Orthopaedic Institute

ANNUAL REPORT 2018/19

Including: Reports on research in collaboration with the Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust and Institute for Science and Technology in Medicine, Keele University, Staffordshire www.orthopaedic-institute.org CONTENTS 2 Orthopaedic Institute...... Donations andFundraising...... GENERAL Francis CostelloLibrary...... PUBLICATIONS Annual Research Day...... RESEARCH DAY Orthopaedic InstituteCourses2018-2019...... EDUCATION Spinal StudiesResearch Group ...... SPINAL STUDIES FSHD Study...... TEPIS Study...... Biomechanics Lab...... BIOMECHANICS ANDORTHOPAEDIC INTERVENTIONS ASCOT Trial ...... Cartilage Research Group ...... CELL THERAPIES ORLAU (OrthoticResearch andLocomotorAssessmentUnit)...... The Wolfson Centre ForInheritedNeuromuscular Disease(CIND)...... MOBILITY GROUP Metabolic MedicineandBone...... Rheumatology Research ...... RHEUMATOLOGY ANDMETABOLIC MEDICINE Chairman’s Report...... Introduction ...... ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 36 35 34 33 32 28 27 26 23 22 15 13 10 9 6 4 3 INTRODUCTION 3

Charity No: 1044906 A full set of Finance Accounts is available upon request, please contact A full set of Finance Accounts is available upon request, [email protected] The research work results in new and improved methods of treatment as well as additions as well as methods of treatment in new and improved work results The research account of orthopaedic comprehensive a to medical knowledge. The Report provides and Agnes Hunt Orthopaedic carried out over the past year at The Robert Jones research Hospital NHS Foundation Trust. Research staff employed on the projects are either supported by the Orthopaedic either supported by the Orthopaedic are employed on the projects staff Research the Hospital or the School of Postgraduate working within Departments of Institute or are from and involve staff interdisciplinary are Many programmes Medicine, Keele University. departments. one or more This includes research projects funded by the Orthopaedic Institute and projects for which and projects funded by the Orthopaedic Institute projects This includes research external and organisations. Foundation Trust funds have been obtained by the NHS The research referred to in this Annual Report has been undertaken by the Orthopaedic to in this Annual Report has been undertaken by the referred The research Hunt Orthopaedic Hospital and the Institute Institute, the Robert Jones and Agnes in close which all work in Medicine of Keele University, for Science and Technology collaboration. The Executive Committee, under the Chairmanship of Dr Brian Ashton, decides the under the Chairmanship of Dr The Executive Committee, Panel, under the temporary A Research and monitors its progress. policy of the Institute by research proposed projects new research considers Robin Butler, Chairmanship of Dr be to to the Executive Committee, the projects and clinicians, and recommends staff received. by grants and donations the income provided funded from ) (www.orthopaedic-institute.org founded in 1971, Institute Limited The Orthopaedic to fund research contributions, helps voluntary and, through national charity is a registered within the Robert Jones and Agnes and departments centres in the specialist research It also Shropshire. in Oswestry, Hospital NHS Foundation Trust Hunt Orthopaedic such as organising training of educational facilities and activities supports the funding trainees and allied health professionals. courses for orthopaedic INTRODUCTION INTRODUCTION ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC CHAIRMAN’S REPORT courses andworkingwithour clinicalcolleaguesto and effectively, bringinginanumberofexcitingnew Our CourseOrganiser, SianJones, hasworkedhard and attentionthatshebringstothepost. support totheboard andweare gratefulforthecare Mrs JudyHarriscontinuestoprovide administrative current performance. management ofourinvestmentsandissatisfiedwiththe of ourresources. TheBoard keepsawatchonthe bookkeeper FionaBainfortheircareful management we are indebtedtoourtreasurer LouiseOsseltonand The financialstandingoftheInstitute remains soundand constitution andprocedures committee andhasrecently instigatedareview ofits The board hasconstitutedanemploymentsub- Board ofDirectors duringthecurrent year. businessman. There were nootherchangesinthe in publichealth,MrEricEvans,retired automotive Prof RajanMadhok,OrthopaedicSurgeonandexpert Directors: MrStephenBratt,CEOBiocompositesLtd., We havewelcomednewfacestotheBoard of Administration integrated intothecore clinicalworkofthehospital. are thrivingandnowintheirpost-research phase, instigated withthesupportofOrthopaedicInstitute It isalsopleasingtoseethatmanyresearch initiatives continue withthesevitalservices. the supportreceived yearon yearwhichenablesusto members ofthepublic.We are extremely gratefulfor CharitableTrusts,external Foundations,patientsand many innovativeprojects being fundedthrough usby and teachingwithmore courses beingheldandwith It ispleasingtoreport continued progress inresearch orthopaedics. Trust, alongstandingcentre ofexcellenceinworld Jones &AgnesHuntOrthopaedicHospitalFoundation that affect themusculo-skeletal systemattheRobert to improve thetreatment ofpatientswithconditions The OrthopaedicInstitutefundsresearch andeducation CHAIRMAN’S REPORT 4 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 day andourthanksgotoallwhocontributed. the SpecialistOrthopaedicRegistrarswasastimulating Research DayheldonFriday26thAprilintandemwith attending ourhospital. well designedstudiesonconditionsaffecting patients cerebral palsy. Theunifyingfactors are thattheyare all patients withbackpaintogaitanalysisinchildren with of musculardystrophy, from radiologicalstudieson molecular biologyapproaches tolesscommonforms from clinicaltrialsincommonorthopaedicproblems to pipeline. Therangeofresearch isimpressive, ranging were approved forfundingandafurthersixare inthe 6 were successfullycompletedandtwonewprojects Of the31projects supportedbytheInstitutethisyear, submitted forfundingandmonitoringtheirprogress. perform itsdutyofproviding peerreview forprojects successor toAndrew isfound.ThePanelcontinuesto for standinginasActingChairmanuntilanexternal years tothePanel.IamgratefulDrRobinButler and wethankhimforhiscontributionoveralmost10 chairman oftheResearch Panelforpersonalreasons, Mr Andrew Clarkesadlyhadtostepdownasthe Research and Charitiesthathavesupportedourrequests. and weareTrusts, gratefultothe external Foundations items ofequipmenthavesignificantlyincreased thisyear event. Donationstosupportresearch projects andsmall become aneagerlyanticipatedandprofitable annual hike upSnowdonforex-patientsandsupporters,has as Fundraiser. TheSnowpaedicChallenge,asponsored Debra Alexanderhashadasuccessfulyearinherrole renowned reputation. with ourtrainerstoensure that Oswestrymaintainsits is undergoingsignificantchangeandSianwillwork courses. PostgraduatemedicaleducationintheNHS secure thecontinueddevelopment ofourflagship CHAIRMAN’S REPORT 5 Dr Brian Ashton Chairman Orthopaedic Institute Ltd The Institute has worked with the hospital to upgrade the hospital to upgrade has worked with The Institute but it is clear and Library, theatre Lecture our current to near future will be needed in the Centre that a new of training for all clinical specialties. allow an expansion which is the an options review The Institute has funded plan for the project. first stage of a business In conclusion of the innovation and gives a flavour This report the being carried out by of the research precision at the Robert Jones & Agnes clinicians and scientists Trust. Hunt Orthopaedic Hospital NHS Foundation support the financial The Orthopaedic Institute provides started and to get projects sought by researchers also play an of concept phase. We to proof through the technology to keep our in providing important role at the cutting edge. researchers we have a great Please help us help them – together of success. record Education/Training Centre Education/Training Financed by the Orthopaedic Institute twenty years ago, cells for clinical the Oscell Cell Therapy Unit provides of damaged joint cartilage. Changes trials into repair framework under which cells are to the regulatory and extension modification have required produced is pleased to have pledged The Institute of the facility. the work, which is now planned. The £40000 towards of the long-term Institute has also supported a review development of cell therapies. Cell Therapy Unit This important initiative is the first of its kind in the UK. This important initiative is the first of to support The Orthopaedic Institute was pleased to the the visit of a team of clinicians and managers Reed National Military Medical Center to US Walter service is organised see how a world class veteran’s a fund to finance the building are We and provided. the new specialised training of clinicians who will provide service. Veteran’s Outpatient Centre Veteran’s Current Projects Current with the leadership The Institute has excellent relations and is working team of the RJAH Foundation Trust to take forward with them, within its charitable aims, Outpatient important initiatives such as the Veteran’s of the OsCell cell therapy unit and a a revamp Centre, Centre. new Education/Training The reputation of the courses has been built on the of the courses The reputation variety of model patients and participation of a huge and Lecturers the commitment of the highest quality grateful to all involved. Examiners and we are Our flagship courses, the Clinical Examination and Our flagship courses, Viva and Courses, have earned world-class reputations them to be the ‘best of their kind’ delegates consider clamour to book, indeed we have a and new delegates for both October 2019 and full paid-up list of delegates lists. with reserve January 2020, both The Institute has convened 29 courses in the review review 29 courses in the has convened The Institute and faculty grateful to the convenors we are period and in. the work they put of each for Teaching ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC RHEUMATOLOGY AND METABOLIC MEDICINE are presentingtheirworkatthe conferences. Figure 1.MaireadHyland(top) and OksanaKehoe(bottom) 2019, MayRhodes,Greece. Annual Research dayatthe RJAH,April2019andTERMISEU Extracellular Vesicles AnnualMeeting,April2019,Japan;the Societyfor Forum, December2018,Sheffield;theInternational Birmingham; theUKSocietyforExtracellularVesicles Annual Alliance EighthAnnualScientificMeeting,December2018, Therapy, theMercia October2018,Hanoi,Vietnam; StemCell Conference2018, USA;the2ndVinmec onCell&Gene the Gordon Research Conference onProteoglycans, July the AnnualTCESmeeting,June2018,KeeleUniversity; meetingssuchas work atseveralnationalandinternational & TherapyandeCMPeriodical.We havepresented our We havebeenpublishingourfindingsinArthritisResearch rheumatoid arthritis(RA)progression andpossibletreatments. basic scienceworkintounderstandingmechanismsof Our teamhascontinuedtobeactivethisyearcarryingout and DrAyman Askari Dr RoshanAmarasena(Lead),RobButler Clinical Support: and MissMaireadHyland Dr OksanaKehoe(Lead),MissRebeccaMorgan Members oftheResearch Team: RHEUMATOLOGY RESEARCH 6 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 mechanisms involved. therapeutic intervention.Further investigationwillidentifythe treatment demonstratestheireffectiveness asanew The significant reduction injointswellingfollowingEVs improved scores forcartilageandarthritisindex(Figure 2B). absence ofextracellularvesicles.Histologicalanalysisreviled to control animalswhere kneejointscontinuedtoswellinthe (Figure 2A).Reductionswere highlysignificantincomparison 24 and48hoursaftertreatment inourpre-clinical model of vesicles,kneejointswellingsignificantly reduced atboth used toderiveextracellularvesicles.Followingtheapplication Stem cellsisolatedfrom humanbonemarrow aspiratewere polarisation towards either pro- oranti-inflammatorycelltypes. histological outcomesofdiseaseprogression andTcell experimental arthritis,lookingattheireffects oninflammation, vesicles are appliedasatreatment inourpre-clinical modelof to enhancetheirtherapeuticeffectiveness. Extracellular the culture microenvironment ofMSCscanbemanipulated vesicles tothistherapeuticoutcome,andexamininghow This current studyisassessing thecontributionofextracellular immune response inamurine modelofinflammatoryarthritis. swelling andcartilagedestructionthrough modulationofthe Our previous project demonstratedthatCM-MSCreduces in mesenchymalstemcellconditionedmedium(CM-MSC). bioactive, membrane-boundextracellularvesicles(EVs)found mechanisms, viagrowth factors, cytokines,chemokinesand properties andfunctionpredominantly through paracrine (MSCs) possessanti-inflammatoryandimmunosuppressive and more effective therapyforRA.Mesenchymalstemcells up to18years.Forthatreason, itisvitaltodevelopanew for RAandlifeexpectancyofsufferers maybereduced by progressive destructionofarticularcartilage.There isnocure characterised bysynovialinflammationthatleadsto Rheumatoid arthritisisapainfulautoimmunedisorder Charity RheumatologyAssociationandRJAHHospital Oswestry Funding wasprovidedbytheOrthopaedicInstituteLtd, Stefan, OksanaKehoe Alasdair Kay, RebeccaMorgan,MaireadHyland,Andrei Arthritis Severity inInflammatory Vesicles A Derived Extracellular Mesenchymal StemCell- below; The projects whichweare currently workingare explained ttenuate Disease RHEUMATOLOGY AND METABOLIC MEDICINE 7 Figure 3. The effect of intra-articular injections of MSCs in Figure 3. The effect of intra-articular injections of AIA animals AIA model. Change in knee diameter (swelling) significantly following MSCs treatment (or control) shows 3 post arthritis greater alleviation of swelling at days 2 and induction. the histology of the joints from the AIA arthritis model. Semi- model. AIA arthritis the from the joints of the histology groups and untreated treated assessments of the quantitative the influence of to determine being acquired currently are cell types of RA. Both the development MSCs in ameliorating we 3). Currently, in our model (Figure joint swelling reduced on has effect deletion of syndecan-3 assessing whether are of RA such as hyperplasia of histopathological symptoms of inflammatory cells and cartilage synovium lining, infiltration whether deletion will demonstrate depletion. The results an alternative therapeutic of syndecan-3 may represent in inflammatory disease. approach of Uncovering the role in exosome proteoglycans biogenesis for improved medicine regenerative therapies Rebecca Morgan, Cathy Merry*, Oksana Kehoe, *University of Nottingham in Funded by EPSRC/MRC Centre for Doctoral Training Regenerative Medicine small particles called exosomes which contain Cells secrete various components that give the exosomes a specific activity. These exosomes could be used as an advanced therapeutic depending on the particular variety for a number of disorders, of components incorporated into the exosomes during their to develop a method of manipulating the aim We production. for these components, thus gaining control selection process aim to do of the end therapeutic activity of the exosome. We called this by disrupting a complex carbohydrate structure heparan sulphate (HS). HS is believed to be involved in the of exosomes and may also be a key factor in production incorporated into exosomes. selecting which components are We are examining the effect of a single injection of syndecan-3 the effect examining are We mesenchymal stem cells knockout and wild type bone marrow analysing currently are in our model of rheumatoid arthritis. We Andrei Stefan, Alasdair Kay, Nick Forsyth, Fiona Jones*, Dada Nick Forsyth, Fiona Andrei Stefan, Alasdair Kay, Pisconti*, Oksana Kehoe *University of Liverpool Funded by Orthopaedic Institute, Keele University School of Medicine and Oswestry Rheumatology Association The in vitro effect of syndecan-3 gene knockout on bone marrow derived mesenchymal stem cells’ (Preclinical properties studies) Figure 2. Therapeutic outcomes in an inflammatory arthritis as a measure of model (AIA). (A) Alleviation of joint swelling show significant therapeutic efficacy following EV treatments day 2 and day influence of EVs compared to controls at swelling. (B) 3 after arthritis induction, normalised to peak pathogenesis Examination of histological signs of arthritis therapeutic effects following EV treatment shows significant of EVs sourced from normoxic and pro-inflammatory pre- conditioned MSC cultures. B A ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC RHEUMATOLOGY AND METABOLIC MEDICINE 8 Funded bytheOrthopaedic Institute #University ofChester;*#Cardiff University) (* RJAHOrthopaedicHospital NHS FoundationTrust; AledClayton*#, OksanaKehoe Amarasena*, EmmaWilson#, Mairead Hyland,ClaireMennan,KarinaWright,Roshan Arthritis Agents forRheumatoid Vesicles asTherapeutic Derived Extracellular Mesenchymal StemCell- so thatfurtheranalysiscanbecarriedout. cultured inbioreactors toobtainlargequantitiesofexosomes been characterised.Thesemutatedcelllineshavenow Cas9). Theresulting alterations totheHSstructures have production ofHSusinggenetic editingtechnology(CRISPR- lines withknockoutmutationstoenzymesinvolvedinthe Disruptions toHShasbeencarriedoutbyproducing cell exosomes. of theexosomestructure(C).Arrowsindicatepresence out onthesameEMgridtoobtainhighresolutionimages microscopy (B).Electroncouldthenbecarried seen bothbynormallightmicroscopy(A)andfluorescent (calcein AM)toallowforvisualisation.Exosomescanbe Exosomes havebeenstainedwithagreenfluorescentdye bioreactor culturesonelectronmicroscopy(EM)grids. Figure 4.Fluorescentimagingofexosomesobtainedfrom (Figure 4). by fluorescent imagingofexosomesandelectron microscopy surfaces isunderwaywhichinvolvesflowcytometryfollowed Development ofamethodtolookatcomponentsonexosome methods tocharacteriseexosomesandtheirHSstructures. techniques. Thishasallowedfortheoptimisationof exosomes. Thiswasnotpossibleusingstandard culture for theculture ofcellsinorder toobtainlargeamounts of In thepast12months,bioreactors havebeenestablished ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 Figure 6.SoapboxScienceevent atStoke-on-Trent, July2019 discussion topic“Couldstemcellscure arthritis?” Hanley on6thJuly2019.DrKehoeshared herworkwiththe on-Trent hostedthefirsteverSoapboxScienceeventin promoting womenscientists andthesciencetheydo.Stoke- Soapbox Scienceisanovelpublicoutreach platformfor Soapbox Scienceevent,Stoke-on-Trent, July2019 isolated EVs. Figure 5.Transmission electronmicroscopyimagingof in theblood. it aimstoseeifthesevesiclescansupress inflammatorycells the bloodfrom patientswithrheumatoidarthritis.Specifically, project explores thefunctionoftheseextracellularvesicles on sphere shapeofvesicles(Figure 5).Thenextstageof this transmission electron microscopy andrevealed aconsistent Morphological evaluationofisolatedEVswasperformedby size andprotein characteristicshavealsobeenidentified. successfully isolatedfrom stemcellsandtheconcentration, reduce inflammation.Sofar, extracellularvesicleshavebeen understand howtheycanhaveanimpactinourbodiesto characterising thesevesiclesfrom thestemcellsinorder to particles calledextracellularvesicles.Thisproject focuseson stem cellsworktoreduce theinflammationby releasing tiny have beenshowntoreduce inflammationinthebody. These arthritis, specificallyumbilicalcord mesenchymalstemcells cells hasemergedasapromising treatment forrheumatoid swelling injoints.Research lookingatmesenchymalstem is achronic inflammatoryconditionwhichcausespainand as atreatment forrheumatoidarthritis.Rheumatoidarthritis This project aimstoseeifextracellularvesiclescanbeused RHEUMATOLOGY AND METABOLIC MEDICINE 9 Dr Diane Powell (pictured below) also received the Education the below) also received (pictured Dr Diane Powell of Achievement at the Celebration and Learning Award by Chris Beacock, Non- in November 2018 presented awards of RJAH Hospital. Executive Director Research in the Charles Salt Research Laboratories completed on the study of long term intravenous was Work on quality of life, bone density and fracture. Pamidronate is the longest This study with a median follow up of 9 years with osteoporosis. study investigating quality of life in patients and with initial scores by 25% compared Pain had improved experienced an 52% of patients at the end of 9 years had in pain. improvement in the spine, such Although bone density had increased was not evident at the femoral neck. Vertebral an increase with time. rates tended to increase fracture had a beneficial effect suggest that Pamidronate These results on vertebral fracture on pain, but over time a lesser effect and bone density at the femoral neck. These and other data 20 years ago that earlier prediction supported our previous identification of low bone density (a significant risk factor might attenuate the with subsequent treatment for fracture) age. rate in patients with increasing fracture bone density In a study commenced in 1997 we measured applying in almost 12,000 women aged 50-98yr and we are these patients to find out their for ethical permission to revisit rates. persistence and fracture subsequent treatment to follow up body composition Following ethical agreement completed in patients with coeliac disease, we have recently hope to be in a accessing and encoding all the data. We position to commence writing up by the end of this year.

The data was presented as an oral presentation by Dr Diane as an oral presentation The data was presented We Abstract Award. a Conference Powell and also received a paper on the data. A poster was preparing currently are incidence in subjects who had on fracture also presented found that the We treatment. 5 years of alendronate received 12% of subjects on a bisphosphonate holiday had a fracture fracture of an osteoporotic with the biggest single predictor being age over 75 years. We presented data at the National Osteoporosis Society data at the National Osteoporosis presented We of alendronate in December 2018 on the effect Conference and discontinuation on femoral neck bone density. treatment that subjects who had a better bone density showed We at the hip also had a treatment to alendronate response at the lumbar spine than those with a bigger response following at the hip. However, poor bone density response at the hip response discontinuation the subjects with a better treatment. likely to lose bone off more were Last year in the laboratory over 1600 patient samples were over 1600 patient samples were Last year in the laboratory marker urinary N-telopeptide analysed for the bone resorption of type I collagen (uNTx), a long established marker crosslink as part of the clinical service. The marker of bone breakdown monitor treatment efficacy, is used to monitor treatment Our turnover. holidays and to determine baseline bone is primarily in the use of uNTx to interest research current during a and the bone response response monitor treatment of a drug continuing to study the effect are We drug holiday. on bone turnover, bisphosphonate treatment holiday from and bone mineral density. rates fracture The bone health service currently has eight members of staff has eight members of staff currently The bone health service service and clinical service in covering clinical measurement unit. The service also has 5 part the DXA (bone densitometry) speciality doctors and a specialist nurse time consultants, two both at the RJAH and in treatments who gives intravenous year we scanned over clinics. In the last financial outreach the from treatment patients received 8200 patients and 1400 nurse for their bones. Bone Health Clinical Service Clinical Bone Health METABOLIC MEDICINE AND BONE AND MEDICINE METABOLIC ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC THE WOLFSON CENTRE FOR INHERITED NEUROMUSCULAR DISEASE (CIND).

Inherited muscle-wasting conditions affect approximately 1 in The Muscle Team won a Meridian “Celebration of Innovation” 1000 people, and to date, there are upwards of 50 discrete award for embracing genomic medicine and the potential diseases, each of which is defined by a distinct genetic of 100,000 Genomes Project to transform the way health is mutation. Patients commonly present with progressive muscle delivered in rare disorders. weakness but the severity and complications vary dramatically between the different diseases.

Research at the Wolfson Centre for Inherited Neuromuscular Disease is focused on some of the most severe and devastating muscle-wasting diseases including muscular

MOBILITY GROUP dystrophies, and the childhood form of motor neuron disease, spinal muscular atrophy. The clinical research team are actively engaged in several pioneering clinical trials and studies involving patients at RJAH and further afield. The internationally-recognised laboratory team, meanwhile, work to find new ways to diagnose and treat inherited neuromuscular diseases. By designing and developing highly specialised research tools and combining these with the use of cutting edge “omics” technology, their research aims to unravel the complexities of disease mechanisms and identify new targets for therapy development.

The laboratory team work closely with the clinical team so that scientific advancements can benefit patients as quickly as possible. As a group, they are highly committed to training the next generation of scientists and doctors at RJAH, and work closely with affiliated Universities at Keele, Manchester and Chester, to deliver this. The Clinical Research Team: RJAH “Best Individual Achiever” and Meridien “Celebration of Prof Tracey Willis, Dr Richa Kulshrestha, Mr Nigel Kiely, Dr Innovation” Awards Yvette Easthope-Mowatt, Mr Nick Emery, Mrs Claire Bassie, Mrs Kerry Jones, Mrs Jenny Moustakas The Laboratory Research Team welcomed two new members, The Laboratory Research Team: Dr Sharon Owen and Emily Storey, both working with Dr Prof. Caroline Sewry, Prof. Glenn Morris, Dr. Heidi Fuller, Dr Ian Heidi Fuller on new projects. Sharon is working on a Spinal Holt, Dr Le Thanh Lam, Dr Sharon Owen, Darija Šoltić, Emily Muscular Atrophy project funded by Sparks and Great Storey Affiliate member: Dr Melissa Bowerman (Keele) Ormond Street Hospital while Emily Storey is a Keele PhD Funded by the Orthopaedic Institute Ltd student working on congenital muscular dystrophy. Dr Fuller The Muscle Team has successfully retained its status as a was promoted to Senior Lecturer at Keele University and has ‘Centre of Clinical Excellence’ for paediatric and adult patients, joined the editorial boards of both “PLOS ONE” and “Scientific an award given by the Muscular Dystophy UK (MDUK) Charity Reports”. at a ceremony on 15th September 2019. MDUK reviews the Dr Heidi Fuller and Dr Sharon Owen presented their research centres providing neuromuscular care every three years. into identifying treatment strategies for children with spinal Tracey Willis has been appointed by Chester University as muscular atrophy (SMA) at the launch event of No Time Professor of Paediatric Neurology and recognized by RJAH as to Lose, a campaign by children’s medical research charity “Best Individual Achiever, 2018”. Sparks. This charity fundraising event in London was hosted by its patron, Gabby Logan.

10 ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 UK. Although recent research has led to breakthroughs in the MOBILITY GROUP treatment of SMA type 1, it is not clear whether the underlying causes of this type are shared by other types of SMA. In the new Sparks research project, led by Dr Heidi Fuller, Dr Owen will study the biology of the different types of SMA and identify new drugs that could help to treat those children.

Darija Soltic gave an oral presentation of her work at the annual “Cure SMA” Congress, held in July this year in Anaheim, California, and work based on her Ph.D. thesis has been accepted for publication in “Human Molecular Genetics”. Dr Fuller chaired a session at the UK SMA Research Conference at Keele University in January, 2019.

The MDA Monoclonal Antibody Resource

Monoclonal antibodies produced by CIND are made freely Dr Owen and Dr Fuller at the “No Time to Lose” launch event available internationally and the cell lines that produce in London them have been given a safe and permanent home in the Developmental Studies Hybridoma Bank (University of Clinical Research Projects Iowa). However, Dr Le Thanh Lam is continuing to respond to antibody requests from academic researchers worldwide. The Muscle Team has participated in multicentre studies of the These mAbs have played a major role worldwide in clinical natural history of SMA (SMA Reach project) and the genetics trials of new treatments for the muscular dystrophies. of Duchenne muscular dystrophy. Prof Morris was a co-author on “Report of a TREAT-NMD/ The Muscle Team has successfully recruited patients to two World Duchenne Organisation Meeting on Dystrophin pharmaceutical trials: SIDEROS, a placebo-controlled trial Quantification Methodology” published in Neuromuscular with idebenone, targeting mitochondrial function in Duchenne Disorders in June 2019. muscular dystrophy, and ITALFARMECO, another placebo- controlled trial aiming to reduce fibrosis in dystrophic muscle. Nemaline Myopathy It has also successfully completed a pilot study of arm cycling in patients with facioscapulohumeral dystrophy. Nebulin is a very large (600-900kDa) protein of the muscle contractile system and genetic mutations are a major cause The results were presented at UK Neuromuscular Translational of the inherited mobility disorder, nemaline myopathy. There Research conference in Newcastle-upon-Tyne. Funding are two forms of nebulin, one containing “exon 143 protein” is secured for another study in this patient group to study and another in which this is replaced by “exon 144 protein”. biomarkers and their variation with exercise. We used new monoclonal antibodies, specific for 143 or 144, to show that 144 is the isoform present in cultured muscle Spinal Muscular Atrophy precursors.

During the last two years, treatment of SMA has been Our collaborative work with the University of Helsinki was greatly advanced by availability of Nusinersen, an intrathecal supported by the Orthopaedic Institute and has now been treatment, for patients with severe SMA type 1 through published in Scientific Reports. In a new project (2018-2020) Managing Access Program. The Clinical Team has been supported by the Orthopaedic Institute, we are seeking to the main hub in collaboration with University Hospital of identify proteins that bind to nebulin isoforms with either exon North Midlands in the West Midlands region for delivering 143 or exon 144. A protein called KHLH40 seemed a likely this complex treatment. The recent approval of this drug by candidate because human mutations in KHLH40 can also NICE and NHS England will now allow for the treatment to be cause nemaline myopathy. However we found that both accessed by less severe SMA type 2 and type 3 patients. nebulin isoforms, when attached to beads, showed equal binding to KHLH40 in human muscle or myotube extracts. SMA is the most common genetic cause of death in infants in Other candidates are being investigated. the UK, and it is estimated that there are approximately 2,000 – 2,500 children and adults living with the condition in the

ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 11 MOBILITY GROUP 12 POPDC2 (green)andXIRP1(red)arebothfoundatintercalated disks(arrow)andatactinbandsofmusclefibresintheheart London, Sep3rd-5th, 2019. MeetingonLaminopathiesheldin and 2ndInternational UK NuclearEnvelopeandChromatin OrganizationMeeting been submittedforpublicationandwaspresented atthe9th cause Emery-Dreifuss MuscularDystrophy. Thisworkhas different genes(emerin,laminA,SUNandnesprin-1) canall These studieshelpustounderstandhowmutationsinseveral cardiomyocyte nucleiinvolvedincardiac function. neuromuscular junctions.Inheart,itwasfoundonlyinthe found, togetherwithkinesin,onlyonnucleiassociated muscle cellcultures. Inadultmuscle,nesprin-1-alpha2was alpha2 andnesprin-1-giantco-localisewithkinesininhuman Foundation, wehavenowshowndirectly thatbothnesprin-1- specific antibodiesinastudysupportedbytheBritishHeart for relocation ofnucleiduringmuscledevelopment.Using of nuclei.Theshortisoform,nesprin-1-alpha2,isrequired by theSYNE1andSYNE2genes,are involvedinlocalization Nesprins (nuclearenvelopespectrin-repeat proteins) encoded muscular dystrophy Nesprins andEmery -Dreifuss ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 conduction defects. known tobeassociatedwithheartpathologyandcardiac actin andXIRP1(Xinactin-bindingrepeat protein 1),a protein interaction ofbothPOPDC1andPOPDC2withcardiac requires apacemakertobefitted. We havenowshownan that mimic“sicksinussyndrome” inhumans,adisorder that Mice lackingPopeyeproteins havecardiac conduction defects dystrophy. conduction defects,similartoEmery-Dreifuss muscular can causeaformoflimb-girdle musculardystrophy with the BritishHeartFoundation.MutationsinPopeyeproteins the NationalHeartandLungInstitute(London)fundedby proteins foracollaborativeproject withThomasBrand of monoclonal antibodies(mAbs)againstPopeye(POPDC) Dr IanHolthascontinuedtodevelopandcharacterizenew Conduction Popeye roteinsandCardiac MOBILITY GROUP 13 set up a national programme for sharing and learning coding, set up a national programme is being labs. That programme working in gait aimed at staff Keele a collaborator of ours from run by Dimitra Blana, University. Movement Analysis to ORLAU. Gross In January 2019 we welcomed Dr Raphael Nantes in France and doctor from Raphael is a rehabilitation he joined us for a 6 month fellowship to study muscle co- by the covered in the upper limb. His costs were ordination Orthopaedic Institute, funding which made the visit possible. He and the ORLAU team have been busy collecting and looking are We lots of volunteer children. analysing data from to our and applying his approach to seeing the results forward patients with hemiplegia. key funding for our The Institute have also provided is postgraduate students. PhD student Shallum Sardar looking at the calf muscle, in particular how the morphology He has been working of the muscle changes after treatment. with Myurah Nathan, our clinical scientist trainee. Myruah but she was for her MSc project looked at the same children in studying the muscle using imaging. She worked interested with consultant radiologist Naomi Winn to collect ultrasound is an imaging Elastography elastography data. Shear Wave Myurah technique which aims to quantify tissue stiffness. in the Spring, whilst successfully completed her research Shallum continues to collect data.

ORLAU technical staff have been developing their expertise ORLAU technical staff in 2019 Early in writing computer code over the last year. a grant by CMAS (the gait analysis society awarded we were The grant has allowed us to covering the UK and Ireland). Individual members of staff are involved in teaching nationally are Individual members of staff and internationally came together to run but in 2018 we our first gait analysis course in some years. The course of the was organised by Sarah Jarvis under the umbrella excellent feedback Orthopaedic Institute and we received our delegates. The same course ran again in June from planning a new course, in contracture 2019 and we are management, for the Autumn, led by engineer Keith Miller and physiotherapist Will Bromwich. Education very keen to pass on our expertise and learning to are We As the last year. others and this work has continued over a department we support national training initiatives for have also put a physiotherapists and clinical scientists. We to support his bespoke course together for Matthew Hardy in the community. new role All this clinical work feeds into our research plans for the All this clinical work feeds into our research future. Our rehabilitation engineering team have also been busy, engineering team have also been busy, Our rehabilitation our patient developing and testing new designs to improve services in the devices. The team also look after ORLAU’s has been busy running our Matthew Hardy community. taken over from Community Standing Frame Service, having have also in the Summer of 2018. We Graham Richards new digital technology to our transportable gait introduced laboratory. ORLAU is a busy department and there has been plenty going and there ORLAU is a busy department of patients a steady stream continue to see We on this year. or supply of assistive devices for analysis of their movement the years we have built up a reputation and orthotics. Over which inevitably means walk better, for helping patients to limb service has been our upper recently studying legs. More the number of clinics in the and we hope to expand growing their arm function. adults with so we can help more future continuing to develop our gait analysis services too are We with the working recently, and saw our first amputee patient Wrexham. at Artificial Limb and Appliance Service (ALAC) ctivity Clinical A

LOCOMOTOR ASSESSMENT UNIT) ASSESSMENT LOCOMOTOR ORLAU (ORTHOTIC RESEARCH AND AND RESEARCH (ORTHOTIC ORLAU ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC MOBILITY GROUP Manufacturing Services(RMS)Ltd,whonowsupplyuswith we havedevelopedanewrelationship withRehabilitation particularly importantforourdevelopmentworkandthisyear significant developmentsthisyear. Industrialpartnersare The RehabilitationEngineeringteamhaveseenanumberof Rehabilitation Engineering Simon Pickard. Ed Chadwickfrom KeeleUniversity, workingwiththeTrust’s arm functioninpeoplewithhigh-leveltetraplegia’,ledbyDr for astudyentitled‘Personalisedapproach torestoration of have beensuccessfulingainingfundingfrom theEPSRC research. AlongwithRaphaelandMohammad’s workwe to seeourgrowing upperlimbclinicsalsoreflected in our to quantifythebenefitsofusing Lycra garments.Itisgreat upper limbfunctionincerebral palsy. Mohammadhopes working hard togainethicalapproval forhisstudy, assessing Another PhDstudent,MohammadAlshehab,hasbeen 14 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 year. forward togivingmore detailsaboutthesenewprojects next study ofthesubtalarjointincerebral palsy. We willlook for 2020,includingworkinthesocialsciencesandadetailed in growing ourknowledge and havenewprojects linedup alongside teachingandresearch. We are alwaysinterested In conclusionORLAUiscontinuingtodevelopclinicalservices, patients. to developourown,thatmeetsthespecificneedsof that weadapttosuitourneedsbutthetimehascome standing frames.Thecurrent bracketisacommercial one bracket tohelpusattachheadsupportsourrangeof Engineer, Simon Marchant isalsodevelopingabespoke families. home shouldbemademucheasierforthepatientsandtheir device transportationtoandfrom clinic,aswellstorageat and weight.Bysafelydisconnectingthetwohalvesof struggle totransportthemduetheircumbersomesize we seenumerous patients withthesetypesofframeswho Standing Frame.Thisisamuchneededdevelopmentas detaching theupperandlowersectionsofanAdultORLAU are currently developingasafeandsimplemethodof By usingmoneyprovided byacharitabledonation,we with thehelpofanappropriate industrialpartner. opportunities tofurtherimprove andcommercialise this device through ORLAU.Inthecomingyearourintentionistoexplore supplying thenewleversroutinely toallankleCCDssupplied CCD wasdesignedanddevelopedinORLAU.We are now (CCD) incollaborationwithRicohRapidFabLtd.Theoriginal doffing leverforouranklecontracture correction device Last yearwereported theearlydevelopmentofadonning/ Grillo widensouroffering forwalkingdeviceassessments. delay, italsoresults inafurtherpatientappointment.The typically 6-12weeks,sonotonlycanthatcauseaninevitable our otherdeviceshavemuchlongerleadtimesfordelivery, they canoftentaketheframehomeimmediately. Manyof has adramaticeffect onthedeliverytimeforpatient,as patient, withRMSchargingforthem,asweissuethem.This of thesedevices,whichwecanusetoassessandsupplythe relationship thathasresulted inthemproviding asmall‘stock’ Italy. We haveworkedhard behindthescenestodevelopa the Grillorangeofdevices,manufactured byOrmesain CELL THERAPIES 15 questionnaire completed by patients who have previously have previously by patients who completed questionnaire for cartilage at this hospital here this treatment received the quality of the have assessed their knee. We defects of defect using magnetic treated tissue which forms in the repair with clinical if it correlates imaging (MRI) to see resonance outcomes. on the MRIs identifiable found that certain features We well the patient felt at a year significantly with how correlated and composition of repair (eg the amount after treatment how well it was integrated with the tissue which had formed, bone, how smooth the surface was adjacent cartilage and beneath). What may no cysts in the bone were and if there at 1 year be particularly useful is that 3 of these parameters (how much tissue, its composition and the after treatment the clinical outcome smoothness of the surface) all affected This could in the long term (up to 17 years after treatment). that long term be particularly useful for clinical trials, meaning led multicentre follow up such as is ongoing in the Oswestry Implantation (ACI) in ACTIVE, trial of Autologous Chondrocyte up for 10 years could be avoided. Instead of following patients how well those in person, an MRI at 1 year could predict which could be a huge patients would do with this treatment, et al (2018) cost-saving in running such trials. (McCarthy Orthop J Sports Med. 2018 Aug; 6(8): 325967118788280) ER DISCOVERY IN BIOMARKER DISCOVERY MATCHING ORTHOPAEDICS: TO THE BEST PATIENTS TREATMENT Sally Roberts, Peter Gallacher, Charlotte Hulme, Heidi Fuller, Karina Wright Arthritis Funded by Versus a few patients who have their As in all treatments, such as using biological approaches, osteoarthritis treated do not respond cell therapies, osteotomy or microfracture, Our previous so well as others, though we do not know why. work has identified particular molecules in synovial fluid or blood known as ‘biomarkers’ that have the potential to identify clinically following the unlikely to improve which patients are implantation cell therapy known as autologous chondrocyte markers (ACI). These investigations focussed on protein of cartilage to poor repair whose biology is known to relate and or general inflammation e.g. an enzyme, aggrecanase-1, another molecule involved in the immune system, CD14. has used a highly specialised work, however, Our recent to identify larger numbers of technique called proteomics within the synovial fluid in the knee altered which are proteins well to ACI. The of patients who either do or do not respond include many that have identified using this approach proteins provide and which therefore never been investigated before

Since 2010, we have been collating data from a Retrospective a Retrospective Since 2010, we have been collating data from study of Autologous Cell Therapy (REACT), using a postal Helen McCarthy, Iain McCall, Claire Mennan, Mike Williams, Iain McCall, Claire Mennan, Helen McCarthy, James Richardson and Sally Roberts Arthritis and the MRC Funded by Versus PREDICTION OF CLINICAL OUTCOME FOLLOWING AUTOLOGOUS CHONDROCYTE BY MAGNETIC IMPLANTATION RESONANCE IMAGING Most research is funded by grant applications, for example, is funded Most research council or charities such as Versus the Medical Research from very grateful to the Orthopaedic however are Arthritis. We Institute as the large grant-giving bodies usually require that the Institute fund are data, and the projects preliminary wonderful for obtaining this and help to get the larger grants. Scientists based in the Leopold Muller Arthritis Research Leopold Muller Arthritis Research Scientists based in the continue the long history of and TORCH laboratories Centre to understand joint the RJAH Orthopaedic Hospital seeking has continued them. The group and ways of treating disorders such areas over the last 12 months focussing on particular cells in the as chemical assays of ‘biomarkers’, growing their behaviour laboratory and seeing how we can influence very are We to cell therapy. aspects related and different with clinicians fortunate in RJAH to be able to work closely in often very interested and surgeons who themselves are Much of the work involves analysing material from research. (eg an removed patients undergoing surgery which is being in the bin. thrown arthritic knee joint) and would otherwise be by happy to allow us and the work is approved If patients are Ethics Committee, then we can put this ‘surgical a Research studies can waste’ to good use. For example, biomarker chemical pathways involved in diseases help unravel different of patients can be identified and also to in see if sub-groups than others. The cell more who may suit a certain treatment ‘off-the- if we can produce therapy work includes researching easier for the patient shelf’ which could be much cell products that growing and surgeon to use, as well as being cheaper patients’ own cells in the laboratory as happens now. Members of the Scientific Research Team: Research of the Scientific Members Mennan, Jan Herman Karina Wright, Claire Sally Roberts, Hulme, Charlotte Johanna Wales, Helen McCarthy, Kuiper, Garcia, Mike Williams,Sharon Owen, John Barbara Linklater- Nikki Kuiper and PhD students, Jade Jones, Paul Harrison, Sykes (Kobe), Jessica Hopkins, Jingsong Wang Tim Perry, (Cardiff). and Angus Armstrong-Twigg Clinical Support: Paul Jermin, Drs Bernhard Tins, Messrs Peter Gallacher, Iain McCall and all surgeons in RJAH Professor Andrea Bailey, CARTILAGE RESEARCH GROUP RESEARCH CARTILAGE ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC CELL THERAPIES individuals whocurrentlydonotbenefitfromACI. pre-operative levels.Thissignallingpathwayisthereforelikely tobeagoodtargetfornewdrugsimprovetheoutcome comparedto following ACI.Proteinsinredwereincreasedandproteinsgreendecreased followinginitialACIsurgery Figure 1:AcutePhaseSignallingisanexampleofabiologicalpathwaythatalteredinpeoplewhodopoorly successful. outcomes forpatientsinwhichitwouldnotcurrently be 1). Thesestudiesmayhelpusidentifywaystoimprove ACI improve followingACIcompared tothosewhodonot (Figure such as‘acutephaseresponse signalling’inindividualswho procedure maybeaffecting different biologicalmechanisms, complex computerprogrammes, toinformusofhowtheACI In addition,wehaveused‘bioinformatic’analysis,using discovery platform,providing addedconfidencetoour results. an independentgroup ofpatientsusingadifferent multi-plex addition, theMMPcandidateshaverecently beenvalidatedin a patientissuitabletocontinuethrough theACIprocedure. In and MMP3,havethepotentialtoinformusofwhetherornot four oftheseproteins, S100A13,MMP1,ComplementC1S attractive newcandidates.To date,wehaveconfirmedthat 16 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 people painfree andbacktotheirnormallivesquicker. only savethehealthservicemoney, butmostimportantlyget the besttreatment forthatparticularperson.Thiswouldnot be usedtohelpthesurgeonandpatientdecideonwhatis to identifyareliable panelofmolecularmarkerswhichcan after theirosteotomy. We hopethatthisworkwillhelpus to theclinicalfunctionalscores thatpatientsachieveayear of protein withinthesynovialfluidbefore anoperation relates shown thattheamountofbothS100A13andtotal treatments, suchasosteotomyormicrofracture. We have help uspredict whattheoutcomemightbefollowingother We havegoneontoseeifanyofthese‘biomarkers’can CELL THERAPIES 17 ACTORS THAT THAT ACTORS Timothy Hopkins, Karina Wright, Sally Roberts, Nicola Kuiper, Nicola Kuiper, Hopkins, Karina Wright, Sally Roberts, Timothy Jan Herman Kuiper. Institute Funded by the Orthopaedic to investigate approaches uses several different This project impact on human knee health. factors that have an the most common joint disease in Osteoarthritis (OA) is not fully still are and progression the world, but its onset specifically a traditionally considered understood. Although cartilage (AC), OA is now regarded disease of the articular involves all tissues and affects that as an ‘organ-level failure’ tissues, the of the joint rather than the AC alone. Of these given the subchondral bone (SB) is of particular interest signalling pathways close physical interaction and shared a series project, between the two tissues. In this part of the being performed to test if cells taken from of experiments are unhealthy areas of the SB, and those taken from healthy areas characteristics that could point to of the SB, have different we are 2 and 3). Subsequently, their involvement in OA (figure have regions these different investigating whether cells from the of cells isolated from on the characteristics effects different This is carried out using a ‘co-culture’ cartilage (chondrocytes). the SB and cells from 4), in which the cells from model (figure that together but separated by a membrane grown the AC are contact but allows communication between the cells. prevents is to try and characterise The aim of this part of the project between the AC and SB and the part that this the relationship of OA in the plays on the onset and progression relationship knee. Figure 2. Cartilage (left) and bone (right) removed during A: Healthy region of the SB. routine knee replacement surgery. B. Unhealthy region of the SB. Figure 3. Subchondral bone cell outgrowth culture. Bone chips removed from A. ‘Healthy’ site (left) and B. ‘Unhealthy’ site (right) are seeded into cell culture flasks. Cells migrate out of the bone chips after 7-10 days. BIOLOGICAL, PHYSICAL AND AND PHYSICAL BIOLOGICAL, F PSYCHOSOCIAL F THE O HEALTH AFFECT THE KNEE. HUMAN We are working on using state of the art RNA-sequencing of working on are We the transcriptome of UC-MSC donors with either high or low to inflammatory cytokines (as assessed via IDO gene response This should help to identify the most potent cells expression). for allogeneic cell therapy and cell banking. The International Society for Cell Therapy (ISCT) advises that therapy should characterisation of MSCs destined for cell include activation or ‘licensing’, which involves stimulation gamma with inflammatory molecules such as interferon (IFN-γ), either alone or with TNF-α. These molecules are often found in joints of patients with rheumatoid arthritis of molecule such as or osteoarthritis. The production known to indoleamine 2,3-dioxygenase (IDO), which are dampen down inflammation, only occurs following activation We have found, however, with these inflammatory cytokines. in how differently cells can respond peoples’ that different This suggests that it would be much IDO they produce. important for cells destined for allogeneic cell banks to have their immunomodulatory potential tested prior to banking, to to inflammatory cytokines for each characterise the response donor. Mesenchymal Stromal Cells (MSCs) isolated from bone isolated from Cells (MSCs) Mesenchymal Stromal for to be the “gold standard” considered are (BM) marrow However, cell therapy. MSC populations which can be used for limited numbers them can be painful and provide sourcing potential as an (UCs) show great of cells. Umbilical Cords away normally thrown alternative of MSCs as they are source than BM-MSCs, faster in culture and also UC-MSCs proliferate quicker which would allowing larger numbers to be produced large numbers of allogeneic cells for be necessary for creating numbers of patients. UC-derived MSCs also greater treating immunomodulatory have an immune-privileged status and an less likely to elicit an immune phenotype (meaning they are from), not sourced when used in a person they were response for allogeneic cell again making them attractive candidates on has focussed work in our group based therapies. Previous whole UC and characterising the cells’ MSCs from sourcing such in an inflammatory environment, modulatory properties joint. as that which may be found in an inflamed Claire Mennan, Helen McCarthy, Daniel Tonge & Sally Roberts Daniel Tonge McCarthy, Claire Mennan, Helen Institute and Versus Funded by the Orthopaedic Arthritis TRANSCRIPTOME ANALYSIS ANALYSIS TRANSCRIPTOME CORD- OF THE UMBILICAL STROMAL MESENCHYMAL RESPONSE THERAPEUTIC CELLS’ WITH A TO INFLAMMATION, KING THE MOST VIEW TO BAN FOR ALLOGENEIC POTENT CELLS THERAPY. ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC CELL THERAPIES function variation intherelationshipbetween activitylevelsandknee Figure 5.Sampleof27patients demonstratingindividual function andattitudestopain. activity levels,alongsidevalidatedscoringsystemsforknee (Figure 6)toprovide amore accuratemeasure ofpatients’ an activityquestionnaire, using wearableactivitytrackers rehabilitation. We nowplantobuildonthisstudy, whichused and viceversa.Thishasimplicationsfortheprescription of report improved kneefunctionwithincreased activitylevels affect score andlownegativeaffect score are more likelyto symptoms. We demonstrated thatpatientswithahighpositive to varybetweenpatientsandinfluenceperceived disease is describedintermsofpositiveandnegativeknown this variationbetweenpatients.Affect, thefeelingofemotion, Figure 5).We thensoughttofindfactorsthatcould explain between patients(asampleoftheseisshownin between activitylevelsandkneefunctionvariessignificantly rehabilitation followingcelltherapy, thattherelationship We haverecently shown,inastudyof64patientsundergoing to playapartinthisvariabilityisthepatient’s activitylevels. basis, week-to-weekorevenday-to-day. Onefactorthought there alsoappearstobevariationoveramore short-term knee functionisknowntovaryovertheirlifetime.However, Another partofthisproject isbasedintheclinic.Apatient’s and cartilagecells. Figure 4.Schematicillustratingtheco-culturesystemofbone 18 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 even thoughtheywere from adifferent species(atleastat to elicitaninflammatory response inthetreated groups, tomography (micro CT),theimplantedcellsdidnotappear by thePMM,asassessedhistologically orbymicro computed transplanted UC-MSCsdidnotrecover jointdamageinduced operated groups. Ourresults demonstratedthatalthoughthe of cartilageandosteophyteformationappearinginthe model) mimicsend-stageosteoarthritis,withsevere loss One ofthese(calledthePMMorpartialmedialmeniscectomy treatment ofOA. allogeneic (i.e.from anotherperson)source ofcellsforthe joints. Ifsuccessful,itislikelytheycouldbeanexcellent to determineiftheycanhelprepair orregenerate damaged are examiningtheeffect ofasingleinjectionUC-MSCs could delayosteoarthritisintheirmodels.Specifically, we other universitiestoseeifthecellsprepared here inOswestry individual. We are currently workingwithcollaboratorsin and makeanimmunereaction lesslikelyifusedinadifferent to haveanti-inflammatoryproperties, whichmaybeuseful they are fairlyeasytoobtain andgrow andtheyalsoappear an attractivesource ofcells forregenerative medicinesince umbilical cords (UC-MSCs) forsomeyearsnow. Theseare mesenchymal stromal orstem cells(MSCs)from human be useful.Here inOswestry, wehavebeenobtaining seeing ifabiologicalapproach suchascelltherapycould around theworldare seekingnewapproaches, including non-surgical therapiestoreverse osteoarthritis.Researchers forming. Currently, there are noeffective pharmaceuticalor in thebone,suchasabnormalbonyspursor‘osteophytes’ (causing thejointspacetonarrow), aswellalotofchanges characterised bydegradationandlossofarticularcartilage Osteoarthritis (OA)isacomplexdegenerativejointdisease, Funded byKeeleUniversity&Versus Arthritis Roberts. *LiverpoolUniversity;#AberdeenUniversity Anke Roelofs#,KarinaWright,JamesRichardson&Sally Gharios*, RobVan’T Hof*,PeterMilner*,CosimoDeBari#, Jade Perry, ClaireMennan,HelenMcCarthy, GeorgeBou- Two Preclinical Studies PATIENTS WITHOSTEOARTHRITIS? CORDS BEUSEDTOTREAT CAN CELLSFROMUMBILICAL Figure 6.Wearable activitytracker CELL THERAPIES 19 Jade Perry, Helen S. McCarthy, Sally Roberts, Paul Jermin, S. McCarthy, Helen Jade Perry, B. Richardson, Michael Williams, James Peter D. Gallacher, Bernhard Tins. Arthritis and Versus Funded by Keele University sizes of as to appropriate given guidance Clinicians are estimating However, cell therapy. with cartilage defects to treat scans such as magnetic resonance the size of a defect using situation. the ‘real-life’ from imaging (MRI) may in fact differ study to evaluate the accuracy a retrospective performed We the size of articular cartilage lesions of MRI scans to predict them against actual defect sizes in the knee and compared surgically. recorded 64 patients, all of whom underwent autologous included We RJAH cell implantation (ACI) performed by two different a pre- surgeons (PDG and JBR). Each patient received 6 weeks prior to cell implantation. operative MRI approximately analysed by a Consultant radiologist (BT) and MRIs were PhD student (JP) trained by the radiologist to a research and the ascertain the full-thickness defect measurement that they believed would require total abnormal defect area of damaged/ unhealthy tissue). At the debridement (removal surgeontime of cell implantation, the Consultant orthopaedic and post-debridement. The the defect sizes pre- measured have been used as post-debridement surgical measurements further were All measurements in this study. the ‘gold standard’ to defect location within the knee (patella, assessed according medial or lateral femoral condyle (MFC and LFC)). trochlea, assessed a total of 92 cartilage defects and, as expected, We than found them to be significantly smaller pre-debridement during arthroscopy. post-debridement when measured a radiological perspective (BT), MRI scans date, from To defect size the (pre-debridement) significantly underestimated (so this was found to be similar but not the total abnormal area to the post-debridement size and not significantly different surgically). When considering defect location, MRI measured defect sizes pre-debridement still significantly underestimated Total on the patella and MFC but not the LFC and trochlea. by defect assessment on MRI was not affected abnormal area location. data indicates that measuring only the This preliminary full-thickness component of a cartilage defect on MRI will for ACI; evaluating to treat the area significantly underestimate accurate estimate a more will provide the whole abnormal area This is critical for treatment. of the actual defect size requiring surgical planning. F PRE- O THE SUITABILITY MAGNETIC OPERATIVE IN IMAGING RESONANCE ACCURATE PREDICTING FOR DEFECT SIZES CARTILAGE WITH CELL THERAPY TREATMENT H&E Figure 7. Histology and immunohistochemistry showing the repair tissue which has formed 8 weeks after injury (arrow), with less metachromasia (less staining for Saf O) but significant collagen type II immunostaining compared to the adjacent native cartilage. Cells populating the repaired region appear to have originated from the embryologically-derived cells from the joint interzone, as shown by ‘tomato-positive’ brown staining. The second model used a small isolated injury to the cartilage, a small isolated injury to the cartilage, The second model used osteoarthritis (and so significantly which can lead to secondary In this injury model). than the aforementioned less severe and bone marrow human UC-MSCs model we compared (Quantum®), at a bioreactor in grown (BM)-derived MSCs, secondary OA. preventing cartilage damage and repairing cells did not with treated groups the As in the other study, signs or microscopic macroscopic appear to show any implantation. of swelling/inflammation due to human cell when assessed histologically both human MSC Furthermore, with repair compared had significantly better groups treated 7). Additionally, (ie without cells; Figure group the untreated type II was more immunohistochemistry showed that there tissue of those joints with better cartilage collagen in the repair as well as it containing many ‘tomato’- morphologically, the joint interzone). derived from positive cells (which are UC-MSCs suggest that up-scale manufactured These results therapy for treating and BM-MSCs could be an effective not appear to elicit cartilage injuries. The implanted MSCs did response, further supporting their potential as an inflammatory an allogeneic treatment. the timepoints examined). Furthermore, there was marked was marked there Furthermore, examined). the timepoints reduced with a significantly the UC donors, variability between donor but 12 weeks with one space appearing at loss of joint donors’ suggests that some 2 donors’ cells. This not the other than others, therapeutic potential a greater cells may have of characterising each batch of highlighting the importance therapies. cells for allogeneic cell ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC CELL THERAPIES tibial side. Figure 8:MRIfindingsforPatientsAandB.TheBoneMarrowLesionvolumesdecreasedbothpatients,particularlyon the Though bothscaffolds sometimes showsomeclinicalbenefit, CMI® (collagenscaffold) and Actifit®(polyurethane scaffold). used inclinicacell-free approach asreplacement menisci: the riskofearlyosteoarthritis.Currently, twoscaffolds are is exposedtoexcessiveloading,whicheventuallyincreases vessels in)isdamaged,thearticularcartilageofkneejoint irreparable meniscus(theinneravascularzonewithnoblood meniscal injurieseachyearper100,000people.Whenthe observed intra-articularkneeinjury. IntheUK,there are 60-70 of thekneejoint.Meniscustearsare themostcommonly absorption, jointstability, lubrication,andproprioception Menisci playanimportantrole inforce transmission, shock Funded bytheOrthopaedicInstitute Richardson, KarinaWright Jingsong Wang, SallyRoberts,BernhardTins, James SCAFFOLDS CO-CULTURES ONSYNTHETIC CHONDROCYTES, BMSCSAND COMPARING MENISCUSCELLS, TISSUE ENGINEERING: CELL-BASED MENISCUS 20 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 time (Figure 8). in theirbonebeneaththecartilageappearinglessobviouswith than mightbeexpected,withdefectsorlesionsseenonMRI Interestingly bothpatientsappeartohaveimproved for longer MSCs from thepatients’bonemarrow), 8and9years ago. a combinationofcells(bothautologouschondrocytes and who havepreviously beentreated byProf Richardson with published acasereport lookingat2patients(AandB) Jingsong, withothermembersoftheteamhavealsojust whether thisapproach canbeappliedintheclinic. this purpose.Theresults ofthisstudywillhopefullydetermine Currently heistestingdifferent formulationsoffibringluefor synthesising themoleculesneededforahealthymeniscus. the syntheticscaffolds andseehoweffective theywill beat second year. Heaimstodevelopwaysofseedingcellsinto Chinese orthopaedicsurgeon(JingsongWang) whoisinhis as potentialcellsources. ThisworkisformingaPhDfor (MSCs) from bonemarrow are beingstudiedinthisproject cells (chondrocytes) andmesenchymalstromal/stem cells scaffolds wouldimprove things.Meniscalcells,cartilage failure rate.Therefore, weaimtoseeifaddingcellsthese well withthepatients’owntissuesandtheyhaveafairlyhigh there remain limitations:thegraftsshrink,donotintegrate CELL THERAPIES 21 John Garcia, Charlotte Hulme, Claire Mennan, Sally Roberts John Garcia, Charlotte and Karina Wright Research UK and MRC Funded by Arthritis BCT) is an 9; Terumo (Fig The Quantum® bioreactor which has an internal system, surface automated hollow fibre flasks), tissue culture T-175 of 2.1m2 (equivalent to 120 area published of cells. In recently allowing large scale expansion the Quantum® to assess the work we have been using and umbilical bone marrow human from characteristics of cells to the expansion in the system compared culture after cords plastic technique (TCP), with the aim tissue culture standard for cartilage of using these cells in cell therapies for example, In a newly funded ‘Confidence in Concept’ MRC repair. have looked to transfer these techniques to cells we project in the development of up-scale of cartilage (chondrocytes), therapies. allogeneic chondrocyte manufactured adult donors 4 samples obtained from So far cells from and 2 samples obtained (undergoing total knee replacements) in the (polydactyl) donors have been cultured juvenile from being analysed. currently are Quantum® and the results and harvest using the growth for chondrocyte Techniques being optimised and further MRC Biomedical system are GMP compliance of the Catalyst funded work will ensure manufacturing process. Figure 9: The Quantum® cell expansion system. A. Computerised incubator and control panel. B. Disposable hollow fibre bioreactor module composed of ~11,500 fibres. HUMAN CHONDROCYTES CHONDROCYTES HUMAN IN THE QUANTUM® EXPANDED W-FIBRE BIOREACTOR HOLLO FIRST TIME. FOR THE SYSTEM Figure 9: Illustration of the organisation of collagens type II and type VI in naturally repair cartilage. Brown staining indicates the presence of the collagens. When the cartilage in your joint is damaged, it is often When the cartilage in not heal and would eventually lead to thought that it does we have found evidence that joint degeneration. However, itself without surgical can repair in some instances, cartilage natural healing in patients who studied this intervention. We in their knees as part defect created had an artificial cartilage cartilage Biopsies of the regenerated of a cell therapy trial. after the defect was taken about 12 months tissues were examined in our lab to determine their quality and and created What structure. whether the tissues returned to their original cartilage did we found showed that although the damaged at least it did not return to its normal structure, itself, repair very important are in that timescale. For instance, collagens their organisation molecules in cartilage, and we found that to cartilage compared in the naturally repaired was different that it may help to normal. This information is useful to us in ways of encouraging better understand how we can improve to form. tissue repair John Garcia, Sally Roberts, Bernhard Tins, Paul Jermin, Peter Paul Jermin, Tins, Sally Roberts, Bernhard John Garcia, Caroline Stewart, Kehoe, Karina Wright, Oksana Gallacher, Kuiper Jan Herman Research Council (MRC) Funded by Medical SPONTANEOUS HEALING OF HEALING SPONTANEOUS (SHARC) CARTILAGE ARTICULAR ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC Figure 1: A knee joint with mild osteoarthritis http://www.arthritisresearchuk.org/arthritis-information/conditions/ ASCOT Muscle cell osteoarthritis-of-the-knee/how-is-the-knee-structures.aspx

For the last 3 years we have been recruiting patients into the AUTOLOGOUS STEM CELLS, ASCOT clinical trial, to compare chondrocytes with other CHONDROCYTES OR THE TWO? types of cells which can be obtained from the patient’s bone Autologous cell therapy for osteoarthritis: An evaluation of the marrow, called mesenchymal stem or stromal cells (MSCs). safety and efficacy of autologous transplantation of articular These have been used in a similar procedure to ACI in Japan. chondrocytes and/or bone marrow-derived stromal cells to Stem cells have the potential to develop into many different repair chondral/osteochondral lesions of the knee cell types, including those that form both cartilage and bone. CELL THERAPIES The late Professor James Richardson, Pete Gallacher, Sally MSCs have now also been shown to produce many other Roberts, Jan Herman Kuiper, Helen McCarthy, Bernhard chemicals, some of which seem to reduce inflammation and Tins, Karina Wright, Claire Mennan, Paul Harrison, Barbara help reduce pain. The question we want to answer is would Linklater-Jones, Johanna Wales these MSCs, either alone or combined with chondrocytes, be Funded by the Orthopaedic Institute, Arthritis Research better at repairing cartilage and bone defects in the knee joint, UK and the Medical Research Council than chondrocytes alone.

The trial aims to recruit 114 patients eventually, divided into the 3 different treatment ‘arms’ with the 3 different cell populations (MSCs, cartilage cells or a combination of the two). Progress in the study is shown in Table 1, figures correct as of 20/08/2019.

Target number of patients 114 Subjects Enrolled (randomised) 98 Subjects treated 82 Subjects completed final 15 month follow-up 60

Table 1: Current progress in recruitment and follow-up.

The diagram in figure 2 shows the range of information that Autologous Chondrocyte Implantation (or ACI) is a treatment we will obtain from this study, and which will help us to decide which has been used here in the RJAH Orthopaedic Hospital not only which cell type gives the best result, but also help us in Oswestry for about 20 years on a select group of patients to understand why some patients respond better than others who have injured or have damaged cartilage in their knees to this type of treatment. or ankles. Instead of using artificial material or the more usual drugs, such as steroids or pain killers, cartilage cells (called chondrocytes) have been prepared from the patient’s own cartilage and grown in the RJAH’s cell culture facility, OsCell’s John Charnley Laboratory. The cultured cells are then implanted back into the damaged area in the joint. If left untreated it is believed that these patients would likely go on to develop osteoarthritis with all the changes that this brings in the different parts of the knee (see Figure 1); many would need a joint replacement eventually.

Figure 2: Outcome measures in the ASCOT Trial

22 ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 BIOMECHANICS LAB BIOMECHANICS AND ORTHOPAEDIC INTERVENTIONS

Head of Research: Dr. Jan Herman Kuiper Orthopaedic interventions Collaborators: Mr Simon Pickard, Mrs Sohad Sajid, Miss Emily Day, Dr Bernhard Tins, Miss Mara Muellensiefen, Mrs Kelly Campbell, Dr Shailesh Naire

Comparing two suture techniques to join flexor Figure 1 Tendons joined using the Pulvertaft technique (top) tendons and the side-to-side technique (bottom).

Tendon grafting and tendon transfer surgery are common hand procedures at our hospital. Tendon grafting can be necessary following a severe tendon injury and involves replacing part of the patient’s tendon with a donor tendon. Tendon transfer surgery can be used following nerve palsy, where the loss of control over a muscle has caused lost movement and function. Tendon transfer relocates the insertion of a functioning muscle-tendon unit to the tendon whose muscle control was lost, thus restoring function and movement. Both types of surgery rely on joining two tendons, normally using some form of suturing.

Immediate movement of the hand following surgery is important as it allows patients to start rehabilitating and adapt to the graft or transfer. Early rehabilitation prevents adhesions, gives earlier restoration of function and eventually results in a stronger tendon with improved vascularity. Of course the repair needs to be strong enough to withstand the mechanical loads during rehabilitation. Traditionally, tendons are joined using the Pulvertaft weave (PTW) technique. This relatively complicated technique involves first weaving the end of one Figure 2 Tendons joined using the Pulvertaft technique, tendon through slits in the end of the other tendon, before clamped in the materials testing machine. suturing them. An alternative is side-to-side (STS) repair, which We found that the tendons joined using the STS technique involves simply laying the ends of the two tendons side-by- were better at resisting cyclic loading at average rehabilitation side and then suture them together. Several studies have loads. The repair elongated less and the increase of elongation compared the strength of PTW and STS and found that STS after each load cycle was less. Nevertheless, all samples is stiffer and has a higher load to failure. However, PTW seems joined using either technique were strong enough to resist the to work under physiological loading conditions, which are average physiological load. However, when we applied the typically low intensity cyclic loads. largest load measured in humans, only 4 out of 10 samples We therefore performed an experiment to find out how joined using the PTW technique stayed intact, whereas all 10 tendons joined using either of the repair methods behave samples joined using the STS technique did. Clearly, once the when loaded cyclically at physiological levels. For this we rehabilitation loads reach the upper range of those measured, used flexor tendons from pigs, which we cut through and the PTW may not be strong enough. then joined using either of the techniques (Figure 1). We then Given these results, it should not surprise that the mean placed the samples in our materials testing machine (Fig. force to reach 25mm of elongation was much (four times) 2) where we first loaded them cyclically to mimic average larger for the STS samples than for the PTW samples. We rehabilitation loads measured in humans. Next we loaded therefore concluded that although the PTW joining technique them cyclically using the largest rehabilitation load measured is probably sufficient strong for the average patient, some in humans. If they had not failed at this stage, we pulled them patients will generate large enough forces to damage the slowly apart to find how much force they would take before connection. Therefore the STS technique is the safer choice. failing. We considered them failed if the elongation of the Moreover, the STS technique is less complicated. tendon was above 25mm.

ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 23 BIOMECHANICS AND ORTHOPAEDIC INTERVENTIONS Figure 3OutsideappearanceofourhipandkneeCTphantom mask thebonedefects. a consequence,theCTscancontains“metalartefacts”that CT scancannotpenetratethemetalfrom theprosthesis. As for thispurposebutunfortunatelytheX-raysusedtobuilda More andmore therefore, radiologiststrytouseCT-scans much bonehasresorbed around akneeorhipprosthesis. is a3-Dimageandshouldgivebetterimpression ofhow much bonewaslost.Acomputedtomography(CT)scan image anddoesnotalwaysgiveaclearimpression ofhow bone hasbeenlost.However, anX-rayisa2-dimensional if there are bonedefectsaround aprosthesis andhowmuch Traditionally, radiologistsand cliniciansuseX-raystodecide surrounding bone. because theyhaveloosenedandcausedresorption ofthe between 15and20%oftheimplantsneedrevision, mainly joint replacement surgery. However, overaperiodof20years no surprisethatthemainclinicalactivityofourhospitalis is oneofthesuccessstoriesinorthopaedics.Ittherefore Being abletoreplace painfulhipsandkneesbyartificialjoints Phantoms forCTscanners 24 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 clearly betterimagequality. software. CTimagesfromanotherscanner(c)showa made without(a)andwith(b)usingmetalartefactreduction different scanners.TheimagesfromoneCTscannerwere Figure 4CTimagesofourkneephantomfromtwo the papersotheycouldalsomaketheirownphantom. knee phantom,andseveralpeoplealready askedforacopyof as wehoped(Fig.4).We recently publishedapaper about the allowed ustocompare imagequalitybetweenscanners,just could beeasilytransportedtoothersites.TheCTimages (Fig. 3).Bothwere veryinexpensive(below£50each)and replacement andoneforakneereplacement We managedtomaketwosuchphantoms,oneforahip to assessiftheCTscannerscorrectly visualisesthedefects. Such aphantomcanbetakentohospitalsormanufacturers prosthesis insideitsurrounded byvarious-sizedbone defects. “phantom”, whichisanartificialbonewithahiporknee between scanners.We therefore triedifwecouldmakea different software, whichmakesitimportanttocompare the imagequality. However, different manufacturers use designing software toremove themetalartefactsand improve Manufacturers ofCTscanstrytohelpradiologistsby BIOMECHANICS AND ORTHOPAEDIC INTERVENTIONS 25 advice and Statistical analysis Dr Richa James Richardson, Collaborators: The late Prof. Mr Shaughn O’Brien, Dr Mr Naveen Kumar, Kulshrestha, Sally Roberts, Mr Eric Robinson, Mr Bushra Naheed, Prof. Mike Williams. into This year saw our department again put much effort statistical advice and analysis. This helped in the design and successful funding or ethical applications of several new clinical studies or trials, and in the analysis and publication on of several completed studies. One example is a report a discontinued multicenter clinical trial comparing between decided to shoulder dislocation. We bracing and sling to treat had come to a halt, stop the trial early because recruitment still able to draw the meaningful conclusion that but were the clinical benefits it was bracing would be unlikely to provide supposed to. Figure 5 Predicted mean cartilage matrix density inside a Figure 5 Predicted mean cartilage matrix Four cell cartilage defect versus time since cell implantation. (1) Chondrocytes implantation cases were compared, namely of (3) A mixture (2) Marrow stromal cells (MSCs) only, only, mixture of 10% 90% chondrocytes, 10% MSCs, and (4) A represents fully chondrocytes, 90% MSCs. A density of 1 mature cartilage. H. (2011). A J. S., Roberts, S., & Kuiper, M., Naire, 1. Lutianov, after cell therapy. mathematical model of cartilage regeneration J Theor Biol, 289, 136. mixture of chondrocytes and stromal cells, the matrix density the matrix cells, and stromal of chondrocytes mixture it contained whether on the exact mixture, did not depend at all However, chondrocytes. 50%, 25% or 10% 90%, 75%, a mixture after implanting average matrix density time points (Fig. 3). either cell type alone than after implanting was higher mathematical model is with our An important problem between patients. for differences that it does not account our ASCOT from the results Nevertheless, perhaps turn tell if the model predictions trial will randomised controlled out correct. Our model predicted that regardless of the type of cells that regardless Our model predicted it predicted However, implanted, healing would always occur. that the pattern over time clearly differed of matrix density cells stromal marrow only, between implanting chondrocytes (Fig. 3). After implanting chondrocytes, or a cell mixture only, then on matrix started to form almost immediately and from linearly with the mean matrix density in the defect increased cells it took longer stromal time. After implanting marrow 4 months the for matrix formation to start, but after around mean matrix density had caught up with the chondrocyte mean then on the predicted implantation case, and from matrix density was actually higher (Fig. 3). If implanting a To find out if any of these interactions between stromal cells find out if any of these interactions between stromal To influence cartilage healing, we adapted and chondrocytes defect our mathematical model of a healing cartilage [1]. This model took following implantation of chondrocytes cell into account such phenomena as cell proliferation, of nutrients, all of cartilage and diffusion migration, production added equations as mathematical equations. We expressed cells and influences between stromal the mutual representing how then used the model to compare We chondrocytes. cartilage defects heal following implantation of chondrocytes of or various mixtures cells only, stromal only (ACI), marrow cells. stromal and marrow chondrocytes The combination of stromal cells and chondrocytes seems seems cells and chondrocytes The combination of stromal thought to influence attractive because the two cell types are thought to make cells are Stromal each other beneficially. amongst others faster, (proliferate) grow the chondrocytes factor known as FGF-1. This would a growth by producing in the defect, potentially the number of chondrocytes increase are chondrocytes speeding up healing. On the other hand, cells into of stromal thought to enhance the differentiation factor known as a growth mainly by producing chondrocytes, the number of chondrocytes BMP-2. This will also increase seems to chondrocytes having more in the defect. However, at all on the clinical outcome, something we have no effect mathematical have found in our clinical data and our earlier Report). models ([1], summarised in the 2011 Annual Our hospital is at the forefront of the clinical use of cell of the clinical use is at the forefront Our hospital of heading a number are orthopaedics. We therapy in have collected a large amount and clinical trials in this area, using treated defect patients are of clinical data. Cartilage cartilage whereby Implantation, Autologous Chondrocyte and a small biopsy isolated from are cells (chondrocytes) eventually cell manufacturing facility, expanded in our OsCell 20 million cells. These cells are yielding between 1 and new cartilage. after which they grow implanted into the defect, a clinical trial (ASCOT) conducting At the moment, we are cultured chondrocytes, to use cultured to find out if it is best a combination of the two. cells or mesenchymal stromal or cartilage therapy f Cell repair ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC BIOMECHANICS AND ORTHOPAEDIC INTERVENTIONS promote thehealingprocess. barbotage thatdisruptstendon fibres andisalsothought to The injectionisgivenusingatechnique calledneedle through theactionofgrowth factorsontheaffected tendon. Autologous bloodinjectionisthoughttopromote healing the patientandre-injected around theaffected tendon. In anautologousbloodinjection,istakenfrom necessary suchascorticosteroid injectionsorsurgery. such asrest, exercises andbracing,othertreatments maybe of 3months,eitherwithorwithoutnon-surgicaltreatments of theelbow. Althoughmanycasesresolve over aperiod and isthoughttobecausedbymicro-tears inthetendons pain. Itisassociatedwithrepetitive activityatworkandplay Tennis elbowisacommonconditionthatcauseslateral Lavender Medical. equipment arebeingprovidedfreeofchargeby Elbow andShoulderSociety. Consumablesand Funded bytheOrthopaedicInstituteandBritish Jean Denton,Tessa Rowlands,ClaireNicholas Hyne, LeighannSharp,JulieLloydEvans,CharlottePerkins, Cormac Kelly, JohannaWales, JanHermanKuiper, Megan elbow –apilotstudy. versus salineinjectioninthetreatment ofresistant tennis Platelet-rich plasma(PRP)versusautologouswholeblood taken regularly. Evidencearound theeffectiveness ofGnRH time. Iflongerrelief isdesired, progesterone mustalsobe GnRH isindeedeffective, butitcanonlybeusedforashort premenstrual syndrome (PMS).We foundgoodevidencethat releasing hormone(GnRH)totreat thesymptomsof meta-analysis oftrialsontheeffectiveness ofGonadotropin- Another exampleisaCochranesystematicreview and 26 INJECTION STUDY PLATELET-RICH PLASMA TENNIS ELBOW ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19

total of127patientshavebeen screened forthestudy. recruitment willbecompletebyDecember2019.Currently a with 28ofthetarget30enrolled; weanticipatethat Recruitment hasprogressed more slowlythanweanticipated, satisfaction withtreatment. experienced, useofpainmedications,qualitylifeand and 1year. We willalsocollectinformationonanysideeffects function willbecarriedoutat6weeks,12months whole blood,PRPorsaline).Assessmentsofpainandelbow one ofthree treatment groups atrandom,(aninjectionof conservative means.Participantswillthenbeallocatedto to ensure thattheirsymptomscannotberelieved bymore program ofphysiotherapypriortoenrolment inthestudy participants willberequired tocompleteastandardised are bothclinicallyrelevant andimportanttopatients.All needed infuture studiesand investigatemeasures that recruitment targets,helpto informthenumberofparticipants in order toensure awell-designedstudythatwillreach its We chosetocarryoutapilot studyof30patientsinitially, requires furtherresearch. Institute ofClinicalExcellence(NICE)asatechnologythat Autologous bloodinjectionhasbeenidentifiedbytheNational there isalackofwell-designed studiestosupportthis. tendon repair potentialcompared towholebloodhowever blood cellsandtheninjected.PRPmayhaveamore effective platelet-rich plasma(PRP)canbeseparatedfrom thered Either wholebloodcanbeinjected,orafragmentknownas having twoormore defects. before theoperation,havingapatellarortibialdefect,and could bepredicted from three characteristics:theclinicalscore ofclinicaloutcomeACI found thatthelong-termpattern Chondrocyte Implantation(ACI)totreat cartilagedefects. We find predictors ofthelong-termclinicaloutcomeAutologous plus progesterone ishoweverweak.Finally, wemanagedto BIOMECHANICS AND ORTHOPAEDIC INTERVENTIONS 27 started cycling with low resistance and increased speed and speed and increased with low resistance cycling started cycling period of two for a maximum as tolerated, resistance of 30 with a rest performed cycle periods were minutes. Five was required rating of effort Participant seconds between. days after the assessment, for each cycle. Four recorded discomfort was felt to see if any contacted were participants completed the study All participants following the exercise. seen by any of the were effects assessments. No adverse This study confirmed that arm participants in the study. people with FSHD. for cycling is a feasible exercise trial to assess whether arm now plan to design a larger We benefit cardiovascular muscular and/or cycling provides trial will that the future expect We to people with FSHD. of in two groups strength the arm function and compare Completing a 12-week at-home 1: people with FSHD: Group 2: Not completing the Group programme, arm cycling exercise functional, will have regular Both groups programme. exercise plan to apply assessments. We and cardiovascular strength to fund for Patient Benefit programme to the NIHR Research the larger trial. ACIOSCAPULOHUMERAL ACIOSCAPULOHUMERAL We recruited 15 patients into the study, aged 18-60 into the study, 15 patients recruited We years. Each participant attended RJAH and completed a Shoulder Score), on shoulder ability (the Oxford questionnaire of the shoulder and range of movement and muscle strength Participants then completed supervised elbow measured. Participants arm cycling using a table-top arm cycler. The main objective of this pilot study is to determine whether The main objective of this pilot study is to capable of performing arm physically are FSHD sufferers stage of the study is cycling. The secondary objective of this and cadence (speed) to determine what duration, resistance plan to use We of arm cycling each participant can achieve. an at- this information to design a larger trial incorporating programme. home arm cycling exercise Facioscapulohumeral Dystrophy (FSHD) is a muscular Dystrophy Facioscapulohumeral in the UK. 2400 people approximately that affects dystrophy Symptoms may long life with disability. FSHD patients live a and weakness usually noticeable in develop in early childhood individuals manifesting 95% of affected the teenage years with impacts on the arm, The disorder disease by age 20 years. muscle mass, in reduced shoulders and torso, resulting day to day tasks. At shoulder mobility and ability to undertake Surgery is used to stabilise is no known cure. there present a significant the shoulder blades, but this does not have Several studies have shown disease progression. on effect is not with moderate weights or resistance that exercise a study recently, detrimental to patients with FSHD. More training in patients with FSHD showed that consistent aerobic fitness but also improves cardiovascular not only improves believe that arm cycling has the potential to We strength. shoulder muscle in maintaining or improving be effective or is no evidence for its safety there functioning. However, in the upper extremity. effectiveness Dr Tracey Willis Nick Dr Richa Kulshrestha, (Chief Investigator), Dr Tracey Charlotte Perkins, Barbara Turner, Jean Denton, Sarah Emery, Arkesteijn (Sports and Exercise and Marco Linklater-Jones Research Scientist, Aberystwyth University). Institute Ltd Funded by the Orthopaedic ARM CYCLING IN IN ARM CYCLING F (FSHD) STUDY DYSTROPHY ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC SPINAL STUDIES Alongside thiswork,weare alsousingcomplexanalytical predicting neurological outcomeinSCIpatients. and usingstatisticaltechniques todeterminetheirpotentialin (important structuralelementsofneurons) inpatient’s bloods by cellsofthecentralnervoussystem)andneurofilaments calcium bindingprotein β(S100)(whichisaprotein secreted collected onspecificneurological biomarkerssuchasS100 Over thenext12monthswewillbeaddingtodataalready potential topredict neurological andclinicaloutcome. techniques thedatawillthenbeassessedtodetermineits the bloodmeasures are beingrecorded. Using statistical the initialinjuryandanyotherfactorsthatmayinfluence (motor) inthesepatients.Inaddition,informationregarding on sensory(painandtouchsensation)musclefunction approximately 1yearpost-injury (chronic) andwillprovide data approximately 3monthspost-injury (sub-acute)andathird at being collatedfrom three timepoints;aninitial(acute),oneat electrolytes andinflammation levels.Neurology scores are also full bloodcounts,bonehealthmeasures, liverfunction,urea, information onthepatient’s generalhealthandwillinclude are currently beingassessed.Thesebloodswillprovide Routine bloodsandneurology scores from ~500patients their bestclinicaloutcome. treatments andrehabilitation regimes sothatpatientsachieve of thepatient’s neurological outcomebutdirect current biomarkers willbeabletonotonlyenhancetheprediction be assessedfrom bloodsamples. Itishopedthatthese its workonspecificneurological markersthatcanalso larger group ofpatients(>500) inadditiontocontinuing great news,theteamisnow focussingitsefforts onamuch ofNeurotrauma.publication intheJournal Althoughthisis small group ofSCIpatients hasrecently beenacceptedfor from thegroup lookingatroutine bloodsfrom arelatively injury (SCI)toassistpredicting clinicaloutcome.Apaper biomarkers inthebloodsofpatientsfollowingaspinalcord The teamhascontinueditsworkonidentifyingpotential Centre forSpinalInjuries(MCSI),Oswestry Funded bytheOrthopaedicInstituteandMidland Srinivasa Budithi,PaulCoolandKarinaWright Heidi Fuller, NaveenKumar, JoyChowdhury, AheedOsman, Mateus BernardoHarrington,SharonOwen,CharlotteHulme, CLINICAL OUTCOME MARKERS FORPREDICTING TREATMENT TARGETS AND PATIENTS: IDENTIFYINGNEW USE INSPINALCORDINJURY BIOMARKER DISCOVERY AND SPINAL STUDIESRESEARCHGROUP 28 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 slice tissues7-dayspostseeding,10xmagnification. AM (green)/Ethediumbromide(red)stainingofratspinalcord Figure 1:Ratspinalcordslicemodel.Live/dead,Calcein identified formourproteomics/bioinformatics analyses. model. Thesecouldincludeexperimentstotargetbiomarkers the effects ofdifferent targetedtherapiesonourSCIexplant be devisedwhichwillallowforexperimentsinvestigating has beenfullyoptimised,areproducible injurysystemwill cord sliceculture modelsystems(Figure 1),oncetheculture In thepastyearwehavealsobeendevelopingratspinal to dampenthebodiesresponse toaSCI. response signalling’,whichmaybetargetsfornewtherapies might bealtered inresponse toSCI,including‘acute phase has alsohighlightedsomeofthebiologicalmechanismsthat SCI. Assessmentoftheseproteins thatchangefollowingSCI are beingfurtherstudiedfortheirpotentialasbiomarkersof that are altered overtimefollowingaSCI,severalofwhich investigations wehaveidentifiedalargenumberofproteins mild ‘contusion’ injury and severe ‘complete’ injury. From these date, wehaveexaminedtwodifferent modelsofSCI in rats, appropriate andeffective biomarkersare beingconsidered. To candidate biomarkerscanbefoundtoensure thatthemost is relatively limited,therefore there isapossibilitythatnew to othermedicalfields,identificationofbiomarkersforSCI previously beeninvestigatedinrelation toSCI.Compared techniques totryandidentifynewbiomarkersthathavenot SPINAL STUDIES 29 is formed from the cell’s centrioles. Both of these structures these structures centrioles. Both of the cell’s is formed from within them. proteins can be detected via staining for specific the cell cytoskeleton The base of the primary cilium is linked to of cell division whilst signalling and is involved in the control involved in the Hedgehog, Wnt and TGF cellular proteins ’carried’ along the ‘axoneme’ via a unique pathways are transport system. Any changes to the primary cilium structure in impairment of its signalling functions. can result Fellowship (Dec a Travelling Dr Sue McGlashan was awarded Institute of Liberal Keele University’s 2017 – Jan 2018) through Arts and Science, the purpose of which was to establish a Owen. collaboration between Dr McGlashan and Dr Sharon The primary goal of the visit, was to investigate, for the first time, primary cilia in pathological human intervertebral discs, expertise in the primary cilia thus combining Dr McGlashan’s field and the unique bank of intervertebral disc samples and patients following from cells held by the Spinal Studies Group Using a combination of surgery for a variety of back problems. methods and antibodies to the distinct structural elements of able to the primary cilium (axoneme and basal body) we were determine the incidence and length of primary cilia in cultured human disc cells and to identify them within pathological disc tissues. dermis (Allosource®) (Figure 2B). Histological analysis of the analysis Histological 2B). (Figure (Allosource®) dermis proliferated and the cells had adhered revelled seeded grafts of the dermis. on the surface to establish that we have begun this data suggests Together which could be system for PrUs, cell delivery an effective of the and revascularisation repopulation used to enhance cell wound bed. A B ulcers Figure 2: Allograft solutions for chronic pressure treated with (PrUs). A: Photograph of the first PrU case to be on admission this graft in the UK (left panel illustrates PrUs allograft secured (May-2018), right panel shows the dermal Histological B: to the largest PrU (Applied November-2018). light and analysis of the allograft (left panel under polarised right panel with H&E staining. The primary cilium is typically seen as a small projection on The primary cilium is typically seen as a small projection increasingly almost all non-dividing cells. These organelles are capable of being seen as ‘signalling hubs’ which are to biomechanical stimulation but have many other responding involved in localised to them which are and receptors proteins a spectrum of cell signalling pathways. Defects in the primary associated with diseases termed ‘ciliopathies’ and cilium are work has shown that malfunctioning primary cilia are recent in conditions such as arthritis and alkaptonuria. also present a microtubule-based Primary cilia consist of two main regions: by a membrane which is distinct from ‘axoneme’ surrounded plasma membrane, and a base (basal body) which the cell’s Sharon Owen, Sue McGlashan*, Sarfraz Ahmad, Birender Sujay Neil Davidson, Balain, Shashank Chitgopkar, Dheerendra, Sudarshan Munigangaiah, Matthew Ockendon, Auckland, New and Sally Roberts *University of Jayesh Trivedi Zealand Funded by the Orthopaedic Institute and Institute of Liberal Arts and Sciences, Keele University ARE PRIMARY CILIA INVOLVED CILIA INVOLVED ARE PRIMARY OF THE IN DEGENERATION DISC? INTERVERTEBRAL Earlier this year we were the first group in the UK to apply in the UK to apply the first group Earlier this year we were 2A). PrU (Figure an acellular dermal allograft to a very severe and been safely discharged. The This patient has recovered assessing whether seeding these dermal team is currently or bone grafts with allogeneic human dermal fibroblasts have cells will enhance PrU healing. We stromal marrow primary dermal characterised polydactyly-derived juvenile from with stimulation (JPDFs) by flow cytometry, fibroblasts γ (IFN-γ) for 24h at 25ng/ml (inflammatory either Interferon- stimuli) at stimuli) or lipopolysaccharide for 24h (microbial without stimulation, and 10ng/ml, alongside matched cultures acellular assessed their biocompatibility with a commercial Pressure ulcers (PrUs), are a frequent and serious a frequent ulcers (PrUs), are Pressure (SCI), with subsequent injury cord complication of spinal to £374 per day per individual. costing the NHS up treatment loss of local sensation following SCI The partial or complete one of the highest at-risk populations makes these patients a requires effectively PrUs Treating for PrU development. close monitoring of the including multifaceted approach, nutrition. wound and appropriate Angus Armstrong Twigg, Mateus Bernardo Harrington, Mateus Bernardo Twigg, Angus Armstrong Aheed Osman, Srinivasa Joy Chowdhury, Naveen Kumar, Budithi and Karina Wright Institute Funded by Orthopaedic DEVELOPING A CELL THERAPY THERAPY A CELL DEVELOPING FOR CHRONIC SYSTEM DELIVERY WOUNDS ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC SPINAL STUDIES were mucheasiertovisualiseincultured disccellsandthe some ciliawere detected(Figure 3).Incontrast,primarycilia tissue beinghighlydisorganised,agedandautofluorescent, structures inintervertebraldisctissuewasdifficult,duetothe during December2018.Althoughvisualisingprimarycilia & NewZealandmeetingheldattheUniversityofAuckland McGlashan’s workattheMatrixBiologySocietyofAustralia attend andpresent thefindings from bothherandDr Funding from theILASFellowship enabledDrOwento nuclei arelabelledblue.Notecellcytoplasmalsohaspositivestaining;imagesondifferentscales. cilia.Cell alpha-tubulin (green)intheendplate,annulusfibrosus(AF)andnucleuspulposus(NP).Arrowsindicateprimary Figure 3.CiliainhumanIVD.Immunofluorescentlabellingofdegenerateddiscusingantibodiesagainstacetylated 30 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 may bethrough primaryciliamanipulation. a noveltherapeuticapproach forrestoring dischomeostasis function, dotheyalsohavearole indiscdegeneration?Ifso, disc cells.Iftheseabnormalitiescontributetoimpaired cilia common indisccellsfrom degeneratehumanintervertebral Thus itappearsthatstructuralabnormalitiesinprimaryciliaare cells whencompared with ‘normal’ bovinedisccells(7-10%). to besignificantlygreater (p<0.01) inhumanpathologicaldisc presence ofaberrantciliary structures (16-44%)were found SPINAL STUDIES 31 30 16 14 13 Figure 1 Magnetic stimulator in use. number of patients Target (randomised) Subjects Enrolled Subjects treated Subjects completed follow up (28 days) follow-up. 1: Current progress in recruitment and Table Current inpatients on the Midland Centre for Spinal Injuries for Spinal the Midland Centre inpatients on Current injury (Frankel spinal cord with an established Unit at RJAH also months who are or C) of at least two grade A, B take part. legs will be invited to spasticity in their experiencing are: The aims of the study by using a very low dose of magnetic identify whether To abnormal connections in the the reduce stimulation we could that cause spasticity. spinal cord Study Progress study was 02/01/2018. recruited to the The first patient has been extended by eighteen Recruitment to the study the target of thirty patients April 2019 to ensure months from can be reached. Patient Population Patient We now know that the nervous system reorganises itself on now know that the nervous system reorganises We For a continuous basis even after we have finished growing. example, it has to do this so that we can form memories and learn. is necessary in healthy life and is This process the central through by an army of cells that roam regulated These cells known nervous system including the spinal cord. pruning connections that cells act as gardeners, as microglial needed. connections that are strengthening needed and aren’t in the field of biology we now understand work recent From that a chemical called complement is used as a marker a bit that is to be trimmed, to tell the microglial like paint on a tree low level Very to strengthen. to cut or where cells where pulsed magnetic stimulation can mark connections that need cells can go about their to be trimmed so that the microglial because it is using believe this is a very safe treatment job. We at a 10th of the level magnetic stimulation on the spinal cord that is commonly used on the brain. What is the purpose of the study? trying to understand the potential for low-dose are We unwanted symptoms including magnetic stimulation to reduce to the After an injury injury. spasticity following a spinal cord below the level the nerves within the spinal cord spinal cord themselves. This leads to unwanted of the injury reorganise a condition known as spasticity. connections producing muscle Spasticity is experienced by patients as unwanted In patients with some sensation this can cause pain stiffness. with bones and joints and and can often lead to problems standing. Along difficulties with positioning for seating and functioning in the nerves that control altered with spasticity, bowel and bladder can all create sweating, blood pressure, difficulties for someone who has had such an injury. Andrew Roberts (Chief Investigator), Sarah Turner, Aheed Sarah Turner, (Chief Investigator), Andrew Roberts Kuiper, Jan Herman Joy Chowdhury, Osmanz, Naveen Kumar, Edwards, Lisa Burgess-Collins Anand Pandyan, Jayne Institute Funded by the Orthopaedic - Stimulation Magnetic Pulsed in Spinal Spasticity Managing Stim) (Os Injury Cord ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 LIMITED ANNUAL REPORT INSTITUTE ORTHOPAEDIC EDUCATION 10 Dec 8 Dec 3-5 Dec 27 Nov 7-8 Nov 2 Nov 18-19 Oct 17 Oct 15-16 Oct 21 Sept 18 Sept 4-5 July 27-29 June 23 June 16 May 15 May 14 May 18 April 16-17 April 2018 COURSE LISTFOR2018/2019 clinicians. expertise topassontheirknowledgethenextgenerationof centres whocontinuetobewillingshare theirtime and quality facultybothfrom ourownhospitalandfrom other and facultyalike.We are indebted,asalways,tothe high 2018/2019 attractedveryflatteringfeedbackfrom delegates courses andnewcourses.All23inthefinancialyear highly popularprogramme withamixture ofannually-repeated The OrthopaedicInstitute’s courseprovision continuestobea EDUCATION 32 Sports KneeMeeting ST3 interviewCourse 17th OswestryFootandAnkleCourse Inaugural OswestrySpinalCourse Spinal ImagingCourse GP StudyDay‘TheBigFour’Chronic Diseases Anatomy andSurgicalExposures inOrthopaedicsCourse CourseforFRCS(Tr&OrthOne DayViva Intensive CourseinClinicalExaminationforFRCS(Tr&Orth) Intra-Operative Neuro-Monitoring (IONM)forSpinalSurgery 3rd Shropshire Workshop forSASDoctors 11th OswestryShoulderandElbowCourse ORLAU GaitCourse Radiography StudyDay Tumour Course Imaging ofOrthopaedicImplantsCourse Spine PainandSpinalPainTreatments Course One DayVIVA courseforFRCS(Tr &Orth) Intensive CourseinClinicalExaminationforFRCS(Tr&Orth) ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 Course Organiser [email protected] For furtherinformationpleasecontactSianJones, exciting programme ofeducational opportunities. return withanewformatin2020.Itpromises tobean the Hand&Wrist courseoriginally introduced in2017will and acontracture coursefrom theORLAUteam.Inaddition Consultant, DrLalam,twofrom SpinalSurgeon,MrBalain another clutchofnewcoursesincludingtwofrom Radiology In 2019-2020,alongwithourregular courses,weexpect be offered againnextyear. and thecoursebookedupveryquickly. Allthesecourseswill the facilitiesonboard. Cadaveric coursesare alwayspopular Oswestry. A steady stream ofcliniciansvisitedthelabtosee mobile lab,thefirsttimethishasbeenutilisedhere at support from Arthrex whoprovided thecoursewiththeir presented acadavericSports Kneecoursewithsubstantial was significantlyover-subscribed. Finally, theSportsKneefirm sought-after clinicalarea for thetargetaudiencecourse and treatment plansforspinal conditions.Clearlyamuch history, physical examination,interpretation ofinvestigation the samelanguageandhaveunderstandingabout to worktowards asharedtospeak goalforallconcerned aimed atGPsandAlliedHealthProfessionals wasdesigned was exceptionallywellreceived. MrBalain’s SpinalCourse various sessionswithintheORLAUdepartments.It of lectures andworkshopswithhalfadaycommittedto do. Thecoursewasfullanddelegatesenjoyedamixture day gaitcourseconcentratingonwhywewalktheway new courses.TheORLAUteampresented anewthree- 2018-2019 wasayearwhichsawtheintroduction ofseveral 17-18 January 16 January 14-15 January 6-11 January 2019 Delegates stillsmilingafterleaving alonghardstudyday. Anatomy andSurgicalExposures inOrthopaedicsCourse CourseforFRCS(Tr&Orth)One DayViva Intensive CourseinClinicalExaminationforFRCS(Tr&Orth) in Orthopaedics 27th OswestryIntensivecourseinBasicScience 20th ANNUAL RESEARCH DAY RESEARCH DAY Friday 26th April 2019

Friday 26th April hailed our 20th Annual Research Day. Over Mennan for her poster “Characterisation of a Sub-population the last two decades this day has become a firm date on the of Macrophages from Human Bone Marrow”. Winner of hospital and orthopaedic teaching calendars and is always the best clinical poster was Catriona Heaver with her entry awaited with eager anticipation and hopeful expectation. It is entitled “Reliability of Templating for the BOX Total Ankle the occasion when Specialty Registrars have the opportunity Replacement”. to present their research projects and for our Scientific John Garcia waltzed away with the “Golden Test Tube” for his Colleagues to showcase the outstanding research projects presentation entitled “Up-Scale Manufacture of Chondrocytes they undertake with the anticipation of expanding our research in the Development of Allogeneic Cartilage Therapies”. The portfolio by collaboration. Much of this work receives “Programme Director’s Trophy” was awarded to Catriona substantial financial support from the Orthopaedic Institute Heaver for her presentation “What does your Google search Ltd. say about you?”

The day began with a Q&A session with the Director of The prestigious Professor’s Medal for the best clinical Research and the Chief Executive. This was followed by presentation was conferred on Caroline Dover for her parallel scientific and clinical presentations running through presentation entitled “A Biomechanical Study of Greater until lunchtime. During the afternoon both researchers and Tuberosity Fracture Fixation – Comparing Plate, Screw, and clinicians joined together for the final combined session. Suture Fixation Methods using Porcine Model”. Caroline was We are indebted to our judges who gave up their valuable officially presented with her medal at the Old Oswestrians’ time for the entire day; Mr Ed Bache, Professor Paul Cool, Club Meeting held on 7th June. She will also be given Professor Alistair Hart, Mr Paul Jermin, Mr Steve White, the opportunity to represent the Oswestry/Stoke Training Professor Nick Forsyth and Professor Paul Kingston. It was Programme in the BOA “Best of the Best” Competition at the also the ideal opportunity to welcome Mr Geraint Thomas our BOA Congress being held in Liverpool in September. new Senior Lecturer in Population Orthopaedics. Finally we must thank all consultant trainers for their input, The Guest Lecturer this year was Professor Anthony dedication and continuing support of the trainees and to the Hollander, Pro-Vice Chancellor for Research and Impact from Orthopaedic Institute Ltd for the generous support of the the University of Liverpool who gave a most informative lecture many outstanding research projects carried out within the on “Using Mesenchymal Stem Cells as a Tool in the Armoury Trust. of Treatments for Diseases of Cartilage”. A Roberts R D Banerjee The posters were of their customary excellent standard Director of Consultant Orthopaedic Surgeon/ and the judges once again had a difficult task picking the Research Director of Clinical Studies winners. Award for the best scientific poster went to Claire

ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 33 PUBLICATIONS little sincethe1970sandhave wanted tocreate aspace that We are aware thatthelibraryenvironment haschangedvery services, whichcontinuestoprove popularwithourpatients. to enablesomeofourlongterm patientstoaccesslibrary continue toworkinpartnershipwithourlocalpubliclibrary requirement clubsession.We toattendaphysicaljournal encourage discussionandreview oftheliterature, withoutthe clubwhich the developmentofanonlinenursingjournal clinical staff haveattendingmeetingswefacilitated evidence basedworkoftheTrust. Recognisingthedifficulties for literature searches continuetogrow, reflecting the meet theinformationneedsofournon-clinicalstaff. Requests the FinanceandHRteamstoestablishhowwecanbetter the servicesavailabletothem.We are currently workingwith and therapiesteamsacross theTrust, raisingawareness of continuing workwithnursingteams,thepharmacyteam, by ourmore flexibleteam. Ouroutreach workincludesour students, bothclinicalandnon-clinicalhasbeenstrengthened Our commitmenttoproviding aservicetoallRJAHstaff and sessions andattendingteammeetingstodemonstrateitsuse. information tosupportclinicalpractice;offering information promoting thistool,which provides thelatestevidence-based available toallNHSstaff in England,andwehavebeen relevant totheirrole. NationallyBMJBestPracticeisnow they haveaccesstotimely, current evidence-basedmaterial to setuptailored information updatesforourstaff, ensuring a webbasedcurrent awareness service,whichallowsus to clinicalpractice.We continue toprovide KnowledgeShare, group, whichworkstowards evidencedbasedimprovements support totheMusculoskeletalCriticallyAppraisedTopics well received. FCLcontinues toprovide specialistlibrarian This trainingwasfacilitatedbyFCL,andasalwaysvery sessions oncriticalappraisalskillsandmedicalstatistics. We are onceagaingratefultoJanHermanKuiperfor delivering non-clinical teamsacross thehospital. to extendouroutreach model,workingwithourclinicaland in December2018.Thisappointmentreflects ourcommitment tothepostofOutreach appointed KennaBlackburn Librarian team. We tooktheopportunitytorestructure theteamand at theUniversityofAberystwyth,leavingavacancyin Samantha West lefttheTrust tostudyArchives Management and successfulyear. InSeptemberourSeniorLibraryAssistant develop theserviceswedeliveracross theTrust overabusy The FrancisCostelloLibrary(FCL)teamhavecontinuedto COSTELLO LIBRARY REPORT –FRANCIS INSTITUTE ANNUAL ORTHOPAEDIC 34 ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 and KarenJames Team;Library Louisa Fulbrook,LisEdwards,KennaBlackburn Manager Services Library Lis Edwards developing ourservicefurtherinthecomingyear. year fortheFrancisCostelloLibrary, andwelookforward to remained at100%.2018-19 hasbeenabusyandsuccessful for theLibraryQualityAssuranceFramework,whichhas service toourusers,andthisisreflected inourannualscore The FCLteamcontinuetodeliveranextremely highquality away from theofficeenvironment. work collaboratively, read orsimplyhavesomeheadspace staff whichwillgivetheman area where theycaneitherstudy, confident thatwenowhaveacommunityspaceforallofour the improvements wehave madetothelibraryspaceandfeel funding andsupportforthisproject. We are delightedwith grateful totheInstituteofOrthopaedicsfortheirgenerous Centre. Theworkisnowcomplete, andweare enormously potential configurationofanewlibrarywithinEducation functional useofthelibrary, itwouldallowustoenvisagethe designated quietarea. We alsofeltthatbyenablingbetter some ofthefurniturewithsmallerstudydesks,andcreate a in thelibrarytoenableuschangespaceandreplace to theInstituteofOrthopaedicsforfundingcarryoutwork for quietstudy. Earlierthisyearweputinasuccessfulbid consistently showthatouruserswantadesignatedspace used toinuniversity. Ourannuallibrarysurveyresults also environment more inkeepingwithwhattheyhavebeen been aware oftheexpectationsourSPRsforamulti-use discussion orsimplysomewhere tositquietly. We havealso combines somewhere forquietstudy, collaborativeworking, GENERAL DONATIONS AND FUNDRAISING

Our sincere thanks goes out to all those who have supported us throughout the year from grant giving trusts and charities to individual donors. Not forgetting the kind participants and supporters of our fundraising events! It is through your generosity and kindness that the Orthopaedic Institute is able to continue help fund the vital Research and Education here at the Robert Jones & Agnes Hunt Orthopaedic Hospital. During the coming year we plan to have a Research Open Day. This provides a perfect opportunity to visit our laboratories and talk to members of the teams. We want to show how your donations help us to research new and improved methods of treatment and provide a better understanding of orthopaedic diseases and conditions. Everyone is welcome and further details will be shared nearer the time. What has become our Annual Snowpaedic Challenge will take place again in September. If you would like to join us or organise your own fundraising event please contact Debra Alexander, details below.

Snaps from the Snowpaedic Challenge

Please visit the Fundraising Page on our website: www.orthopaedic-institute.org For further information please contact: Donating is easy via; Debra Alexander • Virgin Money Giving: Orthopaedic Institute Ltd, http://uk.virginmoneygiving.com/fund/ Arthritis Research Centre, orthopaedic-institute Oswestry, Shropshire, SY10 7AG Or Email: [email protected] • Cheques made payable to: Tel: 01691 404561 The Orthopaedic Institute Ltd Don’t forget to Gift Aid it! If you are a UK taxpayer, we can increase the value of your donation by 25% by claiming a rebate from the Inland Revenue. Just include the following declaration with your donation and we do the rest! “I would like the Orthopaedic Institute Ltd to treat this as a Gift Aid Donation”

Please consider the Orthopaedic Institute by leaving a gift in your Will Help us to continue to support vital research and teaching for patient benefit in including; Children’s Orthopaedics • Walking Abnormalities & Bone Diseases • Osteoporosis & Rheumatoid Arthritis Correcting Chronic Deformities • Joint Replacement & Reconstruction • Stem Cell Implantation

Registered Charity Number 1044906

ORTHOPAEDIC INSTITUTE LIMITED ANNUAL REPORT 2018/19 35 GENERAL Course Organiser Fundraising Manager Institute Administrator Dr SKatti Mr SKarlakki Mr PJermin Mr DCJaffray Dr CHulme Dr IHolt Mr SHay Mr IHanif Mr NGraham Dr JGarcia Mr PGallacher Dr HFuller Mr DJFord Dr MWJDavie Mr PCool Dr SConry Mr AClarke Mr JChowdhury Mr SChitgopkar Dr RButler Mr SCBudithi Mr MBrandreth Mr ABing Mr BBalain Dr AAskari Members Mr E.Evans Mr R.Lumby Mr S.Bratt Mr R.Madhok Mr C.Niblock Professor S.Roberts Mr R.Freeman MA,FRCS (T&O) Professor W. S.ElMasryMB,BCh,FRCS(Ed) Mrs L.Osselton(Treasurer) Mrs V. Edwards (CompanySolicitor) Dr B.A.AshtonBSc,DPhil(Chairman) Trustees Rt HonOWPatersonMP HRH TheDuchessofKent Patrons Registered CharityNumber1044906 Orthopaedic InstituteLtd 36 Mrs SianJones Ms DebraAlexander Mrs JudithHarris Dr KWright Dr NWinn Mr JPWhittaker Mr MvanLiefland Mr JTrivedi Dr BTins Mrs BTabernacle Dr SShapter Mr ARoberts Dr VCPullicino Mr SJPickard Dr JPattison Dr SOwen Mr AOsman Dr CMennan Mr CMarquis Mr NMakwana Dr RLongfellow Mr SLewthwaite Dr RLalam Dr RKulshrestha Dr NKuiper Mr NKiely Mr CKelly ORTHOPAEDIC INSTITUTE LIMITEDANNUAL REPORT 2018/19 Orthopaedic Institute

Orthopaedic Institute, Arthritis Research Centre, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire SY10 7AG

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