Autologous Platelet-rich Plasma vs Conventional Dressing in the Management of Chronic Diabetic Foot Ulcers

The term chronic wound was first used in the literature in the 1950s to refer to wounds that were difficult to heal or did not follow a normal healing process.¹ However, the term has been met with criticism for its uncertainty regarding the duration of chronicity.² Martin and Nunan³ define a chronic wound as a barrier defect that has not healed in 3 months, and Leaper and Durani⁴ define it as a wound that does not reduce 20% to 40% in size after 2 to 4 weeks of optimal treatment or when healing is incomplete after 6 weeks. Sheehan et al⁵ considered patients eligible for enrollment in their study if they had a diabetic foot ulcer (DFU) of more than 30 days’ duration.

Diabetic foot ulcers are a major complication of diabetes mellitus and the major component of diabetic foot syndrome. This medical condition affects 15% of all patients with diabetes mellitus.⁶ In 2012, Alvarsson et al⁷ reported that up to 88% of all lower leg amputations were related to DFUs.

The effect of chronic wounds on the health and quality of life for patients and their caregivers should not be underestimated. Patients with chronic wounds may experience chronic pain, loss of function and mobility, depression and anxiety, increased social stress and isolation, prolonged hospitalization, increased financial burden, and increased morbidity and mortality.⁸

Growth factors play an essential role in wound healing and tissue regeneration.⁹ Each growth factor has more than 1 effect on the healing process and acts by binding to specific cell membrane receptors on the target cells.¹⁰ The effects of growth factors include promoting chemotaxis, inducing cell migration and proliferation, and stimulating upregulating protein production.¹¹ Growth factors not only regulate cell migration and proliferation but also promote angiogenesis and remodel the extracellular matrix, creating an ideal environment that favors the cutaneous wound healing process.¹²

Since the 1990s, the use of emerging cellular therapies, particularly platelet-rich plasma (PRP), has gained more attention for a variety of diseases and in a variety of settings for its potential use in regenerative medicine as a therapeutic agent; additionally, it can have an adjunctive role in a standardized, quality treatment plan.¹³ The use of PRP, which is rich in growth factors and cytokines that may enhance the natural wound healing process, is gaining popularity.¹⁴

Platelet-rich plasma is defined as plasma containing concentrations of platelets above baseline, from 150 × 10³/dL to 400 × 10³/dL.¹⁵ Platelet-rich plasma is isolated through the centrifugation of whole blood. Its actions are based on the infusion of an increased number of platelets, thereby theoretically enhancing the biologic healing capacity as well as tissue generation in the wound bed. Enzyme-linked immunosorbent assay studies of PRP have quantified the presence of increases in growth factors such as transforming growth factor β, epidermal growth factor, and platelet-derived growth factor.¹⁶ Through degranulation of the alpha granules in platelets, PRP can release various growth factors that have been documented to initiate the wound healing process.¹⁷ The goal of this study was to evaluate the efficacy of autologous PRP in managing chronic DFUs.

A prospective, randomized controlled study was conducted on 72 patients with chronic DFUs who presented to the surgery department of Zagazig University, Zagazig, Egypt, from November 2016 to January 2021. Patients were divided into 2 groups; 36 patients were treated with PRP, and the other 36 patients were treated with conventional wound dressing.

Inclusion criteria

Patients eligible for inclusion included those with chronic DFUs larger than 1 cm in diameter that had not healed within 3 months after wound debridement and dressing by a surgeon.

Exclusion criteria

Patients with evident local infection or gangrene (ie, presence of redness, hotness, purulent discharge, radiographic evidence of osteomyelitis, positive probe-to-bone test, and positive C-reactive protein test) were excluded, as well as patients with end-stage organ failure, hepatic failure, or renal failure. Additional exclusion criteria consisted of patients receiving anticoagulants or antiplatelet agents (patients who could not cease anticoagulants or antiplatelet agents), those with thrombocytopenia or receiving steroid therapy, those with ulcers measuring less than 1 cm or greater than 8 cm in diameter or with deep ulcers (>2 cm in depth), and those with lower limb ischemia (acute or chronic). Limb ischemia was excluded by detecting the distal limb pulsations and ABI pressure value of 0.9 to 1.1.

Preparation of platelet-rich plasma

The patient should cease use of nonsteroidal anti-inflammatory drugs, steroids, anticoagulants, or antiplatelets for at least 10 days preoperatively because they interfere with platelet functions. For each patient, 20 mL of blood was sampled into two 10-mL syringes containing anticoagulant sodium citrate. The syringes were designed to be used in the centrifuge by cutting the plunger and finger grip (Figure 1A). The authors adopted the double-spin technique for PRP preparation using an 800D centrifuge (Figure 1B, 1C). The first spin was at a speed of 1000 rotations per minute (RPM) for 10 minutes, and the second spin was at a speed of 3000 RPM for another 10 minutes. The initial spin was to separate red blood cells, and the second centrifugation was done to concentrate platelets in the smallest final plasma volume, after which the superficial platelet-poor plasma was discarded (Figure 1D). The platelet count was measured in the blood sample from the patient and in the PRP to confirm the success of PRP separation. After which, it was activated by adding calcium gluconate 10%; every 9 mL was activated by adding 1 mL of calcium gluconate.

Dressing technique

The edges and the top of the wound base were debrided, and any callosities around the wound were removed. This process was repeated if necessary when callosities around the wound reappeared. By this technique, the chronic wound was transformed into an acute wound. In plantar ulcers, offloading was achieved using a total contact cast in addition to crutches or a wheelchair. Patients were randomly divided into treatment groups using the systematic random sampling technique.

In the PRP group, a portion of the activated PRP was injected around the wound and under the base of the wound, while another portion of PRP was applied over the top of the wound base and left to coagulate and form a gel. Petrolatum gauze then was applied, followed by a sterile dressing. The dressing was changed every 2 days, and PRP was applied every week until complete healing was achieved or a maximum of 10 applications were completed. For ulcers that had not healed by then, wound dressing was done every 2 days without PRP application for another 10 weeks. The total period of wound dressing was 20 weeks. If the wound had not healed by the end of that period, failure of healing was considered.

Wound debridement and offloading were the same for the conventional dressing group as for the PRP group. The wound was irrigated with normal saline, then covered with petrolatum gauze and sterile dressing. Wound dressing was repeated every 2 days for 20 weeks. If the wound had not healed by the end of that period, failure of healing was considered.

Statistical analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (version 25.0; IBM SPSS Inc.). A P value of less than .05 was considered significant.

From November 2016 to January 2021, 72 patients in whom chronic diabetic foot ulcers were diagnosed were enrolled in the study. Thirty-six patients were treated with PRP, and 36 patients were treated with conventional wound dressing. All patients showed no signs of infection, gangrene, or limb ischemia. There were 20 male and 16 female patients (mean age, 56 years ± 8.39 SD) in the PRP group and 21 male and 15 female patients (mean age, 59 years ± 6.68 SD) in the conventional dressing group (Table 1).

In the PRP group, wound diameter ranged from 1 cm to 7 cm (mean, 3.33 cm ± 1.31), with a chronicity duration of 46.64 weeks ± 31.47. In the conventional dressing group, the wound diameter ranged in size from 1 cm to 6 cm (mean, 3.23 cm ± 1.20), with a chronicity duration of 46.67 weeks ± 39.87 (Table 1).

All patients in this study had a normal blood platelet count. The mean platelet count was 257.72 × 10³/dL ± 70.21 in the PRP group vs 265.39 × 10³/dL ± 81.18 in the conventional dressing group (Table 1). There was no significant difference between the PRP and conventional dressing groups regarding age, chronicity, wound size, and platelet count (Table 1).

Different ulcer sites were noted among the patients in this study. In the PRP group, there were 26 patients with plantar ulcers, 1 patient with an ulcer on the dorsum of the foot, and 9 patients with ulcers at a toe amputation site. In the conventional dressing group, 24 patients presented with plantar ulcers, 2 presented with ulcers on the dorsum of the foot, and 10 presented with ulcers at a toe amputation site (Table 1).

Wound healing was achieved in 31 of 36 patients (86.11%) in the PRP group and 23 of 36 patients (63.89%) in the conventional dressing group. Improved healing occurred in both groups, but the healing rate was higher in the PRP group (P =.029) (Table 2).

Healing by the anatomic site in the PRP group showed healing in 23 of 26 plantar ulcers, the 1 ulcer on the dorsum of the foot, and 7 of 9 ulcers at a toe amputation site. There was no significant difference in healing rate by ulcer site (P =.67). Healing by the anatomic site in the conventional dressing group showed healing in 15 of 24 plantar ulcers, both ulcers on the dorsum of the foot, and 6 of 10 ulcers at a toe amputation site (P =.544) (Table 3). There was a higher rate of healing in the PRP group compared with the conventional dressing group, with the healing of plantar ulcers in 23 of 26 (88.46%) patients and 15 of 24 (62.5%) patients, respectively.

Of the 31 patients in the PRP group who achieved wound healing, the mean time to healing was 10.90 weeks ± 3.40, and of the 23 patients in the conventional dressing group who achieved wound healing, the mean time to healing was 13.48 weeks ± 3.37 (P =.01 for both) (Table 4). Figure 2 demonstrates hastened ulcer healing after the application of PRP.

The following had no significant effect on the healing rate in the PRP group: age (P =.282), sex (P =.508), chronicity duration (P =.070), wound size (P =.075), platelet count (P =.178), or site of the ulcer (P =.301). In the conventional dressing group, the ulcer diameter had a positive effect on the healing rate (P =.017); however, there was no significant effect regarding age (P =.115), sex (P =.733), chronicity duration (P =.349), platelet count (P =.33), or site of the ulcer (P =.274).

Among patients with diabetes, a foot ulcer develops in 2% to 3% each year, and 15% of that population develops a foot ulcer during their lifetime.¹⁸ The main principles of treatment are relief of any pressure from the wound, adequate control of infection, debridement of devitalized tissue, and control of blood sugar levels. If the standard measures are unsuccessful, new therapeutic options such as recombinant human growth factors and bioengineered skin substitutes may be beneficial; however, the cost of these options is limiting. Autologous PRP is a cost-effective treatment method. Platelet-rich plasma enhances wound healing by promoting the healing process through local release of growth factors. These growth factors are essential in modulating mesenchymal cell recruitment, proliferation, and extracellular matrix synthesis during the healing process.¹⁹

In the current prospective, randomized controlled trial on the use of PRP for the treatment of DFUs, 72 patients were randomly divided into 2 groups of 36 patients each—the PRP group and the conventional dressing group. The duration of ulcer healing was significantly shorter in the PRP group than in the conventional dressing group (P =.01). Additionally, the rate of healing was higher in the PRP group than in the conventional dressing group (31 patients [86.11%] and 23 patients [63.89%], respectively; P =.029). This study showed no difference in healing rates according to ulcer site in the PRP group vs the conventional dressing group (P =.67 vs P =.544, respectively). There was, however, a higher rate of healing of plantar ulcers in patients in the PRP group than in the conventional dressing group (23/26 [88.46%] and 15/24 [62.5%], respectively).

A 2010 systematic review and meta-analysis by Villela and Santos²⁰ reported scientific evidence regarding favorable outcomes, especially the healing rate in patients treated with PRP, reflecting the effectiveness of its use in the management of diabetic ulcers. In the same year, Jeong et al²¹ published a prospective controlled study of 100 patients with chronic DFUs. They found a significantly higher rate of complete healing in patients treated with blood bank platelet concentrate compared with the control treatment of topical fibrinogen and thrombin (79% and 46%, respectively; P <.05). In a systematic review published in 2018, Hirase et al²² reported that topical application of PRP for management of diabetic foot ulcers resulted in significantly superior healing rates and lower complication rates compared with a control group (P <.001 and P =.115, respectively).

The current study showed no significant effects of age, sex, chronicity duration, blood platelet count, or ulcer site on healing. The ulcer size significantly affected the healing rate in the conventional dressing group but did not affect the healing rate in the PRP group.

In a study of 194 patients, Oyibo et al²³ found that the ulcer area in patients with diabetes was correlated with healing time (P <.0001) and was predictive of healing (P =.04). Patient age, sex, and ulcer duration did not affect healing. Oyibo et al²³ used the conventional wound treatment (as used in part of the current study), and they also found a significant correlation between the ulcer diameter and the healing rate (P =.033) as mentioned in the current authors’ work.

The resulting burden to the community in terms of costly health care is substantial. As of this writing, the 800D centrifuge cost $70. The cost of a single PRP dressing episode was $25, compared with $10 per episode for conventional dressing. In this study, the mean overall cost of care for a single foot ulcer approached $504.58 with PRP compared with $484.17 with conventional dressing. Although the cost of PRP appears to be higher initially, this treatment results in a higher rate of wound healing in less time, thus improving morbidity. The use of PRP is expected to positively affect patient care, reduce health care costs in general, and minimize long-term health care expenditure on foot ulcers.

The first limitation of this study is the relatively small number of cases; a larger study population may be required to prove the efficacy of PRP in the management of chronic DFUs. A second limitation is that the participating patients had noninfected ulcers; thus, the results may not be generalizable to all patients with foot ulcers.

As indicated in the current study, the use of autologous PRP resulted in a higher rate of wound healing in less time compared with conventional wound care in the management of chronic DFUs. Platelet-rich plasma may be an effective and promising treatment for chronic DFUs; PRP enabled healing in a shorter time. This is expected to positively affect the individual’s performance and minimize long-term health care expenditure on foot ulcers.

Authors: Yasser A Orban, MD¹; Mahmoud AE Soliman, MD²; Yasmine Hany Hegab, MD¹; and Mohamed M Alkilany, MD¹

Affiliations: ¹Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig, Egypt; ²Department of Vascular Surgery, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Correspondence: Yasser Orban, MD, Zagazig University Faculty of Medicine, Algamaa St, Zagazig, Alsharkia 44519, Egypt; yasser_ali_orban@yahoo.com

Disclosure: The authors disclose no financial or other conflicts of interest.