There are a variety of ureteral stent configurations with different anchoring systems. Most stents today have a double [http://linkinghub.elsevier.com/retrieve/pii/S014067360002674X pigtail anchoring system]. (Tolley, 2000), Dunn et al, (2000) conducted a randomized, single-blind study comparing a Tail stent (proximal pigtail with a shaft which tapers to a lumenless straight tail) to a double pigtail stent. The Tail stent was found to be better tolerated than the double-pigtail concerning
lower urinary tract irritative symptoms. A double-J ureteral stent and a flexible ureteropyeloscope are shown in the first diagram. The other two diagrams show a pigtail ureteral stent in place; the end of the pigtail is facing away fiom the ureteral opening in the second of these two diagrams.
Early adverse effects of ureteral stenting include lower abdominal pain, dysuria, fever, urinary frequency, nocturia and hematuria. Patient discomfort and microscopic hematuria happen often. Major late complications include stent migration, stent fragmentation or more serious hydronephrosis with flank pain and infections.
Late complications occurred in one third of the patients in a prospective study using both silicone and polyurethane double pigtail stents (110 stents) in 90 patients. Stent removal was necessary in these patients. Others also have found this percentage of late complications. Device-related urinary tract infection and encrustation can lead to significant morbidity and even death and are the primary factors limiting long-term use of indwelling devices in the urinary tract. Microbial biofilm and encrustation may lead to stone formation. This is typically not a problem when stents are used
for short-term indications. Problems of biofilm formation, encrustation and stent fracture occur in patients with long-term indwelling stents.
Typically, manufacturers advise periodic stent evaluation. Cook polyurethane stent removal is recommend at 6 months and 12 months for silicone (Cook product literature). However, stents that are intended for long-term use are usually changed at regular intervals, as frequently as every 3 months.
Forgotten stents are a problem. Monga et al., 1995 found that 68% of stents forgotten more than 6 months were calcified and 10% were fragmented. Multiple urologic procedures were necessary to remove the stones. Long-term effects of these forgotten stents may lead to voiding dysfunction and renal insufficiency. Schlick, et al., 1998 are developing a biodegradable stent that will preclude the need for stent removal.
The urinary system presents a challenge because of its chemically unstable environment. Long-term biocompatibility and biodurability of devices have been problems due to the supersaturation of uromucoids and crystalloids at the interface between urine and the device. Encrustation of ureteral stents is a well-known problem, which can be treated easily if recognized early. However, severe encrustation leads to renal failure and is difficult to manage (Mohan-Pillai et al., 1999). All biomaterials currently used become encrusted to some extent when exposed to urine.
The encrusted deposits can harbor bacterial biofilms. In addition, they can render the biomaterial brittle which causes fracture in-situ, a serious problem especially associated with the use of polyethylene and polyurethane ureteral stents (although silicone stents have also been
reported to fracture). Stent fragments can migrate to the bladder or renal pelvis with serious repercussions.
Surface science techniques were used to study three stent types
after use in patients. The stent type, duration of insertion and age or sex of
the patient did not correlate significantly with the amount of encrustation
(Wollin et al., 1998). However, it has been suggested that factors which
affect the amount of encrustation include the composition or the urine, the
type of invading and colonizing bacteria and the structure and surface
properties of the biomaterial used (Gorman 1995). A low surface energy
surface seems to resist encrustation compared with a high surface energy
surface (Denstedt et al., 1998).
Many different types of stone can form in the urinary tract.
Calcium oxalate, calcium phosphate, uric acid and cystine stones are
metabolic stones because they form as a result of metabolic dysfunction.
They usually are excreted from the urinary tract. Struvite (magnesium
ammonium phosphate) and hydroxyapatite (calcium phosphate) are
associated with infection (infection stones). These account for 1520% of
urinary calculi. ESWL is used to break up the larger infection stones
because they don't pass; recurrence of the problem occurs with incomplete
removal. Infection stones can manifest as poorly mineralized matrix
stones, highly mineralized staghorn calculi or as bladder stones which
often form in the presence of ureteral stents. Urea-splitting bacteria
colonize the surface and cause alkalinization of the urine, which lowers
the solubility of struvite and hydroxyapatite, and they deposit on the
surface. Bacterial biofilm associated with encrustation is a common
clinical occurrence. (Gorman and Tunney, 1997). It has been suggested
that prevention of bacterial colonization would prevent encrustation
because of their ultimate responsibility for its formation (Bibby et al.,
1995).
An in vitro model was developed that produces encrustation
similar to those seen in vivo (Tunney et al., 1996a). An experiment was
conducted to compare the encrustation potential of various ureteral stent
materials. The long-term struvite and hydroxyapatite encrustation of
silicone, polyurethane, hydrogel-coated polyurethane, Silitek and
Percuflex were compared. All of the materials developed encrustation,
however, it was found by image analysis that the rates of encrustation
varied on the different materials. Silicone had less encrustation (69% at
10 weeks) compared to the other materials (1 00%) at the same time point
(Tunney et al., 1996b). Continuous flow models have also been developed
which are more representative of conditions in the upper urinary tract.
They are discussed by Gorman and Tunney, (1 997).
Efforts to reduce encrustation using new materials, smoother
surfaces and hydrogel coatings have been attempted. A hydrogel-coated
C-flex stent (Hydroplus, Boston Scientific) was shown to have less
epithelial cell damage and encrustation than other biomaterials and was
recommended by the investigators for long-term use (Cormio, 1995). In
addition, a poly(ethy1ene oxide)/polyurethane composite hydrogel
(Aquavenem, J & J) resisted intraluminal blockage in a urine flow model
compared with silicone and polyurethane (Gorman et al., 1997a). Another
advantage with Aquavene is that it is rigid in the dry state, which
facilitates insertion past obstructions in the ureter and becomes soft on
hydration providing comfort (Gorman and Tunney, 1997). Gorman et al.
(1 997b) concluded that the chance of stent fracture would be reduced if
the ureteral stent side holes were eliminated.
Urinary tract infection is another common major problem with the
usage of ureteral stents. Initially, a conditioning film is deposited on the
ureteral stent surface. The film is made up of proteins, electrolyte
materials and other unidentified materials that obscure the surface
properties of the stent material. Electrostatic interactions, the ionic
strength and pH of the urine and differences in fluid surface tensions affect
bacterial adhesion to the conditioning film. Subsequently, a microbial
biofilm forms over time. The biofilm is composed of bacterial cells
embedded in a hydrated, predominantly anionic mixture of bacterial
exopolysaccharides and trapped host extracellular macromolecules.
Obstruction of urine flow and urinary tract sepsis can result in continued
growth of the biofilm. Colonization of devices implanted in the urinary
tract can lead to dysfunction, tissue intolerance, pain, subclinical or overt
infection and even urosepsis. Device related infections are difficult to
treat and device removal is usually necessary. The biofilm has been found
to impede the diffusion of antibiotics; in addition, the bacteria in the
biofilm have a decreased metabolic rate , which also protects them against
the effects of antibiotics (Wollin et al., 1998).
Riedl, et al. (1 999) found 100% ureteral stent colonization rates in
permanent and 69.3% in temporary stents. Antibiotic prophylaxis did not
prevent bacterial colonization and it was recommended that it not be used.
On the other hand, Tieszer, et al. (1 998) believe that fluoroquinolones can
prevent infection. They also have found that some stents have denser
encrustation than others, however, the stent material did not change the
elements of the "conditioning film" adsorbed or alter its receptivity to
bacterial biofilms.
The predictive value of urine cultures in the assessment of stent
colonization was examined in 65 patients with indwelling ureteral stents.
It was found that a sterile urine culture did not rule out the stent itself
being colonized (Lifshitz, et al., 1999). Patients with sterile urine culture
may benefit from prophylactic antibiotics; however, the authors contended
that the antibiotics must work against gram-negative uropathogens and
gram-positive bacteria including enterococci.
It is obvious that there is controversy in the literature whether
prophylactic systemic antibiotics are useful with ureteral stent implant.
However, antibiotics do not seem to prevent stent colonization. Denstedt
et al. (1998) have found that ciprofloxacin, with a 3 day burst every 2
weeks, actually is adsorbed onto the stent which makes longer term
treatment possible with reduced risk of bacterial resistance. There has
been research targeted at coating or impregnating urinary catheters with
antimicrobials and products are on the market, however, there are no
antimicrobial ureteral stents approved by the FDA.
It is clear that there is a need for a new material that will be able to
resist encrustation and infection in the urinary tract.
According to Merrill Lynch, ureteral stents represent an $80 MM
US market. Boston Scientific is in the lead with -50% of the market
followed by Maxxim (Circon), Cook and Bard is a smaller player. There
are a number of other small contenders.
The use of ureteral stents is increasing; the indications for ureteral
stenting have broadened from temporary or permanent relief or ureteric
obstruction to include temporary urinary diversion following surgical
procedures such as endopyelotomy and ureteroscopy and facilitation of
stone clearance after ESWL (Tolley, 2000). The use of ureteral stents for
patients having ESWL for renal calculi is however controversial and
seems to be related to the size of the stones and invasiveness of the
procedure. According to survey results reported by Hollowell, et al.
(2000), there is a significant difference in opinion concerning the use of
stents with ESWL. The number of ureteral stents used in patients with
stones 2 cm or less treated with ESWL is significant in spite of the lack
scientific evidence in support of this practice. Of 1,029 urologists
returning surveys, for patients with renal pelvic stones 10, 15 or 20 rnm
treated with ESWL, routine stent placement was preferred by 25.3%,
57.1 % and 87.1 %, respectively. Urologists recommend using
ureteroscopy rather than ESWL for distal ureteral calculi 5-1 0 mm.
1.2 Fit with Gore Corporate Strategy
+ This product fits into Gore's DSP market segment
+ A family of products is needed to market through a distributor
+ A possible family of products includes ureteral stents, urethral
slings, urologic suture, urethral stents and urethral catheters
(Foley), renal artery stent?
+ It is preferable that a stand alone product be of high value
+ Gore is interested in exploiting PATT technology in products where
silicone and polyurethanes have not met expectations and where PATT
has potential product performance benefit
1.3 Prototypes
The amount of encrustation on PATT tubes (measured by weight
gain) was compared with that on silicone (Bard) and Percuflex (Boston
Scientific) catheters after being subjected to in vitro static and dynamicflow
synthetic urine models.
Static Model
Dried tube pieces were suspended in stirring synthetic urine for up
to 3 months. Samples were taken at 1,2 and 3 months at which time they
were dried and weighed. The results of this experiment can be found in a
graph of Absolute Weight Change vs Time in the Appendix. There are no
error bars because this was a destructive test and there was only one
sample in each group. The PATT catheter was found to encrust to a lesser
extent than the other catheters: 6 times less than the Boston Scientific stent
and almost half as much as the Bard stent at two months. Note that the 1 -
%-.L month Bard data is in error because the sample broke during preparation
& & and the lost segment was not recovered. The 3-month data is pending. In
dA'eadndcrituiostna,t iSoEnM ons tahree cinacthluedteerd l uinm tihnea lA apnpde anbdliuxm, winhailc shu vrfisaucaelsi.z eT thhee SEMs
suggest that PATT has a clean surface relative to the other two materials.
Dynamic Model
Straight pieces cut from the stents (approximately 4.5 cm) were
attached to nozzles through which artificial urine passed from a reservoir.
"," @ The artificial urine was recirculated from the collecting tank to the P " " >
$4
reservoir. The experiment was run for two months. Unfortunately, the
&/J' data from this experiment proved inconclusive. It appears that the nozzles were the weak link in this experiment as they were found to encrust which
..rp."e ;p"
'
led to the decreased flow rates through the test articles downstream. In
addition, the test articles were found to weigh less after the experiment
than they did before, an artifact that is probably a result of the scale being
moved and recalibrated while the experiment was ongoing.
\L -
Ndm 2.0 Intellectual Property Assessment
Z3.L
+ Will be verbally communicated at the meeting
3.0 Sales and Marketing Assessment
3.1 Market Opportunities - - + Urological surgeons are the potential customers for the Gore ureteral
stent.
+ Merrill Lynch estimates the US market for ureteral stents is $80 MM
and that Boston Scientific has -50% of the market. Steve Nordstrom
(worked at Boston Scientific for -10 years) believes that the Boston
Scientific US revenues are $38 MM with 70% of a $50 MM market.
+ It is very difficult to obtain an accurate estimate of the number of
procedures using a ureteral stent. This is because temporary stents are
not coded and therefore their use in a given procedure is not recorded.
In 1998, MDI estimated that there were 212,000 procedures in the U.
S. (corresponding revenue $26.5 MM). MDI would have had the same
problem we encounter. The only hard data that Helene Johns is able to
obtain in which a stent definitely was used in the procedure is 147,000
inpatient ureteral catheterization procedures in 1999 from NIPS data.
In the 1998 Outpatient Handbook, there were 7,003 cystoscopies with
stone removal in which 30% of the time a ureteral stent placement
occurred; there were 30,5 19 cystoscopies and ureteral catheterizations
in which there were ureteral stents placed 6.3% of the time. This gives
a total of 15 1,033 procedures. Based on information obtained from
Merrill Lynch and Steve Nordstrom, this number must be substantially
higher.
+ Ureteral stents are the standard of care even though the available stents
have issues of encrustation, fracturing and infection and need to be
replaced frequently.
3.2 Competitive Assessment
+ There are different types of ureteral stents on the market. Merrill
Lynch (May 2000) estimates that Boston Scientific is the leader with
-50% of the market followed by Maxxim (Circon), Cook and Bard
with the smallest share. There are other smaller players. Steve
Nordstrom estimates that Boston Scientific has 70% of the market.
+ There are various ureteral stent designs: Double J, Double Pig Tail,
Multi Coil, etc., some with hydrophilic coatings. Ureteral stents are
typically silicone, polyolefin or polyurethane. There are no FDA
approved antimicrobial ureteral stents. Europe?
+ We do not foresee alternative technologies that will replace the need
for ureteral stenting because it has various intraoperative and
postoperative indications. It was predicted that the number of stenting
procedures would decrease with ESWL, however, this does not seem
to be the case. The indications have actually broadened.
+ In general, encrustation and infection are the main problems
associated with all available ureteral stents.
+ See Appendix for a comparison of existing products (living document)
3.3 Value Price
+ In 1998, MDI estimated the current average selling price of ureteral
stents to be a p p r o x i m a t e l m Gore purchased stents from various
3 5 u ' t *r companies through the Science Center for approximately $1 50 each.
+.p QOaJ '. 4- Steve Nordstrom stated that the average sellin rices for the Boston
Scientific, Bard and Cook ureteral stents ar& $90 and $70,
3 1 6 respectively, with discounts.
7 ? - + + Bard increased the price of their Foley Catheters from- to ,with a
silver coating. We estimate that if the Gore ureteral stent were to add
value by improved encrustation and biofilm resistance, a- small increase could be commanded. s di A .-.L ? e-k LA&v 3+ &
+ According to estimates by Steve Nordstrom and John Brinkman, a ~ ;;+ s
corporate partner such as Boston Scientific, who makes ureteral stents
at approximatel&- would only pay more if our stent were
clearly superior to theirs.
+ At this time, it is premature to estimate the cost of a GORE stent due
to potential changes in process equipment and raw material cost.
4.0 Regulatory and Clinical Assessment
+ A new ureteral stent requires a 5 1 OK
+ We will propose a 5 1 OK with no clinical trial to FDA based on:
+ Safety and efficacy data in a pig model with histology of the
urothelium
+ Extensive PATT biocompatibility in PATT Master File
+ Antimicrobial performance to claim inhibition of bacterial
colonization of the devices for up to 2 weeks after implantation.
Sequential zone-of-inhibition assays will be conducted to show
substantial preservative activity against the following clinical isolates
of gram-positive and grarn-negative organisms: Candida sp.,
rb Citrobacter diversus, Enterobacter cloacae, Enterococcus, Escherichia
coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas
aeruginosa, Staphylococcus saprophyticus and Streptococcus fecalis.
+ It is possible FDA will require a clinical trial because of the antimicrobial
substances andlor because PATT is a new material for a ureteral stent
application.
+ If FDA requires a clinical trial, we believe it will be relatively short-term (3-6
months) and will require a relatively low number of patients (under 100).
5.0 Manufacturing Assessment
5.1 Process Technology- PATT-EXT (extrusion grade)
+ Tube extrusion-screw extrusion of PATT into catheter size tubes
+ Possible co-extrusion if filled material becomes necessary
+ Antimicrobial coating and filled technologies
5.2 Manufacturing Approach
+ The ureteral stent can be manufactured at Elk Hill
+ Capital requirements: existing equipment, possible scale-up and
additional equipment for antimicrobial incorporation
+ Greatest uncertainty to success in manufacturing: cost of final device,
$uy-c-timicrobial incorporation without affecting the mechanical
&J...bGs roperties of the overall device
5.3 Materials Strategy
+ Greatest uncertainty for success with materials: measurable difference
in efficacy in-vivo demonstrating that PATT + antimicrobial
technology meets performance criteria. -r iuhrd & ~ e ~ s + & r ?
oatarc+- -K-buh?
6.0 Risk Assessment M<~-A+ cld9XPU4+3yr
6.1 Probability of Project success exiting Phase 4: 80% s Ce-0 q
-
6.2 Critical assumptions
+ Key criteria that would trigger an interim review: toxicity in the - -
urinary tract, encrustation performance inferior to competition.
+ Technology (technology feasibility; IP protection; scale-up): safe and
efficacious in vivo; we can practice and are protected; we can scale-up
+ Market and competitive: we will partner with a major player
+ Manufacturing (costs; ramp-up; yields; sourcing): TBD
s i t e of
s+aK;C, + Project commitments (objectives; targets; resources): evaluation of
prototypes with antimicrobial, in vitro antimicrobial activity studies,
pig implant data, encrustation testing of comparative catheters, surface
lubricity tests (coefficient of friction); resources will include three fulltime
associates for engineering, NPD, project management and sales &
marketing.
6.3 Death Blow
+ In vitro tests show no difference in encrustation compared with
competitors
+ Toxicity in the urinary tract in pig model
+ Surgeons do not see value in a perfluoroelastomeric device and its
attributes
+ Lack of distribution partner (Phase 11)
+ Cost to manufacture is more than we could sell for
6.4 Plan to test Critical Assumptions and Death Blow
+ Prototypes with antimicrobial
+ ASTM encrustation model
+ In vivo safetyltoxicity study in pig
+ Understand surgical techniques
+ Survey surgeons
+ Develop strategy for alliance
+ Estimate costs to make device from synthesis to final device
6.5 Risks to Gore
+ A business partner is needed
+ It needs to be decided what our product offering will be: the catheter
only or the entire package (or something in between). Depending on
what is decided, this may have impact on our profitability.
+ No potential legal conflicts foreseen
7.0 Project Plan
7.1 Phase I Plan
+ Objectives and deliverables:
+ Detailed Plan
+ Understand surgical procedures
+ Survey surgeons
+ + Prototypes with antimicrobials
+ Antimicrobial elution study
-b *4 + In vitro antimicrobial testing (zones of inhibition)
-it&-
pe++de"". + Mechanical and surface testing (tensile, elongation, etc. according
to Draft Guidance; coefficient of friction, surface energy, etc.)
+ In vitro encrustation further testing A S~L+S&.?
+ Animal experiment (pig) toxicity in urinary tract; toxicity to
urinary mucosa
+ Critical Path: same as above
+ Milestones: same as above
7.2 Core Team
+ Cindy Eaton, Thane Kranzler, Ruth Cutright?, Norman Pih