ReCor Medical Paradise® Renal Denervation System



Fig. 9.1
The paradise renal denervation system. (a) Paradise generator. (b) Paradise catheter: ultrasound transducer within cooling balloon. (c) The paradise system in situ (artistic rendering)





Paradise Generator


The Paradise Generator contains a touch screen which allows users to operate the Paradise System in a stepwise fashion to prepare the balloon for insertion, to inflate and/or deflate the balloon and also to deliver energy (Fig. 9.1a). This manner of operation, combined with a series of sensors, both internally and within the disposable cartridge allows the main central processing unit within the generator to monitor and control the state of the Paradise System at any moment in time. The dosage settings of the Paradise Generator are fixed and based on the efficiency of the transducer and the balloon size. Each catheter has an embedded chip that communicates to the generator the specific power settings to be applied.


Paradise Cartridge


The Paradise Cartridge when used in conjunction with the Paradise Generator controls the fluid flow into and out of the Paradise Catheter. Fluid flows in a closed-loop through the Paradise Cartridge and the Paradise Catheter.


Paradise Connection Cable


The Paradise Connection Cable allows for the communication of transducer information from the Paradise Catheter to the Paradise Generator as well as the transfer of electrical energy during the procedure.



Preclinical Results


The Paradise System has been developed to optimize safety and effectiveness by creating a cooled zone to ensure safety, and an ablation zone, to optimize effectiveness. Extensive in vitro and in vivo testing has been conducted to evaluate system functionality, device deliverability, thermal and cooling settings, treatment parameters and the overall safety and effectiveness of the system.


Thermal Profile


The target thermal profile for energy delivery determined by ReCor Medical Inc. includes a cooled zone wherein tissue temperatures are maintained between 37 and 55 °C to minimize endothelial or medial cell damage; a target ablation zone 1–6 mm from the arterial lumen wherein tissue temperatures should reach >60 °C for short durations to achieve immediate neural cell death; and a far field cooled zone wherein tissue temperatures do not exceed physiologic temperatures to ensure there is no damage to non-target tissues (Fig. 9.2). Optimization of the tissue thermal profile can be achieved through management of the power of energy delivered, the duration of energy delivery, and the cooling flow rate.

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Fig. 9.2
Target thermal profile for ablation of renal nerves while preserving renal arterial wall

In vitro and in vivo studies have been conducted to optimize the thermal profile of the Paradise System to effectively ablate the renal nerves. The cooling flow rate, power, and duration of energy delivered were varied in preclinical studies (in vitro initially and subsequently confirmed in vivo). Optimization of the thermal profile/thermal dose, and optimization of the number of ablations, was performed in vivo.


Computer Simulations


Computer simulation models were developed to characterize and optimize the thermal profile of the system. Simulations provide information regarding the heating pattern and depth of thermal energy delivered from the transducer. The model demonstrates the heating pattern emanating from the length of the transducer and the depth of heating with peak temperatures reached at several millimeters of depth with cooling on the surface.


Bench Models


In vitro studies confirmed the thermal profile observed in computer simulations. A gel model was utilized which mimics characteristics of tissue. The Paradise Catheter was inserted into the gel and thermocouples were placed at specific depths surrounding the balloon/transducer to measure the energy (heat) delivered. A temperature curve was generated based on the thermocouple readings. Based on this model and animal data, treatment parameters have been optimized for clinical use. At near depths (0–0.5 mm) temperatures remained below 60 °C and then reached ablation temperatures in the 0.5–6 mm range. Beyond 6 mm, the temperatures dropped off again below ablation levels. Figure 9.3 shows the average temperature at specific depths (thermal profile) in the gel model.

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Fig. 9.3
In vitro gel model demonstrating target thermal profile (average temperature achieved with the paradise system) for ablation of renal nerves while preserving renal arterial wall


In Vivo Studies


Animal studies were performed in either porcine or ovine models due to similarities in renal anatomy with humans. These in vivo studies have demonstrated the ability of the system to allow for appropriate insertion of the device and positioning of the transducer in the renal arteries. Bilateral renal ablation was performed in all studies and the safety and effectiveness of the system evaluated via histologic assessment of the renal arteries, kidneys, and abdominal peripheral organs. Additionally, effectiveness was assessed via measurement of kidney norepinephrine levels.


Effectiveness


The animal studies have demonstrated that the target thermal profile has been achieved in vivo with preservation through cooling of the arterial wall, and ablation of nerves at the target ablation zone of 1–6 ± 2 mm. The actual tissue ablation zone varies depending on the biological structures present. The renal vein, arterioles, and lymph nodes serve as heat sinks, preventing adjacent tissues from reaching ablation temperatures. Effective ablation of the nerves, characterized by irreversible necrosis, has been demonstrated histologically. A decrease in nerve function has further been demonstrated by immunohistochemical staining for specific nerve proteins; and by measurement of norepinephrine levels in the kidney, the end organ target of the renal sympathetic nerves.

Figure 9.4 is a representative histologic image of a porcine renal artery treated with the Paradise System at 7 days. As indicated, the renal artery (first millimeter of tissue) is spared whereas the ablation zone extends out to 6 mm, to target the majority of sympathetic nerves surrounding the renal artery. Quantification of affected nerves determined that on average 75 % of the nerves along the length of the artery were ablated with the Paradise System in animal models. In contrast, radiofrequency ablation ablates in a non-circumferential manner and heats at depths of 0–3 mm thereby potentially missing a large percentage of nerves.

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Fig. 9.4
Paradise system ablation zone in vivo. Photomicrograph of a histologic cross-section of a porcine renal artery treated with the paradise system (H&E). The renal arterial intimal and medial layers are preserved through system cooling whereas the renal sympathetic nerves (←) within the adventitia and peri-adventitia are ablated

Further confirmation of the effectiveness of the Paradise System was demonstrated through specific immunostaining of the renal nerves for structural nerve and functional nerve proteins. Positive staining was observed for two structural proteins [neurofilament protein, NFP, and S-100, nervous system specific protein] whereas reduced staining was observed for tyrosine hydroxylase (TH), a functional nerve protein. These data illustrate that in nerves (clearly identified through the structural proteins), function was greatly diminished consistent with thermal ablation.

Further evidence for a decrease in nerve function is demonstrated by kidney norepinephrine levels (Table 9.1). Eight animals were selected to get either one (n = 3), two (n = 3), or three (n = 2) 30 s treatments in the proximal, mid, and/or distal regions of both renal arteries. A significant decrease in norepinephrine levels was evident at 7 days for 1, 2 or 3 treatment emissions per artery when compared to control animals (n = 2), which correlated with the percentage of ablated nerves. Two or three emissions resulted in far greater reduction than one emission, consistent with the current clinical protocol.


Table 9.1
Percentage reduction of kidney norepinephrine levels and percent of ablated nerves based on number of ultrasound emissions


































Ultrasound emissions

Mean norepinephrine level

Percent reduction of norepinephrine vs. control

Percent of ablated nerves

0 Emission (control)

969 ± 44 ng/g



1 Emission

435 ± 217 ng/g

55 %

44 %

2 Emissions

104 ± 164 ng/g

89 %

76 %

3 Emissions

30 ± 36 ng/g

97 %

76 %


Renal Artery Safety


In addition, in vivo animal studies confirmed that the Paradise System does not cause clinically significant renal artery damage or functional impairment. As illustrated in the histology image in Fig. 9.4, the renal arterial wall (endothelium and medial layer) is preserved with minimal to no injury, which is important in minimizing any risk of renal stenosis. Preservation of the arterial wall is primarily due to the cooling feature of the system. Further, there is no evidence of ultrasound related damage to the renal vein, ureter, or kidney detected.

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Jun 20, 2017 | Posted by in NEPHROLOGY | Comments Off on ReCor Medical Paradise® Renal Denervation System

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