STUDY ABOUT DIFFERENT APPROACHES IN

BIOMEDICAL FOR TREATMENT OF WOUND

HEALING
PRACTICE SCHOOL REPORT

Submitted To
G.V. M COLLEGE OF PHARMACY, SONIPAT

B. PHARMACY 7TH SEMESTER

Submitted by
NAME- RITU PANDEY
CLASS- B. PHARMACY 7TH SEMESTER
ROLL NO. - 1777

Under the guidance of

Supervisor

Mrs. JYOTI MALIK

ASSISTANT PROFESSOR
G.V. M COLLEGE OF PHARMACY, SONIPAT

PT. B. D. SHARMA UNIVERSITY OF HEALTH SCIENCES,

ROHTAK- 124001, HARYANA, INDIA
 CONTENTS

S.NO TITLE Page No

i) List of tables
ii) List of figures
iii) Chapter 1 Introduction
1.1 Wound healing
1.2 Process of wound healing
1.3 Types of Wound healing
1.4 Types of Wound
1.5 The roles of Physiological factors and
antimicrobial agents in wound healing
1.6 Various approaches for wound healing

iv) Chapter 2 literature Review

v) Chapter 3 Discussion
vi) Chapter 4 Conclusion
vii) References
 CHAPTER -1

INTRODUCTION

1.1 Wound healing: Wound healing is a complex process involving interactions among a
variety of different cell types. The normal wound repair process consists of three phases-
inflammation, proliferation, and remodeling that occur in a predictable series of cellular and
biochemical events. Wounds are classified according to various criteria: etiology, lasting,
morphological characteristics, communications with solid or hollow organs, the degree of
contamination. In the last few years many authors use the Colour Code Concept, which
classifies wounds as red, yellow and black wounds. [1]

1.2 The process of wound healing typically involves several overlapping phases:

Fig.1: Phases of wound healing [2]

1.2.1 Hemostatis: Hemostasis is the first stage in wound healing that can last for two days. As
soon as there is a wound on the body, the blood vessels in the wound area constrict to reduce
the blood flow. This is known as vasoconstriction. At the same time, clotting factors are
released at the wound site to coagulate with fibrin, resulting in a thrombus, which is more
commonly known as a blood clot. The clot acts as a seal between the broken blood vessels to
prevent blood loss. [3]

1.2.2 Inflammatory Phase: The second phase of wound healing is called the Inflammatory
Phase. It involves phagocytic cells that release reactive oxygen species, lasting for up to seven
days in acute wounds and longer in chronic wound [4]. During this phase, white blood cells
and some enzymes enter the wound area to stave off infection by clearing bacteria and debris
and preparing the wound bed for new tissue growth. Physical characteristics of the phase
include inflammation or redness at the wound site, edema, heat, and pain.During Phase 2, a
type of white blood cells called neutrophils enter the wound to destroy bacteria and remove
debris. These cells often reach their peak population between 24 and 48 hours after injury,
reducing greatly in number after three days. As the white blood cells leave, specialized cells
called macrophages arrive to continue clearing debris. These cells also secrete growth factors
and proteins that attract immune system cells to the wound to facilitate tissue repair. This phase
often lasts four to six days and is often associated with edema, erythema (reddening of the
skin), heat and pain. [5]

1.2.3 Proliferative Phase: Once the wound is cleaned out, the wound enters Phase 3, the
Proliferative Phase, where the focus is to fill and cover the wound. The Proliferative phase
features three distinct stages: 1) filling the wound; 2) contraction of the wound margins; and 3)
covering the wound (epithelialization). During the first stage, shiny, deep red granulation tissue
fills the wound bed with connective tissue, and new blood vessels are formed. During
contraction, the wound margins contract and pull toward the center of the wound. In the third
stage, epithelial cells arise from the wound bed or margins and begin to migrate across the
wound bed in leapfrog fashion until the wound is covered with epithelium. The Proliferative
phase often lasts anywhere from four to 24 days. [6]

1.2.4 Remodeling Phase: Scar tissue formation characterizes the final Remodeling Phase (also
known as Maturation). It may occur over months or years, depending on the initial severity of
the wound, its location, and treatment methods. During this phase, the new tissue gradually
becomes stronger and more flexible. Collagen production continues to build the tensile strength
and elasticity of the skin. The build-up of collagen in the granulation tissue leads to scar tissue
formation, which is 20 percent weaker and less elastic than pre-injured skin.the new
tissue slowly gains strength and flexibility. Here, collagen fibers reorganize, the tissue
remodels and matures and there is an overall increase in tensile strength (though maximum
strength is limited to 80% of the pre-injured strength). The Maturation phase varies greatly
from wound to wound, often lasting anywhere from 21 days to two years. The healing process
is remarkable and complex, and it is also susceptible to interruption due to local and systemic
factors, including moisture, infection, and maceration (local); and age, nutritional status, body
type (systemic). When the right healing environment is established, the body works in
wondrous ways to heal and replace devitalized tissue.[7]

1.3 Types of wound Healing

 Wound healing

Primary wound healing

Tertiary wound healing

Secondary wound healing

Fig.2 Types of wound healing [8]

 Primary wound healing

 Secondary wound healing
 Tertiary wound healing

1.3.1 Primary wound healing: occurs when a wound is closed within 12–24 hours of its
creation (e.g. clean surgical incision, clean laceration). The wound edges are approximated
directly using sutures, tissue glue, tapes or a mechanical device.The incision causes only
focal disruption of the continuity of the epithelial basement membrane, and the death of a
relatively few epithelial and underlying connective tissue cells.As a result, epithelial
regeneration predominates over. Primary wound healing, or primary intention wound healing,
refers to when doctors close a wound using staples, stitches, glues, or other forms of wound-
closing processes.Closing a wound in this way reduces the tissue lost and allows the body to
focus on closing and healing a smaller-area wound rather than the larger initial wound.For
example, a doctor might stitch up a large cut rather than allow the body to heal over the entire
cut.[8]

1.3.2 Secondary wound healing: Secondary wound healing, or secondary intention wound
healing, occurs when a wound that cannot be stitched causes a large amount of tissue loss.
Doctors will leave the wound to heal naturally in these cases. This may be more common for
wounds that have a rounder edge, cover uneven surfaces, or are on surfaces of the body where
movement makes stitches or other closure methods impossible. Secondary wound healing
relies on the body’s own healing mechanisms. This process takes longer, which may be due to
increased wound size, the risk of infection and contamination, and other factors, such as the
use of certain medications In this type of healing, a full-thickness wound is allowed to close
and heal. Secondary healing results in an inflammatory response that is more intense than with
primary wound healing. In addition, a larger quantity of granulomatous tissue is fabricated
because of the need for wound closure. Secondary healing results in pronounced contraction of
wounds. Fibroblastic differentiation into myofibroblasts, which resemble contractile smooth
muscle, is believed to contribute to wound contraction. These myofibroblasts are maximally
present in the wound from the 10th-21st days.[8]

1.3.3 Tertiary wound healing: Tertiary wound healing, or healing by delayed primary closure,
occurs when there is a need to delay the wound-closing process. This could be necessary if a
doctor fears that they may trap infectious germs in a wound by closing it. In these cases, they
may allow the wound to drain or wait for the effects of other therapies to take place before
closing the wound. In tertiary intention healing, there is a need for the wound to be open for a
period of time before it can be sutured. Examples can be a wound left open to allow drainage
and later is closed or a wound that is left to heal by secondary intention but encounters
complications, where after a very thorough debridement is performed followed by an
approximation of the wound edges. [8]

1.4 Types of wounds

There are several types of wounds, depending on factors such as the source of the wound and
any underlying issues that may lead to it. The type may alter how doctors treat the wound or
other factors in the healing process.Wounds are typically open or closed. A closed wound is an
injury that does not break the surface of the skin but causes damage to the underlying tissues.
A bruise is a common example of this. On the other hand, open wounds break the surface of
the skin and may also damage underlying tissues. [9]

Some types of open wounds include:

 Abrasions: These form as a result of rubbing or scraping the skin against a hard
surface.

 Lacerations: These are deeper cuts caused by sharp objects, such as a knife, or sharp
edges.

 Punctures: These are small yet deep holes caused by a long, pointed object, such as a
nail.

 Burns: These result from contact with an open flame, a strong heat source, severe cold,
certain chemicals, or electricity.

 Avulsions: This refers to the partial or complete tearing away of skin and tissues.
Chronic wounds may also cause breakages in the skin that need to heal. These include bedsores,
other pressure injuries, and diabetes-related ulcers. [10]

Fig.3: Type of wounds [11]

1.5 The role of Physiological factors and antimicrobial agents in wound

healing: Growth factors play a role in cell division, migration, differentiation, protein
expression, enzyme production and have a potential ability to heal wounds by stimulating
angiogenesis and cellular proliferation, affecting the production and the degradation of the
extracellular matrix, and by being chemotactic for inflammatory cells and fibroblasts.

There are seven major families of growth factors: epidermal growth factor (EGF), transforming
growth factor-beta (TGF-beta), insulin-like growth factor (IGF), platelet-derived growth factor
(PDGF), fibroblast growth factor (FGF), interleukins (ILs), and colony-stimulating factor
(CSF). Acute wounds contain many growth factors that play a crucial role in the initial phases
of wound healing. The events of early wound healing reflect a finely balanced environment
leading to uncomplicated and rapid wound healing. Chronic wounds, for many reasons, have
lost this fine balance. Applications of some drugs (antioxidants--asiaticoside, vitamin E and
ascorbic acid; calcium D-pantothenate, exogenous fibronectin; antileprosy drugs--oil of
hydnocarpus; alcoholic extract of yeast) accelerate wound healing. Thymic peptide thymosin
beta 4 (T beta 4R) topically applicated, increases collagen deposition and angiogenesis and
stimulates keratinocyte migration. [12]
Thymosin alpha 1 (T alpha 1R), peptide isolated from the thymus, is a potent chemoattractant
which accelerates angiogenesis and wound healing. On the contrary, steroid drugs, hemorrhage
and denervation of wounds have negative effect on the healing process.

1.6 VARIOUS APPROACHES FOR WOUND HEALING:

 Skin grafts
 Wound dressing
 Vacuum assisted wound closure
 Engineered skin subtitutes
 Stem cell therapy
 Growth factor and cytokines
 Cell therapy
 Bioactive therapeutic delivery
 Gene therapy
 Growth factor delivery
 Scaffolds / biomaterial assisted wound healing

1.6.1 Skin Grafts: Skin grafts are used when wounds have sustained a large amount of tissue
loss by trauma or chronic ulceration. The grafts can be classified into split-thickness skin grafts
(STSGs) and full-thickness skin grafts (FTSGs) according to the thickness. STSGs can
guarantee the cutaneous covering for practically any defect, and is regarded as the surgical
standard of care for various types of wounds. Atypical STSG involves harvesting the epidermis
and superficial dermis from healthy skin but not the whole dermis. However, limitations still
exist with this method. When skin loss of a patient exceeds 30% of the total body skin area
(TBSA), skin is not available in sufficient quantity for an STSG. Skin grafts can also be
classified as autografts, allografts and xenografts based upon the donor origins. [13]

Fig.4: Skin Grafts [14]

1.6.2 Wound dressing: The ideal wound dressing must possess the following characteristics:
providing wound protection, ability to remove excess exudate, anti-microbial properties,
maintaining a humid environment, high permeability to oxygen, easy removal from the wound
site and non-anaphylactic characteristics[15]. The most commonly used materials are as
follows.

 Cotton gauze dressings

 Human amniotic membrane
 Polysaccharides based dressings
 Chitosan and chitin based dressings
 Alginate based dressings
 Hyaluronic acid base dressings
 Microbial cellulose based dressings
 Hydrocolloid dressings
 Foam dressings
 Transparent film dressings [16]

Fig.5: Wound Dressing [17]

1.6.3 Vacuum assisted skin substitutes : VAWC dressing utilizes a closed and sealed system
to place negative pressure on a surface and thus produces traction of soft tissues and diminishes
the surface and depth of the injury Patients who received VAWC within 3 months of ulcer onset
had a greater likelihood of wound healing than those who received VAWC 1 year or later after
onset. VAWC can observably diminish water loss of the STSG area, shorten healing time. and
duration of hospital stay and lower the recurrence of infection during wound healing. [18-19]
 Fig.6: Vacuum assisted skin substitutes [20]

1.6.4 Engineered skin substitutes : The three major components of currently available ESSs
are scaffold materials, growth factors and cells. Exploration of ESS was started from the
success in cultivating epithelial cells. However, substitutes simply composed of epidermis are
fragile and least efficient in both antimicrobial activity and promotion of wound contraction .
As a result, epidermal ESSs are not widely used in clinical practice and current commercialized
ESSs are mostly dermal substitutes or substitutes with both epidermis and dermis. Commonly
used dermal substitutes include Integra, Alloderm, Dermagraft, Biobrane, Permacol,
Dermacell, Transcyte and Matriderm. Alloderm is a good option for treating major burns to
prevent scar formation and loss of joint function, whereas Dermacell is an appropriate adjunct
to breast reconstruction. Similar to Dermacell and Alloderm, Permacol is based on aporcine
acellular dermal matrix but with the combination of hexamethylene dissocyanate. [21-22]

Overall, ESS shows potential in treating different types of acute and chronic skin wounds, as
is mentioned above. Nowadays, developments in science and technology contribute to the
promise of ESSs. For example ,base on the need for diverse therapeutic factors at different
healing stages, a novel textile dressing, which utilizes composite fibers to release different
drugs in a controlled temporal profile at different stages of healing, was developed .In addition,
scientists have shown that topical application of artificial spider silk, which is able to control
the delivery of drugs, significantly accelerates the process of skin reconstruction and re duces
wound surface area in vitro.[23-24]

1.6.5 Stem cell therapy: To optimize wound healing, ESS can be used in combination with
stem cell therapy. Stem cells are attractive for cell-based therapies because of their capacity for
self-renewal and differentiation. For the past few years, advances in stem-cell biology have
given hope for treatment of chronic wounds that cannot be healed with conventional therapy.
stem cells can be defined as pluripotent (can give rise to any specialized cells in the
humanbody) andmultipotent (can give riseto manybut not all cell types). Embryonic stem cells
(ESCs; pluripotent) and adult mesenchymal stem cells (MSCs; multipotent) are two common
and promising populations of stem cells used in both laboratory studies and clinical
therapy.[25-28]

In order to improve the effectiveness of stem cell therapy, scaffold-based therapeutic strategies,
e.g., use of a decellularized silk fibroin scaffold or a nanoscaffold, have been used to preserve
cell function and improve healing . Matrigel, a gelatinous protein mixture secreted by mouse
sarcoma cells, with Matriderm, an ESS mentioned above, are both excellent matrices for
delivery of MSCs . A microsphere-based engineered skin with murine BM-MSCs and
epidermal growth factors achieved a higher rate of wound repair, thicker granulation tissue and
better vasculature, when compared with that without growth factors in vitro. These studies
suggest that a scaffold-based de livery system with the addition of growth factors might achieve
better effects when applying stem cells. [29-31]

Fig.7: Stem cell therapy [32]

1.6.6 Growth factor and cytokines: Growth factors and cytokines are biologically active
proteins that can control all stages of the wound-healing process. Although shown to have
noticeable benefits, growth factors and cytokines have stability problems due to proteases
present at the wound site. However, incorporation of growth factors within a fibrin biomatrix
has been shown to prolong growth factor stimulation at wound site. Scaffolds with hyaluronic
acid and slowly released growth factors have also been shown to promote the recovery of skin
wounds.[33-35]
There are other innovative approaches that can improve wound healing. For debridement, non-
contact, low frequency ultrasound therapy, which separates denatured protein, directly kills
surface bacteria and increases blood flow, can improve healing rates of venous leg ulcers.
Hydrosurgical debridement using a razor-thin saline jet can reduce both operative times and
intraoperative blood loss, compared to traditional debridement techniques. [36-38]

1.6.7 Cell therapy : Cell delivery, which in this regard is described as transporting either skin
or vascular cells to the site of injury, has attracted much attention in the acceleration of
regenerative wound healing. Among the different cells, stem cells, due to their potential to
differentiate into several cell types and self-renewal properties, have been suggested specially
for the treatment of chronic and non-healing wounds. The majority of the cells are used for
skin regeneration, including adipose derived stem cells (ADSCs), MSCs, endothelial
progenitor cells (EPCs), induced pluripotent stem cells (iPSCs).It should be noted that low cell
viability is one of the main problems in conventional cell therapy . In order to address this
problem, cell delivery within hydrogels and cell imprinting are suggested as an alternative
cellular approach to achieve better healing. Using bioprinting and modified laser induced
forward transfer technologies; it is possible to make a 3D skin graft . Koch et al. used a laser
assisted method to print fibroblasts and keratinocytes embedded in collagen gel, layer by layer.
After 10 days of culturing, cells proliferated and showed high viability, making an integrated
graft with tight cellular junction. [39-43]

Fig.8: Cell therapy

1.6.8 Bioactive Therapeutic Delivery : An ideal carrier for bioactive therapeutic delivery
should be biocompatible, biodegradable, non-cytotoxic, and easy to fabricate by tailoring the
physical/chemical properties. Till now, therapeutics have been loaded into different
nano/micro carriers such as fibers, spheres, capsules, sheets, rods, and dot arrays. These
carriers can be produced in form of core shell structures with the benefit of storing the drug in
the core cavity, while modifying shell composition (polymers or lipids) to adjust the release
pattern.[44]

The vast lists of drugs known to have antibacterial, regenerative, and angiogenic effects from
natural bioactive and biochemical therapeutics have been used in wound healing treatments.
For example curcumin, berberine, rosemary oil, thyme extract, Aloe vera, and honey, as natural
agents, and gentamicin, tetracycline hydrochloride, vancomycine, melatonin, simvastatin, and
erythropoietin as chemical agents, can be suggested.[45-46]

1.6.9 Gene Therapy : Skin is considered as a suitable target for delivery of genetic-based
therapeutics, due to the readily attainable anatomical position for gene transfer and visually
observable therapeutic effects. Among several studies performed for skin gene therapy, those
encapsulated into the nano/ micro carriers, tissue scaffolds, or even using genetic manipulated
cells are more prosperous regarding their potential to both protect genetic based therapeutics
from enzymatic degradation and improve their healing effects.In addition, several studies are
aimed to use siRNAs as therapeutics for selective inhibition of MMP, fibrotic tissue growth
factors, inflammatory cytokines, p53, and also prolyl hydroxylase domain (PHD) proteins to
induce fast healing and angiogenesis in specially chronic and non-healing wounds. [47]

Fig.9: Gene Therapy [48]

1.6.10 Growth Factor Delivery : Growth factors are polypeptides released by numerous cells
in a given time to stimulate cellular proliferation, differentiation, and migration. Regarding the
key role of growth factors in the regulation of the wound healing process, controlled and
sequential delivery to the wound sites is the topic of many current researches. Numerous
growth factors such as EGF, VEGF, FGF, TGF, and PDGF have been studied in order to induce
wound healing through angiogenesis, matrix deposition and re epithelialization. One of the
main concerns in the delivery of growth factors is their short half-life, which instantly produces
enzymatic degradation, thereby making their sustained release crucial in tissue engineering.
Research findings have confirmed increased epithelialization, neovascularization, migration of
keratinocytes, and fast healing of venous and diabetic foot ulcers after applying EGF on the
wound site.[49]

On the other hand, clinical trials conducted on second-degree burn patients suggested that
instant application of FGF on the wound surface can accelerate wound healing rates and
formation of protective and strong granulated tissue. Interestingly, utilization of growth factors
in combination with cells or natural materials for chronic and non-healing wound treatment has
attracted extensive attention. For example, neovascularization, re-epithelialization, and wound
closure have been documented in the results of studies using MSCs that secrete VEGF and
platelet-rich plasma as potent sources of growth factors in full-thickness wounds.[50-51]

1.6.11 Scaffolds /biomaterial assisted wound healing: Scaffolds can be made of either natural
or synthetic biomaterials, as well as a com bination of them in the form of hydrogels,
electrospun fibers, films, etc. Biocompatibility, biodegradation, bioactivity, and cellular
adhesion, are some of the properties of natural biomaterials. Collagen, gelatin, HA, chitosan,
alginate, elastin, and silk fibroin are some of the natural polymers providing bioactive scaffolds
that can create complex cellular interactions during healing . Among these natural materials,
several studies have emphasized the significant effect of GAGs, and in particular HA, in wound
healing. Presence of high water content in their molecular chain, along with the ability to act
as a reservoir of growth factors, makes them ideal for the scope of tissue regeneration.[52-53]

From various forms of scaffolds, nanofibers and hydro gels are frequently utilized as a skin
substitute with or without cells or bioactive therapeutics. Nanofibers can assist increasing
cellular interactions by simulating a native ECM microenvironment, thereby improving
adhesion and forming a porous structure. Nanofibrous wound dressings readily absorb exudates
from the wound site while keeping them moistened as well as promoting oxygen diffusion
through the injury. Moreover, owing to the high sur face to volume ratio, nanofibers can be
easily modified for delivery of bioactive therapeutics. There are numerous methods for
nanofiber synthesis such as phase separation, template synthesis, self-assembly, and
electrospinning.[54]
 Table 1: Various approaches used in wound healing

S.NO Approaches Material Used Advantages Reference

1) Wound
1. Skin grafts 1) Autografts coverage Robinson, J. K., & Dillig, G.
2) Allografts 2) Improve (2002). The advantages of
3) Xenografts Aesthetic delayed nasal full‐thickness
4) Synthetic Appearance skin grafting after Mohs
grafts 3) Function micrographic
Restoration surgery. Dermatologic
4) Promotes surgery, 28(9), 84851.[55]
healing

1) Controls
2. Wound 1) Gauze Exudate Zeng, Z., Zhu, M., Chen, L.,
dressing 2) NonAdherent 2) Reduces Zhang, Y., Lu, T., Deng, Y., ...
Dressing pain & Xiong, R. (2022). Design
3) Foam 3) Protects the molecule structures to
dressing from achieve functional advantages
4) Hydrocolloid infection of hydrogel wound dressings:
Dressing 4) Enhance Advances and
cosmesis strategies. Composites Part B:
Engineering, 247,
110313.[56]
 1) Promote
3. Vacuum 1) Vacuum healing Singh, D., Chopra, K., Sabino,
assisted pump 2) Reduces J., & Brown, E. (2020).
wound care 2) Tubing Edema Practical things you should
3) Canister 3) Remove know about wound healing
4) Adhesive Exudate andvacuum-assisted closure
Tape 4) Manages management. Plastic
wounds
andreconstructive
surgery, 145(4),839e-854e.
[57]

1) Regenerative Kim, H. J., & Park, J. S.

4. Stem cell 1) Culturing potential (2017). Usage of human
therapy media 2) Treatment of mesenchymal stem cells in
2) Extracellular chronic cell-based therapy:
matrix conditions advantages and
3) Biomaterial 3) Reduced risk disadvantages. Development
scaffolds of rejection & reproduction, 21(1), 1 [58]
4) Injectable 4) Tissue
hydrogen engineering

Iancu, E. M., & Kandalaft, L.

5. Cell therapy 1) Cell 1) Regenerate E. (2020). Challenges and
Culture damaged advantages of cell therapy
media tissues manufacturing under Good
2) Cell source 2) Reduced Manufacturing Practices
3) Biomaterial side effects within the hospital
scaffolds 3) Treatment of setting. Current Opinion in
various Biotechnology, 65, 233-241
conditions [59]
4) Long term
benefits
 CHAPTER – 2

LITERATURE SURVEY

1. Dimple Chouhan, et.al (2019) studied or concluded that Development of a variety of

constructs in the form of wound dressing and skin grafts provide a clear picture of the
advanced therapeutic strategies over the conventional gauze treatment. Ongoing research
in the exploration of bioactive molecules and functionalization of constructs with those
compounds has led to the fabrication of smart wound dressings containing functional
biomolecules. [60]
2. Tomasz Arodz, et.al (2012) studied and concluded that high degree genes are more likely
to be associated with disease but this rule does not hold universally in all contexts. For
example, genes associated with heritable genetic disease are enriched in hubs. However,
this correlation results from a subset of essential genes, for which any aberration leads to
lethal phenotype.[61]
3. Ruijie Zeng ,et.al (2018) studied and concluded that when treating patients with cutaneous
wounds, basic principles of care need to be generally followed and additional methods will
help to advance therapeutic man agement. It is important to explore more affordable, conve
nient and efficient approaches to cutaneous wound healing.[62]
4. Shirin Nour, et.al (2019) studied and concluded that Understanding the dynamics of cell-
cell and cell-ECM interactions in healthy and impaired wound healing also could help
identify the most appropriate stra tegies to overcome disadvantages of currently applied
wound dressings.[63]
5. June K. Robinson, et.al (2002) studied and concluded that Prolonged delay al lows
contraction of the wound base, creating a crenated graft and distortion of the free margins
near to the grafted area. In this instance, immediate reconstruction with a flap may avoid
further complications. Assessment of the wound base and the presence of granulation tissue
are key factors in the success of FTSGs [64]
6. Emanuela M Iancu, et.al (2020) studied and concluded that A dedicated GMP facility within
a hospital setting has many operational advantages and allows patients access to innovative
treatments that are personalized to their needs. [65]
7. Ana Cristina de Oliveira Gonzalez, et.al (2015) studied and concluded that Regeneration
and tissue repair processes consist of a sequence of molecular and cellular events which
occur after the onset of a tissue lesion in order to restore the damaged tissue. The
exsudative, proliferative, and extracellular matrix remodeling phases are sequential events
 that occur through the integration of dynamic processes involving soluble mediators, blood
cells, and parenchymal cells[66]
8. Stuart Enoch, et.al (2007) studied and concluded that Acute wound healing involves a
complex series of events including chemotaxis, cell division, neovascularization, synthesis
of new extracellular matrix, and the formation and remodelling of the scar tissue.[67]
9. JoAn L. Monaco, et.al (2003) studied and concluded that Two broad categories exist for
the classification of wounds: chronic and acute. Acute wounds undergo a complex
interactive process involving a variety of cell types that leads to a healed wound.
Conversely, chronic wounds have proceeded through portions of the repair process without
establishing a functional anatomic result [68]
10. Melanie Rodrigues, et.al (2019) studied and concluded that advantage of designing cell-
based therapies for wound heal-ing is that there are reliable and reproducible models of
wound healing in both small and large animals , which can be used to test the preclinical
effectiveness of the therapies before application of the patient.[69]
11. Frances Strodtbeck, et.al (2001) studied and concluded that Wound healing is a fascinating
biologic event essential for human survival.Although many of the physiologic processes
have been studied in animal and adult models, little information is available regarding
wound healing in infants.Because of the immaturity of their skin, many hospitalized infants
are at high risk for skin injuries [70]
12. Broughton, et.al (2006) studied and concluded that Wound healing is a complex series of
reactions and interactions among cells and “mediators.” Each year, new mediators are
discovered and our understanding of inflammatory mediators and cellular interactions
grows. [71]
13. Anna T. Grazul-Bilska , et.al (2003) studied and concluded that Wound healing is a complex
biological process that requires cellular interactions between a variety of cells, including
fibroblasts, myofibroblasts, smooth muscle cells, endothelial cells, keratinocytes and
immune cells.[72]
14. Samantha Ellis , et.al (2018) studied and concluded that Cutaneous wound healing occurs
through an intricate and delicate interplay between the immune system, keratinocytes, and
dermal cells such as platelets, fibroblasts, and myofibroblasts[73]
15. Thomas Wild M.D, et.al (2010) studied and concluded that Wound healing is a process that
can be divided into three different phases (inflammatory, proliferative, and maturation).
Each is characterized by certain events that require specific components[74]
16. Ikramuddin Aukhil , et.al (2000) studied and concluded that As per the classic description
of wound healing, initially there is temporary repair characterized by the formation of a
 clot in the wounded tissues. Inflammatory cells followed by fibroblasts and endothelial
cells then invade the clot to form a granulation tissue [75]
17. Irena Pastar , et.al (2013) studied and concluded that Advances in tissue engineering have
facilitated the progress of the development of diverse models to study wound re-
epithelialization and provided our research community with both murine and human skin
equivalents.[76]
18. Barbara Blanco-Ferandez, et.al (2021) studied and concluded that the incidence of chronic
wounds is increasing due to our aging population and the augment of people afflicted with
diabetes. With the extended knowledge on the biological mechanisms underlying these
diseases, there is a novel influx of medical technologies into the conventional wound care
market.[77]
19. Michael B. Dreifke, et.al (2014) studied and concluded that Wound healing, including acute
and chronic wounds, is one of the major clinical challenges in the world. Even though split-
thickness autograft was considered as a gold standard in chronic wound management,
several limitations exist in these autografts including severe donor site morbidity and
pain.[78]
20. Gerard c, et.al (2000) studied and concluded that Traditional medicine, used widely by rural
communities in most developing countries, serves as a mainstay for everyday health care
for the majority of the world’s population.[79]
 CHAPTER – 3

DISCUSSION

Wound healing is a complex biological process that involves the body's natural response to
injury, aiming to restore the damaged tissue's structure and function. There are several
approaches to wound healing, each with its advantages and considerations. The primary
methods include natural healing, mechanical closure, and advanced therapies.

Wound healing typically progresses through several overlapping phases: Hemostasis,

inflammation, proliferation, and Remodeling. During Hemostasis, blood vessels constrict to
reduce bleeding, and platelets form a clot to seal the wound. In the inflammatory phase,
immune cells like neutrophils and macrophages clear debris and defend against infection. The
proliferation phase involves the formation of new tissue, including blood vessels and collagen
deposition. Finally, Remodeling occurs as the scar tissue matures and contracts, improving the
wound's strength and appearance over time.

Various factors can influence the wound healing process, such as age, nutrition, chronic
illnesses like diabetes, and medications like steroids that impair immune function. Proper
wound care, including cleaning, debridement (removal of dead tissue), and dressing selection,
plays a crucial role in supporting optimal healing outcomes. Additionally, smoking and
excessive alcohol consumption can delay wound healing by impairing blood flow and immune
response.

Natural healing, also known as primary intention healing, occurs when the wound edges are
closely approximated, allowing for direct healing without significant tissue loss. This approach
is often seen in surgical incisions where the wound is sutured or stapled, promoting rapid
healing and minimal scarring.

Mechanical closure involves techniques such as sutures, staples, or adhesive strips to bring the
wound edges together. These methods are effective for larger wounds or those with irregular
edges, facilitating the formation of a strong scar tissue matrix. However, they may require
careful monitoring for infection and proper wound care to prevent complications.Advanced
therapies encompass a range of techniques and technologies aimed at enhancing the healing
process. This includes the use of growth factors, stem cells, bioengineered skin substitutes, and
negative pressure wound therapy. These approaches are particularly beneficial for chronic
wounds, diabetic ulcers, and severe burns, where traditional methods may be less effective
.Despite advances in wound care, challenges such as chronic wounds, infections, and scarring
remain significant concerns. Researchers continue to explore innovative technologies like 3D
bioprinting of skin substitutes, nanomaterial-based dressings for targeted drug delivery, and
gene therapy to enhance wound healing processes. These emerging approaches hold promise
for improving outcomes and addressing the complexities of wound management in diverse
clinical scenarios.

In summary, wound healing is a dynamic process influenced by various factors such as wound
size, location, and patient's overall health. Understanding the different approaches to wound
healing enables healthcare professionals to choose the most appropriate strategy for optimal
outcomes and patient well-being.
 CHAPTER – 4

CONCLUSION

In conclusion, wound healing is a sophisticated biological process that involves a sequence of

events to repair damaged tissue and restore its normal function. The diverse approaches to
wound healing reflect the complexity of this process and the need for tailored interventions
based on the specific characteristics of each wound.Natural healing, characterized by primary
intention healing, is optimal for wounds with clean, well-apposed edges, as it promotes rapid
closure and minimal scarring. Mechanical closure methods, such as sutures, staples, and
adhesive strips, are effective for wounds with irregular edges or significant tissue loss,
providing mechanical support and facilitating healing.

Advanced therapies represent a frontier in wound care, leveraging cutting-edge technologies

and treatments to address challenging wounds such as chronic ulcers, burns, and traumatic
injuries. These therapies include the use of growth factors to stimulate tissue regeneration,
bioengineered skin substitutes to promote wound closure, and negative pressure wound therapy
to enhance healing in complex wounds.Moreover, factors such as patient age, comorbidities
like diabetes or vascular disease, and lifestyle choices like smoking can significantly impact
the wound healing process. Healthcare professionals must consider these factors when
choosing an appropriate approach and implementing comprehensive wound management
strategies.

Ultimately, the goal of wound healing approaches is not just to close the wound but to promote
optimal healing outcomes, reduce the risk of complications such as infection or scarring, and
improve patients' overall quality of life during the recovery process. Achieving these goals
requires a multidisciplinary approach, integrating medical expertise, technological
innovation,and patient-centered care to ensure the best possible outcomes for individuals
undergoing wound healing.
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