# Medicinal Plants for the Treatment of Hypertrophic Scars

Authors: Qi Ye; Su-Juan Wang; Jian-Yu Chen; Khalid Rahman; Hai-Liang Xin; Hong Zhang
Journal: Evidence-Based Complementary and Alternative Medicine
 (2015)

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## Abstract

Hypertrophic scar is a complication of wound healing and has a high recurrence rate which can lead to significant abnormity in aesthetics and functions. To date, no ideal treatment method has been established. Meanwhile, the underlying mechanism of hypertrophic scarring has not been clearly defined. Although a large amount of scientific research has been reported on the use of medicinal plants as a natural source of treatment for hypertrophic scarring, it is currently scattered across a wide range of publications. Therefore, a systematic summary and knowledge for future prospects are necessary to facilitate further medicinal plant research for their potential use as antihypertrophic scar agents. A bibliographic investigation was accomplished by focusing on medicinal plants which have been scientifically testedin vitro and/or in vivo and proved as potential agents for the treatment of hypertrophic scars. Although the chemical components and mechanisms of action of medicinal plants with antihypertrophic scarring potential have been investigated, many others remain unknown. More investigations and clinical trials are necessary to make use of these medical plants reasonably and phytotherapy is a promising therapeutic approach against hypertrophic scars.


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## Body

## 1. Introduction

Scar formation strongly depends on the presence of contraction during healing and the nature of the scar is actually the uneven look of the healed tissue resulting from disfigured tissue deformation and overaligned collagen fibers [1]. Collagen in hypertrophic scars is found to be in a disorganized, whorl-like arrangement rather than in the normal parallel orientation manner. Therefore, hypertrophic scars are indurate, elevated, poorly extensible, and also characterized by hypervascularity, thereby providing their erythematous appearances [2]. HS can cause significant abnormality in aesthetic and functional symptoms and to date no recognized treatment has been established. It commonly occurs after surgical incision, thermal injury, and traumatic injuries to the dermis with a subsequent abnormal healing response [3]. Furthermore, it is often associated with contractures that can lead to considerably reduced functional performance in patients.The development of antihypertrophic scars is an unsolved problem in the process of scar treatment. For this reason, some undiscovered successful treatments are needed to prevent excessive hypertrophic scarring. The reported preventions include topical medical application, cryotherapy, use of silicone gel sheets, injection of steroids, radiotherapy, and an early surgical procedure for wound closure [2]. In the last decade, there has been a renewed interest in the use of indigenous medicine worldwide, arising from the realization that orthodox medicine is not widespread. Although modern medicine may be available in some communities, herbal medicines have often maintained popularity for historical and cultural reasons, in addition to their cheaper costs [4]. Recent research has introduced the uses of phytochemical compounds and extracts isolated from medicinal plants in an attempt to resolve these problems as a promising therapy.Many treatment strategies are sought to prevent scar formation without compromising the wound healing process [5]. The effectiveness of currently used therapy against hypertrophic scar arises most probably from the increase of the medicinal plants reported. In the modern system of medicine, about 25% of prescriptions contain active principle(s) derived from plants [4]. A significant correlation between medicinal plants and their use in the treatment of many types of scars has been shown in epidemiological data generated throughout the world. Published clinical trials have, as yet, largely focused on characterizing the pharmacokinetics and metabolism of medicinal plants. Despite experimental advances in medicinal plant research against scars, findings in humans are still limited. However, in recent years, diverse benefits of medicinal plants in the treatment of hypertrophic scars have been described [6–9].In line with the latest findings responsible for the increased recognition of medicinal plants as potential therapeutic and/or preventative agents, the aim of the present review is to focus on recent experimental findings and clinical trials of medicinal plants and other preparations with similar actions that could account for beneficial effects on hypertrophic scars in patients. Natural products, such as plant extracts, either as pure compounds or as standardized extracts, provide unlimited opportunities for control of hypertrophic scarring owing to their chemical diversity [10]. Currently, a great deal of effort is being expended to find alternative sources of safe, effective, and acceptable natural medicinal plants for the treatment or prevention of hypertrophic scars; hence, all literature available was reviewed.


## 2. Suggested Mechanism of Hypertrophic Scarring

The molecular mechanism of hypertrophic scarring is associated with the unusual proliferation of fibroblasts and overproduction of collagen and extracellular matrix [70]. An array of intra- and extracellular mechanisms is essential in the prevention of scar formation. With the help of molecular biology, cell biology technology, hypertrophic scar animal models, and the setting-up of scar tissue engineering, the mechanism of hypertrophic scarring has been clearly defined (Figure 1). It is usually considered as migration and proliferation of different cell types such as keratinocytes, myofibroblasts [59], and mast cells [71]. Fibroblasts play an essential role in new tissue formation during wound repair [33], but their abnormal low death rate and high proliferation rate can cause scar tissue formulation [11]. Meanwhile, keratinocytes are indispensable in signal transduction between paracrine secretion and epithelium matrix. When cultured in the presence of keratinocytes, fibroblasts exhibit significant proliferation activity [72], showing the contribution of keratinocytes to fibroblasts proliferation. Myofibroblasts, which are different from fibroblasts and are related to the composition, organization, and mechanical properties of ECM [73], increase collagen synthesis and retard cell migration [71], thus resulting in excessive and rigid scarring. Fibroblasts are transformed into myofibroblasts by heterocellular gap junction intercellular communications between mast cells (RMC-1) and fibroblasts [71, 74]. In the process of wound healing, the combination of fibroblasts and myofibroblasts triggers excessive production of abnormal extracellular matrix protein [75], eliciting scarring [1, 75]. With the assistance of keratinocytes and mast cells, proliferative fibroblasts produce massive collagen which makes extracellular matrix accumulate below dermis, leading to scar formation. The complex forming process consists of three different phases, inflammation, proliferation, and maturation, which leads to hypertrophic scarring in the end [76]. The ratio of I to III collagens in healthy adults ranges from 3.5 to 6.1, while in patients with hypertrophic scars, it could be down to 2 and in keloid patients it can be as high as 19, which is related to the abnormal metabolism of collagens I and III in pathological scars, including more collagen synthesis and less collagen degradation.Figure 1
The mechanism of hypertrophic scarring.Although many targets of action, by which scarring can be inhibited, have been experimentally studied or postulated, few are well known or defined for inhibition of hypertrophic scarring by plant-derived compounds. Figure2 and Tables 5 and 6 summarize and enumerate the suggested mechanisms and correlative medicinal plants.Figure 2
The mechanisms by which extracts and compounds from medicinal plants display antihypertrophic scar activity.The size of a scar is influenced by many factors, such as wound size, wound contraction, and healing time. Wound contraction makes an important contribution to scar formation also the larger the area of the wound, the more cells migrate, resulting in more prominent scarring [1]. Therefore, induction of fibroblast apoptosis and reduction of extracellular matrix and collagen I/III production may be the pivotal measures against hypertrophic scarring.Many kinds of test models are applied to investigate wound healing mechanisms and inhibition of scar formation, including 2D hybrid agent-based model [1], pig surgical injury model, fibroblast populated collagen lattice (FPCL) model, rat laminectomies at Lumbar-1 level [5], incisional wound healing model [6], and rabbit ear model [54]. These models provide a mean for detecting and evaluating the mechanobiology in wound healing and scar formation [1].However, the complex mechanism of hypertrophic scarring still remains unknown which raises the question of how to control scar hyperplasia.


## 3. Medicinal Plants against Hypertrophic Scarring

Many beneficial uses of medicinal plants are extensively documented in the traditional medicine systems in many cultures. To collect the data which supports this finding, we performed a systematic review using PubMed, Elsevier, Springer, and Google Scholar databases and peer-reviewed articles published in the last 10 years. The search terms included scar, scaring, fibroblast, extract, and preparation. The phytochemicals from medicinal plants against scar hyperplasia are presented in Tables1 and 2, respectively, whilst the medicinal plant extracts are listed in Table 3. Their activities and mechanisms for antihypertrophic scarring were also described, respectively, in Tables 1, 2, and 3. There are five preparations (Table 4) reported on their effects and mechanisms of antihypertrophic scarring, namely, liposome-encapsulated 10-HCPT, oxymatrine-phospholipid complex (OMT-PLC), solid lipid nanoparticle-enriched hydrogel (SLN-gel), Ginsenoside Rg3/poly (l-lactide) (G-Rg3/PLLA), andCentella asiatica extract capsule, which are composed of different medicinal plants and vehicles. Medicinal plants can be used for different therapeutic purposes or as precursors of useful drugs containing different types of phytochemicals.Table 1
The components from medicinal plants with antihypertrophic scar activity.
Component
Botanical name
Family
Medicinal part
Observation
Dose
Effect
Mechanism of action
References
Madecassoside
Centella  asiatica
Umbelliferae
Whole plant
In vitro
10~100μM
Antiproliferation of HSFBsPromotion of apoptosis Diminishment of scar formationFacilitation of wound healing
Inhibition of HKF migration, F-actin filaments protein, and cytoskeletal protein. Promotion of nuclear shrinkage and mitochondrial membrane depolarization Condensation of chromatin and fragment of nuclei Inhibitory phosphorylation of p38, PI3K, AKT, and cofilin. Activation of caspase-3/caspase-9 Facilitation of Bax mRNA expression and decrease of Bcl-2 and MMP-13 mRNA expression
[11, 12]
Genistein
Glycine max
Leguminosae
Fruit
In vitro
25~100μg/mL
Anti-proliferation of HSFBsSuppression of mitosisPromotion of apoptosis
Inhibition of TPKs, increase of caspase-3, and decreases ofα-SMA and Bcl-2 protein Enhancement of Bax protein Inhibition of types I/III precollagen mRNA expression, down-regulation of collagen I/III mRNA, reduction of PCNA expression, and inhibitory phosphorylation of c-Raf, MEK1/2, ERK1/2, and p38 Induction of morphology changes of apoptosis cells Inhibitory transdifferentiation of fibroblasts into myofibroblasts
[13–17]
37~370µM
Decrease of G0-G1 phase and increase of G2-M phase Increase of C-JUN mRNA expression and decrease of FOS-B mRNA expression in skin keratinocytes Inhibitory mRNA expression of C-JUN and C-FOS in human fibroblasts In keloid fibroblasts, decrease of C-JUN and C-FOS mRNA expression at 37 µM, but enhancement at 370 µM
Astragaloside IV
Astragalus  Membranaceus
Leguminosae
Root
In vitro
12.5~200μM
Antiproliferation of HSFBs
Decrease of collagen I/collagen III and TGF-β1 secretion
[18]
Tetrandrine
Stephania  tetrandra
Menispermaceae
Root
In vitro
10~80 μM
Antiproliferation of HSFBs
Inhibition of TGF-β1 mRNA transcription, promotion of Smad7 and MMP-1 mRNA expression, and inhibition of Smad2 mRNA expression Decrease of protein expression of collagen I/collagen III, Bcl-2, and MKP-1. Reduction of total collagen volume and S phase, increase of  G0/G1 phase, and prevention of G0/G1 into G2 phase Inhibitory phosphorylation of MEK1/2 and ERK1/2
[19–22]
In vivo
1~10 mg/L
Local injection
0.5~2 mg/L50 mg/mL, 20 μL
Aloe-emodin
Rheum palmatum
Polygonaceae
Root, rhizome
In vitro
20~80 mg/L
Antiproliferation of HSFBs
Increase of S phase
[23]
5F
Pteris semipinnata
Pteridaceae
Whole plant
In vitro
20~80 μg/mL
Antiproliferation of HPS
Blockage of fibroblasts from G1 to S phase Decreased protein expression of TGF-β1 and type I collagen, increase of caspase-3, and reduction of total collagen and fibroblasts PCNA protein (cyclin) Inhibitory mRNA expression of type I/type III procollagen in SSSF
[24–26]
In vivo
10~40 mg/L
Reduction of PS volume
40~120 mg/L
Antiproliferation of SSSF
Local injection
20~80 mg/L
Promotion of HPS apoptosis Decrease of hypertrophic index
Reduction of collagen fiber content
Oxymatrine
Sophora japonica
Leguminosae
Root
In vitro
0.125~1.0 mg/mL2 μM
Antiproliferation of   KFb and HFb Promotion of KFb apoptosis
Increase of S phase, inhibitory mRNA expression of collagen I/collagen III and reduction of protein expression of Smad3 and ERK1 Promotion of Smad7 protein expression Inhibition of p-Smad3 and nuclear translocation of Smad3
[27, 28]
Ginsenoside Rg3 (G-Rg3)
Panax ginseng
Araliaceae
Root, rhizome
In vivo Local injection
3 mg/mL, 0.1 mL
Inhibition of HSDecrease of scar tissue fibrosis
Increase of protein expression of PCNA, Bax, caspase-3, and Cyt-c Decrease of Bcl-2 protein expression
[29, 30]
Osthole
Cnidium monnieri
Apiaceae
Fruit
In vitro
5~50μM
Antiproliferation of HSFBs and Induction of apoptosis
Promotion of Bax mRNA expression and inhibition of Bcl-2 mRNA expression Decreases of TGF-β1 protein expression and facilitation of HSFBs shrinkage, chromatin condensation, membrane blebbing, apoptotic body formation, and DNA ladder formation
[31]Table 2
Antihypertrophic scar displaying phytochemicals widely distributed in medicinal plants.
Phytochemicals
Observation
Dose
Effect
Mechanism of action
References
10-Hydroxycamptothecin (HCPT)
In vivo
0.01~0.1 mg/mL
Decrease of the area of epidural scar tissue and the number of fibroblasts. Reduction of epidural adhesion and inhibitory proliferation of RESF
Inhibition of topoisomerase I
[5]
Angelica naphtha
In vitro
1~16 mg/L
Antiproliferation of HSFBs and induction of HSFBs apoptosis
Inhibition of G0/G1 and G2/M phases, promotion of S phase, and reduction of collagen protein in fibroblasts
[32]
Asiaticoside
In vivo   In vitro
25~50 mg/mLLocal injection25~1000 μM300 μg/mL
Reduction of scar hyperplasia of HSREDecrease of hypertrophic indexPromotion of keratinocytes migrationAnti-proliferation of HSFBs
Inhibition of the mRNA expression of TGF-β1, RhocA, ROCK-I, and CTGF, facilitation of TGF-β3 mRNA expression, and decrease of the expression of types I/III collagen and TIMP-1 proteins
[33–36]
Matrine
In vitro
0.01~5.00 g/L
Antiproliferation and induction of apoptosis in HSFBs
Promotion of G2-M phase, inhibition of lactate dehydrogenase and Hyp and enhancement of I/III collagen ratio
[37]
Quercetin
In vivo
0.05%~1%, w/oLocal Application
Inhibition of scarring in hairless mice
Increase of the protein and mRNA expression of MMP-1 and enhancement of the phosphorylation of JNK and ERK
[38]
In vitro
10~40μM
Antiproliferation of HSkF
Emodin
In vitro
50~200μg/mL
Antiproliferation of HSFBs
Inhibition of G0/G1 phase, increase of intracellular calcium, and decrease of collagen synthesis
[39–41]
Resveratrol
In vitro  In vivo
25~400μM 150~400 μM Local injections
Antiproliferation of HSFBs Reduction of hypertrophic scar index
Inhibition of the mRNA expression of type I/type III procollagens
[42]
Tan IIA
In vitro
20~80μg/mL0.05~0.15 mg/mL
Antiproliferation of HSFBsInduction of HSFBs apoptosis
Facilitation of nuclei shrinkage, condensation and fragmentation, blockage of HSFBs from G1 to S phases, downregulation of MDA content and XOD activity, increase of T-SOD and GSH-Px activity, and promotion of MMP-1 mRNA expression
[43–45]
Curcumin
In vitro
12.5~100μM
Antiproliferation of HSFBs
Inhibition of procollagen 1 mRNA expression Reduction of hypertrophic index and collagen fiber area density
[46]
In vivo
0.5~2.0 mM, 0.1 mL/d Local injections
Dihydroartemisinin
In vivo
180 mg/kg
Inhibition of HSRE scarring
Inhibition of collagen fibers and hypertrophic index
[47]
10 mL intragastric administration
Antifibroblast proliferation of HSRE
Arteannuin
In vitro
0.103~0.206 mg/mL
Antiproliferation of HSFBs
Congregation of nuclear chromatin, promotion of calcium concentration, increase of G0-G1 phase, and reduction of collagen levels and hypertrophic index of HSRE
[48–51]
In vivo
60 mg/mL/2 d
Decrease of HSRE scarring
20μL local injection
Antiproliferation of mastocyte
Panax notoginseng saponins (PNS)
In vitro
400~800μg/mL
Antiproliferation of HSFBs
Inhibition of G2-M and G0-G1 phases, increase of S phase, reduction of the protein expression of TGF-β1 and α-SMA, and inhibition of intracellular free calcium concentration
[52, 53]
Oleanolic Acid
In vivo
Topical application of 2.5, 5, and10%  for 28 consecutive days
Inhibition of hypertrophic scarring, induction of apoptosis, and reduction of scar elevation index
Inhibition of the mRNA expression of TGF-β1 mRNA, MMP-1, TIMP-1, and P311. Increase of the mRNA expression of MMP-2, caspase-3, and caspase-9. Reduction of the protein expression of TGF-β1 and collagen I/collagen III
[54]
Hirudin
In vitro
1~50μM
Promotion of apoptosis
Increase of Gl phase and inhibition of S phase Enhancement of the protein expression of MMP-2, MMP-9, and p27, reduction of the protein expression of cyclin E and TGF-β1, and inhibition of the mRNA expression of I/III procollagens
[55]
Xiamenmycin
In vivo
10 mg/kg·d−1, intraperitoneal injection for 10 days
Attenuation of hypertrophic scarring and suppression of local inflammation in a mechanical stretch-induced mouse mode
Reduction of CD4+ lymphocyte and monocyte/macrophage retention in fibrotic foci Blockage of fibroblast adhesion with monocytes.Inactivation of FAK, p38, and Rho guanosine triphosphatase signaling
[56]
In vitro
5–30μg/mL
Inhibition of proliferation of HSFBsTable 3
The extracts from medicinal plants displaying anti-hypertrophic scarring.
Extract
Botanical name
Family
Medicinal part
Observation
Dose administration
Effect
Mechanism of action
References
Ethanolic extract
Calotropis gigantea
Asclepiadaceae
Root, bark
In vivo
100~400 mg/kgintragastric administration
Increase of wound contraction and decrease of scar area and the time of epithelization
Increase of hydroxyproline and collagen synthesis
[6]
Ethanolic extract
Daucus carota
Apiaceae
Root
In vivo
1, 2, and 4%epidermal administration
Decrease of wound area, epithelization period, and scar width. Increase of wound contraction
Increase of hydroxyproline content. Antioxidant and antimicrobial activities
[7]
Methanolic extract
Pistia stratiotes
Araceae
Leave
In vivo
5 and 10%epidermal administration
Decrease of wound area
Inhibition of hydroxyl radical scavenging and increase of fibroblast blood vessels and collagen fibers
[8]
Ethyl acetate extract
Gelidium amansii
Gelidiaceae
Whole plant
In vitro
5~10 mg/mL
Antiproliferation of HSFBs
Decrease of the protein expression of I/III collagens and TGF-β1
[9]
Ethanolic extract
Carthamus tinctorius
Asteraceae
Flower
In vitro
2~8μg/mL
Antiproliferation of HSFBs
Inhibition of collagen protein synthesis and promotion of fibroblast shrinkage
[57]
Aqueous extract
Oenothera paradoxa
Onagraceae
Seed
In vitro
0.1~10μg/mL
Protection of normal dermal fibroblasts
Decrease of LDH and ROS
[58]
Aqueous extract
Cigarette Smoke
Unknown
Unknown
In vitro
100% saturated solution
Antiproliferation of skin fibroblasts and promotion of cellular senescence
Inhibition of SOD and GSH-Px and promotion of ROS
[59]
Ethyl acetate extract
Rheum palmatum
Polygonaceae
Root, rhizome
In vitro
25μg/mL
Antiproliferation of HSFBs
Increase of G0/G1 phase
[60]
Methanol extract
Broussonetia kazinoki
Moraceae
Bark, root
In vitro
Unknown
Inhibition of hyperpigmentation
Reduction of tyrosinase enzyme synthesis
[61]
Ethanol extract
Scutellaria baicalensis Georgi
Lamiaceae
Root
In vivo
10 mg/mL epidermal administration
Inhibition of scarring
Reduction of the protein expression of TGF-β1
[62]
Aqueous extract
Allium cepa
Liliaceae
Corm
In vivo
1~2.5%, v/vlocal application
Suppression of scarring in hairless mice
Upregulation of MMP-1 and type I collagen expression
[38]
In vitro
1~2.5%, v/v
Antiproliferation of fibroblasts
Aqueous extract
Tamarindus indica
Fabaceae
Bark, leave
In vivo
Unknown
Anti-inflammation
Elimination of death cells and necrotic tissues
[63]
Ethanol extract
Aneilema keisak
Commelinaceae
Whole plant
In vitro
40μg/mL
Decrease of scarring
Inhibition of TGF-β1-dependent signalling by reducing Smad2 protein. Reduction of various hKF pathological responses, including hyperplastic growth, collagen production, and migration without DNA damage
[64]Table 4
The preparations from different medicinal plants with antihypertrophic scar activity.
Preparations
Botanical name
Family
Medicinal part
Preparation
Vehicle
Delivery system
Observation
Effect
Mechanism of action
References
Hydroxycamptothecin (HCPT)
Camptotheca acuminata
Nyssaceae
Fruit, leave
Liposome-encapsulated 10-HCPT
Liposome
Liposome-encapsulated
In vivo Implant
Antiproliferation of fibroblasts and reduction of epidural adhesion
Decrease of epidural scar area and fibroblast number in the epidural scar tissue
[65, 66]
Oxymatrine (OMT)
Sophora flavescens, Sophora alopecuroides, and Sophora subprostrata
Leguminosae
Unknown
Oxymatrine-phospholipid complex (OMT-PLC)
Phospholipid
Microemulsion
In vitro  In vivo topical  delivery
Antiproliferation of fibroblasts
Improvement of OMT skin permeability and increase of retention ratio of OMT in skin.
[67]
Astragaloside IV
Astragalus membranaceus
Leguminosae
Root
Solid lipidnanoparticle-enriched hydrogel (SLN-gel)
Lipid hydrogel
Solid lipid nanoparticle, hydrogel
In vitro In vivo,topical delivery
Enhancement of keratinocytes migration and proliferation Increase of drug uptake in fibroblasts Promotion of  wound  healing  and  inhibition of scar  formation
Caveolae endocytosis pathway. Increase of wound closure rate and angiogenesis Improvement of collagen regular organization
[68]
Ginsenoside Rg3 (G-Rg3)
Red Panax ginseng
Araliaceae
Root, rhizome
Ginsenoside Rg3/Poly (l-lactide) (G-Rg3/PLLA)
Electrospun poly(L-lactide) fiber
Electrospun fibrous scaffolds, nanofibers
In vitro In vivo
Inhibition of fibroblast cell growth, antiproliferation of fibroblasts, and prevention of scar formation
Improvement of dermis layer thickness, collagen fibers, and microvessels
[29]
Centella asiatica extract
Centella asiatica
Apiaceae
Whole plant
Centella asiatica extract capsule
Capsule
Nothing
In vivo
Inhibition of tissue overgrowth, reduction of scar and keloid, and anti-inflammation
Promotion of collagen I protein expression, collagen remodeling, and    glycosaminoglycan synthesis Enhancement of collagen and acidic mucopolysaccharides
[69]Table 5
Summary of antiscarring mechanisms of medicinal plant components.
Mechanism
Medicinal plant component
MAPK pathway
Inhibition of p-p38 signaling
Madecassoside, Genistein, and Xiamenmycin
Inhibition of p-ERK1/2 signaling
Genistein, Tetrandrine, Cryptotanshinone, and Quercetin
Inhibition of p-JNK signaling
Quercetin
PI3K/AKT signaling
Madecassoside
Mitochondrial-dependent pathway
Increase of Bax
Madecassoside, Genistein, Ginsenoside Rg3, and Osthole
Decrease of Bcl-2
Madecassoside, Genistein, Tetrandrine, Ginsenoside Rg3, and Osthole
Increase of cytoplasm Cyt-c
Ginsenoside Rg3
Cell cycle
Decrease of G0-G1 phase
Genistein, Angelica naphtha, Emodin, and Panax notoginseng saponins
Increase of G2-M
Genistein
Decrease of S phase
10-Hydroxycamptothecin, Tetrandrine, Aloe emodin, and Hirudin
Prevention from G0/G1 into G2 phase
Tetrandrine
RhoA/ROCK-I signal pathway
Inhibitory secretion of RhocA, ROCK-I, and CTGF
Xiamenmycin
VEGF signal pathway
Cryptotanshinone
FAK signal pathway
Cryptotanshinone, Xiamenmycin
TGF-β/Smad signaling pathway
Oxymatrine
Downregulation of collagen I/III expression
Genistein, Astragaloside IV, Tetrandrine, Resveratrol, 5F, Curcumin, Oleanolic Acid, and Hirudin
Decrease ofα-SMA
Genistein, Panax notoginseng saponins
Activation of caspases
Activation of caspase-3
Madecassoside, Genistein, 5F, Cryptotanshinone,  Oleanolic Acid, and Ginsenoside Rg3
Activation of caspase-9
Madecassoside, Oleanolic Acid
Suppression of TPK activation
Kazinol F
Inhibition of topoisomerase I
10-Hydroxycamptothecin
Decrease of TGF-β1 secretion
Tetrandrine, Panax notoginseng saponins, Osthole, and Hirudin
Inhibition of TGF-β1 transcription
Astragaloside IV, Oleanolic Acid
Downregulation of TIMP-l expression
Oleanolic Acid
Reduction of LDH and increase of the ratio of collagen I/collagen III
Matrine
Increase of T-SOD and GSH-Px activity
Tan IIA
MMP
Enhancement of MMP-1
Tetrandrine, Tan IIA, and Oleanolic Acid
Enhancement of MMP-2 and MMP-9
Hirudin
Enhancement of MMP-13
Madecassoside
Increase of intracellular calcium
Emodin, ArteannuinTable 6
Summary of antiscarring mechanisms of plant extracts.
Mechanism
Medicinal plants extract
Cell cycle
Increase of G0-G1 phase
Rhubarb
Collagen
Downregulation of collagen l expression
Gelidium amansii
Downregulation of collagen III expression
Gelidium amansii, Scutellaria baicalensis Georgi
Enhancement of collagen synthesis
Calotropis gigantea
Inhibition of collagen synthesis
Carthamus tinctorius
Promotion of collagen I
Onion
MMP
Enhancement of MMP-1
Neonauclea reticulata, Onion
Increase of MMP-3 and MMP-9
Neonauclea reticulata
Elimination of hydroxyl radical
Pistia stratiotes
Decrease of LDH
Oenothera paradoxa
Decrease of ROS
Oenothera paradoxa, Neonauclea reticulata
Increase of ROS and reduction of SOD and GSH-Px
Cigarette SmokeThe use of herbal medicine remedy has been steadily increasing worldwide in recent years, as well as the search for new phytochemicals that could be potentially developed as useful drugs for the treatment of hypertrophic scar and other scar diseases [4]. The antihypertrophic scar activity of medicinal plants results from a variety of components contained in these plants (Tables 1 and 2). Many plant extracts (Table 3) have antihypertrophic scar activity owing to their phytochemical constituents. However, more work is needed to focus on purification and identification of active components and to elucidate the roles that these play in inhibition of scars when used alone or jointly. Moreover, many of them have not been tested for their cytotoxicity to normal cells, which seriously blocksin vivo investigations. Undeniably, no toxic and side effects have been proved for some active components. For example, Genistein, which is easily obtained and commonly used for hypertrophic scar treatment, has strong pharmacological effects, with no obvious toxicity or side effects [13].


## 4. New Preparations of Medicinal Plants

A large number of extracts and compounds of medicinal plants display antiscar activity. Nevertheless, drugs are difficult to get through the stratum corneum due to the natural barrier of skin, which causes lower permeability of drugs. The oral bioavailability of drugs at the permissive dose is very low, owing to their hydrophilicity (low permeability), poor absorption, and biotransformation or compact scar tissue. The appropriate form of prepared drugs can evidently improve drug permeability, lipid solubility, skin permeability, retention ratio, release time, and cytotoxicity. Hydroxycamptothecin (HCPT) is thought to be one of the most effective components against scars. However, the poor solubility and short half-life severely limit its clinical applications [65]. Compared with HCPT, the liposome-encapsulated HCPT (L-HCPT) can reduce epidural fibrosis by preventing the proliferation of fibroblasts in the scar tissue with longer half-life and better solubility [65]. The application of a silicone derivative to herbal extracts can improve skin pliability and alleviate the concomitant symptoms of scars including pain and itching [2]. However, it is extremely important to control the cytotoxicity of biomaterials for their clinical applications. Microemulsion, a transparent dispersion system, is a good vehicle for drug delivery due to its many advantages such as thermodynamic stability (long shelf life), easy formation (zero interfacial tension), low viscosity, high surface area (high solubilization capacity), and small droplet size [67]. It has been revealed that drug-free microemulsion is a promising preparation due to inapparent cytotoxicity [67]. The local or transdermal application of water-soluble pharmaceutical formulation may be suitable for medicinal plant extracts and compounds.Owing to compact scar tissue, it is necessary for the combination of natural products or crude extracts with some adjuvant as new dosage forms to increase their solubility, content, release time, uptake, and penetrability. These dosage forms include microemulsion [67], liposomes [66], solid lipid nanoparticle [68], and electrospun fibrous scaffolds [29]. Improvement of drug permeation may be a promising treatment in future research on the basis of the known medicinal plants.In addition, some of these plant extracts or purified chemical components are prepared as traditional medicinal injections for the deep antiscar treatment. For example,Carthamus tinctorius injection, whose primary component is hydroxysaflor yellow A, softens hypertrophic scar tissue and inhibits fibroblast proliferation by decreasing the type I/type III collagens ratio and the TGF-β1 level after local treatment [77]. Theradix astragali injection also inhibits the proliferation and reduces scar thickness and hardness by reducing Smad3 and TGF-β1 levels [78].


## 5. Current Treatment and Prospects for Future Therapies

Currently, occlusive dressings, compression therapy, intralesional steroid, cryosurgery, laser, radiation, surgical excision, and interferon therapy are curative for the majority of patients with hypertrophic scars [79]. Surgical therapy and excising fiber fraction are the common approaches for the treatment of hypertrophic scars. However, significant disadvantages were reported, such as the recurrence of adhesion after surgery as high as 45%–100% [54], which seriously limits its extensive application to scar prevention. Accordingly, physiotherapy is established, including occlusive dressings, pressure therapy, cryosurgery, radiation therapy, and laser therapy. Meanwhile, pharmacotherapy is also frequently applied, such as intralesional corticosteroid injection and topical drug treatment with interferon, bleomycin, 5-fluorouracil, verapamil, vitamin E, imiquimod, TGF-β3, or interleukin-10 [79, 80]. Pharmacotherapy mainly inhibits inflammation, proliferation, and remodeling phase [7] or modifies ECM metabolism via interfering the pivotal molecules of MAPK, TGF-β, and PI3K signaling transduction.However, there is no ideal treatment for hypertrophic scars so far and some chemical drugs also cause mal-effects simultaneously. Many kinds of natural products from medicinal plants have good antiscar activity and show notable advantages due to their fewer side-effects. Therefore, in addition to widespread uses of surgical therapy, physiotherapy, and pharmacotherapy, there is a great need for developing new natural drugs more efficient than or synergizing with the existing ones. Many kinds of purified natural products originated from medicinal plants are abundant in the natural environment, such as Ginsenoside Rg3 [29], Oleanolic Acid [54], Resveratrol [42], Asiaticoside [34], and Genistein [13], and are popular as antiscar agents due to their easy obtainment and fewer side-effects. Hence, we overviewed the major current herbs and their preparations applied to the treatment of hypertrophic scars.It is a challenge to identify and evaluate a safe, wholesome, and effective natural product against scars. Even though a number of new products have been reported by pharmacological tests in the last decades, many others remain unknown or untested.


## 6. Discussion

In this review, we gathered publications on medicinal plants with antihypertrophic scar activity and addressed the question whether the treatment of scars with medicinal plants is effective in humans. Althoughin vivo andin vitro investigations play an important role in the evaluation of safety and effectiveness of medicinal plants in preclinical trials, there is no perfect denouncement for their ultimate success as human drugs. Clearly, animal data are not sufficient for the confirmation of the safety and efficacy of medicinal plants in humans owing to their physiological structure differences. Furthermore, there are some conflicting clinical trials reported. For example, it has been reported that honey was effective in rapidly cleaning infection and promoting wound healing, indicating that honey possessed anti-infection activity [81]. However, it was also reported that honey did not affect the wound, scar, length, and remained length [82]. Therefore, the effectiveness of some drugs needs to be further clarified.On the other hand, only four publications reported negative results in our retried papers. Genistein phosphorylated c-Raf, MEK1/2, ERK1/2, and p38 proteins, but not JNK protein [14]. Asiaticoside had no effect on the expression of Smad2, Smad3, and Smad4 [34], while madecassoside regulated keloid-derived fibroblasts proliferation, migration, F-actin filaments, cytoskeletal protein actin, and the phosphorylation of cofilin via p38 MAPK and PI3K/AKT signaling, but not ERK1/2 and caspase-8 signaling [12]. Quercetin promoted phosphorylation of JNK and ERK, but not p38; it increased the protein and mRNA expression of MMP-1, but not type I collagen and TIMP-1 [38]. These studies indicate that the antiscar activity of medicinal plants needs to be scrutinized further.Many traditional medicines used in folk medicine are reported to have antiscar activity, but only a few have been studied systematicallyin vitro or/andin vivo, such as rhubarb [60] and tamarind [63]. Although numerousin vitrostudies have substantiated the antiscar activity of plant extracts and phytochemicals, there is very little evidence in humans. The number of clinical trials and their highlighted results are limited. The numerous traditional formulations effectively and extensively used in clinics have not been investigated. Also, the majority of the plants (Tables 1, 2, and 3) traditionally used as antiscar agents have not been investigated in animals. The phytochemicals within vitro antiscar activity may have no effectsin vivo due to the exceedingly high doses. Moreover, many of these phytochemicals have not been tested for their cytotoxicity, acute toxicity, or/and long-term toxicity in normal cells and animals, which seriously limitsin vivo investigations. Only two medicinal plants have been reported on their untoward reactions and cytotoxic effects. The clinical efficacy and safety should be investigated simultaneously for medicinal plant extracts and compounds.The natural barrier of skin can block drug getting through stratum corneum or decrease the amount of drug permeation, causing inefficiency or low-efficiency of drugs. Some adjuvants can significantly improve the penetrability of drugs and the desired therapeutic effects can be achieved. For example, hydroxycamptothecin (HCPT) is considered one of the most effective agents against scars, which prevents fibroblast proliferation and reduces epidural adhesion, but the poor solubility and short half-life severely limits its clinical application [65]. Some new dosage forms evidently reverse these conditions, such as microemulsion [67], liposomes [66], solid lipid nanoparticle [68], and electrospun fibrous scaffolds [29]. Therefore, the development of new dose types is necessary in order to ameliorate drug effects.Although enormous progress has been achieved over the last years, the impact of medicinal plants on individual types of scars needs to be explored in more detail. Polymechanistic phytochemicals such as Genistein may have an advantage over targeted therapeutics, which simultaneously tackle scar treatment from multiple angles. Genistein can act on many target points, including suppression of PDGF-promoted TPK activation, decrease of types I/III precollagen and PCNA expression, reduction of c-Raf, MEK1/2, ERK1/2, and p38 protein phosphorylation, and inhibition of RTK-Ras-MAPK (ERK/p38) [13]. Further insights into the molecular mechanisms of phytochemicals will facilitate the development of new drugs for the prevention and treatment of human scars.


## 7. Conclusion

In conclusion, the scaring process is complicated. The characteristics of an appropriate therapy for the prevention and treatment of scars should comprise the following: simple and easy delivery, comparability (effectiveness) with current therapies, and minimal drug interaction with concomitant treatments and lack of significant side effects [83]. Manyextracts and compounds from medicinal plants can inhibit scarring. The main mechanisms are suppression of proliferation and/or induction of apoptosis in scar fibroblasts by regulation of several pathways, such as MAPK, PI3K/AKT, RhoA/ROCK-I, VEGF, FAK, and TGF-β/Smad. Although the approaches described here are quite different and mechanisms are complicated, the utility should be maximized for medicinal plants as antihypertrophic scar agents. However, screening is necessary to minimize any potentially harmful side effects on human skin and health.



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