**2. Historical perspectives and advancements in ischemic wounds treatment**

Wound healing approaches are probably old as the history of medicine. During centuries, several significant breakthroughs, however, marked significant progress in wound repair, following thorough scientific understanding. Starting with the Ancient World, according to the oldest medical record found on a Sumerian clay tablet (2100 BC) [4], cleansing and bandaging the wound was noted to represent the central "healing gestures" to be practiced in the healing course [4]. The Ancient Egyptians (1600 BC–1550 BC) also mention the use of mixtures (honey, grease, and lint) for wound regeneration, however, without apparent etiologic segregation [5, 6]. They also displayed an impressive science of bandaging, including herbal extracts and resins (probably the first coordinated bandages ever mentioned) [5]. Hippocrates in the ancient Greece originally devised approach methods for acute and chronic wounds [6]. Later on, Cornelius A. Celsius marked a momentous step in wound care history by his original description of the "four cardinal signs of inflammation," including first "gangrenous foot" delineation in his eight-volume *Compendium of Medicine* (41 BC) [6]. A substantial contribution to ulcer's classification and healing understanding is appointed by outstanding surgical work of Ambroise Parré in the Renaissance era about the treatment of gunshot wounds including "the gangrenous battlefield limb" [7]. During the next centuries, many new ideas in wound management were unfortunately rejected by lack of validation and time-related historical tendencies. Wound healing understanding was subsequently developed by Joseph Lister's [8] and by Louis Pasteur's remarkable clinical research [8, 9] adding relevant knowledge for bacterial colonization and sepsis development, particularly in the ischemic ground [9]. More recently, notable breakthroughs in comprehending the complexity of wound healing cascade were added by Virchow [10], owning establishment of histopathology as an autonomous discipline [6, 10], and by first isolation of "epidermal growth factor" as a mitotic stimulant in 1962 [11].

**1. Introduction**

248 Wound Healing - New insights into Ancient Challenges

During centuries, wound healing was believed to be part of a mysterious process that addresses only inspirational approaches of secret practitioner's experience. Outstanding scientific advances over the last 50 years revealed real complexity of this staged process, astonishing as life's unfolding itself. This natural course seems to bear thousands of overlapping and indissoluble processes [1]. Today's knowledge, beyond new high-performance techniques for revascularization and tissue engineering [1], affords additional key data about intimate mechanisms of ischemic threat, ulcer formation, and steps to wound recovery [1, 2]. In the recent decades, this proper knowledge enhanced complementary diagnostic and interventional strategies with high serviceableness in patient's selection, arterial recanalization, and dedicated ulcer follow-up [1, 3]. However, despite soaring progress in medical technology and clinical judgment for critical limb ischemia (CLI) wound treatment, limb salvage, and patient's survival seem only scarcely affected [1–3]. This assertion dwells particularly true in diabetic and renal patients who exhibit ischemic foot wounds [1, 2]. Outstanding advances in basic research and clinical management toward better tissue regeneration, unfortunately, seem to confront with parallel increasing of CLI subjects each year [1]. It becomes obvious nowadays that ischemic ulcer healing implies a convergent treatment for multifaceted presentations in

The present chapter endeavor to summarize main treatment principles for CLI ulcer recovery that every modern practitioner eventually disposes in an updated contemporary view.

**2. Historical perspectives and advancements in ischemic wounds treatment**

Wound healing approaches are probably old as the history of medicine. During centuries, several significant breakthroughs, however, marked significant progress in wound repair, following thorough scientific understanding. Starting with the Ancient World, according to the oldest medical record found on a Sumerian clay tablet (2100 BC) [4], cleansing and bandaging the wound was noted to represent the central "healing gestures" to be practiced in the healing course [4]. The Ancient Egyptians (1600 BC–1550 BC) also mention the use of mixtures (honey, grease, and lint) for wound regeneration, however, without apparent etiologic segregation [5, 6]. They also displayed an impressive science of bandaging, including herbal extracts and resins (probably the first coordinated bandages ever mentioned) [5]. Hippocrates in the ancient Greece originally devised approach methods for acute and chronic wounds [6]. Later on, Cornelius A. Celsius marked a momentous step in wound care history by his original description of the "four cardinal signs of inflammation," including first "gangrenous foot" delineation in his eight-volume *Compendium of Medicine* (41 BC) [6]. A substantial contribution to ulcer's classification and healing understanding is appointed by outstanding surgical work of Ambroise Parré in the Renaissance era about the treatment of gunshot wounds including "the gangrenous battlefield limb" [7]. During the next centuries, many new ideas in wound management were unfortunately rejected by lack of validation and

patients with multiple arterial and systemic affectations [1–3].

Probably one of the most ponderous discoveries in the same period was the defining structure of DNA and RNA by Franklin, Watson, and Crick [6]. Parallel advances were noted in surgical and interventional revascularization techniques for *tissue healing* perceived in a hemodynamic ischemic perspective. Leading milestones in arterial flow imaging were marked by first arteriographic diagnostic reported by Brooks in 1924 [12], followed by first translumbar aortography described by Dos Santos in 1929 [13], both with considerable influence in more accurate inferior limb arterial disease diagnostic. First Doppler ultrasound assessment of atherosclerotic occlusive disease by noninvasive method was reported by Strandness [14] in 1966. All these diagnostic methods have borne huge influence first in distinguishing arterial from nonischemic wounds, and further for separating arterial from venous limb ulceration. The current ischemic injury diagnostic era yet institutes since the computed tomography (CT) scanning and magnetic resonance imaging (MRI) have become an integrated part of ongoing peripheral arterial flow evaluation [15]. For that arterial surgery enables high limb salvage nowadays, the achievement of several important steps was mandatory. The first lumbar sympathectomy in 1924 by Labat [16], the heparin use since 1937 [17], the Kunlin's first saphenous vein graft in 1951 [18] and the first Dacron [19], and polytetrafluoroethylene (PTFE) [20] prothesis utilization, all had tremendous influences in modern surgical revascularization for wound healing [1–3, 20].

Traditionally during years, open surgical bypass represented the main effective treatment strategy for tissue recovery and limb salvage [1, 21]. In addition to outstanding surgical revascularization advances, new transcatheter endovascular techniques emerged and rapidly evolved in CLI treatment arena during the last three decades [21]. They seem to improve the perioperative morbidity-mortality and the length of hospital stay, affording comparable limb preservation rates [1–3, 21]. Owning remarkable low invasiveness and reproducibility, the percutaneous transluminal angioplasty (PTA) and stenting (first promoted by Gruntzig in 1974 and by Dotter [20] in 1964) rapidly gained a wide utilization in the coronary, but also in the peripheral arterial disease (PAD) current treatment [21]. Although the "stent" term derives from Charles Stent (1807–1885), an English dentist who used this term for creating customed dental molds [21], the idea to modulate vascular lumen by diligent metallic implants had great issues in vascular practice. During the next decades, new "bare" or "covered stents" were imagined, together with new "stent grafts" originally pioneered by Volodos and Parodi in the treatment of aortic aneurysmal disease around 1985–1990s [22]. Novel "drug eluted" devices including balloons and stents have been successfully launched during the last decade with promising clinical results [1, 21].

Following parallel scientific emancipation, new strategies as to improve ischemic tissue healing were cast in parallel medical disciplines. Thus, in 1987, Taylor and Palmer initially described the "angiosome" model of human body vascularization [23] and auspiciously implemented the concept among particular plastic reconstructive surgery applications. This significant breakthrough in tissue perfusion understanding was succeeded by its first use in CLI limb salvage by Attinger and colleagues 20 years later [24], using "topographical" or angiosome-guided bypasses to the foot ischemic wounds [24]. Not surprisingly, starting with 2008–2010s, and up to the contemporary period, new endovascular "wound-directed" revascularization applications were described with promising wound healing and limb preservation results [25, 26]. All these progresses have added and undoubtedly will add complementary understanding in ischemic ulcer treatment, owning more precise revascularization selection since specific "wound-targeted" revascularization is performed [24–26].
