During the last 20 years, the world has witnessed an unparalleled increase in the incidence of diabetes mellitus, to the extent, that today, diabetes is considered a global epidemic. Of the overall disease spectrum, diabetic complications account for the greater part of diabetes-related morbidity and healthcare costs. These well-known complications include diabetes related nephropathy, retinopathy, peripheral neuropathy and what is now well known as the ‘diabetic foot’ a spectrum of foot disorders seen in diabetics, occurring as a result of various factors like vasculopathy, neuropathy, immune-compromised status of the patient, etc [1,2].

Indeed, the diabetic foot is now well established as the leading cause of non-traumatic lower extremity amputations the world over, frequently contributing to the mortality of diabetes. The International Working Group on the Diabetic Foot estimated the loss of a foot or leg attributable to diabetes occurring every 30 seconds in the world. In addition, foot complications in diabetic patients inflict an enormous financial burden on the society, since amputations are associated with substantial direct (i.e. hospitalization and medication) as well as indirect (i.e. loss of working days) costs [1,2].

Diabetic foot ulcers have a complex pathophysiology and are notoriously difficult to heal. The complex interplay of various factors in diabetic patients such as vasculopathy, autonomic, motor and sensory neuropathy, increased circulating blood sugar levels and other contributory patient/disease related factors all lead to a redistribution of pressures on the weight bearing areas in the feet of these patients, with subsequent ulcerations and infection. Therefore, various strategies have been formulated with the target of improving ulcer healing rates based on the management of peripheral arterial disease, neuropathy, relief of high pressure areas, control of diabetic status, along with aggressive debridement and antibiotic therapy for infection control. At the same time, newer treatments like growth factors, bioengineered skin substitutes, extracellular matrix proteins and various other products are continuously being explored in attempts to increase the success rates when dealing with diabetic foot infections [1,2]. 

A number of studies have been done on different growth factors in patients with diabetic foot infections, but with disappointing results. Only the Platelet Derived Growth Factor (PDGF) has shown promise. Although the first ever study on growth factors was published in 1970, very limited work has been done on the use of PDGF in the clinical setting.1,2 Although a few studies have shown promise in the use of PDGF on wound healing in diabetic foot infections, more research is needed to establish its clinical benefits vis-a-vis other treatment modalities.

Aims and Objectives

To study the effect of PDGF on wound healing in diabetic foot ulcers as compared to controls (normal saline dressing).

This study was carried out prospectively on 60 patients of diabetic foot ulcerations presenting to the Diabetic Foot Clinic in the OPD of the Department of Surgery, Government Medical College and Hospital, Sector 32, Chandigarh. All these patients were screened to assess their suitability for inclusion into the present study, according to the inclusion and exclusion criteria and recruited once they met these requirements

Sample size calculation was done using the formula (Zα)2 X (P) X (1-P)/ (0.5)2. Z stands for the confidence limit, P stands for the incidence of the disease and 0.5 stands for 1SD ie one standard deviation. Taking 95 % confidence limit for Z that is 1.96 and squaring it and taking incidence as 2% and 0.5 as one standard deviation the sample size comes out to be close to 30. Taking sample size 30 takes into account the 95% confidence limit. 

Of these, 30 patients were recruited into the study group which comprised of patients who underwent dressings with PDGF in addition to therapy for diabetes and other associated diseases, if any. Another 30 patients were recruited as controls in which dressing with normal saline was carried out in addition to therapy for diabetes and other associated diseases, if any. Normal saline was used in the control group as this does not interfere with wound healing and infact has been shown to promote wound healing.

Randomization was done using coded sealed envelopes after obtaining written and informed consent from the patients being considered for inclusion into the study. The patients were informed of the risks and benefits of the study. Once consent was obtained from the patient, the patient was enrolled into the study and examined/investigated and followed up for a period of 12 weeks.

All patients underwent daily dressings with PDGF or NS as per their study group. All enrolled patients were asked to attend the diabetic foot clinic for follow up every week for the first month and then every two weeks for the next two months. Wound size was measured for every patient, on every visit for the period of study. The maximum width and maximum length of the wound was measured to give an estimated wound surface area. The progress of the wound healing was measured in terms of a decrease in the estimated wound surface area and that gave the estimated rate of healing in both – the study and control groups

At any point of time, if there was gross deterioration in the status of the wounds of patients in the study group, they were taken up for other treatments as deemed suitable (e.g. amputation, etc) and recorded as failures for the purpose of the study. No further recruitment to replace such patients was made for the purpose of study. On completion of the study, comparison was made to assess the rates of wound healing in both groups and to judge the efficacy, if any, of patients who underwent treatment with PDGF gel as compared to the control group.

Statistical analysis was carried out between the study and control groups to analyze the various parameters and interpreted using appropriate statistical tests.

Observations

This study was conducted in the Department of Surgery, Government Medical College and Hospital, Chandigarh. Sixty patients with diabetic foot were recruited into the study. These patients were divided into two groups, the study group and the control group. Thirty patients received PDGF based dressing and were labeled as study group whereas the rest received normal saline dressings and were labeled as control group. One patient due to amputation was lost in the study group and three patients were lost in the control group.

In the study group 86% were males and 13% were females whereas in the control group out of 30 patients, 88% were males and 11% were females. As for the age distribution in the study group more than 82% patients were more than 30yrs as is in the control group that is more than 88% (Table 1).

Table 1: Age and Sex Distribution, Duration of Diabetes

Regarding diabetic status in the study group 86% of patients were known diabetics and 13% were recently diagnosed with diabetes same holding true for the control group ie 88% were known diabetics and 11% were recently diagnosed to have diabetes (Table 2).

Table 2: Quantitative Analysis Results of Metformin and Sitagliptin

As for the neurological status in the study group 82% patients had neuropathy for hot sensations, 51% for cold sensations and 44% for vibration sensations where as in the control group all patients had neuropathy for hot sensations, 29% for cold sensations and 55% for vibration sense. For hot analysis p value is 0.6 and for cold p value is 0.7 which is not significant (Table 3).

Table 3: Sensory Examination

On radiological examination 20% patients in the study group had collapse of foot arches in the study group, same 20% had collapse of foot arches in the control group. Rest 80% had normal radiological features in foot. None of the patients had charcots foot or features of osteomyelitis (Table 4).

Table 4: X-Ray Changes

For the culture trends 35% of study group patients had Klebsiella as the predominant organism with 21 % having Proteus as the causative organism. In the control group also Klebsiella and Proteus were the predominant organisms accounting for 51 % of the total bacterial load. 

For the blood sugar control most of the patients had fasting blood sugar levels in the range of 126-200mg/dl and post prandial 200-250mg/dl in both the groups. Very few patients had fully controlled or very poorly uncontrolled blood sugar levels in both the groups. The p value for fasting and post prandial is 0.1 and 0.3 (Table 5).

Table 5: Culture Trends and Blood Sugar

As for the BMI is concerned in the study group 90% patients were overweight 5% were obese. In the control group 74% were overweight and about 15 % were obese. The p-value is 0.32 which is not significant. 

In the present study 82% of study group patients had ABI >0.9 and 75 % had ABI >0.9 in the control group. The p value is 0.82 which is not significant. In the present study in the study group 68% were taking oral hypoglycemic agents, 25 % were taking insulin whereas 7% were on no treatment. In the control group 77% of patients were taking oral hypoglycemic agents whereas 11% were taking insulin and 11% were on no treatment (Table 6).

Table 6: ABI and Treatment

In the study group 78% of the patients had wound healing more than 80% whereas 21% had wound healing less than 80%. The mean healing in the study group was 86%. In the control group 59% of the patients had wound healing more than 80% whereas 40% had healing less than 80%. The mean healing in the study group was 72%. Statistical analysis shows p-value as 0.002which is significant (Table 7).

Table 7: Wound Healing

There has been a very limited work done on the role of topical PDGF in the management of diabetic foot ulcers. Most of this work has been done in the west. So this study was aimed at studying the role of topical PDGF on wound healing in diabetic foot ulcers in the Indian setup. This study was also meant to reconfirm the wound healing property of topical PDGF in diabetic foot ulcers. 

In the present study majority of the patients in the study and the control group were above the age of 50 yrs. 58% of patients in the study group and 74% of patients in the control group were above the age of 50 yrs. In the study group 86% of these patients were males and 88% in the control group. Reiber et al. have reported similar findings in their study. They reported that among hospital discharges presenting with diabetic foot ulcers the highest percentage was in persons aged 45-64 years [3]. Levin also reported that older the patient, the more likely are the chances of developing peripheral vascular disease [4]. He also stated that most of the patients are males. Sussman stated that males are more affected than females by diabetic foot which is evident in both the groups [5]. Ahuja have also reported the male preponderance in diabetic foot patients. He has reported the male female ratio to be 2:1 [6].

Long term uncontrolled diabetes is a well-known risk factor for diabetic foot. CH Tseng in his study in 2003 has also emphasized the effect of long term diabetes on diabetic foot problems [7]. Root et al. in their study showed that people with diabetes for more than 6 years had a higher prevalence of diabetic foot complications [8], Reiber et al. in his study also stated that diabetic foot complications occurred in patients with long standing diabetes of more than 15 years’ duration [9]. In the study also majority of the patients with long standing diabetes were the one to have diabetic foot problems.

Persons of type 2 diabetes are at increased risk of developing peripheral and autonomic neuropathies. Peripheral polyneuropathy is associated with sensory symptoms such as numbness, pain and hyperaesthesia. In the present study study group patients had 82% patients having sensory neuropathy for hot sensations and about fifty percent had sensation loss for vibration and cold sensations. In the control group all patients had sensation loss for hot sensations whereas the same was true for vibration and cold sensations as in the study group.

Lehhnen et al. have documented the incidence of peripheral neuropathy in the range of 70% to 90%. He reported that diabetic neuropathy in the extremity tends to be bilateral and symmetrical [10]. Study conducted by Greene et al showed that distal mixed sensory motor autonomic neuropathy was most common. There was predominance of sensory neuropathy over motor neuropathy [11]. Levin stated that most important neuropathic factor in ulcer formation was loss of pain and temperature sensation. He defined two symptom complexes one consisting of pain and paraesthesia and the other of decreased or absent sensation of pain and temperature [12]. Boultan stated that plantar ulceration was significantly associated with decreased vibratory sensations [13]. Mayne stated that with time the sensory neuropathy tends to deteriorate with loss of vibration and position sense. He also noted that the hyperaesthesia and hyperalgesia usually improved with treatment [14].

In the present study 20% of patients in the study group had loss of foot arches. Similarly, 20% patients in the control group had loss of foot arches. Similar changes were reported by Hardy et al. and Clouse et al. in their studies. They reported that skeletal changes in diabetic foot may be manifested by several findings including generalized demineralization, focal osteolysis, Charcots joint and infection. All foot bones may be diffusely demineralized. He also showed that focal osteolysis mainly involved the phalanges and the metatarsal heads [15].

According to Reiber et al. midtarsal joint is the most common joint to get involved in diabetic foot. In diabetic foot, deformities are a result of motor and sensory neuropathies. He also stated that Charcots foot or neuroarthropathy occurs in less than 1% of the people with diabetes. Charcots joints occur unilaterally but in 20% of the people it develops bilaterally [16].

In the present study predominant organisms were Proteus and Klebsiella followed by Pseudomonas and gram positive Staphylococcus and Streptococcus. In the study group about 50 % of patients had cultures positive for Klebsiella and Proteus. Similarly, in the control group about 50 % had cultures positive for Klebsiella and Proteus. Pathare NA et al. have also cited similar organisms in their studies. He reported that important aerobic pathogens include Proteus 20%, Klebsiella 14%, Streptococcus 12%, E. coli 9% and Pseudomonas 7% [17]. Joseph WS has cited gram positive organisms as important organisms in his study [18]. Bacteriological spectrums in our study is also consistent with the following study patterns.

In the present study most of the patients had poorly controlled blood sugar levels. In the study group about 99 % patients had poorly controlled blood sugar levels. Similar results were seen in the control group. As per Rozsos et al. poorly controlled blood sugar level is responsible for majority of diabetic foot problems [19]. Kabak et al. have reported higher incidence of gangrenous lesions in patients with poorly controlled blood sugar levels [20] Kapil et al. in their study showed that multidrug resistant organisms are more common in patients with poorly controlled blood sugar levels [21]. 

In our study in the study group most of the patients were in the overweight category. Similarly control group also had most of the patients in the overweight category. Sohn et al. in their study have showed a J shaped association between BMI and diabetic foot ulcers [22]. These trends are seen in the western population. Similar trends are not reproduced in the study but still most of the patients in the present study were overweight. This may be attributed to the poor economic background and poorer nutritional status seen in the Indian setup. 

In the recent study in the study group 82 % of patients had ABI more than 0.9. Similarly, in the control group 75 % of the patients had ABI more than 0.9. Khammash MR and Obeidat KA in their study documented that estimating the ABI is an easy, reliable way to determine foot blood flow and to detect patients who require further vascular workup and treatment [23]. They also recommended that ABI less than 0.5 was associated with critical ischaemia and high rates of amputation. In one of the study an index of more than 0.6 was necessary to heal most foot ulcers. In another study ABI less than 0.8 has been shown to be associated with increased risk of diabetic foot complications [24].

In the present study in the study group 78 % of patients had their ulcers healed more than 80%. In the control group 59 % patients had wound healing more than 80 %. The mean healing rate in the study group was 86 % which was significantly less in the control group at 72 %. The difference is significant with a p-value of 0.0021. The results are consistant with the other studies conducted worldwide. 

As per Steed there was significant decrease in the healing rates when PDGF was applied to diabetic foot ulcers [24]. There was also a significant decrease in the time required for wound healing when using PDGF. Study by Vishvanathan has also emphasized the importance of PDGF and other growth factors in diabetic foot ulcers. He stated that PDGF and many other growth factors are normally needed for healing of diabetic foot ulcers where as MMP’s and serine proteases normally retard the healing process [25]. Nagai and Embil in their study have shown that Recombinant DNA engineered PDGF is as effective as endogenous PDGF in healing of diabetic foot ulcers [26].

As per Ladin there was a significant improvement in healing rates in patients of diabetic foot ulcers who showed resistance to healing inspite of best of the wound care and medical therapy. For diabetic patients who have poorly healing ulcers despite good perfusion and a reasonable trial of wound care, this product may be of considerable benefit. It should be tried for a 2-week time period and the results objectively assessed before continuation [27]. Schaper et al. in their study have also emphasized the effectiveness of PDGF in healing of diabetic foot ulcers [28].

This study concluded that healing in diabetic foot ulcers when subjected to treatment with PDGF showed better healing rates as compared to the control group. The study also concluded that diabetic foot ulcers were associated with poor self-care, poorly controlled diabetes, obesity and increasing age and increased duration of diabetes.

1. Boulton, A.J.M. et al. “The global burden of diabetic foot disease.” The Lancet, vol. 366, 2005, pp. 1719–1724.

2. Bennet, S.P. et al. “Growth factors in diabetic foot.” British Journal of Surgery, vol. 90, 2003, pp. 13.

3. Reiber, G.E. et al. “The burden of diabetic foot ulcers.” American Journal of Surgery, vol. 176, no. 2, 1998, pp. 155–195.

4. Gaskell, P. and W.J. Becker. “The erect positive aid to circulation in the feet in the presence of arterial obstruction.” Canadian Medical Association Journal, vol. 155, 1971, pp. 930.

5. Sussman, K.E. “Juvenile type diabetes and its complications.” Diabetes Research and Clinical Practice, vol. 22, no. 1, 1993, pp. 1–2.

6. Oakley, W.G. “Diabetes in surgery.” Annals of the Royal College of Surgeons, vol. 15, 1954, pp. 108–119.

7. Tseng, C.H. “Prevalence and risk factors of diabetic foot problems in Taiwan: A cross-sectional survey of non–type 1 diabetic patients from a nationally representative sample.” Diabetes Care, vol. 26, no. 12, 2003, pp. 3351.

8. Keiding, N.R. et al. “Importance of control of diabetes in the prevention of vascular complications.” Journal of the American Medical Association, vol. 150, 1952, pp. 964.

9. Levin, M.E. The diabetic foot. 4th ed., Mosby, 1988, pp. I–IX.

10. Pirart, J. “Diabetes mellitus and its degenerative complications: A prospective study of 4400 patients between 1947 and 1973.” Diabetes Care, vol. 1, 1978, pp. 168–188 and 252–263.

11. Greene, D.A. and M.I. Brown. “Diabetic polyneuropathy.” Seminars in Neurology, vol. 7, 1987, pp. 18–29.

12. Dahn, I. et al. “Conservative treatment of severe ischaemia of the leg.” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 19, 1967, pp. 160–166.

13. Boulton, A.J.M. et al. “Dynamic foot pressure and other studies as diagnostic and management aids in diabetic neuropathy.” Diabetes Care, vol. 6, 1983, pp. 26–33.

14. Mayne, N. “The short-term progress in diabetic neuropathy.” Diabetes, vol. 17, 1968, pp. 270.

15. Hardy, D.C. and T.W. Staple. “Imaging of diabetic foot.” The diabetic foot, edited by M.E. Levin, Mosby Year Book, 1993, pp. 131–149.

16.  Clouse, M.E. et al. “Diabetic osteoarthropathy: Clinical and roentgenographic observations in 90 cases.” American Journal of Roentgenology, vol. 1, 1974, pp. 121–134.

17. Pathare, N.A. et al. “Diabetic foot infections: A study of microorganisms associated with the different grades.” Indian Journal of Pathology and Microbiology, vol. 41, no. 4, 1998, pp. 437–441.

18. Joseph, W.S. “Treatment of lower extremity infections in diabetes.” Drugs, vol. 42, 1991, pp. 984–996.

19. Rozsos, I. et al. “The basic and practical way of treating diabetic foot.” Acta Chirurgica Hungarica, vol. 36, nos. 1–4, 1997, pp. 299–301.

20. Kabak, S. et al. “Serum lipoprotein(a) levels in patients with diabetic foot lesions.” Diabetes Research and Clinical Practice, vol. 71, no. 2, 2006, pp. 119–123.

21. Dhawan, B. et al. “A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital.” Diabetes Care, vol. 29, no. 8, 2006, pp. 1727–1732.

22. Sohn, M.W. et al. “Significant J-shaped association between body mass index (BMI) and diabetic foot ulcers.” Diabetes/Metabolism Research and Reviews, vol. 27, no. 4, 2011, pp. 402–409.

23. Khammash, M.R. and K.A. Obeidat. “Prevalence of ischemia in diabetic foot infection.” World Journal of Surgery, vol. 27, no. 7, 2003, pp. 797–799.

24. Woskova, V. and V. Bartos. “Identification of patients at risk for diabetic foot: A comparison of standardized noninvasive testing with routine practice at community diabetes clinics.” Diabetes Center, Institute for Clinical and Experimental Medicine, 1958–1959.

25. Vishvanathan, V. “Epidemiology of diabetic foot and management of foot problems in India.” International Journal of Lower Extremity Wounds, vol. 9, no. 3, 2010, pp. 122–126.

26. Nagai, M.K. and J.M. Embil. “Becaplermin: Recombinant platelet-derived growth factor, a new treatment for healing diabetic foot ulcers.” Expert Opinion on Biological Therapy, vol. 2, no. 2, 2002, pp. 211–218.

27. Ladin, D. “Becaplermin gel (PDGF-BB) as topical wound therapy.” Plastic and Reconstructive Surgery, vol. 105, no. 3, 2000, pp. 1230–1231.

28. Schaper, N.C. et al. “Treatment of diabetic foot ulcers.” Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry, vol. 7, 2007, pp. 95–104.