Improved Orthopaedic Repairs through Mechanically Optimized, Adhesive Biomaterials

Despite countless surgical advances over the last several decades refining surgical approaches, repair techniques, and tools to treat tendon and tendon-to-bone injuries, we are still left with repair solutions that rely on fairly crude underlying mechanical principles. Musculoskeletal soft tissues have evolved to transfer high loads by optimizing stress distribution profiles across the tissue at each length scale. However, instead of mimicking these natural load transfer mechanisms, conventional suture approaches are limited by high load transfer across only a small number of anchor points within tissue. This leads to stress concentrations at anchor points that often cause repair failure as the sutures cut longitudinally through the fibrous tendon tissue like a wire cutting through cheese. Most tendon reconstruction ruptures occur within the first several weeks to months after repair, indicating that the initial strength of the repair is critical for its success. Over time under favorable conditions, the healing response can strengthen the repair sufficiently to function under typical physiologic forces. Here, we developed adhesive-based technologies to distribute load transfer more effectively across tendon and tendon-to-bone repairs, thus reducing peak stress and enabling repairs to sustain higher load before failure. First, we hypothesized that using the lateral surfaces along the length of suture to transfer load in shear would improve repair strength. We evaluated the mechanical principles of an adhesive-coated suture using a shear lag model to identify properties of suitable adhesives. Examination of the design space for an optimal adhesive demonstrated requirements for strong adhesion and low stiffness to maximize the strength of the adhesive-coated suture repair construct. When this design space was compared to real material properties in an Ashby plot, the model anticipated theoretical load transfer improvements of more than 7-fold over current tendon suture repairs using optimal elastomeric adhesives. We validated these model predictions experimentally using idealized single-strand pullout tests and clinically relevant flexor tendon repairs in cadaver canine flexor tendon. Clinically relevant repairs performed with Loctite 4903 cyanoacrylate-coated suture had significantly higher strength (17%) compared to standard repairs without adhesive. Notably, cyanoacrylate provided strong adhesion with high stiffness and brittle behavior, and was therefore not an ideal adhesive for enhancing suture repair. Nevertheless, the improvement in repair properties in a clinically relevant setting, even using a non-ideal adhesive, demonstrated the potential for the proposed approach to improve outcomes for treatments requiring suture fixation. We expanded this approach to assess the potential of adhesive films to increase the load tolerance of tendon-to-bone repairs. We hypothesized that adhesive films would redistribute load over the tendon footprint area where tendon inserts into bone, instead of focusing stress at just a few anchor points where suture from bone anchors punctures through tendon. Based on a shear lag model corroborated by a finite element model to establish the limits of the shear lag assumptions for thick or stiff adhesives, desirable adhesives again required compliance and high strength under shear loading. Models predicted an opportunity to increase transfer across tendon-to-bone repairs by over 10-fold. To rapidly evaluate adhesive mechanical properties for both applications using relevant tissue adherends, we developed a new method for consistent lap shear testing using tendon and bone planks. We validated shear lag predictions using this idealized test scenario and further assessed the ability of adhesives to provide additive benefit to rotator cuff repair strength using a clinically relevant human cadaver rotator cuff repair model with and without adhesive. Using this idealized adhesive testing platform, we demonstrated the potential of the proposed approach to improve outcomes in arthroscopic repair settings by applying a catechol-derived, marine mussel-mimetic adhesive with relevant mechanical properties that binds under water. Further study is needed to optimize adhesive binding properties and assess this approach in preclinical surgical tendon-to-bone repair scenarios. Finally, we developed a new approach to deliver adhesives and biofactors in tendon repairs using sutures with a porous outer sheath. These porous sutures were mechanically non-inferior to conventional sutures in single strand tests and clinically relevant tendon repairs. The porosity dramatically increased the suture surface area, which we conjectured would facilitate adhesive interdigitation and strong binding. Furthermore, this porous suture enabled growth factor or other bioactive factor addition to the inside of the suture for increased loading capacity and sustained release over the first 14 days, determined using connective tissue growth factor. In a clinically relevant canine in vivo injury and repair model, we assessed the effects of porous suture delivery of CTGF on the proliferative stage of repair at 14 days. This approach is hypothesized to act as a biological adhesive, increasing repair strength by modulating healing and encouraging tissue ingrowth into the suture pores. Taken together, these technologies represent dramatic departures from the traditional mechanical principles underlying tendon and tendon-to-bone repair, enabling large improvements in surgical repair strength without significantly changing the procedure in the operating room

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.We thank members of the Cambridge BioResource Scientific Advisory Board and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. K.D. is funded as a HSST trainee by NHS Health Education England. M.F. is funded from the BLUEPRINT Grant Code HEALTH-F5-2011-282510 and the BHF Cambridge Centre of Excellence [RE/13/6/30180]. J.R.S. is funded by a MRC CASE Industrial studentship, co-funded by Pfizer. J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. S.M., S.T, M.H, K.M. and L.D. are supported by the NIHR BioResource-Rare Diseases, which is funded by NIHR. Research in the Ouwehand laboratory is supported by program grants from the NIHR to W.H.O., the European Commission (HEALTH-F2-2012-279233), the British Heart Foundation (BHF) to W.J.A. and D.R. under numbers RP-PG-0310-1002 and RG/09/12/28096 and Bristol Myers-Squibb; the laboratory also receives funding from NHSBT. W.H.O is a NIHR Senior Investigator. The INTERVAL academic coordinating centre receives core support from the UK Medical Research Council (G0800270), the BHF (SP/09/002), the NIHR and Cambridge Biomedical Research Centre, as well as grants from the European Research Council (268834), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), Merck and Pfizer. DJR and DA were supported by the NIHR Programme ‘Erythropoiesis in Health and Disease’ (Ref. NIHR-RP-PG-0310-1004). N.S. is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510). The INTERVAL study is funded by NHSBT and has been supported by the NIHR-BTRU in Donor Health and Genomics at the University of Cambridge in partnership with NHSBT. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health of England or NHSBT. D.G. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship