Who are our proposed end users?
In order to tailor our project design to the needs of our customers, we had to set out and identify several parameters such as who our stakeholders were. Our initial response to who our proposed end users and stakeholders would be were SCI patients and also the surgeons implanting our medical device. We also identified researchers in the field of spinal cord injuries, bioengineering and mussel foot proteins as other potential stakeholders whose insight could benefit our product. We decided to attend a SCI cafe hosted by Spinal Injury Society (SIA) to talk to patients about their struggle in an ethical way without giving a false sense of hope; from this, we quickly realised that another stakeholder would be the patient’s carers as the success of our device would also have a direct impact on them. Furthermore, we also arranged meetings with specialists in regulatory pathways such as Travis Schallapi and Jim Sterling who helped us realise that stakeholders also include insurance companies (and private hospitals) and public health bodies (such as the NHS) who would be paying for our product. After reviewing our notes from the following meetings, we came to the conclusion that our final users would be the SCI patients, however, our proposed facilitators of our treatment would be surgeons. We only intend for our scaffold to be used for patients with serious chronic cervical SCIs that will result in quadriplegia and tetraplegia; our hope is that the scaffold will promote axonal regeneration, thus reconnecting the severed axons, and potentially restore some function. We would advise patients with less serious SCI to seek less invasive therapies and currently approved treatments that focuses primarily on preventing further injury and establishing a routine which enables the patient to live with their injury. Presently, there are no licensed treatments that serve to reverse the damage to the spinal cord.
How do you envision others using your project?
Just like how existing proteins are reengineered and given a new purpose in synthetic biology, we envision others redesigning, repurposing and reengineering our mussel foot protein bioadhesive covered scaffold for spinal cord injuries. Our project comprises two different parts, the bioadhesive polymer and the scaffold, each of which can be further broken down into subparts which can all be reengineered for other applications. Another way in which we hope our project can be used is through the adaptation and modification of our cysteinyl-dopa crosslinking polymerisation protocol in order to create other protein based bioadhesives for other clinical applications such as wound dressings for trauma surgery and everyday use or ligament repair in sports injuries. Furthermore, our protocol for using iGAM that we will develop in phase 2 of the project, to model mutagenesis studies could also be adapted by other iGEM groups in order to simulate their mutations. Finally, there is also currently a lack of literature surrounding repairing SCI with bioadhesive covered scaffolds - we hope the work we have done will attract more interest in this field of synthetic biology.
How would you implement your project in the real world?
A patent is a type of intellectual property (IP) for technological inventions. Intellectual property is used to prevent anyone within a specific country for a length of time to use the patented invention for commercial purposes ( EPO - Home , n.d.). To develop our project, we must first protect our invention in order to give us a competitive advantage over similar products and protect our unique selling point.
At present, in the UK, we must follow European law and UK national laws when certifying our product. In the EU there is no medical device agency like in the US (FDA), instead the manufacturers are the ones that declare conformity by filling out a conformity assessment procedure to obtain the CE marking. However, such procedure must be accompanied by an annex certificate and depending on the class of the device, may need to be assessed by a notified body. We used the criteria found in annex VIII of the Medical Device Regulations (MDR) (Regulation (EU) 2017/745) to classify our scaffold. In our case, the scaffold is a class III medical device (surgically invasive device which will be used in direct contact with the central nervous system) and will therefore require a notified body to carry out an audit for our device using the procedures from the MDR. Notified bodies will assess technical documentation and evaluate our own quality management system. Aside from issuing annex certificates, notified bodies will also issue ISO 13485 certificates when the quality management has been approved. The technical documentation that needs to be compiled is found in annex I of the MDR and Harmonised Standards should be used as guidance to complete the documentation (Johner Institute, n.d.) (Manufacturers - Internal Market, Industry, Entrepreneurship and SMEs - European Commission, n.d.). Our detailed CE certification process is in the Entrepreneurship page.
Using the New Approach to Notified and Designated Organisms (NANDO) we identified two notified bodies in the UK for our specific project which could carry out our assessment:
However BSI Assurance UK Ltd seems to be the most appropriate since it uses the Regulation (EU) 2017/745 for medical devices while SGS United Kingdom Limited only uses the 93/42/EEC for Medical Devices legislation, which is not the up to date legislative document for medical devices (EUROPA - European Commission - Notification Body BSI Assurance UK Ltd, n.d.) (EUROPA - European Commission - Notification Body SGS United Kingdom Limited, n.d.).
Clinical investigation is a crucial part of being able to place our device on the market. Clinical trials are intended to prove the device we have developed serves its purpose well, is safe to be used and that any involved risk is documented and ways to mitigate it are investigated. When planning the clinical investigation it is important to refer to annex XV of the MDR which dictates a set of requirements for the clinical investigations. For a project like Renervate which requires a high level assurance of safety and functionality of the product, the most time consuming and expensive part of the development tends to be the clinical investigation. A report of our current plan to tackle the clinical investigations can be found in the Entrepreneurship page.
What are the safety aspects you would need to consider?
Safety of Pvfp-5β
In order to ensure that our product would be fit for use in humans, we had to consider several safety aspects and precautions we had to take. We took the safety aspect of immunogenicity into consideration during our design process. We decided to use the beta isoform of Pvfp-5 for our bioadhesive as it has been shown to not elicit any immune response in a previous study. We also plan on conducting immunogenicity studies of our protein, however, due to COVID we were unable to access the labs - we have therefore planned to conduct immunogenicity studies in phase 2 of our project. We also thoroughly researched several purification methods such as His-tag purification, Ni-NTA systems and streptavidin purification, that would ensure our end product is 100% pure and that there will be no contaminants in our bioadhesive. Furthermore, the mussel foot protein team also tried to study the consequences of mutating our protein by collaborating with a previous iGEM team that developed the software iGAM. The mussel foot protein team has done the preliminary research and will be conducting further mutagenesis studies in phase 2 of our project.
Sterility is also an issue that must be tackled in our project since we must ensure patient safety. We were able to discuss this topic in a meeting with Dr Rachel Sparks. We discussed that in cases where the device is autoclavable (a device that is able to be autoclaved, which is a process by which an object is sterilised using elevated pressure and heat) there are companies that will test your device by autoclaving it and then taking a CT (computed tomography) scan of your device to ensure the device is still intact and that your packaging has not been compromised by autoclaving it. These companies will also provide a certificate which will be essential in proving the sterility of your product when applying for the CE certification. PLC, however, is not autoclavable due to its low melting point and we will therefore need to prove that the production facility is sterile. These facilities are called sterile manufacturing facilities and the facility as well as the protocols set up in it must follow the Good Manufacturing Practices (GMP) set by the MHRA and the European Medicines Agency (EMA) (Good manufacturing practice and good distribution practice, n.d.). King’s College London is currently building its own sterile manufacturing facility. We plan on discussing the considerations and specific requirements the sterile manufacturing facility would have to follow to produce our scaffold with the experts in charge of the King’s College London facility.
When we discussed the safety of our device with Dr Rachel Sparks, she suggested we use the Manufacturer and User Device Experience (MAUDE) database, which is a registry of issues arising from medical devices in the USA. Using MAUDE, we were able to find devices with similar properties or functions to ours and find issues that their manufacturers or patients have had with them. This in turn would help us identify safety issues that we could focus on during the clinical trials to find ways to mitigate them. A list of the reports we found along with a description of the safety issues can be found on the Entrepreneurship page.
Maximum dimensions of scaffold
The spine is a very flexible area of the body which can bend in multiple directions, therefore a safety concern is the maximum size of the implant so that if the patient moves it does not further damage the surrounding tissue. The rigidity of the scaffold is a factor that was considered when selecting the material, and we aimed to use a material with similar properties to the spinal cord which was elastic enough not to fracture with deformations of the spine. Find more details about our selection of properties in the Scaffold Requirements section of the Scaffold Design page. Nonetheless, the spinal cord is a very fragile tissue and we must ensure it is not further damaged. The first thing to consider is that patients who will receive our treatment will be bed bound for long periods of time and if not, they will probably have limited mobility. However, involuntary movements such as a fall or when being moved by carers, could cause the patient to bend their backs. To ensure that such a movement does not damage the spinal cord tissues on the edges of the scaffold, due to its rigidity, a set of maximum dimensions for the scaffold will have to be determined. This is among the simulations that we plan on carrying out during phase 2 of our project to determine the maximum size of the implant.
What other challenges would you need to consider?
In our meeting with Dr Travis Schlappi, we realised that our personalised approach (printing a scaffold specific to a patient’s injury and cyst size) could be problematic for the scaling up of our project. We came to the conclusion that we could not use injection moulding; which is currently used to mass manufacture 3D printed diagnostic devices, due to the fact that it does not allow for personalisation. Nonetheless we would still be able to scale up the MFP production. Furthermore, with the growing accessibility and demand for 3D printers we could explore the possibility of expanding through a different business model. Scaling up our project to become international would imply that we would need to protect our product in all other countries where we operate in (patents), as well as obtaining approval of the country’s independent regulatory bodies. A good way to ensure recognition of quality and safety of our project worldwide would be to obtain FDA approval along with Pharmaceuticals and Medical Devices Agency (PMDA) approval, since they are highly recognised.
We also discussed the ways in which we could test a product without the standard phase 1-4 clinical trial as it would be very unethical to implant our scaffold into a healthy person’s spinal cord or to treat patients with placebo surgery. Therefore, we will have to test the safety and efficacy of our scaffold using public data about SCI patient recovery as our control group and consenting SCI patients as our trial group.
We are making a conscious effort to ensure that the product we create is made of environmentally friendly materials. PCL is a type of biodegradable plastic, therefore aside from the intended bioabsorbable property that it will exhibit once it is implanted, any faulty print as well as excess material can be discarded easily. The downside of PCL is that typically its production is not the most eco-friendly commonly due to the use of metal catalysts which are toxic. To reduce Renervate’s environmental impact we plan on using PCL that has been produced in an environmentally friendly manner such as the method described in the paper “Sustainable synthesis and precise characterisation of bio-based star polycaprolactone synthesised with a metal catalyst and with lipase” (Baheti et al., 2018) which even though it uses a metal catalyst it is more ecofriendly than other methods.
The environmental impact of our MFP would also have to be considered, because even though the protein on its own is 100% biodegradable, the procedure can be quite polluting due to the large amount of plastics and chemicals used in the lab. A detailed study of our lab protocols during phase 2 will help us decide where we might be able to reduce our environmental impact through the use of alternative materials for the MFP production.
- Ec.europa.eu. n.d. EUROPA - European Commission - Notification Body BSI Assurance UK Ltd. Available at: (https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=notifiedbody.notifiedbody&refe_cd=EPOS%5F43408) Accessed 10 September 2020.
- Ec.europa.eu. n.d. EUROPA - European Commission - Notification Body SGS United Kingdom Limited. Available at: (https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=notifiedbody.notifiedbody&refe_cd=EPOS%5F43442) Accessed 10 September 2020.
- European Patent Office (EPO) (https://www.epo.org/) Accessed 16 October 2020
- GOV.UK. n.d. Good Manufacturing Practice And Good Distribution Practice. Available at: (https://www.gov.uk/guidance/good-manufacturing-practice-and-good-distribution-practice) Accessed 21 October 2020.
- GOV.UK. n.d. Regulating Medical Devices From 1 January 2021. Available at: (https://www.gov.uk/guidance/regulating-medical-devices-from-1-january-2021#CE) Accessed 21 October 2020.
- Internal Market, Industry, Entrepreneurship and SMEs - European Commission. n.d. Manufacturers - Internal Market, Industry, Entrepreneurship And Smes - European Commission. Available at: (https://ec.europa.eu/growth/single-market/ce-marking/manufacturers) Accessed 20 August 2020.
- Johner Institute, “Starter-Kit: How To Quickly, Easily And Safely Master The Medical Device Approval Process” (https://www.johner-institute.com/starter-kit/) accessed October 2020.
- Baheti, P., Gimello, O., Bouilhac, C., Lacroix-Desmazes, P. and Howdle, S., 2018. Sustainable synthesis and precise characterisation of bio-based star polycaprolactone synthesised with a metal catalyst and with lipase. Polymer Chemistry, 9(47), pp.5594-5607.
- Krebs, J., Koch, H., Hartmann, K. The characteristics of posttraumatic syringomyelia. Spinal Cord 2016 ; 54: 463–466.