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Abstract: Objective: The aim of this study was to evaluate the performance of a hand‐held indentation device for fast and reliable determination of skin stiffness. Methods: Device accuracy to indentation depths of 0.6 and 1.3 mm was first evaluated on plastic foam materials with mechanical properties verified by a laboratory material testing device. Subsequently, the device's sensitivity to detect age‐related changes in skin stiffness was evaluated among 46 healthy women (18–79 years). Finally, the reproducibility of the method was tested with six healthy subjects. Results: High correlation was detected between indentation stiffness of reference material and Young's modulus determined with mechanical testing device (0.6 mm indenter: r = 0.97, P = 0.05; 1.3 mm indenter: r = 0.98, P = 0.04). Age‐related decrease of 38% in skin stiffness was observed in healthy volunteers (P < 0.05). The coefficient of variation for 0.6 and 1.3 mm indenters was 7.4% and 8.5%, respectively. No trend related to hysteresis effect was observed from repeated measurements. Conclusions: The presented indentation technique was accurate against the laboratory material testing device. Furthermore, skin changes related to ageing could be detected with the indentation technique. The new device was found to be feasible for monitoring skin stiffness in cosmetics and clinical conditions. [ABSTRACT FROM AUTHOR]

Background: The advancements in artificial intelligence and computational power have made deep learning an attractive tool for radiotherapy treatment planning. Deep learning has the potential to significantly simplify the trial-and-error process involved in inverse planning required by modern treatment techniques such as volumetric modulated arc therapy (VMAT). In this study, we explore the ability of deep learning to predict organ-at-risk (OAR) dose-volume histograms (DVHs) of left-sided breast cancer patients undergoing VMAT treatment based solely on their anatomical characteristics. The predicted DVHs could be used to derive patient-specific dose constraints and dose objectives, streamlining the treatment planning process, standardizing the quality of the plans, and personalizing the treatment planning., Purpose: This study aimed to develop a deep learning-based framework for the prediction of organ-specific dose-volume histograms (DVH) based on structures delineated for left-sided breast cancer treatment., Methods: We used a dataset of 249 left-sided breast cancer patients treated with tangential VMAT fields. We extracted delineated structures and dose distributions for each patient and derived slice-by-slice DVHs for planning target volume (PTV) and organs-at-risk. The patients were divided into training (70%, n = 174), validation (10%, n = 24), and test (20%, n = 51) sets. Collected data were used to train a deep learning model for the prediction of the DVHs based on the delineated structures. The developed deep learning model comprised a modified DenseNet architecture followed by a recurrent neural network., Results: In the independent test set (n = 51), the point-wise differences in the slice-by-slice DVHs between the clinical and predicted DVHs were small; the mean squared errors were 3.53, 1.58, 2.28, 3.37, and 1.44 [×10 -4 ] for PTV, heart, ipsilateral lung, contralateral lung, and contralateral breast, respectively. With the derived cumulative DVHs, the mean absolute difference ± standard deviation of mean doses between the clinical and the predicted DVH were 0.08 ± 0.04 Gy, 0.24 ± 0.22 Gy, 0.73 ± 0.46 Gy, 0.07 ± 0.06 Gy, and 0.14 ± 0.14 Gy for PTV, heart, ipsilateral lung, contralateral lung, and contralateral breast, respectively., Conclusions: The deep learning-based approach enabled automatic and reliable prediction of the DVH based on delineated structures. The predicted DVHs could potentially serve as patient-specific clinical goals used to aid treatment planning and avoid suboptimal plans or to derive optimization objectives and constraints for automated treatment planning., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Cartilage and synovial fluid are challenging to observe separately in native computed tomography (CT). We report the use of triple contrast agent (bismuth nanoparticles [BiNPs], CA4+, and gadoteridol) to image and segment cartilage in cadaveric knee joints with a clinical CT scanner. We hypothesize that BiNPs will remain in synovial fluid while the CA4+ and gadoteridol will diffuse into cartilage, allowing (1) segmentation of cartilage, and (2) evaluation of cartilage biomechanical properties based on contrast agent concentrations. To investigate these hypotheses, triple contrast agent was injected into both knee joints of a cadaver (N = 1), imaged with a clinical CT at multiple timepoints during the contrast agent diffusion. Knee joints were extracted, imaged with micro-CT (µCT), and biomechanical properties of the cartilage surface were determined by stress-relaxation mapping. Cartilage was segmented and contrast agent concentrations (CA4+ and gadoteridol) were compared with the biomechanical properties at multiple locations (n = 185). Spearman's correlation between cartilage thickness from clinical CT and reference µCT images verifies successful and reliable segmentation. CA4+ concentration is significantly higher in femoral than in tibial cartilage at 60 min and further timepoints, which corresponds to the higher Young's modulus observed in femoral cartilage. In this pilot study, we show that (1) large BiNPs do not diffuse into cartilage, facilitating straightforward segmentation of human knee joint cartilage in a clinical setting, and (2) CA4+ concentration in cartilage reflects the biomechanical differences between femoral and tibial cartilage. Thus, the triple contrast agent CT shows potential in cartilage morphology and condition estimation in clinical CT., (© 2023 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Purpose: Earlier evidence suggests that extremely low frequency magnetic fields (ELF MFs) can modify the effects of carcinogenic agents. However, the studies conducted so far with ionizing radiation as the co-exposure agent are sparse and have provided inconclusive results. We investigated whether 50 Hz MFs alone, or in combination with ionizing radiation alter cell biological variables relevant to cancer and the biological effects of ionizing radiation., Materials and Methods: Human SH-SY5Y neuroblastoma cells were sham exposed or exposed to 100 or 500 µT MF for 24 h either before or after ionizing radiation exposure (0, 0.4 or 2 Gy). After the exposures, cells were assayed for viability, clonogenicity, reactive oxygen species, caspase-3 activity, and cell cycle distribution. Cell cycle distribution was assayed with propidium iodide staining followed by flow cytometry analysis and ROS levels were assayed together with cell viability by double staining with DeepRed and Sytox Blue followed by flow cytometry analysis., Results: Increased caspase-3 activity was observed in cells exposed to 500 µT MF before or after ionizing radiation. Furthermore, exposure to the 500 µT MF after the ionizing radiation decreased the percentage of cells in S-phase. No changes in the ROS levels, clonogenicity, or viability of the cells were observed in the MF exposed groups compared to the corresponding sham exposed groups, and no MF effects were observed in cells exposed at 100 µT., Conclusions: Only the 500 µT magnetic flux density affected SH-SY5Y cells significantly. The effects were small but may nevertheless help to understand how MFs modify the effects of ionizing radiation. The increase in caspase-3 activity may not reflect effects on apoptosis, as no changes were observed in the subG1 phase of the cell cycle. In contrast to some earlier findings, 50 Hz MF exposure after ionizing radiation was not less effective than MF treatment given prior to ionizing radiation.

Background and Purpose: The interplay effect of respiratory motion on the planned dose in free-breathing right-sided whole-breast irradiation (WBI) were studied by simulating hypofractionated VMAT treatment courses., Materials and Methods: Ten patients with phase-triggered 4D-CT images were included in the study. VMAT plans targeting the right breast were created retrospectively with moderately hypofractionated (40.05 Gy in 15 fractions of 2.67 Gy) and ultra-hypofractionated (26 Gy 5 fractions of 5.2 Gy) schemes. 3D-CRT plans were generated as a reference. All plans were divided into respiratory phase-specific plans and calculated in the corresponding phase images. Fraction-specific dose was formed by deforming and summing the phase-specific doses in the planning image for each fraction. The fraction-specific dose distributions were deformed and superimposed onto the planning image, forming the course-specific respiratory motion perturbed dose distribution. Planned and respiratory motion perturbed doses were compared and changes due to respiratory motion and choice of fractionation were evaluated., Results: The respiratory motion perturbed PTV coverage (V95%) decreased by 1.7% and the homogeneity index increased by 0.02 for VMAT techniques, compared to the planned values. Highest decrease in CTV coverage was 0.7%. The largest dose differences were located in the areas of steep dose gradients parallel to respiratory motion. The largest difference in DVH parameters between fractionation schemes was 0.4% of the prescribed dose. Clinically relevant changes to the doses of organs at risk were not observed. One patient was excluded from the analysis due to large respiratory amplitude., Conclusion: Respiratory motion of less than 5 mm in magnitude did not result in clinically significant changes in the planned free-breathing WBI dose. The 5 mm margins were sufficient to account for the respiratory motion in terms of CTV dose homogeneity and coverage for VMAT techniques. Steep dose gradients near the PTV edges might decrease the CTV coverage. No clinical significance was found due to the choice of fractionation., (© 2022. The Author(s).)

To investigate the near-surface doses and target coverage in modulated arc radiotherapy (RT) of the breast or chest wall in two treatment planning systems (TPS) in the presence of soft tissue deformations. This retrospective study consisted of 10 breast cancer patients with axillary lymph node inclusion. For each case, five RT plans were created: (1) tangential 3D conformal field-in-field (FinF) technique; (2) 200° to 240° arcs with optimization bolus (OB) in Eclipse (EB); (3) 243° to 250° arcs with an 8-mm OB in Monaco (MB); (4) 243° to 250° arcs with automatic skin flash tool (ASF) in Monaco TPS (MA); (5) 243° to 250° arcs with both ASF and OB in Monaco (MAB). Soft tissue deformation was simulated by editing CT-images with 4-, 8-, and 12-mm swelling and recalculating the dose. The increasing swelling from 0 to 12 mm caused the coverage (V95%) in clinical target volume to decrease from 96% ± 2% to 90% ± 6% for the FinF plans. For volumetric-modulated arc therapy (VMAT), the coverage decreased from 99% ± 1% to 92% ± 4% in the EB plans, and from 97% ± 1% to 68% ± 8%, 85% ± 6%, and 86% ± 5% for MA, MB, and MAB, respectively. The mean dose in the surface extending from 0 to 3 mm from the skin decreased on average 5%, 17%, 20%, 15%, and 8% in FinF, EB, MA, MB, and MAB, respectively. In the Monaco plans, the use of an OB(+ASF) provided better target coverage and lower dose maxima despite of tissue swelling than the ASF alone. With modulated arc therapy, we recommend the use of an OB instead of or in addition to the ASF. The use of 8 mm OB with VMAT plans is robust to account deformations extending outside up to 8mm. If soft tissue deformation is larger than 8 mm, the need for replanning should be evaluated., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: Our aim was to evaluate whether mitochondrial DNA (mtDNA) damage in hair bulbs could be a suitable biomarker for the detection of local exposure to ionizing radiation. Materials and methods: Mouse hair was collected 4 and 24 hours, 3 and 10 days after single whole-body exposure to 0, 0.1, and 2 Gy radiation. Pubic hair (treated area) and scalp hair (control area) were collected from 13 prostate cancer patients before and after fractioned radiotherapy with an average total dose of 2.7 Gy to follicles after five fractions. Unspecified lesion frequency of mtDNA was analyzed with long PCR, large mtDNA deletion levels were tested with real-time PCR. Results: Unspecified lesion frequency of mtDNA significantly increased in mouse hair 24 hours after irradiation with 2 Gy, but variance among samples was high. No increase in lesion frequency could be detected after 0.1 Gy irradiation. In prostate cancer patients, there was no significant change in either the unspecified lesion frequency or in the proportion of 4934-bp deleted mtDNA in pubic hair after radiotherapy. The proportions of murine 3860-bp common deletion, human 4977-bp common deletion and 7455-bp deleted mtDNA were too low to be analyzed reliably. Conclusions: Our results suggest that the unspecified lesion frequency and proportion of large deletions of mtDNA in hair bulbs are not suitable biomarkers of exposure to ionizing radiation.

Impact injuries of cartilage may initiate post-traumatic degeneration, making early detection of injury imperative for timely surgical or pharmaceutical interventions. Cationic (positively-charged) CT contrast agents detect loss of cartilage proteoglycans (PGs) more sensitively than anionic (negatively-charged) or non-ionic (non-charged, i.e., electrically neutral) agents. However, degeneration related loss of PGs and increase in water content have opposite effects on the diffusion of the cationic agent, lowering its sensitivity. In contrast to cationic agents, diffusion of non-ionic agents is governed only by steric hindrance and water content of cartilage. We hypothesize that sensitivity of an iodine(I)-based cationic agent may be enhanced by simultaneous use of a non-ionic gadolinium(Gd)-based agent. We introduce a quantitative dual energy CT technique (QDECT) for simultaneous quantification of two contrast agents in cartilage. We employ this technique to improve the sensitivity of cationic CA4+ (q =+4) by normalizing its partition in cartilage with that of non-ionic gadoteridol. The technique was evaluated with measurements of contrast agent mixtures of known composition and human osteochondral samples (n = 57) after immersion (72 h) in mixture of CA4+ and gadoteridol. Samples were arthroscopically graded and biomechanically tested prior to QDECT (50/100 kV). QDECT determined contrast agent mixture compositions correlated with the true compositions (R 2 = 0.99, average error = 2.27%). Normalizing CA4+ partition in cartilage with that of gadoteridol improved correlation with equilibrium modulus (from ρ = 0.701 to 0.795). To conclude, QDECT enables simultaneous quantification of I and Gd contrast agents improving diagnosis of cartilage integrity and biomechanical status.

An ultrasound arthroscopy (UA) technique is a promising tool for the evaluation of the articular cartilage during arthroscopic examination. However, the applicability of UA for the evaluation of the hip joint is unknown. We describe a UA assessment of a patient with osteochondritis dissecans at the femoral head. An ultrasound catheter designed for intravascular imaging was inserted into the hip joint by use of conventional arthroscopic portals, and the cartilage surfaces of the femoral head and acetabulum were investigated with ultrasound. UA provided essential quantitative information on the integrity of the articular cartilage and the condition of the subchondral plate not assessable with conventional arthroscopy. Furthermore, the UA technique provided the possibility to monitor arthroscopy-assisted retrograde drilling and bone transplantation in the hip joint.

Background: This study aimed to determine the geometrical uncertainty of the position of the heart with daily cone beam computed tomography (CBCT) during deep-inspiration breath-hold (DIBH) treatment of the left breast., Material and Methods: A visually guided optical respiratory monitoring system was used in DIBH treatment of 15 breast cancer patients. Heart position was determined in relation to the planning target volume (PTV) in 225 fractions in which daily low-dose CBCT images were compared with planning CT images. In addition, the position of the left lung apex and diaphragm was measured to evaluate the success of the DIBH., Results: The median shift of the heart was 1 mm to the left, 1 mm superiorly and 0 mm in the anterior-posterior (AP) direction during the treatment course when compared to the PTV position in planning CT. Based on these movements, an AP margin of 4 mm, a lateral (LR) margin of 3 mm, and a superior-inferior (SI) margin of 5 mm should be added to the heart contour to ensure avoiding the heart when planning treatment. The distance between the left lung apex and diaphragm, applied as a surrogate for lung volume, was 2mm (median) smaller during the CBCT acquisitions than during the planning CT acquisition. The correlation coefficient between the surrogate of lung volume and the distance between the heart and PTV was r = .46 in the AP, r = .72 in the LR and r = .79 in the SI directions., Conclusion: Residual variation was observed in the position of the heart in comparison to PTV, even with a visually guided DIBH technique. These geometrical uncertainties should be taken into account when planning radiotherapy treatment. The success of DIBH may make a major contribution to the variation of the heart position during treatment.

Focal cartilage lesions can proceed to severe osteoarthritis or remain unaltered even for years. A method to identify high risk defects would be of utmost importance to guide clinical decision making and to identify the patients that are at the highest risk for the onset and progression of osteoarthritis. Based on cone beam computed tomography arthrography, we present a novel computational model for evaluating changes in local mechanical responses around cartilage defects. Our model, based on data obtained from a human knee in vivo, demonstrated that the most substantial alterations around the defect, as compared to the intact tissue, were observed in minimum principal (compressive) strains and shear strains. Both strain values experienced up to 3-fold increase, exceeding levels previously associated with chondrocyte apoptosis and failure of collagen crosslinks. Furthermore, defects at the central regions of medial tibial cartilage with direct cartilage-cartilage contact were the most vulnerable to loading. Also locations under the meniscus experienced substantially increased minimum principal strains. We suggest that during knee joint loading particularly minimum principal and shear strains are increased above tissue failure limits around cartilage defects which might lead to osteoarthritis. However, this increase in strains is highly location-specific on the joint surface.

Background and purpose - Arthroscopic estimation of articular cartilage thickness is important for scoring of lesion severity, and measurement of cartilage speed of sound (SOS)-a sensitive index of changes in cartilage composition. We investigated the accuracy of optical coherence tomography (OCT) in measurements of cartilage thickness and determined SOS by combining OCT thickness and ultrasound (US) time-of-flight (TOF) measurements. Material and methods - Cartilage thickness measurements from OCT and microscopy images of 94 equine osteochondral samples were compared. Then, SOS in cartilage was determined using simultaneous OCT thickness and US TOF measurements. SOS was then compared with the compositional, structural, and mechanical properties of cartilage. Results - Measurements of non-calcified cartilage thickness using OCT and microscopy were significantly correlated (ρ = 0.92; p < 0.001). With calcified cartilage included, the correlation was ρ = 0.85 (p < 0.001). The mean cartilage SOS (1,636 m/s) was in agreement with the literature. However, SOS and the other properties of cartilage lacked any statistically significant correlation. Interpretation - OCT can give an accurate measurement of articular cartilage thickness. Although SOS measurements lacked accuracy in thin equine cartilage, the concept of SOS measurement using OCT appears promising.

Measurement of ultrasound backscattering is a promising diagnostic technique for arthroscopic evaluation of articular cartilage. However, contribution of collagen and chondrocytes on ultrasound backscattering and speed of sound in cartilage is not fully understood and is experimentally difficult to study. Agarose hydrogels have been used in tissue engineering applications of cartilage. Therefore, the aim of this study was to simulate the propagation of high frequency ultrasound (40 MHz) in agarose scaffolds with varying concentrations of chondrocytes (1 to 32 × 10(6) cells/ml) and collagen (1.56-200 mg/ml) using transversely isotropic two-dimensional finite difference time domain method (FDTD). Backscatter and speed of sound were evaluated from the simulated pulse-echo and through transmission measurements, respectively. Ultrasound backscatter increased with increasing collagen and chondrocyte concentrations. Furthermore, speed of sound increased with increasing collagen concentration. However, this was not observed with increasing chondrocyte concentrations. The present study suggests that the FDTD method may have some applicability in simulations of ultrasound scattering and propagation in constructs containing collagen and chondrocytes. Findings of this study indicate the significant role of collagen and chondrocytes as ultrasound scatterers and can aid in development of modeling approaches for understanding how cartilage architecture affects to the propagation of high frequency ultrasound.

Objective: Accurate arthroscopic evaluation of cartilage lesions could significantly improve the outcome of repair surgery. In this study, we investigated for the first time the potential of intra-articular ultrasound as an arthroscopic tool for grading cartilage defects in the human shoulder joint in vivo and compared the outcome to results from arthroscopic evaluation and magnetic resonance imaging findings., Design: A total of 26 sites from 9 patients undergoing routine shoulder arthroscopy were quantitatively evaluated with a clinical intravascular (40MHz) ultrasound imaging system, using the regular arthroscopy portals. Reflection coefficient (R), integrated reflection coefficient (IRC), apparent integrated backscattering (AIB), and ultrasound roughness index (URI) were calculated, and high-resolution ultrasound images were obtained per site. Each site was visually graded according to the International Cartilage Repair Society (ICRS) system. "Ultrasound scores" corresponding to the ICRS system were determined from the ultrasound images. Magnetic resonance imaging was conducted and cartilage integrity at each site was classified into 5 grades (0 = normal, 4 = severely abnormal) by a radiologist., Results: R and IRC were lower at sites with damaged cartilage surface (P = 0.033 and P = 0.043, respectively) and correlated with arthroscopic ICRS grades (r s = -0.444, P = 0.023 and r s = -0.426, P = 0.03, respectively). Arthroscopic ICRS grades and ultrasound scores were significantly correlated (rs = 0.472, P = 0.015), but no significant correlation was found between magnetic resonance imaging data and other parameters., Conclusion: The results suggest that ultrasound arthroscopy could facilitate quantitative clinical appraisal of articular cartilage integrity in the shoulder joint and provide information on cartilage lesion depth and severity for quantitative diagnostics in surgery.

Evaluation of articular cartilage and subchondral bone is essential in the diagnosis of joint diseases and injuries. Interobserver and intraobserver reproducibilities of arthroscopic grading are only poor to moderate. Thus, for quantitative and objective evaluation of cartilage and subchondral bone, ultrasound arthroscopy (UA) has been introduced to clarify this dilemma. Assessment of the clinical feasibility of high-frequency ultrasonography (US) during 6 knee arthroscopies was conducted, and the surgical technique is presented. US imaging was conducted with a flexible 9-MHz US catheter inserted into the joint through conventional portals. US and arthroscopy videos were synchronously recorded, and US parameters for cartilage and subchondral bone characteristics were measured. Arthroscopy and US imaging were combined to perform cartilage grading. UA produced quantitative data on lesion size, as well as cartilage quality, and showed subchondral bone changes. Visualization of an osteochondritis dissecans lesion not detected by conventional arthroscopy and US-guided retrograde drilling were possible with UA. To conclude, UA proved to be clinically feasible and aided in the diagnosis when assessing knee osteochondral lesions.

Collagen, proteoglycans and chondrocytes can contribute to ultrasound scattering in articular cartilage. However, anisotropy of ultrasound scattering in cartilage is not fully characterized. We investigate this using a clinical intravascular ultrasound device with ultrasound frequencies of 9 and 40 MHz. Osteochondral samples were obtained from intact bovine patellas, and cartilage was imaged in two perpendicular directions: through articular and lateral surfaces. At both frequencies, ultrasound backscattering was higher (p < 0.05) when measured through the lateral surface of cartilage. In addition, the composition and structure of articular cartilage were investigated with multiple reference methods involving light microscopy, digital densitometry, polarized light microscopy and Fourier infrared imaging. Reference methods indicated that acoustic anisotropy of ultrasound scattering arises mainly from non-uniform distribution of chondrocytes and anisotropic orientation of collagen fibers. To conclude, ultrasound backscattering in articular cartilage was found to be anisotropic and dependent on the frequency in use., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)