NextLens-The Next Generation of Surgical Navigation: Proof of Concept of an Augmented Reality System for Surgical Navigation.

Objective The aim of this work was the development of an augmented reality system including the functionality of conventional surgical navigation systems. Methods An application software for the Augmented Reality System HoloLens 2 from Microsoft was developed. It detects the position of the patient as well as position of surgical instruments in real time and displays it within the two-dimensional (2D) magnetic resonance imaging or computed tomography (CT) images. The surgical pointer instrument, including a pattern that is recognized by the HoloLens 2 sensors, was created with three-dimensional (3D) printing. The technical concept was demonstrated at a cadaver skull to identify anatomical landmarks. Results With the help of the HoloLens 2 and its sensors, the real-time position of the surgical pointer instrument could be shown. The position of the 3D-printed pointer with colored pattern could be recognized within 2D-CT images when stationary and in motion at a cadaver skull. Feasibility could be demonstrated for the clinical application of transsphenoidal pituitary surgery. Conclusion The HoloLens 2 has a high potential for use as a surgical navigation system. With subsequent studies, a further accuracy evaluation will be performed receiving valid data for comparison with conventional surgical navigation systems. In addition to transsphenoidal pituitary surgery, it could be also applied for other surgical disciplines.

Analysis of the Technical Accuracy of a Patient-Specific Stereotaxy Platform for Brain Biopsy.

The use of stereotactic frames is a common practice in neurosurgical interventions such as brain biopsy and deep brain stimulation. However, conventional stereotactic frames have been shown to require modification and adaptation regarding patient and surgeon comfort as well as the increasing demand for individualized medical treatment. To meet these requirements for carrying out state-of-the-art neurosurgery, a 3D print-based, patient-specific stereotactic system was developed and examined for technical accuracy. Sixteen patient-specific frames, each with two target points, were additively manufactured from PA12 using the Multi Jet Fusion process. The 32 target points aim to maximize the variability of biopsy targets and depths for tissue sample retrieval in the brain. Following manufacturing, the frames were measured three-dimensionally using an optical scanner. The frames underwent an autoclave sterilization process prior to rescanning. The scan-generated models were compared with the planned CAD models and the deviation of the planned target points in the XY-plane, Z-direction and in the resulting direction were determined. Significantly lower (p < 0.01) deviations were observed when comparing CAD vs. print and print vs. sterile in the Z-direction (0.17 mm and 0.06 mm, respectively) than in the XY-plane (0.46 mm and 0.16 mm, respectively). The resulting target point deviation (0.51 mm) and the XY-plane (0.46 mm) are significantly higher (p < 0.01) in the CAD vs. print comparison than in the print vs. sterile comparison (0.18 mm and 0.16 mm, respectively). On average, the results from the 32 target positions examined exceeded the clinically required accuracy for a brain biopsy (2 mm) by more than four times. The patient-specific stereotaxic frames meet the requirements of modern neurosurgical navigation and make no compromises when it comes to accuracy. In addition, the material is suitable for autoclave sterilization due to resistance to distortion.

Mixed reality for spine surgery: a step into the future with a human cadaveric accuracy study.

OBJECTIVE: Current application of mixed reality as a navigation aid in the field of spinal navigation points to the potential of this technology in spine surgery. Crucial factors for acceptance include intuitive workflow, system stability, reliability, and accuracy of the method. The authors therefore aimed to investigate the accuracy of the system in visualization of anatomical structures using mixed reality in the example of pedicles of the thoracic spine in a human cadaveric study. Potential difficulties and limitations are discussed. METHODS: CT scans of a human cadaveric spinal column specimen were performed. After segmentation and import into the advanced HoloLens 2 software, the vertebrae were exposed. The vertebral arches were preserved on one side for a landmark-based surface registration, whereas pedicles were exposed on the other side in order to measure and evaluate deviation of the overlay holographs with regard to the exact anatomical structure. Accuracy was measured and statistically evaluated. RESULTS: In this work it was demonstrated that the overlay of the virtual 3D model pedicles with the real anatomical structures with anatomical landmark registration was within an acceptable surgical accuracy with the mean value of 2.1 mm (maximum 3.8 mm, minimum 1.2 mm). The highest accuracy was registered at the medial and lateral pedicle wall, and the measurement results were best in the region of the middle thoracic spine. CONCLUSIONS: The accuracy analysis for mixed reality (i.e., between the virtual and real anatomical situation of the thoracic spine) showed a very good agreement when focus was on the pedicles. This work is thus a rare proof of the precision of segmentation to the potential surgical area. The results encourage researchers to open up mixed reality technology in its development and application for spinal navigation.

A new concept for expansion screws on the cervical spine using shape memory alloy - a feasibility study.

BACKGROUND: In general, sufficient anchoring of screws in the bone material ensures the intended primary stability. METHODS: Shape memory materials offers the option of using temperature-associated deformation energy in a targeted manner in order to do justice to the special situation of osteoporotic bones or the potential lack of anchoring. An expansion screw was developed that takes this possibility and these requirements into account. Using finite element analysis, the variability of screw configuration and actuator was assessed from shape memory. In particular, the dimensioning of the screw slot, the actuator length and the actuator diameter as well as the angle of attack in relation to the intended force development were considered. RESULTS: As a result of the finite element analysis, a special configuration of expansion screw and shape memory element could be found. Accordingly, with an optimal screw diameter of 4 mm, an actuator diameter of 0.8 mm, a screw slot of 7.8 mm in length and an angle of attack of 25 degrees, the best compromise between individual components and high efficiency in favor of maximum strength can be predicted. CONCLUSION: Shape memory material offers the possibility of using completely new forms of power development. By skillfully modifying the mechanical and shape memory elements, their interaction results in a calculated development of force in favor of a high primary stability of the screw material used. Activation by means of body temperature is a very elegant way of initializing the intended locking and screw strength.

3D-printing of the elbow in complex posttraumatic elbow-stiffness for preoperative planning, surgery-simulation and postoperative control.

BACKGROUND: Restoration of mobility of the elbow after post-traumatic elbow stiffening due to osteophytes is often a problem. METHODS: The anatomical structures were segmented within the CT-scan. Afterwards, the Multi Jet Fusion 3D-printing was applied to create the model made of biocompatible and steam-sterilizable plastic. Preoperative simulation of osteophyte resection at the 3D-model was performed as well as the direct comparison with the patient anatomy intraoperatively. RESULTS: The patient-specific was very helpful for the preoperative simulation of the resection of elbow osteophytes. The 3D anatomical representation improved the preoperative plan its implementation. A high degree of fidelity was found between the 3D Printed Anatomical representation and the actual joint pathology. CONCLUSIONS: Arthrolysis of complex post-traumatic bony changes is an important indication for the use of 3D models for preoperative planning. Due to the use of 3D printing and software simulation, accurate resection planning is feasible and residual bony stiffening can be avoided. 3D printing models can lead to an improvement in surgical quality.

Case Report: Clinical Use of a Patient-Individual Magnetic Resonance Imaging-Based Stereotactic Navigation Device for Brain Biopsies in Three Dogs.

Three-dimensional (3D) printing techniques for patient-individual medicine has found its way into veterinary neurosurgery. Because of the high accuracy of 3D printed specific neurosurgical navigation devices, it seems to be a safe and reliable option to use patient-individual constructions for sampling brain tissue. Due to the complexity and vulnerability of the brain a particularly precise and safe procedure is required. In a recent cadaver study a better accuracy for the 3D printed MRI-based patient individual stereotactic brain biopsy device for dogs is determined compared to the accuracies of other biopsy systems which are currently used in veterinary medicine. This case report describes the clinical use of this 3D printed MRI-based patient individual brain biopsy device for brain sampling in three dogs. The system was characterized by a simple handling. Furthermore, it was an effective and reliable tool to gain diagnostic brain biopsy samples in dogs with no significant side effects.

Facial Nerve Function After Microsurgical Resection in Vestibular Schwannoma Under Neurophysiological Monitoring.

Background: The use of intraoperative neurophysiological monitoring, including direct nerve stimulation (especially the facial nerve), acoustic evoked potentials (AEP) and somatosensory evoked potentials (SSEP), is a helpful tool in the microsurgery of vestibular schwannoma to prevent nerve injury. Patient characteristics and intraoperative and postoperative variables might also influence the postoperative facial nerve function. The study was performed to investigate these variables and the intraoperative neurophysiological monitoring values. Methods: Seventy-nine patients with vestibular schwannoma were included consecutively into this study. Intraoperative neurophysiological monitoring, including SSEP, AEP, and direct nerve stimulation for facial and trigeminal nerve electromyography, was performed utilizing digital data storage in all cases. The intensity (in volts) of the direct stimulation and the latency (in ms) for the orbicularis oculi and the orbicularis oris muscle and the amplitude (in mV) was measured. Univariate and multivariate statistical analyses concerning the different parameters was performed directly after the operation and in the subsequent follow-ups 3 and 6 months after the operation. Results: The mean intensity was 0.79 V (SD.29). The latency and amplitude for the oris muscle was 5.2 ms (SD 2.07) and 0.68 mV (SD.57), respectively. The mean latency for the occuli muscle was 5.58 ms (SD 2.2) and the amplitude was 0.58 mV (SD 1.04). The univariate and multivariate statistical analyses showed significance concerning the postoperative facial nerve function and the amplitude of the direct stimulation of the facial nerve in the orbicularis oris muscle (p = 0.03), so repeated direct nerve stimulation might show FN function deterioration. The mean diameter of the tumors was 24 mm (range 10-57 mm). Cross total resection and near total was achieved in 76 patients (96%) and subtotal in three patients (4%). The preoperative House-Brakeman score (HBS) 1 was constant in 65 (82%) cases. The mortality in our series was 0%; the overall morbidity was 10%. The HBS was not influenced concerning the extent of resection. The mean follow-up was 28 months (range 6 to 60 months). The limitations of the study might be a low number of patients and the retrospective character of the study. Conclusion: Intraoperative neurophysiological monitoring is crucial in vestibular schwannoma surgery. Repeated direct nerve stimulation and a detected decreased amplitude might show facial nerve function deterioration.

Neurosurgical Care during the COVID-19 Pandemic in Central Germany: A Retrospective Single Center Study of the Second Wave.

The healthcare system has been placed under an enormous burden by the SARS-CoV-2 (COVID-19) pandemic. In addition to the challenge of providing sufficient care for COVID-19 patients, there is also a need to ensure adequate care for non-COVID-19 patients. We investigated neurosurgical care in a university hospital during the pandemic. We examined the second wave of the pandemic from 1 October 2020 to 15 March 2021 in this retrospective single-center study and compared it to a pre-pandemic period from 1 October 2019 to 15 March 2020. Any neurosurgical intervention, along with patient- and treatment-dependent factors, were recorded. We also examined perioperative complications and unplanned readmissions. A statistical comparison of the study groups was performed. We treated 535 patients with a total of 602 neurosurgical surgeries during the pandemic. This compares to 602 patients with 717 surgeries during the pre-pandemic period. There were 67 fewer patients (reduction to 88.87%) admitted and 115 fewer surgeries (reduction to 83.96%) performed, which were essentially highly elective procedures, such as cervical spinal stenosis, intracranial neurinomas, and peripheral nerve lesions. Regarding complication rates and unplanned readmissions, there was no significant difference between the COVID-19 pandemic and the non-pandemic patient group. Operative capacities were slightly reduced to 88% due to the pandemic. Nevertheless, comprehensive emergency and elective care was guaranteed in our university hospital. This speaks for the sufficient resources and high-quality processes that existed even before the pandemic.

A Comparative Study of Automatic Localization Algorithms for Spherical Markers within 3D MRI Data.

Localization of features and structures in images is an important task in medical image-processing. Characteristic structures and features are used in diagnostics and surgery planning for spatial adjustments of the volumetric data, including image registration or localization of bone-anchors and fiducials. Since this task is highly recurrent, a fast, reliable and automated approach without human interaction and parameter adjustment is of high interest. In this paper we propose and compare four image processing pipelines, including algorithms for automatic detection and localization of spherical features within 3D MRI data. We developed a convolution based method as well as algorithms based on connected-components labeling and analysis and the circular Hough-transform. A blob detection related approach, analyzing the Hessian determinant, was examined. Furthermore, we introduce a novel spherical MRI-marker design. In combination with the proposed algorithms and pipelines, this allows the detection and spatial localization, including the direction, of fiducials and bone-anchors.

Striatal dopamine transporter availability and individual clinical course within the 1-year follow-up of deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

OBJECTIVE: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of this study was therefore to evaluate whether 1) DAT availability changes within 1 year of STN-DBS and 2) the clinical outcome can be predicted based on preoperative DAT availability. METHODS: Twenty-seven PD patients (mean age 62.7 ± 8.9 years; mean duration of illness 13.0 ± 4.9 years; PD subtypes: akinetic-rigid, n = 11; equivalence, n = 13; and tremor-dominant, n = 3) underwent [123I]FP-CIT SPECT preoperatively and after 1 year of STN-DBS. DAT availability as determined by the specific binding ratio (SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side. RESULTS: Unified Parkinson's Disease Rating Scale (UPDRS) III scores improved significantly (mean preoperative on medication 25.6 ± 12.3, preoperative off medication 42.3 ± 15.2, postoperative on medication/off stimulation 41.4 ± 13.2, and postoperative on medication/on stimulation 16.1 ± 9.4; preoperative on medication vs postoperative on medication/on stimulation, p = 0.006), while the levodopa-equivalent daily dose was reduced (mean preoperative 957 ± 440 mg vs postoperative 313 ± 189 mg, p < 0.001). The SBR did not differ significantly before and 1 year after DBS, regardless of PD subtype. Preoperative DAT availability was not related to the change in UPDRS III score, but the change in DAT availability was significantly correlated with the change in UPDRS III score (contralateral head of the caudate VOI, p = 0.014; contralateral putamen VOI, p = 0.018). CONCLUSIONS: Overall, DAT availability did not change significantly after 1 year of STN-DBS. However, on an individual basis, the improvement in UPDRS III score was associated with an increase in DAT availability, whereas DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of preoperative DAT availability can become a reliable predictor of successful STN-DBS must be evaluated in larger study cohorts.

Accuracy of a magnetic resonance imaging-based 3D printed stereotactic brain biopsy device in dogs.

BACKGROUND: Brain biopsy of intracranial lesions is often necessary to determine specific therapy. The cost of the currently used stereotactic rigid frame and optical tracking systems for brain biopsy in dogs is often prohibitive or accuracy is not sufficient for all types of lesion. OBJECTIVES: To evaluate the application accuracy of an inexpensive magnetic resonance imaging-based personalized, 3D printed brain biopsy device. ANIMALS: Twenty-two dog heads from cadavers were separated into 2 groups according to body weight (<15 kg, >20 kg). METHODS: Experimental study. Two target points in each cadaver head were used (target point 1: caudate nucleus, target point 2: piriform lobe). Comparison between groups was performed using the independent Student's t test or the nonparametric Mann-Whitney U Test. RESULTS: The total median target point deviation was 0.83 mm (range 0.09-2.76 mm). The separate median target point deviations for target points 1 and 2 in all dogs were 0.57 mm (range: 0.09-1.25 mm) and 0.85 mm (range: 0.14-2.76 mm), respectively. CONCLUSION AND CLINICAL IMPORTANCE: This magnetic resonance imaging-based 3D printed stereotactic brain biopsy device achieved an application accuracy that was better than the accuracy of most brain biopsy systems that are currently used in veterinary medicine. The device can be applied to every size and shape of skull and allows precise positioning of brain biopsy needles in dogs.

Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin >3.5 mg/dL, lymphocyte doubling time (LDT) <12 months, and age >60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P < 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.

Automated Solid-Phase Peptide Synthesis.

The development of solid-phase peptide synthesis by Bruce Merrifield paved the way for a synthesis carried out by machines. Automated peptide synthesis is a fast and convenient way of synthesizing many peptides simultaneously. This chapter tries to give a general guidance for the development of synthesis protocols for the peptide synthesizer. It also provides some suggestions for the modification of the synthesized peptides. Additionally, many examples of possible challenges during and after the synthesis are given in order to support the reader in finding the best synthesis strategy. Numerous references are given to many of the described matters.

SPOT Synthesis: The Solid-Phase Peptide Synthesis on Planar Surfaces.

Peptide libraries are a highly useful tool for drug development. While most preparations of peptide libraries are laborious during either the synthesis or its screening, the SPOT synthesis offers the possibility of directly synthesizing large numbers of peptides on a planar surface. As a positionally addressable, multiple solid-phase synthesis technique, the synthesis allows a very convenient handling during the screening of that peptide library in a form of an array. This publication will provide protocols for the basic procedures of the SPOT synthesis and references to some important literature regarding that technique and its application.

A concept for a 3D-printed patient-specific stereotaxy platform for brain biopsy -a canine cadaver study.

The treatment of intracranial lesions requires a precise diagnosis with subsequent identification of an adequate therapeutic approach. Stereotactic tumor biopsy may be considered the safest neurosurgical procedure in terms of anticipated results and potential surgical complications. The aim of the present paper was to demonstrate a new method of stereotactic biopsy, based on a patient-specific 3D printed platform in dogs. The system was tested on two canine cadavers, a small (Shih Tzu) and a large (Labrador) breed. Imaginary biopsy targets were defined in a superficial (caudate nucleus) and a deep (piriform lobe) position. Based on 3 Tesla MRI, individualized stereotactic platforms were designed using a semi-automatic approach, and manufactured additively using ABS M30. A pre- and intra-operative CT was performed to compare the planned vs. the realized needle position for precision analyses of the procedure. The target points varied with a precision between 0.09 mm and 0.48 mm. Manufacturing time required 480 to 700 min per platform. The presented patient-specific stereotactic system seems a suitable instrument for application in small animal neurosurgery. In particular, the implementation of relevant stereotactic data may help performing the procedure in rapid sequence and with higher precision than currently-used systems. Required adjustments and adaptions to the respective anatomical conditions are omitted and make the procedure reliable and safe.

Subthalamic nucleus volumes are highly consistent but decrease age-dependently-a combined magnetic resonance imaging and stereology approach in humans.

The subthalamic nucleus (STN) is a main target structure of deep brain stimulation (DBS) in idiopathic Parkinson's disease. Nevertheless, there is an ongoing discussion regarding human STN volumes and neuron count, which could potentially have an impact on STN-DBS. Moreover, a suspected functional subdivision forms the basis of the tripartite hypothesis, which has not yet been morphologically substantiated. In this study, it was aimed to investigate the human STN by means of combined magnetic resonance imaging (MRI) and stereology. STN volumes were obtained from 14 individuals (ranging from 65 to 96 years, 25 hemispheres) in 3 T MRI and in luxol-stained histology slices. Neuron number and cell densities were investigated stereologically over the entire STN and in pre-defined subregions in anti-human neuronal protein HuC/D-stained slices. STN volumes measured with MRI were smaller than in stereology but appeared to be highly consistent, measuring on average 99 ± 6 mm3 (MRI) and 132 ± 20 mm3 (stereology). The neuron count was 431,088 ± 72,172. Both STN volumes and cell count decreased age-dependently. Neuron density was different for the dorsal, medial and ventral subregion with significantly higher values ventrally than dorsally. Small variations in STN volumes in both MRI and stereology contradict previous findings of large variations in STN size. Age-dependent decreases in STN volumes and neuron numbers might influence the efficacy of STN-DBS in a geriatric population. Though the study is limited in sample size, site-dependent differences for the STN subregions form a morphological basis for the tripartite theory. Hum Brain Mapp 38:909-922, 2017. © 2016 Wiley Periodicals, Inc.

Determination of the Substrate Specificity of Protein Kinases with Peptide Micro- and Macroarrays.

Elucidation of the key determinants for the phosphorylation site specificities of protein kinases facilitates identification of their physiological substrates, and serves to better define their critical roles in the signaling networks that underlie a multitude of cellular activities. Albeit with some apparent limitations, such as the lack of contextual information for secondary substrate-binding sites, the synthetic peptide-based approach has been adopted widely for the kinase specificity profiling studies, especially when they are used in an array format, which permits the screening of large numbers of potential peptide substrates in parallel. In this chapter, we present detailed protocols for determining protein kinase substrate specificity using an approach that involves both peptide microarrays and macroarrays. In particular, SPOT synthesis on macroarrays can be used to follow up on in silico predictions of protein kinase substrate specificity with predictive algorithms.

A comparison of two surgical approaches in functional neurosurgery: individualized versus conventional stereotactic frames.

OBJECT: The individualized Starfix® miniframe belongs to a new generation of stereotactic systems enabling high-precision electrode placement with considerably better time-efficiency in deep brain stimulation (DBS). We evaluated the usability and reliability of this novel technique in patients with idiopathic Parkinson's disease (IPD) and compared surgical and clinical results with those obtained in a historical group in which a conventional stereotactic frame was employed. METHODS: Sixty patients underwent surgery for implantation of DBS electrodes in the subthalamic nucleus. In 31 of them (group I) a conventional Zamorano-Dujovny frame was used and in 29 of them (group II) a Starfix® miniframe was used. Image fusion of preoperatively acquired 3D T1w and T2w 1.5 T MR-image series was used for the targeting procedure. Placement of the test electrodes and permanent electrodes corresponded to standard functional neurosurgery and included microelectrode recording and macrostimulation. Clinical (L-Dopa equivalent dose, United Parkinson's disease rating scale part III) and time for surgical electrode implantation were evaluated postoperatively in a 3-, 6- and 12-month follow-up. RESULTS: Twelve months postoperatively, L-Dopa dose was significantly reduced from 685.19 to 205.88 mg/day and from 757.92 to 314.42 mg/day in groups I and II, respectively. A comparable reduction of the LED could be observed 1 year after surgery. Motor function has improved in a significant and identical manner with 59% (group I) and 61% (group II). Besides clinical effects by stimulation therapy there was a significantly reduced surgery time required for electrode implantation using the Starfix® miniframe (group I: 234.1 min, group II: 173.6 min; p < 0.001). CONCLUSIONS: Individualized miniframes such as the Starfix® miniframe allow implantation of DBS electrodes in IPD that is equally effective as conventional systems. The time efficiency achieved in surgery using of the Starfix® system helps to minimize patients' discomfort during DBS surgery.

Investigation of the automated solid-phase synthesis of a 38mer peptide with difficult sequence pattern under different synthesis strategies.

Difficult peptides are a constant challenge in solid-phase peptide synthesis. In particular, hydroxyl amino acids such as serine can cause severe breakdowns in coupling yields even several amino acids after the insertion of the critical amino acid. This paper investigates several methods of improving synthesis yields of difficult peptides including the use of different resins, activators and the incorporation of a structure-breaking pseudoproline dipeptide building block both alone and in combination with each other.