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Berkeley
Pharma Tech
Journal of Medicine

Correspondence:
jghazzawi24@gmail.com

Keywords:
Burn wound injury
Lnc RNA XIST
IL-33
miR-19b
Wound healing stages 
Inflammatory pathways

Submitted: May 5, 2023 
Accepted: June 30, 2023 
Published: December 30, 2023

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
As the largest organ of the body, it is crucial that the skin, and all it protects, remain 
healthy and functioning. However, burn injuries may result as a serious threat to the 
skin, possibly forming greater health issues depending on the severity of the issue. 
Burn wound injury is characterized as damage to the skin or other organic tissue 
originating from sources such as heat, friction, radiation, radioactivity, electricity, 
and/or chemical contact. Different degrees of burn wounds make it increasingly more 
difficult to treat the more severe the wound is. For this reason, it is crucial to study 
how skin can not only heal itself via its own equipped healing related pathways, but 
also what treatments exist outside of the ongoing biochemical mechanisms in order to 
accelerate healing and repair the body’s greatest defense. More standard forms of 
treatment that currently exist adopt a more holistic approach, treating at the surface 
level, while treatments targeting the molecular level are less well studied. This review 
paper assesses several novel therapeutic alternatives including, but not limiting to, 
targeting lncRNA XIST, IL-33, and miR-19b through analyzing the molecular 
pathways in which wound healing is performed.

Advancing Wound Healing: 
Innovative Pathway Strategies for 
Enhanced Recovery
By: Jowana Ghazzawi, Crystal Yu, and Maria Favela



1. Introduction

According to the World Health Organization, approximately 180,000+
deaths per year are a result of burns, with the majority taking place in low
and middle income countries. The leading cause of morbidity is non-fatal
burn injuries, leaving both infants and older adults at the greatest risk for
burn injury4. According to Johns Hopkins, the leading causes of burn
injury for adults are smoking and open �ame, while the leading cause of
burn injury for children is scalding⁵.

Depending on the cause of the burn injury itself, there are four de�ned
degrees of burn wounds that increase in severity6. Though treating �rst or
second degree burns may be more manageable and not require intensive
therapies, third and fourth degree burns may cause trauma to both the
external surface and the internal environment⁷. Therefore, it is important
to learn more about molecular pathways that currently exist in order to
treat burn wound injuries at all levels.

Current therapeutics focus on topical treatment and management, especially 
when it comes to keeping the injury clean and reducing the severity of scars as a 
result. In terms of assessing whether novel treatments are e�ective, there are 
several factors to identify that have been proven to indicate e�cient burn 
wound repair. These factors include the reduction of healing rates and 
in�ammatory in�ltration, scar scores, an increase in collagen deposition, and 
other markers that will de�ne successful treatment execution. Novel targets of 
therapy including LncRNA XIST, IL-33, and miR-19b, are proven to be 
e�cient mechanisms of accelerating burn wound healing through the 
enhancement of cell proliferation, extracellular matrix synthesis, and the 
inhibition of �broblast apoptosis. Several clinical trials were reviewed with 
their respective results contributing to the understanding of novel approaches 
in treating burn wound injury⁸. Scienti�c literature was necessary in order to 
gather more information on the background of burn wound injury, its 
pathological course of events, and current treatment e�ectiveness.

2. Pathophysiology of Burn Wound Injury

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Burn wounds can be classi�ed into four stages: hemostasis, in�ammation,
tissue proliferation, and tissue maturation/remodeling⁹⁻¹¹. Each stage involves a
complex interplay of molecular mechanisms, growth factors, and signaling
pathways.

Hemostasis is the �rst stage of the wound healing process, which stops bleeding
and prevents further damage¹². This stage is composed of several processes that
occur simultaneously. Primary hemostasis involves the formation of a platelet
clot, where platelets attach to damaged tissue and activate to attract more
platelets. Vasoconstriction, the narrowing of blood vessels by small muscles,
slows blood �ow. Secondary hemostasis involves the activation of coagulation
factors in the blood, which amplify the clotting e�ect. Fibrin is then formed,
which acts as a stable blood clot. Fibrin clot remodeling or �brinolysis occurs
when the temporary seal is removed, and the blood clot is remodeled into the
tissue that was there before the injury. Growth factors involved in this process
include platelet-derived growth factor (PDGF), epidermal growth factor
(EGF), transforming growth factor-beta (TGF-β), insulin-like growth factor-1,
and platelet factor-IV.

The second stage of wound healing is in�ammation, where platelets aggregate
to block bleeding and release a chemoattractant to activate in�amed cells for
wound healing. Edema, or swelling and in�ammation, occurs in the �rst phase
after the secretion of histamine/leukotrienes. Vasodilation and increased
capillary permeability lead to �uid leaking from blood vessels. The second
phase involves �uid penetration through capillaries and activation of cytokines,
enhancing cellular immune response. White blood cells are driven into the
interstitial space surrounding the wound, and protease enzymes degrade dead
cells. Macrophages defend against dead cells and bacteria. Growth factors
stimulate the generation of new capillaries and promote the synthesis of
�broblasts¹³.

The third stage of wound healing is tissue proliferation, where cells of the
epidermis and dermis migrate to the wound site. Fibroblasts migrate to the
wound site and synthesize collagen and elastin. Collagen causes the wound to
adhere, and keratinocytes cause re-epithelialization. Angiogenesis occurs, and

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new blood vessels form within the healing tissue. Burns that a�ect deep layers
of the skin heal slower because they don't have as many helper cells, and new
skin can only grow after the dead tissue is removed. New blood vessels initially
form densely, but later reduce to levels similar to the surrounding skin.

The �nal stage of wound healing is tissue maturation/remodeling, which is the
formation of new epithelium and scar tissue. Fibroblasts degrade protein and
realign collagen �bers. Apoptosis of �broblasts and myo�broblasts prevent
excessive scarring. Realignment of collagen �bers transforms the initial collagen
matrix into a highly organized collagen matrix whose structure mimics that of
the native tissue. New tissue with a high tensile strength and a minimal
number of cells and vascularization is formed. A visual diagram of the four
burn wound stages is displayed in Figure 1.

Figure 1: The four stages of wound healing. (A) Hemostasis: Clotting factors 
such as platelets aggregate to form a blood clot. (B) Inflammation: White blood cells 
like neutrophils and macrophages fight off potential infection by clearing bacteria. 
They also prepare the area for fibroblast proliferation. (C) Tissue proliferation: 
Fibroblasts begin the process of epithelialization. (D) Remodeling: There is a build up 
of collagen and scar tissue becomes visible while the new tissue is stronger and flexible.

3. Molecular Mechanisms of Treatment
Wound healing is a complex process involving numerous molecular 
mechanisms. Recently, long non-coding RNA (LncRNA) XIST, 
interleukin-33 (IL-33), and microRNA-19b (miR-19b) have been identi�ed as 
key regulators in wound healing-related pathways. This section will discuss

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how LncRNA XIST binds to miR-19b, which binds to IL-33 and activates
M2 macrophages in burn injury healing in human skin �broblast (HSF) cells
(Figure 2)¹⁴. It will also explore how these molecules contribute to the
proliferation, migration, and extracellular matrix (ECM) production of HSFs,
and their role in the regulation of wound healing.

Figure 2: Molecular pathways of LncRNA XIST and miR-19b. In the process of
wound healing, LncRNA XIST binds and inhibits miR-19b, which in turn binds and
inhibits IL-33. The binding of LncRNA XIST to miR-19b decreases the amount of
miR-19b that is available freely, leading to an increase in IL-33. Thus, LncRNA-XIST
indirectly activates IL-33, leading toM2macrophage activation

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Figure 3: Relative expression of LncRNA XIST & miR-19b. In the process of
wound healing, regulator expression is time dependent and varies throughout the
process. LncRNA XIST & IL-33 increase while miR-19b decreases. LncRNA XIST
and IL-33 expression are proportional because XIST activates IL-33.

LncRNA XIST is a key regulator in wound healing-related pathways¹⁵. Studies
have found that LncRNA XIST expression increases during the healing
process after a burn injury in a time-dependent manner¹⁴. LncRNA XIST
contributes to the proliferation and migration of HSFs by inhibiting miR-19b
and enhancing �broblast ECM production by promoting the transformation
of macrophages into the M2 phenotype. In this way, XIST can promote the
repair of the injured dermis. Moreover, LncRNA XIST targets
miR-29b-3p/COL1A1¹⁶ and can also inhibit miR-29a and promote LIN28A
expression, e�ectively contributing to the synthesis of HSFs¹⁴,17. Finally, XIST
is also crucial in alleviating pain behavior as it suppresses cytokines that cause
in�ammation14,18. These results suggest that LncRNA XIST may be a
promising therapeutic target for promoting wound healing.

IL-33 is an immune cytokine that plays a critical role in wound healing. IL-33
participates in the pathological process of many diseases and acts as an alarm to
alert the immune system when released by epithelial barrier tissues during
injury, e�ectively it acts as a link between the skin and the immune system14,19.

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A study shows that IL-33 is not detected in healthy, undamaged human skin 
cells, but its expression increases when there is a wound and the immune 
system is alerted. It is not normally produced and is only synthesized when 
needed. IL-33 promotes the repair of skin damage and enhances wound healing 
through mucosal healing and epithelial restoration and repair14,20. It further 
plays a role in the regulation of wound healing by upregulating the expression 
of M2 macrophages, which are the proliferative, anti-in�ammatory form 
compared to the M1 macrophages. These �ndings suggest that IL-33 may be a 
potential therapeutic target for wound healing21.

miR-19b is a microRNA that has been implicated in wound healing-related 
pathways. Studies have found that miR-19b expression decreases during the 
healing process after a burn injury in a time-dependent manner14. It can be 
concluded that miR-19b has roles that are more important at the beginning of 
the healing process. Studies show that miR-19b increases the proliferation and 
migration of cardiac �broblasts14,22,23 and inhibits the apoptosis of endothelial 
cells24. miR-19b also promotes the activation of M1 macrophages, 
TLR3-mediated NF-κB activation by targeting SHCBP1, and reducing the 
production of in�ammatory chemokines and cytokines by keratinocytes. To 
account for the decrease in expression, studies have shown that overexpression 
of miR-19b may inhibit the expression of CGTF25, which is a connective tissue 
growth factor. CGTF plays a crucial conducive role in wound healing so its 
decreased expression due to the overexpression of miR-19b is detrimental to 
the healing process. These results suggest that targeting miR-19b may be a 
promising therapeutic pathway for promoting wound healing.

4 .Treatments of Interest andMeasurement of E�cacy
The treatment of patients who experience di�culty and obstacles during burn 
wound healing is a signi�cant hurdle in clinical practice26. Therefore, gaining a 
deeper comprehension of the molecular mechanisms underlying burn wounds 
can facilitate the development of more e�cacious treatments, which can 
ultimately enhance patients’ life quality. The main ways LncRNA XIST, 
miR-19b, and IL-33 have been used treatment-wise is through expression 
modulation via gene knockdowns, small molecule inhibitors, and RNA 
interference27.

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The measurement of e�cacy of LncRNA XIST can be assessed through
several methods, including in-vitro and in-vivo studies. In-vitro studies can be
executed using HSF cells or other appropriate cell lines to assess LncRNA
XIST e�ects. These in-vitro studies use techniques like western-blotting,
quantitative polymerase chain reaction (qPCR) and immuno�uorescence to
detect changes in gene and protein expression28. For example, in a clinical trial
involving 25 burn patients16, total RNA was extracted from HSF cells and
reversely transcribed to cDNA followed by qPCR. A western blot was then
applied for protein identi�cation. Using these methods, the researchers were
able to demonstrate that upregulation of XIST expression boosts �broblast
proliferation and migration via mIR-29b-3p/COL1A1 pathway16, which
regulates collagen synthesis, resulting in improved wound healing. Other
in-vitro studies that use qPCR and western blotting include a study where
results show that overexpression of LncRNA XIST in HSF cells signi�cantly
increased cell proliferation and migration with a decrease in apoptosis,
suggesting a possible for XIST in burn injury wound healing28.

Fewer studies have been conducted in-vivo to investigate the role of LncRNA
XIST in burn wound healing. These studies use animal models of burn injury
to evaluate the e�ects of LncRNA XIST on wound healing and scar
formation. These studies use techniques such as immunohistochemistry,
histological analysis, and mechanical testing to evaluate changes in wound
healing parameters29. For example, in a study involving mice6, burn wounds
were induced and the wound tissues were processed for histological analysis,
immunohistochemistry, and qPCR data. The results reveal that LncRNA
XIST targets the IL-33/miR-19b axis to promote wound healing. Results from
other in-vivo experiments include seeing an increase in HSF proliferation and
ECM synthesis when XIST is overexpressed7 and inhibition of XIST leads to a
decrease in wound healing acceleration29.

Through in-vitro and in-vivo studies, IL-33 has been shown to accelerate
wound closure, help reduce scar formation in animal models, and aid in
�broblast proliferation, which are cells that help form new tissue30-32. In
addition to the techniques mentioned in the previous paragraphs, cytokine and
chemokine levels are measured to evaluate IL-33’s role in regulating

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in�ammation and immune response. Some examples are using histological
analysis on wound tissue samples to evaluate the degree of in�ammation and
tissue repair and qPCR to measure gene expression levels, in which it was
found that IL-33 recruits group 2 innate lymphoid cells (ILC2s) to promote
wound healing via re-epithelization30.

Using a full-thickness skin wound model on mice, where the wound extends
below the epidermis and dermis layers, researchers assessed wound healing at
four time points (days 0, 1, 3, and 14)31. They also researched how autophagy,
or the clearance of damaged or old cells, is involved in wound closure rate by
looking at the YAP/IL-33 pathway. The yes-associated protein (YAP) has been
shown to regulate in�ammation33, speci�cally, it increases the articulation of
proin�ammatory cytokines34. The researchers utilized an autophagy inhibitor
(3-MA) as well as vertepor�n, a YAP inhibitor, and anti-IL-33, an IL-33
inhibitor to observe wound healing results. Their results reveal that with
autophagy inhibition, there is an upregulation of IL-33 along with a
suppression of tumor necrosis factors. Vertepor�n decreased the expression of
YAP while increasing the expression of IL-33, in which the upregulation of
IL-33 contributed to wound healing in both cases. Anti-IL-33 downregulated
IL-33 leading to no promotion of wound healing. Thus, IL-33 can increase
wound closure and help decrease wound size.

There is limited research speci�cally investigating the role of miR-19b in burn
wound healing, however, some studies show that miR-19b could be a potential
therapeutic target35-37. In an in-vitro experiment, the researchers investigated
the potential of exosomes derived from human adipose-derived mesenchymal
stem cells (ADSCs) containing miR-19b35. Their results reveal that treatment
with miR-19b enhanced cell proliferation and migration, and in a mouse
model, miR-19b increased the deposition of collagen and blood vessel
formation. In a clinical trial, 18 human samples were collected and results show
that miR-19b is an important factor in wound healing by reducing
in�ammation while an absence of miR-19 reduces wound healing capabilities.
Their methods involve qPCR, Western blotting, miR-19 antisense inhibitors
and luciferase reporter assay36.

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5. Practical Applications

In the case of LncRNA XIST, IL-33, and miR-19b, although they show 
promising burn wound healing results in preclinical studies, more research is 
needed to determine the safety and e�cacy of these molecules in practical 
settings. They are currently not commonly used as a clinical treatment for burn 
wounds, but ongoing clinical trials are exploring its potential use38,39. For more 
severe injuries, like third and fourth degree burns, more intensive treatment is 
required, particularly at the molecular-level, to restore healing related 
pathways40. However, for minimal burn wounds requiring repair at a 
super�cial level, such as �rst degree burns, minimally invasive treatments may 
be more appropriate, including holistic applications.

Holistic treatments for burn injuries include a combination of traditional and 
medical treatments and alternative therapies to promote physical, mental and 
emotional healing. Some holistic approaches that have been explored include: 
acupuncture, eating a good and healthy diet, massages, and herbs41,42. 
Acupuncture helps decrease pain and shock after a burn injury and may also 
decrease infection43,44. As for a diet, with the right amounts of vitamins and 
nutrients, as well as su�cient protein and calorie intake, the body can promote 
new skin and tissue in a timely manner37. In a review paper, the authors suggest 
that burn patients may have increased requirements for certain micronutrients, 
and that supplementation with these nutrients may help improve outcomes45. 
Like acupuncture, massages help decrease pain and itching46, 47. Several herbs 
have been traditionally used for their potential wound healing and 
anti-in�ammatory properties, for example, aloe vera and calendula can help 
reduce pain and in�ammation in �rst and second-degree burns48, 49.

6. Prevention Strategies

Burns are preventable, especially when considering the majority of burns take 
place in the home and workplace. In order to strategize prevention plans, it is 
important to address impactful factors that heighten/lessen burn wound 
injuries. These factors include knowledge regarding the hazards related to 
speci�c burn injuries, access to education for vulnerable populations, and �rst 
aid training in case of an emergency. It is insightful to study which populations

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are most a�ected, especially as it was mentioned previously that the majority of 
burn wound injuries occur in low and middle income countries. After 
considering the following factors, an e�ective prevention procedure can be 
produced and include several initiatives. Initiatives such as heightened 
awareness within the community, e�cient policy enforced in order to safely 
prevent burn wounds if possible, prioritized research endeavors committed to 
learning more about not only prevention plans but also treatment options 
available, and the revaluation of current burn care therapeutics in order to 
ensure success alongside verifying new treatments being studied currently are 
all necessary to research when prevention strategies are organized50. As initial 
strategies have targeted more physical and pathophysiological consequences, 
research has also suggested signi�cant mental health outcomes, especially for 
the parents of burn wound victims51, that should be studied further in order to 
provide the necessary resources. According to Stanford Children’s Health, 
burn injuries and fatalities have signi�cantly decreased throughout the last 20 
years52. This is promising when addressing the e�ect that increasing public 
awareness may result in more adequate resources, further pushing the 
importance of �re safety and burn wound injury research. Though these 
statistics suggest the harm is not as intense as it might have been in the past, it is 
still just as important to continue studying both the medical and sociological 
factors to enhance burn wound injury healing.

7. Future Directions

LncRNA XIST, IL-33, and miR-19b all contribute to burn wound healing 
repair and their results thus far should permit them to be treatment options to 
be further studied. It is still important to compare the e�ectiveness between 
these novel therapeutic options and other standard treatments for burn wound 
healing in order to identify any gaps or contrasting ideas that might exist and 
inhibit e�ciency. By studying the molecular pathways in which these 
treatment options interact with, other factors that are also present in the repair 
mechanism may also come to light in terms of promising targets, as well as 
targeting other related or unrelated biological pathways. Studying the 
association between LncRNA XIST in particular, and burn wound repair 
presents promising results, though an exact mechanism is unclear. By studying

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its role in depth, it is possible to speci�cally investigate the network of cell 
proliferation and extracellular matrix synthesis, accelerating repair further.

8. Conclusion

The investigation of novel therapeutic options for burn wound injury has 
advanced in the last 20 years, and continues to produce promising results the 
more the scienti�c literature is discussed. Targets of therapeutic strategies 
including LncRNA XIST, IL-33, and miR-19b as well as more standard and 
holistic approaches to burn wound healing have proven to be e�ective options 
for the acceleration of burn wound repair as it results in cell proliferation, 
extracellular matrix synthesis, and an inhibition of �broblast apoptosis, all 
resulting in overall healing on a molecular and more surface level. The 
combination of both topical and standard products that serve as treatments for 
less severe wounds, as well as the incorporation of molecular acceleration via 
targeting key receptors collectively aid repair. Due to the lack of substantive 
results, more diversi�ed and inclusive trials are necessary to solidify their role as 
viable treatment options for long-term use.

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