As scientists advance their manipulation of stem cells, cell-based therapies become more sophisticated. Cell therapy involves transferring regenerative cellular material into patients for therapeutic purposes (24). Examples include cord blood used for hematopoietic disorders, B-cell maturation agents used for large B-cell lymphoma, and autologous cellular products consisting of fibroblasts used for nasolabial fold wrinkles (24). Autologous therapies may deploy one cell type or leverage the synergy of multiple cells. For instance, Recell (ReCell® Avitas Medical Associates, Valencia, CA, USA) is an autologous suspension of keratinocytes, fibroblasts, and melanocytes that work in unison for both dermal and epidermal regrowth. Skin samples are obtained in the operating room and transferred to the laboratory for processing and preparation prior to reapplication (25).

Allogeneic therapies, such as Apligraf (Apligraf® Organogenesis, Canton, MA, USA) and Grafix (Grafix® Osiris Therapeutics, Inc., Columbia, MD), vary in the number of cell types included in its therapies (26). Apligraf is a bovine type I collagen matrix seeded with neonatal fibroblasts and keratinocytes (27). Over time, the fibroblasts produce a new dermis which is then overlaid by epidermal keratinocytes that eventually form stratified layers (27). Apligraf is known to contribute to faster healing and less fibrosis than natural skin (28). Placental constructs have been important in improving wound healing and decreasing inflammation and can come cryopreserved or dehydrated. Grafix, an example of a cryopreserved amniotic membrane containing mesenchymal stem cells, has improved outcomes for wound healing for diabetic and vascular patients (29).

Cell-based therapies also include the utilization of mesenchymal stem cells (MSCs) and adipose-derived stem cells (ASCs). MSCs are multipotent stem cells originating from bone marrow, and they release proangiogenic factors. They are more limited in their ability to differentiate compared to ESCs. However, multiple studies show the improvement of wound healing through the application of MSCs (29–32). ASCs are a subset of MSCs found in adipose. ASCs have promise in the field of tissue regeneration and wound healing as they are easily found in adipose tissue, differentiate into many lineages, and secrete a variety of cytokines (33). They have been used to reduce scarring in mice (34). Factors secreted by ASCs increased the rate of healing and reduced the deposition of collagen, allowing for finer and more organized tissues (34).

In recent years, there has been growing interest in the paracrine mechanisms of MSCs, particularly through MSC-derived exosomes (MSC-exos). These extracellular vesicles carry a variety of bioactive molecules including miRNAs, growth factors, cytokines, and lipids that play essential roles in angiogenesis, immune modulation, fibroblast activation, and extracellular matrix remodeling (35). Exosomal delivery of miR-21, miR-126, and other regulatory molecules has been shown to accelerate reepithelialization and improve vascularization in cutaneous wounds (36). Recent preclinical studies have demonstrated the utility of MSC-exos as a cell-free therapy. In murine and porcine wound models, MSC-exos enhanced reepithelialization, reduced inflammation, and promoted collagen maturation (37). In one study, exosomes derived from hypoxia-preconditioned MSCs further amplified these effects by increasing VEGFand TGF-β1 expression, suggesting a strategy for improving therapeutic potency (38).

Beyond wound care, MSC-exos have shown anti-aging effects, including reduction of oxidative stress, increased dermal thickness, and restoration of skin elasticity (39, 40). Their ability to promote mitochondrial function, reduce senescence markers, and increase collagen and elastin synthesis positions them as promising agents in regenerative dermatology and aesthetic medicine (39, 40).

MSC-exos offer a compelling advantage over traditional cell-based therapies: they mitigate risks of tumorigenicity, immune rejection, and ectopic tissue formation, making them a safer and more scalable alternative for clinical translation (38–41).

Cell-based therapies have expanded to include the addition of scaffolds, which have proven beneficial towards wound healing (Figure 3) (42). Scaffold-based therapies utilize a polymer or scaffold impregnated with cell types, drugs, nutrients, metabolites, or other substances to facilitate delivery or propagation within the body. Scaffolds can be synthetic, semisynthetic, decellularized, or composed of permanent and degradable materials (43).

The NovoSorb® Biodegradable Temporizing Matrix (BTM) (PolyNovo Biomaterials Pty Ltd., Port Melbourne, Australia) is a synthetic scaffold made of biodegradable polyurethane open-cell foam enclosed by a non-biodegradable membrane. This synthetic scaffold encourages vascular ingrowth, the development of new dermal tissue, and improved success rates of split-thickness skin grafts in burn victims (44). Integra (Integra® LifeSciences, Plainsboro, New Jersey), an acellular dermal matrix made of bovine tendon collagen, shark glycosaminoglycans, and silicone (45), is an example of a semisynthetic scaffold. With high take-rates, Integra matrices have helped improve wound healing in a plethora of clinical conditions, including lower extremity soft-tissue trauma, degloving injuries, hand wounds with exposed bone, and more (46). Decellularized scaffolds include Alloderm (Alloderm^™ Allergan Aesthetics, Irvine California/ Dublin, Ireland), a dermal matrix made of human cadaveric collagen, lamin, and elastin (47), and Strattice (Allergan Aesthetics, Irvine California/ Dublin), a porcine-derived dermal matrix (48). Both have implications in reducing inflammation and fibrosis during the wound healing process (49).

There are also scaffold-free products that serve as tissue analogs and comprise an extracellular matrix. Epicel (Epicel® Vericel Corporation, Cambridge, MA, USA), a petroleum gauze made of sheets of autologous keratinocytes and proliferation-arrested murine fibroblasts, exemplifies a scaffold-free cell-based product that had been used for burn healing and cytokine and growth factor production (24).

Investigation into using hiPSCs in scaffold-free products has been robust. hiPSCs hold great promise for fabricating whole organs from patients' own cells, obviating the current limitations of immunogenic rejection and donor organ shortages. In 2017, Japanese researchers successfully transplanted a sheet of patient-specific hiPSC-derived retinal pigment epithelial cells into a patient with age-related macular degeneration, which remained intact at one year post-operatively but without significant improvement in visual acuity (50). The first in-human clinical trial of hiPSC-derived cardiomyocyte (hiPSC-CM) transplantation, published in 2023, reported three cases of hiPSC-CM patch constructs transplanted in patients with New York Heart Association Class III or higher heart failure. Results showed an improvement in heart failure symptoms and exercise tolerance as well as reduction in left ventricular diameter post-operatively (51). Finally, in the area of liver regeneration, researchers have successfully generated early fetal liver-like hiPSC-derived liver buds (52). These buds improved survival in murine subacute liver failure models (53).

Extending from this idea is that of the organoid, which is made of patient-derived stem cells grown in carefully selected media that determines differentiation then put onto an extracellular matrix to function as an organ (54). hiPSC-liver organoids have improved liver function and ameliorated chemically-induced liver fibrosis in murine models (55), suggesting that hiPSC-derived liver tissue may serve as a promising future therapeutic alternative to allogenic liver transplantation. Organoids have also been useful for drug screening, disease modeling, and tissue-specific functioning, successfully modeling lung and kidney function in vitro (24).

Recent studies have expanded the utility of organoids to model complex genetic disorders and to enhance their function through vascularization. In 2023, Bu et al. demonstrated that cerebral organoids derived from hiPSCs with NANS mutations accurately recapitulate human neurodevelopmental defects, offering insight into the mechanisms of cortical malformations and disease progression (56). In parallel, efforts to improve organoid viability and maturation have led to the development of kidney organoids co-cultured with human endothelial cells on microfluidic chips, resulting in vascular networks and enhanced organoid functionality (57).

Despite these advancements, ongoing challenges remain. One obstacle is that of precisely recapitulating the complex three-dimensional structure of native organs. Another concern is the risk of tumorigenicity and teratoma formation from proliferating progeny should hiPSCs or hiPSC-derived organs be transplanted into patients in the clinical setting.

Just as scaffold-free products promote cytokine and growth factor production, other cell-based therapies rely on the interplay between cells and their environments. Paracrine signaling is a crucial mechanism by which transplanted stem cells operate. Stem cells release paracrine factors that alter their extracellular matrix and ultimately influence their function. One example of this can be seen with post-infarction remodeling of heart chambers (58), where stem cells use paracrine signaling to enhance healing and reduce fibrosis. Researchers are exploring the isolation of these factors to develop therapies that could substitute stem cell treatments with soluble factor-based approached. If these factors can be effectively isolated, therapies may simply introduce them to enhance healing.

Platelet rich plasma (PRP) is made of the isolation of components of blood that consist of platelets, platelet-related growth factors, and plasma-derived fibrinogen. The platelets work differently from stem-cell based therapies in that they release growth factors for tissue repair rather than differentiate and divide to replace damaged tissue (59). PRP has been used for hair regrowth, tissue regeneration, wound healing, and musculoskeletal regeneration (60–63). In those with patellar tendinopathy, Achilles tendinopathy, and osteoarthritis, initial tests of injection of PRP have shown decreased inflammation, faster healing, and reduced the risk of tendon rupture (61, 63).

Given that PRP decreases inflammation, heals tissue damage, and reduces senescence, it naturally works against the accumulation of damage that leads to cellular aging (60). Injection of PRP has been used to stimulate ovulation in those with premature ovarian insufficiency and regenerate bone in osteoporosis and other conditions associated with aging (60, 64). However, there are inconsistencies within the literature regarding how to formulate the PRP for best use, and there is continued debate on the effectiveness of PRP (60). More robust prospective randomized clinical studies will be needed to better assess this therapy, and if the use of PRP can be perfected, the incidence of age-related disease may be able to be slowed.

Exosomes are another component that have promise in the realm of non-cell-based therapy. They are nanoparticles that hold molecules such as lipids, growth factors, and micro-RNA (mi-RNA). Different processes in the human body, such as cell development, growth, migration, and aging are mediated by particles released by exosomes (41). For example, specific mi-RNA in these exosomes may affect tissue regeneration and subsequently aging (41).

The science behind aging has become more advanced in recent decades, and patients have long been interested in how to avoid the effects of aging. Aging is often perceived as the cumulative result of cellular damage from environmental factors, leading to the natural possibility that the concepts of wound healing, which work to heal cellular injury, may be applicable to the aging process. In fact, young organisms, such as first and second trimester human fetuses, exhibit an ability to avoid scarring altogether. The mechanism of this process is unclear, but one hypothesis suggests intrinsic differences between fetal and adult skin rather than differences in the external environment (65). However, there are several hypotheses that argue for the role of the external environment's influence in aging. Epigenetic programming exemplifies this, and the “reprogramming” of a person's epigenetics has been studied as a means of reversing aging (66). Models based on DNA methylation levels have been shown to estimate the age of a person and predict risk of age-related disease with low precision, explaining 73% of age variance with a prediction error of 5.2 years (67). Another study hypothesized the benefit of heterochronic parabiosis, a procedure in which young and old mice are joined and share a circulatory system. The exposure of the old mouse to the young mouse improved the function of several organs and tissues in the old mouse (68). Studies have shown that circulating and systemic factors in young blood functionally improve aged brains, and counterpart factors in old blood contribute to aging phenotypes in younger tissues (68). If these factors are able to be isolated, patients might be able to benefit from a reduction in age-related chronic diseases.

Currently, popular, non-surgical anti-aging products include a range of topicals, metabolic supplements, and procedures. Topical products typically deliver antioxidants to neutralize free radical production from environmentally induced cell damage, improve moisturization and collagen production to restore the barrier between the environment and the skin, and increase cell turnover to remove pollutants that could contribute to cell injury (Figure 4) (69, 70). At the molecular level, antioxidants combat oxidative stress by neutralizing reactive oxygen species (ROS), which are byproducts of ultraviolet radiation, pollution, and metabolic processes that accelerate skin aging. Excessive ROS disrupt mitochondrial function, DNA integrity, and cellular membranes, leading to fibroblast senescence and impaired collagen synthesis (35, 71). Endogenous antioxidant systems including superoxide dismutase (SOD), catalase, and glutathione peroxidase work in tandem with exogenous antioxidants like vitamin C, vitamin E, and polyphenols to restore redox homeostasis (70, 72, 73). Activation of the Nrf2–ARE (antioxidant response element) signaling pathway is central to this process, triggering transcription of cytoprotective genes that reduce inflammation and support tissue repair (74). Furthermore, antioxidants enhance moisturization by stabilizing the skin barrier and boost collagen production by upregulating procollagen gene expression and inhibiting matrix metalloproteinases (MMPs), which degrade collagen during oxidative stress (75). These mechanisms collectively improve skin elasticity and hydration, key targets in regenerative anti-aging therapies.

Ultrasound technologies and laser therapies work by triggering a controlled wound-healing response so that collagen production, tissue remodeling, and cellular metabolism can be activated. Common supplements, like fish oil, lipoic acid, metformin, and nicotinamide mononucleotide work by reducing oxidative cellular injury.

Many surgical procedures performed to reduce signs of aging work to reverse visible damage at the macroscopic level rather than the cellular. Popular procedures performed on adult skin include brow or forehead lifts, blepharoplasty to reduce droopy eyelids, injectable facial fillers, and anti-wrinkle injectables such as Botox and laser skin resurfacing. Therefore, the utility of surgical procedures in anti-aging may be limited to cosmetic and physical alterations rather than targeting and preventing aging at a cellular level.