**4. Critical limb ischemia ulcers: do we meet the current clinical needs?**

Postischemic tissue recovery implies simultaneous alignment of several distinct physiological processes [33]. Inasmuch their entire clinical signification remains only partially controlled [27, 30, 33], their unaltered unfolding dwells prerequisite. Among numerous molecular and cellular events that clearly overpass the purposes of this chapter, some practical aspects may be however useful to be highlighted and are briefly summarized in the sections below.

### **4.1. Leading physiological mechanisms in wound recovery and appended phases of revascularization**

It is accepted that mechanisms concerning tissue regeneration are strongly influenced by the type and thickness of tissue layer affectation, also by their capacity for healing [1, 33]. The retrieval of CLI threat resets in motion the regular "cascade" of reconstructive tissue events leading in normal circumstances (absence of systemic risk factors for healing) to long-lasting tissue repair [33, 34]. Full-thickness wound regeneration following most CLI revascularizations concerns the skin, the underlying subcutaneous and the deep muscular compartments. Currently, this process is depicted in three schematic phases: the inflammatory stage (the "lag" phase), the "tissue formation" (or the "proliferative") phase, and the "tissue remodeling" phase [34]. It is important to note that this "allotment" is somewhat conventional since all three stages are commonly overlapping to some degree [33, 34]. Activating cells that participate in one phase usually produce biological triggers indispensable to interlock tissue molding into the next phase [34]. These stages are routinely *conditioned* by initial hemostasis and by intentional *arterial revascularization*, both representing fundamental activating processes [33– 35]. Most details concerning these enthralling multimodal events are largely depicted in available histopathology literature and will not be further characterized in this section.

During the same sequential process, the ischemic burden relief sets in motion three parallel *hemodynamic* regenerative phases [35]. These stages are conceptualized as (1) *the initiatory* flow redistribution phase (concerning "large" remnant collaterals surrounding the ischemic wound zone), (2) *the early* or "mid-term" flow dispensation (regarding the "rescue" or "small" collaterals and arterioles), and (3) *the retarded* postischemic phase, essentially characterized by the arteriogenesis, the angiogenesis processes [33–35]. Alike most biological chain-processes, these three flow-redistribution phases exhibit specific time overlapping in their activation, according to concomitant vascular risk factors and individual patterns of arterial occlusive disease [35]. This particular knowledge may enable the clinician to choose better appropriate diagnostic and treatment methods in a timely approach for every ischemic wound follow-up [33, 35].

### **4.2. Main pathophysiological aspects in ischemic wound healing and related clinical presentations**

To date, the exact mechanisms and time periods conducting to chronic ischemic ulceration are not completely understood [30, 31, 33, 34, 36]. Most arterial ulcers are encountered over the age of 65 as people live longer nowadays [3, 33]. Arterial ulcers are ranked to constitute about 12–19% among all leg ulcers [33, 37] while mixed venous-arterial or combined neuro-ischemic tissue defects may concern 15% [37] up to 24% [29–31] of these patients, respectively. There were described either as "spontaneous" ulcerations (typically involving the forefoot and toes as progressive collateral occlusion occurs) or as "post-minor trauma" wounds since inadequate arterial flow proves ineffective to increased oxygen demands for cicatrization [34, 38]. Bedridden patients with PAD represent another high-risk category to develop pressure heel ischemic ulcers on preexisting vascular impairment [37, 38]. For this particular cohort exhibiting ischemic hind foot ulcers, current guidelines emphasize that prevention by scrupulous heel elevation or soft tissue contact interposition is mandatory [3, 28, 38].

The TASC II fundamental CLI criteria [3] as absolute ankle pressure (AP) inferior to 50–70 mm Hg, or diminished toe pressure (TP) below 30–50 mm Hg are unanimously accepted [3]. A series of parallel predisposing factors for ischemic tissue damage were evinced in the last decade. They either concern the arterial perfusion (tobacco use, dyslipidemia, hypertension, weight excess, hyperglycemia, hyperhomocysteinemia, etc.), or specific foot conditions (peripheral neuropathy, inflammation, edema, infection, bedridden status, hypoalbuminemia, hyperglycemia, uremia, cortisone therapy, etc.), all with huge influence on peripheral tissue regeneration [1–3, 27, 33–35, 37, 38]. Although arterial ulcers theoretically may appear anywhere on the ischemic limb [3, 33], the presence of multilevel CLI arterial disease inflicts more distal localizations, particularly in subjects with deprived foot collateral reserve [1, 25, 29, 30].

stages are commonly overlapping to some degree [33, 34]. Activating cells that participate in one phase usually produce biological triggers indispensable to interlock tissue molding into the next phase [34]. These stages are routinely *conditioned* by initial hemostasis and by intentional *arterial revascularization*, both representing fundamental activating processes [33– 35]. Most details concerning these enthralling multimodal events are largely depicted in available histopathology literature and will not be further characterized in this section.

During the same sequential process, the ischemic burden relief sets in motion three parallel *hemodynamic* regenerative phases [35]. These stages are conceptualized as (1) *the initiatory* flow redistribution phase (concerning "large" remnant collaterals surrounding the ischemic wound zone), (2) *the early* or "mid-term" flow dispensation (regarding the "rescue" or "small" collaterals and arterioles), and (3) *the retarded* postischemic phase, essentially characterized by the arteriogenesis, the angiogenesis processes [33–35]. Alike most biological chain-processes, these three flow-redistribution phases exhibit specific time overlapping in their activation, according to concomitant vascular risk factors and individual patterns of arterial occlusive disease [35]. This particular knowledge may enable the clinician to choose better appropriate diagnostic and treatment methods in a timely approach for every ischemic wound follow-up

**4.2. Main pathophysiological aspects in ischemic wound healing and related clinical**

heel elevation or soft tissue contact interposition is mandatory [3, 28, 38].

To date, the exact mechanisms and time periods conducting to chronic ischemic ulceration are not completely understood [30, 31, 33, 34, 36]. Most arterial ulcers are encountered over the age of 65 as people live longer nowadays [3, 33]. Arterial ulcers are ranked to constitute about 12–19% among all leg ulcers [33, 37] while mixed venous-arterial or combined neuro-ischemic tissue defects may concern 15% [37] up to 24% [29–31] of these patients, respectively. There were described either as "spontaneous" ulcerations (typically involving the forefoot and toes as progressive collateral occlusion occurs) or as "post-minor trauma" wounds since inadequate arterial flow proves ineffective to increased oxygen demands for cicatrization [34, 38]. Bedridden patients with PAD represent another high-risk category to develop pressure heel ischemic ulcers on preexisting vascular impairment [37, 38]. For this particular cohort exhibiting ischemic hind foot ulcers, current guidelines emphasize that prevention by scrupulous

The TASC II fundamental CLI criteria [3] as absolute ankle pressure (AP) inferior to 50–70 mm Hg, or diminished toe pressure (TP) below 30–50 mm Hg are unanimously accepted [3]. A series of parallel predisposing factors for ischemic tissue damage were evinced in the last decade. They either concern the arterial perfusion (tobacco use, dyslipidemia, hypertension, weight excess, hyperglycemia, hyperhomocysteinemia, etc.), or specific foot conditions (peripheral neuropathy, inflammation, edema, infection, bedridden status, hypoalbuminemia, hyperglycemia, uremia, cortisone therapy, etc.), all with huge influence on peripheral tissue regeneration [1–3, 27, 33–35, 37, 38]. Although arterial ulcers theoretically may appear anywhere on the ischemic limb [3, 33], the presence of multilevel CLI arterial disease inflicts

[33, 35].

**presentations**

252 Wound Healing - New insights into Ancient Challenges

Beyond common atherosclerotic arterial ulcers, other *arterial*-related ulcers were described such as superficial hypertensive wounds, peripheral embolic tissue defects (owning 0.01–0.2 mm. cholesterol particles), those associated with connective tissue arteritis, those affecting hypercoagulable states, or following microangiopathic lesions, within parallel to mixed nutritional, hemolytic, or neurologic disorders [33, 34, 36].

### **4.3. What determines ischemic tissue defects to slide toward chronicity and necrosis? Is there a conjuring threshold to consider?**

It has been showed that in healthy individuals, peripheral wounds promptly tend to recover owning adapted cell's metabolism, appropriate oxygen supply, essential growth factors, cytokines, and matrix proteins inflow (Section 5.1.2.) that all endeavor to orient local tissue damage on "steady" sequential healing process [27, 33, 36].

Since initial ischemic changes last beyond local individual compensatory reserves [30, 35], the readapting mechanisms are gradually exhausted and local tissue homeostasis finally drifts toward biological extinction [36, 39, 40]. Inasmuch CLI wound onset may be commonly displayed over days or weeks [3], local infection and collateral depletion by septic thrombosis can urge irrecoverable tissue loss appearance and make it devastating [30, 32, 35]. Probably the real "tipping point" between viable or perished, for every inch of ischemic tissue around the wound relies on local collateral adaptation vigor [39]. Alike other ischemic models described in human tissues (stroke, myocardial infarction), the extent of necrosis core depends on rescue capacity inside the "penumbra" or intermediary neighboring zone [35]. For this transitional layer of undecided viability, a few factors strongly influence its fate. The timing and intensity of main ischemic threat, the type of arterial pathology, the remnant upstream arterial trunks and collaterals, and the elapsed interval to prompt debridement and revascularization, play a pivotal role in any arterial ulcer progress [30, 33, 36, 40].

Daily vascular practice proves that interventionists are more likely confronted with patients exhibiting more than one *long acting* adverse factors for tissue healing [39, 40]. These conditions can be summarized as malnutrition and hypoalbuminemia, lack of compensatory arterial collateral network, diminished arterio- and angiogenesis, peripheral edemas enhancing local compartmental syndromes, low cardiac output, and prolonged bony prominences pressure that collectively contribute as notable interferences in physiological cicatrization [34, 35, 37, 40].
