Wirelessly Powered-Electrically Conductive Polymer System for Stem Cell Enhanced Stroke Recovery.

Effective stroke recovery therapeutics remain limited. Stem cell therapies have yielded promising results, but the harsh ischemic environment of the post-stroke brain reduces their therapeutic potential. Previously, we developed a conductive polymer scaffold system that enabled stem cell delivery with simultaneous electrical modulation of the cells and surrounding neural environment. This wired polymer scaffold proved efficacious in optimizing ideal conditions for stem cell mediated motor improvements in a rodent model of stroke. To further enable preclinical studies and enhance translational potential, we identified a method to improve this system by eliminating its dependence upon a tethered power source. We have herein developed a wirelessly powered, electrically conductive polymer system that eases therapeutic application and enables full mobility. As a proof of concept, we demonstrate that the wirelessly powered scaffold is able to stimulate neural stem cells in vitro, as well as in vivo in a rodent model of stroke. This system modulates the stroke microenvironment and increases the production of endogenous stem cells. In summation, this novel, wirelessly powered conductive scaffold can serve as a mobile platform for a wide variety of therapeutics involving electrical stimulation.

A report on a modified protocol for flow cytometry-based assessment of blood group erythrocyte antigens potentially suitable for analysis of weak ABO subgroups.

BACKGROUND: Flow cytometry (FC) has proven its utility in scrutinizing AB antigen expression in red blood cells (RBCs), cooperating with serological tests for accurate blood group typing. However, technical difficulties may impair the characterization of weak ABO subtypes when background noises appear at non-negligible levels. STUDY DESIGN AND METHODS: We sought to establish an FC method that could prevent antibody-induced hemagglutination and an increase in cellular autofluorescence, two major issues inherent to RBC-FC analysis of AB expression. We optimized fixatives, multicolor-staining protocols, and sequential gating strategies. Blood samples from weak ABO subtype cases, Bm and Ael , were analyzed with the established protocol. RESULTS: The optimized mixture of glutaraldehyde and formaldehyde successfully generated fixed RBCs resistant to agglutination while maintaining low autofluorescence. These features allowed co-staining of leukocyte- and erythrocyte-markers, which enabled sequential gating strategies facilitating the precise AB antigen analysis in purely single RBCs with minimum background noises. By the established FC analysis, we could detect in the Bm sample a small RBC population exhibiting weak B antigen expression. The assay also proved it feasible to identify a small population (0.04%) of RBCs weakly expressing the A antigen in the Ael sample confirmed as harboring a rare c.816dupG ABO variant allele. CONCLUSION: The RBC-FC analysis described here allows the detection of AB antigens weakly expressed in RBCs while achieving minimum background noise levels in negative control samples. Overall, the modified protocol provides a quick and reliable assay valuable in transfusion medicine and is potentially applicable to the characterization of rare weak ABO variants.

Biomechanical effect of fibular osteotomy on the knee joint in high tibial osteotomy: A cadaveric study.

BACKGROUND: Closed-wedge high tibial osteotomy (CWHTO) with a fibular osteotomy (FO) causes medial joint space widening in the knee. However, the effect of FO on the joint space width remains unclear. OBJECTIVE: This study aimed to examine the effect of FO on the knee in HTO. METHODS: A compression load test was performed on two amputated human limbs under four conditions: (1) normal (without any osteotomy), (2) open-wedge HTO (OWHTO), (3) OWHTO with FO, and (4) CWHTO. The contact area of the femoral and tibial cartilages and the medial and lateral joint space widths in each condition were evaluated using a motion capture system with computed tomography (CT) and magnetic resonance imaging (MRI) data. RESULTS: The contact area increased on the lateral side after OWHTO, which increased more on the lateral side with a concomitant decrease on the medial side in both subjects when FO was added to OWHTO. An increase in the medial joint space width and a decrease on the lateral side were seen in both OWHTO with FO and CWHTO. CONCLUSIONS: The contact area and joint space widths are affected by the FO, and the effect is more pronounced than the way of HTO (OWHTO or CWHTO).

Remotely controlled near-infrared-triggered photothermal treatment of brain tumours in freely behaving mice using gold nanostars.

Current clinical brain tumour therapy practices are based on tumour resection and post-operative chemotherapy or X-ray radiation. Resection requires technically challenging open-skull surgeries that can lead to major neurological deficits and, in some cases, death. Treatments with X-ray and chemotherapy, on the other hand, cause major side-effects such as damage to surrounding normal brain tissues and other organs. Here we report the development of an integrated nanomedicine-bioelectronics brain-machine interface that enables continuous and on-demand treatment of brain tumours, without open-skull surgery and toxicological side-effects on other organs. Near-infrared surface plasmon characteristics of our gold nanostars enabled the precise treatment of deep brain tumours in freely behaving mice. Moreover, the nanostars' surface coating enabled their selective diffusion in tumour tissues after intratumoral administration, leading to the exclusive heating of tumours for treatment. This versatile remotely controlled and wireless method allows the adjustment of nanoparticles' photothermal strength, as well as power and wavelength of the therapeutic light, to target tumours in different anatomical locations within the brain.

Variations in Strain Distribution at Distal Radius under Different Loading Conditions.

Distal radial fractures exhibit various fracture patterns. By assuming that the strain distribution at the distal radius affects the diversification of the fracture pattern, a parameter study using the finite element model of a wrist developed from computed tomography (CT) images was performed under different loading conditions. The finite element model of the wrist consisted of the radius, ulna, scaphoid, lunate, triquetrum, and major carpal ligaments. The material properties of the bone models were assigned on the basis of the Hounsfield Unit (HU) values of the CT images. An impact load was applied to the scaphoid, lunate, and triquetrum to simulate boundary conditions during fall accidents. This study considered nine different loading conditions that combine three different loading directions and three different load distribution ratios. According to the analysis results, the strain distribution at the distal radius changed with respect to the change in the loading condition. High strain concentration occurred in regions where distal radius fractures are commonly developed. The direction and distribution of the load acting on the radius were considered to be factors that may cause variations in the fracture pattern of distal radius fractures.

Activation of UCP1-Independent Ca2+ Cycling Thermogenesis by Wireless Optogenetics.

The identification of non-canonical UCP1-independent thermogenic mechanisms offers new opportunities to target such pathways to improve metabolic health. Based on our recent studies on Ca2+ futile cycling thermogenesis in beige fat, we applied the newly developed implantable wireless optogenetic system to activate Ca2+ cycling in an adipocyte-specific manner without external stimuli, i.e., fat-specific cold mimetics. Here, we describe the detailed methodology and application to the prevention of obesity.

New evaluation indices for rotational knee angles in standing anteroposterior knee radiographs.

BACKGROUND: Identifying the time course of rotational knee alignment is crucial for elucidating the etiology in knee osteoarthritis. OBJECTIVE: The aim of this study was to propose new rotational indices for calculating the change in relative rotational angles between the femur and tibia in standing anteroposterior (AP) radiographs. METHODS: Forty healthy elderly volunteers (20 women and 20 men; mean age, 70 ± 6 years) were assessed. The evaluation parameters were as follows: (1) femoral rotational index: the distance between the sphere center of the medial posterior femoral condyle and the lateral edge of the patella, and (2) tibial rotational index: the distance between the medial eminence of the tibia and the lateral edge of the fibula head. The indices were standardized by the diameter of the sphere of the medial posterior femoral condyle. This study (1) identified the relationship between changes in rotational indices and the simulated rotational knee angles in the standing position, (2) proposed a regression equation for the change in relative rotational angles between the femur and tibia in standing AP radiographs, and (3) verified the accuracy of the regression equation. RESULTS: The rotational indices increased in direct proportion to simulated rotational knee angles (femoral index: r > 0.9,p < 0.0001; tibial index: r > 0.9, p < 0.0001). Based on the results, the regression equation with the accuracy of 0.45 ± 0.26° was determined. CONCLUSIONS: The proposed regression equations can potentially predict the change in relative rotational angles between the femur and tibia in a pair of standing AP radiographs taken at different dates in longitudinal studies.

Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis.

Cold stimuli and the subsequent activation of ß-adrenergic receptor (ß-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the ß3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the ß-AR pathway and triggers Ca2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.

Articular surface of the medial proximal tibia is aligned parallel to the ground in three-dimensional space under weight-bearing conditions in healthy and varus osteoarthritic knees.

PURPOSE: To test the hypothesis that an inclined articular surface on the medial proximal tibia is aligned more parallel to the ground in three-dimensional (3D) space under weight-bearing (WB) conditions (parallel phenomenon) than under non-WB (NWB) conditions in healthy and varus osteoarthritic knees. METHODS: We examined 55 healthy knees (26 women, 29 men; mean age, 70 ± 6 years) and 108 varus osteoarthritic knees (66 women, 16 men; mean age, 74 ± 7 years). For the evaluation under WB conditions, a 3D assessment system was used on biplanar long-leg radiographs and 3D bone models using a 3D-to-2D image registration technique. In addition, the least square method was used to determine the approximation plane. The angles between the normal vector for the approximation plane of an articular surface on the medial proximal tibia and each axis of the tibial or world coordinate system were calculated. RESULTS: Morphologically, the inclination of the approximation plane was steeper in osteoarthritic knees than in healthy knees (p < 0.0001). The approximation plane was aligned more parallel to the ground under WB conditions than under NWB conditions in healthy (p < 0.0001) and osteoarthritic knees (p < 0.0001). CONCLUSIONS: The parallel phenomenon in the medial proximal tibia was confirmed for healthy and varus osteoarthritic knees. The medial proximal tibia plays an important role in the parallel phenomenon, assumingly associated with varus alignment and varus thrust. The inclination of the medial proximal tibia may become a new parameter for imaging investigations. LEVEL OF EVIDENCE: III.

Comparison of Locking and Frag-Loc Screws for Fixation of Die-Punch Fragments.

Background The Frag-Loc (FL) compression screw system was designed to stabilize dorsally displaced intra-articular dorsoulnar (die-punch) fragments in distal radius fractures. Purpose Comparison of the biomechanical properties of fixation of the die-punch fragment (stiffness, ultimate strength, and displacement ratio of the fragment), using the FL and traditional locking screw (LS), and using simulated distal radial fractures in cadaveric specimens under axial compressive loading. Both screws were used with a volar locking plate (VLP). Materials and Methods Eight matched pairs of formalin-fixed cadaveric specimens of the radius were used to simulate distal radius fractures with die-punch fragments. The die-punch fragment was fixed using VLP with either FL group or LS group. Biomechanical properties for the two fixation systems were evaluated under axial compression loading, applied at a constant rate of 0.5 mm/min until failure. Load data were recorded and the ultimate strength and change in the gap between the die-punch and proximal fragments measured, with the displacement ratio calculated by dividing the value of the gap before loading by the gap after loading. Failure was defined as 10 mm or more of fragment displacement, or screw failure. Results There were no differences in ultimate strength ( p = 0.47) or stiffness ( p = 0.061) between the two fragment fixation systems. However, the displacement ratio was lower for the FL than for the LS system ( p = 0.049). Conclusion Compared with LS, the FL system lowers the displacement of die-punch fragments under compressive loading. Clinical Relevance The FL system is effective for the treatment of distal radius fractures with die-punch fragments.

Conformal phased surfaces for wireless powering of bioelectronic microdevices.

Wireless powering could enable the long-term operation of advanced bioelectronic devices within the human body. Although both enhanced powering depth and device miniaturization can be achieved by shaping the field pattern within the body, existing electromagnetic structures do not provide the spatial phase control required to synthesize such patterns. Here, we describe the design and operation of conformal electromagnetic structures, termed phased surfaces, that interface with non-planar body surfaces and optimally modulate the phase response to enhance the performance of wireless powering. We demonstrate that the phased surfaces can wirelessly transfer energy across anatomically heterogeneous tissues in large animal models, powering miniaturized semiconductor devices (<12 mm3) deep within the body (>4 cm). As an illustration of in vivo operation, we wirelessly regulated cardiac rhythm by powering miniaturized stimulators at multiple endocardial sites in a porcine animal model.

High-performance wireless powering for peripheral nerve neuromodulation systems.

Neuromodulation of peripheral nerves with bioelectronic devices is a promising approach for treating a wide range of disorders. Wireless powering could enable long-term operation of these devices, but achieving high performance for miniaturized and deeply placed devices remains a technological challenge. We report the miniaturized integration of a wireless powering system in soft neuromodulation device (15 mm length, 2.7 mm diameter) and demonstrate high performance (about 10%) during in vivo wireless stimulation of the vagus nerve in a porcine animal model. The increased performance is enabled by the generation of a focused and circularly polarized field that enhances efficiency and provides immunity to polarization misalignment. These performance characteristics establish the clinical potential of wireless powering for emerging therapies based on neuromodulation.

External torsion in a proximal tibia and internal torsion in a distal tibia occur independently in varus osteoarthritic knees compared to healthy knees.

INTRODUCTION: The relative torsional angle of the distal tibia is dependent on a deformity of the proximal tibia, and it is a commonly used torsional parameter to describe deformities of the tibia; however, this parameter cannot show the location and direction of the torsional deformity in the entire tibia. This study aimed to identify the detailed deformity in the entire tibia via a coordinate system based on the diaphysis of the tibia by comparing varus osteoarthritic knees to healthy knees. METHODS: In total, 61 limbs in 58 healthy subjects (age: 54 ± 18 years) and 55 limbs in 50 varus osteoarthritis (OA) subjects (age: 72 ± 7 years) were evaluated. The original coordinate system based on anatomic points only from the tibial diaphysis was established. The evaluation parameters were 1) the relative torsion in the distal tibia to the proximal tibia, 2) the proximal tibial torsion relative to the tibial diaphysis, and 3) the distal tibial torsion relative to the tibial diaphysis. RESULTS: The relative torsion in the distal tibia to the proximal tibia showed external torsion in both groups, while the external torsion was lower in the OA group than in the healthy group (p < 0.0001). The proximal tibial torsion relative to the tibial diaphysis had a higher external torsion in the OA group (p = 0.012), and the distal tibial torsion relative to the tibial diaphysis had a higher internal torsion in the OA group (p = 0.004) in comparison to the healthy group. CONCLUSION: The reverse torsional deformity, showing a higher external torsion in the proximal tibia and a higher internal torsion in the distal tibia, occurred independently in the OA group in comparison to the healthy group. Clinically, this finding may prove to be a pathogenic factor in varus osteoarthritic knees. LEVEL OF EVIDENCE: Level Ⅲ.

Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice.

To enable sophisticated optogenetic manipulation of neural circuits throughout the nervous system with limited disruption of animal behavior, light-delivery systems beyond fiber optic tethering and large, head-mounted wireless receivers are desirable. We report the development of an easy-to-construct, implantable wireless optogenetic device. Our smallest version (20 mg, 10 mm(3)) is two orders of magnitude smaller than previously reported wireless optogenetic systems, allowing the entire device to be implanted subcutaneously. With a radio-frequency (RF) power source and controller, this implant produces sufficient light power for optogenetic stimulation with minimal tissue heating (<1 °C). We show how three adaptations of the implant allow for untethered optogenetic control throughout the nervous system (brain, spinal cord and peripheral nerve endings) of behaving mice. This technology opens the door for optogenetic experiments in which animals are able to behave naturally with optogenetic manipulation of both central and peripheral targets.

Three-dimensional dynamic analysis of knee joint during gait in medial knee osteoarthritis using loading axis of knee.

We recently developed a new method for three-dimensional evaluation of mechanical factors affecting knee joint in order to help identify factors that contribute to the progression of knee osteoarthritis (KOA). This study aimed to verify the clinical validity of our method by evaluating knee joint dynamics during gait. Subjects were 41 individuals (14 normal knees; 8 mild KOAs; 19 severe KOAs). The positions of skin markers attached to the body were captured during gait, and bi-planar X-ray images of the lower extremities were obtained in standing position. The positional relationship between the markers and femorotibial bones was determined from the X-ray images. Combining this relationship with gait capture allowed for the estimation of relative movement between femorotibial bones. We also calculated the point of intersection of loading axis of knee on the tibial proximal surface (LAK point) to analyze knee joint dynamics. Knee flexion range in subjects with severe KOA during gait was significantly smaller than that in those with normal knees (p=0.011), and knee adduction in those with severe KOA was significantly larger than in those with mild KOA (p<0.000). LAK point was locally loaded on the medial compartment of the tibial surface as KOA progressed, with LAK point of subjects with severe KOA rapidly shifting medially during loading response. Local loading and medial shear force were applied to the tibial surface during stance phase as medial KOA progressed. Our findings suggest that our method is useful for the quantitative evaluation of mechanical factors that affect KOA progression.

Wireless power transfer to deep-tissue microimplants.

The ability to implant electronic systems in the human body has led to many medical advances. Progress in semiconductor technology paved the way for devices at the scale of a millimeter or less ("microimplants"), but the miniaturization of the power source remains challenging. Although wireless powering has been demonstrated, energy transfer beyond superficial depths in tissue has so far been limited by large coils (at least a centimeter in diameter) unsuitable for a microimplant. Here, we show that this limitation can be overcome by a method, termed midfield powering, to create a high-energy density region deep in tissue inside of which the power-harvesting structure can be made extremely small. Unlike conventional near-field (inductively coupled) coils, for which coupling is limited by exponential field decay, a patterned metal plate is used to induce spatially confined and adaptive energy transport through propagating modes in tissue. We use this method to power a microimplant (2 mm, 70 mg) capable of closed-chest wireless control of the heart that is orders of magnitude smaller than conventional pacemakers. With exposure levels below human safety thresholds, milliwatt levels of power can be transferred to a deep-tissue (>5 cm) microimplant for both complex electronic function and physiological stimulation. The approach developed here should enable new generations of implantable systems that can be integrated into the body at minimal cost and risk.

Prediction of risk of fracture in the tibia due to altered bone mineral density distribution resulting from disuse: a finite element study.

The disuse-related bone loss that results from immobilisation following injury shares characteristics with osteoporosis in post-menopausal women and the aged, with decreases in bone mineral density leading to weakening of the bone and increased risk of fracture. The aim of this study was to use the finite element method to: (i) calculate the mechanical response of the tibia under mechanical load and (ii) estimate of the risk of fracture; comparing between two groups, an able-bodied group and spinal cord injury patients group suffering from varying degrees of bone loss. The tibiae of eight male subjects with chronic spinal cord injury and those of four able-bodied age-matched controls were scanned using multi-slice peripheral quantitative computed tomography. Images were used to develop full three-dimensional models of the tibiae in Mimics (Materialise) and exported into Abaqus (Simulia) for calculation of stress distribution and fracture risk in response to specified loading conditions - compression, bending and torsion. The percentage of elements that exceeded a calculated value of the ultimate stress provided an estimate of the risk of fracture for each subject, which differed between spinal cord injury subjects and their controls. The differences in bone mineral density distribution along the tibia in different subjects resulted in different regions of the bone being at high risk of fracture under set loading conditions, illustrating the benefit of creating individual material distribution models. A predictive tool can be developed based on these models, to enable clinicians to estimate the amount of loading that can be safely allowed onto the skeletal frame of individual patients who suffer from extensive musculoskeletal degeneration (including spinal cord injury, multiple sclerosis and the ageing population). The ultimate aim is to reduce fracture occurrence in these vulnerable groups.

Automatic construction of an anatomical coordinate system for three-dimensional bone models of the lower extremities--pelvis, femur, and tibia.

Automated methods for constructing patient-specific anatomical coordinate systems (ACSs) for the pelvis, femur and tibia were developed based on the bony geometry of each, derived from computed tomography (CT). The methods used principal axes of inertia, principal component analysis (PCA), cross-sectional area, and spherical and ellipsoidal surface fitting to eliminate the influence of rater's bias on reference landmark selection. Automatic ACSs for the pelvis, femur, and tibia were successfully constructed on each 3D bone model using the developed algorithm. All constructions were performed within 30s; furthermore, between- and within- rater errors were zero for a given CT-based 3D bone model, owing to the automated nature of the algorithm. ACSs recommended by the International Society of Biomechanics (ISB) were compared with the automatically constructed ACS, to evaluate the potential differences caused by the selection of the coordinate system. The pelvis ACSs constructed using the ISB-recommended system were tilted significantly more anteriorly than those constructed automatically (range, 9.6-18.8°). There were no significant differences between the two methods for the femur. For the tibia, significant differences were found in the direction of the anteroposterior axis; the anteroposterior axes identified by ISB were more external than those in the automatic ACS (range, 17.5-25.0°).

[Determination of joint contact area using MRI].

Elevated contact stress on the articular joints has been hypothesized to contribute to articular cartilage wear and joint pain. However, given the limitations of using contact stress and areas from human cadaver specimens to estimate articular joint stress, there is need for an in vivo method to obtain such data. Magnetic resonance imaging (MRI) has been shown to be a valid method of quantifying the human joint contact area, indicating the potential for in vivo assessment. The purpose of this study was to describe a method of quantifying the tibiofemoral joint contact area using MRI. The validity of this technique was established in porcine cadaver specimens by comparing the contact area obtained from MRI with the contact area obtained using pressure-sensitive film (PSF). In particular, we assessed the actual condition of contact by using the ratio of signal intensity of MR images of cartilage surfaces. Two fresh porcine cadaver knees were used. A custom loading apparatus was designed to apply a compressive load to the tibiofemoral joint. We measured the contact area by using MRI and PSF methods. When the ratio of signal intensity of the cartilage surface was 0.9, the error of the contact area between the MR image and PSF was about 6%. These results suggest that this MRI method may be a valuable tool in quantifying joint contact area in vivo.

Automated image registration for assessing three-dimensional alignment of entire lower extremity and implant position using bi-plane radiography.

An automated image-matching technique is presented to assess alignment of the entire lower extremity for normal and implanted knees and the positioning of implants with respect to bone. Sawbone femur and tibia and femoral and tibial components of a total knee arthroplasty system were used. Three spherical markers were attached to each sawbone and each component to define the local coordinate system. Outlines of the three-dimensional (3D) bone models and component computer-aided design (CAD) models were projected onto extracted contours of the femur, tibia, and implants in frontal and oblique X-ray images. Three-dimensional position of each model was recovered by minimizing the difference between the projected outline and the contour. Median values of the absolute error in estimating relative positions were within 0.5mm and 0.6 degrees for the femur with respect to the tibia, 0.5mm and 0.5 degrees for the femoral component with respect to the tibial component, 0.6mm and 0.6 degrees for the femoral component with respect to the femur, and 0.5mm and 0.4 degrees for the tibial component with respect to the tibia, indicating significant improvements when compared to manually obtained results.