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126 T. K. Biswas et al.
pre-clinical trial reports of many drugs of plant origin which can perform these
biochemical and pharmacological activities though reports from randomized controlled clinical trial are rare. However, stimulating reports from RCT using Aloe
Vera exist and follow.
Aloe Vera
Aloe vera (L) Burm. f. (family Asphodelaceae) is a plant of cactus species, widely
available throughout the world. The plant is being used for various therapeutic
purposes since 1500 BC in Egypt, India, Greece, Rome and China (Oliveira et al.
2016). The fleshy mucilaginous part of the centre of leaves of the plant is used for
different therapeutic purpose including wound healing (Fig. 2).
The plant is often confused with its other variety Aloe barbadensis is but these two
are separate plants and have differences of therapeutic activities. It is reported that
about seventy-five varieties of chemical components are available in Aloe vera gel
like vitamins, minerals, sugar, lignin, saponins, phenolic compounds, etc. (Hamman
2008). There are several scientific reports of the gel of the plant for its woun d
healing potential.
A randomized, double blind clinical trial was conducted on N = 64 patients with
2nd degree burns. Patients were divided into two equal groups of thirty-two each.
A group was topically treated with 1% silver sulphadiazine while other group was
Fig. 2 Aloe vera herb and its fleshy juice
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treated with1% Aloe vera gel. Wound healing effects were assessed using the
Bates-Jenson scale. There was a significant difference between groups on the fifteenth day (P = 0.000, F = 467.602) and it was argued that the Aloe vera gel is an
effective treatment for burn wounds (Hosseini et al. 2013). In another clinical trial
Aloe vera gel was applied on N = 27 patients of burn wounds from flames,
scalding, and electric injuries, rangi ng of area of involvement between 5 and 45.7%,
over different body parts. Complete healing of wounds within 14th day was
observed. Efficacy of the plant for wound healing potential was confirmed by
relevant histological screening (Visuthikosol et al. 1995). In another randomized
split body controlled clinical trial, Aloe vera gel was used in N = 30 patients on
superficial partial thickness burns having wounds in less than 20% of involvement
and occurring in more than one site of the body with wound diameters within
16 cm. In the trial, wounds of one side of the body were treated with Aloe vera gel
while the other side received 2% Nitrofurazone ointment, treatments being randomly assigned. Burn area was evaluated according to the criteria of American
Burn Association Consensus Conferences and healing of wounds was assessed
using the Baes-Jensen Wound Assessment tool (BWAT). The study revealed no
differences in BWAT scores between these two groups the 2nd and 3rd weeks.
Wound closure in both groups was statistically significantly less than at the start of
the study (p = 0.037) although there were no differences between the groups
(Varaei et al. n.d).
Another randomized double blind clinical trial was done on N = 90 mothers
aged 18 to 36 who underwent Caesarean section. They were divided into two equal
groups of forty-five and were treated with either fresh Aloe vera gel or conservative
dressing (control) respectively. Treatments were randomly assigned. The inclusion
criteria were term pregnancy (37–42 weeks) Bod y Mass Index (BMI) > 29, not
having a history more than two caesarean sections, and willingness to participate in
the study. Pregnant mothers with a hist ory of placenta previa, placental abruption,
chorioamnionitis, meconium discharge, polyhydramnios, dysfunctional uterine
bleeding, hysterectomy, myomectomy, suffering with any serious dreadful diseases
were excluded from the study.
Aloe vera gel was applied on the wound edges of caesarean section area along
with systemic anti-inflammatory and antibiot ic drugs. The other group received
simple dressing with same group of anti-inflammatory and antibiotic drugs. Healing
effects of these two treatments were observed using the REEDA scale. It is an
instrument containing five factors, namel y redness, oedema, ecchymosis, discharge,
and approximation of the two edges of the wound. A significant (P = 0.003) results
of wound healing effect were found in Aloe vera gel treated group within 24 h with
REEDA scale value zero. Mean REEDA scale value in other group was 0.11 after
8 days of caesarean section (Molazem et al. 2014). The results showed that Aloe
Vera is useful adjuvant to reduce post operative inflammation.
Aloe vera-olive oil (AVO) combination therapy compared with phenytoin
ointment was tried on N = 60 patients, 30 per group to treat such chronic wounds as
pressure ulcers, diabetic foot ulcer and venous ulcer. Treatment effects were
assessed based on VAS (visual analogue scale). The total score of wound healing
128 T. K. Biswas et al.
showed significant improvement within both AVO (p < 0.001) and phenytoin
(p < 0.01) groups: between groups, the AVO group fared marginally better
(p < 0.001). Although both treatments had reduced VAS score, the efficacy of AVO
significantly at a higher level (p < 0.001) (Panahi et al. 2015). It was argued that the
due to presence of various chemical components, Aloe vera is able retain skin
moisture and integrity. Further it was argued that the healing of wounds was
accelerated in these studies to presence of mucopolysaccharides, amino acids, zinc,
and water in Aloe Vera (Hekmatpou et al. 2019).
Hypericum Perforatum
The plant belongs to the family Hypericaceae, commonly known as St. John’s Wort
and is traditionally used across the Europe for the treatment of wounds (Scotti et al.
2019). It is a leafy herb that grows in open space (see Fig. 3) and whole part is used
to treat various diseases, as well as cuts and burns. Recent research suggests that the
plant has multiple therapeutic effects against cancer, inflammation-related disorders,
and act as antioxidant, anti-bacterial and anti-vir al as well as neuroprotective agents
(Klemow et al. 2011). Neuroprotective effect of the standard extract of the plant on
rat pheochromocytoma cell line PC12 as well as in Parkinsonism are also reported
(Oliveira et al. 2016). Study reveals that the plant contains two major chemical
components such as avicularin and guaiaverin (Scotti et al. 2019).
An experimental study was conducted at the Department of Plastic, Reconstructive and Aesthetic Surgery, MuğlaSıtkıKoçman University, Turkey in
Spraque-Dawley rats on incised wounds with combination of extract of H. perfo-
ratum and olive oil. Effect of the preparation showed that tensile strength of the
wound as well as angiogenesis and epithelialization improved significantly
(p < 0.05), which was corroborated by histological study of the wound tissues
(Altıparmak and Kule 2019).
A randomized clinical trial was conducted with this plant for evaluating wound
healing activity on N = 125 women who underwent having Caesarean childbirth.
Oily extract of the flowering top of the plant was prepared and mixed with grape seed
oil in a ratio of 1:3 and then a 20% ointment was prepared with petroleum jelly.
Patients were randomly divided into three groups twenty-four (24) hours after
caesarean. First group consistin g of N = 47 patients were treated with H. perforatum
ointment, second group (N = 44 patients) received placebo ointment (petroleum
jelly) and third or control group (N = 34 patients) remained without any intervention. Patients of first two treatment groups treated with the ointment three times a day
for a period of 16 days. The randomization was based on consecutive numbering and
ointments were coded by a staff member of the team and none of the members of the
research team knew about the intervention group. Assessment of healing was
observed at the 10 and 40th days using the REEDA scale (REEDA stands for
redness, oedema, ecchymosis, discharge, and approximation) (Hill 1990). A total
REEDA score ranges from 0 to 15 and score of 0 reflects normal skin. The study
showed that there was significant reduction (p < 0.4–0.008) of all the characteristics
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Fig. 3 Hypericum perforatum Linn. (Hypericaceae) [Courtesy: flagstaffotos @gmail.com]
features of REED except ecchymosis in H. Perforatum treated group with respect to
placebo and untreated control groups (Samadi et al. 2010). The chemical analysis of
the plant by HPLC methods showed reveals that the plant is enriched with phenolics
and flavonoids. Hypericin was found to be main active principle which was isolated
from the plant during flowering. The plant also possesses comparable property of
antioxidant activity as observed based on DPPH∙ scavenging assay (Kladar et al.
2017). The antioxidant property plays a key role for healing of wound by activation
of pro-healing and anti-inflammatory genes pathways (Comino-Sanz et al. 2021).
Hypericin is reported that it significantly helps in proliferation phase of the
wound-healing cascade, contributing to increased fibroblast proliferation, maturation, and subsequent collagen deposition (Ozturk et al. 2007). The plant is, therefore,
found to be useful for healing of post Cesarean incision wounds.
Honey
Honey is used as food and medicine for the management of varieties of diseases
since a long time in various parts of the world. Honey is derived from flowers of
diverse types of plants. Therapeutic use of honey was first mentioned in India, in
Ayurveda and honey from the Sundarbans (Worlds’ largest mangrove forest lies on
the delta of Ganges, Meghna and Brahmaputra on the Bay of Bengal) is claimed to
130 T. K. Biswas et al.
be the best among all. Honey can be produced by a synthetic process though that
offers opportunities for adulteration. Natural processing of honey is important for its
therapeutic application, particularly in wounds of various origins. Traditionally
there is anecdotal evidence of the use of honey to treat the chronic non-healing
wounds like diabetic foot ulcers (DFU), burn wounds, pressure ulcers and so on
(Fig. 4) but reports of RCT are limited.
Natural honey contains many essential amino acids like arginine, proline, alanine, isoleucine, serine, valine and glycine (Biswas and Honey 2019). In a
meta-analysis done from 1966 to 2008 covering PubMed, Medline, Embase,
Cochrane database for topical application of honey in the treatment of wound
healing, which revealed that in ten randomized controlled trials, covering nine
hundred and sixty three patients, N = 511 were treated with honey and rest treated
with silver sulfadizine, antiseptic, soframycin and acriflavin, etc., considered as
Fig. 4 Application of honey a in a male uncontrolled diabetic patient, aged 45 years, with a
non-healing leg ulcer for more than 30 days and progress of healing b after 7 days. Intervention
done at J. B. Roy State Ayurvedic Medical College and Hospital, Kolkata, India
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control group. In treated group modest improvement was there (56%) and duration
of healing ranged from 5 to 30 days while in control group duration of healing
ranged from 7 days to 17 months (Medhi et al. 2008). Evidence of a prospective,
randomized, double blind, controlled study on eighty-seven patients among workers
from a gold mine: the study was done on shallow wounds and abrasions not deeper
than 2 cm and not larger than one hundred sq.cm. with honey in comparison with
hydrogel (Intrasite gel®, Smith & Nephew). Honey was applied topically on
forty-two patients and hydrogel to forty patients. The study showed that the healing
time and reduction of wound sizes with honey treated group was faster than
Hydrogel (Ingle et al. 2006). There is also evidence of prospective randomized
controlled clinical study of honey with respect to silver sulfadiazine in superficial
burn wound. In this study a total fifty patients with superficial burns involving 40%
of body surface were randomly divided into two groups comprising of twenty-five
patients in each group and were topically treated with honey and silver sulfadiazine
(SSD) respectively. Topical applications of intervention (honey) or standard control
(silver sulfadiazine) were done once a day for twenty one days. In honey treated
wounds, there was no eschar, the margins of the wounds were free of oedema. On
day twenty-one, in the honey treated group only one had fluid exudate as compared
to four in SSD treated wounds. In honey treated patients, all the wounds healed by
day 21 (100%) and in the SSD treated group in N = 21 patients (84%) (p < 0.001).
On the other hand, honey treated group showed epithelialization and granulation
tissue formation to all the patients on day twenty one as compared to the SSD
treated group where N = 13 wounds showed reparative changes and granulation
formation (52%), no evidence of granulation and reactive changes in one (4%) and
in N = 11 wounds evidence of infection was present on the 7th day. The acceleration of epithelialization in the honey treated group appeared to occur between 6
and 9 days clinically as well as histologically (Subhramanayam 1998). In comparison to silver sulfadiazine, honey is better as a topical treatment for superficial
burns because it promotes fast re-epithelialization and decreased inflammatory
reaction. Most of the FDA approved honey-based wound agents are prepared with
medical grade Manuka honey (Albaridi 2019) which is reported to have potent
anti-bacterial activity against anti-biotic resistance bacteria resistant. The mechanism of honey in wound and burn healing involves several biochemical and
pharmacological pathways. Honey itself act as antibacterial agent due to its high
osmolarity, low water activity, and acidity as well as some compounds, such as
hydrogen peroxide, phenolic compounds, methylglyoxal, or bee defensin-1 peptide,
directly affect the bacterial growth and survival (Albaridi 2019; Proaño et al. 2021;
Peršuri´and Paveli´ 2021). Stimulation of angiogenesis by honey was demonstrated
in an in vitro study with analogues of angiogenesis and an endothelial proliferation
assay (Rossiter et al. 2010).Wound debridement is a principal issue for healing and
honey facilitates the wounds’ autolytic debridement process due to its high osmotic
pressure which pulls out lymphatic fluid from the deeper zones followed by
automatic removal of dead, damaged or infected scar tissue (ScepankovaH 2021).
Other two important biological functions that honey performed are
anti-inflammatory by reducing COX-1 and COX-2 (Silva et al. 2021) and
132 T. K. Biswas et al.
anti-oxidant (Yadav et al. 2018) activities that help in promotion of healing process.
Honey was recommended for topical use as a potent wound dressing agent (Molan
1999). Besides, honey is cost effective than any other natural or synthetic agents
used for the healing of wounds. These are widely available, easily affordable
alternatives. The processing of synthetic honey involves several technologies.
Systemic Uses of Curcumin
A meta-analysis of plant drugs used as healing agent was done and only one plant
Curcuma longa so far been reported as potent healing agent for systemic use.
Curcuma Longa
The plant, commonly known as ‘Haridra’ or ‘Haldi’ in India and adjacent countries
as well as Turmeric, is described in different traditional classical texts for various
therapeutic purposes like anti-inflammatory, analgesic, antifungal, anti-viral,
antibacterial and antioxidant activities (Bhat et al. 2015). Reports are also available
of the paste of turmeric for its wound healing activity in the rabbit model in which it
was found quite comparable with honey (Kundu et al. 2005). In another study wound
healing potential of the plant was assayed using nanostructure porous curcumin
loaded electrospun polyhydroxybutrate (PHB) mat (Fig. 5) and its was observed that
the natural process of formation of extracellular matrix (ECM) scaffold as wound bed
was formed through in vitro study in cell culture. Moreover, it was also observed that
rate of release of 1 and 3% PHB-curcumin composition from nanofibrils are 37 and
46% respectively within a time of 6 h. Almost half of the drug is released from the
nanofibril coated with curcumin within 72 h which is important from the point of
view of its pharmacodynamics and pharmacokinetics (Ghavami e t al. 2020).
However, a prospective, randomized, double blind, placebo controlled clinical
trial was undertaken on final fifty patients aged between 45 and 85 years of grade 3
DFU having features like deep wounds with abscess or osteomyelitis according to
“Wagner-Meggitt’s” scores. The test drug C. longa was administered in the form of
nanocurcumin tablets 80 mg per day for a period of 12 weeks and compared with
placebo control with equal number of patients distribution (25) in each group in a
randomized technique. All the patients were conventionally treated with antibiotic
Ciprofloxacin and relevant antidiabetic therapy. Assessment was made based on the
physical parameters like ulcer length, width, and depth (cms). Besides, diabetic
profile like FPG, plasma insulin levels, HOMA-IR, QUICKI and some lipid profiles
including total-and LDL-cholesterol were also estimated periodically. The study
showed that in-spite there were n o significant improvement of change of ulcer size
with curcumin nanoparticle treated group with respect to placebo but there was
significant change (p < 0.01−0.001) of glycaemic and lipid profiles (Mokhtari et al.
2020). In most of the DFU there are insulin resistance resulting delayed and poor
healing progress. Improvement of glycaemic and lipid profile by oral administration
of curcumin may indirectly help in acceleration of healing or may resist the deterioration of healing process. Simultaneous oral and topical application of C. longa
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Fig. 5 SEM images of curcumin-loaded nanofibers. a and b Unloaded PHB nanofibers; c and
d loaded PHB nanofibers with curcumin 1%; and e and f loaded PHB nanofibers with curcumin
3%. (Magnification: 1000 and 2000 ) (Courtesy Dr. Esmaeil Biazar Department of Biomaterials
Engineering, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran]
may have promising results in this direction, specifically to prevent wounds in
diabetic patients. Tho ugh no direct evidence for wound healing of this plant is
observed but it may prompt a future study to explore its preventive benefit in DFU
as it can control diabetes. Chances of bacterial and/or fungal infections in DFU are
very much common and the healing in this condition can be modulated by any
drugs which have protective role against these noxious agents. The crude extract of
curcuminoids and essential oil of C. longa has most sensitive effect against Bacillus
subtilis with a minimum zone of inhibition of 20.6 mm diameter (Nazi et al. 2010).
The aqueous extract from the rhizome powder of Curcuma longa is reported to
have most sensitive effect against the filamentous fungi Cladosporium exospore and
Cladosporium subliforme with inhibitory concentrations of 3.12 mg/ml and
6.25 mg/ml respectively (Marchia et al. 2019). This evidence lends support to the
role of C. longa in wound healing.
Centella Asiatica (L.)
The plant is commonly known as Gotu kola or Mandukaparni in India (family
Apiaceae) (Fig. 6) and therapeutically used for the treatment of various diseases in
Southeast Asian countries such as India, Sri Lanka, China, Indonesia, and Malaysia
as well as South Africa and Madagascar (Jamil et al. 2007). The most imp ortant
clinical use in various traditional system of medicine is mood elevation and
anti-depressant activity and this folklore evidence was scientifically screened as
neuroprotective potentiality. In the study it was observed that ethanol extract of C.
asiatica could inhibit acetylcholinesterase (AchE), butyrylcholinesterase (BChE)
and tyrosine (TYRO) through in vitro study. Study reveals that it can prevent
134 T. K. Biswas et al.
Fig. 6 Centella asiatica (L) creeper
neurological diseases like Alzheimer’s disease (AD) or Parkinson’s disease
(PD) (Orhan 2012).
Wound healing potential of the plant was tested in fundamental research on
several aspects. In a study , effect of the aqueous extract of C. asiatica was evaluated
at different concentrations like 7.8, 15.6, 31.2, 62.5, 125, 250, 500 and 1000 ppm
on scratched isolated rabbit corneal epithelium (RCE) and it was observed that
number of viable RCE was promisingly increased with 1000 pp m of C. asiatica
based on the MTT assay and gene expression analysis (Idrusa et al. 2012). The
plant contains many chemical components of which major are Asiatic acid,
madecassic acid, asiaticoside, madecassoside, madasiatic acid, etc. (Pan et al.
2007). Fundamental study also carried out with isolated compound madecassoside
for its facilitating effect on burn wound in mice. In the study aqueous solution of
madecassoside was applied in a dose of 24 mg/kg b.w. on artificial induced 30%
burn in mice. Result showed that there were remarkable proliferation of fibroblast
cells and neoangiogenesis on histological examination as well as antioxidant
activities (Liu et al. 2008). A study also conducted towards the genetic expression
of C. asiatica triterpenoids on normal human fibroblasts (ATCC CRL-2450) where
proliferation was observed in terms of cDNA microarray sequence indicating it
potent wound healing profile (Coldren et al. 2003). Study on isolated compound of
0.2% solution of asiaticoside from C. asiatica also carried out in delayed type of
wounds in guinea pig model and it was observed that there were 56% increase in
hydroxyproline, 57% increase in tensile strength, increased collagen content,
angiogenesis and better epithelisation (Shukla et al. 1999). A trial was specifically
carried out with the plant C. asiatica for their woun d healing activity. A detailed
RCT on this aspect on two hundred diabetic patients with chronic wounds were
done dividing patients into two groups distributed with equal number of patients.
Finally, N = 170 patients were included: eighty-four patients in group-I and
eighty-six in group-II were included. In group–I the isolated chemical component
asiaticoside at a dose of 300 mg in three divided doses after meal were administered
orally for 21 days and group-II were treated with placebo. Effects were evaluated
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based on the physical parameters like wound contraction and granulation tissue
formation on open eye observation. Effects was found significantly higher
(p < 0.001) than the placebo group (Paocharoen 2010). However, more extensive
RCTs are needed to establish its role in wound healing.
Taking a Wound Healing Agent from Bench to Bedside:
Validating a Natural Wonder with Advanced Technology
There are numbers of medicinal plants which have been screened primarily in lower
animal models and screened with sophisticated molecular markers for establishing
wound healing efficacy. However, the efficacy of few of these are rigorously tested
using RCT. Pterocarpus santalinus or red sandal wood is an exception. The plant is
found in the southern India and had been screened by preparation of 15% w/w
crude powder ointment with petroleum jelly in 8 mm diameter punch wound model
on Charles foster rats. There was significant (p < 0.05) reduction of wound size
within a time of nine days. Tissue molecular markers like DNA, RNA, Protein and
Hydroxyproline generation were also found to be significantly increased
(p < 0.001). The healed tissue showed remarkable generation of biological factors
like collagenesis, epithelial tissue formation and neovascularisation on histological
investigation indicating its potent role in wound healing (Biswas et al. 2004a).
Thereafter, the ointment was applied on selected N = 6 patients with non-hea ling
wounds where significant reduction of wound size was observed within a period of
fifteen days and was comparable with Racketing® ointment (Biswas et al. 2004b).
Owing to the results of crude powder of the plant, further studies were carried out
with 5% ointment of the ethanol extract of the plant in ointment base of petroleum
jelly. In the same experimental model, the extracted plant ointment with low
concentration (5%w/w) showed more potent reduction of wound size (p < 0.05)
within a period of 8 days which was significantly better than vehicle control
(petroleum jelly) or Framycetin® ointment treated group. Genesis of hydroxyproline, one of the three components of collagen, was also found to be significantly
(p < 0.001) better than the previous experiment. Formation of tissue markers
responsible for healing process like ECM, collagen, new blood vessel and epithelial
tissues were also synthesized faster than the crude powder ointment.
A pilot clinical study was carried out where the ointment (5% w/w) of ethanol
extracted P. santalinus was applied on six (6) patients of non-healing chronic
wounds like DFU and pressure ulcer and it was observed that wounds could healed
up within 08.25 days while it required about 21.26 days in vehicle control (soft
paraffin) group. The formation of granulation and epithelia tissues were also faster
than the vehicle control group. A detail toxicity study was carried out with the
ethanol extract of P. santalinus, and no toxic effect was observed. A special test for
assessment of DNA damage by comet assay was performed with the extract and
found to be safe. More interestingly the crude extract also showed potent DPPH
radical scavenging activity in vitro, indicating its’ possible good antioxidant activity
(Biswas et al. 2021). However, an RCT remain to be reported.
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