This year we completed research into the implementation of our therapeutic device within a clinical setting. We have assessed different risk mitigations, challenges and identified our proposed end users. Our work on proposed implementation has provided a concrete foundation for our Entrepreneurship research, found here.
Figure 1: Our three primary proposed end groups are spinal cord injury patients, NHS and charities and Biomedical Companies
There are currently 50, 000 spinal cord injury patients in the UK, with approximately 2500-3500 new cases being diagnosed annually (Song et al., 2019). Our treatment is therefore targeted towards these individuals with injury to the thoracic region of the spine, the reasoning is discussed in more detail on our project design page.
The target age for our treatment is the adult population defined as those aged over 18 years of age. SCI in children is unique because the spinal cord continues to grow as the individual develops into their adolescence (Escobar et al., 2011). This makes the addition of a rigid scaffold a difficult task, as the spinal cord remains dynamic post injury. However, the majority of individuals affected by spinal cord injury are adults, allowing our treatment to reach the majority of the demographic until further research and development (Song et al., 2019).
Our initial pool of patients under Renervate Therapeutics will likely be residents of the United Kingdom (UK) as this is where our therapeutic can make the most impact in its initial phases. The ‘National Health Service’ (NHS) constitutes the UK’s largest healthcare provider, highlighting them as an essential stakeholder and end-user of our therapeutic. The NHS is constructed by various Trusts which serve specific geographical areas or specialised functions (NHS Providers, 2015). Each Trust has their own medical device management policy, but all follow guidance set out by the Medicines and Healthcare products Regulatory Agency (MHRA), Care Quality Commission (CQC), and NHS Resolution.
Our proposed end users include the many doctors which make up the services provided by the NHS. As indicated by a 2020 survey carried out for clinicians in both the UK and the US, there is an openness to and increased awareness concerning the importance of implementing medical devices across various specialties. Some of the most commonplace devices include injectors and inhalers, which facilitate the delivery of drugs to patients. From the perspective of patients, these can offer convenience of use, consequently enhancing adherence to medication regimes and, from the view of doctors, medical devices can play a hand in prescription decisions with varying importance depending upon the condition, facilitating medical professionals ability to provide fast and effective treatments (Team Consulting, 2020).
Outside of the NHS, the UK is home to a variety of spinal cord injury (SCI) charities, providing support to patients and families, accessible housing and assistive technology, rehabilitation and funding for life-improving medical devices (UKSSB, 2021). Among these charities are research organisations including Spinal Research and the National Institute for Health Research (NIHR), which provide grants for research projects into SCI (National Institute for Health Research, 2021; Spinal Research, 2021). In particular, the NIHR provides support for medical devices, digital technology and diagnostic companies (MedTech) to help put novel ideas into practice (NIHR, 2021). Partnering with such organisations could have unique benefits for Renervate Therapeutics. Having researched and designed a therapy for SCI, our next step would be to begin marketing our treatment towards SCI patients. Charities have a thorough understanding of patient needs, and could thereby provide assistance in efficiently bringing our therapy to patients and wider communities, and increase sales (AMRC, 2019).
Biomedical and Therapeutics companies play a significant role in our project and are an additional end-user of our product. Invivo therapeutics (Keown, 2021) is a company based in Massachusetts working with biodegradable neuro-scaffolds that promote neuronal recovery following SCI. The project named “Inspire” was successful in providing stability to the injured cord and promoting functional and sensory recovery (Kim, 2021). They are already in the process of enrolling patients for a second pivotal clinical study. Other companies working on SCI research include:
These companies may benefit from distributing our project, partnering with Renervate Therapeutics or acquiring one of the components of our project. These companies are only a small example of potential partnerships, demonstrating the reach, flexibility and collaborative potential of our project. After detailed research on combinatorial approaches, focusing on growth factors and other growth permitting drugs, we have specified all the potential combinations that can be implemented alongside our project. To review different combinatorial approaches you can observe Table 1 on the SCI Biochemistry page. This serves as a reference for reaching out to companies working on such products and forming future collaborations.
Our treatment plan consists of a combination of different parts that are in itself valuable for medical applications. The different parts are:
We can therefore market these different parts composing our overall therapy to the companies mentioned through combination of different elements and research, a more holistic treatment for spinal cord injury can be created.
Furthermore, we aim to target medical device companies such as Medtronics whose values are to contribute towards human welfare by the application of biomedical engineering to alleviate pain, restore health and extend life. Our proposed scaffold; having the purpose of restoring motor function and giving patients a better quality of life, has great potential for collaborating with such biomedical companies.
Medtronics, alongside companies such as Saluda Medical (Mekhail et al., 2020), are creating closed-loop chronic pain therapies that optimise pain relief in SCI patients, allowing for the completion of rehabilitation exercises and reducing pain. A partnership with SCS (spinal cord stimulation) systems or other therapies whose goals are to reduce chronic pain in SCI patients - allowing for a better patient quality of life - would be complementary to our therapy’s long term goal of decreasing the consequences of SCIs. Collaborations of this type are extremely important because chronic pain affects around 70% of SCI patients (Hadjipavlou, Cortese and Ramaswamy, 2016) and SCSs could be beneficial for Renervate Therapeutics by stimulating the spinal cord injury site after the implantation of our therapy, allowing for potential motor recovery from our therapy aided by the stimulation device, leading to reduced pain and allowing for more rigorous rehabilitation protocols.
Companies that work with bioadhesives or MFP hydrogels such as natureglue, would also benefit from using our fully characterised MFP for implementation in the SCI.
Our therapy and the parts developed have multiple potentials as shown above, it is also worth mentioning its applications in veterinary practices, dentistry and other therapeutic approaches such as bone/organ repair/regeneration.
We at Renervate Therapeutics have developed a novel mussel foot protein (PVFP-5), optimised for expression in E. coli . With the sequence readily available as a biobrick on the iGEM registry, any laboratory with access to this strain of bacteria can utilize our protein. PVFP-5 has shown minimal cytotoxic and immunogenic activity in vitro (Santonocito et al., 2019) and as such, shows great promise in the biomedical research field. We envision researchers synthesizing and utilizing our proteins in a wide range of biomedical experiments as a non-reactive adhesive, posing minimal risk to scientists and being disposed of easily.
The ability of our protein to bind to PCL in the spinal environment opens the door to a wide range of applications of PVFP-5 in the medical field. Research has already been conducted on l-3,4-dihydroxyphenylalanine (L-DOPA) based polymers that use the same L-DOPA groups as PVFP-5 in adhesion in scenarios ranging from wound closure (Jeong et al., 2011), to pancreatic islet transplantation (Mehdizadeh et al., 2012).Despite our focus towards the applications of PVFP-5 within the spinal cord, in the future we envision others using our project as a foundation to investigate the potential of PVFP-5 in the development of other treatments.
ChABC is an enzyme derived from Proteus vulgaris that has the ability to evoke axonal regeneration, neuroplasticity and neuroprotection, leading to functional recovery through the degradation of CSPGs (see SCI Biochemistry) (Fawcett, 2015). During our research, we discovered some challenges of conducting studies to investigate the therapeutic effects of ChABC in-vivo, namely its thermal instability at physiological temperature and difficulties in delivery. To resolve this issue, we have computationally thermostabilised ChABC (see Modelling). These improved characteristics of ChABC would provide useful insights in maximizing ChABC-mediated effects, understanding its working mechanism and pharmacokinetics when implemented in in-vivo studies investigating the therapeutic effect of ChABC in peripheral and central nervous system disorders.
Upon collaboration with biotechnology companies, the therapeutic potential of our thermostabilized ChABC can be exploited in combinatorial approaches with other agents, for instance stem cells and or growth factors synergistically in above medical conditions.
Chondroitin sulphate proteoglycans (CSPGs) are present in the extracellular matrix (ECM) of various central nervous system (CNS) and peripheral nervous system (PNS) disorders. In the CNS, the upregulation of CSPGs in the CNS of neurodegenerative diseases, CNS injuries and SCI lesions limit axonal regeneration and functional recovery (Fawcett, 2015).
In CNS disorders, ChABC has been shown to possess the potential to improve memory plasticity and retention in Alzheimer's disorder, promote forelimb sensorimotor recovery after ischemic stroke, increase visual cortex plasticity and visual acuity in monocular damage (Soleman et al., 2013). ChABC has also been demonstrated to encourage myelination in multiple sclerosis and direct rewiring of network and homeostatic plasticity to prevent epileptic seizures (Fawcett, 2015).
Figure 2: Depicting the applications of ChABC beyond spinal cord injury. The ability of ChABC to break down the extracellular matrix lends it to a wide range of therepeutic applications.
In the PNS, ChABC contributed to the repair of the sciatic nerve gap in rats (Wang et al., 2011). After myocardial infarction, CSPGs prevent sympathetic reinnervation of the cardiac scar following ischemia-reperfusion resulting from myocardial infarction. With similar cellular constituents to a glial scar, ChABC could restore axon regeneration and reinnervation on the cardiac scar, which may improve myocytes functional contraction (Gardner and Habecker, 2013).
As all the above studies were conducted in animal models - the potential of the use of ChABC in veterinary medicine could be considered in all cases above, particularly useful in injured animals with SCI due to trauma or infarction.
Renervate Therapeutics is providing a novel treatment to treat spinal cord injury. This therapy is composed of a 3D printed polycaprolactone (PCL) scaffold coated with a layer of Pvfp-5 as a bioadhesive. We plan to personalise the scaffold to the patient by taking MRI images of the lesion and adjust the design accordingly. This will then be 3D printed at “super hospitals'' (a mega-medical centre) located across the UK. The PCL used will be provided by 3D4Makers PCL 100, of size 1.75mm. PCL 100 is frequently used for scaffolds, implants, hydrogels, tissue engineering, and drug delivery. After printing, they will be distributed to the required hospital whilst following the Standard Operating Procedure 5 (SOP 5), Transportation of Medical Devices (Yorkshire Hospital Service., 2018). The SOPs are a set of protocols aiming to issue a system that oversees the transportation of medical devices, predominantly for the staff as well as those who use medical devices in their profession, to establish effective and safe healthcare.
From speaking with Dr Byeong Seon Yang, we identified a major difficulty in the mass production of MFPs. Multiple papers discuss these difficulties and attribute them to the highly biased amino acid composition, codon usage preference and the small amount of MFP obtained from each culture (Hwang et al., 2004). This is likely linked with the adhesive nature of these proteins, which Dr Yang discussed becomes trapped within elution columns. With this, we decided to begin researching the ease in which we could implement our adhesive in our complete treatment, alongside the scaffold and ChABC.
The amounts we obtained from our laboratory experiments didn’t match those observed in recent literature (Santonocito et al., 2019) of roughly 50-100mg per litre of culture as stated by Dr Yang. However, he also stressed that medical devices usually require a significantly greater amount of MFP, reaching around the gram scale.
Following this, we began to evaluate the amount of MFP required for a sample scaffold. We based our preliminary calculations off of Cell-Tak™, a commercially sold polyphenolic adhesive of proteins harvested from the exocrine phenol glands of Mytilus edulis. Using the recommended density of 3.5μg cm² highlighted in the product specification sheet and a sample scaffold surface area of 122.67925 cm², we identified that 0.43mg of MFP (assuming the Cell-Tak™ formulation was 100% MFP) would be required. However, to provide a more accurate account for the amount of PVFP-5 required, we developed a model which predicts the amount of MFP molecules by extrapolating values from the dimensions of the scaffold and PVFP-5 protein units. Unfortunately, as we were unable to gather a value for the amount of PVFP-5 we could produce for a specific cost with our limited laboratory time, we utilised the values taken for Cell-Tak™ mentioned previously. The documentation and evaluation for this can be found on our Business Plan.
We identified that we would not need to utilise fermentation in order to produce a feasible amount of MFP. This value should reflect patient demand, which is difficult to assess pre-approval. However, assuming the 900 individuals making part of the predicted serviceable obtainable market (SOM) would be treated over the period of one year, we identify an average of 2-3 patients per day, which following values presented in literature is feasible without batch production (Santonocito et al., 2019). With regards to the feasibility of batch production, there are multiple considerations for the expression of proteins with fermentation as described by Rosano and Ceccarelli, 2014. From literature, we identified that no methods exist for the mass production of these proteins synthetically for reasons explained previously. However, new methods are being developed to improve yields of MFP production, which may provide efficient means for production in the near future (Choi et al., 2014).
In order to improve the prospects of PVFP-5 production, before submitting our sequences to IDT for synthesis, we optimised the codons of the PVFP-5 coding sequence for E. coli, to combat the issues of production stated in the Hwang et al., 2004 publication.
With regards to the production of our adhesive, tyrosinase serves a crucial function in enhancing the adhesive properties on PVFP-5 described Here.
In future, we would consider conducting a mutagenesis study, following our documented list of mutations here, with the intention of controlling the conversion of tyrosine residues into DOPA to tweak the percentage of adhesive residues and therefore the overall adhesive force to enable for nerve growth. Furthermore, the CNK-Tyrosinase used by Great Bay iGEM SCIE in 2019 shows great potential for the synthetic production of MFPs (Do et al., 2017), however, it has shown limited efficacy in vivo. Therefore, before it can be considered as a potential therapeutic, more research needs to be conducted.
A patent is a form of intellectual property (IP) that protects an invention from being made, used or sold by anyone else without permission for a limited amount of time (Gibson, J.E., 2012). Patenting our design would provide us with a unique marketing advantage, allowing us to market our therapy, sell the patent or sell the rights to use it (Mayfield, 2016).
The process of successfully getting our patent granted on average takes between 9 months to 5 years when applying in the UK through the Intellectual Property Office (IPO) (MPA Group, n.d.). The application would include a written description of our product, relevant diagrams, and clear legal statements that would define the invention. It would also have to highlight key technical details, including an abstract that summarises these details (GOV.UK, n.d.). This description document should be less than 35 pages long to avoid incurring additional fees Additionally, Renervate Therapeutics would also submit a ‘Statement of inventorship’ form alongside this application. This is necessary for our invention, as it was created with the contributions of a large number of people (GOV.UK, n.d.). Within approximately 4 weeks of filing this application and paying the fee, a preliminary examination report should be issued back to us from the IPO (GOV.UK, n.d.).
The next step would be to request a search by the IPO to confirm that our invention is indeed new. This search must be requested before a year has passed from the date of applying. Within approximately 6 months of this request, a search report will be issued by the IPO (GOV.UK, n.d.). If the search is successful in concluding that our invention is new, our application would be published 18 months from filing it (GOV.UK, n.d.).
Before 6 months of publishing the application, we must file for a ‘Substantive examination’ to ensure our invention is novel and to check that the descriptions we provide match the claims made (GOV.UK, n.d.). To help get our patent to be granted more quickly this request can be filed alongside the search request at no extra cost. Between approximately 4 to 6 years after filing our application, a ‘substantive examination of application’ would be issued to Renervate Therapeutics. If amendments to our application are required as per this examination, we must apply for re-examination upon rectifying the amendments made (GOV.UK, n.d.). Our patent would be granted within a year of the IPO completing the substantive examination if our application meets all the requirements.
The nature of iGEM is to share our work in the public domain, therefore to obtain a patent in the UK IPO for our invention, we would have to attain patent pending status before disclosing details of our project on our team wiki. Any disclosure made after filing an initial application and prior to being granted the patent would not be legally detrimental to our efforts in obtaining a patent (Hocking, 2019). We would have to file an application before October 2021 for any intellectual property developed during Phase 2 to be considered protectable, which is not feasible with our current timeline. Therefore, with respect to the UK, Renervate Therapeutics would be looking to file patent applications for intellectual property developed after the iGEM 2021 season.
Licensing a patent is usually more profitable than selling the patent itself. Patent licensing refers to granting a third-party permission to use, sell or make the patented device or invention, and is usually done (GOV.UK, 2016):
To licence our patented therapy to specific companies, we first must identify potential users/ distributors. For our project, potential licensees would be biosynthetic and medical device companies such as GlueTech, Medtronics and Invivo Therapeutics. Some good ways of advertising our patented product would be attending innovation events and publishing advertisements in industry/ research publications (NI Business Info, 2021).
Licensing a patent on our scaffold has various benefits such as transferring manufacturing risks to another party, eliminating patent infringement and most importantly, global distribution. As a startup company, patent licensing would allow Renervate Therapeutics to manufacture and distribute our product on a much wider scale through a third party than manufacturing independently, therefore generating a higher revenue (GOV.UK, 2016). Once a licensee has been chosen, the terms of a licensing agreement can then be negotiated.
Figure 3: Depicting timeline of IP and licensing strategy of Renervate Therepeutics for the next five year
A licensing agreement is a contract that allows a licensee to use intellectual property owned by the licensor (CFI, 2021). In the case of Renervate Therapeutics, this would mean allowing a third party such as a medical device company to manufacture and sell our scaffold under agreed terms. Some common terms of a licensing agreement are (NI Business Info, 2021):
In order for our scaffold to be able to make it to market there are two things we need to consider. The first one is the material itself - we need to source polycaprolactone (PCL) and ship it to a manufacturing facility. The second one is that the scaffolds need to be sized to each patient individually.
The normal way to source PCL is to order it from a company that provides scientific grade tools and materials. Sigma-Aldrich, which is one of the more famous among those, sells half a kilogram of PCL for 217.00 british pounds. While the price is relatively high, it is reasonable as an initial source of high quality material for our project. As our project grows we would need to find a chemical industry supplier to source from directly, which should greatly reduce our materials cost. The main manufacturer of PCL currently is Ingevity with their chemical plant in Warrington, England. They provide several grades of PCL under the Capa® brand. We are likely to need the Capa® 6500D version specifically.
Once we have sourced the PCL, the next challenge is producing a scaffold that is correctly sized for each individual patient. A solution might be to ask our end users, such as doctors working with SCI, to design and print the scaffold themselves. It is a practice common in the dentistry industry that might be successfully adapted to our project. After the scaffold has been printed it can be sent to us in order for it to be coated with PVFP-5 and prepared for surgical insertion. To learn more about our market strategy and supply chain, please see our Business Plan on our Entrepreneurship Page .
Our therapeutic scaffold is being put into an anatomically delicate region of the body. As such, safety and a thorough understanding of the nature of our device is of the essence.
Prior to implantation, we will need to ensure that our scaffold is sterile - i.e., void of all viable microorganisms - to reduce the risk of pathogenesis. In this regard, many sterilisation approaches currently exist and are readily applied during the production of medical devices. Nevertheless, specific care must be taken given the delicate nature of our scaffold and use of PCL. For example, due to the low melting point of PCL, heat based sterilisation approaches such as autoclaving would not be appropriate. A review of the existing literature found no clear consensus regarding the most superior technique, however, gamma irradiation seemed appropriate in many instances (Horakova et al., 2020; Lopianiak and Butruk-Raszeja, 2020). Here, high frequency ionising radiation is used to disrupt cellular DNA and render any microorganisms non-functional. This approach is commonly used in the sterilisation of medical devices, particularly for polymers, with a wealth of literature providing clear protocols. Nevertheless, it is important to note that some researchers have indicated that gamma irradiation may cause scission of chemical bonds, subsequently lowering mechanical strength (Cottam et al., 2009). As such, we will need to thoroughly test how this sterilisation approach impacts our finalised scaffold to ensure optimal functionality.
Before our scaffold can be implanted into humans, it is important that we consider the safety issues that could potentially arise. This is particularly pertinent regarding immunogenicity and cytotoxicity. These concerns must be one of our main focuses during the design process and when developing our therapy. Consequently, we aim to mitigate immunogenic responses by using the beta isoform of PVFP-5 (Santonocito et al., 2019). Moreover, this reduces the risk of scaffold detachment, preventing secondary immune response post-surgery.
Another aspect of immunogenicity to consider is the foreign body reaction (FBR). This would be induced by our PCL scaffold, as it is a foreign biomaterial, and can elicit harmful inflammation and fibrotic encapsulation that hinders the scaffold’s function. Various pharmacological treatments have been suggested by other researchers to reduce the effects of the FBR. However, we chose to leave these avenues for future research and implementation, potentially as combinatorial approaches. Below is a summary of some treatment options:
Table 1: depicting various pharmacological treatments to reduce the effects of the foreign body reactions.
The Manufacturer and User Device Experience (MAUDE) database is a large registry consisting of issues that have been raised from medical devices in the USA. The MAUDE database, thus, proves crucial to identifying devices with similar targeted therapeutic approaches, properties and associated concerns that manufacturers have identified. Therefore, this has enabled us to identify key safety issues that would otherwise dramatically reduce the effectiveness of our scaffold, and to investigate methods of overcoming them during clinical trials.
Report MW5095987 describes an incident of medical malpractice during which a patient was incorrectly advised to undergo surgery to implant a spinal cord stimulator resulting in severe complications and the patient being declared disabled. Medical malpractice is a key issue we aim to avoid by producing surgical protocols detailing the implantation procedure. Additionally, we would like to provide specialised training programmes to allow surgeons and medical staff to recognise the appropriate patients for surgery based on their symptoms and diagnostic imaging.
Furthermore, the MAUDE database highlights multiple safety aspects we need to consider after scaffold implantation. These issues are typically associated with scaffold:tissue interaction at the site of injury and surrounding environment. These concerns include nerve damage, infections and immunogenic responses, and the stability of our scaffold at the injury site. To navigate around these issues, we have ensured that we coat our scaffold in a sufficient amount of MFP to prevent the detachment of our scaffold from its target site. Post-surgery complications such as infections and immune responses can be overcome through the development of pre- and post-surgery protocols. This includes the prescription of antibiotics and through investigating the amount of MFP required for complete adhesion to the lesion site. Hence, this would be one of our primary focuses for clinical trials.
Since Renervate Therapeutics focuses on developing a novel therapy for spinal cord injuries, we need to take into account the risk that is incurred by implanting a foreign body in the spinal cord. This was particularly relevant in choosing the region of the spinal cord we would want to operate on. As highlighted by neurosurgeon Mr. Gordan Grahovac, there is always a risk of further exacerbating the injury when administering one’s therapy. To combat this, we conducted extensive literature reviews to identify which lesions would be best suited for Renervate Therapeutics’ treatment. We concluded that focusing on C6 - T12 lesions would take utmost priority. Avoiding cervical regions from C1 - C4 was an evidence-based decision due to their function in maintaining respiratory function. Ultimately, when administering our therapy, it is vital to establish concrete surgical and rehabilitation protocols as this will ensure the sustained welfare of our patient post-operation.
While some biosynthetic spinal scaffolds have undergone extensive research and have shown promising therapeutic benefits, the widespread use of scaffolds in the treatment of severe spinal cord injuries remains a target for the future (Qu et al., 2020). This is primarily due to complications associated with the implantation of the scaffold. The thoracic region of the spinal cord consists of 12 vertebrae and its associated nerve fibres that are responsible for the motor and sensory function at the chest, arms, and hands. The C3, C4, and C5 thoracic nerves are essential for breathing function, thus it is important that we address the safety and precision of surgical protocols to ensure breathing function is not impaired. This could potentially have detrimental effects that may lead to the requirement of a ventilator for breathing control (Sekhon and Fehlings, 2001).
During Phase I of our project, we recognised the need to tailor our scaffold design to the requirements of patients we would potentially be treating. It soon became apparent that our target population consists of those suffering from cervical spinal cord injuries (SCIs). Due to the severity and effects of the injury, however (and after collaborating with researchers and surgeons), we have decided to broaden the spectrum of targeted injuries to include both cervical and thoracic SCIs. Our decision to target cervical SCIs stem from the quadriplegia and tetraplegia experienced by patients. These diagnoses, understandably, severely impact one's quality of life. Consequently, by targeting this region of the spinal cord and promoting axonal regeneration, we endeavour to restore some of the function lost.
This year, we were able to expand our knowledge on the types of SCIs and therapeutic benefits associated with targeting these SCIs via our scaffold. After extensive literature reviews alongside conversing with surgeons and researchers specialising in SCI, we decided to also target thoracic SCIs. Though thoracic SCIs often have less severe effects than cervical, the resulting paraplegia was deemed significant enough to target during our therapy (Sekhon and Fehlings, 2001, Warren et al., 2018). Breathing function is more strongly associated with the cervical region. Hence, this is beneficial as surgical intervention at the thoracic region should have fewer complications.
Our scaffold faces a wide range of unique challenges when introducing it to the market. Presented below are a series of risks and factors that we need to address as our project moves from iGEM into the real world.
It is imperative to assess the environmental impact of scaffold fabrication as a further principal challenge associated with production. The scaffold material of choice, polycaprolactone (PCL), is biodegradable - yet is predominantly derived from non-renewable petrochemicals (Kalita et al., 2021). There are two methods of producing this synthetic polymer: condensing 6-hydroxyhexanoic acid, or utilising the ring-opening polymerisation of ε-caprolactone (ε-CL) (Labet and Thielemans, 2009). However, recent demand for fossil-free eco-friendly polymers has soared (Hatti-Kaul et al., 2020). This trend has fuelled the desire to develop green routes for the creation of polymer ‘building-blocks’ - including 6-hydroxyhexanoic acid and ε-CL (Pyo et al., 2020). Recent work by Pyo et al. (2020) explored a sustainable synthetic alternative for producing 6-hydroxyhexanoic acid and ε-CL from 1,6-hexanediol. This shows promise for the future of PCL developed from renewable sources, considering the advancement of current work. With respect to the present, nevertheless, the scaffold (while possessing an open-path design) is optimised for providing as much guidance as possible, but requires less material than traditional cylindrical scaffold designs (Wong et al., 2008). Therefore, the material usage is more economical.
A further environmental concern is the disposal of the PCL. 79% of plastic waste between 1950 and 2015 (equivalent to 238.6 tonnes in 2015) was directly landfilled or disposed of in the natural environment, with 12% being incinerated and a mere 9% recycled (Geyer, Jambeck, and Law, 2017). Concerning the scaffold, the PCL is expected to fully degrade in vivo - unlike alternative scaffold materials (e.g., silicone-based nerve guides (Madaghiele, Salvatore, and Sannino, 2014)). This eliminates the end-of-life impact of the thermoplastic; there isn’t need for disposal post-treatment (Civancik-Uslu et al., 2018). However, the waste material produced during production must still be acknowledged. The degradation of PCL can be pollution-free, although it takes a long time naturally (Zhu et al., 2021). Therefore, to avoid issues with discarding the PCL, methods for accelerating the degradation could be explored. An example of such is presented in the work by Abdel-Motaal et al. (2014), whereby the fungus Alternaria alternata-ST01 was used as an eco-friendly catalyst for the biodegradation of PCL - shortening its breakdown to 15 days. In the worst case, if the PCL is disposed of otherwise, it can degrade in many biotic environments - including, but not limited to, bodies of water (sea, rivers and lakes), sewage, farm soil and compost - within 15 weeks (Krasowska, Heimowska, and Morawska, 2016).
The method of fabrication should also be assessed when considering the environmental impact - in this case additive manufacturing/3D printing (specifically Fusion Deposition Modelling (FDM)). It is widely believed that additive manufacturing technologies are advantageous, concerning the environment, over other production techniques because less material is consumed; the material used to create the product is close to that of the final product (Suárez and Domínguez, 2020). Conversely, there is not a universally agreed method of studying and quantifying the environmental impact of 3D printing (Suárez and Domínguez, 2020). Therefore, it is difficult to pinpoint its exact impact - although some works have concerns with respect to energy consumption (Yoon et al., 2014).
The markets we are considering for the initial phase of the Renervate Therapeutics project are mainly the United Kingdom. However as we expand beyond the UK we face new challenges as we deal with the legislation of various international markets. As a case study here we observe the USA and in particular, the FDA. The first thing to consider about our therapy is its safety for patients. In the US, this is officially determined by the Food and Drug Administration. The FDA has regulatory control over what therapies are allowed to be used and is meant to protect patients. Our scaffold is a type of implant, and therefore falls under the guidelines meant for Medical Devices.
The guidelines are separated based on a system of classification of potential risk. Class I and II devices have a relatively lower amount of associated regulation. For them to be allowed to market, an applicant must usually submit a 510(k) Premarket Notification to the FDA. However, Class III devices require the more stringent Premarket Approval Application (PMA) before they are allowed to be sold (Classify Your Medical Device, 2020).
There are two main ways to classify a Medical Device. The first one is to make a compelling argument that the proposed device is similar to a previously approved one, the latter being called the predicate. To that end the FDA also provides a reference list of classification panels that may be used to establish a predicate. The second way is to apply for a DeNovo classification, if the proposed device is unique. There is also the possibility to submit a 513(g) request to get an official classification decision by the FDA (Classify Your Medical Device, 2020).
The scaffold itself is very similar to several Class II devices. The following classification panels describe devices that are similar in terms of location and impact on the patient: 882.5880 - “Implanted spinal cord stimulator for pain relief”, 882.5550 - “Central nervous system fluid shunt and components”, and 882.5275 - “Nerve cuff”. More detail can be found by referring to Title 21 of the Code of Federal Regulations.
The PVFP-5 protein coating that we will be using, however, is likely to fall under 878.4010(b) - “Tissue adhesive for non-topical use”. This is regulated under Class III and therefore needs to undergo the Premarket Approval Application (PMA) process.
This process requires an applicant to provide clear and detailed information to the FDA about the product. The detailed guidelines can be found in Title 21 of the Code of Federal Regulations under Section 814. The most important section in a PMA is the Technical Section, which refers to the non-clinical and clinical trials that have been conducted for the product. The expected non-clinical laboratory studies are: microbiological, toxicological, immunological, biocompatibility, stress, wear, shelf-life, “and other laboratory or animal tests as appropriate.” The clinical trials themselves are expected to have been conducted to the level of quality outlined in Sections 56 and 812 of the CFR (Premarket Approval (PMA), 2019).
Other than the time and material costs to run all the tests outlined above, the application process itself also requires certain fees. Since Renervate Therapeutics can be classified as a small business, we would get a reduction. Even then the fees are a definite future consideration. The PMA application would cost $91,414, while the 510(k) would only be about $3,108. There are also associated annual fees in order to maintain the validity of the application (Medical Device User Fee Amendments (MDUFA), 2021).
Overall, the safety approval process for our device would likely be long and involved. However, it does come with certain benefits. First, since UK and EU regulatory bodies follow similar guidelines to the FDA, if we get approval in the US we would also likely gain approval in those countries as well within a short timespan. Second, there is a reason this process exists and once we complete it we would be sure that our device is safe and effective.