Mechanism of Action of Wound Healing Activity of Calendula officinalis: A Comprehensive Review
Bhargab Deka1, Bedanta Bhattacharjee1, Anshul Shakya1, Abu Md Ashif Ikbal2*, Chayanika Goswami3, Santa Sarma3
1Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh – 786 004, Assam, India
Received: 24-Oct-2020 , Accepted: 30-Dec-2020
Keywords: Calendula officinalis, Wound healing, Tissue regeneration
How To Cite
Calendula officinalis is a short-lived aromatic herbaceous perennial plant. According to scientific literature, Calendula officinalis can also boost the wound healing activity. While the precise means it does is still unclear, it was assumed that the herb would increases the blood flow to the wound area, therefore supplying oxygen and nutrients necessary for tissue regeneration. The objective of the review is to understand and explore the relevant phytochemical and pharmacological information which will enhance it effective wound healing mechanism. The data were identified using PubMed, Google Scholar, Scopus and bibliographic reviews of recent and old articles from an English literature search. After independent analysis by co-authors of the identified articles, data were analysed and extracted for the stated purpose.Calendula officinalis with its high quantity of flavonoids, it can help to minimize inflammation and speed up the healing process. Additional usage for Calendula officinalis is that it can be a calming ointment, wash or tincture , since it can help to alleviate irritated wounds and minimize swelling and inflammation. Wound healing is a complex process, and Calendula officinalis have been historically used to treat minor wounds, skin irritation and minor burns. Data from large comparative clinical trials are needed before routine use can be recommended. Pharmacists and clinicians can effectively address patient questions about wound care and herbal therapies to help promote wound care practices that encourages wound healing and minimize poor outcomes such as infection or scaring.
Wounds and skin disease can be both socially and financially burdensome to an individual. Skin ulcers and wounds ranked in the top 5 of the most economically burdensome skin diseases1. Wound care products and therapies can promote the healing process, decreased the formation of wounds and enhances the properties of the fresh skin. Certain natural compounds have demonstrated potential anti-inflammatory, antimicrobial, and cell-stimulating properties that may aid wound healing2,3. These complementary and alternative medicine (CAM) therapies using plant extracts have been used in wound healing for centuries. Homeopathic treatments as discussed here are a branch of CAM therapy.
Approximately 33% of US adults use some form of CAM4,5. In addition, over 15 million Americans use CAM (herbal products [including homeopathic] or high-dose vitamins) with their prescription medications4. Comparative clinical trials for homeopathic medications are becoming more common; however, the complexity of standardizing scientific methods for CAM therapies is difficult. The evidence-based data supporting the use of CAM is lacking4. CAM therapies for wound healing are typically less expensive than prescription medications but have not been associated with bacterial resistance2,3. Several CAM therapies have been used historically for potential effect s on skin healing; however, these products have not shown clear benefits in clinical trials. Some of these well-known products include aloe vera, ginkgo biloba, St. John’s wort, and honey. Additionally, other plant extracts such as tea tree oil, oak bark, and Calendula officinalis extract have also been used for their effects on wound healing. This article focus on CAM in wound healing and, more specifically, the use of Calendula officinalis.
Skin disorders and wounds are generally defined based on the depth of injury, healing time, healing progression, underlying pathology, associated risk of mortality, and the effect on quality of life 6,7. Surgical and traumatic wounds, burns, radiation dermatitis, and abrasions (including scrapes and microdermabrasion) are considered acute wounds, while venous and arterial leg ulcers, fungating wounds, pressure ulcers, and diabetic ulcers are classified as chronic wounds. Healing time and sequence also delineates acute versus chronic wounds. In general, acute wounds can repair themselves in an orderly and timely manner unlike chronic wounds 8.
Typical wound healing progresses through key phases. All phases must occur in an overlapping sequence and progress until healing is complete 9,10. Minor wounds are superficial, shallow, noninfected wounds that occur in patients without comorbid conditions that could complicate treatment (such as diabetes or immune deficiencies). Phase 1 of wound healing controls bleeding9,11. Vascular constriction, platelet migration, and fibrin clot formation reestablish hemostasis shortly after vascular injury and provide an extracellular matrix for cell migration. Through this process, mediators of wound healing attract inflammatory cells to the area of injury progressing into the next phase of inflammation10. Phase 2 overlaps with the previous hemostasis and coagulation phase and begins within a few hours of injury. It is primarily defined by the accumulation of leukocytes and macrophages11,12. Macrophages enter the wound site and release growth factors, such as platelet- derived growth factor, which facilitate the formation of new connective tissue (i.e. granular tissue)11. Macrophages also help resolve inflammation and stimulate tissue regeneration, facilitating the transition from the inflammatory to reparative phases of proliferation and remodeling9. Occurring between 3 to 21 days post injury, phase 3 (proliferation) is characterized by granulation tissue formation, re-epithelialization of the wound surface, and contraction of the wound margins9.12. Granulation tissue will contain macrophages, fibroblasts, and immature collagen, all of which stimulate granulation tissue formation. Concurrently, blood vessels will stimulate capillary growth. Fibroblasts within the wound bed stimulate the production of collagen, one of the key components of the extracellular matrix.
The final phase of wound healing (phase 4) can last for years and involves the reorganization of collagen fibers to create new skin9,12. New skin may gain less than a quarter of its final strength in the first 3 weeks and rarely ever reaches the same strength as uninjured skin11.
MOLECULAR MECHANISM OF WOUND HEALING
Molecular Mechanism of Platelets on Wound Healing
In the initial stage of injury platelets were activated and it has an important role in clot formation during hemostasis after aggregation and attachment to the exposed collagen surfaces. The cytokines and other growth factors regulate the process. Cytokines acts on target cells by various routes like endocrine, paracrine, autocrine or intracrine routes and activate target cells thereby activating other cell signalling pathway. Cytokines can play various roles by acting on different targets.
Molecular Mechanism in the Inflammatory Cells on Wound Healing
Chemokines, which are small heparin binding proteins, promotes the movement of circulating inflammatory cells to the injury sites through the interaction with specific membrane bound receptors. Neutrophiles are the main cell type in the initial inflammation phase and begins to disappear after 24 – 36 h by cell death in the time of circulating monocytes enter the wound and mature into tissue macrophages that play crucial role in the healing of wounds. This mechanism is regulated by the chemokines IL – 8 which is released by neutrophiles which attracts the macrophages and other cells to the wound site.
Molecular biology in repair cells on wound healing
In correlation to macrophage – synthesized growth factors viz. PDGF, FGF, VEGF, TGF-alpha, TGF- beta, KGF etc. the fibroblast a component of granulation tissue, starts to migrate, proliferate and produce the components of ECM, such as glycosaminoglycans and proteoglycans as well as collagen, a critical event in the proliferation phase and wound healing in general. Collagen is secreted to the extracellular space in the form of procollagen and then cleaved of its terminal segments, which is known as tropocollagen. Tropocollagen aggregates with other similar molecules to form collagen filaments that are enriched in hydroxylysine and hydroxyproline moieties and enable it to form strong cross links.
The stability of the collagen fiber is based on the intermolecular cross – links makes collagen fiber more resistant. Higher the cross – links of collagen, more will be the bursting strength in wound healing.Thus, collagen forms close cross – links with other collagens and with protein molecules thereby increasing the tensile strength of the healing wound13.
REGULATIONS OF HERBAL MEDICINES
WHO has updated and released the guidelines and policies regarding herbal medicines time to time including the areas ranging from GACP (Good Agricultural and Collection Practices), GMP (Good Manufacturing Practices) etc. These guidelines and policies taken by WHO will help to address the variations in regulations and place the herbal medicine in the Global Market. Under the Drug and Cosmetic Act 1940 and Rules 1945 in India, herbal drugs are regulated which controls licensing, formulations, manufacturing, labeling, packing, import and export14.
Calendula officinalis is a well known medicinal plants, and plant image display in Fig 1. It is native to Asia and southern Europe, but commonly found in gardens around the world. It is commonly known as Pot marigold , has been used in many forms and for centuries as an herbal remedy belonging to the family Asteraceae used for the treatment of wounds, burns, abrasions and dermatitis17. Calendula officinalis leaves, flowers, extract possess wide range of pharmacological activity viz wound healing, diaphoretic, analgesic, anti-inflammatory, anti-HIV18.
The chemical components include triterpenoids, saponins, flavonoids, carotenoids, fatty acids, polysaccharides, essential oils. The concentrations of these compounds vary depending on geographical area, although the observed physiological effects of topical Calendula officinalis appear to be consistent. In vitro studies shown that plant extract of Calendula officinalis show cytotoxic and tumor reducing potential on various tumor cell lines derived from cervix, breast, leukemias, prostate, fibrosacomas17,19. Generally, for the treatment of peptic ulcer, duodenal ulcer , gastritis, colitis, mucous membrane inflammation it has also been used internally. Calendula officinalis is available in various formulations including creams, lotions, ointments, and gels. For general use, 2%-5% ointment may be applied 3 to 4 times daily as needed. After tooth extraction it is also used as a mouth wash20. The Pharmacognostical profile and Organoleptic properties of the Calendula officinalis have been compiled in the Table 1.
PHYTOCHEMISTRY OF Calendula officinalis
Calendula officinalis flower, leaves , root is a rich source of secondary plant metabolites and they differ in different part of the plant25. The amount of these phytometabolites may varies according to the season, soil composition and harvesting time25,27,28. Terpenoids, Flavonoids, quinones, coumarins and volatile oils are commonly present in Calendula officinalis29,30. The major phytochemicals present in different parts of the plants are mentioned in Table 2. The structure of some important bioactive components are illustrated in Fig 2.
WOUND HEALING ACTIVITY OF Calendula officinalis
In ayurvedic system of medicine , it seems like Calendula officinalis possess scar easing and emollient properties by significantly raising the amount of collagen metabolism , wound angiogenesis in wound areas43 . By addition of Calendula officinalis flower extract , Hill et al ., demonstrated a experimentation conducted on scar reducing and massage emollient properties produce promising effective results44. Ethanolic , hexane and dichloromethane fraction of Calendula officinalis in experimental model enhance wound healing and angiogenic activities. Treatment with ethanolic extract of Calendula officinalis increased the amount of blood vessel and decreased in wound area compared to reference group45. Another study suggested that application of Calendula officinalis extract profoundly enhances epithelization in chronic venous ulceration. In the thermal induced burns in rats, treatment with ethanolic floral extact of Calendula officinalis showed significant improvement in wound healing activity by increasing the level of hexosamine and collagen hydroxyproline content. Similarly, the levels of tissue damage markers (alanine and aspartate amino transferase, alkaline phosphatase), acute phase protein (orosomycid, heptaglobulin), lipid peroxidation should be decreased due to its potential antioxidant property46. Ethanolic extract of Calendula officinalis significantly increase collagen synthesis and blood flow to the effective wounded sites47. Due to its antimicrobial and antioxidant action, 2% Calendula officinalis gel and its daily application produces better healing of wounds48. Antiseptic and anti-inflammatory properties of Calendula officinalis extract heals wound along with internal as well as external ulcers. Because of its good stability, penetrability and ease of application the ointment base of Calendula officinalis is more acceptable in hydrophobic medium49,50.
10% Calendula officinalis ointment prescribed for Cheilitis exfoliative51. In vivo model of excisional wounds of BALB/c mice, Calendula officinalis may help to induce granulation tissue formation by altering the appearance of connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA)52. An overview of wound healing mechanism of Calendula officinalis as presented in Fig 3.
THERAPEUTIC USES OF Calendula Officinalis
Minor Wounds, Burns, And Abrasions
Historically, topical Calendula officinalis was used to treat minor wounds, burns, and abrasions; however, few clinical trials have been conducted to assess its efficacy and safety for these indications.
An animal study suggests that Calendula officinalis is beneficial for wound healing, though, such conclusions cannot be reasonably extrapolated to humans87. Currently, more clinical studies need to be conducted in humans for this specific indication48.
Venous ulcer or stasis ulcer is the most common etiology of lower extremity ulceration and affects approximately 1% of Americans88. Venous ulcers are irregular, shallow, and usually recurrent. Treatment typically includes leg elevation, compression therapy, wound dressings, pentoxifylline, and aspirin88. Calendula officinalis has been studied as a possible treatment for venous leg ulcers.
In an open, comparative clinical trial, 34 patients with venous leg ulcers were treated with either an ointment containing 7.5% marigold extract in a neutral petrolatum base (from a local source in Serbia and Montenegro) applied twice daily for 3 weeks or saline solution dressings applied for 3 weeks89.
At the end of the 3-week study period, patients treated with the Calendula officinalis ointment had a statistically significant reduction in the aggregate ulcer surface area compared with those in the placebo group (-41.71% vs -14.52%, respectively; P < 0.05). The number of wounds achieving complete epithelialization was similar in both groups (7/21 Calendula officinalis vs 4/13 placebo). Adverse effects were not reported. Despite the positive results, this study lacked an adequate control group, was not blinded, and had a small study population. Further clinical trials are warranted as benefit was shown89.
Radiation Dermatitis in Patients With Breast Cancer
Radiation dermatitis is a cutaneous repercussion of the external beam ionizing radiation used to treat malignancies90. Also called “radiation skin damage” or a “radiation burn,” it affects approximately 95% of patients receiving radiotherapy. Skin changes after radiotherapy may be minor, reversible, and self-limiting, but can be serious and lead to ulceration, infection, or permanent skin damage in some patients. Protective agents have been investigated. Controlled studies have not shown conclusive results in favor of specific agents, but patients have anecdotally noted satisfaction with ointments90. Calendula officinalis has also been studied in the prevention of radiation dermatitis.
Calendula officinalis was evaluated in an open, phase 3, single center clinical trial for the prevention of radiation dermatitis following radiotherapy for breast cancer91. Women (n = 254) were randomized to be treated with Calendula officinalis extract in petroleum jelly (Pommade au Calendula officinalis par Digestion; n= 126) or trolamine, the standard of care, (n = 128) applied by patients at least twice daily. Patients with more pain or erythema applied the products more frequently.
At the end of the study, Radiation Therapy Oncology Group (RTOG) grade 2 or higher dermatitis was reported less by patients receiving Calendula officinalis compared with those in the trolamine group (41% vs 63%, respectively; P < .001). Fewer patients treated with Calendula officinalis vs trolamine experienced grade 3 toxicity (7% vs 20%, respectively; P = .034), required treatment interruption (1 vs 15 patients), or had an allergic reaction to the cream (0 vs 4 patients). Despite better overall outcomes, patients reported that it was more difficult to use the Calendula officinalis formulation than trolamine (30% vs 5%, respectively) and more physicians felt that there was less compliance with Calendula officinalis than with trolamine (84% vs 92%, respectively)91. Study limitations include a lack of treatment blinding and the use of petroleum jelly (which itself may have beneficial effects) in the Calendula officinalis formation.
A randomized, phase 3 study compared a 10% Calendula officinalis cream to an aqueous cream (moisturizer) without parabens (standard of care) applied twice daily before, during courses, and after radiation therapy for breast cancer92. Each treatment was applied starting with the initial radiotherapy session and was continued until 2 weeks after the last session or until any acute radiation skin reaction was healed. There were 390 patients included in the study with 194 receiving Calendula officinalis cream and 196 receiving aqueous cream. No difference was observed between the use of Calendula officinalis cream compared with aqueous cream for the incidence of RTOG grade 2 or greater dermatitis (23% vs 19%, respectively; P = .39). In addition, no differences were reported for other efficacy outcomes such as patient-reported symptoms like itchiness and pain. However, patients reported that the Calendula officinalis product was not as easy to apply and had worse absorption quality than the aqueous cream92.
Excessivedoses of Calendula officinalis has been found to possess hypertensive effects. Thereby, in combination with hypertensive drugs may result in additive effects93.
Excessive doses of ingested preparation of Calendula officinalis has been found to possess sedative effects. Thereby, in combination with sedative agents may attributed additive effects. Calendula officinalis has been shown to increase the sleep time caused by hexobarbital in rats93.
Calendula officinalis can increased the activity of insulin or hypoglycemic drugs93.
Lipid lowering agent
Agents that minimize lipids and triglycerides , Calendula officinalis can have an additive effect93.
ROLE OF THE PHARMACIST AND CLINICIAN IN THERAPY
When recommending a topical product for wound care, one should consider the proper dosage and frequency of application, patient age and weight, and the physical form of the preparation to be applied. Various drug vehicles have specific advantages and disadvantages, as described previously66.
Patient assessments and histories are necessary to develop a plan of care for any skin condition. Items identified through a patient interview should guide treatment and identify areas of additional need, such as patient and family support, education, and goals of care. Patient information that should be obtained include: chief complaint; a detailed medical history including concurrent illnesses; allergies and past medical conditions; medication history, as well as herbal and nutritional supplements; use of self- care products; current diet; tobacco use, alcohol consumption, and exercise routine; and social interactions, hobbies, and mobility, with a focus on the effects of these on wound healing.
Safety risks, such as allergic reactions, exist with any product, but may be increased with herbal products. In addition, a lack of regulation in the production of herbal and alternative products could result in products having additives and preservatives94. To address these concerns, pharmacists and other health care practitioners should always recommend using products from trusted manufacturers and, in the case of supplements taken by mouth, ensure that they are US Pharmacopeia (USP) verified. The label with USP Verified Mark shows that the product95 :
Carries the proclaim potency and amount of the ingredients listed
- Does not have specified contaminants present in harmful levels
- Meets dissolution standards
- Has been manufactured according to FDA and USP guidelines for safe, sanitary, and well-controlled manufacturing practices
Advise patients to know and watch for symptoms of an allergic reaction and discontinue using the product if allergy symptoms appear. For minor skin wounds and abrasions, pharmacists and nurse practitioners may assist with proper selection of self-care products for appropriate wound dressing and infection prevention. Pharmacists and clinicians can help patients navigate the multitude of available preparations and recommend appropriate delivery systems that are best suited for particular skin conditions (as described previously). Additional Calendula officinalis and wound care resources for pharmacists, nurse practitioners, and patients are provided in the table. As front-line health care providers, pharmacists and nurse practitioners may also identify patients with more serious or nonhealing wounds that require the care of a physician. These patients should be referred immediately96.
TOXICOLOGICAL EFFECT OF Calendula officinalis
Calendula officinalis extract has been found to be safe, non irritating, non genotoxic and nonmutagenic97. Oral administration of floral extract of C.officinalis 0.15g/kg/day given for a period of 18 months in hamstr were found to be non toxic98. Dermal application of floral extract of C.officinalis produces allergic reaction in human evaluated by the patch testing method reported in clinical studies99. Similarly, Bone; Braun and Cohen also advised to patients and use Calendula officinalis preparation with caution. Patients with low immunity who are in close contact with Calendula officinalis showed an allergic reaction100. Calendula officinalis has the ability to stimulate labor , so pregnant women are specially recommended to take care when using Calendula officinalis preparation101.
In traditional medicine system , C.officinalis flowers are reported to be used for treating wounds, scars, skin damage, ulcers. The therapeutic application of Calendula officinalis having promising effect are assessed in human studies are compiled in Table 3. Topical application of Calendula officinalis suspension or in tincture is used for the treatment of reducing inflammation, controlling bleeding, acne. Additionally, it improve the blood flow to the affected areas and it heals internal as well as external ulcers.
FUTURE PROSPECTS OF HERBAL DRUGS
Now a days people are showing more interest towards the herbal medicines compared to synthetic drug due to its minimum side effects and economic. The various types of Phyto-pharmaceutical are present in the natural products which deliver different types pharmacological activities. The therapeutic efficacy of medicinal plant depends upon the concentration of phytochemical components such as alkaloid, glycoside, tannin, polyphenol, flavonoids, steroids, terpenoids, etc.
The extract of medicinal plant contains more than one phytoconstituents and produce synergistic effects along with antioxidant property. The flavonoids and polyphenol present in Calendula officinalis reduced the oxidative stress in the body and boost the normal cells to fight the diseases with more potency. These antioxidant components are used as nutrient supplement which keep body healthy by increasing the immunity system. It has been reported that the herbal medicines eradicate the diseases from the root level, while the synthetic drug suppressed the diseases. Presently, the novel drug delivery system such as Phytosomes, Liposomes, Niosomes etc improved the bioavailability and therapeutic efficacy of herbal extract.
Calendula officinalis is a important medicinal plant and used for the treatment of various diseases. Calendula officinalis is mostly used for the healing of wound by herbal practitioner and the data presented in the paper support significant wound healing activity. Further, health care practitioners should understand the use of CAM for wound healing to assist patients seeking self-care.
CONFLICT OF INTEREST
BD, BB, AS, AMAI, CG and SS equally contributed in the preparation of manuscript, and all author approved for the publication.
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