Publications by authors named "Mikhail Golman"

7 Publications

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The role of loading in murine models of rotator cuff disease.

J Orthop Res 2021 Jun 3. Epub 2021 Jun 3.

Department of Orthopaedic Surgery, Columbia University Irving Medical Center, New York, New York, USA.

Rotator cuff disease pathogenesis is associated with intrinsic (e.g., age, joint laxity, muscle weakness) and extrinsic (e.g., mechanical load, fatigue) factors that lead to chronic degeneration of the cuff tissues. However, etiological studies are difficult to perform in patients due to the long duration of disease onset and progression. Therefore, the purpose of this study was to determine the effects of altered joint loading on the rotator cuff. Mice were subjected to one of three load-dependent rotator cuff tendinopathy models: underuse loading, achieved by injecting botulinum toxin-A into the supraspinatus muscle; overuse loading, achieved using downhill treadmill running; destabilization loading, achieved by surgical excision of the infraspinatus tendon. All models were compared to cage activity animals. Whole joint function was assessed longitudinally using gait analysis. Tissue-scale structure and function were determined using microCT, tensile testing, and histology. The molecular response of the supraspinatus tendon and enthesis was determined by measuring the expression of 84 wound healing-associated genes. Underuse and destabilization altered forepaw weight-bearing, decreased tendon-to-bone attachment strength, decreased mineral density of the humeral epiphysis, and reduced tendon strength. Transcriptional activity of the underuse group returned to baseline levels by 4 weeks, while destabilization had significant upregulation of inflammation, growth factors, and extracellular matrix remodeling genes. Surprisingly, overuse activity caused changes in walking patterns, increased tendon stiffness, and primarily suppressed expression of wound healing-related genes. In summary, the tendinopathy models demonstrated how divergent muscle loading can result in clinically relevant alterations in rotator cuff structure, function, and gene expression.
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June 2021

Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model.

Am J Sports Med 2021 03 28;49(3):780-789. Epub 2021 Jan 28.

Department of Biomedical Engineering, Columbia University, New York, New York, USA.

Background: More than 450,000 rotator cuff repairs are performed annually, yet healing of tendon to bone often fails. This failure is rooted in the fibrovascular healing response, which does not regenerate the native attachment site. Better healing outcomes may be achieved by targeting inflammation during the early period after repair. Rather than broad inhibition of inflammation, which may impair healing, the current study utilized a molecularly targeted approach to suppress IKKβ, shutting down only the inflammatory arm of the nuclear factor κB (NF-κB) signaling pathway.

Purpose: To evaluate the therapeutic potential of IKKβ inhibition in a clinically relevant model of rat rotator cuff repair.

Study Design: Controlled laboratory study.

Methods: After validating the efficacy of the IKKβ inhibitor in vitro, it was administered orally once a day for 7 days after surgery in a rat rotator cuff repair model. The effect of treatment on reducing inflammation and improving repair quality was evaluated after 3 days and 2, 4, and 8 weeks of healing, using gene expression, biomechanics, bone morphometry, and histology.

Results: Inhibition of IKKβ attenuated cytokine and chemokine production in vitro, demonstrating the potential for this inhibitor to reduce inflammation in vivo. Oral treatment with IKKβ inhibitor reduced NF-κB target gene expression by up to 80% compared with a nontreated group at day 3, with a subset of these genes suppressed through 14 days. Furthermore, the IKKβ inhibitor led to enhanced tenogenesis and extracellular matrix production, as demonstrated by gene expression and histological analyses. At 4 weeks, inhibitor treatment led to increased toughness, no effects on failure load and strength, and decreases in stiffness and modulus when compared with vehicle control. At 8 weeks, IKKβ inhibitor treatment led to increased toughness, failure load, and strength compared with control animals. IKKβ inhibitor treatment prevented the bone loss near the tendon attachment that occurred in repairs in control.

Conclusion: Pharmacological inhibition of IKKβ successfully suppressed excessive inflammation and enhanced tendon-to-bone healing after rotator cuff repair in a rat model.

Clinical Relevance: The NF-κB pathway is a promising target for enhancing outcomes after rotator cuff repair.
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March 2021

Rethinking Patellar Tendinopathy and Partial Patellar Tendon Tears: A Novel Classification System.

Am J Sports Med 2020 02 8;48(2):359-369. Epub 2020 Jan 8.

Center for Shoulder, Elbow and Sports Medicine, Columbia University, New York, New York, USA.

Background: Patellar tendinopathy is an overuse injury of the patellar tendon frequently affecting athletes involved in jumping sports. The tendinopathy may progress to partial patellar tendon tears (PPTTs). Current classifications of patellar tendinopathy are based on symptoms and do not provide satisfactory evidence-based treatment guidelines.

Purpose: To define the relationship between PPTT characteristics and treatment guidelines, as well as to develop a magnetic resonance imaging (MRI)-based classification system for partial patellar tendon injuries.

Study Design: Cohort study (prognosis); Level of evidence, 2.

Methods: MRI characteristics and clinical treatment outcomes were retrospectively reviewed for 85 patients with patellar tendinopathy, as well as 86 physically active control participants who underwent MRI of the knee for other conditions. A total of 56 patients had a PPTT and underwent further evaluation for tear size and location. The relationship between tear characteristics and clinical outcome was defined with use of statistical comparisons and univariate and logistic regression models.

Results: Of the 85 patients, 56 had partial-thickness patellar tendon tears. Of these tears, 91% involved the posterior and posteromedial regions of the proximal tendon. On axial MRI views, patients with a partial tear had a mean tendon thickness of 10 mm, as compared with 6.2 mm for those without ( < .001). Eleven patients underwent surgery for their partial-thickness tear. All of these patients had a tear >50% of tendon thickness (median thickness of tear, 10.3 mm) on axial views. Logistic regression showed that tendon thickness >8.8 mm correlated with the presence of a partial tear, while tendon thickness >11.45 mm and tear thickness >55.7% predicted surgical management.

Conclusion: Partial-thickness tears are located posterior or posteromedially in the proximal patellar tendon. The most sensitive predictor for detecting the presence of a partial tear was patellar tendon thickness, in which thickness >8.8 mm was strongly correlated with a tear of the tendon. Tracking thickness changes on axial MRI may predict the effectiveness of nonoperative therapy: athletes with patellar tendon thickness >11.5 mm and/or >50% tear thickness on axial MRI were less likely to improve with nonoperative treatment. A novel proposed classification system for partial tears, the Popkin-Golman classification, can be used to guide treatment decisions for these patients.
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February 2020

Biomechanical Testing of Murine Tendons.

J Vis Exp 2019 10 15(152). Epub 2019 Oct 15.

Department of Orthopedic Surgery, Columbia University; Department of Biomedical Engineering, Columbia University;

Tendon disorders are common, affect people of all ages, and are often debilitating. Standard treatments, such as anti-inflammatory drugs, rehabilitation, and surgical repair, often fail. In order to define tendon function and demonstrate efficacy of new treatments, the mechanical properties of tendons from animal models must be accurately determined. Murine animal models are now widely used to study tendon disorders and evaluate novel treatments for tendinopathies; however, determining the mechanical properties of mouse tendons has been challenging. In this study, a new system was developed for tendon mechanical testing that includes 3D-printed fixtures that exactly match the anatomies of the humerus and calcaneus to mechanically test supraspinatus tendons and Achilles tendons, respectively. These fixtures were developed using 3D reconstructions of native bone anatomy, solid modeling, and additive manufacturing. The new approach eliminated artifactual gripping failures (e.g., failure at the growth plate failure rather than in the tendon), decreased overall testing time, and increased reproducibility. Furthermore, this new method is readily adaptable for testing other murine tendons and tendons from other animals.
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October 2019

Targeting the NF-κB signaling pathway in chronic tendon disease.

Sci Transl Med 2019 02;11(481)

Department of Orthopedic Surgery, Columbia University, 650 W 168th St, New York, NY 10032, USA.

Tendon disorders represent the most common musculoskeletal complaint for which patients seek medical attention; inflammation drives tendon degeneration before tearing and impairs healing after repair. Clinical evidence has implicated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway as a correlate of pain-free return to function after surgical repair. However, it is currently unknown whether this response is a reaction to or a driver of pathology. Therefore, we aimed to understand the clinically relevant involvement of the NF-κB pathway in tendinopathy, to determine its potential causative roles in tendon degeneration, and to test its potential as a therapeutic candidate. Transcriptional profiling of early rotator cuff tendinopathy identified increases in NF-κB signaling, including increased expression of the regulatory serine kinase subunit IKKβ, which plays an essential role in inflammation. Using cre-mediated overexpression of IKKβ in tendon fibroblasts, we observed degeneration of mouse rotator cuff tendons and the adjacent humeral head. These changes were associated with increases in proinflammatory cytokines and innate immune cells within the joint. Conversely, genetic deletion of IKKβ in tendon fibroblasts partially protected mice from chronic overuse-induced tendinopathy. Furthermore, conditional knockout of IKKβ improved outcomes after surgical repair, whereas overexpression impaired tendon healing. Accordingly, targeting of the IKKβ/NF-κB pathway in tendon stromal cells may offer previously unidentified therapeutic approaches in the management of human tendon disorders.
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February 2019

Enhanced tendon-to-bone repair through adhesive films.

Acta Biomater 2018 04 8;70:165-176. Epub 2018 Feb 8.

Department of Orthopedic Surgery, Columbia University, New York, NY 10032, United States; Department of Biomedical Engineering, Columbia University, New York, NY 10027, United States. Electronic address:

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.
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April 2018

Quantifying Diastolic Function: From E-Waves as Triangles to Physiologic Contours via the 'Geometric Method'.

Cardiovasc Eng Technol 2018 03 16;9(1):105-119. Epub 2018 Jan 16.

Cardiovascular Biophysics Laboratory, Cardiovascular Division, Washington University School of Medicine, 660 South Euclid Ave, Box 8086, St. Louis, MO, 63110, USA.

Conventional echocardiographic diastolic function (DF) assessment approximates transmitral flow velocity contours (Doppler E-waves) as triangles, with peak (E), acceleration time (AT), and deceleration time (DT) as indexes. These metrics have limited value because they are unable to characterize the underlying physiology. The parametrized diastolic filling (PDF) formalism provides a physiologic, kinematic mechanism based characterization of DF by extracting chamber stiffness (k), relaxation (c), and load (x ) from E-wave contours. We derive the mathematical relationship between the PDF parameters and E, AT, DT and thereby introduce the geometric method (GM) that computes the PDF parameters using E, AT, and DT as input. Numerical experiments validated GM by analysis of 208 E-waves from 31 datasets spanning the full range of clinical diastolic function. GM yielded indistinguishable average parameter values per subject vs. the gold-standard PDF method (k: R = 0.94, c: R = 0.95, x : R = 0.95, p < 0.01 all parameters). Additionally, inter-rater reliability for GM-determined parameters was excellent (k: ICC = 0.956 c: ICC = 0.944, x : ICC = 0.993). Results indicate that E-wave symmetry (AT/DT) may comprise a new index of DF. By employing indexes (E, AT, DT) that are already in standard clinical use the GM capitalizes on the power of the PDF method to quantify DF in terms of physiologic chamber properties.
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March 2018