4.1. PRP Compared with Minoxidil® and Finasteride®
AGA produces a yearly worldwide market income of US$
4 billion and a growth rate of 1.8%, demonstrating a developing consumer market [35
Current drugs indicated for AGA with approval from the U.S. Food and Drugs Administration (FDA) include Minoxidil® and Finasteride®.
(pyrimidine derivate) lotion 2% was the first drug to receive approval by the FDA for AGA treatment in males (1988) and in females (1991) [36
lotion 5% received approval in 1997 for males who suffered AGA followed by approval of the 5% foam in 2006 [36
prolongs the anagen and increases the HF diameter through activation of prostaglandin endoperoxide synthase-1, which increases the level of prostaglandin E2 [36
increases the survival of DPCs by increasing the Bcl-2/Bax ratio and by activating ERK and Akt [37
is a type II 5-alpha-reductase-inhibitor, which decreases dihydrotestosterone (DHT) by about 65% in the serum, prostate, and scalp. It was registered in Europe in 1992 for the treatment of benign prostatic hyperplasia [38
]. The drug was registered in the U.S. (1993) and Europe (1994) for the therapy of mild to moderate AGA in male patients [38
]. Oral Finasteride®
also prolongs anagen, with a gradual improvement of HT [38
has been shown to reduce the pattern of hair loss associated with an increased expression of caspase and apoptosis inhibitors, stimulating HG [39
Alternative procedures, based on autologous regenerative therapies and a minimally invasive approach, are represented, as introduced, by PRP (A-PRP and AA-PRP) and ASCs-BT as adipose-derived mesenchymal stem cells (AD-MSCs) and HFSCs [1
]. A more invasive surgical approach is represented by hair transplants, which is indicated only for patients affected by aggressive conditions of AGA and complete HLs [1
Adil A et al. [41
] conducted a systematic review and meta-analysis of randomized controlled clinical trials indexed in PubMed, Embase, and Cochrane, and searched up to December 2016, with no lower limit on the year. They selected only randomized controlled trials, based on the U.S. Preventive Services Task Force quality assessment process, conducted separately for five groups of studies, in which they tested in male patients low-level laser therapy (LLL-T), 5% Minoxidil®
, 2% Minoxidil®
, 1 mg Finasteride®
, and 2% Minoxidil®
in females [41
]. All treatments were superior to the placebo (p
< 0.0001) in the five meta-analyses, suggesting that Minoxidil®
, and LLL-T were effective at promoting HG in male patients who suffered AGA and that Minoxidil®
was effective in females with AGA.
To better compare the size of clinical outcomes obtained by the use of Minoxidil®
with those obtained by A-PRP, AA-PRP, and HFSCs, it is necessary to analyze the most recent results in HD and HC improvement obtained for these treatments. In detail, in a recent article by Gentile et al. [2
], the HD improvement for A-PRP 23 weeks after the third injection (each injection was performed three times every 30 days) was 28 ± 2% hairs/cm2
compared with the placebo (saline solution). In the same article, an HD improvement for HFSCs treatment 23 weeks after the second injection (each injection was performed two times every 60 days) was 29 ± 5% hairs/cm2
compared with saline [2
In a study by Van Nestle et al. [42
], 212 males suffering AGA were randomized to receive Finasteride®
1 mg daily or a placebo for 48 weeks. At baseline, the mean total and anagen HC in the Finasteride®
group were 200 and 124 hairs, respectively (% anagen = 62%), and the anagen to telogen ratio was 1.74 (geometric mean). In the placebo group, the respective values were 196 and 119 hairs (% anagen = 60%) and 1.57. At week 48, the Finasteride®
group had a net improvement (mean ± SE) compared with the placebo in total and anagen HC of 17.3 ± 2.5 hairs (8.3% ± 1.4%) and 27.0 ± 2.9 hairs (26% ± 3.1%), respectively (p
< 0.001). Furthermore, treatment with Finasteride®
resulted in a net improvement in the anagen to telogen ratio of 47% (p
< 0.001), supporting favorable results on hair quality that contribute to improvements in HG.
In a recent study of Bao L. et al. [43
] on the use of Minoxidil®
5%, the mean improvement in the total HD from baseline to 24 weeks was 18.8/cm2
in patients managed with a topical application and 38.3/cm2
in patients managed with electrodynamics micro-needling treatments plus topical 5% Minoxidil®
Regarding the expenses/effectiveness ratio, if on the one side, the drugs discussed appear to be effective in AGA patients, on another side, they cause a dependence promoted by the need to take daily Finasteride®
or to apply Minoxidil®
topically for a long period of time; however, this was not inferior to 12–24 months according to the evaluated studies [42
On the other hand, the use of autologous treatments may free the patient from the daily routine, but the greater invasiveness of the procedures may lead to people having less compliance.
4.2. PRP Comparison with Autologous Adult Stem Cell-Based Therapy (ASCs-BT)
Adult stem cells can be harvested, prevalently, from two different kinds of tissues: Fat and scalp. Adipose tissue (AT) is a very interesting source of MSCs, having multi-lineage separation potential. AT may be collected using a minimally invasive procedure represented by liposuction. The AT must be identified as an effective alternative source of stem cells (SCs) with respect to bone marrow (BM) during intra-surgical ACB-T, both for cellular wealth and expansion potential. A few patients may have constrained AT or insufficient levels for autologous cell collection, but, given the high frequency of AD-MSCs (their amount is 100 to 300 times higher than in BM), a small AT amount may be considered adequate for SC collection and isolation [1
]. AD-MSCs and stromal vascular fraction cells (SVFs) are essential for the activation of the scalp’s ESCs, thus releasing GFs.
VEGF drives HG and the improvement of HFs’ size by the stimulation of angiogenesis. PDGF maintains the anagen phase, while IGF-I controls the HG cycle and hair cells’ separation [1
]. Their action is aimed at angiogenesis improvement and enhancement of the blood supply to DPCs. Likewise, they have immune-modulatory and immune-suppressive actions via the release of prostaglandin E2 (PGE2), leukemia-inhibiting factor (LIF), and kynurenine [1
]. MSCs and SVFs have paracrine effects via TB4, EGR-1, SDF-1, and MCP-1, acting on human HF cells [1
]. In fact, TB4 contributes to the SCs being triggered in HF, improving their relocation into the follicle and their separation. SDF-1 acts by triggering EGR-1, expanding the cell tropism toward the follicle and stimulating angiogenesis. The activity of MCP-1, despite being an inflammatory factor, has a demonstrated tissue regenerative impact [1
Since AGA is characterized by an important inflammatory infiltrate, being responsible for the release of a variety of inflammatory cytokines [44
], it is likely that the anti-inflammatory and immune-modulatory properties of PRP or dermal and progenitor stem cells may favor HRG [44
Stoll et al. [47
] hypothesized in a pre-clinical model that superficial mechanical skin trauma produced with a micro-needling device would induce long-term HRG at the treated areas. Five weeks after micro-needling, HRG started, followed by a reduction in hyperpigmentation of the affected skin. After 12 weeks, there was a 90% improvement in scalp coverage on areas that previously suffered from HLs. Twelve months after the treatment, coat conditions remained stable [47
As reported in a clinical model review performed by Ferting et al. [48
], micro-needling may be considered a minimally invasive dermatological procedure in which fine needles roll over the skin to puncture the stratum corneum. This therapy may induce collagen formation, neovascularization, and it may favor GF release in the treated sites. It has been used in a wide range of dermatologic conditions, including AGA and alopecia areata (AA) [48
For scalp tissue, recently, in two interesting articles published by Gentile et al. [10
], a minimal manipulation procedure was tested and developed to separate HFSCs, based on the centrifugation of the scalp’s micro fragments obtained by several biopsies (2 mm), without an expansion or cell culture. In this procedure, cell counting and identification of CD44+ HF-MSCs and the CD200+ HF-ESCs were performed.
In patients suffering AGA with important HLs, the HFSCs number remains unaltered; however, the quantity of the more effectively multiplying progenitor cells significantly decreases, as reported by Garza et al. [49
The reconstitution and/or the regeneration of a complete HF from seeded cells in culture conditions is yet to be investigated in tissue engineering [50
HFs are known to contain a well-characterized niche for grown-up SCs: The bulge, which contains epithelial and melanocytic SCs [51
SCs in the bulge area, an obviously differentiated structure inside the lower permanent portion of HFs, may create the inter-follicular epidermis, HF structures, and sebaceous glands [52
ESCs can likewise reconstitute in a simulated in vivo framework into a new HF [54
Yu et al. [51
] displayed that human HFs contain an SC population with the potential of separation, with the consequent possibility of their differentiation in neurons, smooth muscle cells, and melanocyte progenitors in the induction medium. The information analyzed and reported demonstrates that Oct4-positive cells are available in human skin, and the majority of them are located in the HFs in vivo. Oct4 has a place with the family of POU-domain transcription factors that are regularly communicated in pluripotent cells of the developing embryo and mediate pluripotency [56
]. Each mature HF is a regenerating framework, which physiologically experiences cycles of growth (anagen), relapse (catagen), and rest (telogen) various times in a grown-up’s life [57
]. In catagen, HF SCs are kept in the bulge. At this point, the resting follicle re-enters anagen (regeneration) when legitimate molecular signals are given. Amid late telogen to early anagen change, signals from the dermal papilla (DP) induce the triggering of quiescent SCs into the bulge [58
Numerous paracrine factors are involved with this crosstalk at various H-C stages and some signaling pathways have been implicated [59
]. In anagen, SCs in the bulge offer ascent to hair germs; at this point, the transient increasing cells in the grid of the new follicle proliferate quickly to frame another hair filament [62
As a matter of fact, the authors feel the need to better know and investigate which stage requires action is important, with the aim of improving HRG and obtaining HF regeneration. The regeneration of HFs was likewise observed in patients [34
] when dermal sheath tissue was used; moreover, this is useful for regeneration of the DP structure. After implantation, the whisker DP was equipped for the promotion of HF regeneration by holding the data to decide the hair fiber type and follicle size [63
]. The grafting of dermal-inductive tissue was limited as it is impractical to produce more HFs than the one obtained from the donor tissues. To defeat this constraint, diverse methodologies and exploratory models utilizing fresh or cultured isolated cells from both dermal and dermal/epidermal origins were investigated. The vast majority of them included neonatal and embryonic murine cells.
Balañá ME et al. [50
] realized a dermal-epidermal skin substitute by seeding an a-cellular dermal grid with cultured HF-ESCs and DPCs, both obtained from the adult human scalp. This construct was grafted into a full-thickness wound produced on nude mice skin. In 14 days, microscopical structures reminiscent of a wide range of HFs’ embryonic structures were observed in the grafted region. These structures displayed concentric cellular layers of human origin and expressed k6hf, the keratin present in epithelial cells. Despite the fact that the presence of completely mature HFs was not seen, these results demonstrated that both epithelial and dermal cultured cells from the adult human scalp in a dermal scaffold can create in vivo structures similar to HF’s embryonic/germ structures, thus resulting in an HG improvement and hair regeneration.
Kalabusheva et al. [64
] combined post-natal human DPCs and skin epidermal keratinocytes (KCs) in a hanging drop culture to build a simulated HF germ. Blended HF germ-like structures showed the initiation of epithelial-mesenchymal collaboration, including Wnt pathway activation and the expression of follicular markers. In this article, the authors analyzed the impact of DP cell niche components, including soluble components and extracellular matrix (ECM) molecules, during the time spent on the organoid assembly and growth. Their outcomes showed that soluble components had little effect on HF germ generation and the Ki67+ cell score inside the organoids despite the fact that BMP6 and VD3 effectively maintained the DP character in the monolayer culture.
Talavera-Adame et al. [35
] reported the bio-molecular pathway involved in cellular treatment. Specifically, Wnt/β-catenin signaling was displayed as being fundamental for the growth and upkeep of DPCs [65
]. The increment of Wnt signaling in DPCs evidently must be considered one of the most important factors that enhances HG, as reported by Tsai et al. [65
Festa et al. [67
] detailed that adipocyte progenitor cells bolster the SCs niche and help drive the complex HG cycle. This follicular regenerative approach is fascinating and raises the likelihood that one can drive or reestablish the H-C in males and females who suffer from HLs by stimulating the niche with autologous fat improved with stromal cells.
Furthering this concept, Perez-Meza D et al. [68
] described and reported the safety and tolerability of advanced fat tissue injection in the subcutaneous scalp in patients who suffer from hereditary alopecia. The outcomes obtained displayed that the stem cell-enriched fat grafting in the scalp may represent a promising elective way to deal with treating HLs in people.
Additionally, Fukuoka et al. [69
] displayed a mean increment of 29 ± 4.1 hairs in male patients and 15.6 ± 4.2 hairs in females treated with fat-derived stem cell-conditioned medium infusion.
As reported, the PRP-based therapy must be compared with ASCs-BT. It appears to be necessary to perform this comparison not only in HRG but also in different regenerative fields, such as wound healing [70
], that may present similar bio-molecular pathway aspects.
The authors’ goals are to elaborate on a cellular mechanism approach in order to regenerate and promote one’s own natural GF release.
The use of autologous A-PRP/AA-PRP, ASCs-BT, and biotechnology aims to promote HRG via their use in isolated suspensions or in combination. This stems from the necessity to move from “substitutive surgery”, represented by transplants (organs, skin, cartilage, bone, etc.), to “regenerative plastic surgery” with the regeneration of organs, tissues, and hairs induced via autologous GFs and cells.
4.3. Evidence-Based Medicine’s Impact of PRP in AGA Treatment
One of the problems most encountered in the scientific community is the level of consolidated evidence-based medicine (EBM) offered by PRP in the treatment of AGA and hair loss, compared with FDA-approved treatments like Minoxidil® and Finasteride®.
Many institutional guidelines of several countries are based on the EBM impact of a procedure/drug. Regarding PRP in hair loss and AGA, as reported, 19 systematic reviews, 9 meta-analyses, and 12 clinical trials are indexed currently. The number is theoretically more than sufficient to demonstrate a consolidated EBM and related effectiveness of PRP’s use in AGA. Practically, several governments affirm the need for more clinical trials, systemic reviews, and meta-analyses to accept, definitely, consolidated EBM related to PRP in AGA. The rationale of the present study was to contribute a systemic review of randomized/controlled/clinical trials (identified as EBM level 1a study), on the knowledge in this field, consolidating the EBM of PRP use in AGA, and reporting the most updated information compared with the last systemic reviews, and adding an EBM 1a study to this topic.
Most recently, a systemic review was published by Hausauer and Humphrey [74
] on the PRP effects in several hair loss kinds, analyzing the impact, limits, and advantages. Moreover, they described its role in soft-tissue remodeling and rejuvenation. In agreement with Hausauer and Humphrey’s works, and starting on this basis, the authors decided to contribute as these authors, with an EBM 1a study focused only on one theme: “PRP use in AGA”.