Title: Development and clinical evaluation of FibroFix Cartilage: a load bearing, tissue regenerative knee cartilage resurfacing implant
Funder: Department of Health and Social Care

Abstract: Phase 1, Design Verification/Validation, will conclude final design verification/validation studies to support entry to the Clinical Phase. Implant mechanical properties, durability, and surface tribology will be tested by Orthox, the University of Ulm and Dr Jonathan Jeffers of Imperial College who will also conduct human cadaveric implant load cycling. This will be performed using Zwick and Instron tensile, compression, and shear rigs, a Bose 10Hz load cycling bioreactor, and a friction analyser; to give Deliverable 1 (D1): The Physico-Mechanical-Topographical Report which will be compiled by R&D lead and Project Manager (PM), Dr Robert Walker. ISO10993 in vitro biocompatibility reporting will be subcontracted to Envigo Ltd (D2). These data, together with off-project macroscopic and histological conclusions from the report on a 6 month GLP study in an FDA approved ovine femoral defect model of cartilage resurfacing and in vivo ISO10993 test data will be compiled by Design Control Manager Dr Jo Proffitt in D3: The Biological Safety Report. Surgical technique development will be conducted at the Vesalius Centre human cadaver labs by surgeons from the co-applicant and captured in the Implant and Surgical Tooling Usability Report. Implant Packaging Validation Sterility, and Shelf Life reports will form D4, D5 and D6. Dr Proffitt will review / approve protocol designs and be responsible for sign off to meet regulatory requirements. Milestone1: All phase 1 deliverables achieve threshold criteria for clinical submissions is Go/No-Go decision 1: If product data is unsuitable for clinical submissions the project will be paused to allow for redevelopment/verification activities, or stopped if redevelopment is not feasible. Phase 2, Clinical Preparation and Assessment, is led by Clinical Trials Manager, Dr Pete Wall. Orthox staff and Clinical Investigators will finalise surgical technique and trial inclusion/exclusion criteria. Clinical statistician, Dr Kim Cocks will validate a suitably powered trial design with the output being the Clinical Investigation Plan (D11). Patient information literature (D19) will be developed and reviewed with the University of Bristol's 'Patient Experience Partnership in Research' Group. Supporting scientific information will be prepared by the Orthox R&D function and compiled for clinical submissions by the Quality function assisted by Dr Proffitt and RA/QA advisor Anne Jury, who will also prepare procedures to control product release for clinical assessment. Anne Jury is responsible for regulatory compliance and will approve D14, the General Safety and Performance Requirements. The final output is the Clinical Trials Notification Dossier, D15, to be submitted to the MHRA and LREC/R&D committee. Milestone 2 Clinical trial approval is Go/No-Go decision 2. If Regulators require further verification studies to address concerns the project may be paused to allow completion or stopped if not achievable. Clinical Assessment will be a phase I study of the implant and accessory tools in minimum 10 patients conducted by co-applicant NBT, with primary end points of MRI and standardised pain/mobility questionnaires at 12 months. Laboratory Manager Michael Tomlinson will lead manufacture of implants at Orthox's GMP facility, subcontractor OZ Designs will produce accessory surgical tools to provide clinical trial stock. A CRO will be appointed by competitive tender process and a trial Data Monitoring Committee (DMC) will be established. Milestone 3: DMC Confirmation of no serious adverse events in the first 2 recruits at 6 months follow up , will allow full trial recruitment to open. Project Go/No-Go decision 3: Should the DMC conclude recruitment should not proceed the project will stop, except for root cause investigation and to support the closure of the clinical trial. End of project Milestone 5 and D18 are respectively, fully recruited trial' and 'clinical trial status report with 12 month follow up on the first two patients'.

Lay abstract: The project will test an implant called FibroFix Cartilage for use in treating major injuries to the smooth stiff cartilage that covers the ends of the bones in the knee where the painful condition osteoarthritis may already be present. 370 million people suffer knee osteoarthritis globally, and currently the only effective treatment is major surgery to replace the affected knee joint with a metal or plastic implant (TKR). Unfortunately this treatment has frequent complications and is rarely suitable for the 70 million patients under 60 with knee osteoarthritis. FibroFix Cartilage implants are formed from a protein called fibroin that is extracted by the lead applicant, Orthox Ltd. Uniquely, these implants capture the strong, smooth, resilient, hydrated properties of knee cartilage while supporting regeneration of the cartilage tissue itself. The implant could provide an alternative to TKR for cartilage injuries in degenerative knee joints. Patients benefit from prolonged use of the joint, increased mobility, reduced pain and postponement/ prevention of TKR. FibroFix Cartilage has been extensively tested with very positive results, and has achieved &ldquo;design freeze&rdquo;, meaning further changes are not expected. It is inexpensive to manufacture and, unlike knee joint replacement, is implanted without a major surgical procedure. The project aims to complete final testing of the implants in laboratory trials, demonstrating they are safe and effective, and will develop the surgical technique and trial instruments to implant FibroFix Cartilage. An application to the Regulatory Authorities for approval to conduct a clinical trial with the co-applicants at The University of Bristol and North Bristol NHS Trust (NBT) will then be submitted. The clinical trial will investigate the implant s performance in 10 patients who have damage to their knee joint cartilage and may also have osteoarthritis present in the joint. Success will be demonstration of implant safety and reduction in pain.

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