Medicinal Plants for the Treatment of Hypertrophic Scars

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 tested in 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.


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][7][8][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.

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. 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. Figure 2 and Tables 5 and 6 summarize and enumerate the suggested mechanisms and correlative medicinal plants.
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.

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 Tables 1 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)  The 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 blocks in 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].

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), 4 Evidence-Based Complementary and Alternative Medicine    Evidence-Based Complementary and Alternative Medicine 9 10 Evidence-Based Complementary and Alternative Medicine 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 halflife 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 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-1 level after local treatment [77]. The radix astragali injection also inhibits the proliferation and reduces scar thickness and hardness by reducing Smad3 and TGF-1 levels [78].

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-3 , 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-, and PI3K signaling transduction. However, there is no ideal treatment for hypertrophic scars so far and some chemical drugs also cause maleffects 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.

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. Although in vivo and in 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 systematically in vitro or/and in vivo, such as rhubarb [60] and tamarind [63]. Although numerous in vitro studies 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 with in vitro antiscar activity may have no effects in 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 limits in 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.

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-/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.