Faculty Opinions Faculty Reviews 2022 11:(1)

Advances in hair growth

Dmitri Wall 1–3*,X
Nekma Meah 4,5*,X
Nicole Fagan 6
Katherine York 7
Rodney Sinclair 8

1
National and International Skin Registry Solutions (NISR), Charles Institute of Dermatology, University College Dublin, Dublin, Ireland
2
Hair Restoration Blackrock; Dublin, Ireland
3
Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland
4
St Helens & Knowsley NHS Trust, Prescot, UK
5
Manchester University, Faculty of Biology, Medicine and Health, Oxford Road, Manchester, UK
6
St. James’s Hospital, Dublin, Ireland
7
Netcare Greenacres Hospital, Port Elizabeth, South Africa
8
Sinclair Dermatology, Melbourne, Australia

X
Equal Contributors

Abstract
Hair is a deeply rooted component of identity and culture. Recent articles in this series have focused on scientific evidence relat-
ing to hair growth and new insights into the pathogenesis and mechanism of hair loss. This article reviews emerging evidence
that has advanced our understanding of hair growth in both of these areas to provide a context for outlining current and emerging
therapies. These include finasteride, minoxidil, topical prostaglandins, natural supplements, microneedling, low-level laser light,
platelet-rich plasma, fractional lasers, cellular therapy, Wnt activators and SFRP1 antagonism.

Keywords
Alopecia, hair growth, androgenetic alopecia, male pattern hair loss, female pattern hair loss, antiandrogens, minoxidil, platelet
rich plasma, prostaglandins, exosomes, low-level laser light, fractional lasers, micro-needling, hair cycling

Peer Review
The peer reviewers who approve this article are:
1. Jeffrey Rapaport, Cosmetic Skin and Surgery Center, New Jersey, USA
Competing interests: JR is consultant to Crown Aesthetics and the director of the Rapaport Hair Institute.

2. Poonkiat Suchonwanit, Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital,
Mahidol University, Bangkok, Thailand
Competing interests: No competing interests were disclosed.
Faculty Opinions Faculty Reviews 2022 11:(1)

*Corresponding author: Dmitri Wall ([email protected]); Nekma Meah ([email protected])

Competing interests: DW has received personal fees (honoraria) from Janssen and Eli Lilly and Company (consultancy fees) and non-financial

support (travel fees/grant) from Pfizer but not in relation to this article. RS is a principal investigator in clinical trials sponsored by Janssen, Eli Lilly

and Company, Pfizer, Leo Pharma, Amgen, Novartis, Merck and Co., Celgene, Coherus BioSciences, Janssen, Regeneron, Medimmune,

GlaxoSmithKline, Samson Clinical, Boehringer Ingelheim, Oncobiologics, Roche, Ascend, Dermira, AstraZeneca, Akesobio, Rhinestone, UCB,

Aerotech, Sanofi, Connect, Arcutis, Arena, Sun Pharma, Bristol Myers Squibb, Abbvie and Galderma, outside the submitted work. NM, NF, and KY

declare that they have no competing interests.

Grant information: The authors declare that no grants were involved in supporting this work.

Copyright: © 2022 Wall D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which

permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite this article: Wall D, Meah N, Fagan N, York K and Sinclair R. Advances in hair growth. Faculty Reviews 2022 11:(1) https://doi
.org/10.12703/r/11-1

Published: 12 Jan 2022, Faculty Reviews 11:(1) https://doi.org/10.12703/r/11-1

 Faculty Opinions Faculty Reviews 2022 11:(1)

Introduction portion of the hair follicle contains the isthmus and infundibu-
A deeply rooted component of identity and culture, the role of lum, which are separated by the sebaceous gland duct. The
hair extends far beyond function, while hair disorders can sig- hair bulge sits on the outer root sheath (ORS) at the lowest
nificantly impact wellbeing and quality of life1. One example point of isthmus, where the APM inserts. The inner root sheath
is in patients with breast cancer, where chemotherapy-induced provides a mechanical barrier between the isthmus and
anagen effluvium has been reported to be “psychologically the outside world and provides a protective microenviron-
more difficult than the loss of a breast”2–4. Another example is ment for the bulge. The bulge is a stem cell niche for hair
alopecia areata, where suicide has been described5. Androgenetic follicle keratinocytes and melanocytes as well as arrector pili
alopecia (AGA) is characterised by patterned hair loss in both myocytes23,24. Bulge keratinocyte stem cells activate at the
men (male pattern hair loss, or MPHL) and women (female transition from telogen to anagen and promote regeneration
pattern hair loss, or FPHL)6–8. While the incidence of AGA of the bulb. Transient amplifying cells rapidly proliferate,
varies across races, its prevalence increases with age, visibly migrate downwards into the dermis, reconnect with the dermal
affecting 57% of women and 73.5% of men who are at least papilla (DP) to reform the hair bulb and differentiate into matrix
80 years old9. cells. Hair bulb matrix cells are rapidly dividing cells that give
rise to ORS, inner root sheath, cuticle, cortex and medulla of
The frequency and impact of hair loss continue to fuel a search the hair shaft during anagen. Anagen can continue uninterrupted
for greater understanding of hair growth and resulting devel- for many years before ending abruptly at the onset of catagen.
opments in therapeutics. This article aims to build on previ- Catagen, characterised by rapid apoptotic destruction of the
ous articles in this series that provide an excellent overview of entire hair bulb and partial separation from the DP, is com-
the scientific evidence relating to hair growth10 and new insights plete in less than 2 weeks. The hair follicle remnant consists of
into the pathogenesis and mechanism of hair loss11. We will the bulge, isthmus and infundibulum and contains a club fibre
also endeavour to outline current and emerging therapies to with no inner root sheath. Exogen exposes the isthmus to the
promote hair growth. environment. During telogen, the bulb and papilla remain con-
nected by a fibrous tract. Cross-signalling between the papilla
Hair cycling and bulge at the onset of anagen induces the new bulb to
The hair follicle is a “complex miniorgan” that produces hair migrate down the fibrous tract into the same position as its
shafts from terminally differentiated keratinocytes12. In asso- ancestral bulb25–27.
ciation with the sebaceous gland, apocrine gland and arrec-
tor pili muscle (APM), the hair follicle forms the pilosebaceous The DP also undergoes dynamic changes during hair cycling.
unit. Eccrine glands have also recently been shown to be At the onset of catagen, DP fibroblasts migrate into the dermal
integrated within the pilosebaceous unit13,14. Scalp hair folli- sheath that surrounds the ORS of the hair follicle and act as
cles cluster to form compound pilosebaceous units, consisting a smooth muscle. The dermal sheath, which becomes contrac-
of one primary follicle and one or more secondary follicles tile during catagen, pushes the hair follicle and the surviving
associated with a single APM and single sebaceous gland11. DP upwards, enabling its relocation to the upper reticular der-
All the hairs from a follicular unit emerge through a shared mis, just below the bulge27. At the onset of anagen, dermal
infundibulum11. sheath cells migrate into the DP. Dynamic changes in hair
follicle size and hair fibre diameter are a consequence of
On average, a human has between 2 and 5 million hair follicles, the relative influx/efflux of DP cells into the dermal sheath
of which 100,000 are on the scalp. Blonde-haired Caucasians during hair cycling. The development of secondary sexual
typically have a higher hair density than dark-haired Caucasians, hair at puberty involves net recruitment of dermal sheath cells
who in turn have a higher hair density than red-haired into the DP with each hair cycle. The development of AGA
Caucasians, Africans and Asians15–18. The hair follicle is a complex involves the net loss of DP cells into the dermal sheath with
structure that integrates tissues that arise embryologically from each hair cycle (Figure 1), leading to miniaturisation of the
ectoderm, neuroectoderm and mesoderm. Epidermal and mes- hair follicle (Figure 1 and Figure 2).
enchymal cells integrate, proliferate, differentiate and cycle
through phases of the hair cycle called anagen, catagen and Regulation of the hair cycle
telogen. The hair fibre forms and elongates during anagen, Regulation of the hair cycle involves multiple, incompletely
is retained during catagen and early telogen and then is shed understood endocrine, autocrine and paracrine signalling path-
mid-telogen at a point in time called exogen. The late-telogen ways in complex interplay. Of particular note is the Wnt fam-
period after exogen and before the onset of the next anagen, ily, and specific roles of members of this family are still to be
where the follicle is empty, is called kenogen12,19–22. As the elaborated. Beta-catenin is a core factor of the Wnt signal-
rate of linear hair growth remains relatively constant through- ling pathway and an essential enabler of stem cell differentia-
out life, the main determinant of hair length is anagen duration. tion into follicular keratinocytes28. Anagen-to-telogen transition
Kenogen duration has an impact on hair density but not length. is induced by transient β-catenin signalling29,30 and is influ-
enced by cyclical expression of bone morphogenic proteins
Hair cycling involves remodelling of the lower “bulb” por- (BMP2 and 4), produced by dermal fibroblasts and subcu-
tion of the hair follicle during catagen. The non-cycling, upper taneous adipocytes31, by fibroblast growth factors (FGF 7
 Faculty Opinions Faculty Reviews 2022 11:(1)

Figure 1. Miniaturisation of the hair follicle. In a previous F1000 article, a model of androgenetic alopecia is presented11. Through
consecutive hair cycles, progressive miniaturisation of the hair follicle unit occurs, initially affecting secondary follicles, associated with hair
density reduction, before the arrector pili muscle is replaced by fat32. Ultimately, detachment of this muscle from the regenerative bulge area
is associated with irreversible hair loss11,32. This figure was adapted from Sinclair et al.11 which is licensed under Creative Commons Attribution
4.0 International (CC BY 4.0) (https://creativecommons.org/licenses/by-nc/4.0/).

Figure 2. Androgenetic alopecia miniaturised follicles. In androgenetic alopecia, there is a reduction in the number of hairs per follicular
unit (white arrow) versus in the normal hair follicular unit (red arrow), where multiple hairs emerge from a single infundibulum. This image was
kindly provided by RS from his clinic.

and 10), BMP inhibitors (transforming growth factor b2 Over the previous decade, a therapeutically relevant new method
[TGF-b2] and noggin) and Wnt7b31,33–36. Additionally, adipocyte of paracrine signalling has been identified by means of nano-
precursor cells express platelet-derived growth factor (PDGF) sized extracellular phospholipid bilayer membranous vesicles
alpha to activate the PDGF receptor in the DP, resulting in (exosomes 30–120 nm and microvesicles 100–1000 nm) that
hair germ activation37. Perifollicular vascularisation has been can transport lipids, metabolites, nucleic acids and proteins43–45.
shown to increase during anagen and regress during cata- Zhou et al. reported that DP cell-exosomes, isolated from
gen and is related to ORS keratinocyte vascular endothelial healthy human scalp specimens, accelerated the onset of anagen
growth factor (VEGF) mRNA over- and under-expression and delayed catagen in mouse models, resulting in increased
respectively38. Hepatocyte growth factor/scatter factor has levels of β-catenin and Sonic hedgehog (Shh)46. A recent
been shown to stimulate hair follicle growth in vitro39,40, and study identified that human dermal papillae exposed to acti-
insulin-like growth factor 1 (IGF-1) has been identified as a vated human dermal fibroblasts (hDFs) produce stimulated
significant regulator in the hair follicle41,42. extracellular vesicles (st-EVs) that secrete the non-Wnt ligand
 Faculty Opinions Faculty Reviews 2022 11:(1)

Norrin43. It is hypothesised that subsequent activation of the in men under the age of 46; however, sensitivity analyses
β-catenin pathway is enhanced by hDF-provided Frizzled-4 suggested that this may be influenced by “stimulated reporting”57.
(Fzd4), the specific receptor for Norrin, resulting in the
identified enhanced hair follicle growth ex vivo43. The side effects associated with systemic finasteride may limit
its long-term use. This has led to increased interest in topical
Beyond signalling, lymphatic vessels (LVs) have been shown finasteride, which is not currently FDA-approved, as an alter-
to localise adjacent to the bulge, with increased density and native therapy. The safety and efficacy of topical finasteride
absence respectively in transgenic mice associated with pro- were first investigated over 20 years ago in a single-blind,
longed anagen or accelerated entry into catagen47. Furthermore, placebo-controlled study over a 16-month period58. Patient
LV-promoting VEGF-C injections have been shown to promote outcomes were favourable, and 73% of patients in the treated
hair follicle growth in mice. group reported “high effectiveness”. Recently, a review explor-
ing topical finasteride in male AGA and FPHL identified
Therapeutics that many studies out of the 33 analysed showed positive
The aim of therapeutics is to safely and effectively harness the results and a good safety profile59. Recent reviews of the use
mechanisms outlined above, to promote anagen, delay cata- of topical finasteride in the treatment of AGA suggest that
gen and ultimately prevent or reverse AGA miniaturisation although topical finasteride is a promising therapy that may be
with a view to restoring or maintaining visible hair density. non-inferior to systemic finasteride, there is a paucity of evi-
Finasteride and topical minoxidil are the most widely recog- dence-based research48. Studies included in the reviews showed
nised agents for the treatment of AGA. Both are approved by decreased hair loss, reduction in balding areas, and increased
the US Food and Drug Administration (FDA) and the European hair diameter, follicular density, and total hair count. Combi-
Medicines Authority48. These and other treatments which pro- nation therapy of topical finasteride with other oral and topi-
mote hair regrowth and target specific regulators involved in cal agents, such as minoxidil, may have synergistic effects.
hair growth will be discussed below. Although studies showed that DHT levels may be altered, no
sexual side effects were noted as a result. Adverse events, such
Finasteride as contact dermatitis, irritation, pruritus and dryness, were
Finasteride competitively inhibits the 5-alpha-reductase type due mainly to topical application but were well tolerated. Fur-
2 enzyme, thus preventing conversion of testosterone to dihy- ther research, however, was advised to examine the efficacy
drotestosterone (DHT)49. Finasteride is a potential teratogen of topical finasteride in long-term regrowth, tolerability and
and generally is contraindicated in women of childbearing side effect profile as well as to assess the optimum topical
potential while the efficacy of topical therapy is limited by delivery method in monotherapy and combination therapy.
poor adherence to treatment. Response varies: some achieve
significant regrowth whereas others benefit most from slowing Minoxidil
of additional hair loss50. Minoxidil is a 2,4-di-amino-6-piperidinopyrimidine-3-oxide
and works in AGA by prolonging anagen, shortening telogen
A meta-analysis of placebo-controlled randomised trials iden- and enlarging miniaturised follicles60. Although its mechanism
tified moderate-quality evidence supporting the use of finas- of action has not yet been fully elucidated, transcriptome and
teride for AGA in men51. At the end of 48 months of treatment, proteome analysis has demonstrated differential upregulation
the mean percentage change in hair count was 24% higher of genes in vertex versus occipital scalp of patients with AGA
in patients receiving finasteride. Most studies reporting on and has demonstrated alteration in expression following treat-
the benefit of finasteride have focused on the scalp vertex, ment with minoxidil61–64. It has been shown to increase para-
but importantly a randomised trial of 326 men found it was crine growth factor release from and motility of adipose-derived
efficacious for frontal scalp hair thinning as well52. It may stem cells (ADSCs), enhancing hair growth in mice65.
occasionally adversely affect sexual function, and a system-
atic review of nine trials, totalling 3570 patients, identified an Minoxidil is converted to its active form, minoxidil sulphate,
absolute increase of 1.5% in the risk of erectile dysfunction51. by sulfotransferase enzymes in the hair follicle ORS66–68. Stud-
These effects usually resolve after discontinuation of the ies from the previous decade have demonstrated the potential to
medication53,54; however, a small percentage have reported con- predict response to minoxidil on the basis of sulfotransferase
tinued symptoms for years after stopping the medication55. activity in plucked hair follicles66,69,70. Interestingly, low-dose
In this regard, a single-centre survey study using a sexual expe- aspirin has been shown to inhibit hair follicle sulfotransferase
rience scale comparing 99 non-finasteride and 663 finas- activity, possibly impacting on response to topical minoxidil71.
teride users identified no significant difference in reporting of About 30 to 40% of patients will experience visible regrowth
sexual dysfunction56. with 6 months of twice-daily application of 5% topical
minoxidil66,72,73. Early reports from one double-blind study74
More recently, a pharmacovigilance case–non-case study, ana- suggest that increasing the concentration of topical minoxidil,
lysing the World Health Organization’s VigiBase individual case which is not commercially available, to 15% can achieve a
safety report database, showed signals of suicidality and psy- clinically significant response in 60% of non-responders to 5%
chological adverse events associated with the use of finasteride topical minoxidil74,75.
 Faculty Opinions Faculty Reviews 2022 11:(1)

The efficacy of minoxidil lotion, however, is limited by poor the number of hairs and their duration in the anagen phase91–93.
solubility. Solutions greater than 5% are unstable. Percuta- To determine the efficacy and safety of bimatoprost scalp solu-
neous absorption is saturated after twice-daily application. tion on scalp hair growth in mild to moderate AGA, a number
Crystallisation (or powdering) of minoxidil occurs on the of clinical trials have been performed94–96 and they indicate
scalp when the solvent evaporates. Powdering leads to a loss that topical bimatoprost is not superior in efficacy to topical
of active substance and also has an undesirable cosmetic effect minoxidil. Latanoprost, a PGF2a analogue, can induce anagen
on the hair. Co-solubilising agents used to prevent powdering and hypertrophic changes in hair follicles97,98. A randomised
further limit usability as they make the hair gummy, sticky double-blind placebo-controlled pilot study99 assessing 0.1%
or greasy. Usability is especially a problem for women with topical latanoprost daily in 16 men with AGA found that, com-
FPHL who have long hair. Whereas the hair-promoting effect pared with placebo-treated areas and baseline, hair density
of topical minoxidil generally takes 6 months to become increased significantly99,100.
apparent, the median duration of use is 6 weeks. Continuous
use is required to maintain the hair-promoting effects of topical Topical cetirizine
minoxidil, yet many who initiate treatment will discontinue Cetirizine is a second-generation H1 blocker. It has
use beyond 12 months. anti-inflammatory properties and decreases production of
PGD2, which, unlike other PGs, is thought to play a negative
Oral minoxidil initially was developed in the 1950s to treat role in hair growth. It is safe and has a lower potential side
hypertension. Hypertrichosis was identified as an unwanted effect profile than other topical therapies, potentially resulting
side effect but prompted redevelopment as a treatment for AGA in improved compliance compared with treatments such as
as Regaine/Rogaine in the 1980s. Owing to dose-related side topical minoxidil and finasteride. One case-controlled study
effects, namely postural hypotension, fluid retention and hyper- of 60 patients with AGA showed significantly higher hair
trichosis, it has not been used routinely in standard doses for regrowth and patient satisfaction in the group that received
AGA treatment76. Its efficacy and safety were evaluated in 1% topical cetirizine (n = 30) than in the control group101. In a
a 2015 study of 30 men with AGA given 5 mg daily for 24 pilot study of 67 patients who received 1% topical ceti-
weeks77. Hair growth and total hair count significantly increased rizine, there were increases in total and terminal hair density
in the vertex area, but hypertrichosis and pedal oedema were as well as diameter102. Currently, a number of clinical trials
still common side effects. A recent study on treatment of FPHL are looking at the use of topical cetirizine in AGA, including
involved therapy with 0.25 mg minoxidil combined with in females103, and comparing 1% topical cetirizine with 5%
25 mg spironolactone to reduce the risk of fluid retention and minoxidil104.
augment therapy with its antiandrogen effect76. This dose was
well tolerated by the majority, and most noticed a reduction in Natural ingredients
hair shedding at 3 months and increased density at 6 months76. Analysis of hair has revealed a composition of iron, oxygen,
A randomised, open, 24-week study comparing oral minoxi- hydrogen, nitrogen and sulphur. Thus, an adequate supply of
dil 1 mg with topical minoxidil 5% solution in 52 patients blood containing these minerals is essential for hair growth dur-
with FPHL identified oral minoxidil as safe and well tolerated, ing anagen. Anagen is associated with a rearrangement of skin
and there was a reduction in shedding superior to topical vasculature, an increase in skin perfusion, and angiogenesis105.
minoxidil78. Although there was no significant difference in Various vitamins and minerals are responsible for the modula-
hair density, there was a trend towards greater improvement tion of angiogenesis during anagen and therefore are impor-
in the oral group. Further data from a large multicentre study tant. In addition, multiple vitamins, minerals, and herbal drugs
have demonstrated its efficacy and safety in AGA79. stimulate hair growth or prevent hair loss by various mechanisms
(Table 1)106–108 and thus deficiencies in these can cause alo-
Topical prostaglandins pecia. Supplementation with these, in theory, should improve
Several studies have highlighted the important role of prostag- hair growth and this is particularly true for iron deficiency.
landins (PGs) in governing the hair cycle80. Prostaglandin D2
(PGD2) has hair growth–inhibitory effects and is present in Microneedling
increased levels in the AGA-affected scalp, whereas prostag- Microneedling is the process of using a roller device appara-
landin E2 (PGE2), present in reduced levels in AGA scalps, tus of small fine needles to micro-puncture the stratum cor-
and prostaglandin F2a (PGF2a) have hair growth–stimulating neum of the epidermis. Although the procedure alone can
effects81,82. A 2019 study in which 32 Hispanic patients with stimulate neovascularisation, growth factor activity and Wnt
AGA were biopsied demonstrated that men with early MPHL protein expression109, it is often used in AGA in conjunction
overexpressed the enzyme prostaglandin E synthase (PTGES), with hair growth stimulants: minoxidil, plasma-rich protein
which synthesises PGE2, suggesting that PGs may play or topical steroids. When combined, microneedling can facili-
differing roles, depending on the stage of AGA83. tate the percutaneous delivery of topical therapies. Lee et al.
conducted a split-scalp study in 11 women with FPHL110.
Bimatoprost, a synthetic PGF2a analogue84, has been demonstrated Microneedling was performed on half the scalp treated with
to increase the thickness, length and darkness of eyelashes85 growth factors and the other half treated with normal saline. At
and the fullness and darkness of eyebrow hair86–90 by increasing 5 weeks, the microneedling with growth factor–treated scalp
 Faculty Opinions Faculty Reviews 2022 11:(1)

Table 1. Vitamins, minerals and herbal drugs that stimulate hair growth or prevent hair
loss by various mechanisms106–108.

Agents improving blood supply to the scalp

Niacin (vitamin B3)
Vitamin B complex
Ascorbic acid (vitamin C)
Tocopherol (vitamin E)
Grape seed
Rosemary oil
Sage
Nettles
Hibiscus rosasinensis108
Cofactors for carboxylases that catalyse an essential step in intermediate metabolism
Biotin
Antioxidants
Zinc and grape seed
Agents that inhibit or reduce 5 alpha reductase activity
Inhibitors: green tea107, ginkgo biloba and emu oil
Agents improving hair texture and thus preventing loss of dry brittle hairs
Essential fatty acids (primrose and salmon oil)
Amino acids (l-cysteine and l-methionine)

had an increase in hair count (52.91 ± 10.85) compared with receive different models of the HairMax® LaserComb (7-beam,
the microneedling with saline-treated scalp (45.91 ± 9.98) 9-beam, 12-beam and 9- and 12-beam) or a sham device.
(P = 0.0001). The mean terminal hair count at 26 weeks from baseline
was higher in the LaserComb subjects compared with the
Low-level laser sham-treated subjects. The LaserComb patients also reported
Low-level laser therapy (LLLT) is occasionally synonymous a higher percentage of overall improvement with their hair
with red light therapy, cold laser and soft laser111. It is thought (with respect to hair thickness and fullness) compared with
to exert a biomodulation/biostimulation effect on tissue, pro- sham-treated subjects118. However, in an earlier case series of
moting anti-inflammatory effects111–115. The exact mechanism seven patients receiving twice-weekly LLLT, the findings were
of action in stimulating hair regrowth is not known. Improved not conclusive. Although increases in terminal hairs and in
cellular activity, reduced inflammation and improved micro- hair shaft diameter were noted, the findings were not statisti-
circulation may be involved108. The therapeutic effects are cally significant and global image assessment did not sup-
delivered in wavelengths ranging from 500 to 1100 nm (red to port an improvement with LLLT119. Liu et al. conducted a
near infrared) at low energy density (3 to 90 mW/cm2)111,116. system review and meta-analysis of RCTs, reviewing eight
A variety of LLLT devices, including in-salon hoods or over- studies with 11 double-blind RCTs, and concluded that LLLT
head panels, are available to patients with hair loss. Bonnets, resulted in a significant increase in hair density and that
helmets or hand-held combs are suitable for home use. Both low-frequency treatment can result in a better effect than high,
the HairMax® LaserComb and the head cap TOPHAT 665 have and types of devices and course duration did not impact the
had FDA clearance for treatment in AGA. effectiveness on hair growth120.

Kim et al. conducted a 24-week, double-blind randomised Platelet-rich plasma

controlled trial (RCT) comparing sham device to LLLT hel- Treatment with platelet-rich plasma (PRP) involves intra-
mets (emitting wavelengths of 630-nm, 650-nm and 660-nm dermal injection of the scalp with a concentrated volume
light-emitting diodes) in 40 patients with AGA117. The mean hair of platelets, within a small volume of plasma, that has been
density was significantly greater in the LLLT group versus the derived from the centrifugation of a patient’s own venous
sham group. A 26-week RCT involving 269 patients with AGA blood121,122. PRP contains numerous PDGFs, including PDGF,
produced similar results. Patients were randomly assigned to TGF-b1 and TGF-b2, VEGF, basic fibroblast growth factor,
 Faculty Opinions Faculty Reviews 2022 11:(1)

endothelial growth factor and insulin-like growth factors121–124. assessment, was noted to be very low135. Although meta-analysis
It is proposed that PRP prolongs anagen, prevents catagen and highlights evidence of increases in hair number and thick-
shortens the period from telogen to anagen through the release ness with PRP in small studies, it is important to recognise that
of growth factors that stimulate “cell survival, proliferation, these studies lack comparability, highlighting an unmet need
and differentiation”125–128. for larger RCTs122,136.

A mechanistic model from Gupta and Carviel describes the Fractional lasers
stimulation of hair growth with key roles played by “growth fac- Fractional lasers are indicated for the treatment of rhytides
tor mediated increased activation of wingless (Wnt)/β-catenin, and scarring; however, the role of lasers in treating alopecia is
extracellular signal-regulated kinase (ERK), and protein kinase relatively new. Ablative (fractional 10,600-nm carbon dioxide
B (Akt) signalling pathways”127, to improve vascularisation129 and fractional 2940-nm erbium: yttrium aluminium garnet
and prolong anagen127. A meta-analysis of six studies and [YAG]) and nonablative (fractional 1550-nm erbium glass) lasers
177 patients demonstrated increased hair number per square cen- have been investigated in the context of alopecia areata and
timetre after PRP versus control in addition to a significantly AGA124,137. Fractional lasers are unique in creating pixelated
increased hair thickness cross-section per 10−4 mm2 in the microthermal injury zones (sparing the epidermis and der-
PRP group122. Earlier studies demonstrated greater improvement mis), allowing better tolerability and fewer cutaneous side
in hair thickness when combined with additional therapies. effects137.
Combination therapy of PRP and polydeoxyribonucleotide
(PDRN), delivered over 12 sessions, yielded a greater improve- In a study involving 28 patients with FPHL, patients received
ment in hair thickness in subjects with FPHL than treatment 10 treatments with 1550-nm fractional erbium glass laser
with PDRN therapy alone130. The largest study, involving at 2-week intervals138. Improvement in hair density and mean
64 patients with AGA, is by Schiavone et al.131 Patients received hair thickness was observed after 5 months of treatment;
leukocyte PRP plus concentrated plasmatic proteins at base- mean percentage changes from baseline were 57% and 77%
line and at 3 months. Using macrophotographs and Jaeschke respectively. Global photographs also confirmed improvement
rating of clinical change, two unblinded assessors noted some in 24 patients138. Furthermore, Kim et al. investigated “the
improvement in 62 patients. The mean changes in clinical rat- effects of a 1,550 -nm fractional erbium-glass laser on the hair
ing were 3.2 (95% confidence interval [CI] 2.9–3.5) and 3.9 cycle in an alopecia areata mouse model” by laser irradiating
(95% CI 3.5–4.3). the shaved backs of C3H/HeN mice whose hair was in telo-
gen stage. Molecular studies revealed an increase in Wnt 5a
In a double-blind, controlled study of 26 patients randomly and β-catenin signal levels, while histopathologic studies
assigned to receive four injections of saline or PRP, those receiv- demonstrated conversion from telogen to anagen conversion.
ing the latter were found to have significant increases in hair Following these results, the authors conducted a pilot study of
density, count and percentage of anagen hairs132. Interestingly, 20 patients with MPHL treated with 1550-nm fractional erbium
there was no correlation with either platelet counts or meas- glass laser (five sessions at 2-weekly intervals) and found
ured growth factors, including epidermal growth factor, VEGF improvements in hair density and growth rates139.
or PDGF, prompting the authors to speculate whether other,
unmeasured growth factors are related to the measured Hair Stimulating Complex
response to treatment. Clinical practice often involves intro- Hair Stimulating Complex™ (HSC), patented by Histogen (San
duction of PRP in combination with other therapies. In a ret- Diego, CA, USA)140, comes as an injectable, cell-conditioned
rospective review, a significant increase in hair density, but media made up of keratinocyte growth factor, VEGF and
not calibre, was seen in 17 out of 24 patients 2 months after follistatin. These growth factors are involved in stem cell
initial injections133. All 24 patients were already using 5% proliferation and stimulate hair growth. In an RCT of 26 sub-
topical minoxidil, while 20 patients were also taking an oral jects receiving HSC, significant improvement in hair growth
antiandrogen. was noted over placebo at 12 and 52 weeks141. HSC-treated
areas had increased hair shaft thickness (6.3% ± 2.5%
A meta-analysis of 10 studies (n = 165 participants) examin- vs. −0.63% ± 2.1%; P = 0.046), thickness density (12.8% ±
ing PRP treatment compared with baseline calculated a sta- 4.5% vs. −0.2% ± 2.9%; P = 0.028) and terminal hair density
tistically significant overall standardised mean difference in (20.6 ± 4.9% vs. 4.4 ± 4.9%; P = 0.029).
PRP-treated patients of 0.58134. Six of the studies (n = 99 par-
ticipants) compared PRP with placebo, and the PRP group Cellular therapy
showed greater efficacy (standardised mean difference of Autologous dermal sheath/dermal papilla/epidermal cells.
0.51). This led the authors to conclude that PRP treatment is Hair follicle regeneration is initiated by mesenchymal DP
beneficial in AGA. Another systematic review and network cell signalling to stem cells in the bulge region of the hair
meta-analysis comparing relative efficacy of 2% minoxidil, follicle. A viable pool of functional DP cells is necessary to
5% minoxidil, finasteride, PRP and LLLT indicated that maintain this process long-term. In healthy follicles, dermal
LLLT had a greater increase in mean difference in hair count sheath cup (DSC) cells may help to repopulate DP cells for
compared with the other treatments, which were nearly equiva- each regenerative hair cycle. A gradual decline in DP num-
lent, although the quality of evidence, based on risk-of-bias bers may account for AGA142,143. Research has shown that
 Faculty Opinions Faculty Reviews 2022 11:(1)

transplanted DP and DSC cells can promote DP formation and largely unmet need and is a significant challenge in the study
hair follicle induction144. Therefore, DP/DSC cells harvested of regenerative medicine in hair therapy.
from androgen-resistant areas, expanded in culture and then
injected into balding scalp potentially stimulate hair growth. Concerns exist that evidence generated regarding cellular
Several phase II trials have attempted to explore the efficacy and regenerative therapies can be over-hyped or unreproduc-
of autologous dermal cells and/or epidermal cells injected ible or have insufficient power to reasonably address safety
into balding scalp to reverse miniaturisation in AGA145,146. concerns. Financial gain motivating the provision of unregu-
Although study statuses are confirmed as complete, results are lated services with safety concerns or little evidence must also
outstanding and not yet published. be considered161. A report published in 2020 by the European
Academies’ Science Advisory Council and the Federation of
RepliCel (Vancouver, BC, Canada) have conducted a ran- European Academies of Medicine identified significant ethi-
domised, double-blind, placebo-controlled phase I/IIa trial cal and regulatory challenges associated with regenerative
to evaluate the safety and efficacy of intradermal injection of medicine162. The report highlights how the ethical concerns
human autologous hair follicle DSC cells in 10 men and 9 of regenerative medicine, like those of many other fields of
women with AGA147. Stabilisation of hair loss was seen in all cellular research, typically relate to safety and efficacy, patient
per-protocol participants at 24 months. Of those participants consent, misleading information, professional responsibility,
who achieved greater than a 5% hair density increase over equity and fairness as well as issues surrounding donated
baseline at 6 months, the top ten were noted to benefit from biological material162. Although there are strict regulatory
a sustained response (average 4.2%) at 24 months148. Over a frameworks for clinical experimental studies, there can often
5-year follow-up period, no serious adverse events were reported. be premature marketing of therapies, facilitated by regulatory
bodies promoting initiatives such as rapid and accelerated
Adipose-derived stem cells. Mesenchymal stem cells, rich in approval. Cossu et al. urge that regulatory procedures for
adipose tissue (ADSCs)149, are multipotent cells that influence regenerative medicine be transparent, robust, evidence-based,
surrounding cells through the generation of growth factors150,151 rapid and accurate and argue that much work still needs
and have demonstrated a capacity to promote hair growth to be done, including engaging with the public, to counter
in vitro and in vivo151–154. ADSCs are available as a prepared misinformation163.
conditioned media or extracted from adipose tissue using lipo-
suction. This is administered to the balding scalp by serial Wnt activators – Valproic acid
injections. A pilot case series has suggested a possible role Lee et al. demonstrated hair regrowth with topical applica-
for autologous stem cell–enriched fat grafting for the treat- tion of valproic acid to C3H mice164. Unlike minoxidil, valproic
ment of AGA155. In an observational study of 27 patients with acid was found to activate the Wnt/β-catenin pathway. Other
FPHL, improved hair density was observed in patients who inducers of the Wnt/β-catenin pathway, including 4-phenyl
received commercially available ADSC-conditioned media151. butyric acid (PBA), lithium chloride and beryllium chloride,
Stromal vascular fraction, containing adipose tissue–derived were also investigated and found to stimulate hair regrowth
mesenchymal stem cells alone155 and in combination with in vivo. Treatment with lithium chloride or beryllium chloride,
PRP, has demonstrated significant benefit in a small number in particular, triggered anagen entry. In an RCT of patients
of AGA patients in one study156 and superior results compared with AGA treated with topical valproic acid (VPA) or placebo
with PRP alone in a further study157. Stem cell–conditioned for 24 weeks165, the mean change in total hair count was
media, rich in paracrine factors, has also been investigated as found to be significantly higher in the VPA group than in the
an alternative to cell-based therapy158,159. placebo group (P = 0.047). Both groups experienced mild
adverse effects.
Issues relating to cellular and regenerative therapies. Although
advances in cellular and regenerative therapies for hair growth Miscellaneous
continue to evolve, many regulatory and ethical challenges Newer therapies have recently emerged. Microarray analysis
exist. These include problems with activation of stem cells, led to the discovery of downregulation of secreted frizzled-
which are dependent on pathways that may be lost in an envi- related protein 1 (SFRP1), a Wnt inhibitor, by cyclosporine
ronment altered by AGA160. As demonstrated by the use of A166. In hair follicles, SFRP1 regulates Wnt/β-catenin activity.
stem cell–conditioned media as a therapy in hair loss158,159, Using an SFRP1 antagonist (WAY-316606), the authors were
it is becoming increasingly clear that the environment that able to demonstrate enhanced hair regrowth ex vivo. Sildenafil,
the stem cell is exposed to is equally as important as the cell a phosphodiesterase 5 (PDE5) inhibitor, has been shown to
itself160. Indeed, both the cellular and acellular components of promote hair growth in mice. Sildenafil was found to
the physical environment of the stem cell are important and stimulate growth factor expression (VEGF and PDGF), upregu-
complicate in vitro analysis and the prediction of behaviour in late ERK phosphorylation and promote angiogenesis. Finally,
a degrading in vivo state. Therefore, the ability to model the 7-phloroeckol, a metabolite of a brown marine algae, has been
stem cell niche in vitro and predict efficacy in vivo remains a shown to stimulate DP cells and ORS cells in vitro, inducing
 Faculty Opinions Faculty Reviews 2022 11:(1)

IGF-1 and promoting hair growth in human hair follicles Abbreviations

in vitro167. ADSC, adipose-derived stem cell; AGA, androgenetic alopecia;
Akt, protein kinase B; APM, arrector pili muscle; BMP, bone
Conclusions morphogenic protein; CI, confidence interval; DHT, dihy-
Treatment of AGA remains a challenge and patients with drotestosterone; DP, dermal papilla; DSC, dermal sheath cup;
AGA often have a heterogenous response to treatment, partly ERK, extracellular signal-regulated kinase; FDA, US Food and
because the complex aetiopathogenesis, particularly in affected Drug Administration; FPHL, female pattern hair loss; hDF,
women, has not yet been fully elucidated. Intricate path- (activated) human dermal fibroblast; HSC, Hair Stimulating
ways regulate hair cycling and anagen duration and determine Complex; IGF-1, insulin-like growth factor 1; LLLT, low-level
hair growth. As we discover more about these pathways, we laser therapy; LV, lymphatic vessel; MPHL, male pattern hair
move into an era of a growing number of potential therapeutics loss; ORS, outer root sheath; PDGF, platelet-derived growth
for hair growth promotion. A number of ongoing clinical tri- factor; PDRN, polydeoxyribonucleotide; PG, prostaglandin;
als are exploring novel treatments; however, it is unlikely that PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGF2a,
one therapy alone will result in a desired, sustainable outcome. prostaglandin F2a; PRP, platelet-rich plasma; RCT, randomised
Combination therapy incorporating systemic therapy and adju- controlled trial; SFRP1, secreted frizzled-related protein 1;
vant procedural modalities (PRP, LLLT or fractional laser) TGF, transforming growth factor; TGF-b1, transforming growth
may well represent the optimal strategy to produce long-lasting factor b1; TGF-b2, transforming growth factor b2; VEGF,
results, prior to surgical considerations. vascular endothelial growth factor; VPA, topical valproic acid

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