Therapeutic potential of adipose tissue derivatives in skin photoaging

Background: classic & novel adipose tissue derivatives

Since the maturation of fat-grafting technology in the 1990s, fat grafting has been widely used in the field of plastic surgery and has been gaining increasing attention in the field of regenerative medicine, including dermatology. In the recent decade, many new theories and technologies have emerged on methods of fat harvesting and processing, such as stromal vascular fraction (SVF), purified adipose-derived stem cells (ASCs), nanofat, SVF-gel, and so on (Figure 1). Different fat preparations are physically processed to meet corresponding clinical needs depending on patient characteristics and the filling effect desired in the treatment of photoaging (Table 1 & Figure 1).

Particle fat grafting

In 1992, American fat transplant expert Coleman proposed a revolutionary fat-extraction technique. In his first literature on structural fat grafting, he mentioned that patients showed improvements in skin texture and elasticity after treatment [1], which was broadly recognized by plastic surgeons in their clinical work. Particle fat transplantation, as a key technology in the case of volumetric defects, has the advantage of quick and easy restoration of soft-tissue volume loss (Table 1). However, Coleman's fat particles were reported to be large and difficult to precisely fill the face, leading to irregular fat accumulation [2]. Moreover, they tend to release abundant free lipid droplets after post-transplantation lipolysis, developing side effects such as facial swelling, fat cysts and even lipogranulomas (Table 1) [3].

Minimally manipulated adipose tissue derivatives

With the gradual standardization and management of stem cell applications, the concept of minimal manipulation was proposed by the US FDA in 2005, which involved treating adipose tissue through pure physical methods such as injection, centrifugation and homogenization [4]. To avoid severe ischaemia and fat necrosis occurring with excessive volume injection on the treatment plane, requirements for the fineness of adipose tissue particles are rising. Millifat applying 2.4 mm or fewer holes and microfat applying 1.2 mm or fewer holes have been devised with more delicate particles compared with traditional fat grafts, which use 2–3-mm holes [10,46,47].

Mechanically fragmented fat

To obtain more exquisite fat particles with better regeneration ability, simple physical fat homogenization technology without enzyme digestion has rapidly been developed (Figure 1). ‘One-stop’ ready-to-use systems such as condensation, Lipogems and squeezed fat have been put into use in the operating room (Figure 1) [48]. Among them, supported by more clinical and experimental literature are the microfragmented fat technique, reported by the Italian scholar Bianchi in 2013 [49]. Microfragmented fat with a positive effect on the maintenance of AT histology has not only been used in the field of orthopedic and aesthetic surgery, but has also been reported in the field of fecal incontinence, degenerative osteoarthritis [5] and chemotherapeutic sustained release (Table 1) [6]. Unlike SVF cells obtained by enzymatic digestion, microfragmented fat contains more perivascular cells and better secretory capacity in tissue repair and regeneration (Table 1) [7], as it contains more natural niches that can be recognized by host immune-mediated cells in the first stage of fat grafting [8].

Fat enzymation technique

The representative technique for fat enzymation is the emulsification nanofat technique, published by Tonnard et al. in 2013. The adipose tissue is rinsed, filtered and then placed between two syringes for emulsification [10]. ASCs have been observed in nanofat [10]. However, nanofat also contains a large number of lipids shed from broken necrotic adipocytes, implying a prolonged local inflammatory response (Table 1) [9]. Based on the technique, in 2016 our team reported on the adipose extracellular matrix (ECM), namely SVF-gel, showing good skin-regeneration ability [11]. On the basis of enzymation, a removal step of water and oil was added to concentrate the fat matrix components into a delicate colloidal injection (Figure 1) [11]. Currently, adipose tissue derivatives that have been reported to contain abundant ASCs or SVF are: squeezed fat (1.1  ×  10⁶ASC/ml) [12], SVF-gel (1.8 × 10⁵ASC/ml) [11] and nanofat (1.2  ×  10⁶ SVF/ml) (Figure 1).

Adipose-derived secretary products

In addition to the adipose tissue-derived products described above, lipoaspirates can also be prepared as cell-free adipose secretory products that are highly effective in stimulating angiogenesis and adipogenesis (Table 1). The aims of extracellular elements of adipose tissue are to promote an autogenous regenerative microenvironment at the recipient site. Adipose tissue extract (ATE), an immersion product of minced fresh adipose tissue, has shown dose-dependent proangiogenic and proadipogenic potential [50]. Adipose liquid extract, obtained during fat emulsification, can promote the healing of chronic skin ulcers [26]. Cell-free fat extract is a liquid component purified by centrifugation from nanofat containing proinflammatory and proapoptotic growth factors [27,28]. Its subcutaneous injection has been shown to increase capillary density, which subsequently promotes skin regeneration [29]. Lipoaspirate liquid extracellular vesicles are an enrichment of extracellular vesicles obtained after ultracentrifugation of lipoaspirate fluid, and they also play a proangiogenic and proadipogenic role in studies of adjuvant fat grafting [30]. Adipose tissue extracellular vesicles (ATEVs) are then enriched in secretory vesicles after fat homogenization, and through the combination of hydrogel material, ATEVs can promote de novo synthesis of adipose tissue [31,32].

In addition to stimulating the expression of antioxidant enzymes, adipose tissue secretomes also exhibit good inherent superoxide dismutase and catalase activity [33]. The main difference between this type of product and purified stem cells in terms of anti-inflammatory function is that they not only contain growth factor-like cytokines, but also contain an immense number of inflammatory factor signals that initiate repair mechanisms (Table 1). High-throughput analysis of adipose tissue extract revealed that they contained classical proinflammatory factors such as IL-2, IL-6 and IL-8, neutrophil-activating protein, TIMP-2 and giant cell-related inflammatory protein [50].

ASC secretome

Abundant in adipose tissue, mesenchymal stem cells play a key role in maintaining skin homeostasis through paracrine effects. Under solar radiation, premature ASC aging can gradually lead to the loss of their ability to maintain homeostasis and the biological function of skin tissue. Therefore, the ‘regeneration’ of ASCs and other skin-resident cells are highly attractive strategies to combat photoaging and premature senility. ASC-secretome encourages fibroblast, epithelial and endothelial cell proliferation, migration and secretory activity [51,52]. This may considerably benefit skin damage, requiring minimal or no volumetric correction remodeling.

SVF and ASCs have great application value in indications such as scars, refractory wounds, burns, auxiliary fat grafting, anal fistula, and so on. SVF, as an effective component extracted from adipose tissue after efficient removal of oil droplets, is rich in a variety of cells with repair functions as well as a mixture of bioactive factors, and has shown promising applications in the treatment of diabetic foot, cartilage regeneration in arthritis and gastrointestinal syndromes [13,14,53]. ASC medium, ASC exosomes and ASC extracellular vesicles (ASC-EVs) have been reported to protect against ultraviolet B (UVB)-induced skin photoaging [15]. Cell secretary products have gained attention due to their better safety profile and commercialization potential of allogeneic applications (Table 1).

Decellularized adipose matrix products

Decellularized adipose matrix (DAT) has been applied to the construction of engineered fat for combatting clinical dilemmas such as traumatic injury or tumor resection [54,55]. The application of stem cell-mediated therapies in regenerative medicine, along with its biomaterials and growth factors, is expanding beyond the dermatological sector at an alarming pace (Table 1). Since adipose tissue-derived substances are relatively soft, they often perform poor supportive shaping effects for the loss of soft tissue in the middle of the face, wrinkles, dry lines, and so on. Based on this, DAT-hydrogel has been introduced into clinical application, which can be injected subcutaneously and has plasticity for irregular soft tissue defects, and is considered to be one of the most suitable materials for soft tissue filling [22,56].

Concerning insufficient early angiogenesis after DAT transplantation, DAT hydrogel loaded with bFGF and extracellular vesicles were developed [57]. bFGF-DAT can significantly induce capillary formation within neoadipose tissue and has a mature morphology quite similar to that of endogenous adipose tissue [18,19,57]. DAT enriched with EVs also shows significant proangiogenic and proadipogenesis effects in the early post-transplantation period (Table 1 & Figure 2) [20]. In the administration form of hydrogel dressing, γ-PGA hydrogels loading cell-free fat extracts have promoted diabetic ulcers in a mouse model [21]. This may become a potential avenue for adipose-derived secretary products to participate in tissue engineering to construct anti-photoaging strategies.

Concurrent with the continued approval of commercialized collagen products, autologous adipose matrix products that require only minimal processing have joined the ranks of dermal fillers (Table 1). Adipose collagen fragment (ACF), as a sustained-release system for adipokines, exerts strong therapeutic effects to enhance angiogenesis, antiapoptosis, antioxidant activity and collagen synthesis in photoaging models [56]. ACF has also shown long-term filling effects for deep wrinkles in clinical studies [58]. Adipose matrix complex is a fiber-rich adipose tissue derivative obtained by intercepting fat aspirates through a macroporous filter [23]. With a stiffness up to about 6 kPa (adipose tissue 2–4 kPa [24]) and rich in fibrous tissue of the fascia layer, it has the clinical practice potential for better supportive filling effects for sites such as the mentum and the dorsum of nose [23].

Therapeutic potential & strategies of adipose tissue derivatives in antiphotoaging

UV radiation can deeply penetrate the skin and induce profound alterations of the dermal connective tissue. With further purification of bioactive components from the adipose tissue fraction, the effects of adipose tissue derivatives on resistance to photoaging can have remarkable biomedical and clinical relevance. Adipose tissue derivatives have shown different degrees of therapeutic efficacy in multiple aspects such as clearance of denatured collagen fibers, regeneration of collagen fibers, inflammation regulation and inhibition of reactive oxygen species (ROS) (Figure 2).

Antiphotoaging effects of classical minimally processed adipose tissue derivatives

For minimally manipulated adipose tissue derivatives, with the integrity of the tissue structure, stem cells embedded in their natural niche may perform better antiphotoaging effects in the short and long term. Crucial to the success of fat transplantation is the percentage of fat cells that survive. A comparative study showed that compared with plain nanofat, SVF and ASC-enriched nanofat demonstrated superior improvements in reducing wrinkles and increasing dermal thickness, collagen content and neocollagen morphology (Table 1 & Figure 1) [25]. Another comparative study revealed that compared with nanofat and microfat in vitro culture, the SVF-gel group had higher long-term cell density and activity, while in the clinical trial of antiwrinkle injections in the neck and face, the microfat group restored better instant subcutaneous volume and better skin texture owing to a more integrated extracellular structure (Table 1 & Figure 1) [16]. While SVF-gel has a higher density and survival rate of ASCs, it is more conducive to the recovery of subcutaneous adipose tissue content, which may affect the survival of adipocytes and play a lasting secretory role at a later stage [17,59]. The therapeutic effect of SVF-gel on photoaging and wrinkles was considered mainly through promoting TGF-β1 expression and activation of fibroblasts to produce type I collagen prepreptide, thereby increasing the density of collagen in the dermis [60], which corresponds to the collagen-egeneration effects of adipose-derived stem cells described below (Figure 2).

Antiphotoaging mechanism of ASCs & their derivatives

Collagen protection & antioxidation

Long-term exposure to sunlight will produce harmful intracellular stress and accumulate ROS and proinflammatory cytokines, accelerating skin aging and resulting in premature skin senescence. UV radiation causes direct damage to the structure of epidermal lipids, fibroblast DNA, mitochondria, telomeres and other structures, further forming peroxidized lipids, pyrimidine dimers and photoproducts, and leading to a decrease in the viability or even apoptosis of skin-resident cells [61]. Simultaneously, a large amount of ROS is generated in the skin irradiated by UVB and UVA. UV-induced ROS accumulation stimulates proinflammatory, antioxidant-related signal pathways in cells, which subsequently induces cell apoptosis and reduces the synthesis and increases the degradation of collagen and elastin, and finally forms wrinkles, pigmentation, coarser skin and other premature manifestations (Figure 2) [62–64].

The antiphotoaging effect of ASCs has been gradually recognized in studies involving humans and animal photoaging models. In a small-scale, self-controlled clinical study it was found that after autologous ASC therapy were applied, the number of anti-inflammatory M2 phenotype macrophages in the skin was significantly increased compared with the control group. Meanwhile, ASCs were observed to stimulate cathepsin K and matrix metalloproteinase (MMP)-2 pathways to better clear denaturated fibers, promote the deposition of newly produced collagen and deepen the papillary structure of the basement membrane [65]. ASCs overexpressing TGF-β1-related genes ameliorated UVB-induced photoaging by increasing the collagen content and decreasing protein levels of MMP-1, MMP-3 and p-P38 [34]. The TGF-β pathway could be relevant to upstream signaling (Table 1 & Figure 2).

ASCs improve collagen degradation and neoformation [35] thanks to their abundant exocrine factors (Figure 2). ASC medium, on the one hand, upregulates antioxidant response elements and inhibits ROS; on the other hand, it can increase the expression of inhibitors that promote TGF-β1, MMP-1 and inhibit the expression of type I procollagen synthesis inhibitors such as IL-6 [36]. ASC-EVs enriched with a variety of miRNAs and proteins contribute to fibrocyte proliferation, collagen synthesis and regulation of cellular senescence [40]. Unlike ASCs, which are proinflammatory and highly efficient at participating in denatured tissue removal, ASC-EVs have antioxidant and anti-inflammatory functions (i.e., preventing macrophages from differentiating into the proinflammatory M1 phenotype) and are involved in ECM synthesis through upregulating TIMP-1 and increasing fibroblast activity and TGF-β secretion to maintain collagen fiber content (Table 1) [40–42]. The ASC-secreted derivatives mentioned above, compared with ASCs, have better allogeneic therapeutic value and higher potential for commercialization and clinical translation [43,44].

Mitophagy promotion effects of ASCs

When the skin is under harsh conditions, it is autophagy that effectively maintains intracellular homeostasis and is one of the important survival mechanisms for cells to resist internal and external stresses. Mitochondrial membrane damage and DNA deletions are common in photoaged skin [45]. This damage can lead to abnormal mitochondrial metabolism and aggravate skin oxidative stress [45,66]. Cells under photosensitive oxidative attack face intense redox stress and rely on autophagy and mitophagy to maintain the survival or replenishment of cells within the skin [67,68]. Mitophagy removes oxidized and depolarized mitochondria and prevents the release of proapoptotic proteins, the production of ROS, and the futile hydrolysis of ATP [69,70]. The self-saving process of senescence and autophagy of skin-resident cells may be linked through the MAPK pathway [71]. Studies have shown that autophagic dysfunction in cells after parallel UV damage to the mitochondrial and lysosomal membrane can greatly increase the efficiency of cell death by photosensitizers [72].

In addition to the classical antiphotoaging mechanisms described above, recent studies have revealed that ASCs could maintain an orderly renewal of skin-resident cells by promoting solar-induced autophagic apoptosis. ASCs can delay premature skin senescence by promoting mitophagy. In a mouse model of premature aging with mitochondrial DNA polymerase PolG gene knockout, ASCs have been shown to facilitate mitochondrial phagocytosis and then delay aging [73]. ASCs may break the cascade of oxidative stress, improve the quality of mitochondria in skin-resident cells, achieve REDOX balance, and increase macromolecular synthesis and cell proliferation in the long term.

Immunomodulation of ASCs against inflammaging & immunosenescence

Inflammaging is the key term in the exponentially growing field of aging in the last decade. The presence of chronic inflammation causes an imbalance of epidermal and dermal homeostasis, leading to premature aging caused by cellular dysfunction. Gene-expression profiling studies involving multiple human species have linked immunity and inflammation to photoaging [74,75]. Senescence-associated secretory phenotype marker proteins IL-8 and IL-1RA/IL-1 are consistently elevated at UV exposed areas (Figure 2) [76]. UV-induced aged fibroblasts produce senescence-associated secretory phenotype factors that not only stimulate chemokines to release from surrounding nonsenescent fibroblasts, but also interfere with TLR2, TLR6 and CD36 to reduce the phagocytic capacity of macrophages, thereby promoting immune evasion of photoaged damaged cells and resulting in prolonged low-grade chronic inflammation within the skin [77]. There is an infiltration of more monocytes in chronically UV exposed skin [78], and they can directly differentiate into macrophages, inducing ROS accumulation [79], induce MMP transcription in dermal fibroblasts and degrade the ECM [80,81]. Skin inflammaging also results in functional decline of innate and acquired immunity in the dermal layer during aging [82]. It has been suggested that both photoaging and endogenous aging trigger inflammatory aging resulting from remodeling of the immune system [83]. Photoaging as an inflammatory stimulus greatly increases the infiltration of immunosuppressive cells, such as regulatory T cells, myeloid derived suppressor cells and regulatory dendritic cells, which coincides with the manifestation of immunosenescence [84–86].

ASCs as well-sourced mesenchymal stem cells are often considered an important tool for treating autoimmune diseases or as antiaging therapy. The widely recognized powerful immunomodulatory and exocrine effects of ASCs also have definite inhibitory effects on key marker proteins of inflammaging [87]. Studies have found that ASCs can improve the phagocytotic function and polarization ability of aging macrophages (Table 1) [37,38]. In terms of acquired immunity, ASC transplantation can improve regulatory T-cell proliferation and Th1 to Th2 cell transformation of T-cell senescence in acquired immunity [39,88], thereby improving necessary immune senescence.

Reconstruction potential of dermal white adipose tissue against photoaging

Adipose stem cells and preadipocytes resident in white adipose tissue are considered to be the main stem cell population contributing to skin tissue regeneration [89], and over the past decades dermal white adipose tissue (dWAT) has been viewed as an antiaging target that was distinguished from the deeper subcutaneous fat. In an adipocyte progenitor cell derivation observation study, only one group of seven progenitors contained a mixed population of both subcutaneous and visceral adipose tissue-derived cells [90]. dWAT is a unique adipose layer within the reticular dermis of the skin, where fat and precursor cells have been found to play unique roles other than antimicrobial, antifibrotic, healing and energy metabolism [91,92]. The thickness of the adipose layer beneath UV-exposed skin decreases with age [93]. Decreased adipogenesis and increased fibrosis were also found in the thinned dermis of photoaged skin [94]. The mechanism may be related to the high concentration of IL-11, IL-1α, IL-6 and TNF-α secreted at the dermal junction after sun exposure, which can greatly inhibit the lipogenic differentiation of precursor cells [95]. In addition, repeated UV radiation, drug and other stimuli can lead to the conversion of precursor cells into myofibroblasts [96]. It has also been suggested that the regulatory mechanism in the differentiation of subcutaneous ASCs originates from epigenetic modification without changing their basic DNA sequence [97], which are less easily affected by ROS, UV radiation and other aging factors than other skin stem cells are, making them an excellent cell target of antiphotoaging. Replacement of dermal fat by fibrous tissue will lead to mechanical abnormalities caused by microscopic skin structure and loss of true skin volume, namely true wrinkles and skin relaxation [98]. Whereas these various types of ingredients enriched, intradermally injectable fat products offer great possibilities for remodeling of dWAT.

Attempts at antiphotoaging of adipose tissue derivatives

Cell-free adipose tissue secretory product effects in photoaging

Stem cells extracted from lipoaspirate fluid have shown osteogenic and adipogenic potential in studies [99,100], and the antiphotoaging function of lipoaspirate liquid extracellular vesicles is perhaps related to these stem cells. ATEVs are then enriched in secretory vesicles after fat homogenization, and through the combination of this and hydrogel material, ATEVs can promote de novo synthesis in adipose tissue [20]. Platelet-rich plasma (PRP), with a similar healing capacity as fat derivatives, is also commonly used clinically as an adjunct to skin therapy as a growth factor cocktail. In a model of PRP combined with ASC transplantation to treat photoaging, PRP caused marked inflammatory infiltration and vascular reactivity [101]. Meanwhile, the dermal thickening caused by PRP is an unnatural deposition of elastic fibers in the reticular dermis layer, and the tight adhesion between subcutaneous fat and appendages is no longer maintained after treatment, thus some researchers have suggested that the dermal thickening effect of PRP is actually a kind of dermal fibrosis manifestation caused by it [102,103].

DAT product effects in photoaging

DAT, as an important tissue engineering scaffold tool, is used to piggyback on different types of stem cells to achieve tissue generation. Studies have shown that DAT has low cytotoxicity and immunogenicity, and contains functional proteins involved in ASC metabolism and collagen neoformation, providing a good microenvironment for inducing adipogenesis (Figure 2) [104]. ACF, rich in type I collagen, type IV collagen and Lamin, showed favorable anti-inflammatory ability in a UVB-induced aging mouse model, characterized by inhibiting the expression of SA-β-gal and ROS, and promoting high expression of antioxidant enzymes [105]. In a clinical study, the results of precise neck wrinkles filling with ACF on 21 women showed that 85.7% of patients were satisfied with the treatment outcome, and no infection, injection site nodules or other adverse side effects were observed [58]. Meanwhile, ACF, as a sustained-release system for adipokines, exerts a rejuvenating effect beyond the filling effect by the sustained release of cytokines through local survival [105].

Adipose tissue derivatives combined with microneedles for photoaging

Adipokine treatment of skin photoaging has shortcomings such as poor permeability and poor biological stability. Meanwhile, skin photoaging is a gradual process, so multiple subcutaneous or intracutaneous injections become inevitable for photoaging treatment [106]. Microneedles combined with cell-free adipose tissue derivatives have the advantage of small wound surface and subdermal administration through the skin barrier, which is a more acceptable treatment method for patients in the future. Percutaneous microneedles promote neocollagen formation in a manner that produces minimal damage and initiates skin self-repair. Treatment in combination with ASC-EVs and microneedles can accelerate the recovery mechanism with minimal invasive incisions and is more effective in treating coarse wrinkles and erythema caused by photoaging [107]. ACF-loaded long-acting microneedle patch-treated skin could release ACF components over a long period, having a long-term antiphotoaging effect [108]. Therefore, the long-term adipokine-microneedle system mediated by microtrauma could be a potential strategy to prevent skin photoaging in the future.

Safety & risks for the application of adipose tissue derivatives

For autologous fat transfer, there isn't yet a definitive gold standard for the procedure. Because the patient's own fat is used, the technique has been considered to be low risk of hypersensitivity reactions, foreign body reactions or autoinflammatory reactions [109,110]. However, like any other facial filler or medical intervention, adipose tissue derivatives containing intracellular and extracellular structures can be subjected to adverse events and complications including embolism, skin necrosis, hematoma, bruising, swelling, dysesthesia and contour imperfection at both the donor and the recipient site [111,112]. In addition, adipose tissue derivatives intended for filling face the risk of poor survival after grafting, resulting in nodules, oil cysts, calcifications, and so on [113,114].

A meta-analysis involving microfat and nanofat demonstrated that minimally processed adipose tissue derivatives had lower complication rates than unprocessed fat [115]. Nanofat and SVF-gel, as minimally processed products with a delicate texture, have fewer complications of lumpiness after grafting than normal donor site-harvested fat [116,117]. Nanofat has been reported to have a longer erythematous phase in only the recovery phase of grafting [10], which may be the result that the effects of nanofat therapy are based on upregulated inflammatory signals [118].

Multiple processing technologies of adipose tissue can be regarded as ways of screening fat components. This makes adipose tissue derivatives endowed with different biological and physical properties from simply harvested fat, and the outcome after transplantation is no longer limited to the form of fat lumps. For instance, although nanofat has no outstanding volume-filling effect, even difficult-to-fill deep wrinkles [119], it can be used as a dermal filler to improve pockmarks and skin texture, and produce a clear thickening effect in the dermis [116,120].

On the other hand, long-term volume filling effects with no serious adverse events during the follow-up period have also been validated in other types of adipose tissue-derived products. ACF can be stored subcutaneously in the form of collagen for a long time and can maintain stable volume after 14 weeks [58]. Adipose matrix complex has been shown to maintain its hardness after 3 months of subcutaneous transplantation in mice, and the survival graft was a type I collagen dominated fibrous tissue mass interspersed with mature live adipose tissue rather than fibrotic mass [23]. It can be said that the model of applying fat derivatives to restore soft tissue is a strategy of supplying a biological scaffold to maintain the original microenvironment of stem progenitor cells, thus making the final fate of the graft predictable.

However, some products that lack scaffolds have potential risks worth noting. It is generally accepted that SVF-assisted fat grafting enhances tissue resistance to ischemia and hypoxia, which in turn improves graft survival after large-volume engrafting [121,122] without causing more complications [122]. However, these complex fat products rich in dissociative stem progenitor cells may also have stem cell-related risks after transplantation such as heterotopic fibrosis, lymphatic ganglia and other abnormal differentiation outside the transplant site. Patients who underwent SVF-assisted fat grafting were reported to develop postoperative lymphadenopathy of the abdominal wall and inguinal region [123]. Stem cells in nonphysiological environments are difficult to control, which is also the reason why transplanting fat derivatives is required by various laws and regulations to satisfy the ‘minimum treated’ standard [124].

Secreted products such as EVs and the exosomes of stem cells have the corresponding advantages of simple composition, a well-defined pathway and low tumorigenicity. However, when it comes to secretory derivatives of infected or malignant cells, those safe secresomes can transfer substances that initiate infection or play a role in innating the autoimmune response [125,126]. In a randomized, controlled, split-face trial of 25 people receiving CO₂ laser treatment, the side of the face treated with adipose-derived exosome gel showed better erythema reduction [127]. Most of the novel adipose tissue derivatives are in the preclinical exploration phase, and there are currently a lack of clinical cases and follow-up reports of a certain scale. Most importantly, there is still a lack of standardized procedures for harvesting, processing and injection techniques worldwide.

Conclusion

With the increasing longevity of global population aging, the focus of medical research has gradually shifted to the prevention and management of aging and the optimization of an overall healthy life span. Therefore, more and more attention has been given to the treatment of skin photoaging in the field of cosmetic minimally invasive surgery. As a widely used, readily available and inexpensive autogenous material in clinical practice, adipose tissue derivatives show great application potential by promoting tissue regeneration through various functions, including regulating the immune response, providing differentiation, migration and enzyme reaction signals, and promoting tissue balance. Cumulative evidence shows that adipose derivatives can inhibit oxidative stress, remove solar degenerative collagen, induce endogenous collagen regeneration, increase dermal thickness and improve skin firmness in antiphotoaging regeneration of skin. Adipose tissue engineering technology combined with adipose tissue derivatives also shows attractive antiaging and application potential. However, at present there is still a lack of high-level evidence-based medical evidence for adipose tissue derivatives in the treatment of photoaging. The optimal therapeutic introduction of adipose tissue derivatives, the safety of tissue engineering products and the mechanism of action of different adipose components remain to be clarified. We believe that with the introduction of the orderly opening and access system for cell therapy and biological drugs, medicinal adipose technology will become an important regenerative tool in the field of antiaging skin repair.

Future perspective

The evolution of fat processing has not only offered valuable autologous fillers to treat cell-depleted conditions, but has also received tremendous commercial success in antiaging cosmetic therapeutics. Fat tissue manipulation allows better injection accessibility such as superficial or accurate delivery in filling fine lines or fibrotic skin while introducing stem cells or trophic factors to the site. Future studies should focus on each adipose component's role in fat retention in the multiple aged tissue microenvironment with respect to providing reliable and reproducible outcomes for different patients with various accelerated aging conditions. However, for many cosmetic surgeons, preserving the intact adipose microstructure may still be a key principle in successful fat grafting procedures, especially for tissue defects that require large-volume delivery. Decision-making should balance out the volume-gain ratio in a donor site shortage situation. Simultaneously, with the development of adipose medicine, induced or manipulated adipose tissue may also be valuable as a metabolically and hormonally active drug in reconstituting soft tissue homeostasis.