Publications by authors named "Dawn Elliott"

152 Publications

Part 2. Review and meta-analysis of studies on modulation of longitudinal bone growth and growth plate activity: A micro-scale perspective.

J Orthop Res 2021 Jan 17. Epub 2021 Jan 17.

School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA.

Macro-scale changes in longitudinal bone growth resulting from mechanical loading were shown in Part 1 of this review to depend on load magnitude, anatomical location, and species. While no significant effect on longitudinal growth was observed by varying frequency and amplitude of cyclic loading, such variations, in addition to loading duration and species, were shown to affect the morphology, viability, and gene and protein expression within the growth plate. Intermittent compression regimens were shown to preserve or increase growth plate height while stimulating increased chondrocyte presence in the hypertrophic zone relative to persistent and static loading regimens. Gene and protein expressions related to matrix synthesis and degradation, as well as regulation of chondrocyte apoptosis were shown to exhibit magnitude-, frequency-, and duration-dependent responses to loading regimen. Chondrocyte viability was shown to be largely preserved within physiological bounds of magnitude, frequency, amplitude, and duration. Persistent static loading was shown to be associated with overall growth plate height in tension only, reducing it in compression, while affecting growth plate zone heights differently across species and encouraging mineralization relative to intermittent cyclic loading. Lateral loading of the growth plate, as well as microfluidic approaches are relatively understudied, and age, anatomical location, and species effects within these approaches are undefined. Understanding the micro-scale effects of varied loading regimes can assist in the development of growth modulation methods and device designs optimized for growth plate viability preservation or mineralization stimulation based on patient age and anatomical location.
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http://dx.doi.org/10.1002/jor.24992DOI Listing
January 2021

Identifiability of tissue material parameters from uniaxial tests using multi-start optimization.

Acta Biomater 2021 Mar 11;123:197-207. Epub 2021 Jan 11.

Department of Biomedical Engineering, University of Delaware, Newark, DE, USA.

Determining tissue biomechanical material properties from mechanical test data is frequently required in a variety of applications. However, the validity of the resulting constitutive model parameters is the subject of debate in the field. Parameter optimization in tissue mechanics often comes down to the "identifiability" or "uniqueness" of constitutive model parameters; however, despite advances in formulating complex constitutive relations and many classic and creative curve-fitting approaches, there is currently no accessible framework to study the identifiability of tissue material parameters. Our objective was to assess the identifiability of material parameters for established constitutive models of fiber-reinforced soft tissues, biomaterials, and tissue-engineered constructs and establish a generalizable procedure for other applications. To do so, we generated synthetic experimental data by simulating uniaxial tension and compression tests, commonly used in biomechanics. We then fit this data using a multi-start optimization technique based on the nonlinear least-squares method with multiple initial parameter guesses. We considered tendon and sclera as example tissues, using constitutive models that describe these fiber-reinforced tissues. We demonstrated that not all the model parameters of these constitutive models were identifiable from uniaxial mechanical tests, despite achieving virtually identical fits to the stress-stretch response. We further show that when the lateral strain was considered as an additional fitting criterion, more parameters are identifiable, but some remain unidentified. This work provides a practical approach for addressing parameter identifiability in tissue mechanics.
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http://dx.doi.org/10.1016/j.actbio.2021.01.006DOI Listing
March 2021

Part 1. Review and meta-analysis of studies on modulation of longitudinal bone growth and growth plate activity: A macro-scale perspective.

J Orthop Res 2020 Dec 30. Epub 2020 Dec 30.

School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA.

Growth modulation is an emerging method for treatment of angular skeletal deformities such as adolescent idiopathic scoliosis (AIS). The Hueter-Volkmann law, by which growth is stimulated in tension and inhibited in compression, is widely understood, and applied in current growth-modulating interventions such as anterior vertebral body tethering (AVBT) for AIS. However, without quantification of the growth rate effects of tension or compression, the possibility of under- or over- correction exists. A definitive mechanical growth modulation relationship relating to treatment of such skeletal deformities is yet to exist, and the mechanisms by which growth rate is regulated and altered are not fully defined. Review of current literature demonstrates that longitudinal (i.e., lengthwise) growth rate in multiple animal models depend on load magnitude, anatomical location, and species. Additionally, alterations in growth plate morphology and viability vary by loading parameters such as magnitude, frequency, and whether the load was applied persistently or intermittently. The aggregate findings of the reviewed studies will assist in work towards increasingly precise and clinically successful growth modulation methods. Part 1 of this review focuses on the effects of mechanical loading, species, age, and anatomical location on the macro-scale alterations in longitudinal bone growth, as well as factors that affect growth plate material properties. Part 2 considers the effects on micro-scale alterations in growth plate morphology such as zone heights and proportions, chondrocyte viability, and related gene and protein expression.
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http://dx.doi.org/10.1002/jor.24976DOI Listing
December 2020

Tendon Multiscale Structure, Mechanics, and Damage Are Affected by Osmolarity of Bath Solution.

Ann Biomed Eng 2020 Oct 30. Epub 2020 Oct 30.

Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, 150 Academy Street, Newark, DE, 19716, USA.

One of the most common bath solutions used in musculoskeletal mechanical testing is phosphate buffered saline (PBS). In tendon, swelling induced by physiological PBS results in decreased tendon modulus and induces microstructural changes. It is critical to evaluate the multiscale mechanical behavior of tendon under swelling to interpret prior work and provide information to design future studies. We compared the effects of physiological PBS and 8% polyethylene glycol and saline bathing solutions on tendon multiscale tendon mechanics and damage as well as microstructure with TEM in order to understand the effect of swelling on tendon. At the tissue level, tendons in PBS had a lower modulus than SPEG samples. PBS samples also showed an increased amount of non-recoverable sliding, which is an analog for microscale damage. SPEG had a higher microscale to tissue-scale strain ratio, showing the fibrils experienced less strain attenuation. From the TEM data, we showed the fibril spacing of SPEG samples was more similar to fresh control than PBS. We concluded that swelling alters multiscale mechanics and damage in addition to tendon microstructure. Future mechanical testing should consider using SPEG as a bath solution with an osmotic pressure which preserves fresh tissue water content.
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http://dx.doi.org/10.1007/s10439-020-02649-zDOI Listing
October 2020

Impact of pulse sequence, analysis method, and signal to noise ratio on the accuracy of intervertebral disc measurement.

JOR Spine 2020 Sep 26;3(3):e1102. Epub 2020 Jun 26.

Biomedical Engineering University of Delaware Newark Delaware USA.

Noninvasive assessments of intervertebral disc health and degeneration are critical for addressing disc degeneration and low back pain. Magnetic resonance imaging (MRI) is exceptionally sensitive to tissue with high water content, and measurement of the MR transverse relaxation time, , has been applied as a quantitative, continuous, and objective measure of disc degeneration that is linked to the water and matrix composition of the disc. However, measurement is susceptible to inaccuracies due to Rician noise, contamination, and stimulated echo effects. These error generators can all be controlled for with proper data collection and fitting methods. The objective of this study was to identify sequence parameters to appropriately acquire MR data and to establish curve fitting methods to accurately calculate disc in the presence of noise by correcting for Rician noise. To do so, we compared calculated from the typical monoexponential (MONO) fits and noise corrected exponential (NCEXP) fits. We examined how the selected sequence parameters altered the calculated in silico and in vivo. Typical MONO fits were frequently poor due to Rician noise, and NCEXP fits were more likely to provide accurate calculations. NCEXP is particularly less biased and less uncertain at low SNR. This study showed that the NCEXP using sequences with data from 20 echoes out to echo times of ~300 ms is the best method for calculating of discs. By acquiring signal data out to longer echo times and accounting for Rician noise, the curve fitting is more robust in calculating despite the noise in the data. This is particularly important when considering degenerate discs or AF tissue because the SNR of these regions is lower.
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http://dx.doi.org/10.1002/jsp2.1102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524248PMC
September 2020

Evaluation of transverse poroelastic mechanics of tendon using osmotic loading and biphasic mixture finite element modeling.

J Biomech 2020 Aug 26;109:109892. Epub 2020 Jun 26.

Department of Biomedical Engineering, University of Delaware, Newark, DE, United States. Electronic address:

Tendon's viscoelastic behaviors are important to the tissue mechanical function and cellular mechanobiology. When loaded in longitudinal tension, tendons often have a large Poisson's ratio (ν>2) that exceeds the limit of incompressibility for isotropic material (ν=0.5), indicating that tendon experiences volume loss, inducing poroelastic fluid exudation in the transverse direction. Therefore, transverse poroelasticity is an important contributor to tendon material behavior. Tendon hydraulic permeability which is required to evaluate the fluid flow contribution to viscoelasticity, is mostly unavailable, and where available, varies by several orders of magnitude. In this manuscript, we quantified the transverse poroelastic material parameters of rat tail tendon fascicles by conducting transverse osmotic loading experiments, in both tension and compression. We used a multi-start optimization method to evaluate the parameters using biphasic finite element modeling. Our tendon samples had a transverse hydraulic permeability of 10 to 10 mm. (Ns) and showed a significant tension-compression nonlinearity in the transverse direction. Further, using these results, we predict hydraulic permeability during longitudinal (fiber-aligned) tensile loading, and the spatial distribution of fluid flow during osmotic loading. These results reveal novel aspects of tendon mechanics and can be used to study the physiomechanical response of tendon in response to mechanical loading.
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http://dx.doi.org/10.1016/j.jbiomech.2020.109892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438606PMC
August 2020

Combined Hydrogel and Mesenchymal Stem Cell Therapy for Moderate-Severity Disc Degeneration in Goats.

Tissue Eng Part A 2021 Jan 7;27(1-2):117-128. Epub 2020 Aug 7.

Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, Philadelphia, Pennsylvania, USA.

Intervertebral disc degeneration is a cascade of cellular, structural, and biomechanical changes that is strongly implicated as a cause of low-back pain. Current treatment strategies have poor long-term efficacy as they seek only to alleviate symptoms without preserving or restoring native tissue structure and function. The objective of this study was to evaluate the efficacy of a combined triple interpenetrating network hydrogel (comprising dextran, chitosan, and teleostean) and mesenchymal stem cell (MSC) therapy targeting moderate-severity disc degeneration in a clinically relevant goat model. Degeneration was induced in lumbar discs of 10 large frame goats by injection of chondroitinase ABC. After 12 weeks, degenerate discs were treated by injection of either hydrogel alone or hydrogel seeded with allogeneic, bone marrow-derived MSCs. Untreated healthy and degenerate discs served as controls, and animals were euthanized 2 weeks after treatment. Discs exhibited a significant loss of disc height 12 weeks after degeneration was induced. Two weeks after treatment, discs that received the combined hydrogel and MSC injection exhibited a significant, 10% improvement in disc height index, as well as improvements in histological condition. Discs that were treated with hydrogel alone exhibited reduced tumor necrosis factor-α expression in the nucleus pulposus (NP). Microcomputed tomography imaging revealed that the hydrogel remained localized to the central NP region of all treated discs after 2 weeks of unrestricted activity. These encouraging findings motivate further, longer term studies of therapeutic efficacy of hydrogel and MSC injections in this large animal model. Impact statement Low-back pain is the leading cause of disability worldwide, and degeneration of the intervertebral discs is considered to be one of the most common reasons for low-back pain. Current treatment strategies focus solely on alleviation of symptoms, and there is a critical need for new treatments that also restore disc structure and function. In this study, using a clinically relevant goat model of moderate-severity disc degeneration, we demonstrate that a combined interpenetrating network hydrogel and mesenchymal stem cell therapy provides acute improvements in disc height, histological condition, and local inflammation.
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http://dx.doi.org/10.1089/ten.TEA.2020.0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826444PMC
January 2021

Fabrication, maturation, and implantation of composite tissue-engineered total discs formed from native and mesenchymal stem cell combinations.

Acta Biomater 2020 09 4;114:53-62. Epub 2020 Jun 4.

McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 308A Stemmler Hall, 36th Street and Hamilton Walk, Philadelphia, PA 19104, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA; Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Low back pain arising from disc degeneration is one of the most common causes of limited function in adults. A number of tissue engineering strategies have been used to develop composite tissue engineered total disc replacements to restore native tissue structure and function. In this study we fabricated a composite engineered disc based on the combination of a porous polycaprolactone (PCL) foam annulus fibrosus (AF) and a hyaluronic acid (HA) hydrogel nucleus pulposus (NP). To evaluate whether native tissue cells or mesenchymal stem cells (MSCs) would perform better, constructs were seeded with native AF/NP cells or with MSCs in the foam and/or gel region. Maturation of these composite engineered discs was evaluated for 9 weeks in vitro culture by biochemical content, histological analysis and mechanical properties. To evaluate the performance of these constructs in the in vivo space, engineered discs were implanted into the caudal spines of athymic rats for 5 weeks. Our findings show that engineered discs comprised of AF/NP cells and MSCs performed similarly and maintained their structure after 5 weeks in vivo. However, for both cell types, loss of proteoglycan was evident in the NP region. These data support the continued development of the more clinically relevant MSCs population for disc replacement applications. STATEMENT OF SIGNIFICANCE: A number of tissue engineering strategies have emerged that are focused on the creation of a composite disc replacement. We fabricated a composite engineered disc based on the combination of a porous foam AF and a HA gel NP. We used these constructs to determine whether the combination of AF/NP cells or MSCs would mature to a greater extent in vitro and which cell type would best retain their phenotype after implantation. Engineered discs comprised of AF/NP cells and MSCs performed similarly, maintaining their structure after 5 weeks in vivo. These data support the successful fabrication and in vivo function of an engineered disc composed of a PCL foam AF and a hydrogel NP using either disc cells or MSCs.
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http://dx.doi.org/10.1016/j.actbio.2020.05.039DOI Listing
September 2020

Structure, function, and defect tolerance with maturation of the radial tie fiber network in the knee meniscus.

J Orthop Res 2020 12 30;38(12):2709-2720. Epub 2020 Apr 30.

Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

The knee menisci are comprised of two orthogonal collagenous networks-circumferential and radial-that combine to enable efficient load bearing by the tissue in adults. Here, we assessed how the structural and functional characteristics of these networks developed over the course of skeletal maturation and determined the role of these fiber networks in defect tolerance with tissue injury. Imaging of the radial tie fiber (RTF) collagen structure in medial bovine menisci from fetal, juvenile, and adult specimens showed increasing heterogeneity, anisotropy, thickness, and density with skeletal development. The mechanical analysis showed that the tensile modulus in the radial direction did not change with skeletal development, though the resilience (in the radial direction) increased and the tolerance to defects in the circumferential direction decreased, in adult compared to fetal tissues. This loss of defect tolerance correlated with increased order in the RTF network in adult tissue. These data provide new insights into the role of the radial fiber network in meniscus function, will lead to improved clinical decision-making in the presence of a tear and may improve engineering efforts to reproduce this critical load-bearing structure in the knee.
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http://dx.doi.org/10.1002/jor.24697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572531PMC
December 2020

Transection of the medial meniscus anterior horn results in cartilage degeneration and meniscus remodeling in a large animal model.

J Orthop Res 2020 12 23;38(12):2696-2708. Epub 2020 Apr 23.

Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

The meniscus plays a central load-bearing role in the knee joint. Unfortunately, meniscus injury is common and can lead to joint degeneration and osteoarthritis (OA). In small animal models, progressive degenerative changes occur with the unloading of the meniscus via destabilization of the medial meniscus (DMM). However, few large animal models of DMM exist and the joint-wide initiation of the disease has not yet been defined in these models. Thus, the goal of this study is to develop and validate a large animal model of surgically induced DMM and to use multimodal (mechanical, histological, and magnetic resonance imaging) and multiscale (joint to tissue level) quantitative measures to evaluate degeneration in both the meniscus and cartilage. DMM was achieved using an arthroscopic approach in 13 Yucatan minipigs. One month after DMM, joint contact area decreased and peak pressure increased, indicating altered load transmission as a result of meniscus destabilization. By 3 months, the joint had adapted to the injury and load transmission patterns were restored to baseline, likely due to the formation and maturation of a fibrovascular scar at the anterior aspect of the meniscus. Despite this, we found a decrease in the indentation modulus of the tibial cartilage and an increase in cartilage histopathology scores at 1 month compared to sham-operated animals; these deleterious changes persisted through 3 months. Over this same time course, meniscus remodeling was evident through decreased proteoglycan staining in DMM compared to sham menisci at both 1 and 3 months. These findings support that arthroscopic DMM results in joint degeneration in the Yucatan minipig and provide a new large animal testbed in which to evaluate therapeutics and interventions to treat post-traumatic OA that originates from a meniscal injury.
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http://dx.doi.org/10.1002/jor.24694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735384PMC
December 2020

Inflammatory cytokine and catabolic enzyme expression in a goat model of intervertebral disc degeneration.

J Orthop Res 2020 11 3;38(11):2521-2531. Epub 2020 Mar 3.

Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, Philadelphia, Pennsylvania.

Intervertebral disc degeneration is implicated as a leading cause of low back pain. Persistent, local inflammation within the disc nucleus pulposus (NP) and annulus fibrosus (AF) is an important mediator of disc degeneration and negatively impacts the performance of therapeutic stem cells. There is a lack of validated large animal models of disc degeneration that recapitulate clinically relevant local inflammation. We recently described a goat model of disc degeneration in which increasing doses of chondroitinase ABC (ChABC) were used to reproducibly induce a spectrum of degenerative changes. The objective of this study was to extend the clinical relevance of this model by establishing whether these degenerative changes are associated with the local expression of inflammatory cytokines and catabolic enzymes. Degeneration was induced in goat lumbar discs using ChABC at different doses. After 12 weeks, degeneration severity was determined histologically and using quantitative magnetic resonance imaging (MRI). Expression levels of inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], and IL-6) and catabolic enzymes (matrix metalloproteinases-1 [MMPs-1] and 13, and a disintegrin and metalloproteinase with thrombospondin type-1 motifs-4 [ADAMTS-4]) were assessed as the percentage of immunopositive cells in the NP and AF. With the exception of MMP-1, cytokine, and enzyme expression levels were significantly elevated in ChABC-treated discs in the NP and AF. Expression levels of TNF-α, IL1-β, and ADAMTS-4 were positively correlated with histological grade, while all cytokines and ADAMTS-4 were negatively correlated with MRI T2 and T1ρ scores. These results demonstrate that degenerate goat discs exhibit elevated expression of clinically relevant inflammatory mediators, and further validate this animal model as a platform for evaluating new therapeutic approaches for disc degeneration.
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http://dx.doi.org/10.1002/jor.24639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483272PMC
November 2020

Helical fibrillar microstructure of tendon using serial block-face scanning electron microscopy and a mechanical model for interfibrillar load transfer.

J R Soc Interface 2019 11 20;16(160):20190547. Epub 2019 Nov 20.

Department of Biomedical Engineering, University of Delaware, Newark, DE, USA.

Tendon's hierarchical structure allows for load transfer between its fibrillar elements at multiple length scales. Tendon microstructure is particularly important, because it includes the cells and their surrounding collagen fibrils, where mechanical interactions can have potentially important physiological and pathological contributions. However, the three-dimensional (3D) microstructure and the mechanisms of load transfer in that length scale are not known. It has been postulated that interfibrillar matrix shear or direct load transfer via the fusion/branching of small fibrils are responsible for load transfer, but the significance of these mechanisms is still unclear. Alternatively, the helical fibrils that occur at the microstructural scale in tendon may also mediate load transfer; however, these structures are not well studied due to the lack of a three-dimensional visualization of tendon microstructure. In this study, we used serial block-face scanning electron microscopy to investigate the 3D microstructure of fibrils in rat tail tendon. We found that tendon fibrils have a complex architecture with many helically wrapped fibrils. We studied the mechanical implications of these helical structures using finite-element modelling and found that frictional contact between helical fibrils can induce load transfer even in the absence of matrix bonding or fibril fusion/branching. This study is significant in that it provides a three-dimensional view of the tendon microstructure and suggests friction between helically wrapped fibrils as a mechanism for load transfer, which is an important aspect of tendon biomechanics.
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http://dx.doi.org/10.1098/rsif.2019.0547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893486PMC
November 2019

Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss.

Nat Biomed Eng 2019 12 14;3(12):998-1008. Epub 2019 Oct 14.

University of Pennsylvania, Philadelphia, PA, USA.

In fibrous tissues, prestressed boundary constraints at bone interfaces instil residual strain throughout the tissue, even when unloaded. For example, internal swelling pressures in the central nucleus pulposus of the intervertebral disc generate prestrain in the outer annulus fibrosus. With injury and depressurization, these residual strains are lost. Here we show that the loss of residual strains in the intervertebral disc alters the microenvironment and instigates aberrant tissue remodelling and the adoption of atypical cellular phenotypes. By using puncture surgery of the annulus fibrosus in rabbits, ex vivo puncture experiments and electrospun nanofibrous scaffolds recapitulating these evolving boundary constraints, we show that the loss of residual strain promotes short-term apoptosis and the emergence of a fibrotic phenotype. We also show that local fibre organization and cellular contractility mediate this process and that the aberrant cellular changes could be abrogated by targeting the cell-mechanosensing machinery with small molecules. Our findings indicate that injury to dense connective tissues under prestrain alters boundary constraints and residual strain; this leads to aberrant mechanosensing, which in turn promotes disease progression.
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http://dx.doi.org/10.1038/s41551-019-0458-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899202PMC
December 2019

Off-axis response due to mechanical coupling across all six degrees of freedom in the human disc.

JOR Spine 2019 Mar 22;2(1):e1047. Epub 2019 Mar 22.

Department of Biomedical Engineering University of Delaware Newark Delaware.

The kinematics of the intervertebral disc are defined by six degrees of freedom (DOF): three translations (Tz: axial compression, Tx: lateral shear, and Ty: anterior-posterior shear) and three rotations (Rz: torsion, Rx: flexion-extension, and Ry: lateral bending). There is some evidence that the six DOFs are mechanically coupled, such that loading in one DOF affects the mechanics of the other five "off-axis" DOFs, however, most studies have not controlled and/or measured all six DOFs simultaneously. Additionally, the relationships between disc geometry and disc mechanics are important for evaluation of data from different sized donor and patient discs. The objectives of this study were to quantify the mechanical behavior of the intervertebral disc in all six degrees of freedom (DOFs), measure the coupling between the applied motion in each DOF with the resulting off-axis motions, and test the hypothesis that disc geometry influences these mechanical behaviors. All off-axis displacements and rotations were significantly correlated with the applied DOF and were of similar magnitude as physiologically relevant motion, confirming that off-axis coupling is an important mechanical response. Interestingly, there were pairs of DOFs that were especially strongly coupled: lateral shear (Tx) and lateral bending (Ry), anterior-posterior shear (Ty) and flexion-extension (Rx), and compression (Tz) and torsion (Rz). Large off-axis shears may contribute to injury risk in bending and flexion. In addition, the disc responded to shear (Tx, Ty) and rotational loading (Rx, Ry, and Rz) by increasing in disc height in order to maintain the applied compressive load. Quantifying these mechanical behaviors across all six DOF are critical for designing and testing disc therapies, such as implants and tissue engineered constructs, and also for validating finite element models.
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http://dx.doi.org/10.1002/jsp2.1047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686826PMC
March 2019

Human Disc Nucleotomy Alters Annulus Fibrosus Mechanics at Both Reference and Compressed Loads.

J Biomech Eng 2019 May 29. Epub 2019 May 29.

ASME Member, Biomedical Engineering, University of Delaware, 160 Colburn Lab, 150 Academy St, Newark, DE, 19716.

Nucleotomy is a common surgical procedure and is also performed in ex vivo mechanical testing to model decreased nucleus pulposus (NP) pressurization that occurs with degeneration. Here, we utilize magnetic resonance imaging (MRI) to study internal 3D annulus fibrosus (AF) deformations after partial nucleotomy and during axial compression by evaluating changes in internal AF deformation at reference loads (50N) and physiological compressive loads (~10% strain). Intact grade II L3-L4 discs before and after nucleotomy were subjected to identical mechanical testing and imaging protocols. Internal disc deformation fields were calculated by registering MR images captured in each loading state (reference and compressed) and each condition (intact and nucleotomy). Comparisons were drawn between the resulting three deformation states (intact at compressed load, nucleotomy at reference load, nucleotomy at compressed load) with regards to the magnitude of internal strain and direction of internal displacements. Under compressed load, internal AF axial strains averaged -18.5% when intact and -22.5% after nucleotomy. Deformations of intact discs under compressed load oriented in-plane, whereas deformations after nucleotomy oriented axially. For intact discs, in-plane components of displacements under compression loads were oriented radially outward and circumferentially. After nucleotomy, in-plane displacements oriented radially inward under reference load and were not significantly different from the intact state at compressed loads. Re-establishment of outward displacements after nucleotomy indicates increased axial loading restores the characteristics of internal pressurization. Results may have implications for the recurrence of pain, design of novel therapeutics, or progression of disc degeneration.
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http://dx.doi.org/10.1115/1.4043874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808005PMC
May 2019

Evaluating Plastic Deformation and Damage as Potential Mechanisms for Tendon Inelasticity using a Reactive Modeling Framework.

J Biomech Eng 2019 Apr 20. Epub 2019 Apr 20.

ASME Fellow, Department of Biomedical Engineering, Department of Mechanical Engineering, University of Delaware Newark, Delaware 19716.

Inelastic behaviors, such as softening, a progressive decrease in modulus before failure, occur in tendon and are important aspect in degeneration and tendinopathy. These inelastic behaviors are generally attributed to two potential mechanisms: plastic deformation and damage. However, it is not clear which is primarily responsible. In this study, we evaluated these potential mechanisms of tendon inelasticity by using a recently developed reactive inelasticity model (RIE), which is a structurally-inspired continuum mechanics framework that models tissue inelasticity based on the molecular bond kinetics. Using RIE, we formulated two material models, one specific to plastic deformation and the other to damage. The models were independently fit to published experimental tensile tests of rat tail tendons. We quantified the inelastic effects and compared the performance of the two models in fitting the mechanical response during loading, relaxation, unloading, and reloading phases. Additionally, we validated the models by using the resulting fit parameters to predict an independent set of experimental stress-strain curves from ramp-to-failure tests. Overall, the models were both successful in fitting the experiments and predicting the validation data. However, the results did not strongly favor one mechanism over the other. As a result, to distinguish between plastic deformation and damage, different experimental protocols will be needed. Nevertheless, these findings suggest the potential of RIE as a comprehensive framework for studying tendon inelastic behaviors.
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http://dx.doi.org/10.1115/1.4043520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807995PMC
April 2019

Multi-Scale Loading and Damage Mechanisms of Plantaris and Rat Tail Tendons.

J Orthop Res 2019 08 2;37(8):1827-1837. Epub 2019 May 2.

Department of Biomedical Engineering, University of Delaware, Newark, Delaware 19716.

Tendinopathy, degeneration of the tendon that leads to pain and dysfunction, is common in both sports and occupational settings, but multi-scale mechanisms for tendinopathy are still unknown. We recently showed that micro-scale sliding (shear) is responsible for both load transfer and damage mechanisms in the rat tail tendon; however, the rat tail tendon is a specialized non-load-bearing tendon, and thus the load transfer and damage mechanisms are still unknown for load-bearing tendons. The objective of this study was to investigate the load transfer and damage mechanisms of load-bearing tendons using the rat plantaris tendon. We demonstrated that micro-scale sliding is a key component for both mechanisms in the plantaris tendon, similar to the tail tendon. Namely, the micro-scale sliding was correlated with applied strain, demonstrating that load was transferred via micro-scale sliding in the plantaris and tail tendons. In addition, while the micro-scale strain fully recovered, the micro-scale sliding was non-recoverable and strain-dependent, and correlated with tissue-scale mechanical parameters. When the applied strain was normalized, the % magnitudes of non-recoverable sliding was similar between the plantaris and tail tendons. Statement of clinical significance: Understanding the mechanisms responsible for the pathogenesis and progression of tendinopathy can improve prevention and rehabilitation strategies and guide therapies and the design of engineered constructs. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1827-1837, 2019.
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http://dx.doi.org/10.1002/jor.24309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790141PMC
August 2019

Short cracks in knee meniscus tissue cause strain concentrations, but do not reduce ultimate stress, in single-cycle uniaxial tension.

R Soc Open Sci 2018 Nov 14;5(11):181166. Epub 2018 Nov 14.

Department of Biomedical Engineering, University of Delaware, Newark, DE, USA.

Tears are central to knee meniscus pathology and, from a mechanical perspective, are crack-like defects (cracks). In many materials, cracks create stress concentrations that cause progressive local rupture and reduce effective strength. It is currently unknown if cracks in meniscus have these consequences; if they do, this would have repercussions for management of meniscus pathology. The objective of this study was to determine if a short crack in meniscus tissue, which mimics a preclinical meniscus tear, (a) causes crack growth and reduces effective strength, (b) creates a near-tip strain concentration and (c) creates unloaded regions on either side of the crack. Specimens with and without cracks were tested in uniaxial tension and compared in terms of macroscopic stress-strain curves and digital image correlation strain fields. The strain fields were used as an indicator of stress concentrations and unloaded regions. Effective strength was found to be insensitive to the presence of a crack (potential effect < 0.86 s.d.; = 0.2), but significant strain concentrations, which have the potential to lead to long-term accumulation of tissue or cell damage, were observed near the crack tip.
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http://dx.doi.org/10.1098/rsos.181166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281910PMC
November 2018

Comparative multi-scale hierarchical structure of the tail, plantaris, and Achilles tendons in the rat.

J Anat 2019 02 28;234(2):252-262. Epub 2018 Nov 28.

Department of Biomedical Engineering, University of Delaware, Newark, USA.

Rodent tendons are widely used to study human pathologies such as tendinopathy and repair, and to address fundamental physiological questions about development, growth, and remodeling. However, how the gross morphology and multi-scale hierarchical structure of rat tendons, such as the tail, plantaris, and Achilles tendons, compare with that of human tendons are unknown. In addition, there remains disagreement about terminology and definitions. Specifically, the definitions of fascicle and fiber are often dependent on diameter sizes, not their characteristic features, and these definitions impair the ability to compare hierarchical structure across species, where the sizes of the fiber and fascicle may change with animal size and tendon function. Thus, the objective of the study was to select a single species that is commonly used for tendon research (rat) and tendons with varying mechanical functions (tail, plantaris, Achilles) to evaluate the hierarchical structure at multiple length scales using histology, SEM, and confocal imaging. With the exception of the specialized rat tail tendon, we confirmed that in rat tendons there are no fascicles and the fiber is the largest subunit. In addition, we provided a structurally based definition of a fiber as a bundle of collagen fibrils that is surrounded by elongated cells, and this definition was supported by both histologically processed and unprocessed samples. In all rat tendons studied, the fiber diameters were consistently between 10 and 50 μm, and this diameter range appears to be conserved across larger species. Specific recommendations were made highlighting the strengths and limitations of each rat tendon as a research model. Understanding the hierarchical structure of tendon can advance the design and interpretation of experiments and development of tissue-engineered constructs.
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http://dx.doi.org/10.1111/joa.12913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326909PMC
February 2019

Long-term mechanical function and integration of an implanted tissue-engineered intervertebral disc.

Sci Transl Med 2018 11;10(468)

Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA.

Tissue engineering holds great promise for the treatment of advanced intervertebral disc degeneration. However, assessment of in vivo integration and mechanical function of tissue-engineered disc replacements over the long term, in large animal models, will be necessary to advance clinical translation. To that end, we developed tissue-engineered, endplate-modified disc-like angle ply structures (eDAPS) sized for the rat caudal and goat cervical spines that recapitulate the hierarchical structure of the native disc. Here, we demonstrate functional maturation and integration of these eDAPS in a rat caudal disc replacement model, with compressive mechanical properties reaching native values after 20 weeks in vivo and evidence of functional integration under physiological loads. To further this therapy toward clinical translation, we implanted eDAPS sized for the human cervical disc space in a goat cervical disc replacement model. Our results demonstrate maintenance of eDAPS composition and structure up to 8 weeks in vivo in the goat cervical disc space and maturation of compressive mechanical properties to match native levels. These results demonstrate the translational feasibility of disc replacement with a tissue-engineered construct for the treatment of advanced disc degeneration.
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http://dx.doi.org/10.1126/scitranslmed.aau0670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380504PMC
November 2018

A Reactive Inelasticity Theoretical Framework for Modeling Viscoelasticity, Plastic Deformation, and Damage in Soft Tissue.

J Biomech Eng 2018 Sep 26. Epub 2018 Sep 26.

ASME Fellow, Department of Biomedical Engineering, Department of Mechanical Engineering, University of Delaware, Newark, Delaware 19716.

Fibrous tissues are biopolymeric materials that are made of extracellular proteins including several collagens and proteoglycans, and have a high water content. These tissues have non-linear, anisotropic, and inelastic mechanical behaviors that are often categorized into viscoelastic behavior, plastic deformation, and damage. While tissue's elastic and viscoelastic mechanical properties have been measured for decades, there is no comprehensive theoretical framework for modeling inelastic behaviors of these tissues that is based on their structure. To model the three major inelastic mechanical behaviors of tissue's fibrous matrix we formulated a structurally inspired continuum mechanics framework based on the energy of molecular bonds that break and reform in response to external loading (reactive bonds). In this framework, we employed the theory of internal state variables and kinetics of molecular bonds. The number fraction of bonds, their reference deformation gradient, and damage parameter were used as state variables that allowed for consistent modeling of all three of the inelastic behaviors of tissue by using the same sets of constitutive relations. Several numerical examples are provided that address practical problems in tissue mechanics, including the difference between plastic deformation and damage. This model can be used to identify relationships between tissue's mechanical response to external loading and its biopolymeric structure.
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http://dx.doi.org/10.1115/1.4041575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298536PMC
September 2018

Towards the scale up of tissue engineered intervertebral discs for clinical application.

Acta Biomater 2018 04 8;70:154-164. Epub 2018 Feb 8.

Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Replacement of the intervertebral disc with a viable, tissue-engineered construct that mimics native tissue structure and function is an attractive alternative to fusion or mechanical arthroplasty for the treatment of disc pathology. While a number of engineered discs have been developed, the average size of these constructs remains a fraction of the size of human intervertebral discs. In this study, we fabricated medium (3 mm height × 10 mm diameter) and large (6 mm height × 20 mm diameter) sized disc-like angle ply structures (DAPS), encompassing size scales from the rabbit lumbar spine to the human cervical spine. Maturation of these engineered discs was evaluated over 15 weeks in culture by quantifying cell viability and metabolic activity, construct biochemical content, MRI T2 values, and mechanical properties. To assess the performance of the DAPS in the in vivo space, pre-cultured DAPS were implanted subcutaneously in athymic rats for 5 weeks. Our findings show that both sized DAPS matured functionally and compositionally during in vitro culture, as evidenced by increases in mechanical properties and biochemical content over time, yet large DAPS under-performed compared to medium DAPS. Subcutaneous implantation resulted in reductions in NP cell viability and GAG content at both size scales, with little effect on AF biochemistry or metabolic activity. These findings demonstrate that engineered discs at large size scales will mature during in vitro culture, however, future work will need to address the challenges of reduced cell viability and heterogeneous matrix distribution throughout the construct.

Statement Of Significance: This work establishes, for the first time, tissue-engineered intervertebral discs for total disc replacement at large, clinically relevant length scales. Clinical translation of tissue-engineered discs will offer an alternative to mechanical disc arthroplasty and fusion procedures, and may contribute to a paradigm shift in the clinical care for patients with disc pathology and associated axial spine and neurogenic extremity pain.
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http://dx.doi.org/10.1016/j.actbio.2018.01.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593900PMC
April 2018

Freezing does not alter multiscale tendon mechanics and damage mechanisms in tension.

Ann N Y Acad Sci 2017 12 25;1409(1):85-94. Epub 2017 Oct 25.

Department of Biomedical Engineering, University of Delaware, Newark, Delaware.

It is common in biomechanics to use previously frozen tissues, where it is assumed that the freeze-thaw process does not cause consequential mechanical or structural changes. We have recently quantified multiscale tendon mechanics and damage mechanisms using previously frozen tissue, where damage was defined as an irreversible change in the microstructure that alters the macroscopic mechanical parameters. Because freezing has been shown to alter tendon microstructures, the objective of this study was to determine if freezing alters tendon multiscale mechanics and damage mechanisms. Multiscale testing using a protocol that was designed to evaluate tendon damage (tensile stress-relaxation followed by unloaded recovery) was performed on fresh and previously frozen rat tail tendon fascicles. At both the fascicle and fibril levels, there was no difference between the fresh and frozen groups for any of the parameters, suggesting that there is no effect of freezing on tendon mechanics. After unloading, the microscale fibril strain fully recovered, and interfibrillar sliding only partially recovered, suggesting that the tendon damage is localized to the interfibrillar structures and that mechanisms of damage are the same in both fresh and previously frozen tendons.
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http://dx.doi.org/10.1111/nyas.13460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611696PMC
December 2017

Strain Distribution of Intact Rat Rotator Cuff Tendon-to-Bone Attachments and Attachments With Defects.

J Biomech Eng 2017 Nov;139(11)

Mem. ASME Department of Biomedical Engineering, University of Delaware, 5 Innovation Way, Newark, DE 19716 e-mail: .

This study aimed to experimentally track the tissue-scale strains of the tendon-bone attachment with and without a localized defect. We hypothesized that attachments with a localized defect would develop strain concentrations and would be weaker than intact attachments. Uniaxial tensile tests and digital image correlation were performed on rat infraspinatus tendon-to-bone attachments with defects (defect group) and without defects (intact group). Biomechanical properties were calculated, and tissue-scale strain distributions were quantified for superior and inferior fibrous and calcified regions. At the macroscale, the defect group exhibited reduced stiffness (31.3±3.7 N/mm), reduced ultimate load (24.7±3.8 N), and reduced area under the curve at ultimate stress (3.7±1.5 J/m2) compared to intact attachments (42.4±4.3 N/mm, 39.3±3.7 N, and 5.6±1.4 J/m2, respectively). Transverse strain increased with increasing axial load in the fibrous region of the defect group but did not change for the intact group. Shear strain of the superior fibrous region was significantly higher in the defect group compared to intact group near yield load. This work experimentally identified that attachments may resist failure by distributing strain across the interface and that strain concentrations develop near attachment defects. By establishing the tissue-scale deformation patterns of the attachment, we gained insight into the micromechanical behavior of this interfacial tissue and bolstered our understanding of the deformation mechanisms associated with its ability to resist failure.
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http://dx.doi.org/10.1115/1.4038111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676647PMC
November 2017

Special Issue: Spotlight on the Future of Musculoskeletal Biomechanics: Frontiers and Challenges in Musculoskeletal Biomechanics.

J Biomech Eng 2017 11;139(11)

Department of Biomedical Engineering, University of Florida, P.O. Box 116131, Gainesville, FL 32611

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http://dx.doi.org/10.1115/1.4038049DOI Listing
November 2017

Translation of an injectable triple-interpenetrating-network hydrogel for intervertebral disc regeneration in a goat model.

Acta Biomater 2017 09 19;60:201-209. Epub 2017 Jul 19.

Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States; Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Degeneration of the intervertebral discs is a progressive cascade of cellular, compositional and structural changes that is frequently associated with low back pain. As the first signs of disc degeneration typically arise in the disc's central nucleus pulposus (NP), augmentation of the NP via hydrogel injection represents a promising strategy to treat early to mid-stage degeneration. The purpose of this study was to establish the translational feasibility of a triple interpenetrating network hydrogel composed of dextran, chitosan, and teleostean (DCT) for augmentation of the degenerative NP in a preclinical goat model. Ex vivo injection of the DCT hydrogel into degenerated goat lumbar motion segments restored range of motion and neutral zone modulus towards physiologic values. To facilitate non-invasive assessment of hydrogel delivery and distribution, zirconia nanoparticles were added to make the hydrogel radiopaque. Importantly, the addition of zirconia did not negatively impact viability or matrix producing capacity of goat mesenchymal stem cells or NP cells seeded within the hydrogel in vitro. In vivo studies demonstrated that the radiopaque DCT hydrogel was successfully delivered to degenerated goat lumbar intervertebral discs, where it was distributed throughout both the NP and annulus fibrosus, and that the hydrogel remained contained within the disc space for two weeks without evidence of extrusion. These results demonstrate the translational potential of this hydrogel for functional regeneration of degenerate intervertebral discs.

Statement Of Significance: The results of this work demonstrate that a radiopaque hydrogel is capable of normalizing the mechanical function of the degenerative disc, is supportive of disc cell and mesenchymal stem cell viability and matrix production, and can be maintained in the disc space without extrusion following intradiscal delivery in a preclinical large animal model. These results support evaluation of this hydrogel as a minimally invasive disc therapeutic in long-term preclinical studies as a precursor to future clinical application in patients with disc degeneration and low back pain.
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http://dx.doi.org/10.1016/j.actbio.2017.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688915PMC
September 2017

Exposure to buffer solution alters tendon hydration and mechanics.

J Biomech 2017 08 6;61:18-25. Epub 2017 Jul 6.

Department of Mechanical Engineering, University of Delaware, Newark, DE, United States; Department of Biomedical Engineering, University of Delaware, Newark, DE, United States. Electronic address:

A buffer solution is often used to maintain tissue hydration during mechanical testing. The most commonly used buffer solution is a physiological concentration of phosphate buffered saline (PBS); however, PBS increases the tissue's water content and decreases its tensile stiffness. In addition, solutes from the buffer can diffuse into the tissue and interact with its structure and mechanics. These bathing solution effects can confound the outcome and interpretation of mechanical tests. Potential bathing solution artifacts, including solute diffusion, and their effect on mechanical properties, are not well understood. The objective of this study was to measure the effects of long-term exposure of rat tail tendon fascicles to several concentrations (0.9-25%) of NaCl, sucrose, polyethylene glycol (PEG), and SPEG (NaCl+PEG) solutions on water content, solute diffusion, and mechanical properties. We found that with an increase in solute concentration the apparent water content decreased for all solution types. Solutes diffused into the tissue for NaCl and sucrose, however, no solute diffusion was observed for PEG or SPEG. The mechanical properties changed for both NaCl solutions, in particular after long-term (8h) incubation the modulus and equilibrium stress decreased compared to short-term (15min) for 25% NaCl, and the cross sectional area increased for 0.9% NaCl. However, the mechanical properties were unchanged for both PEG and SPEG except for minor alterations in stress relaxation parameters. This study shows that NaCl and sucrose buffer solutions are not suitable for long-term mechanical tests. We therefore propose using PEG or SPEG as alternative buffer solutions that after long-term incubation can maintain tissue hydration without solute diffusion and produce a consistent mechanical response.
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http://dx.doi.org/10.1016/j.jbiomech.2017.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659756PMC
August 2017

Investigating mechanisms of tendon damage by measuring multi-scale recovery following tensile loading.

Acta Biomater 2017 07 21;57:363-372. Epub 2017 Apr 21.

Department of Biomedical Engineering, University of Delaware, United States. Electronic address:

Tendon pathology is associated with damage. While tendon damage is likely initiated by mechanical loading, little is known about the specific etiology. Damage is defined as an irreversible change in the microstructure that alters the macroscopic mechanical parameters. In tendon, the link between mechanical loading and microstructural damage, resulting in macroscopic changes, is not fully elucidated. In addition, tendon damage at the macroscale has been proposed to initiate when tendon is loaded beyond a strain threshold, yet the metrics to define the damage threshold are not determined. We conducted multi-scale mechanical testing to investigate the mechanism of tendon damage by simultaneously quantifying macroscale mechanical and microstructural changes. At the microscale, we observe full recovery of the fibril strain and only partial recovery of the interfibrillar sliding, indicating that the damage initiates at the interfibrillar structures. We show that non-recoverable sliding is a mechanism for tendon damage and is responsible for the macroscale decreased linear modulus and elongated toe-region observed at the fascicle-level, and these macroscale properties are appropriate metrics that reflect tendon damage. We concluded that the inflection point of the stress-strain curve represents the damage threshold and, therefore, may be a useful parameter for future studies. Establishing the mechanism of damage at multiple length scales can improve prevention and rehabilitation strategies for tendon pathology.

Statement Of Significance: Tendon pathology is associated with mechanically induced damage. Damage, as defined in engineering, is an irreversible change in microstructure that alters the macroscopic mechanical properties. Although microstructural damage and changes to macroscale mechanics are likely, this link to microstructural change was not yet established. We conducted multiscale mechanical testing to investigate the mechanism of tendon damage by simultaneously quantifying macroscale mechanical and microstructural changes. We showed that non-recoverable sliding between collagen fibrils is a mechanism for tendon damage. Establishing the mechanism of damage at multiple length scales can improve prevention and rehabilitation strategies for tendon pathology.
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http://dx.doi.org/10.1016/j.actbio.2017.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688648PMC
July 2017

Optimization of Preculture Conditions to Maximize the In Vivo Performance of Cell-Seeded Engineered Intervertebral Discs.

Tissue Eng Part A 2017 09 19;23(17-18):923-934. Epub 2017 Apr 19.

1 Department of Orthopedic Surgery, University of Pennsylvania , Philadelphia, Pennsylvania.

The development of engineered tissues has progressed over the past 20 years from in vitro characterization to in vivo implementation. For musculoskeletal tissue engineering in particular, the emphasis of many of these studies was to select conditions that maximized functional and compositional gains in vitro. However, the transition from the favorable in vitro culture environment to a less favorable in vivo environment has proven difficult, and, in many cases, engineered tissues do not retain their preimplantation phenotype after even short periods in vivo. Our laboratory recently developed disc-like angle-ply structures (DAPS), an engineered intervertebral disc for total disc replacement. In this study, we tested six different preculture media formulations (three serum-containing and three chemically defined, with varying doses of transforming growth factor β3 [TGF-β3] and varying strategies to introduce serum) for their ability to preserve DAPS composition and metabolic activity during the transition from in vitro culture to in vivo implantation in a subcutaneous athymic rat model. We assayed implants before and after implantation to determine collagen content, glycosaminoglycan (GAG) content, metabolic activity, and magnetic resonance imaging (MRI) characteristics. A chemically defined media condition that incorporated TGF-β3 promoted the deposition of GAG and collagen in DAPS in vitro, the maintenance of accumulated matrix in vivo, and minimal changes in the metabolic activity of cells within the construct. Preculture in serum-containing media (with or without TGF-β3) was not compatible with DAPS maturation, particularly in the nucleus pulposus (NP) region. All groups showed increased collagen production after implantation. These findings define a favorable preculture strategy for the translation of engineered discs seeded with disc cells.
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http://dx.doi.org/10.1089/ten.tea.2016.0491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610389PMC
September 2017

Evidence that interfibrillar load transfer in tendon is supported by small diameter fibrils and not extrafibrillar tissue components.

J Orthop Res 2017 10 31;35(10):2127-2134. Epub 2017 Jan 31.

Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, 150 Academy Street, Newark, Delaware, 19716.

Collagen fibrils in tendon are believed to be discontinuous and transfer tensile loads through shear forces generated during interfibrillar sliding. However, the structures that transmit these interfibrillar forces are unknown. Various extrafibrillar tissue components (e.g., glycosaminoglycans, collagens XII and XIV) have been suggested to transmit interfibrillar loads by bridging collagen fibrils. Alternatively, collagen fibrils may interact directly through physical fusions and interfibrillar branching. The objective of this study was to test whether extrafibrillar proteins are necessary to transmit load between collagen fibrils or if interfibrillar load transfer is accomplished directly by the fibrils themselves. Trypsin digestions were used to remove a broad spectrum of extrafibrillar proteins and measure their contribution to the multiscale mechanics of rat tail tendon fascicles. Additionally, images obtained from serial block-face scanning electron microscopy were used to determine the three-dimensional fibrillar organization in tendon fascicles and identify any potential interfibrillar interactions. While trypsin successfully removed several extrafibrillar tissue components, there was no change in the macroscale fascicle mechanics or fibril:tissue strain ratio. Furthermore, the imaging data suggested that a network of smaller diameter fibrils (<150 nm) wind around and fuse with their neighboring larger diameter fibrils. These findings demonstrate that interfibrillar load transfer is not supported by extrafibrillar tissue components and support the hypothesis that collagen fibrils are capable of transmitting loads themselves. Conclusively determining how fibrils bear load within tendon is critical for identifying the mechanisms that impair tissue function with degeneration and for restoring tissue properties via cell-mediated regeneration or engineered tissue replacements. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2127-2134, 2017.
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http://dx.doi.org/10.1002/jor.23517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503823PMC
October 2017