Title: Development of manufacturing capability and pilot clinical evaluation of FibroFix: A mechanically advanced, tissue regenerative, meniscal cartilage repair device.
Funder: Department of Health (England)

Abstract: Research Plan Patent Attorneys, Wilson Gunn LLP (WG), have conducted searches in 2010 and based on these, and the International Preliminary Reports on Patentability and International Search Reports, have been commissioned by Orthox to provide Opinions on the Patentability of the key Orthox patents 1 and 2 (described above). Patent 1: Nine documents of particular note were identified by WG and considered. They observe: “None of the reviewed documents disclose the combinations of features claimed by claims 1, 20, 27, 29 and 31 [of patent 1] and so we propose that there are arguments in favour of novelty and inventive step of each of these claims Only claim 30 [of patent 1], which is exceptionally broad, would seem vulnerable to patentability objections as a result of the TUFTS UNIVERSITY 2 disclosure. Claim 30 could potentially be amended to comprise a porous hydrogel.... ...In our opinion, the original claims and proposed amended claim 30 are new and inventive over the documents reviewed above and subject to the national/ regional examination phases uncovering no closer prior art, we expect patents should be granted based on either the proposed amended claims (above), or claims similar to those amended claims” Patent 2: Eleven documents of particular note were identified by WG and considered. Following review of these, Claim one was redrafted and a new claim was developed, drawing from observations made in the main body of the patent. These amended claims were subsequently submitted for search at the regional and national stage in October 2010. WG observe: “None of the documents reviewed teach or suggest the method as defined in the amended claims and therefore, the method (and so the solution and material claims made there from) is new.... Referring to inventive step, by first treating with an ionic reagent, subsequently drying the silk fibroin and then dissolving the silk fibroin in a chaotropic agent, the solubility of the silk fibroin in the chaotropic agent is significantly improved...which has the positive effect of avoiding irreversible degradation of the silk fibroin. Where a fibroin solution with minimally degraded silk fibroin can be achieved, improved materials can be produced therefrom. ...In our opinion, the amended claims are new and inventive over the documents reviewed above and subject to the examination phases in the countries in which the application is later pursued uncovering no closer prior art, we expect patents should be granted based on either the proposed amended claims (above), or claims similar to those amended claims” Patent 3 was filed recently and extensive searches were conducted by Orthox and WG in drafting claims Patents 4 and 5 are granted or approaching grant, and it is noteworthy that these patents have been scrutinised during the due diligence processes by the Wellcome Trust for the Translation Award and also for the establishment of two other equity financed companies to which they are also licensed. Aims The project aims are to finalise development FibroFix and gather evidence supportive of efficacy in vitro, before demonstrating safety and efficacy in a `first in man' clinical trial. Research on this project will focus on developing a device specification possessing the correct kinematics for functioning in harmony with the anatomy of the human knee joint, before translating this design into the FibroFix manufacturing process. The resultant devices will be evaluated in knee load simulators and by cadaver implantation to demonstrate they function as intended and can be swiftly, reliably and effectively implanted and fixated. In parallel, but not as part of the i4i project, Orthox will conduct the requisite animal work and implement the quality systems and regulatory framework to enable progression to a pilot human clinical trial at the AOC by Project Month16 (PM16). This trial will assess FibroFix in a partial meniscal replacement model in patients who would otherwise have received a standard partial meniscectomy procedure, with the aim that follow up data at 6 months post-operative demonstrates FibroFix to be safely fixated, with acceptable performance as measured by standard pain and mobility scoring and without significant adverse clinical observations. The aims will be achieved through execution of the following Work Packages (WP): WP1: Development of Device Specification. PM1-4. The strength and high modulus of Spidrex® mean it is important to develop a precise anatomical replication of the meniscal size and shape in the final FibroFix device. If not it may impinge on other tissues in the knee joint, damaging them, the device, or both. This has been shown in sheep cadavers using a knee load simulator at The Institute of Orthopaedic Research and Biomechanics (IORB) at the University of Ulm. As a result a version of FibroFix which accurately replicated the anatomy of the sheep medial meniscus was developed for the current FibroFix large animal studies, which to date have returned positive results. As literature studies of human meniscal sizing are insufficiently detailed to develop a suitable specification Orthox will access a database of 4000 digital scans of human menisci at the Scripps Clinic, California through collaboration with Prof D'Lima and with him establish precise data on human meniscal dimensions and variation. Orthox request a subcontract to fund this work as the database is a unique resource and viewed as critical to success of the eventual device. From the analyses, specifications for medial and lateral human meniscal devices will be developed. A number of high resolution digital scans will also be taken to help build the CAD files required for translation of the data into the rapid prototype moulds used in FibroFix manufacture. MILESTONES (M):M1 Access to Scripps Clinic meniscal scan database: PM1M2 High resolution scans of 10 cadaveric human menisci PM3M3 Quantification of variation in human meniscal sizes PM4M4 Identification of Device Specifications PM4KEY DELIVERABLES (D):D1 Report on variations in human meniscal anatomy PM4D2 Specifications for human medial and lateral meniscal devices PM4 WP2: Development of Manufacturing Capability to meet Specification. PM1-27: FibroFix is manufactured through casting the liquid fibroin polymer in moulds developed by rapid prototyping. Device Specifications will be translated to CAD files and mould inserts compatible with existing manufacturing equipment will be manufactured by direct laser sintering at 3T-RPD Ltd. Specifications for novel cutting dies will be designed by Orthox and manufactured by Performance Cutters Ltd. to correctly cut the newly shaped devices from the cast polymer, and a foil pouch vacuum sealer will be sourced for packaging devices. Manufacture is aseptic to the point of cutting and packaging but these final steps will be conducted in a laminar flow clean room environment. Devices will be sterilised by Gamma Irradiation and sterility validated in Bioburden and VDMax testing at Isotron UK. M5 CAD files to meet Device Specifications PM5M6 Correctly proportioned mould inserts PM5M7 Manufacture new specification FibroFix devices PM7 M8 Bioburden and VDMax validation of devices PM8M9 Production of devices for clinical trial PM15M10 80% Batch acceptance PM24D3 Solidworks CAD representations of devices meeting new specifications PM5D4 New mould inserts PM6D5 Delivery of 30 FibroFix devices for trial PM15D6 Delivery of 250 devices meeting specification in the previous quarter PM27 WP3: In vitro evaluation of new specification devices. PM8-11 New specification devices must demonstrate appropriate kinematic and mechanical function before implantation in patients. Consequently they will be trialled in a knee load and motion simulator at the IORB at the University of Ulm. This bespoke testing rig mounts cadaver knees in which the device has been implanted, manipulating them in six degrees of freedom to emulate the full range of possible knee motion and flexion, under differing loading regimens. An arthroscopic camera mounted in the tibial plateau permits monitoring of device performance throughout the simulation. This will reveal any impingements with other tissues, gapping of the device from the remaining meniscus which would prevent integration, and effectiveness of the fixation anchors. Devices will also be trialled in long term fatigue trials of up to 10m cycles, and surface tribology will be evaluated using a custom friction assay rig. Orthox request a subcontract to the IORB for this work as they are one of Europe's leading biomechanics institutes with whom Orthox have established a close working relationship over the previous 2 years. Their knee simulator is unique and previous results have been instrumental in directing FibroFix development. M11 First knee simulation PM8M12 Initiation of mechanical, tribological and fatigue tests PM8M13 Completion of knee simulation studies PM11M14 Completion of mechanical, tribological and fatigue tests PM11D7 Report and film of FibroFix performance in simulator studies PM11D8 Report on FibroFix performance in mechanical, tribological & fatigue tests PM11 WP4: Development of surgical instrumentation and technique. PM1-11 Implantations in a human cadaver knee in partnership with Arthrex at their Arthrolabs in Munich have provided supportive preliminary evidence that FibroFix can be secured to the remaining meniscal tissue by means of arthroscopic fixation devices (Annex 5, p3 fig.9). To develop the surgical technique further cadaver trials will be carried out by Prof Blom and dr Eldridge of the AOC and Orthox's CMO, Prof Kessler. This is likely to be at the Arthrex Arthrolabs in Munich. Arthroscopic fixation devices such as Smith & Nephew's FasT-Fix and Arthrex's Meniscal Cinch will be trialled as standard, and concepts for novel fixation devices will be explored. FibroFix has high fixation pull out strength so surgeons will not need as many anchors to stably fixate FibroFix as with the weaker ActiFit and Menaflex scaffolds. This removes a major barrier to usability and will be quantified in the cadaver experiments. To measure the meniscal defect a novel arthroscopic ruler is required which will be developed with Orthopaedic Innovation Ltd, under subcontract. M15 Design freeze of prototype arthroscopic ruler PM2M16 Successful human cadaveric implantation trial PM9D9 Receipt of prototype arthroscopic ruler PM6D10 Final protocol for arthroscopic implantation of FibroFix PM11 WP5: Pilot Clinical trial. PM1-27 Clinical evaluation of FibroFix is the next major goal. To ensure efficient management of the trial, compliance with regulatory requirements and compatibility with the subsequent CE mark clinical trial, a third party Clinical Research Organisation (CRO) will be engaged to manage this trial. Outline quotes from CRO's have been received by Orthox. The FibroFix Device Master File (DMF) and Clinical Trial Notification (CTN) dossier will be compiled and submitted to the Competent Authority and Research Ethics Committee as described in Section 15. The study will be conducted under the supervision of Prof Blom of the AOC at Southmead Hospital, Bristol and the final clinical protocol will be developed by Prof Blom and Prof Kessler. 10 patients will be recruited by informed consent, and clinical follow up will be at 1, 3, and 6 weeks, 3 and 6 months, and 1, 2 and 5 years. Follow up measures will include MRI at 3 and 6 months and standard knee pain and mobility scores including IKDC, KOOS and VAS at 6 months. M17 Engagement of CRO PM9M18 Ethical Approval for FibroFix Clinical Study PM15M19 First Patient Implantation of FibroFix PM16M20 FibroFix implanted in 10 Patients PM19M21 Clinical End Points Achieved PM25D11 Completed CTN and DMF PM12D12 Final Clinical Trials Protocol PM12D13 Report on completed surgeries in 10 patients PM18D14 Report on 6 month follow up analyses in 10 patients PM27 WP6: Clinical Advisory & Health Economics. PM3-27 Orthox will formalise its Clinical Advisory Board (CAB), commission an independent health economics analysis and engage a part time commercial manager to develop product literature and lead the sales team post project. M22 First meeting of CAB PM3M23 Engagement of Commercial Manager PM18D15 draft IFU Literature PM27D16 Health economics analysis PM27 WP7:IP Management, Exploitation & Dissemination of Results. PM1-27: See Sections 10, 12 & 14 M24 Signature of contracts & collaboration agreement PM1M25 Presentation of project results at ICRS 2012 and ORS 2013 PM10, PM18D17 Press release on Project Start PM1D18 Press release on First patient implantations PM17D19 Project Exploitation Plan PM14, PM27 WP8: Project Management. PM1-27: See Section 14 M26 Updated Project Plan & Risk Register PM2D20 Mid Term Project Report PM14D21 Final Project Report PM27 Benefit FibroFix will lead to the following patient benefits: 1. Rapid patient rehabilitation through the capacity of FibroFix to assume load independently of tissue regeneration. With the exception of partial meniscectomy, this differentiates FibroFix from all other therapeutic alternatives, in particular the only products currently available to patients following partial meniscectomy, the scaffolds ActiFit® and Menaflex®. To allow the tissue regeneration upon which they rely for efficacy, these devices have rehabilitation periods of 6 months during which the knee cannot assume full loading and flexion. Any cell therapy developed is likely to require a similar rehabilitation period for the same reasons. FibroFix, with the same compressive strength as meniscal tissue, will allow full loading as soon as it is comfortable for the patient to do so and full knee usage as soon as peripheral tissue integration has occurred, after circa 6 weeks. As well as fewer physiotherapy follow ups and violations/abandonments of the rehabilitation programme, this early load bearing and full knee usage is viewed as a major benefit to patients in allowing them to rapidly resume a fully active lifestyle and functional role in society. In addition, literature studies suggest early load bearing will lead to a further major benefit: 2. Alignment of new collagen fibrils deposited in the porous structure of FibroFix leading to strong, functional new tissue. Collagen, the principle component of meniscal tissue, is highly aligned in the meniscus leading to a high compressive modulus and strength. Cells responsible for the deposition of new collagen do not orientate and align the new collagen fibrils deposited unless they receive adequate mechanical stimulus during regeneration(22). Without aligned collagen, tissues are much weaker (e.g. skin or fascia). By early loading during rehabilitation, provision of the correct mechanical environment, and hence appropriate mechanical stimuli to regenerating meniscal cells, FibroFix will ensure strong, aligned collagen in the new tissue - this is observed in FibroFix animal trials (Annex 5 p3 fig.7). Conversely it is questionable whether products which require long non-load bearing rehabilitation, will deliver strong, functional regenerated meniscal tissue. 3. Immediate, and long term chondroprotection. No other products offer the shock absorbing mechanics or smooth surface kinematics offered by FibroFix. In vitro, FibroFix withstands at least 8m knee load cycles, equivalent to ~5 years in the human knee while a continuous, low friction surface integrated with the porous body of the device prevents wear on juxtaposed articular cartilage surfaces - a significant advantage over ActiFit® and Menaflex®. This will help ensure the long term health of the patients knee. 4. Fewer adverse clinical events (e.g. subluxations) or product failures (e.g. ruptures, pull outs) due to the strength and capacity of FibroFix to sustain normal loading.


Research activity codes: 6.3 MEDICAL DEVICES;5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL