A wound as per definition is out-and-out destruction of the living tissue, such as the skin, mucous membranes, and organs. Alternative definitions include interruption in the skin or mucosal epithelial lining's continuity expediated by heat or physical injury.^1,2 This split can also impact the Musculo-skeletal, neuro-vascular, subcutaneous and bony structures. Skin being the largest human organ is most vulnerable to injury.³ Since the creation of Adam wounds have been accompanying him. The knowledge of treatment of wounds have advanced over the years yet wound healing remains a conundrum.⁴ Chronic wound occurrence has been rising like a "silent epidemic." A 2018 retrospective study states that wounds agonize around 8 million individuals globally.

The clinical and financial impact of wounds on the world's healthcare systems is significant, and it noticeably reduces the quality of life of the injured. Consequences of the wounds are not only limited to the discomfort from the wound itself but they extend to the afflicter’s social, physical, or psychosocial well-being.⁵ Insulin has been studied for topical application in wound healing. Numerous biochemical mechanisms are implicated in enhancement of wound healing in diabetics. Insulin employs both the Phosphatidylinositol 3-kinase (PI3K) /AKT and Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways that have critical growth and development impacts.⁶

Prior research suggests that insulin advances wound healing in non-diabetics by boosting re-epithelialization and angiogenesis. Insulin receptor substrate (IRS) proteins are crucial insulin signalling injured skin insulin-regulated cellular proliferation in skin. Insulin is essential for controlling cellular proliferation. It regulates post injury inflammation in the surrounding tissues by stimulated migration and propagation. After removing the exudate and necrotic tissue it promotes surrounding cellular layer regeneration. Insulin in addition impedes bacterial colonization.⁷

Furthermore, topical insulin treatment for wound healing produced fewer adverse drug reactions (ADRs) and is less expensive as per research.⁸ The World Health Organization defines ADR’s as “a response to a medication that is noxious and unintended and occurs at doses normally used in man.”⁹

According to the literature, available topical therapies like Growth factors are significant technological developments that have the potential to revolutionize the overlook of wound healing. Recombinant human platelet-derived growth factor-BB (PDGF), granulocyte colony-stimulating factor (CSF), and epidermal growth factor are the most important growth factors employed. The research done so far utilizing these agents has not yielded significant results. Furthermore, these growth factors are customarily highly-priced expensive.¹⁰

Secondly, safety profile of insulin is well known.  Thirdly, new drug development is a costly affair and drug repurposing reduces time and cost effective.¹¹ With this prior database, we may consider that topical insulin is a less expensive and more effective supplementary active wound care, particularly in developing countries like India. Hence, we planned to conduct this pilot study to evaluate the efficacy of topical insulin in wound healing as a new hope and possibly a revolution in the field of this silent epidemic of wounds and if later on expand it further.

AIM

To assess effectiveness and safety of topical insulin on wound healing.

OBJECTIVE

·         To study the effectiveness of topical insulin on wound healing

·         To assess the safety of topical Insulin

·         To compare the topical insulin with normal saline in terms of efficacy and safety

This open-label, single-centric, parallel group, randomized controlled pilot study was done on patients visiting the General Surgery OPD as well as the in-patients visiting a tertiary care hospital in northern India. In accordance with the Indian Council of Medical Research (ICMR) National Ethical Guidelines, post- approval from College Research Committee and Institutional Ethical Committee, informed consent was taken individually from each patient after debriefing the subjects about the purpose of the research.   Calculation of sample size for a pilot study is not usually done as it primarily does not test the hypothesis. Nonetheless, as per research suggesting 12 subjects per group, we took 24 total patients.¹² However, to keep sample size identical with the further planned study inclusion and exclusion criteria were kept same.

The subjects were selected according to the following inclusion and exclusion criteria.

INCLUSION CRITERIA

·         Age18-65 years old¹³

·         Either gender

·         Class II wound classifications as per Centers for Disease Control and Prevention ¹⁴

·         Wound surface area 10 (less than 20cm2)

·         Patients willing to give informed consent

EXCLUSION CRITERIA

·         Pregnancy

·         Patients on immunosuppressive treatment

·         Wounds that are complicated (e.g., Bleeding or infection)

·         Medications that may impact the study’s outcome

·         Cardiovascular illnesses (uncontrolled hypertension, recent myocardial infarction or cardiac surgery), Peripheral artery disease or Renal and hepatic failure

Once enrolled the patients were randomized into two groups A and B using a random number table. Participant enrolment is depicted in Figure 1.

Figure 1: CONSORT diagram: Enrolment, randomization, and allocation of patients participating in the study.

TREATMENT

Group A:  wound was cleaned with normal saline and then irrigated with 4 units (0.1 ml) of human soluble insulin (same brand was consistently used which was available at our institution) in 1 ml normal saline (0.9%) for each 10 cm2 of wound.¹⁴ The solution prepared was sprayed on the wound surface with an insulin syringe and wound was left to dry and then covered with sterile cotton gauzes.

Group B: wound was cleaned with 1 ml normal saline (0.9%) for each 10 cm2 of wound without insulin, allowed to dry and covered with sterile gauzes.

Both the groups received the designated dressings every 48 hours for 14 days.

EFFECTIVENESS ASSESMENT

Wound surface area and VAS (visual analog scale) pain score at day zero,7 and 14 were noted. Wounds were measured using a sterile transparent paper placed on the wound to mark the wound borders. The two largest perpendicular diameters were measured using a ruler (in millimetres). To calculate the wound area, these two diameters were multiplied to obtain area of ulcer in mm². Percentage reduction in wound surface area was calculated using formula:

[(A₀ − A_t)/A₀] × 100,

where A₀ is the initial wound area and A_t is the wound area at each time point.¹⁶ More than 50% reduction in percentage of surface area in 4 weeks is considered a good indicator of healing in research.¹⁷ Our research was for two weeks, therefore we considered 25% reduction as cut off to determine good or inadequate healing.

Pain was assessed using VAS as an indicator of healing.¹⁸ A 33% change in VAS score from baseline implies significant pain control as per research.¹⁹ Hence, we considered a round off of 30% or less score to suggest adequate pain control and an indirect indicator of wound healing. For maintaining the accuracy of the test all the readings were taken by a single observer and same instruments.

SAFETY ASSESMENT

Spontaneous ADRs were noted as well as utilising a self-structured pre-validated checklist for local or systemic ADRs were monitored. The Naranjo Adverse Drug Reaction Probability Scale was used to establish causality while Hartwig and Siegel Severity Assessment Scale to determine the severity of Adverse Drug Reactions.²⁰ Data obtained was entered and transferred to excel sheet- master chart prepared.

STATISTICAL ANALYSIS

Twenty- four subjects were enrolled with no loss to follow up hence were used for the analysis. For statistical analysis the wound healing was categorised as good healing or inadequate healing (considering 25 % reduction in wound surface area in 2 weeks as threshold) and VAS score as adequate and inadequate pain control (change of 30% taken a scut off). To define the characteristics of subjects, descriptive statistics was used. The Chi square test was used for categorical variables. Age being a continuous variable was categorised into two groups considering median age.  The association of age, gender, occupation, education qualifications, aetiology of wound, smoking status, alcoholic status, to wound healing was assessed by doing the chi square tests and estimating the odds ratio. A p-value ≤ 0.05 were considered significant. The analysis was done using SPSS version 21.

The baseline demographic characteristics of the 24 patients enrolled are depicted in Table 1. Majority of patients were males, employed, educated upto10^th or more, non -smokers and non- alcoholics. Most wounds were due to trauma. Mean age was 37.3± 15. Median age was 33.5 years, based on that patients were divided into two categories age £33.5 years and > 33.5 years.

Table 1: Baseline Demographic characteristics

The concomitant medications taken by the enrolled patients is depicted in Figure 2, whereas the Figure 3 displays the various co-morbidities endured by them. Majority (62.5%) of the patients had no co-morbidities followed by hypertension (12.5%) hence the concomitant medication mostly (29%) prescribed was losartan-hydrochlorothiazide.

Figure 2: Concomitant medications

Figure 3: Co-morbidities.

EFFECTIVENESS

For statistical analysis purpose the wound healing was categorised as a Good healing or inadequate healing in accordance with recent research. Table 2 demonstrates the association of various demographic parameters with healing as reflected by percentage reduction in wound surface area. The data suggests that only the group i.e. Insulin or saline had statistically significant association with Healing, with Insulin group reflecting good healing, χ²(1, N = 24) = 8.22, p = 0.004. (OR = 15, 95% CI [2.02, 111.71])

Table 2: Association between demographic parameters and percentage reduction in surface area of wound

* - statistically significant p value (>0.05), ^# - Phi value, ^$ -Cramer’s V value

For statistical analysis purpose the difference in VAS was categorised as adequate pain control or inadequate pain control based on the difference in VAS score in alignment with current research. Table 3 demonstrates the association of various demographic parameters with VAS score as indirect measure of healing or effectiveness of therapy in terms of pain control. It was observed that only the group i.e. Insulin or saline had statistically significant association with pain control, with Insulin group displaying adequate pain control and therefore reflecting better healing., χ²(1, N = 24) = 17.14, p = >0.001. (OR = 6, 95% CI [1.69, 21.26])

Table 3: Association between demographic parameters and change in Visual analog scale score

* - statistically significant p value (>0.05), ^# - Phi value, ^$ -Cramer’s V value

SAFETY PROFILE

Upon using the pre-validated checklist for noting the local and systemic ADRs, both Insulin and Saline displayed a good tolerability profile. None of the groups reported spontaneous ADRs. where one patient developed transient itching at site of insulin application in insulin group (Group A) with no systemic adverse effects reported. However, in Saline group i.e. Group B, one patient complained of increased pain, while one complaint of headache. The adverse drug reactions observed had possible causality and severity of mild level 1. Overall safety profile for both groups was good.

Research suggests that wounds especially non-healing chronic ones are implicated to be causative in significant burden not only on a person, but the entire society and health-care infrastructure. The thrust of the wounds encompasses socio- economic as well as psychological aspects and is a major emerging concern.²¹

Wound healing is a complex process and currently continues to be challenging as the available therapeutic options are not very effective and are not cost-effective and not affordable by all.²² The supportive management includes protection of the exposed healthy tissue, reducing risk of infection, preventing pigmentation and promoting skin regeneration.²³ 

Wound healing involves re-epithelialisation and research suggests that induction of neo-angiogenesis as well as re-epithelialisation is an intricate process which is  mediated by release of various cytokines such as insulin-like growth factor (IGF), epidermal growth factors (EFG), fibroblast growth factors (FGF), platelet-derived growth factor (PDGF), transforming growth factor-beta 1 (TGF-β1), tumour necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF). A number of proteins like insulin, collagen, keratin, gelatin  are also vital for assisting in effective wound healing.²⁴

Numerous pre-clinical and clinical studies suggest that insulin being a peptide when topically applied hastens wound healing, stimulates early neutrophil recruitment and displays anti-inflammatory properties.²⁵  Wound studies meta- analysis report that granulation tissue growth is enhanced and new blood vessels are formed in the insulin treated group as compared to controls in various animals.  Also, in various clinical studies the time to healing is also significantly cut short.²⁶

Topically applied insulin augments wound healing due to its antioxidant and anti-inflammatory characteristics.  Topical insulin has been found to mitigate reactive oxygen species in thermal injury wounds in rodents. Another research implicates this property due to enhancement in the levels of IL-10 levels and therefore removing necrotic tissue. Additionally, by stimulating the PI3K-AktRac1 pathway it facilitates migration of keratinocyte and kick starts fibroblasts.²⁷

In our research we used regular insulin keeping in consideration the available current research which predominantly uses the same preparation. We also kept the brand (no funding received)  same to avoid any inconsistencies.²⁸ In our research the median age of patients was 33.7. This goes parallel with another research which reported young patients with average age of 33.4 years.²⁹ However, another research suggests otherwise where the overall median age of patients with traumatic injuries was 63.6 years.³⁰ The possible reason for our study having more young individuals could be attributed to the fact that they are more outgoing in terms of job and employment and are more exposed to occupational as well as traumatic injuries and in our study most of the subjects were working and had trauma as their aetiology of wounds.

On careful observation of published materials, it has been observed that studies done on wounds and wound healing incorporate a higher proportion of males. This goes in alignment with our study where male patients constituted majority.³¹ This fact can be attributed to a number of social, cultural and behavioural factors which mainly include men in India who are the main bread winners and are prone to occupational injuries.  Our study had most patients who were employed and were well educated, it is often observed that people who are educated more have better safety perceptions and also those who are employed and have source of income will readily seek medical help for the same.³²

Our research documents most wounds to be of traumatic origin which goes along with another research reporting most wounds due to trauma which included Most wounds were as a consequence of stabs or cuts (32.8 %), falls (22.4 %), or road traffic accidents (16.4 %).³³ Another research conducted  in Sothern Tunisia also affirms to the fact that traumatic wounds are the commonest type.³⁴  Research does suggest global reduction in thermal injuries, yet the incidence continues to be still high in country like India.

Observations made from our research suggests that most injuries were reported by non-alcoholics. This is in non- alignment with some research that suggests that injuries especially road traffic accidents are more common among alcoholics.^35,36 This mismatch can be attributed to false reporting of alcoholism due to social stigma associated with it and also due to the fact that the injuries reported in research are linked with heavy alcohol use and not occasional light drinking.

Most people enrolled in our study reported themselves to be non-smokers. Even though not smoking does not offer any additional benefit in prevention or safety from injuries that are unintentional, and their reported incidents of injuries due to road traffic injuries and falls is same as the general population, such as road traffic incidents and falls. Nonetheless, the available research does reflect that non-smokers face a significantly lower risk of injury compared to smokers.³⁷ Most patients had hypertension as their co-morbidity which is comparable with another study done on wound healing which had the same co-morbidity in most (78%) of the patients enrolled in the study.³⁸

The wound healing in terms of percentage reduction in surface area of wound as well as clinically meaningful difference in VAS score were all demonstratable in the patients receiving topical insulin for wound healing in this pre-liminary study. Another research also suggests that topical insulin application augments wound healing.³⁹ In another study topical insulin significantly enhanced wound healing outcomes, demonstrating a greater percentage reduction in wound surface area (p < 0.001) at day 7 in the insulin group compared to the saline group.⁴⁰

As per the observed changes in VAS score from baseline to follow up at 14 days our research suggested meaningful pain reduction post application of topical insulin on wounds. Another research utilising novel organo-gel preparation of Insulin had reduction in pain in diabetic foot ulcers.⁴¹ Another research suggested topical insulin application aided in pain relief in a case study of hidradenitis suppurativa.⁴²  Research done with a topical application of a combination of polymyxin B ointment, insulin and recombinant human basic fibroblast growth factor in second -degree thermal wounds in diabetic patients reported positive results suggesting reduction in pain at wound site along with reduced infection rates.⁴³

Moreover, this pilot study also suggested a good tolerability of topical insulin on wound healing as no major local or systemic adverse effects were observed during the study which reflects a good safety profile of topical insulin in this context.¹⁵ Another research conducted in Poland suggested that basic and preclinical studies affirm the fact that bio-engineered insulin matrix demonstrates promising effectiveness and good safety profile as a topical agent for promotion of wound healing.⁴⁴ 

Various modified preparations of insulin such as insulin–cobalt core–shell nanoparticles also have demonstrated to be highly efficient as a therapeutic option in wound healing as well as monitoring its binding to insulin receptors through bio-imaging.⁴⁵ Even combination therapies have been shown to be synergistic and beneficial. Combining Insulin with traditional and European medicine in a study in China reported promising results in a study done on management of diabetic foot ulcers.⁴⁶ Topical insulin with micro needling has found to be beneficial in healing as well. Post- micro needling there occurs release of growth factors of Platelet rich plasma and deposition of collagen in a lattice fashion which augments post- acne scars healing.  There is augmentation of vascular endothelial growth factor (VEGF)which promotes angiogenesis and maturation of type III collagen fibres in a weaved basket like pattern simulating normal skin structure.⁴⁷ These numerous studies demonstrate a promising future of topical insulin in the arena of wound healing.

LIMITATIONS OF THE STUDY

We acknowledge that the research was open -label, it could have been even better if the study was blinded, even single-blinded where the researcher would have been blinded could suffice. However, since it’s a pilot study, in subsequent further larger study the design can be modified. It’s a small sampled single- centric study so it has limited generalizability in terms of large population. The expected impact of co-morbidities and concomitant medications on wound healing outcomes also could not be ascertained probably due to limited sample size. Many such confounding factors could be tackled by planning larger multi-centric trails will help affirm and build up on the data observed from this pre-liminary research.

Topically applied Insulin may be beneficial as a safe and feasible wound healing treatment in patients with wounds as per our research findings. Nonetheless, larger sample-sized, multi-centre clinical trials are a necessity to affirm and further build up on the data obtained from our research.

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