Lower extremity ulcers in diabetic patients are difficult to treat. Recently, the use of human blood platelet-derived components in this indication has been raising interest. In this study, we have evaluated the safety and efficacy of the combination of autologous platelet gel (PG) and skin graft for treating large size recalcitrant ulcers. Eight consecutive diabetic patients aged 25 to 82 with nine nonhealing lower extremity ulcers (median size of 50 cm2; range 15–150 cm2) were treated. Skin ulcer was debrided, and the wound was sprayed after 7 to 10 days with autologous platelet-rich plasma and thrombin. Thin split-thickness skin graft with multiple slits was then applied on the wound bed and fixed with staples or cat-gut sutures. There were no adverse reactions observed during the study. Eight out of 9 skin grafts took well. The interval between skin graft and complete wound healing ranged from 2 to 3 weeks in the 8 successful cases. No ulcer recurrence was noted in those patients during the follow-up period of 2 to 19 months. In this study, the combination of autologous platelet gel and skin grafting has proven beneficial to heal large-size recalcitrant ulcers.
About 15% of diabetic patients will develop chronic ulcer, and about 25% of those will have to undergo foot amputation [
Platelet-rich plasma (PRP) has been proposed as an adjunct for the treatment of diabetic foot ulcers [
In a recent study with 17 ulcers of various etiology, we have shown that a skin grafting was improved by a combination of single-donor allogeneic platelet gel and fibrin glue [
This clinical study was a prospective pilot trial approved by the Institutional Review Board of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Protocol 098–05-301). Eligible patients were enrolled after informed written consent was obtained. The protocol conformed to ethical guidelines of the 1975 Declaration of Helsinki. From January 2010 to September 2012, eight consecutive diabetic patients with nine nonhealing lower extremity ulcers were treated. The ulcers were not curable for at least 3 months prior to the enrollment using conservative treatments including daily dressing change, topical application of antibiotic ointment, and synthetic dressing coverage using Aquacel and DuoDERM (ConvaTec, Garenne-Colombes, France). Pregnant women, patients with ischemic change of leg (Transcutaneous oxygen tension
Patients demography, clinical situation, ulcer location and size, and time to healing.
Patient | Age | Gender | Diabetes duration (year) | Glycated hemoglobin (%) | Cause of ulcer | Comorbidity | Ulcer location | Ulcer Size (cm) | Duration of ulcer | Take of skin graft | Time to healing | Follow-up |
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 62 | F | 25 | 10.2 | Pressure sore | Renal failure; hypertension; |
Right heel | 4 × 7 | 4 months | Complete | 2 weeks | 12 |
2 | 25 | F | 5 | 7.1 | Falling down | Rheumatoid arthritis | Right ankle | 5 × 8 | 2 years | Complete | 3 weeks | 13 |
3 | 82 | F | 11 | 6.8 | Cellulitis | Hypertension | Right lower leg | 3 × 5 | 2 months | Complete | 2 weeks | 13 |
4 | 47 | M | 7 | 6.5 | Traffic accident | Nil | Right lower leg | 4 × 5 | 3 months | Complete | 3 weeks | 10 |
5 | 65 | M | 6 | 6.0 | Stasis dermatitis | Varicose vein |
Left lower leg | 15 × 10 |
6 months | Complete | 2 weeks | 10 |
6 | 80 | F | 10 | 8.2 | Falling down | peripheral arterial |
Right ankle | 3 × 5 | 3 months | Complete | 2 weeks | 19 |
7 | 72 | F | 8 | 5.5 | Contusion injury | Hypertension |
Left heel | 8 × 10 | 2 months | 3 × 3 cm2 skin graft loss | Residual ulcer | Passed away |
8 | 45 | F | 13 | 7.7 | Infrared radiation burn | Spinal cavernous angioma s/p OP with paralysis | Right ankle | 6 × 10 | 2 months | Complete | 3 weeks | 18 |
PRP was prepared using the SEPAX system (Biosafe SA, Eysins, Switzerland) (Figure
Biosafe SEPAX system (a). Autologous PRP and plasma to prepare platelet gel and thrombin (b). Thrombin generation device to activate plasma (c). Double-syringe applicator containing PRP and thrombin (d).
Thrombin was prepared as in our previous studies [
Autologous platelet gel was obtained by spraying simultaneously equal volumes of PRP and thrombin using a spray applicator (Merries International Inc.) (Figure
The nonhealing ulcers were first debrided to remove the infected and necrotic tissues. The wounds were covered with moist saline dressing. Daily dressing change without additional treatment was performed. Repeated debridement was necessary in 6 patients because of residual necrotic tissue. The interval between the debridement and skin graft ranged from 7 to 10 days. During skin graft surgery, the wound bed was sprayed evenly with equal volumes (5 to 7 mL) of autologous PRP and autologous thrombin to form the platelet gel, and a split-thickness skin graft with multiple slits was put on the gel-covered bed, fixed with staples or cat-gut sutures, while a short leg P-P splint was used to immobilize the lower extremity. Every patient was placed on antibiotics during the course according to wound cultural results. Bolster dressing with sofa-tulle was used to avoid postgraft hematoma formation. The skin graft was checked 3 days after surgery. Negative pressure wound therapy (VAC) was not used in this study.
Fibrinogen presents in the PRP polymerized into a fibrin gel, leading to the formation of platelet gel that adhered to the wound bed (Figure
Platelet gel formed on the wound by conversion of fibrinogen into fibrin.
A 65-year-old male, diabetic for 6 years, suffered from two nonhealing ulcers of left lower leg, measuring 15 × 10 cm2 and 5 × 7 cm2, respectively, due to stasis dermatitis for 6 months. The surrounding tissue was severely scared (Figure
Two chronic ulcers (15 × 10 cm2 and 5 × 7 cm2) with surrounding scar tissues (a). After adequate debridement, the wound was sprayed with PRP and thrombin (b). Skin graft was applied on gel-covered wound bed (c). Durable wound coverage 10 months after skin graft (d, e).
A 45-year-old female, diabetic for 13 years, suffered from nonhealing ulcer over right ankle, measuring 6 × 10 cm2 due to infrared radiation burn for 2 months (Figure
Burn injury with chronic ulcer (6 × 10 cm2) (a). After adequate debridement, the wound was sprayed with PRP and thrombin (b). Skin graft was applied on gel-covered wound bed (c). Durable wound coverage 12 months after skin graft (d).
A 72-year-old female, diabetic for 8 years, suffered from nonhealing ulcer over left heel, measuring 10 × 15 cm2, due to contusion injury for 2 months. The ulcer was deep to the periosteum of calcaneus bone (Figure
Chronic ulcer (10 × 15 cm2) deep to the periosteum of calcaneus bone (Arrow) (a). After adequate debridement, the wound was sprayed with PRP and thrombin (b). Skin graft was applied on gel-covered wound bed (c). Skin graft loss (3 cm2) over the periosteum, 2 months after skin graft (d).
Chronic nonhealing diabetic ulcers of lower extremity develop as a result of peripheral neuropathy, ischemia, and trauma [
The benefits of PRP in the treatment of severe and large ulcers have not been evaluated in randomized clinical trials [
In the current study, patients expressed some concerns about the use of allogeneic blood components due to perceived viral infectious risks. They were able and willing to donate about 100 mL of blood that was centrifuged in the Biosafe SEPAX system to obtain autologous PRP and PPP. PPP was activated by calcium chloride in a specifically designed medical device to generate thrombin. We could not use fibrin glue as it would have required collecting a large volume of blood (typically 450 mL) from the patients to obtain enough plasma for cryoprecipitation. In addition, preparing autologous cryoprecipitate under safe and standardized conditions is not easy within a hospital setting. After debridement of the ulcers, converting a chronic ulcer into acute wound, autologous platelet gel obtained by mixing PRP and thrombin was applied on the wound to form a platelet gel [
PRP was prepared using a medical device that concentrates platelets 2.5-to 3.5-fold compared to baseline values in whole blood. Activation by thrombin releases multiple growth factors from the platelet alpha-granules [
There are pros and cons in the use of autologous versus allogeneic blood materials. In the absence of pathogen inactivation treatment, a major advantage of using autologous platelet gel is avoiding the ethical and legal concerns of exposing the patient to the viral risks of allogeneic products [
In conclusion, although the clinical safety and effectiveness data is derived from a pilot study rather than from a randomized controlled trial, it provides, together with our previous series [
This study was supported in part by the National Science Council (NSC), Taiwan, under the Grant 99-2314-B-016-008, in part by the Tri-Service General Hospital, Taipei, Taiwan, under the Grant TSGH-C99-105, and in part by the National Defense Medical Center, Taipei, Taiwan, under the Grant I-16.