Advances in Research on Concentrated Growth Factor Applications for Androgenetic Alopecia Treatment: A Review

Introduction

Androgenetic alopecia (AGA) is a chronic progressive form of hair loss closely associated with androgens. Epidemiological studies have demonstrated significant variations in the prevalence of AGA across ethnicities and sexes. A multicenter study revealed that the prevalence of AGA in Chinese males is 21.3%, while in females it is 6.0%, with a marked increase observed with advancing age. Furthermore, 29.7% of male patients and 19.2% of female patients reported a positive family history, highlighting the critical role of genetic factors in the pathogenesis of AGA [1]. In contrast, among Whites, the prevalence of AGA is as high as 80% in males aged 70 years or older, and approximately 40% in females [2].

The primary clinical characteristic of androgenetic alopecia (AGA) is the progressive thinning of scalp hair, which is both age- and sex-dependent. The central pathological mechanism of AGA is the heightened sensitivity of hair follicles to androgens, particularly dihydrotestosterone (DHT). DHT binds to androgen receptors in hair follicles, triggering follicular miniaturization, shortening the anagen (growth) phase of the hair cycle, and consequently leading to gradual thinning, shortening, and eventual loss of hair. Furthermore, polymorphisms in the androgen receptor gene are closely associated with AGA susceptibility and may exacerbate follicular damage by amplifying androgen signaling pathways [3,4].

As one of the longstanding challenges in plastic surgery and dermatology, AGA not only affects the physical appearance of patients but also significantly impacts their mental health. Studies have shown that some patients experience feelings of inferiority and depression, which can interfere with their social activities and even lead to social withdrawal [5].

Although a variety of treatments for hair loss are currently available, each method has notable limitations and adverse effects [6–18] (Table 1). Clinically, only finasteride and minoxidil have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of AGA [19]. However, minoxidil can cause contact dermatitis and hypertrichosis [20], while finasteride has been linked to an increased risk of sexual dysfunction [21]. These significant adverse effects have limited their widespread use, underscoring the need for safer and more effective treatment options.

In recent years, concentrated growth factors (CGF), rich in various growth factors, have been introduced as a novel therapeutic strategy for AGA. CGF offers a new perspective and direction for the treatment of AGA. This article reviews recent research on the use of CGF in AGA therapy to provide a reference for basic research on CGF and to offer theoretical support and guidance for clinicians using CGF in the management of hair loss.

Overview of CGF

CGF is an integrated evolutionary version of both platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). It was first developed in 2006 by Sacco et al using a specialized variable-speed centrifugation technique to extract it from venous blood [22]. Unlike traditional treatments that rely primarily on medications or invasive surgical interventions, which can cause trauma and adverse effects, and lack intrinsic stimulation for tissue regeneration, CGF harnesses regenerative components derived from the patient’s own blood.

When compared with PRP and PRF, PRP, as a first-generation autologous platelet concentrate, is relatively simple to prepare, but the release of growth factors is rapid and short-lived. As a second-generation product, PRF has a more stable fibrin structure and a relatively slow and sustained release of growth factors, but it still has certain limitations in terms of growth factor concentration and other aspects. What makes CGF unique is that this technique endows CGF with a highly elastic fibrin network that provides a three-dimensional structure to support cell adhesion and proliferation while promoting the release of high concentrations of growth factors by platelets [23,24]. Additionally, it enhances the aggregation of leukocytes and platelets within the protein network [25].

Studies have demonstrated that CGF is enriched with a variety of cells associated with angiogenesis, including CD34+ cells, which play a pivotal role in vascular formation and regeneration [26]. In contrast, PRP contains almost no stem cells, while PRF only contains a small amount of CD34+ cells (Table 2).

The preparation of concentrated growth factors (CGF) primarily involves drawing venous blood from the patient and subjecting it to differential centrifugation using a specialized centrifuge [28]. Specifically, the Medifuge® centrifuge is employed, with an initial acceleration phase of 30 seconds, followed by centrifugation at 2700 rpm for 2 minutes, then at 2400 rpm for 4 minutes, followed by 2700 rpm for another 4 minutes, and finally at 3000 rpm for 3 minutes, concluding with a deceleration phase of 36 seconds until complete stop [27]. An alternative method configures the centrifugation process using relative centrifugal force (RCF) as the parameter: the system accelerates for 30 seconds, then centrifuges at 408 g/min (approximately 2700 rpm) for 2 minutes, followed by 323 g/min (approximately 2400 rpm) for 4 minutes, then 408 g/min for another 4 minutes, and finally 503 g/min (approximately 3300 rpm) for 3 minutes, with a final gradual deceleration over 36 seconds until full stop [28]. These 2 methods differ only in the final centrifugation step – 3000 rpm versus 503 g/min (equivalent to approximately 3300 rpm) – but no studies to date have demonstrated significant differences in CGF yield between these 2 centrifugation protocols.

This centrifugation process separates the blood into 3 distinct layers: the top layer consists of platelet-poor plasma (PPP), the middle layer contains CGF, and the bottom layer comprises red blood cells. Unlike traditional PRP preparation techniques, the precise optimization of centrifugal force and centrifugation time in the CGF preparation process ensures a higher platelet recovery rate and a greater variety and concentration of growth factors. CGF can be further processed into various forms, including liquid extracts, CGF gels, lyophilized products, and CGF membranes. These forms have been widely applied in bone tissue regeneration and repair, oral implant restoration, and wound healing. In recent years, research has also begun to explore the role of CGF in hair follicle regeneration. Clinical studies suggest that CGF can significantly promote hair regrowth and increase hair density [29]. However, the specific mechanisms through which CGF exerts its effects remain unclear.

Further research has shown that CGF contains higher levels of growth factors compared to the first and second generations of platelet concentrates [24,30]. The unique differential centrifugation process not only produces a denser and more robust fibrin network [30] but also creates a complex three-dimensional structure within CGF. Scanning electron microscopy (SEM) analysis has revealed that CGF includes highly active platelet regions and a substantial number of cells with stem cell-like characteristics. These cells can adhere to culture plates and proliferate upon exposure to culture media, demonstrating significant regenerative potential.

Additionally, cells in CGF express a variety of stem cell markers, such as CD105 and CD45. Although CD34 expression is relatively low, these cells retain regenerative properties associated with mesenchymal, hematopoietic, and endothelial cells [32]. In summary, compared to earlier generations of platelet concentrates, CGF has a richer composition and higher clinical applicability, offering promising potential in regenerative medicine, particularly in tissue regeneration and repair.

Clinical Applications of CGF in the Treatment of AGA

MONOTHERAPY WITH CGF:

Several clinical studies have evaluated the efficacy of CGF monotherapy in treating AGA. These studies typically involve local injections of CGF into the scalp at the sites of hair loss, with treatments administered every 3–4 weeks for a total of 3 sessions [29]. The outcomes are assessed by calculating hair density (the number of hairs per square centimeter) through dermoscopic imaging of the treated areas, evaluating the anagen-to-telogen hair ratio, the terminal-to-vellus hair ratio, and using the Global Aesthetic Improvement Scale (GAIS) to measure changes in hair density and the severity of hair loss before and after treatment. Results indicate that CGF monotherapy can promote hair regrowth, increase hair density, and reduce hair loss [33]. However, the degree of improvement varies among patients, with some experiencing significant benefits while others show relatively weaker responses [34].

COMBINED APPLICATION OF CGF WITH TRADITIONAL TREATMENT METHODS:

Minoxidil is a commonly used topical medication for the treatment of AGA. Studies have shown that combining CGF with minoxidil results in better therapeutic outcomes compared to using minoxidil alone. CGF injections directly provide growth factor support to hair follicles, while minoxidil externally stimulates follicular growth. The combination of these 2 approaches creates a dual stimulation effect on hair follicles. In clinical practice, patients follow the standard regimen of topical minoxidil application while simultaneously receiving regular CGF scalp injections at intervals of 4 weeks, with a total of 3 injections. Comparative observations after a treatment period (12 weeks following the first CGF injection) revealed that the combination of CGF and minoxidil is safe and effective for male AGA patients. Compared to minoxidil monotherapy, the combination therapy significantly enhances efficacy, shortens the time to noticeable effects, and provides longer-lasting hair growth. Patients also report higher satisfaction with the appearance of their hair [35]. Finasteride and spironolactone are also effective medications for treating AGA. Combining CGF with finasteride or spironolactone has similarly produced promising results. CGF improves the local growth environment of hair follicles, while finasteride and spironolactone systemically reduce the adverse effects of androgens on hair follicles. Clinical studies, which evaluate parameters such as hair count and hair diameter, have demonstrated that the combination therapy produces superior hair regeneration compared to monotherapy.

Mechanisms of CGF in AGA Treatment

REGULATION OF GROWTH FACTORS:

CGF is rich in various growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF). VEGF enhances angiogenesis, hair follicle growth, and nutrient supply by activating endothelial cells and promoting their proliferation and migration, while also facilitating the transition of hair follicles from the telogen phase to the anagen phase [36,37]. PDGF, by binding to its receptor PDGFR-β, activates endothelial cells and dermal stem cells, promoting neovascularization and maintaining the structural stability of hair follicles [38–40]. TGF-β plays a critical role in hair follicle morphogenesis and maturation by upregulating alkaline phosphatase activity and activating the SMAD signaling pathway, which coordinates intercellular communication within the hair follicle [41]. IGF extends the anagen phase and promotes hair growth through its anti-apoptotic properties [42]. FGF accelerates the transition of quiescent hair follicles into the anagen phase and prolongs its duration by activating the β-catenin and Sonic Hedgehog (Shh) signaling pathways [43]. EGF enhances the proliferative capacity of hair follicle cells by upregulating hair follicle-related gene expression through the Notch signaling pathway [44]. HGF stimulates hair growth by promoting the proliferation of keratinocytes in hair follicles and inhibiting apoptosis [45].These growth factors work synergistically by regulating angiogenesis, cell proliferation, and signaling pathways, providing a critical molecular basis for hair follicle regeneration and hair growth. Growth factors in CGF, such as VEGF and PDGF, can also promote hair growth by binding to their respective transmembrane receptors and activating protein kinase B (Akt). This process is achieved primarily through 2 mechanisms: (1) Protecting and promoting dermal papilla cell (DPC) proliferation: In DPCs, the upregulation of Bcl-2 expression inhibits apoptosis, while high levels of Bax expression restrict DPC growth. Akt activation enhances Bcl-2 expression and increases the Bcl-2/Bax ratio, thereby delaying the transition of hair follicles into the catagen phase, prolonging the anagen phase, and helping to mitigate hair loss [46]. (2) Inhibiting β-catenin degradation: Glycogen synthase kinase-3β (GSK-3β) impairs hair follicle development by degrading β-catenin. However, Akt activation inhibits GSK-3β activity, reducing β-catenin degradation. This regulation further activates the Wnt/β-catenin signaling pathway, thereby promoting hair follicle regeneration.

Other studies have demonstrated that the YAP signaling pathway plays a critical role in cell proliferation, migration, and tissue regeneration. The nuclear translocation of YAP activates the expression of genes associated with cell proliferation and differentiation, thereby maintaining cellular activity [47]. Due to its abundance of various growth factors, CGF effectively activates the YAP signaling pathway through intrinsic synergistic interactions. This promotes YAP accumulation in the nucleus, where it interacts with transcription factors to regulate the expression of genes related to cellular regeneration. Moreover, YAP activation amplifies regenerative signaling through the interplay with pathways such as Wnt/β-catenin and AKT. This interaction creates an ideal microenvironment for supporting regeneration in hair follicles, facilitating the activation of follicular stem cells and promoting sustained hair growth [47,48].

REGULATION OF ACTIVE CELLS:

CD34 is essential for hair follicle progenitor cells, and its decreased expression is regarded as a crucial factor in the pathogenesis of AGA. Studies have shown that although hair follicle stem cells (eg, KRT15+ highly-expressed cells) in the balding areas of AGA patients remain present, their conversion into CD34+ progenitor cells is significantly impaired. CD34+ cells are primarily located in the outer root sheath of hair follicles, particularly in follicles during the anagen phase, and are closely associated with hair follicle regeneration and maintenance of the follicular microenvironment’s homeostasis [49].

CD34+ progenitor cells not only possess a high proliferative capacity but also actively participate in the process of hair follicle regeneration. Experimental studies have shown that these cells support hair follicle growth by promoting angiogenesis and repairing the local microenvironment [49]. However, in AGA patients, the significant reduction in this cell population leads to a decline in the regenerative capacity of hair follicles, causing them to progressively miniaturize, enter a resting phase, and eventually result in hair loss. Research has suggested that the loss of CD34+ cells is associated with the androgen-dependent mechanisms of AGA. Androgens are converted to dihydrotestosterone (DHT) by 5α-reductase, which directly affects the function and survival of hair follicle progenitor cells. DHT not only inhibits the differentiation of CD34+ cells but can also aggravate follicular degeneration by inducing local inflammation or reducing the expression of angiogenic factors. Therefore, the reduction in CD34+ cell numbers is not only a pathological hallmark of AGA but also provides critical insights into its underlying mechanisms. This discovery establishes a theoretical foundation for developing AGA treatment strategies targeting CD34+-related mechanisms [50]. Studies have shown that CD34+ cells significantly enhance the effectiveness of PRP therapy for hair loss without causing notable adverse reactions [50], and CGF, as a natural biomaterial abundant in CD34+ cells, demonstrates even greater advantages.

The pathogenesis of AGA is closely associated with localized inflammatory responses in the scalp, and CGF exhibits remarkable benefits in modulating inflammation and immune responses. Growth factors in CGF, such as interleukin-8 (IL-8), can effectively alleviate perifollicular inflammation, reducing inflammatory damage to hair follicles. This creates a more favorable environment for hair follicle growth and facilitates hair regeneration. Additionally, CGF contains a substantial number of leukocytes that regulate macrophage-mediated immune responses by modulating their secretory functions. It also suppresses the secretion of interleukin-1β (IL-1β) while inducing the production of chemokines such as RANTES (regulated upon activation, normal T-cell expressed, and secreted), promoting the recruitment and activation of immune cells. These processes accelerate tissue repair and regeneration, providing crucial support for mitigating follicular degeneration and restoring hair follicle function [51].

REGULATION OF OXIDATIVE STRESS LEVELS:

Oxidative stress is one of the core mechanisms underlying AGA. Dermal papilla cells (DPCs) in hair follicles of AGA patients exhibit heightened sensitivity to oxidative stress. Oxidative stress generates excessive reactive oxygen species (ROS), leading to DNA, protein, and lipid damage in hair follicle stem cells. This results in reduced follicle vitality and limited regenerative capacity, ultimately shortening the anagen phase and prematurely transitioning the follicles to the telogen phase [52]. Oxidative stress is closely linked to suppression of the Wnt/β-catenin signaling pathway, which is critical for the growth and maintenance of hair follicles. Moreover, ROS induced by oxidative stress activates inflammatory signaling pathways, increasing the release of inflammatory factors such as IL-6, IL-1β, and TNF-α. These factors inhibit the proliferation of hair follicle cells, shorten the anagen phase, and trigger chronic inflammation around the follicles [53]. This chronic inflammatory response further disrupts the follicular microenvironment, impeding normal hair growth [54]. Therefore, reducing oxidative stress and enhancing antioxidant defense mechanisms are potential therapeutic strategies for treating androgenetic alopecia.

CGF (concentrated growth factor), as an autologous blood-derived product rich in growth factors, demonstrates significant antioxidant properties through mechanisms primarily involving the regulation of reactive oxygen species (ROS) levels, enhancement of antioxidant enzyme activity, and improvement of the cellular microenvironment. The specific mechanisms are as follows: (1) ROS Scavenging and Enhancement of Antioxidant Enzyme Activity. CGF exerts its antioxidant effects by reducing intracellular ROS accumulation. In vitro studies have shown that CGF treatment decreases ROS production, thereby mitigating cellular damage [54]. Additionally, CGF significantly increases the activity of antioxidant enzymes such as superoxide dismutase (SOD), enhancing the cellular defense against oxidative stress [55]. (2) Multidimensional Antioxidant Mechanisms. CGF contains abundant growth factors that regulate cellular antioxidant responses, strengthen the endogenous antioxidant system, and reduce the generation of free radicals and oxidative damage. Beyond its direct antioxidant effects, CGF promotes cell proliferation and migration, improving cellular survival and repair capacities. Research indicates that CGF-treated cells have higher proliferative and migratory capacities following oxidative stress stimulation, further supporting the role of CGF in combating oxidative stress and facilitating cellular repair [55]. (3) Inhibition of Oxidative Stress-Induced Apoptosis. In vitro experiments have demonstrated that CGF significantly reduces cell death caused by oxidative stress, indicating its ability to effectively regulate oxidative stress-related cell death pathways, thereby mitigating cellular damage caused by oxidative stress [54].

In summary, the antioxidant effects of CGF are mediated through multiple mechanisms, including the direct scavenging of ROS, enhancement of SOD activity, and indirect actions such as improving cellular growth and repair capacities and inhibiting oxidative stress-induced apoptosis. These properties highlight the significant potential of CGF in combating oxidative stress-related aging and tissue damage. Androgenetic alopecia (AGA) is closely associated with oxidative stress, which increases ROS production, resulting in impaired function of hair follicle stem cells, follicular miniaturization, and disruption of the hair growth cycle. CGF effectively mitigates oxidative damage in the scalp and hair follicles, restores the activity and proliferative capacity of follicular cells, improves the scalp microenvironment, and promotes hair regeneration.

Safety evaluation of CGF in the treatment of AGA

In the treatment of AGA with CGF, most patients do not experience significant adverse reactions, and only a small proportion develop mild local reactions. The most common local reactions include transient redness and swelling or pain at the injection site, which typically resolve spontaneously within 2 days without requiring special intervention. In rare cases, localized hematoma may occur, but it can be properly managed without resulting in long-term complications [34]. Since CGF is derived from the patient’s own blood, allergic reactions are extremely rare. However, it is still essential to thoroughly inquire about the patient’s allergy history prior to treatment and closely monitor for any signs of allergic reactions, such as rash or itching, after the procedure. While there are numerous studies on the short-term safety of CGF in the treatment of AGA, its long-term safety requires further investigation. For instance, it is unclear whether repeated CGF injections can lead to abnormal tissue overgrowth in the scalp or pose other potential long-term risks. These aspects necessitate further large-scale, long-term follow-up studies to provide more definitive evidence.

Limitations of the Study

Although many studies have suggested that CGF has efficacy in the treatment of AGA, most had relatively small sample sizes and lacked large-scale, multicenter clinical trials. The duration of these studies is often short, and there is insufficient evidence regarding the long-term efficacy and safety of CGF in treating AGA. Furthermore, research on CGF treatment for AGA shows variability in the evaluation criteria and methods used to assess treatment outcomes. For example, some studies used hair density as the primary evaluation metric, while others focused on hair diameter or subjective patient satisfaction. The lack of standardized and objective evaluation criteria makes it challenging to accurately compare and synthesize results across studies. Future research should focus on conducting large-scale, multicenter, randomized controlled clinical trials with long-term follow-up to more precisely assess the efficacy and safety of CGF in the treatment of AGA and to clarify its role in AGA management.

Conclusions

In recent years, significant advances have been made in the application of concentrated growth factor (CGF) in the treatment of androgenetic alopecia (AGA). This review systematically examined CGF’s preparation techniques, underlying biological mechanisms, and clinical efficacy in monotherapy and combination treatments. CGF has demonstrated the ability to promote hair follicle regeneration through the regulation of growth factors, cellular activity, inflammatory response, and oxidative stress, with minimal adverse reactions.

Importantly, this review aimed to provide a theoretical foundation for future basic and clinical research on CGF in hair follicle regeneration, which was addressed through a comprehensive analysis of previous studies. However, limitations such as small sample sizes, short follow-up periods, and the lack of standardized evaluation criteria persist. Therefore, future efforts should focus on conducting large-scale, long-term clinical trials, optimizing CGF preparation methods, and integrating CGF with other emerging therapies. By aligning this research with the goal of advancing safer and more effective treatment strategies for AGA, CGF holds promise as a valuable tool for regenerative treatment.