**6.1. The "angiosome concept" in ischemic wound healing: a succinct overview**

Among all innovative strategies in CLI wound treatment, a remarkable leap was undoubtedly marked by *topographic*, or intentional, *wound directed* arterial reconstruction [23–26, 35, 72, 91– 93]. This theory represents a unique clinical application of the *angiosome concept* initially pioneered in 1987 by Taylor et al. in the plastic reconstructive surgery field [23].

**Figure 1.** A schematic anatomic representation of the six angiosomes of the lower leg in a forefoot/hindfoot topographic view. (**1**) The *medial calcaneal* angiosome (from the posterior tibial artery). (**2**) The *medial plantar* angiosome (posterior tibial artery). (**3**) The *lateral plantar* angiosome (posterior tibial artery). (**4**) The *dorsalis pedis* angiosome (from the anterior tibial artery). (**5**) The *lateral calcaneal* angiosome (from the peroneal artery). (**6**) The *antero*-*lateral malleolar* angiosome (currently from the anterior tibial, also from the perforator branch of the peroneal artery).

The angiosome conceptualization describes more than 44 specific 3-D *tissue sectors* of the human body nourished by individual arterio-venous bundles called "the angiosomes" [23]. This anatomical representation was further referred to CLI treatment two decades later by Attinger et al. [24], owning encouraging clinical results.

*The lower leg angiosome territories*. The following skin and underlying tissue zones were earlier described as to nearly encompass six main *angiosomes* (**Figure 1**) of the foot and ankle [23–26, 91–93]:


**Figure 2.** A diabetic neuro-ischemic ulcer associating cutaneous sepsis on the antero-medial aspect of the foot. (**a**) The initial clinical aspect (CLI, Rutherford 5). (**b**) The appended angiographic aspect showing complete occlusions of the dorsalis pedis and distal posterior tibial artery. (**c**) Healing aspect at three months, following (**d**) angiosome-targeted revascularization by deliberately opening the dorsalis pedis artery territory (arrow).

These vascular territories are closely interconnected by numerous *arterial-arterial* communicants [23, 24], whose caliber and density are strongly influenced by the age of patients, by each region's anatomy and by the manifest arterial disease triggering CLI [24, 35, 72, 96–98]. Every individual collateral system essentially assists blood supply between neighboring angiosomes. These compensatory branches the so-called "choke vessels" include *large-, middle-*, and *small*sized arterial-arterial communicants, beyond the arterioles and capillary vessels in a vast "compensatory arterial foot network" [24, 29, 35]. All collateral interconnections between adjacent angiosomes are submitted to specific hemodynamic influences related to local *arterio*genesis and *angio*genesis processes [35, 59, 60].

The angiosome conceptualization describes more than 44 specific 3-D *tissue sectors* of the human body nourished by individual arterio-venous bundles called "the angiosomes" [23]. This anatomical representation was further referred to CLI treatment two decades later by

*The lower leg angiosome territories*. The following skin and underlying tissue zones were earlier described as to nearly encompass six main *angiosomes* (**Figure 1**) of the foot and ankle [23–26,

**•** The *medial calcaneal* and appended *medial* and *lateral plantar* arteries angiosomes arising all from the *posterior tibial artery*. They supply the entire plantar heel and the medial and lateral

**•** The *dorsalis pedis* angiosome, downstream to the *anterior tibial artery* that nourishes the dorsal foot and toes areas, also ensures the upper and anterior peri-malleolar vascularization. **•** The *lateral calcaneal artery* angiosome branching from the *peroneal artery* and that supplies

**•** At a higher level of the superior ankle, other angiosomes were described, such as *the antero*-*lateral malleolar* owning its correspondent *antero-medial malleolar* angiosomes (both from the *anterior tibial artery*), and the *pstero-medial malleolar* angiosome following corre-

**Figure 2.** A diabetic neuro-ischemic ulcer associating cutaneous sepsis on the antero-medial aspect of the foot. (**a**) The initial clinical aspect (CLI, Rutherford 5). (**b**) The appended angiographic aspect showing complete occlusions of the dorsalis pedis and distal posterior tibial artery. (**c**) Healing aspect at three months, following (**d**) angiosome-targeted

These vascular territories are closely interconnected by numerous *arterial-arterial* communicants [23, 24], whose caliber and density are strongly influenced by the age of patients, by each region's anatomy and by the manifest arterial disease triggering CLI [24, 35, 72, 96–98]. Every

revascularization by deliberately opening the dorsalis pedis artery territory (arrow).

spondent branch from the *posterior tibial artery*, respectively [23–26, 91–93].

Attinger et al. [24], owning encouraging clinical results.

91–93]:

plantar surface to the toes.

260 Wound Healing - New insights into Ancient Challenges

the lateral, plantar heel.

*The angiosome clinical model* implies a conspicuous vascular anatomical order, although subject to specific pathophysiological changes in every CLI individual pattern. Optimal *wound-targeted revascularization* probably means correct angiosome-related anatomical evaluation associated with individual collateral-related pathophysiological judgment for each CLI presentation [30].

**Figure 3.** Wound-targeted revascularization for severe forefoot sepsis and tissue necrosis, extending to the plantar side of the hallux and toes. (**a**) The initial clinical aspect (CLI, Rutherford 5). (**b**) Healing after topographic revascularization and multidisciplinary team care at five months. (**c**) The starting angiographic image showing complete posterior tibial artery occlusion (the dominant wound territory), and the dorsalis pedis thrombosis. We can remark only a few remnant collaterals (the characteristic diabetic foot collateral deprivation) represented by two lasting diagonal arteries. (**d**) Endovascular plantar angiosomes-targeted revascularization by posterior tibial artery intentional reopening. (**e**) The end-procedural result showing the posterior tibial, the plantar arteries, and the plantar arch reperfusion in an intentional wound-directed revascularization.

In young subjects with unaltered collateral network possible post-traumatic or ischemic injuries activate unmitigated "choke-vessels" that warrant (at some point) effective compensatory blood pressure between adjacent angiosomes [24, 39, 96, 97]. Atherosclerotic, inflammatory, or local thrombotic conditions may alter this unique natural compensatory system. As previously described [23, 24], the foot angiosomes are 3-D dynamic and continuously interacting structures [30]. Although their primary anatomical distribution seems accurately reproduced in more than 90% of subjects (owing 6–9% eventual anatomival variants) [23, 24, 26, 91], their interconnections ("choke vessels") are yet submitted to continuous changes, according to each type of CLI pathology [72, 95–98].

Assessing and treating ischemic wounds in the light of the angiosome theory imposes a flexible reflection upon *how* utilizing the remnant arterial-arterial connections (**Figures 2** and **3**) at best flow benefit for the patient [88, 97].

### **6.2. What group of ischemic ulcers may need WDR?**

Inasmuch genetic collateral network warrants a remarkable "rescue system" in non-atherosclerotic patients, it can be dramatically hindered in specific diabetic or uremic ischemic wounds [24, 35, 72, 96–98]. The interventionist should be aware of treating peculiar diabetic and ESRD *ischemic ulcers*, for that these patients may hide huge collateral decay and poor arterial-arterial connections among adjacent foot angiosomes [72, 97]. Eventual *indirect* [26] or *nonspecific* revascularization [25, 93] in these subjects may fail to afford correct arterial flow to the wound by a lack of collateral resources [25, 59, 72, 96].

Alternatively, the use of WDR principle in these cases seems to provide improved healing results [24, 39, 72, 96–98] owning scrupulous *macro-* and *microcirculatory* evaluation, planning for intervention and follow-up [39, 96, 97].

Despite encouraging tissue healing and limb salvage results for both, bypass and endovascular treatment [24–26, 91–93], uncertainty still dwells concerning the utility of angiosome-oriented revascularization in specific CLI groups of patients dysplaying different etiologies of arterial disease [35, 72, 96, 97]. Growing clinical expertise, however, seems to support WDR in "lowcollateral" CLI patients such as those presenting DFS (**Figures 2** and **3**), or ESRD ischemic wounds [72, 91–93, 96–98].

### **6.3. Does topographic WDR allow unrestricted anatomical applications?**

The angiosome-oriented revascularization theoretically offers superior chances for healing in selected ischemic wounds, yet this theory still awaits for further prospective validation in larger groups of equivalent CLI patients [92, 97].

Lower limb topographic anatomy addressed to date unnumbered ex vivo or clinical works [99– 102] (most of them in the last 50 years) and their analysis largely overpasses the purposes of this chapter. However, some compelling points should be probably mentioned for better picturing this impressive graduation in the distribution of the arterial tree toward the target tissue [35, 101, 102]. The whole body vasculature can be delineated from a "fractal" point of view, as harmonious repetitive patterns of peripheral tissue irrigation [35, 101]. Particularly concerning the inferior limb vascularization, this archetype evinces some specific *levels of irrigation* [35]. A primary *level I* of perfusion contains the main arterial and venous bundles (i.e. iliac and common femoral), the *level II* gathers first rank arterial branches in the thigh and calf (i.e. the superficial and profonda femoris and the three tibial trunks), and the next *level III* features distinct ramifications for *specific skin and underlying tissue zones* in the foot [35]. This level also encompasses the *large* collaterals (around 1 mm diameter), including *the angiosomes branches*, the appended *foot arches*, and the *metatarsal perforators* [24, 35, 101], yielding specific interest in topographic revascularization [23–26, 35, 93, 100]. The next *level IV* holds the *medium*and *small*-size (<0.5 mm) collaterals, while next microcirculatory ranks assemble *level V* that gathers *the arterioles* and the *level VI* connecting the *capillary* tier (around 8-µm diameter) [39, 101, 103]. This latest convenes several millions of small micrometric conduits in the whole human body, approximating 60,000 miles of estimated length [102].

Another parallel and more common anatomical partition used in CLI literature roughly distinguishes the *macrocirculatory* rank (that embodies previous *levels I–IV*) from the *microcirculatory* level (equivalent to other *levels V* and *VI*) of limb perfusion [1, 27, 29, 30, 103–106]. By bridging these two levels, the *medium* and *small* muscular arteries and adjacent *arterioles* contribute to a continuous *pacing system* of local tissular perfusion [103–105]. Since CLI threat appears, this function seems to be notably distorted until focused revascularization is applied [25, 60, 106].

**6.2. What group of ischemic ulcers may need WDR?**

262 Wound Healing - New insights into Ancient Challenges

the wound by a lack of collateral resources [25, 59, 72, 96].

for intervention and follow-up [39, 96, 97].

larger groups of equivalent CLI patients [92, 97].

wounds [72, 91–93, 96–98].

Inasmuch genetic collateral network warrants a remarkable "rescue system" in non-atherosclerotic patients, it can be dramatically hindered in specific diabetic or uremic ischemic wounds [24, 35, 72, 96–98]. The interventionist should be aware of treating peculiar diabetic and ESRD *ischemic ulcers*, for that these patients may hide huge collateral decay and poor arterial-arterial connections among adjacent foot angiosomes [72, 97]. Eventual *indirect* [26] or *nonspecific* revascularization [25, 93] in these subjects may fail to afford correct arterial flow to

Alternatively, the use of WDR principle in these cases seems to provide improved healing results [24, 39, 72, 96–98] owning scrupulous *macro-* and *microcirculatory* evaluation, planning

Despite encouraging tissue healing and limb salvage results for both, bypass and endovascular treatment [24–26, 91–93], uncertainty still dwells concerning the utility of angiosome-oriented revascularization in specific CLI groups of patients dysplaying different etiologies of arterial disease [35, 72, 96, 97]. Growing clinical expertise, however, seems to support WDR in "lowcollateral" CLI patients such as those presenting DFS (**Figures 2** and **3**), or ESRD ischemic

The angiosome-oriented revascularization theoretically offers superior chances for healing in selected ischemic wounds, yet this theory still awaits for further prospective validation in

Lower limb topographic anatomy addressed to date unnumbered ex vivo or clinical works [99– 102] (most of them in the last 50 years) and their analysis largely overpasses the purposes of this chapter. However, some compelling points should be probably mentioned for better picturing this impressive graduation in the distribution of the arterial tree toward the target tissue [35, 101, 102]. The whole body vasculature can be delineated from a "fractal" point of view, as harmonious repetitive patterns of peripheral tissue irrigation [35, 101]. Particularly concerning the inferior limb vascularization, this archetype evinces some specific *levels of irrigation* [35]. A primary *level I* of perfusion contains the main arterial and venous bundles (i.e. iliac and common femoral), the *level II* gathers first rank arterial branches in the thigh and calf (i.e. the superficial and profonda femoris and the three tibial trunks), and the next *level III* features distinct ramifications for *specific skin and underlying tissue zones* in the foot [35]. This level also encompasses the *large* collaterals (around 1 mm diameter), including *the angiosomes branches*, the appended *foot arches*, and the *metatarsal perforators* [24, 35, 101], yielding specific interest in topographic revascularization [23–26, 35, 93, 100]. The next *level IV* holds the *medium*and *small*-size (<0.5 mm) collaterals, while next microcirculatory ranks assemble *level V* that gathers *the arterioles* and the *level VI* connecting the *capillary* tier (around 8-µm diameter) [39, 101, 103]. This latest convenes several millions of small micrometric conduits in the whole

**6.3. Does topographic WDR allow unrestricted anatomical applications?**

human body, approximating 60,000 miles of estimated length [102].

According to the above considerations, several anatomical variants were equally described, mainly concerning level III of limb flow distribution [104, 105]. Following two recent metaanalysis gathering 7671 [107] or 5790 inferior limbs [108], and two "in vivo" analogous angiographic observations [109, 110], *native atypical leg arteries* were described in utmost 7.9– 10% individuals out of general population [107–110]. Among these variants, hypoplastic or aplastic posterior tibial artery was encountered in 3.3% cases, whereas the anterior tibial trunk was absent in about 1.5% of instances [108]. The presence of highly emergent anterior tibial artery or irregular tibial trifurcation was described in 5.6–6% cases [109–110], while anomalous origins of the dorsalis pedis artery were encountered in 4.3–6% presentations [109, 111]. Aberrant first dorsal metatarsal artery and appended first toe dominant irrigation was described in 8.1% cases [112], parallel variants of the arcuate artery in 5% [113], and modified courses of the plantar arch and plantar arteries in 5% of presentations [114]. The intimate knowledge of these variants seems significant for the advised interventionist since *wounddirected revascularization* is planned [30, 100]. The presence of one anatomical popliteal variation (i.e. high origin of the anterior tibial trunk) on one side may indicate possible ipsilateral foot vessel abnormalities in about 21% of cases [107, 109], and similar contralateral leg variants in 48% of instances [109, 110]. Concomitant *acquired arterial flow disturbances* were also cited in lower leg ischemic presentations, most of them accompanying the diabetic neuro-ischemic foot syndrome [34, 53, 59]. The majority of these anomalies were represented by occlusions of at least two or all tibial arteries in more than 70% of CLI diabetic subjects [110, 115]. A higher prevalence of long (>15 cm) obstructions in the posterior tibial and plantar arteries [25, 116, 117] and extensive (type II) calcifications [25, 91] in most diabetic calf and foot arterial segments were also demonstrated [91]. Our group experience over 232 diabetic CLI limbs [91] with Wagner grade 2–4 foot wounds [64] availing *angiosome-targeted* revascularization [24, 96–98], also confirmed more frequent posterior tibial atherosclerotic occlusive disease (68% of cases versus 25% anterior tibial and 7% peroneal presentations) [91]. Moreover, the posterior tibial hypoperfusion showed significant (>90%) concordance with distinct plantar, heel and forefoot (on the plantar side) skin, and adjacent tissue trophic lesions [25–91].

Although precise below-the-knee arterial *anatomical knowledge* is of paramount importance in planning "angiosome-directed" revascularization [91–93], the skilled interventionist should also corroborate additional *hemodynamic information* enabled by each collateral pattern [24, 93, 96–98, 118].

Even in the presence of unusual anatomical variants to supply the foot, topographic revascularization still appears feasible [39] by taking advantage either on visible or on unmasked arterial branches (the "dormant" collaterals) that gradually reveal during CTO recanalization [24, 35, 56].

It becomes clearer that since all tibial trunks become occluded, the tipping point between hypoxic tissue regeneration versus chronic ulceration and necrosis hinges upon *the remnant individual collateral reserve* and ways to deliberately use it in addressing the ischemic threat [24, 30, 34, 59].

Despite encouraging results to date [91–93, 96], the angiosome concept may provide better, yet not complete, ischemic tissue control [35, 61, 72, 118].

Topographic WDR for ulcer healing remains an enthralling subject of discussion. Certainly, alike similar new openings of flourishing interest in tissue regeneration, the scarcer the available evidence, the acrider the current debate, mostly based on heterogeneous retrospective deliberations [35, 72, 92, 96–98, 118].
