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The Biodesign Process: Intro and Overview
June 28, 2022

By Omar Ahmed

As a field reliant on innovation, product development, and device optimization, the biodesign process is inherently rooted within Interventional Radiology (IR). That process, however, can be quite daunting for those who lack a technical or engineering background. Here, we are going to methodically break down how to approach the biodesign process and discuss an overview of the essential preliminary steps required to turn your idea into a reality. 

Step 1: Defining the Problem 

This first step is both the most important and often the most difficult: defining a problem to address. The only thing worse than developing a faulty product is to waste precious time, energy, and resources on a product no customer wants or needs. To avoid this situation, it is essential to employ a needs-based approach when defining a problem. You first must ask yourself: What is the problem I am trying to solve? What unmet need am I trying to address? At this stage, avoid presuming any solutions. Below is a simple template for generating a problem thesis:

[Customer] will buy/use/implement/benefit from [Product/Solution] because of [Proposed value of product/solution].

A strong thesis is extremely broad and avoids catering towards any specific solution. As an example, let’s return to the year 1815, one year before the stethoscope was invented. An engineer of that time may have observed that physicians have no way of listening to bodily sounds, leading them to make inaccurate and incomplete diagnoses. Rather than ideating a stethoscope, they would first have generated this problem thesis: Physicians will buy auscultation devices because they will have the ability to listen to internal bodily sounds, leading to more informed diagnoses. This problem thesis is broad and can be approached in multiple ways. A device that magnifies and transmits sound directly into a physiancs ears (i.e. a stethoscope) is one possible solution to this problem. However, it is not the only solution. A different engineer may see the same problem statement and conceptualize a device that, when placed on the skin, vibrates with the same energy as an underlying bodily sound. Another engineer may ideate a device that converts mechanical sound energy into electrical energy that lights up an LED with an intensity directly proportional to the intensity of the original sound. 

A broad thesis leaves the door open for creativity. This allows the biodesign team to objectively compare many different solutions with the ultimate goal of selecting the one that best meets the needs of the customer. 

Step 2: User Needs and Design Inputs

Congratulations! You have successfully defined your problem and created a functional problem statement. The next step in the biodesign process is to highlight key features of your proposed solution and the customer segment you aim to market your product towards. Here are a few questions to get you started: 

User needs:

  • Who will use this product/solution? (e.g., physicians, patients, nurses, etc.)

  • What does the user need? (What unmet need does the user have that you are trying to address with your product?)

  • In what context will your product/solution be used? (e.g., outpatient, inpatient, administrative services, etc)

    Design inputs:

  • What are the objectives of your product/solution? 

  • What constraints are you facing? (e.g., physical, financial, mechanical, etc.)

  • What type of product is it? (e.g., physical device, website, app, etc.)

    Here, we must discuss two important design related terms: verification and validation. Verification is the process of ensuring a device works as intended and meets its design inputs. In other words, Am I building the device right? Validation confirms that the product being designed accurately addresses the user needs. That is, Am I building the right device? 

    Verifying any particular device is rather straight-forward. To do so, one must objectively evaluate the device’s ability to meet the constraints defined within its original design inputs. If the device was meant to be less than one pound, is it? If part of the device needed to freely rotate 90 degrees, can that piece freely rotate 90 degrees? If the device was meant to withstand high temperatures for more than 48 hours, can it? Importantly, these questions can only be answered with objective, quantitative evidence. To verify a device, engineering teams are required to submit a performance evaluation in which they report what functional testing they conducted and what results were found. These tests vary in complexity. They can be as simple as weighing a device or as involved as a six-month long stress test in which a device is constantly used to demonstrate longevity. 

    Validating a device is more nuanced. In order to ensure one is building the right device, one must meticulously observe people using the device in the actual (or simulated) environment in which it may be implemented. This allows an engineer to witness first-hand whether the device is effectively meeting the needs of the user and what problems persist. Another way to gain information on the validity of a device is to ask users whether or not the device has helped them overcome their original problem. However, since user feedback is more subjective and can be riddled with bias, observation remains the gold standard. As author Marilyn vos Savant once said, “To acquire knowledge, one must study; to acquire wisdom, one must observe.” 

Comprehensively and thoroughly defining the user needs and design inputs early on is critical for future verification and validation approval. Throughout the biodesign process, always refer back to the original user needs (to ensure the right device is being built) and to the design inputs (to ensure the device is being built correctly). 

   

   

Step 3: Ideation

With your problem thesis, user needs, and design inputs in mind, it is time to brainstorm as many unique and novel solutions as possible. Allow yourself to conceptualize seemingly ridiculous and improbable solutions to the problem; you may later find that combining ideas from various concepts leads you to the most innovative solution possible. Undergraduate engineering students are often asked to sketch 100 potential solutions during the ideation phase. Do not confine yourself to one or two ideas, the more the better!

Next Steps

Once you have chosen a concept (or concepts), you are ready to begin prototyping your device! For assistance and guidance regarding the prototyping stage and other future steps in the biodesign process, we have written additional articles on topics such as computer modeling, 3D printing, implementation of electronic controllers, and many others. We are constantly writing new articles on helpful topics, but if you have any specific recommendations, please reach out to the SIR Tools of Biodesign Committee. We hope this article has helped you understand the basic fundamentals of biodesign and wish you luck as you move forward in this exciting process.

Cement, Balloons, and Race Cars: On the Evolution of Vertebroplasty
May 14, 2022

Author & Illustrator: Tiffany Ni | Medical Student at University of Toronto, Temerty Faculty of Medicine
Editor: Rohan Patil | Medical Student at…Read more

Percutaneous AV Fistula Creation using Ellipsys and WavelinQ
September 27, 2021

Author(s):
Griffin McNamara
Johnathan Neshiwat
Chris Childers
Jonah Adler

Editor(s):
Tushar Garg, MD

History
Dialysis treatment for chronic kidney disease was first developed by Dr. Willem Kolff in 1943, after various iterations and advances its availability began to grow in 1962 after which it has become a mainstay treatment for patients with chronic kidney disease [1,2]. It is estimated that, in 2021, 15 percent of adults in the United States (approximately 37 million people) have chronic kidney disease, of which 661,000 individuals have renal failure, and 468,000 individuals require dialysis [3,4]. There have been a number of advancements in dialysis treatment since its advent; most notably, the creation of arteriovenous fistulas (AVF) for chronic venous access in 1966 [5].

AVF formation is traditionally performed by vascular surgeons by creating radiocephalic, brachiocephalic, or brachiobasilic transpositions and suturing the anastomoses. According to Dr. Dheeraj Rajan, division head and professor of vascular and interventional radiology at the University of Toronto, “the basic technique of creating an AV fistula has not changed considerably since 1966 when initially described by Brescia and Cimino. The sutured anastomosis also has not significantly changed since initially described by Carrel in 1902” [6]. As a result, patients often require post-creation interventions such as in order to maintain patency and facilitate proper maturation of the fistula. For example, in a 2018 study, patients receiving endovascular AVF placement were found to have an event rate per patient-year of 0.74, compared to 7.22 in patients who received surgical intervention (P<.0001) [7].

In recent years, the FDA has approved two new methods for AV fistula creation using a percutaneous approach. These include the WavelinQ (Beckton Dickinson, NJ) and Ellipsys (Avenu Medical, CA) endovascular arteriovenous fistula devices that use radiofrequency and thermal technologies, respectively, to fuse vessels. In 2014, William Cohn, M.D., vice president and director of Johnson and Johnson Center for Device Innovation at TMC, presented a prototype of the Wavelinq endoAVF System, known as everlinq endoAVF system [8]. In 2018, everlinq was approved by the FDA for marketing alongside the Ellipsys endovascular AVF system [9] (5). Several follow-up studies since the introduction of these technologies have shown that they are associated with fewer additional procedures in the 12 months following the initial procedure, suggesting better outcomes and decreased cost [10,11]. Implementation of endovascular AVF placement is also associated with more rapid maturation of the AVF and decreased time to initiation of dialysis [12].

Current
These two techniques are performed by vascular specialists who use a wire to advance a probe in retrograde fashion through the superficial veins in the upper extremity into the radial/ ulnar artery. A probe is then advanced and uses magnets to align the artery and vein and uses thermal energy or radiofrequency to fuse the arteriovenous anastomoses to create the fistula. This technique has favorable outcomes when compared to the traditional surgical technique. First, this is a minimally invasive procedure, and results in minimal scarring and tissue damage around the fistula. Additionally, the formation of a “side by side” anastamoses lessens stress from blood flow, decreases the risk for vessel wall thickening, and has favorable effects on blood flow [15].

WavelinQ:
WavelinQ was given 510(k) clearance by the FDA in 2018 [13]. WavelinQ is indicated for the creation of an arteriovenous fistula using the concomitant ulnar artery and vein in patients who have chronic kidney disease and need hemodialysis. A minimally invasive approach using WavelinQ is achieved using magnets. WavelinQ allows increased physician flexibility by allowing for AV Fistula creation using the ulnar and radial veins and concomitant arteries [13] . Two catheters are inserted, initially into the brachial vein and artery. Using magnetism, the catheters are aligned and confirmed using fluoroscopy. The venous site contains the electrode which emits a burst of radiofrequency energy that introduces a connection between the arterial and venous system [14] .

Figure 1. WavelinQ AV Fistula creation using either the radial/ulnar artery and vein using magnets and radiofrequency to create a fistula.

Ellipsys:
FDA approved in 2018 [9] and one of two newly approved devices for percutaneous arteriovenous fistula creation, the Ellipsys vascular access system from Avenu Medical utilizes a novel technique in pAVF creation. Like the WavelinQ system, Ellipsys takes advantage of the proximity of the upper forearm deep communicating vein and the proximal radial or proximal ulnar arteries [15]. An alternative to WavelinQ’s magnetic and radiofrequency method, Ellipsys utilizes a combination of thermal energy and ultrasonographic guidance in the creation of pAVF. [14,16].

Figure 2. Various options for AV Fistula creation [12]

Under ultrasound guidance, access is gained to a perforating vein adjacent to the radial artery and punctured into the radial artery. A guidewire is then advanced into the radial artery followed by sheath insertion over the guidewire. The Ellipsys catheter device is then inserted. Once positioned to capture both arterial and venous walls, the Ellipsys device is activated. Simultaneously cutting and fusing adjacent arterial and venous walls using thermal energy, our AV fistula is created. Balloon angioplasty follows pAVF creation to reduce post-anastomotic stenosis [15].

Figure 3. Percutaneous AV Fistula creation using Ellipsys [7].

Impact
Since first described by Brescia and Cimino in 1966, AV fistulas have been at the cornerstone of treatment for patients with chronic renal failure. Often these fistulas serve as a lifeline for these patients. Initially, the surgical placement of an AV fistula was revolutionary and its technology not only extended the life but also the quality of patients with renal disease. However, since 1966, the surgical placement of AV fistulas has not changed much. Open surgical placement of these AV fistulas poses some initial limitations such as needing additional procedures within the preceding 12 months after procedure, slow AV fistula maturation and increased time to initial dialysis.

To further advance the technology of AV fistula placement and provide better outcomes for patients both the WavelinQ and Ellipsys systems have been developed. Both technologies provide a new means for minimally invasive placement of AV fistulas. Each of these systems uses a novel approach to create robust fistulas via minimally invasive techniques. The hope is that this technology will provide a new means to perform AV fistulas placement without the complications seen in open surgical placements. Rather than needing general anesthesia and open surgery AV fistulas can now be placed under minimal sedation and minor surgical intervention.

Recent studies done using the wavelineQ have shown promising results. A recent study comparing the wavelineQ AVFs compared to surgically placed radiocephalic AV fistulas showed that the wavelineQ AVFs showed higher rates of fistula primary patency at 400 days [17]. These results indicate that the use of the wavelineQ prolongs time from initial fistula placement to first thrombosis or any intervention needed for recanalization. For patients, this means that they will have a longer complication free interval after initial placement as compared to surgical AVF creation. These results also indicate that the use of the wavelineQ will increase the time and likelihood of fistula functionality before the need for abandonment. When comparing the WavelineQ to the Ellipsys we see similar results. A study conducted comparing the two showed that the rates of primary patency were equivalent between the two. However, it was noted that the rates of secondary patency in this study favored the Ellipsys [17]. These two single center studies suggest that these new technologies are superior to that of open surgical AF fistula placement in terms of primary and secondary patency.

Not only do both the WavelinQ and Ellipsys provide superior patency but they also provide a superior aesthetic appearance without a scar. This outcome is favorable as it improves patient satisfaction with the procedure. Further, these technologies require less postoperative follow up as no surgical incision care is needed. Finally, the increase in patency and need for intervention shown in the previous studies reduces the post fistula creation cost [18].

In conclusion the development of these two new technologies provides a novel and superior method of placement of AF fistulas. The combination of increased efficacy, reduced costs, and increased patient satisfaction make these technologies a welcome addition to the growing procedural base in interventional radiology.

References:
1. Themes UFO. Arteriovenous Fistulas. Radiologykey.com. Published June 30, 2019. Accessed April 7, 2021.

2. Bracamonte H. A brief history of dialysis. Dpcedcenter.org. Published March 10, 2016. Accessed April 7, 2021.

3. Chronic kidney disease in the United States, 2021. Cdc.gov. Published March 9, 2021. Accessed April 7, 2021.

4. Kidney disease statistics for the United States. Nih.gov. Accessed April 7, 2021.

5. Arteriovenous Fistulas. Radiologykey.com. Published June 30, 2019. Accessed April 7, 2021.

6. Mallios A, Jennings WC, Boura B, Costanzo A, Bourquelot P, Combes M. Early results of percutaneous arteriovenous fistula creation with the Ellipsys Vascular Access System. J Vasc Surg. 2018;68(4):1150-1156.

7. Arnold, Renée JG, et al. “Comparison between surgical and endovascular hemodialysis arteriovenous fistula interventions and associated costs.” Journal of Vascular and Interventional Radiology 29.11 (2018): 1558-1566.

8. Tmc.edu. Accessed April 7, 2021.
https://www.tmc.edu/news/2018/12/pumps-pipes-2018-conference-shared-greatness-of-in
novation-across-medicine-energy-and-aerospace/

9. Office of the Commissioner. FDA permits marketing of first catheter-based systems used to create vascular access for hemodialysis patients. Fda.gov. Published 2018. Accessed April 7, 2021.

10. Shahverdyan R, Beathard G, Mushtaq N, Litchfield TF, Nelson PR, Jennings WC. Comparison of Outcomes of Percutaneous Arteriovenous Fistulae Creation by Ellipsys and WavelinQ Devices. J Vasc Interv Radiol. 2020 Sep;31(9):1365-1372. doi: 10.1016/j.jvir.2020.06.008. Epub 2020 Aug 11. PMID: 32792280.

11. Hull J, Deitrick J, Groome K. Maturation for hemodialysis in the ellipsys post-market registry. J Vasc Interv Radiol. 2020;31(9):1373-1381.
12. How it works. Wavelinq.bd.com. Published December 17, 2018. Accessed April 7, 2021.
https://wavelinq.bd.com/how-it-works/

13. Inston N, Khawaja A, Tullett K, Jones R. WavelinQ created arteriovenous fistulas versus surgical radiocephalic arteriovenous fistulas? A single-centre observational study. The Journal of Vascular Access. 2020;21(5):646-651. doi:10.1177/1129729819897168

14. Avenu – Ellipsys – Avenu Medical. Avenumedical.com. Published February 17, 2016. Accessed April 7, 2021. https://avenumedical.com/ellipsys/

15. Wasse H. Place of percutaneous fistula devices in contemporary management of vascular access. Clin J Am Soc Nephrol. 2019;14(6):938-940.

16. BD receives FDA 510(k) clearance of WavelinQ 4F endoAVF system. Vascularnews.com. Published February 14, 2019. Accessed April 7, 2021.
https://vascularnews.com/bd-fda-510k-wavelinq-4f-endoavf-system/

17. R. Shahverdyan, G. Beathard, N. Mushtaq, T. F. Litchfield, P. R. Nelson, and W. C. Jennings, “Comparison of Outcomes of Percutaneous Arteriovenous Fistulae Creation by Ellipsys and WavelinQ Devices,” Journal of Vascular and Interventional Radiology, vol. 31, no. 9, pp. 1365-1372, 2020/09/01/ 2020, doi:

18. Hebibi, H., Achiche, J., Franco, G. and Rottembourg, J. (2019), Clinical hemodialysis experience with percutaneous arteriovenous fistulas created using the Ellipsys® vascular access system. Hemodialysis International, 23: 167-172.

The Leaching Problem: A Short Story about Y-90
September 25, 2021

By Jacob Poliskey & Joseph McFarland

A small village lay nestled on an island on the western side of Sweden. Carl Arrhenius, a lieutenant from the nearby city of Stockholm, was indulging his interest in gunpowder in search of new combustible elements near a mine. He noticed a most unusual band of dark, heavy metal running in the rock. This “new earth,” as he called it, was named Yttria after this small Swedish village of Ytterby.1 Little did the lieutenant know that his discovery would later serve as the foundation of one of the most fashionable and fascinating procedures in Interventional Radiology: Y-90 Radioembolization.

The liver is an incredible metabolizer of nutrients, as well as a filter of toxins, that come directly from the gut. Normal hepatic parenchyma actually receives most of its blood supply from the very gastrointestinal system that it is designed to filter. A key discovery about the liver that paved the way towards Selective Internal Radiation Therapy (SIRT) or Radioembolization, was that hepatocellular carcinomas (HCC) do not have the same dominant portal blood supply as the rest of the liver. HCC receives 80% of its blood from the hepatic artery (Figure 1).

Figure 1. Y-90 Radioembolization can successfully ablate an HCC tumor, while mostly sparing the normal hepatic parenchyma, because the HCC’s vasculature primarily comes from the hepatic artery. A catheter is guided into the supplying arteries of the tumor, and then radioactive Y-90 ceramic or glass beads are deployed at carefully dosed amounts. The beads are manufactured at such a size that they can lodge in the tumor’s capillaries without stopping blood flow. The proximity of the tumor to the lodged radioactive beads allows for selective destruction of the tumor.

Shortly after angiographers discovered the blood supply of HCC, early reports of radioembolization with Y-90 appeared. Several small studies over the 1960s-1980s demonstrated feasibility in humans, but the adverse effects outweighed the benefits of the therapy. This was often due to the toxic effects of radiation such as pneumonitis, liver disease, and gastrointestinal ulceration. Some patients even developed the most serious adverse effect of myelosuppression, attributed to yttrium leaching from the spheres and into the bone marrow. The yttrium leaching problem greatly lessened interest in and use of SIRT technology.

TheraSphere, developed in 1988, was the first technology to overcome the leaching problem. Melting aluminum oxide and silicon dioxide at 1,500°C in the presence of Y-89 forms a glass matrix with embedded non-radioactive yttrium. Neutron bombardment then transforms the Y-89 into the radioactive Y-90. As Y-90 is completely embedded within the glass, there is virtually no possibility of leakage. However, this glass-based approach came with the limitation that the glass particles were denser than blood, possibly limiting the even distribution in the tumor.1

SIR-Spheres, developed about a decade later, solved this seeping difficulty in a different way. The SIR-Spheres are composed of a cation-exchange resin. Pure radioactive Y-90 is exchanged for sodium and then precipitated with phosphate, immobilizing it within the resin. This technique leaves no room for radioactive impurities and has a theoretical benefit of better tumor distribution due to their density. To minimize Y-90 leakage, however, the SIR-Spheres were initially suspended and dosed in a non-ionic solution: pure water. This led to arterial stasis and intra-procedural pain. Subsequently, this changed to 5% dextrose in water, which helps alleviate these issues.2

Both TheraSphere and SIR-Spheres have effectively solved the leaching problem and are widely used today. There have been no trials demonstrating superiority of either method, so the platform used is simply a matter of physician or institutional preference.2

From advancements in sphere size for optimal tumor deposition to intraprocedural affirmation of tumor targeting with radio-opaque glass microspheres, this promising technology continues to forge ahead. Even now, Y-90 radioablation therapy is being explored as a curative option when historically, it has been considered only a palliative therapy3. It will be exciting to see what advances are made in the future.

Sources
1. Marshall JL, Eta B. Yttrium and Johan Gadolin. Unt.edu. Accessed November 26, 2020. http://www.chem.unt.edu/~jimm/REDISCOVERY%207-09-2018/Hexagon%20Articles/gadolin.pdf

2. Westcott MA, Coldwell DM, Liu DM, Zikria JF. The development, commercialization, and clinical context of yttrium-90 radiolabeled resin and glass microspheres. Adv Radiat Oncol. 2016;1(4):351-364.

3. What’s new in Y-90? – endovascular today. Accessed November 26, 2020. https://evtoday.com/articles/2019-oct/whats-new-in-y-90

Innovations in Uterine Fibroid Embolization
September 25, 2021

Author(s):
Matthew Henry
Wayne State University SOM ’22

Christine Lin
Pennsylvania State University SOM ’23

Vimal Gunasekaran
Medical College of Wisconsin ’22

Anushree Rai
SIR MSC Reserves Member

History
Uterine fibroids are a common occurrence in middle aged females that can cause painful and heavy menstrual bleeding.  With a prevalence of uterine fibroids estimated to be 65% in women greater than 50, successful treatment of these patients is crucial [1].  One of the growing treatment options include uterine fibroid embolization (UFE) performed by an Interventional Radiologist.

While embolizations were first described in the 1970’s for treatment of postpartum hemorrhage, vascular malformations, or devascularization of tumors, it was not until 1995 that Ravina et al. proposed embolization for treatment of uterine fibroids [2]. With 16 patients under neuroleptic analgesia, access of the right femoral artery with subsequent catheterization of the right and left uterine arteries and embolization with inert particles of Ivalon was performed until fibroid blood flow was completely interrupted. 75% of patients had a 20-80% reduction in fibroid volume and 64% of patients had symptom resolution. Additionally, in 1997 Goodwin et al. reported successful reduction of fibroid related symptoms in 88% patients treated with UFE. To date, over 40,000 UFE’s have been performed [3].

Historically, alternative treatment options for uterine fibroids include hormonal/oral contraceptive medical and surgical approaches–however, these options are not without risks. Oral contraceptive side effects include venous thromboembolism and a 20-40% increased risk of stroke. Furthermore, hormonal therapies can cause recurrence of symptoms and fibroid size after cessation. Hysterectomy is a definitive therapy of uterine fibroids and while it has the highest rate of symptom relief compared to UFE in nonrandomized controls, it carries significant major complications such as deep venous thrombosis (5%), surgical wound abscess (15%), intraabdominal abscess (5%) and transfusion (20%) [4-5].

Current Applications
Uterine fibroid embolization (UFE) is a uterus-sparing procedure performed by interventional radiologists through a transcutaneous femoral artery approach to treat symptomatic uterine fibroids [6].  Since 2008, UFE has been endorsed by the American College of Obstetricians and Gynecologists (ACOG) as a safe and effective alternative to hysterectomy to treat fibroids [7].  In this procedure, transcutaneous femoral artery approach is used to access the uterine artery, which is then embolized using embolic agents, including polyvinyl alcohol particles, trisacryl gelatin microspheres, and gelatin sponge [8]. Contraindications to this procedure include pregnancy, pelvic malignancies, and uterine or adnexal infection. Preparing for this procedure requires close collaboration among the patient, interventional radiologist, and gynecologist to assess preferences, benefits and risks [9]. As this is a minimally invasive procedure, patients often have shorter hospital stays compared to patients who undergo hysterectomies, on average by 4 days [10]. A recent single institutional study has found that same-day discharge with low rate of patient return is possible [11].

Current literature reviews of effect on fertility identify limitations in current data with small sample sizes and lack of randomization, but emphasizes that pregnancy is attainable after UFE with an approximate pregnancy rate of 38.3%, but compared to myomectomy, may have increased risk of preterm delivery and spontaneous abortion [12]. Similarly, a systematic review studying this same question found low quality of evidence and highlights the need for higher quality prospective randomized studies [13].

Patient symptom control and post-procedure satisfaction are highest in “ideal” candidates, which are women with no contraindications to UFE and with all of the characteristics like heavy regular menstrual bleeding or dysmenorrhea associated with intramural fibroids, Premenopausal and no desire for future pregnancy [14]. But the majority of women report high satisfaction with the procedure and improved quality of life. Ten year results of the randomized  Embolization vs Hysterectomy (EMMY) trial showed that close to 80% of women who received UFE were satisfied with their treatment. Eighty-one percent would suggest a friend undergo the procedure, and 74% of women who underwent UFE preferred their treatment modality compared to hysterectomy [15]. Several other studies also report sustained improvement in symptom severity and overall quality of life. [16, 17].

After UFE, patients can reasonably expect resolution of symptoms such as menorrhagia (90 – 92% of patients), pelvic pressure, and pelvic pain (88 – 96% of patients). Although infrequent, major adverse events can occur and include ovarian failure and future amenorrhea (7.5% of patients in FIBROID Registry), fibroid expulsion, and rarely venous thromboembolism with possible pulmonary embolism[18]. However, at one year post-embolization, UFE significantly improves all aspects of sexual function measured by Female Sexual Function Index (FSFI) and quality of life [19].

UFE is generally safe in patients with symptomatic fibroids. Obese patients (BMI > 30) and those with large volume uteri (> 1000cm3) are at slight increased risk of developing infection and require appropriate pre-procedural counselling, as well as careful post-UFE follow-up. BMI and uterine volume may be useful to assess before the procedure to help to determine post-UFE infection risk [20].

Impact and Future Directions
While uterine artery embolization (UAE) has demonstrated short term advantages, such as shorter and less painful recovery compared to surgery, the long-term outcomes are not as clear. The 10-year results of the EMMY trial, which was a randomized controlled trial of UAE versus hysterectomy for the treatment of symptomatic leiomyomas, showed that 31% of patients who received successful UAE underwent secondary hysterectomy [21]. Similarly, a meta-analysis examining UAE compared to surgical procedures for the treatment of symptomatic leiomyomas reported increased risk of re-intervention in the UAE group after both two and five years [22]. Incomplete infarction of the leiomyoma, which subsequently results in the growth of the non-infarcted tissue, may lead to symptom recurrence and the indication for additional intervention [23].

Future innovations of UAE are looking to address the current inadequacies of the treatment modality. For example, a recent study explored the use of a convolutional neural network (ResNet) model to predict UAE outcomes using routine magnetic resonance imaging [24]. ResNet is a deep learning model that learns hierarchical representations of imaging data. Using T1-weight contrast-enhanced (T1C) sequence images, the model demonstrated a better test accuracy, sensitivity, and specificity than four radiologists. Similar to other machine learning technologies, this model is unlikely to replace radiologists. Instead, it is likely that in the not-so-distant future that both diagnostic and interventional radiologists will use machine learning models to aid in the selection of patients that are most likely to benefit from UAE.

In addition to utilization of imaging models to improve clinical outcomes of UAE, the continued advancement of embolic materials deployed in UAE will likely also improve patient outcomes. A recent randomized controlled trial published by Han et al. investigated pain following UAE for symptomatic leiomyomas with either non-spherical polyvinyl alcohol particles (PVA) or tris-acryl microspheres (TAGM) [25]. Although patients who received PVA and TAGM showed equivalent pain scores and fentanyl dose, the two groups were not completely equivalent. The authors concluded that the utilization of PAV led to a greater inflammatory response and subsequently higher analgesic use, and more frequent transient global uterine ischemia.

Uterine artery embolization has significantly advanced the treatment of uterine fibroids. Nonetheless, there are still advances to be made. Additional research in all aspects of UAE will result in identification of variables that interventional radiologists can address in order to improve clinical outcomes.

References:
1. Ghant MS, Sengoba KS, Recht H, Cameron KA, Lawson AK, Marsh EE. Beyond the physical: a qualitative assessment of the burden of symptomatic uterine fibroids on women’s emotional and psychosocial health. J Psychosom Res. 2015 May;78(5):499-503. doi: 10.1016/j.jpsychores.2014.12.016. Epub 2015 Feb 2. PMID: 25725565.

2. Ravina JH, Herbreteau D, Ciraru-Vigneron N, Bouret JM, Houdart E, Aymard A, Merland JJ. Arterial embolisation to treat uterine myomata. Lancet. 1995 Sep 9;346(8976):671-2. doi: 10.1016/s0140-6736(95)92282-2. PMID: 7544859

3. Raikhlin A, Baerlocher MO, Asch MR. Uterine fibroid embolization: CME update for family physicians. Can Fam Physician. 2007;53(2):250-256.

4. Silberzweig JE, Powell DK, Matsumoto AH, Spies JB. Management of Uterine Fibroids: A Focus on Uterine-sparing Interventional Techniques. Radiology. 2016 Sep;280(3):675-92. doi: 10.1148/radiol.2016141693. PMID: 27533290.

5. Pinto I, Chimeno P, Romo A, Paúl L, Haya J, de la Cal MA, Bajo J. Uterine fibroids: uterine artery embolization versus abdominal hysterectomy for treatment–a prospective, randomized, and controlled clinical trial. Radiology. 2003 Feb;226(2):425-31. doi: 10.1148/radiol.2262011716. PMID: 12563136.

6. Ravina JH, Ciraru-Vigneron N, Bouret JM, et al. Arterial embolisation to treat uterine myomata. The Lancet. 1995;346(8976):671-672. doi:10.5555/uri:pii:S0140673695922822

7. ACOG Practice Bulletin No. 96: Alternatives to Hysterectomy in the Management of Leiomyomas. Obstet Gynecol. 2008;112(2 Part 1):387-400. doi:10.1097/AOG.0b013e318183fbab

8. Goodwin SC, Spies JB. Uterine Fibroid Embolization. doi:10.1056/NEJMct0806942

9. Bulman JC, Ascher SM, Spies JB. Current Concepts in Uterine Fibroid Embolization. RadioGraphics. 2012;32(6):1735-1750. doi:10.1148/rg.326125514

10. Silberzweig JE, Powell DK, Matsumoto AH, Spies JB. Management of Uterine Fibroids: A Focus on Uterine-sparing Interventional Techniques. Radiology. 2016;280(3):675-692. doi:10.1148/radiol.2016141693

11. Sher A, Garvey A, Kamat S, et al. Single-System Experience With Outpatient Transradial Uterine Artery Embolization: Safety, Feasibility, Outcomes, and Early Rates of Return. AJR Am J Roentgenol. Published online February 3, 2021:1-6. doi:10.2214/AJR.20.23343

12. Ludwig PE, Huff TJ, Shanahan MM, Stavas JM. Pregnancy success and outcomes after uterine fibroid embolization: updated review of published literature. Br J Radiol. 2019;93(1105):20190551. doi:10.1259/bjr.20190551

13. Karlsen K, Hrobjartsson A, Korsholm M, Mogensen O, Humaidan P, Ravn P. Fertility after uterine artery embolization of fibroids: a systematic review. Arch Gynecol Obstet. 2018;297(1):13-25. doi:10.1007/s00404-017-4566-7

14. Young M, Coffey W, Mikhail LN. Uterine Fibroid Embolization. 2020 Jul 10. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 30085558.

15. de Bruijn, A. M., Ankum, W. M., Reekers, J. A., Birnie, E., van der Kooij, S. M., Volkers, N. A., & Hehenkamp, W. J. (2016). Uterine artery embolization vs hysterectomy in the treatment of symptomatic uterine fibroids: 10-year outcomes from the randomized EMMY trial. American journal of obstetrics and gynecology, 215(6), 745-e1.

16. Goodwin, S. C., Spies, J. B., Worthington-Kirsch, R., Peterson, E., Pron, G., Li, S., & Myers, E. R. (2008). Uterine artery embolization for treatment of leiomyomata: long-term outcomes from the FIBROID Registry. Obstetrics & Gynecology, 111(1), 22-33.

17. Smith, W. J., Upton, E., Shuster, E. J., Klein, A. J., & Schwartz, M. L. (2004). Patient satisfaction and disease specific quality of life after uterine artery embolization. American journal of obstetrics and gynecology, 190(6), 1697-1703.

18. Bulman JC, Ascher SM, Spies JB. Current concepts in uterine fibroid embolization. Radiographics. 2012 Oct;32(6):1735-50. doi: 10.1148/rg.326125514. PMID: 23065167.

19. Kovacsik HV, Herbreteau D, Bommart S, Beregi JP, Bartoli JM, Sapoval M; French Society of Interventional and cardiovascular Imaging (SFICV) research group. Evaluation of Changes in Sexual Function Related to Uterine Fibroid Embolization (UFE): Results of the EFUZEN Study. Cardiovasc Intervent Radiol. 2017 Aug;40(8):1169-1175. doi: 10.1007/s00270-017-1615-3. Epub 2017 Mar 20. PMID: 28321542.

20. Mollier J, Patel NR, Amoah A, Hamady M, Quinn SD. Clinical, Imaging and Procedural Risk Factors for Intrauterine Infective Complications After Uterine Fibroid Embolisation: A Retrospective Case Control Study. Cardiovasc Intervent Radiol. 2020 Dec;43(12):1910-1917. doi: 10.1007/s00270-020-02622-2. Epub 2020 Aug 26. PMID: 32851424; PMCID: PMC7649153.

21. de Bruijn, A. M., Ankum, W. M., Reekers, J. A., Birnie, E., van der Kooij, S. M., Volkers, N. A., & Hehenkamp, W. J. (2016). Uterine artery embolization vs hysterectomy in the treatment of symptomatic uterine fibroids: 10-year outcomes from the randomized EMMY trial. American journal of obstetrics and gynecology, 215(6), 745-e1.

22. Fonseca, M. C., Castro, R., Machado, M., Conte, T., & Girao, M. J. (2017). Uterine artery embolization and surgical methods for the treatment of symptomatic uterine leiomyomas: a systemic review and meta-analysis followed by indirect treatment comparison. Clinical therapeutics, 39(7), 1438-1455.

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Challenging the Zeitgeist of Stereotactic Surgical Oncology: The Past, Present, and Future of Percutaneous Tumor Ablation Therapy
September 25, 2021

Author(s):
Sherayar Orakzai
Medical College of Georgia ’21

Ivan Dimov
University of Montreal School of Medicine ’23

Devin DeLuna
University of Nebraska Medical Center ’22

Editor(s):
Yang (John) Qiao, M.D.
PGY-2 Integrated Interventional and Diagnostic Radiology
University of Texas Health Science Center at Houston / M.D. Anderson Cancer Center

Introduction
As cross-sectional imaging became widely available in the 1970s, so did the ability to precisely-target visceral tumors in a percutaneous approach with ablative therapies.  Percutaneous ablation is a modern-day technique in oncological care which utilizes thermal or cryogenic modalities for in situ destruction of solid tumors via induction of cellular injury, ultimately leading to tumor apoptosis, necrosis, and death.  Although historically utilized when disease stage, tumor location, and/or poor patient fitness status preclude the option of surgical resection or whole organ transplantation, the choice of percutaneous ablation over surgical resection is continuously gaining ground as an equal stereotactic method when a number of factors are taken into account including tumor type, size, organ, number of tumors, and the technology available to the operator.  Today, evidence-based treatment algorithms support its use by Interventional Radiologists for a wide-array of tumor etiologies including hepatocellular carcinoma, liver metastasis, non-small cell lung cancer, and renal cell carcinoma.  In general, tumors are ablated using 3 temperature-based techniques: radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation. These modalities use percutaneous probes inserted within the tumor that heat up to temperatures above 55 C in case of RFA and MWA, or freeze below -20 to -35 C in cryoablation, which results in cell death.  This article will focus on the historical developments of these three predominant ablation modalities; address the technical aspects, challenges, and limitations of percutaneous ablation modalities in a variety of organ- and tissue-specific cancers; and provide future outlook on percutaneous ablation therapies, as well as an introduction to combination ablation therapies, and the investigational next-generation modality of percutaneous electroporation therapy.

The Development of Percutaneous Ablation Therapies- How it Happened
Although the first clinically-documented RFA for percutaneous cancer treatment was performed in 1988 within the liver, the basic technique of utilizing radiofrequency currents as a general thermogenic clinical treatment modality was first investigated over a century ago by the French Physician Jacques-Arsène d’Arsonval using high frequency electrical currents (10,000 cycles per second) in animal models.1 This technique became known as “darsonvalization” and was mostly used to remove cutaneous and mucous membrane growths.  Later on in the 1930s, American Physician Edwin Beer pioneered the ability of applying direct targeted radiofrequency waves via cystoscopy for removing urologic papillary tumors. As advanced research led to better understanding of differential organ-specific conductivities and the relationship between wavelength and heat generation, the precision of RFA therapy became further calibrated for percutaneous ablation of organ-specific malignancies.  Recent advancements, including internal electrode cooling and multi-electrode application are constantly fine-tuning its clinical efficacy.

The more recently developed percutaneous thermal ablation modality of microwave ablation (MWA) was initially studied in Japan and China in the early 2000s.2 MWA utilizes a process of dielectric hysteresis (rotating dipoles) for generating heat within an aqueous environment. The rotation of dipoles within an applied electromagnetic field generates kinetic energy, which is transferred to adjacent local tissue in the form of ablation-grade heat energy. Despite its recent emergence as an accepted percutaneous cancer ablation modality, MWA has undergone rapid advancements, notably in active antenna cooling and high-power generation technologies.

Unlike thermal ablation, cryoablation utilizes the application of subzero temperatures to facilitate local tumor destruction. Observational damage of frost-bite was first empirically-tested as a therapeutic agent in the 1800s by English Physician James Arnott.3 Using a mixed salt and ice solution, Arnott designed an apparatus for applying frost as a localized therapeutic agent for treating cancers of the breast and female cervix, demonstrating pain palliation and a decrease in overall tumor size.  Subsequently, the term “cryogen” was coined.  Shortly after in 1889, cryogens made from various liquified gasses (including oxygen, nitrogen, and hydrogen) and applied via spray or brass roller devices became used for the treatment of various skin lesions, including epitheliomas.  In 1960, modern percutaneous solid organ cryoablation became feasible with advances in trocar-based cryogenic delivery systems.4 With the initiation of cryogenic therapy using nitrogen-cooled probes for neurovascular cryosurgery of the basal ganglia in Parkinson Disease patients, cryosurgery began rapidly evolving into an inclusive modality for the treatment of various localized cancers in breast, brain, prostate, kidney, and bone lesions.3 Recent advancements include argon-based cryogen generation technologies, and the role of intraoperative ultrasound in monitoring real-time tissue cryogenesis.

Organ-Specific Applications- Choosing the Appropriate Percutaneous Ablation Modality
Tumor ablation in the liver is typically performed for hepatocellular carcinoma (HCC) and metastatic disease, but can also be used to treat benign tumors such as hemangiomas and adenomas.5 HCC is staged using the Barcelona Clinic Liver Cancer (BCLC) scale, with ablation offered in early stage disease (stage 0 or A), with curative intent equal to tumor resection or transplantation.6 In these tumors, heat-based ablation is typically preferred as it avoids the complications related to cryotherapy, including the risk for hemorrhage and cryo-shock (a term used to describe a reaction similar to disseminated intravascular coagulation caused by the release of cellular debris following cryoablation).7 Another difficulty with cryoablation is predicting coverage of tumor margins, since tissues can remain viable at the margins of the iceball where temperatures are not below -20 to -35 C. In general, RFA is used for HCC 2-3 cm in diameter, and MWA is preferred for larger tumors, multiple tumors, and for tumors located within liver parenchyma near neighboring larger vessels.5 since MWA is less susceptible to the heat-sink effect (a phenomenon in which blood flow from neighboring vessels draws out heat from the adjacent ablation zone and thereby decreases the ablative efficacy).2 However, cryoablation can sometimes be considered when treatment of lesions near important hilar structures requires close monitoring of the ablation zone, as cryogenesis allows for a more graduated control of ablation margins.

Although the current preferred treatment modality for renal cell carcinoma is partial nephrectomy, patients who are poor surgical candidates (such as those with compromised kidney function and poor fitness status) can benefit from percutaneous ablative therapy.8 Due to the kidneys’ relatively small size and proximity to other important retroperitoneal and abdominal organs, ablation in this region requires careful targeting with cross sectional imaging and the use of hydrodissection (a technique in which saline is injected adjacent to the kidney, separating it from adjacent organs such as bowel to prevent iatrogenic injury during ablation). To protect against iatrogenic collecting system damage, warm saline is sometimes preoperatively infused retrograde through the ureters, via a technique called pyeloperfusion.8 Apart from renal cell carcinoma, benign tumors such as angiomyolipoma and oncocytoma have been treated with all three modalities. Due to its greater precision and slower action of onset, cryoablation is advantageous for the treatment of larger tumors and of tumors closer to the renal pelvis. In fact, recent retrospective studies have demonstrated favorable oncologic outcomes and decreased perioperative complications of cryoablation for treating stage T1a renal cell carcinoma compared with partial nephrectomy.9 RFA is also utilized, although it is empirically less effective for targeting angioliposarcomas, where adipose tissue increases electrical impedance. MWA is preferred for exophytic tumors surrounded by a safety margin of capsular fat.

Ablation of primary and metastatic tumors in the lung presents technical challenges for all three modalities. Since RFA has produced mixed results due to the inherent impedance of air in lung tissue (which hampers the effective formation of an ablation zone), MWA is therefore the ablation-of-choice for most lung lesions due to its rapid and efficient heat production.2  For lesions closer to the chest wall or mediastinum, cryoablation is used as it is less painful and better tolerated by nerve fibers in the adjacent chest wall.

Soft tissue and bone tumors can also be effectively treated with percutaneous ablation. As an alternative to radiation therapy, both thermal and cryogenic techniques are used to treat metastatic tumors within bone, which causes prolonged and treatment-resistant pain for many patients with advanced malignancy. Cryoablation is empirically the preferred modality for effective pain management and relief for bone metastases.8 Additionally, percutaneous ablation is now also the preferred treatment for osteoid osteoma, a benign but painful tumor most often found in the long bones of children and young adults.  Here, RFA delivers an excellent cure rate with minimal treatment related morbidity, as opposed to conventional surgical curettage.

The Future of Percutaneous Ablation Therapies – Where it’s Going
The outlook for the future growth and development of percutaneous tumor ablation is positive. Recent market research estimates the global market for tumor ablation will expand from 646.4 million USD in 2020, to 2.4 billion USD in 2028. This projection is attributed to the increasing incidence of cancer from an aging population, and the benefits of minimally invasive procedures such as shorter hospital stays and greater patient comfort.10 Although conventional techniques of tumor ablation have their limitations, these same limitations will reciprocally spur innovation for further development of more effective ablation modalities.

Progress is quickly being advanced in the realm of combination ablation therapies, in which concurrent application of local therapies augment the effect of tumor ablation.  Transarterial chemoembolization in combination with radiofrequency or microwave ablation is a well-established example of combination ablation therapy.  Of particular interest is the combination of ablation with immunotherapy. Tumor ablation, and in particular cryoablation, has demonstrated an ability to generate a systemic postablative anti-tumor response against exposed tumor poly-antigens following in situ ablation, which is largely not seen following surgical resection.  A study performed utilizing murine models of mammary adenocarcinoma demonstrated resistance to growth against re-implanted mammary cancer cells in 84% of mice that underwent cryoablation of the initial in situ tumor, providing empirical evidence of long-term potentiation and the generation of an adaptive tumor-specific immune response from cryoablation. Comparatively, only 14% of mice that underwent surgical resection resisted tumor growth following re-implantation of the mammary adenocarcinoma cell line. A wide variety of immunologic targets are now under investigation for their post-ablative tumor response-enhancing potential, including CpG-oligodeoxynucleotides (Toll-Like receptor [TLR] 9 agonist), imiquimod (TLR7 agonist), anti-CD25 antibodies, and anti-PD-1 antibodies.  Each of these therapies have so far demonstrated promising effects on survival following tumor ablation, and champion the importance of continued research into the synergistic effects and identification of future combination ablation therapies.11

New ablation modalities are also on the horizon for the interventional oncologist. Although thermal energy is currently most widely used for oncologic tissue ablation, limitations from the heat sink effect for targeting lesions near large vessels have driven innovation towards forms of non-thermal ablation, such as the relatively novel irreversible electroporation (IRE).  Although the technology behind electroporation has been utilized since the 1980s for genetics and chemotherapy applications, it wasn’t until the early 2000s that IRE was studied for tissue ablation. IRE is a non-thermal ablation modality that utilizes electrical pulses to disrupt the cellular membrane integrity by puncturing hydrophilic holes within the lipid bilayer of tumor cells, which disrupts voltage-gated protein channels, and ultimately leads to a loss cellular homeostasis resulting in cell death.12  Although IRE has been shown to create some thermal energy sufficient to induce thermal coagulation in specific settings, the primary mechanism-of-action for inducing cellular apoptosis via IRE is still non-thermal.13  Freedom from the thermal heat sink effect positions IRE as a potential modality-of-choice for treating tumors in close proximity to larger vessels (such as HCC located near large hepatic or portal veins) without losing ablative efficacy.14  Additionally, cellular proteins and surrounding microvasculature within the electrolytic ablation zone is spared with IRE, which preserves tumor damage-associated molecular pattern molecules for enhancing immunogenic anti-tumor T-cell responses in the post-ablative tumor bed.15  Overall, these features of IRE could potentially expand the indications for percutaneous tumor ablation. The future of IR will likely involve integration of IRE as this modality is further studied and refined.

Lastly, future advances in new imaging and guidance technology will be crucial in facilitating and expanding the scope of tumor ablation for the Interventional Radiologist. Percutaneous tumor ablation can be hindered by the need for frequent adjustments in needle positioning within tumors situated in difficult anatomy.16 One of the most recent and significant advances in interventional radiology comes from the introduction of cone beam CT, an imaging modality which allows for intraoperative evaluation of a target-of-interest with reconstructive 3D volumetric imaging. Cone beam CT has vastly improved targeting of tumors intraoperatively, which previously depended on 2D digital subtraction angiography for localization.17 Further development of fusion imaging such as real-time US/CT-MR imaging is also enhancing visualization of tumors that would have otherwise been inconspicuous using conventional B-mode US.18 Looking further into the future, augmented-reality (AR) technology may be the next imaging modality that becomes incorporated into the IR suite. Although this technology is still being refined, it is easy to imagine how AR could provide pragmatic assistance in the IR suite from displaying 3D needle trajectories to visualizing tumor ablation margins.19 Clinical trials are currently underway for investigating the feasibility of AR for peri-operative planning and assistance in percutaneous liver ablation.20

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