Effect of X-ray irradiation on the elastic strain evolution in the mineral phase of bovine bone under creep and load-free conditions

Both the load partitioning between hydroxyapatite (HAP) and collagen during compressive creep deformation of bone and the HAP residual strain in unloaded bone have been shown in previous synchrotron X-ray diffraction studies to be affected by the X-ray irradiation dose. Here, through detailed analysis of the X-ray diffraction patterns of bovine bone, the effect of X-ray dose on (i) the rate of HAP elastic strain accumulation/shedding under creep conditions and (ii) the HAP lattice spacing and average root mean square (RMS) strain under load-free conditions are examined. These strain measurements exhibit three stages in response to increasing X-ray dose. Up to ～75 kGy (stage I) no effect of dose is observed, indicating a threshold behavior. Between ～75 and ～300 kGy (stage II) in unloaded bone the HAP d-spacing increases and the RMS strain decreases with dose, indicating strain relaxation of HAP. Furthermore, under constant compressive load creep conditions, the rate of compressive elastic strain accumulation in HAP decreases with increasing dose until, at ～115 kGy, it changes sign, indicating that the HAP phase is shedding load during creep deformation. These stage II behaviors are consistent with HAP–collagen interfacial damage, which allows the HAP elastic strain to relax within both the loaded and unloaded samples. Finally, for doses in excess of ～300 kGy (stage III, measured up to 7771 kGy) the HAP lattice spacing and RMS strain for load-free samples and the rate of HAP elastic strain shedding for crept samples remain independent of dose, suggesting a saturation of damage and/or stiffening of the collagen matrix due to intermolecular cross-linking.     

GAG depletion increases the stress-relaxation response of tendon fascicles,but does not influence recovery

Cyclic and static loading regimes are commonly used to study tenocyte metabolism in vitro and to improve our understanding of exercise-associated tendon pathologies. The aims of our study were to investigate if cyclic and static stress relaxation affected the mechanical properties of tendon fascicles differently, if this effect was reversible after a recovery period, and if the removal of glycosaminoglycans (GAGs) affected sample recovery. Tendon fascicles were dissected frombovine-foot extensors and subjected to 14% cyclic (1 Hz) or static tensile strain for 30 min. Additional fascicles were incubated overnight in buffer with 0.5 U chondroitinase ABC or in buffer alone prior to the static stress-relaxation regime. To assess the effect of different stress-relaxation regimes, a quasi-static test to failure was carried out, either directly post loading or after a 2 h recovery period, and compared with unloaded control fascicles. Both stress-relaxation regimes led to a significant reduction in fascicle failure stress and strain, but this was more pronounced in the cyclically loaded specimens. Removal of GAGs led to more stress relaxation and greater reductions in failure stress after static loading compared to controls. The reduction in mechanical properties was partially reversible in all samples, given a recovery period of 2 h. This has implications for mechanical testing protocols, as a time delay between fatiguing specimens and characterization of mechanical properties will affect the results. GAGs appear to protect tendon fascicles from fatigue effects, possibly by enabling sample hydration.     

Synchrotron X-ray diffraction study of load partitioning during elastic deformation of bovine dentin

The elastic properties of dentin, a biological composite consisting of stiff hydroxyapatite (HAP) nano-platelets within a compliant collagen matrix, are determined by the volume fraction of these two phases and the load transfer between them. We have measured the elastic strains in situ within the HAP phase of bovine dentine by high energy X-ray diffraction for a series of static compressive stresses at ambient temperature. The apparent HAP elastic modulus (ratio of applied stress to elastic HAP strain) was found to be 18 ± 2 GPa. This value is significantly lower than the value of 44 GPa predicted by the lower bound load transfer Voigt model, using HAP and collagen volume fractions determined by thermo-gravimetric analysis. This discrepancy is explained by (i) a reduction in the intrinsic Young’s modulus of the nano-size HAP platelets due to the high fraction of interfacial volume and (ii) an increase in local stresses due to stress concentration around the dentin tubules.     

Abnormal tibiofemoral kinematics following ACL reconstruction are associated with early cartilage matrix degeneration measured by MRI T1rho

PurposeAltered kinematics following ACL-reconstruction may be a cause of post-traumatic osteoarthritis. T_1ρ MRI is a technique that detects early cartilage matrix degeneration. Our study aimed to evaluate kinematics following ACL-reconstruction, cartilage health (using T_1ρ MRI), and assess whether altered kinematics following ACL-reconstruction are associated with early cartilage degeneration.MethodsEleven patients (average age: 33 ± 9 years) underwent 3 T MRI 18 ± 5 months following ACL-reconstruction. Images were obtained at extension and 30° flexion under simulated loading (125 N). Tibial rotation (TR) and anterior tibial translation (ATT) between flexion and extension, and T_1ρ relaxation times of the knee cartilage were analyzed. Cartilage was divided into five compartments: medial and lateral femoral condyles (MFC/LFC), medial and lateral tibias (MT/LT), and patella. A sub-analysis of the femoral weight-bearing (wb) regions was also performed. Patients were categorized as having “abnormal” or “restored” ATT and TR, and T_1ρ percentage increase was compared between these two groups of patients.ResultsAs a group, there were no significant differences between ACL-reconstructed and contralateral knee kinematics, however, there were individual variations. T_1ρ relaxation times of the MFC and MFC-wb region were elevated (p ≤ 0.05) in the ACL-reconstructed knees compared to the uninjured contralateral knees. There were increases (p ≤ 0.05) in the MFC-wb, MT, patella and overall average cartilage T_1ρ values of the “abnormal” ATT group compared to “restored” ATT group. The percentage increase in the T_1ρ relaxation time in the MFC-wb cartilage approached significance (p = 0.08) in the “abnormal” versus “restored” TR patients.ConclusionsAbnormal kinematics following ACL-reconstruction appear to lead to cartilage degeneration, particularly in the medial compartment.     

The stress state of the fraenal notch region in complete upper dentures

The present study determines the stress field in the region of the labial flange of the complete upper denture (CUD).Using commercial edentulous molds and standardized procedures eight identical CUDs were fabricated with an initial fraenal notch of 5 mm. Three addition notch conditions were produced by deepening the notch two times giving a total depth of the notch of 7 and 9 mm respectively. Finally an incisal diastema of 7 mm was created in every CUD.Three elements rosette strain gauge was cemented onto the midline of each denture specimen near the fraenal notch, for calculating the two principal stresses and the maximum shear stress.It is less possible that a failure crack in a CUD will be initiated from the region of the fraenal notch, due to the compressive nature of the principal stresses (they are varied significantly among the four notch conditions with P = 0.035 for σ₁ and P = 0.007 for σ₂) and the low value of the maximum shear stress. The creation of an incisal diastema significantly decreased the values of the principal stresses σ₁ (P = 0.012) and σ₂ (P = 0.025). Further investigation is needed to detect the region of the CUD where a failure crack may be initiated.     

Photogrammetric measurement of initial tooth displacement under tensile force

The purpose of this study was to quantitatively measure tooth displacement under low horizontal tensile force (≤18 N) and to test the reproducibility of measurements. Anterior tooth mobility was measured using a photogrammetric measurement technique in 23 periodontally healthy subjects. While slowly increasing the tension on each tooth, an automated software program recorded three-dimensional tooth displacement at 3 N intervals, up to 18 N. Measurements were repeated three-times for each tooth. The vector of absolute tooth mobility in the buccal direction was calculated. Intra-class correlations of the three repeated measurements of each tooth were calculated and ranged between “good” and “optimal”. The agreement of measurements was significant (p ≤ 0.05). The analysis of differences between the deviation vectors of contralateral teeth revealed that most differences emerged to be statistically non-significant. The combination of a mechanical loading approach with the optoelectronic system allowed the measurement of three-dimensional tooth mobility in vivo.     

Organized nanofibrous scaffolds that mimic the macroscopic and microscopic architecture of the knee meniscus

The menisci are crescent-shaped fibrocartilaginous tissues whose structural organization consists of dense collagen bundles that are locally aligned but show a continuous change in macroscopic directionality. This circumferential patterning is necessary for load transmission across the knee joint and is a key design parameter for tissue engineered constructs. To address this issue we developed a novel electrospinning method to produce scaffolds composed of circumferentially aligned (CircAl) nanofibers, quantified their structure and mechanics, and compared them with traditional linearly aligned (LinAl) scaffolds. Fibers were locally oriented in CircAl scaffolds, but their orientation varied considerably as a function of position (P < 0.05). LinAl fibers did not change in orientation over a similar length scale (P > 0.05). Cell seeding of CircAl scaffolds resulted in a similar cellular directionality. Mechanical analysis of CircAl scaffolds revealed significant interactions between scaffold length and region (P < 0.05), with the tensile modulus near the edge of the scaffolds decreasing with increasing scaffold length. No such differences were detected in LinAl specimens (P > 0.05). Simulation of the fiber deposition process produced “theoretical” fiber populations that matched the fiber organization and mechanical properties observed experimentally. These novel scaffolds, with spatially varying local orientations and mechanics, will enable the formation of functional anatomic meniscus constructs.     

The effect of blood phenylalanine concentration on Kuvan™ response in phenylketonuria

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase gene (PAH) with consequent elevation of blood phenylalanine (Phe), reduction in tyrosine (Tyr) and elevation of Phe/Tyr ratio (P/T). Although newborn screening for PKU with early dietary treatment improved severe, irreversible brain damage, older patients suffer reversible losses in executive function when Phe concentrations are elevated. The maintenance of strict nutritional control in older children and adults remains difficult. An adjunct to dietary therapy, oral tetrahydrobiopterin (BH₄) has recently been approved by the Food and Drug Administration as a stable, synthetic BH₄ called Kuvan?. Published studies of Kuvan response in PKU varies and involved primarily children. In this prospective study we evaluated dose–response, response frequency and factors predicting response in 21 patients with PKU (aged 8–30 years), who required life-long dietary treatment. Response to Kuvan was defined at 24 h (acute) and over 4 weeks (chronic) as a ≥ 30% decline in the Phe or P/T ratio. A dose of 20 mg/kg Kuvan was chosen with 29% responding in 24 h and 33% of patients at 4 weeks. We then compared baseline Phe, Tyr, P/T, Phe intake, and frequency of “severe” versus “moderate” mutant PAH alleles among acute and chronic responders and non-responders to Kuvan. Predictors of response to Kuvan, both acute and chronic were baseline Phe and baseline P/T. Baseline Phe and P/T were higher among non-responders (P < 0.05). By contrast baseline Tyr was similar (P = 0.45). Phe intake tended to be higher (18 ± 20 mg/kg/24 h) among Kuvan responders than non-responders (15 ± 11 mg/kg/24 h), P < 0.07 NS. Similarly the frequency of “severe” mutant PAH alleles tended to be more frequent (67%) among non-responders than responders (40%) by Chi² test, P = 0.08 NS. These results were reproducible in a “responder” to Kuvan. To assess directly the effect of elevated blood Phe, Phe was lowered in four, “non-responder” patients, but all failed to respond to Kuvan. We conclude that baseline blood Phe and P/T ratio can predict increased probability for response to Kuvan by patients with classic PKU, but the in vivo mechanisms of response to Kuvan remain enigmatic.     

Structure–function relationships and source-to-ground distance in electrospun polycaprolactone

The strength of electrospun scaffolds has direct relevance to their function within tissue engineering. We characterized the effects of source-to-ground distance on the mechanical properties of electrospun poly(ε-caprolactone) (PCL). Source-to-ground distances of 10, 15 and 20 cm, solids concentrations of 12 and 18 wt.% and mandrel rotation surface speeds of 0–12 m s^?1 were utilized. Tensile tests evaluated elastic modulus, tensile strength and elongation at failure. Scanning electron microscopy provided morphology and quantified fiber alignment. Increased source-to-ground distance yielded a microstructure allowing greater fiber rearrangement under load, tripling the observed tensile strength. Increases in rotational speed generally increased fiber alignment and strength at high but not low to moderate speeds. As fiber is quickly pulled out of a comparatively gentle falling process, collision with neighboring fibers moving at different speeds and in different directions can occur. The source-to-ground distance influences these collisions and thus has critical implications for microstructure and biocompatibility. In larger diameter (18 wt.% PCL), heavily point-bonded fibers (produced using a shorter, 10 cm source-to-ground distance), elongation at failure in the aligned direction increases dramatically due to severe localized necking. These specimens show only half of the tensile strength (from 2.6 to 4.5 MPa) and a dramatic increase (from 94% to 503%) in elongation at failure vs. a longer 20 cm source-to-ground distance. Strains of several hundred per cent are accompanied by periodic necking of large-diameter fibers in which microstructural failure appears to occur in a sequential manner involving an equilibrium between localized strain in the tensile direction and anisotropic point bonding that locally resists strain.     

Mechanical Analysis of Extra-Articular Knee Ligaments. Part One: Native knee ligaments

Background

The aim of this study was to provide a characterization of the tensile properties of the medial collateral ligament (MCL), lateral collateral ligament (LCL), anterolateral ligament (ALL) and medial patellofemoral ligament (MPFL). Our hypothesis was that extra-articular knee ligaments are heterogeneous in nature and possess distinct material properties.

Effects of orthostasis on endocrine responses to psychosocial stress

Standardized psychological procedures have been designed to induce physiological stress responses. However, the impact of standing (orthostasis) on the physiological reaction after psychological stress remains unclear. The purpose of the current analysis was to examine and quantify the relative contribution of orthostasis to the physiological stress response by comparing a “standing with stress” to a “standing without stress” condition. We investigated the effect of standing with and without stress on responses of the sympathetic–adrenomedullary (SAM) system and the hypothalamic–pituitary–adrenal (HPA) axis using a standardized psychosocial stress protocol (Trier Social Stress Test) and a non-stress condition in a repeated measures design. Subjects (N = 30) were exposed to both conditions in randomized order and had to maintain a standing, upright position for 10 minutes. In the “standing with stress” condition, significant increases in repeatedly assessed plasma norepinephrine (NE) and epinephrine (EP), as well as in saliva cortisol were found, while in the “standing without stress” condition, no significant changes in plasma epinephrine and saliva cortisol were observed. Calculations of the relative contribution of orthostasis to physiological stress responses revealed that 25.61% of the NE increase, 82.94% of the EP increase, and 68.91% of the cortisol increase, could be attributed to psychosocial stress adjusted for the effects of orthostasis and basal endocrine output. Although these results are indicative for a marked endocrine reaction that is caused by psychosocial stress alone, our findings show that the contribution of orthostasis must be taken into account when interpreting endocrine data collected in a psychosocial stress test.     

Experimental characterization and constitutive modeling of the mechanical behavior of the human trachea

Background and aimsCartilage and smooth muscle constitute the main structural components of the human central airways, their mechanical properties affect the flow in the trachea and contribute to the biological function of the respiratory system. The aim of this work is to find out the mechanical passive response of the principal constituents of the human trachea under static tensile conditions and to propose constitutive models to describe their behavior.MethodsHistological analyses to characterize the tissues and mechanical tests have been made on three human trachea specimens obtained from autopsies. Uniaxial tensile tests on cartilaginous rings and smooth muscle were performed. Tracheal cartilage was considered an elastic material and its Young's modulus and Poisson's coefficient were determined fitting the experimental curves using a Neo-Hookean model. The smooth muscle was proved to behave as a reinforced hyperelastic material with two families of collagen fibers, and its non-linearity was investigated using the Holzapfel strain-energy density function for two families of fibers to fit the experimental data obtained from longitudinal and transversal cuts.ResultsFor cartilage, fitting the experimental curves to an elastic model, a Young's modulus of 3.33 MPa and ν = 0.49 were obtained. For smooth muscle, several parameters of the Holzapfel function were found out (C₁₀ = 0.877 kPa, k₁ = 0.154 kPa, k₂ = 34.157, k₃ = 0.347 kPa and k₄ = 13.889) and demonstrated that the tracheal muscle was stiffer in the longitudinal direction.ConclusionThe better understanding of how these tissues mechanically behave is essential for a correct modeling of the human trachea, a better simulation of its response under different loading conditions, and the development of strategies for the design of new endotracheal prostheses.     

Biomechanical characterization of ascending aortic aneurysm with concomitant bicuspid aortic valve and bovine aortic arch

Studies have shown that patients harboring bicuspid aortic valve (BAV) or bovine aortic arch (BAA) are more likely than the general population to develop ascending aortic aneurysm (AsAA). A thorough quantification of the AsAA tissue properties for these patient groups may offer insights into the underlying mechanisms of AsAA development. Thus, the objective of this study was to investigate and compare the mechanical and microstructural properties of aortic tissues from AsAA patients with and without concomitant BAV or BAA. AsAA (n = 20), BAV (n = 20) and BAA (n = 15) human tissues were obtained from patients who underwent elective AsAA surgery. Planar biaxial and uniaxial failure tests were used to characterize the mechanical and failure properties of the tissues, respectively. Histological analysis was performed to detect medial degenerative characteristics of aortic aneurysm. Individual layer thickness and composition were quantified for each patient group. The circumferential stress–strain response of the BAV samples was stiffer than both AsAA (p = 0.473) and BAA (p = 0.152) tissues at a low load. The BAV samples were nearly isotropic, while AsAA and BAA samples were anisotropic. The areal strain of BAV samples was significantly less than that of AsAA (p = 0.041) and BAA (p = 0.004) samples at a low load. The BAA samples were similar to the AsAA samples in both mechanical and failure properties. On the microstructural level, all samples displayed moderate medial degeneration, characterized by elastin fragmentation, cell loss, mucoid accumulation and fibrosis. The ultimate tensile strength of BAV and BAA sampleswere also found to decrease with age. Overall, the BAV samples were stiffer than both AsAA and BAA samples, and the BAA samples were similar to the AsAA samples. The BAV samples were thinnest, with less elastin than AsAA and BAA samples, which may be attributed to the loss of extensibility of these tissues at a low load. No apparent difference in failure mechanics among the tissue groups suggests that each of the patient groups may have a similar risk of rupture.     

A pilot investigation of “metaphor blindness” in a college student population

Previous research from our group suggests that patients with lesions in the left inferior parietal lobule (IPL)—which is concerned with abstract numerical cognition and cross-modal association (which is consistent with its strategic location at the crossroads between the temporal, parietal and occipital lobes) have difficulty understanding proverbs and metaphors (Ramachandran and Hubbard, 2001). In the current pilot investigation, we report “metaphor blindness” in a college student population; that is, either the complete inability or difficulty for otherwise intellectually non-challenged individuals to comprehend metaphors of language. Participants (N = 205) read 12 metaphorical (“The detective jumped at the clue”) and 12 literal (“The accident was a fall”) sentences and had to decide whether the sentences conveyed a metaphorical or literal meaning. The mean accuracy for these metaphorical sentences was 11.0 (SD = 2.3; RNG = 0–12); the mean accuracy for literal sentences was 7.2 (SD = 1.8; RNG = 2–10). We found that 5% of participants (11/205) were unable or had difficulty understanding metaphors (i.e., were statistical outliers), while their score for literal sentences felt within a normal statistical range M = 8.3 (SD = 2.3; RNG = 5–10). Follow-up control procedures were conducted in order to help ascertain that the results were not due to low verbal IQ and task difficulty. Likewise, none of the “metaphor blind” participants reported any psychiatric or neurological histories that would impair language comprehension, including strokes, brain injuries, language problems dyslexia, and signs of late language onset. The results are very preliminary and future studies are needed to confirm these findings. We suggest that brain modules may be specialized even for subtle functions like metaphor and their formation in embryogenesis may be controlled by small handfuls of genes whose expression can go awry—as in “metaphor blindness”.     

A viscoelastic,viscoplastic model of cortical bone valid at low and high strain rates

The stress–strain behavior of cortical bone is well known to be strain-rate dependent, exhibiting both viscoelastic and viscoplastic behavior. Viscoelasticity has been demonstrated in literature data with initial modulus increasing by more than a factor of 2 as applied strain rate is increased from 0.001 to 1500 s^?1. A strong dependence of yield on strain rate has also been reported in the literature, with the yield stress at 250 s^?1 having been observed to be more than twice that at 0.001 s^?1, demonstrating the material viscoplasticity. Constitutive models which capture this rate-dependent behavior from very low to very high strain rates are required in order to model and simulate the full range of loading conditions which may be experienced in vivo; particularly those involving impact, ballistic and blast events. This paper proposes a new viscoelastic, viscoplastic constitutive model which has been developed to meet these requirements. The model is fitted to three sets of stress–strain measurements from the literature and shown to be valid at strain rates ranging over seven orders of magnitude.     

A fatigue assessment technique for modular and pre-stressed orthopaedic implants

Orthopaedic implants experience large cyclic loads, and pre-clinical analysis is conducted to ensure they can withstand millions of loading cycles. Acetabular cup developments aim to reduce wall thickness to conserve bone, and this produces high pre-stress in modular implants. As part of an implant development process, we propose a technique for preclinical fatigue strength assessment of modular implants which accounts for this mean stress, stress concentrating features and material processing.A modular cup's stress distributions were predicted computationally, under assembly and in vivo loads, and its cyclic residual stress and stress amplitude were calculated. For verification against damage initiation in low-cycle-fatigue (LCF), the peak stress was compared to the material's yield strength. For verification against failure in high-cycle-fatigue (HCF) each element's reserve factor was calculated using the conservative Soderberg infinite life criterion.Results demonstrated the importance of accounting for mean stress. The cup was predicted to experience high cyclic mean stress with low magnitude stress amplitude: a low cyclic load ratio (R_l = 0.1) produced a high cyclic stress ratio (R_s = 0.80). Furthermore the locations of highest cyclic mean stress and stress amplitude did not coincide. The minimum predicted reserve factor N_f was 1.96 (HCF) and 2.08 (LCF). If mean stress were neglected or if the stress ratio were assumed to equal the load ratio, the reserve factor would be considerably lower, potentially leading to over-engineering, reducing bone conservation.Fatigue strength evaluation is only one step in a broader development process, which should involve a series of verifications with the full range of normal and traumatic physiological loading scenarios, with representative boundary conditions and a representative environment. This study presents and justifies a fatigue analysis methodology which could be applied in early stage development to a variety of modular and pre-stressed prosthesis concepts, and is particularly relevant as implant development aims to maximise modularity and bone conservation.     

Genetic polymorphisms in TNFSF13 and FDX1 are associated with IgA nephropathy in the Han Chinese population

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and its pathogenesis is influenced by both genetic and environmental factors. In this study, we evaluated 23 tag single-nucleotide polymorphisms (tSNPs) in 21 IgAN-associated genes, in 200 subjects with IgAN and 310 healthy gender- and age-matched unrelated control subjects with no history of renal disease or hypertension. Using the co-dominant model, we found that two genotypes of rs3803800 in TNFSF13 were associated with an increased risk of IgAN: “GA” (OR = 1.03, 95% CI = 0.71–1.51, p = 0.018) and “AA” (OR = 2.45, 95% CI = 1.29–4.65, p = 0.018). The “AA” genotype was also associated with an increased risk of IgAN in the recessive model (OR = 2.41, 95% CI = 1.30–4.46, p = 0.018), as was the genotype “AA” rs10488764 in FDX1 (OR = 1.88, 95% CI = 1.01–3.53, p = 0.048). Interestingly, we found that the allele “A” of rs3803800 in TNFSF13 is associated with a decreased risk of IgAN in females (OR = 0.43, 95% CI = 0.20–0.95, p = 0.009), but with an increased risk in males (OR = 1.78, 95% CI = 0.86–3.66, p = 0.009). Our findings, combined with previously reported results, suggest that TNFSF13 and FDX1 have potential roles in IgAN in the Han Chinese population. This information may be useful in the development of early prognostics for IgAN.     

Increasing pre-activation of the quadriceps muscle protects the anterior cruciate ligament during the landing phase of a jump: An in vitro simulation

We hypothesize that application of an unopposed quadriceps force coupled with an impulsive ground reaction force may induce anterior cruciate ligament (ACL) injury. This situation is similar to landing from a jump if only the quadriceps muscle is active; an unlikely but presumably dangerous circumstance. The purpose of this study was to test our hypothesis using in vitro simulation of jump landing. A jump-landing simulator was utilized. Nine cadaveric knees were tested at an initial flexion angle of 20°. Each ACL was instrumented with a differential variable reluctance transducer (DVRT). Quadriceps pre-activation forces (QPFs) ranging from 25 N to 700 N were applied to each knee, followed by an impulsive ground reaction force produced by a carriage-mounted drop weight (7 kg) that impulsively drove the ankle upward. ACL strain was monitored before landing due to application of QPF (pre-activation strain) and at landing due to application of the ground reaction force (landing strain). No ACLs were injured. Pre-activation strains exhibited a positive correlation with QPF (r = 0.674, p < 0.001) while landing strains showed a negative correlation (r = ? 0.235, p = 0.032). Total ACL strain (pre-activation + landing strain) showed no correlation with QPF (r = 0.023, p = 0.428). Our findings indicate that elevated QPF increases pre-activation strain but reduces the landing strain and is therefore protective post-landing. Overall, there is a complete lack of correlation between “total” ACL strain and QPF suggesting that the total strain in the ACL is independent of the QPF under the simulated conditions.     

Accounting for disagreements on average cone loss rates in retinitis pigmentosa with a new kinetic model: Its relevance for clinical trials

Since 1985, at least nine studies of the average rate of cone loss in retinitis pigmentosa (RP) populations have yielded conflicting average rate constant values (−k), differing by 90–160%. This is surprising, since, except for the first two investigations, the Harvard or Johns Hopkins’ protocols used in these studies were identical with respect to: use of the same exponential decline model, calculation of average −k from individual patient k values, monitoring patients over similarly large time frames, and excluding data exhibiting floor and ceiling effects.A detailed analysis of Harvard’s and Hopkins’ protocols and data revealed two subtle differences: (i) Hopkins’ use of half-life t_0.5 (or t_1/e) for expressing patient cone-loss rates rather than k as used by Harvard; (ii) Harvard obtaining substantially more +k from improving fields due to dormant-cone recovery effects and “small −k” values than Hopkins’ (“small −k” is defined as less than −0.040 year⁻¹), e.g., 16% +k, 31% small −k, vs. Hopkins’ 3% and 6% respectively. Since t_0.5 = 0.693/k, it follows that when k = 0, or is very small, t_0.5 (or t_1/e) is respectively infinity or a very large number. This unfortunate mathematical property (which also prevents t_0.5 (t_1/e) histogram construction corresponding to −k to +k) caused Hopkins’ to delete all “small −k” and all +k due to “strong leverage”. Naturally this contributed to Hopkins’ larger average −k. Difference (ii) led us to re-evaluate the Harvard/Hopkins’ exponential unchanging −k model. In its place we propose a model of increasing biochemical stresses from dying rods on cones during RP progression: increasing oxidative stresses and trophic factor deficiencies (e.g., RdCVF), and RPE malfunction. Our kinetic analysis showed rod loss to follow exponential kinetics with unchanging −k due to constant genetic stresses, thereby providing a theoretical basis for Clarke et al.’s empirical observation of such kinetics with eleven animal models of RP. In contrast to this, we show that cone loss occurs in patients with increasing −k values during RP progression. And as the Hopkins’ protocol selects more advanced RP cases than Harvard’s to assure avoidance of ceiling effects (Harvard does this by kinetic monitoring), we show increasing −k kinetics to be the reason Harvard obtains more +k and small −k values. Thus the combined effects of (i) and (ii) produce Harvard’s smaller average −k value. The relevance of the increasing biochemical stress model for optimizing clinical trials is discussed.     

In vitro characterization of polycaprolactone matrices generated in aqueous media

In this study, a novel process of dissolving polycaprolactone (PCL) matrices in glacial acetic acid was explored in which matrices spontaneously formed upon contact with water. Scanning electron microscopy analysis showed rough architecture and holes on the self-assembled matrix relative to matrices formed after dissolving in chloroform. Immersion in the gelatin solution reduced its roughness and number of micropores. Atomic force microscopy (AFM) analysis confirmed the increased roughness of the self-assembled matrices. The roughness of the matrices decreased after incubation in 1 N NaOH for 10 min. AFM analysis also revealed that the self-assembled matrix had a net positive surface charge, whereas chloroform–cast matrix had a negative surface charge. The surface charge of self-assembled matrix after immersion in gelatin changed to negative. However, incubation in NaOH did not affect the surface charge. The tensile properties were tested in both the dry state (25 °C) and the wet state (37 °C) by immersion in phosphate-buffered saline. Self-assembled matrix had lower elastic modulus, break stress and break strain than chloroform–cast matrix in both states. The elastic modulus in the wet condition was reduced by half in self-assembled matrix but tensile strain increased. Samples were further analyzed by ramp-hold test for assessing stress relaxation behavior. Both self-assembled and chloroform–cast matrices had similar trends in stress relaxation behavior. However, stress accumulation in self-assembled matrix was half that of chloroform–cast matrix. In vitro cell cultures were conducted using human foreskin fibroblast (HFF-1) in serum-free medium. Cytoskeletal actin staining showed cell adhesion and spreading on all matrices. Cell retention was significantly increased in self-assembled matrix compared to chloroform–cast matrix. Addition of gelatin improved the retention of seeded cells on the surface. In summary, PCL matrices generated using this novel technique show significant promise in biomedical applications.