**3. Demographics, etiologic factors, and social implications of PAD with its most severe presentation represented by critical limb ischemia**

Recent demographic data suggest that more than 200 million individuals worldwide suffer from varied forms of the PAD that represent a 24% increase over the last decade and concern all socioeconomic strata [27, 28]. The economic weight of PAD was proven to be ponderous [28]. It has meant that the total costs of vascular-related hospitalizations climbed to 21 billion dollars in the USA in 2004, and this threshold seems to rise each year continually [28]. Critical limb ischemia as a consequence of severe infra-inguinal atherosclerosis embodies extreme forms of PAD and currently associates rest pain and ischemic ulcers (corresponding to Fontaine stages III/IV and Rutherford categories 4-5 ischemic limb presentations) [1–3].

The term of CLI is commonly used for patients who exhibit symptoms of severe arterial hypoperfusion for more than 2 weeks [3, 27]. Elementary CLI diagnosis is made by clinical exam, anatomical stratification, and hemodynamic evaluation of flow disturbances over accessible arterial paths [1, 3, 27]. Defining and analyzing large CLI groups of patients, however, prove to be difficult [2–4].

These hindrances are mainly determined by (1) the vast heterogeneity of underlying arterial diseases [1, 27], (b) the various appended risk factors [1–3, 27], (c) the multilevel spread of arterial lesions [1, 27] (d) by concurrent systemic pathologies [27], (e) the scarce follow-up data [3, 27], and (f) the lack of synchronous macro- and microvascular apprehension for gradual hypoxic limb changes [1, 27–31]. It is known that without precocious recognition and aggressive treatment, CLI invariably inflicts significant morbidity and high rates of major amputation and mortality [1–3, 27–30].

To date, the likelihood of death within the first 6 months of CLI diagnosis has been estimated to reach 20% (all etiologies confounded) and exceeds 50% at 5 years following prime documented onset [27–32]. Contemporary studies reveal that patients with PAD (and particularly those with CLI) are more likely to experience simultaneous coronary or cerebral vascular disease, bearing a higher risk of early death [1–3, 27]. The risk for developing PAD seems considerably increased in diabetic and renal patients, prone to more frequently experience systemic ischemic events compared to general population [1–3, 27–31].

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].

**3. Demographics, etiologic factors, and social implications of PAD with its**

Recent demographic data suggest that more than 200 million individuals worldwide suffer from varied forms of the PAD that represent a 24% increase over the last decade and concern all socioeconomic strata [27, 28]. The economic weight of PAD was proven to be ponderous [28]. It has meant that the total costs of vascular-related hospitalizations climbed to 21 billion dollars in the USA in 2004, and this threshold seems to rise each year continually [28]. Critical limb ischemia as a consequence of severe infra-inguinal atherosclerosis embodies extreme forms of PAD and currently associates rest pain and ischemic ulcers (corresponding to Fontaine

The term of CLI is commonly used for patients who exhibit symptoms of severe arterial hypoperfusion for more than 2 weeks [3, 27]. Elementary CLI diagnosis is made by clinical exam, anatomical stratification, and hemodynamic evaluation of flow disturbances over accessible arterial paths [1, 3, 27]. Defining and analyzing large CLI groups of patients,

These hindrances are mainly determined by (1) the vast heterogeneity of underlying arterial diseases [1, 27], (b) the various appended risk factors [1–3, 27], (c) the multilevel spread of arterial lesions [1, 27] (d) by concurrent systemic pathologies [27], (e) the scarce follow-up data [3, 27], and (f) the lack of synchronous macro- and microvascular apprehension for gradual hypoxic limb changes [1, 27–31]. It is known that without precocious recognition and aggressive treatment, CLI invariably inflicts significant morbidity and high rates of major amputation

To date, the likelihood of death within the first 6 months of CLI diagnosis has been estimated to reach 20% (all etiologies confounded) and exceeds 50% at 5 years following prime documented onset [27–32]. Contemporary studies reveal that patients with PAD (and particularly those with CLI) are more likely to experience simultaneous coronary or cerebral vascular disease, bearing a higher risk of early death [1–3, 27]. The risk for developing PAD seems

**most severe presentation represented by critical limb ischemia**

stages III/IV and Rutherford categories 4-5 ischemic limb presentations) [1–3].

however, prove to be difficult [2–4].

250 Wound Healing - New insights into Ancient Challenges

and mortality [1–3, 27–30].

Several risk factors that lead to lower limb major amputation in patients having ischemic wounds were described, including increasing age, being male, being African American, having peripheral neuropathy, and developing infected ulcers [1, 2, 27–29]. The Trans-Atlantic Inter-Society initial Consensus (TASC) II document showed that more than 15% of diabetic subjects will unfold a foot ulcer during their lifetime while 14–24% of them, unfortunately, will require amputation [3]. It is also valued that more than 170 million people suffer nowadays from diabetes mellitus, and their worldwide number is anticipated to attain 366 million by 2030 [1]. In this particular cohort of diabetic patients during the first year of CLI diagnosis, 40–50% among them may experience foot amputation while 20–25% among them will die [1, 2, 27].

Nevertheless, by applying optimal revascularization and local wound treatment as early as possible, up to 85% of amputations can be prevented [3].

The social burden of the metabolic syndrome and particularly the diabetic systemic atherosclerotic disease is tremendous for the patient, the medical care organization, and public communities [1, 2, 28, 31].

Particularly concerning *arterial* inferior limb *ulcers* (all arterial pathologies confounded), current reports document 18–29% prevalence among 60 years or older patients who interestingly bear equal rates as much younger (50-year-old) individuals associating diabetes or tobacco use [33].
