Advancements in drug delivery methods for the treatment of brain disease.

The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the brain. These technologies have addressed many of the limitations imposed by the BBB by: (1) designing or modifying the physiochemical properties of therapeutic compounds to allow for transport across the BBB; (2) bypassing the BBB by administration of drugs via alternative routes; and (3) transiently disrupting the BBB (BBBD) using biophysical therapies. Here we specifically review colloidal drug carrier delivery systems, intranasal, intrathecal, and direct interstitial drug delivery methods, focused ultrasound BBBD, and pulsed electrical field induced BBBD, as well as the key features of BBB structure and function that are the mechanistic targets of these approaches. Each of these drug delivery technologies are illustrated in the context of their potential clinical applications and limitations in companion animals with naturally occurring intracranial diseases.

Association of Normal vs Abnormal Meary Angle With Hindfoot Malalignment and First Metatarsal Rotation: A Short Report.

BACKGROUND: Recent work has reported a significant association between first metatarsal (M1) rotation and hindfoot alignment, with the finding of a moderate association between the calcaneal moment arm (CMA) and 2 M1 pronation angular measures: Saltzman (r = 0.641, P < .01) and Kim (r = 0.615, P < .01). The aim of the current post hoc investigation was to determine if this association is related with Meary angle. METHODS: We reanalyzed previously published data set separating patients into 2 groups: (1) those with normal Meary angle (n = 128) and (2) those with abnormal Meary angle (n = 147). Hindfoot alignment and M1 rotation were measured on weightbearing computed tomography. Statistical analyses were performed to evaluate for association between these variables among the groups. RESULTS: The correlation between CMA and M1 rotation of the entire cohort was r = 0.577 (Saltzman ankle) and r = 0.540 (Kim angle). For the subset with a normal Meary angle, this association was negligible (Saltzman and Kim angles, r = 0.194 and 0.240, respectively). Conversely, for the abnormal Meary angle subset, the association was substantial (Saltzman and Kim angles, r = 0.733 and 0.675, respectively). CONCLUSION: Patients presenting with an abnormal Meary angle and hindfoot deformity have a high likelihood of manifesting a proportionate degree of M1 rotation. LEVEL OF EVIDENCE: Level III, Retrospective Cohort Study.

Association Between Hindfoot Alignment and First Metatarsal Rotation.

BACKGROUND: The association between forefoot and hindfoot position for planus and cavus feet is fundamental to the treatment of these deformities. However, no studies have evaluated the association between hindfoot alignment and first metatarsal (M1) axial rotation. Understanding this possible relationship may help to understand the deformity and improve patient care. The purpose of this study is to determine a correlation between hindfoot alignment and metatarsal rotation as assessed by weightbearing computed tomography (WBCT). METHODS: Patients who underwent weightbearing plain radiography (WBPR) and WBCT between 2015 and 2018 were evaluated. Hindfoot alignment was measured with the calcaneal moment arm (CMA). M1 rotation was measured using the Kim and Saltzman angles. Patient subgroups were created according to the severity of valgus/varus hindfoot alignment. Statistical analyses were performed to evaluate for association between variables. RESULTS: Among the 196 patient feet included in the study, the average CMA was 6.0 ± 16.2 mm. The average Kim and Saltzman angles were 7.7 ± 12.9 degrees and 2.8 ± 13.1 degrees, respectively. The average Meary angle was 182.0 ± 11.9 degrees. A moderately strong association was found between the CMA and the Saltzman (r = 0.641, P < .01) and Kim angles (r = 0.615, P < .01). Hindfoot valgus was associated with M1 pronation and hindfoot varus with M1 supination. Additionally, inverse relationships between the Meary angle and the Saltzman (r = -0.600, P < .01) and Kim angles (r = -0.529, P < .01) were identified. CONCLUSION: In this well-defined cohort, we found substantial correlation between hindfoot alignment and M1 rotation. Hindfoot valgus was associated with M1 pronation, and hindfoot varus was associated with M1 supination. Surgeons correcting cavovarus/planovalgus deformities should be aware of this association and evaluate the need for first-ray derotation. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

An Investigation for Large Volume, Focal Blood-Brain Barrier Disruption with High-Frequency Pulsed Electric Fields.

The treatment of CNS disorders suffers from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). Herein, we investigated high-frequency pulsed electric field (HF-PEF) therapy of various pulse widths and interphase delays for BBB disruption while selectively minimizing cell ablation. Eighteen male Fisher rats underwent craniectomy procedures and two blunt-tipped electrodes were advanced into the brain for pulsing. BBB disruption was verified with contrast T1W MRI and pathologically with Evans blue dye. High-frequency irreversible electroporation cell death of healthy rodent astrocytes was investigated in vitro using a collagen hydrogel tissue mimic. Numerical analysis was conducted to determine the electric fields in which BBB disruption and cell ablation occur. Differences between the BBB disruption and ablation thresholds for each waveform are as follows: 2-2-2 µs (1028 V/cm), 5-2-5 µs (721 V/cm), 10-1-10 µs (547 V/cm), 2-5-2 µs (1043 V/cm), and 5-5-5 µs (751 V/cm). These data suggest that HF-PEFs can be fine-tuned to modulate the extent of cell death while maximizing peri-ablative BBB disruption. Furthermore, numerical modeling elucidated the diffuse field gradients of a single-needle grounding pad configuration to favor large-volume BBB disruption, while the monopolar probe configuration is more amenable to ablation and reversible electroporation effects.

Assessment of Hindfoot Alignment Comparing Weightbearing Radiography to Weightbearing Computed Tomography.

BACKGROUND: Hindfoot alignment view (HAV) radiographs are widely utilized for 2-dimensional (2D) radiographic assessment of hindfoot alignment; however, the development of weightbearing computed tomography (WBCT) may provide more accurate methods of quantifying 3-dimensional (3D) hindfoot alignment. The aim of this study was to compare the 2D calcaneal moment arm measurements on HAV radiographs with WBCT. METHODS: This retrospective cohort study included 375 consecutive patients with both HAV radiographs and WBCT imaging. Measurement of the 2D hindfoot alignment moment arm was compared between both imaging modalities. The potential confounding influence of valgus/varus/neutral alignment, presence of hardware, and motion artifact were further analyzed. RESULTS: The intraclass correlation coefficients (ICCs) of interobserver and intraobserver reliability for measurements with both imaging modalities were excellent. Both modalities were highly correlated (Spearman coefficient, 0.930; P < .001). HAV radiographs exhibited a mean calcaneal moment arm difference of 3.9 mm in the varus direction compared with WBCT (95% CI, -4.9 to 12.8). The difference of hindfoot alignment between both modalities was comparable in subgroups with neutral/valgus/varus alignment, presence of hardware, and motion artifact. CONCLUSION: Both HAV radiographs and WBCT are highly reliable and highly correlated imaging methods for assessing hindfoot alignment. Measurements were not influenced by severe malalignment, the presence of hardware, or motion artifact on WBCT. On average, HAV radiographs overestimated 3.9 mm of varus alignment as compared with WBCT. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Normative Distribution of First Metatarsal Axial Rotation.

BACKGROUND: First metatarsal (M1) axial rotation is recognized as a clinically relevant component of hallux valgus deformity. Methods to realign the M1 in 3 dimensions have been developed. One goal of these operations is to restore normal rotation of the first ray. The aim of this study is to provide estimates for the normal distribution of M1 rotation in patients without relevant anatomic pathology. METHODS: Using stringent clinical and radiographic criteria, we evaluated a set of plain radiograph and weightbearing computed tomography (WBCT) images of 62 feet from a consecutive patient database. Subjects included had normal foot alignment without bunion symptoms. M1 rotation of each foot was measured using 2 unique methods (Saltzman et al and Kim et al methods). Measurement of rotation was performed by 2 observers from coronal WBCT images. Mean values and confidence intervals (CIs) of M1 rotation were calculated for each method. Inter- and intraobserver reliability values were also reported. RESULTS: Mean M1 rotation values of 2.1 degrees (95% CI: 0.9-3.4) and 6.1 degrees (95% CI: 4.4-7.8) were identified using the Saltzman et al and Kim et al methods, respectively. Inter- and intraobserver reliability values were interpreted as excellent for both methods. CONCLUSION: In this study, we describe the natural distribution of the M1 axial rotation in subjects without bunion or other identifiable bony foot deformities. This information should provide a normative reference for surgeons correcting rotational issues of the first metatarsal. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Rapid Impedance Spectroscopy for Monitoring Tissue Impedance, Temperature, and Treatment Outcome During Electroporation-Based Therapies.

OBJECTIVE: Electroporation-based therapies (EBTs) employ high voltage pulsed electric fields (PEFs) to permeabilize tumor tissue; this results in changes in electrical properties detectable using electrical impedance spectroscopy (EIS). Currently, commercial potentiostats for EIS are limited by impedance spectrum acquisition time (  âˆ¼ 10 s); this timeframe is much larger than pulse periods used with EBTs (  âˆ¼ 1 s). In this study, we utilize rapid EIS techniques to develop a methodology for characterizing electroporation (EP) and thermal effects associated with high-frequency irreversible EP (H-FIRE) in real-time by monitoring inter-burst impedance changes. METHODS: A charge-balanced, bipolar rectangular chirp signal is proposed for rapid EIS. Validation of rapid EIS measurements against a commercial potentiostat was conducted in potato tissue using flat-plate electrodes and thereafter for the measurement of impedance changes throughout IRE treatment. Flat-plate electrodes were then utilized to uniformly heat potato tissue; throughout high-voltage H-FIRE treatment, low-voltage inter-burst impedance measurements were used to continually monitor impedance change and to identify a frequency at which thermal effects are delineated from EP effects. RESULTS: Inter-burst impedance measurements (1.8 kHz - 4.93 MHz) were accomplished at 216 discrete frequencies. Impedance measurements at frequencies above  âˆ¼ 1 MHz served to delineate thermal and EP effects in measured impedance. CONCLUSION: We demonstrate rapid-capture ( 1 s) EIS which enables monitoring of inter-burst impedance in real-time. For the first time, we show impedance analysis at high frequencies can delineate thermal effects from EP effects in measured impedance. SIGNIFICANCE: The proposed waveform demonstrates the potential to perform inter-burst EIS using PEFs compatible with existing pulse generator topologies.

Web Conferencing Facilitation Within Problem-Based Learning Biomedical Engineering Courses.

Problem-based learning (PBL) has been effectively used within BME education, though there are several challenges in its implementation within courses with larger enrollments. Furthermore, the sudden transition to online learning from the COVID-19 pandemic introduced additional challenges in creating a similar PBL experience in an online environment. Online constrained PBL was implemented through asynchronous modules and synchronous web conferencing with rotating facilitators. Overall, facilitators perceived web conferencing facilitation to be similar to in-person, but noted that students were more easily "hidden" or distracted. Students did not comment on web conferencing facilitation specifically, but indicated the transition to online PBL was smooth. Course instructors identified that a fully synchronous delivery as well as modifications of Group Meeting Minutes assignments as potential modifications for future offerings. Future work will aim to address the perceptions and effectiveness of web conferencing facilitation for PBL courses within an undergraduate BME curriculum, as web conferencing could prove to be another significant breakthrough in addressing challenges of problem-based learning courses.

What Is the Definition of Acute and Chronic Periprosthetic Joint Infection (PJI) of Total Ankle Arthroplasty (TAA)?

RECOMMENDATION: There is a paucity of data for defining acute or chronic periprosthetic joint infection (PJI) following total ankle arthroplasty (TAA) in the literature. Any discussion of PJI after ankle replacement is entirely reliant on the literature surrounding knee and hip arthroplasty. LEVEL OF EVIDENCE: Consensus. DELEGATE VOTE: Agree: 100%, Disagree: 0%, Abstain: 0% (Unanimous, Strongest Consensus).

Numerical simulation modeling of the irreversible electroporation treatment zone for focal therapy of prostate cancer, correlation with whole-mount pathology and T2-weighted MRI sequences.

BACKGROUND: At present, it is not possible to predict the ablation zone volume following irreversible electroporation (IRE) for prostate cancer (PCa). This study aimed to determine the necessary electrical field threshold to ablate human prostate tissue in vivo with IRE. METHODS: In this prospective multicenter trial, patients with localized PCa were treated with IRE 4 weeks before their scheduled radical prostatectomy. In 13 patients, numerical models of the electrical field were generated and compared with the ablation zone volume on whole-mount pathology and T2-weighted magnetic resonance imaging (MRI) sequences. Volume-generating software was used to calculate the ablation zone volumes on histology and MRI. The electric field threshold to ablate prostate tissue was determined for each patient. RESULTS: A total of 13 patients were included for histological and simulation analysis. The median electrical field threshold was 550 V/cm (interquartile range 383-750 V/cm) for the software-generated histology volumes. The median electrical field threshold was 500 V/cm (interquartile range 386-580 V/cm) when the ablation zone volumes were used from the follow-up MRI. CONCLUSIONS: The electrical field threshold to ablate human prostate tissue in vivo was determined using whole-mount pathology and MRI. These thresholds may be used to develop treatment planning or monitoring software for IRE prostate ablation; however, further optimization of simulation methods are required to decrease the variance that was observed between patients.

Distal fibula osteotomies improve tibiotalar joint compression: A biomechanical study in a cadaveric model.

BACKGROUND: Successful tibiotalar joint fusion relies on adequate compression. Compression following joint preparation may be affected by the extent to which the fibula holds the joint out to anatomical length. The purpose of this study was to evaluate the effect of various distal fibula osteotomies on tibiotalar joint compression. METHODS: Eight adult cadaveric lower extremity specimens with an intact ankle joint and syndesmotic complex were evaluated. The ankle joint cartilage was denuded to subchondral bone. The fibula was surgically modified with three progressing procedures including an oblique fibula osteotomy, 1 cm resection, and distal fibula resection. A transducer was utilized to measure tibiotalar joint force, contact area, and peak pressure values while compressive forces of 30 N, 50 N, and 100 N were applied to the proximal tibia/fibula. FINDINGS: Distal fibula resection significantly increased tibiotalar joint force, contact area, and peak pressure the most of all fibula conditions tested compared to intact fibula control (p < .05). Tibiotalar joint force and peak pressures were significantly increased with a distal fibula oblique osteotomy, 1 cm resection, and complete resection under both 30 and 50 N applied compressive force (p < .05). INTERPRETATION: Complete distal fibular resection results in higher tibiotalar joint force, contact area, and peak pressure which may improve clinical rates of successful ankle fusion.

Diagnostic Criteria and Treatment of Acute and Chronic Periprosthetic Joint Infection of Total Ankle Arthroplasty.

BACKGROUND: Prosthetic joint infection (PJI) after total ankle arthroplasty (TAA) is a serious complication that results in significant consequences to the patient and threatens the survival of the ankle replacement. PJI in TAA may require debridement, placement of antibiotic spacer, revision arthroplasty, conversion to arthrodesis, or potentially below the knee amputation. While the practice of TAA has gained popularity in recent years, there is some minimal data regarding wound complications in acute or chronic PJI of TAA. However, of the limited studies that describe complications of PJI of TAA, even fewer studies describe the criteria used in diagnosing PJI. This review will cover the current available literature regarding total ankle arthroplasty infection and will propose a model for treatment options for acute and chronic PJI in TAA. METHODS: A review of the current literature was conducted to identify clinical investigations in which prosthetic joint infections occurred in total ankle arthroplasty with associated clinical findings, radiographic imaging, and functional outcomes. The electronic databases for all peer-reviewed published works available through January 31, 2018, of the Cochrane Library, PubMed MEDLINE, and Google Scholar were explored using the following search terms and Boolean operators: "total ankle replacement" OR "total ankle arthroplasty" AND "periprosthetic joint infection" AND "diagnosis" OR "diagnostic criteria." An article was considered eligible for inclusion if it concerned diagnostic criteria of acute or chronic periprosthetic joint infection of total ankle arthroplasty regardless of the number of patients treated, type of TAA utilized, conclusion, or level of evidence of study. RESULTS: No studies were found in the review of the literature describing criteria for diagnosing PJI specific to TAA. CONCLUSIONS: Literature describing the diagnosis and treatment of PJI in TAA is entirely reliant on the literature surrounding knee and hip arthroplasty. Because of the limited volume of total ankle arthroplasty in comparison to knee and hip arthroplasty, no studies to our knowledge exist describing diagnostic criteria specific to total ankle arthroplasty with associated reliability. Large multicenter trials may be required to obtain the volume necessary to accurately describe diagnostic criteria of PJI specific to TAA. LEVEL OF EVIDENCE: Level III, systematic review.

High-Frequency Irreversible Electroporation for Intracranial Meningioma: A Feasibility Study in a Spontaneous Canine Tumor Model.

High-frequency irreversible electroporation is a nonthermal method of tissue ablation that uses bursts of 0.5- to 2.0-microsecond bipolar electric pulses to permeabilize cell membranes and induce cell death. High-frequency irreversible electroporation has potential advantages for use in neurosurgery, including the ability to deliver pulses without inducing muscle contraction, inherent selectivity against malignant cells, and the capability of simultaneously opening the blood-brain barrier surrounding regions of ablation. Our objective was to determine whether high-frequency irreversible electroporation pulses capable of tumor ablation could be delivered to dogs with intracranial meningiomas. Three dogs with intracranial meningiomas were treated. Patient-specific treatment plans were generated using magnetic resonance imaging-based tissue segmentation, volumetric meshing, and finite element modeling. Following tumor biopsy, high-frequency irreversible electroporation pulses were stereotactically delivered in situ followed by tumor resection and morphologic and volumetric assessments of ablations. Clinical evaluations of treatment included pre- and posttreatment clinical, laboratory, and magnetic resonance imaging examinations and adverse event monitoring for 2 weeks posttreatment. High-frequency irreversible electroporation pulses were administered successfully in all patients. No adverse events directly attributable to high-frequency irreversible electroporation were observed. Individual ablations resulted in volumes of tumor necrosis ranging from 0.25 to 1.29 cm3. In one dog, nonuniform ablations were observed, with viable tumor cells remaining around foci of intratumoral mineralization. In conclusion, high-frequency irreversible electroporation pulses can be delivered to brain tumors, including areas adjacent to critical vasculature, and are capable of producing clinically relevant volumes of tumor ablation. Mineralization may complicate achievement of complete tumor ablation.

Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery.

Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet's sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using » dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.

Avoiding nerve stimulation in irreversible electroporation: a numerical modeling study.

Electroporation based treatments consist in applying one or multiple high voltage pulses to the tissues to be treated. As an undesired side effect, these pulses cause electrical stimulation of excitable tissues such as nerves and muscles. This increases the complexity of the treatments and may pose a risk to the patient. To minimize electrical stimulation during electroporation based treatments, it has been proposed to replace the commonly used monopolar pulses by bursts of short bipolar pulses. In the present study, we have numerically analyzed the rationale for such approach. We have compared different pulsing protocols in terms of their electroporation efficacy and their capability of triggering action potentials in nerves. For that, we have developed a modeling framework that combines numerical models of nerve fibers and experimental data on irreversible electroporation. Our results indicate that, by replacing the conventional relatively long monopolar pulses by bursts of short bipolar pulses, it is possible to ablate a large tissue region without triggering action potentials in a nearby nerve. Our models indicate that this is possible because, as the pulse length of these bipolar pulses is reduced, the stimulation thresholds raise faster than the irreversible electroporation thresholds. We propose that this different dependence on the pulse length is due to the fact that transmembrane charging for nerve fibers is much slower than that of cells treated by electroporation because of their geometrical differences.

An evaluation of the sonoporation potential of low-boiling point phase-change ultrasound contrast agents in vitro.

BACKGROUND: Phase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. As a first step towards the goal of extravascular cell permeabilization, we aim to characterize the sonoporation potential of a low-boiling point formulation of PCCAs in vitro. METHODS: Parameters to induce acoustic droplet vaporization and subsequent microbubble cavitation were optimized in vitro using high-speed optical microscopy. Sonoporation of pancreatic cancer cells in suspension was then characterized at a range of pressures (125-600 kPa) and pulse lengths (5-50 cycles) using propidium iodide as an indicator molecule. RESULTS: We achieved sonoporation efficiencies ranging from 8 ± 1% to 36 ± 4% (percent of viable cells), as evidenced by flow cytometry. Increasing sonoporation efficiency trended with increasing pulse length and peak negative pressure. CONCLUSIONS: We conclude that PCCAs can be used to induce the sonoporation of cells in vitro, and our results warrant further investigation into the use of PCCAs as extravascular sonoporation agents in vivo.

An evaluation of irreversible electroporation thresholds in human prostate cancer and potential correlations to physiological measurements.

Irreversible electroporation (IRE) is an emerging cancer treatment that utilizes non-thermal electric pulses for tumor ablation. The pulses are delivered through minimally invasive needle electrodes inserted into the target tissue and lead to cell death through the creation of nanoscale membrane defects. IRE has been shown to be safe and effective when performed on tumors in the brain, liver, kidneys, pancreas, and prostate that are located near critical blood vessels and nerves. Accurate treatment planning and prediction of the ablation volume require a priori knowledge of the tissue-specific electric field threshold for cell death. This study addresses the challenge of defining an electric field threshold for human prostate cancer tissue. Three-dimensional reconstructions of the ablation volumes were created from one week post-treatment magnetic resonance imaging (MRIs) of ten patients who completed a clinical trial. The ablation volumes were incorporated into a finite element modeling software that was used to simulate patient-specific treatments, and the electric field threshold was calculated by matching the ablation volume to the field contour encompassing the equivalent volume. Solutions were obtained for static tissue electrical properties and dynamic properties that accounted for electroporation. According to the dynamic model, the electric field threshold was 506 ± 66 V/cm. Additionally, a potentially strong correlation (r = -0.624) was discovered between the electric field threshold and pre-treatment prostate-specific antigen levels, which needs to be validated in higher enrollment studies. Taken together, these findings can be used to guide the development of future IRE protocols.

Mini-open Subpectoral Biceps Tenodesis Using a Suture Anchor.

The long head of the biceps (LHB) tendon is a potential source of shoulder pain encountered by orthopaedic surgeons. A multitude of approaches to addressing LHB tendinopathy have been described. These include various surgical techniques such as tenodesis versus tenotomy, an arthroscopic versus an open approach, and differing methods of tenodesis fixation. Our preferred approach to addressing LHB tendinopathy is through a mini-open approach using a double-loaded 4.5-mm suture anchor. This Technical Note with accompanying video describes our technique for performing this procedure, as well as supporting clinical evidence and technical pearls.