Final Report Summary - STIMULAIS (A novel muscular micro-electro-stimulation device for the enhanced treatment of adolescent idiopathic scoliosis avoiding bracing and invasive open surgery)
Executive Summary:
The StimulAIS project has developed an implantable electro-stimulator within an experimental frame of the 7th frame program of the European Comission, called Research for SME’s, capable of stimulating the pathological paraspinal muscles that present a dysfunction which could be the origin of the pathology of scoliosis idiopathic of adolescent. This stimulation would restore to the muscles until they acquire the required toning to perform their tensile function of the vertebral spine, together with stimulation feedback provided by a sensor on the opposed and healthy side. This way they actuate balancing the tensile forces of the spine while at the same time they provide a personalized treatment for each individual patient.
The electro-stimulator pretends to be an alternative treatment to the current orthopedic one with a corset, indicated for idiopathic scoliosis between 20 and 40°Cobb. This treatment is not well accepted by the patients, creating psychosis concerning the use of a corset in public spaces as well as it limits physical activities of the patients.
The project has developed a system composed of an electro-stimulator and its accessories, charger and wireless reader, software and control. The tools necessary for a minimal invasive surgical intervention have also been developed and validated.
All the components have been developed in a laboratory and prototypes were manufactured for experimentation in animals, and laboratory verification of the characteristics.
The project consortium was formed by three Companies: Tequir I+D+i in Spain which actuated as project coordinator, Synimed in France and Bentronic in Germany, as well as three technological centers such as the Catholic University of Valencia in Spain (UCV), the Biomechanical Institute of Valencia (IBV) also located in Spain and Fraunhofer (IPMS) in Dresden, Germany.
The principal activities of the project were directed to the sampling and study of basal electromyography data in healthy patients, the design of all the necessary components, definition of the required requisites, development of a stimulation protocol, manufacturing of prototypes for laboratory and animal tests, verification in the laboratory and experimental process in animals.
The animal experiments were done under strict ethical norms and requisites expressed in the Directive 2010/63/UE and counted with all the necessary authorizations.
We can satisfactorily conclude the results of this ambitious project with the following achievements:
- Design and development of an implantable device with a stimulation and sensor function in a laboratory environment as well as its integration with different non-implantable grade components required for its functionality and monitorization.
- Development of a stimulation protocol adapted to the basal EMG data in a personalized way.
- Validation of a surgical procedure and development of specific surgical instruments necessary for the implantation of the device.
- Observation of scoliosis generation after a stimulation protocol performed in an animal.
Because of the experienced protototypes' manufacturing and animal experimentation complexity, some deviations took place with regards to the original planning:
Thanks to the implemented measures:
- Corrective actions for manufacuring (costs re-shuffling among consortium partners) and for animal experimentation (improvements in surgical technique, animals intensive cares, surgical re-interventions, etc.)
- Project extension (+3 months) requested and approved
most objectives have been successfully achieved.
Further work is needed for the next generation of prototypes, in order for them to be used in clinical trials.
However, this multidisciplinary project has provided relevant results in the scope of the programme, which are very useful for continuation towards a market-ready system.
Future steps have been defined in the exploitation strategy, which can be sumarized in:
- Industrial validation (prototypes validated industrially -manufacturing and testing- according to all the applying regulatory framework, for CE marking) for upscaling industrialization.
- Clinical validation (through clinical trials).
Project Context and Objectives:
Adolescent idiopathic scoliosis (AIS) is a progressive structural spinal deformity of unknown origin that affects around 2-3% of children aged between 10 and 16 in the world. Scoliosis is defined as a curve of at least 10º, measured on a standing radiograph using the Cobb technique (Figure 1.1) with rotation of the vertebral bodies (3-dimensional deformity). The resulting surface deformity has a strongly negative impact on adolescents, giving rise to psychological distress, behavioral disorders, and other emotional and social problems that reduce drastically their quality of life (QOL).
About 90% of diagnosed AIS patients usually do not receive specific therapy except observation, as this is the standard treatment for curves up to 25º for young patients in age of development. The other 10% (160.000 people in Europe every year) receive different kinds of conservative treatment in an attempt to halt the progressive nature of the deformity, since if scoliosis surpasses a critical threshold, usually considered to be 30º Cobb at the end of growth, the risk of health problems in adulthood increases significantly. These problems include disability, pain, increased cosmetic deformity, functional limitations, pulmonary and cardiac compromise, and possible further progression during adulthood. Of all the European diagnosed patients, up to 40.000 per year require a very invasive corrective surgery, due to failure of conservative treatment, sudden progression of the curvature or late diagnosis.
Recent studies evidenced that the spine deformity is a musculoskeletal expression of a central nervous system disorder that affects the paraspinal muscles inducing an imbalance of forces acting over the vertebral segments.
The overall technological aim for the project is to produce a fully working prototype of a device for the electro stimulation of the paraspinal deep rotator muscles with programmable stimulating protocol and real-time adaptation of stimulus through a feedback loop control system. In the realization of this overall project aim, we identify the following overall technical aims:
1. Develop a subcutaneous programmable device for sensing in a maximum range of +/-5.0 mV and stimulating the deep paraspinal rotator muscle.
2. Develop stimulation control software, for customizable treatment and including a feedback loop algorithm for automatic stimulus fine adjustment.
3. Develop minimally invasive surgical instruments for the implantation of the subcutaneous devices through an incision less than 50 mm in length and surgery time less than 90 minutes.
4. Achieve an integrated working medical system according to EU regulations applicable to active medical devices, for performing customized treatment of the AIS during a period of at least 6 months.
Specific Scientific Objectives:
Enhancement of scientific knowledge is needed, as defined in the following list of scientific objectives:
-Analysis of electromyography and electro-stimulation data of the paraspinal muscles, proceeding from preliminary tests and previous studies, to correlate the electrical signal with the muscle activity.
-Determination of parameters for main muscular stimulation protocol.
-Identification of the components of the electromyography signal to generate and control the stimulus through the feedback loop control.
-Data processing and control system strategies feasibility study, in order to define specific software structure to fulfill the technological aims.
-Feasibility study of the biomechanical and hardware design of the subcutaneous device.
Specific technological objectives for the subcutaneous programmable device:
-Miniaturize an EMG sensor electronics capable of measuring responses between 20 Hz and 5 KHz, an amplifier sensitivity of 50 μV, and a sweep duration of 10 ms.
-Miniaturize stimulation electronics, capable of providing adjustable pulse strength for the stimulation of the paraspinal deep rotator muscles, with a variable stimulation current of 1-50 Hz for 1 s and an adjustable intensity between 0.2 and 50 mA, for a mono-phasic stimulation pulse.
-Select and integrate a power battery conforming to the power requirements of the system (Control Circuit minimal voltage: 2.2V pulse range 15-40 J).
-Select and integrate an RFID tag for wireless communication working with frequencies of 125 kHz.
-Develop optimized hardware technology for protocol housing and controlling. All evelopments
include hardware (schematics and layout) development and firmware development (controller based) of the components.
-Develop a body-friendly case with shape biomechanically adapted to the subcutaneous location, housing sensor and stimulator, power supply and RFID tag for wireless communication, with maximum volume of 9 cm3 and maximum main dimension of 30 mm.
Specific technical objectives for the stimulation control software:
-Develop the main stimulation protocol capable of providing stimulus in a frequency range of 1-50 Hz.
-Develop the feedback loop algorithm for automatic adjustment of the stimulus within 5•10-1 seconds since EMG signal acquisition.
Specific technical objectives for surgical instruments:
-Develop minimally invasive surgical instrument (laparoscopic or needle-like) for the implantation of the subcutaneous device in the anatomical location through an incision of the skin less than 50 mm in length and for the connection of the electrodes to the key muscles through incisions of less than 5 mm in diameter. Total surgery time should be less than 90 minutes.
-Develop ergonomic solutions for minimally invasive instruments.
Specific technological objectives for the integrated fully working medical system
-Obtain a subcutaneous device with integrated stimulation control software
-Programme the external console to control the subcutaneous device.
-Obtain a programmable working system, producing stimulations according to the established
Protocol.
-Verify the safety and operation of integrated medical device by carrying out tests according to
European regulations applicable to active medical devices: 90/385/CEE; 93/42/CEE; IEC 60601-1; IEC 60601-2; EN 45502-1; RD 1591, ISO 13485.
-Verify the characteristics
** RELEVANT MEASURES FOR PROJECT SUCESS **
1) Because of the ambitious nature of the project and manufacturing complexity, CORRECTIVE ACTIONS were needed at the end of RP1, for balancing the resources across the project, and ensuring that there were resources available for design iterations.
For this purpose, a "Financial needs analysis" report agreed by all consortium partners was provided to the project officer (January-2014).
This report aimed to provide an analysis comprising the financial needs and resources, in order to clarify the situation after implementation of corrective actions in WP2, as requested after RP1 assessment.
- Firstly, we provided an overview of the needs, reached by consortium consensus, for a successful achievement of project results. Then, the associated costs were shown.
- Secondly, actions to decrease costs in order to seek feasibility ensuring that outcomes are fit-for-purpose and balanced with the work plan, were implemented.
- Lastly, StimulAIS consortium re-shuffled costs (according with Project Officer indications) for placing more consumables related with the subcutaneous device's manufacturing, because of the initial underestimation when compared with the current manufacturing context. Manufacturing costs distribution were stated, and all partners agreed with these actions.
Tables showing the costs re-shuffling, agreed among consortium partners, are summarized in the "Attachment_4.1 Final publishable summary report".
2) After a period under control, problems persisted, in this case regarding manufacturing delays.
On 05/05/2014 an amendment request was sent by Tequir, on behalf of the consortium, to REA for assessment, in order to modify the Grant Agreement, regarding project duration (27 months).
A supporting letter was attached to the amendment request, which can be summarized as follows:
- Background. Considering RP1 convergence efforts, by 2nd February, the project was under control. However, we soon were informed about different manufacturing suppliers associated delays (4 months in total)
- Current overview. Time-optimizing measures were tackled concerning feasibility of manufacturing and animal preliminary experiments.
Combining the needs for manufacturing, later functionality verification and sterilization prior animal experimentation, the schedule was settled, providing consistent explanations that supported the need for a project extension of 3 months.
- Foresight. All other boundary conditions (experiments and authorizations needed) were shown to be controlled so that definitive animal experimentation could take place as soon as we received the manufactured and sterilized devices, avoiding further unexpected delays.
Project extension (+3 months) was approved.
3) Encountered animal experimentation problems & implemented actions:
- Once started the project a new exigency regarding experimentation popped up: New Royal Decree (RD53/2013), which establishes basic rules applicable for protection of animals used in experimentation. This RD is more restrictive and time-consuming. We had to change the hospital to carry out the animal experimentation, which is prepared for the new limitations (CIPF research centre).
- First charger failed to communicate with the implanted device in preliminary experimentations. A new charger had to be developed for this purpose.
- Some implanted devices experienced failures during animal experiments: electrodes/devices expulsion and deiscence of the wound that led to infections. Solutions: Surgical re-interventions and improvements of surgical technique (implanting devices under the first muscular plane instead subcutaneously, electrodes tunnelled under the first paraspinal muscles, and suturing of the tip).
- Communication and charging problems were also experienced in-vivo. Solutions: Use of tight strips to increase pressure, reduce interface, and minimize movements while charging process with animals together with close monitoring; Work with a wireless console developed for this purpose, in order to facilitate the experimental conditions.
Thanks to the corrective actions and the commitment of project parners, experimental group B double-folded the hours of stimulation, with respect to group A.
Due to the cited problems the therapy was not continuous (5 intermediate periods of non-stimulation: surgical re-interventions and intensive cares). However, even under this situation, we've seen evidence of spinal curvature alteration due to electrostimulation of the target muscles.
4) The work has been actively monitored and hand-over of deliverables during the whole project cycle, looking for thorough coherence and fitness for purpose. the coordination of the project has guaranteed quality of the information provided and adequate integration of partners contributions in order to show the work done in line with the SMEs interests and original purpose.
Thanks to the implemented measures, most objectives have been successfully achieved, in line with SMEs expectations in the scope of the project.
Project Results:
Main S&T results
The developed StimulAIS system offers a novel system for treatment of AIS, by muscular sensing and electro-stimulation of the target muscles.
After technological development stages, three main results have been achieved and integrated in a working active implantable medical device, in accordance to some extent with EU directives, for performing customized treatment of AIS:
- RESULT 1. Implantable device (with accessories)
- RESULT 2. MIS instruments
- RESULT 3. External console
RESULT 1. The Implantable Device is programmable (for sensing and stimulating) in order to provide a wide range of treatment protocols, while muscle selectivity will allow targeted stimulation to maximize treatment outcome. Moreover, the integrated stimulation control software (to modulate it into safety thresholds) implements an innovative technology with sensor (EMG) and motor function, which could allow real-time adaptation in order to maintain stimulation effectiveness and provide progressive correction of the pathology, by toning pathological muscles that do not receive any stimulus because of the illness.
All these features are integrated in a small implantable device, providing the advantages of fully implanted systems with a minimally invasive associated procedure.
Accessories associated with R1 that have been developed for testing and animal experimentation purposes:
- Chargers have been also developed, as ACCESSORIES ASSOCIATED WITH R1, for their laboratory testing (standard charger) and animal experimentation (long-range charger) purposes.
* Description of the achieved functionalities of Result 1:
IMPLANTABLE DEVICE
R1.a) Mechanical features:
- 8 x 4.5cm x 1.6 cm
- Titanium housing
- Implantable resin connectors block
- 8 electrodes IS-1 female connections
- Desirable features:
- Size optimization;
- Integration of communication and power antennas inside the housing;
- External silicone coating.
R1.b) Electrical features:
- Stimulus pulse generation up to 25mA (on 500 Ohm resistance) programmable using up to 6 bipolar electrodes.
- EMG measurement with up to 8 bipolar electrodes with sampling frequency up to 1 KHz.
- 1MB internal data memory.
- Antennas complex (copper material)
- Communication antenna: Data communication inductive coupled with near field communication transponder (13.56MHz) [6 coil turns]
- Power antenna: Wireless charging inductive coupled with Qi receiver (125kHz…200kHz) [15 coil turns]
- Internal power source with standard (non-implantable) rechargeable battery 3.7 V 380mAh.
- Desirable features:
- Incorporate implantable battery and feedthroughs (currently, NDAs have been shared with the supplier GreatBatch for the components needed for the exploitable product;
- Implementation of high density internal memory: 1-2 Gb (it could not be implemented in current design because of power consumption and data transfer duration reasons. However, a wireless console was developed to overcome this limit for its use in experimentation).
R1.c) AUTONOMY
In a worst case scenario, a continuous stimulus generation with all maximum settings and 500 Ohm load resistance, the autonomy is 18 hours. However, in a standard therapy the device has an autonomy of about 201 hours (with full pulse amplitude and adequate therapy times). Hence, the device would have to be recharged at least after 8-9 days.
R1.d) Special functionalities
- Magnetic emergency switch-off (by means of a magnet, when necessary)
- Motion sensor with accelerometer, gyroscope and magnetometer (included in the implantable device for its future use in humans: Obtaining personalized basal signals under daily life positions)
- Device temperature measurement (the charging process is reduced at 45°C and stopped at 60°C internal battery temperature for safety reasons)
- Battery observation (by means of the developed software)
- Firmware upgradeable (current updated firmware version 2.01.13)
ACCESSORIES OF THE IMPLANTABLE DEVICE
R1.e1) STANDARD CHARGER
- Wireless charger inductive coupled Qi conform (125kHz…200kHz) for charging the StimulAIS implantable device.
- For use while the device is not implanted (laboratory use).
- Charging distance 1cm.
- Charging time < 2 h.
- Power supply 5Volts, 1A.
- Dimensions: 13 x 7 x 1.5 cm
R1.e2) LONG-RANGE CHARGER
- Wireless charger inductive coupled (125kHz…200kHz) for charging the StimulAIS implantable device.
- For use while the device is implanted.
- Charging distance minimum 4 cm.
- Charging time < 2 h.
- Power supply 18Volts, 0.5A.
- Two versions: Cable and battery powered
- Autonomy in the battery powered option: Batteries has to be changed after every charging cycle. Rechargeable batteries can be used when 500mAh capacity minimum.
- Dimensions: 7.5cm x 7.5cm x 4cm
- Desirable features:
- Combine the performance of both chargers to get just one stand-alone charger, to be used in all the foreseeable use scenarios (either in preparation of the implantable device prior surgery and while treatment period) without distance limitations.
RESULT 2. SPECIFIC SURGICAL INSTRUMENTS were developed in order to implant the electro-stimulation device and for the connection of electrodes to the key muscles.
* Description of the achieved surgical instruments kit:
- CANNULA: The cannula is aimed for the initial puncture to reach the target muscles in accordance with the planned electrodes placement, as well as to provide a canal for a safe and easy placement of the electrode to be anchored in the target muscles.
- LEADS PASSER: The leads passer is used to pass the electrodes from the incision where they are anchored to the incision where the subcutaneous device is implanted.
The Leads Passer is provided in different versions for passing 1, 3 and 4 leads a time. Two handles and bars of different diameter are included for each combination in order to adapt the instrument to the specific needs in surgery.
- Desirable features:
Decrease diameter of the leads passer connectors, as feedback-reported from surgical interventions carried out in animal experimentation stage.
The developed minimally invasive instruments and associated surgical technique have been validated in-vitro (cadaveric test). The achieved results have demonstrated to be better than the initial objectives:
A. Minimally invasive surgical instrument for the implantation of the subcutaneous device in the anatomical location through an incision of the skin less than 50 mm in length and for the connection of the electrodes to the key muscles through incisions of less than 5 mm in diameter.
A1. Incision of the skin around 20 mm (much less invasive than originally conceived: << 50 mm).
A2. Since the surgery has been performed in the most critical scenario in terms of incision demands (electrodes at three levels have been implanted through each incision), success in this test will guarantee the minimally invasive approach (20 mm) under all circumstances in real practice.
B. Total surgery time should be less than 90 minutes.
B1. The time needed to perform the test with human cadaveric model was around 30 minutes.
B2. In the cadaveric test, anaesthesia was not needed, so we did not compute the time that is around 10 minutes.
B3. In the cadaveric test, suture of incisions was not performed, since an open surgery was carried out after the minimally invasive procedure, for verification issues. The time needed for suturing all incisions is around 5-10 minutes.
B4. In the scenario of 8 electrodes needed, two incisions will have to be made at each side of the spine to cover the electrodes arrangement. This will increase the surgery time less around 10 minutes.
B5. In the worst case scenario, total surgery time will be around 60 minutes (less than the expected 90 minutes), with enough margin for any event that may occur during the surgery.
RESULT 3. The EXTERNAL CONSOLE to program the subcutaneous device and to collect bioelectric data of the patient. There is not a console itself. The development consists of a control software with an intuitive user interface, which is installed in a laptop and a reader through which wireless communication with the implanted device is established. This result is aimed to be handled by clinicians for programming the implantable device with the most appropriate stimulation protocol and follow-up treatment.
* Description of the achieved functionalities of R3:
R3.a) Reader
- Wireless reader inductive coupled NFC compliant (13.56 MHz) for communication with the StimulAIS implantable device.
- Communication range minimum 4 cm.
- USB connection to host computer. USB powered.
- Dimensions: 6 x 9.5 x 1.8 cm
- Desirable features:
- Final housing design of the reader, appropriate to clinical use.
R3.b) Software for controlling the StimulAIS implantable device via the reader device.
- Identification of the device.
- Checking the functionality of the device including charging state.
- Check the electrode connections (Stimulus).
- THERAPIES for stimulation protocols application:
Setup the therapy/stimulus parameters, start/stop the therapies directly or timer controlled. List of parameters and available settings:
- Amplitude [1 – 25 mApp, in 0.2 mApp steps]
- Pulse Width [25 - 500 µs, in 25 µs steps]
- Time On [1 – 10 seconds, in 1 s steps]
- Time Off [10 s – 20 min, in 1 s steps]
- Therapy duration [0h:01 to 23h:59, in 1 min steps]
- Therapy start time [0h:00 to 23h:59, in 1 min steps]
- Curve type [Pre-selectable curve types for appropriate configuration according to the kind of scoliotic curvature: Main thoracic, double thoracic, double major, triple major; scoliosis left, scoliosis right]
- Programme EMG measurements, read out the EMG data and visualize them.
- Firmware update (current updated software version 1.13)
- Software manual available.
All three results have been realized at lab-scale (not marketable), following as far as possible the applicable European regulation on active implantable medical devices. Although they have been verified as far as possible, according with the regulatory framework, they have been manufactured with non-validated industrial processes and prototypes have been used in animal experimentation, according to the procedures authorized by the ethics committee. Despite having multitude of unexpected events during animal experimentation, the involved partners have hard-worked and, finally, positive results after stimulation therapies have been obtained.
INTELLECTUAL PROPERTY RIGHTS (IPR)
According with the Consortium Agreement, The basic rule for IPR management in the StimulAIS project is that the achieved knowledge belongs to the three participating SMEs and that the RTD performers provide the SME participants with the full ownership and exploitation rights of all the results generated by the project.
StimulAIS system consists of the integration of the mentioned 3 results. Each participating SME will retain the IPR as described next:
Final StimulAIS system:
R1. SUBCUTANEOUS ELECTROSTIMULATOR DEVICE
- TEQUIR (OWNERSHIP)
- BENTRONIC (LICENSING)
R2. SURGICAL INSTRUMENTS
- TEQUIR (OWNERSHIP)
- SYNIMED (OWNERSHIP)
R3. EXTERNAL CONSOLE
- TEQUIR (OWNERSHIP)
- BENTRONIC (OWNERSHIP)
IPR and a breakdown on the agreements about IPR and rights of use of the results are shown in the attached pdf for this section (Illustrations 1 and 2).
* COMMERCIALIZATION RIGHTS
According with the described allocation of IPR and rights, commercialization rights were agreed among SME partners, which is gathered in Consortium Agreement (deliverable D8.1).
- SYNIMED AND BENTRONIC GIVES TEQUIR THE RIGHTS OF USE OF KNOWLEDGE AND DEVELOPMENT OF THEIR SURGICAL INSTRUMENTS (R2) AND THE EXTERNAL CONSOLE (R3) FOR THE EXPLOITATION OF THE FINAL SYSTEM BY TEQUIR.
- IN RETURN, TEQUIR WILL GIVE SYNIMED AND BENTRONIC EXCLUSIVE COMMERCIALIZATION RIGHTS TO MARKET THE FINAL SYSTEM IN THEIR RESPECTIVE COUNTRIES (FRANCE AND GERMANY). Furthermore, TEQUIR will offer SYNIMED and BENTRONIC a preferential opportunity of being the outsourced manufacturers for the final system, always in accordance to standard competitive production costs.
- TEQUIR will commercialize the final StimulAIS System in the remaining potential markets. If BENTRONIC and/or SYNIMED are interested in the commercialization of the Final System in other countries, they may negotiate and reach an agreement with TEQUIR.
- In addition, SYNIMED and BENTRONIC will be able to use the foreground during its particular development in other applications, PROVIDED THAT THESE APPLICATIONS ARE NOT-COMPETITIVE WITH THE FINAL STIMULAIS SYSTEM OBJECT OF THE PRESENT PROJECT.
* ENSURING EXPLOITABILITY OF THE RESULTS ACHIEVED
TEQUIR applied for a patent at national level previous to the project (Patent No. 201230093) with "Moya y Asociados" consultants, and is maintaining this patent at least in Europe. Hence, TEQUIR will own the industrial property of the patent of the medical device.
As summary of the technological report (P5343), "it is excluded the possibility that the invention proposed by the applicant is affected by objections of the novelty."
During the project, Tequir applied to an international patent nº PCT/2013/070004 ("System for treatment of idiopathic scoliosis") in Spanish stage. The applied PCT was reviewed positively in the report. The patent has been extended internationally.
Geographic area covered by the PCT:
- Japan [No. 100094640]
- USA [No.14/3731834]
- Canada [No.P4629CAOO]
- Australia [No.2013213494]
- Europe: The applied PCT/ES2013/070004 has proceeded with the entry into Regional phase to the European Patent Office (EPO) in August, 2014. The corresponding number to this European patent application is: EP13740736.7. The 37 countries designated in this application have been:
Albania, Austria, Belgium, Bulgaria, Croatia, Cyprus, Denmark, Slovakia, Slovenia, Spain, Estonia, Finland, France, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Macedonia, Malta, Monaco, Norway, Netherlands, Poland, Portugal, United Kingdom, Czech Republic, Romania, San Marino, Serbia, Sweden, Switzerland and Turkey.
This process was performed with "ABG patents" consultants.
FUTURE STEPS
As it was pointed out by European Commission, at project assessment, the expectations were high and ambitious. Nevertheless, the high demand of project results has allowed us to get the knowledge of the required development also very high and satisfactory.
This way, despite not having an immediate exploitable system (mainly because of the laboratory non-validated manufacturing process instead of specialized manufacturers of the active implantable medical device), the main initial project aims have already been fulfilled, providing the consortium with VALUABLE EXPERIENCE ABOUT THE COMPLEX INDUSTRIAL AND REGULATORY CONTEXTS OF THE FINAL PRODUCT, for its future development steps.
Hence, StimulAIS system, according with the logical development of an active implantable medical device, NEEDS SOME NEXT STEPS AFTER THE PROJECT ENDS TO BE A FULLY MARKETABLE PRODUCT, as it was already foreseen at proposal stage. According to the outcomes achieved, the continuation of StimulAIS will entail:
1) INDUSTRIAL VALIDATION (through specialized manufacturers). To produce prototypes validated industrially according to all the applying regulatory framework, for CE marking.
It is imperative to fine-tuning manufacturing for up-scaling industrialization, relying on specialized companies in the field of active implantable medical devices that currently manufacture/assembly similar devices such as pacemakers or neurostimulators. Their valuable expertise in this specific and complex sector will help us to succeed in the next development and go closer to market. Tasks to achieve in this development:
- Redesign of the system components for an industrial regulated manufacture.
- Establish the fundamental requirements of the production line of the device.
- Assembly of the production line including acquisition of any necessary manufacturing equipment. Installation Qualification (IQ) and Operation Qualification (OQ) validation.
- Prototypes manufacturing. Performance Qualification (PQ) validation of the device in the established production line.
- Prototypes testing. Homologated testing applicable to neurostimulators in certified/ homologated laboratories.
- Establishment of the Clinical Validation Protocol to be presented to the Clinical Research Ethics Committees.
2) CLINICAL VALIDATION (through Clinical Trials) in order to validate the device for its intended use in humans.
Tequir is currently negotiating with Synimed and Bentronic the possible ways for StimulAIS system continuation:
- Sign agreements for participating in next development steps, sharing the investment
- or wait until the StimulAIS system reaches de market and obtain a commercial advantage in the commercialization in their respective countries (France-Synimed; Germany-Bentronic), according with Consortium Agreement's commercialization rights.
There is work already done in line with next step 1). Project promoter (Tequir) is leading the search for manufacturing and clinical partners who can upwardly scale production towards industrial volumes, mainly able to validate the productive processes, according with the regulatory framework applicable to active implantable medical devices. Next tasks have been carried out in this respect:
1.1. MONITORING OF SPECIALIZED COMPANIES
An intensive search of specialized companies has been already performed, in line with the needs stated previously, in order to look for potential collaboration for the next development steps of the StimulAIS system.
In order to produce a prototype validated industrially, according to all the regulatory framework applicable to active implantable medical devices, able to participate in subsequent clinical trials and rollout into the marketplace (after CE marking), this search is highly relevant. The establishment of a validated production line of the implant is the main objective of this endeavor.
The expertise and know-how of the potential organizations/companies, to be included in a future consortium, because of the value added in different value-chain of the manufacturing/assembly of the StimulAIS system, should be focused on:
- Experienced manufacturers of active implantable medical devices.
- Experienced manufacturers of implantable electrodes and lead wires.
- Certificated and homologated laboratories to perform all the validation testing of the active implantable medical device accordingly to the essential requirements of 93/42/EEC and 90/385/EECDirectives.
- Experience in software development (medical devices).
- Referral Hospital to perform clinical trials.
Three major actions were taken to track this objective:
- DISSEMINATION ON OFFICIAL WEBPAGE: Publication of official ad on Tequir webpage, announcing the current search for medical devices companies experts for consortium’s formation.
- PUBLICATION OF PARTNER REQUEST AT SEIMED PLATFORM: A research development request profile was filled with the requested information in order to build an adequate profile, indicating the detailed information of the partner’s profile that Tequir is seeking. At this date, the draft of the request form was send and we’re waiting for feedback so that the final version can be uploaded and published at SEIMED network platform.
- TEQUIR PRIVATE SEARCH FOR PARTNERS: An independent search was made based on internet, searching for medical devices companies/organizations that met the profile conditions mentioned above.
A total of 20 companies within the EU and with diverse expertise were contacted via email or phone in our private search.
Currently, Tequir has sent NDA to the companies whose expertise and core activity have been assessed to be the most appropriate to the value-chain and a preliminary consortium has been developed.
At this moment we’ve obtained positive response of 6 companies from Germany, Switzerland, Slovenia and Finland, making a total of 30% of partnership positive response. Each one of these companies have a different expertise and field of activity within the medical devices field e.g. manufacturers of active implantable devices including neuromuscular stimulators and pacemakers, manufacturers of electrodes, batteries and lead wires, electronics and software developers, implantable devices telemetry systems experts. After a period of communication to assess their capabilities, we’ve selected 4 companies out of the initial 6 to be part of the primary structure of the consortium, forming the heart of the industrial manufacture and validation of the StimulAIS system.
Adding to this, we’ve already received 12 Expressions Of Interest from the request of co-operation published in SEIMED network platform from different countries as Turkey, Hungary, Macedonia, Ireland, Lithuania and France. Accordingly to the expertise profile presented we’ve already selected 4 out of 12 potential companies to be part of this consortium, mainly for establishing clinical trials in different EU countries which guarantees a wide EU coverage once the clinical trials begin.
With this diversity of positive feedback from different companies with wide expertise, we have the security that we’ll accomplish all the stated criteria of expertise and know-how of the initial partnership requirements for the correct consortium formation for continuation of StimulAIS development.
We go in conversations with potential partners in order to know more information about their manufacturing capacities/facilities so that Tequir can have all the guarantees that the manufacturing of the stated prototype will be performed in validated conditions, and all the requirements will be met.
1.2. H2020 PROPOSAL - FAST TRACK TO INNOVATION
Current and immediate activities related with the preparation of the proposal for continuation of StimulAIS system, under "Fast Track to Innovation" program (cut-off April 29, 2015), with the associated schedule, are shown in the attached pdf for this section (Illustration 3).
* EXPLOITATION STRATEGY AMONG SMES, IN NEXT DEVELOPMENT STEPS
Being aware of the required next steps to be carried out after StimulAIS project ends, in order to validate the StimulAIS system for its intended use in humans, the involved SMEs have long discussed on how to plan the strategy.
Thanks to the current development, we experienced the tough requirements and specific needs for industrializing such a complex device (active implantable medical device) like StimulAIS system is, so we have had to re-focus the stakeholders needed in the value-chain. Hence, other players are needed in the value chain (experienced manufacturer/assembler of pacemakers or neurostimulators), as stated previously. This will allow a securer step towards a product that accomplish all regulatory requirements, because of the inherent expertise in design and testing of this kind of devices.
Tequir, which is the project coordinator, is going to lead and invest in all necessary steps to successfully achieve a marketable product from StimulAIS concept. Tequir will go on as far as it is possible. Nevertheless, some scenarios were proposed, regarding the participation willingness from Synimed and Bentronic in the envisaged pre-market development:
• To support and be fully involved in the next development steps.
• To support partially, through collaboration with Clinical Trial (relevant contacts - hospitals in EU, etc.).
• Other kinds of collaboration (to be specified by Synimed and Bentronic)
• Or keep in stand-by until the product reaches the market, moment when they will obtain the commercial advantages (according to the exploitation rights in the signed Consortium Agreement).
Due to the magnitude impact of this strategic decision, currently, discussions among all three SMEs (Tequir-Bentronic-Synimed) are being performed to this regard.
Tequir will provide specific license agreements, adapted to the answer from Synimed and Bentronic, which will be bi-laterally signed by the involved SMEs.
Potential Impact:
Socio-Economic Impact of the Project
Affected Population: Overall Prevalence of AIS
According to the Scoliosis Research Society (SRS), idiopathic scoliosis is diagnosed when a patient has asymmetry on forward bending combined with a curve of at least 10° [2]. By this definition and accordingly to the literature, the prevalence of adolescent idiopathic scoliosis in children from 10 to 16 years of age is approximately 2% to 3% [1] [3] [4] of which 0.3% to 0.5% have progressive curves requiring treatment [5].
Because scoliosis is not a medical condition that must be reported, the prevalence of this condition is only estimated [1]. For this reason, considering that there are no sufficient epidemiological data in the literature for the prevalence of idiopathic scoliosis in several geographical areas, different studies published recently were analyzed in order to determine if they are consistent with the literature epidemiological data from former years.
Konieczny et al. [6] in 2013, conducted a review of current literature about school screening studies that took place in different countries – Germany, Singapore, Barsil, Korea, Turkey and Grece – with a total of 1,423,390 children screened, showing data of AIS prevalence interval of 0.47-5.2%. This correspond to an estimated mean of 2,8% of AIS prevalence consistent to the literature rate of 2-3%.
Du et al. [7] in 2014 performed a cross-sectional study in Chinese children, to exam if there were any differences between the scoliotic characteristics that could reflect prevalence changes. A total of 6824 children aged from 6 to 17 years old were recruited and the study determined a prevalence rate of idiopathic scoliosis of 2.52%. This represents also a value consistent to the 2-3% prevalence value mentioned previously.
Based on these studies, it seems that the aproxiamte prevalence rate of AIS nowadays is still around 2-3% worldwide with 600.000 visits to private physicians offices in the USA only [8]. Nevertheless it’s important to recognize that the epidemiological data presented maight vary accordingly to genetic, cultural, environmental, social, racial or other differences across the various countries and regions.
Current Available Treatements Inefficacy
Currently there is no cure for AIS. Depending on the curvature progression and clinical evaluation there are different treatments available: conservative treatments as observation, exercise/physiotherapy and bracing for curvatures lesser than 45-50 degrees; and surgical spinal fusion for curves larger than 50 degrees that usually are associated with hight risk of continued worsening throughout adulthood [5].
Brace treatment and observation
In brace treatment’s studies of scoliosis have historically lacked randomized clinical trials. The very nature of this disease is very difficult to blind and randomize, adding the difficulty of being a long treatment process. Published studies about brace treatment efficacy versus observation alone, are observational studies [8], generally of low quality with methodological therefore a high risk of bias.
A Cochrane systematic review of 2010 [10] found insufficient evidence to support the brace usage. Only two items were included in the systematic review: a study comparing two different types of braces [11] and a prospective controlled trial comparing a brace, treatment with Electrical stimulation and observation without intervention, with a foloow-up of 16 years in a subgroup of patients [12].
The authors concluded that “Due to the very low quality of the evidence in favor of bracing, patients and their parents should regard these results with caution and discuss their treatment options with a multi-professional team.”
Most studies used the amount of curve progression measured by the Cobb angle to determine the effectiveness of brace treatment. Some defined success as 5° or less curve progression [12]. The failure of brace treatment is determined when, despite the treatment applied, the patient need to undergo surgery due to curve progression.
Accordingly to literature, the overall surgical rate for failed bracing is approximately 23 percent when used as a treatment for idiopathic scoliosis [14] and in adolescent male patients, bracing had unsuccessful results in 76 percent of the cases, with 46 percent requiring surgery for idiopathic scoliosis [13]. Regarding the untreated patients (non-bracing patients) there is literature rates of surgery incidence varying from from 10 to 38% [9] [15] [16] [17]. This variation could be due to differences in case mix, inconsistent indications for surgery, differences in the quality of the brace and in patient compliance with brace wear, and nonblinded outcome evaluation [5]; nevertheless both rates of braced patient versus observational only doesn’t show a significant difference, supporting the conclusions that bracing doesn’t reduce dramasticly the surgery incidence in adolescent scoliotic patients .
Physiotherapy and physical exercise
As for the physiotherapy and physical exercises treatment, a Cochrane systematic review [18], which included two studies, found low quality evidence from a randomized controlled study [19] that certain specific exercises along with orthopedic treatment may increase the effectiveness of orthopedic treatment. And finds evidence of very low quality from a prospective controlled cohort study, that specific exercises integrated in a program can reduce prescribing orthotics [20] compared with usual physiotherapy. The review Cochrane concluded that there should conduct research of better quality before to recommend the use of specific exercises for scoliosis in clinical practice.
Costs of Current AIS Treatments
Based on the scientif evidences presented above, none of these AIS treatments are effective, and in addition bracing can stop progression but in any case corrects the scoliotic deformity. The consequence of these currently inneffective solutions represent a significant economical impact in the Health System with important level of costs.
Surgery
As for Surgery costs Kamerlink et al. 2010 [21] conducted a retrospective review of 16,536 individual expenses and charges, including overall reimbursements, for 125 consecutive patients who were managed surgically for the treatment of adolescent idiopathic scoliosis by three different surgeons between 2006 and 2007. The mean age of the patients was 15.2 years. Costs ranged from $29,995 to $33,652, averaging $31,832.50 per case. In addition, accordingly to Weinstein et al [5] in the United States in 2009, there were more than 3600 hospital discharges for spinal surgery to correct adolescent idiopathic scoliosis with the total costs of $514 million, ranked second only to apendicitis among children to 10 to 17 years of age.
Bracing
The most common type of scoliosis treatment is Bracing, and it is estimated to be used for 30,000 children in the USA [21] [22]. Considering the statistic data of 85% for adolescent idiopathic scoliosis, the approximate number of children braced for idiopathic scoliosis is 25,500. According to MG Labs, a prosthetic and orthotic lab in New York, the national average cost of a thoracolumbosacral orthosis is $2,100. That places the national USA cost for bracing at over $53 million ($53,550,000) [21]. As for European prices of bracing, we can use the example of the Valencian Community stipulated orthopedic pricing for scoliosis orthotic braces. The most used types of braces used for scoliosis treatment are Boston, Cheneau, Milwauke, with the corresponding prices of 771.25 €, 823.21 €, 822.82 € [23]. Considering a patient that starts a bracing treatment at the age of 10-11, it’s probable that in the following two years the brace has to be renewed every 6 months due to rapid growth of the child, and renewed each year from the age of 13 until it’s reached skeletal maturity. For a patient of 10 years old with a Boston brace this represents a year bracing cost of 1542,5€ in first two years of treatment and 771,25€ each year until bracing removal. Considering 6 years of brace usage (from 10 until 16 years old) this represents a approximate total cost of 6170€ for patient for brace treatment only, not considering the X-rays, MRI, and other medical appointments and physiotherapy sessions that also are necessary.
Revision appointments
The National Scoliosis Foundation estimates that the number of physician visits per year for scoliosis is 600,000 [8]. Again, taking the 85% percent statistic for idiopathic scoliosis, the number of physician visits would have an approximate value of 510,000 visits per year. Omitting X-rays, MRIs and other required services for scoliosis, the average cost for a doctor's visit is conservatively $100, averaging both primary and specialist care. This would put the national USA price tag of hospital visit cost in $51 million. If it is considered the cost of each complementary exams that need to be done to assess the curvature progression each year, as the above mention X-rays, this overall cost is significantly increased.
StimulAIS system finds a niche in the treatment of adolescent idiopathic scoliosis by muscular electro-stimulation of the paraspinal deep rotator muscles. This system will be capable not only of stopping progression of curvature, but also to potentially correcting it. This represents a strong differentiation in AIS treatment, since it will avoid all the side effects of the actual conservative and spinal fusion treatments, but also reducing dramatically the actual costs of Health Systems derived of the current ineffective AIS treatments.
A summary of current available solutions with associated costs and potential advantages of StimulAIS system over all of them is provided in the following table:
Current treatments Costs (estimated values) Limitations StimulAIS expectations
Conservative Observation N/D A high number of curves progress and require bracing and/or invasive surgery Restorative, avoids invasive fusion surgery and bracing
Exercise and physiotherapy N/D No conclusive evidences of its effectiveness Restorative, avoids invasive fusion surgery and bracing.
Focused treatment and auto-regulation of stimulus
Bracing Cost of $53 million in the USA per year plus $51 million for the associated revision appointments to the physician making an estimated total cost: $104 million/year - No permanent correction of curvature
- Functional discomfort
- Leads to psychosocial and body image concerns
- Restriction of movement
- Ineffective in overweight patient ( and leads to increase progression)
- Ineffective to most cervithoracic curves and curves greater than 40 degrees
- Final surgical rate similar to non-braced
- Active correction of curvature. Not only stop progression, but also potentially correct the curvature
- No discomfort
- Low obtuseness (implanted subcutaneously)
- No restriction movement
- Effectiveness not dependant on patient weight
- Applicable on most AIS curve locations with less exclusion criteria than bracing
- Effective, avoids surgery
Non-conservative Surgical fusion treatment Cost of $31,832.50 per surgery/patient with a total of total cost of $514 million a year (USA) - Invasive
- Spinal fusion
- High risk of complications (infection, hardware breakage, pseudoarthrosis, nerve damage and sexual dysfunction) - Minimally invasive technique
- Motion preserving
- Low risk complications
Dissemination activities
Multiple dissemination activities were carried out during the project, aiming for internal diffusion of information among the partners of the consortium as well as external diffusion of StimulAIS device into the technical, clinical and scientific community. Please note that all dissemination material produced by the StimulAIS consortium included the official logo.
The main dissemination activities include:
- Web portal: a project website was created, including a restricted area where only the consortium members and EC Project Officer have access, containing among other information, documentation regarding the status of the project such as reports, pictures, presentations and results.
- Brochures: designed brochures containing the main information in English about the project, in order to inform the scientific and medical community, patients and potential users about the results of the project.
- Video: production of a video containing a short description of the project and its objectives and focused on the advantages of its clinical use.
- Participation in conferences and trade fairs:
o World of MEDICA Düsseldorf (Germany), November 2014
o Silicon Saxony (Germany), December 2013
o Sociedad de Estudios de Enfermedades del Raquis GEER XXVII (Spain), May 2013
o 8th World Combined Meeting of Orthopaedic Research Societies (Italy), October 2013
o Asociación Española de Investigación en Cirugía Ortopédica IVESCOT X (Spain), February 2014
- Publication in magazines with European Impact (>53.00 subscribers in EU):
o Article Published in Science, Technology and Innovation Projects (Insight Publishers).
- Publication in Specialized Journal (EU and worldwide)
o Abstract publication in Bone & Joint Surgery, Journal Orthopedic Proceedings Supplement
- Press Releases:
o Ruvid
o ABC newspaper
o Canarias7 newspaper
o Crónica de Cantabria
o Diario Siglo XXI newspaper
o El Confidencial newspaper
o El Día newspaper
o Europa Press
o Gente Digital
o Heraldo newspaper
o Telecinco web
o La información
o La Razón newspaper
o Las Provincias
o La Vanguardia
o Te Interesa web
o Yahoo Noticias web
o Diario de Pontevedra
o El Progreso
o Levante EMV
o AlphaGalileo
Exploitation plan
Being aware of the required next steps to be carried out after StimulAIS project end, as device validation for its intended use in humans, the involved SMEs have long discussed on how to plan the exploitation strategy.
Thanks to the current development, though requirements and specific need for industrializing a complex device as StimulAIS were experienced, leading to re-focus the stakeholders needed in the value-chain, seeking for experienced manufacturers/assemblers of pacemakers and neurostimulators. This will allow a securer step towards the product that accomplishes all regulatory requirements, due to their inherent expertise in design, manufacture and testing of these kind of devices.
Tequir, being the project coordinator, will lead and invest all the necessary steps to successfully achieve a marketable product from StimulAIS concept. These actions include:
• Ensuring exploitability of the results achieved. Tequir applied for a patent (No. 201230093) previous to the project (Europe), owing the industrial property of the patent of the medical device; and for a international patent No PCT/2013/070004 “System for treatment of idiopathic scoliosis” which have been extended internationally at Europe, Japan, USA, Canada and Australia. In addition, there is no business agreements, laws or market blockings, which may impose limitations on the subsequent exploitation.
• Monitoring specialized companies. An intensive search of specialized companies has been performed in order to look for potential collaboration for StimulAIS next development steps, which include manufacturing an industrially validated prototype according to regulatory framework of active implantable medical devices, in order to participate in subsequent clinical trials, achieve CE marking and rollout into the marketplace.
• Making contact with selected specialized companies. A total of 20 companies whitihn the EU and with diverse expertise were contacted via email or phone. At the present moment we’ve obtained positive response of companies from Germany, Slovenia and Finland, making a total of 30% of partnership positive response. Each one of these companies have a different expertise and activity field, allowing us to form a well established complementary co-operation. As we anticipate to receive more confirmations soon, this value of positive feedbacks expected to rise at least up to 50%, guarantying that we’ll accomplish the seek criteria of expertise and know-how that will allow us to continue the next development steps of StimulAIS project towards placing it in the market.
• Rising Awareness among general public and clinical community (bottom-up demand). After the project end, and while developing the next needed steps, our clinical group (UCV) will train their closer circle of experts in scoliosis, with detail training protocol on the use of StimulAIS system as well as the surgical technique, thus generating other training groups, leading to a quick diffusion of knowledge.
• Place the device on the market. The exploitation of StimulAIS system, when it’s market-available, will be mainly carried out in public and high quality private healthcare hospitals. The introduction in the private sector will require shorter time, as there is no need to wait for the admission to the competitions that regulate the provisions in the public health system. Several strategies are being taken into consideration in order to achieve prescription endorsement.
• Well established distribution networks. In order to introduce the new device through Europe and emerging markets, is needed to have a solid distribution network. Distribution will start from Spain, Portugal, France and Germany, which are the countries that will be potentially involved in the multicenter clinical trials short-term. This will allow an immediate access to their markets, adding the wide distribution network of the consortium SMEs (Synimed, Bentronic and Tequir) with more than 100 countries in Europe, Central and South America and Asia.
References
[1] SRS, "Scoliosis Reaserch Society," 2015. [Online]. Available: http://www.srs.org/professionals/glossary/SRS_revised_glossary_of_terms.htm. [Accessed 02 2015].
[2] S. Anderson, "Spinal Curves and Scoliosis," Radiologic Technology, vol. 79, no. 1, pp. 44-65, 2007.
[3] M. Lenssinck, A. Frijlink, M. Berger, S. Bierma-Zeinstra, K. Verkerk and A. Verhagen, "Effect of Bracing and Other Conservative Interventions ion the Treatment of Idiopathic Scoliosis in Adolescents: A Systematic Review of Clinical Trials," Journal, vol. 85, pp. 1329-1339, 2005.
[4] T. Kotwicki, J. Chowanska, E. Kinel, D. Czaprowski, M. Tamaszewski and P. Janusz, "Optimal management of idiopathic scoliosis in adolescence," Adolescent Health, Medicne and Therapeutics, pp. 59-73, 2013.
[5] S. Weinstein, L. Dolan, J. Wright and M. Dobbs, "Effects of bracing in adolescents with idiopathic scoliosis," The New Engalnd Journal of Medicine, pp. 1-10, 2013.
[6] M. Konieczny, H. Senyurt and R. Krauspe, "Epidemiology of adolescent idiopathic scoliosis," Journal of Children Orthopaedics, vol. 7, pp. 3-9, 2013.
[7] Q. Du, S. Negrimi, X. Zhou, X. He, J. Li, L. Zhao and P. Chen, "Scoliosis epidemiology is not all the same all around the world: a study from a scoliosis school screening in the island of Chongming, China," in 11th International Conference on Conservative Management of Spinal Deformities, Wiesbaden, Germany, 2014.
[8] N. S. Foundation, "National Scoliosis Foundation," n.d. [Online]. Available: http://www.scoliosis.org/info.php. [Accessed 02 2015].
[9] A. Danielsson, R. Hasseriuus, A. Ohlin and A. Nachemson, "A prospective study of brace treatment versus observation alone in adolescent idiopathic scoliosis: a follow-up mean of 16 years after maturity," Spine, vol. 32, no. 20, pp. 2198-207, 2007.
[10] S. Negrini, S. Minozzi, J. Bettany-Saltikov, F. Zaina, N. Chockalingam and T. Grivas, "Braces for idiopathic scoliosis in adolescents.," Cochrane database Systematic Review, vol. 1, no. CD006850, 2010.
[11] M. Wong, J. Cheng, T. Lam, N. B, S. Sin and S. Lee-Shum, "The effect of rigid versus flexible spinal orthosis on the critical efficacy and acceptance of the patients with adolescent idiopathic scoliosis," Spine, vol. 33, no. 12, pp. 1360-5, 2008.
[12] A. Nachemson and L. Peterson, "Effectiveness of treatment with a brace in girls who have adolescent idiopathic scoliosis. A prospective, controlled study based on data from the Brace Study of the Scoliosis Research Society," Journal of Bone and Joint Surgery Am., vol. 77, no. 6, pp. 815-22, 1995.
[13] E. Lou, D. Hill, M. J, M. Moreau and J. Raso, "An objective measurement of brace usage for the treatment of adolescent idiopathic scoliosis," Medical Engineering and Physics, vol. 33, no. 3, pp. 290-294, 2010.
[14] L. Dolan and S. Weinstein, "Surgical rates after observation and bracing for adolescent idiopathic scolisis: an evidence-based review. (Abstract)," Spine , vol. 32, no. 19S, pp. S91-S100, 2007.
[15] R. Fernandez-Feliberti, J. Flynn, N. Ramirez, M. Trautmann and M. Alegria, "Effectivenness of TLSO bracing in the conservative treatment of idiopathic scoliosis," Journal of Pediathric Orthopaedics, vol. 15, pp. 176-81, 1995.
[16] C. Goldberg, D. FE, H. JE and J. Emans, "A statistical comparision between natural history of idiopathic scoliosis and brace treatment in skeletally immature adolescent girls," Spine, vol. 18, pp. 902-8, 1993.
[17] C. Goldberg, D. Moore, E. Fogarty and F. Dowling, "Adolescent idiopathic scoliosis: the effect of brace treatment on the incidence of surgery," Spine, vol. 26, pp. 42-7, 2001.
[18] M. Romano, S. Minozzi, J. Bettany-Saltikov, F. Zaina, N. Chokalingam and T. Kotwicki, "Exercises for adolescent idiopathic scoliosis," Cochrane Datyabase System Review, vol. 8, no. CD007837, 2012.
[19] S. Negrini, F. Zaina, R. M, A. Negrini and S. Parzini, "Specific exercises reduce brace prescription in adolescent idiopathic scoliosis: a prospective controlled cohort study with worst-case analysis," Journalk of Rehabilitation Medicine, vol. 40, no. 6, pp. 451-5, 2008.
[20] W. Wan Li, "Results of exercise therapy in treatment of essentially S-shaped scoliosis patients: Evaluation of Cobbs angle in the breast and lumbar segment," Chinese J Clin Rehabili, vol. 9, no. 34, pp. 82-4, 2005.
[21] J. Kamerlink, M. Quirno, J. Auerbach, A. Milby, L. Windsro, L. Dean, J. Dryer, T. Errico and B. Lonner, "Hospital Cost Analysis od adolescent idiopathic scolisis correction surgery in 125 consecutive cases," The Journal of Bone and Joint Surgery, vol. 95, no. 5, pp. 1097-1104, 05 2010.
[22] M. Studin, "Chiropractic vs Medical Management of scoliosis Let's look at the numbers," Dynamic Chripractic, vol. 30, no. 22, 2012.
[23] G. Valenciana, "Catalogo de articulos de Exoprótesis," in 060309 - Ortesis Dorso-Liumbo-Sacras, 2012.
List of Websites:
www.stimulais.com
Polígono Industrial El Oliveral, C/C, s/n
CP. 46190 Ribarroja del Turia (Valencia), SPAIN
Telf: +00 34 961 668 795
Fax: +00 34 961 668 889
Contact persons: Álvaro Alonso, Magdalena Bresó
Email: info@tequir.com
Email: magdabreso@tequir.com
Web: www.tequir.com
The StimulAIS project has developed an implantable electro-stimulator within an experimental frame of the 7th frame program of the European Comission, called Research for SME’s, capable of stimulating the pathological paraspinal muscles that present a dysfunction which could be the origin of the pathology of scoliosis idiopathic of adolescent. This stimulation would restore to the muscles until they acquire the required toning to perform their tensile function of the vertebral spine, together with stimulation feedback provided by a sensor on the opposed and healthy side. This way they actuate balancing the tensile forces of the spine while at the same time they provide a personalized treatment for each individual patient.
The electro-stimulator pretends to be an alternative treatment to the current orthopedic one with a corset, indicated for idiopathic scoliosis between 20 and 40°Cobb. This treatment is not well accepted by the patients, creating psychosis concerning the use of a corset in public spaces as well as it limits physical activities of the patients.
The project has developed a system composed of an electro-stimulator and its accessories, charger and wireless reader, software and control. The tools necessary for a minimal invasive surgical intervention have also been developed and validated.
All the components have been developed in a laboratory and prototypes were manufactured for experimentation in animals, and laboratory verification of the characteristics.
The project consortium was formed by three Companies: Tequir I+D+i in Spain which actuated as project coordinator, Synimed in France and Bentronic in Germany, as well as three technological centers such as the Catholic University of Valencia in Spain (UCV), the Biomechanical Institute of Valencia (IBV) also located in Spain and Fraunhofer (IPMS) in Dresden, Germany.
The principal activities of the project were directed to the sampling and study of basal electromyography data in healthy patients, the design of all the necessary components, definition of the required requisites, development of a stimulation protocol, manufacturing of prototypes for laboratory and animal tests, verification in the laboratory and experimental process in animals.
The animal experiments were done under strict ethical norms and requisites expressed in the Directive 2010/63/UE and counted with all the necessary authorizations.
We can satisfactorily conclude the results of this ambitious project with the following achievements:
- Design and development of an implantable device with a stimulation and sensor function in a laboratory environment as well as its integration with different non-implantable grade components required for its functionality and monitorization.
- Development of a stimulation protocol adapted to the basal EMG data in a personalized way.
- Validation of a surgical procedure and development of specific surgical instruments necessary for the implantation of the device.
- Observation of scoliosis generation after a stimulation protocol performed in an animal.
Because of the experienced protototypes' manufacturing and animal experimentation complexity, some deviations took place with regards to the original planning:
Thanks to the implemented measures:
- Corrective actions for manufacuring (costs re-shuffling among consortium partners) and for animal experimentation (improvements in surgical technique, animals intensive cares, surgical re-interventions, etc.)
- Project extension (+3 months) requested and approved
most objectives have been successfully achieved.
Further work is needed for the next generation of prototypes, in order for them to be used in clinical trials.
However, this multidisciplinary project has provided relevant results in the scope of the programme, which are very useful for continuation towards a market-ready system.
Future steps have been defined in the exploitation strategy, which can be sumarized in:
- Industrial validation (prototypes validated industrially -manufacturing and testing- according to all the applying regulatory framework, for CE marking) for upscaling industrialization.
- Clinical validation (through clinical trials).
Project Context and Objectives:
Adolescent idiopathic scoliosis (AIS) is a progressive structural spinal deformity of unknown origin that affects around 2-3% of children aged between 10 and 16 in the world. Scoliosis is defined as a curve of at least 10º, measured on a standing radiograph using the Cobb technique (Figure 1.1) with rotation of the vertebral bodies (3-dimensional deformity). The resulting surface deformity has a strongly negative impact on adolescents, giving rise to psychological distress, behavioral disorders, and other emotional and social problems that reduce drastically their quality of life (QOL).
About 90% of diagnosed AIS patients usually do not receive specific therapy except observation, as this is the standard treatment for curves up to 25º for young patients in age of development. The other 10% (160.000 people in Europe every year) receive different kinds of conservative treatment in an attempt to halt the progressive nature of the deformity, since if scoliosis surpasses a critical threshold, usually considered to be 30º Cobb at the end of growth, the risk of health problems in adulthood increases significantly. These problems include disability, pain, increased cosmetic deformity, functional limitations, pulmonary and cardiac compromise, and possible further progression during adulthood. Of all the European diagnosed patients, up to 40.000 per year require a very invasive corrective surgery, due to failure of conservative treatment, sudden progression of the curvature or late diagnosis.
Recent studies evidenced that the spine deformity is a musculoskeletal expression of a central nervous system disorder that affects the paraspinal muscles inducing an imbalance of forces acting over the vertebral segments.
The overall technological aim for the project is to produce a fully working prototype of a device for the electro stimulation of the paraspinal deep rotator muscles with programmable stimulating protocol and real-time adaptation of stimulus through a feedback loop control system. In the realization of this overall project aim, we identify the following overall technical aims:
1. Develop a subcutaneous programmable device for sensing in a maximum range of +/-5.0 mV and stimulating the deep paraspinal rotator muscle.
2. Develop stimulation control software, for customizable treatment and including a feedback loop algorithm for automatic stimulus fine adjustment.
3. Develop minimally invasive surgical instruments for the implantation of the subcutaneous devices through an incision less than 50 mm in length and surgery time less than 90 minutes.
4. Achieve an integrated working medical system according to EU regulations applicable to active medical devices, for performing customized treatment of the AIS during a period of at least 6 months.
Specific Scientific Objectives:
Enhancement of scientific knowledge is needed, as defined in the following list of scientific objectives:
-Analysis of electromyography and electro-stimulation data of the paraspinal muscles, proceeding from preliminary tests and previous studies, to correlate the electrical signal with the muscle activity.
-Determination of parameters for main muscular stimulation protocol.
-Identification of the components of the electromyography signal to generate and control the stimulus through the feedback loop control.
-Data processing and control system strategies feasibility study, in order to define specific software structure to fulfill the technological aims.
-Feasibility study of the biomechanical and hardware design of the subcutaneous device.
Specific technological objectives for the subcutaneous programmable device:
-Miniaturize an EMG sensor electronics capable of measuring responses between 20 Hz and 5 KHz, an amplifier sensitivity of 50 μV, and a sweep duration of 10 ms.
-Miniaturize stimulation electronics, capable of providing adjustable pulse strength for the stimulation of the paraspinal deep rotator muscles, with a variable stimulation current of 1-50 Hz for 1 s and an adjustable intensity between 0.2 and 50 mA, for a mono-phasic stimulation pulse.
-Select and integrate a power battery conforming to the power requirements of the system (Control Circuit minimal voltage: 2.2V pulse range 15-40 J).
-Select and integrate an RFID tag for wireless communication working with frequencies of 125 kHz.
-Develop optimized hardware technology for protocol housing and controlling. All evelopments
include hardware (schematics and layout) development and firmware development (controller based) of the components.
-Develop a body-friendly case with shape biomechanically adapted to the subcutaneous location, housing sensor and stimulator, power supply and RFID tag for wireless communication, with maximum volume of 9 cm3 and maximum main dimension of 30 mm.
Specific technical objectives for the stimulation control software:
-Develop the main stimulation protocol capable of providing stimulus in a frequency range of 1-50 Hz.
-Develop the feedback loop algorithm for automatic adjustment of the stimulus within 5•10-1 seconds since EMG signal acquisition.
Specific technical objectives for surgical instruments:
-Develop minimally invasive surgical instrument (laparoscopic or needle-like) for the implantation of the subcutaneous device in the anatomical location through an incision of the skin less than 50 mm in length and for the connection of the electrodes to the key muscles through incisions of less than 5 mm in diameter. Total surgery time should be less than 90 minutes.
-Develop ergonomic solutions for minimally invasive instruments.
Specific technological objectives for the integrated fully working medical system
-Obtain a subcutaneous device with integrated stimulation control software
-Programme the external console to control the subcutaneous device.
-Obtain a programmable working system, producing stimulations according to the established
Protocol.
-Verify the safety and operation of integrated medical device by carrying out tests according to
European regulations applicable to active medical devices: 90/385/CEE; 93/42/CEE; IEC 60601-1; IEC 60601-2; EN 45502-1; RD 1591, ISO 13485.
-Verify the characteristics
** RELEVANT MEASURES FOR PROJECT SUCESS **
1) Because of the ambitious nature of the project and manufacturing complexity, CORRECTIVE ACTIONS were needed at the end of RP1, for balancing the resources across the project, and ensuring that there were resources available for design iterations.
For this purpose, a "Financial needs analysis" report agreed by all consortium partners was provided to the project officer (January-2014).
This report aimed to provide an analysis comprising the financial needs and resources, in order to clarify the situation after implementation of corrective actions in WP2, as requested after RP1 assessment.
- Firstly, we provided an overview of the needs, reached by consortium consensus, for a successful achievement of project results. Then, the associated costs were shown.
- Secondly, actions to decrease costs in order to seek feasibility ensuring that outcomes are fit-for-purpose and balanced with the work plan, were implemented.
- Lastly, StimulAIS consortium re-shuffled costs (according with Project Officer indications) for placing more consumables related with the subcutaneous device's manufacturing, because of the initial underestimation when compared with the current manufacturing context. Manufacturing costs distribution were stated, and all partners agreed with these actions.
Tables showing the costs re-shuffling, agreed among consortium partners, are summarized in the "Attachment_4.1 Final publishable summary report".
2) After a period under control, problems persisted, in this case regarding manufacturing delays.
On 05/05/2014 an amendment request was sent by Tequir, on behalf of the consortium, to REA for assessment, in order to modify the Grant Agreement, regarding project duration (27 months).
A supporting letter was attached to the amendment request, which can be summarized as follows:
- Background. Considering RP1 convergence efforts, by 2nd February, the project was under control. However, we soon were informed about different manufacturing suppliers associated delays (4 months in total)
- Current overview. Time-optimizing measures were tackled concerning feasibility of manufacturing and animal preliminary experiments.
Combining the needs for manufacturing, later functionality verification and sterilization prior animal experimentation, the schedule was settled, providing consistent explanations that supported the need for a project extension of 3 months.
- Foresight. All other boundary conditions (experiments and authorizations needed) were shown to be controlled so that definitive animal experimentation could take place as soon as we received the manufactured and sterilized devices, avoiding further unexpected delays.
Project extension (+3 months) was approved.
3) Encountered animal experimentation problems & implemented actions:
- Once started the project a new exigency regarding experimentation popped up: New Royal Decree (RD53/2013), which establishes basic rules applicable for protection of animals used in experimentation. This RD is more restrictive and time-consuming. We had to change the hospital to carry out the animal experimentation, which is prepared for the new limitations (CIPF research centre).
- First charger failed to communicate with the implanted device in preliminary experimentations. A new charger had to be developed for this purpose.
- Some implanted devices experienced failures during animal experiments: electrodes/devices expulsion and deiscence of the wound that led to infections. Solutions: Surgical re-interventions and improvements of surgical technique (implanting devices under the first muscular plane instead subcutaneously, electrodes tunnelled under the first paraspinal muscles, and suturing of the tip).
- Communication and charging problems were also experienced in-vivo. Solutions: Use of tight strips to increase pressure, reduce interface, and minimize movements while charging process with animals together with close monitoring; Work with a wireless console developed for this purpose, in order to facilitate the experimental conditions.
Thanks to the corrective actions and the commitment of project parners, experimental group B double-folded the hours of stimulation, with respect to group A.
Due to the cited problems the therapy was not continuous (5 intermediate periods of non-stimulation: surgical re-interventions and intensive cares). However, even under this situation, we've seen evidence of spinal curvature alteration due to electrostimulation of the target muscles.
4) The work has been actively monitored and hand-over of deliverables during the whole project cycle, looking for thorough coherence and fitness for purpose. the coordination of the project has guaranteed quality of the information provided and adequate integration of partners contributions in order to show the work done in line with the SMEs interests and original purpose.
Thanks to the implemented measures, most objectives have been successfully achieved, in line with SMEs expectations in the scope of the project.
Project Results:
Main S&T results
The developed StimulAIS system offers a novel system for treatment of AIS, by muscular sensing and electro-stimulation of the target muscles.
After technological development stages, three main results have been achieved and integrated in a working active implantable medical device, in accordance to some extent with EU directives, for performing customized treatment of AIS:
- RESULT 1. Implantable device (with accessories)
- RESULT 2. MIS instruments
- RESULT 3. External console
RESULT 1. The Implantable Device is programmable (for sensing and stimulating) in order to provide a wide range of treatment protocols, while muscle selectivity will allow targeted stimulation to maximize treatment outcome. Moreover, the integrated stimulation control software (to modulate it into safety thresholds) implements an innovative technology with sensor (EMG) and motor function, which could allow real-time adaptation in order to maintain stimulation effectiveness and provide progressive correction of the pathology, by toning pathological muscles that do not receive any stimulus because of the illness.
All these features are integrated in a small implantable device, providing the advantages of fully implanted systems with a minimally invasive associated procedure.
Accessories associated with R1 that have been developed for testing and animal experimentation purposes:
- Chargers have been also developed, as ACCESSORIES ASSOCIATED WITH R1, for their laboratory testing (standard charger) and animal experimentation (long-range charger) purposes.
* Description of the achieved functionalities of Result 1:
IMPLANTABLE DEVICE
R1.a) Mechanical features:
- 8 x 4.5cm x 1.6 cm
- Titanium housing
- Implantable resin connectors block
- 8 electrodes IS-1 female connections
- Desirable features:
- Size optimization;
- Integration of communication and power antennas inside the housing;
- External silicone coating.
R1.b) Electrical features:
- Stimulus pulse generation up to 25mA (on 500 Ohm resistance) programmable using up to 6 bipolar electrodes.
- EMG measurement with up to 8 bipolar electrodes with sampling frequency up to 1 KHz.
- 1MB internal data memory.
- Antennas complex (copper material)
- Communication antenna: Data communication inductive coupled with near field communication transponder (13.56MHz) [6 coil turns]
- Power antenna: Wireless charging inductive coupled with Qi receiver (125kHz…200kHz) [15 coil turns]
- Internal power source with standard (non-implantable) rechargeable battery 3.7 V 380mAh.
- Desirable features:
- Incorporate implantable battery and feedthroughs (currently, NDAs have been shared with the supplier GreatBatch for the components needed for the exploitable product;
- Implementation of high density internal memory: 1-2 Gb (it could not be implemented in current design because of power consumption and data transfer duration reasons. However, a wireless console was developed to overcome this limit for its use in experimentation).
R1.c) AUTONOMY
In a worst case scenario, a continuous stimulus generation with all maximum settings and 500 Ohm load resistance, the autonomy is 18 hours. However, in a standard therapy the device has an autonomy of about 201 hours (with full pulse amplitude and adequate therapy times). Hence, the device would have to be recharged at least after 8-9 days.
R1.d) Special functionalities
- Magnetic emergency switch-off (by means of a magnet, when necessary)
- Motion sensor with accelerometer, gyroscope and magnetometer (included in the implantable device for its future use in humans: Obtaining personalized basal signals under daily life positions)
- Device temperature measurement (the charging process is reduced at 45°C and stopped at 60°C internal battery temperature for safety reasons)
- Battery observation (by means of the developed software)
- Firmware upgradeable (current updated firmware version 2.01.13)
ACCESSORIES OF THE IMPLANTABLE DEVICE
R1.e1) STANDARD CHARGER
- Wireless charger inductive coupled Qi conform (125kHz…200kHz) for charging the StimulAIS implantable device.
- For use while the device is not implanted (laboratory use).
- Charging distance 1cm.
- Charging time < 2 h.
- Power supply 5Volts, 1A.
- Dimensions: 13 x 7 x 1.5 cm
R1.e2) LONG-RANGE CHARGER
- Wireless charger inductive coupled (125kHz…200kHz) for charging the StimulAIS implantable device.
- For use while the device is implanted.
- Charging distance minimum 4 cm.
- Charging time < 2 h.
- Power supply 18Volts, 0.5A.
- Two versions: Cable and battery powered
- Autonomy in the battery powered option: Batteries has to be changed after every charging cycle. Rechargeable batteries can be used when 500mAh capacity minimum.
- Dimensions: 7.5cm x 7.5cm x 4cm
- Desirable features:
- Combine the performance of both chargers to get just one stand-alone charger, to be used in all the foreseeable use scenarios (either in preparation of the implantable device prior surgery and while treatment period) without distance limitations.
RESULT 2. SPECIFIC SURGICAL INSTRUMENTS were developed in order to implant the electro-stimulation device and for the connection of electrodes to the key muscles.
* Description of the achieved surgical instruments kit:
- CANNULA: The cannula is aimed for the initial puncture to reach the target muscles in accordance with the planned electrodes placement, as well as to provide a canal for a safe and easy placement of the electrode to be anchored in the target muscles.
- LEADS PASSER: The leads passer is used to pass the electrodes from the incision where they are anchored to the incision where the subcutaneous device is implanted.
The Leads Passer is provided in different versions for passing 1, 3 and 4 leads a time. Two handles and bars of different diameter are included for each combination in order to adapt the instrument to the specific needs in surgery.
- Desirable features:
Decrease diameter of the leads passer connectors, as feedback-reported from surgical interventions carried out in animal experimentation stage.
The developed minimally invasive instruments and associated surgical technique have been validated in-vitro (cadaveric test). The achieved results have demonstrated to be better than the initial objectives:
A. Minimally invasive surgical instrument for the implantation of the subcutaneous device in the anatomical location through an incision of the skin less than 50 mm in length and for the connection of the electrodes to the key muscles through incisions of less than 5 mm in diameter.
A1. Incision of the skin around 20 mm (much less invasive than originally conceived: << 50 mm).
A2. Since the surgery has been performed in the most critical scenario in terms of incision demands (electrodes at three levels have been implanted through each incision), success in this test will guarantee the minimally invasive approach (20 mm) under all circumstances in real practice.
B. Total surgery time should be less than 90 minutes.
B1. The time needed to perform the test with human cadaveric model was around 30 minutes.
B2. In the cadaveric test, anaesthesia was not needed, so we did not compute the time that is around 10 minutes.
B3. In the cadaveric test, suture of incisions was not performed, since an open surgery was carried out after the minimally invasive procedure, for verification issues. The time needed for suturing all incisions is around 5-10 minutes.
B4. In the scenario of 8 electrodes needed, two incisions will have to be made at each side of the spine to cover the electrodes arrangement. This will increase the surgery time less around 10 minutes.
B5. In the worst case scenario, total surgery time will be around 60 minutes (less than the expected 90 minutes), with enough margin for any event that may occur during the surgery.
RESULT 3. The EXTERNAL CONSOLE to program the subcutaneous device and to collect bioelectric data of the patient. There is not a console itself. The development consists of a control software with an intuitive user interface, which is installed in a laptop and a reader through which wireless communication with the implanted device is established. This result is aimed to be handled by clinicians for programming the implantable device with the most appropriate stimulation protocol and follow-up treatment.
* Description of the achieved functionalities of R3:
R3.a) Reader
- Wireless reader inductive coupled NFC compliant (13.56 MHz) for communication with the StimulAIS implantable device.
- Communication range minimum 4 cm.
- USB connection to host computer. USB powered.
- Dimensions: 6 x 9.5 x 1.8 cm
- Desirable features:
- Final housing design of the reader, appropriate to clinical use.
R3.b) Software for controlling the StimulAIS implantable device via the reader device.
- Identification of the device.
- Checking the functionality of the device including charging state.
- Check the electrode connections (Stimulus).
- THERAPIES for stimulation protocols application:
Setup the therapy/stimulus parameters, start/stop the therapies directly or timer controlled. List of parameters and available settings:
- Amplitude [1 – 25 mApp, in 0.2 mApp steps]
- Pulse Width [25 - 500 µs, in 25 µs steps]
- Time On [1 – 10 seconds, in 1 s steps]
- Time Off [10 s – 20 min, in 1 s steps]
- Therapy duration [0h:01 to 23h:59, in 1 min steps]
- Therapy start time [0h:00 to 23h:59, in 1 min steps]
- Curve type [Pre-selectable curve types for appropriate configuration according to the kind of scoliotic curvature: Main thoracic, double thoracic, double major, triple major; scoliosis left, scoliosis right]
- Programme EMG measurements, read out the EMG data and visualize them.
- Firmware update (current updated software version 1.13)
- Software manual available.
All three results have been realized at lab-scale (not marketable), following as far as possible the applicable European regulation on active implantable medical devices. Although they have been verified as far as possible, according with the regulatory framework, they have been manufactured with non-validated industrial processes and prototypes have been used in animal experimentation, according to the procedures authorized by the ethics committee. Despite having multitude of unexpected events during animal experimentation, the involved partners have hard-worked and, finally, positive results after stimulation therapies have been obtained.
INTELLECTUAL PROPERTY RIGHTS (IPR)
According with the Consortium Agreement, The basic rule for IPR management in the StimulAIS project is that the achieved knowledge belongs to the three participating SMEs and that the RTD performers provide the SME participants with the full ownership and exploitation rights of all the results generated by the project.
StimulAIS system consists of the integration of the mentioned 3 results. Each participating SME will retain the IPR as described next:
Final StimulAIS system:
R1. SUBCUTANEOUS ELECTROSTIMULATOR DEVICE
- TEQUIR (OWNERSHIP)
- BENTRONIC (LICENSING)
R2. SURGICAL INSTRUMENTS
- TEQUIR (OWNERSHIP)
- SYNIMED (OWNERSHIP)
R3. EXTERNAL CONSOLE
- TEQUIR (OWNERSHIP)
- BENTRONIC (OWNERSHIP)
IPR and a breakdown on the agreements about IPR and rights of use of the results are shown in the attached pdf for this section (Illustrations 1 and 2).
* COMMERCIALIZATION RIGHTS
According with the described allocation of IPR and rights, commercialization rights were agreed among SME partners, which is gathered in Consortium Agreement (deliverable D8.1).
- SYNIMED AND BENTRONIC GIVES TEQUIR THE RIGHTS OF USE OF KNOWLEDGE AND DEVELOPMENT OF THEIR SURGICAL INSTRUMENTS (R2) AND THE EXTERNAL CONSOLE (R3) FOR THE EXPLOITATION OF THE FINAL SYSTEM BY TEQUIR.
- IN RETURN, TEQUIR WILL GIVE SYNIMED AND BENTRONIC EXCLUSIVE COMMERCIALIZATION RIGHTS TO MARKET THE FINAL SYSTEM IN THEIR RESPECTIVE COUNTRIES (FRANCE AND GERMANY). Furthermore, TEQUIR will offer SYNIMED and BENTRONIC a preferential opportunity of being the outsourced manufacturers for the final system, always in accordance to standard competitive production costs.
- TEQUIR will commercialize the final StimulAIS System in the remaining potential markets. If BENTRONIC and/or SYNIMED are interested in the commercialization of the Final System in other countries, they may negotiate and reach an agreement with TEQUIR.
- In addition, SYNIMED and BENTRONIC will be able to use the foreground during its particular development in other applications, PROVIDED THAT THESE APPLICATIONS ARE NOT-COMPETITIVE WITH THE FINAL STIMULAIS SYSTEM OBJECT OF THE PRESENT PROJECT.
* ENSURING EXPLOITABILITY OF THE RESULTS ACHIEVED
TEQUIR applied for a patent at national level previous to the project (Patent No. 201230093) with "Moya y Asociados" consultants, and is maintaining this patent at least in Europe. Hence, TEQUIR will own the industrial property of the patent of the medical device.
As summary of the technological report (P5343), "it is excluded the possibility that the invention proposed by the applicant is affected by objections of the novelty."
During the project, Tequir applied to an international patent nº PCT/2013/070004 ("System for treatment of idiopathic scoliosis") in Spanish stage. The applied PCT was reviewed positively in the report. The patent has been extended internationally.
Geographic area covered by the PCT:
- Japan [No. 100094640]
- USA [No.14/3731834]
- Canada [No.P4629CAOO]
- Australia [No.2013213494]
- Europe: The applied PCT/ES2013/070004 has proceeded with the entry into Regional phase to the European Patent Office (EPO) in August, 2014. The corresponding number to this European patent application is: EP13740736.7. The 37 countries designated in this application have been:
Albania, Austria, Belgium, Bulgaria, Croatia, Cyprus, Denmark, Slovakia, Slovenia, Spain, Estonia, Finland, France, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Macedonia, Malta, Monaco, Norway, Netherlands, Poland, Portugal, United Kingdom, Czech Republic, Romania, San Marino, Serbia, Sweden, Switzerland and Turkey.
This process was performed with "ABG patents" consultants.
FUTURE STEPS
As it was pointed out by European Commission, at project assessment, the expectations were high and ambitious. Nevertheless, the high demand of project results has allowed us to get the knowledge of the required development also very high and satisfactory.
This way, despite not having an immediate exploitable system (mainly because of the laboratory non-validated manufacturing process instead of specialized manufacturers of the active implantable medical device), the main initial project aims have already been fulfilled, providing the consortium with VALUABLE EXPERIENCE ABOUT THE COMPLEX INDUSTRIAL AND REGULATORY CONTEXTS OF THE FINAL PRODUCT, for its future development steps.
Hence, StimulAIS system, according with the logical development of an active implantable medical device, NEEDS SOME NEXT STEPS AFTER THE PROJECT ENDS TO BE A FULLY MARKETABLE PRODUCT, as it was already foreseen at proposal stage. According to the outcomes achieved, the continuation of StimulAIS will entail:
1) INDUSTRIAL VALIDATION (through specialized manufacturers). To produce prototypes validated industrially according to all the applying regulatory framework, for CE marking.
It is imperative to fine-tuning manufacturing for up-scaling industrialization, relying on specialized companies in the field of active implantable medical devices that currently manufacture/assembly similar devices such as pacemakers or neurostimulators. Their valuable expertise in this specific and complex sector will help us to succeed in the next development and go closer to market. Tasks to achieve in this development:
- Redesign of the system components for an industrial regulated manufacture.
- Establish the fundamental requirements of the production line of the device.
- Assembly of the production line including acquisition of any necessary manufacturing equipment. Installation Qualification (IQ) and Operation Qualification (OQ) validation.
- Prototypes manufacturing. Performance Qualification (PQ) validation of the device in the established production line.
- Prototypes testing. Homologated testing applicable to neurostimulators in certified/ homologated laboratories.
- Establishment of the Clinical Validation Protocol to be presented to the Clinical Research Ethics Committees.
2) CLINICAL VALIDATION (through Clinical Trials) in order to validate the device for its intended use in humans.
Tequir is currently negotiating with Synimed and Bentronic the possible ways for StimulAIS system continuation:
- Sign agreements for participating in next development steps, sharing the investment
- or wait until the StimulAIS system reaches de market and obtain a commercial advantage in the commercialization in their respective countries (France-Synimed; Germany-Bentronic), according with Consortium Agreement's commercialization rights.
There is work already done in line with next step 1). Project promoter (Tequir) is leading the search for manufacturing and clinical partners who can upwardly scale production towards industrial volumes, mainly able to validate the productive processes, according with the regulatory framework applicable to active implantable medical devices. Next tasks have been carried out in this respect:
1.1. MONITORING OF SPECIALIZED COMPANIES
An intensive search of specialized companies has been already performed, in line with the needs stated previously, in order to look for potential collaboration for the next development steps of the StimulAIS system.
In order to produce a prototype validated industrially, according to all the regulatory framework applicable to active implantable medical devices, able to participate in subsequent clinical trials and rollout into the marketplace (after CE marking), this search is highly relevant. The establishment of a validated production line of the implant is the main objective of this endeavor.
The expertise and know-how of the potential organizations/companies, to be included in a future consortium, because of the value added in different value-chain of the manufacturing/assembly of the StimulAIS system, should be focused on:
- Experienced manufacturers of active implantable medical devices.
- Experienced manufacturers of implantable electrodes and lead wires.
- Certificated and homologated laboratories to perform all the validation testing of the active implantable medical device accordingly to the essential requirements of 93/42/EEC and 90/385/EECDirectives.
- Experience in software development (medical devices).
- Referral Hospital to perform clinical trials.
Three major actions were taken to track this objective:
- DISSEMINATION ON OFFICIAL WEBPAGE: Publication of official ad on Tequir webpage, announcing the current search for medical devices companies experts for consortium’s formation.
- PUBLICATION OF PARTNER REQUEST AT SEIMED PLATFORM: A research development request profile was filled with the requested information in order to build an adequate profile, indicating the detailed information of the partner’s profile that Tequir is seeking. At this date, the draft of the request form was send and we’re waiting for feedback so that the final version can be uploaded and published at SEIMED network platform.
- TEQUIR PRIVATE SEARCH FOR PARTNERS: An independent search was made based on internet, searching for medical devices companies/organizations that met the profile conditions mentioned above.
A total of 20 companies within the EU and with diverse expertise were contacted via email or phone in our private search.
Currently, Tequir has sent NDA to the companies whose expertise and core activity have been assessed to be the most appropriate to the value-chain and a preliminary consortium has been developed.
At this moment we’ve obtained positive response of 6 companies from Germany, Switzerland, Slovenia and Finland, making a total of 30% of partnership positive response. Each one of these companies have a different expertise and field of activity within the medical devices field e.g. manufacturers of active implantable devices including neuromuscular stimulators and pacemakers, manufacturers of electrodes, batteries and lead wires, electronics and software developers, implantable devices telemetry systems experts. After a period of communication to assess their capabilities, we’ve selected 4 companies out of the initial 6 to be part of the primary structure of the consortium, forming the heart of the industrial manufacture and validation of the StimulAIS system.
Adding to this, we’ve already received 12 Expressions Of Interest from the request of co-operation published in SEIMED network platform from different countries as Turkey, Hungary, Macedonia, Ireland, Lithuania and France. Accordingly to the expertise profile presented we’ve already selected 4 out of 12 potential companies to be part of this consortium, mainly for establishing clinical trials in different EU countries which guarantees a wide EU coverage once the clinical trials begin.
With this diversity of positive feedback from different companies with wide expertise, we have the security that we’ll accomplish all the stated criteria of expertise and know-how of the initial partnership requirements for the correct consortium formation for continuation of StimulAIS development.
We go in conversations with potential partners in order to know more information about their manufacturing capacities/facilities so that Tequir can have all the guarantees that the manufacturing of the stated prototype will be performed in validated conditions, and all the requirements will be met.
1.2. H2020 PROPOSAL - FAST TRACK TO INNOVATION
Current and immediate activities related with the preparation of the proposal for continuation of StimulAIS system, under "Fast Track to Innovation" program (cut-off April 29, 2015), with the associated schedule, are shown in the attached pdf for this section (Illustration 3).
* EXPLOITATION STRATEGY AMONG SMES, IN NEXT DEVELOPMENT STEPS
Being aware of the required next steps to be carried out after StimulAIS project ends, in order to validate the StimulAIS system for its intended use in humans, the involved SMEs have long discussed on how to plan the strategy.
Thanks to the current development, we experienced the tough requirements and specific needs for industrializing such a complex device (active implantable medical device) like StimulAIS system is, so we have had to re-focus the stakeholders needed in the value-chain. Hence, other players are needed in the value chain (experienced manufacturer/assembler of pacemakers or neurostimulators), as stated previously. This will allow a securer step towards a product that accomplish all regulatory requirements, because of the inherent expertise in design and testing of this kind of devices.
Tequir, which is the project coordinator, is going to lead and invest in all necessary steps to successfully achieve a marketable product from StimulAIS concept. Tequir will go on as far as it is possible. Nevertheless, some scenarios were proposed, regarding the participation willingness from Synimed and Bentronic in the envisaged pre-market development:
• To support and be fully involved in the next development steps.
• To support partially, through collaboration with Clinical Trial (relevant contacts - hospitals in EU, etc.).
• Other kinds of collaboration (to be specified by Synimed and Bentronic)
• Or keep in stand-by until the product reaches the market, moment when they will obtain the commercial advantages (according to the exploitation rights in the signed Consortium Agreement).
Due to the magnitude impact of this strategic decision, currently, discussions among all three SMEs (Tequir-Bentronic-Synimed) are being performed to this regard.
Tequir will provide specific license agreements, adapted to the answer from Synimed and Bentronic, which will be bi-laterally signed by the involved SMEs.
Potential Impact:
Socio-Economic Impact of the Project
Affected Population: Overall Prevalence of AIS
According to the Scoliosis Research Society (SRS), idiopathic scoliosis is diagnosed when a patient has asymmetry on forward bending combined with a curve of at least 10° [2]. By this definition and accordingly to the literature, the prevalence of adolescent idiopathic scoliosis in children from 10 to 16 years of age is approximately 2% to 3% [1] [3] [4] of which 0.3% to 0.5% have progressive curves requiring treatment [5].
Because scoliosis is not a medical condition that must be reported, the prevalence of this condition is only estimated [1]. For this reason, considering that there are no sufficient epidemiological data in the literature for the prevalence of idiopathic scoliosis in several geographical areas, different studies published recently were analyzed in order to determine if they are consistent with the literature epidemiological data from former years.
Konieczny et al. [6] in 2013, conducted a review of current literature about school screening studies that took place in different countries – Germany, Singapore, Barsil, Korea, Turkey and Grece – with a total of 1,423,390 children screened, showing data of AIS prevalence interval of 0.47-5.2%. This correspond to an estimated mean of 2,8% of AIS prevalence consistent to the literature rate of 2-3%.
Du et al. [7] in 2014 performed a cross-sectional study in Chinese children, to exam if there were any differences between the scoliotic characteristics that could reflect prevalence changes. A total of 6824 children aged from 6 to 17 years old were recruited and the study determined a prevalence rate of idiopathic scoliosis of 2.52%. This represents also a value consistent to the 2-3% prevalence value mentioned previously.
Based on these studies, it seems that the aproxiamte prevalence rate of AIS nowadays is still around 2-3% worldwide with 600.000 visits to private physicians offices in the USA only [8]. Nevertheless it’s important to recognize that the epidemiological data presented maight vary accordingly to genetic, cultural, environmental, social, racial or other differences across the various countries and regions.
Current Available Treatements Inefficacy
Currently there is no cure for AIS. Depending on the curvature progression and clinical evaluation there are different treatments available: conservative treatments as observation, exercise/physiotherapy and bracing for curvatures lesser than 45-50 degrees; and surgical spinal fusion for curves larger than 50 degrees that usually are associated with hight risk of continued worsening throughout adulthood [5].
Brace treatment and observation
In brace treatment’s studies of scoliosis have historically lacked randomized clinical trials. The very nature of this disease is very difficult to blind and randomize, adding the difficulty of being a long treatment process. Published studies about brace treatment efficacy versus observation alone, are observational studies [8], generally of low quality with methodological therefore a high risk of bias.
A Cochrane systematic review of 2010 [10] found insufficient evidence to support the brace usage. Only two items were included in the systematic review: a study comparing two different types of braces [11] and a prospective controlled trial comparing a brace, treatment with Electrical stimulation and observation without intervention, with a foloow-up of 16 years in a subgroup of patients [12].
The authors concluded that “Due to the very low quality of the evidence in favor of bracing, patients and their parents should regard these results with caution and discuss their treatment options with a multi-professional team.”
Most studies used the amount of curve progression measured by the Cobb angle to determine the effectiveness of brace treatment. Some defined success as 5° or less curve progression [12]. The failure of brace treatment is determined when, despite the treatment applied, the patient need to undergo surgery due to curve progression.
Accordingly to literature, the overall surgical rate for failed bracing is approximately 23 percent when used as a treatment for idiopathic scoliosis [14] and in adolescent male patients, bracing had unsuccessful results in 76 percent of the cases, with 46 percent requiring surgery for idiopathic scoliosis [13]. Regarding the untreated patients (non-bracing patients) there is literature rates of surgery incidence varying from from 10 to 38% [9] [15] [16] [17]. This variation could be due to differences in case mix, inconsistent indications for surgery, differences in the quality of the brace and in patient compliance with brace wear, and nonblinded outcome evaluation [5]; nevertheless both rates of braced patient versus observational only doesn’t show a significant difference, supporting the conclusions that bracing doesn’t reduce dramasticly the surgery incidence in adolescent scoliotic patients .
Physiotherapy and physical exercise
As for the physiotherapy and physical exercises treatment, a Cochrane systematic review [18], which included two studies, found low quality evidence from a randomized controlled study [19] that certain specific exercises along with orthopedic treatment may increase the effectiveness of orthopedic treatment. And finds evidence of very low quality from a prospective controlled cohort study, that specific exercises integrated in a program can reduce prescribing orthotics [20] compared with usual physiotherapy. The review Cochrane concluded that there should conduct research of better quality before to recommend the use of specific exercises for scoliosis in clinical practice.
Costs of Current AIS Treatments
Based on the scientif evidences presented above, none of these AIS treatments are effective, and in addition bracing can stop progression but in any case corrects the scoliotic deformity. The consequence of these currently inneffective solutions represent a significant economical impact in the Health System with important level of costs.
Surgery
As for Surgery costs Kamerlink et al. 2010 [21] conducted a retrospective review of 16,536 individual expenses and charges, including overall reimbursements, for 125 consecutive patients who were managed surgically for the treatment of adolescent idiopathic scoliosis by three different surgeons between 2006 and 2007. The mean age of the patients was 15.2 years. Costs ranged from $29,995 to $33,652, averaging $31,832.50 per case. In addition, accordingly to Weinstein et al [5] in the United States in 2009, there were more than 3600 hospital discharges for spinal surgery to correct adolescent idiopathic scoliosis with the total costs of $514 million, ranked second only to apendicitis among children to 10 to 17 years of age.
Bracing
The most common type of scoliosis treatment is Bracing, and it is estimated to be used for 30,000 children in the USA [21] [22]. Considering the statistic data of 85% for adolescent idiopathic scoliosis, the approximate number of children braced for idiopathic scoliosis is 25,500. According to MG Labs, a prosthetic and orthotic lab in New York, the national average cost of a thoracolumbosacral orthosis is $2,100. That places the national USA cost for bracing at over $53 million ($53,550,000) [21]. As for European prices of bracing, we can use the example of the Valencian Community stipulated orthopedic pricing for scoliosis orthotic braces. The most used types of braces used for scoliosis treatment are Boston, Cheneau, Milwauke, with the corresponding prices of 771.25 €, 823.21 €, 822.82 € [23]. Considering a patient that starts a bracing treatment at the age of 10-11, it’s probable that in the following two years the brace has to be renewed every 6 months due to rapid growth of the child, and renewed each year from the age of 13 until it’s reached skeletal maturity. For a patient of 10 years old with a Boston brace this represents a year bracing cost of 1542,5€ in first two years of treatment and 771,25€ each year until bracing removal. Considering 6 years of brace usage (from 10 until 16 years old) this represents a approximate total cost of 6170€ for patient for brace treatment only, not considering the X-rays, MRI, and other medical appointments and physiotherapy sessions that also are necessary.
Revision appointments
The National Scoliosis Foundation estimates that the number of physician visits per year for scoliosis is 600,000 [8]. Again, taking the 85% percent statistic for idiopathic scoliosis, the number of physician visits would have an approximate value of 510,000 visits per year. Omitting X-rays, MRIs and other required services for scoliosis, the average cost for a doctor's visit is conservatively $100, averaging both primary and specialist care. This would put the national USA price tag of hospital visit cost in $51 million. If it is considered the cost of each complementary exams that need to be done to assess the curvature progression each year, as the above mention X-rays, this overall cost is significantly increased.
StimulAIS system finds a niche in the treatment of adolescent idiopathic scoliosis by muscular electro-stimulation of the paraspinal deep rotator muscles. This system will be capable not only of stopping progression of curvature, but also to potentially correcting it. This represents a strong differentiation in AIS treatment, since it will avoid all the side effects of the actual conservative and spinal fusion treatments, but also reducing dramatically the actual costs of Health Systems derived of the current ineffective AIS treatments.
A summary of current available solutions with associated costs and potential advantages of StimulAIS system over all of them is provided in the following table:
Current treatments Costs (estimated values) Limitations StimulAIS expectations
Conservative Observation N/D A high number of curves progress and require bracing and/or invasive surgery Restorative, avoids invasive fusion surgery and bracing
Exercise and physiotherapy N/D No conclusive evidences of its effectiveness Restorative, avoids invasive fusion surgery and bracing.
Focused treatment and auto-regulation of stimulus
Bracing Cost of $53 million in the USA per year plus $51 million for the associated revision appointments to the physician making an estimated total cost: $104 million/year - No permanent correction of curvature
- Functional discomfort
- Leads to psychosocial and body image concerns
- Restriction of movement
- Ineffective in overweight patient ( and leads to increase progression)
- Ineffective to most cervithoracic curves and curves greater than 40 degrees
- Final surgical rate similar to non-braced
- Active correction of curvature. Not only stop progression, but also potentially correct the curvature
- No discomfort
- Low obtuseness (implanted subcutaneously)
- No restriction movement
- Effectiveness not dependant on patient weight
- Applicable on most AIS curve locations with less exclusion criteria than bracing
- Effective, avoids surgery
Non-conservative Surgical fusion treatment Cost of $31,832.50 per surgery/patient with a total of total cost of $514 million a year (USA) - Invasive
- Spinal fusion
- High risk of complications (infection, hardware breakage, pseudoarthrosis, nerve damage and sexual dysfunction) - Minimally invasive technique
- Motion preserving
- Low risk complications
Dissemination activities
Multiple dissemination activities were carried out during the project, aiming for internal diffusion of information among the partners of the consortium as well as external diffusion of StimulAIS device into the technical, clinical and scientific community. Please note that all dissemination material produced by the StimulAIS consortium included the official logo.
The main dissemination activities include:
- Web portal: a project website was created, including a restricted area where only the consortium members and EC Project Officer have access, containing among other information, documentation regarding the status of the project such as reports, pictures, presentations and results.
- Brochures: designed brochures containing the main information in English about the project, in order to inform the scientific and medical community, patients and potential users about the results of the project.
- Video: production of a video containing a short description of the project and its objectives and focused on the advantages of its clinical use.
- Participation in conferences and trade fairs:
o World of MEDICA Düsseldorf (Germany), November 2014
o Silicon Saxony (Germany), December 2013
o Sociedad de Estudios de Enfermedades del Raquis GEER XXVII (Spain), May 2013
o 8th World Combined Meeting of Orthopaedic Research Societies (Italy), October 2013
o Asociación Española de Investigación en Cirugía Ortopédica IVESCOT X (Spain), February 2014
- Publication in magazines with European Impact (>53.00 subscribers in EU):
o Article Published in Science, Technology and Innovation Projects (Insight Publishers).
- Publication in Specialized Journal (EU and worldwide)
o Abstract publication in Bone & Joint Surgery, Journal Orthopedic Proceedings Supplement
- Press Releases:
o Ruvid
o ABC newspaper
o Canarias7 newspaper
o Crónica de Cantabria
o Diario Siglo XXI newspaper
o El Confidencial newspaper
o El Día newspaper
o Europa Press
o Gente Digital
o Heraldo newspaper
o Telecinco web
o La información
o La Razón newspaper
o Las Provincias
o La Vanguardia
o Te Interesa web
o Yahoo Noticias web
o Diario de Pontevedra
o El Progreso
o Levante EMV
o AlphaGalileo
Exploitation plan
Being aware of the required next steps to be carried out after StimulAIS project end, as device validation for its intended use in humans, the involved SMEs have long discussed on how to plan the exploitation strategy.
Thanks to the current development, though requirements and specific need for industrializing a complex device as StimulAIS were experienced, leading to re-focus the stakeholders needed in the value-chain, seeking for experienced manufacturers/assemblers of pacemakers and neurostimulators. This will allow a securer step towards the product that accomplishes all regulatory requirements, due to their inherent expertise in design, manufacture and testing of these kind of devices.
Tequir, being the project coordinator, will lead and invest all the necessary steps to successfully achieve a marketable product from StimulAIS concept. These actions include:
• Ensuring exploitability of the results achieved. Tequir applied for a patent (No. 201230093) previous to the project (Europe), owing the industrial property of the patent of the medical device; and for a international patent No PCT/2013/070004 “System for treatment of idiopathic scoliosis” which have been extended internationally at Europe, Japan, USA, Canada and Australia. In addition, there is no business agreements, laws or market blockings, which may impose limitations on the subsequent exploitation.
• Monitoring specialized companies. An intensive search of specialized companies has been performed in order to look for potential collaboration for StimulAIS next development steps, which include manufacturing an industrially validated prototype according to regulatory framework of active implantable medical devices, in order to participate in subsequent clinical trials, achieve CE marking and rollout into the marketplace.
• Making contact with selected specialized companies. A total of 20 companies whitihn the EU and with diverse expertise were contacted via email or phone. At the present moment we’ve obtained positive response of companies from Germany, Slovenia and Finland, making a total of 30% of partnership positive response. Each one of these companies have a different expertise and activity field, allowing us to form a well established complementary co-operation. As we anticipate to receive more confirmations soon, this value of positive feedbacks expected to rise at least up to 50%, guarantying that we’ll accomplish the seek criteria of expertise and know-how that will allow us to continue the next development steps of StimulAIS project towards placing it in the market.
• Rising Awareness among general public and clinical community (bottom-up demand). After the project end, and while developing the next needed steps, our clinical group (UCV) will train their closer circle of experts in scoliosis, with detail training protocol on the use of StimulAIS system as well as the surgical technique, thus generating other training groups, leading to a quick diffusion of knowledge.
• Place the device on the market. The exploitation of StimulAIS system, when it’s market-available, will be mainly carried out in public and high quality private healthcare hospitals. The introduction in the private sector will require shorter time, as there is no need to wait for the admission to the competitions that regulate the provisions in the public health system. Several strategies are being taken into consideration in order to achieve prescription endorsement.
• Well established distribution networks. In order to introduce the new device through Europe and emerging markets, is needed to have a solid distribution network. Distribution will start from Spain, Portugal, France and Germany, which are the countries that will be potentially involved in the multicenter clinical trials short-term. This will allow an immediate access to their markets, adding the wide distribution network of the consortium SMEs (Synimed, Bentronic and Tequir) with more than 100 countries in Europe, Central and South America and Asia.
References
[1] SRS, "Scoliosis Reaserch Society," 2015. [Online]. Available: http://www.srs.org/professionals/glossary/SRS_revised_glossary_of_terms.htm. [Accessed 02 2015].
[2] S. Anderson, "Spinal Curves and Scoliosis," Radiologic Technology, vol. 79, no. 1, pp. 44-65, 2007.
[3] M. Lenssinck, A. Frijlink, M. Berger, S. Bierma-Zeinstra, K. Verkerk and A. Verhagen, "Effect of Bracing and Other Conservative Interventions ion the Treatment of Idiopathic Scoliosis in Adolescents: A Systematic Review of Clinical Trials," Journal, vol. 85, pp. 1329-1339, 2005.
[4] T. Kotwicki, J. Chowanska, E. Kinel, D. Czaprowski, M. Tamaszewski and P. Janusz, "Optimal management of idiopathic scoliosis in adolescence," Adolescent Health, Medicne and Therapeutics, pp. 59-73, 2013.
[5] S. Weinstein, L. Dolan, J. Wright and M. Dobbs, "Effects of bracing in adolescents with idiopathic scoliosis," The New Engalnd Journal of Medicine, pp. 1-10, 2013.
[6] M. Konieczny, H. Senyurt and R. Krauspe, "Epidemiology of adolescent idiopathic scoliosis," Journal of Children Orthopaedics, vol. 7, pp. 3-9, 2013.
[7] Q. Du, S. Negrimi, X. Zhou, X. He, J. Li, L. Zhao and P. Chen, "Scoliosis epidemiology is not all the same all around the world: a study from a scoliosis school screening in the island of Chongming, China," in 11th International Conference on Conservative Management of Spinal Deformities, Wiesbaden, Germany, 2014.
[8] N. S. Foundation, "National Scoliosis Foundation," n.d. [Online]. Available: http://www.scoliosis.org/info.php. [Accessed 02 2015].
[9] A. Danielsson, R. Hasseriuus, A. Ohlin and A. Nachemson, "A prospective study of brace treatment versus observation alone in adolescent idiopathic scoliosis: a follow-up mean of 16 years after maturity," Spine, vol. 32, no. 20, pp. 2198-207, 2007.
[10] S. Negrini, S. Minozzi, J. Bettany-Saltikov, F. Zaina, N. Chockalingam and T. Grivas, "Braces for idiopathic scoliosis in adolescents.," Cochrane database Systematic Review, vol. 1, no. CD006850, 2010.
[11] M. Wong, J. Cheng, T. Lam, N. B, S. Sin and S. Lee-Shum, "The effect of rigid versus flexible spinal orthosis on the critical efficacy and acceptance of the patients with adolescent idiopathic scoliosis," Spine, vol. 33, no. 12, pp. 1360-5, 2008.
[12] A. Nachemson and L. Peterson, "Effectiveness of treatment with a brace in girls who have adolescent idiopathic scoliosis. A prospective, controlled study based on data from the Brace Study of the Scoliosis Research Society," Journal of Bone and Joint Surgery Am., vol. 77, no. 6, pp. 815-22, 1995.
[13] E. Lou, D. Hill, M. J, M. Moreau and J. Raso, "An objective measurement of brace usage for the treatment of adolescent idiopathic scoliosis," Medical Engineering and Physics, vol. 33, no. 3, pp. 290-294, 2010.
[14] L. Dolan and S. Weinstein, "Surgical rates after observation and bracing for adolescent idiopathic scolisis: an evidence-based review. (Abstract)," Spine , vol. 32, no. 19S, pp. S91-S100, 2007.
[15] R. Fernandez-Feliberti, J. Flynn, N. Ramirez, M. Trautmann and M. Alegria, "Effectivenness of TLSO bracing in the conservative treatment of idiopathic scoliosis," Journal of Pediathric Orthopaedics, vol. 15, pp. 176-81, 1995.
[16] C. Goldberg, D. FE, H. JE and J. Emans, "A statistical comparision between natural history of idiopathic scoliosis and brace treatment in skeletally immature adolescent girls," Spine, vol. 18, pp. 902-8, 1993.
[17] C. Goldberg, D. Moore, E. Fogarty and F. Dowling, "Adolescent idiopathic scoliosis: the effect of brace treatment on the incidence of surgery," Spine, vol. 26, pp. 42-7, 2001.
[18] M. Romano, S. Minozzi, J. Bettany-Saltikov, F. Zaina, N. Chokalingam and T. Kotwicki, "Exercises for adolescent idiopathic scoliosis," Cochrane Datyabase System Review, vol. 8, no. CD007837, 2012.
[19] S. Negrini, F. Zaina, R. M, A. Negrini and S. Parzini, "Specific exercises reduce brace prescription in adolescent idiopathic scoliosis: a prospective controlled cohort study with worst-case analysis," Journalk of Rehabilitation Medicine, vol. 40, no. 6, pp. 451-5, 2008.
[20] W. Wan Li, "Results of exercise therapy in treatment of essentially S-shaped scoliosis patients: Evaluation of Cobbs angle in the breast and lumbar segment," Chinese J Clin Rehabili, vol. 9, no. 34, pp. 82-4, 2005.
[21] J. Kamerlink, M. Quirno, J. Auerbach, A. Milby, L. Windsro, L. Dean, J. Dryer, T. Errico and B. Lonner, "Hospital Cost Analysis od adolescent idiopathic scolisis correction surgery in 125 consecutive cases," The Journal of Bone and Joint Surgery, vol. 95, no. 5, pp. 1097-1104, 05 2010.
[22] M. Studin, "Chiropractic vs Medical Management of scoliosis Let's look at the numbers," Dynamic Chripractic, vol. 30, no. 22, 2012.
[23] G. Valenciana, "Catalogo de articulos de Exoprótesis," in 060309 - Ortesis Dorso-Liumbo-Sacras, 2012.
List of Websites:
www.stimulais.com
Polígono Industrial El Oliveral, C/C, s/n
CP. 46190 Ribarroja del Turia (Valencia), SPAIN
Telf: +00 34 961 668 795
Fax: +00 34 961 668 889
Contact persons: Álvaro Alonso, Magdalena Bresó
Email: info@tequir.com
Email: magdabreso@tequir.com
Web: www.tequir.com
