ArticlePDF Available

Standardized Scalp Massage Results in Increased Hair Thickness by Inducing Stretching Forces to Dermal Papilla Cells in the Subcutaneous Tissue

Authors:

Abstract and Figures

Objective: In this study, we evaluated the effect of scalp massage on hair in Japanese males and the effect of stretching forces on human dermal papilla cells in vitro. Methods: Nine healthy men received 4 minutes of standardized scalp massage per day for 24 weeks using a scalp massage device. Total hair number, hair thickness, and hair growth rate were evaluated. The mechanical effect of scalp massage on subcutaneous tissue was analyzed using a finite element method. To evaluate the effect of mechanical forces, human dermal papilla cells were cultured using a 72-hour stretching cycle. Gene expression change was analyzed using DNA microarray analyses. In addition, expression of hair cycle-related genes including IL6, NOGGIN, BMP4, and SMAD4 were evaluated using real-time reverse transcription-polymerase chain reaction. Results: Standardized scalp massage resulted in increased hair thickness 24 weeks after initiation of massage (0.085 ± 0.003 mm vs 0.092 ± 0.001 mm). Finite element method showed that scalp massage caused z-direction displacement and von Mises stress on subcutaneous tissue. In vitro, DNA microarray showed gene expression change significantly compared with nonstretching human dermal papilla cells. A total of 2655 genes were upregulated and 2823 genes were downregulated. Real-time reverse transcription-polymerase chain reaction demonstrated increased expression of hair cycle-related genes such as NOGGIN, BMP4, SMAD4, and IL6ST and decrease in hair loss-related genes such as IL6. Conclusions: Stretching forces result in changes in gene expression in human dermal papilla cells. Standardized scalp massage is a way to transmit mechanical stress to human dermal papilla cells in subcutaneous tissue. Hair thickness was shown to increase with standardized scalp massage.
Content may be subject to copyright.
Standardized Scalp Massage Results in Increased
Hair Thickness by Inducing Stretching Forces to
Dermal Papilla Cells in the Subcutaneous Tissue
Taro Koyama, PhD, MD,a,b Kazuhiro Kobayashi, MD,aTakanori Hama,cKasumi
Murakami,cand Rei Ogawa, PhD, MDb
aMen’s Health Clinic Tokyo, Tokyo, Japan; bDepartment of Plastic, Reconstructive and Aesthetic
Surgery, Nippon Medical School, Tokyo, Japan; and cANGFA Co, Ltd, Tokyo, Japan
Correspondence: t-koyama@menshealth-tokyo.com
Keywords: hair, dermal papilla cells, scalp massage, mechanobiology, stretching force
Published January 25, 2016
Objective: In this study, we evaluated the effect of scalp massage on hair in Japanese
males and the effect of stretching forces on human dermal papilla cells in vitro.
Methods: Nine healthy men received 4 minutes of standardized scalp massage per
day for 24 weeks using a scalp massage device. Total hair number, hair thickness, and
hair growth rate were evaluated. The mechanical effect of scalp massage on subcutaneous
tissue was analyzed using a finite element method. To evaluate the effect of mechanical
forces, human dermal papilla cells were cultured using a 72-hour stretching cycle. Gene
expression change was analyzed using DNA microarray analyses. In addition, expression
of hair cycle-related genes including IL6, NOGGIN, BMP4, and SMAD4 were evaluated
using real-time reverse transcription-polymerase chain reaction. Results: Standardized
scalp massage resulted in increased hair thickness 24 weeks after initiation of massage
(0.085 ±0.003 mm vs 0.092 ±0.001 mm). Finite element method showed that scalp
massage caused z-direction displacement and von Mises stress on subcutaneous tis-
sue. In vitro, DNA microarray showed gene expression change significantly compared
with nonstretching human dermal papilla cells. A total of 2655 genes were upregulated
and 2823 genes were downregulated. Real-time reverse transcription-polymerase chain
reaction demonstrated increased expression of hair cycle–related genes such as NOG-
GIN, BMP4, SMAD4, and IL6ST and decrease in hair loss–related genes such as IL6.
Conclusions: Stretching forces result in changes in gene expression in human dermal
papilla cells. Standardized scalp massage is a way to transmit mechanical stress to hu-
man dermal papilla cells in subcutaneous tissue. Hair thickness was shown to increase
with standardized scalp massage.
This study was funded in part by ANGFA Co, Ltd.
53
ePlasty VOLUME 16
Aging results in a decrease in the total number and thickness of hair, termed andro-
genetic alopecia (AGA) in the male and female pattern hair loss (FPHL) in the female
population.1Both represent a major concern in appearance in the affected population.
Finasteride, an oral 5-αreductase inhibitor, is an effective drug to prevent progression
of AGA.2Minoxidil, an ATP-sensitive potassium channel opener, enhances hair growth
in both AGA and FPHL.3,4 While these medications are effective, some patients are not
completely satisfied with the results. Moreover, many patients are hesitant to start medica-
tion or consider their hair loss as not severe enough to start medication. Therefore, many
people turn toward supplements, hair care products, and scalp massage with the expectancy
to increase hair growth. Scalp massage, in addition to having a relaxing effect, results in
increased blood flow and skin softening.5Therefore, patients have the notion that it can
also increase hair growth rates. However, the effect of scalp massage on hair growth has
not been evaluated in sound clinical trials and its effect remains unclear.6
Organs, tissues, and cells are constantly exposed to mechanical forces and subsequently
react to them. For example, blood vessels are subject to shear stress of blood flow, bones
receive pressure due to weight bearing, cartilage is exposed to hydrostatic pressure by
weight bearing, and hypertrophic scars develop with increased tension to the wound.7We
hypothesize that scalp massage is a way to deliver mechanical forces to the scalp including
epidermis, dermis, skin appendages, blood vessels, and nerves. In this study, we evaluated
the effect of scalp massage on hair number, thickness, and growth rate. We also used
finite element method (FEM) to analyze the mechanical effect of scalp massage on the
subcutaneous tissue and the dermal papilla cells in the hair follicle. Finally, we evaluated
the effect of mechanical forces on human dermal papilla cells (hDPCs), which play an
important role in hair growth due to interaction with hair matrix cells. Mechanical stress to
the scalp was applied via stretching forces by scalp massage.
MATERIALS AND METHODS
Effect of scalp massage on human hair in 9 healthy men
Nine healthy Japanese men aged 25 to 46 (mean ±SD =34.8 ±8) years participated in
the study. The study subjects showed no obvious hair loss. In the study, they received scalp
massage using a scalp massage device, Panasonic EH-HM75 (Panasonic, Osaka, Japan),
on one side of their temporal scalp every day for 4 minutes at 170 rpm. International
10-20 system for electroencephalography was used to define the area for scalp massage
(Fig 1). The symmetrical position on the contralateral side served as a control without any
massage treatment. The massage and control sides were chosen randomly for each subject.
Total hair number, thickness, and growth speed were measured at 0, 4, 12, and 24 weeks
following initiation of massage. The massage area and the control area were clipped prior
to measurement of hair count and hair thickness. Three days after clipping, hair length was
measured to evaluate the hair growth rate. A folliscope (LeadM Corporation, Seoul, Korea)
was used for measurement. Each parameter in the massage area and the control area was
compared with the initial point. The tenets of the Declaration of Helsinki were followed,
and the written informed consent was obtained from the volunteers.
54
KOYAM A E T AL
Tabl e 1 . Mechanical property of scalp for finite element method analysis
Mechanical property
Thickness, mm Young modulus, MPa Poisson ratio
Epidermis 0.0614 0.85 0.4
Dermis 1.4643 0.85 0.4
Subcutaneous tissue 1.9289 0.182 0.4
Galea 1.5569 0.85 0.4
Skull 6.1 17,000 0.25
Figure 1. C3 and C4 determined by International 10-20 sys-
tem for electroencephalography were applied for the massage
area and the control area.
Effect of scalp massage on subcutaneous tissue using FEM
The geometry of the scalp massage device and scalp was reproduced to evaluate the me-
chanical effect of scalp massage to subcutaneous tissue by using KSWAD Ver 7.10 (Kubota
System Inc, Osaka, Japan) and ADVENTURECluster Win Ver4.5 (Allied Engineering Cor-
poration, Tokyo, Japan). The scalp was divided into 5 layers including epidermis, dermis,
subcutaneous tissue, galea, and bone. We set mechanical property of thickness, Young mod-
ulus, and Poisson ratio in each layer from previous reports (Table 1). Composite component
displacement of the skin surface, z-direction displacement of the subcutaneous tissue, and
von Mises stress of the subcutaneous tissue were analyzed.
Cell cultures
Human dermal papilla cells (ScienCell Research Laboratories, Carlsbad, CA) were thawed
according to manufacturer’s instructions and plated at a density of 2500 cells/cm2in
55
ePlasty VOLUME 16
10 mL of culture media comprising Dulbecco’s Modified Eagle Medium supplemented
with 10% fetal bovine serum (Thermo Fisher Scientific, Waltham, MA) and 1% Antibiotic-
Antimycotic (Thermo Fisher Scientific, Waltham, MA). The cells were expanded at 37C
with 5% CO2and 90% humidity until they reached 80% to 90% confluence. At passages
3, the hDPCs were seeded into a silicone chamber at a density of 1 ×105cells/chamber.
The chamber measured 32 ×32 ×10 mm in dimensions and consisted of a 400-mm-thick
outer wall and a 200-mm-thick membrane bottom.
Application of mechanical stretch
To generate the stretch group, the hDPCs were allowed to attach for 24 hours to the chamber
surface in 5 mL of culture medium. After changing the medium, the silicon chambers
were attached to a stretching apparatus driven by a computer-controlled step motor (STB-
140; Strex Ltd, Osaka, Japan). Continuous uniaxial sinusoidal stretch (10 cycles/min) was
applied at 37C, 5% CO2for 72 hours. The stretching stimulation was set at 20% stretch.
To generate the control group, the culture medium was changed and the silicon chambers
were incubated as described earlier for 72 hours without stretching.
DNA microarray analysis
RNA was isolated by using standard RNA extraction protocols (NucleoSpin_ RNAII), and
its quality was checked using the Agilent 2100 Bioanalyzer platform (Agilent Technologies,
Santa Clara, Calif) through gel imaging and with an electropherogram. Each total RNA
sample (100 ng) was used for linear T7-based amplification. The resulting cRNA (comple-
mentary RNA) was measured by using a ND-1000 spectrophotometer (Thermo NanoDrop,
Wilmington, Del). The control samples were labeled with Cy3, whereas the experimental
samples were labeled with Cy5. Hybridization was performed using the Agilent Gene Ex-
pression Hybridization Kit (Agilent Technologies). The fluorescence signals generated by
the hybridized Agilent oligo microarrays were detected using the Agilent DNA microarray
scanner (Agilent Technologies). The data were extracted from images using the Agilent
Feature Extraction Software.
Gene expression evaluation using real-time reverse transcription-polymerase chain
reaction
Real-time polymerase chain reaction (PCR) was performed using a standard TaqMan PCR
kit protocol on an Applied Biosystems 7900HT Sequence Detection System (P/N: 4329002;
Applied Biosystems, Carlsbad, CA). The 10 μL PCR solution included 0.67 μLofRT
product, 1×TaqMan Universal PCR Master Mix (P/N: 4324018; Applied Biosystems),
0.2 μM TaqMan probe, 1.5 μM forward primer, and 0.7 μM reverse primer. The incu-
bation reactions were performed in a 384-well plate at 95C for 10 minutes, followed by
40 cycles of 95C for 15 seconds and 60C for 1 minute. All reactions were run in trip-
licate. The threshold cycle (CT) is defined as the fractional cycle number at which the
fluorescence passes the fixed threshold. TaqMan CT values were converted into absolute
copy numbers using a standard curve. GAPDH (glyceraldehyde-3-phosphate dehydroge-
nase) served as the internal control. The following primers were used: Homo sapiens bone
56
KOYAM A E T AL
morphogenetic protein 4 (BMP4), transcript variant 1, mRNA [NM_001202], Homo sapi-
ens NOGGIN (NOG), mRNA [NM_005450], Homo sapiens SMAD family member 4
(SMAD4), mRNA [NM_005359], Homo sapiens interleukin 6 (interferon, beta 2) (IL6),
mRNA [NM_000600], Homo sapiens interleukin 6 signal transducer (gp130, oncostatin
M receptor) (IL6ST), transcript variant 1, mRNA [NM_002184]. Relative expression was
calculated using the 2−Ct method with a correction for different amplification efficiencies.
Statistical analysis
A Man-Whitney Utest was used for comparison of total hair counts, hair thickness, and
hair growth rate between the scalp massage area and the control area. In experiments
using microarray and real-time reverse transcription (RT)-PCR, statistical comparisons
were carried out by means of analysis of variance. Results were considered significant
when Pvalue was less than .05.
RESULTS
Effect of scalp massage on human hair in 9 healthy men
The control area showed no significant change in hair count, hair thickness, and hair growth
rate throughout the 24-week study period (Figs 2–4). The scalp massage area showed no
significant change in the hair growth rate throughout the study period (Fig 4). However, the
scalp massage area showed a significant increase in hair thickness at 24 weeks compared
with the initiation point (0.085 ±0.003 mm vs 0.092 ±0.001 mm) and significant decrease
in hair count at 12 weeks (163.889 ±7.237/cm2vs 155.500 ±5.607/cm2) (Figs 2 and 3).
Effect of scalp massage on subcutaneous tissue using FEM
Finite element method demonstrated that scalp massage resulted in horizontal movement
of skin surface and z-direction displacement of the subcutaneous tissue (Figs 5 and 6);
z-direction displacement shows a wave pattern. The maximum von Mises stress was shown
in the center of the displaced area (Fig 7).
DNA microarray analyses
Following 72 hours of stretching hDPCs, 2655 genes were upregulated and 2823 genes were
downregulated more than 2.0-fold compared with genes in the control group (Table 2).
Gene expression evaluation using real-time RT-PCR
Among the genes screened by microarray analysis, hair cycle–related genes including
BMP4, NOGGIN, SMAD4, IL6, and IL6ST were tested using real-time RT-PCR. IL6
was downregulated in hDPCs after 72 hours of stretching compared with control cells,
and BMP4, NOGGIN, SMAD4, and IL6ST were upregulated in hDPCs after 72 hours of
stretching when compared with control cells (Fig 8).
57
ePlasty VOLUME 16
Figure 2. Change from baseline in hair density. Throughout the 24-week study period, hair density
showed no significant difference between the massage area and the control area. Hair density in
the massage area showed significant decrease at 12 weeks compared with baseline (163.889 ±
7.237/cm2vs 155.500 ±5.607/cm2). Hair density in the control area showed no significant change
at any point compared with baseline.
DISCUSSION
Mechanobiology and mechanotherapy
At the cellular level, cells can change shape, and molecules are transferred into and out of the
cell through the cell membrane. These processes are all driven by mechanical forces, which
activate molecular cascades within the cells that alter gene expression and thereby play an
important role in the life cycle of the cell. “Mechanobiology” is the study of those molecular
cascades and cellular responses: key questions relate to how cells sense and respond to the
mechanical forces of the physical microenvironment. A more comprehensive and improved
understanding of mechanobiology may greatly facilitate the development of new therapies
that control mechanical forces and thereby specifically induce desired molecular, cellular,
tissue, and/or organ formation, changes, or repair. Recently, we denoted these therapies as
“mechanotherapies.” While the term “mechanotherapy” was originally synonymous with
physical therapy, massotherapy, and the rehabilitation of musculoskeletal systems, our new
definition reflects the multidimensional medical possibilities of the field now. An example
of potential mechanotherapies was recently proposed by our article,8which suggested that
various skin disorders, including keloids, can be treated by mechanobiological methods.
Moreover, mechanobiology-mediated medicine could be used to analyze and/or treat many
disorders/diseases, accelerate wound healing, reduce scarring during wound healing, and
repair and regenerate injured/aged tissues and organs.7
58
KOYAM A E T AL
Figure 3. Change from baseline in hair thickness. Throughout the 24-week study period, hair
thickness showed no significant difference between the massage area and the control area. Hair
thickness in the massage area showed significant increase at 12 weeks compared with baseline
(0.085 ±0.003 mm vs 0.092 ±0.001 mm). Hair thickness in the control area showed no significant
change at any point compared with baseline.
Figure 4. Change from baseline in hair growth rate. Throughout the 24-week study period, hair
growth rate showed no significant difference between the massage area and the control area. In
addition, hair growth rate both in the massage area and in the control area showed no significant
change at any point compared with baseline.
59
ePlasty VOLUME 16
At present, we are studying mechanobiology and mechanotherapy at both the basic
research and clinical levels. Specifically, we are searching for methods to regenerate nail
and hair and are conducting research in the medical fields of aesthetics and antiaging.9
Figure 5. Image demonstrating horizontal skin surface (green) movement with the scalp massage
device (red).
Mechanotherapy for hair: Effects of scalp massage
Hair number decreased in the massage area at 12 weeks after initiation of standardized
scalp massage. Some telogen hair in the massage area might have fallen by scalp massage
and decrease in the number of hair occurred temporarily. On the contrary, hair thickness
increased significantly at 24 weeks after initiation of standardized scalp massage. Im-
provement in blood flow is one possible explanation for hair thickness improvement as
previously reported10; however, this was not evaluated in the current study. In addition to an
increase in blood flow, direct stimulation of mechanical force to dermal papilla cells would
be another explanation for increased hair thickness. Using FEM, we demonstrated that
z-direction displacement of subcutaneous tissue including dermal papilla cells was initiated
by standardized scalp massage. We also demonstrated that mechanical stress such as von
Mises stress was transmitted to the subcutaneous tissue layer. We did not perform tissue
biopsies following scalp massage and therefore were not able to analyze any histological
changes in hair follicles after scalp massage; however, we could show that stretching forces
changed the gene expression in hDPCs in vitro. These genes included hair cycle–related
genes such as IL6, IL6ST, BMP4, NOGGIN, and SMAD4.11-13 Therefore, scalp massage
could have the potential to influence hDPCs via stretching the scalp skin. Mechanical stress
60
KOYAM A E T AL
has been reported to influence various signaling pathways in many different cell groups.
For example, stretching forces have been shown to stimulate Wnt signaling in dermal fi-
broblasts as well as in bone.14,15 In hair follicles, Wnt signaling accelerated the anagen
phase of the hair cycle.16,17 In addition, ATP-sensitive potassium channels in the atrium
have been shown to be mechanosensitive.18 Minoxidil used as hair growth medication is an
ATP-sensitive potassium channel opener that works on ATP-sensitive potassium channels
in dermal papilla cells.19 If optimal stretching forces in hair follicles are applied for an
appropriate time period to stimulate hair growth genes selectively, mechanical forces could
be useful in hair tissue engineering. Moreover, scalp massage as a form of mechanical
stimulation of the scalp may become a natural, easy, and economical way to stimulate hair
growth rates. Further research is required to confirm these possibilities.
Figure 6. z-direction displacement occurred in subcutaneous tissue like a wave, whereas the scalp
massage device shows movement of skin surface only in x-direction.
CONCLUSION
We demonstrated changes in gene expression in hDPCs following application of stretching
forces in vitro. By FEM analysis, scalp massage has been shown to induce mechanical
stress on hDPCs. Hair thickness increased following standardized scalp massage in healthy
Japanese men.
61
ePlasty VOLUME 16
Figure 7. von Mises stress occurred in subcutaneous tissue. Stress is the highest in the middle of
the wave.
Figure 8. IL6 was downregulated in stretching hDPCs compared with control cells. BMP4,
NOGGIN, SMAD4, and IL6ST were upregulated in stretching hDPCs compared with control cells.
hDPCs indicates human dermal papilla cells.
62
KOYAM A E T AL
Tabl e 2 . Up- and downregulated genes related to
hair cycle in human hair dermal papilla cells in
response to 72 -hour stretching determined by mi-
croarray hybridization
Upregulated genes
WNT1 6.65
FGF9 6.23
VEGF-D 5.38
FGF12 5.14
BMP4 4.29
WISP1 (WNT inducible signal. path. protein) 4.26
HBEGF (heparin-binding EGF-like GF) 3.36
PGF (placental growth factor) 3.36
PDGF-D 2.66
TNFaSF11b 2.52
TNFaSF10a 2.57
TNFaSF11a 2.59
WNT11 2.42
TGFbR3 2.29
VEGF-C 2.04
Downregulated genes
IL6 2.69
FGF7 2.39
PDGF-A 2.34
TNFaIP2 2.19
TNFaIP8 2.11
REFERENCES
1. Lee WS, Ro BI, Hong SP, et al. A new classification of pattern hair loss that is universal for men and
women: basic and specific (BASP) classification. J Am Acad Dermatol. 2007;57(1):37-46.
2. Kaufman KD, Rotonda J, Shah AK, Meehan AG. Long-term treatment with finasteride 1 mg decreases the
likelihood of developing further visible hair loss in men with androgenetic alopecia (male pattern hair loss).
Euro J Dermatol. 2008;18(4):400-6.
3. Tsuboi R, Arano O, Nishikawa T, Yamada H, Katsuoka K. Randomized clinical trial comparing 5% and 1%
topical minoxidil for the treatment of androgenetic alopecia in Japanese men. J Dermatol. 2009;36(8):437-
46.
4. Dinh QQ, Sinclair R. Female pattern hair loss: current treatment concepts. Clin Interv Aging. 2007;2(2):189-
99.
5. Ando T, Takeda M, Maruyama T, et al. 2013. Biosignal-based relaxation evaluation of head-care robot.
Annual International Conference of the IEEE Engineering in Medicine and Biology Society. Piscataway,
NJ:IEEE Engineering in Medicine and Biology Society, pp. 6732-5.
6. Hoffmann R, Happle R. Current understanding of androgenetic alopecia, part II: clinical aspects and
treatment. Eur J Dermatol. 2000;10(5):410-7.
7. Wong VW, Akaishi S, Longaker MT, Gurtner GC. Pushing back: wound mechanotransduction in repair
and regeneration. J Invest Dermatol. 2011;131(11):2186-96.
8. Huang C, Ogawa R. Fibroproliferative disorders and their mechanobiology. Connect Tissue Res.
2012;53(3):187-96.
9. Sano H, Shionoya K, Ogawa R. Finger nail configuration is influenced by mechanical forces on finger pads.
J Dermatol. 2013;40(12):1056-7.
10. Lewallen R, Francis S, Fisher B, et al. Hair care practices and structural evaluation of scalp and hair shaft
parameters in African American and Caucasian women. J Cosmetic Dermatol. 2015;14(3):216-23.
63
ePlasty VOLUME 16
11. Plikus MV, Mayer JA, de la Cruz D, et al. Cyclic dermal BMP signalling regulates stem cell activation
during hair regeneration. Nature. 2008;451(7176):340-4.
12. Solanas G, Benitah SA. Regenerating the skin: a task for the heterogeneous stem cell pool and surrounding
niche. NatRevMolCellBiol.2013;14(11):737-48.
13. Kwack MH, Ahn JS, Kim MK, Kim JC, Sung YK. Dihydrotestosterone-inducible IL-6 inhibits elongation
of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in
mice. J Invest Dermatol. 2012;132(1):43-9.
14. Huang C, Miyazaki K, Akaishi S, Watanabe A, Hyakusoku H, Ogawa R. Biological effects of cellular
stretch on human dermal fibroblasts. J Plast Reconstr Aesthet Surg. 2013;66(12):e351-61.
15. Lau KH, Kapur S, Kesavan C, Baylink DJ. Up-regulation of the Wnt, estrogen receptor, insulin-like
growth factor-I, and bone morphogenetic protein pathways in C57BL/6J osteoblasts as opposed to
C3H/HeJ osteoblasts in part contributes to the differential anabolic response to fluid shear. J Biol Chem.
2006;281(14):9576-88.
16. Andl T, Reddy ST, Gaddapara T. Millar SE. WNT signals are required for the initiation of hair follicle
development. Dev Cell. 2002;2(5):643-53.
17. Kishimoto J, Burgeson RE, Morgan BA. Wnt signaling maintains the hair-inducing activity of the dermal
papilla. Genes Dev. 2000;14(10):1181-5.
18. Van Wagoner DR. Mechanosensitive gating of atrial ATP-sensitive potassium channels. Circ Res.
1993;72(5):973-83.
19. Shorter K, Farjo NP, Picksley SM, Randall VA. Human hair follicles contain two forms of ATP-sensitive
potassium channels, only one of which is sensitive to minoxidil. FA S E B J . 2008;22(6):1725-36.
64
... When exposed to mechanical force, cells respond in a dose-dependent manner by altering gene expression to initiate cellular damage or repair [13]. Mechanotherapy is the manipulation of cellular responses by way of stretching, contraction, or compression for therapeutic effect [14]. Depending on the device, duration, and technique, soft tissue manipulation may activate wound-healing and mechanotherapeutic mechanisms to elicit positive outcomes in a variety of disorders. ...
... In humans, cyclical tissue stretch-and compression-based therapies decrease scar thickness and improve skin elasticity following soft tissue injury [18]. Interestingly, standardized scalp massages (SSMs) increase hair thickness in nonbalding men [14]. Human scalp DP cell stretching in vitro upregulates anagen-associated noggin, SMAD4, interleukin 6 signal transducer, and bone morphogenetic protein 4 while downregulating catagen-associated interleukin 6 [14]. ...
... Interestingly, standardized scalp massages (SSMs) increase hair thickness in nonbalding men [14]. Human scalp DP cell stretching in vitro upregulates anagen-associated noggin, SMAD4, interleukin 6 signal transducer, and bone morphogenetic protein 4 while downregulating catagen-associated interleukin 6 [14]. However, the effects of SSMs on AGA have not yet been investigated. ...
Article
Full-text available
Introduction Standardized scalp massages (SSMs) improve hair thickness in nonbalding men, but their effects on androgenic alopecia (AGA) have not yet been evaluated. The objective of this study was to investigate the effect of SSMs on self-assessed AGA sufferers (SAGASs). Methods Between October 2016 and October 2017, 1899 SAGASs searching online for hair loss treatments beyond AGA management drugs accessed literature explaining SSMs as a potential therapy for AGA, then watched a demonstration video detailing twice-daily, 20-min SSMs segmented by three rotational scalp regions using hand-generated presses, pinches, and stretches. In December 2017, SAGASs were contacted once to participate in a retrospective survey study to assess SSM adherence and hair changes. Age, gender, hair loss region and gradient, diet, supplement and topical use, AGA management drug use, estimations for minutes daily and months of massaging, and self-perceived hair changes were reported. Some participants also submitted photosets documenting hair changes throughout SSM adherence. Results A total of 340 (17.9%) respondents completed the survey, and 327 (17.2%) reported attempting the SSMs. SSM participants reported a median daily massage effort of 11–20 min and mean adherence of 7.4 ± 6.6 months, with 68.9% reporting hair loss stabilization or regrowth. Estimated minutes daily, months, and total SSM effort (i.e., minutes daily × months) were positively associated with self-perceived hair changes. On average, perceived hair loss stabilization and regrowth occurred after 36.3 h of SSM effort. Results did not vary across age, gender, Norwood gradient, or concomitant supplement, topical, finasteride, minoxidil, or microneedling use. However, hair change improvements were marginally lower for participants reporting diffuse versus frontal/temporal or vertex thinning. Conclusions While further research is warranted, these results align with previous findings and suggest the potential for SSMs to improve AGA.
... Activation of transient receptor potential cation channel, subfamily V, member 1, which involves mechanical transduction processes, also inhibits hair shaft lengthening and induces a premature catagen phase [79]. With continuous cyclic stretch, human dermal papilla (DP) cells demonstrated upregulation of hair cycle-related genes and downregulation of hair loss-related genes [80]. Hair bulge stem cells, via nephronectin expression, create a niche for the attachment of arrector pili muscles (APM) and might be impacted by the contractile forces of smooth muscles [81]. ...
... In addition, AGA subjects injected with botulinum toxin into the muscles surrounding the scalp showed increased hair counts between baseline and week 48 [85]. Scalp massage resulted in increased hair thickness in 24 weeks [80]. Ultrastructurally thickening of perifollicular dermal sheath results from increased deposition of collagen observed in advanced AGA cases [86]. ...
Article
Mechanical forces are known to regulate homeostasis of the skin and play a role in the pathogenesis of skin diseases. The epidermis consists of keratinocytes that are tightly adhered to each other by cell junctions. Defects in keratins or desmosomal/hemidesmosomal proteins lead to the attenuation of mechanical strength and formation of intraepidermal blisters in the case of epidermolysis bullosa simplex. The dermis is rich in extracellular matrix, especially collagen, and provides the majority of tensile force in the skin. Keloid and hypertrophic scar, which is the result of over-production of collagen by fibroblasts during the wound healing, are associated with extrinsic tensile forces and changes of intrinsic mechanical properties of the cell. Increasing evidences shows that stiffness of the skin environment determines the regenerative ability during wound healing process. Mechanotransduction pathways are also involved in the morphogenesis and cyclic growth of hair follicles. The development of androgenetic alopecia is correlated to tensile forces generated by the fibrous tissue underlying the scalp. Acral melanoma predominantly occurs in the weight-bearing area of the foot suggesting the role of mechanical stress. Increased dermal stiffness from fibrosis might be the cause of recessive dystrophic epidermolysis bullosa associated squamous cell carcinoma. Strategies to change the mechanical forces or modify the mechanotransduction signals may lead to a new way to treat skin diseases and promote skin regeneration.
... Hair loss is a result of hair thinning. The dermal papilla (DP), which is located at the base of the hair follicle, plays a crucial role in regulating hair shaft thickness [1][2][3]. The roles of growth factors in this process have received considerable attention recently. ...
Article
Full-text available
Dermal papilla cells (DPCs) are growth factor reservoirs that are specialized for hair morphogenesis and regeneration. Due to their essential role in hair growth, DPCs are commonly used as an in vitro model to investigate the effects of hair growth-regulating compounds and their molecular mechanisms of action. Cyclic adenosine monophosphate (cAMP), an intracellular second messenger, is currently employed as a growth-promoting target molecule. In a pilot test, we found that α-phellandrene, a naturally occurring phytochemical, increased cAMP levels in DPCs. Therefore, we sought to determine whether α-phellandrene increases growth factors and proliferation in human DPCs and to identify the underlying mechanisms. We demonstrated that α-phellandrene promotes cell proliferation concentration-dependently. In addition, it increases the cAMP downstream effectors, such as protein kinase A catalytic subunit (PKA Cα) and phosphorylated cAMP-responsive element-binding protein (CREB). Also, among the CREB-dependent growth factor candidates, we identified that α-phellandrene selectively upregulated vascular endothelial growth factor (VEGF) mRNA expression in DPCs. Notably, the beneficial effects of α-phellandrene were nullified by a cAMP inhibitor. This study demonstrated the cAMP-mediated growth effects in DPCs and the therapeutic potential of α-phellandrene for preventing hair loss.
... For instance, hypertrophic and keloids scars are dermal fibroproliferative diseases that are defined by chronically inflamed scars. There is strong evidence that the positional microenvironment, mechanical force distribution, in particular, have a pivotal role in the expansion of these scars [129]. Hence, it has been assumed that the creation of hypertrophic and keloids scars is driven by the shortage of mechanosignaling pathway. ...
Article
Mechano-transduction is the procedure of mechanical stimulus translation via cells, among substrate shear flow, topography, and stiffness into a biochemical answer. TAZ and YAP are transcriptional coactivators which are recognized as relay proteins that promote mechano-transduction within the Hippo pathway. With regard to healthy cells in homeostasis, mechano-transduction regularly restricts proliferation, and TAZ and YAP are totally inactive. During cancer development a YAP/TAZ - stimulating positive response loop is formed between the growing tumor and the stiffening ECM. As tumor developments, local stromal and cancerous cells take advantage of mechanotransduction to enhance proliferation, induce their migratory into remote tissues, and promote chemotherapeutic resistance. As a newly progresses paradigm, nanoparticle-conjunctions (such as magnetic nanoparticles, and graphene derivatives nanoparticles) hold significant promises for remote regulation of cells and their relevant events at molecular scale. Despite outstanding developments in employing nanoparticles for drug targeting studies, the role of nanoparticles on cellular behaviors (proliferation, migration, and differentiation) has still required more evaluations in the field of mechanotherapy. In this paper, the in-depth contribution of mechano-transduction is discussed during tumor progression, and how these consequences can be evaluated in vitro.
... This limitation made the findings insufficient in proving the absolute effects of ADSC-CM on hair regeneration because manual stimulation, by itself, has a certain effect on hair growth by helping blood flow in the applied area. 34 Therefore, a slight increase in hair density (+7.1%) and hair diameter (+6.3%) was observed in CG in this study after 16 weeks of the intervention. ...
Article
Full-text available
Accumulating evidence suggests that adipose-derived stem cell constituent extract (ADSC-CE) helps hair regrowth in patients with androgenetic alopecia (AGA). However, the effects of ADSC-CE have not been demonstrated in a randomized, double-blind, vehicle-controlled clinical trial. In this randomized, double-blind, vehicle-controlled clinical trial, 38 patients (29 men) with AGA were assigned to an intervention group (IG), with twice-daily self-application of the ADSC-CE topical solution over the scalp with fingers, or to a control group (CG). Changes in hair count and thickness at 16 weeks from the baseline were evaluated using a phototrichogram. Overall, 34 (89%) patients (mean age, 45.3 years) completed the study. The phototrichogram at week 8 showed more increase in hair count in the IG than in the CG, and intergroup differences in the change of hair count remained significant until week 16 with overall changes of 28.1% vs 7.1%, respectively. Similarly, a significant improvement in hair diameter was observed in the IG (14.2%) after 16 weeks when compared with hair diameter in the CG (6.3%). Our findings suggest that the application of the ADSC-CE topical solution has enormous potential as an alternative therapeutic strategy for hair regrowth in patients with AGA, by increasing both hair density and thickness while maintaining adequate treatment safety. Significance statement This study suggests the application of adipose-derived stem cell constituent extract topical solution has the potential as an alternative therapeutic strategy for hair regrowth in patients with androgenetic alopecia by increasing both hair density and thickness while maintaining adequate treatment safety.
... Scalp massage with localized pressure points has been identified as a method to increase blood perfusion. 28,29 Therefore, similar biomechanical mechanism may contribute to increase the blood perfusion in the plantar soft tissue. To test this hypothesis, in this study TLS that can be 3D printed in the form of dense flexible fibers were utilized. ...
Article
Objective Improving perfusion under the skin can potentially reduce ulceration and amputation risk in people with diabetic foot. Localised pressure stimulation has been proven capable of improving skin perfusion in the scalp but its effectiveness for the foot has not been tested. In this study, localised pressure stimulation was realised using flexible turf‐like structures with dense vertical fibres and their ability to increase perfusion was assessed. Methods The skin in the rear‐foot, mid‐foot and forefoot of nine healthy volunteers was stimulated using two turf‐like structures with different stiffness and one wound filler material that generated a uniform compression. Changes in perfusion were assessed using laser speckle. Results Mechanical stimulation significantly increased perfusion in the forefoot and mid‐foot areas with the turf‐like structures achieving higher and more long‐lasting increase compared to the wound filler. The stiffer of the two turf‐like structure appeared to be the most effective for the forefoot achieving a significant increase in perfusion that lasted for 25.5s immediately after stimulation. Conclusion The results of this study indicate that localised pressure stimulation is a more effective compared to uniform compression for improving skin perfusion in the healthy foot. Further research in people with diabetic foot disease is needed to verify the clinical value of the observed effect. This article is protected by copyright. All rights reserved.
... Standardized scalp massage is a way to transmit mechanical stress to human dermal papilla cells in subcutaneous tissue. 22 Similarly, shiro abhyanga practiced in Ayurveda consists of soft and gentle massage of the scalp by finger tips was conducted in two parts of 400 matrakala each. The first part consists of shiro abhyanga of right and left parietal regions. ...
Article
Sweet potato shochu oil is one of the by-products of sweet potato shochu production. We investigated the functionality and industrial use of shochu oil as a food-derived raw material. Because of the increased incidence of self-consciousness in people owing to thinning hair, in this study, we examined the hair growth-inducing effects of shochu oil. Minoxidil, the only topical medication approved for hair growth treatment in Japan, was used as a control for the evaluation of hair growth-promoting activity of shochu oil. Human follicle dermal papilla cells treated with shochu oil showed upregulated expression of vascular endothelial growth factor in a concentration-dependent manner, indicating that shochu oil induced the activation of the hair growth cycle. In vivo, epidermal treatment with shochu oil also promoted hair growth in C3H mice. More than 35 components were detected in shochu oil via gas chromatography–mass spectrometry. The main components, accounting for 98.5% of shochu oil, were as follows, in order of decreasing concentration: ethyl palmitate, ethyl linoleate, ethyl oleate, ethyl stearate, ethyl caprate, ethyl laurate, ethyl myristate, and ethyl α-linolenate. Among these, ethyl palmitate, ethyl linoleate, and ethyl α-linolenate promoted hair growth in C3H mice. These results indicate that shochu oil can be used as a hair restorer. To the best of our knowledge, this study is the first to demonstrate the hair growth-promoting activity of shochu oil.
Article
Advances in skin regeneration have resulted in techniques and products that have allowed regeneration of both the dermis and epidermis. Yet complete skin regeneration requires the adnexal skin structures. Thus it is crucial to understand the regenerative potential of hair follicles where genetic, nutritional, and hormonal influences have important effects and are critical for skin regeneration. The follicular stem cell niche serves as an anatomical compartment, a structural unit, a functional integrator, and a dynamic regulator necessary to sustain internal homeostasis and respond to outside stimuli. In particular, mechanics such as pressure, compression, friction, traction, stretch, shear, and mechanical wounding can influence hair loss or growth. Relevant niche signaling pathways such as Wnt, bone morphogenetic protein, fibroblast growth factor, Shh, and Notch may yield potential targets for therapeutic interventions.
Article
The formation of the hair follicle and its cyclical growth, quiescence, and regeneration depend on reciprocal signaling between its epidermal and dermal components. The dermal organizing center, the dermal papilla (DP), regulates development of the epidermal follicle and is dependent on signals from the epidermis for its development and maintenance. GFP specifically expressed in DP cells of a transgenic mouse was used to purify this population and study the signals required to maintain it. We demonstrate that specific Wnts, but not Sonic hedgehog (Shh), maintain anagen-phase gene expression in vitro and hair inductive activity in a skin reconstitution assay.
Article
How African American hair fragility relates to hair care practices and biologic differences between races is not well understood. To assess the differences between perceptions of hair health, hair care practices, and several biologic hair parameters between Caucasian and African American women. A questionnaire on perceptions of hair health and hair care practices was administered. Biological and structural parameters of hair shaft and scalp, including growth, density, diameter, cycle, breakage, and scalp blood flow were also assessed in this case-control study. Significant differences between the Caucasian and African American women were observed in the questionnaire and biologic study data. Regarding self-reported perceptions of hair health, there were differences in the following: hair shaft type (P < 0.001), hair breakage (P = 0.040), and desire to change hair (P = 0.001). Regarding self-reported hair care practices, there were differences in the following: location of haircutting (P = 0.002) and washing (P = 0.010), washing frequency (P < 0.001), chemical relaxer use (P < 0.001), hooded hair dryer use (P < 0.001), and hair shaft conditioner use (P = 0.005). The two groups had similar practices in regard to the use of hair color, frequency of hair color use, chemical curling agents, and handheld blow dryer use. Regarding biological and structural parameters, there were differences in the following: hair growth rate (P < 0.001), density (P = 0.0016), diameter (P = 0.01), number of broken hairs (P < 0.001), and blood flow (P = 0.03). There was no significant difference in hair cycle parameters.The differences in hair care practices and hair fiber morphology among African American women may contribute to clinically observed variation in hair fragility and growth. © 2015 Wiley Periodicals, Inc.
Article
Such popular head care procedures as shampooing and scalp massages provide physical and mental relaxation. However, they place a big burden such as chapped hands on beauticians and other practitioners. Based on our robot hand technology, we have been developing a head care robot. In this paper, we quantitatively evaluated its relaxation effect using the following biosignals: accelerated plethymography (SDNN, HF/TP, LF/HF), heart rate (HR), blood pressure, salivary amylase (sAA) and peripheral skin temperature (PST). We compared the relaxation of our developed head care robot with the head care provided by nurses. In our experimental result with 54 subjects, the activity of the autonomic nerve system changed before and after head care procedures performed by both a human nurse and our proposed robot. Especially, in the proposed robot, we confirmed significant differences with the procedure performed by our proposed head care robot in five indexes: HF/TP, LF/HF, HR, sAA, and PST. The activity of the sympathetic nerve system decreased, because the values of its indexes significantly decreased: LF/HF, HR, and sAA. On the other hand, the activity of the parasympathetic nerve system increased, because of the increase of its indexes value: HF/TP and PST. Our developed head care robot provided satisfactory relaxation in just five minutes of use.
Article
In the past years, our view of the molecular and cellular mechanisms that ensure the self-renewal of the skin has dramatically changed. Several populations of stem cells have been identified that differ in their spatio-temporal contribution to their compartment in steady-state and damaged conditions, suggesting that epidermal stem cell heterogeneity is far greater than previously anticipated. There is also increasing evidence that these different stem cells require a tightly controlled spatial and temporal communication between other skin residents to carry out their function.
Article
Pathological scars are fibroproliferative skin disorders that are characterised by the accumulation of fibroblasts and collagens. It is increasingly understood that their development and progression may be related to local skin mechanics, such as stretching. The present study evaluated the morphological and functional effects of cellular stretch on normal human dermal fibroblasts and explored the mechanotransduction mechanisms that may be involved. When fibroblasts were subjected to 24 h of cyclic axial stretching (10 cycles min(-1)), they migrated faster and for a longer distance than unstretched cells. The increased migration resulted in the cells reorienting themselves perpendicular to the direction of stretching. This was associated with reduced cellular apoptosis and unchanged proliferation. Stretching did not increase collagen synthesis but did elevate collagen degradation. These biological effects appeared to be mediated by the integrin and Wnt mechanotransduction pathways, which transmitted the mechanical stimulus via cell-substrate interactions, cell-cell junctions and indirect cell-cell communications. A better understanding of such fibroblast mechanoresponses in vitro will help the development of novel interventions that can prevent, reduce or even reverse pathological scar formation and/or progression in vivo.
Article
Benign and malignant fibroproliferative disorders (FPDs) include idiopathic pulmonary fibrosis, hepatic cirrhosis, myelofibrosis, systemic sclerosis, Dupuytren's contracture, hypertrophic scars, and keloids. They are characterized by excessive connective tissue accumulation and slow but continuous tissue contraction that lead to progressive deterioration in the normal structure and function of affected organs. In recent years, research in diverse fields has increasingly highlighted the potential role of mechanobiology in the molecular mechanisms of fibroproliferation. Mechanobiology, the heart of which is mechanotransduction, is the process whereby cells sense mechanical forces and transduce them, thereby changing the intracellular biochemistry and gene expression. Understanding mechanosignaling may provide new insights into the convergent roles played by interrelated molecules and overlapping signaling pathways during the inflammatory, proliferative, and fibrotic cellular activities that are the hallmarks of fibroproliferation. The main cellular players in FPDs are fibroblasts and myofibroblasts. Consequently, this article discusses integrins and the roles they play in cellular-extracellular matrix interactions. Also described are the signaling pathways that are known to participate in mechanosignaling: these include the transforming growth factor-β/Smad, mitogen-activated protein kinase, RhoA/ROCK, Wnt/β-catenin, and tumor necrosis factor-α/nuclear factor kappa-light-chain-enhancer of activated B cells pathways. Also outlined is the progress in our understanding of the cellular-extracellular matrix interactions that are associated with fibroproliferative mechanosignaling through matricellular proteins. The tensegrity and tensional homeostasis models are also discussed. A better understanding of the mechanosignaling pathways in the FPD microenvironment will almost certainly lead to the development of novel interventions that can prevent, reduce, or even reverse FPD formation and/or progression.
Article
Autocrine and paracrine factors are produced by balding dermal papilla (DP) cells following dihydrotestosterone (DHT)-driven alterations and are believed to be key factors involved in male pattern baldness. Herein we report that the IL-6 is upregulated in balding DP cells compared with non-balding DP cells. IL-6 was upregulated 3  hours after 10-100  nM DHT treatment, and ELISA showed that IL-6 was secreted from balding DP cells in response to DHT. IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) were expressed in follicular keratinocytes, including matrix cells. Recombinant human IL-6 (rhIL-6) inhibited hair shaft elongation and suppressed proliferation of matrix cells in cultured human hair follicles. Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen. Taken together, our data strongly suggest that DHT-inducible IL-6 inhibits hair growth as a paracrine mediator from the DP.
Article
Human skin is a highly specialized mechanoresponsive interface separating our bodies from the external environment. It must constantly adapt to dynamic physical cues ranging from rapid expansion during embryonic and early postnatal development to ubiquitous external forces throughout life. Despite the suspected role of the physical environment in cutaneous processes, the fundamental molecular mechanisms responsible for how skin responds to force remain unclear. Intracellular pathways convert mechanical cues into biochemical responses (in a process known as mechanotransduction) via complex mechanoresponsive elements that often blur the distinction between physical and chemical signaling. For example, cellular focal adhesion components exhibit dual biochemical and scaffolding functions that are critically modulated by force. Moreover, the extracellular matrix itself is increasingly recognized to mechanically regulate the spatiotemporal distribution of soluble and matrix-bound ligands, underscoring the importance of bidirectional crosstalk between cells and their physical environment. It seems likely that a structural hierarchy exists to maintain both cells and matrix in mechanical homeostasis and that dysregulation of this architectural integrity may underlie or contribute to various skin disorders. An improved understanding of these interactions will facilitate the development of novel biophysical materials and mechanomodulatory approaches to augment wound repair and regeneration.
Article
Minoxidil is efficacious in inducing hair growth in patients with androgenetic alopecia by inducing hair follicles to undergo transition from the early to late anagen phase. Although the efficacy of 1% topical minoxidil has been confirmed in Japan, no controlled study of 5% topical minoxidil has been conducted using male Japanese subjects. The objective of this trial was to verify the superiority in clinical efficacy of 5% topical minoxidil to 1% topical minoxidil in a double-blind controlled study with male, Japanese androgenetic alopecia patients as the subjects. The trial included 300 Japanese male patients aged 20 years or older with androgenetic alopecia who were administered either 5% topical minoxidil (n = 150) or 1% topical minoxidil (n = 150) for 24 weeks. The mean change from the baseline in non-vellus hair/cm(2), the primary efficacy variable, was 26.4 (n = 142) in the 5% topical minoxidil group and 21.2 (n = 144) in the 1% topical minoxidil group at 16 weeks, the main time point for the evaluation. The difference between the groups was significant (P = 0.020). The incidence of adverse events was 8.7% (13/150) in the 5% group and 5.3% (8/150) in the 1% group, with no significant difference between the groups (chi(2)-test: P = 0.258). Our findings confirmed the superiority of 5% topical minoxidil to 1% topical minoxidil in treating Japanese men with androgenetic alopecia.