Calendula officinalis and Wound Healing: A Systematic Review

     Whether acute or chronic, wounds can compromise an individual’s wellbeing, self-image, working capacity, and independence.¹ These financial, social, and physical implications suggest that good wound management is necessary not only for the individual, but also for the community. While appropriate wound management by qualified healthcare professionals is an integral part of treatment success, dressing choice and specification is equally important. As previously argued, wound-healing agents should adhere to certain specifications. It has been suggested that these agents should facilitate granulation and collagen formation; promote normal immunity; debride wound slough and necrotic tissue; minimize microbial colonization; alleviate pain; and facilitate angiogenesis and tissue perfusion.² From a clinical perspective, an ideal wound dressing should also be cost-effective, produce minimal patient discomfort, and be easily applied and removed. However, few dressings satisfy all these criteria, although many therapies from the field of complementary and alternative medicine, particularly plant extracts, come close to resembling an ideal wound-healing agent. Such agents include aloe, Calendula, Gotu kola, Echinacea, St. John’s Wort, and Comfrey.³ Of these plants, traditional and laboratory evidence points toward Calendula as being the most favorable wound healing extract to date.      

Background

Description of Calendula.      Calendula officinalis, or pot marigold, is a common garden plant belonging to the Compositae family. Native to Southern Europe, Calendula grows up to 60 cm in height and produces large yellow or orange flowers.^4–6 The flowers are the part of the herb used medicinally,^6–8 either in the form of infusions, tinctures, liquid extracts, creams or ointments, or in one of a number of skin and hair products available over-the-counter across the globe.⁹      Indications and actions.      For centuries, Calendula flowers have been used to treat a number of clinical conditions, specifically, the treatment of dermatological disorders (Table 1). Whilst the many chemical constituents within Calendula and the numerous actions of the plant (Table 2) suggest that Calendula may be effective in treating a myriad of complaints, there is currently insufficient clinical evidence to support the use of pot marigold in conditions other than cutaneous lesions.
     Chemical components.      The clinical effects of pot marigold are attributed to a number of chemical constituents (Table 3). The main compounds within Calendula are the triterpenoids,¹⁰ which are claimed to be the most important anti-inflammatory and antiedematous components within the plant, particularly faradiol and the faradiol monoester, respectively, which both exert a dose-dependent effect comparable to indomethacin.^10,11 Other constituents identified in Calendula such as the saponins, micronutrients, flavonoids, and polysaccharides, may also be responsible for the antiedematous, anti-inflammatory, antioxidant, and wound healing effect of the plant.^11–14      Apart from the effects aforementioned, the polysaccharides in Calendula flowers also demonstrate strong bioadhesion to porcine buccal membranes when compared to Dextran and 9 other plant extracts.¹³ This bioadhesive or mucilaginous effect may not only help to decrease local inflammation by shielding tissues from irritants, but also facilitate tissue hydration.¹³ However, it is unclear if this effect would be evident clinically using a standard plant extract, or when other physiological factors are taken into account such as wound exudation, salivation, and cellular interaction.      Despite the potential application of pot marigold in conventional wound management, there has been no systematic review of the recent literature to evaluate the clinical effectiveness of Calendula. Thus, there is a need to address this gap in the literature in order to provide health professionals with the best available evidence on the use of Calendula in wound management.

Methods

     A comprehensive search of the literature was conducted in April 2007 using the following databases: AARP Ageline, Allied and Complementary Medicine; Australasian Medical Index (AMI); BioMed Central Gateway, CAM on PubMed, CENTRAL, CINAHL, Cochrane Library, Current Contents Connect, Current Controlled Trials, Database of Abstracts of Reviews of Effectiveness (DARE), Dissertations Abstracts International, EMBASE, Health Source nursing/academic edition, International Pharmaceutical Abstract, MEDLINE, and Turning Research Into Practice (TRIP). Manufacturers of Calendula products were also contacted to identify studies that were not listed in the search. The key terms used in the search were Asteraceae, burns, Calendula, clinical trial, controlled clinical trial, compositae, double-blind method, injuries, foot ulcer, leg ulcer, marigold, placebo, pressure ulcer, prospective studies, randomized controlled trial, single-blind method, skin, skin ulcer, skin diseases, ulcer, varicose ulcer, wounds, and wound healing. The search was limited to randomized controlled trials that used topically administered monopreparations of Calendula officinalis for wounds of any type. Combination or homeopathic preparations of Calendula, and studies with insufficient detail were excluded from the review. Six clinical trials that met the inclusion criteria were identified.      To determine whether the identified studies were of good quality, each publication was critically appraised using the Joanna Briggs Institute (JBI) critical appraisal of evidence of effectiveness tool, which required the reviewer to respond to 11 questions about the design of the study. A trial with a score of 6/11 or above was considered to have low to moderate bias.

Results

     Of the 6 trials identified, 1 had moderate bias (appraisal score 6/11);¹⁶ 4 had high bias (appraisal score
< 4/11),^17–20 and 1 provided insufficient details in English.²¹ Thus, given that only 1 trial was of good quality, and that the Calendula formulations used in the identified trials, as well as the types of wounds treated were not comparable, statistical pooling of results was not appropriate. Therefore, this review can only provide a narrative review of Calendula officinalis for wound healing. This review will structure the discussion around the properties that constitute an ideal wound-healing agent.      

Discussion

     Anti-inflammatory activity. The acute inflammatory response during the early stages of injury generates factors that are essential for tissue growth and repair.²² When prolonged, however, chronic inflammation can be detrimental, preventing wound remodeling and matrix synthesis, leading to delays in wound closure and an increase in wound pain.²³ Thus, it is plausible that an anti-inflammatory effect could facilitate wound healing and improve patient comfort. Although traditional texts and animal studies indicate that Calendula extract exerts an anti-inflammatory effect,^11,24,25 there is a paucity of clinical evidence to support this claim. In one single-blind randomized controlled trial of 254 patients with breast cancer, the topical administration of Calendula officinalis ointment twice daily to irradiated skin resulted in a significantly lower incidence of acute radiation induced dermatitis (P < 0.001), as well as lower maximal pain scores (P = 0.03) when compared to trolamine—a topical analgesic.¹⁶ Whilst a reduction in the occurrence of dermatitis could be explained by an anti-inflammatory effect, it is also possible that the dermatitis was prevented by way of an antioxidant effect. Thus, the efficacy of Calendula as an anti-inflammatory agent in humans remains inconclusive.
     Antioxidant effect. The production of free radicals at or around the wound bed may contribute to delays in wound healing through the destruction of lipids, proteins, collagen, proteoglycan, and hyaluronic acid.²⁶ Agents that demonstrate significant antioxidant activity may, therefore, preserve viable tissue and facilitate wound healing. Given that the butanolic extract of Calendula demonstrates free radical scavenging activity against superoxide radicals and hydroxyl radicals in vitro in a dose dependent manner; that the same extract inhibits iron ascorbate-induced lipid peroxidation in rat liver microsomes;²⁷ and that several organic solvent extracts of Calendula inhibit lipid peroxidation of liposomes in vitro,¹² it is argued that Calendula may facilitate wound healing via an important antioxidant effect. Clinical research is needed to validate these findings.      Antimicrobial activity. Wound healing can also be delayed when microorganisms are present in large enough numbers.^22,28 Therefore, reducing the bacterial load of a wound may be necessary to facilitate wound healing, as well as reduce local inflammation and tissue destruction.²⁹ An ideal agent for the prevention and control of wound infection would therefore be one that directly destroys pathogens, while also stimulating immune activity. Calendula is one agent that possesses both of these properties. Studies have shown that the polysaccharide fraction of Calendula officinalis stimulates phagocytic activity of human granulocytes in vivo³⁰ and phagocytic activity in mice,^31,32 while the ethanolic extract of Calendula stimulates mixed human lymphocyte proliferation in vitro.³³ Adding to this, when applied to rats with ellipsoid cutaneous excisions, the daily application of 4% Calendula and 1% allantoin ointment for 21 days generated greater phagocytic activity, macrophage differentiation, granulation, and epithelialization than the use of either allantoin or plain ointment alone.³⁴ The clinical significance of this immunomodulatory effect is further highlighted in the following studies where wound infection was used as the main outcome measure.      An open, randomized, controlled, multicenter trial involving 156 patients compared the effectiveness of daily applications of 3 different ointments in the management of second- and third-degree burns over a mean period of 17 days^.20 Although the prevention of eschar formation and local infection was similar between the Calendula (ointment containing 20% fresh plant in a petroleum jelly base) and Elase (proteolytic ointment) groups, a marginally significant difference in these outcomes favored Calendula over petroleum jelly (P = 0.05). The open design of this study, however, suggests that these findings be considered with caution.      In another randomized, controlled trial, 18 patients with trophic ulceration were randomly allocated to 1 of 3 blinded treatments: 10% Calendula ointment, topical neomycin, or placebo paraffin ointment. The topical application of Calendula ointment prevented secondary infection and demonstrated a 30%–40% reduction in wound diameter and depth within 4 weeks.¹⁸ The comparative effects of neomycin and placebo ointment on wound healing, however, were not detailed.      The ability of Calendula to prevent wound infection may not only be attributed to the immunomodulating effect of the plant, but also to an antimicrobial effect. Experimental studies have demonstrated that extracts of Calendula flower have a high degree of activity against 18 different strains of anaerobic and facultative aerobic periodontal bacteria in vitro,³⁵ and against 4 different types of fungi, with the inhibitory effect being comparable to that exerted by the antifungal agents Amphotericin B and Nystatin.³⁶ While this antibacterial effect has been demonstrated clinically in 65 patients with chronic suppurative otitis using a 20% tincture of Calendula flowers,³⁷ details of this study are limited, and therefore, these findings should be interpreted with caution. It should also be noted that in order for the above mentioned laboratory findings to be clinically relevant, further investigation is needed to identify whether the antimicrobial effect of Calendula can be altered by the presence of bodily fluids or by the carrier agent used in the formulation, much like reports in studies on essential oils.³⁸      Wound healing activity. The most important clinical endpoint in wound management is wound closure or 100% epithelialization.³⁹ Given that wound closure is critically important; it is argued that any agent demonstrating significant wound-healing activity should be seriously considered in conventional practice. Calendula, for example, may facilitate wound healing by increasing both wound angiogenesis40 and collagen, nucleoprotein, and glycoprotein metabolism^34,41 leading to improvements in both local circulation and granulation tissue formation.⁴² Several experimental studies lend support to these claims demonstrating that the daily application of a 1:10 alcoholic extract of Calendula⁴³ or Calendula cream⁴⁴ to paravertebral incisions in rats facilitates collagen maturation and epithelialization within 10 to 25 days.      In a poorly defined trial of 50 patients with slowly healing wounds and amputation stumps, treatment with a topical Calendula preparation for an unknown period was examined.⁴⁵ The trial found wound granulation appeared within several days of initiating the Calendula treatment, and secondary skin development had occurred within 10–14 days. Researchers also found that the Calendula treatment reduced discomfort during dressing changes, and that the treatment was more cost effective than other medicines used. However, given the lack of details on the study design and interventions, these results must be considered with caution.      The wound healing effect of 2 different Calendula preparations were compared in another poorly defined trial involving 38 patients with venous ulceration, burns, or skin lesions.²¹ Patients from each wound class were equally divided into 2 groups. In the first group (n = 19), wounds were cleaned daily with a solution containing 90% distilled water and 10% Calendula officinalis tincture until the wound healed. In the second group (n = 19), the Calendula solution was also used to clean the wound, but in addition, wounds were dressed with a thin film of Carbopol 900 gel containing 2% Calendula tincture. The study found that cleaning venous ulcers, burns, and skin lesions with 10% Calendula solution followed by daily application of 2% Calendula gel resulted in a greater number of healed wounds, as well as a reduction in the median time to heal when compared to using Calendula solution alone. The outcome of this study is further supported by a more recent controlled trial in which the effect of twice-daily applications of 7.5% Calendula ointment were compared to daily applications or saline dressings in 34 patients with venous leg ulcers.¹⁷ After 3 weeks of treatment the total surface area of wounds in the Calendula group decreased by 42% compared to 15% in the control group. The difference between the 2 groups was statistically significant (P < 0.05). While these results are promising, there is a lack of information from both trials about the controls used, the selection of participants, and the secondary dressings applied, which casts doubt over the generalizability of these findings.      A number of other studies have examined the healing effects of Calendula within combination preparations,^46–48 but given the nature of these formulations, it is impossible to isolate the effects of Calendula from the other extracts. Therefore, these studies were omitted from this review.      Analgesic activity. Given that open wounds can generate pain and subsequent disability, it is important that the dressing applied does not increase pain, and if possible, lessens pain. To date, no studies have specifically investigated the analgesic effects of Calendula, but there is some suggestion that Calendula may decrease wound pain. For example, in one open-label study, 30 patients with grade 1 and 2a burns were treated topically with a hydrogel preparation containing 10% Calendula officinalis tincture 3 times a day for 13–14 days.⁴⁹ While details of this trial are limited, researchers indicated improvement in pain control, erythema, swelling, soreness, blistering, and heat sensitivity; tolerance to the topical preparation was also good. Even so, no firm conclusions can be made from this small, uncontrolled pilot study until more rigorous research is conducted.      Adverse effects. Calendula officinalis is considered a safe herb with only a few cases of allergy reported in susceptible individuals.⁵⁰ In terms of toxicity, in-vitro testing of 6 saponins (400 µg) from an ethanolic extract of Calendula officinalis flowers found the saponins to be nontoxic and nonmutagenic.⁵¹ Three of the 6 saponins decreased the mutagenic effects of smoker urine on various strains of Salmonella typhimurium.⁵¹ These antimutagenic effects have also been supported in studies on mice using 80% ethanolic extracts of Calendula.⁵² The safety of Calendula is further supported by data from toxicity studies using the whole plant extract, which reported the oral and intraperitoneal LD-50 of Calendula officinalis extract in mice to be > 4640 mg/kg and 300 mg/kg, respectively.⁹ There is, however, insufficient data on the chronic toxicity of orally administered pot marigold. Nevertheless, given that Calendula is most frequently administered as an external agent, the safety of the topical formulation is most important to clinicians. To date, reports affirm that topical applications of Calendula are safe. Studies have shown topical Calendula causes no dermal irritant effect in rabbits, minimal ocular irritation in rabbits and humans, and no sensitization or photosensitivity reaction in guinea pigs or humans.⁹ As such, Calendula officinalis has been approved by the German Health Commission for topical administration in oral and pharyngeal mucosal inflammation, poorly healing wounds, and leg ulceration.⁵³      Cautions and contraindications. There are no reported contraindications with the use of Calendula officinalis and no known interactions between Calendula and other medications when administered topically.^50,54,55 However, it is advised that individuals with a known sensitivity to other species in the Compositae family, such as Ragweed, Chrysanthemum, and Daisy avoid using Calendula due to the potential risk of allergic reaction.⁵⁰ Yet, there are little data to support this claim. Bruynzeel et al⁵⁶ report that of 1032 consecutive patients attending 6 different patch testing clinics across the Netherlands, of which each patient was patch tested with 5 ointments each containing a different plant extract, only 2/1032 (0.2%) demonstrated contact sensitivity to an ointment containing 10% Calendula tincture. Furthermore, Bruynzeel et al did not establish whether the sensitivity reaction was attributed to the Calendula tincture, the preservative, or the ointment base. It must also be noted that patch testing can produce false positives and therefore, the incidence of contact sensitization to Calendula is likely to be less than 0.2%.⁵⁷ The low incidence of contact dermatitis associated with topical Calendula extract is further supported by a number of other studies.⁹
     

Conclusion

Calendula officinalis possesses a number of properties that are conducive to wound healing. Clinical data support several of these properties using topical applications of 2%–10% Calendula ointment or ethanolic extract in a number of acute and chronic wounds, particularly for its effect on inflammation, microbial load, and epithelialization. However, such evidence is weak and warrants further investigation using more rigorous clinical trials.