56 INTERNATIONAL PHARMACEUTICAL INDUSTRY Summer 2015 Volume 7 Issue 2

Clinical Research

The Present and Future of Non-Vascular StentsIn our fascination for new-age medical devices such as smart pills and wearable health devices, we do not often pause to think about some of the less-fancy, but equally important medical devices. A class of devices in particular – non-vascular stents – receives much less attention than its 500 million dollar market size demands. At over 5 per cent compounded annual growth, they are a fast-growing market, underscoring their growing importance globally. It would be well worth our time to know a bit more about the device that we could one day end up using personally…

The human body consists of a network of vessels and ducts that transport fluids necessary for physiological functions across the body. A block in these vessels can obstruct the flow of body fluids, resulting in serious physiological consequences; sometimes even death. It is therefore imperative that the patency of the vessel is maintained, or the cross-section of the vessel is unobstructed by hardening of the walls, calcified deposits, tumours or kinks.

Cholesterol and mineral deposits along the inner walls of coronary arteries reduce blood flow through the vessel, a condition known as atherosclerosis. Reduced blood flow to an organ results in the tissues being deprived of oxygen (ischemia), tissue death and depending on the organ which it vascularises – heart attack or stroke (brain). Likewise, obstruction of non-blood-carrying vessels such as the gastrointestinal and urinary tracts can have dire and fatal consequences as well. For example, tumours or calcifications can cause obstruction to the urinary tract, hindering the flow of urine through it, resulting in pain, infection, loss in renal function, and in extreme cases, death.

Narrowing of the vessel cross-section is known as stenosis or a stricture. Stenosis is most commonly remedied by a minimally-invasive corrective procedure involving a device known as a stent. A stent is an implantable medical device that is used to maintain the patency of stenotic vessels. Stents are usually tubular in shape; they are

inserted into blocked vessels in order to “push out” the narrowing walls and to restore an unhindered cross-section for fluid transport. Depending on the type of vessel they are used in, they are classified as vascular and non-vascular stents.

Non-vascular StentsNon-vascular stents are a family of devices for a variety of applications, including biliary, oesophageal, colonic, bronchial and tracheal implantations. The use of non-vascular stents in these applications is fuelled by a number of market drivers. Key among them is the benefit offered by the device and its way of implantation. Stents employ a minimally-invasive procedure for implantation, which is in contrast to an open surgical procedure that surgical treatment procedures require. A minimally-invasive procedure also ensures lesser pain; faster recovery period and a shorter hospital stay (and hence, lower medical bills).

Non-vascular stents find increasing application in gastrointestinal, urological and pulmonary diseases, owing to an

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ageing population, changing lifestyle habits and environmental conditions. Besides these, ophthalmic and neural applications are fast-emerging as important non-vascular stent applications. A large addressable market underscores the importance of and the growing need for non-vascular stents. Large medical device companies such as Boston Scientific Corp., Covidien Ltd., and C. R. Bard, Inc. have recognised this market need, and developed a portfolio of non-vascular stent products.

Gastrointestinal: The family of gastrointestinal (GI) stents includes biliary, duodenal, trans-hepatic, oesophageal and pancreatic stents. Globally, there is an acknowledged increase in the incidence of GI diseases. In 2014, the United European Gastroenterology Society, a not-for-profit professional society of digestive health professionals, conducted a survey on the changing trends in GI disorders. The pan-European survey, covering 28 European countries, revealed a marked increase in conditions such as upper GI bleeding, inflammatory

bowel disease, colorectal cancer and many other diseases, particularly among the elderly.

The American Cancer Society estimates approximately 93,000 new cases of colon cancer and nearly 40,000 new cases of rectal cancer are diagnosed in the US every year. These new cases are in addition to the millions already suffering from colorectal cancer. Surveys conducted by the National Institutes of Health estimate that at least 10-15% of adults in the US suffer from gallstones in the biliary tract. These conditions and others such as bile duct injury, oesophageal perforations, and gallstones require non-vascular stenting either as a remedial procedure, or as a supplementary procedure.

Urological: Obstructions in the ureter necessitate stenting procedures to alleviate the blockage or provide a shunt for fluid drainage. Ureteral stents are commonly used to alleviate obstruction in cases of nephrolithiasis (kidney stones), tumours, strictures, or retroperitoneal fibrosis.

Stents are also used in cases of prostatic obstructions or due to a complication of prostatectomy. The American Urological Foundation estimates that approximately 15 million Americans suffer from urinary incontinence (accidental loss of urine) and between 25 and 30% of American adults suffer from obstructive uropathy (blockage of urine).

In such cases, particularly in cases of blockages, a ureteral (also known as or ureteric stent) is inserted into the ureter to bypass the blockage and enable urine flow from the kidneys. A ureteral stent varies in diameter and length, with some stents as long as 12 inches. These stents are often temporary stents, intended to provide relief from pain and difficulty in passing urine.

Pulmonary: Pulmonary or airway stents are designed to keep the tubular structures in the pulmonary system (trachea-bronchial tree) open. Globally, there is a growing patient pool with airway obstruction along with the number of pulmonary surgical

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interventions. Conditions such as central airway obstruction, chronic obstructive pulmonary disease (COPD) and asthma necessitate the use of airway stents, to open up narrowed airways and ease the burden of respiration. The National Heart, Lung, and Blood Institute estimates over 23 million Americans currently suffer from asthma. Global health surveys peg this number around 350 million, with another 300 million suffering from COPD.

Healthcare databases record that more than 500,000 procedures of bronchoscopy are performed annually in the US, showing the prevalence of pulmonary surgical intervention. The trachea-bronchial obstructions requiring pulmonary stents include complications relating to lung cancer, respiratory infection, tuberculosis, and so on.

Depending on the nature of the blockage, pulmonary stents are either Y-shaped (to prop-up narrowed airway bifurcation), or are tubular in shape for relieving blockages further down the pulmonary system. Factors such as smoking and global environmental factors such as air pollution and exposure to inflammatory chemicals, particularly in developing countries, are expected to increase the market need for airway stents.

Innovations in Design and MaterialsNon-vascular stents vary greatly in size specifications, materials and design. Depending on the nature of the stent, the length could be as much as 18cm (typically gastrointestinal or urological stents) or as low as microns in length (known as micro-stents, used in ophthalmic applications). Tabular Column 1 highlights a few design characteristics

for different stent applications.

Biodegradable Polymers: The use of biodegradable polymers such as poly acryl amine, poly lactic acid-glycolic acid, poly capro-lactone and others, in non-vascular stents, are recent material innovations. Biodegradable materials present the advantage of biocompatibility and eliminate the necessity of stent removal. The stent either degrades over time or gets assimilated into the body (bio-resorbable materials). Esophageal stents manufacturer ELLA-CS (Czech Republic) uses polydioxanone, a material used to manufacture sutures, in their oesophageal stents. Boston Scientific uses poly lactic acid for its bio-absorbable biliary wall stents.

Self-Expanding Stents: In order to reach particularly narrowed vessels, self-expanding plastic stents (SEPS) and self-expanding metallic stents (SEMS) are used. These stents are present in deflated or collapsed state, so that they can pass through narrowed structures and they are expanded upon reaching the site of implantation. They find application as palliative or assistive devices during advanced stages of gastrointestinal cancer.

These are some of the innovations that non-vascular stents have benefitted from in the last few years. Already device manufacturers are taking cues from coronary stent devices, which have a longer track record of innovation and market acceptance. Design improvements such as heparin-coating of stents to prevent blood coagulation, anti-microbial coating to prevent infection and addition of anti-restenotic drugs to the stents, are some of the design innovations already in development stages.

Emerging Application Areas Ophthalmic and neural applications of non-vascular stents are among the new and niche markets that have opened up in the last few years. Both application areas – eyes and the brain – are sensitive areas for implantation of devices. They also necessitate a much smaller stent device (in the order of microns, or micrometres), known as a micro-stent. In most cases, these stents do not so much perform the role of opening up blocked vessels, as they act as the vessels themselves. In other words, the stents act as shunts for relieving an organ or a part of the organ from pressure due to fluid build-up.

Design Considerations Uses Examples

Coil geometry

Pros: Flexible and easily retrievable

Cons: Limited strength

• Esophacoil by EV3 Corporation• Silhouette® Ureteral Stents by Applied

Medical with coil-reinforced technology

Woven or braided design

Used in self-expanding structures. Knitted Nitinol used in tracheo-bronchial stents as it can change its shape according to the contours of the airway as well as can exert pressure against acute compression forces

• Wallflex by Boston Scientific• Ultraflex tracheo-bronchial stent by Boston

Scientific

Anti-migratory design – Anti-migration collar (with rings)

The designs are to prevent stent migration due to the peristaltic movement of the gastrointestinal tract or the urinary tract

• HV Stent Plus and SX-ELLA Stent Esophageal HV by ELLA-CS are equipped with a unique anti-migration collar.

• Tracheal Stents with Posts or Rings by Hood Laboratories.

• ALIMAXX-ES™ Esophageal Stent by Merit MedicaEndotek has anti-migration struts

• Hanarostent by M.I.Tech with large flare ends for anti-migration effect

Anti-reflux design-stents with valves

The gastrointestinal stents are designed to decrease the risk of reflux and aspiration of the gastric juice

• Esophageal stent Flexella plus by ELLA-CS has a special anti-reflux valve.

• Esophageal Z-Stent by Cook Medical has a unique windsock design with Dua Anti-Reflux Valve

• Hanarostent and Choostent by M.I.Tech, with anti-reflux esophagus valve

Stent coating

Hydrophilic coating which results in low friction, high ring stability and low tendency of encrustation.

Antibiotic-coated stents prevents infection

• iStent - Teutaflex Ureteral Stent by HospitalInnovations

• Percuflex™ Stent with HydroPlus™ Coating by Boston Scientific

• INLAY OPTIMA® ureteral stent by BARD Medical with pHreeCoat to stabilize the PH.

• Triclosan eluting stents Triumph® by Boston Scientific

Stent covering

Stents are covered with silicone or polyurethane to prevent tumour ingrowth and reduce food impaction

• Permalume covered WallFlex™ Esophageal Stents by Boston Scientific.

• ATRIUM ICAST™ balloon expandable covered tracheobronchial stent

Tabular column 1: Non-Vascular Stents Design Innovations

Key properties of the materials used in the non-vascular stent are biocompatibility, resistance to corrosion, flexibility, expandability, and high strength. Some of the materials used to develop stents are given in the table below:

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60 INTERNATIONAL PHARMACEUTICAL INDUSTRY Summer 2015 Volume 7 Issue 2

Clinical Research

Ophthalmic: Glaucoma is a group of eye disorders that are caused due to an increase in the intraocular pressure (IOP), or the pressure due to fluid build-up in the eye. The Glaucoma Research Foundation lists glaucoma as the leading cause of blindness in the world. An estimated 2.2 million Americans and tens of millions more worldwide, have glaucoma.

There is no cure for glaucoma as of now, but the use of a micro-stent to reduce the IOP, so that the optic nerve is not damaged, is an approach that is most commonly resorted to. At a maximum length of 1 millimetre and weighing a few micrograms, ocular stents are fast becoming a preferred glaucoma management option. Ophthalmic stents are also surgical options for diseases like monocanalicular trauma and for structurally correcting the irideocorneal angle.

Neural: With the increasingly ageing and obese population, the pool of ischemic and haemorrhagic stroke patients is also increasing. The United States Centers for Disease Control and Prevention lists stroke as the third leading cause of death, killing more 140,000 people each year.

While there are a number of reasons for a stroke to occur, a sizeable number – around 40,000 to 60,000 incidences per year in the US alone – are due to intracranial cerebral atherosclerosis. Similar to the plaque build-up in coronary arteries, there is protein, cholesterol and mineral accumulation along the vessels in the brain, resulting in narrowed ducts.

When primary options such as blood thinner medications and anti-coagulants do not effectively work, stenting becomes a vital go-to option. There is an increasing demand for minimally-invasive surgical procedures to treat these patients. Micron-sized neural stents, such as those developed by Stryker Corporation, are used as implants to treat brain aneurysm and intracranial stenosis.

The different types of non-vascular stents that have received approval for clinical use, or are currently in the process, are listed in Tabular Column 3.

The Road AheadThe global non-vascular market landscape is a mix of large and small companies, those with varied product focus and others with focus exclusively on non-vascular stent products. On one

hand are medical device giants such as Boston Scientific Corp., Cook Medical, Inc. and Covidien, Ltd. In addition to being important players in the non-vascular stent market, these companies also have a substantial global presence in coronary and peripheral stents. On the other hand, companies such as ELLA-CS, s.r.o and South Korea-based Taewoong Medical Co., Ltd. focus exclusively on gastrointestinal stents. There are also single-product start-up companies such as Ivantis Medical, Aquesys and Transcend Medical (all based in California), material and pharmaceutical companies that play a crucial role in market innovations.

The growing importance of non-vascular stents has been illustrated with a snapshot of the total addressable market, key growth drivers, recent innovations in product design and new application areas. In addition to these, the possibilities of partnerships, strategic alliances and business partnerships make the non-vascular stent market an exciting space to watch out for in the coming years.

Materials Pros and Cons Key Players

Silicone

Pros: Non-adherent, highly flexible, and has shape memory; easy to insert and remove.

Cons: Less strength, migration

• Dumon stents by Novatech• Mini Monoka silicone monocanalicular lacrimal

stents by FCI Ophthalmics• Mono Stent monocanalicular stent by Eagle

Vision Inc.

Nitinol

Pros: Super-elasticity and shape memory, highly biocompatible, flexible, has excellent shape memory and is corrosion-resistant, MRI-compatible

Cons: Tissue trauma by metals

• Ultraflex tracheobronchial stent by Boston Scientific

• Niti-S Enteral Colonic stent by Taewoong Medical

• Nitinella Plus biliary stent by ELLA CS

Stainless steel

Pros: High strength, flexibility, cost-effective

Cons: Not biocompatible, MRI incompatible, cause restenosis and thrombosis

• Omnilink® .035 Biliary Stent System by Abbott Vascular

• Visi-Pro® Balloon-Expandable Biliary Stent System by Covidien

Cobalt-chromium alloys

Pros: Super-elasticity, shape memory, MRI-compatible, corrosion-resistant, biocompatible

Cons: Tissue trauma by metals

• Resonance® ureteral stent by Cook Medical

Tabular column 2: Non-Vascular Stent Material Innovations

Biodegradable Polymers: The use of biodegradable polymers such as poly acryl amine, poly lactic acid-glycolic acid, poly capro-lactone and others, in non-vascular stents, are recent material innovations. Biodegradable materials present the advantage of biocompatibility and eliminate the necessity of stent removal. The stent either degrades over time or gets assimilated into the body (bio-resorbable materials). Esophageal stents manufacturer ELLA-CS (Czech Republic) uses polydioxanone, a material used to manufacture sutures, in their oesophageal stents. Boston Scientific uses poly lactic acid for its bio-absorbable biliary wall stents.

Self-Expanding Stents: In order to reach particularly narrowed vessels, self-expanding plastic stents (SEPS) and self-expanding metallic stents (SEMS) are used. These stents are present in deflated or collapsed state, so that they can pass through narrowed structures and they areexpanded upon reaching the site of implantation. They find application as palliative or assistive devices during advanced stages of gastrointestinal cancer.

These are some of the innovations that non-vascular stents have benefitted from in the last few years. Already device manufacturers are taking cues from coronary stent devices, which have a longer track record of innovation and market acceptance. Design improvements such as heparin-coating of stents to prevent blood coagulation, anti-microbial coating to prevent infection and addition of anti-restenotic drugs to the stents, are some of the design innovations already in development stages.

Emerging Application Areas

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Bhargav Rajan is a Research Analyst working with the Healthcare Division of Technical Insights, Frost & Sullivan. He tracks innovations in medical devices, medical imaging, clinical diagnostics and healthcare practices. Bhargav holds a Master’s degree in Biomedical Engineering from the University of Florida, Gainesville, and has academic and industry experience in regenerative medicine and tissue engineering. He can be reached at bhargavr@frost.com.

Product nameApplication Area Product Status Importance

XEN 45 gel stent (Aquesys, Inc.)

World’s first minimally invasive sub-conjunctival stent for the treatment of glaucoma

Met the completion of enrolment in the US clinical trial

This 12-month, multicentre single-arm study data will facilitate the US FDA approval for this stent. This is an important milestone for obtaining US market clearance.

Receives Class 3 Medical Device License from Health Canada

With commercialisation existing in Europe, this approval expands Aquesys’s footprint into another large market of Canada.

InnFocus micro shunt (InnFocus)

Ocular stent for the reduction in intra-ocular pressure.

This patented micro-stent showed good results. It showed 80% reduction in eye-drop medication use--over 70% off medications completely at 3 years

Company believes that these positive results will convince the surgeons to use the MicroShunt for treatment of glaucoma.

AEROmini Tracheo-bronchial stent (Merit Medical)

It is indicated for use in the treatment of tracheobronchial strictures produced by malignant neoplasms.

U.S. Food and Drug Administration approval under section 510(k)

The approval is expected to boost the growth of Merit Medical System,Inc.

WallFlex biliary stent (Boston Scientific)

Biliary stent for the palliative treatment of biliary strictures produced by malignant neoplasms.

Positive results in the trial showing the effectiveness and safety of fully covered self-expanding metal stents in the treatment of biliaryobstruction in benign bile duct strictures patients.

The positive result substantiates the US FDA and CE mark approval. Itshowcases the strong presence of Boston Scientific in the gastrointestinal stent market.

WallFlex esophageal stent (Boston Scientific)

Fully-covered stent is used for treatment of refractory benign esophageal strictures.

Has received the CE mark approval in Europe.

The commercial availability of WallFlex in the European market promises revenue growth for Boston Scientific.

Evolution oesophageal stent (Cook Medical)

This stent is indicated for obstruction that is caused by malignant or benign oesophageal stricture.

Cook Medical initiates the first multicentre US study to evaluate the possibility of removing a self-expanding metal stent after malignant and benign strictures have been treated.

If this study shows the possibility of safely removing metal stents, it can widen the medical options for different varieties of patients and can increase their potential patient market.

Evolution®

Biliary stent (Cook Medical)

Indicated to relieve symptoms associated with obstruction of the bile duct.

US FDA has granted 510(k) clearance.

With a CE mark already granted in Europe, this approval will expand its market into the United States.

Tabular column 3: Recent and Upcoming Product Launches The Road Ahead

The global non-vascular market landscape is a mix of large and small companies, those with varied product focus and others with focus exclusively on non-vascular stent products. On one hand are medical device giants such as Boston Scientific Corp., Cook Medical, Inc. and Covidien,Ltd. In addition to being important players in the non-vascular stent market, these companies also

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Debarati Sengupta is a Research Analyst working with the Technical Insights Healthcare division of Frost & Sullivan, a growth partnership services company. Debarati graduated with the first class Master’s degree in pharmacy (pharmaceutical chemistry) from Birla Institute of Technology. She has industry expertise in competitive intelligence and healthcare market research. She has an experience base covering sectors like pharmaceutical, biotechnology and medical devices. Email: debaratis@

frost.com