Publications by authors named "Stavros Thomopoulos"

136 Publications

Cyclic strain enhances the early stage mineral nucleation and the modulus of demineralized bone matrix.

Biomater Sci 2021 Jul 21. Epub 2021 Jul 21.

Department of Energy, Environmental & Chemical Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA.

The adaptive response of bones to mechanical loading is essential for musculoskeletal development. Despite the importance of collagen in bone mineralization, little is known about how cyclic strain influences physicochemical responses of collagen, especially at the early stage of mineralization when the levels of strain are higher than those in mature bones. The findings in this study show that, without any cell-mediated activity, cyclic strain increases nucleation rates of calcium phosphate (CaP) nanocrystals in highly-organized collagen matrices. The cyclic strain enhances the transport of mineralization fluids with nucleation precursors into the matrix, thus forming more CaP nanocrystals and increasing the elastic modulus of the collagen matrix. The results also suggest that the multiscale spatial distribution of nanocrystals in the fibrous collagen network determines tissue-level mechanical properties more critically than the total mineral content. By linking nano- and micro-scale observations with tissue-level mechanical properties, we provide new insights into designing better biomaterials.
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http://dx.doi.org/10.1039/d1bm00884fDOI Listing
July 2021

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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http://dx.doi.org/10.1002/jor.25113DOI Listing
June 2021

Biomimetic Scaffolds with a Mineral Gradient and Funnel-Shaped Channels for Spatially Controllable Osteogenesis.

Adv Healthc Mater 2021 May 29:e2100828. Epub 2021 May 29.

The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.

A facile method is described herein for generating a mineral gradient in a biodegradable polymer scaffold. The gradient is achieved by swelling a composite film made of polycaprolactone (PCL) and hydroxyapatite (HAp) nanoparticles with a PCL solution. During the swelling process, the solvent and PCL polymer chains diffuse into the composite film, generating a gradient in HAp density at their interface. The thickness of the mineral gradient can be tuned by varying the extent of swelling to match the length scale of the natural tendon-to-bone attachment (20-60 µm). When patterned with an array of funnel-shaped channels, the mineral gradient presents stem cells with spatial gradations in both biochemical cues (e.g., osteoinductivity and conductivity associated with the HAp nanoparticles) and mechanical cues (e.g., substrate stiffness) to stimulate their differentiation into a graded distribution of cell phenotypes. This new class of biomimetic scaffolds holds great promise for facilitating the regeneration of the injured tendon-to-bone attachment by stimulating the formation of a functionally graded interface.
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http://dx.doi.org/10.1002/adhm.202100828DOI Listing
May 2021

Augmenting Tendon-to-Bone Repair with Functionally Graded Scaffolds.

Adv Healthc Mater 2021 05 10;10(9):e2002269. Epub 2021 Mar 10.

The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.

Tendon-to-bone repair often fails because the functionally graded attachment is not regenerated during the healing process. Biomimetic scaffolds that recapitulate the unique features of the native tendon-to-bone attachment hold great promise for enhancing the healing process. Among various types of scaffolds that are developed and evaluated for tendon-to-bone repair, those with gradations (in either a stratified or a continuous fashion) in composition, structure, mechanical properties, and cell phenotype have gained the most attention. In this progress report, the recent efforts in the rational design and fabrication of functionally graded scaffolds based upon electrospun nanofiber mats and inverse opal structures, as well as the evaluation of their applications in augmenting tendon-to-bone repair, are reviewed. This report concludes with perspectives on the necessary future steps for clinical translation of the scaffolds.
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http://dx.doi.org/10.1002/adhm.202002269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102396PMC
May 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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http://dx.doi.org/10.1177/0363546520985203DOI Listing
March 2021

Flexor Tendon Injury and Repair: The Influence of Synovial Environment on the Early Healing Response in a Canine Mode.

J Bone Joint Surg Am 2021 05;103(9):e36

Washington University in St. Louis, St. Louis, Missouri.

Background: Environmental conditions strongly influence the healing capacity of connective tissues. Well-vascularized extrasynovial tendons typically undergo a robust wound-healing process following transection and repair. In contrast, avascular intrasynovial tendons do not mount an effective repair response. The current study tests the hypothesis that flexor tendons, as a function of their synovial environment, exhibit unique inflammatory, angiogenic, and metabolic responses to injury and repair.

Methods: Flexor tendons present a distinct opportunity to test the study hypothesis, as they have proximal regions that are extrasynovial and distal regions that are intrasynovial. In an internally controlled study design, the second and fifth forepaw flexor tendons were transected and repaired in either the extrasynovial or the intrasynovial anatomical region. Histological, gene expression, and proteomics analyses were performed at 3 and 7 days to define the early biological events that drive synovial environment-dependent healing responses.

Results: Uninjured intrasynovial tendons were avascular, contained high levels of proteoglycans, and expressed inflammatory factors, complement proteins, and glycolytic enzymes. In contrast, extrasynovial tendons were well vascularized, contained low levels of proteoglycans, and were enriched in inflammation inhibitors and oxidative phosphorylation enzymes. The response to injury and repair was markedly different between the 2 tendon regions. Extrasynovial tendons displayed a robust and rapid neovascularization response, increased expression levels of complement proteins, and an acute shift in metabolism to glycolysis, whereas intrasynovial tendons showed minimal vascularity and muted inflammatory and metabolic responses.

Conclusions: The regional molecular profiles of intact and healing flexor tendons revealed extensive early differences in innate immune response, metabolism, vascularization, and expression of extracellular matrix as a function of the synovial environment. These differences reveal mechanisms through which extrasynovial tendons heal more effectively than do intrasynovial tendons.

Clinical Relevance: To improve outcomes after operative repair, future treatment strategies should promote features of extrasynovial healing, such as enhanced vascularization and modulation of the complement system and/or glucose metabolism.
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http://dx.doi.org/10.2106/JBJS.20.01253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192118PMC
May 2021

Primary cilia as the nexus of biophysical and hedgehog signaling at the tendon enthesis.

Sci Adv 2020 Oct 30;6(44). Epub 2020 Oct 30.

Department of Orthopedic Surgery, Columbia University, New York, NY, 10032, USA.

The tendon enthesis is a fibrocartilaginous tissue critical for transfer of muscle forces to bone. Enthesis pathologies are common, and surgical repair of tendon to bone is plagued by high failure rates. At the root of these failures is a gap in knowledge of how the tendon enthesis is formed and maintained. We tested the hypothesis that the primary cilium is a hub for transducing biophysical and hedgehog (Hh) signals to regulate tendon enthesis formation and adaptation to loading. Primary cilia were necessary for enthesis development, and cilia assembly was coincident with Hh signaling and enthesis mineralization. Cilia responded inversely to loading; increased loading led to decreased cilia and decreased loading led to increased cilia. Enthesis responses to loading were dependent on Hh signaling through cilia. Results imply a role for tendon enthesis primary cilia as mechanical responders and Hh signal transducers, providing a therapeutic target for tendon enthesis pathologies.
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http://dx.doi.org/10.1126/sciadv.abc1799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608799PMC
October 2020

Developing a STEM+M Identity in Underrepresented Minority Youth Through Biomechanics and Sports-Based Education.

J Biomech Eng 2021 Apr;143(4)

Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Avenue, New York, NY 10027.

A Science, Technology, Engineering, Math, and Medicine (STEM+M) identity, a form of social identity, is the extent to which an individual feels accepted in the STEM+M career fields. The development of a strong STEM+M identity hinges largely on one's perceived self-efficacy in STEM+M and can be bolstered by associating STEM+M with other areas in which an individual already exhibits self-efficacy. In this study, a basketball camp served as a platform for STEM+M education in an effort to link participants' self-efficacy in basketball to STEM+M concepts where they may feel less self-efficacious. Over the first 2 years of the program, known as the Youth Sports Lab (YSL), two cohorts of underrepresented minority (URM) middle school students attended a 4-day long basketball camp hosted at Columbia University in partnership with Harlem- and Albany-based afterschool programs. The camp consisted of basketball training, jump plate fabrication, data collection, invited speakers, and group-based research projects. Our hypotheses were that participation in the program would lead to improved (1) familiarity, (2) perceived importance, and (3) interest in STEM+M. Participant responses, gathered from a 17-question Likert-scale survey administered before and after the camp, demonstrated 10 questions with significantly increased responses due to the program. The results support the conclusion that the sports-based engineering program increased STEM+M identity in the URM cohort. Future improvements to the program will include midyear student engagement and long-term follow-up.
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http://dx.doi.org/10.1115/1.4047548DOI Listing
April 2021

Correction of bias in the estimation of cell volume fraction from histology sections.

J Biomech 2020 05 2;104:109705. Epub 2020 Mar 2.

Department of Mechanical Engineering & Materials Science, Washington University in St. Louis, United States; NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, United States; Bioinspired Engineering and Biomechanics Center, School of Life Sciences and Technology, Xi'an Jiaotong University, China. Electronic address:

Accurate determination of the fraction of a tissue's volume occupied by cells is critical for studying tissue development, pathology, and biomechanics. For example, homogenization methods that predict the function and responses of tissues based upon the properties of the tissue's constituents require estimates of cell volume fractions. A common way to estimate cellular volume fraction is to image cells in thin, planar histologic sections, and then invoke either the Delesse or the Glagolev principle to estimate the volume fraction from the measured area fraction. The Delesse principle relies upon the observation that for randomly aligned, identical features, the expected value of the observed area fraction of a phase equals the volume fraction of that phase, and the Glagolev principle relies on a similar observation for random rather than planar sampling. These methods are rigorous for analysis of a polished, opaque rock sections and for histologic sections that are thin compared to the characteristic length scale of the cells. However, when histologic slices cannot be cut sufficiently thin, a bias will be introduced. Although this bias - known as the Holmes effect in petrography - has been resolved for opaque spheres in a transparent matrix, it has not been addressed for histologic sections presenting the opposite problem, namely transparent cells in an opaque matrix. In this note, we present a scheme for correcting the bias in volume fraction estimates for transparent components in a relatively opaque matrix.
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http://dx.doi.org/10.1016/j.jbiomech.2020.109705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594628PMC
May 2020

Connexin 43 Is Necessary for Murine Tendon Enthesis Formation and Response to Loading.

J Bone Miner Res 2020 08 22;35(8):1494-1503. Epub 2020 Apr 22.

Department of Orthopedic Surgery, Columbia University, New York, NY, USA.

The enthesis is a mineralized fibrocartilage transition that attaches tendon to bone and is vital for musculoskeletal function. Despite recent studies demonstrating the necessity of muscle loading for enthesis formation, the mechanisms that regulate enthesis formation and mechanoresponsiveness remain unclear. Therefore, the current study investigated the role of the gap junction protein connexin 43 in these processes by deleting Gja1 (the Cx43 gene) in the tendon and enthesis. Compared with their wild-type (WT) counterparts, mice lacking Cx43 showed disrupted entheseal cell alignment, reduced mineralized fibrocartilage, and impaired biomechanical properties of the supraspinatus tendon entheses during postnatal development. Cx43-deficient mice also exhibited reduced ability to complete a treadmill running protocol but no apparent deficits in daily activity, metabolic indexes, shoulder muscle size, grip strength, and major trabecular bone properties of the adjacent humeral head. To examine enthesis mechanoresponsiveness, young adult mice were subjected to modest treadmill exercise. Gja1 deficiency in the tendon and enthesis reduced entheseal anabolic responses to treadmill exercise: WT mice had increased expression of Sox9, Ihh, and Gli1 and increased Brdu incorporation, whereas Cx43-deficient mice showed no changes or decreased levels with exercise. Collectively, the results demonstrated an essential role for Cx43 in postnatal tendon enthesis formation, function, and response to loading; results further provided evidence implicating a link between Cx43 function and the hedgehog signaling pathway. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725385PMC
August 2020

American Society for Bone and Mineral Research-Orthopaedic Research Society Joint Task Force Report on Cell-Based Therapies - Secondary Publication.

J Orthop Res 2020 03 29;38(3):485-502. Epub 2020 Jan 29.

University of Alabama at Birmingham, AL, USA.

Cell-based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell-based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web-based marketing and patient testimonials supporting cell-based therapy. Both the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS) are committed to ensuring that the potential of cell-based therapies is realized through rigorous, reproducible, and clinically meaningful scientific discovery. The two organizations convened a multidisciplinary and international Task Force composed of physicians, surgeons, and scientists who are recognized experts in the development and use of cell-based therapies. The Task Force was charged with defining the state-of-the art in cell-based therapies and identifying the gaps in knowledge and methodologies that should guide the research agenda. The efforts of this Task Force are designed to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell-based therapies for skeletal tissues. The design and implementation of rigorous, thorough protocols will be critical to leveraging these innovative treatments and optimizing clinical and functional patient outcomes. In addition to providing specific recommendations and ethical considerations for preclinical and clinical investigations, this report concludes with an outline to address knowledge gaps in how to determine the cell autonomous and nonautonomous effects of a donor population used for bone regeneration. © 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:485-502, 2020.
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http://dx.doi.org/10.1002/jor.24485DOI Listing
March 2020

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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http://dx.doi.org/10.1177/0363546519894333DOI Listing
February 2020

Direct Estimation of Surface Strain Fields From a Stereo Vision System.

J Biomech Eng 2020 07;142(7)

Department of Mechanical Engineering and Materials Science, NSF Science and Technology Center for Engineering MechanoBiology, Washington University, St Louis, MO 63130.

Estimating strain on surfaces of deforming three-dimensional (3D) structures is a critical need in experimental mechanics. Although single-camera techniques excel at estimating deformation on a surface parallel to the imaging plane, they are prone to artifact for 3D motion because they cannot distinguish between out-of-plane motion and in-plane dilatation. Multiview (e.g., stereo) camera systems overcome this via a three-step process consisting of: (1) independent surface registration, (2) triangulation to estimate surface displacements, and (3) deformation estimation. However, existing methods are prone to errors associated with numerical differentiation when computing estimating strain fields from displacement fields unless regularization schemes are used. Such regularization schemes can introduce inaccuracy into strain estimation. Inspired by previous work which combined registration and deformation estimation into a single step for 2D images and 3D imaging stacks, we developed a theory for simultaneous image registration, 3D triangulation, and deformation estimation in a multiview system. The deformation estimation does not require numerical differentiation of displacement fields to estimate strain fields. We present here the theoretical foundations and derivation of two related implementations of this approach, and discuss their strengths and weaknesses.
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http://dx.doi.org/10.1115/1.4045813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104767PMC
July 2020

Discovery to delivery in tendon research.

J Orthop Res 2020 01;38(1):5-6

Department of Orthopedic Surgery, Columbia University, New York, NY.

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http://dx.doi.org/10.1002/jor.24549DOI Listing
January 2020

Multiscale effects of spaceflight on murine tendon and bone.

Bone 2020 02 12;131:115152. Epub 2019 Nov 12.

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

Despite a wealth of data on the effects of spaceflight on tendons and bones, little is known about its effects on the interfacial tissue between these two structures, the enthesis. Mice were sent to space on three separate missions: STS-131, STS-135, and Bion-M1 to determine how spaceflight affects the composition, structure, mechanics, and gene expression of the humerus-supraspinatus and calcaneus-Achilles entheses. At the nanoscale, spaceflight resulted in decreased carbonate levels in the bone, likely due to increased remodeling, as suggested by increased expression of genes related to osteoclastogenesis (CatK, Tnfsf11) and mature osteoblasts (Col1, Osc). Tendons showed a shift in collagen fibril size towards smaller diameters that may have resulted from increased expression of genes related to collagen degradation (Mmp3, Mmp13). These nanoscale changes did not result in micro- and milliscale changes to the structure and mechanics of the enthesis. There were no changes in bone volume, trabecular structure, failure load, or stiffness with spaceflight. This lack of tissue-level change may be anatomy based, as extremities may be less sensitive to spaceflight than central locations such as vertebrae, yet results highlight that the tendon enthesis may be robust against negative effects of spaceflight.
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http://dx.doi.org/10.1016/j.bone.2019.115152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138367PMC
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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http://dx.doi.org/10.3791/60280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217614PMC
October 2019

In situ tissue engineering of the tendon-to-bone interface by endogenous stem/progenitor cells.

Biofabrication 2019 11 18;12(1):015008. Epub 2019 Nov 18.

Regenerative Engineering Laboratory, Columbia University Medical Center, 630 W. 168th Street, VC12-230, NY 10032, New York.

The long-term success of surgical repair of rotator cuff tears is largely dependent on restoration of a functional tendon-to-bone interface. We implemented micro-precise spatiotemporal delivery of growth factors in three-dimensional printed scaffolds for integrative regeneration of a fibrocartilaginous tendon-to-bone interface. Sustained and spatially controlled release of tenogenic, chondrogenic and osteogenic growth factors was achieved using microsphere-based delivery carriers embedded in thin membrane-like scaffolds. In vitro, the scaffolds embedded with spatiotemporal delivery of growth factors successfully guided regional differentiation of mesenchymal progenitor cells, forming multiphase tissues with tendon-like, cartilage-like and bone-like regions. In vivo, when implanted at the interface between the supraspinatus tendon and the humeral head in a rat rotator cuff repair model, these scaffolds promoted recruitment of endogenous tendon progenitor cells followed by integrative healing of tendon and bone via re-formation of strong fibrocartilaginous interfaces. Our findings demonstrate the potential of in situ tissue engineering of tendon-to-bone interfaces by endogenous progenitor cells. The in situ tissue engineering approach shows translational potential for improving outcomes after rotator cuff repair.
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http://dx.doi.org/10.1088/1758-5090/ab48caDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904927PMC
November 2019

American Society for Bone and Mineral Research-Orthopaedic Research Society Joint Task Force Report on Cell-Based Therapies.

J Bone Miner Res 2020 01 23;35(1):3-17. Epub 2019 Sep 23.

University of Alabama at Birmingham, AL, USA.

Cell-based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell-based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web-based marketing and patient testimonials supporting cell-based therapy. Both the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS) are committed to ensuring that the potential of cell-based therapies is realized through rigorous, reproducible, and clinically meaningful scientific discovery. The two organizations convened a multidisciplinary and international Task Force composed of physicians, surgeons, and scientists who are recognized experts in the development and use of cell-based therapies. The Task Force was charged with defining the state-of-the art in cell-based therapies and identifying the gaps in knowledge and methodologies that should guide the research agenda. The efforts of this Task Force are designed to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell-based therapies for skeletal tissues. The design and implementation of rigorous, thorough protocols will be critical to leveraging these innovative treatments and optimizing clinical and functional patient outcomes. In addition to providing specific recommendations and ethical considerations for preclinical and clinical investigations, this report concludes with an outline to address knowledge gaps in how to determine the cell autonomous and nonautonomous effects of a donor population used for bone regeneration. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3839DOI Listing
January 2020

Adhesive-based tendon-to-bone repair: failure modelling and materials selection.

J R Soc Interface 2019 04;16(153):20180838

6 NSF Science and Technology Center for Engineering Mechanobiology, Department of Mechanical and Aerospace Engineering, Washington University , St Louis, MO 63130 , USA.

Surgical reattachment of tendon to bone is a procedure marked by high failure rates. For example, nearly all rotator cuff repairs performed on elderly patients with massive tears ultimately result in recurrence of tearing. These high failure rates have been attributed to stress concentrations that arise due to the mechanical mismatch between tendon and bone. Although recent studies have identified potential adhesives with mechanical properties tuned to alleviate these stress concentrations, and thereby delay the onset of failure, resistance to the progression of failure has not been studied. Here, we refined the space of adhesive material properties that can improve surgical attachment by considering the fracture process. Using cohesive zone modelling and physiologically relevant values of mode I and mode II adhesive fracture toughnesses, we predicted the maximum displacement and strength at failure of idealized, adhesively bonded tendon-to-bone repairs. Repair failure occurred due to excessive relative displacement of the tendon and bone tissues for strong and compliant adhesives. The failure mechanism shifted to rupture of the entire repair for stiffer adhesives below a critical shear strength. Results identified a narrow range of materials on an Ashby chart that are suitable for adhesive repair of tendon to bone, including a range of elastomers and porous solids.
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http://dx.doi.org/10.1098/rsif.2018.0838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505561PMC
April 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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http://dx.doi.org/10.1126/scitranslmed.aav4319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534967PMC
February 2019

CTGF induces tenogenic differentiation and proliferation of adipose-derived stromal cells.

J Orthop Res 2019 03 28;37(3):574-582. Epub 2019 Feb 28.

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

Intrasynovial tendons are paucicellular and hypovascular, resulting in a poor response to injury. Surgical repair of ruptured or lacerated tendons often lead to complications such as adhesions, repair site gapping, and repair site rupture. Adipose-derived stem cells (ASCs) have shown promise for enhancing tendon repair, as they have the capacity to differentiate into tendon fibroblasts and augment the healing response. Furthermore, connective tissue growth factor (CTGF) has been shown to promote tendon regeneration via the stimulation of endogenous tendon stem cells. Here, we evaluated the potential of CTGF to promote tenogenic differentiation of ASCs in vitro. Gene and protein expression, cell proliferation, and FAK and ERK1/2 signaling were assessed. CTGF increased tenogenic genes in mouse ASCs in a dose- and time-dependent manner. Western blot and immunostaining analyses demonstrated increases in tenogenic protein expression in CTGF-treated ASCs at all timepoints studied. CTGF increased ASC proliferation in a dose-dependent manner. CTGF induced phosphorylation of ERK1/2 within 5 min and FAK within 15 min; both signals persisted for 120 min. Blocking FAK and ERK1/2 pathways by selective inhibitors SCH772984 and PF573228, respectively, attenuated the CTGF-induced tenogenic differentiation and proliferation of ASCs. These results suggest that CTGF induces tenogenic differentiation of ASCs via the FAK and ERK1/2 pathway. Statement of clinical significance: Although prior research has led to advances in tendon operative techniques and rehabilitation methods, clinical outcomes after tendon repair remain variable, with high rates of repair site gapping or rupture. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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http://dx.doi.org/10.1002/jor.24248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467286PMC
March 2019

The multiscale structural and mechanical effects of mouse supraspinatus muscle unloading on the mature enthesis.

Acta Biomater 2019 01 17;83:302-313. Epub 2018 Oct 17.

Department of Orthopedic Surgery, Columbia University, New York, NY, USA; Department of Biomedical Engineering, Columbia University, New York, NY, USA. Electronic address:

The musculoskeletal system is sensitive to its loading environment; this is of particular concern under conditions such as disuse, paralysis, and extended-duration space flight. Although structural and mechanical changes to tendon and bone following paralysis and disuse are well understood, there is a pressing need to understand how this unloading affects the bone-tendon interface (enthesis); the location most prone to tears and injury. We therefore elucidated these effects of unloading in the entheses of adult mice shoulders that were paralyzed for 21 days by treatment with botulinum toxin A. Unloading significantly increased the extent of mechanical failure and was associated with structural changes across hierarchical scales. At the millimeter scale, unloading caused bone loss. At the micrometer scale, unloading decreased bioapatite crystal size and crystallographic alignment in the enthesis. At the nanometer scale, unloading induced compositional changes that stiffened the bioapatite/collagen composite tissue. Mathematical modeling and mechanical testing indicated that these factors combined to increase local elevations of stress while decreasing the ability of the tissue to absorb energy prior to failure, thereby increasing injury risk. These first observations of the multiscale effects of unloading on the adult enthesis provide new insight into the hierarchical features of structure and composition that endow the enthesis with increased resistance to failure. STATEMENT OF SIGNIFICANCE: The musculoskeletal system is sensitive to its loading environment; this is of particular concern under conditions such as disuse, paralysis, and extended-duration space flight. Although changes to tendon and bone following paralysis are understood, there is a pressing need to clarify how unloading affects the bone-tendon interface (enthesis), which is the location most prone to tears and injury. We elucidated the effects of enthesis unloading in adult mice shoulders showing, for the first time, that unloading significantly increased the risk and extent of mechanical failure and was associated with structural changes across hierarchical scales. These observations provide new insight into the hierarchical features of structure and composition that endow the enthesis with resilience. This knowledge can be used to develop more targeted treatments to improve mobility and function.
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http://dx.doi.org/10.1016/j.actbio.2018.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343501PMC
January 2019

The effect of modified locking methods and suture materials on Zone II flexor tendon repair-An ex vivo study.

PLoS One 2018 5;13(10):e0205121. Epub 2018 Oct 5.

Department of Orthopaedic Surgery, Washington University, St. Louis, Missouri, United States of America.

The failure rate of intrasynovial tendon repair is high due to substantial elongation at the repair site and to the development of adhesions between the tendon's surface and the surrounding digital sheath. To minimize these complications, we sought to reduce the incidence of gapping and to facilitate the initiation of early motion by improving the time zero structural properties of repair. The Winters-Gelberman 8-strand repair technique was modified by adding surface lock loops and by using Fiberwire suture material. Forty-eight canine flexor digitorum profundus tendons were transected and repaired with one of three 8-strand techniques (Pennington modified Kessler, half hitch loops, or surface locking Kessler) using either 3-0 Supramid or 4-0 Fiberwire suture. Biomechanical testing was performed to determine the physiologic and failure mode properties of the repairs. The surface locking Kessler technique improved repair maximum load, load necessary to create a 2 mm repair site gap, and yield force compared to the modified Kessler and half hitch loop techniques. Fiberwire suture improved maximum load, the load necessary to create a 2 mm repair site gap, stiffness, and yield force compared to Supramid suture. Failure occurred by both suture pull out and by suture breakage in the modified Kessler, Supramid suture repair group. Failure occurred consistently by suture breakage in the surface locking Kessler, Supramid suture repair group. These results reveal that a novel locking Kessler repair is significantly stronger than the current state-of-the art flexor tendon suture repair technique. The use of a surface locking Kessler technique with Fiberwire suture markedly improves the mechanical properties of intrasynovial tendon repair by reducing the risk of post-operative gapping and rupture.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205121PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173425PMC
March 2019

Regularization-Free Strain Mapping in Three Dimensions, With Application to Cardiac Ultrasound.

J Biomech Eng 2019 01;141(1)

Fellow ASME Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130; NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, Green Hall, CB 1099, 1 Brookings Drive, St. Louis, MO 63130 e-mail: .

Quantifying dynamic strain fields from time-resolved volumetric medical imaging and microscopy stacks is a pressing need for radiology and mechanobiology. A critical limitation of all existing techniques is regularization: because these volumetric images are inherently noisy, the current strain mapping techniques must impose either displacement regularization and smoothing that sacrifices spatial resolution, or material property assumptions that presuppose a material model, as in hyperelastic warping. Here, we present, validate, and apply the first three-dimensional (3D) method for estimating mechanical strain directly from raw 3D image stacks without either regularization or assumptions about material behavior. We apply the method to high-frequency ultrasound images of mouse hearts to diagnose myocardial infarction. We also apply the method to present the first ever in vivo quantification of elevated strain fields in the heart wall associated with the insertion of the chordae tendinae. The method shows promise for broad application to dynamic medical imaging modalities, including high-frequency ultrasound, tagged magnetic resonance imaging, and confocal fluorescence microscopy.
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http://dx.doi.org/10.1115/1.4041576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298532PMC
January 2019

Energy dissipation in mammalian collagen fibrils: Cyclic strain-induced damping, toughening, and strengthening.

Acta Biomater 2018 10 19;80:217-227. Epub 2018 Sep 19.

Aerospace Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

As the fundamental structural protein in mammals, collagen transmits cyclic forces that are necessary for the mechanical function of tissues, such as bone and tendon. Although the tissue-level mechanical behavior of collagenous tissues is well understood, the response of collagen at the nanometer length scales to cyclical loading remains elusive. To address this major gap, we cyclically stretched individual reconstituted collagen fibrils, with average diameter of 145 ± 42 nm, to small and large strains in the partially hydrated conditions of 60% relative humidity. It is shown that cyclical loading results in large steady-state hysteresis that is reached immediately after the first loading cycle, followed thereafter by limited accumulation of inelastic strain and constant initial elastic modulus. Cyclic loading above 20% strain resulted in 70% increase in tensile strength, from 638 ± 98 MPa to 1091 ± 110 MPa, and 70% increase in toughness, while maintaining the ultimate tensile strain of collagen fibrils not subjected to cyclic loading. Throughout cyclic stretching, the fibrils maintained a steady-state hysteresis, yielding loss coefficients that are 5-10 times larger than those of known homogeneous materials in their modulus range, thus establishing damping of nanoscale collagen fibrils as a major component of damping in tissues. STATEMENT OF SIGNIFICANCE: It is shown that steady-state energy dissipation occurs in individual collagen fibrils that are the building blocks of hard and soft tissues. To date, it has been assumed that energy dissipation in tissues takes place mainly at the higher length scales of the tissue hierarchy due to interactions between collagen fibrils and fibers, and in limited extent inside collagen fibrils. It is shown that individual collagen fibrils need only a single loading cycle to assume a highly dissipative, steady-state, cyclic mechanical response. Mechanical cycling at large strains leads to 70% increase in mechanical strength and values exceeding those of engineering steels. The same cyclic loading conditions also lead to 70% increase in toughness and loss properties that are 5-10 times higher than those of engineering materials with comparable stiffness.
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http://dx.doi.org/10.1016/j.actbio.2018.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510236PMC
October 2018

Enthesis Repair: Challenges and Opportunities for Effective Tendon-to-Bone Healing.

J Bone Joint Surg Am 2018 Aug;100(16):e109

Department of Orthopedic Surgery, Department of Biomedical Engineering, Columbia University, New York, NY.

On May 22, 2017, the National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) hosted a roundtable on "Innovative Treatments for Enthesis Repair." A summary of the roundtable discussion, as well as a list of the extramural participants, can be found at https://www.niams.nih.gov/about/meetings-events/roundtables/roundtable-innovative-treatments-enthesis-repair. This paper reviews the challenges and opportunities for developing effective treatment strategies for enthesis repair that were identified at the roundtable discussion.
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http://dx.doi.org/10.2106/JBJS.18.00200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133216PMC
August 2018

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

Sci Rep 2018 07 23;8(1):11078. Epub 2018 Jul 23.

Department of Orthopedic Surgery, Department of Biomedical Engineering, Columbia University, New York, NY, USA.

Intrasynovial tendon injuries are among the most challenging in orthopedics. Despite significant improvements in operative and rehabilitation methods, functional outcomes continue to be limited by adhesions, gap formation, and rupture. Adhesions result from excessive inflammation, whereas tendon gapping and rupture result from inflammation-induced matrix degradation and insufficient regeneration. Therefore, this study used a combined treatment approach to modulate inflammation with adipose-derived mesenchymal stromal cells (ASCs) while stimulating tendon regeneration with connective tissue growth factor (CTGF). ASCs were applied to the repair surface via cell sheets and CTGF was delivered to the repair center via porous sutures. The effect of the combined treatment was assessed fourteen days after repair in a canine flexor tendon injury model. CTGF, either alone or with ASCs, reduced inflammatory (IL1B and IL6) and matrix degrading (MMP3 and MMP13) gene expression, while increasing anti-inflammatory gene (IL4) expression and collagen synthesis compared to control repairs. The combined treatment was more effective than CTGF treatment alone, reducing the inflammatory IFNG and scar-associated COL3A1 gene expression and increasing CD146 tendon stem/progenitor cells at the tendon surface and interior along the core suture tracks. Therefore, the combined approach is promising in promoting early flexor tendon healing and worthy of further investigation.
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http://dx.doi.org/10.1038/s41598-018-29474-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056475PMC
July 2018

Potential strain-dependent mechanisms defining matrix alignment in healing tendons.

Biomech Model Mechanobiol 2018 Dec 12;17(6):1569-1580. Epub 2018 Jul 12.

Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, VA, 22908, USA.

Tendon mechanical function after injury and healing is largely determined by its underlying collagen structure, which in turn is dependent on the degree of mechanical loading experienced during healing. Experimental studies have shown seemingly conflicting outcomes: although collagen content steadily increases with increasing loads, collagen alignment peaks at an intermediate load. Herein, we explored potential collagen remodeling mechanisms that could give rise to this structural divergence in response to strain. We adapted an established agent-based model of collagen remodeling in order to simulate various strain-dependent cell and collagen interactions that govern long-term collagen content and fiber alignment. Our simulation results show two collagen remodeling mechanisms that give rise to divergent collagen content and alignment in healing tendons: (1) strain-induced collagen fiber damage in concert with increased rates of deposition at higher strains, or (2) strain-dependent rates of enzymatic degradation. These model predictions identify critical future experiments needed to isolate each mechanism's specific contribution to the structure of healing tendons.
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http://dx.doi.org/10.1007/s10237-018-1044-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330133PMC
December 2018

Inverse Opal Scaffolds with Gradations in Mineral Content for Spatial Control of Osteogenesis.

Adv Mater 2018 May 30:e1706706. Epub 2018 May 30.

The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.

The design and fabrication of inverse opal scaffolds with gradations in mineral content to achieve spatial control of osteogenesis are described. The gradient in mineral content is established via the diffusion-limited transport of hydroxyapatite nanoparticles in a closely packed lattice of gelatin microbeads. The mineral-graded scaffold has an array of uniform pores and interconnected windows to facilitate efficient transport of nutrients and metabolic wastes, ensuring high cell viability. The graded distribution of mineral content can provide biochemical and mechanical cues for spatially regulating the osteogenic differentiation of adipose-derived stromal cells. This new class of scaffolds holds promise for engineering the interfaces between mineralized and unmineralized tissues.
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http://dx.doi.org/10.1002/adma.201706706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269221PMC
May 2018

Design and Fabrication of a Hierarchically Structured Scaffold for Tendon-to-Bone Repair.

Adv Mater 2018 Apr 13;30(16):e1707306. Epub 2018 Mar 13.

The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.

A hierarchically structured scaffold is designed and fabricated for facilitating tendon-to-bone repair. The scaffold is composed of three regions with distinct functions: (i) an array of channels to guide the in-growth of cells and aligned deposition of collagen fibers, as well as integration of the scaffold with the tendon side, (ii) a region with a gradient in mineral composition to facilitate stress transfer between tendon and bone, and (iii) a mineralized inverse opal region to promote the integration of the scaffold with the underlying bone. Cell culture experiments confirm that adipose-derived stromal cells are able to infiltrate and proliferate through the entire thickness of the scaffold without compromised cell viability. The seeded stem cells exhibit directed differentiation into tenocytes and osteoblasts along the mineral gradient as a response to the gradient in Young's modulus. This novel scaffold holds great promise to promote the formation of a functional tendon-to-bone attachment by offering a structurally and compositionally appropriate microenvironment for healing.
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http://dx.doi.org/10.1002/adma.201707306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130203PMC
April 2018