Cell-Free Therapy Based on Adipose Stem Cell-Derived Exosomes to Inhibit Scar Formation Proactively: Mechanisms and Clinical Targeting Applications

This review provides an in-depth analysis of the potential benefits of cell-free therapy based on adipose-derived exosomes (ADSC-Exos) in inhibiting scar formation. The review highlights the advantages of using ADSC-Exos. It also explores the complex mechanisms by which ADSC-Exos inhibit scar formation, including their role in hemostasis, inflammation, cell proliferation, tissue remodeling, and their regulation of critical molecules (platelets, inflammatory factors, extracellular matrix molecules, collagen molecules) and crucial cells (macrophages, endothelial cells, fibroblasts), as well as their modulation of epithelial-mesenchymal transition. Additionally, the article examines different delivery methods and engineering approaches for optimizing the targeting of adipose stem cell-derived exosomes in traumatic scarring. It points out the potential of using liposomes to construct molecular-targeted exosomes in precision medicine. Finally, the review summarizes current research and provides insights into the future development of exosomes in scar treatment. In conclusion, this article reveals the potential of cell-free therapy based on ADSC-Exos as a promising treatment for inhibiting scar formation.

Pathologic scars often cause tremendous psychological pressure on patients. Currently, the main treatment methods for scarring include compression therapy, topical drug therapy, laser therapy, plasma ion beam therapy, intra-scar drug injection therapy, cryotherapy, radiation therapy, surgery, and silicone gel application. These methods have specific efficacy and shortcomings [1]. Therefore, the need for an ideal method for treating hyperplastic scarring has become a worldwide problem. In previous studies, ADSCs have been successfully studied as a means of promoting scarless healing of minor wounds [2], and cell-free therapies based on adipose-derived stem cell exosomes (ADSC-exosomes/exos) have more advantages and potentials in terms of therapeutic efficacy and clinical application and have a bright future for development.

Exosomes

Exosomes are extracellular lipid bilayers released by cells (Figure 1). These microvesicles have diameters ranging from 30 to 200 nanometers, and nanoparticle tracking analyzers have shown that their densities range from 1.09 to 1.18 g/ml [3,4]. Additionally, they appear "disk-like," "cup-like," or "teat-like" under an electron microscope due to their negative staining; “cup-like” can be used to distinguish cell-derived vesicles from similarly sized particles [5,6].

Figure 1: Processes by which exosomes are secreted, released, and facilitated intercellular communication.

Currently, there is no gold standard for the isolation and purification of exosomes. Methods for exosome isolation include sequential Ultracentrifugation (UC), gradient ultracentrifugation, ultrafiltration, size-exclusion chromatography, polymer precipitation, immunoaffinity capture, and microfluidics-based techniques [7]. UC is the most commonly used (Figure 2). The combination of separation methods is an effective method and a future trend to improve the purity of exosomes.

Figure 2: Schematic representation of ultracentrifugation-based adipose-derived stem cell exosomes isolation.

The cells with the most exosome secretion capacity are Mesenchymal Stem Cells (MSCs) [8]. Among them, ADSCs are ideal for obtaining exosomes in scar inhibition. Regarding their characteristics, ADSCs play a crucial role in skin functionality [8]. Firstly, resident ADSCs in the skin are considered key regulators of skin function and play a vital role in tissue repair and regeneration. On one hand, they replace, repair, and regenerate dead or damaged cells [9]. On the other hand, they allow for the continuous recruitment of mature specialized cells from the basal epidermal layer to its outer layers [10,11]. Their interaction with skin cells regulates skin homeostasis and healing [12]. Secondly, ADSCs secrete abundant substances, including exosomes, growth factors, and cytokines. ADSCs and the Dermal Fibroblasts (DF) differentiated from them [13,14] are the primary sources of extracellular matrix proteins that maintain skin structure and function. These molecules can regulate the functions of surrounding cells and participate in skin growth, repair, and regeneration. Additionally, ADSCs possess anti-inflammatory and antioxidant properties by alleviating skin inflammation and protecting the skin from oxidation stress damage achieved by clearing free radicals [15,16]. This is of great significance in improving skin health and delaying the skin aging process. Compared to MSCs from other sources, ADSCs offer a number of advantages [16,17]. Compared to bone marrow stem cells, ADSCs exhibit higher collection rates, lack donor/recipient cell fusion characteristics, are less prone to contamination in culture, have higher proliferation activity during long-term cultivation, are better suited to survive in hypoxic environments and demonstrate outstanding anti-inflammatory, phagocytic, and anti-apoptotic abilities [18-20]. Compared to embryonic stem cells, they have no ethical restrictions and lower immunogenicity. In contrast to induced pluripotent stem cells, ADSCs have higher purity and can be better controlled to prevent generating unwanted heterogeneous cell types. In addition, ADSCs are more effective in producing collagen than other types of stem cells. They can also differentiate into three developmental types of dermal cells, including the endoderm, mesoderm, and ectoderm [21]. These characteristics make them an ideal stem cell source for obtaining exosomes.

ADSC-Exos carry essential information and macromolecules from their source ADSC [6,22,23] (Figure 3), and their compositions may vary depending on the research method; in general, they encompass a range of essential components that include:1)Proteins: ADSC-Exos contain various proteins such as cytokines, growth factors, and collagen, among others. Notably, they harbor a diverse array of angiogenic factors, including VEGFB, VEGFD, ANG, ANGPTL2, and ANGPTL5, with VEGFD and VEFGB being predominantly expressed within ADSC-Exos [15]. These proteins play pivotal roles in cellular signaling, facilitating cell repair and regeneration. 2) RNA and DNA: ADSC-Exos encompass different types of nucleic acids such as mRNA, miRNA, and lncRNA. For instance, miRNAs present in ADSC-Exos inhibit genes like NPM1, PDCD4, CCL5, and NUP62, promoting dermal fibroblast proliferation. Additionally, ADSC-Exos releases lncRNA MALAT1, which enhances dermal fibroblast migration and accelerates the healing of ischemic wounds [24]. Furthermore, ADSC-Exos releases lncRNA Let-7a-5p, specifically targeting TGF-R1 to modulate the Smad pathway, effectively reducing fibrosis in LSF [25]. Moreover, ADSCP2, a novel peptide derived from ADSC-Exos, exhibits remarkable attenuation of proliferative scar fibrosis both in vitro and in vivo [26]. 3)Lipids: ADSC-Exos contain lipids such as membrane lipids, lipohormones, and lipid degradation products, which contribute to critical cellular functions, including cell membrane repair and cell signaling processes. ADSC-Exos not only substantially contributes to the efficacy of ADSCs but also plays a prominent role in tissue repair and regeneration by acting as paracrine mediators of intercellular signaling [4].

Figure 3: Structure of exosomes and their contents.

The importance of ADSC-based stem cell therapies in regenerative medicine has been confirmed by tissue engineering and cellular therapy strategies [17,27-29] which have shown positive effects on promoting wound healing and scar prevention. However, exosomes and other active substances have been reported to be the main factors through which ADSCs exert their biological effects [30,31]. Additionally, ADSCs-Exos have more advantages in terms of therapeutic efficacy and clinical applications (Figure 4), so cell-free therapies based on ADSC-Exos have broader prospects for application [32,33].

Figure 4: The advantages of applying adipose-derived stem cell exosomes. 1. Rich content; 2. High yield and less invasive harvesting; 3. No ethical issues; 4. Pain-relieving properties; 5. Fusing with the target cells to exert biological effects directly, which is more efficient; 6. Longer life span, higher proliferative capacity, shorter doubling time, later in vitro senescence, and prolonged maintenance of phenotype; 7. Easy to control the time of use and the concentration, dosage, and route of use; 8. The active ingredients are protected by the exosome lipid membrane, which is not easy to destroy and is easier to transport; 9. Capability of being stored at -80°C for at least 90 days; 10. Overcoming challenges such as low survival of implanted cells or the potential risk of tumorigenesis.

Inflammatory cytokine and scar formation

Scar formation is intricately linked to wound healing, and inflammatory cytokines play a major role in both processes [34]. The typical progression of wound healing involves four interconnected phases, each governed by growth factors released by different cells involved in tissue repair. Scarring can occur when these cells or growth factors are disrupted or imbalanced during any stage of the healing process [35-38].

Hemostasis

This phase should be initiated as soon as possible after an injury has occurred. Platelets play a critical role by aggregating, followed by degranulating [39-43], releasing and activating a series of favorable growth factors (e.g., TGF-β, EGF, IGF-I, and PDGF.) and producing Fibronectin(FN), the former of which regulates relevant physiological processes including the coagulation cascade, and the latter of which can control the wandering course of inflammatory cells. (e.g., polymorphonuclears, macrophages, mastocytes, epithelial cells, vascular endothelial cells, and fibroblasts) [44,45]. At this stage, increased FN and granulation tissue due to platelet dysfunction can result in wound tissue hyperplasia and the formation of pathological scars.

Inflammatory

After successful hemostasis, the subsequent phase typically lasts 3-5 days, and the essence and core of this phase are the results of growth factor regulation. Vascular and cellular responses, immune reactions, blood clotting, and breakdown of fibrous material characterize this phase. At the end of this phase and during proliferative phases, macrophages mainly secrete growth factors when neutrophils are replaced with macrophages. The recruitment and activation of various cells, including fibroblasts, endothelial cells, and epithelial cells, are stimulated by growth factors. These growth factors play an important role in initiating the healing process. At the wound site, the growth factors draw in and activate fibroblasts, endothelial cells, and epithelial cells, which begin the healing process. Moreover, the inflammatory response is converted to tissue hyperplasia [46-48] from the early stages to pathological scar formation, macrophage polarization results in spatiotemporal diversity of M1 and M2 macrophages, and there is a close relationship between an increase in M2 cells and susceptibility to abnormal scar pathogenesis [49]. At this stage, macrophages inappropriately release cytokines, such as increased local profibrotic cytokines PDGF, TGF-β, and IGF-Ⅰ, which can lead to proliferative scar formation [50-52]. An imbalance between a sustained inflammatory response and a local immune inflammatory response is the leading cause of scar formation [37].

Cell multiplication and formation of connective tissue

During wound healing, cells enter this phase on day three postinjury, when the inflammatory response subsides and tissue-repairing cells gradually proliferate. Two primary events occur during this phase: the formation of granulation tissue, which involves neovascularization, the deposition of ECM, and re-epithelialization [53,54].

Neovascularization:. Neovascularization provides the necessary oxygen supply to stimulate repair [55]. The endothelium is mainly responsible for vascular construction during this period [56]. Growth factors with chemotactic effects and collagenases with degradative effects secreted by inflammatory cells are associated with the initiation of endothelial cell migration, especially growth factors such as aFGF, bFGF, TGF-β, and EGF, which play a vital role in regulating the whole process of neovascularization [57]. Wound hypoxia enhances the inflammatory state and affects various metabolic processes, including fibroblast activity and collagen synthesis, leading to hyperplastic scar formation [58-60].Extracellular matrix: The formation of ECM is the key to this stage [61]. It initiates during the inflammatory response, during which macrophages secrete signaling molecules such as TGF-β, PDGF, IL-1, TNF, and FGF. Additionally, factors such as collagen peptides, FGF-7, C5a, fibronectin peptides, EGF, PDGF, and TGF-β contribute to the migration of fibroblasts. [52,53,62,63]. Fibroblasts exhibit high sensitivity to TGF-1. Fibroblasts express PDGF, TCF-p, and other growth factors that regulate the production of large amounts of the matrix proteins hyaluronate, fibronectin, and types I and III procollagen. [64,65]. Proliferative scars can be formed if the ECM is insufficiently degraded or synthesized too much, or both [52].

Epithelialization: Epithelialization is essential for wound coverage and healing [66]. Keratinocytes at the wound margin are regulated primarily by matrix Metalloproteinases (MMPs), which detach from the dermis and migrate toward the wound defect, continue to proliferate, and migrate laterally across the wound, altering the epidermal layer, i.e., re-epithelialization. Scar hyperplasia is highly likely to occur if the wound completes re-epithelialization more than three weeks before the wound is closed [63,67-69].

Epithelial-mesenchymal transition: Epithelial-Mesenchymal Transition (EMT) refers to the biological process by which different types of epithelial cells are transformed into mesenchymal cells through a series of biological changes under the influence of different factors [70,71]. During EMT, pseudopods appear at the anterior end of cuboid bone keratinocytes, and the cells transform into a spindle shape that promotes cell migration. EMT is necessary for normal re-epithelialization and ECM deposition: persistent and uncontrolled transformation from epithelial cells to fibroblasts and myofibroblasts may lead to pathological scarring; in later stages, unabated inflammation can affect EMT and lead to abnormal scarring [6,72].

Wound contraction and tissue remodeling

This stage is initiated after re-epithelialization is complete and can continue for several weeks or even two years postinjury, during which wound contraction and the conversion of granulation tissue to scar tissue occurs predominantly.

Wound contraction: Fibroblasts are recruited to the wound site by the chemokine CCL-2 and differentiate into myofibroblasts [73]. Myofibroblasts can attach to matrix elements such as collagen and fibronectin through integrin receptors in the extracellular matrix. Furthermore, fibroblasts are stimulated by TGF-β1 to express α-smooth muscle actin, which initiates the contraction of the fiber matrix gel. Prolonged contraction leads to permanent tissue retraction [74].

Tissue remodeling: New ECM molecules (e.g., fibronectin, Col-III, and Col-I) are sequentially deposited. This deposition process leads to a gradual increase in the strength of scar tissue, which eventually plateaus at approximately seven weeks post trauma. Subsequently, various cell types, including keratinocytes, fibroblasts, and macrophages, secrete an array of matrix-degrading enzymes that degrade excess ECM components. For instance, types I, II, III, X, and VIII of collagen are particularly susceptible to Mesenchymal Collagenase (MCC) or MMP-1 degradation; we discuss the breakdown of denatured collagen by gelatinase (MMP-2), which is capable of breaking down all forms of denatured collagen, including types V and X; and we discuss the role of stromelysin (MMP-3) in degrading collagen types IV, V, VI, and IX, as well as adhesive glycoproteins and proteoglycans. As the tissue remodeling process progresses, Col-I replaces Col-III, and dermal fibroblasts produce elastin and fibronectin, contributing to the formation of elastic fibers. Fibroblasts and vascular cells eventually undergo apoptosis [75,76]. The extent of scarring is determined by the amount of ECM synthesized and degraded [77]. Excessive collagen deposition during this stage can lead to the formation of pathological scars [78,79].

ADSC-Exos is active in regulating the cells and inflammatory factors involved in newly formed wounds and established scars. Active involvement is critical in promoting optimal wound healing and preventing scar formation. The authors emphasized the significant contribution of ADSC-Exos to the active modulation of inflammatory factors throughout this process.

Bidirectional regulation of the whole process of wound healing

Due to the nature of scar formation mechanisms, the process of inhibiting scar formation is multifaceted and intricate. The review categorizes the mechanisms of inhibiting scar formation by ADSC-Exos into three categories and summarizes the specific mechanisms in table 1.

From table 1, it can be seen that:

1. the regulatory mechanism of ADSC-Exos for the overall wound healing process is bidirectional, with an overall forward predominance; at the same time, the regulation of some molecules like collagen by ADSC-Exos will also be bidirectional, with an overall predominance of regulatory mechanisms favoring the inhibition of scarring [80-87].
2. It cannot be said that promoting the regulation of reverse development is detrimental to wound healing because sometimes reverse regulation is beneficial for wound healing [84-87]. Similarly, it cannot be said that promoting positive regulation is always beneficial [81-83].
3. ADSC-Exos can be actively involved throughout the entire process of wound healing and prevention of scar formation. During the second stage, ADSC-Exos regulates the mechanism of the immunological-inflammatory response. During the third stage, they promote neovascularization and enhance skin cell proliferation. ADSC-Exos also controls collagen remodeling during the fourth stage of wound healing.
4. ADSC-Exos do not only directly regulate inflammatory factors but also indirectly regulate them by modulating multiple signaling pathways, including the Wnt/β-catenin, PK 1/2, ERK/MAPK, and PI3K/AKT pathways, thereby facilitating wound healing and scar formation [91-96].
5. Research on the regulatory mechanism of ADSC-Exos on cells has focused mainly on fibroblasts [45,92,97-100] and macrophages [83-87].
6. The function of ADSC-Exos usually depends on the nucleic acids or proteins they carry and express, and some scholars have focused on the role of a series of Exo-miRs in regulating wound healing via ADSC-Exos [83,84,88,91-98,100-107].
7. The nucleic acids or proteins carried by ADSC-Exos are secreted by the cell of origin. Therefore, exosomes usually play the same biological roles as their cell of origin.
8. ADSC-Exos can improve their biological ability after pretreatment, such as with a low oxygen environment for operational pretreatment and with H2O2 for pharmacological pretreatment. For example, ADSC-Exos pretreated with hypoxia can improve their biological ability. The ability of hypoxia-pretreated ADSC-Exos to form neovascularization networks was greater than that of nonhypoxia-pretreated ADSC-Exos, and the ability of H2O2-pretreated ADSC-Exos to promote angiogenesis was greater than that of non-H2O2 pretreated ADSC-Exos [113].

Some fundamental mechanisms and molecules in preventing scar formation

ADSC-Exos prevents scar formation through various molecular mechanisms, primarily involving the transfer of specific miRNAs and proteins. Some fundamental mechanisms and molecules involved are as follows:

1. Regulation of fibrosis signaling pathways: ADSC-Exos can modulate the activation of several signaling pathways involved in scar formation, such as Wnt/β-catenin, TGF-β2/Smad3, and PI3K/AKT, by carrying or expressing miR-19b [95,96], miR-29a [107], and miR-125a-3p [91], thereby reducing fibrosis and scar formation.
2. Anti-inflammatory effects: Delivering miR-155, miR-34a-5p, miR-124-3p, and miR-146a-5p, they can regulate the balance of macrophage differentiation, inhibit the release of pro-inflammatory cytokines like IL-1β and TNF-α, and promote the secretion of anti-inflammatory cytokines like IL-10. This balanced immune response helps limit inflammation and subsequent scar formation [83,84].
3. Modulation of fibroblast activity: ADSC-Exos carrying miR-21 and miR-let7b can target and inhibit the expression of destructive genes in fibroblasts, thereby reducing scar formation. In addition to its potential role in promoting fibroblast activity, GDF11 may interact with TGF-β signaling pathways, which are crucial for producing skin cells with youthful characteristics [9,120-123]. Certain inflammatory factors, such as IL-10, can promote the conversion of fibroblasts to mature fibrocytes and inhibit scar tissue formation.
4. Induction of angiogenesis: Adequate blood supply is crucial for wound healing and scar prevention. ADSC-Exos contain angiogenic factors such as VEGF and can regulate the promotion of neovascularization through the delivery of miR-125a, miR-31, miR-126-3p, miR378a-3p, and miR-21, thereby improving tissue regeneration and reducing scar formation [90,97,101,102]. ADSCs also interact with endothelial cells of microvessels, secreting increasing levels of IL-6, IL-8, and MCP-1 to regulate skin inflammation [124].
5. Promotion of cell migration and proliferation: ADSC-Exos can stimulate the migration and proliferation of various cell types involved in wound healing, such as by delivering Exo-miR-378 [104]. This contributes to normal tissue regeneration and minimizes scar formation. ADSCs regulate and resolve their microenvironmental problems by secreting inflammatory factors such as TGF-β and ECM to optimize the involvement of corneal-forming cells and DFs in the healing process [9,120-122].
6. Regulation of collagen remodeling: ADSC-Exos can reduce hypertrophic scar formation by delivering miR-192-5p, which decreases fibrotic proteins and collagen deposition and the differentiation level of fibroblasts into myofibroblasts [125].

It is important to note that inflammatory factors can contribute to scar inhibition through various mechanisms, such as regulating immune responses, inhibiting excessive proliferation, and promoting cell apoptosis, and that the specific miRNAs and proteins present in ADSC-Exos may vary depending on various factors, including the origin and culture conditions of the ADSCs. Different studies have identified multiple miRNAs and proteins associated with the anti-scarring effects of ADSC-Exos, and ongoing research continues to uncover additional molecules and mechanisms involved.

Multi-process intervention for wound healing

Considering how dynamic and interactive the processes of scar formation and wound healing are, therapeutic strategies in which ADSC-Exos are actively involved in multiple processes for wound healing can lead to better healing outcomes. For example, ADSC-Exos exerts its effect on fibroblasts, macrophages, and skin cells by secretion of inflammatory factors (Figure 5). GDF11 and TGF-β are present at almost all stages, and they promote the proliferation of fibroblasts, macrophages, and ADSCs, leading to immune responses, cell proliferation, and angiogenesis [12]. ADSC-Exo-miR-486-5p (Exo: 200 μg/100 μL) increases the viability and migratory properties of HSF and HMEC by decreasing Sp5/cyclinD2 (CCND2) pathway activity and increasing HMEC neovascularization activity, and it accelerates wound healing throughout the skin, increases epithelial regeneration, reduces scar thickness, and enhances collagen synthesis and angiogenesis [126]; the upregulation of MMP-7 expression has been shown to accelerate wound healing in diabetic rats by promoting the proliferation and migration of keratinocytes, leading to improved inflammation control, re-epithelialization, tissue matrix remodeling, vascular growth, and maturation [127-129]; and when ADSCs are present, skin fibroblasts proliferate more easily during the early phases of wound healing, which promotes collagen production as well as the healing process. However, during the later stages of wound healing, ADSCs have been shown to inhibit fibroblast proliferation and collagen synthesis [13-139].

Figure 5: Functions of scarring inhibition by inflammatory factors in adipose stem cell-derived exosomes.

The targeted application of ADSC-Exos to human wounds can be achieved through various methods, depending on the specific therapeutic goals and applications. These approaches include injection or infusion, local application, and bioengineering techniques, all beneficial in wound healing.

Injection or infusion

ADSC-Exos can be applied to the body by injection or intravenous infusion [89,132]. ADSC-Exos are emerging as promising candidates for delivering therapeutic substances such as drugs, genes, or other functional molecules with remarkable precision and specificity; thus, ADSC-Exos, which can act as ideal carriers for targeted therapy, enable the efficient delivery of therapeutic substances to specific sites of interest [132-135]. For example, ADSC-Exos can be modified to target cellular vesicles and release drugs that promote wound healing in treating large generalized wounds.

Local application

Locally applied ADSC-Exos can be applied directly to specific injury sites in the body by binding to gels, Microneedles (MNs), etc. Exosomes are pivotal in promoting wound healing and regeneration by selectively targeting specific growth factors and cell signaling molecules.

Adipose stem cell-derived exosomes in combination with hydrogels: The building blocks of hydrogels are hydrophilic polymers that undergo physical or chemical cross-linking to form three-dimensional networks [136-138] and are considered ideal alternatives for tissue repair engineering due to their ability to resist infection, absorb wound exudates, maintain water balance and gas exchange, load and deliver bioactive factors, and bioadaptability [139-142]. Gel-based drug delivery systems, as opposed to conventional systems, preserve the form and function of cells or bioactive molecules for an extended amount of time [143]; At present, hydrogel matrix-loaded ADSC-Exos are manifested in three primary forms: (1) physical binding to hydrogels, (2) covalent cross-linking based on the active precursor, and (3) in-situ gelation method. 3D printing technology has rapidly advanced and is widely utilized to enhance the functional aspects of hydrogel scaffolds, which enables precise manipulation of the scaffolds' porosity, pore shape, and overall geometry, leading to improved performance and functionality.

Compared with other hydrogels, DNA hydrogels are 3D polymer networks with DNA as the structural unit. Which combines the matrix structure of hydrogels with DNA's unique biological functions, such as precise and efficient self-assembly ability, excellent structural precision controllability, diversified stimulus responsiveness, good biocompatibility, and biodegradability [141,144,145]. Therefore, DNA hydrogels have certain advantages as carriers for exosome delivery systems, such as biocompatibility, effective binding to drugs, easy triggering of stimuli, and effective active targeting. Additionally, different types of inorganic nanoparticles, small molecules of drugs, and functional biomolecules can be used to dope porous networks with moderate loading efficiencies. In addition, highly programmable DNA hydrogels allow for synergistic loading of drugs with different physicochemical properties, enabling high-performance delivery systems, and release rates are controlled by DNA hydrogels modulating the type of DNA strand segments [146-150].

Currently, a significant number of multifunctional DNA hydrogels capable of delivering ADSC-Exos have been created by researchers, particularly in the areas of tissue repair and drug delivery [151,152], such as a novel multifunctional DNA hydrogel with a collodion structure, MpHt-DNA hydrogel-A/b with a wound patch structure, and E7-P-b-DNA gel for targeted recruitment of stem cells.

Adipose stem cell-derived exosomes in combination with microneedles: Microneedles (MNs) have attracted attention for their unique minimally invasive nature, visualization performance, ability to overcome biological barriers, accurate and sustained drug release performance [153,154]. The combined application of exosome-injected MNs can achieve both advantages to promote each other. In addition to improving the stability and adhesion of microneedles and reducing their resistance when entering the skin, Zhou, et al. [155] designed and 3D printed biomimetic and macro deformable DNA gel microneedles (P-DNAgelMNs) with a shark's barbed groove structure and a flat, angled structure resembling a crab claw. These MNs also have intrinsic adhesive properties that allow them to avoid the laborious dressing application. At the same time, P-DNAgelMNs also have excellent characteristics as follows. P-DNAgelMNs exhibit strong biocompatibility and induce biological behaviors in cells [155]. Biomaterials with particular biochemical properties, growth factors, active substances, and EVs can regulate their polarization, i.e., ADSC-Exos can regulate their polarization [156,157]. Concurrently, P-DNAgelMNs can activate pathways that reduce inflammation and pain; mRNA expression of Trpvl and CCL2, two common inflammatory pain signaling factors, gradually decreases with optimization of the MNs design structure, resulting in less pain. [158,159]. Its needle cap exhibits excellent tensile and elastic deformation ability at concentrations of 10%, and the elastic deformation dressing can better accommodate patients' joints [160-162]. Its dissolution rate decreases as concentration increases, offering a solution to excess tissue fluid in ulcerative wounds. Bacteria can have their cell membranes destroyed by the cationic peptide that MNs inject into the exosome, allowing the contents of the bacterium to seep out and ultimately leading to its death, so the MNs are suitable for the wounds of diabetic patients with low immunity and high risk of infection [160-163].

Engineering of adipose stem cell-derived exosomes

The use of natural ADSC-Exos is limited by limited drug loading capacity, insufficient yield for clinical use, limited biodistribution, targeting dependent on the parent cell, and some off-target effects [166-168]. Engineered approaches can help increase the scalability of ADSC-Exos, improve their targeting properties, and expand the range of biomedical applications of ADSC-Exos beyond their intrinsic capabilities [169]. In this context, constructing engineered ADSC-Exos as alternatives to natural ADSC-Exos has become an effective strategy for addressing the above issues.

Typical methods: Currently, there are two main techniques for preparing engineered ADSC-Exos: surface modification and content modification. Surface modification techniques include covalent modification (using covalent bonds to attach specific molecules to the surface of exosomes, such as spot chemistry), donor cell modification (using gene transfection, changing the donor cell culture environment, and drug-cell incubation method), and noncovalent modification (using electrostatic, receptor-ligands, and other non-covalent bonding to attach particular substances to the exosome membrane binding). While content modification techniques include bioengineering (where the medication binds to the donor cells or exosomes by co-incubation), genetic engineering transfection, and physical methods (such as ultrasound, electroporation, freeze-thaw cycling, extrusion, etc.) [171-175] (Figure 6).

Figure 6: Classic modification strategies for exosomes.

Nanoengineering: Typical approaches for harvesting targeted exosomes typically involve using antibodies and peptides as targeting ligands. Still, several inherent drawbacks hamper their clinical application, including batch-to-batch variability, decreased specificity, immunogenicity, instability, safety concerns, variable transfection results, and mutagenesis. In addition, this bioengineering strategy is very time-consuming, and the identification of the molecule will have to be repeated each time the molecule is targeted for a new entire process.

Through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) screening, single-stranded DNA or RNA molecules known as aptamers or chemical antibodies can be generated. These molecules exhibit high affinity and specificity when binding to their targets through the same mechanism as antibody-antigen binding, forming specific three-dimensional structures [176-179]. Aptamers are superior to antibodies in precision medicine because their molecular mass, immunogenicity, and toxicity are lower, as well as their greater stability, ease of modification, and superior tissue penetration [176,180,181]. From a translational research perspective, the main advantages of aptamers are their scalability and absence of batch-to-batch variation in drug production, as they are synthetic nanocarriers chemically synthesized without the involvement of animals or cultured cells [182].

The synthetic nanocarriers used to construct molecularly targeted exosomes are mainly liposomes, metal nanocarriers, silica carriers, and polymer nanocarriers. Lipid ligands are usually used to utilize the specific biochemical properties of exosomal lipid bilayers for surface nanoengineering [183-188]. Molecularly targeted exosomes can be prepared by three main methods: (1) intracellular preloading; (2) surface modification of exosomes by antibody coupling; and (3) physical methods, which are used to hybridize exosomes with nanocarriers utilizing membrane extrusion, freeze-thaw cycling, ultrasound, electroporation, PEG induction, coincubation, etc [189-196].

Traditional drug delivery vehicles (such as metal particles, nanogels, and liposomes) have been widely used, but their synthesis costs are high, and their stability could be better.

Combining an aptamer-functionalized exosome drug delivery system (Figure 7). with traditional therapeutic means, such as acoustic power therapy, RNA interference technology, and chemical treatment, synergizes active and passive targeting mechanisms, thereby maximizing the effectiveness of the drug and enhancing therapeutic efficiency. Combining exosomes and aptamers to form molecularly targeted exosomes is expected to constitute the next generation of intelligently engineered nanovesicles for precision medicine.

Figure 7: Aptamer-functionalized exosome drug delivery system.

In conclusion, ADSC-Exos are critical for wound healing and reducing the growth of excessive scars. Cell-free therapies offer numerous advantages in mitigating pathological scarring, as they actively regulate relevant cells and their associated inflammatory factors throughout the different phases of wound healing. Furthermore, the multiple regulatory mechanisms employed by ADSC-Exos are complementary. There are various clinical approaches for targeting ADSC-Exos, among which 3D-printed hydrogel drug delivery systems and nanoengineered aptamer-functionalized exosome drug delivery systems have the most potential for research and translational applications. Finally, we can infer that ADSC-Exos exhibits active targeting effects in inhibiting scar formation, suggesting their potential application in overcoming the challenges of scar management in clinical settings. However, there are still challenges to using this treatment in several areas.

Long-term efficacy and safety of adipose stem cell-derived exosomes

First, in terms of long-term effectiveness, most of the studies have observed an improvement in the therapeutic efficacy of ADSC-Exos in scar prevention in the short term, but the long-term effect requires longer follow-up and observation; in addition, exosomes may be affected by storage and handling conditions, which also need to be studied further. Secondly, in terms of safety, ADSC-Exos is basically safe because it is derived from autologous tissues without rejecting allografts and has no cytoplasmic nucleus. Still, more evaluations are needed to determine whether other adverse reactions, such as infections and allergies, may occur during treatment.

Impact of recipients-individualized factors on efficacy

Firstly, age is associated with the ability to repair and regenerate tissue. Younger people typically have better self-healing and repair capabilities and, therefore, may be more likely to benefit from ADSC-Exos treatment. Secondly, different skin types have different physiological characteristics and responsiveness. Certain skin types may be more susceptible to scar formation; therefore, individualized treatment regimens may be needed for recipients based on their skin types. Lastly, a recipient's underlying health condition may also impact the efficacy of ADSC-Exos; for example, recipients with chronic inflammatory or immune system disorders and recipients with other chronic diseases or have been on some medications for a long time may require more attention and monitoring. It is important to note that while these specific factors may impact the efficacy of ADSC-Exos in preventing scarring, the current research needs to be more comprehensive to determine the exact relationship between them. Therefore, physicians and researchers must consider their recipients' individual differences and specific circumstances in practice and conduct detailed evaluation and monitoring.

Clinical translation of adipose stem cell-derived exosomes in scar inhibition

There needs to be clear guidelines for determining the optimal dose of exosomes. Secondly, choosing the appropriate route of administration is also an important issue. ADSC-Exos can be administered by several routes, such as injection, intravenous infusion, or local application; however, different administration routes may impact exosome distribution, bioavailability, and therapeutic efficacy.

Scalability and production challenges

The production of ADSC-Exos is a technology-intensive task requiring highly specialized equipment and personnel. Currently, ADSC-Exos production is mainly prepared by culturing ADSCs and extracting the exosomes they secrete. Although this approach is feasible for scaling up ADSC-Exos production for clinical use, it still presents several challenges.

One major challenge is that increasing production requires a large number of ADSCs, which need to be provided with sufficient donors to enable the engineered preparation of ADSC-Exos. Another challenge is that, unlike traditional drug manufacturing, exosome production requires more time and effort to monitor and control the details of the production process, and a standardized production process and quality control system needs to be established to ensure the consistency and quality of the exosome. The current cost of ADSC-Exos production is also very high, mainly due to the need for equipment, which is very expensive, complex cultivation processes, and specialized personnel. Technological improvements and process optimization are needed to reduce costs and increase production efficiency. Lastly, quality control is also an essential issue in ADSC-Exos production. Since ADSC-Exos is a biological product, its quality is affected by many factors, such as cell differentiation status, purity of exosome isolation, etc. A comprehensive quality control system is needed to ensure that the quality of ADSC-Exos meets the clinical requirements.

Regulation and ethics

Regarding regulatory pathways, the approval of ADSC-Exos as therapeutic requires undergoing clinical trials. Regulatory agencies have the authority to impose requirements on the design and execution of these trials, which may include aspects such as sample size, treatment protocols, data collection, and analysis. Additionally, regulatory agencies should mandate pharmaceutical companies to submit comprehensive quality control and production process documentation to ensure the consistency and quality of ADSC-Exos. These measures aim to achieve the intended regulatory objectives.

Regarding ethical considerations, using ADSC-Exos as a therapeutic requires adherence to moral principles and regulations, including patient informed consent, protection of personal privacy, data security, and fair allocation of resources. Biological ethical issues related to ADSC-Exos must also be considered, including cell source selection, donor-informed consent, rights protection, and treatment safety and efficacy evaluation.

Patient education

Patient education and awareness must be considered in preventing and managing scars. Firstly, we can disseminate information about ADSC-Exos to patients through various online and offline channels, organize regular lectures and seminars specifically tailored for patients, and invite experts to share relevant knowledge about ADSC-Exos. Secondly, doctors should communicate thoroughly with patients, jointly develop treatment plans, and provide necessary guidance and support. Additionally, doctors should conduct regular follow-ups with patients undergoing ADSC-Exos treatment to understand their treatment outcomes and responses, emphasizing the importance of scar prevention and management. Thirdly, we should strive to establish patient support groups, enabling patients to share experiences and information. Patients can gain comprehensive information about ADSC-Exos through these measures, empowering them to actively choose and participate in treatment while better controlling and managing their health conditions.

In vivo and Ex vivo model selection

In the research on preventing scars using adipose-derived stem cell exosomes, selecting appropriate in vivo and in vitro models for investigation is crucial. In vivo models can more accurately simulate the complex physiological environment of human tissues and organs, but they also involve issues related to animal ethics and experimental regulations. On the other hand, in vitro models offer better controllability and maneuverability, allowing for precise control of experimental conditions and easier acquisition and processing of samples. Based on four criteria- research objectives, degree of simulation, controllability, maneuverability, and ethical and safety requirements- scientists can choose the model that best suits their research needs. By combining the advantages of different models, a comprehensive evaluation and validation can be conducted.

To date, the mechanisms underlying the generation of ADSC-Exos and their role in wound healing have been extensively investigated domestically and internationally. Significant progress has been made in developing diverse and comprehensive techniques for isolating and enriching exosomes. Moreover, research on exosomes as a targeted drug delivery system is also flourishing. However, the safe and sustainable clinical application of targeted scar prevention using extracellular vesicles has not yet been achieved, nor has its engineering production. In addition, the delivery pathways of ADSC-Exos for targeted scar prevention are also limited. Building upon these advancements, future research directions hold promise in exploring the content of ADSC-Exos, nonstem cell-derived ADSC-Exos, laser delivery of exosomes, and the combination of ADSCs-Exos and surgical techniques.

Research on the contents of ADSC-Exos holds the potential to advance cell-free therapy using these vesicles toward further molecularly targeted therapies. This advancement can pave the way for precision medicine in scar prevention, wherein customized treatment plans can be provided based on individual genetic and phenotypic characteristics. This approach aims to enhance the effectiveness of scar prevention and minimize adverse reactions. Exosomes derived from non-stem cell sources can be obtained from animals and plants. They offer the advantages of convenient acquisition and low cost, making them more suitable for the engineered production of exosomes. Additionally, plant-derived exosomes do not carry zoonotic or human pathogens compared to mammalian-derived exosomes. This facilitates engineered exosomes' streamlined extraction and production processes while improving their safety in clinically targeted applications. Laser therapy has been widely used to improve the appearance and texture of scars. Using lasers' focusing and directional properties, exosomes can be precisely delivered to wound areas by adjusting laser parameters, achieving high-precision positioning and non-contact selective delivery. ADSC-Exos can provide growth factors and ECM components, promoting skin healing and repair after laser treatment. For larger or depressed scars, surgical techniques may be necessary. During surgery, ADSC-Exos can facilitate wound healing, reduce inflammation, and improve postoperative scar formation, thereby contributing to better surgical outcomes and reduced complications.

Resource identification initiative

Not applicable.

Life science identifiers

Not applicable.

None.

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

XMW: Final review of the manuscript and overall supervision; XHC & HJD: Conceived and designed the study, performed literature sorting, and drafted the manuscript; YL: Revised and edited the manuscript; SYY& GRY: preparation of the initial draft. All authors agree to be accountable for the content of the work.

Not applicable.

Thanks to Komla-Dzah Julius Kodzo for his linguistic support of the manuscript.

The review highlights adipose stem cell-derived exosomes' potential to revolutionize scar management. Understanding their mechanisms offers a non-invasive, cell-free alternative to traditional therapies. This approach could significantly improve scar treatment outcomes, addressing a critical need in clinical practice. The study's findings have translational and clinical significance, paving the way for innovative scar prevention strategies with broad therapeutic implications.

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