AAPS PharmSciTech (2023) 24:155

https://doi.org/10.1208/s12249-023-02616-6

REVIEW ARTICLE

Therapeutic Potential of Nanocarrier‑Mediated Delivery

of Phytoconstituents for Wound Healing: Their Current Status
and Future Perspective
Mohit Kumar1 · Puja Keshwania2 · Shruti Chopra3 · Syed Mahmood4 · Amit Bhatia1

Received: 15 May 2023 / Accepted: 1 July 2023 / Published online: 20 July 2023
© The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists 2023, corrected publication 2023

Abstract
The treatment of wounds is a serious problem all over the world and imposes a huge financial burden on each and every nation.
For a long time, researchers have explored wound dressing that speeds up wound healing. Traditional wound dressing does not
respond effectively to the wound-healing process as expected. Therapeutic active derived from plant extracts and extracted bioac-
tive components have been employed in various regions of the globe since ancient times for the purpose of illness, prevention,
and therapy. About 200 years ago, most medical treatments were based on herbal remedies. Especially in the West, the usage of
herbal treatments began to wane in the 1960s as a result of the rise of allopathic medicine. In recent years, however, there has been
a resurgence of interest in and demand for herbal medicines for a number of reasons, including claims about their efficacy, shifting
consumer preferences toward natural medicines, high costs and negative side effects of modern medicines, and advancements in
herbal medicines brought about by scientific research and technological innovation. The exploration of medicinal plants and their
typical uses could potentially result in advanced pharmaceuticals that exhibit reduced adverse effects. This review aims to present
an overview of the utilization of nanocarriers in plant-based therapeutics, including its current status, recent advancements, chal-
lenges, and future prospects. The objective is to equip researchers with a comprehensive understanding of the historical background,
current state, and potential future developments in this emerging field. In light of this, the advantages of nanocarriers based delivery
of natural wound healing treatments have been discussed, with a focus on nanofibers, nanoparticles, nano-emulsion, and nanogels.

Keywords biomaterial · nano-carriers · phytoconstituents · wound healing

Introduction
Wound evaluation has always been difficult, even outside of
the realm of medicine. Wounds often cause not just increased
morbidity but also severe death. Any serious cracks to the
skin may cause changes in the body’s structure and function,
and these are medically referred to as wounds [1, 2]. This
crack may spread to the underlying muscle, tendon, nerve,
Mohit Kumar, Puja Keshwania have equal contribution.
* Amit Bhatia
dramitbhatia04@gmail.com
1
Department of Pharmaceutical Sciences and Technology,
Maharaja Ranjit Singh Punjab Technical University
(MRSPTU), Bathinda 151001, Punjab, India
2 4
Department of Microbiology, Maharishi Markandeshwar
Institute of Medical Sciences and Research, Mullana,
Ambala, Haryana 133207, India
vessel, or artery as well as the bone. The skin is the chief
organ of body and hence one of its most vulnerable parts
due to its susceptibility to trauma, surgical incisions, and
burns [3]. Acute wounds show clear evidence of recovery
within 4 weeks; however, chronic wounds do not show typi-
cal progression through the healing stages and recovery is
not apparent within this time frame. One of the most compli-
cated processes in multicellular organisms is wound healing,
which occurs in four stages known as the hemostasis/inflam-
matory phase, the proliferation phase, and the remodeling
phase [4, 5]. An imbalance in any of these stages may cause
3
Amity Institute of Pharmacy, Amity University, Noida,
Uttar Pradesh 201313, India
Department of Pharmaceutical Technology, Faculty
of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur,
Malaysia

13
Vol.:(0123456789)
155 Page 2 of 26
hypertrophic scarring or keloid formation [6], both of which
are undesirable. Local wound variables, systemic mediators,
any underlying illness, and the nature of the injury all play a
dynamic role in the healing process [7]. Clinical guidelines
suggest that using sutures, clips, or skin adhesive to close
wound borders is the main goal of wound healing. When
the wound’s margins are inaccessible, the secondary goal is
to allow connective tissue to gradually fill up the deficiency
while the wound remains open. These types of wounds take
a long time to heal and are prone to infection. Those with
underlying diseases, including diabetic or pressure ulcers,
and the patients with post-surgical wound infections, hema-
tomas, or mechanical strain, are particularly at risk. The third
kind of intention is called “delayed main intention,” and it
entails leaving the incision open until the non-viable tissue
has been removed owing to infection or contamination [8].
Classification of Wound
Acute wounds range from those caused by surgery to those
caused by bites, burns, abrasions, and even severe traumatic
lacerations or those produced by a crush or gunshot. Acute
wounds may also be caused by minor cuts and abrasions. It
is common knowledge that acute wounds, regardless of the
kind of cutaneous damage, may be expected to heal within
a period of time that is predetermined. However, the healing
therapy that is decided upon will be altered in accordance
with the kind of wound, the location of the damage, and the
depth of the wound. For the primary closure of a clean surgi-
cal wound, little intervention is required in order to facilitate
the natural and expedient progression of the healing process.
However, in the case of serious traumatic injury, such as a
gunshot or a burn wound, the presence of devitalized tissue
as well as infection with non-viable and viable foreign mate-
rial necessitates surgical debridement as well as antimicro-
bial treatment. Because of this, the healing process may go
through its normal stages, which include inflammation and
granulation, before reaching its conclusion in the form of re-
epithelization and remodeling. Chronic wounds, on the other
hand, are almost often caused by endogenous processes as
a result of a predisposing condition that, in the end, impairs
the dermal and epidermal tissue integrity [9].
The Chronic Wound Microbiology
The primary challenge that is associated with chronic wound
is susceptibility to bacterial infection. Some bacteria may
speed up the healing process of wounds. On the other hand,
it would seem that the way in which the presence of the bac-
teria interacts with the patient and defines how it affects the
wound healing process. Clinicians should distinguish wound
contamination, colonization, and infection.
13
AAPS PharmSciTech (2023) 24:155
Contamination of Wounds
Any wound contaminated for a long time by the pollutants.
These pollutants originate from the native microbiota or the
environment, whichever comes first.
Wound Colonization
The presence of growing bacteria without a reaction from the
host, is known as colonization. The majority of these species,
such as Staphylococcus epidermidis and other coagulase-neg-
ative bacteria, are considered to be typical skin microbiota.
Species of Staphylococcus, Corynebacterium, Brevibacterium,
and Pityrosporum, as well as Propionibacterium acnes [9].
Infection of the Wound
At this stage, the growing bacteria entered not only the sur-
face of the wound but also the deeper, healthy living tissue on
the perimeter of the wound, which prompted a reaction from
the host. “Escherichia coli (E. coli), Proteus, Pseudomonas,
Acinetobacter, and Stenotrophomonas (Xanthomonas) Staphy-
lococcus aureus (S. aureus) and beta-hemolytic Streptococcus
(Streptococcus pyogenes, Streptococcus agalactiae)” are the
primary bacteria [10]. It has been shown that the normal skin
microbiota predominates in the early stages of acute wounds.
S. aureus and β-hemolytic streptococcus are coming up next.
These are some of the organisms that are often discovered in
diabetic foot ulcers. Around the fourth week after the injury,
facultative anaerobic gram-negative rods such Proteus, E. coli,
and Klebsiella will begin to colonize the wound [11–13].
Wound Healing Process
The dynamic process of wound healing is a superb illustra-
tion of the interplay between our body systems and the wound
care products, we use to restore their function and health.
However, how precisely does our body repair itself? After an
injury to the skin, our body initiates a sequence of processes
that are often mentioned as the “cascade of healing” in order
to restore the wounded tissues. This process begins imme-
diately after the injury occurs. Hemostasis, inflammation,
proliferative, and maturation are the four overlapping steps
(Table I) that make up the healing cascade [14–16].
Biomaterial Used in the Management
of Wound
Wound repair often involves the use of biopolymers, which
are polymers that are created by utilizing living microor-
ganisms. However, it would seem that some polymers get
AAPS PharmSciTech (2023) 24:155 Page 3 of 26 155

Table I  Phases of wound healing

Phase Comments References

Phase 1: hemostasis phase In this phase, the body engages the blood clotting mechanism to restrict drainage. Platelets engage [15, 17]
collagen, activating and aggregating them. An enzyme called thrombin forms a fibrin mesh that
reinforces platelet aggregates into a solid clot
Phase 2: inflammatory phase In this phase, neutrophils eliminate microorganisms and clear debris. These cells achieve their maxi- [18]
mal population 24 to 48 h after damage and decline after three days
Phase 3: proliferative phase After the wound is cleansed, it enters Phase 3, proliferative phase, where it is filled and covered. [19]
Proliferative has three stages: (1) wound filling; (2) wound boundary contraction; and (3) wound
coverage (epithelialization)
Phase 4: maturation phase In maturation, new tissue gains strength and stretchability. The collagen fibers rearrange, the tissue [20]
remodels and develops, and tensile strength increases. The maturation period of a wound may
range anywhere from 21 days to 2 years

more attention than others when used as wound dressings.
Dressings for wounds have to be made in such a way as
to assist and speed up the process of healing. This objec-
tive may be accomplished by shielding the wound from
aggravating factors such pollution and loss of moisture,
both of which can slow down or impede the healing pro-
cess. Films, fibers, and hydrogels made from synthetic and
natural polymers, as well as mixtures of these materials
are utilized in wound dressings. The perfect wound dress-
ing should have good oxygen permeability, but more sig-
nificantly, it should replicate the structural and biological
properties of the skin’s extracellular matrix (ECM).
Natural Polymers in Wound Healing
In most cases, naturally occurring polymers are preferred
over synthetic polymers for the treatment of wounds because
naturally existing polymers are more cost-effective, non-
toxic to the human body, and environmentally benign
(Fig. 1). Polysaccharides are a kind of naturally occur-
ring polymer that is often used in the medical industry as
a wound dressing material. Some of most common types
of polymers used in the wound dressing include cellulose,
chitosan, starch, hyaluronic acid, and alginate are also often
employed.
Chitosan
Chitosan (CS) is a natural polymer that has been researched
extensively and is commonly utilized in biomedical claims
due to its capability to impede the growth of microorgan-
isms and to stimulate the body’s natural healing processes.
Chitosan’s unique features, such as biocompatibility, bio-
degradability, and non-toxicity impact, are responsible for
its wound healing action. The healing process may be sped
up with the help of chitosan since it stimulates cell growth,
blood vessel formation, and extracellular matrix (ECM)
creation [21]. Additionally, it facilitates drainage, stops the

Fig. 1  Natural polymer-based HO OH

wound healing
-O

OH

O O

OH

Alginate Chitosan Hyaluronic acid

OH
O
O O O
H H
C N CH C NH CH C N CH C N
O O CH2 H CH2 H
O OH H H H
N HC C N C C N CH2 CH2 C NH CH C
CH3 H CH2 O O
HO OH C O
C
NH O-
C NH2
O
NH2
HO

Cellulose Gelatin

13
155 Page 4 of 26
accumulation of exudates, and acts as a bed for autograft-
ing when used in wound care. In addition, CS encourages
gas exchange, which is a crucial component of the process
by which wounds heal [22–26]. There is a wealth of infor-
mation in the literature on CS-based delivery methods for
wound treatment. This innovative polymer might hold the
answer for the treatment of acute and chronic, whether in
the form of wound dressings or hydrogels, nanoparticles or
microparticles containing CS, or any combination of these.
CS may produce gels in acidic environments due to its
chemical characteristics. The created Three-dimensional
(3D) network structure when exposed to aqueous media
is an excellent property for CS utilized as wound dress-
ings [26]. The hydrogels show strong swelling behavior
by absorbing a substantial quantity of water. Because of
their biocompatibility and antimicrobial action, CS-based
hydrogels have seen extensive use in wound healing. For
instance, Ferreira et al. created and studied a chlorhexidine
(2% and 4%)-associated CS gel system. S. aureus was used
in a study to demonstrate the hydrogel system’s antibacterial
and healing characteristics, and it was shown to suppress
bacterial growth by a whole 100%. Histological examination
on the 14th day after treatment with CS hydrogel contain-
ing 2% chlorhexidine in animals showed that the wounds
had healed. All other lesions were closed by the 14th day
in the 4% chlorhexidine groups, indicating superior healing
[27, 28]. These findings suggest that a promising substance
with antibacterial capabilities has been created for use in
medicine. To improve wound healing activity in an exci-
sion wound model, Mukherjee et al. [29] created hydrogel
dressings via interpolymeric complexation. Sodium alginate
and polyvinyl alcohol were combined with CS in varying
proportions to create crosslinks. Hydrogel dressing effec-
tiveness was determined by measuring the total healing time
of wounds produced on the dorsal surface of rats using a
biopsy punch. CS and sodium alginate-based formulations
were found to have the highest water vapors transmission
value in hydrogel characterization studies. Hydrogels com-
posed of CS and polyvinyl alcohol showed impressive ten-
sile strength. Within 15 days, Pluronic F68 and CS hydrogels
demonstrated a faster rate of wound healing than alternative
formulations. Hydrogel dressings made from a mixture of
CS and hydrophilic polymers were shown to be effective in
treating wounds.
The primary drawbacks that restricted the usage of CS-
based hydrogel were its poor mechanical qualities and
unsatisfactory efficacy against microorganisms. As a result,
a great number of research organizations are focusing their
efforts on the use of CS in conjunction with other polymers
in an effort to further improve its hydrophilic nature, boost
its antibacterial impact, and improve its mechanical quali-
ties. Yao et al. [39] created CS-based hydrogels by grafting
poly (acrylic acid) and poly (hydroxyethyl methacrylate). To
13
AAPS PharmSciTech (2023) 24:155
boost the wound healing effect, the epidermal growth factor
(EGF) was also added into the hydrogels. The hydrophilicity
of hydrogels was shown by their physical characterization,
which also demonstrated that they had acceptable wound
dressing capabilities. According to the findings of the bio-
logical characterization experiments, the thrombogenic and
antibacterial characteristics of the CS-based hydrogel are
still present. The EGF-incorporated hydrogel system has
a greater wound healing rate than conventional dressings,
according to an experiment that was conducted in vivo to
study the healing of wounds [30].
Gelatin
Gelatin’s film-forming ease, air-permeability, biocompatibil-
ity, non-toxicity, and hemostatic properties make it an excel-
lent wound dressing. Because of this, Tavakoli et al. created
a crosslinked foam from starch and gelatin using borax. The
antibacterial activity of erythromycin was increased when
it was taken at its optimum concentration. Their findings
demonstrated that foams, owing to their porous shape, high
swelling capacity, and minimal cytotoxicity in L929 cells,
may be used as wound coverings. The inclusion of borax
also increased mechanical strength and changed eryth-
romycin release in the foams. In particular, erythromycin
was shown to be released in less than 3 h when using low
borax density, however drug release was regulated by raising
borax concentration to 40% [31]. In another research, gelatin
microspheres were utilized to transport neurotensin, a neuro-
peptide with wound-healing properties that are particularly
useful for the treatment of diabetic foot ulcers. To speed up
the healing process, neurotensin was infused into silk fibroin
(SF) scaffolds made from gelatin microspheres. The scaf-
folds' porous structure makes them well-suited for regenerat-
ing damaged tissue, while gelatin microspheres release the
drug in controlled manner. Furthermore, the composite scaf-
fold showed encouraging outcomes in terms of macroscopic
healing, fibroblast, collagen deposition, and expression, at
the wound site [32]. As a therapy for diabetic foot ulcers, the
aforementioned scaffolds are highly recommended.
Other Natural Polymers
Scientists are investigating not just CS, but also other natural
polymers that show promise for use in the development of
competent wound dressings. It is fair to say, nevertheless, that
most of the investigations use some kind of natural polymer
mixture. If you are looking for a renewable polymer, cellulose
is by far the most common. The advantages of the biopoly-
mer bacterial cellulose (BC) include its purity, high porosity,
and good biocompatibility. In addition, BC is amenable to
modification to acquire antibacterial activity and potential
local drug delivery characteristics [33]. Wound dressings of
AAPS PharmSciTech (2023) 24:155
alginate (AG), an anionic biopolymer extracted from brown
seaweed, provide a moist environment and prevent bacterial
infections, both of which are crucial for wound healing [34].
Collagen stimulates cellular migration and aids in the forma-
tion of new tissues. Wound healing is facilitated and influ-
enced by collagen-based biomaterials because these materials
attract and encourage the activity of particular cells, such as
macrophages and fibroblasts [35]. It is a glycosaminoglycan
called hyaluronic acid (HA) that is abundant in the skin and
other elastin-rich connective tissues. During inflammation,
wound healing, and embryonic development, HA facilitates
cell adhesion and differentiation and plays a crucial role in
preserving tissue integrity. Because of its potential benefits
in combination with its biocompatibility and biodegradabil-
ity, HA has been included into a variety of wound dressings
intended for human medicinal use [36].
Synthetic Polymers in Wound Healing
The usage of synthetic polymers such as “poly (ethylene
glycol) (PEG), poly (vinyl alcohol) (PVA), poly (lactic-co-
glycolic acid) (PLGA), and poly(caprolactone) (PCL)” are
widespread. Wound dressings made from synthetic poly-
mers are (Fig. 2) suitable biomaterials due to their excel-
lent biodegradability and biocompatibility, and the presence
of active groups (-OH), which may be covalently coupled
or conjugated with various receptors to enhance cellular
absorption and circulation time to RES [37, 38]. A variety of
polymers, including micro- and nano-particles, electrospun
fiber structures, etc., are used as wound dressings, whether
the wound is acute or chronic. Antibiotics and growth hor-
mones are common additions to polymeric formulations.
Fig. 2  Synthetic polymers used
in wound healing
Poly (lactic-co-glycolic acid)
Poly-lactic acid
Page 5 of 26 155
Polyvinyl Alcohol
Polyvinyl alcohol (PVA) is a hydrogel that is neutral in pH
and has excellent biocompatibility, hydrophilic qualities,
and biomechanical capabilities. Because PVA can readily
create hydrogels and is commonly utilized in applications
that need controlled release, it has recently gained traction
as a candidate for use in wound dressing [39]. During the
review of the relevant literature, it was discovered that PVA
electrospun fibers were present. In addition, this method of
producing structures that resemble the extracellular matrix
is the most straightforward and illustrative way to do it. In
addition to nanofibrous systems, PVA hydrogels and NPs are
also quite common in the published research on this topic.
Honey with an integrated AG/PVA-based electrospun
nanofibrous membrane was created by Tang et al. for the
purpose of developing an effective wound dressing mate-
rial. Increased honey content in the nanofibrous membranes
resulted in higher antioxidant activity, demonstrating the
capacity to limit the overproduction of reactive oxygen spe-
cies. In addition, the honey-loaded nanofibers’ antibacterial
efficacy against S. aureus and E. coli was enhanced. This
was demonstrated by the fact that both of these bacteria were
inhibited by the honey loaded nanofibers [40]. The utiliza-
tion of Carica papaya included PVA-mixed gelatin nanofib-
ers was also investigated by a separate group. The scaffolds
exhibited remarkable antibacterial activity against both the
E. coli and S. aureus bacteria that were tested. In addition,
the nanofibrous membranes did not exhibit any cytotoxicity
against fibroblast cells (NIH 3T3), suggesting that they are
suitable for use as wound healing agents without the risk of
adverse effects [41].
Poly (caprolactone)
Polyvinyl alcohol
13
155 Page 6 of 26
Poly‑lactic Acid and Poly (Lactic‑co‑Glycolic Acid)
Other aliphatic polyesters reported in the literature as potential
wound dressing options include PLA and PLGA. PCL is the
only exception. Due to the fact that it is cyto-compatible and
biodegradable, polylactic acid (PLA) has emerged as a sig-
nificant candidate for use in a variety of biomedical applica-
tions, including drug delivery systems, gene transfer, surgical
sutures, tissue engineering, and regenerative medicine [42,
43]. A copolymer known as PLGA is produced when polylac-
tic acid (PLA) and poly (glycolic acid) (PGA) are combined
[44]. The biocompatibility, mechanical strength, and other
properties of this copolymer are all above average. In addition,
the rate of deterioration and the mechanical characteristics
of PLGA may be controlled to a certain extent, depending
on the application. In addition, the breakdown rate of PLGA
is shown to be synchronized with the epithelization rate and
further the healing process when it is employed as dressing
materials [37]. This heals the wound more quickly.
Electrospun nanofibrous dressings made from PLA and
PLGA, are more effective than PCL-based wound dress-
ings. On the other hand, the aforementioned polymers are
often combined with a number of other macromolecules. For
instance, PLA was mixed with poly (ethylene succinate) so
that it may be used to create topical mats for the treatment
of skin infections caused by fungal species. The first findings
were encouraging, thus the authors advocated using the topical
mats in additional wound healing research [45]. PLA and poly
(1, 8-octanediol-co-citric acid) (POC) have been used as raw
materials in the production of elastic nanofibrous membranes
manufactured using electrospinning. As a result of their phys-
icochemical characteristics, the mixture that is composed of
75% PLA was chosen to act as the drug carrier for aspirin. The
authors have a firm conviction that the film containing aspirin
may function admirably as a carrier for wound applications
[46]. Electrospun polylactide: poly (vinyl pyrrolidone)/polylac-
tide: PEG core–shell fibers coated with antimicrobial peptides
were also developed by Li et al. for the purpose of treating
burns effectively. The produced dressings demonstrated bio-
compatibility by allowing fibroblasts to attach and proliferate
inside them. The authors assert that the presence of PLA beads
imitate the structure of lotus leaves, and that the fascinating
architecture has a superhydrophobic feature, which leads to the
suppression of foreign bacteria and other pathogens. In a simi-
lar manner, electrospun polylactide: poly (vinyl pyrrolidone)/
polylactide: PEG core/shell fibers filled with bioactive com-
pounds were produced into a functional wound dressing for the
effective treatment of burns. The super-hydrophobic surface,
which resembled a lotus leaf and was loaded with medicines
in the fibers, demonstrated desired antibacterial activity. It is
possible to say that the production of surfaces with hierarchi-
cally organized features has better mechanical strength as well
as excellent wound exudate absorption [47].
13
AAPS PharmSciTech (2023) 24:155
Poly(Caprolactone)
Poly(caprolactone) (PCL) is an aliphatic polyester that finds
widespread usage in the pharmaceutical industry as a result of
its excellent biocompatibility, bio-degradability, and mechani-
cal qualities [48, 49]. The vast majority of aliphatic polyesters,
however, have a high hydrophobicity and a high crystallinity,
which prevents them from being used as wound dressing mate-
rials. In order to over this issue that were caused by PCL, poly-
chloroethylene is often mixed with substances that are hydro-
philic in nature [22]. A great number of studies looked at the
possibility of using PCL as a wound dressing material [50–54].
PCL is a hydrophobic substance that is also biocompatible, as
was just explained. So many investigations have concentrated
on PCL electrospun fibers or micro- or nano-particles that
contain active substances such as growth factors or antibiot-
ics [55–57]. Alternatively, these studies employ PCL blends
with hydrophilic polymers such as CS, PEG, etc. Many studies
examine the wound healing effect of PCL when employed with
extracts from medicinal plants or other natural components
[55, 58, 59]. Egri et al. developed Hypericum perforated oil
loaded electrospun PCL fibers with the knowledge that the oil
has a curative impact on the process of wound healing. Nev-
ertheless, the dressing was comprised of two layers: the first
layer was made of PCL in order to preserve the membrane’s
integrity and the mechanical strength of the dressing; the sec-
ond layer, which was intended to be applied to the wound, was
formed by electrospraying and electrospinnig. According to
the findings of the research, the dressing has both an intrigu-
ing antibacterial activity and a high biocompatibility, both of
which are features that are fairly significant for the treatment
of wounds [60]. Some examples of polymers that are used in
nano-formulation for wound healing is shown in Table II.
Natural Actives in Nanocarriers
Therapeutic active derived from plant extracts and extracted
bioactive components have been employed in many parts
of the globe since ancient times for the purpose of illness
prevention and therapy [81]. Herbal medications include any
preparation made from plants that is intended to promote
or restore health [82]. About 200 years ago, most medical
treatments were on herbal remedies. Especially in the West,
the usage of herbal treatments began to wane in the 1960s
as a result of the rise of allopathic medicine [83]. In recent
years, however, there has been a resurgence of interest in
and demand for herbal medicines for a number of reasons,
including claims about their efficacy, shifting consumer pref-
erences toward natural medicines, the high costs and nega-
tive side effects of modern medicines, and advancements
in herbal medicines brought about by scientific research
and technological innovation [84]. Research into medicinal
AAPS PharmSciTech (2023) 24:155 Page 7 of 26 155

Table II  Examples of polymers utilized in nano-formulations for wound healing

S. no Natural/synthetic polymer Formulation type Special comments References

1 Chitosan Nanocomposite films Nanocomposite films had a higher swelling index, and lower tensile [61]
strength, than CS film. Moxifloxacin permeability from the films was
above 60% in 24 h. This research showed that CS nanocomposite
films had antibacterial capabilities and used as wound dressings
2 3D hydrogel 3D hydrogels had dimensional integrity, skin adhesion, and water [62]
absorption. These findings suggest they might absorb exudates and
keep wounds moist. This research found 3D-printed hydrogel to be a
good wound treatment
3 Hydrogels Antimicrobial and antioxidant activity in the loaded hydrogels was [63]
significantly increased, making them a better choice as a wound
dressing. In addition, the hydrogel maintains a steady release of
Ag-NPs for at least 7 days. According to the results shown above, the
produced hydrogels exhibit fairly promising features crucial to the
healing of chronic diabetic lesions
4 Polymeric film The antibacterial action of CS against E. coli was boosted when CP [64]
was added to the formulation of the film. Last but not least, it was
discovered that the proliferation of human fibroblast cells was accel-
erated over the course of 7 days, which demonstrated that the created
films did not have any detrimental effects on healthy cells
5 Nanocomposite NPs in CS subjected to freezing and thawing. The produced PVA [65]
hydrogels loaded nanocomposite hydrogels loaded with CS NPs shown enhanced
with CS NPs mechanical strength and swelling capabilities, outstanding barrier
(nanoparticles) activity. As a result, the produced nanocomposites provide for an
excellent wound dressing
6 Polyvinyl alcohol Nanofibers The nanofiber stimulated the functional regeneration of the dermis as [66]
well as the repair of differentiated adipocytes. The sponge has been
shown to endorse wound healing and lessen the formation of scar
tissue in studies conducted in vivo with model mice. The produced
nanofibrous sponges are extremely auspicious for future wound
applications due to the fact that they are simple to make and exhibit
considerable wound healing characteristics
7 Hydrogels An impressive degree of hydrophilicity and swelling behavior was [67]
shown by the synthetic porous mat. After determining that the PVA
hydrogel was highly cytocompatibility with mammalian cells, the
scientists loaded the hydrogel with gentamicin to enhance its bacte-
riostatic capabilities
8 Hyaluronic acid Hydrogels Hydrogels made with varying amounts of HA displayed either a [68]
porous or fibrous structure. Furthermore, HA enhances hydrophilic-
ity and water vapor transfer, both of which are crucial for wound
healing agents
9 Film The films were found to be non-cytotoxic to L929 fibroblast cells [69]
while exhibiting potent antibacterial action against S. aureus, E. coli,
and S. epidermidis. Application of the Wistar rat skin model demon-
strated a hastening of the wound healing process. The resultant film
has the potential to be used in wound care
10 Scaffold The porous scaffolds were soft and elastic, with increased mechanical [32]
strength and thermal stability. NIH-3T3 fibroblasts adhere, thrive,
and proliferate in composite scaffolds. A full-thickness burn model
in rats showed better re-epithelization and extracellular matrix
remodeling. The aforementioned findings may offer an alternate
wound dressing
11 Poly (caprolactone) Nanofibers The prepared PCL nanofibers showed excellent anti-microbial as well [70]
as wound healing activity
12 Nanofiber scaffolds These produced membranes have sufficient mechanical strength and [71]
antibacterial action against P. aeruginosa and S. aureus suggesting
they may be effectively utilized as antibacterial wound dressing

13
155 Page 8 of 26 AAPS PharmSciTech (2023) 24:155

Table II  (continued)
S. no Natural/synthetic polymer Formulation type Special comments References
13 Electrospun mats In a multi-immersion process, AgNPs were encased in gelatin and then [72]
coated on electrospun PCL mats. This method was used to enhance
the mats' antibacterial action and lessen their wound-scaffold adhe-
sion. The in vitro and in vivo findings also demonstrated that the
membrane’s antibacterial efficacy increased in proportion to the
number of times it was coated with gelatin and silver
14 Poly (lactic-co-glycolic Nanofiber scaffolds Sponging index, hydrophilicity, and degradation rates of the [73]
acid) PLGA scaffolds with randomly oriented fibers were much higher
than those of pure PLGA. Mesenchymal stem cells (MSCs) showed
no cytotoxicity in vitro viability assays, and a high proliferation rate
was seen for cells cultured on PLGA/Gelatin (7:3) scaffolds. For
long-term wound care, this particular scaffold is an excellent choice
15 Nanofiber scaffold Compared to PLGA mats, the fibrous membranes performed better [74]
as an antibacterial barrier. Using a combination of hydrophilic AG
(Alginate) and hydrophobic PLGA polymers, the optimal wound
dressing was achieved
16 Electrospun sand- The SSC membranes with antioxidant and antibacterial capabilities [75]
wich-structured were made from three layers: polyvinylidene fluoride, curcumin/PLA
composite (SSC) microspheres, and enrofloxacin/PLA fibers. SSC membranes showed
antibacterial efficacy against S. aureus, E. coli, S. pneumoniae, P.
aeruginosa, and C. albicans
17 Poly-lactic acid (PLA) Nanofibers PLA and HPG (hyperbranched polyglycerol) nanofibers coated with [76]
curcumin were evaluated as wound dressings. Electrospun scaf-
folds (PLA/HPG/CUR) enhance superior cell survival, adhesion,
and proliferation than PLA/CUR nanofibers. Even after 14 days in
Phosphate Buffered Saline, nanofiber shape was unaltered. In vitro
scratch experiment shows PLA/HPG/CUR completes cell migration
within 36 h
18 Nanofibers Electrospun PLA nanofibrous membranes with antioxidant character- [47]
istics were made. Authors load grape seed extract (GSE), a natural
antioxidant, into the nanofibers. In vitro experiments using human
foreskin fibroblast (HFF1) cells show biocompatibility, cell adhe-
sion, and proliferation
20 Nanofibers The cephradine loaded nanofibers prevent the bacterial infection and [77]
diabetic wound spreading
21 Nanofibers It is utilized in the management of diabetic foot ulcer and has antibac- [78]
terial activity
22 Scaffolds Enhance the in vivo wound healing process and growth factor expan- [79]
sion
23 Scaffolds The diameter of the fiber was enhanced because to the incorporation [80]
of the bio-ceramic NAGEL (Ca7Si2P2O16). NAGEL’s stimulation
of epithelial migration, proliferation, angiogenesis, and A-SMA
expression, diabetic rats exhibited significantly better wound healing.
The scaffolds were made of biodegradable materials and served as a
transitional matrix for the development and migration of cells

plants' chemical compounds and their traditional applica-
tions might lead to cutting-edge pharmaceuticals with fewer
side effects [85]. There are wide variety of reported plant-
based active compounds that are currently utilized in the
wound healing such as Hibiscus sabdariffa [86], Malva syl-
vestris [87], and Aloe barbadensis [88]. Some examples of
plants with wound healing properties shown in Table III.
However, the use of phytoconstituents and extracts in
phytopharmaceuticals is still restricted owing to certain
difficulties. These problems include an un-favorable taste,
very-less permeability, low solubility, and low bioavail-
ability [103, 104]. In order to circumvent these restrictions,
nanotechnological methods have been investigated for use
as potential medication delivery systems [105]. The phys-
icochemical and biological features of nanostructured drug
delivery systems are much superior to those of microscale
drug delivery systems. The earlier systems exhibit superior
optical characteristics, greater surface areas, enhanced con-
ductivity, and enhanced interactions with biological mol-
ecules [106]. Figure 3 provides a visual representation of

13
AAPS PharmSciTech (2023) 24:155 Page 9 of 26 155

Table III  Plant-based active components with wound healing property nanocarriers as a result of their increased efficacy, stabil-
S. no Plant part Botanical name Wound type References
ity, enhanced bioavailability of drugs, target specificity,
and capability for the prolonged release of the medication
1 Leaves Clinacanthus Excision wound [89] [108–110]. In addition, nanocarriers are capable of trans-
nutans
porting a wide variety of medications, each of which has its
2 Leaves Vitex negundo Excision wound [90]
own unique biological characteristics [28]. Figure 4 depicts
3 Flower Oliveria decum- Diabetic wound [91]
there is a wide variety of nanocarriers on the market that
bens
have the ability to encase natural substances. These carriers
4 Leaves Tridax procumbens Excision wound [92]
can carry the medication to different skin layers through
5 Leaves Bidens pilosa Fresh wound [93]
one or many mechanisms, depending on their compositional
6 Leaves Psorolea coryli- Excision wound [94]
falia characteristics shown in Fig. 5. There is a lot novel drug
7 Leaves Pothos scandens Burn wound [95] delivery system are utilized as carrier to deliver the drugs at
8 Fruit Pistaciaatlantica Incision wound [96] their target site in order to increase their efficacy, stability
9 Seeds Mucuna pruriens Excision wound [97] and safety. For example niosomes used as a delivery carrier
10 Leaves Centella asiatica Burn wound [98, 99] for many drugs like gliclazide [111], ketoconazole [112],
11 Bark Terminalia arjuna Excision wound [100] transdermal formulations [113], timolol maleate [114], folic
12 Leaves Azadirachta indica Excision wound [101] acid [115] etc. Nowadays liposomes are utilized to delivered
13 Stem Dracaena reflexa Excision wound [102] many drugs such as paclitaxel [116], cyclosporine [117],
cefepime [118], cabazitaxel [119], glycyrrhetinic acid [120],
curcumin [121], ibuprofen [122], tedizolid phosphate [123]
each of the benefits associated with the administration of etc. in order to improve their efficacy and stability. Simi-
pharmaceuticals and natural remedies using nanocarriers. larly, Ethosomes may impair drug molecules with various
physicochemical characteristics [124], including hydrophilic
[125], lipophilic, and amphiphilic [126]. Many drugs such as
Types of Nanocarrier for Wound Healing aceclofenac [127], diclofenac diethylamine [128], mycophe-
Using Natural Actives nolic acid [129], etc. have been delivered by ethosomes. In
order to in increase the therapeutic efficacy of drug phyto-
Nanocarriers have been utilized to deliver active drugs to somes are utilized to supply numerous medicines including
specific areas, and their sizes range from 1 to 100 nm [107]. mitomycin C [130], bosewellia serrata extract [131], cur-
Conventional drug delivery methods are losing ground to cumin [132], quercetin [133] etc. For instance, a number of

Fig. 3  Advantages of using

nanocarriers for plant extracts  Biodegradable, Biocompatible
 Allow higher and more efficient
and bioactive constituents
concentrations in the target site
 Decrease in severity of undesired
side effects
 Protect the drug from degradation

 Surface functional  Increase absorption

 Drug stability  Remove water solubility
 Drug target to specific  Improve water solubility
site Advantages  Sustained drug release
of
nanocarriers

 Cancer therapy
 Gene delivery
 Therapeutic and molecular imaging
 Diagnosis and biomolecule
detection
 Tissue engineering and regenerative
medicine

13
155 Page 10 of 26 AAPS PharmSciTech (2023) 24:155

Hydrophobic Drug Hydrophilic

External Phase

Phospholipid Bilayer Drug

(Hydrophilic Head & Hydrophobic Cosurfactant
Phase Oil or aqueous core
Hydrophilic Lipophilic Tail)
Surfactant
Drug Aqueous core Polymeric membrane

Liposomes Micro/Nanoemulsion Polymeric nanoparticles (Nano capsule)

Ethanol
Drug Edge Activator (Single
chain surfactant
Rigid crystalline molecule)
Hydrophilic Drug structure
Hydrophobic Drug Hydrophilic Drug
Hydroethanolic Solid core
Drug Solution Hydrophobic Drug

Ethosomes Solid lipid nanoparticle Transfersomes

Drug
Hydrophobic Drug

Nonaqueous, Nonionic
Phosphatidyl choline
Surfactant Bilayer
(Hydrophilic Head & and drug complex
Hydrophilic Drug
Lipophilic Tail)
Polymeric
Aqueous core matrix

Polymeric nanoparticles Phytosomes

Niosomes
(Nanosphere)

Fig. 4  Different kinds of nano-carriers used for wound healing

drugs carriers, such as Lipusu (liposomal paclitaxel), Amb-
isome (liposomal amphotericin B), Psorisome (liposomal
dithranol), and Fungisome (liposomal amphotericin B), are
successful examples of NDDS system [134–137]. However,
the scope of this analysis is limited to certain nanocarriers
that have been investigated for usage in conjunction with
plant-based wound healing agents.
Liposomes
Liposomes are the phospholipid molecules that are self-
assembled in water to form closed bilayer vesicles [138,
139]. Liposomes were used as carriers in order to admin-
istered the drugs through oral, pulmonary, nasal, trans-
dermal, and parenteral route [140]. Liposomes feature an
aqueous compartment surrounded by one or more cell-like
lipid bilayers, making them ideal for cellular research.
They also have vital physiological activities including
motility and shape changes, as well as the capacity to
mimic the biophysical features of live [141–143]. Phos-
pholipids are amphipathic molecules that are water
(hydrophilic) and fat-loving (hydrophobic) [144]. Water
molecules repel the hydrophobic tails of the phospholip-
ids, resulting in liposome self-assembly through hydro-
philic contacts, van der Waals interactions, and hydrogen
bonding interactions [145]
Liposomes have the ability to encapsulate pharmaceu-
ticals that are hydrophilic, hydrophobic, and amphiphilic
[146]. Phospholipids have amphipathic properties, which
make this kind of behavior conceivable. Encapsulation of
hydrophilic drugs takes place in the aqueous core, while
encapsulation of hydrophobic drugs takes place in the
bilayer membrane between the tails of the phospholipids.
On the other hand, amphiphilic medicines are segregated
into their respective compartments at the surface of the
bilayers. The medications are arranged in their distinct
places because of the varied regions of the liposomes to
which they are most strongly attracted [146]. The lipo-
somal membrane has the capacity to shield the encapsu-
lated medications from light, moisture, and oxygen [147].
This is in addition to the liposomal membrane’s ability to
regulate and maintain the release of pharmaceuticals at
specified places. Liposomes have the ability to increase
the physicochemical characteristics of the compounds,

13
AAPS PharmSciTech (2023) 24:155 Page 11 of 26 155

Fig. 5  Topical delivery of plant-

based components employing
NDDS [176]

Wound

Penetration
Routes

6 Pilosebaceous mediated transport

5 Adsorption
2 Intracellular 1 Integration with lipids
3 Osmoregulated
delivery 4 Transcellular transport penetration

Stratum
corneum
Epidermis

Hair-follicles
Moisture clouds Micro-reservoir Dermis

Sebaceous gland
Subcutaneous
tissue
Vein

Capillary

as well as the onset time of these features, and to lessen
the toxicity of these compounds [148, 149]. Because of
their ability to remain stable in colloidal solution, bio-
degradability, and biocompatibility, liposomes satisfy the
parameters necessary to serve as effective drug carriers
[150–156].
Jangde et. al. developed liposomes encapsulated with
quercetin in order to heal the wound in a better way.
Quercetin, phospholipids, and cholesterol were dissolved
in a 4:1 chloroform–methanol combination to make
liposomes. Liposomes sustained the quercetin release
in wounds [157]. Cui et al. used a thin-film dispersion-
ultrasonic technique to generate Danggui Buxue loaded
liposomes, which they subsequently put into a thermosen-
sitive gel. The excision wound model was used in order to
assess how well it healed wounds. The findings revealed a
discernible acceleration in the process of wound healing.
This gel proved to be an effective strategy for increased
wound healing as it offered a prolonged supply for the
extract [158]. Castangia et al. investigated the wound heal-
ing activity of liposomes loaded with curcumin and querce-
tin. The prepared liposomes have greater penetrability and
release the drug in sustained manner for prolong period of
time when tested on full-thickness mice model [159].
Nanofibers
Nanofibers have outstanding qualities that promote
wound healing with size range from 1–1000 nm. Their
microstructure is well adapted to the ECM structure of
the human body, which makes it an environment that is
favorable to the development, proliferation, and adhe-
sion of cells [160–162] Also, the high absorption and
permeability rate may absorb the exudate that has built
up on the wound surface and maintain a moist environ-
ment, both of which are necessary for the healing pro-
cess.. Additionally, the huge surface area makes it eas-
ier to load and transport bioactive components like as
medicines and growth hormones [163–165]. Zheng et.
al. developed liposome-based hydrogel of asiaticoside.
The asiaticoside released from the hydrogel had a sub-
stantial inhibitory impact on fibroblast proliferation
and collagen production, removing scars for regenera-
tion nerves, which can enhance the function recovery of

13
155 Page 12 of 26
damaged peripheral nerves. These encouraging findings
taken together suggest that the hydrogel may be a poten-
tial option for regeneration of peripheral nerves [166].
In another investigation, ultra-deformable liposomes
increased in vitro skin penetration of asiaticoside (AC)
by a factor of ten when compared to the free drug solu-
tion and promoted an increase in in vivo collagen produc-
tion. The liposomes based asiaticoside delivery through
topical route is promising delivery system for effective
wound healing [167]. Nanofibers have been proposed as
transdermal delivery systems for natural substances. Due
to increased water retention, weight loss, and a bigger
surface area of the nanofiber mat, the AC was added to
ultrafine cellulose acetate electrospun nanofibers, which
demonstrated enhanced skin permeability of the drug
[168]. Similarly, compared to as-cast films, an ultra-fine
cellulose acetate nanofiber mat containing Asiaticoside or
curcumin demonstrated improved drug release [169]. Zhu
et. al. prepared Asiaticoside-loaded coaxial electrospun
nanofibers for the treatment of profound partial-thickness
burn injuries. The vascular endothelial growth factor, pro-
liferating cell nuclear antigen and tumor necrosis factor,
were upregulated and interleukin 6, and tumor necrosis
factor alpha were downregulated in order to improve
wound healing in vivo [170]. In similar study, authors
developed curcumin loaded nanofibers. The prepared
fibers increase the production of collagen, improve the
proliferation of fibroblast and defend the fibroblast cell
from oxidative stress [171]. Khan et. al. investigated the
wound healing potential of Berberis lyceum extract. The
authors reveals that the prepared PVA nanofibers loaded
with Berberis lyceum possess excellent wound healing
and antibacterial activity [172].
Nano‑Hydrogels
Nanohydrogels are thought to be efficient carriers for the
treatment of wounds because they have three-dimensional
polymeric networks. They can absorb fluids because of their
porous network, which keeps the wound moist and speeds up
the healing process by maintaining the correct oxygen level.
Nanohydrogels have gained widespread acceptance due to
their efficacy, compatibility, and ability to demonstrate posi-
tive effects on skin rejuvenation [173].
The baicalin-submerged gellan cholesterol nanohydrogel
is intended to enhance wound healing activities. When used
on a mouse model of epidermal inflammation, the baicalin-
loaded nanohydrogels exhibit optimum effectiveness for
skin regeneration and also operate as inflammation inhibi-
tors [174]. The newly created nanocrystal bacterial cellulose
hydrogels instantaneously adhere to fibroblasts, support the
shape of human dermal fibroblasts, prevent cell migration,
promote cell proliferation, and affect nine gene expressions
13
AAPS PharmSciTech (2023) 24:155
related to damage repair. As a result, nanohydrogels are cru-
cial for skin regeneration [175].
Metallic Nanoparticles
The metallic nanoparticles have antibacterial, antimicro-
bial, and anti-inflammatory properties, so that these nano-
particles are used in scientific research. The ability of a
nanoparticle to penetrate and/or bind to target cells with
the potential to engage with their biological machinery
and trigger a response depends on its chemical and physi-
cal structures. The most well-liked metallic nanoparticles
are silver- and gold-based nanostructures. Metal-based
nanoparticles are commonly used in medicine. Because
they have fewer negative effects and better therapeutic
benefits than traditional dosage forms, herbal plants are
commonly used in the production of metallic nanoparti-
cles [177]. Most herbal extracts have been combined with
metallic nanoparticles, including Cladophora fascicularis
[178], Aerva lanata [179], Hippophae rhamnoides [180],
Eucommia ulmoides [181], Black tea leaf [182], Averrhoa
bilimbi [183], Salicornia brachiate [184], Abelmoschus
esculentus [185], olive leaf [186].
Silver nanoparticles are often utilized due to their
antimicrobial, antibacterial, and anti-inflammatory char-
acteristics [187]. The size of the silver particles affects
their solubility and bioactivity in the injured region; the
smaller the size, the more intense the interaction with the
skin. Vesicle diameters for silver nanoparticles vary from
1 to 100 nm. One research found that the combination
of lower graphene oxide nanovesicles and silver-silver
chloride nanoparticles accelerated the healing process
by producing more oxygen free radicals than silver ions.
These particles may promote wound healing activity, as
shown in in vivo investigations on mice [188]. They have
been proven to have a favorable influence on the antibac-
terial activity against both gram-negative and gram-pos-
itive bacteria. A new kind of silver antibacterial barrier
wound dressing called ACTICOAT avoids the complica-
tions that might result from using earlier agents. Inflam-
mation is reduced and the healing process is improved
as a result of the decreased bacterial activity [189]. The
bio-prepared plant-based nanoparticles have the ability
to treat wounds and prevent bacterial infections [190].
There are several techniques used to create silver nano-
particles. The two most used techniques are photochemi-
cal and chemical reduction [190]. For the purpose of pro-
moting wound healing, several plant extracts, including
alkaloids, glycosides, corticosteroids, and essential oils,
have been mixed into silver nanoparticles [191]. Due to
their considerable antibacterial and antifungal activity,
Cassia roxburghii produced silver nanoparticles have the
potential to improve wound healing.
AAPS PharmSciTech (2023) 24:155
Transfersomes
Transfersomes are advanced generation deformable
liposomes that are used as topical formulations in the skin
regeneration and wound healing processes. These vesicles
may serve as drug carriers to transfer drug molecules or
herbal extracts over the skin to increase the absorption of
drug compounds due to their composition, deformable quali-
ties, and skin permeability. The use of a topical vesicular for-
mulation might lessen undesirable side effects while increas-
ing the amount of herbal medication that accumulates at the
administration site. The integration of materials that impart
elasticity on the outer surface also contributes to the high
elasticity of transfersomes. The high degree of elasticity of
the vesicles enhances the delivery of herbal remedies across
the skin and accelerates the rate of absorption during the
healing process [192].
Manconi and colleagues have investigated the use of bai-
calin for the treatment of wounds [193]. The same research
had discovered that baicalin had skin-restorative capabili-
ties utilizing the nanohydrogel platform [194]. According
to assessment, the idea of core–shell gellan transfersomes
loaded with baicalin increased skin deposition in the deeper
skin tissues, increasing it by about 8% in the dermis layer
while decreasing it by around 11% overall. The anti-inflam-
matory response in the experimental animals and subsequent
repair of injured skin were indications of the deposition of
baicalin in the skin layers [193].
Phytosomes
Herbosomes, also referred to as phytosomes, are sophis-
ticated new drug delivery systems made of phospholipids
like lecithin (phosphatidylcholine) and natural bioactive
substances. The phospholipids surround the herbal bio-
actives through chemical hydrogen bonds. In relation to
the bioavailability and stability of natural plant extracts or
drugs derived from plants, these are traditional drug delivery
systems [195, 196]. Additionally, phytosomes exhibit supe-
rior absorption to other traditional phyto molecules or plant
extracts when applied topically, improving the bioavailabil-
ity of herbal extracts and boosting their therapeutic potency.
When using this phytosomes delivery method, the required
dose can be decreased because the absorption of the active
ingredients could be improved [197]. Additionally, by creat-
ing chemical bonds between phosphatidylcholine and herbal
extracts, phytosomes can increase the stability of their con-
stituents. Similar to this, sinigrin and phytosomes complexes
showed 50% wound closure activity at lower doses (0.07 mg/
ml), but 100% effects at higher concentrations (0.14 mg/ml).
Compared to individual treatments with sinigrin and blank
phytosomes, this combination showed a greater proportion
of wound closing activity [198]. In a different article, the
Page 13 of 26 155
authors discussed the possibility of increased sinigrin per-
meability over the stratum corneum [199].
Ethosomes
Ethosomes are lipid-based nanovesicles with good penetra-
tion ability, often containing 20—45% ethanol. Ethanol in
ethosomes increases membrane fluidity and permeability
by interacting with the lipid molecules of the hydrophilic
head regions of the bilayer. This synergy permits the effi-
cient transdermal delivery of herbal medicines for medicinal
purposes [192]. For instance, curcumin in ethosomal formu-
lation might be used as a cutaneous delivery for improved
wound healing and antimicrobial activity. The ethosomes-
curcumin complex was shown to be the most effective treat-
ment for wound conditions in experimental rats, with the
least amount of wound area after 16 days of injury. Perhaps
the vesicular formulation’s enhanced effectiveness, as a
result of its ability to reach more deeply into the skin [200].
In conclusion, these nano-carriers provide the platform
for transporting drugs with better penetration and accelerate
the process of wound healing [110, 201]. The phytocon-
stituents loaded nanocarriers, increases the bioavailability of
herbal components, which boosts their wound-healing prop-
erties [202]. The enhancement of these structured vesicles
may pave the way for a prosperous future in the treatment of
wound healing. The nano-carrier based delivery of phyto-
constituents for wound healing shown in Table IV.
Challenges in Delivering Therapeutics Using
Nanocarriers
Nano-carriers display a wide range of characteristics and
behaviors due to their remarkable physical and chemical
interactions. All of the physical, chemical, optical, and
other features of materials might be altered by confinement
of matter and energy at surfaces and interfaces, leading to
surprising new behaviors. The European Medicines Agency
is up-to-date on research and methodologies for gauging the
long-term safety and bio permanence of nanomaterials. The
composition, aggregation, charge, size, shape, and solubility
of nanocarriers, as well as their reactivity with coatings and
excipients, all play a role in the characterization of nano-
systems [227]. Table V highlights the challenges associated
with nanocarrier.
Conclusion and Future Prospective
The key objective of this article is to discuss, several posi-
tive aspects associated with the usage of nano-systems in
the wound management. Nano-systems are an outstanding
13
 Table IV  Plant-based nano-formulations for wound healing
155

Type of nanocarrier Size Polymers/materials used Animal/cell line/microorgan- Active compound Remarks References
ism

13
Niosomes 150 nm Labrasol, cholesterol Sprague Dawley strain rats Andrographis paniculate The AP loaded niosomal gel enhance [203]
(AP) wound healing in Sprague Dawley
Page 14 of 26

rats
Composite Scaffold Less than 50 µm Chitosan and collagen –- Aloe vera In the SEM examination, a pore size of [204]
less than 50 microns was measured.
The prepared composite was non-
toxic in nature, and the time it took
for it to degrade was more than two
weeks
Nanofiber mats 160 nm Gelatin and glutaraldehyde HS-27 cells, Sprague–Dawley Curcumin Accelerating the healing process of [205]
rats newly produced acute wounds was
shown to be possible because to the
synergistic effect of nanofibrous mats
loaded with curcumin
Nanofiber 200 nm Polyvinyl alcohol (PVA) and Escherichia coli, Pseudomonas Tecomella undulata A greater capacity for drug loading and [206]
poly ε-caprolactone (PCL) aeruginosa, Staphylococcus drug stability. There was no discern-
aureus ible change in the morphology of the
loaded nanofiber in comparison to the
blank nanofiber
313.2 Polyvinyl alcohol (PVA) and –- Aloe vera The aloe vera-loaded nanofibers accel- [207]
poly ε-caprolactone (PCL) erate the wound healing process
562 nm Poly-lactic acid, chitosan, and Mouse myoblast cell line, Curcumin The cell proliferation is significantly [208]
collagen 57BL/6 mice improved by nanofiber of curcumin.
When compared to the nanofibers
that were blank, the rate of the wound
was 87%
723 nm Poly-caprolactone and polyethyl- RAW264.7 mouse macrophages, Curcumin The nanofiber improves the vitality of [209]
ene glycol S. aureus the cells. Antibacterial activity may
be shown using nanofibers against S.
aureus. On day 10, the wound healing
was 99%, but the blank nanofiber
exhibited just 59% wound closure
AAPS PharmSciTech (2023) 24:155
 Table IV  (continued)
Type of nanocarrier Size Polymers/materials used Animal/cell line/microorgan- Active compound Remarks References
ism

200–300 nm PVA and PCL Ovo chicken chorioallantois Salvianolic acid B and Nanofibers have angiogenic potential [210]
membrane Bromelain and have the ability to deliver a medi-
cation in a sustained way
88.44 nm Polyacrylonitrile Mouse fibroblast cells and Kleb- Lavender oil Cyto-compatible on fibroblast cells [211]
siella pneumonia derived from mice. S. aureus and
AAPS PharmSciTech (2023) 24:155

Klebsiella pneumonia were both suc-

cessfully fought off by the antibacte-
rial activity
– Gelatin SD female rats Astragaloside IV The wound closure achieved by the [212]
nanofiber loaded with astragalo-
side IV was much greater than that
achieved by the blank nanofiber
Liposomes 151 nm Cholesterol and sodium dihydro- Sprague Dawley rats Madecassoside Because of their greater penetration [213]
gen phosphate rate, liposomes demonstrated an
improvement in wound treatment
- Gelatin, propylene glycol Pigs Usnic acid When compared with a commercial [214]
burn wound preparation, it was
discovered that wound healing was
accelerated with the use of liposomes
70 nm Gelatin, propylene glycol Rabbits Usnic acid The introduction of liposomes based [215]
on gelatin accelerated the healing of
corneal wounds. The ensuing rise in
VEGF and TGF- levels at the wound
site causes the wound to heal more
quickly
100 nm Phosphatidyl choline, sodium Male Sprague–Dawley Asiaticoside The ultra-deformable vesicles boost [167]
cholate asiaticoside percutaneous permea-
tion owing to both the carrier’s direct
penetration enhancer effect on the
skin and the drug-loaded carrier’s
percutaneous passage…

13
Page 15 of 26 155
 Table IV  (continued)
155

Type of nanocarrier Size Polymers/materials used Animal/cell line/microorgan- Active compound Remarks References
ism

13
Transferosomes 107 nm Soy phosphatidylcholine and Mice Baicalin Enhanced baicalin skin deposition. [193]
Gellan gum Because of this deposition, the
Page 16 of 26

experimental animals experience a

greater reduction in inflammatory
symptoms
Phytosomes 153 ± 39 nm l-α-Phosphatidylcholine hydro- HaCaT cells Sinigrin HaCaT cells were only slightly affected [198]
genated by the complex’s toxicity. The com-
plexes demonstrated 50% wound clo-
sure at a concentration of 0.07 mg/ml,
while they demonstrated 100% wound
closure at a dosage of 0.14 mg/ml
Ethosomes 143 nm Phosphatidyl choline and cho- Rat Curcumin After 16 days, curcumin encapsulated [200]
lesterol ethosomes was the most effective in
healing wounds and inhibiting bacte-
rial growth
127.8 nm Phosphatidyl choline and cho- Kunming mice Thymosin β-4 The prepared gel showed excellent [216]
lesterol wound healing activity
371 nm Phosphatidylcholine (SPC), Wistar rats Curcuma longa As compared to the control group, the [217]
sodium lauryl sulfate (SLS), early and improved wound healing
and Tween 80 that resulted from the topical adminis-
tration of extract-loaded ethosomes
in the rat wound model occurred at
dosage rates of 0.5 g/cm2 and 1.0 g/
cm2, respectively
AAPS PharmSciTech (2023) 24:155
 Table IV  (continued)
Type of nanocarrier Size Polymers/materials used Animal/cell line/microorgan- Active compound Remarks References
ism

Nanoparticles - Chitosan S. aureus and P. aeruginosa,
human dermal fibroblasts cell
line
Curcumin Nanoparticles have a tremendous load- [218]
ing capacity and positive zeta poten-
tial. Cell migration was stimulated
by nanoparticles without causing any
harm to the cells
AAPS PharmSciTech (2023) 24:155

176.5 nm PLGA NMRI female mice Curcumin When compared to free curcumin, [219]
PLGA-curcumin shows improved
wound healing. Anti-inflammatory
activity, granulation, and re-epitheli-
alization are all enhanced by PLGA-
curcumin nanoparticles
278 nm Poly caprolactone and gelatin EnSCs cell line Curcumin In contrast to the PCL scaffold alone, [220]
cell adhesion and proliferation were
enhanced in the scaffold including
curcumin-loaded chitosan nanoparti-
cles. Indications are promising that it
may serve as a suitable alternative in
cases of skin damage and regenerative
medicine
63 nm Sodium alginate S. aureus, E. coli, and C. Essential oil An inhibiting impact was seen on the [221]
albicans ability of S. aureus to adhere when
silver nanoparticles were present. The
use of nanoparticles and essential oils
in a dressing has a synergistic impact
in preventing the development of
biofilm
40 nm Poly caprolactone and gelatin S. aureus and S. epidermidis Zataria multiflora essen- The antibacterial impact that Z-EO had, [222]
tial oil (Z-EO) when combined with silver nanopar-
ticles, was cumulative and promoted
successful wound healing
20 nm Collagen Methicillin-resistant S. aureus Aloe barbadensis The bioresorbable scaffolds demon- [223]
(MRSA), P. aeruginosa, and strated great biocompatibility. Both
E. coli in vitro and in vivo wound healing
was sped up by the use of wound
dressings, which stopped the develop-
ment of germs

13
Page 17 of 26 155
 Table IV  (continued)
155

Type of nanocarrier Size Polymers/materials used Animal/cell line/microorgan- Active compound Remarks References
ism

13
Nano-emulsion 93.64 ± 6.48 nm PEG-400, PEG-200, propylene Wistar rats Curcumin and clove oil Wound contraction was seen in [224]
glycol 12–24 days using curcumin nano-
Page 18 of 26

emulsion and commercially available

fusidic, compared to placebo. When
comparing nano-emulsion with
fusidic acid, the epithelization time
was likewise comparable
32.45 nm Tween-85, Transcutol Wistar rats Eucalyptus oil (EO) When compared to pure EO, nano- [225]
emulsions containing EO caused a
greater constriction of the wound
Nano-hydrogel 350 nm N-methyl-2-pyrrolidone, cho- 3T3 fibroblasts, CD-1 mice Baicalin Compared to betamethasone and phos- [194]
lesterol, 4-bromobutyric acid, phate buffer solution, nanohydrogel
N-(3-dimethylaminopropyl)- baicalin hastened wound healing
N′-ethylcarbodiimide hydro-
chloride
Nanogel 458 nm Tween 80 and polyethylene Diabetic rats Aloe vera Results showed wound healing [226]
glycol 400 improved with higher contraction
(75% contraction resulted in 15 days
of experiment). In a skin irritation
investigation on diabetic rats, it was
proven harmless
AAPS PharmSciTech (2023) 24:155
AAPS PharmSciTech (2023) 24:155
Table V  Challenges associated Challenges
with nanocarrier
Development and validation of analyti-
cal method
Surface charge
Aggregation
Surface area and shape
Aspect ratio
option for the application of wound healing because of their
unique physiochemical features, which make them stand out
from other potential candidates. When compared to other
traditional methods of wound healing, the nanotechnology-
based wound treatment procedure displays superior effec-
tiveness in terms of its therapeutic impact. Due to the fact
that it contains antibacterial, anti-inflammatory, and anti-
proliferative actions, nanotechnology-based systems have
the potential to alter more than one phase of the wound
healing process while it is in progress. The study on natu-
ral and herbal compounds has been carried out all over the
world owing to the fact that these compounds have greater
therapeutic benefits and negligible adverse effects. There
is a pressing need for the development of better methods
for the delivery of medications to the target location in a
dosage that does not interfere with the treatment of dis-
eases that are already being administered. The herbal com-
pounds have a significant amount of potential and, hence,
a brighter future; this is particularly true when the herbal
compounds are combined into nanocarriers for the treatment
of chronic wounds, since the outcomes of this therapy have
been encouraging. Novel drug delivery methods that are
based on herbal medicine have recognized the techniques
that have been taken in the area of pharmaceuticals, which
will benefit the health of the general population. It was also
determined that the addition of the herbal ingredient to the
nano-vehicle would increase the magnitude of the delivery
system that is already in use. In any case, several meth-
odologies have been used in the pursuit of the privileged
utilization of nanocarriers in the treatment of wounds. Toxi-
cology is the primary worry with nano-vehicles because
of the potential for the vehicles to have unintended conse-
quences in the human body. Because of this, it is necessary
to make the necessary adjustments right from the beginning
in order to make additional progress with wound healing
treatments in clinical trials. In in vivo models, there is a
limited understanding of the non-material-mediated wound
healing mechanisms, which is one of the issues that has
been noted. In vitro studies, or studies that primarily rely on
a single species of bacteria, provide the basis for research
on the healing processes of non-material wounds. In order
to conduct in-depth experiments using gram-positive and
Page 19 of 26 155
Associated toxicity References
The drug release estimation is difficult [227]
Oxidative stress [228]
Activate cellular apoptosis [229]
It delays the release of loaded drug [230]
Chance of toxicity due to aggregation of nano- [231]
carriers
gram-negative bacterial strains, an in vivo wound healing
application is necessary. As a consequence, the primary
focus needs to be placed on boosting and enhancing tar-
get efficiency in order to facilitate more effective wound
healing. As a result, the researchers need to work toward
the production of a nano-material that is both biodegrad-
able and biocompatible, and which also has the capacity
to improve upon all stages of the wound healing process.
Acknowledgements The authors would like to thank Maharaja Ranjit
Singh Punjab Technical University (MRSPTU) in Bathinda, India, for
providing the research facilities. The authors would like to thank the
Indian Council of Medical Research New Delhi, India, and the Faculty
of Pharmacy, Kuala Lumpur, Malaysia for their contributions to the
completion of this study.
Author Contribution Mohit Kumar: writing—original draft preparation,
collecting information, methodology; Syed Mahmood: collecting infor-
mation, revising draft; Shruti Chopra: collecting information, revising
draft; Amit Bhatia: revising draft, conceptualization, finalizing the manu-
script; Puja Keshwania: revising and finalizing the manuscript.
Funding Research grant (5/8–4/5/Env/2020-NCD-II Dated
22/12/2021) Under Indian Council of Medical Research (ICMR), New
Delhi, India.
Declarations
Conflict of Interest The authors declare no competing interests.
References
1. Siafaka PI, Zisi AP, Exindari MK, Karantas ID, Bikiaris DN.
Porous dressings of modified chitosan with poly (2-hydroxyethyl
acrylate) for topical wound delivery of levofloxacin. Carbohydr
Polym Elsevier. 2016;143:90–9.
2. Gao S, Zhang W, Zhai X, Zhao X, Wang J, Weng J, et al. An anti-
bacterial and proangiogenic double-layer drug-loaded micronee-
dle patch for accelerating diabetic wound healing. Biomater Sci
Royal Society of Chemistry. 2023;11:533–41.
3. Gonzalez AC de O, Costa TF, Andrade Z de A, Medrado ARAP.
Wound healing-a literature review. An Bras Dermatol. SciELO
Brasil. 2016;91:614–20.
4. Rajendran NK, Kumar SSD, Houreld NN, Abrahamse H. A
review on nanoparticle based treatment for wound healing. J
Drug Deliv Sci Technol Elsevier. 2018;44:421–30.
13
155 Page 20 of 26
5. Han S-K. Basics of wound healing. Innov Adv Wound Heal.
Springer; 2023. p. 1–42.
6. Kiritsi D, Nyström A. The role of TGFβ in wound healing pathol-
ogies. Mech Ageing Dev Elsevier. 2018;172:51–8.
7. Schreml S, Szeimies R-M, Prantl L, Landthaler M, Babilas P.
Wound healing in the 21st century. J Am Acad Dermatol Else-
vier. 2010;63:866–81.
8. Beldon P. Basic science of wound healing. Surg Elsevier.
2010;28:409–12.
9. Bowler PG, Duerden BI, Armstrong DG. Wound microbiology
and associated approaches to wound management. Clin Micro-
biol Rev Am Soc Microbiol. 2001;14:244–69.
10. Ovington L. Bacterial toxins and wound healing. Ostomy Wound
Manage. 2003;49:8–12.
11. Edwards R, Harding KG. Bacteria and wound healing. Curr Opin
Infect Dis LWW. 2004;17:91–6.
12. Manzoureh R, Farahpour MR. Topical administration of hydro-
ethanolic extract of Trifolium pratense (red clover) accelerates
wound healing by apoptosis and re-epithelialization. Biotech
Histochem Taylor & Francis. 2021;96:276–86.
13. Velnar T, Bailey T, Smrkolj V. The wound healing process:
an overview of the cellular and molecular mechanisms. J Int
Med Res. London, England: Sage Publications Sage UK;
2009;37:1528–42.
14. Kumar M, Ge Y, Hilles AR, Bhatia A, Mahmood S. A review
on polysaccharides mediated electrospun nanofibers for diabetic
wound healing: their current status with regulatory perspective.
Int J Biol Macromol. Elsevier; 2023;234:123696.
15. Kumar M, Mahmood S, Mandal UK. An updated account on
formulations and strategies for the treatment of burn infection-a
review. Curr Pharm Des. 2022;28:1480–92.
16. De Luca I, Pedram P, Moeini A, Cerruti P, Peluso G, Di Salle
A, et al. Nanotechnology development for formulating essential
oils in wound dressing materials to promote the wound-healing
process: a review. Appl Sci. MDPI; 2021;11:1713.
17. El Ayadi A, Jay JW, Prasai A. Current approaches targeting the
wound healing phases to attenuate fibrosis and scarring. Int J Mol
Sci. MDPI; 2020;21:1105.
18. Xu Z, Han S, Gu Z, Wu J. Advances and impact of antioxidant
hydrogel in chronic wound healing. Adv Healthc Mater. Wiley
Online Library; 2020;9:1901502.
19. Jatoi AW, Ogasawara H, Kim IS, Ni Q-Q. Polyvinyl alcohol
nanofiber based three phase wound dressings for sustained wound
healing applications. Mater Lett Elsevier. 2019;241:168–71.
20. Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of
macrophages in acute and chronic wound healing and interven-
tions to promote pro-wound healing phenotypes. Front Physiol.
Frontiers Media SA; 2018;9:419.
21. Vijayan A, Nanditha CK, Kumar GSV. ECM-mimicking nanofi-
brous scaffold enriched with dual growth factor carrying nano-
particles for diabetic wound healing. Nanoscale Adv Royal Soci-
ety of Chemistry. 2021;3:3085–92.
22. Ehterami A, Salehi M, Farzamfar S, Vaez A, Samadian H, Sah-
rapeyma H, et al. In vitro and in vivo study of PCL/COLL wound
dressing loaded with insulin-chitosan nanoparticles on cutane-
ous wound healing in rats model. Int J Biol Macromol Elsevier.
2018;117:601–9.
23. Okur NÜ, Hökenek N, Okur ME, Ayla Ş, Yoltaş A, Siafaka PI,
et al. An alternative approach to wound healing field; new com-
posite films from natural polymers for mupirocin dermal deliv-
ery. Saudi Pharm J Elsevier. 2019;27:738–52.
24. Siafaka PI, Üstündağ Okur N, Karavas E, Bikiaris DN. Surface modi-
fied multifunctional and stimuli responsive nanoparticles for drug tar-
geting: current status and uses. Int J Mol Sci. MDPI; 2016;17:1440.
25. Filippousi M, Siafaka PI, Amanatiadou EP, Nanaki SG, Nerant-
zaki M, Bikiaris DN, et al. Modified chitosan coated mesoporous
13
AAPS PharmSciTech (2023) 24:155
strontium hydroxyapatite nanorods as drug carriers. J Mater
Chem B Royal Society of Chemistry. 2015;3:5991–6000.
26. Bayindir Bilgic M, Lacin NT, Berber H, Mansuroglu B. In vitro
evaluation of alpha-tocopherol loaded carboxymethylcellulose
chitosan copolymers as wound dressing materials. Mater Technol
Taylor & Francis. 2019;34:386–93.
27. Ferreira MOG, de Lima IS, Morais AÍS, Silva SO, de Carvalho
RBF, Ribeiro AB, et al. Chitosan associated with chlorhexidine
in gel form: synthesis, characterization and healing wounds
applications. J Drug Deliv Sci Technol Elsevier. 2019;49:375–82.
28. Kumar M, Dogra R, Mandal UK. Nanomaterial-based deliv-
ery of vaccine through nasal route: opportunities, challenges,
advantages, and limitations. J Drug Deliv Sci Technol. Elsevier;
2022;74:103533.
29. Mukherjee D, Azamthulla M, Santhosh S, Dath G, Ghosh A,
Natholia R, et al. Development and characterization of chitosan-
based hydrogels as wound dressing materials. J Drug Deliv Sci
Technol Elsevier. 2018;46:498–510.
30. Yao H-Y, Lin H-R, Sue G-P, Lin Y-J. Chitosan-based hydro-
gels prepared by UV polymerization for wound dressing. Polym
Polym Compos. London, England: SAGE Publications Sage UK;
2019;27:155–67.
31. Tavakoli J. Physico-mechanical, morphological and biomedical
properties of a novel natural wound dressing material. J Mech
Behav Biomed Mater Elsevier. 2017;65:373–82.
32. Liu J, Yan L, Yang W, Lan Y, Zhu Q, Xu H, et al. Controlled-release
neurotensin-loaded silk fibroin dressings improve wound healing
in diabetic rat model. Bioact Mater Elsevier. 2019;4:151–9.
33. Portela R, Leal CR, Almeida PL, Sobral RG. Bacterial cellulose:
a versatile biopolymer for wound dressing applications. Microb
Biotechnol Wiley Online Library. 2019;12:586–610.
34. Aderibigbe BA, Buyana B. Alginate in wound dressings. Phar-
maceutics. MDPI. 2018;10:42.
35. Fleck CA, Simman R. Modern collagen wound dressings:
function and purpose. J Am Col Certif Wound Spec. Elsevier.
2010;2:50–4.
36. Longinotti C. The use of hyaluronic acid based dressings to
treat burns: a review. Burn Trauma Oxford University Press.
2014;2:2321–3868.
37. Mir M, Ali MN, Barakullah A, Gulzar A, Arshad M, Fatima
S, et al. Synthetic polymeric biomaterials for wound healing: a
review. Prog Biomater Springer. 2018;7:1–21.
38. Siafaka PI, Üstündağ Okur N, Mone M, Giannakopoulou S, Er
S, Pavlidou E, et al. Two different approaches for oral administra-
tion of voriconazole loaded formulations: electrospun fibers versus
β-cyclodextrin complexes. Int J Mol Sci. MDPI. 2016;17:282.
39. Tavakoli J, Tang Y. Honey/PVA hybrid wound dressings with
controlled release of antibiotics: structural, physico-mechani-
cal and in-vitro biomedical studies. Mater Sci Eng C Elsevier.
2017;77:318–25.
40. Tang Y, Lan X, Liang C, Zhong Z, Xie R, Zhou Y, et al.
Honey loaded alginate/PVA nanofibrous membrane as poten-
tial bioactive wound dressing. Carbohydr Polym Elsevier.
2019;219:113–20.
41. Ahlawat J, Kumar V, Gopinath P. Carica papaya loaded poly
(vinyl alcohol)-gelatin nanofibrous scaffold for potential
application in wound dressing. Mater Sci Eng C. Elsevier.
2019;103:109834.
42. Perumal G, Pappuru S, Chakraborty D, Nandkumar AM, Chand
DK, Doble M. Synthesis and characterization of curcumin
loaded PLA—Hyperbranched polyglycerol electrospun blend
for wound dressing applications. Mater Sci Eng C Elsevier.
2017;76:1196–204.
43. Siafaka PI, Barmbalexis P, Bikiaris DN. Novel electrospun
nanofibrous matrices prepared from poly (lactic acid)/poly
AAPS PharmSciTech (2023) 24:155
(butylene adipate) blends for controlled release formula-
tions of an anti-rheumatoid agent. Eur J Pharm Sci Elsevier.
2016;88:12–25.
44. Chatterjee S, Ghosal K, Kumar M, Mahmood S, Thomas S. A
detailed discussion on interpenetrating polymer network (IPN)
based drug delivery system for the advancement of health care
system. J Drug Deliv Sci Technol Elsevier. 2022;79.
45. Okur NÜ, Filippousi M, Okur ME, Ayla Ş, Çağlar EŞ, Yoltaş A, et al.
A novel approach for skin infections: controlled release topical mats
of poly (lactic acid)/poly (ethylene succinate) blends containing
Voriconazole. J Drug Deliv Sci Technol Elsevier. 2018;46:74–86.
46. Zou F, Sun X, Wang X. Elastic, hydrophilic and biodegradable
poly (1, 8-octanediol-co-citric acid)/polylactic acid nanofibrous
membranes for potential wound dressing applications. Polym
Degrad Stab Elsevier. 2019;166:163–73.
47. Li W, Yu Q, Yao H, Zhu Y, Topham PD, Yue K, et al. Superhy-
drophobic hierarchical fiber/bead composite membranes for effi-
cient treatment of burns. Acta Biomater Elsevier. 2019;92:60–70.
48. Siafaka PI, Barmpalexis P, Lazaridou M, Papageorgiou GZ,
Koutris E, Karavas E, et al. Controlled release formulations of
risperidone antipsychotic drug in novel aliphatic polyester carri-
ers: data analysis and modelling. Eur J Pharm Biopharm Elsevier.
2015;94:473–84.
49. Filippousi M, Turner S, Leus K, Siafaka PI, Tseligka ED, Van-
dichel M, et al. Biocompatible Zr-based nanoscale MOFs coated
with modified poly (ε-caprolactone) as anticancer drug carriers.
Int J Pharm Elsevier. 2016;509:208–18.
50. Alven S, Aderibigbe BA. Fabrication of hybrid nanofibers from
biopolymers and poly (Vinyl alcohol)/poly (ε-caprolactone)
for wound dressing applications. Polymers (Basel). MDPI.
2021;13:2104.
51. Merrell JG, McLaughlin SW, Tie L, Laurencin CT, Chen AF, Nair
LS. Curcumin loaded poly (ε-caprolactone) nanofibers: diabetic
wound dressing with antioxidant and anti-inflammatory properties.
Clin Exp Pharmacol Physiol. NIH Public Access. 2009;36:1149.
52. He J, Liang Y, Shi M, Guo B. Anti-oxidant electroactive and
antibacterial nanofibrous wound dressings based on poly
(ε-caprolactone)/quaternized chitosan-graft-polyaniline for
full-thickness skin wound healing. Chem Eng J. Elsevier.
2020;385:123464.
53. Naseri-Nosar M, Farzamfar S, Sahrapeyma H, Ghorbani S,
Bastami F, Vaez A, et al. Cerium oxide nanoparticle-containing
poly (ε-caprolactone)/gelatin electrospun film as a potential
wound dressing material: in vitro and in vivo evaluation. Mater
Sci Eng C Elsevier. 2017;81:366–72.
54. Reshmi CR, Suja PS, Manaf O, Sanu PP, Sujith A. Nanochi-
tosan enriched poly ε-caprolactone electrospun wound dress-
ing membranes: a fine tuning of physicochemical properties,
hemocompatibility and curcumin release profile. Int J Biol
Macromol Elsevier. 2018;108:1261–72.
55. Ghorbani M, Nezhad-Mokhtari P, Ramazani S. Aloe vera-
loaded nanofibrous scaffold based on Zein/Polycaprolactone/
Collagen for wound healing. Int J Biol Macromol Elsevier.
2020;153:921–30.
56. Chong LH, Lim MM, Sultana N. Fabrication and evaluation
of polycaprolactone/gelatin-based electrospun nanofibers with
antibacterial properties. J Nanomater. Hindawi Limited Lon-
don, UK, United Kingdom. 2015;2015:15.
57. Yang S, Li X, Liu P, Zhang M, Wang C, Zhang B. Multi-
functional chitosan/polycaprolactone nanofiber scaffolds with
varied dual-drug release for wound-healing applications. ACS
Biomater Sci Eng ACS Publications. 2020;6:4666–76.
58. Mary SA, Ariram N, Gopinath A, Chinnaiyan SK, Raja IS,
Sahu B, et al. Investigation on centrifugally spun fibrous
PCL/3-methyl mannoside mats for wound healing application.
Polymers (Basel). MDPI. 2023;15:1293.
Page 21 of 26 155
59. Martin A, Cai J, Schaedel A-L, van der Plas M, Malmsten M,
Rades T, et al. Zein-polycaprolactone core–shell nanofibers for
wound healing. Int J Pharm. Elsevier. 2022;621:121809.
60. Eğri Ö, Erdemir N. Production of Hypericum perforatum oil-
loaded membranes for wound dressing material and in vitro
tests. Artif cells, nanomedicine, Biotechnol. Taylor & Francis.
2019;47:1404–15.
61. Shah A, Yameen MA, Fatima N, Murtaza G. Chemical syn-
thesis of chitosan/silver nanocomposites films loaded with
moxifloxacin: their characterization and potential antibacte-
rial activity. Int J Pharm Elsevier. 2019;561:19–34.
62. Long J, Etxeberria AE, Nand A V, Bunt CR, Ray S, Seyfoddin
A. A 3D printed chitosan-pectin hydrogel wound dressing for
lidocaine hydrochloride delivery. Mater Sci Eng C. Elsevier.
2019;104:109873.
63. Masood N, Ahmed R, Tariq M, Ahmed Z, Masoud MS, Ali I,
et al. Silver nanoparticle impregnated chitosan-PEG hydro-
gel enhances wound healing in diabetes induced rabbits. Int J
Pharm Elsevier. 2019;559:23–36.
64. Akhavan-Kharazian N, Izadi-Vasafi H. Preparation and charac-
terization of chitosan/gelatin/nanocrystalline cellulose/calcium
peroxide films for potential wound dressing applications. Int J
Biol Macromol Elsevier. 2019;133:881–91.
65. Romić MD, Špoljarić D, Klarić MŠ, Cetina-Čižmek B,
Filipović-Grčić J, Hafner A. Melatonin loaded lipid enriched
chitosan microspheres–hybrid dressing for moderate exuding
wounds. J Drug Deliv Sci Technol Elsevier. 2019;52:431–9.
66. Zhang K, Bai X, Yuan Z, Cao X, Jiao X, Li Y, et al. Layered
nanofiber sponge with an improved capacity for promoting
blood coagulation and wound healing. Biomaterials Elsevier.
2019;204:70–9.
67. Tao G, Wang Y, Cai R, Chang H, Song K, Zuo H, et al. Design
and performance of sericin/poly (vinyl alcohol) hydrogel as a
drug delivery carrier for potential wound dressing application.
Mater Sci Eng C Elsevier. 2019;101:341–51.
68. Iacob A-T, Drăgan M, Ghețu N, Pieptu D, Vasile C, Buron F,
et al. Preparation, characterization and wound healing effects
of new membranes based on chitosan, hyaluronic acid and argi-
nine derivatives. Polymers (Basel). MDPI. 2018;10:607.
69. Eskandarinia A, Kefayat A, Rafienia M, Agheb M, Navid S,
Ebrahimpour K. Cornstarch-based wound dressing incorporated
with hyaluronic acid and propolis: In vitro and in vivo studies.
Carbohydr Polym Elsevier. 2019;216:25–35.
70. Ravichandran S, Radhakrishnan J, Jayabal P, Venkatasubbu GD.
Antibacterial screening studies of electrospun Polycaprolactone
nano fibrous mat containing Clerodendrum phlomidis leaves
extract. Appl Surf Sci Elsevier. 2019;484:676–87.
71. He F, Deng X, Zhou Y, Zhang T, Liu Y, Ye Y, et al. Controlled
release of antibiotics from poly-ε-caprolactone/polyethyl-
ene glycol wound dressing fabricated by direct-writing melt
electrospinning. Polym Adv Technol Wiley Online Library.
2019;30:425–34.
72. Shi R, Geng H, Gong M, Ye J, Wu C, Hu X, et al. Long-
acting and broad-spectrum antimicrobial electrospun poly
(ε-caprolactone)/gelatin micro/nanofibers for wound dressing. J
Colloid Interface Sci Elsevier. 2018;509:275–84.
73. Locilento DA, Mercante LA, Andre RS, Mattoso LHC, Luna GLF,
Brassolatti P, et al. Biocompatible and biodegradable electrospun
nanofibrous membranes loaded with grape seed extract for wound
dressing application. J Nanomater Hindawi. 2019;2019:1–12.
74. Vázquez N, Sánchez-Arévalo F, Maciel-Cerda A, Garnica-Pala-
fox I, Ontiveros-Tlachi R, Chaires-Rosas C, et al. Influence of
the PLGA/gelatin ratio on the physical, chemical and biological
properties of electrospun scaffolds for wound dressings. Biomed
Mater. IOP Publishing. 2019;14:45006.
13
155 Page 22 of 26
75. Varshosaz J, Jahanian A, Maktoobian M. Montelukast incorpo-
rated poly (methyl vinyl ether-co-maleic acid)/poly (lactic-co-
glycolic acid) electrospun nanofibers for wound dressing. Fibers
Polym Springer. 2017;18:2125–34.
76. Dekina S, Romanovska I, Sevastyanov O, Shesterenko Y, Ryjak
A, Varbanets L, et al. Development and characterization of chi-
tosan/polyvinyl alcohol polymer material with elastolytic and
collagenolytic activities. Enzyme Microb Technol. Elsevier.
2020;132:109399.
77. Razzaq A, Khan ZU, Saeed A, Shah KA, Khan NU, Menaa B,
et al. Development of cephradine-loaded gelatin/polyvinyl alco-
hol electrospun nanofibers for effective diabetic wound healing:
in-vitro and in-vivo assessments. Pharmaceutics. Multidiscipli-
nary Digital Publishing Institute. 2021;13:349.
78. Samadian H, Zamiri S, Ehterami A, Farzamfar S, Vaez A,
Khastar H, et al. Electrospun cellulose acetate/gelatin nanofi-
brous wound dressing containing berberine for diabetic foot ulcer
healing: in vitro and in vivo studies. Sci Rep Nature Publishing
Group. 2020;10:1–12.
79. Singaravelu S, Ramanathan G, Sivagnanam UT. Dual-layered
3D nanofibrous matrix incorporated with dual drugs and their
synergetic effect on accelerating wound healing through growth
factor regulation. Mater Sci Eng C Elsevier. 2017;76:37–49.
80. Lv F, Wang J, Xu P, Han Y, Ma H, Xu H, et al. A conducive
bioceramic/polymer composite biomaterial for diabetic wound
healing. Acta Biomater Elsevier. 2017;60:128–43.
81. Khan MSA, Ahmad I. Herbal medicine: current trends and future
prospects. New look to phytomedicine. Elsevier. 2019. p. 3–13.
82. Rashrash M, Schommer JC, Brown LM. Prevalence and predic-
tors of herbal medicine use among adults in the United States.
J patient Exp. Los Angeles, CA :SAGE Publications Sage;
2017;4:108–13.
83. Nooreen Z, Rai VK, Yadav NP. Phytopharmaceuticals: a new
class of drug in India. Ann Phytomed. 2018;7:27–37.
84. Ekor M. The growing use of herbal medicines: issues relating
to adverse reactions and challenges in monitoring safety. Front
Pharmacol. Frontiers Media SA. 2014;4:177.
85. Bonifacio BV, da Silva PB, dos Santos Ramos MA, Negri KMS,
Bauab TM, Chorilli M. Nanotechnology-based drug delivery sys-
tems and herbal medicines: a review. Int J Nanomedicine. Dove
Press. 2014;9:1.
86. Builders PF, Kabele-Toge B, Builders M, Chindo BA, Anwunobi
PA, Isimi YC. Wound healing potential of formulated extract
from hibiscus sabdariffa calyx. Indian J Pharm Sci. Wolters
Kluwer--Medknow Publications. 2013;75:45.
87. Fahimi S, Mortazavi SA, Abdollahi M, Hajimehdipoor H. For-
mulation of a traditionally used polyherbal product for burn heal-
ing and HPTLC fingerprinting of its phenolic contents. Iran J
Pharm Res IJPR. Brieflands. 2016;15:95.
88. Jahandideh M, Hajimehdipoor H, Mortazavi SA, Dehpour A,
Hassanzadeh G. Evaluation of the wound healing activity of a
traditional compound herbal product using rat excision wound
model. Iran J Pharm Res IJPR. Shahid Beheshti University of
Medical Sciences. 2017;16:153.
89. Aslam MS, Ahmad MS, Mamat AS, Ahmad MZ, Salam F. Anti-
oxidant and wound healing activity of polyherbal fractions of
Clinacanthus nutans and Elephantopus scaber. Evidence-based
Complement Altern Med. Hindawi. 2016;2016.
90. Talekar YP, Apte KG, Paygude SV, Tondare PR, Parab PB.
Studies on wound healing potential of polyherbal formulation
using in vitro and in vivo assays. J Ayurveda Integr Med Elsevier.
2017;8:73–81.
91. Mahboubi M, Taghizadeh M, Khamechian T, Tamtaji OR,
Mokhtari R, Talaei SA. The wound healing effects of herbal
cream containing Oliveria decumbens and Pelargonium gra-
veolens essential oils in diabetic foot ulcer model. World J Plast
13
AAPS PharmSciTech (2023) 24:155
Surg. Iran Society of Plastic, Reconstructive and Aesthetic Sur-
geons. 2018;7:45.
92. Yaduvanshi B, Mathur R, Mathur SR, Velpandian T. Evaluation
of wound healing potential of topical formulation of leaf juice
of Tridax procumbens L. in mice. Indian J Pharm Sci. Wolters
Kluwer--Medknow Publications. 2011;73:303.
93. Namunana S, Lutoti S, Nyamaizi G, Agaba G, Apun I, Ssebunnya
C, et al. Formulation, development and validation of a wound
healing herbal ointment from extracts of Bidens pilosa and Aloe
barbadensis. J Pharm Pharmacol Res. 2018.
94. Kolhe SS. Evaluation of polyherbal ointment for wound healing
activity in Wistar rats. J Drug Deliv Ther. 2018;8:26–31.
95. KP MH, Saraswathi R, Mohanta GP, Nayar C. Formulation and
evaluation of herbal gel of Pothos scandens Linn. Asian Pac J
Trop Med. Elsevier. 2010;3:988–92.
96. Hamidi SA, Naeini AT, Oryan A, Tabandeh MR, Tanideh N,
Nazifi S. Cutaneous wound healing after topical application of
pistacia atlantica gel formulation in rats. Turk J Pharm Sci. Turk-
ish Pharmacists’ Association. 2017;14:65.
97. Toppo FA, Pawar RS. Development, optimization and evaluation
of different herbal formulations for wound healing. Int J Pharm
Pharm Sci. 2015;7:447–52.
98. Kumar M, Mandal UK. Asiaticoside: a wonderful herbal com-
ponent of versatile therapeutic benefits with special reference to
wound healing activity. J Clin Exp Dermatol Res. 2021;12:1–7.
99. Hossain ML, Rahman MA, Siddika A, Adnan MH, Rahman H,
Diba F, et al. Burn and wound healing using radiation sterilized
human amniotic membrane and centella asiatica derived gel: a
review. Regen Eng Transl Med Springer. 2020;6:347–57.
100. Chaudhari M, Mengi S. Evaluation of phytoconstituents of Ter-
minalia arjuna for wound healing activity in rats. Phyther Res An
Int J Devoted to Pharmacol Toxicol Eval Nat Prod Deriv. Wiley
Online Library. 2006;20:799–805.
101. Ugoeze KC, Aja PC, Nwachukwu N, Chinko BC, Egwurugwu
JN. Assessment of the phytoconstituents and optimal applicable
concentration of aqueous extract of Azadirachta indica leaves for
wound healing in male Wistar rats. Thai J Pharm Sci. 2021;45.
102. Raslan MA, Afifi AH. In vitro wound healing properties, antioxi-
dant activities, HPLC–ESI–MS/MS profile and phytoconstituents
of the stem aqueous methanolic extract of Dracaena reflexa Lam.
Biomed Chromatogr. Wiley Online Library. 2022;36:e5352.
103. Harwansh RK, Deshmukh R, Rahman MA. Nanoemulsion:
promising nanocarrier system for delivery of herbal bioactives.
J Drug Deliv Sci Technol Elsevier. 2019;51:224–33.
104. Shishir MRI, Karim N, Gowd V, Zheng X, Chen W. Liposo-
mal delivery of natural product: a promising approach in health
research. Trends Food Sci Technol Elsevier. 2019;85:177–200.
105. Kumar M, Thakur A, Mandal UK, Thakur A, Bhatia A. Foam-
based drug delivery: a newer approach for pharmaceutical dosage
form. AAPS PharmSciTech. Springer. 2022;23:244.
106. Gondim BLC, Oshiro-Júnior JA, Fernanandes FHA, Nóbrega
FP, Castellano LRC, Medeiros ACD. Plant extracts loaded in
nanostructured drug delivery systems for treating parasitic and
antimicrobial diseases. Curr Pharm Des Bentham Science Pub-
lishers. 2019;25:1604–15.
107. Subramanian AP, Jaganathan SK, Manikandan A, Pandiaraj
KN, Gomathi N, Supriyanto E. Recent trends in nano-based
drug delivery systems for efficient delivery of phytochemi-
cals in chemotherapy. RSC Adv Royal Society of Chemistry.
2016;6:48294–314.
108. Dewanjee S, Chakraborty P, Mukherjee B, De Feo V. Plant-based
antidiabetic nanoformulations: the emerging paradigm for effec-
tive therapy. Int J Mol Sci. MDPI. 2020;21:2217.
109. Kumar M, Kumar D, Kumar S, Kumar A, Mandal UK. A recent
review on bio-availability enhancement of poorly water-soluble drugs
AAPS PharmSciTech (2023) 24:155
by using bioenhancer and nanoparticulate drug delivery system. Curr
Pharm Des Bentham Science Publishers. 2022;28:3212–24.
110. Kumar M, Dogra R, Mandal UK. Novel formulation approaches
used for the management of osteoarthritis: a recent review. Curr
Drug Deliv: Bentham Science Publishers; 2023;20(7):841–56.
111. Tamizharasi S, Dubey A, Rathi V, Rathi JC. Development and
characterization of niosomal drug delivery of gliclazide. J Young
Pharm. 2009;1:205–9.
112. Shirsand SB, Para MS, Nagendrakumar D, Kanani KM, Keer-
thy D. Formulation and evaluation of Ketoconazole niosomal
gel drug delivery system. Int J Pharm Investig. Wolters Kluwer-
-Medknow Publications. 2012;2:201.
113. Muzzalupo R, Tavano L, Cassano R, Trombino S, Ferrarelli T,
Picci N. A new approach for the evaluation of niosomes as effec-
tive transdermal drug delivery systems. Eur J Pharm Biopharm
Elsevier. 2011;79:28–35.
114. Aggarwal D, Kaur IP. Improved pharmacodynamics of timolol
maleate from a mucoadhesive niosomal ophthalmic drug delivery
system. Int J Pharm Elsevier. 2005;290:155–9.
115. Ravouru N, Kondreddy P, Korakanchi D. Formulation and evalu-
ation of niosomal nasal drug delivery system of folic acid for
brain targeting. Curr Drug Discov Technol. Bentham Science
Publishers. 2013;10:270–82.
116. Jiménez-López J, Bravo-Caparrós I, Cabeza L, Nieto FR, Ortiz R, Per-
azzoli G, et al. Paclitaxel antitumor effect improvement in lung cancer
and prevention of the painful neuropathy using large pegylated cati-
onic liposomes. Biomed Pharmacother. Elsevier. 2021;133:111059.
117. Walunj M, Doppalapudi S, Bulbake U, Khan W. Preparation,
characterization, and in vivo evaluation of cyclosporine cationic
liposomes for the treatment of psoriasis. J Liposome Res Taylor
& Francis. 2020;30:68–79.
118. Moyá ML, López-López M, Lebrón JA, Ostos FJ, Pérez D,
Camacho V, et al. Preparation and characterization of new
liposomes. Bactericidal activity of cefepime encapsulated into
cationic liposomes. Pharmaceutics. Multidisciplinary Digital
Publishing Institute. 2019;11:69.
119. Mahira S, Kommineni N, Husain GM, Khan W. Cabazitaxel
and silibinin co-encapsulated cationic liposomes for CD44 tar-
geted delivery: a new insight into nanomedicine based combi-
national chemotherapy for prostate cancer. Biomed Pharmaco-
ther Elsevier. 2019;110:803–17.
120. Chang M, Wu M, Li H. Antitumor activities of novel glycyr-
rhetinic acid-modified curcumin-loaded cationic liposomes in
vitro and in H22 tumor-bearing mice. Drug Deliv Taylor &
Francis. 2018;25:1984–95.
121. Jose A, Labala S, Venuganti VVK. Co-delivery of curcumin
and STAT3 siRNA using deformable cationic liposomes to treat
skin cancer. J Drug Target Taylor & Francis. 2017;25:330–41.
122. Gai X, Cheng L, Li T, Liu D, Wang Y, Wang T, et al. In vitro
and in vivo studies on a novel bioadhesive colloidal system:
cationic liposomes of ibuprofen. Aaps Pharmscitech Springer.
2018;19:700–9.
123. Yang Z, Tian L, Liu J, Huang G. Construction and evalua-
tion in vitro and in vivo of tedizolid phosphate loaded cationic
liposomes. J Liposome Res Taylor & Francis. 2018;28:322–30.
124. Mbah CC, Builders PF, Attama AA. Nanovesicular carriers as
alternative drug delivery systems: ethosomes in focus. Expert
Opin Drug Deliv. Taylor & Francis. 2014;11:45–59.
125. Jafari A, Daneshamouz S, Ghasemiyeh P, Mohammadi-Samani
S. Ethosomes as dermal/transdermal drug delivery systems:
applications, preparation and characterization. J Liposome Res
Taylor & Francis. 2022;33:1–19.
126. Parashar T, Sachan R, Singh V, Singh G, Tyagi S, Patel C,
et al. Ethosomes: a recent vesicle of transdermal drug delivery
system. Int J Res Dev Pharm life Sci. Citeseer. 2013;2:285–92.
Page 23 of 26 155
127. Sharma G, Goyal H, Thakur K, Raza K, Katare OP. Novel elas-
tic membrane vesicles (EMVs) and ethosomes-mediated effec-
tive topical delivery of aceclofenac: a new therapeutic approach
for pain and inflammation. Drug Deliv. 2016;23:3135–45.
128. Jain S, Patel N, Madan P, Lin S. Quality by design approach
for formulation, evaluation and statistical optimization of
diclofenac-loaded ethosomes via transdermal route. Pharm
Dev Technol Taylor & Francis. 2015;20:473–89.
129. Limsuwan T, Amnuaikit T. Development of ethosomes
containing mycophenolic acid. Procedia Chem Elsevier.
2012;4:328–35.
130. Hou Z, Li Y, Huang Y, Zhou C, Lin J, Wang Y, et al. Phyto-
somes loaded with mitomycin C–soybean phosphatidylcholine
complex developed for drug delivery. Mol Pharm ACS Publica-
tions. 2013;10:90–101.
131. Sahu AR, Bothara SB. Formulation and evaluation of phytosome
drug delivery system of boswellia serrata extract. Int J Res Med.
2015;4:94–9.
132. Karimi N, Ghanbarzadeh B, Hamishehkar H, KEYVANI F, Pez-
eshki A, Gholian MM. Phytosome and liposome: the beneficial
encapsulation systems in drug delivery and food application.
Appl Food Biotechnol. 2015;2:17.
133. Riva A, Ronchi M, Petrangolini G, Bosisio S, Allegrini P.
Improved oral absorption of quercetin from quercetin Phyto-
some®, a new delivery system based on food grade lecithin. Eur
J Drug Metab Pharmacokinet Springer. 2019;44:169–77.
134. Koudelka Š, Turánek J. Liposomal paclitaxel formulations. J
Control Release Elsevier. 2012;163:322–34.
135. Clemons KV, Capilla J, Sobel RA, Martinez M, Tong A-J, Ste-
vens DA. Comparative efficacies of lipid-complexed ampho-
tericin B and liposomal amphotericin B against coccidioidal
meningitis in rabbits. Antimicrob Agents Chemother Am Soc
Microbiol. 2009;53:1858–62.
136. Singh AK, Narsipur SS. Cyclosporine: a commentary on brand
versus generic formulation exchange. J Transplant Hindawi.
2011;2011:1–7.
137. Pardeike J, Hommoss A, Müller RH. Lipid nanoparticles (SLN,
NLC) in cosmetic and pharmaceutical dermal products. Int J
Pharm Elsevier. 2009;366:170–84.
138. Li M, Du C, Guo N, Teng Y, Meng X, Sun H, et al. Composition
design and medical application of liposomes. Eur J Med Chem
Elsevier. 2019;164:640–53.
139. Pandey H, Rani R, Agarwal V. Liposome and their applications
in cancer therapy. Brazilian Arch Biol Technol SciELO Brasil.
2016;59:1–10.
140. He H, Lu Y, Qi J, Zhu Q, Chen Z, Wu W. Adapting liposomes for
oral drug delivery. Acta Pharm Sin B Elsevier. 2019;9:36–48.
141. Pattni BS, Chupin VV, Torchilin VP. New developments in lipo-
somal drug delivery. Chem Rev. 2015;115:10938–66.
142. Hua S, Wu SY. The use of lipid-based nanocarriers for targeted
pain therapies. Front Pharmacol. 2013;4:143.
143. Sharma VK, Sarwa KK, Mazumder B. Fluidity enhancement:
a critical factor for performance of liposomal transdermal drug
delivery system. J Liposome Res. 2014;24:83–9.
144. Alavi M, Karimi N, Safaei M. Application of various types
of liposomes in drug delivery systems. Adv Pharm Bull.
2017;7:3–9.
145. Valenzuela SM. Liposome techniques for synthesis of biomimetic
lipid membranes. Nanobiotechnol Biomim Membr Springer.
2007;1:75–87.
146. Greish K. Enhanced permeability and retention effect for selec-
tive targeting of anticancer nanomedicine: are we there yet? Drug
Discov Today Technol Elsevier. 2012;9:e161–6.
147. Assis LM de, Zavareze E da R, Prentice-Hernández C, Souza-
Soares LA de. Revisão: características de nanopartículas e
13
155 Page 24 of 26
potenciais aplicações em alimentos. Braz J Food Technol. Sci-
ELO Brasil. 2012;15:99–109.
148. Babazadeh A, Ghanbarzadeh B, Hamishehkar H. Phosphatidyl-
choline-rutin complex as a potential nanocarrier for food applica-
tions. J Funct Foods Elsevier. 2017;33:134–41.
149. Camilo CJ, Leite DOD, SILVA ARA, Menezes IRA, Coutinho
HDM, Da Costa JGM. Lipid vesicles: applications, principal
components and methods used in their formulations. A review.
Acta Biológica Colomb. Universidad Nacional de Colombia.
2020;25:339–52.
150. Barea MJ, Jenkins MJ, Gaber MH, Bridson RH. Evaluation of
liposomes coated with a pH responsive polymer. Int J Pharm
Elsevier. 2010;402:89–94.
151. Hosny KM, Ahmed OAA, Al-Abdali RT. Enteric-coated alen-
dronate sodium nanoliposomes: a novel formula to overcome
barriers for the treatment of osteoporosis. Expert Opin Drug
Deliv. Taylor & Francis. 2013;10:741–6.
152. Kazakov S. Liposome-nanogel structures for future pharmaceuti-
cal applications: an updated review. Curr Pharm Des Bentham
Science Publishers. 2016;22:1391–413.
153. Klemetsrud T, Jonassen H, Hiorth M, Kjøniksen A-L, Smistad
G. Studies on pectin-coated liposomes and their interaction with
mucin. Colloids Surf B Biointerfaces Elsevier. 2013;103:158–65.
154. Parmentier J, Hofhaus G, Thomas S, Cuesta LC, Gropp F,
Schröder R, et al. Improved oral bioavailability of human growth
hormone by a combination of liposomes containing bio-enhanc-
ers and tetraether lipids and omeprazole. J Pharm Sci Elsevier.
2014;103:3985–93.
155. Pons M, Lizondo M, Gallardo M, Freixas J, Estelrich J. Enro-
floxacin loaded liposomes obtained by high speed dispersion
method. Chem Pharm Bull. The Pharmaceutical Society of
Japan. 1995;43:983–7.
156. Schneider T, Sachse A, Röbling G, Brandl M. Large-scale pro-
duction of liposomes of defined size by a new continuous high
pressure extrusion device. Drug Dev Ind Pharm. Taylor & Fran-
cis. 1994;20:2787–807.
157. Jangde R, Singh D. Preparation and optimization of quercetin-
loaded liposomes for wound healing, using response surface
methodology. Artif cells, nanomedicine, Biotechnol. Taylor &
Francis. 2016;44:635–41.
158. Cui M-D, Pan Z-H, Pan L-Q. Danggui Buxue extract-loaded
liposomes in thermosensitive gel enhance in vivo dermal
wound healing via activation of the VEGF/PI3K/Akt and
TGF-β/Smads signaling pathway. Evidence-Based Comple-
ment Altern Med. Hindawi. 2017;2017:1-13
159. Castangia I, Nácher A, Caddeo C, Valenti D, Fadda AM,
Díez-Sales O, et al. Fabrication of quercetin and curcumin
bionanovesicles for the prevention and rapid regeneration of
full-thickness skin defects on mice. Acta Biomater Elsevier.
2014;10:1292–300.
160. Alavi M, Nokhodchi A. Antimicrobial and wound healing activi-
ties of electrospun nanofibers based on functionalized carbohy-
drates and proteins. Cellulose Springer. 2022;100:1–17.
161. Momin M, Patel Z, Gharat S, Altabakha M, Ashames A, Boddu
S. Recent advancements in electrospun nanofibers for wound
healing: polymers, clinical and regulatory perspective. Crit Rev
Ther Drug Carr Syst Begel House Inc. 2022;39:83–118.
162. Hromadka M, Collins JB, Reed C, Han L, Kolappa KK, Cairns
BA, et al. Nanofiber applications for burn care. J Burn care Res.
Oxford University Press. 2008;29:695–703.
163. Cerchiara T, Abruzzo A, Palomino RAÑ, Vitali B, De Rose R,
Chidichimo G, et al. Spanish Broom (Spartium junceum L.)
fibers impregnated with vancomycin-loaded chitosan nanopar-
ticles as new antibacterial wound dressing: preparation, charac-
terization and antibacterial activity. Eur J Pharm Sci. Elsevier.
2017;99:105–12.
13
AAPS PharmSciTech (2023) 24:155
164. Aytac Z, Uyar T. Electrospun nanofibers for drug delivery
applications. Appl Polym Nanofibers Wiley Online Library.
2022;15:202–54.
165. Gao C, Zhang L, Wang J, Jin M, Tang Q, Chen Z, et al. Electro-
spun nanofibers promote wound healing: theories, techniques,
and perspectives. J Mater Chem B. Royal Society of Chemistry.
2021;9:3106–30.
166. Zheng F, Li R, He Q, Koral K, Tao J, Fan L, et al. The elec-
trostimulation and scar inhibition effect of chitosan/oxidized
hydroxyethyl cellulose/reduced graphene oxide/asiaticoside lipo-
some based hydrogel on peripheral nerve regeneration in vitro.
Mater Sci Eng C. Elsevier. 2020;109:110560.
167. Paolino D, Cosco D, Cilurzo F, Trapasso E, Morittu VM, Celia
C, et al. Improved in vitro and in vivo collagen biosynthesis by
asiaticoside-loaded ultradeformable vesicles. J Control Release
Elsevier. 2012;162:143–51.
168. Suwantong O, Ruktanonchai U, Supaphol P. Electrospun cel-
lulose acetate fiber mats containing asiaticoside or Centella asi-
atica crude extract and the release characteristics of asiaticoside.
Polymer (Guildf). Elsevier. 2008;49:4239–47.
169. Suwantong O, Ruktanonchai U, Supaphol P. In vitro biological
evaluation of electrospun cellulose acetate fiber mats containing
asiaticoside or curcumin. J Biomed Mater Res Part A. Wiley
Online Library. 2010;94:1216–25.
170. Zhu L, Liu X, Du L, Jin Y. Preparation of asiaticoside-loaded
coaxially electrospinning nanofibers and their effect on deep
partial-thickness burn injury. Biomed Pharmacother Elsevier.
2016;83:33–40.
171. Mutlu G, Calamak S, Ulubayram K, Guven E. Curcumin-loaded
electrospun PHBV nanofibers as potential wound-dressing mate-
rial. J Drug Deliv Sci Technol Elsevier. 2018;43:185–93.
172. Khan AK, Kaleem S, Pervaiz F, Sherazi TA, Khan SA, Khan
FA, et al. Antibacterial and wound healing potential of electro-
spun PVA/MMT nanofibers containing root extract of Berberis
lycium. J Drug Deliv Sci Technol. Elsevier. 2023;79:103987.
173. Manca ML, Matricardi P, Cencetti C, Peris JE, Melis V, Car-
bone C, et al. Combination of argan oil and phospholipids for
the development of an effective liposome-like formulation able
to improve skin hydration and allantoin dermal delivery. Int J
Pharm Elsevier. 2016;505:204–11.
174. Zhao Y-Z, Lu C-T, Zhang Y, Xiao J, Zhao Y-P, Tian J-L, et al.
Selection of high efficient transdermal lipid vesicle for curcumin
skin delivery. Int J Pharm Elsevier. 2013;454:302–9.
175. El Maghraby GM, Barry BW, Williams A. Liposomes and skin:
from drug delivery to model membranes. Eur J Pharm Sci Else-
vier. 2008;34:203–22.
176. Raza K, Kumar M, Kumar P, Malik R, Sharma G, Kaur M, et al.
Topical delivery of aceclofenac: challenges and promises of novel
drug delivery systems. Biomed Res Int Hindawi. 2014;2014:1–12.
177. Guo M, Li W, Yang F, Liu H. Controllable biosynthesis of gold
nanoparticles from a Eucommia ulmoides bark aqueous extract.
Spectrochim acta part A Mol Biomol Spectrosc. Elsevier.
2015;142:73–9.
178. Begum NA, Mondal S, Basu S, Laskar RA, Mandal D. Biogenic
synthesis of Au and Ag nanoparticles using aqueous solutions of
Black Tea leaf extracts. Colloids Surf B Biointerfaces Elsevier.
2009;71:113–8.
179. Isaac RS, Sakthivel G, Murthy CH. Green synthesis of gold and
silver nanoparticles using Averrhoa bilimbi fruit extract. J Nano-
technol Hindawi. 2013;2013:1–6.
180. Ahmed KBA, Subramanian S, Sivasubramanian A, Veerappan G,
Veerappan A. Preparation of gold nanoparticles using Salicornia
brachiata plant extract and evaluation of catalytic and antibacte-
rial activity. Spectrochim Acta Part A Mol Biomol Spectrosc.
Elsevier. 2014;130:54–8.
AAPS PharmSciTech (2023) 24:155
181. Mollick MMR, Bhowmick B, Mondal D, Maity D, Rana D,
Dash SK, et al. Anticancer (in vitro) and antimicrobial effect of
gold nanoparticles synthesized using Abelmoschus esculentus
(L.) pulp extract via a green route. RSC Adv. Royal Society of
Chemistry. 2014;4:37838–48.
182. Khalil MMH, Ismail EH, El-Magdoub F. Biosynthesis of Au
nanoparticles using olive leaf extract: 1st nano updates. Arab J
Chem Elsevier. 2012;5:431–7.
183. Abbasi T, Anuradha J, Ganaie SU, Abbasi SA. Gainful utilization
of the highly intransigent weed ipomoea in the synthesis of gold
nanoparticles. J King Saud Univ Elsevier. 2015;27:15–22.
184. Franco-Romano M, Gil MLA, Palacios-Santander JM, Delgado-
Jaén JJ, Naranjo-Rodríguez I, De Cisneros JLH-H, et al. Sono-
synthesis of gold nanoparticles from a geranium leaf extract.
Ultrason Sonochem. Elsevier. 2014;21:1570–7.
185. Rajeshkumar S, Menon S, Kumar SV, Tambuwala MM, Bakshi
HA, Mehta M, et al. Antibacterial and antioxidant potential of
biosynthesized copper nanoparticles mediated through Cissus
arnotiana plant extract. J Photochem Photobiol B Biol. Elsevier.
2019;197:111531.
186. Jain P, Pradeep T. Potential of silver nanoparticle-coated polyu-
rethane foam as an antibacterial water filter. Biotechnol Bioeng
Wiley Online Library. 2005;90:59–63.
187. Rivas L, Sanchez-Cortes S, Garcia-Ramos JV, Morcillo G.
Growth of silver colloidal particles obtained by citrate reduc-
tion to increase the Raman enhancement factor. Langmuir ACS
Publications. 2001;17:574–7.
188. Srinivas Reddy K, Reddy CS, Sanjeeva KA. Antimicrobial poten-
tial of Cassia roxburghii leaves. J Pharm Res. 2011;4:4278–9.
189. Balakumaran MD, Ramachandran R, Balashanmugam P, Mukesh-
kumar DJ, Kalaichelvan PT. Mycosynthesis of silver and gold nano-
particles: optimization, characterization and antimicrobial activity
against human pathogens. Microbiol Res Elsevier. 2016;182:8–20.
190. Krychowiak M, Grinholc M, Banasiuk R, Krauze-Baranowska
M, Głód D, Kawiak A, et al. Combination of silver nanoparticles
and Drosera binata extract as a possible alternative for antibiotic
treatment of burn wound infections caused by resistant Staphy-
lococcus aureus. PLoS One. Public Library of Science San Fran-
cisco, USA. 2014;9:e115727.
191. Niska K, Zielinska E, Radomski MW, Inkielewicz-Stepniak I.
Metal nanoparticles in dermatology and cosmetology: inter-
actions with human skin cells. Chem Biol Interact Elsevier.
2018;295:38–51.
192. Zylberberg C, Matosevic S. Pharmaceutical liposomal drug deliv-
ery: a review of new delivery systems and a look at the regulatory
landscape. Drug Deliv. 2016;23:3319–29.
193. Manconi M, Manca ML, Caddeo C, Valenti D, Cencetti C, Diez-
Sales O, et al. Nanodesign of new self-assembling core-shell
gellan-transfersomes loading baicalin and in vivo evaluation of
repair response in skin. Nanomedicine Nanotechnology, Biol
Med. Elsevier. 2018;14:569–79.
194. Manconi M, Manca ML, Caddeo C, Cencetti C, di Meo C,
Zoratto N, et al. Preparation of gellan-cholesterol nanohydro-
gels embedding baicalin and evaluation of their wound healing
activity. Eur J Pharm Biopharm Elsevier. 2018;127:244–9.
195. Alhakamy NA, A. Fahmy U, Badr-Eldin SM, Ahmed OAA,
Asfour HZ, Aldawsari HM, et al. Optimized icariin phytosomes
exhibit enhanced cytotoxicity and apoptosis-inducing activities
in ovarian cancer cells. Pharmaceutics. MDPI. 2020;12:346.
196. Kumar S, Baldi A, Sharma DK. Phytosomes: a modernistic
approach for novel herbal drug delivery—enhancing bioavail-
ability and revealing endless Frontier of Phytopharmaceuticals.
J Dev Drugs. 2019;9:1–8.
197. Lu M, Qiu Q, Luo X, Liu X, Sun J, Wang C, et al. Phyto-phos-
pholipid complexes (phytosomes): a novel strategy to improve
Page 25 of 26 155
the bioavailability of active constituents. Asian J Pharm Sci Else-
vier. 2019;14:265–74.
198. Mazumder A, Dwivedi A, Du Preez JL, Du Plessis J. In vitro
wound healing and cytotoxic effects of sinigrin–phytosome com-
plex. Int J Pharm Elsevier. 2016;498:283–93.
199. Mazumder A, Dwivedi A, Fox LT, Brümmer A, Du Preez JL,
Gerber M, et al. In vitro skin permeation of sinigrin from its phy-
tosome complex. J Pharm Pharmacol Oxford University Press.
2016;68:1577–83.
200. Partoazar A, Kianvash N, Darvishi MH, Nasoohi S, Rezayat SM,
Bahador A. Ethosomal curcumin promoted wound healing and
reduced bacterial flora in second degree burn in rat. Drug Res
(Stuttg). © Georg Thieme Verlag KG. 2016;66:660–5.
201. Kumar M, Sharma A, Mahmood S, Thakur A, Mirza MA, Bhatia
A. Franz diffusion cell and its implication in skin permeation
studies. J Dispers Sci Technol. Taylor & Francis. 2023;1–14.
202. Dutt Y, Pandey RP, Dutt M, Gupta A, Vibhuti A, Raj VS, et al.
Liposomes and phytosomes: nanocarrier systems and their appli-
cations for the delivery of phytoconstituents. Coord Chem Rev.
Elsevier. 2023;491:215251.
203. Jamaludin R, Daud NM, Sulong RSR, Yaakob H, Aziz AA,
Khamis S, et al. Andrographis paniculata-loaded niosome for
wound healing application: characterisation and in vivo analyses.
J Drug Deliv Sci Technol. Elsevier. 2021;63:102427.
204. Isfandiary A, Widiyanti P, Hikmawati D. Composite of chitosan-
collagen-aloe vera for scaffolds application on skin tissue. J Bio-
mimetics, Biomater Biomed Eng. Trans Tech Publ. 2017:82–9.
205. Dai X, Liu J, Zheng H, Wichmann J, Hopfner U, Sudhop S,
et al. Nano-formulated curcumin accelerates acute wound heal-
ing through Dkk-1-mediated fibroblast mobilization and MCP-
1-mediated anti-inflammation. NPG Asia Mater Nature Publish-
ing Group. 2017;9:e368–e368.
206. Suganya S, Senthil Ram T, Lakshmi BS, Giridev VR. Herbal
drug incorporated antibacterial nanofibrous mat fabricated by
electrospinning: an excellent matrix for wound dressings. J Appl
Polym Sci. Wiley Online Library. 2011;121:2893–9.
207. Hikmawati D, Rohmadanik AR, Putra AP. The effect of aloe vera
extract variation in electrospun polyvinyl alcohol (PVA)-Aloe
vera-based nanofiber membrane. J Phys Conf Ser IOP Publish-
ing. 2018;1120:12096.
208. Nguyen TTT, Ghosh C, Hwang S-G, Dai Tran L, Park JS. Char-
acteristics of curcumin-loaded poly (lactic acid) nanofibers for
wound healing. J Mater Sci Springer. 2013;48:7125–33.
209. Bui HT, Chung OH, Cruz J Dela, Park JS. Fabrication and char-
acterization of electrospun curcumin-loaded polycaprolactone-
polyethylene glycol nanofibers for enhanced wound healing.
Macromol Res. Springer. 2014;22:1288–96.
210. Shoba E, Lakra R, Kiran MS, Korrapati PS. Fabrication of core–
shell nanofibers for controlled delivery of bromelain and salvia-
nolic acid B for skin regeneration in wound therapeutics. Biomed
Mater. IOP Publishing. 2017;12:35005.
211. Balasubramanian K, Kodam KM. Encapsulation of therapeutic
lavender oil in an electrolyte assisted polyacrylonitrile nanofibres
for antibacterial applications. Rsc Adv Royal Society of Chem-
istry. 2014;4:54892–901.
212. Zhang D, Li L, Shan Y, Xiong J, Hu Z, Zhang Y, et al. In vivo
study of silk fibroin/gelatin electrospun nanofiber dressing
loaded with astragaloside IV on the effect of promoting wound
healing and relieving scar. J Drug Deliv Sci Technol Elsevier.
2019;52:272–81.
213. Li Z, Liu M, Wang H, Du S. Increased cutaneous wound healing
effect of biodegradable liposomes containing madecassoside:
preparation optimization, in vitro dermal permeation, and in vivo
bioevaluation. Int J Nanomedicine Dove Press. 2016;11:2995.
214. Nunes PS, Rabelo AS, de Souza JCC, Santana BV, da Silva
TMM, Serafini MR, et al. Gelatin-based membrane containing
13
155 Page 26 of 26
usnic acid-loaded liposome improves dermal burn healing in a
porcine model. Int J Pharm Elsevier. 2016;513:473–82.
215. da Silva FR, Silva RO, de Castro Oliveira HM, Dourado LFN, da
Costa BL, Lima BS, et al. Gelatin-based membrane containing
usnic acid-loaded liposomes: a new treatment strategy for corneal
healing. Biomed Pharmacother. Elsevier. 2020;130:110391.
216. Fu X, Shi Y, Wang H, Zhao X, Sun Q, Huang Y, et al. Ethosomal
gel for improving transdermal delivery of thymosin β-4. Int J
Nanomedicine. Dove Press. 2019;14:9275.
217. Kumar S, Kumar A, Kumar N, Singh P, Singh TU, Singh BR,
et al. In vivo therapeutic efficacy of Curcuma longa extract
loaded ethosomes on wound healing. Vet Res Commun Springer.
2022;46:1–17.
218. Basit HM, Mohd Amin MCI, Ng S-F, Katas H, Shah SU,
Khan NR. Formulation and evaluation of microwave-modified
chitosan-curcumin nanoparticles—a promising nanomaterials
platform for skin tissue regeneration applications following burn
wounds. Polymers (Basel). MDPI. 2020;12:2608.
219. Chereddy KK, Coco R, Memvanga PB, Ucakar B, des Rieux A,
Vandermeulen G, et al. Combined effect of PLGA and curcumin on
wound healing activity. J Control Release. Elsevier. 2013;171:208–15.
220. Zahiri M, Khanmohammadi M, Goodarzi A, Ababzadeh S, Fara-
hani MS, Mohandesnezhad S, et al. Encapsulation of curcumin
loaded chitosan nanoparticle within poly (ε-caprolactone) and
gelatin fiber mat for wound healing and layered dermal reconsti-
tution. Int J Biol Macromol Elsevier. 2020;153:1241–50.
221. Vasile BS, Birca AC, Musat MC, Holban AM. Wound dress-
ings coated with silver nanoparticles and essential oils for the
management of wound infections. Materials (Basel). MDPI.
2020;13:1682.
222. Sheikholeslami S, Mousavi SE, Ashtiani HRA, Doust SRH,
Rezayat SM. Antibacterial activity of silver nanoparticles and
their combination with zataria multiflora essential oil and metha-
nol extract. Jundishapur J Microbiol Brieflands. 2016;9:36070.
223. Balaure PC, Holban AM, Grumezescu AM, Mogoşanu GD,
Bălşeanu TA, Stan MS, et al. In vitro and in vivo studies of novel
fabricated bioactive dressings based on collagen and zinc oxide
3D scaffolds. Int J Pharm Elsevier. 2019;557:199–207.
13
AAPS PharmSciTech (2023) 24:155
224. Ahmad N, Ahmad R, Al-Qudaihi A, Alaseel SE, Fita IZ, Khalid
MS, et al. Preparation of a novel curcumin nanoemulsion by
ultrasonication and its comparative effects in wound healing and
the treatment of inflammation. RSC Adv Royal Society of Chem-
istry. 2019;9:20192–206.
225. Alam P, Shakeel F, Anwer MK, Foudah AI, Alqarni MH. Wound
healing study of eucalyptus essential oil containing nanoemulsion
in rat model. J Oleo Sci Japan Oil Chemists’ Soc. 2018;67:8005.
226. Chakraborty T, Gupta S, Nair A, Chauhan S, Saini V. Wound
healing potential of insulin-loaded nanoemulsion with Aloe
vera gel in diabetic rats. J Drug Deliv Sci Technol. Elsevier.
2021;64:102601.
227. Harshitha C, Bhattacharyya S. A brief review on nanotechnology
as a challenging field in pharmaceuticals and their regulatory
approval. J Crit Rev. 2020;7:963–8.
228. Murray AR, Kisin ER, Tkach AV, Yanamala N, Mercer R, Young
S-H, et al. Factoring-in agglomeration of carbon nanotubes and
nanofibers for better prediction of their toxicity versus asbestos.
Part Fibre Toxicol BioMed Central. 2012;9:1–19.
229. Abrams MT, Koser ML, Seitzer J, Williams SC, DiPietro MA,
Wang W, et al. Evaluation of efficacy, biodistribution, and
inflammation for a potent siRNA nanoparticle: effect of dexa-
methasone co-treatment. Mol Ther Elsevier. 2010;18:171–80.
230. Sousa D, Ferreira D, Rodrigues JL, Rodrigues LR. Nanotechnol-
ogy in targeted drug delivery and therapeutics. Appl Target nano
drugs Deliv Syst Elsevier. 2019:357–409.
231. Tripathy N, Hong T-K, Ha K-T, Jeong H-S, Hahn Y-B. Effect
of ZnO nanoparticles aggregation on the toxicity in RAW 264.7
murine macrophage. J Hazard Mater. Elsevier. 2014;270:110–7.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Springer Nature or its licensor (e.g. a society or other partner) holds
exclusive rights to this article under a publishing agreement with the
author(s) or other rightsholder(s); author self-archiving of the accepted
manuscript version of this article is solely governed by the terms of
such publishing agreement and applicable law.