Comprehensive Identification of Tibiofemoral Joint Anatomy and Mechanical Response: Pathway to Multiscale Characterization

The human knee joint is a complex multi-body structure, whose substructures greatly affect its mechanical response. An understanding of the multiscale mechanics of the joint is essential for the prevention and treatment of knee joint injuries and pathologies. Due to the limitations associated with in vivo experimentation, mechanical characterization of the knee joint has commonly relied on in vitro experimentation [1,2]. Predictive and descriptive studies of the mechanical function of the knee and its substructures have commonly employed computational modeling, in particular finite element (FE) analysis, which can be driven by experimental data. With the recent focus on the use of FE models of the knee joint for scientific and clinical purposes [3–5], data for model development, verification, and validation became increasingly important, especially when relying on FE analysis for decision making. An adequate representation of a joint not only depends on the specimen-specific anatomy but may also need to be informed by specimen-specific tissue properties for model development, and specimen-specific joint/tissue response to confirm model response.

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In Silico Performance of a Recellularized Tissue-Engineered Transcatheter Aortic Valve

Journal of Biomechanical Engineering ◽

10.1115/1.4043209 ◽

2019 ◽

Vol 141 (6) ◽

Cited By ~ 3

Author(s):

Christopher Noble ◽

Joshua Choe ◽

Susheil Uthamaraj ◽

Milton Deherrera ◽

Amir Lerman ◽

...

Keyword(s):

Mechanical Behavior ◽

Heart Valves ◽

Mechanical Response ◽

Mechanical Performance ◽

Fe Analysis ◽

Model Parameters ◽

Biaxial Testing ◽

Principal Stresses

Commercially available heart valves have many limitations, such as a lack of remodeling, risk of calcification, and thromboembolic problems. Many state-of-the-art tissue-engineered heart valves (TEHV) rely on recellularization to allow remodeling and transition to mechanical behavior of native tissues. Current in vitro testing is insufficient in characterizing a soon-to-be living valve due to this change in mechanical response; thus, it is imperative to understand the performance of an in situ valve. However, due to the complex in vivo environment, this is difficult to accomplish. Finite element (FE) analysis has become a standard tool for modeling mechanical behavior of heart valves; yet, research to date has mostly focused on commercial valves. The purpose of this study has been to evaluate the mechanical behavior of a TEHV material before and after 6 months of implantation in a rat subdermis model. This model allows the recellularization and remodeling potential of the material to be assessed via a simple and inexpensive means prior to more complex ovine orthotropic studies. Biaxial testing was utilized to evaluate the mechanical properties, and subsequently, constitutive model parameters were fit to the data to allow mechanical performance to be evaluated via FE analysis of a full cardiac cycle. Maximum principal stresses and strains from the leaflets and commissures were then analyzed. The results of this study demonstrate that the explanted tissues had reduced mechanical strength compared to the implants but were similar to the native tissues. For the FE models, this trend was continued with similar mechanical behavior in explant and native tissue groups and less compliant behavior in implant tissues. Histology demonstrated recellularization and remodeling although remodeled collagen had no clear directionality. In conclusion, we observed successful recellularization and remodeling of the tissue giving confidence to our TEHV material; however, the mechanical response indicates the additional remodeling would likely occur in the aortic/pulmonary position.

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Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04302-5 ◽

2021 ◽

Author(s):

Venkatesh Pilla Reddy ◽

Adrian J. Fretland ◽

Diansong Zhou ◽

Shringi Sharma ◽

Buyun Chen ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Kinase Inhibitors ◽

Pbpk Model ◽

Model Development ◽

Limited Information ◽

Time Curve ◽

Btk Inhibitor ◽

Chop Therapy

Abstract Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

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An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

International Journal of Molecular Sciences ◽

10.3390/ijms22041996 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1996 ◽

Cited By ~ 1

Author(s):

Christine M. Khella ◽

Rojiar Asgarian ◽

Judith M. Horvath ◽

Bernd Rolauffs ◽

Melanie L. Hart

Keyword(s):

Synovial Fluid ◽

Knee Joint ◽

Ex Vivo ◽

Disease Process ◽

Early Disease ◽

Knee Trauma ◽

Post Traumatic ◽

Acute Knee

Understanding the causality of the post-traumatic osteoarthritis (PTOA) disease process of the knee joint is important for diagnosing early disease and developing new and effective preventions or treatments. The aim of this review was to provide detailed clinical data on inflammatory and other biomarkers obtained from patients after acute knee trauma in order to (i) present a timeline of events that occur in the acute, subacute, and chronic post-traumatic phases and in PTOA, and (ii) to identify key factors present in the synovial fluid, serum/plasma and urine, leading to PTOA of the knee in 23–50% of individuals who had acute knee trauma. In this context, we additionally discuss methods of simulating knee trauma and inflammation in in vivo, ex vivo articular cartilage explant and in vitro chondrocyte models, and answer whether these models are representative of the clinical inflammatory stages following knee trauma. Moreover, we compare the pro-inflammatory cytokine concentrations used in such models and demonstrate that, compared to concentrations in the synovial fluid after knee trauma, they are exceedingly high. We then used the Bradford Hill Framework to present evidence that TNF-α and IL-6 cytokines are causal factors, while IL-1β and IL-17 are credible factors in inducing knee PTOA disease progresssion. Lastly, we discuss beneficial infrastructure for future studies to dissect the role of local vs. systemic inflammation in PTOA progression with an emphasis on early disease.

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Bioprinted Nanoparticles for Tissue Engineering Applications

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206760 ◽

2009 ◽

Author(s):

Kivilcim Buyukhatipoglu ◽

Robert Chang ◽

Wei Sun ◽

Alisa Morss Clyne

Keyword(s):

Tissue Engineering ◽

Tissue Growth ◽

Bioactive Components ◽

Engineering Applications ◽

Tissue Properties ◽

Native Tissue ◽

3D Architecture

Tissue engineering may require precise patterning of cells and bioactive components to recreate the complex, 3D architecture of native tissue. However, it is difficult to image and track cells and bioactive factors once they are incorporated into the tissue engineered construct. These bioactive factors and cells may also need to be moved during tissue growth in vitro or after implantation in vivo to achieve the desired tissue properties, or they may need to be removed entirely prior to implantation for biosafety concerns.

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The Biological Effects of Combining Metals in a Posterior Spinal Implant: In Vivo Model Development Report of the First Two Cases

Advances in Orthopedic Surgery ◽

10.1155/2014/761967 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Christine L. Farnsworth ◽

Peter O. Newton ◽

Eric Breisch ◽

Michael T. Rohmiller ◽

Jung Ryul Kim ◽

...

Keyword(s):

Galvanic Corrosion ◽

Biological Effects ◽

Model Development ◽

Spinal Instrumentation ◽

Pedicle Screws ◽

Tissue Response ◽

In Vivo Model ◽

Particle Count ◽

Spinal Implant

Study Design. Combinations of metal implants (stainless steel (SS), titanium (Ti), and cobalt chrome (CC)) were placed in porcine spines. After 12 months, tissue response and implant corrosion were compared between mixed and single metal junctions. Objective. Model development and an attempt to determine any detriment of combining different metals in posterior spinal instrumentation. Methods. Yucatan mini-pigs underwent instrumentation over five unfused lumbar levels. A SS rod and a Ti rod were secured with Ti and SS pedicle screws, SS and Ti crosslinks, SS and CC sublaminar wires, and Ti sublaminar cable. The resulting 4 SS/SS, 3 Ti/Ti, and 11 connections between dissimilar metals per animal were studied after 12 months using radiographs, gross observation, and histology (foreign body reaction (FBR), metal particle count, and inflammation analyzed). Results. Two animals had constructs in place for 12 months with no complications. Histology of tissue over SS/SS connections demonstrated 11.1 ± 7.6 FBR cells, 2.1 ± 1.7 metal particles, and moderate to extensive inflammation. Ti/Ti tissue showed 6.3 ± 3.8 FBR cells, 5.2 ± 6.7 particles, and no to extensive inflammation (83% extensive). Tissue over mixed components had 14.1 ± 12.6 FBR cells and 13.4 ± 27.8 particles. Samples surrounding wires/cables versus other combinations demonstrated FBR (12.4 ± 13.5 versus 12.0 ± 9.6 cells, P = 0.96), particles (19.8 ± 32.6 versus 4.3 ± 12.7, P = 0.24), and inflammation (50% versus 75% extensive, P = 0.12). Conclusions. A nonfusion model was developed to study corrosion and analyze biological responses. Although no statistical differences were found in overlying tissue response to single versus mixed metal combinations, galvanic corrosion between differing metals is not ruled out. This pilot study supports further investigation to answer concerns when mixing metals in spinal constructs.

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A New Load Application System for In Vitro Study of Ligamentous Injuries to the Human Knee Joint

Journal of Biomechanical Engineering ◽

10.1115/1.2794195 ◽

1995 ◽

Vol 117 (4) ◽

pp. 373-382 ◽

Cited By ~ 49

Author(s):

J. M. Bach ◽

M. L. Hull

Keyword(s):

Knee Joint ◽

Degree Of Freedom ◽

Load Application ◽

Accuracy Evaluation ◽

Application System ◽

Human Knee ◽

Human Knee Joint ◽

Flexion Extension ◽

External Loads

This paper describes the design and accuracy evaluation of a new six degree of freedom load application system for in vitro testing of the human knee joint. External loads of both polarity in all six degrees of freedom can be applied either individually or in any combination while the knee is permitted to move unconstrained in response to applied loads. The flexion/extension degree of freedom permits the full physiological range of motion. In addition to external loads, forces of the three major muscle groups (quadriceps, hamstrings, gastrocnemius) crossing the joint can be developed. Full automation and rapid convergence of loads to programmed values are achieved through a computer which feeds command signals to servo controller/electro-pneumatic servo valves. The servo valves regulate pressure to pneumatic actuators which develop the various loads. Experiments undertaken to quantify the accuracy of both load and displacement measurements reveal that errors particularly in load measurement are effectively controlled through the apparatus design.

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A New Load Application System for In Vitro Study of Ligamentous Injuries to the Human Knee Joint

Skiing Trauma and Safety: Tenth Volume ◽

10.1520/stp37933s ◽

2009 ◽

pp. 232-232-12

Author(s):

JM Bach ◽

ML Hull

Keyword(s):

Knee Joint ◽

In Vitro Study ◽

Vitro Study ◽

Load Application ◽

Application System ◽

Human Knee ◽

Human Knee Joint

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Mechanical response characteristics of the hearing organ in the low-frequency regions of the cochlea

Journal of Neurophysiology ◽

10.1152/jn.1996.76.6.3850 ◽

1996 ◽

Vol 76 (6) ◽

pp. 3850-3862 ◽

Cited By ~ 31

Author(s):

M. Ulfendahl ◽

S. M. Khanna ◽

A. Fridberger ◽

A. Flock ◽

B. Flock ◽

...

Keyword(s):

Temporal Bone ◽

Mechanical Response ◽

Low Frequency ◽

Cell Receptor ◽

Sound Stimulation ◽

Supporting Cells ◽

Tuning Curves ◽

Electrical Responses

1. With the use of an in vitro preparation of the guinea pig temporal bone, in which the apical turns of the cochlea are exposed, the mechanical and electrical responses of the cochlea in the low-frequency regions were studied during sound stimulation. 2. The mechanical characteristics were investigated in the fourth and third turns of the cochlea with the use of laser heterodyne interferometry, which allows the vibratory responses of both sensory and supporting cells to be recorded. The electrical responses, which can be maintained for several hours, were recorded only in the most apical turn. 3. In the most apical turn, the frequency locations and shapes of the mechanical and electrical responses were very similar. 4. The shapes of the tuning curves and the spatial locations of the frequency maxima in the temporal bone preparation compared very favorably with published results from in vivo recordings of hair cell receptor potentials and sound-induced vibrations of the Reissner's membrane. 5. Compressive nonlinearities were present in both the mechanical and the electrical responses at moderate sound pressure levels. 6. The mechanical tuning changed along the length of the cochlea, the center frequencies in the fourth and third turns being approximately 280 and 570 Hz, respectively. 7. The mechanical responses of sensory and supporting cells were almost identical in shape but differed significantly in amplitude radially across the reticular lamina.

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NO modulates myocardial O2consumption in the nonhuman primate: an additional mechanism of action of amlodipine

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.6.h2069 ◽

1999 ◽

Vol 276 (6) ◽

pp. H2069-H2075 ◽

Cited By ~ 7

Author(s):

Paul R. Forfia ◽

Xiaoping Zhang ◽

Delvin R. Knight ◽

Andrew H. Smith ◽

Christopher P. A. Doe ◽

...

Keyword(s):

Nitric Oxide ◽

Oxygen Consumption ◽

Nonhuman Primate ◽

Myocardial Oxygen Consumption ◽

Channel Blocker ◽

Tissue Response ◽

Canine Heart ◽

Additional Mechanism

Recent evidence from our laboratory and others suggests that nitric oxide (NO) is a modulator of in vivo and in vitro oxygen consumption in the murine and canine heart. Therefore, the goal of our study was twofold: to determine whether NO modulates myocardial oxygen consumption in the nonhuman primate heart in vitro and to evaluate whether the seemingly cardioprotective actions of amlodipine may involve an NO-mediated mechanism. Using a Clark-type O2 electrode, we measured oxygen consumption in cynomologous monkey heart at baseline and after increasing doses of S-nitroso- N-acetylpenicillamine (SNAP; 10−7–10−4M), bradykinin (10−7–10−4M), ramiprilat (10−7–10−4M), and amlodipine (10−7–10−5M). SNAP (−38 ± 5.8%), bradykinin (−19 ± 3.9%), ramiprilat (−28 ± 2.3%), and amlodipine (−23 ± 4.5%) each caused significant ( P < 0.05) reductions in myocardial oxygen consumption at their highest dose. Preincubation of tissue with nitro-l-arginine methyl ester (10−4 M) blunted the effects of bradykinin (−5.4 ± 3.2%), ramiprilat (−4.8 ± 5.0%), and amlodipine (−5.3 ± 5.0%) but had no effect on the tissue response to SNAP (−38 ± 5.8%). Our results indicate that NO can reduce oxygen consumption in the primate myocardium in vitro, and they support a role for the calcium-channel blocker amlodipine as a modulator of myocardial oxygen consumption via a kinin-NO mediated mechanism.

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