Bioengineering, Volume 11, Issue 6 (June 2024) – 92 articles

(1) Background: Medical devices, especially neuromodulation devices, are often explanted for a variety of reasons. The removal process imparts significant forces on these devices, which may result in device fracture and tissue trauma. We hypothesized that a device’s form factor interfacing with tissue is a major driver of the force required to remove a device, and we isolated helical and linear electrode structures as a means to study atraumatic removal. (2) Methods: Ductile linear and helical microwire structure electrodes were fabricated from either Gold (Au) or Platinum–Iridium (Pt-Ir, 90-10). Removal forces were captured from synthetic gel models and following chronic implantation in rodent and porcine models. Devices were fully implanted in the animal models, requiring a small incision (<10 mm) and removal via tissue forceps. (3) Results: Helical devices were shown to result in significantly lower maximal removal forces in both synthetic gel and rodent studies compared to their linear counterparts. Chronically (1 yr.), the maximal removal force of helical devices remained under 7.30 N, for which the Platinum–Iridium device’s tensile failure force was 32.90 ± 2.09 N, resulting in a safety factor of 4.50. (4) Conclusion: An open-core helical structure that can freely elongate was shown to result in reduced removal forces both acutely and chronically. Full article

The continuous manufacturing of biologics offers significant advantages in terms of reducing manufacturing costs and increasing capacity, but it is not yet widely implemented by the industry due to major challenges in the automation, scheduling, process monitoring, continued process verification, and real-time control of multiple interconnected processing steps, which must be tightly controlled to produce a safe and efficacious product. The process produces a large amount of data from different sensors, analytical instruments, and offline analyses, requiring organization, storage, and analyses for process monitoring and control without compromising accuracy. We present a case study of a cyber–physical production system (CPPS) for the continuous manufacturing of mAbs that provides an automation infrastructure for data collection and storage in a data historian, along with data management tools that enable real-time analysis of the ongoing process using multivariate algorithms. The CPPS also facilitates process control and provides support in handling deviations at the process level by allowing the continuous train to re-adjust itself via a series of interconnected surge tanks and by recommending corrective actions to the operator. Successful steady-state operation is demonstrated for 55 h with end-to-end process automation and data collection via a range of in-line and at-line sensors. Following this, a series of deviations in the downstream unit operations, including affinity capture chromatography, cation exchange chromatography, and ultrafiltration, are monitored and tracked using multivariate approaches and in-process controls. The system is in line with Industry 4.0 and smart manufacturing concepts and is the first end-to-end CPPS for the continuous manufacturing of mAbs. Full article

Multivariate pattern analysis (MVPA) has played an extensive role in interpreting brain activity, which has been applied in studies with modalities such as functional Magnetic Resonance Imaging (fMRI), Magnetoencephalography (MEG) and Electroencephalography (EEG). The advent of wearable MEG systems based on optically pumped magnetometers (OPMs), i.e., OP-MEG, has broadened the application of bio-magnetism in the realm of neuroscience. Nonetheless, it also raises challenges in temporal decoding analysis due to the unique attributes of OP-MEG itself. The efficacy of decoding performance utilizing multimodal fusion, such as MEG-EEG, also remains to be elucidated. In this regard, we investigated the impact of several factors, such as processing methods, models and modalities, on the decoding outcomes of OP-MEG. Our findings indicate that the number of averaged trials, dimensionality reduction (DR) methods, and the number of cross-validation folds significantly affect the decoding performance of OP-MEG data. Additionally, decoding results vary across modalities and fusion strategy. In contrast, decoder type, resampling frequency, and sliding window length exert marginal effects. Furthermore, we introduced mutual information (MI) to investigate how information loss due to OP-MEG data processing affect decoding accuracy. Our study offers insights for linear decoding research using OP-MEG and expand its application in the fields of cognitive neuroscience. Full article

Muscle fascicles are shorter and stiffer than normal in spastic Cerebral Palsy (CP). Increasing fascicle length (FL) has been attempted in CP, the outcomes of which have been unsatisfactory. In healthy muscles, FL can be increased using eccentric exercise at high velocities (ECC). Three conditions are possibly met during such ECC: muscle micro-damage, positive fascicle strain, and momentary muscle deactivation during lengthening. Participants with and without CP underwent a single bout of passive stretching at (appropriately) high velocities using isokinetic dynamometry, during which we examined muscle and fascicle behaviour. Vastus lateralis (VL) FL change was measured using ultrasonography and showed positive fascicle strain. Measures of muscle creatine kinase were used to establish whether micro-damage occurred in response to stretching, but the results did not confirm damage in either group. Vastus medialis (VM) and biceps femoris muscle activity were measured using electromyography in those with CP. Results supported momentary spastic muscle deactivation during lengthening: all participants experienced at least one epoch (60 ms) of increased activation followed by activation inhibition/deactivation of the VM during knee flexion. We argue that high-velocity passive stretching in CP provides a movement context which mimics ECC and could be used to increase spastic FL with training. Full article

(1) Background: A rise in intraocular pressure (IOP) and decreased retinal ganglion cells are frequent indicators of effective modeling of chronic ocular hypertension in mice. In this study, the sensitivity of the mouse model to pharmaceutical therapy to reduce intraocular tension was assessed, the model’s safety was confirmed using a cytotoxicity test, and the success rate of the mouse model of ocular hypertension was assessed by assessing alterations in IOP and neurons in the ganglion cell layer. (2) Methods: A mouse model of chronic ocular hypertension was produced in this study by employing photocrosslinkable sericin hydrogel injection and LED lamp irradiation. The eyes of 25 C57BL/6 male mice were subjected to 405 nm UV light from the front for 2 min after being injected with 5 μL of sericin hydrogel in the anterior chamber of the left eye. IOP in the mice was measured daily, and IOP rises greater than 5 mmHg were considered intraocular hypertension. When the IOP was lowered, the intervention was repeated once, but the interval between treatments was at least 2 weeks. The right eyes were not treated with anything as a normal control group. Mice eyeballs were stained with HE, Ni-type, and immunofluorescence to assess the model’s efficacy. Two common drugs (tafluprost eye drops and timolol eye drops) were provided for one week after four weeks of stable IOP, and IOP changes were assessed to determine the drug sensitivity of the mouse model of chronic ocular hypertension. Furthermore, CellTiter 96^® AQueous One Solution Cell Proliferation Assay (MTS) was utilized to investigate the safety of the ocular hypertension model by evaluating the deleterious effects of photocrosslinkable sericin hydrogel on cells. (3) Results: Before injection, the basal IOP was (9.42 ± 1.28) mmHg (1 kPa = 7.5 mmHg) in the experimental group and (9.08 ± 1.21) in the control group. After injection, cataract occurred in one eye, corneal edema in one eye, endophthalmitis in one eye, iris incarceration in one eye, and eyeball atrophy in one eye. Five mice with complications were excluded from the experiment, and twenty mice were left. Four weeks after injection, the IOP of the experimental group was maintained at (19.7 ± 4.52) mmHg, and that of the control group was maintained at (9.92 ± 1.55) mmHg, and the difference between the two groups was statistically significant (p < 0.05). Before the intervention, the IOP in the experimental group was (21.7 ± 3.31) mmHg in the high IOP control group, (20.33 ± 2.00) mmHg in the tafluprost eye drops group, and (20.67 ± 3.12) mmHg in the timolol maleate eye drops group. The IOP after the intervention was (23.2 ± 1.03) mmHg, (12.7 ± 2.11) mmHg, and (10.4 ± 1.43) mmHg, respectively. Before and after the intervention, there were no significant differences in the high-IOP control group (p > 0.05), there were statistically significant differences in the timolol eye drops group (p < 0.05), and there were statistically significant differences in the tafluprost eye drops group (p < 0.05). One week after drug withdrawal, there was no significant difference in IOP among the three groups (p > 0.05). In the high-IOP group, the protein (sericin hydrogel) showed a short strips or fragmented structure in the anterior chamber, accompanied by a large number of macrophages and a small number of plasma cells. The shape of the chamber angle was normal in the blank control group. The number of retinal ganglion cells decreased significantly 8 weeks after injection of sericin hydrogel into the anterior chamber, and the difference was statistically significant compared with the blank control group (p < 0.05). After the cells were treated with photocrosslinkable sericin hydrogel, there was no significant difference in the data of the CellTiter 96^® assay kit of MTS compared with the blank control group (p > 0.05). (4) Conclusions: A mouse model of chronic intraocular hypertension can be established successfully by injecting sericin in the anterior chamber and irradiating with ultraviolet light. The model can simulate the structural and functional changes of glaucoma and can effectively reduce IOP after the action of most antihypertensive drugs, and it is highly sensitive to drugs. Sericin has no obvious toxic effect on cells and has high safety. Full article

Digital twins are a relatively new form of digital modeling that has been gaining popularity in recent years. This is in large part due to their ability to update in real time to their physical counterparts and connect across multiple devices. As a result, much interest has been directed towards using digital twins in the healthcare industry. Recent advancements in smart wearable technologies have allowed for the utilization of human digital twins in healthcare. Human digital twins can be generated using biometric data from the patient gathered from wearables. These data can then be used to enhance patient care through a variety of means, such as simulated clinical trials, disease prediction, and monitoring treatment progression remotely. This revolutionary method of patient care is still in its infancy, and as such, there is limited research on using wearables to generate human digital twins for healthcare applications. This paper reviews the literature pertaining to human digital twins, including methods, applications, and challenges. The paper also presents a conceptual method for creating human body digital twins using wearable sensors. Full article

Background/Objectives: We defined the value of a machine learning algorithm to distinguish between the EEG response to no light or any light stimulations, and between light stimulations with different brightnesses in awake volunteers with closed eyelids. This new method utilizing EEG analysis is visionary in the understanding of visual signal processing and will facilitate the deepening of our knowledge concerning anesthetic research. Methods: X-gradient boosting models were used to classify the cortical response to visual stimulation (no light vs. light stimulations and two lights with different brightnesses). For each of the two classifications, three scenarios were tested: training and prediction in all participants (all), training and prediction in one participant (individual), and training across all but one participant with prediction performed in the participant left out (one out). Results: Ninety-four Caucasian adults were included. The machine learning algorithm had a very high predictive value and accuracy in differentiating between no light and any light stimulations (AUCROC_all: 0.96; accuracy_all: 0.94; AUCROC_individual: 0.96 ± 0.05, accuracy_individual: 0.94 ± 0.05; AUCROC_oneout: 0.98 ± 0.04; accuracy_oneout: 0.96 ± 0.04). The machine learning algorithm was highly predictive and accurate in distinguishing between light stimulations with different brightnesses (AUCROC_all: 0.97; accuracy_all: 0.91; AUCROC_individual: 0.98 ± 0.04, accuracy_individual: 0.96 ± 0.04; AUCROC_oneout: 0.96 ± 0.05; accuracy_oneout: 0.93 ± 0.06). The predictive value and accuracy of both classification tasks was comparable between males and females. Conclusions: Machine learning algorithms could almost continuously and reliably differentiate between the cortical EEG responses to no light or light stimulations using visual evoked potentials in awake female and male volunteers with eyes closed. Our findings may open new possibilities for the use of visual evoked potentials in the clinical and intraoperative setting. Full article

The majority of observations and criteria related to brain injuries predominantly focus on acceleration and forces, leaving the understanding of the brain in the frequency domain relatively limited. The impact of an injury can be more profound when considering the brain’s resonant frequencies in conjunction with external applied loading and motion. This paper employs a finite element method to conduct an analysis of a human brain under impacts from various angles on the human head. A numerical technique, specifically dynamic mode decomposition (DMD), is utilized to extract modal properties for brain tissue in regions proximate to the corpus callosum and brain stem. Three distinct modal frequencies have been identified, spanning the ranges of 44–68 Hz, 68–155 Hz, and 114–299 Hz. The findings underscore the significance of impact angle, displacement direction, and the specific region of the brain in influencing the modal response of brain tissue during an impact event. Full article

During systole, longitudinal shortening of the left ventricle (LV) displaces the aortic root toward the apex of the heart and stretches the ascending aorta (AA). An in silico study (Living Left Heart Human Model, Dassault Systèmes Simulia Corporation) demonstrated that stiffening of the AA affects myocardial stress and LV strain patterns. With AA stiffening, myofiber stress increased overall in the LV, with particularly high-stress areas at the septum. The most pronounced reduction in strain was noted along the septal longitudinal region. The pressure–volume loops showed that AA stiffening caused a deterioration in LV function, with increased end-systolic volume, reduced systolic LV pressure, decreased stroke volume and effective stroke work, but elevated end-diastolic pressure. An increase in myofiber contractility indicated that stroke volume and effective stroke work could be recovered, with an increase in LV end-systolic pressure and a decrease in end-diastolic pressure. Longitudinal and radial strains remained reduced, but circumferential strains increased over baseline, compensating for lost longitudinal LV function. Myofiber stress increased overall, with the most dramatic increase in the septal region and the LV apex. We demonstrate a direct mechanical pathophysiologic link between stiff AA and reduced longitudinal left ventricular strain which are common in patients with HFpEF. Full article

Advanced glycation end product (AGE) accumulation due to diabetes causes vascular and neurological lesions, delaying healing. The use of stem cells could overcome these problems. Although many studies have shown the potential beneficial effects of stem cell therapies in the treatment of chronic and refractory skin ulcers, their delivery methods are still under investigation. Human periodontal ligament stem cells (hPDLSCs) can spontaneously differentiate into myofibroblasts in specific cultures; therefore, they have the potential to effectively treat diabetic wounds and may also have applications in the field of medical cosmetics. The myofibroblastic differentiation ability of hPDLSCs in the presence of AGEs was evaluated by the expression of α-SMA and COL1A1 using RT-qPCR and WB technology. Wound healing in diabetic mice, induced by streptozotocin (STZ) and assessed using H&E staining, Masson staining, and immunohistochemical (IHC) and immunofluorescence (IF) staining, was used to validate the effects of hPDLSCs. In the wound tissues, the expression of α-SMA, COL1A1, CD31, CD206, iNOS, and vimentin was detected. The findings indicated that in H-DMEM, the expression of COL1A1 exhibited a significant decrease, while α-SMA demonstrated an increase in P7 cells, ignoring the damage from AGEs (p < 0.05). In an STZ-induced diabetic C57BL/6J mice whole-skin defect model, the healing rate of the hPDLSCs treatment group was significantly higher than that in the models (on the 7th day, the rate was 65.247% vs. 48.938%, p < 0.05). hPDLSCs have been shown to spontaneously differentiate into myofibroblasts in H-DMEM and resist damage from AGEs in both in vivo and in vitro models, suggesting their potential in the field of cosmetic dermatology. Full article

Tumor organoid cultures play a crucial role in clinical practice, particularly in guiding medication by accurately determining the morphology and size of the organoids. However, segmenting individual tumor organoids is challenging due to their inhomogeneous internal intensity and overlapping structures. This paper proposes a convexity-preserving level-set segmentation 4 model based on the characteristics of tumor organoid images to segment individual tumor organoids precisely. Considering the predominant spherical shape exhibited by organoid growth, we propose a level-set model that includes a data-driven term, a curvature term, and a regularization term. The data-driven term pulls the contour to the vicinity of the boundary; the curvature term ensures the maintenance of convexity in the targeted segmentation, and the regularization term controls the smoothness and propagation of the contour. The proposed model aids in overcoming interference from factors such as overlap and noise, enabling the evolving curve to converge to the actual boundary of the target accurately. Furthermore, we propose a selectable and targeted initialization method that guarantees precise segmentation of specific regions of interest. Experiments on 51 pancreatic ductal adenocarcinoma organoid images show that our model achieved excellent segmentation results. The average Dice value and computation time are $98.81\pm 0.48$% and 20.67 s. Compared with the C-V and CPLSE models, it is more accurate and takes less time. Full article

Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by the accumulation of excess fat in the liver. If left undiagnosed and untreated during the early stages, NAFLD can progress to more severe conditions such as inflammation, liver fibrosis, cirrhosis, and even liver failure. In this study, machine learning techniques were employed to predict NAFLD using affordable and accessible laboratory test data, while the conventional technique hepatic steatosis index (HSI)was calculated for comparison. Six algorithms (random forest, K-nearest Neighbors, Logistic Regression, Support Vector Machine, extreme gradient boosting, decision tree), along with an ensemble model, were utilized for dataset analysis. The objective was to develop a cost-effective tool for enabling early diagnosis, leading to better management of the condition. The issue of imbalanced data was addressed using the Synthetic Minority Oversampling Technique Edited Nearest Neighbors (SMOTEENN). Various evaluation metrics including the F1 score, precision, accuracy, recall, confusion matrix, the mean absolute error (MAE), receiver operating characteristics (ROC), and area under the curve (AUC) were employed to assess the suitability of each technique for disease prediction. Experimental results using the National Health and Nutrition Examination Survey (NHANES) dataset demonstrated that the ensemble model achieved the highest accuracy (0.99) and AUC (1.00) compared to the machine learning techniques that we used and HSI. These findings indicate that the ensemble model holds potential as a beneficial tool for healthcare professionals to predict NAFLD, leveraging accessible and cost-effective laboratory test data. Full article

Bone regeneration is a complex multicellular process involving the recruitment and attachment of osteoprogenitors and their subsequent differentiation into osteoblasts that deposit extracellular matrixes. There is a growing demand for synthetic bone graft materials that can be used to augment these processes to enhance the healing of bone defects resulting from trauma, disease or surgery. P-15 is a small synthetic peptide that is identical in sequence to the cell-binding domain of type I collagen and has been extensively demonstrated in vitro and in vivo to enhance the adhesion, differentiation and proliferation of stem cells involved in bone formation. These events can be categorized into three phases: attachment, activation and amplification. This narrative review summarizes the large body of preclinical research on P-15 in terms of these phases to describe the mechanism of action by which P-15 improves bone formation. Knowledge of this mechanism of action will help to inform the use of P-15 in clinical practice as well as the development of methods of delivering P-15 that optimize clinical outcomes. Full article

Autologous-engineered artificial tissues constitute an ideal alternative for radical surgery in terms of natural anticoagulation, self-repair, tissue regeneration, and the possibility of growth. Previously, we focused on the development and practical application of artificial tissues using “in-body tissue architecture (iBTA)”, a technique that uses living bodies as bioreactors. This study aimed to further develop iBTA by fabricating tissues with diverse shapes and evaluating their physical properties. Although the breaking strength increased with tissue thickness, the nominal breaking stress increased with thinner tissues. By carving narrow grooves on the outer periphery of an inner core with narrow grooves, we fabricated approximately 2.2 m long cord-shaped tissues and net-shaped tissues with various designs. By assembling the two inner cores inside the branched stainless-steel pipes, a large graft with branching was successfully fabricated, and its aortic arch replacement was conducted in a donor goat without causing damage. In conclusion, by applying iBTA technology, we have made it possible, for the first time, to create tissues of various shapes and designs that are difficult using existing tissue-engineering techniques. Thicker iBTA-induced tissues exhibited higher rupture strength; however, rupture stress was inversely proportional to thickness. These findings broaden the range of iBTA-induced tissue applications. Full article

Cataracts are characterized by the crystalline lens of the eye becoming cloudy, and dry eye disease (DED) is a multifactorial disease in which the homeostasis of the tear film is lost. As the prevalence of both diseases increases with age, there is a high prevalence of DED among patients who are candidates for cataract surgery. In recent years, cataract surgery has evolved from vision restoration surgery to refractive surgery. To achieve good surgical outcomes, it is necessary to minimize postoperative refractive error in intraocular lens (IOL) power calculation, which requires accurate preoperative keratometry measurements. A stable tear film is important for the accuracy and reproducibility of keratometry measurements, and DED may have a deleterious effect. In this study, original articles that focused primarily on findings related to this topic were evaluated. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Although appropriate DED diagnoses were not presented in the articles evaluated in this review, it was confirmed that the clinical signs of DED, particularly the shortening of the tear film break-up time (TBUT), negatively impact IOL power calculations. Improvement in these clinical signs might mitigate the negative effects on these calculations. Full article

In recent decades, much work has been implemented in heart rate (HR) analysis using electrocardiographic (ECG) signals. We propose that algorithms developed to calculate HR based on detected R-peaks using ECG can be applied to seismocardiographic (SCG) signals, as they utilize common knowledge regarding heart rhythm and its underlying physiology. We implemented the experimental framework with methods developed for ECG signal processing and peak detection to be applied and evaluated on SCGs. Furthermore, we assessed and chose the best from all combinations of 15 peak detection and 6 preprocessing methods from the literature on the CEBS dataset available on Physionet. We then collected experimental data in the lab experiment to measure the applicability of the best-selected technique to the real-world data; the abovementioned method showed high precision for signals recorded during sitting rest (HR difference between SCG and ECG: 0.12 ± 0.35 bpm) and a moderate precision for signals recorded with interfering physical activity—reading out a book loud (HR difference between SCG and ECG: 6.45 ± 3.01 bpm) when compared to the results derived from the state-of-the-art photoplethysmographic (PPG) methods described in the literature. The study shows that computationally simple preprocessing and peak detection techniques initially developed for ECG could be utilized as the basis for HR detection on SCG, although they can be further improved. Full article

This paper presents an eye image segmentation-based computer-aided system for automatic diagnosis of ocular myasthenia gravis (OMG), called OMGMed. It provides great potential to effectively liberate the diagnostic efficiency of expert doctors (the scarce resources) and reduces the cost of healthcare treatment for diagnosed patients, making it possible to disseminate high-quality myasthenia gravis healthcare to under-developed areas. The system is composed of data pre-processing, indicator calculation, and automatic OMG scoring. Building upon this framework, an empirical study on the eye segmentation algorithm is conducted. It further optimizes the algorithm from the perspectives of “network structure” and “loss function”, and experimentally verifies the effectiveness of the hybrid loss function. The results show that the combination of “nnUNet” network structure and “Cross-Entropy + Iou + Boundary” hybrid loss function can achieve the best segmentation performance, and its MIOU on the public and private myasthenia gravis datasets reaches 82.1% and 83.7%, respectively. The research has been used in expert centers. The pilot study demonstrates that our research on eye image segmentation for OMG diagnosis is very helpful in improving the healthcare quality of expert doctors. We believe that this work can serve as an important reference for the development of a similar auxiliary diagnosis system and contribute to the healthy development of proactive healthcare services. Full article

Right-sided mechanical support of the Fontan circulation by existing devices has been compounded by the cross-sectional design of vena cava anastomosis to both pulmonary arteries. Our purpose was to investigate whether increasing inferior vena cava (IVC) flow with a rotary blood pump in the IVC only in an ovine animal model of Fontan would lead to acceptable superior vena cava (SVC) pressure. To achieve this, a Fontan circulation was established in four female sheep by anastomosing the SVC to the main pulmonary artery (MPA) and by interposing a Dacron graft between the IVC and the MPA. A rotary blood pump was then introduced in the graft, and the effect of incremental flows was observed at increasing flow regimen. Additionally, to stimulate increased pulmonary resistance, the experience was repeated in each animal with the placement of a restrictive band on the MPA distally to the SVC and Dacron graft anastomosis. Circulatory support of IVC flow alone increased the systemic cardiac output significantly, both with and without banding, indicating the feasibility of mechanical support of the Fontan circulation by increasing the flow only in the inferior vena cava. The increase in SVC pressure remained within acceptable limits, indicating the potential effectiveness of this mode of support. The findings suggest that increasing the flow only in the inferior vena cava is a feasible method for mechanical support of the Fontan circulation, potentially leading to an increase in cardiac output with acceptable increases in superior vena cava pressure. Full article

Scaffold-guided breast tissue regeneration (SGBTR) can transform both reconstructive and cosmetic breast surgery. Implant-based surgery is the most common method. However, there are inherent limitations, as it involves replacement of tissue rather than regeneration. Regenerating autologous soft tissue has the potential to provide a more like-for-like reconstruction with minimal morbidity. Our SGBTR approach regenerates soft tissue by implanting additively manufactured bioresorbable scaffolds filled with autologous fat graft. A pre-clinical large animal study was conducted by implanting 100 mL breast scaffolds (n = 55) made from medical-grade polycaprolactone into 11 minipigs for 12 months. Various treatment groups were investigated where immediate or delayed autologous fat graft, as well as platelet rich plasma, were added to the scaffolds. Computed tomography and magnetic resonance imaging were performed on explanted scaffolds to determine the volume and distribution of the regenerated tissue. Histological analysis was performed to confirm the tissue type. At 12 months, we were able to regenerate and sustain a mean soft tissue volume of 60.9 ± 4.5 mL (95% CI) across all treatment groups. There was no evidence of capsule formation. There were no immediate or long-term post-operative complications. In conclusion, we were able to regenerate clinically relevant soft tissue volumes utilizing SGBTR in a pre-clinical large animal model. Full article

Bone drilling is a common procedure used to create pilot holes for inserting screws to secure implants for fracture fixation. However, this process can increase bone temperature and the excessive heat can lead to cell death and thermal osteonecrosis, potentially causing early fixation failure or complications. We applied a three-dimensional dynamic elastoplastic finite element model to evaluate the propagation and distribution of heat during bone drilling and assess the thermally affected zone (TAZ) that may lead to thermal necrosis. This model investigates the parameters influencing bone temperature during bone drilling, including drill diameter, rotational speed, feed force, and predrilled hole. The results indicate that our FE model is sufficiently accurate in predicting the temperature rise effect during bone drilling. The maximum temperature decreases exponentially with radial distance. When the feed forces are 40 and 60 N, the maximum temperature does not exceed 45 °C. However, with feed forces of 10 and 20 N, both the maximum temperatures exceed 45 °C within a radial distance of 0.2 mm, indicating a high-risk zone for potential thermal osteonecrosis. With the two-stage drilling procedure, where a 2.5 mm pilot hole is predrilled, the maximum temperature can be reduced by 14 °C. This suggests that higher feed force and rotational speed and/or using a two-stage drilling process could mitigate bone temperature elevation and reduce the risk of thermal osteonecrosis during bone drilling. Full article

Degenerative disc disease (DDD) is a pervasive condition that limits quality of life and burdens economies worldwide. Conventional pharmacological treatments primarily aimed at slowing the progression of degeneration have demonstrated limited long-term efficacy and often do not address the underlying causes of the disease. On the other hand, orthobiologics are regenerative agents derived from the patient’s own tissue and represent a promising emerging therapy for degenerative disc disease. This review comprehensively outlines the pathophysiology of DDD, highlighting the inadequacies of existing pharmacological therapies and detailing the potential of orthobiologic approaches. It explores advanced tools such as platelet-rich plasma and mesenchymal stem cells, providing a historical overview of their development within regenerative medicine, from foundational in vitro studies to preclinical animal models. Moreover, the manuscript delves into clinical trials that assess the effectiveness of these therapies in managing DDD. While the current clinical evidence is promising, it remains insufficient for routine clinical adoption due to limitations in study designs. The review emphasizes the need for further research to optimize these therapies for consistent and effective clinical outcomes, potentially revolutionizing the management of DDD and offering renewed hope for patients. Full article

Pediatric gait rehabilitation and guidance strategies using robotic exoskeletons require a controller that encourages user volitional control and participation while guiding the wearer towards a stable gait cycle. Virtual constraint-based controllers have created stable gait cycles in bipedal robotic systems and have seen recent use in assistive exoskeletons. This paper evaluates a virtual constraint-based controller for pediatric gait guidance through comparison with a traditional time-dependent position tracking controller on a newly developed exoskeleton system. Walking experiments were performed with a healthy child subject wearing the exoskeleton under proportional-derivative control, virtual constraint-based control, and while unpowered. The participant questionnaires assessed the perceived exertion and controller usability measures, while sensors provided kinematic, control torque, and muscle activation data. The virtual constraint-based controller resulted in a gait similar to the proportional-derivative controlled gait but reduced the variability in the gait kinematics by 36.72% and 16.28% relative to unassisted gait in the hips and knees, respectively. The virtual constraint-based controller also used 35.89% and 4.44% less rms torque per gait cycle in the hips and knees, respectively. The user feedback indicated that the virtual constraint-based controller was intuitive and easy to utilize relative to the proportional-derivative controller. These results indicate that virtual constraint-based control has favorable characteristics for robot-assisted gait guidance. Full article

Agarose gels are often used as a tissue mimic. The goal of this work was to determine the appropriate agarose concentrations that result in mechanical properties that match three different porcine organs. Strain tests were carried out with an amplitude varying from 0.01% to 10% at a frequency of 1 Hz on a range of agarose concentrations and porcine organs. Frequency sweep tests were performed from 0.1 Hz to a maximum of 9.5 Hz at a shear strain amplitude of 0.1% for agarose and porcine organs. In agarose samples, the effect of pre-compression of the samples up to 10% axial strain was considered during frequency sweep tests. The experimental measurements from agarose samples were fit to a fractional order viscoelastic (springpot) model. The model was then used to predict stress relaxation in response to a step strain of 0.1%. The prediction was compared to experimental relaxation data, and the results agreed within 12%. The agarose concentrations (by mass) that gave the best fit were 0.25% for the liver, 0.3% for the kidney, and 0.4% for the heart. At a frequency of 0.1 Hz and a shear strain of 0.1%, the agarose concentrations that best matched the shear storage modulus of the porcine organs were 0.4% agarose for the heart, 0.3% agarose for the kidney, and 0.25% agarose for the liver. Full article

Chronic wounds present a significant socioeconomic burden forecasted to increase in prevalence and cost. Minimally manipulated human placental tissues have been increasingly employed and proven to be advantageous in the treatment of chronic wounds, showing improved clinical outcomes and cost-effectiveness. However, technological advances have been constrained by minimal manipulation and homologous use criteria. This study focuses on the characterization of a novel dehydrated human umbilical cord particulate (dHUCP) medical device, which offers a unique allogeneic technological advancement and the first human birth tissue device for wound management. Characterization analyses illustrated a complex extracellular matrix composition conserved in the dHUCP device compared to native umbilical cord, with abundant collagens and glycosaminoglycans imbibing an intricate porous scaffold. Dermal fibroblasts readily attached to the intact scaffold of the dHUCP device. Furthermore, the dHUCP device elicited a significant paracrine proliferative response in dermal fibroblasts, in contrast to fibrillar collagen, a prevalent wound device. Biocompatibility testing in a porcine full-thickness wound model showed resorption of the dHUCP device and normal granulation tissue maturation during healing. The dHUCP device is a promising advancement in wound management biomaterials, offering a unique combination of structural complexity adept for challenging wound topographies and a microenvironment supportive of tissue regeneration. Full article

Gene pathways and gene-regulatory networks are used to describe the causal relationship between genes, based on biological experiments. However, many genes are still to be studied to define novel pathways. To address this, a gene-clustering algorithm has been used to group correlated genes together, based on the similarity of their gene expression level. The existing methods cluster genes based on only one type of omics data, which ignores the information from other types. A large sample size is required to achieve an accurate clustering structure for thousands of genes, which can be challenging due to the cost of multi-omics data. Meta-analysis has been used to aggregate the data from multiple studies and improve the analysis results. We propose a computationally efficient meta-analytic gene-clustering algorithm that combines multi-omics datasets from multiple studies, using the fixed effects linear models and a modified weighted correlation network analysis framework. The simulation study shows that the proposed method outperforms existing single omic-based clustering approaches when multi-omics data and/or multiple studies are available. A real data example demonstrates that our meta-analytic method outperforms single-study based methods. Full article

Respiratory diseases are among the leading causes of death, with many individuals in a population frequently affected by various types of pulmonary disorders. Early diagnosis and patient monitoring (traditionally involving lung auscultation) are essential for the effective management of respiratory diseases. However, the interpretation of lung sounds is a subjective and labor-intensive process that demands considerable medical expertise, and there is a good chance of misclassification. To address this problem, we propose a hybrid deep learning technique that incorporates signal processing techniques. Parallel transformation is applied to adventitious respiratory sounds, transforming lung sound signals into two distinct time-frequency scalograms: the continuous wavelet transform and the mel spectrogram. Furthermore, parallel convolutional autoencoders are employed to extract features from scalograms, and the resulting latent space features are fused into a hybrid feature pool. Finally, leveraging a long short-term memory model, a feature from the latent space is used as input for classifying various types of respiratory diseases. Our work is evaluated using the ICBHI-2017 lung sound dataset. The experimental findings indicate that our proposed method achieves promising predictive performance, with average values for accuracy, sensitivity, specificity, and F1-score of 94.16%, 89.56%, 99.10%, and 89.56%, respectively, for eight-class respiratory diseases; 79.61%, 78.55%, 92.49%, and 78.67%, respectively, for four-class diseases; and 85.61%, 83.44%, 83.44%, and 84.21%, respectively, for binary-class (normal vs. abnormal) lung sounds. Full article

Securing high-quality cell sources is important in regenerative medicine. In this study, we developed a device that can accumulate autologous stem cells in the body. When small wire-assembled molds were embedded in the dorsal subcutaneous pouches of beagles for several weeks, collagen-based tissues with minimal inflammation formed inside the molds. At 3 weeks of embedding, the outer areas of the tissues were composed of immature type III collagen with large amounts of cells expressing SSEA3 or SSEA4 markers, in addition to growth factors such as HGF or VEGF. When separated from the tissues by collagenase treatment, approximately four million cells with a proportion of 70% CD90-positive and 20% SSEA3- or SSEA4-positive cells were recovered from the single mold. The cells could differentiate into bone or cartilage cells. The obtained cell-containing tissues are expected to have potential as therapeutic materials or cell sources in regenerative medicine. Full article

The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative intraocular tissue-derived cell types, including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cells, the intraocular origins of FABP4 were determined by qPCR analysis, and the intracellular functions of FABP4 were investigated by seahorse cellular metabolic measurements and RNA sequencing analysis using a specific inhibitor for FABP4, BMS309403. Among these four different cell types, FABP4 was exclusively expressed in HOCF cells. In HOCF cells, both mitochondrial and glycolytic functions were significantly decreased to trace levels by BMS309403 in a dose-dependent manner. In the RNA sequencing analysis, 67 substantially up-regulated and 94 significantly down-regulated differentially expressed genes (DEGs) were identified in HOCF cells treated with BMS309403 and those not treated with BMS309403. The results of Gene Ontology enrichment analysis and ingenuity pathway analysis (IPA) revealed that the DEGs were most likely involved in G-alpha (i) signaling, cAMP-response element-binding protein (CREB) signaling in neurons, the S100 family signaling pathway, visual phototransduction and adrenergic receptor signaling. Furthermore, upstream analysis using IPA suggested that NKX2-1 (thyroid transcription factor1), HOXA10 (homeobox A10), GATA2 (gata2 protein), and CCAAT enhancer-binding protein A (CEBPA) were upstream regulators and that NKX homeobox-1 (NKX2-1), SFRP1 (Secreted frizzled-related protein 1) and TREM2 (triggering receptor expressed on myeloid cells 2) were causal network master regulators. The findings in this study suggest that intraocularly present FABP4 originates from the ocular choroid and may be a critical regulator for the cellular homeostasis of non-adipocyte HOCF cells. Full article

Ischemic heart disease remains a leading cause of mortality worldwide, which has promoted extensive therapeutic efforts. Stenting has emerged as the primary intervention, particularly among individuals aged 70 years and older. The geometric specifications of stents must align with various mechanical performance criteria outlined by regulatory agencies such as the Food and Drug Administration (FDA). Finite element method (FEM) analysis and computational fluid dynamics (CFD) serve as essential tools to assess the mechanical performance parameters of stents. However, the growing complexity of the numerical models presents significant challenges. Herein, we propose a method to determine the mechanical performance parameters of stents using a simplified FEM model comprising solid and shell elements. In addition, a baseline model of a stent is developed and validated with experimental data, considering parameters such as foreshortening, radial recoil, radial recoil index, and radial stiffness of stents. The results of the simplified FEM model agree well with the baseline model, decreasing up to 80% in computational time. This method can be employed to design stents with specific mechanical performance parameters that satisfy the requirements of each patient. Full article

While technological advances have made implants a good treatment option with a good long-term prognosis, peri-implantitis, which results in alveolar bone resorption around implants, has been observed in some cases. Micromotion at the implant abutment connection can cause peri-implantitis. However, the temporal progression of micromotion upon loading remains unclear. Therefore, we aimed to longitudinally measure micromotion upon loading application on an implant. Implants with Morse-tapered connections were prepared. Custom titanium abutments were fabricated and tightened onto implant bodies at 35 N. A 100 N vertical load was applied for 200,000 cycles. Micromotion was measured when the load was applied, as was the total implant length and removal torque before and after loading. The micromotion was measured from the position data of the jig of the testing machine during loading. The average removal torque was 30.67 N after 10 min of tightening and 27.95 N after loading, indicating a decrease due to loading. The implant length reduced by 3.6 μm under the load. The average micromotion was 0.018 mm at 2 cycles, 0.016 mm at 100,000 cycles, and 0.0157 mm at 200,000 cycles, indicating implant length reduction under the load but not reaching 0. The micromotion between the implant and abutment under a cyclic load decreased over time but did not completely cease. These results highlight the relationship between micromotion and loading, underscoring the importance of careful monitoring and management to mitigate potential complications, such as peri-implantitis, and ensure optimal performance and durability of the implant. Full article