gene
during the inflammatory phase. The inflammatory phenotype (M1) of expression. For siRNA to be delivered in vivo and shield cells from
macrophages is involved in clearing debris and germs [25]. The in­ physiological nucleases, a carrier must be incorporated into the cell.
flammatory phase is terminated by macrophages that polarize towards Human efforts delivering siRNA to cure many diseases have shown
the anti-inflammatory (M2) state of the wound when it is clear of foreign promise; nevertheless, main human trials failed because of substantial
material. Angiogenesis, nerve regeneration fibrous tissue deposition off-target effects or insufficient effectiveness. Before RNAi technology is
combined with fibroplasia, and re-epithelialization are characteristics of used widely in clinical settings, it has to be further refined [32]. Table 1.
the proliferative phase. About two to three days after the damage, depicted the different type of nucleic acid targeted systems.
proliferation begins. To start the creation of collagen, fibroblasts go into
the wound region [26]. The process of wound closure is initiated and
siRNA
covered by the growth of keratinocytes. Pro-angiogenic substances, such
as fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor
Using small interfering RNA (siRNA) to regulate gene expression has
(VEGF), and platelet-derived growth factor (PDGF), are produced to
become a widely used TNA technique for persistent wounds. Using a
cause the onset of vascularization. Schwann cells help damaged nerves
matching siRNA, this method identifies a gene transcript that is over-
regenerate [27]. Usually, the proliferative period extends for many
expressed in chronic wounds with diabetes and targets it for knock­
weeks. After an accident, the remodeling period might persist for
down. While siRNAs are now accessible for many genes, computational
months and starts two to three weeks later. Vascularization is decreased
methods can assist in identifying suitable sequences for gene silencing in
and granulation tissue is broken down by collagenases during the
other cases. Here, we outline many siRNA genes that have been targeted
remodeling phase. As collagen type III breaks down, collagen type I is
in light of the biology underpinning chronic wound healing as well as
produced illustrated in Fig. 2 [28]. The injured tissue ages and becomes
techniques for delivering these genes locally to the wound bed [33].
functioning again.
The benefits of siRNA-based treatment might be significantly
To locally restore the wound to its natural healing process, TNAs are
increased by two very recent technologies. Nanoneedles offer a unique

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Table 1
Different types of nucleic acids targeted.
Targets Nucleic Delivery method/ Model system Wound Result Ref.
acid carrier

MMP-9 siRNA Delivery of siRNA via In vivo, in vitro After administering STZ, MMP-9 of skin wound tissues, which [56]
Hyperbranched healthy SD rats venous blood was extracted subsequently improved wound
cationic from the tail. recovery
polysaccharide
derivatives

prostaglandin siRNA DsiRNA-loaded gold In vitro, in vivo Wisterrats model − DsiRNA-AuNPs have antibacterial and [57]
transporter nanoparticles therapeutic qualities, it is known that
(PGT) they can safely stimulate wound
healing in vitro.

AZD8601 mRNA Lipofectamine 2000(in Human aortic smooth muscle in Full-thickness cutaneous increased vascularization enhanced [39]
situ citrate/saline (in situ Live cells Mice C57BL/ lesions on the dorsum of oxygenation of the tissues elevated
vivo) 6BrdCrHsd-Tyrc (microvasculature genetically diabetic mice, reepithelialization
of the ears) Leprdb/J mice measuring one centimeter
(diabetes wound) B6.BKS(D) in diameter
healing)
Res &VEGF Plasmid Hydrogel loading Male Sprague Dawley (SD) rats, age A copper cod was used to Rerelease has the potential to enhance [58]
plasmid DNA 6 weeks create two full-thickness wound healing by delivering a more
burn wounds on either side gratifying anti-inflammatory
of the dorsal skin (11 mm, response.
90 ◦ C, 25 s).

Plasmid encoding Plasmid Polyhedral oligomeric In vivo, in vitro Full-thickness skin wounds Prolonged release for 35 days while [59]
green DNA silsesquioxane (POSS) 16Male Sprague-Dawley rats, were burnt for 50 s at maintaining a high transfection
fluorescence nanoparticles 200–300 g 100 ◦ C with a hot circular efficiency of genes. The wound
protein (GFP) copper billet (diameter = healing rate is accelerated by the pAng
16 mm). encapsulated nanofibers, in addition
to stimulating angiogenesis.
M1 macrophages miRNAs exosomes In vivo, in vitroMice B6.BKS(D)- 8 mm skin wounds were MiR-222 suppression reduced anti- [60]
Leprdb/J (db/db) made using a biopsy punch inflammatory gene expression even
. during a naïve LPS response, which in
turn inhibited the production of many
inflammatory mediators.
TGF-b1 pDNA Electroporation In vivo, in vitro Wounds measuring 7 x 7 Increased angiogenesis [61]
C57BL/6 C57BKS.Cg-m+/+Leprdb mm and fully thick on the Increased reepithelization rate
female mice back of a genetically Increased collagen synthesis
diabetic mouse

VEGF pDNA Electroporation In vivo, in vitro Rats’ backs were incised Five days of elevated VEGF expression [62]
Male SD rats using an 8 x 3 cm full- Necrosis of the distal region of RSFs
thickness incision was reduced by upregulating eNOS.

PDGF-B pDNA Cholesterol and Male SD rats in vivo and 3 T3 2.1-cm incision made on promotes re-epithelialization [63]
cationic liposomes murine fibroblast cells in vitro the dorsal skin of an STZ- increased keratin and fibro collagen
diabetic rat up to the level synthesis enhanced blood vessel
of the loose subcutaneous creation
tissues
VEGF-A pDNA Modified PLGA Nano 3T3 mouse fibroblast cells in vitro; 6-mm full-thickness skin VEGF-A and PDGF-B expression levels [64]
PDGF-B sphere with PEI female SD rats in vivo wound on the diabetic rat S were raised, which decreased the
TZ’s dorsal hind foot ulceration area.

way to transfer DNA and siRNA without requiring transfection reagents, Plasmid
however to the best of our knowledge, they are not directly employed for
treating chronic wounds. Through the use of this technique, which is Although there have been many different strategies for delivering
made possible by the ability of nanoneedles to permeate cell membranes plasmids to promote wound healing, angiogenesis stimulators have been
and tissue, the medications interact directly with the target cells’ cyto­ the primary focus of these strategies, with VEGF gene delivery being one
plasm through a process that is still unknown. This method can drasti­ of the most thoroughly researched. One team attempted to address the
cally alter TNA delivery by doing away with the difficulty of endosomal limited half-life of growth hormones by introducing EGF and VEGF
escape [34]. The efficiency of siRNA-based treatments may be signifi­ plasmids. Diabetes was shown to reduce blood flow in the wound,
cantly increased thanks to some of the recent work done in our lab on co- whereas local VEGF plasmid administration restored blood flow by
delivery of siRNA and Argonaute 2 (Ago2), the protein responsible for encouraging angiogenesis. Day 8 following the injury did not follow this
siRNA-mediated mRNA degradation. Gene knockdown produced by co- pattern, although it did for days two and six. The study used sonopo­
delivering self-assembled Ago2 and siRNA is more efficient and durable ration to help in plasmid absorption; however, because of its inability to
than siRNA alone..83 Such strategies might be modified for direct local affect broad sections of tissue efficiently and the possibility of damaging
administration to wound [35]. nearby tissue, sonoporation is not a therapeutically practical TNA de­
livery approach [36].
One group investigated the use of plasmid distribution to manage the
protracted inflammatory condition associated with chronic wounds.

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They used a PEI-DNA combination linked to silica nanoparticles to caged state, the enclosed, light-activatable AMOs function, hence
deliver plasmids expressing the interleukin-10, an anti-inflammatory avoiding the blocking impact of the AMO. This photo-labile connection
cytokine (IL-10). Since the intravenous administration ofThe half-life may be broken by the blue light emanating from a diode, enabling
of IL 10 protein is only a few hours, TNA delivery is essential if duplex synthesis. The scientists demonstrate that their AMO which is a
extended activity is sought [37]. Although the plasmid’s release kinetics light-activated system may be used to induce local suppression of miR-
were not disclosed, the levels of IL-10 peaked on day five or so. Re­ 92a while having no effect on skin that has not been exposed to radia­
ductions in TNFα and interleukin-1 β (IL-1β) transcript expression sug­ tion. This approach offers an exciting way to manage local delivery of
gest that this method lessened the overall inflammatory status of the TNA, especially for accessible or shallow wounds where blue light can
wounds. There is a need for research on this strategy’s effectiveness in penetrate [51].
promoting chronic wound healing [38].
To improve epithelialization, researchers have finally employed miRNA mimics
plasmid DNA. Fig. 1 shows how the Saltzman group created nanofiber
scaffolds by electrospinning poly (caprolactone) or poly (L-lactide) Anti-miRNA oligonucleotides (AMOs) are widely used to regulate
(PCL). The keratinocyte growth factor (FGF7, or KGF)-encoding plas­ transcription by controlling the amount of miRNA, however, some have
mids were successfully transfected onto the surface thanks to the LbL produced endogenous miRNA mimics to promote upregulation as
assembly’s addition of PEI and DNA. A burst release of around 10 % was opposed to downregulation. While miRNA mimics are chemically
seen in the scaffolds, and during the next week, an additional 5 % of the manufactured and computationally developed, they behave similarly to
loaded plasmid was released. Increased keratinocyte proliferation, miRNAs linked to certain biological pathways. Compared to endogenous
granulation tissue development, and epithelialization were how this miRNAs, they are more stable. Furthermore, because they have two
tactic supported improved healing [39]. strands, they may load straight into the RISC stands for RNA-induced
silencing complex and start working right away without requiring the
Anti-miRNA oligonucleotides (AMO) processing of the Dicer enzyme. However, due to their artificial char­
acter, experts have issued a warning that miRNA mimics might have
The expression levels of non-protein-coding genes, including miR­ strong off-target impacts on gene regulation [52].
NAs, are not as well understood as those of protein-coding genes in
wounds. Recent research is providing insight into the potential role of Anti-sense oligonucleotides (ASOs)
the miRNAs that have been experimentally linked to poor wound heal­
ing and discovered in screens [40,41]. Number-inhibitingmiRNAs (anti- Anti-sense oligonucleotides (ASOs), the final main type of thera­
miRNA oligonucleotides, or AMOs) or mimicking miRNAs have been the peutic nucleic acid (TNAs) used for targeted delivery, regulate gene
subject of localized delivery experiments recently [42]. Due to their expression via three different mechanisms (Fig. 2).122 The Becker group
capacity to simultaneously regulate the expression of many genes, looked at the long-term administration of an ASO against the gap
miRNA-based therapies provide both additional complexity and poten­ junction protein Cx43. It was previously demonstrated that this gene is
tial. Around 100 mRNAs’ expression can be hypothesized to be increased in diabetic wounds but downregulated near the wound mar­
controlled by a single miRNA [43]. The difficulty of targeting specific gins to permit cell migration [53]. By increasing wound re-
gene networks including protein-coding genes, where each gene re­ epithelialization, The balance of Cx43 levels was restored by an ASO
quires a different sequencecan be mitigated in part by this special against Cx43 [54]. They were able to sustain release over seven days by
quality of miRNAs [44]. While it doesn’t address polymeric delivery of using collagen scaffolds coated with ASOs in PLGA or PCL. The
AMOs and miRNA mimics, particularly for wound healing applications, controlled delivery of ASOs to target Cx43 for improved wound healing
a recent study from Day Lab goes into additional depth about these hasshown encouraging results. Specifically, the results indicated
techniques [45]. Although the wounds had less granulation tissue over time and were
Increasing VEGF through different channels is the foundation of smaller after receiving local treatment with this ASO, indicating that the
many of the miRNA circuits that they target. Inhibitors of miR-615-5p, a wounds healed over time [55].
miRNA that is approximately twice as abundant in diabetic skin as
normal skin and is engaged in the VEGF-AKT-eNOS signaling cascade, The future of nucleic acid delivery of wound healing
were shown to promote wound healing by local injection. There was no
usage of any medication delivery system in targeting miR-135a-3p has Shortly, it is anticipated that the frequency of chronic wounds will
been shown to similarly alter the VEGF response, albeit it does so via the rise making it an important worldwide concern. Hardly any novel
VEGF HIP1-p38K signaling axis [46]. There was no medication delivery treatments for chronic wounds have made it into clinical practice
vehicle employed, much like in the lab’s prior work. With this meth­ throughout the previous several decades of study. Delivering TNAs non-
odology, they discovered a three-fold rise in CD31 positive, a marker of virally may provide the solution-new tactics are required. The most
angiogenesis, in vivo [47]. Eventually, they demonstrated how SMAD1- recent research on using TNAs for chronic wounds is outlined in this
mediated suppression of miR-26a may also cause angiogenesis in dia­ review. This article summarizes the pharmaceutical industry’s interest
betic wound [48,49]. in using TNA to treat wounds, in addition to the numerous drug delivery
Additionally, anti-miR-92a was studied as a potential therapeutic methods and therapeutic targets that have been studied.
target for promoting angiogenesis following cutaneous wounds, bone The following features of a medication delivery system, in our
fractures, myocardial infarction, limb ischemia, and vascular damage. opinion, are essential to changing the treatment methods for persistent
Anti-miR-92a demonstrated re-epithelialization and granulation tissue wounds and eventually other healing problems:
creation that was somewhat equal to the recombinant growth factors,
and it beat the effects of recombinant human VEGF and PDGF-BB on • Sustained TNA administration systems in wound dressings are
angiogenesis. The proof of principle study indicates that drug delivery probably more translational than injectable techniques because they
systems might potentially augment the effects of intradermal injection, may be adjusted to fit the wound’s contour and cover the whole area,
which was the method used to administer the AMO [50]. To improve reducing the therapy’s diffusion distance.
geographical specificity and lower the likelihood of AMO’s off-target • Certain TNAs must be released by systems at different stages of the
effects entering the bloodstream, the Dimmeler and Heckel labora­ dynamic wound healing process, indicating that a phased release
tories investigated if they might utilize light to initiate anti-miR-29a strategy would be the best option. The requirement for this might
AMO activity. By preventing duplex formation with the miRNA in its potentially be met by stimulus-responsive systems, which release

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Table 2
Growth factors in hydrogels, scaffolds, and nanoparticles used in experimental research on diabetic wound healing.
GFs Characteristics System Result Ref.

NGF & bFGF Good affinity and regulated release of GFs. Heparin hydrogel Encouraging Schwann cell proliferation, remyelination, and axonal [82]
poloxamer regeneration.

MIP-3α &IL-8 Steady bioactivity and cross-linking in place. Hydrogels made of Enhanced reepithelialization and increased collagen deposition. [83]
gelatin

VEGF, PDGF, A sequenced release of several angiogenic Nanofibrous membrane Increased vascular maturation and collagen deposition. [84]
bFGF and EGF factors. Col-HA-GN

VEGF and bFGF Release of many GFs under control. PLGA particles Achieved total re-epithelialization along with increased collagen [85]
deposition and granulation tissue development.

pVEGF plasmids Regional gene transfer HA-based hydrogels Improved the angiogenic response and encouraged wound closure. [86]

KGF GFs’ activity in vivo can be improved by Biopolymers of elastin Accelerating the healing process by increasing angiogenesis in the [87]
increasing their proteolytic resistance wound bed.

SDF-1 Thermoresponsive antioxidant Hydrogel PPCN Shown the greatest density of perfused blood vessels, rapid granulation [88]
tissue development, and epithelial maturation.

rh-aFGF Strong biostability Hydrogel made of Excellent skin wound healing promotion in diabetic rats after a full- [86]
Carbomer thickness damage.

PDGF biodegradable nanofibers with a sheath core Core-sheath PDGF, vancomycin, and gentamycin were sustainably released over [89]
nanofibrous three weeks.
PLGA scaffolds
EGF pH-variable hydrogel The hydrogels OHA Fibroblast proliferation, preservation of the internal structure of the [90]
and SCS tissue, and collagen and myofibril deposition are all encouraged.

TNAs only in response tofavourablecircumstances around the growth factors. Modulating genes, proteins, and peptides offers new
wound. techniques to manipulate certain genetic or molecular targets to stim­
• A combination strategy would work best to promote healing in ulate healing cascades or block harmful pathways. Using stem cells’
chronic wounds since several variables contribute to poor wound capacity for regrowth to restore damaged tissues and coordinate healing
healing. With only one bandage, TNAs, for instance, can be used in processes, stem cell therapy presents a bright future. These specialized
concert to stimulate the M2 macrophage phenotype, encourage gene therapy approaches represent new directions in the treatment of
angiogenesis, and facilitate re-epithelialization and cell migration. diabetic wounds and offer customized, effective therapies.
It’s important to consider when to release each of these parts.
• The historically poor effectiveness of TNA delivery may be improved Growth factor
by novel co-delivery techniques that increase the activity of the
natural TNA mechanism, such as Ago2 andsiRNA co-delivery Novel Growth factorsarephysiologically active proteins that have a role in
non-viral delivery techniques, such as nanoneedles, have potential as migration, metabolism, cell division and proliferation. Growth factors
well. and cytokines control all healing processes physiologically. Growth
• Multiple gene modulation is a promising application of miRNA-based factors attach to a particular receptor and activate several biochemical
therapeutics; however, before clinical translation, more gene iden­ processes necessary for proper cell activity [66]. Growth factors pro­
tification is essential. In many instances, the biological basis and mote modeling, inflammatory response, granulation of tissue, and
possible therapeutic benefit are well-established. angiogenesis, all of which are critical steps in the wound healing pro­
cess. It has long been known that the pathophysiology of a diabetic
Given the wealth of information on how genes are regulated in wound will reduce the availability of growth factors [67]. Growth fac­
chronic and wound-healing diseases, nucleic acid methods offer the tors can be administered externally, but they are quickly biologically
most efficient way to convert this understanding into treatments with degraded by the proteases found in the wound bed. Moreover, the
significant promise. Improving the stability of nucleic acid vectors and relatively large size and short half-life of growth factors, along with their
producing RNA and DNA constructs have also led to recent advance­ toxicity at increased systemic dosages, indicate that traditional methods
ments that make these therapeutic techniques considerably more of delivering growth factors in a free form are inappropriate for effi­
affordable, feasible to manufacture, and readily available. In the ciently transferring growth factors in the wound bed. Additionally, using
following ten years, promising novel therapies for chronic wounds and a single growth factor to speed up wound closure in diabetic ulcers may
other healing problems will result from the building of delivery systems not always be sufficient since several biomolecules are involved in the
that allow these medicines to reach the right cells and permit regulated wound healing process [68]. These issues have led to the widespread use
and suitably phased-release [65]. of growth factor encapsulation in nanoparticles, which improves the
half-life, encapsulates multiple biomolecules, and protects against pro­
Targeted gene therapy approaches tease breakdown in the wound bed because of the nanoparticles’
defensive qualities [69].
The discussion explores targeted gene therapy strategies, including Many growth factors mediate, coordinate, and drive cellular in­
stem cell therapy, gene/protein/peptide regulation, and the use of teractions during normal wound healing, which is an important function
growth factors. These tactics are cutting-edge approaches meant to treat they perform [70]. However, Several growth elements are in balance,
diabetic wound healing. The goal of therapy is to promote tissue and thrown off in diabetic wounds, harming angiogenesis, upsetting the
regeneration and cellular proliferation at the wound site by utilizing extracellular matrix, and eventually impeding wound healing. Locally

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delivering endogenous therapeutic growth factors is one method of Table 3

modulating diabetic wound signaling. To obtain therapeutic benefits, Genes/Proteins/Peptides used in diabetic wound healing are summarized. Most
growth factors must be administered at large concentrations repeatedly. of the Genes are miRNA, and there are both natural and synthetic peptides.
Furthermore, growth factors deteriorate quickly due to the action of Gene /proteins / Carrier Function Ref.
proteases within the cells [71]. Consequently, a delivery system is Peptides
needed to provide for the prolonged and regulated release of growth Keapl siRNA Lipoproteoplex Normalize the ROS imbalance
factors to the target in addition to maintaining growth factor activity. functions as by activating the endogenous
Presently, several systems such as it has been possible to apply hydro­ antioxidant systems mediated
by Nrf2.
gels, nanofibers, and nanoparticles to apply growth factors to diabetic
wounds [70,72]. The primary pro-angiogenic factor in wounds that heal siRNA В-CD-(D3)7; Reduction in MMP-9 [98]
appropriately is VEGF-A according to earlier research [73]. Its expres­ coatings at the expression
sion peaked two to three days following the injury and increased steadily nanoscale.
for around a week. Nevertheless, unlike normal mice, VEGF rises in db/
Plasmid DNA Ga-BDEs Increased long-term VEGF [99]
db diabetic mice, but it is transient and rapidly falls to almost unde­ encoding expression
tectable levels as granulation tissue develops. The short half-life of VEGF VEGF
makes single-dose administration to wounds ineffective, according to MiR-26a Hydrogel PCN Pro-regenerative wound [91]
clinical study data [74]. Repeated local administration of VEGF-165 microenvironment and
proangiogenic miRNA are
accelerated diabetic wound angiogenesis and re-epithelialization
provided.
[75–77]. Delivering VEGF using a gene activation technique should be
used to get around the drawbacks of its brief half-life and recurrent DMOG Fiber meshes PCL Lowering the expression of pro- [94]
administration. When compared to the quick delivery of growth factors inflammatory factors (TNF-α,
or genes, Nucleic acid-carrier complexes can be physically encapsulated IL-1β, IL-6, & TNF-α), raising
the expression of anti-
in hydrogels to prevent carrier breakdown and enable more sustained,
inflammatory factors (TGF-β1
focused transfection [78]. The primary constituent of hyaluronic acid & IL-4) and GFs (IGF-1, HB-
(HA), the extracellular matrix (ECM), is a biomaterial that is extremely EGF, NGF, & bFGF), and
biocompatible and can stimulate angiogenesis [79]. Porous hydrogel encouraging angiogenesis (CD-
3 I & VEGF-α)
made of HA with proangiogenic (pVEGF) plasmids inside for the goal of
treating diabetic wounds through local gene therapy. These studies Heparin Nanofibers Increased VEGF (major [100]
demonstrated that porous hydrogels acted as a barrier to wound healing mimetic angiogenic growth factor)
that is mechanical and did not break down. Nevertheless, it did not seem peptide production and activity
that the transfected levels of pVEGF were sufficient to improve angio­ amphiphiles
Proline IKFQFHFD Take off the MRSA biofilm [95]
genesis by enlarging or densifying blood vessels.
hydrogel
To stimulate their action in vivo (improving anti-proteolytic capac­ K2(SL)6K2 MDP hydrogel They are perfect for tissue [96]
ity) Devalliere et al. recombined keratinocyte growth factor (KGF) and engineering techniques
cytoprotective peptides into a protein polymer to accelerate chronic because they provide quick
cellular penetration.
wound healing (increasing wound bed angiogenesis). A single growth
factor is less effective than two or more in promoting angiogenesis and MMP-9 inhibitor Linezolid Reducing the harmful MMP-9 [101]
the ensuing tissue healing, according to earlier research [80,81]. For (R) –ND-336 and reducing microphase
instance, when VEGF-A and FGF-2 are co-stimulated in vivo, cell infiltration to reduce
migration and angiogenesis are much enhanced as opposed to when inflammation

angiogenic growth factors are stimulated separately. Moreover, the

Laminin CS hydrogels Increased the attachment and [102]
vascular network was rapidly restored following the administration of mimetic proliferation of BMSCs
dual agents, bFGF and VEGF. Table 2 illustrates the various growth peptide significantly
factors incorporated into hydrogels, scaffolds, and nanoparticles in SIKVAV
Integrin Silk fibroin Modulate angiogenesis and [97]
experimental studies focused on diabetic wound healing.
nanosheets encourage the repair of
diabetic ulcers
Genes/Proteins/Peptides
Nucleic acid TFNAs Antioxidant action through the [103]
Since individual miRNAs have pleiotropic effects, meaning they may signaling pathway Akt/Nrf2/
HO-I
control numerous genes and processes, it could be more beneficial to
target miRNAs associated with illness. Approach than single-target Heparin or CS hydrogels Improved wound healing of [93]
angiogenic growth factors. It has been recently shown that miR-26a is Bemiparin diabetes
a significant antagonist of angiogenesis in diabetic wounds; blocking
Spider silk Nanofibrous mats Effective matrix reconstruction [104]
this miRNA may be a useful diabetes treatment [49]. Wu and colleagues
fusion of AaSF in wounds
created PCN-miR/Col, a redox-modulatory hydrogel that is self- proteins
protective and strengthened by a ceria nanozyme. PCN-miR/Col guar­
anteed to maintain the pro-angiogenic miRNA’s structural integrity in
the oxidative milieu while also changing the oxidative wound micro­ gene carrier, β-CD-(D3)7, designed to effectively inhibit MMP-9
environment [91]. The “seed-and-soil” idea from the area of regenera­ expression, accelerate wound healing, and prevent organ damage and
tive medicine was incorporated into the design toprovide proangiogenic accumulation. The results suggest that this gene carrier could be utilized
miRNA signals to promote wound healing and tissue regeneration in to formulate a new topical treatment for diabetic wounds, as shown in
diabetics(“seed”) and to reshape the oxidative wound microenviron­ Table 3 [92].
ment into one that is pro-regenerative. The suggested “seed-and-soil” Cost and safety concerns still surround the use of genes and growth
approach can be used to regenerate and repair a variety of injured tissue factors, even if their purpose is to improve angiogenesis and re-
that has been exposed to malfunctioning biomacromolecules and highly epithelialization. Peptides have frequently been added to hydrogels or
oxidative sick microenvironments. Li et al. developed a novel siRNA scaffolds to give this Bioactivity of substrates for tissue engineering

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S. Sarthi et al. Journal of Clinical & Translational Endocrinology 37 (2024) 100366

Table 4 successfully promoted by Gingival mesenchymal stem cells (GMSCs)

Summary of Stem Cell/Exosomes towards effective control of diabetic wounds. added to the sponge made of chitosan and silk hydrogel [109]. Macro­
Cell type System Characterization Ref. phages M1, particularly M2, possess the capacity to safeguard and
regulate immune function as the body is mending. Through the pro­
SMCs exosomes Dressings for CS Overexpression exosomes of [121]
wounds microRNA-126-3p. duction of growth factors and anti-inflammatory cytokines like VEGF
and TGF-β, they also aid in reducing inflammation and promoting
ECM-free Biomimetic Without the use of a growth [122] angiogenesis and proliferation. This can expedite the diabetic chronic
biomimetic nanofibrous scaffolds factor. wound healing phase from inflammation to proliferation and remodel­
nanofibrous for the extracellular
matrix of bones
ing. Immune cells may cling to, grow, travel through, and regenerate on
97 different types of hydrogels.
Decellularized dECM hydrogels Genetically modified [123] Exosomes are membrane vesicles that are nanoscale and range in
Extracellular hydrogels. diameter from 30 to 150 nm. They are identified by the expression of
Matrix
exosome-associated markers such as Tgs101, Alix, CD9, CD63, and
M2 macrophage Hydrogels HHA Numerous pathways [124] CD81. They are also known to transport functional complexes of pro­
phenotype modulating angiogenesis teins, lipids, and nucleic acids [110–112]. Because of this, exosomes are
and immunocompromise. thought to be both natural RNA carriers for treating diseases and means
of delivering drugs [113–115]. Furthermore, one of the most important
ADSCs Cryogels GSL To enhance angiogenesis, [125]
ADSCs are delivered on
secretory products of bone marrow mesenchymal stem cells is believed
antioxidant GS scaffolds to be exosomes, which can promote intercellular communication and
coated with GSL, an help in the healing of wounds [116–118], and it can greatly enhance
endothelial basement human umbilical vein endothelial cells (HUVECs) motility, prolifera­
protein.
tion, and angiogenesis. FHE hydrogel based on polypeptides contains
MSCs RGO particles Acellular Dermal Composite [105] adipose-derived mesenchymal stem cell exosomes (AMSCs-exo) (F127/
Scaffold OHA-EPL). Multifunctional biological activity properties are provided
by FHE@exo hydrogel, in addition to injectability, self-healing, anti­
ASCs PEG-hydrogelized Allogenic ASC delivery in [106] bacterial activity, and exosome release. An injectable, thermosensitive,
gelatin vivo
multipurpose polysaccharide-based dressing (FEP) that promotes
hiPSCs Hydrogels AHA Constructing vascularized [126] angiogenesis and the healing of diabetic wounds was developed by
structures Wang et al. It also features a pH-responsive exosome release mechanism
that is maintained [119,120]. Exosome-based hydrogels hold significant
hASC exosomes hASC-exos using ASC-exos and miR-21 [127]
potential for the treatment of skin regeneration and chronic wounds,
electroporation to combined to provide
transport miR-21-5p synergistic therapeutic particularly those associated with diabetes. Consequently, they could be
as cargo effects utilized as a therapeutic tool in the future. Table 4 provides a summary
of the use of stem cells and exosomes for the effective management of
ASCs exosomes FEP clothing Adhesive, thermosensitive, [128] diabetic wounds.
injectable multipurpose
dressing
Drugs employed in the treatment of wounds in individuals with diabetes
GMCs exosomes Hydrogel sponge CS/ Combination of hydrogels [129]
Silk and exosomes produced In light of the clinical and pharmacological challenges associated
from GMSC
with diabetes-related wound infections, the optimal drug delivery
AMSCs exosomes Hydrogels OHA The bioactive [130] method should distribute the medication into the skin’s deeper layers.
multifunctional features When paired with the hydrogel/nanoparticle characteristics, The long-
include stimuli-responsive term release of drugs to the wound may be stabilized and healing pro­
exosome release, self- moted by the nanoscale local drug delivery system [131]. Currently,
healing, antibacterial
activity, and injectability.
several intricate delivery methods have been created to prolong the
duration that drugs are delivered [132–134]. A hybrid hydrogel of
polydopamine and nanocellulose that is multi-responsive and capable of
wound healing and medication release (tetracycline hydrochloride)
[93–95]. To encourage angiogenesis and speed up the healing of dia­ [135]. The drug may be delivered continuously for more than twenty-
betic wounds, Using peptide hydrogel with several domains, Carrejo four hours, and there is no explosive drug release at the beginning of
et al. incite a moderate inflammatory response and rapidly infiltrate the release process. With long-term drug delivery capabilities, the
cells [96]. Angiogenesis regulation and the promotion of diabetic ulcer greatest drug release ratio was 77 %. HIF-1α accumulation has been
healing are possible with a pro-survival peptide-engineered silk fibroin induced by deferoxamine (DFO), a medication that mimics hypoxia.
Nano sheet with therapeutic properties that bind integrin [97]. additionally, it has been demonstrated that HIF-1α is crucial for the
healing of wounds [136]. Hydrogel/scaffolds laden with DFO rapidly
Stem cells/exosomes induce angiogenesis for the regeneration of diabetic skin by upregulat­
ing HIF-1α [137–139]. Furthermore, when both bioglass (BG) and DFO
Stem cell therapy is one of the most promising therapies for diabetic are combined with When combined, sodium alginate hydrogel, BG, and
wounds since stem cells can create a range of bioactive compounds, DFO can increase the production of HIF-1α and VEGF, which will vas­
including growth factors to restore tissue/organ function [105–107]. cularize the wound sites and improve wound healing in diabetic skin
With the help of human ADSCs, or adipose-derived stem cells, and [140]. Hydrogels filled with drugs and cells have been used to treat
epidermal growth factor (EGF)-loaded microcapsules, the collagen wounds recently shown promise. Injectable hydrogels that are sensitive
hydrogel successfully restores blood perfusion and promotes tissue to both pH and glucose can be used to contain protein medications such
regeneration [108]. Hydrogels containing acrylate hyaluronic acid as insulin and living cells called fibroblasts [141]. This hydrogel patch
(AHA) are also used to treat type 1diabetes wounds using pluripotent promotes neovascularization and collagen deposition, which may has­
stem cells (hiPSCs). Furthermore, the skin wound healing process is ten the healing of diabetic wounds [142].

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S. Sarthi et al. Journal of Clinical & Translational Endocrinology 37 (2024) 100366

Table 5
Delivery of drug/natural macromolecular bioactive substances systems with effective control of chronic/diabetic wounds.
Drugs Drug delivery system Function Ref.

Deferoxamine (DMO) TDDS, scaffolds, nanofibrous materials, and Enhances the expression of HIF-I α and elevates that of VEGF. [138,139,143]
multifunctional hydrogels.

Ciprofloxacin Polymer sponges with cyclodextrin and CS There is no danger of toxicity to the body when local [133]
medications are released.

Insulin Hydrogels that are injectable Hydrogels that respond to both glucose and PH. [144]

Statins scaffolding for tissue engineering eNOS/NO up-regulation in situ. [145]

Curcumin Nanoparticles of chitosan and gelatin MMP9-responsive drug delivery system; antioxidant and anti- [146]
inflammatory.

Dimethyloxalylglycine (DMGO) Electrospun fibrous membrane with pores controlled release DMGO medication [147]

Snail glycosaminoglycan Polysaccharide sulfate increased the speed at which a full-thickness incision in diabetic [132]
mice healed.

Kirenol Diterpenoid Promote the growth of fibroblasts and angiogenesis [132]

Quercetin A scaffold made of collagen, nanomaterials, and Enhancing the formation of new blood vessels and collagen in [148]
drugs diabetic wound healing.

Herbal extract of Hydrogels Pdmaema-HA Increased cellular repair as well as improved cutaneous wound [149]
didymocarpuspedicellatus healing.

Drug load and release control can be achieved by optimizing certain Moreover, by adjusting the nanoparticle dispersion, medications that
aspects of hydrogels and composite scaffolds. Drugs are released in an are encapsulated might be supplied continuously and at a pace that is
“on-off” manner with long-term drug delivery performance when scaf­ appropriate for them [154]. Table 6 depicts the nanoparticle-based de­
folds/hydrogels are exposed to specific stimulation (pH or near-infrared livery for diabetic wound repair.
laser irradiation). This avoids explosive drug release at the start of the The utilization of topical delivery of Nanotherapeutics presents sig­
release phase. Precise administration, which may be attained progres­ nificant benefits for chronic wounds, like diabetic wounds. This is
sively as a wound is healing in different stages, should be the focus of our because (a) The medicinal substance is only applied temporarily or until
future study. Since hydrogels may transport more medications, growth the wound heals, and (b) Cell-type specificity and a variety of factorial
factors, peptides, and DNA which support angiogenesis and wound variables work together to effectively promote skin regeneration and
healingthey provide a promising new tool for wound healing research. wound healing. Smart nanomaterials based on nanotechnology include
Determining the optimal hydrogel breakdown rate and water content is liposomes, hydrogel, polymeric, inorganic, and lipid nanoparticles;
also essential to facilitate faster wound healing while maintaining sometimes known as nanofibrous formations. These nanoparticle-loaded
complex release and mechanical support for the wound bed. However, foams can contain extracellular substrates, peptides, growth factors, and
to attain high functional efficiency in terms of permeability, stability, antibiotics. To speed up the healing process, it is also possible to infuse
and therapeutic efficacy, more precise topical drug delivery systems two distinct therapeutic agents together that have different properties
must be designed. These systems could be integrated with 3D technology [155]. Oppositely, there are two possible ways that the drug might bind
due to the increasing issue of drug resistance and the specific physico­ to the surface matrix of nanoparticles: either it is absorbed, distributed,
chemical properties required. Table 5 details the delivery systems for or dissolves around the particle and becomes trapped in an aqueous core
drugs and natural macromolecular bioactive substances that effectively with surrounding shell-like structures [156]. The biological system will
manage chronic and diabetic wounds. release the medications contained in the nanoparticles by a combination
of dissolution, reduction, distension, and diffusion. Additionally, when
included with additional drugs in a nanocomposite system, nano­
Drug delivery system based on nanotechnology
particles can be encased in nanofiber, hydrogel, foam, films, and
nanocrystals. This enables a synergistic interaction between the target
Novel drug-delivery systems (DDSs) may enhance the efficacy of
medicine and the nanoparticles, leading to a unique concept for a wound
current and future therapies for these challenging clinical problems
dressing that promotes better wound healing [157]. These dressings
[150]. One of the most concentrated areas of study in recent times has
promote the adhesion and migration of keratinocytes and fibroblasts,
been nanotechnology therapy of diabetic patients and related issues. The
assisting in the re-epithelialization of wounds and the synthesis of
benefits of nanomaterials (which are between 1 and 100 nm in size) are
collagen. Their composition resembles theendogenous extracellular
their controllable size, adaptability in application, & physiochemical
matrix’s (ECM) topological appearance [158].
characteristics that may be tuned. Greater surface area to volume ratio
Nanomaterials can promote cell adherence and may be able to contain
Advanced technology
more surface functionalized active components to speed up particular
regeneration processes [151]. The benefits of using nanotechnology-
Many advances are currently widely used in the treatment of diabetic
based wound healing techniques include topical medication adminis­
wounds. Multifunctional scaffolds, layer-by-layer (LBL) approach, pho­
tration, cellular selectivity, as well as the controlled, steady release of
tothermal treatment (PTT), 3D printing technology, and hyperbaric
drug-encapsulated substances for the required amount of time until the
oxygen therapy are a few of them.
wound healing [152,153]. Nanoparticles are ideal for topical distribu­
tion in the context of wound healing because of their interactions with
the biological target and improved penetration at the wound sites.

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S. Sarthi et al. Journal of Clinical & Translational Endocrinology 37 (2024) 100366

Table 6 copper sulfide (CuS) in cow-like serum protein. Furthermore, pathogen

Nanoparticles and 3D printing technology for diabetic wound repair. Staphylococcus aureus as well as heat-resistant Escherichia coli and
Technology System Result Ref. ampicillin-resistant Escherichia coli may be successfully inhibited by
MoS2- BNN6. Although PTT based on nanoparticles holds a lot of
Nanoparticles pSi NPs Up to 7 days after [159] promise for treating diabetic wound infections, PTT therapy requires
treatment, FnAb-loaded careful investigation and particular clinical studies because the heat in
pSi NPs treated with the area can potentially gravely damage adjacent healthy tissue [159].
proteases exhibit intact
and functional
antibodies.
LBL self-assembly, or layer-by-layer technique

rGO and ADM-GO-PEG/ Improved wound [165,166] LBL self-assembly, or layer-by-layer is one of several straightforward
Que. healing by increased techniques that some biomaterials might use to enhance their biological
angiogenesis, collagen
properties. Biomedical uses the LBL self-assembly technology exten­
production, and
deposition. sively for distribution from a variety of material surfaces. Furthermore,
the LBL-modified composite material possesses high hydrophilicity,
CW/NPs/HBC-HG The substrate has [167] mechanical characteristics, and stability [160,161]. The LL self-
hydrogel; MEL-NPs; CS/ antimicrobial assembly technique is widely preferred due to its ability to transfer
PVA/ZnO nanofibrous properties and no
membranes; chitosan/ known cytotoxicity.
electrostatic force on the polyelectrolyte matrix surface with an
PVA nanofibers. opposing charge, thereby enhancing drug release continuously. Addi­
tionally, it is cost-effective, simple to operate, and controllable without
3D printing PU&dCA composite Not only permits the [168] any potential complications [162]. Furthermore, to produce fast dia­
dressing in four layers. movement of wound
betic wound healing, therapeutically appropriate amounts of siRNA may
exudates from the
wound bed to the be incorporated and released in a regulated manner via self-assembled
dressing but also nanometer-scale coatings. Thus, using LBL to change localized protein
permits the carefully expression levels has a big influence on treating site-specific diseases
regulated return of a like cancer, DFUs, heart disease, and transplant rejection.
fluid containing
bioactive ions to the
wound bed to promote 3D-printed
angiogenesis.
3D-printed structures for wound healing aim to address many ben­
Gel-pio inner layer and Show a high degree of [169]
efits: the ability to change attributes of layered wound dressings, such as
PCL hydrophobic outer water resistance and a
layer. high level of bacterial thickness, proximity, or hole value; dependable medicine stacking; the
adherence. use of a variety of materials; and O2 availability through a hollow
design. 3D printing advances were employed to build sodium alginate-
Patches with Control diabetic mice’s [170] polyethylene glycol structures by mixing different fixes with 1, 3, 4,
microneedles blood glucose levels for
up to 40 h in the
and 5 wt% of PEG on sodium alginate [163,164]. 3D printing platforms
normoglycemic range. have demonstrated outstanding antibacterial qualities, particularly
against high gram counts of pathogens [163]. This is outlined in Table 6,
Nanofibers oriented Collagen deposition, [171] which details the application of 3D printing technology for diabetic
either vertically or angiogenesis, and
wound repair.
radially combined with granulation tissue
BMSCs. development are all
improved. Negative pressure wound healing

SA/PEG scaffold filled 3D-printed scaffolds [172] Negative pressure was applied to injuries in 1997, and NPWT was
with Saturejacuneifolia have demonstrated a
strong antimicrobial
first implemented in the USA. These devices have the potential to
impact. enhance blood flow, preserve a moist wound environment, remove
exudate from the site, apply pressure to encourage wound healing and
provide additional benefits that may be deficient in wounds caused by
Gelatin cryogels filled In vivo, the substrate [170]
diabetes [166]. Specifically for complex surgical wounds, NPWT has
with silver comprise the was able to encourage
upper layer, while 3D- angiogenesis, collagen shown to be an interesting and emerging use. This innovative technique
printed scaffolds loaded deposition, granulation may promote healing and reduce the size of wounds. NPWT entails
with PDGF-BB comprise tissue development, and connecting a wound filler to a vacuum source to apply negative pressure
the lower layer. re-epithelialization. to the area of the wound. The use of a computer-controlled retraction
device, which continuously injects saline and an antiseptic or antibiotic
solution into the wound, is one novel advancement in NPWT. This
Photothermal therapy modification enhances the therapeutic potential of NPWT by making it
simpler to transport advantageous chemicals to the wound site specif­
Treatment for chronic wounds with photothermal therapy (PTT) is ically [167].
one therapeutic method used. Specifically engineered nanoparticles
interact with a near-infrared (NIR) laser to produce localized heat. Hyperbaric oxygen therapy
Challenge wound healing can be aided by PTT’s ability to specifically
cause cell death in the region of nanoparticles by utilizing this thermal Hyperbaric oxygen is used in wound healing because, among other
energy. The bio-mineralization approach of joining BSA-CuS nano­ things, it stimulates angiogenesis, increases security, and encourages the
particles demonstrated bactericidal properties near-infrared for wound formation and multiplication of fibroblasts. That being said, there has
healing, demonstrating the presence of bovine serum albumin (BSA) and been significant discussion over the applicability of these guidelines
because they have not even remotely proven to be accurate.

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S. Sarthi et al. Journal of Clinical & Translational Endocrinology 37 (2024) 100366

Table 7
Clinical trial on diabetic wounds.
Country Identifier Study title Phase Sponsor/ collaborator Status

Mexico NCT03782155 HMB and Glutamine Supplementation’s Effect on Bloody Area Phase 4 Hospital General de Withdraw
Wound Healing Mexico

Florida NCT00967837 Effects of Pulsatile Intravenous (IV) Insulin Phase 2 Florida Atlantic Interventional
on Wound Healing in Diabetics (wounds) Phase 3 University

Indianapolis, NCT00777712 Mechanisms Underlying Impaired Diabetic Wound Healing Phase 2 Dr. Sashwati Roy, Observational
Indiana Indiana University
(Responsible Party)
Lund, Sweden NCT05608187 The Impact of HMB and Glutamine Supplementation on the Phase 2 Ilya Pharma Interventional
Healing of Bloody Area Wounds (Responsible Party)
North Carolina NCT06028386 Diabetic Foot Ulcers and the AC5® Advanced Wound System Not Applicable Arch Therapeutics Interventional
(Responsible Party)
Singapore, NCT03863054 A Clinical Trial with Observational Design Investigating the Not applicable Singapore General Observational
Impact of Topical Oxygen Therapy (NATROXTM) on the Hospital
Healing Rates of Chronic Diabetic Foot Ulcers
Giza, Egypt NCT05517863 The Impact of Infrared and 650 nm Combined Laser on the Not applicable Heidy F. Ahmed, Cairo Interventional
Surface Area of Chronic Diabetic Foot Ulcers: (wounds) University

Guntersville, NCT04450693 Human umbilical cord cryopreserved (TTAX01) for advanced, Phase 3 Tissue Tech Inc. Interventional
Alabama, united complicated, non-healing diabetic foot ulcers (AMBULATE
states DFU II)

Arizona NCT03230175 Phase 2 Pilot Study of Participants Receiving Standard Care Phase 2 Tissue Tech Inc. Interventional
Phoenix, Arizona and Cryopreserved Umbilical Cord Allograft for Complex Non-
Sylmar, Healing Diabetic Foot Ulcers (TTAX01)
California
Mashhad, razavi NCT05850611 The Impact of Oral MB and PRP-FG Combination Therapy on Daryoush Hamidi Early Phase 1 Interventional
Khorasan, Iran, Patients with Diabetic Foot Ulcers That Don’t Heal Alamdari, PhD, Mashhad
Islamic University of Medical
Sciences
Indianapolis, NCT05191758 Nutritional Regulation of Leukocyte Function (FPP Dr. Sashwati Roy, Indiana Not Applicable Interventional
Indiana, United Supplement) University
States
Vista, California, NCT04207099 Comparing X vs. Standard of Care (WAR) for Wound Area MolecuLight Inc. Not Applicable Observational
United States Reduction of Non-healing DFUs Using MolecuLight

Importantly, restricted oxygen supply is ineffective, hence this proced­ nucleic acid, and gene therapy, alongside innovations in 3D printing
ure is carried out on patients in a hyperbaric oxygen chamber [168,169]. technology and layer-by-layer (LBL) self-assembly techniques, holds
Current study suggests that in wounds where an ischemic diabetic ulcer significant promise for diabetic wound treatment. Effective delivery of
has exhibited hypoxia, hyperbaric oxygen therapy should be considered. small interfering RNA (siRNA) necessitates adept gene vector systems.
A scientific initiative is currently being conducted to explore these issues This comprehensive review elucidates the intricate pathophysiological
by comparing hyperbaric oxygen therapy with modern wound care underpinnings of diabetic wounds, including diminished angiogenesis,
techniques to prevent amputations in non-healing ulcers in individuals elevated reactive oxygen species levels, and compromised immune re­
with diabetes. This observation was no longer suitable for evaluating sponses. Furthermore, it explores recent advancements in nucleic acid
outcomes such as amputation [170,171]. delivery, targeted gene therapy, advanced drug delivery systems,
negative pressure wound therapy (NPWT), hyperbaric oxygen therapy,
Clinical trials and ongoing clinical trials. By synthesizing recent research insights, the
review proposes innovative strategies aimed at enhancing the multi­
Certainly, clinical trials focusing on diabetic wound healing are faceted management of diabetic wounds, thereby fostering improved
crucial for advancing medical treatment in this area. These trials typi­ therapeutic outcomes in the future.
cally aim to evaluate the effectiveness and safety of various in­
terventions or treatments designed to improve wound healing in CRediT authorship contribution statement
individuals with diabetes. Here’s a generalized outline of how such a
clinical trial might be structured shown in Table 7. Soniya Sarthi: Writing – original draft. Harish Bhardwaj: Writing –
review & editing, Conceptualization. Rajendra Kumar Jangde: Writing
Conclusion – review & editing, Visualization, Supervision, Formal analysis,
Conceptualization.
In conclusion, the escalating prevalence of diabetic wounds presents
a formidable medical challenge, characterized by heightened risks of Declaration of competing interest
infection and delayed healing, ultimately contributing to elevated
mortality rates, amputations, and impaired mobility. To address these The authors declare that they have no known competing financial
challenges, researchers have increasingly turned to advanced bioactive interests or personal relationships that could have appeared to influence
molecules such as genes, growth factors, proteins, peptides, stem cells, the work reported in this paper.
and exosomes, harnessing targeted gene therapies as a preferred strat­
egy. Additionally, the amalgamation of photothermal therapy (PTT),

11
S. Sarthi et al. Journal of Clinical & Translational Endocrinology 37 (2024) 100366

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