In silico and structure-based evaluation of deleterious mutations identified in human Chk1, Chk2, and Wee1 protein kinase.

Checkpoint kinases Chk1, Chk2, Wee1 are playing a key role in DNA damage response and genomic integrity. Cancer-associated mutations identified in human Chk1, Chk2, and Wee1 were retrieved to understand the function associated with the mutation and also alterations in the folding pattern. Therefore, an attempt has been made to identify deleterious effect of variants using in silico and structure-based approach. Variants of uncertain significance for Chk1, Chk2, and Wee1 were retrieved from different databases and four prediction servers were employed to predict pathogenicity of mutations. Further, Interpro, I-Mutant 3.0, Consurf, TM-align, and have (y)our protein explained were used for comprehensive study of the deleterious effects of variants. The sequences of Chk1, Chk2, and Wee1 were analyzed using Clustal Omega, and the three-dimensional structures of the proteins were aligned using TM-align. The molecular dynamics simulations were performed to explore the differences in folding pattern between Chk1, Chk2, Wee1 wild-type, and mutant protein and also to evaluate the structural integrity. Thirty-six variants in Chk1, 250 Variants in Chk2, and 29 in Wee1 were categorized as pathogenic using in silico prediction tools. Furthermore, 25 mutations in Chk1, 189 in Chk2, and 14 in Wee1 were highly conserved, possessing deleterious effect and also influencing the protein structure and function. These identified mutations may provide underlying genetic intricacies to serve as potential targets for therapeutic inventions and clinical management.

Novel Dipeptide Inhibitors of PfPNP: In-silico Identification of Promising New Antimalarials.

Malaria, an infectious disease caused by Plasmodium falciparum, is becoming increasingly difficult to treat due to the emergence of drug-resistant strains. Recent studies have proposed purine nucleoside phosphorylase from P. falciparum (pfPNP) as a potential target for malaria treatment. In the present study, we designed a virtual library of 400 dipeptides to discover novel anti-malarial peptide inhibitors. A structure-based molecular docking method was employed to virtually screen the designed library against the wild-type structure of pfPNP (PDB: 5ZNC). The best four (Phe-Arg, Arg-His, Trp-Arg and Tyr-Arg) dipeptides, which were then investigated for their binding potential against pfPNP using Molecular Dynamics simulation studies. Parameters such as RMSD, RMSF, Rg, and SASA were analyzed to understand the structural changes, energetics, and overall behavior of pfPNP -dipeptide complexes. The pfPNP demonstrated significant stability upon binding with each of the identified dipeptides with ΔG of over -168 kcal/mol. Additionally, DFT and ADME predictions indicated that  electronic structure, energetics, and pharmacokinetic properties of  selected dipeptides were favorable for drug development. Our comprehensive computational investigation has identified these four dipeptides as promising candidates. These designed and selected dipeptides may further be modified using peptidomimetic and medicinal chemistry tools to develop a novel class of promising antimalarials.

Current benchtop protocols are not appropriate for the evaluation of distraction-based growing rods: a literature review to justify a new protocol and its development.

PURPOSE: Although distraction-based growing rods (GR) are the gold standard for the treatment of early onset scoliosis, they suffer from high failure rates. We have (1) performed a literature search to understand the deficiencies of the current protocols, (2) in vitro evaluation of GRs using our proposed protocol and performed a finite element (FE) model validation, and (3) identified key features which should be considered in mechanical testing setups. METHODS: PubMed, Embase, and Web of Science databases were searched for articles published on (a) in vivo animal, in vitro cadaveric, and biomechanical studies analyzing the use of GRs as well as (b) failure mechanisms and risk factors for GRs. Both FE and benchtop models of a proposed TGR test construct were developed and evaluated for two cases, long tandem connectors (LT), and side-by-side connectors (SBS). The test construct consisted of five polymer blocks representing vertebral bodies, joined with springs to simulate spinal stiffness. The superior and inferior blocks accepted the pedicle screw anchors, while the three middle blocks were floating. After the pedicle screws, rods, and connectors were assembled onto this construct, distraction was performed, mimicking scoliosis surgery. The resulting distracted constructs were then subjected to static compression-bending loading. Yield load and stiffness were calculated and used to verify/validate the FE results. RESULTS: From the literature search, key features identified as significant were axial and transverse connectors, contoured rods, and distraction, distraction being the most challenging feature to incorporate in testing. The in silico analyses, once they are validated, can be used as a complementing technique to investigate other anatomical features which are not possible in the mechanical setup (like growth/scoliosis curvature). Based on our experiment, the LT constructs showed higher stiffness and yield load compared to SBS (78.85 N/mm vs. 59.68 N/mm and 838.84 N vs. 623.3 N). The FE predictions were in agreement with the experimental outcomes (within 10% difference). The maximum von Mises stresses were predicted adjacent to the distraction site, consistent with the location of observed failures in vivo. CONCLUSION: The two-way approach presented in this study can lead to a robust prediction of the contributing factors to the in vivo failure.

Biomechanical comparison of multi-rod constructs by satellite rod configurations (in-line vs. lateral) and screw types (monoaxial vs. polyaxial) spanning a lumbar pedicle subtraction osteotomy (PSO): is there an optimal configuration?

PURPOSE: Multi-rod constructs are used commonly to stabilize pedicle subtraction osteotomies (PSO). This study aimed to evaluate biomechanical properties of different satellite rod configurations and effects of screw-type spanning a PSO. METHODS: A validated 3D spinopelvic finite element model with a L3 PSO (30°) was used to evaluate 5 models: (1) Control (T10-pelvis + 2 rods); (2) lateral satellite rods connected via offsets to monoaxial screws (LatSat-Mono) or (3) polyaxial screws (LatSat-Poly); (4) in-line satellite rods connected to monoaxial screws (InSat-Mono) or (4) polyaxial screws (InSat-Poly). Global and PSO range of motions (ROM) were recorded. Rods' von Mises stresses and PSO forces were recorded and the percent differences from Control were calculated. RESULTS: All satellite rods (save InSat-Mono) increased PSO ROM and decreased primary rods' von Mises stresses at the PSO. Lateral rods increased PSO forces (LatSat-Mono:347.1 N; LatSat-Poly:348.6 N; Control:336 N) and had relatively lower stresses, while in-line rods decreased PSO forces (InSat-Mono:280.1 N; InSat-Poly:330.7 N) and had relatively higher stresses. Relative to polyaxial screws, monoaxial screws further decreased PSO ROM, increased satellite rods' stresses, and decreased PSO forces for in-line rods, but did not change PSO forces for lateral rods. CONCLUSION: Multi-rod constructs using in-line and lateral satellite rods across a PSO reduced primary rods' stresses. Subtle differences in biomechanics suggest lateral satellite rods, irrespective of screw type, increase PSO forces and lower rod stresses compared to in-line satellite rods, which had a high degree of posterior instrumentation stress shielding and lower PSO forces. Clinical studies are warranted to determine if these findings influence clinical outcomes.

Tibiofemoral Cartilage Contact Pressures in Athletes During Landing: A Dynamic Finite Element Study.

Cartilage defects are common in the knee joint of active athletes and remain a problem as a strong risk factor for osteoarthritis. We hypothesized that landing during sport activities, implication for subfailure ACL loading, would generate greater contact pressures (CP) at the lateral knee compartment. The purpose of this study is to investigate tibiofemoral cartilage CP of athletes during landing. Tibiofemoral cartilage contact pressures (TCCP) under clinically relevant anterior cruciate ligament subfailure external loadings were predicted using four dynamic explicit finite element (FE) models (2 males and 2 females) of the knee. Bipedal landing from a jump for five cases of varying magnitudes of external loadings (knee abduction moment, internal tibial torque, and anterior tibial shear) followed by an impact load were simulated. Lateral TCCP from meniscus (area under meniscus) and from femur (area under femur) increased by up to 94% and %30 respectively when external loads were incorporated with impact load in all the models compared to impact-only case. In addition, FE model predicted higher CP in lateral compartment by up to 37% (11.87 MPa versus 8.67 MPa) and 52% (20.19 MPa versus 13.29 MPa) for 90% and 50% percentile models, respectively. For the same percentile populations, CPs were higher by up to 25% and 82% in smaller size models than larger size models. We showed that subfailure ACL loadings obtained from previously conducted in vivo study led to high pressures on the tibiofemoral cartilage. This knowledge is helpful in enhancing neuromuscular training for athletes to prevent cartilage damage.

Sacroiliac joint stabilization using implants provide better fixation in females compared to males: a finite element analysis.

PURPOSE: This study's objective was to assess biomechanical parameters across fused and contralateral sacroiliac joints (SIJs) and implants during all spinal motions for both sexes. Various SIJ implant devices on the market are used in minimally invasive surgeries. These implants are placed across the joint using different surgical approaches. The biomechanical effects of fusion surgical techniques in males and females have not been studied. METHODS: The validated finite element models of a male, and a female spine-pelvis-femur were unilaterally instrumented across the SIJ using three screws for two SIJ implants, half threaded and fully threaded screws placed laterally and posteriorly to the joint, respectively. RESULTS: Motion and peak stress data at the SIJs showed that the female model exhibited lower stresses and higher reduction in motion at the contralateral SIJ in all motions than the male model predictions with 84% and 71% reductions in motion and stresses across the SIJ. CONCLUSION: Implants exhibited higher stresses in the female model compared to the male model. However, chances of SIJ implant failure in the female patients are still minimal, based on the calculated factor of safety which is still very high. Both lateral and posterior surgical approaches were effective in both sexes; however, the lateral approach may provide a better biomechanical response, especially for females. Moreover, implant design characteristics did not make a difference in the implants' biomechanical performance. SIJ stabilization was primarily provided by the implants which were the farthest from the sacrum rotation center.

Iatrogenic muscle damage in transforaminal lumbar interbody fusion and adjacent segment degeneration: a comparative finite element analysis of open and minimally invasive surgeries.

PURPOSE: Lumbar procedures for Transforaminal Lumbar Interbody Fusion (TLIF) range from open (OS) to minimally invasive surgeries (MIS) to preserve paraspinal musculature. We quantify the biomechanics of cross-sectional area (CSA) reduction of paraspinal muscles following TLIF on the adjacent segments. METHODS: ROM was acquired from a thoracolumbar ribcage finite element (FE) model across each FSU for flexion-extension. A L4-L5 TLIF model was created. The ROM in the TLIF model was used to predict muscle forces via OpenSim. Muscle fiber CSA at L4 and L5 were reduced from 4.8%, 20.7%, and 90% to simulate muscle damage. The predicted muscle forces and ROM were applied to the TLIF model for flexion-extension. Stresses were recorded for each model. RESULTS: Increased ROM was present at the cephalad (L3-L4) and L2-L3 level in the TLIF model compared to the intact model. Graded changes in paraspinal muscles were seen, the largest being in the quadratus lumborum and multifidus. Likewise, intradiscal pressures and annulus stresses at the cephalad level increased with increasing CSA reduction. CONCLUSIONS: CSA reduction during the TLIF procedure can lead to adjacent segment alterations in the spinal element stresses and potential for continued back pain, postoperatively. Therefore, minimally invasive techniques may benefit the patient.

Spinal Balance/Alignment - Clinical Relevance and Biomechanics.

In the normal spine due to its curvature in various regions, C7 plumb line (C7PL) passes through the sacrum so that the head is centered over the pelvis-ball and socket hip joints and ankle joints. This configuration leads to the least muscular activities to maintain the spinal balance. For any reason like deformity, scoliosis, kyphosis, trauma, and/or surgery this optimal configuration gets disturbed requiring higher muscular activity to maintain the posture and balance. Several parameters like the thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), sacral slope (SS), Hip- and leg position influence the sagittal balance and thus the optimal configuration of spinal alignment. Global sagittal imbalance is energy consuming and often painful compensatory mechanisms are developed, that in turn negatively influence the quality of life. This review looks at the clinical aspects of spinal imbalance, and the biomechanics of spinal balance as dictated by the deformities- ankylosing spondylitis, scoliosis and kyphosis; surgical corrections- pedicle subtraction osteotomies and long segment stabilizations and consequent postural complications like the proximal and distal junctional kyphosis. This review suggests several potential research topics as well.

Adjacent-Level Hypermobility and Instrumented-Level Fatigue Loosening With Titanium and PEEK Rods for a Pedicle Screw System: An In Vitro Study.

Adjacent-level disease is a common iatrogenic complication seen among patients undergoing spinal fusion for low back pain. This is attributed to the postsurgical differences in stiffness between the spinal levels, which result in abnormal forces, stress shielding, and hypermobility at the adjacent levels. In addition, as most patients undergoing these surgeries are osteoporotic, screw loosening at the index level is a complication that commonly accompanies adjacent-level disease. Recent studies indicate that a rod with lower rigidity than that of titanium may help to overcome these detrimental effects at the adjacent level. The present study was conducted in vitro using 12 L1-S1 specimens divided into groups of six, with each group instrumented with either titanium rods or PEEK (polyetheretherketone) rods. The test protocol included subjecting intact specimens to pure moments of 10 Nm in extension and flexion using an FS20 Biomechanical Spine Test System (Applied Test Systems) followed by hybrid moments on the instrumented specimens to achieve the same L1-S1 motion as that of the intact specimens. During the protocol's later phase, the L4-L5 units from each specimen were segmented for cyclic loading followed by postfatigue kinematic analysis to highlight the differences in motion pre- and postfatigue. The objectives included the in vitro comparison of (1) the adjacent-level motion before and after instrumentation with PEEK and titanium rods and (2) the pre- and postfatigue motion at the instrumented level with PEEK and titanium rods. The results showed that the adjacent levels above the instrumentation caused increased flexion and extension with both PEEK and titanium rods. The postfatigue kinematic data showed that the motion at the instrumented level (L4-L5) increased significantly in both flexion and extension compared to prefatigue motion in titanium groups. However, there was no significant difference in motion between the pre- and postfatigue data in the PEEK group.

Inherent Strength of the osteo-WEDGE(™) Bone Plate Locking System for Arthrodesis of the First Metatarsocuneiform Joint: A Biomechanical Study.

First metatarsocuneiform joint arthrodesis with a locking bone plate and screw system has been effectively used to correct metatarsus primus varus and instability of the first ray. The goal of the present cadaveric biomechanical study was to quantify and compare the inherent strength of the first metatarsocuneiform joint and surrounding bones fixated with the osteo-WEDGE(™) bone plate locking system (OW) with that of intact specimens. Fourteen fresh-frozen adult human cadaveric foot specimens consisting of the first metatarsal and medial cuneiform bones with intact joint capsules and ligaments were used. The OW was implanted in 7 of these specimens at the first metatarsal cuneiform joint (MCJ), and the remaining 7 specimens were left intact. Each of the specimens was then subjected to axial force to simulate dorsiflexion of the first metatarsal using a cantilever bending test setup. Load was applied on the plantar aspect of the first metatarsal head until failure of the construct. The mean load and bending moment on the first MCJ at failure for the implanted specimens were 119.98 ± 56.76 N and 5.57 ± 2.71 Nm, respectively. For the intact specimens, the mean load and bending moment on the first MCJ at failure were 107.93 ± 60.90 N and 6.07 ± 3.18 Nm, respectively. None of the specimens showed catastrophic failure within the physiologic loading limits. These results imply that the mechanical strength of the OW is comparable to that of intact specimens. Thus, the first MCJ and surrounding bones fixated with an OW should be able to effectively withstand the vertical ground reaction forces the same as intact specimens.

Morphological changes of the caudal cervical intervertebral foramina due to flexion-extension and compression-traction movements in the canine cervical vertebral column.

BACKGROUND: Previous studies in humans have reported that the dimensions of the intervertebral foramina change significantly with movement of the spine. Cervical spondylomyelopathy (CSM) in dogs is characterized by dynamic and static compressions of the neural components, leading to variable degrees of neurologic deficits and neck pain. Studies suggest that intervertebral foraminal stenosis has implications in the pathogenesis of CSM. The dimensions of the cervical intervertebral foramina may significantly change during neck movements. This could have implication in the pathogenesis of CSM and other diseases associated with radiculopathy such as intervertebral disc disease. The purpose of this study was to quantify the morphological changes in the intervertebral foramina of dogs during flexion, extension, traction, and compression of the canine cervical vertebral column. All vertebral columns were examined with magnetic resonance imaging prior to biomechanic testing. Eight normal vertebral columns were placed in Group 1 and eight vertebral columns with intervertebral disc degeneration or/and protrusion were assigned to Group 2. Molds of the left and right intervertebral foramina from C4-5, C5-6 and C6-7 were taken during all positions and loading modes. Molds were frozen and vertical (height) and horizontal (width) dimensions of the foramina were measured. Comparisons were made between neutral to flexion and extension, flexion to extension, and traction to compression in neutral position. RESULTS: Extension decreased all the foraminal dimensions significantly, whereas flexion increased all the foraminal dimensions significantly. Compression decreased all the foraminal dimensions significantly, and traction increased the foraminal height, but did not significantly change the foraminal width. No differences in measurements were seen between groups. CONCLUSIONS: Our results show movement-related changes in the dimensions of the intervertebral foramina, with significant foraminal narrowing in extension and compression.

Biomechanical evaluation of the pedicle screw insertion depth effect on screw stability under cyclic loading and subsequent pullout.

STUDY DESIGN: A biomechanical ex vivo study of the human lumbar spine. OBJECTIVE: To evaluate the effects of transpedicular screw insertion depth on overall screw stability and pullout strength following cyclic loading in the osteoporotic lumbar spine. SUMMARY OF BACKGROUND DATA: Although much is known about the clinical outcomes of spinal fusion, questions remain in our understanding of the biomechanical strength of lumbar pedicle screw fixation as it relates to screw sizing and placement. Biomechanical analyses examining ideal pedicle screw depth with current pedicle screw technology are limited. In the osteoporotic spine, optimized pedicle screw insertion depth may improve construct strength, decreasing the risk of loosening or pullout. METHODS: A total of 100 pedicles from 10 osteoporotic lumbar spines were randomly instrumented with pedicle screws in mid-body, pericortical, and bicortical depths. Instrumented specimens underwent cyclic loading (5000 cycles of ±2 N m pure flexion moment) and subsequent pullout. Screw loosening, failure loads, and energy absorption were calculated. RESULTS: Cyclic loading significantly (P<0.001) reduced screw-bone angular stiffness between prefatigue and postfatigue conditions by 25.6%±17.9% (mid-body), 20.8%±14.4% (pericortical), and 14.0%±13.0% (bicortical). Increased insertion depth resulted in lower levels of reduction in angular stiffness, which was only significant between mid-body and bicortical screws (P=0.009). Pullout force and energy of 583±306 N and 1.75±1.98 N m (mid-body), 713±321 N and 2.40±1.79 N m (pericortical), and 797±285 N and 2.97±2.33 N m (bicortical) were observed, respectively. Increased insertion depth resulted in higher magnitudes of both pullout force and energy, which was significant only for pullout force between mid-body and bicortical screws (P=0.005). CONCLUSION: Although increased screw depth led to increased fixation and decreased loosening, additional purchase of the stiff anterior cortex is essential to reach superior screw-bone construct stability and stiffness.

Effects of flexion and extension on the diameter of the caudal cervical vertebral canal in dogs.

OBJECTIVE: To quantify changes in the diameter of the vertebral canal with flexion and extension in the cervical vertebral column. STUDY DESIGN: Cadaveric biomechanical study. SAMPLE POPULATION: Cadaveric canine cervical vertebral column (n = 16 dogs). METHODS: All vertebral columns were evaluated with MRI. Group 1 consisted of 8 normal vertebral columns. Group 2 included 8 vertebral columns with intervertebral disc degeneration. Flexion, extension, compression, and tension were applied to the caudal cervical region (C4-5, C5-6, C6-7). Sagittal vertebral canal diameters (VCD) were obtained by measuring the distance between the ventral and dorsal aspects of vertebral canal. RESULTS: No differences were seen between groups, thus the results are for both groups. Comparison of VCD between flexion and extension with no load revealed a difference of 2.2 mm (28.9%; P < .001). Comparison between neutral position and extension revealed a reduction of 1.5 mm (16.5%; P < .001), whereas comparison between neutral and flexion showed an increase of 0.7 mm (7.7%; P = .001) in VCD. Comparison between neutral with no load and neutral with compression showed a difference of 0.5 mm, with reduction of 5.5% in the vertebral canal (P = .006). Comparison of extension with no load versus extension with tension revealed an increase of 0.7 mm (9.2%) in the vertebral canal (P < .001). CONCLUSIONS: Cervical vertebral canal diameter decreased significantly with extension and increased with flexion. The results support the presence of dynamic impingement possibly playing a role in diseases characterized by vertebral canal stenosis, such as cervical spondylomyelopathy.

A unique modular implant system enhances load sharing in anterior cervical interbody fusion: a finite element study.

BACKGROUND: The efficacy of dynamic anterior cervical plates is somewhat controversial. Screws in static-plate designs have a smaller diameter and can cut through bone under load. While not ideal, this unintended loosening can help mitigate stress shielding. Stand-alone interbody devices with integral fixation have large endplate contact areas that may inhibit or prevent loosening of the fixation. This study investigates the load sharing ability of a novel dynamic plate design in preventing the stress shielding of the graft material compared to the non-dynamic devices. METHODS: An experimentally validated intact C5-C6 finite element model was modified to simulate discectomy and accommodate implant-graft assembly. Four implant iterations were modeled; InterPlate titanium device with dynamic surface features (springs), InterPlate titanium non-dynamic device, InterPlate titanium design having a fully enclosed graft chamber, and the InterPlate design in unfilled PEEK having a fully enclosed graft chamber. All the models were fixed at the inferior-most surface of C6 and the axial displacement required to completely embed the dynamic surface features was applied to the model. RESULTS: InterPlate device with dynamic surface features induced higher graft stresses compared to the other design iterations resulting in uniform load sharing. The distribution of these graft stresses were more uniform for the InterPlate dynamic design. CONCLUSIONS: These results indicate that the dynamic design decreases the stress shielding by increasing and more uniformly distributing the graft stress. Fully enclosed graft chambers increase stress shielding. Lower implant material modulus of elasticity does not reduce stress shielding significantly.

A computational biomechanical investigation of posterior dynamic instrumentation: combination of dynamic rod and hinged (dynamic) screw.

Currently, rigid fixation systems are the gold standard for degenerative disk disease treatment. Dynamic fixation systems have been proposed as alternatives for the treatment of a variety of spinal disorders. These systems address the main drawbacks of traditional rigid fixation systems, such as adjacent segment degeneration and instrumentation failure. Pedicle-screw-based dynamic stabilization (PDS) is one type of these alternative systems. The aim of this study was to simulate the biomechanical effect of a novel posterior dynamic stabilization system, which is comprised of dynamic (hinged) screws interconnected with a coiled, spring-based dynamic rod (DSDR), and compare it to semirigid (DSRR and RSRR) and rigid stabilization (RSRR) systems. A validated finite element (FE) model of L1-S1 was used to quantify the biomechanical parameters of the spine, such as range of motion, intradiskal pressure, stresses and facet loads after single-level instrumentation with different posterior stabilization systems. The results obtained from in vitro experimental intact and instrumented spines were used to validate the FE model, and the validated model was then used to compare the biomechanical effects of different fixation and stabilization constructs with intact under a hybrid loading protocol. The segmental motion at L4-L5 increased by 9.5% and 16.3% in flexion and left rotation, respectively, in DSDR with respect to the intact spine, whereas it was reduced by 6.4% and 10.9% in extension and left-bending loads, respectively. After instrumentation-induced intradiskal pressure at adjacent segments, L3-L4 and L5-S1 became less than the intact in dynamic rod constructs (DSDR and RSDR) except in the RSDR model in extension where the motion was higher than intact by 9.7% at L3-L4 and 11.3% at L5-S1. The facet loads were insignificant, not exceeding 12N in any of the instrumented cases in flexion. In extension, the facet load in DSDR case was similar to that in intact spine. The dynamic rod constructions (DSDR and RSDR) led to a lesser peak stress at screws compared with rigid rod constructions (DSRR and RSRR) in all loading cases. A dynamic construct consisting of a dynamic rod and a dynamic screw did protect the adjacent level from excessive motion.

Finite element model of the knee for investigation of injury mechanisms: development and validation.

Multiple computational models have been developed to study knee biomechanics. However, the majority of these models are mainly validated against a limited range of loading conditions and/or do not include sufficient details of the critical anatomical structures within the joint. Due to the multifactorial dynamic nature of knee injuries, anatomic finite element (FE) models validated against multiple factors under a broad range of loading conditions are necessary. This study presents a validated FE model of the lower extremity with an anatomically accurate representation of the knee joint. The model was validated against tibiofemoral kinematics, ligaments strain/force, and articular cartilage pressure data measured directly from static, quasi-static, and dynamic cadaveric experiments. Strong correlations were observed between model predictions and experimental data (r > 0.8 and p < 0.0005 for all comparisons). FE predictions showed low deviations (root-mean-square (RMS) error) from average experimental data under all modes of static and quasi-static loading, falling within 2.5 deg of tibiofemoral rotation, 1% of anterior cruciate ligament (ACL) and medial collateral ligament (MCL) strains, 17 N of ACL load, and 1 mm of tibiofemoral center of pressure. Similarly, the FE model was able to accurately predict tibiofemoral kinematics and ACL and MCL strains during simulated bipedal landings (dynamic loading). In addition to minimal deviation from direct cadaveric measurements, all model predictions fell within 95% confidence intervals of the average experimental data. Agreement between model predictions and experimental data demonstrates the ability of the developed model to predict the kinematics of the human knee joint as well as the complex, nonuniform stress and strain fields that occur in biological soft tissue. Such a model will facilitate the in-depth understanding of a multitude of potential knee injury mechanisms with special emphasis on ACL injury.

Biomechanical analysis of various footprints of transforaminal lumbar interbody fusion devices.

STUDY DESIGN: A biomechanical finite element modeling study of the human lumbar spine. OBJECTIVE: To evaluate the effects of a transforaminal interbody device's footprint on lumbar spine biomechanics to further examine the potential subtle biomechanical differences not captured in previous studies. SUMMARY OF BACKGROUND DATA: In recent years, the evolution of interbody fusion devices has provided the surgeons with a multitude of options. An articulating transforaminal lumbar interbody fusion (TLIF) device is developed to overcome the surgical challenges associated with insertion of a large footprint interbody device through a small incision. METHODS: A finite element model of the L3-S1 lumbar segment was modified to simulate replacement of various TLIF constructs with different cage designs including an articulating vertebral interbody (AVID) TLIF device and a generic TLIF device placed in different configurations. The instrumented models were subjected to a 400 N follower load along with a 10 N m bending moment at different physiological planes. The kinematics, loads, and stresses were compared among various models. RESULTS: Simulated cage designs provided similar kinematical stability within the treated segments. However, the articulating and double TLIF implants allowed for better load sharing through the anterior column. These implants resulted in lower endplate and pedicle screw stresses and in more homogenous stress distribution across the peripheral region of the endplate. CONCLUSIONS: An articulating, large footprint, peripherally placed TLIF device affords substantial biomechanical advantages. This device may be able to reduce the incidence of subsidence because of its ability to reduce and distribute the endplate stresses in the stronger peripheral region. It may also reduce the posterior hardware failure incidence owing to its ability to reduce the screw stresses as compared with traditional TLIF. Although double TLIF has been demonstrated to have similar biomechanical advantages as the AVID, complications associated with double TLIF (ie, larger surgical incision, longer surgical procedure, placement and alignment challenges) support AVID as a better optimized alternative.

Biomechanical evaluation of multi-rod constructs to stabilize an S1 pedicle subtraction osteotomy (PSO): a finite element analysis.

PURPOSE: To develop and validate a finite element (FE) model of a sacral pedicle subtraction osteotomy (S1-PSO) and to compare biomechanical properties of various multi-rod configurations to stabilize S1-PSOs. METHODS: A previously validated FE spinopelvic model was used to develop a 30° PSO at the sacrum. Five multi-rod techniques spanning the S1-PSO were made using 4 iliac screws and a variety of primary rods (PR) and accessory rods (AR; lateral: Lat-AR or medial: Med-AR). All constructs, except one, utilized a horizontal rod (HR) connecting the iliac bolts to which PRs and Med-ARs were connected. Lat-ARs were connected to proximal iliac bolts. The simulation was performed in two steps with the acetabula fixed. For each model, PSO ROM and maximum stress on the PRs, ARs, and HRs were recorded and compared. The maximum stress on the L5-S1 disc and the PSO forces were captured and compared. RESULTS: Highest PSO ROMs were observed for 4-Rods (HR + 2 Med-AR). Constructs consisting of 5-Rods (HR + 2 Lat-ARs + 1 Med-AR) and 6-Rods (HR + 2 Lat-AR + 2 Med-AR) had the lowest PSO ROM. The least stress on the primary rods was seen with 6-Rods, followed by 5-Rods and 4-Rods (HR + 2 Lat-ARs). Lowest PSO forces and lowest L5-S1 disc stresses were observed for 4-Rod (Lat-AR), 5-Rod, and 6-Rod constructs, while 4-Rods (HR + Med-AR) had the highest. CONCLUSION: In this first FE analysis of an S1-PSO, the 4-Rod construct (HR + Med-AR) created the least rigid environment and highest PSO forces anteriorly. While 5- and 6-Rods created the stiffest constructs and lowest stresses on the primary rods, it also jeopardized load transfer to the anterior column, which may not be favorable for healing anteriorly. A balance between the construct's rigidity and anterior load sharing is essential.

Validation of a patient-specific finite element analysis framework for identification of growing rod-failure regions in early onset scoliosis patients.

PURPOSE: Growing rods are the gold-standard for treatment of early onset scoliosis (EOS). However, these implanted rods experience frequent fractures, requiring additional surgery. A recent study by the U.S. Food and Drug Administration (FDA) identified four common rod fracture locations. Leveraging this data, Agarwal et al. were able to correlate these fractures to high-stress regions using a novel finite element analysis (FEA) framework for one patient. The current study aims to further validate this framework through FEA modeling extended to multiple patients. METHODS: Three patient-specific FEA models were developed to match the pre-operative patient data taken from both registry and biplanar radiographs. The surgical procedure was then simulated to match the post-operative deformity. Body weight and flexion bending (1 Nm) loads were then applied and the output stress data on the rods were analyzed. RESULTS: Radiographic data showed fracture locations at the mid-construct, adjacent to the distal and tandem connector across the patients. Stress analysis from the FEA showed these failure locations matched local high-stress regions for all fractures observed. These results qualitatively validate the efficacy of the FEA framework by showing a decent correlation between localized high-stress regions and the actual fracture sites in the patients. CONCLUSIONS: This patient-specific, in-silico framework has huge potential to be used as a surgical tool to predict sites prone to fracture in growing rod implants. This prospective information would therefore be vital for surgical planning, besides helping optimize implant design for reducing rod failures.

Two-to-three times increase in natural hip and lumbar non-sagittal plane kinematics can lead to anterior cruciate ligament injury and cartilage failure scenarios during single-leg landings.

BACKGROUND: Analyzing sports injuries is essential to mitigate risk for injury, but inherently challenging using in vivo approaches. Computational modeling is a powerful engineering tool used to access biomechanical information on tissue failure that cannot be obtained otherwise using traditional motion capture techniques. METHODS: We extrapolated high-risk kinematics associated with ACL strain and cartilage load and stress from a previous motion analysis of 14 uninjured participants. Computational simulations were used to induce ACL failure strain and cartilage failure load, stress, and contact pressure in two age- and BMI-matched participants, one of each biological sex, during single-leg cross drop and single-leg drop tasks. The high-risk kinematics were exaggerated in 20% intervals, within their physiological range of motion, to determine if injury occurred in the models. Where injury occurred, we reported the kinematic profiles that led to tissue failure. FINDINGS: Our findings revealed ACL strains up to 9.99%, consistent with reported failure values in existing literature. Cartilage failure was observed in all eight analyzed conditions when increasing each high-risk kinematic parameter by 2.61 ± 0.67 times the participants' natural landing values. The kinematics associated with tissue failure included peak hip internal rotation of 22.48 ± 19.04°, peak hip abduction of 22.51 ± 9.09°, and peak lumbar rotation away from the stance limb of 11.56 ± 9.78°. INTERPRETATION: Our results support the ability of previously reported high-risk kinematics in the literature to induce injury and add to the literature by reporting extreme motion limits leading to injurious cases. Therefore, training programs able to modify these motions during single-leg landings may reduce the risk of ACL injury and cartilage trauma.