INTRODUCTION:

Significant mortality and morbidity can result from burn injuries. Since the skin is the biggest organ in the body, burn injuries can affect many different parts of the organ system. Slow wound healing, contractures, discomfort, infection source, and keloid development are all signs of burn injury¹. The World Health Organization (WHO) states that burn injuries can occur when hot liquids (scald), hot solids (contact burn), or flames (flame burn) damage different layers of skin. Another source of burn harm are radioactivity, UV radiation, electricity or chemicals, and pulmonary damage from smoke inhalation. Every year, burn injuries cause around 195,000 deaths². American Burn Association stated in its 2019 report that the highest causes of burn injury were fire at 41%, scald at 31%, electrical sources at 3.6%, and chemicals at 3.5%^3,4.

There are few treatments that are usually used in burn injuries, such as wound excision and skin grafting. There are few treatments that are usually used in burn injuries, such as wound excision and skin grafting^2,5. To overcome these major challenges, stem cell-based treatments in wound healing are performed with autologous cultured epidermal autografts (CEA) as epidermal substitutes. This alternative for wound healing treatment has results such as similar skin in terms of color, texture, appearance, and metabolic structures⁶. CEA has some limitations, for example, long-term fragility, recurrent open wounds, and increased scar contractions. Adipose-derived stem cells (ADSC) are used to get beyond these restrictions. ADSC can promote tissue growth and remodeling in chronic wounds by secreting extracellular matrix. ADSC can repair tissue damage and enhance skin regeneration, reduce inflammation, and accelerate skin healing⁶. Compared to umbilical cord-mesenchymal stem cells (UC-MSC) and bone marrow-mesenchymal stem cells (BM-MSC), ADSC offers several benefits. Multipotency, increased availability, ease of isolation and acquisition, immunosuppression, increased potential for autograft and allograft, lack of ethical concerns, short replicative lifetime, and absence of immune rejection are some of the characteristics of ADSC⁷.

Different soluble mediators and extravascular vesicles that might mediate therapeutic actions to regenerate are secreted by ADSCs. In stem cell-based treatments, these secretions—known as the ADSC secretome—have the ability to accelerate wound healing. Extravascular vesicles, also known as exosomes, can be produced by the membrane of a cell budding outward. Exosomes have a number of crucial roles in immune modulation, cancer, nerve regeneration, migration, apoptosis, cell proliferation, angiogenesis, and cell metabolism. Utilizing plant extracts in conjunction with stem cells Traditional Indian medicine typically uses Aryuveda, which is well-known for its ability to hasten the healing of wounds. Aloe vera is one of the often utilized substances. Aloe vera and ADSCs together can accelerate wound healing while reducing the risk of infection and the potential for the creation of hypertrophic scars^9,10. According to earlier research, the mechanism of aloe vera and ADSC secretome combo therapy is the first step toward developing enhanced burn damage treatment with better outcomes and fewer adverse effects. This review's objective is to outline the advanced therapy's synergistic potential when aloe vera gel and ADSC secretome are used to treat burn injuries.

REVIEW:

Burn Injury:

Swelling and redness in the immediate area where acute inflammation or damage occurs are characteristics of burn injuries. By stimulating a number of growth factors and cytokines, the inflammatory process aims to promote wound healing and shield tissue from the dangers of infection. But chronic inflammation can cause scarring and fibrosis. Friction, radiation, heat, cold, electricity, or chemicals can all cause burn injuries. The size and depth of the damage determine the degree of burn injury³.

Reddish skin and discomfort that only appear shortly after the incident are characteristics of superficial or I-degree burn injuries. Only the epidermis is impacted by superficial burns, which only happen on the skin's surface. Extremely painful, scarring, and requiring additional wound care without surgery are the characteristics of burn injuries from IIA degree or superficial partial-thickness burns. The dermis has been impacted by superficial partial-thickness burns, which often result in blister-like, homogenous, wet, pale, and hyperemic wounds³. Deep partial-thickness or II-B degree burn injuries are very painful, can leave scars, and need ongoing wound care without surgery. Less painful are deep partial-thickness burns, which have reticular, dry, non-pale erythema patterns. Due to damage to the nerve endings, burn injuries from III-degree or full-thickness burns have spread over the whole dermis and are painless. More thorough wound care is necessary for full-thickness burns in order to avoid infection. IV-degree burn injuries are characterized by a blackish hue and the potential for the burnt region to separate. They have also spread to deeper tissue sections like bone or muscle¹¹. Within hours of burn damage occurring, the host's inflammatory response is disrupted. Acute-phase proteins, chemokines, and cytokines may all rise as a result of the stress and inflammatory reaction that follows. Similar to other inflammatory disorders, the first host response to burn injury causes tissue damage in order to start wound healing and tissue repair^3,12,13.

Burn injuries are divided into severity classes and causative agents (chemical, flame, contact, and scald burns). First-degree epithelial burns affect the epidermis; second-degree burns affect the dermis; and third-degree, or full thickness, burns affect the whole tissue and are followed with eschar development and infection risk. Three stages make up the healing process for burn injuries: Proliferation, which includes fibrogenesis, angiogenesis, and re-epithelization; 2) inflammation, which is defined by vascular permeability, lymphocyte recruitment, and cytokine release; and 3) remodeling, which includes the creation of extracellular matrix (ECM) based on collagen and elastin⁶.

Localized edema, or swelling, and erythema, or redness, in the vicinity of the lesion are characteristics of burn injuries. Burn injury-related inflammation is an indication of an active immune response that aids in wound healing. Despite variations in the cause of burn injuries, the stages of wound healing—hemostasis, inflammation, proliferation, and remodeling—are the same. Acute burn injuries have an inflammatory phase that lasts for five to seven days, whereas chronic burn injuries can cause a longer and persistent inflammatory phase that can cause multiple organ failure (MOF) as a result of systemic inflammatory response syndrome (SIRS). Inflammation, cell recruitment, matrix deposition, epithelialization, and tissue remodeling are the initial steps in the wound healing process following burn damage. Extensive burn injuries can trigger systemic hypermetabolic-catabolic conditions and pathophysiological stress. A few common treatments for burn injuries include skin grafting and wound excision. Burn management presents significant complications even after therapy. Slow wound healing, infection sources, discomfort, and hypertrophic scar development are these main obstacles¹⁴.

Adipose Tissue:

Adipose tissue is present in the bone marrow, subcutaneous, intra-articular, and visceral depots of the human body. Additionally, adipose tissue can be found in the liver and muscles. Adipocytes make up adipose tissue. Numerous adipokines, including resistin, omentin, and adiponectin, can be produced by adipocytes. These adipokines have the ability to control metabolism and produce pro-inflammatory mediators that might cause inflammation, such as Monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFα), Interleukin (IL)-1β, IL-6, and IL-8¹⁵. Three different forms of adipose tissue may be distinguished: beige, white, and brown¹⁴.

Brown adipose tissue is mostly seen in the mediastinum, supraclavicular, parascapular, and neck¹⁶. By causing both shivering and non-shivering, brown adipose tissue plays a key function in thermogenesis. The expression of the mitochondrial membrane protein uncoupling protein 1 (UCP1) promotes thermogenesis in brown adipose tissue. Monolocular adipocytes make up the majority of white adipose tissue, which is found in intra-abdominal or subcutaneous depots. White adipose tissue generates adipokines and stores energy. From a developmental standpoint, beige and white adipose tissue are comparable. Energy storage, UCP1 expression, and thermogenesis are some of the functions of beige adipose tissue¹⁵. The stromal vascular fraction (SVF) is the term used to describe the cellular silt that results from the disintegration of adipose tissue using the collagenase enzyme. With the exception of adipocytes, which are eliminated during the procedure, SVF includes every type of cell found in adipose tissue. After SVF is seeded onto standard cell culture surfaces, ADSCs—a comparatively homogeneous collection of long, fibroblast-like cells—are grown for seven to fourteen days. It is possible to grow the ADSCs to significant sizes and freeze them for use in the future¹⁶.

Adipose Tissue-Derived Stem Cell (ADSC):

Because they are readily available in huge quantities and are found practically everywhere in the human body with no morbidity in the donor area, adipose tissue-derived stem cells (ADSCs) are particularly promising stem cells in the field of cosmetic surgery. Compared to ADSCs taken from deeper regions of the abdomen, upper arm, medial thigh, or trochanter, those taken from the abdominal surface exhibit less apoptosis. Of all the adipose tissue types, subcutaneous adipose tissue is clinically significant as an ADSC source. The subcutaneous adipose tissue found in the arm, thigh, and belly is where these ADSCs may be isolated. More ADSCs can be acquired since adipose tissue is comparatively plentiful in the human body¹⁶. The ability of ADSCs to differentiate into several cell types makes them adaptable and offers promising opportunities in the fields of cell therapy and tissue engineering^17,18.

Standard criteria to identify cells as ADSCs were established by the International Society for Cellular Therapy (ICST) in 2006 through research using flow cytometry analysis. These criteria include: 1) the ability to adhere to plastic when kept in standardized culture conditions; 2) the ability to express CD73, CD90, and CD105 but not well CD14, CD34, CD45 or CD11b, CD79a, or CD19, and HLA-DR molecules; and 3) the capacity to differentiate into osteoblasts, chondrocytes, and pre-adipocytes. The ISCT introduced several new requirements in 2013: the main negative markers CD31, CD45, and CD235a must be expressed, and CD13, CD29, and CD44 must be expressed on more than 80% of the ADSC surface^15,16,19.

Depending on their mesodermis origin, ADSCs can develop into a variety of derivatives both in vivo and in vitro, including adipogenic, chondrogenic, osteogenic, angiogenic, myogenic, tenogenic, periodontogenic, and cardiomyogenic derivatives. Furthermore, ADSCs have the ability to develop into endodermis and ectodermis-derived cells. Mature adipocytes that express extracellular proteins including collagen, fibronectin, and laminin are the end consequence of adipogenic differentiation. Following osteogenic differentiation, osteoblast-like cells will be produced that express the genes for alkaline phosphatase, collagen type 1, osteoponin, bone morphogenetic protein-2 (BMP-2), BMP-4, Runx-1, parathyroid hormone receptor, bone sialoprotein, and osteocalcin^16,20.

Prolyl endopeptidase-like, aggrecan (ACAN), sulfate-proteoglycan, and collagen types II and IV are all expressed by chondrocytes during chondrogenic development. ADSCs have the ability to develop into a variety of other cells, including keratinocytes, hepatocytes, beta-islet cells, and vascular smooth muscle cells. Additionally, ADSCs have the ability to develop into glial and neuronal derivatives16, which are cells derived from the ectodermis. Pre-adipocytes, adipocytes, immune cells (macrophages, innate lymphoid cells, eosinophils, endothelial cells, fibroblasts, T cells, and B cells), and pericytes are all present in ADSCs derived from adipose tissue^19,21.

Through the paracrine production of several substances that can stimulate the proliferation and differentiation of stem cells and surrounding cells, ADSCs possess the ability to repair wounds. These include transforming growth factor-β1 (TGF-β1), fibroblast growth factor 2 (FGF-2), insulin-like growth factor (IGF-1), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). The secretion of VEGF, keratinocyte growth factor (KGF), and anti-inflammatory cytokines by neighboring cells promotes neovascularization at the site of damage. Proangiogenic factors released by ADSC include matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-9 (MMP-9), placental growth factor, interleukin-6 (IL-6), interleukin-8 (IL-8), tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2, and MCP-1. These factors can protect endothelial cells from apoptosis and encourage angiogenesis in injury sites^7,22,23.

Adipose Tissue-Derived Stem Cell (ADSC) Secretome:

Compared to bone marrow-derived mesenchymal stem cells (BM-MSCs), adipose tissue-derived stem cells (ADSCs) produce more growth factors, which can enhance their capacity for regeneration. Additionally, ADSCs release a variety of chemicals that are involved in cell signaling, including chemokines, growth factors, cytokines, extracellular vesicles, and morphogens^19,24. Different soluble mediators and extravascular vesicles that can mediate therapeutic actions to regenerate are secreted by ADSCs⁸.

Anti-inflammatory and pro-inflammatory chemokines, cytokines, antioxidative compounds, adipokines, pro-angiogenic factors, brain-derived neurotrophic factor (BDNF), growth factors, and anti-apoptotic factors are the components of soluble mediators from ADSCs. A variety of cytokines, including proinflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15, and IL-17), anti-inflammatory cytokines (IL-4, IL-10, IL-13, and IL-1Ra), and bifunctional cytokines (IL-2 and IL-6) are secreted by ADSCs^15,19,25.

Transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), nerve growth factor (NGF), colony stimulator of granulocyte-macrophage factor (GM-CSF), monocyte chemotactic protein 1 (MCP-1), granulocyte colony stimulating factor (CSF), and reduced levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2) are among the growth factors released by ADSCs. These growth factors are involved in angiogenesis and vascularogenesis and have the ability to trigger neurogenic responses. These processes are crucial for cell migration, which improves the wound-healing process¹⁹.

Secreted into the extracellular matrix, extravascular vesicles—also referred to as microvesicles—are made up of biomarkers that have the ability to influence cellular functions. Lipid bilayer vesicles containing protein, nucleic acid, and lipid make up extravascular vesicles. Cell membrane budding can occur either inside (endosome) or outward (exosome) to produce extravascular vesicles¹⁸. Nucleic acid, protein (cytokines and enzymes), microRNA (miRNA), mRNA, other coding RNA, lipid, and tRNA are all found in exosomes, which are an intercellular communication system. Exosomes have a number of crucial roles in immune modulation, cancer, nerve regeneration, migration, apoptosis, cell proliferation, angiogenesis, and cell metabolism. By stimulating the production of matrix metalloproteinase 9 (MMP-9) through the PI3/AKT pathway, miR-21 found in ADSC-exosomes promotes the migration and proliferation of HaCaT cells and can improve wound healing. By targeting chemokine C-C motif ligand 1 (CCL1) and altering the CCL1/THF-β signaling pathway, ASC-exosomes also produce miR-19b, which mediates the TGF-β pathway and can promote wound healing. Growth differentiation factor 11 (GDF11) and TGF-β from ADSCs interact to counteract the aging effects of keratinocytes and promote skin renewal. ADSC-exosomes have been used in several studies to treat inflammation, lipid metabolism, cell cycle, and skin barrier protection by restoring the expression of genes¹⁹.

Aloe Vera Gel:

Aryuveda, which is often utilized in traditional Indian medicine, uses a mix of plant extracts and is well-known for its ability to speed up wound healing. Mimosa tenuiflora, aloe vera, Salvia miltiorrhiza, Origanum vulgare L., Alchemilla vulgaris, Lavandula stoechas L., Angelica sinensis, Ageratina pichinchensis, Calendula officinalis, Radix astragali, and Rehmanniae radix are among the medicinal plants that contain bioactive molecules that can be utilized. Plant extracts and stem cells can be combined to prime ADSCs and accelerate the healing process of wounds ^9,10.

Aloe vera, a member of the Liliaceae family, grows well in hot, dry tropical climates. The heart of the leaf contains mucilaginous tissue, often known as aloe vera gel, which has both medicinal and cosmetic uses. The primary indications for aloe vera therapy include burn and wound healing because of its anti-inflammatory, anti-microbial, and antioxidant properties, which can aid in the healing process. Bradykinin and thromboxane, two molecules included in aloe vera, are thought to reduce pain and speed up the healing process of wounds^26,27. Alkaline phosphatase activity, tissue-specific gene expression, and calcium levels can all be raised by aloe vera gel. Acemannan, another substance found in aloe vera, stimulates the growth, differentiation, and mineralization of stem cells²⁸.

Bioactive compounds found in aloe vera include glucomannan, which affects fibroblast growth factor, aloe-emodin, and aloe, which have anti-inflammatory properties. These chemicals allow aloe vera to stimulate the growth of fibroblasts and encourage the remodeling of the extracellular matrix throughout the healing process. When used topically, aloe vera can improve vascularity, encourage the creation of collagen, and supply oxygen, all of which help to speed up the healing process of wounds. When used topically, aloe vera can help promote wound healing and remodeling¹⁰. In addition, aloe vera includes sugar, calcium, vitamins, potassium, magnesium, and amino acids, all of which are essential for its cytoprotective properties. Additionally, aloe vera has physiological pH and osmolarity to preserve cell viability. Because of these characteristics, aloe vera can shield ADSCs from free radicals and increase their chances of surviving in the wound microenvironment. Because of its functions in angiogenesis and growth factor stimulation, aloe vera can also work in concert with ADSCs. Aloe vera and ADSC together can increase capillary density and angiogenesis. Aloe vera's ability to differentiate ADSCs into endothelial cells has demonstrated its impact on angiogenesis. Early wound healing angiogenesis can encourage ADSC migration, differentiation, and proliferation, which raises the production of tropocollagen and procollagen for tissue formation²⁹.

DISCUSSION:

In addition to leaving noticeable scars on the surrounding tissues that may not be noticed in the early post-burn phase, severe burns result in deficiencies in the epidermis, dermis, and underlying soft tissues. The first regeneration processes necessary for proper healing are delayed and disorganized as a result of these injuries' subtle disruption of the wound's biochemical milieu. Unusual scarring characteristic of heat damage is caused by tissue deficiencies and uneven wound recovery. This scar tissue becomes tight, thick, fibrotic bands that are devoid of their typical flexibility, color, and texture if nothing is done. Significant functional and cosmetic disability may result from burn scarring in typically movable anatomical regions, including the face and limbs³⁰. Studies conducted both in vitro and in vivo have demonstrated that ADSCs can lower inflammation and hasten the healing of burn injuries. The development of new blood vessels, known as angiogenesis, which is crucial for delivering nutrients and oxygen to the site of damage, may also be encouraged by ADSCs. In mice without an immune system (nude mice), ADSC can promote the healing of burn wounds. According to the findings, administering ADSCs to naked mice can accelerate wound healing by minimizing tissue damage and encouraging tissue regeneration³¹.

ADSC is superior to umbilical cord-mesenchymal stem cells (UC-MSC) and bone marrow-mesenchymal stem cells (BM-MSC) in a number of ways. Among its many qualities are its multipotency, increased availability, ease of isolation and acquisition, immunosuppressive properties, increased potential for autograft and allograft, lack of ethical concerns, short replicative lifetime, and lack of immunological rejection7. Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor (TGF)-β, von Willebrand factor (vWF), and other pro-angiogenesis factors are all increased by ADSCs, and they also generate proliferating cell nuclear antigen (PCNA). Angiopoietin (Ang)-1 and Ang-2 expression as well as vascular density are both increased by ADSCs^32,33.

Different soluble mediators and extravascular vesicles that can mediate therapeutic actions to regenerate8 are secreted by ADSCs. After conditioning the media by eliminating cell debris, the secretome of ADSCs may be extracted from the in vitro growth medium and utilized either directly or fractionated as a concentrated formula^19,34. Anti-inflammatory and pro-inflammatory chemokines, cytokines, antioxidative compounds, adipokines, pro-angiogenic factors, brain-derived neurotrophic factor (BDNF), growth factors, and anti-apoptotic factors are the components of soluble mediators from ADSCs. These secreted ADSC factors have the ability to trigger a neurogenic response and are implicated in angiogenesis and vasculargenesis. These processes are crucial for cell migration, which improves the wound-healing process¹⁹.

By inhibiting the activity of CD4+ T cells and Th1 cells and encouraging the activation of Tr1 and Treg cells, ADSC-exosome can prolong the survival of transplanted vascularized composite allografts^18,35. Therefore, ADSC-exosomes play a number of crucial roles in immune modulation, carcinogenesis, nerve regeneration, migration, apoptosis, cell proliferation, angiogenesis, and cell metabolism⁸. Utilizing plant extracts in conjunction with stem cells Traditional Indian medicine typically uses Aryuveda, which is well-known for its ability to hasten the healing of wounds. Plant extracts and stem cells can be combined to prime ADSCs and accelerate the healing process of wounds^9,10.

Over time, herbal medication treatments have demonstrated less toxicity and more compromising effects. Aloe vera is well-known for its pharmacological properties, which include wound healing, regenerative, anti-inflammatory, and skin protection²⁵. For grade II burn injuries, the combination of aloe vera and bone marrow-mesenchymal stem cells (BM-MSC) produced a superior result than either aloe vera or BM-MSC alone²⁶. Aloe vera and human Wharton's jelly stem cells (hWJSCs) can also help older individuals recover their wounds. Similar to younger patients, the combination of aloe vera and nanocarriers was able to boost and expedite wound healing rates. The processes based on the paracrine impact caused by the secretome molecules produced by hWJSCs are the hypothesis. According to the study, the secretome of hWJSCs produces a number of chemicals that aid in wound healing, and when combined with a carrier, this might be a very effective advanced application for wound healing treatment³⁶.

CONCLUSION:

This narrative review suggests that the secretome of ADSCs and aloe vera gel can promote wound healing by promoting angiogenesis, granulation tissue development, and faster wound closure rates. To determine the precise mechanism of ADSCs secretome when paired with aloe vera gel for burn damage treatment, more study is required in light of this result.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENT:

We would like to express our gratitude toward Immunology Master Program at Airlangga University for their full support in our research.

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Received on 09.02.2024 Revised on 17.08.2024

Accepted on 26.12.2024 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1913-1919.

DOI: 10.52711/0974-360X.2025.00273

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