Selected Topical Agents Used in Traditional Chinese Medicine in the Treatment of Minor Injuries- A Review

Abstract

Topical medicinal patches have been popular for the treatment of minor injuries like sprains and avulsions. Other inflammatory conditions like chronic musculo-tendinous pain and or fasciitis are also taken care of by local ointments or rubs. In the oriental communities, medicinal herbs frequently form the major components of the patches. In spite of the lack of scientific evidence of efficacy, the popularity of such traditional application persists for centuries. In this era of evidence-based clinical treatment, there is an urgent need to look into this traditional practice. The purpose should include a scientific verification of the efficacy of the practice, and once proven, further explorations would be indicated to bring the practice to a higher level. A system of comprehensive exploration was proposed and practiced in the past years to fulfill the aspiration. The research consisted of four areas:
(1) Identification of the suitable medicinal herbs for the topical study;
(2) Study of the biological activities of the selected herbs, concentrating on the areas of anti-inflammation, anti-oxidation, angiogenesis and cellular proliferation;
(3) Study on the transcutaneous transport of the chemicals of the selected herbs to deeper tissues; and
(4) Pilot clinical studies on common superficial inflammatory musculo-skeletal conditions to give objective clinical evidences to the topical applications.
Five herbs were identified as suitable candidates of study. They were put into relevant laboratory platforms and were proven to be anti-oxidant, anti-inflammatory and pro-angiogenic. Three of the herbs were prepared as topical patches with an enhancer and used to treat three common ailments in pilot clinical trials, viz., plantar fasciitis, undisplaced metatarsal fracture and tendonitis of the wrist (de-Quervain’s disease) and the elbow (Tennis elbow). The clinical results of the pilot studies were very positive. It is therefore concluded that further explorations are justified to create medicinal herb patches of even greater efficacy.

Full text

MINI REVIEW
published: 05 February 2016
doi: 10.3389/fphar.2016.00016
Edited by:
Akio Inui,
Kagoshima University Graduate
School of Medical and Dental
Sciences, Japan
Reviewed by:
Keliang Xie,
General Hospital of Tianjin Medical
University, China
Subhalakshmi Ghosh,
Jadavpur University, India
*Correspondence:
Ping-chung Leung
pingcleung@cuhk.edu.hk
Specialty section:
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 13 October 2015
Accepted: 17 January 2016
Published: 05 February 2016
Citation:
Leung PC, Ko ECH, Siu WS, Pang
ESY and Lau CBS (2016) Selected
Topical Agents Used in Traditional
Chinese Medicine in the Treatment
of Minor Injuries- A Review.
Front. Pharmacol. 7:16.
doi: 10.3389/fphar.2016.00016
Selected Topical Agents Used in
Traditional Chinese Medicine in the
Treatment of Minor Injuries-
AReview
Ping-chung Leung1,2,3*, Erik Chun-hay Ko1, Wing-sum Siu1, Ellie Suet-yee Pang3and
Clara Bik-san Lau1,2
1Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, 2State Key Laboratory of
Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, Hong Kong,
3Centre for Clinical Trials on Chinese Medicine, Institute of Chinese Medicine, The Chinese University of Hong Kong,
Hong Kong, Hong Kong
Topical medicinal patches have been popular for the treatment of minor injuries like
sprains and avulsions. Other inflammatory conditions like chronic musculo-tendinous
pain and or fasciitis are also taken care of by local ointments or rubs. In the oriental
communities, medicinal herbs frequently form the major components of the patches.
In spite of the lack of scientific evidence of efficacy, the popularity of such traditional
application persists for centuries. In this era of evidence-based clinical treatment, there
is an urgent need to look into this traditional practice. The purpose should include a
scientific verification of the efficacy of the practice, and once proven, further explorations
would be indicated to bring the practice to a higher level. A system of comprehensive
exploration was proposed and practiced in the past years to fulfill the aspiration. The
research consisted of four areas:
(1) Identification of the suitable medicinal herbs for the topical study;
(2) Study of the biological activities of the selected herbs, concentrating on the areas
of anti-inflammation, anti-oxidation, angiogenesis and cellular proliferation;
(3) Study on the transcutaneous transport of the chemicals of the selected herbs to
deeper tissues; and
(4) Pilot clinical studies on common superficial inflammatory musculo-skeletal
conditions to give objective clinical evidences to the topical applications.
Five herbs were identified as suitable candidates of study. They were put into relevant
laboratory platforms and were proven to be anti-oxidant, anti-inflammatory and pro-
angiogenic. Three of the herbs were prepared as topical patches with an enhancer
and used to treat three common ailments in pilot clinical trials, viz., plantar fasciitis,
undisplaced metatarsal fracture and tendonitis of the wrist (de-Quervain’s disease) and
the elbow (Tennis elbow). The clinical results of the pilot studies were very positive. It
is therefore concluded that further explorations are justified to create medicinal herb
patches of even greater efficacy.
Keywords: topical agent, herbal, fracture, fasciitis, tendonitis
Frontiers in Pharmacology | www.frontiersin.org 1February 2016 | Volume 7 | Article 16

Leung et al. Topical Herbal Patch for Injury
INTRODUCTION
Centuries before the emergence of chemical drugs and
pharmaceuticals, our ancestors have been making use of
special plants for the control of disease symptoms and clinical
problems. They could have followed the examples of animals
which, by instinct, are capable of creating their primitive way to
combat their odd infections and parasitic infestations (Campion,
1993). Successes of more or less similar applications among
human beings have matured into various forms of Traditional
Medicine which have been responsible for the maintenance of
human health for centuries until more than one hundred years
ago, when chemists started to systemically make use of small
molecules of chemistry to deal with specific bodily ailments
(Eisenberg et al., 1993).
During the long era of Traditional Medicine, the best known
and probably the most widely practiced clinical offer has been
herbal pastes for topical use (Pettman, 2007). The very early
development of topical agents involving the use of medicinal
herbs is natural and expected since external injuries to the
musculo-skeletal system are most frequent. The long tradition
of using topical herbal agents for musculo-skeletal injuries and
pain has hence been well inherited and continued today, long
after the maturation of pharmaceutical research. The sustained
popularity of topical treatment, apart from the strong tradition
inherited, must also be due to the convenience and subjective
heart-felt efficacy (Yang, 2003). However, in spite of the many
claims of efficacy, both from the manufacturers and users,
subjective clinical feelings have not been supported by biological
and pharmacological actions (Goldbeck et al., 1996). Whether
the topical application does penetrate through the skin barrier to
exert its pharmacological effects is equally unknown (Zhang et al.,
2000).
RESEARCH ON TOPICAL AGENTS
Since 10 years ago, the Institute of Chinese Medicine at
The Chinese University of Hong Kong has engaged in a
comprehensive study on topical herbal agents used for skeletal
injuries. The scope of study included the selection of herbs;
investigation on the biological effects of the herbs; the cross-skin
barrier effects; and lastly the clinical evidences.
Selection of Suitable Herbs for Topical
Use
Study of old classics revealed that over 100 herbal items have
been used as topical agents in the treatment of musculo-skeletal
injuries (Yang, 2003;Chinese Pharmacopeia, 2005). How are we
going to decide which are the effective ones to be chosen? The
frequent appearances in classics, viz., the popularity, deserves
special attention. In addition, the current concept of pain control
and regeneration need particular attention. Isolated study reports
on some of the herbs with regard to their anti-oxidant and
anti-inflammatory properties would suggest that they could be
suitable for the control of tissue oedema and pain. Similarly,
those herbs shown to be promoting cell proliferations could
be expected to help with tissue healing (Lundberg et al., 1997;
Carano and Eilvaroff, 2003;Liao et al., 2005).
After a review of the classical records, five herbs were selected
basing on the principles just described. They were Carthami
Flos [Carthamus tinctorius L. (flower)], Dipsaci Radix [Dipsacus
asperoides C.Y.Cheng & T.M.Ai (root)], Rhei Rhizoma [Rheum
officinale Baill. (root and rhizome)], Angelica Sinensis Radix
[A. sinensis (Oliv.) Diels (root)] and Achyranthis Bidentatae
Radix [Achyranthes bidentata Blume (root)]. Carthami is well
known for its antioxidant effects. Dispaci has been described as
an “bone repairing” agent. A. Sinensis, Achyranthis Bidentatae
and Rhei have been studied for their anti-inflammatory and
neo-vascularisation effects (Song, 2007;Peng et al., 2010;Zhou
et al., 2014). Subsequently only three herbs were used in the
study.
Traditionally many herbs are mixed together to achieve
a synergistic combination. We do not advocate the use of
more than 3–5 herbs beyond which quality control of the
selection would become more difficult (Leung, 2015). The major
constituents of the selected herbs are known and their HPLC data
are available in the Chinese Pharmacopeia (2005).
Proper vouchering of sample herbs are standard practices
in order to ensure sustainable development (Bye and Botanico,
1986).
Platform Studies on the Biological
Effects of the Herbs
Platform laboratory studies to confirm the biological properties
of the chosen herbs, included their anti-oxidant, anti-
inflammatory and proangiogenic effects, tested alone and
later, in combination. In vitro studies gave convenient judgments
on the three essential properties. Using RAW264.7 cell line
to suppress the NO production demonstrated the antioxidant
effects; while the promotive effects on HUVEC and UMR106
cells confirmed the anti-inflammatory and vascular proliferative
effects (Peng, 2009;Peng et al., 2010;Siu et al., 2015). The
promotion of osteoblastic proliferation could be demonstrated
in vitro using animal osteoblast cultures (Feng et al., 2004).
In vivo tests included sophisticated angiogenic studies using the
zebra fish embryo model (Zhou et al., 2014). A complicated bone
fracture model was built on the rabbit and rat, which allowed
radiological assessment on the healing as well as concomitant
serological changes (Leung et al., 2010). Mechanistic details
of the biological effects of the herbs have been worked
out by partners in our group (Peng et al., 2010;Siu et al.,
2015). All animal experiments were approved by the animal
experimentation ethics committee at the Chinese University of
Hong Kong.
Confirmation of Transcutaneous
Transport of Chemical Marker Material
Across the Skin Barrier to Achieve its
Direct Pharmacological Effects on the
Injured and Inflamed Tissues
In vitro and in vivo testings of transcutaneous drug transport
are essential steps to confirm the efficacy of topical agents.
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Leung et al. Topical Herbal Patch for Injury
Special device like the Franz Diffusion cell gives in vitro
information about the diffusion of medicinal agents through
a selected membrane, either artificial or prepared from the
skin of an animal (Zhao, 2004). In vivo testings would involve
the appearance of the recognized chemical marker of the
medicinal agent being used, either within the subcutaneous
tissue or in the circulation of the animal used for study (Peng,
2009).
When the topical agent consists of a simple chemical
compound, diffusion study is not complicated because a
direct analysis of the transfer of the compound would fulfill
the requirement. To study the transport of herbal materials
across a membrane or skin, complex chemicals are involved.
Authentication of commonly used medicinal plants is dependent
on the identification of specific chemical markers for a particular
plant. This practice is obviously a compromise since the plant
contains numerous chemicals rather than a single or a few
compounds. However, before a better method can be developed,
the appearance of a known chemical marker of a specific
medicinal plant across a membrane, could be considered an
TABLE 1 | Summary of three pilot studies using the topical herbal application.
Clinical condition Fifth Metatarsal fracture
Tse et al., 2015a
Plantar fasciitis
Tse et al., 2015b
De Quervain’s and Tennis Elbow
Aim Whether topical herbal formula helps to
reduce pain/facilitate healing
Whether topical herbal formula
helps to reduce pain
Whether topical herbal formula helps to reduce pain
Methodology A pilot, open label, one arm
self-controlled, observational study
A pilot, open label, one arm
self-controlled, observational study
A pilot, open label, one arm self-controlled,
observational study
Study duration Six weeks or pain/swelling disappear Six weeks or pain/swelling
disappear
Six weeks or pain/swelling disappear
Number of subjects 10 9 De Quervain’s 5
Tennis Elbow 6
Inclusion criteria Acute traumatic fracture of fifth
metatarsal No displacement
Plantar fasciitis (Heel pain)
18–65 years. History over 4 weeks
History over 4 weeks
Exclusion criteria
(Apart from pregnancy,
breast feeding, TCM
sensitivity)
Open injury Ulceration Acute injury
Study product Formula : semi solid paste containing
concentrate of three herbs
extracts +Borneol
Same formula Same formula
Assessments Interview, orthotics
•American Orthopedic Foot and
Ankle Society +Ankle Hindfoot
Scale (AOFAS)
•Foot/Ankle Ability Measure (FAAM)
•Pain evaluation – visual analog
•Ultrasonic study
•Check blood for inflammation
cytokine
•Water displacement
•Xraysite
•3D Scan Gogh II imaging
Interview, map site of pain
•Foot function index
•Pain evaluation – visual analog
•Ultrasonic study
•Check blood for inflammation
cytokine
Interview, Map site of pain
•Disabilities of the arm, shoulder, and head
•Pain evaluation – visual analog
•Ultrasonic study
Treatment Apply patch over fracture site, change
every 3 days until 6 weeks
Data checking 0 and 6 weeks
Apply patch over heel, change daily
until 6 weeks
Data checking 0 and 6 weeks
Apply patch over the wrist at the base of the thumb for
de Quervain’s and outer side of the elbow joint for
tennis elbow. Change daily until 6 weeks
Data checking 0 and 6 weeks
Outcome measure Swelling assessment/fracture healing Pain relief
Inflammation control
Pain relief
Inflammation control
Results:
Safety/Allergy No serious adverse effects No serious adverse effects No serious adverse effects
Pain evaluation visual
analog scale
28% decrease in morning pain (at
2 weeks vs. baseline)
41% decrease in evening pain (4 weeks
vs. baseline)
56% decrease in morning pain (at
4 weeks vs. baseline)
de Quervain’s
52% decrease in morning pain (6 weeks vs. baseline)
53.8% decrease in evening pain (6 weeks vs. baseline)
Tennis Elbow
47.8% decrease in morning pain (6 weeks vs. baseline)
52% decrease in evening pain (6 weeks vs. baseline)
Ultrasound assessment Para-fracture oedema
20% reduction
Fascia thickness
9.07% reduction
Oedema reduction positive
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Leung et al. Topical Herbal Patch for Injury
objective proof about the transfer, although it is only a qualitative
and partial demonstration of the delivery.
All the five medicinal plants chosen for this study have
officially recognized chemical markers and five of them are
selected for the in vitro and in vivo studies. Using the
Franz diffusion chamber with either an artificial or mouse
skin membrane, the markers were identified in the receptor
compartment, thus proving the across membrane transport
(Zhao, 2004).
Traditionally topical herbal preparations make use of
enhancers to facilitate the quality and quantity of skin transfer.
Borneol has been the most popular agent used for this purpose
in traditional Chinese medicine. Alternatively, a pharmacological
agent, ozone, has been a popular enhancer used in the
pharmaceutical industry with proven facilitating effects (Chen
et al., 1995;Chen and Wang, 2004).
Studying the bioavailability of orally consumed herbal
preparation is a difficult challenging job since the intraluminal
metabolic activities occurring in the small and large bowels
could be affecting the herbal substances in the most complicated
manners. For the topical treatment, once penetration could be
proven, the drug effects could be much similar to the in vitro
studies.
In our study, penetration was further verified using live
animals when the serum was taken for the analysis of the marker
chemicals after the topical application. Small quantities of marker
chemicals were demonstrated in the serum which objectively
indicate the presence of the herbal substance within the site of
application (Peng, 2009).
Collecting Quality Clinical Evidences
Since topical agents are widely used in minor injuries resulting
in pain, swelling and loss of function, testing any new innovative
topical agent could follow this general direction. In the hospital
practice of traumatology and accident-emergency management,
where injuries are usually more serious, topical treatment is
seldom considered. However, topical treatment still retains its
popularity under situations of minor injury or persistent pain and
swelling in spite of standard treatment.
A number of common limb injuries presenting as painful and
inflammatory conditions were chosen for the study of this topical
herbal agent. The conditions involve the inflammation of tendons
and fascia. The three conditions chosen were:-
(a) Undisplaced fracture of the distal metatarsal bone. Swelling
and pain commonly persist in spite of fracture healing.
Topical agent to consolidate the bone healing and to better
control the symptoms of pain and swelling is a logical
consideration.
(b) Plantar fasciitis in the foot classically lead to long lengthy
duration of heel pain which affects walking and standing.
Topical treatment over the heel was chosen as another study
target.
(c) In the upper limb, tendon inflammation like de Quervains
disease of the short extensor and abductor of the thumb and
wrist extensor origin tendonitis (tennis elbow) are common
conditions suitable for clinical study of topical application.
Henceforth, three pilot studies were organized to serve as
“proof of concept” trials in preparation for larger scale studies
in future. The study design followed the standard requirements
for similar clinical trials so that proper clinical data could be built
up to be compared with other options of treatment. The study
protocols followed principles recommended by the Declaration
of Helsinki and had been approved by the hospital ethical
committee. The methodology of study and results of treatment
are presented in the Tab l e 1 . The topical treatment for all three
sites had been very well accepted by patients. Recurrences after
cessation of local treatment were observed in some cases, but the
intensities were apparently much less than before treatment (Tse
et al., 2015a,b).
DISCUSSIONS
Transdermal topical drug delivery offers a non-invasive route
of drug administration. Ten years of large scale explorations
on the clinical science of traditional herbal medicine applied as
topical agents for anti-inflammatory and pain control measures,
using standard laboratory platforms and small scale pilot
clinical studies, have given us confidence that the traditional
method of treatments does have objective evidences of efficacy.
Established surgeons and physicians should refrain from teasing
topical agents as “myths,” “counter-irritants” or “ritual practices.”
Topical agents providing anti-oxidant and anti-inflammation
effects on the diseased tissues after penetrating the skin barrier
is now a proven fact. The vascular promotion ability observed
further supports the revascularization and regeneration of tissues
accordingly. On the other hand, users and advocates should not
dogmatize the old view that the topical agent heals perfectly on
its own. Instead, the topical agent helps to control symptoms,
whereas the primary causes of the pain and swelling could be
the result of more complicated pathologies that requires the joint
efforts of caring teams to achieve the best clinical outcome (Hung
et al., 2015).
The common conditions studied had known predisposing
causes of chronic stress and/or repetitive minor injuries. To
ensure cure and prevention of recurrence, the primary causes
must be dealt with at the same time. Without taking effective
care of the causative mechanisms relief of the symptoms could
be transient. Topical agent administration therefore needs to go
hand in hand with active rehabilitation measures.
Further work needs to be done so as to give more
comprehensive understanding of the mechanisms of action of the
herb extracts. The molecular aspects of the biological effects need
to be explored so that more suitable medicinal herbs could still
be identified and either small chemical molecules or groups of
chemicals from the gross extracts of the herbs could be used to
give more potent effects.
On the skin surface penetration, particle sizes manipulation
has been the many innovations of the nanotechnology experts.
The application of nanotechnology would be able to enhance
penetration, while at the same time ensure that the ideal quality
and quantity of the chemical components with desirable effect be
adequately delivered (Chan et al., 2009).
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Leung et al. Topical Herbal Patch for Injury
AUTHOR CONTRIBUTIONS
PL had responsibility for all parts of the manuscript.
WS, EK, and CL had worked on the herbs biological
and mechanistic and pre-clinical data mentioned in the
manuscript.
FUNDING
This study was financially supported by the Ming Lai
Foundation and the Innovation and Technology Commission,
the government of Hong Kong (Ref. No. GHX/002/11), and
Alberta Technology Limited.
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Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2016 Leung, Ko, Siu, Pang and Lau. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
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