Authors:

Tali Yaakobi, Noa Cohen-Hadar, Hila Yaron, Eran Hirszowicz, Yariv Simantov, Arie Bass, Amihay Freeman; Department of Molecular Microbiology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; 

Chronic limb wounds are associated with tissue ischemia and are typical in patients with diabetes. Such wounds can lead to serious infection, gangrene, and limb loss. Chronic wounds are characterized by the presence of devitalized tissue that enhances bacterial growth, reduces host resistance to infection, and inhibits the formation of granulation tissue.^1–3 Debridement of necrotic tissue is therefore, an essential and crucial step in chronic wound management.^4–7 The main approaches to wound debridement are based on surgical, mechanical, enzymatic, or biological methods.^3,6,8,9
Enzymatic removal of necrotic tissue from chronic wounds and burns by proteases primarily offers selectivity of debridement without impairing adjacent healthy tissue.^10,11 Proteolytic enzymes for wound debridement are commercially available as ointments.¹⁰ The most frequently used products that contain papain are Accuzyme⁹ (Healthpoint, Fort Worth, Tex) and Panafil^11,12 (Healthpoint, Fort Worth, Tex). Comparative preclinical and clinical studies on the efficacy of papain versus other enzyme ointments indicated that papain was the more effective enzyme from this group. ^9,12-14
Papain is a proteolytic enzyme derived from the fruit of Carica papaya, and has been employed for decades in the food and pharmaceutical industries.
Wound debridement using papain-containing ointments is currently practiced with repeated topical applications over a period of 1–3 weeks. The procedure is both labor intensive and time consuming.^12,14
The authors previously proposed and demonstrated feasibility of an alternative mode of delivery and application of proteolytic enzymes for wound debridement and cleansing: continuous controlled streaming of protease solutions onto a targeted treated area, providing optimal and controlled environmental conditions for full exploitation of the protease’s potential debridement activity.¹⁶ The efficacy of the streaming approach was successfully demonstrated in removal of coagulated blood and debridement of experimental burn wounds in small lab animals by a series of proteases.¹⁶
The present study takes the continuous streaming approach one step further, from small lab animal tests to feasibility demonstration of streaming a selected protease solution onto a large (approximately 3.5 cm x 3.5 cm) experimental necrotic wound model in pigs with a clinically-applicable system. 

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