Enhanced zone II flexor tendon repair through a new half hitch loop suture configuration

This study evaluated the impact of a new half hitch loop suture configuration on flexor tendon repair mechanics. Cadaver canine flexor digitorum profundus tendons were repaired with 4- or 8-strands, 4-0 or 3-0 suture, with and without half hitch loops. An additional group underwent repair with half hitch loops but without the terminal knot. Half hitch loops improved the strength of 8-strand repairs by 21% when 4-0, and 33% when 3-0 suture was used, and caused a shift in failure mode from suture pullout to suture breakage. 8-strand repairs with half hitch loops but without a terminal knot produced equivalent mechanical properties to those without half hitch loops but with a terminal knot. 4-strand repairs were limited by the strength of the suture in all groups and, as a result, the presence of half hitch loops did not alter the mechanical properties. Overall, half hitch loops improved repair mechanics, allowing failure strength to reach the full capability of suture strength. Improving the mechanical properties of flexor tendon repair with half hitch loops has the potential to reduce the postoperative risk of gap formation and catastrophic rupture in the early postoperative period

The effect of adipose-derived stem cell sheets and CTGF on early flexor tendon healing in a canine model

Oral History interview of Curt Sawyer. Interview conducted by Robin Dunn

The effect of mesenchymal stromal cell sheets on the inflammatory stage of flexor tendon healing

BACKGROUND: The clinical outcomes following intrasynovial flexor tendon repair are highly variable. Excessive inflammation is a principal factor underlying the formation of adhesions at the repair surface and affecting matrix regeneration at the repair center that limit tendon excursion and impair tendon healing. A previous in-vitro study revealed that adipose-derived mesenchymal stromal cells (ASCs) modulate tendon fibroblast response to macrophage-induced inflammation. The goal of the current study was therefore to explore the effectiveness of autologous ASCs on the inflammatory stage of intrasynovial tendon healing in vivo using a clinically relevant animal model. METHODS: Zone II flexor tendon transections and suture repairs were performed in a canine model. Autologous ASC sheets were delivered to the surface of repaired tendons. Seven days after repair, the effects of ASCs on tendon healing, with a focus on the inflammatory response, were evaluated using gene expression assays, immunostaining, and histological assessments. RESULTS: ASCs delivered via the cell sheet infiltrated the host tendon, including the repair surface and the space between the tendon ends, as viewed histologically by tracking GFP-expressing ASCs. Gene expression results demonstrated that ASCs promoted a regenerative/anti-inflammatory M2 macrophage phenotype and regulated tendon matrix remodeling. Specifically, there were significant increases in M2-stimulator (IL-4), marker (CD163 and MRC1), and effector (VEGF) gene expression in ASC-sheet treated tendons compared with nontreated tendons. When examining changes in extracellular matrix expression, tendon injury caused a significant increase in scar-associated COL3A1 expression and reductions in COL2A1 and ACAN expression. The ASC treatment effectively counteracted these changes, returning the expression levels of these genes closer to normal. Immunostaining further confirmed that ASC treatment increased CD163(+) M2 cells in the repaired tendons and suppressed cell apoptosis at the repair site. CONCLUSIONS: This study provides a novel approach for delivering ASCs with outcomes indicating potential for substantial modulation of the inflammatory environment and enhancement of tendon healing after flexor tendon repair

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

Failure modes.

<p>Repairs completed with 4–0 caliber suture failed almost exclusively by suture breakage. Increasing suture caliber from 4–0 to 3–0 led to a shift in failure mode from suture breakage to suture pullout. The addition of half hitch loops shifted the failure mode in 3–0 suture caliber repairs back to suture breakage, indicating a significant increase in suture-tendon interaction due to the hitches. (G: grasping, H: hitched, K: hitched knotless).</p

Mechanical properties of repairs (mean ± standard deviation).

<p>Mechanical properties of repairs (mean ± standard deviation).</p

Suture configuration.

<p><b>(A-C)</b> The three suture passes required to make a single half hitch loop are shown sequentially as an end view from the transection interface, a side view, and a perspective view. This is a continuous piece of suture, where suture coloration is artificially added to aid in following the suture path, going from blue to purple. The suture diameter is enlarged two-fold for clarity. Looped suture is used surgically, but only one of each pair of suture threads is diagrammed here for simplicity. <b>(D)</b> The complete half hitch loop configuration is enlarged for clarity. <b>(E-F)</b> The locations of half hitch loops are shown in green for 4-strand modified Kessler (E) and 8-strand Winters-Gelberman (F) repairs. In 8-strand repairs, the first four passes were performed on the dorsal side and the last four passes were performed on the ventral side of the tendon.</p

Enhanced Tendon-To-Bone Repair through Adhesive Films

Tendon-to-bone surgical repairs have unacceptably high failure rates, possibly due to their inability to recreate the load transfer mechanisms of the native enthesis. Instead of distributing load across a wide attachment footprint area, surgical repairs concentrate shear stress on a small number of suture anchor points. This motivates development of technologies that distribute shear stresses away from suture anchors and across the enthesis footprint. Here, we present predictions and proof-of-concept experiments showing that mechanically-optimized adhesive films can mimic the natural load transfer mechanisms of the healthy attachment and increase the load tolerance of a repair. Mechanical optimization, based upon a shear lag model corroborated by a finite element analysis, revealed that adhesives with relatively high strength and low stiffness can, theoretically, strengthen tendon-to-bone repairs by over 10-fold. Lap shear testing using tendon and bone planks validated the mechanical models for a range of adhesive stiffnesses and strengths. Ex vivo human supraspinatus repairs of cadaveric tissues using multipartite adhesives showed substantial increase in strength. Results suggest that adhesive-enhanced repair can improve repair strength, and motivate a search for optimal adhesives. Statement of Significance: Current surgical techniques for tendon-to-bone repair have unacceptably high failure rates, indicating that the initial repair strength is insufficient to prevent gapping or rupture. In the rotator cuff, repair techniques apply compression over the repair interface to achieve contact healing between tendon and bone, but transfer almost all force in shear across only a few points where sutures puncture the tendon. Therefore, we evaluated the ability of an adhesive film, implanted between tendon and bone, to enhance repair strength and minimize the likelihood of rupture. Mechanical models demonstrated that optimally designed adhesives would improve repair strength by over 10-fold. Experiments using idealized and clinically-relevant repairs validated these models. This work demonstrates an opportunity to dramatically improve tendon-to-bone repair strength using adhesive films with appropriate material properties

Shear Lag Sutures: Improved Suture Repair through the Use of Adhesives

Conventional surgical suture is mechanically limited by the ability of the suture to transfer load to tissue at suture anchor points. Sutures coated with adhesives can improve mechanical load transfer beyond the range of performance of existing suture methods, thereby strengthening orthopaedic repairs and decreasing the risk of failure. The mechanical properties of suitable adhesives were identified using a shear lag model. Examination of the design space for an optimal adhesive demonstrated requirements for strong adhesion and low stiffness to maximize strength. As a proof of concept, cyanoacrylate-coated sutures were used to perform a clinically relevant flexor digitorum profundus tendon repair in cadaver tissue. Even with this non-ideal adhesive, the maximum load resisted by repaired cadaveric canine flexor tendon increased by ∼ 17.0% compared to standard repairs without adhesive. To rapidly assess adhesive binding to tendon, we additionally developed a lap shear test method using bovine deep digital flexor tendons as the adherends. Further study is needed to develop a strongly adherent, compliant adhesive within the optimal design space described by the model