Silicone tubes with thyroid hormone (Τ3) and BDNF as an alternative to autografts for bridging neural defects.

The way thyroid hormone works in peripheral nerve regeneration has not been fully elucidated, although studies have shown that it has a strong positive effect on nerve regeneration. It is argued that its action is probably stronger than the neurotrophic factors that have been used for some time. It is hypothesized that the use of thyroid hormone in the nerve tubes has a beneficial effect on nerve regeneration to the extent that the results of its use are comparable to those of the autograft technique in bridging small nerve deficits. In this experimental study, we examined the effect of thyroid hormone and BDNF (Brain Derived Neurotrophic Factor) on the repair of 10 mm nerve defects when administered within silicone nerve tubes and compared the results with the autograft method. Thyroid hormone promotes nerve regeneration mainly by increasing its speed and its effect on the maturation of nerve fibers compared to the other groups where the nerve deficit was bridged by entubulation. Also, better organization and the absence of intraneural fibrosis, compared to the other groups, may argue for the action of thyroid hormone in regulating the inflammatory response. Functionally, the AG group showed better results compared to the other groups by the end of the study (16 weeks).

Rotator cuff muscle degeneration and tear severity related to myogenic, adipogenic, and atrophy genes in human muscle.

Large rotator cuff tear size and advanced muscle degeneration can affect reparability of tears and compromise tendon healing. Clinicians often rely on direct measures of rotator cuff tear size and muscle degeneration from magnetic resonance imaging (MRI) to determine whether the rotator cuff tear is repairable. The objective of this study was to identify the relationship between gene expression changes in rotator cuff muscle degeneration to standard data available to clinicians. Radiographic assessment of preoperative rotator cuff tear severity was completed for 25 patients with varying magnitudes of rotator cuff tears. Tear width and retraction were measured using MRI, and Goutallier grade, tangent (tan) sign, and Thomazeau grade were determined. Expression of myogenic-, adipogenic-, atrophy-, and metabolism-related genes in biopsied muscles were correlated with tear width, tear retraction, Goutallier grade, tan sign, and Thomazeau grade. Tear width positively correlated with Goutallier grade in both the supraspinatus (r = 0.73) and infraspinatus (r = 0.77), along with tan sign (r = 0.71) and Thomazeau grade (r = 0.68). Decreased myogenesis (Myf5), increased adipogenesis (CEBPα, Lep, Wnt10b), and decreased metabolism (PPARα) correlated with radiographic assessments. Gene expression changes suggest that rotator cuff tears lead to a dramatic molecular response in an attempt to maintain normal muscle tissue, increase adipogenesis, and decrease metabolism. Fat accumulation and muscle atrophy appear to stem from endogenous changes rather than from changes mediated by infiltrating cells. Results suggest that chronic unloading of muscle, induced by rotator cuff tear, disrupts muscle homeostasis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2808-2814, 2017.

Sclerostin Antibody Treatment Enhances Rotator Cuff Tendon-to-Bone Healing in an Animal Model.

BACKGROUND: Rotator cuff tears are a common source of pain and disability, and poor healing after repair leads to high retear rates. Bone loss in the humeral head before and after repair has been associated with poor healing. The purpose of the current study was to mitigate bone loss near the repaired cuff and improve healing outcomes. METHODS: Sclerostin antibody (Scl-Ab) treatment, previously shown to increase bone formation and strength in the setting of osteoporosis, was used in the current study to address bone loss and enhance rotator cuff healing in an animal model. Scl-Ab was administered subcutaneously at the time of rotator cuff repair and every 2 weeks until the animals were sacrificed. The effect of Scl-Ab treatment was evaluated after 2, 4, and 8 weeks of healing, using bone morphometric analysis, biomechanical evaluation, histological analysis, and gene expression outcomes. RESULTS: Injury and repair led to a reduction in bone mineral density after 2 and 4 weeks of healing in the control and Scl-Ab treatment groups. After 8 weeks of healing, animals receiving Scl-Ab treatment had 30% greater bone mineral density than the controls. A decrease in biomechanical properties was observed in both groups after 4 weeks of healing compared with healthy tendon-to-bone attachments. After 8 weeks of healing, Scl-Ab-treated animals had improved strength (38%) and stiffness (43%) compared with control animals. Histological assessment showed that Scl-Ab promoted better integration of tendon and bone by 8 weeks of healing. Scl-Ab had significant effects on gene expression in bone, indicative of enhanced bone formation, and no effect on the expression of genes in tendon. CONCLUSIONS: This study provides evidence that Scl-Ab treatment improves tendon-to-bone healing at the rotator cuff by increasing attachment-site bone mineral density, leading to improved biomechanical properties. CLINICAL RELEVANCE: Scl-Ab treatment may improve outcomes after rotator cuff repair.

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.

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.

Effect of adipose-derived stromal cells and BMP12 on intrasynovial tendon repair: A biomechanical, biochemical, and proteomics study.

The outcomes of flexor tendon repair are highly variable. As recent efforts to improve healing have demonstrated promise for growth factor- and cell-based therapies, the objective of the current study was to enhance repair via application of autologous adipose derived stromal cells (ASCs) and the tenogenic growth factor bone morphogenetic protein (BMP) 12. Controlled delivery of cells and growth factor was achieved in a clinically relevant canine model using a nanofiber/fibrin-based scaffold. Control groups consisted of repair-only (no scaffold) and acellular scaffold. Repairs were evaluated after 28 days of healing using biomechanical, biochemical, and proteomics analyses. Range of motion was reduced in the groups that received scaffolds compared to normal. There was no effect of ASC + BMP12 treatment for range of motion or tensile properties outcomes versus repair-only. Biochemical assays demonstrated increased DNA, glycosaminoglycans, and crosslink concentration in all repair groups compared to normal, but no effect of ASC + BMP12. Total collagen was significantly decreased in the acellular scaffold group compared to normal and significantly increased in the ASC + BMP12 group compared to the acellular scaffold group. Proteomics analysis comparing healing tendons to uninjured tendons revealed significant increases in proteins associated with inflammation, stress response, and matrix degradation. Treatment with ASC + BMP12 amplified these unfavorable changes. In summary, the treatment approach used in this study induced a negative inflammatory reaction at the repair site leading to poor healing. Future approaches should consider cell and growth factor delivery methods that do not incite negative local reactions.

Shear lag sutures: Improved suture repair through the use of adhesives.

Suture materials and surgical knot tying techniques have improved dramatically since their first use over five millennia ago. However, the approach remains limited by the ability of the suture to transfer load to tissue at suture anchor points. Here, we predict that adhesive-coated sutures can improve mechanical load transfer beyond the range of performance of existing suture methods, thereby strengthening 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 the strength of the adhesive-coated suture repair construct. To experimentally assess the model, we evaluated single strands of sutures coated with highly flexible cyanoacrylates (Loctite 4903 and 4902), cyanoacrylate (Loctite QuickTite Instant Adhesive Gel), rubber cement, rubber/gasket adhesive (1300 Scotch-Weld Neoprene High Performance Rubber & Gasket Adhesive), an albumin-glutaraldehyde adhesive (BioGlue), or poly(dopamine). As a clinically relevant proof-of-concept, cyanoacrylate-coated sutures were then used to perform a clinically relevant flexor digitorum tendon repair in cadaver tissue. The repair performed with adhesive-coated suture had significantly higher strength compared to the standard repair without adhesive. Notably, cyanoacrylate provides strong adhesion with high stiffness and brittle behavior, and is 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, demonstrates the potential for the proposed approach to improve outcomes for treatments requiring suture fixation. Further study is necessary to develop a strongly adherent, compliant adhesive within the optimal design space described by the model.