Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Innovative textile structures designed to prevent type III endoleaks in endovascular stent-grafts.

The damage caused to the fabric of endovascular stent-grafts most often occurs at the contact zones between the fabrics where they are attached to the apices of Z-shaped stents as a result of normal physiologic pulsatile movement within angulated vessels in vivo. Although design improvements were made over the years, the risks were not fully eliminated even with the newer M-shaped stent reconfiguration. In this study, we proposed to create and manufacture a novel fabric for stent-grafts with specifically designed reinforced zones to enhance resistance to fabric abrasion. These reinforced zones are set at the vicinity of the apices of the Z-shaped stents and between two adjacent Z-shaped stents where folding and pleating are commonly observed to occur in angulated vessels. Three innovative weaving structures with two different types of yarns and two controls were designed and prepared. Two commonly used commercial devices supported, respectively, with ringed stents, and Z-shaped stents were selected as the references for comparison. Textile structures including thickness, water permeability, mechanical properties, (more specifically tensile and bursting stress, as well as fatigue simulation) were tested on all fabrics. Compared to commercially available plain weaves, the fabrics with locally reinforced zones showed improved mechanical characteristics and fatigue resistant properties. A fabric designed with specifically reinforced zones has now clearly been shown to effectively reduce the abrasion caused by the apices of Z-shaped stents. However, further optimization may still be possible.

Long-term resistance to fracture and/or corrosion of the nitinol wires of the talent stent-graft: observations from a series of explanted devices.

The biodurability of the Nitinol wires used in stent-grafts retrieved from reoperations and autopsy was analyzed to assess the possible causes of fracture and/or corrosion of the stents. The Nitinol wires of six explanted devices presented a corrosion-free surface after in vivo service. The drawing lines in the control wires were still present, but neither burrs nor flakes were observed. Pits and crevices were rare, but some shallow ones were present. Some abrasions of the surfaces of the Nitinol wires were also observed. The chemical composition of the explanted devices showed the presence of organic contamination that covered the thick layer of titanium oxide before reaching the Nitinol itself. The durability of the Nitinol employed in the manufacture of the Talent stent-grafts was confirmed; the results of this study show the Nitinol to be resistant to corrosion. We have also concluded that the fractures of the Nitinol wires in two devices were unique adverse incidents caused by compression and bending related to the sharp angle of the Nitinol wires.

Absence of tissue ingrowth through the textile fabric in a series of explanted clinic stent-grafts.

Using the retrieved devices from one autopsy and five reoperations, the biocompatibility of explanted Talent stent-grafts was investigated to highlight the capacity of the fabric to act as an effective scaffold to regenerate a blood conduit. The autopsy device was encapsulated both internally and externally, but the capsules did not penetrate through the fabric structure. The reoperation devices showed discrete patches of compact fibrin and irregularly scattered mural thrombi. Positive staining of α-actin, tissue plasminogen activator (tPA), urokinase (uPA), urokinase receptor (uPAR), and urokinase inhibitors (PAI 1, PAI 2, PAI 3, and protease nexin), and D-dimer was more frequently identified in the autopsy sample than in the reoperation samples. This preliminary assessment shows that the stent-graft retrieved during autopsy was better healed than those explanted at reoperation.

Fatigue and/or failure phenomena observed in the fabric of stent-grafts explanted after adverse events.

In this study, we aimed to investigate changes to the fabric of Talent stent-grafts following implantation of aortic endografts and to determine the possible causes of fatigue and/or failure of the grafts. Six devices were explanted at reoperation (N=5) and autopsy (N=1). Selected segments were assessed nondestructively by gross observation and destructively by analyzing textile characteristics and chemical properties. All of the devices showed a 4/4 twill woven fabric of monofilament polyester. These devices, explanted at reoperation and autopsy, presented different levels of fatigue and/or failure. Numerous holes were found in the fabric of two devices. The minor damage caused by the passage of the sutures through the weave to fasten the Nitinol wires did not progress significantly over time. The sutures remained relatively intact, except for some distortions. The main failure mode was the abrasion of the yarns at the apices of adjacent Nitinol stents. In two devices, this abrasion resulted in fraying of the yarns and holes in the fabric tubes. This short series of explanted devices provides evidence of damage to polyester fabric used in aortic endografts and raises questions regarding their resistance to abrasion and the risk of endoleak associated with monofilament fabric yarn.

Electrical stimulation promotes the wound-healing properties of diabetic human skin fibroblasts.

This study evaluated the effect of low (20 and 40 mV/mm) intensities of electrical stimulation on the proliferation and migration of skin fibroblasts from diabetic donors. We also examined the effect of electrical stimulation on modulating the capacity of fibroblasts to contract collagen gel, express alpha-smooth muscle actin, and secrete proteolytic enzymes involved in regulating extracellular matrix synthesis and degradation. Our study shows that 20 and 40 mV/mm of stimulation increased the growth of fibroblasts extracted from diabetic patients but not from non-diabetic donors. Electrical stimulation increased the migration of diabetic fibroblasts, their capacity to contract collagen gel, and the expression of alpha-smooth muscle actin and promoted different proteolytic enzymes involved in accelerating wound healing. Overall results confirm the effectiveness of electrical stimulation in modulating the wound healing activities of fibroblasts extracted from diabetic skin donors. This study, therefore, suggests the possible use of electrical stimulation to promote diabetic foot ulcer healing by stimulating the wound healing properties of skin fibroblasts.

Engineering diabetic human skin equivalent for in vitro and in vivo applications.

The prevalence of diabetes is increasing worldwide. Diabetes contributes to 70% of all non-traumatic lower-limb amputations, which are directly caused by diabetic foot ulcers (DFU) that are difficult to heal. Non-healing diabetic ulcers represent one of modern society's most difficult medical challenges. One of the promising initiatives to treat DFU is the grafting of autologous skin or stimulating the skin cells at the edge of the wound to proliferate and close the wound. The present study was to engineer a diabetic human skin equivalent (DHSE) that contains fibroblasts and keratinocytes extracted from the skin collected from diabetic patients. The DHSE was used to investigate whether exposure to low-intensity electrical stimulation (ES) could promote diabetic cell activity. The ES was generated by a direct current (DC) electric field of 20 or 40 mV/mm. We demonstrated that the fibroblasts and keratinocytes could be extracted from older diabetics, cultured, and used to engineer DHSE. Interestingly, the exposure of DHSE to ES led to a structural improvement through tissue stratification, increased Ki-67 expression, and the deposition of basement membrane proteins (laminin and type IV collagen). The DHSE exposed to ES showed a high level of keratin 5 and 14 expressions in the basal and supra-basal layers. The keratinocyte proliferation was supported by an increased secretion of the keratinocyte growth factor (FGF-7). Exposure to ES decreased the activity of metalloproteinases (MMP) 2 and 9. In conclusion, we extracted keratinocytes and fibroblasts from the skin of diabetic-old donors. These cells were used to engineer skin equivalents and demonstrate that ES can promote diabetic wound healing. This DHSE can be a promising tool for various in vitro studies to understand the wound healing mechanisms under chronic inflammatory conditions such as diabetes. The DHSE could also be used as an autologous substrate to cover the DFU permanently.

Intra-operative fenestration of stent grafts: a note of caution based upon preliminary in vitro observations.

Intra-operative fenestrations of stent grafts make more frail and elderly patients amenable to endovascular surgery but require further assessment of the viability of currently used experimental techniques. Four types of polyester fabrics currently employed in stent grafts were exposed in vitro to various protocols of fenestration: cutting, trocaring, and cantering. The resulting fenestrations were examined by gross observation, light microscopy, and scanning electron microscopy. Blunt fenestration by scissors and sharp penetration led to unpredictable apertures, impairment of the integrity of the grafts, and damage to the filaments. The fenestrations were more likely to extend in the woven fabrics, whereas the knitted fabrics were more resistant to fraying. The use of the electric cautery demonstrated the ability to create a fenestration by simultaneously perforating/cutting and edge sealing. Any safe fenestration requires a perforating method that ensures the sealing of the edge of the graft material with a well-controlled diameter. A preoperative fenestration can be tolerated, but there are risks of damage to the stent grafts when reloading the device. More elegant methods of preoperative fenestration, particularly in situ retrograde laser fenestration, are in development and deserve clinical validation.

Detailed analysis of a series of explanted Talent AAA stent-grafts: biofunctionality assessment.

Six Talent stent-grafts were harvested at reoperations (N=5) and autopsy (N=1). The explants were observed nondestructively, including gross morphology, X-rays, CT scans and closed pressure system analysis. The Nitinol frames in three devices harvested at reoperations and another harvested at autopsy were intact. One had a stent fracture of the proximal bare stent, and one had a wire fracture of a thin proximal external supporting stent as well as a hole in the fabric just above the bifurcation. For the three devices structurally intact, reoperations were performed for a type 1A endoleak (one patient) and aorto-enteric fistulas (two patients). The healing characteristics were poor or absent. The fabric in the main body of the grafts harvested after aorto-enteric fistula was devoid of biological deposits. Two of the grafts harvested at reoperation demonstrated fabric holes of up to 4 mm 2. The device obtained at autopsy showed an almost continuous internal capsule with variable thickness. The luminal surface was smooth, but the capsule detached easily. The devices explanted at reoperations showed various levels of impaired biofunctionality associated with adverse outcomes. The stent-graft retrieved from autopsy was intact.

Effect of Electrical Stimulation on Diabetic Human Skin Fibroblast Growth and the Secretion of Cytokines and Growth Factors Involved in Wound Healing.

Diabetic foot ulcers are indicative of an impaired wound healing process. This delay may be resolved through electrical stimulation (ES). The goal of the present study was to evaluate the effect of ES on diabetic fibroblast adhesion and growth, and the secretion of cytokines and growth factors. Diabetic human skin fibroblasts (DHSF) were exposed to various intensities of direct current ES (100, 80, 40 and 20 mV/mm). The effect of ES on fibroblast adhesion and growth was evaluated using Hoechst staining, MTT and trypan blue exclusion assays. The secretion of cytokine and growth factor was assessed by cytokine array and ELISA assay. The long-term effects of ES on DHSF shape and growth were determined by optical microscopy and cell count. We demonstrated that ES at 20 and 40 mV/mm promoted cell adhesion, viability and growth. ES also decreased the secretion of pro-inflammatory cytokines IL-6 and IL-8 yet promoted growth factor FGF7 secretion during 48 h post-ES. Finally, the beneficial effect of ES on fibroblast growth was maintained up to 5 days post-ES. Overall results suggest the possible use of low-intensity direct current ES to promote wound healing in diabetic patients.

A branched, balloon-deployable, Aortomonoiliac stent-graft for treatment of AAA in a patient with a solitary intrapelvic kidney.

PURPOSE: To report the use of a branched, balloon-deployable stent-graft to treat abdominal aortic aneurysm (AAA) in the setting of a solitary kidney. CASE REPORT: A 72-year-old man with a solitary intrapelvic kidney and multiple comorbid conditions was diagnosed with an asymptomatic 5.3-cm abdominal aortic aneurysm (AAA); the renal artery emerged from the aneurysm sac. A customized branched, balloon-deployable, aortomonoiliac stent-graft was utilized to exclude the AAA and preserve perfusion to the single renal artery. A synthetic bypass was then implanted to restore perfusion to the contralateral limb. The diameter of the aneurysm decreased from 5.3 to 2.7 cm at 18 months. The renal artery was patent without evidence of stenosis; renal function was normal. CONCLUSION: The deployment of a novel branched stent-graft represents an interesting alternative approach to the treatment of a juxtarenal aneurysm.

Electrical stimulation promotes the proliferation of human keratinocytes, increases the production of keratin 5 and 14, and increases the phosphorylation of ERK1/2 and p38 MAP kinases.

Effective wound healing remains a significant clinical challenge in reducing patient morbidity and improving quality of life. Wound healing is a complex process involving the endogenous electrical field. The electrical field can contribute to wound healing by activating keratinocytes to promote reepithelialization. The objective of this study was to determine the effects of exogenous electrical stimulation (ES) on human keratinocyte viability and proliferation and on production of IL-6, IL-8, and keratins (K5 and K14) and to investigate the activated signalling pathways in keratinocytes exposed to ES. Keratinocytes were cultured under ES at different intensities for 6 or 24 hr. Cell proliferation, cytokines and growth factors, K5 and K14, as well as phosphorylated ERK1/2 and p38 MAP kinases, were evaluated. The results showed that the keratinocytes exposed to ES between 100 and 150 mV/mm for 6 or 24 hr showed a significantly increased proliferation rate. However, a 24 hr exposure to 200 mV/mm revealed no significant effect in cell growth. ES at 100 and 200 mV/mm for 6 hr increased the secretion of epidermal growth factor and vascular endothelial growth factor, and the production of K5 and K14. K14 was more sensitive than K5 to ES. However, ES down-regulated the secretions of IL-6 and IL-8. Finally, ES increased the phosphorylation of ERK1/2 and p38 MAP kinases. Overall results suggested that ES can be useful in supporting skin wound healing by activating keratinocytes.

Size of the proximal neck in AAAs treated with balloon-expandable stent-grafts: CTA findings in mid- to long-term follow-up.

PURPOSE: To determine the evolution of the proximal aortic neck diameter in mid- to long-term follow-up after endovascular aneurysm repair of abdominal aortic aneurysm (AAA) with a balloon-expandable stent-graft. METHODS: Thirty patients (27 men; average age 71 years, range 56-87) with infrarenal AAAs were treated with the SETA-Latecba balloon-expandable stent-graft (6 aortomonoiliac and 24 bifurcated configurations). Follow-up ranged from 4 to 8 years (mean 73.4 months). Computed tomography was done systematically before the procedure, after implantation (1-3 months), at 1 year, and annually thereafter. The last follow-up scan was utilized to measure the proximal neck for purposes of comparison with baseline and the initial post-implant scans. RESULTS: Five patients died during follow-up of causes unrelated to the procedure. No endoleaks or graft migrations were observed. The pre-deployment proximal neck diameter (a) averaged 23.4 mm (range 18-32), the diameter after deployment of the stent-graft (b) averaged 24.9 mm (range 18-34), and the most recent follow-up proximal neck measurement (c) averaged 23.8 mm (range 18-31). Comparing the last follow-up to the post-implant measurements (c-b), the neck diameter decreased in 15 (50%) patients [7 with short necks (i.e., <15 mm)] and remained unchanged (no variation) in 15 (50%) patients (4 with short necks). All patients treated with the SETA-Latecba balloon-expandable stent-graft showed stability of the proximal aortic neck diameter in mid- to long-term follow-up. CONCLUSION: The study showed that the diameter reached at initial deployment did not increase further in the long term, which supports the safety and reliability of this modular balloon-expandable stent-graft and illustrates that this device does not produce dilatation of the proximal neck after deployment. Future dilatation of the aortic neck is unlikely, and consequently, migration or delayed type I endoleak are also unlikely.

Analysis of explanted Latecba modular stent-grafts deployed transrenally to repair AAAs with short necks in 29 dogs.

Twenty-nine modular stent-grafts deployed transrenally to repair AAAs with short necks in dogs were harvested at autopsy of the animals after scheduled durations of implantations of 10 days, one month, three months, and six months. Analyses of the explanted devices included non-destructive techniques such as gross observations, X-rays CT scan, IVUS and angioscopy. Further to appropriate dissection, histological investigations were carried out by means of scanning electron microscopy (SEM) and light microscopy. All the 29 specimens were extensively encapsulated with fibrous tissues but the fibrous capsule was thin in six of them; four capsules were ulcerated. The X-rays confirmed the stability of the devices that were still straight (12), slightly bent (12) or bent (4). The modules were misaligned in only one case. IVUS and angioscopy confirmed the patency of all the stent-grafts with thin internal capsules both proximally and distally with variable capsulation in the mid-section of the grafts. The left renal artery orifices were found to be patent at dissection with no obstruction to flow. The luminal flow surface of the stent-grafts was smooth and glistening proximally and distally containing endothelial like cells and vasa-vasorum. Poor healing was noted in the aneurysm area. Transrenal deployment of this modular stent-graft is feasible and gave excellent results with regard to biofunctionality and biocompatibility. The device proved to be safe and efficient.

Transrenal deployment of a modular stent graft to repair AAAs with short necks: experiments in dogs.

Severely angulated (> 60 degrees ) or short (< 15 mm) proximal necks remain significant anatomical limitations for endovascular stent-graft repairs for abdominal aortic aneurysms. Ensuring proper proximal fixation of the stent-graft to the host artery without the short-or long-term risks of endoleak or migration represents a particular technical challenge for these anatomical circumstances. An innovative balloon expandable stent combined with a weft-knitted prosthesis was specifically designed for these situations by modelling the stent to the neck anatomy without overdistension or potential barotrauma allowing better incorporation of the device. The Latecba stent-graft consists of a 2 parts modular design. The first one, Module A, is deployed at the transrenal level and consists of a Palmaz type stent whose first half is bare and second half is sutured to a crimped weft-knitted polyester graft whose distal end holds a constriction. The second Module B is a non-crimped weft-knitted graft attached to 2 stainless steel stents. The first stent is entirely contained in the proximal textile tube, allowing fixation to module A. The second stent, which is left uncovered over the distal third, ensures proper fixation of the stent-graft distally. Following the creation of a prosthetic aneurysm in the infrarenal aorta in 32 dogs, 29 received the Latecba stent-graft for scheduled durations of 10 days, 1 month, 3 months and 6 months. Proper deployment of the stent-grafts was achieved without difficulty. All 29 animals survived and the devices were all patent at sacrifice. No device defects or migrations were observed and the stent-grafts proved to be efficient in this setting to exclude the aneurysm. Analyses of the explanted devices (gross observations, RX, CT scan, IVUS, angioscopy) confirmed the stability of this modular stent-graft. Further on-going clinical investigations are warranted to validate this concept before this stent-graft becomes commercially available without any restriction.

Specific shortcomings of endograft design.

Further to the rapid enlargement of an aneurysm to 5.6 cm in diameter after 3 years of surveillance, a 79-year-old patient was fitted with a Vanguard modular stent graft and monitored on a regular basis for 6 years. Two years later, the aneurysmal sac ruptured. The patient died 1 month after an open surgery. The device was devoid of any encapsulation and the ipsilateral limb was detached from the body. The Nitinol skeleton was mostly maintained, however, some polypropylene sutures were broken. The resulting motion of the sharp-angled Nitinol wires caused abrasion and resulted in a few localized holes that were sufficient to permit blood to percolate through the textile wall. Some polyester yarns in the warp direction were ruptured. The Nitinol wire used in this device was shown to be corrosion resistant but the selection of the polypropylene suture was inappropriate. Because this technology is maturing rapidly, these weaknesses can be avoided in the future generations of endovascular devices. It is recommended that these Nitinol wires be sutured to the fabric and that polyester yarns stronger than 68 decitex in tubes 8 mm in diameter are selected.

Persistent type II endoleak unrelated to an Anaconda aortic stent graft fulfilling the 3Bs requirements of biofunctionality, biodurability, and biocompatibility.

A patient was fitted with an Anaconda stent graft for which there was a persistent type II endoleak. Two subsequent attempts at embolization were unable to resolve the endoleak. The diameter of the aneurysm varied initially from 5.5 cm in diameter down to 4.8 cm but then later re-dilated to 6.1 cm, with evidence of persistent flow into the aneurysmal sac from the inferior mesenteric artery. Results from serial computed tomography scans demonstrated clear evidence of a type II endoleak that originated from the inferior mesenteric artery with outflow to a distal lumbar artery. The harvested stent graft did not show evidence of a device-related failure. The stent graft and its modular segments were found to have been properly deployed. Only a thin external capsule was evident at explantation. The internal wall of the device showed irregular and thin encapsulation with scattered mural thrombi, which were more prominent at the bifurcation of the main body of the device. Blood deposits and tissue development were sufficient to prevent blood oozing through the wall. The explanted Anaconda stent graft was devoid of any construction flaws or damage (fatigue of the textile or corrosion of the Nitinol wires) after implantation.

Transmural communication at a subcellular level may play a critical role in the fallout based-endothelialization of dacron vascular prostheses in canine.

A microporous and permeable wall is important for the healing of vascular prostheses, however, the significance of its permeability to soluble substances at subcellular level has not been demonstrated. Polyester arterial prostheses were prepared in such a way that each of them contained three segments, of which at least one segment was impervious and another segment was permeable to water but impermeable to cells. Twenty graft segments were implanted in 7 dogs as a thoraco-abdominal bypass for 2 months. The prostheses were then harvested, photographed, and treated for histological and morphological studies. The low porosity graft capped by two thrombogenic segments was fully endothelialized, proving the fallout mechanism. The striking contrast with its impermeable counterpart demonstrated that a wall permeable to small substances of subcellular level was critical for the endothelial healing. A wide range of water permeabilities did not reveal advantages of high water permeable segments over low water permeable ones. Endothelial ingrowth from anastomoses was also jeopardized in the absence of wall permeability. In conclusion, transmural communication at a subcellular level may have played a critical role in the fallout based-endothelialization of arterial prostheses in canine. This highlights the potential function of perigraft cytokines and growth factors in endothelial healing.