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DEVELOPMENT OF A SPIRAL LAMINAR FLOW INDUCING ENDOVASCULAR STENT FOR THE TREATMENT OF PERIPHERAL ARTERIAL DISEASE

Periodic Reporting for period 1 - SpiraStent (DEVELOPMENT OF A SPIRAL LAMINAR FLOW INDUCING ENDOVASCULAR STENT FOR THE TREATMENT OF PERIPHERAL ARTERIAL DISEASE)

Reporting period: 2014-10-01 to 2015-02-28

Overall project objective: to develop an innovative endovascular stent to reintroduce the natural spiral laminar flow both through the stent and distal to the stent, that can be manufactured to be deployed using standard delivery system profiles. To understand and overcome the technical requirement for incorporating the nitinol SLF inducer to a nitinol stent, Phase 1 had the following objectives:
1. Validation of the modifications to existing stents as a way forward
Commercially available stents were technically evaluated to assess the capability of modification with a spiral laminar flow inducer. The results demonstrated the ability to create Spiral Laminar Flow and showed that the stent design will need to be customised to meet the performance requirements. A full testing plan (in accordance with the relevant ISO) has been produced for Phase 2.
2. Assess stent covering to see how this will affect the stent
Covered and uncovered stents were modified to determine the effect of stent covering. Mechanical tests assessed whether the covering adversely effects the structure, pliability and expected function of the stent. This allowed us to determine that modification of pre-existing stents is a technically viable option.

3. Determine the nitinol stent patent landscape and additional IP regime
Intellectual property searches were conducted to determine whether patents exist that have claimed the use of nitinol to modify blood flow through medical devices. This indicated that we have freedom to operate in this area. The company has potential to file new Patents in Phase 2 development to strengthen the current 17 Patent families in the Patent estate. The company has a further approved Trademark SLF* which describes the design platform.

4. Identify partners for manufacture and commercialization
We identified and engaged sufficient numbers of relevant, interested parties to participate in the manufacturing and route to market process. These potential partners can provide commercial services, quotations and appropriate lead-times. Parties identified were categorised into the following groups: Metal Stent Manufacture, ePTFE Covering, Assembly/Delivery, System/Sterilisation, ISO Testing and Pre-Clinical Testing.

A business plan and commercialisation plan have also been developed for the implementation of the project.

Phase 1 has shown that the concept is technically and commercially viable and a Phase 2 application is now being developed.
"Task 1: Validation of incorporating SLF inducer into existing stents
This task details the testing activities undertaken on proof of concept Self-Expanding Nitinol Peripheral Stents incorporating a Spiral Flow Inducing Ridge.
The main purpose of the tests was to enable a decision as to whether the development of a stent incorporating spiral laminar flow can be achieved by modifying an existing stent or whether VFT should embark on a programme to design and manufacture a unique stent incorporating SLF.
I. Scope
This task was specific to the products listed in Table 1. Table 2 shows the tests carried out.
Table 1: Product References
Product Code: Optimed/Creamedix
Proof of Concept #1
Description: Spiral Laminar Flow Stent 8 x 70mm

Product Code: Optimed/Creamedix
Proof of Concept #2
Description: Spiral Laminar Flow Stent 8 x 110mm Stent Design: Planis Modified rev.29

Table 2: Associated Document References (available on request)
T014-R Partially covered spiral stent first (acute) animal study
T015-R Partially covered spiral stent pre-clinical Thiel cadaver study
T016-R Partially covered spiral stent flow testing
T017-R Spiral stent coating and flow testing
T021-P Spiral Laminar Flow Stent Development Test Plan

Test Articles
Product Code: Optimed/Creamedix
Proof of Concept #1
Description: Spiral Laminar Flow Stent 8 x 70mm
Stent design based on Optimed Sinus Stent

Product Code: Optimed/Creamedix
Proof of Concept #2
Description: Spiral Laminar Flow Stent 8 x 110mm Stent Design: Planis Modified rev.29
Lot : EW- 2014-205 #1 to EW– 2014 -205 #4
Stent design based on Optimed Sinus Flex Stent

II. Test Summary and Discussion

T017 Spiral stent coating and flow testing (Proof of concept design #1)
The prototype spiral stent (based on an Optimed Stent with closed cell diamond pattern) was successfully modified (using a heat/mechanical deformation process) to incorporate the P3 Ridge Profile as used on the current range of commercially available ePTFE Vascular Grafts. The stent supplied was uncovered and was successfully coated with latex rubber to create the spiral laminar flow fin (an uncovered stent of this design will only create turbulence). A single spiral flow was found in the outflow of the device using colour Doppler and vector Doppler ultrasound imaging. The non uniform nature of this single spiral has been associated with the abrupt termination of the spiral ridge at the end of the stent. This issue will be factored into Proof of Concept design #2.
In addition to verification of Spiral Laminar Flow this testing supports:
T021-P Spiral Laminar Flow Stent Development Test Plan
• Test 1: Visual Inspection and dimensional verification

T016 Partially covered spiral stent flow testing (Proof of concept design #2)
The prototype spiral stent (based on an Optimed Sinus Flex Stent with open cell ring and strut pattern) was successfully modified (using a heat/mechanical deformation process) to incorporate the P3 Ridge Profile as used on the current range of commercially available ePTFE Vascular Grafts. In addition to the change of basic stent design, the inducer ridge was modified at either end to replicate the run in/run out as feature on the graft design. This stent has been further modified to include an ePTFE covering along the length of the flow inducer ridge. This covering process requires further investigation/optimisation/development.
The flow was tested in both ends of the spiral stent after reversion of the flow direction. One strut in one end of the spiral stent was broken.
The non-broken strut end was able to create a uniform and steady single spiral flow. A steady single spiral started to be observed at 3.5 cm after the stent inlet and was completely formed 6.5 cm distal from the stent inlet. This information will be used in future design efforts to decrease the length of the spiral ridge and consequently the overall length of the device.
The flow disturbance at the top side of the colour Doppler images from the broken strut end has been directly associated with the damaged strut. Flow disturbances at the end of the stent seen on POC #1 have been resolved on this prototype due to the incorporation of run in and run out geometry at the end of the ridge.
The partially covered spiral stent was able to induce a steady single spiral flow in both ends.
In addition to verification of Spiral Laminar Flow this testing supports:
T021-P Spiral Laminar Flow Stent Development Test Plan
• Test 1: Visual Inspection and dimensional verification
• Test 12: Vessel wall apposition
• Test 17: Compatibility of parts
• Test 18: Stent Deployment Force
• Test 19: Trackability and Pushability
• Test 20: Simulated use

T015 Partially covered spiral stent pre-clinical Thiel cadaver study (Proof of concept design #2)
The prototype spiral stent (based on an Optimed Sinus Flex Stent with open cell ring and strut pattern) was successfully modified (using a heat/mechanical deformation process) to incorporate the P3 Ridge Profile as used on the current range of commercially available ePTFE Vascular Grafts. In addition to the change of basic stent design, the inducer ridge was modified at either end to replicate the run in/run out as feature on the graft design. Stents were loaded in commercially available delivery catheters.
CONCLUSIONS

• Turbulent flow identified in vessel prior to any intervention
• Device delivered through vascular sheath into common femoral artery
• Deployed in mid CFA and expanded to full vessel diameter
• Expansion and location verified by X-Ray imaging
• Ultrasound assessment demonstrated spiral ridge intact
• Colour flow demonstrated spiral flow within device and propagation up to 5 cm downstream of device.

In addition to verification of Spiral Laminar Flow this testing supports:
T021-P Spiral Laminar Flow Stent Development Test Plan
• Test 1: Visual Inspection and dimensional verification
• Test 12: Vessel wall apposition
• Test 17: Compatibility of parts
• Test 18: Stent Deployment Force
• Test 19: Trackability & Pushability
• Test 20: Simulated use
• Test 21: X-Ray Visibility


T014 Partially covered spiral stent first (acute) animal study (Proof of concept design #2)
The prototype spiral stent (based on an Optimed Sinus Flex Stent with open cell ring and strut pattern) was successfully modified (using a heat/mechanical deformation process) to incorporate the P3 Ridge Profile as used on the current range of commercially available ePTFE Vascular Grafts. In addition to the change of basic stent design, the inducer ridge was modified at either end to replicate the run in/run out as featured on the graft design. Stents were loaded in commercially available delivery catheters.
In both animals the two SpiraStents were successfully deployed, although in one case the control stent was incorrectly deployed due to a misunderstanding regarding the positioning of radio-opaque markers.
A single spiral flow pattern was detected in the outflow of the SpiraStent and a disturbed flow pattern in the outflow of the control stent. There was no difficulty with stent deployments and with using the deploying devices. The inconsistencies regarding the radio-opaque markers will need to be addressed prior to future studies.

In addition to verification of Spiral Laminar Flow this testing supports:
T021-P Spiral Laminar Flow Stent Development Test Plan
• Test 1: Visual Inspection and dimensional verification
• Test 12: Vessel wall apposition
• Test 17: Compatibility of parts
• Test 18: Stent Deployment Force
• Test 19: Trackability and Pushability
• Test 20: Simulated use
• Test 21: X-Ray Visibility


CAD Evaluation
In order to evaluate whether it is technically possible to develop and manufacture a stent incorporating spiral flow either by altering the physical geometry of an existing stent design or developing a unique stent design, a series of Computer Aided Design (CAD) drawings were generated to evaluate the options.

Please see the PDF version of the final report for images
1. CAD Image of inducer ridge formed on Standard Optimed Sinus Flex Stent Design
2. CAD Image of Inducer ridge formed on Standard Cook Zilver Stent Design

It is clear from the CAD graphical representations of both standard stent designs that the deformation of the struts and connecting struts through the inducer ridge is irregular and non-uniform and without question would lead to damage and breakages during the rigorous fatigue testing that is required to be performed as part of the ISO 25539 guideline.
By modifying the existing stent design platforms as shown on the next two images such that the strut orientation is in alignment with the inducer path, it is clear that the deformation of struts and connecting struts through the inducer ridge is regular and uniform and would give a significantly higher performing stent during ISO fatigue testing.

Please see the PDF version of the final report for images
3. CAD Image of Modified generic open mesh stent design
4. CAD Image of Modified Cook Zilver stent design


III. Conclusion and Test Plan for Phase 2
The testing conducted in Task 1 has demonstrated clearly the ability to create Spiral Laminar Flow using a peripheral stent with geometry modifications to create an internal inducer ridge. It is clear that the stent design, whether based on an existing stent platform such as Optimed Sinus Flex or Cook Zilver (as examples) or of a unique VFT design, will have to be customised in order to accommodate the inducer ridge and meet the performance requirements set out in ISO 25539.
In addition to this, several of the characterisation tests as detailed in the Spiral Laminar Flow Stent Development Test Plan have been met, demonstrating that the basic performance parameters of a modified Spiral Flow stent are achievable.
A full testing plan, which will be undertaken within Phase 2 of the SpiraStent Product Development, has now been fully detailed in T021. This testing, which will be conducted in accordance with the relevant ISO standards, will be initiated post design freeze as the testing represents a significant commitment in timescale, resource and cost.
In addition to the ISO testing detailed in T021, FEA (Finite Elemental Analysis) will be conducted on late stage designs prior to a design freeze in order to validate the final stent design, specification and material properties.

Task 2: Intellectual property landscape
Task 2 involved a thorough understanding of the IP landscape and the 3 activities were:
1. Conduct IP searches to determine existing IP rights (patents, trademarks, designs) regarding nitinol self-expanding stents to determine freedom to operate.
2. Examine VFT’s existing patents to determine opportunities for development.
3. Determine novel and patentable features of SpiraStent and opportunities for exploitation.
The output of task 2 is the integration of technology IP rights and commercialisation into company strategy.
The SpiraStent product development strategy calls for the design and modification of an existing nitinol stent frame structure, using proprietary methods, techniques and know how within the company. The next stages in development and in manufacture are covering, loading onto a delivery system and packaging and sterilisation.

Actions and outputs
VFT’s patent estate now consists of 17 patent families and their foreign equivalents. To date five UK patents, five European patents and four US patent grants have been obtained. In addition five US and six European design patents have been granted. The inventive step, and the key to the VFT scientific platform, is the design ability to induce the required spiral flow in a specific application that will have the beneficial effects of reducing turbulence. This principal patent and subsequent research have resulted in the broadening of the patent portfolio.
Patent Attorneys Marks and Clerk were commissioned to undertake a comprehensive Freedom to Operate search of the Covered Stent arena to enable a strong understanding of the existing IP landscape. The general idea of a nitinol frame with a cover of PTFE appears to have been disclosed some time ago, so there do not appear to be specific incidents of clear cut infringement. However there are a number of potential claims which will steer cover material and design.
These will be addressed as follows:
• Nitinol frame design The product development plan and manufacturing plan includes a license and development agreement with Optimed GmbH and an ongoing material supply agreement. This agreement effectively licenses the design IP for the ‘master stent’ design from Optimed and avoids potential conflict on this stent design platform which in turn avoids infringement of any other stents on the market.
• Covering The FTO analysis revealed a number of potential areas of caution . There are a few additional patents with very specific claims which M+C have considered as more remote claims. Each of the claims will be considered in detail in collaboration with the cover material supplier (Zeus Inc) and the SpiraStent product claims modified to avoid infringement. Initial review indicates the patents highlighted in the FTO are not claims which will affect our development.
• Delivery system The stent loading and delivery system will be supplied by Optimed GmbH and as such we will be indemnified from any IP challenge through the license and development and supply agreement.
• IP development The company has potential to file new Patents in a number of areas of Phase 2 development enabling a further strengthening of the current 17 Patent families that comprise the Patent estate. In addition the company has an approved Trademark SLF* which describes the design platform.
Patent family 18 will be filed during Phase 2 and will focus on the method of modification and manufacture. The innovative step has been lodged with M+C in November 2014 and the Patent Attorneys and internal team are in the process of Patent draft.
Further IP development is possible in collaboration with Optimed GmbH with regards to modification of the delivery system. At key stages of Phase 2 and during project plan review gates, a formal IP review will be conducted by the project team to assess potential for further IP development.

Summary
Task 2 required an IP landscape review with a focus on FTO and examination of the existing patent portfolio for potential development with a view to new IP. This task has concluded that there is freedom to operate and highlights additional areas for further patent applications in the Phase 2 project.
Regular IP reviews take place within the company as part of the Management Review process within the scope of the ISO 13485 Standard. The next phase development will implement further IP reviews at each stage gate project review.
VFT has 17 existing Patent families, a group of Trademarks and a growing body of ‘know how’ and these Intellectual Property assets form the commercial foundation of the company.
The company has completed these tasks in line with the business plan and product development strategy and is ready to embark on Horizon 2020 Phase 2 development.

Task 3: Partner identification
The objective of the partner identification is to identify and engage relevant interested parties such as manufacturers and clinical testing providers who are willing to participate in production and validation of SpiraStent during Phase 2 of the project.
VFT has identified and engaged specific, relevant and industry leading parties to participate in the manufacturing and route to market process. These sub-contractors are in position to provide commercial services, quotations and appropriate lead-times.
Parties identified were categorised into a number of groups:
• Metal Stent Manufacture
• ePTFE Covering
• Assembly/Delivery System/Sterilisation
• ISO Testing
• Pre-Clinical Testing

Partner identif
icati"
Peripheral arterial disease (PAD) is one of the fastest-growing and most pervasive diseases, and it is estimated to affect 27m individuals in Europe and North America of which 10.5m are symptomatic and 16.5m asymptomatic. Symptomatic PAD or intermittent caudation (IC) is usually diagnosed by a history of muscular leg pain when exercising and is relieved after a short period of resting. Vascular Flow Technologies has demonstrated with its two graft products that re-introducing spiral blood flow increases the patency of the product in the short and medium term. The SpiraStent project will develop a self-expanding stent that will reintroduce the bloods normal spiral laminar flow both through the stent and downstream to the stent, which will in turn reduces the laterally directed forces and turbulence and therefore lower the rates of distal disease progression.

The SpiraStent project will allow VFT to build on their SLF platform with an innovative stent design that improves outcomes for patients, reduces healthcare costs and will help grow the technical jobs market in the EU