Faculty of Pharmacy

Pharmaceutics Department

A Sustainable Approach for A Novel Greenly-Synthesized

Nanopharmaceutical System for Wound Healing
(RSPT1.9)

Submitted by:

Cheri Ussama Sami ID: 200791

Julliana Ashraf Ghaly ID: 201111
Nermin Hussein Kassem ID: 200957
Salma Mohamed Monir ID: 201515

Under supervision of: Dr. Dina Saeed

Dr. Omar Elkady
Assistants: A.L. Maysoon Mostafa
T.A. Aya Maher

A Project Submitted in Partial Fulfillment of Bachelor of Pharmacy for

October University for Modern Sciences and Arts
Year 2023/2024
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 DECLARATION
The project report is the outcome of the individual work of Cheri Ussama, Julliana Ashraf, Nermin
Hussein, and Salma Mohamed. All the other work reported in the text has been referred to the original
authors and is fully referenced and listed in the reference section.
Signature Date
…...…………….. …………………

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 List of Contents

1.0 Abstract ......................................................... Error! Bookmark not defined.

2.0 Introduction .................................................. Error! Bookmark not defined.

3.0 Review of Literature ...................................................................................... 3

3.1 Wounds and Wound Healing.................................................................................................. 3

3.1.1 Introduction ............................................................................................................... 3

3.1.2 Types of Wounds ....................................................................................................... 4

3.1.3 Burden of Wounds ..................................................................................................... 4

3.1.4 Stages of Healing ....................................................................................................... 5

3.1.5 Challenges in Wound Healing Process .................... Error! Bookmark not defined.

3.1.6 Current Management ............................................... Error! Bookmark not defined.

3.2 Nanotechnology ........................................................................................................................ 8

3.2.1 Definition .................................................................................................................. 8

3.2.2 Benefits of Nanotechnology ...................................................................................... 8

3.2.3 Types of Nanoparticles............................................................................................... 8

3.2.4 Applications of Nanotechnology ............................................................................... 9

3.2.5 Nano-Based Drug Delivery System ........................................................................ 10

3.2.6 Drug Delivery Systems Used for Wound Healing .................................................. 10

3.2.7 A Novel Carrier System of Choice for Wound HealingError! Bookmark not
defined.

3.2.8 Mechanism of Action of Carbon Dots in Wound HealingError! Bookmark not

defined.

3.3 Herbal Medicine in Wound Healing ........................................ Error! Bookmark not defined.

3.3.1 Introduction ............................................................. Error! Bookmark not defined.

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 3.3.2 Garlic (Allium sativum L.) ...................................... Error! Bookmark not defined.

3.3.3 Garlic in Wound Healing ......................................... Error! Bookmark not defined.

3.3.4 Garlic in Advanced Systems.................................................................................... 17

3.4. Alpha Lipoic Acid ..................................................................... Error! Bookmark not defined.

3.4.1 Nature of Alpha Lipoic Acid ................................................................................... 18

3.4.2 Chemical and physical properties of alpha-lipoic acid ............................................ 19

3.4.3 Administration of alpha-lipoic acid......................................................................... 19

3.4.4 Indications of alpha-lipoic acid ............................................................................... 19

3.4.5 Mechanism of actions of alpha-lipoic acid ............. Error! Bookmark not defined.

3.4. 6 Side Effects of Alpha Lipoic Acid ......................... Error! Bookmark not defined.

3.4.7 Drug-drug interactions with alpha lipoic acid ....................................................... 22

3.4. 6 Contraindications of Alpha Lipoic Acid ................ Error! Bookmark not defined.

4.0 Conclusion..................................................................................................... 24

5.0 References ..................................................................................................... 25

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 List of Figures

Figure Title Page

number number
1 Skin layers. 3
2 Stages of wound healing. 6
3 Various classes of nanotechnology-based-materials for the 9
medical domain.
4 Drug delivery systems for wound healing. 11

5 The responsible factors for the antimicrobial effect of cationic 12

CDs.
6 The contribution of ROS to wound decontamination. 13

7 The effect of acidic pH on successful wound healing. 13

8 Herbs used to speed up wound healing. 15
9 Pharmacological activity of Garlic. 16
10 The four main phases of the wound healing process. 17
11 Effect of Hyaluoronate-based oil core nanocapsule. 17
12 The formation process of carbon dots from garlic by 18
hydrothermal treatment.
13 Food sources of alpha lipoic acid. 19

14 Chemical structure of alpha lipoic acid. 19

15 Indications of alpha lipoic acid 21

16 Mechanism of actions of alpha lipoic acid. 22

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 1.0 Abstract
Chronic non-healing wounds cause an immense burden to the wounded individuals reducing
productivity. Some wounds require years for healing. Other wounds may remain unhealed.
Therefore, we aim to take advantage of the wound healing activity of carbon dots (CDs); the carrier
system which is prepared from garlic that has antioxidant, anti-microbial and anti-inflammatory
activities that heal wounds. In addition to loading alpha-lipoic acid (ALA); a drug with a promising
wound healing activity due to its powerful antioxidant activity. This will lead to formation of a
greenly-synthesized nanosystem with the potential to enhance wound healing through synergistic
drug repurposing strategy. So, the main objectives are synthesis and characterization of highly
fluorescent garlic-based carbon dots, physico-chemical characterization of the drug-loaded carbon
dots and then in vitro and ex vivo assessment of the developed system for potential wound healing
activity. To achieve that, the plan is to construct a calibration curve first to predict the concentration
of alpha lipoic acid in any sample. Then, choosing the appropriate method of preparation either
bottom up or top down. After that, synthesizing the garlic-based carbon dots and loading the drug on
the highly fluorescent CDs. Last but not least, in vitro assessment is done using Transmission
Electron Microscopy (TEM) to estimate the particle size, zetasizer to calculate zeta potential, X-Ray
Diffraction (XRD) to check the crystalline nature of drug, Infrared Spectroscopy (IR) to estimate the
interaction between chemical groups within the developed nanosystem, assessment of the in-vitro
drug release from particles and measurement of the loading capacity and entrapment efficiency for
drug and CDs. At last, ex-vivo evaluation is done through applying a cytotoxicity test and scratch
wound healing assay. Implementation of the mentioned plan should ascertain the formation of an
innovative and effective nanosystem with a synergistic wound healing activity.

2.0 Introduction
Wounds are frequent aspects of the human experience whether they result from accidents, traumatic
injuries, or surgical treatments. Wound healing is a mechanism where complex and coordinated
biological actions occur in response to changes in the integrity of the skin, with the final goal of
restoring the functions of the tissue. Numerous natural substances with therapeutic properties have
been investigated to find novel and effective ways to accelerate the healing of wounds. Garlic stands
out among them all as a potential option because of its antimicrobial, anti-inflammatory, and
antioxidant properties. The use of nanotechnology in applications related to wound healing has
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created new opportunities for advanced therapies in recent years. Carbon dots which are nanoscale
carbon particles derived from garlic, have attracted interest due to their unique characteristics and
ability to aid in wound healing. The use of these carbon dots presents a novel method for the
administration of medicinal substances. Of particular note is the possibility of improving the wound
healing process by adding an alpha-lipoic acid drug that has a powerful antioxidant and anti-
inflammatory onto the garlic-based carbon dots.

The current state of knowledge regarding the use of garlic-based carbon dots loaded with alpha lipoic
acid in wound healing is examined in this review of literature. The aim is to present a thorough
overview of the possible benefits of this novel approach in promoting immediate and effective wound
healing by looking at the underlying mechanisms, experimental results, and medicine applications.

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 3.0 review of literature

3.1 wounds and wound management

3.1.1 introduction

Our skin, the largest organ of the human body, plays a vital role in maintaining our overall health.
Covering an expansive 1.85 square meters and accounting for a significant 16% of our body
weight, it serves as a crucial barrier against the external environment. This protective shield
defends us from infections and prevents fluid loss, while also contributing to homeostasis, the
body's ability to regulate its internal state. Maintaining the integrity of our skin is therefore
essential, as injuries or wounds caused by trauma, burns, chronic diseases, or surgery can lead to
disability, and pain, and pose a significant burden on healthcare systems worldwide (Kolimi et al.,
2022).

The skin is divided into three layers: epidermis, dermis, and hypodermis, with about 50 different
cell types. The skin's primary tasks include providing sufficient protection against extreme
variables (ultraviolet light, germs, chemical, thermal, etc.), preventing water loss from the tissues,
regulating body temperature, and promoting metabolic operations (vitamin D synthesis). The
epidermis and dermis are two major structural layers within the skin that are joined by the
foundation membrane. The hypodermis is a subcutaneous layer that sits beneath the other two
layers, coupled with adipose tissue (Figure 1) (Kolimi et al., 2022).

Figure (1): skin layers

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3.1.2 Types of Wounds

Wounds are described as injuries or disorders that threaten the skin integrity or structure caused
by external forces (cuts, burns, pressure), an operation, or pathological conditions like diabetes or
vascular disorders. Wounds are classed as acute or chronic based on their healing duration and
method. Acute wounds are injuries induced by a variety of processes, including radiation, extreme
temperature fluctuations, toxins, etc.

Acute wounds typically heal in 4-12 weeks with the regaining of normal function and structural
skin integrity via an organized classical wound healing process. Chronic wounds, on the other
hand, are difficult to heal due to underlying pathological disorders. Furthermore, past infection,
inflammation, tumors, or other physical factors can all cause chronic wounds (Kolimi et al., 2022).

3.1.3 Burden of Wounds

Wound healing is a hardship and cost to a country's health care system. According to statistics,
more than 13 million individuals worldwide suffer from chronic wounds every year, and the total
number of patients impacted is gradually increasing as the world's population ages (Chakraborty,
Gupta, and Ghosh, 2014). Chronic wounds of the lower leg are commonly hard to heal, resulting
in reduced patient satisfaction, higher morbidity and mortality rates, and considerable increases in
health care expenses (Järbrink et al., 2017).

Wounds are frequently thought to be exclusively medical events however, there is mounting
evidence that the psychological impact on the patient is equally important. The psychological
impacts may be caused by the wound itself, the suffering connected with the wound, or the wound's
social or physical effects. Malodor and excessive exudate are typical signs of chronic wounds.
These can lead to increased anxiety and sadness, shame, bad body image, and social isolation, all
of which have a detrimental influence on quality of life. Some people may try various methods of
dealing with exudate and malodor. Such efforts are frequently ineffectual and, in some situations,
might aggravate the wound. For example, individuals would try to cover wounds to prevent
leakage, drink less fluid to reduce the quantity of exudate produced and discard bandages to let
exudate disperse (Upton and Penn, 2011).
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3.1.4 Stages of Healing

Wound healing is a dynamic process that consists of four continuous, overlapped, and carefully
regulated stages. In adult humans, optimum wound healing consists of the following stages:

i. Hemostasis

Damaged blood arteries constrict, stopping the flow of blood. Platelets, the initial responders,
rush to the wound site and produce a fibrin clot (a temporary plug) to cover the gap (Gonzalez
et al., 2016).

ii. Inflammation
Once the bleeding is under control, neutrophils invade the wound and fight bacteria and
other diseases. They destroy cellular debris, making space for the following cellular
defenders. Macrophages appear to continue to fight infection, while others play a caring
function, releasing growth hormones and indicating the beginning of the rebuilding phase
(Ozgok Kangal and Regan, 2018).

iii. Proliferation

Fibroblasts move forward in response to macrophage signals. They lay the basis of the protein
collagen, called granulation tissue, which acts as the basis for future construction. At the same
time, endothelial cells create a network of new blood arteries that transport important nutrients
and oxygen to the building tissue. Finally, keratinocytes move over the wound area, producing
a new layer of skin, sealing the gap, and rebuilding the skin (Ozgok Kangal and Regan, 2018).

iv. Remodeling

This stage focuses on refining and developing. Excess blood vessels are removed, and collagen
fibers are precisely restructured to ensure maximum strength and flexibility. The rebuilt tissue
regains much of its former strength and function.

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Several different cell types have roles in the wound healing process, and as previously stated, the
cellular activity of any specific cell type can change at different stages of repair. The complexity
and coordination of the healing process present significant challenges to therapeutic techniques,
as any therapy must be effectively sequenced to the right stage (Figure 2) (Gonzalez et al., 2016).

Figure (2): stages of wound healing

3.1.5 Challenges in Wound Healing Process

While the human body's ability to repair itself is truly remarkable, the path to full wound healing
sometimes faces difficulties. These challenges can have an important impact on a patient's physical
and emotional well-being, delaying rehabilitation and lowering quality of life.

i. Delayed Healing

Certain conditions, such as diabetes, malnutrition, and poor circulation, can impair the body's
normal healing processes. This can result in chronic wounds that last for weeks or months,
increasing the risk of infections (Ozgok Kangal and Regan, 2018).

ii. Scar Formation

Hypertrophic scars, which are caused by excessive collagen formation, and keloids, which
spread over the original wound borders, may lead to pain, discomfort, and functional problems
(Juckett and Hartman-Adams, 2009).
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 iii. Pain Management

Wound pain can be devastating, affecting sleep, daily activities, and overall quality of life.
Effective pain management is critical to supporting healing and the well-being of patients
(Bechert and Abraham, 2009).

iv. Wound Management Complexity

Each wound requires a unique and frequently complex care routine. This may include
regular cleaning, dressing changes, and the application of topical agents. Handling this
complexity can be difficult for patients and healthcare practitioners equally (Haesler and
Rice, 2020).

v. Infections

Wounds are prone to infection, especially when hygiene is poor or the immune system is
weakened. Bacterial, fungal, and viral infections can severely slow recovery and cause
serious problems (Rutter, 2018).

3.1.6 Current Managements

i. Conventional Herbal Treatment

Many plants and their extracts have been traditionally employed due to their high potential
for wound management and treatment. Natural substances promote healing and tissue
regeneration through a variety of related pathways. Herbal remedies (such as honey, thyme,
and aloe Vera) in wound management include disinfection, debridement, and the creation of
an appropriate environment to aid in the natural healing process (Maver et al., 2015).

ii. Drugs

In wound healing, three therapeutic agents take center stage: anti-inflammatory drugs,
antioxidants, and antibiotics. Ibuprofen and other anti-inflammatories reduce swelling and
discomfort, allowing cells to heal themselves. Antioxidants, such as vitamin C, neutralize
free radicals and increase collagen formation, strengthening the healing tissue. Furthermore,
antimicrobials, such as topical antibiotics, invade germs, preserving the sensitive site
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 from infection. These aligned actions prepare the path for faster, smoother healing (Enoch,
Grey, and Harding, 2006).

iii. Current Advanced Approaches

The field of wound healing has been growing rapidly and a large number of groups are
investigating various aspects of wound pathogenesis and providing mechanistic insights
about the healing process. There is a vast range of biomaterial-based delivery systems for
proteins, DNA, and small-molecule medicines used in wound healing. Hydrogels, scaffolds,
nanoparticles, complexes, and coacervates have all shown efficacy in various in vivo
models, and each might be best suited for a certain use or situation (Johnson and Wang,
2015).

3.2 nanotechnology

3.2.1 Definition
Particulate matter between 1 and 100 nm in size may be purposefully engineered and
manipulated to create nano-systems with enhanced functioning by rearranging or reassembling
them. This process is known as nanotechnology. In contrast to other large-scale designed objects
and systems, nanoparticles provide a significant surface area-to-volume ratio, making them
distinctive. Significant advancements are being achieved in a variety of applications, making
the subject of nanotechnology one of the fastest-growing fields of scientific study and
development (Haleem et al., 2023).

3.2.2 Benefits of nanotechnology

Numerous advantages come to the field of nanotechnology, such as strengthened, lighter, and
more durable materials, as well as enhanced water filtration and purification, energy efficiency,
and purification. Furthermore, nanotechnology has promise to generate drugs, medical
equipment, and diagnostic tools that are more accurate and effective (Haleem et al., 2023).

3.2.3 Types of nanoparticles

Based on their chemical makeup, nanoparticles are divided into three categories: organic,
inorganic, and carbon-based. These three categories represent some of the main categories for
nanoparticles. Proteins, lipids, carbohydrates, and other organic compounds are synthesized into
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particles known as organic nanoparticles, which have a radius of less than 100 nm. Numerous
distinct material classes and classifications with special medical applications have been
developed as a result of the science of nanotechnology. Various classes of nanomaterials are
reported in the literature, such as hydrogel nanocomposites, metal nanoparticles, carbon- based
nanomaterials, dendrimers, liposomes, biodegradable polymers, and many others, which
enhance and broaden the application of nanotechnology in the medical field (Haleem et al.,
2023) (Figure 3).

Figure (3): Various classes of nanotechnology-based-materials for the medical domain.

3.2.4 Applications of nanotechnology

Nanotechnology has a wide range of applications, including energy, electronics and information
technology, textiles, industrial purposes, environmental remediation, and medicaland healthcare
applications.

In Nanomedicine: The field of medicine known as "nanomedicine" applies the science of

nanotechnology to the prevention and treatment of different diseases by employing very small
materials, such as biocompatible nanoparticles and nanorobots, for a variety of purposes, such
as sensing, delivery, and diagnostics. Nanoparticles and nanomaterials are being rapidly studied
for their potential medical uses. One of the most promising areas of use is drug delivery, which
uses nanoparticles as carriers to deliver medications to particular cells or tissues in the body.
Nanoparticles can be created to have particular surface qualities that allow them to precisely
target sick cells while avoiding healthy ones, thereby increasing efficacy and reducing
therapeutic adverse effects.
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 Because of their nanoscale size, nanoparticles have a high surface-area-to-volume ratio,
allowing them to absorb large quantities of medicine while moving fast through the circulation.
Their enhanced surface area enhances their mechanical, magnetic, optical, and catalytic
properties, allowing them to be employed in more medicinal applications.

The different traditional connected properties and qualities of nanotechnology for the medical
sector include wound healing, antimicrobial therapies, minimizing harm to healthy cells, and
nanomedicine diagnostic techniques.

The use of nanoparticles, particularly a novel carrier system for wound healing, has increased
the effectiveness and productivity of nanotechnology-based principles in medicine, where
precision and smartness are required at a larger scale (Haleem et al., 2023)

3.2.5 Nano-based drug delivery system

The field of delivery systems for delivering therapeutic agents or active chemicals derived from
natural sources to their intended region for the treatment of various ailments has seen significant
advancements in recent times. While there are many effective drug deliverysystems in use today,
there are still certain issues that need to be resolved and cutting-edge technology has to be
created to properly transport medications to their intended locations. Therefore, research is now
being done on nano-based drug delivery systems, which will enable more sophisticated drug
delivery systems. Drug delivery methods use a variety of biopolymeric materials, including
gum, chitosan, alginate, xanthan, liposomes, cellulose,dendrimers, and polymeric micelles (Sim
and Wong, 2021).

3.2.6 Drug delivery systems used for wound healing

Liposomes, niosomes, ethosomes, polymeric micelles, and nanoemulsions are examples of
carrier systems that can carry medications or other substances to the wound site, reducing
side effects and drug toxicity while increasing the effectiveness of therapy. However, they have
limits. These carrier systems may have a low loading capacity, a short shelf life, poor stability
that is prone to aggregation, biocompatibility concerns, and difficulties with large-scale
manufacture (Sim and Wong, 2021) (Figure 4).

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 Figure (4): Drug delivery systems for wound healing.

3.2.7 A novel carrier system of choice for wound healing

Carbon dots are carbon-based nanomaterials with their own antibacterial and antimicrobial
activities, as well as unique optical, electrical, and biological capabilities. They have several
benefits over other carrier systems, including:

I. Zero-dimension: Carbon-based nanomaterial with

ultrafine sizes below 10 nm.
II. Highly fluorescent: Due to their excellent chemical
stability and good solubility in water.
III. Eco-friendly: Carbon dots are derived from natural
sources like garlic or thyme.
IV. Biocompatible: Carbon dots are compatible with biological systems, such as cells,
tissues, or organs. They do not cause any adverse effects.
V. Easy to synthesize: by simple and low-cost methods. They can be produced in large
quantities, with high yield and purity.
VI. Low cytotoxicity: Carbon dots do not damage or kill the cells.

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Due to these several potent advantages of carbon dots, carbon dots have played a major role
in drug delivery systems (Sadat et al., 2022).

3.2.8 Mechanisms of action of carbon dots in wound healing

Carbon dots have multiple mechanisms of action that can enhance the healing process, such
as:

i. Damaging the bacterial membrane to prevent wound infection

Carbon dots can interact with the bacterial membrane, causing damage that eventually
kills the bacterium. One of the main issues with wound healing is infection, which may
be avoided or treated in this way (Ehtesabi and Nasri, 2021) (Figure 5).

Figure (5): The responsible factors for the antimicrobial effect of cationic carbon dots.

ii. Intercellular ROS generation

Reactive oxygen species (ROS) produced by carbon dots can alter geneexpression and
cellular signaling associated with wound healing. This may encourage the migration,
proliferation, and differentiation of endothelial, keratinocyte, and fibroblast cells—all
of which are involved in wound healing (Ehtesabi and Nasri, 2021) (Figure 6).

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 Figure (6): The contribution of ROS to wound decontamination.

iii. Monitoring of wound pH

The pH of the wound environment affects the color and intensity of the fluorescence of
carbon dots. This might give a visual clue as to whether the wound is healing, inflamed, or
infected (Ehtesabi and Nasri, 2021) (Figure7).

Figure (7): The effect of acidic pH on successful wound healing

iv. Photodynamic therapy (bio-imaging) and promoting fibroblast and cell proliferation
Singlet oxygen may be produced by carbon dots by absorbing light and transferring the
energy to oxygen molecules. Singlet oxygen can destroy germs and promote wound
contraction, angiogenesis, and collagen formation (Ehtesabi andNasri, 2021).

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3.3 Herbal Medicines in Wound Healing

3.3.1 Introduction

The relationship between herbs and humans was formed in ancient civilizations and is one of the
longest-standing. Herbal medicines include various plant-based materials such as leaves, roots,
flowers, and seeds each having specific chemical compounds that have medicinal properties. Herbal
medicines have been used to treat diseases and enhance wellness by their bioactive ingredients over
decades as they have low side effects compared to synthetic medications, so it is the best option for
allergic patients. About 25% of the therapeutic drugs are herb-based or herb derivatives and their
therapeutic uses are well-known among indigenous people of rural areas in many countries (Dan et
al., 2018).

Medicinal herbs have a pivotal role in the process of wound healing as they involve debridement,
and disinfection and create a moist environment to promote the formation of a suitable natural
healing climate. Traditional Chinese medicine, Ayurveda, Unani, Russian herbalism, and other
medical systems all routinely employ herbal therapy, using botanicals topically to heal wounds and
other dermatological issues. Many studies in the last several decades have concentrated on
developing an innovative wound dressing containing extracts from medicinal plants or their active
ingredients (Yazarlu et al., 2021).

Many plants have properties in wound healing such as aloe Vera, and curcumin have anti-
inflammatory, antimicrobial, and antioxidant effects that accelerate the healing process; cinnamon
has quercetin that accelerates wound healing through its anti-inflammatory effect. Calendula has a
soothing effect as it aids in tissue regeneration (Reza Farahpour, 2019). Althaea officinalis has
bactericidal activity against gram-positive, jojoba and plantago major have antioxidant and
antibacterial properties, achiote has an anti-inflammatory effect and speed collagen modulation,
and comfrey as it is not used directly on open wounds but can be used in speeding the healing of
bruises. There are 5 most herbal supplements used to speed wound healing presented in Figure 8.

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 Figure (8): Herbs used to speed up wound healing.

3.3.2 Garlic (Allium sativum L.)

Garlic is highly recognized in traditional medical systems as traditional Chinese medicine and
Ayurveda for its ability to strengthen the immune system and enhance general health. Worldwide,
garlic's primary physiologically active component, allicin, and its compounds have several
nutritional and therapeutic uses. According to Nakamato et al. (2020) allium plants, including
garlic, onions, and leeks, are useful in the treatment of infectious disorders, garlic includes various
hydrophobic antibacterial chemicals such as diallyl polysulfides, ajoene, vinyldithins, and allicin
which give it a stronger antimicrobial action than other allium species. It is a plentiful, safe, and
low-toxicity source of physiologically active compounds.

All parts of the plant have been used in traditional medicine and as a spice or seasoning for salads
and sausages since ancient times. Garlic has been linked to many biological processes as ithas
numerous physiologically active components with essential vitamins, minerals, and proteins that
make it a useful ingredient in medicines. According to Gebreab and Thirumurugan (2014), garlic
has many pharmacological effects against several kinds of life-threatening diseases including
Alzheimer's disease, cancer as garlic has potential cancer-preventive properties because of its anti-
inflammatory and antioxidant effect, colds and cough because of its antimicrobial-properties that
fight respiratory infections, digestive disorder as it promotes the growth of beneficial gut bacteria
andaid in digestion, cardiovascular diseases as atherosclerosis, strokes, hypertension, thrombosis
and hyperlipidemias as it lower blood pressure and cholesterol levels and reduces risk of clots
15
formation, dermatological applications, stress, diabetes management as garlic may improve insulin
sensitivity and regulate blood glucose and parasitic infections due to its antimicrobial effect. As
shown in Figure 9 the most important pharmacological effects of garlic.

Figure (9): Pharmacological activity of Garlic.

3.3.3 Garlic in Wound Healing

Garlic plays a crucial role in wound healing as it has many effects as antimicrobial, antioxidant, and
anti-inflammatory so garlic exceeds those for other herbs. Allicin is an active compound in garlic
as it shows broad-spectrum antimicrobial, antiviral, antifungal, and antiparasitic activity (Nakamato
et al.,2020). The mechanism of action of allicin as an antimicrobial is a sulfhydryl modification of
bacterial proteins, it also reduces the a-toxin produced by Staphylococcus aureus as this pathogen
is a common skin infection (leng et al., 2011). In particular, the a-toxin induces apoptosis and
releases proinflammatory mediators and cytokines, which greatly hinder wound healing.
Fibroblasts play a role in wound healing so garlic activates fibroblasts this leads to a more rapid
approximation of edges of the skin, more deposition of collagen, and an increase in the strength of
tensile healing tissue (Alhashim and Lombardo, 2018).

Allicin accelerates the healing process of the wound by aiding in the formation of new tissues,
inflammation is a natural response in the early stage of wound healing, but excessive inflammation
will hinder the healing so the anti-inflammatory effect of garlic can modulate the inflammatory
16
response (Alhashim and Lombardo, 2018). Also, it enhances collagen synthesis and augments the
proliferative phase of dermal wound healing. Garlic has flavonoids and sulfur compounds that have
antioxidant effects and these antioxidant effects help to neutralize free radicals reducing oxidative
stress at the site of the wound. The four main stages of wound healing are shown in Figure 10.
Garlic is generally applied topically to heal the wound and there are precautions for sensitive people
to garlic to avoid irritation of t h e skin that is caused when garlic is put directly into the
wound.

Figure (10): The four main phases of the wound healing process.

3.3.4 Garlic in Advanced Systems

i.Nanocapsules are an efficient delivery system of garlic oil components with anticancer activity.
As this system shows protection of active compounds from degradation and enhances their
bioavailability, this system provides a target for cancer treatment and reduces side effects as in
Figure 11 (Janik-Hazuka et al., 2021).

Figure (11): Effect of Hyaluoronate-based oil core nanocapsule.

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ii.Nanoemulsions are used to enhance the antioxidant effect of garlic and improve drug release and
specific targeting (Lu et al., 2021).
iii.Nanoliposomes incorporate garlic active components into nanoliposomes that have phospholipids
that contain lipid bilayer structures that utilize embedded hydrophobic and hydrophilic compounds
and that increase their transport and bioavailability (Lu et al., 2021).
iv.Carbon dots (carbon nanomaterials) A hydrothermal process is used to form fluorescence
carbon dots from garlic used for cellular imaging and free radical scavenging. Garlic-based carbon
dots are biocompatible and non-toxic to living organisms; these characteristics make them suitable
for biological and medical applications (Zhao et al., 2015) (Figure 12).

Figure (12): The formation process of carbon dots from garlic by hydrothermal treatment.

3.4 Alpha-lipoic Acid

3.4.1 Nature of Alpha Lipoic Acid

Alpha-lipoic acid (ALA) is known to be an organo-sulfur compound. It can be found in nature or

produced by humans, animals, and plants. ALA is synthesized within the body from octanoic acid
in the mitochondrion. It plays a vital role in the Krebs cycle by acting as a cofactor in the process
of energy production. So, it is a naturally occurring fatty acid. However, it is produced in small
amounts that are often considered insufficient to fulfill the requirement for energy to achieve
optimal health status. Thus, ALA is also obtained from dietary sources and supplements. Dietary
sources containing ALA include red meat and vegetables such as spinach, carrots, potatoes, and
broccoli (Figure 13). (Salehi et al., 2019).

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 Figure (13): Food sources of alpha-lipoic acid.

3.4.2 Chemical and physical properties of alpha-lipoic acid:

The chemical structure of the drug is crucial for its biological activities. It is a sulfur-containing
compound in which the sulfur atom is bonded to a hydrogen atom which favors its role in the
enzymatic reactions within the body, especially its reactions in the citric acid cycle (Figure 14).
Regarding its solubility, ALA is soluble in both water and fats. Its dual solubility favors its function
in cellular environments; the inside and the outside of cell membranes, whichis important for its
role as a cofactor in metabolism (Salehi et al., 2019).

Figure (14): Chemical structure of alpha-lipoic acid

3.4.3 Administration of alpha-lipoic acid

ALA is known to be administered in oral supplements or IV injections. However, several studies
suggest that preparing ALA in a topical dosage form will improve its activity as it has an extremely
low bioavailability, which is almost 30% (Külkamp-Guerreiro et al., 2013).

3.4.4 Indications of alpha-lipoic acid:

ALA is mainly used for its various health benefits (Gomes and Negrato, 2014). (Figure 15).

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 I. Traditional uses of the drug:

i. Weight loss and metabolism

ALA is known to help with weight loss as it promotes the breakdown of enzymes, which helps in
glucose transport to create energy in metabolism and provide adenosine triphosphate (ATP)
(Nguyen and Gupta, 2022).

ii. Blood sugar control

ALA has an important role in the management of glucose levels. It is mainly used for type 2
diabetes to improve the insulin sensitivity and reduce insulin resistance.

iii. Nerve health

ALA has a neuroprotective property which is used to alleviate the symptoms of diabetic
neuropathy; a complication developed due to diabetes.

iv. Cognitive function

ALA is known to support cognitive function as it passes the blood-brain barrier exerting its
antioxidant activity that kills the free radicals.

v. Cardiovascular health

ALA has a prophylactic effect against atherosclerosis as it decreases the burden of atherosclerotic
plaques and lowers low-density lipoprotein (LDL) and triglyceride (TG). As a result, it prevents
hyperlipidemia and atherosclerosis.

vi. Skin health

This is based on the antioxidant activity of ALA that protects against oxidative damage giving an
anti-aging effect.

vii. Eye health

ALA is a vitamin-like drug that controls some disorders such as glaucoma, cataract, macular
degeneration, and vision loss due to its antioxidant activity.
viii. Anti-inflammatory

The anti-inflammatory properties of ALA are established by inhibiting cyclooxygenase-2

(COX-2) and the release of cytokines.
20
 Figure (15): Indications of alpha-lipoic acid.

II. Novel use of alpha-lipoic acid for wound healing

Base on the anti-inflammatory, antioxidant, and metal-chelation activities of ALA, recent

investigations found that ALA has a potential activity for healing wounds (Sammour et al., 2019).
ALA can be used for wound healing either alone by taking advantage of its potential activity to
heal wounds or it can be loaded on a carrier system with wound healing activity such as the carbon
dots nanoparticles, which combines the power of wound healing of both; the drug and the carrier
achieving synergism (Quester et al., 2022).

3.4.5 Mechanism of actions of alpha-lipoic acid

i. Antioxidant

ALA is known to have a potent antioxidant activity through the inhibition of oxidative stress and
scavenging the reactive oxygen species (ROS) (Sammour et al., 2019). The drug also increases the
levels of potency of other antioxidants in the body such as vitamin E and glutathione (Salehi et al.,
2019).

ii. Anti-Inflammatory

The drug is known to be a strong anti-inflammatory as it limits the synthesis of prostaglandin E2

due to inhibition of COX-2. In addition to decreasing the content of arachidonic acid. It also reduces
the release of cytokines. As a result, a reduction of inflammation occurs (Salehi et al., 2019).

21
 iii. Metal chelator

ALA is known to form stable chelates with some ions such as iron, copper, and zinc (Shay et al.,
2009). Consequently, it reduces skin inflammation (Figure 16).

Figure (16): Mechanism of actions of alpha-lipoic acid.

3.4.6 Side effects of alpha-lipoic acid

The side effects are mild and infrequent as it is considered safe if used as guided (Nguyen and
Gupta, 2022). However, like any medication, some people may experience adverse reactions. The
side effects include gastrointestinal issues such as nausea, vomiting or even stomach upset. As a
result, it is recommended to take the drug with food to decrease the gastrointestinal adverse effects.
The drug can also cause skin rash and some allergic reactions such as itching and swelling. In
addition to causing thiamine (Vitamin B1) deficiency which is associated with prolonged use of
high doses leading to some neurological issues (Salehi et al., 2019).

3.4.7 Drug-drug interactions with alpha lipoic acid

It is essential to provide the healthcare provider with a list of the medications being taken along
with ALA to identify the potential interactions and avoid them. The drug-drug interactions include
(Gomes and Negrato, 2014):
i. Insulin and Antidiabetic medications
ALA improves the effects of antidiabetic medications and insulin as it causes
hypoglycemia. Accordingly, dose adjustment is required.

22
 ii. Thyroid medications

ALA decreases the thyroid hormone impairing the activity of thyroid medications. So,
it is better to avoid taking them concurrently.
iii. Chemotherapy
ALA has an antioxidant activity which in turn antagonizes the effect of radiotherapy and
chemotherapy. So, it is recommended to avoid this combination.
iv. Iron and other medications that contain metals
ALA interferes with the absorption of other metals due to t h e formation of insoluble
chelates. Thus, drug spacing is required.
v. Antiplatelet and Anticoagulant medications such as warfarin
It is suggested that ALA may slow the blood clotting, which in turn increases the risk of
bruising or bleeding.

3.4.8 Contraindications of alpha lipoic acid

As mentioned before, the drug is considered safe. That being said, ALA has minimal side effects
that cause it to be contraindicated in thiamine deficiency, thyroid disorders, diabetes, liver diseases,
and during large consumption of alcohol (Nguyen and Gupta, 2022). It is safe to be taken during
pregnancy. However, it is better to be avoided during breastfeeding as there is no sufficient
information to support whether it is safe or not to be taken during lactation

23
 4.0 conclusion

In summary, the process of healing a wound is a challenge that negatively impacts one’s quality of
life and is addressed using well- known medical interventions such as drugs, herbal remedies, and
carrier systems. To reduce the negative effects of the earlier approaches, improve the treatment’s
selectivity, and hasten the healing of wounds. Together, alpha lipoic acid and an advanced carrier
system made of carbon dots generated from garlic work as a single agent that accelerates up the
healing of wounds. Consequently, combining the advantages of the three agents into a single agent.

24
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