Switching fatty acid metabolism by an RNA-controlled feed forward loop.

Hfq (host factor for phage Q beta) is key for posttranscriptional gene regulation in many bacteria. Hfq's function is to stabilize sRNAs and to facilitate base-pairing with trans-encoded target mRNAs. Loss of Hfq typically results in pleiotropic phenotypes, and, in the major human pathogen Vibrio cholerae, Hfq inactivation has been linked to reduced virulence, failure to produce biofilms, and impaired intercellular communication. However, the RNA ligands of Hfq in V. cholerae are currently unknown. Here, we used RIP-seq (RNA immunoprecipitation followed by high-throughput sequencing) analysis to identify Hfq-bound RNAs in V. cholerae Our work revealed 603 coding and 85 noncoding transcripts associated with Hfq, including 44 sRNAs originating from the 3' end of mRNAs. Detailed investigation of one of these latter transcripts, named FarS (fatty acid regulated sRNA), showed that this sRNA is produced by RNase E-mediated maturation of the fabB 3'UTR, and, together with Hfq, inhibits the expression of two paralogous fadE mRNAs. The fabB and fadE genes are antagonistically regulated by the major fatty acid transcription factor, FadR, and we show that, together, FadR, FarS, and FadE constitute a mixed feed-forward loop regulating the transition between fatty acid biosynthesis and degradation in V. cholerae Our results provide the molecular basis for studies on Hfq in V. cholerae and highlight the importance of a previously unrecognized sRNA for fatty acid metabolism in this major human pathogen.

Evaluation of a New Virtual Reality Concept Teaching K-Wire Drilling With Force Feedback Simulated Haptic in Orthopedic Skills Training.

PURPOSE: Surgical simulations are becoming increasingly relevant in musculoskeletal training. They provide the opportunity to develop surgical skills in a controlled environment while reducing the risks for patients. For K-wire internal fixation in musculoskeletal surgery, a force feedback virtual reality (VR) simulator was developed. The aim of this study was to evaluate training results using this technology and compare the results with that of standard teaching on cadavers. METHODS: Twenty participants attending an AO Trauma Course during 2020 were randomly allocated in 2 groups. On day 1, group A was trained by senior surgeons using a cadaver and group B was trained by the VR simulator for K-wire insertion in the distal radius. On day 2, all participants performed K-wire insertion on the cadaver model, without assistance, to validate the training effect. RESULTS: On a surgical skills test, group B performed better than group A. In group B, the entry point of the first K-wire was closer to the targeted styloid process of the radius, and the protrusion of the K-wires into soft tissue was less than that in group A. CONCLUSIONS: Training with the VR simulator for K-wire insertion resulted in better surgical skills than training by a surgeon and cadaver model. CLINICAL RELEVANCE: Training with the VR simulator provides the opportunity to improve and refine surgical skills without the risk of harming patients. It offers easier access, unlimited repetitions, and is more cost-effective compared with training sessions with cadavers.

3D analysis of Osteosyntheses material using semi-automated CT segmentation: a case series of a 4 corner fusion plate.

BACKROUND: Scaphoidectomy and midcarpal fusion can be performed using traditional fixation methods like K-wires, staples, screws or different dorsal (non)locking arthrodesis systems. The aim of this study is to test the Aptus four corner locking plate and to compare the clinical findings to the data revealed by CT scans and semi-automated segmentation. METHODS: This is a retrospective review of eleven patients suffering from scapholunate advanced collapse (SLAC) or scaphoid non-union advanced collapse (SNAC) wrist, who received a four corner fusion between August 2011 and July 2014. The clinical evaluation consisted of measuring the range of motion (ROM), strength and pain on a visual analogue scale (VAS). Additionally, the Disabilities of the Arm, Shoulder and Hand (QuickDASH) and the Mayo Wrist Score were assessed. A computerized tomography (CT) of the wrist was obtained six weeks postoperatively. After semi-automated segmentation of the CT scans, the models were post processed and surveyed. RESULTS: During the six-month follow-up mean range of motion (ROM) of the operated wrist was 60°, consisting of 30° extension and 30° flexion. While pain levels decreased significantly, 54% of grip strength and 89% of pinch strength were preserved compared to the contralateral healthy wrist. Union could be detected in all CT scans of the wrist. While X-ray pictures obtained postoperatively revealed no pathology, two user related technical complications were found through the 3D analysis, which correlated to the clinical outcome. CONCLUSION: Due to semi-automated segmentation and 3D analysis it has been proved that the plate design can keep up to the manufacturers' promises. Over all, this case series confirmed that the plate can compete with the coexisting techniques concerning clinical outcome, union and complication rate.

uPAR enhances malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R.

BACKGROUND: Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets. METHODS: Direct interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n = 174). RESULTS: Direct tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p = 0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p = 0.0019) as well as with cathepsin B and D (p ≤ 0.0001) that are implicated in cell invasion and metastasis. CONCLUSIONS: Our outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC.

Effects on the Distal Radioulnar Joint of Ablation of Triangular Fibrocartilage Complex Tears With Radiofrequency Energy.

PURPOSE: This cadaver study investigated the temperature profile in the wrist joint and distal radioulnar joint (DRUJ) during radiofrequency energy (RFE) application for triangular fibrocartilage complex resection. METHODS: An arthroscopic partial resection of the triangular fibrocartilage complex using monopolar and bipolar RFE was simulated in 14 cadaver limbs. The temperature was recorded simultaneously in the DRUJ and at 6 other anatomic locations of the wrist during RFE application. RESULTS: The mean temperature in the DRUJ was 43.3 ± 8.2°C for the bipolar system in the ablation mode (60 W) and 30.4 ± 3.4°C for the monopolar system in the cut mode (20 W) after 30 seconds. The highest measured temperature in the DRUJ was 54.3°C for the bipolar system and 68.1°C for the monopolar system. CONCLUSIONS: The application of RFE for debridement or resection of the triangular fibrocartilage complex in a clinical setting can induce peak temperatures that might cause damage to the cartilage of the DRUJ. Bipolar systems produce higher mean temperatures than monopolar devices. CLINICAL RELEVANCE: RFE application increases the mean temperature in the DRUJ after 30 seconds to a level that may jeopardize cartilage tissue.

RFE based chondroplasty in wrist arthroscopy indicates high risk for chrondocytes especially for the bipolar application.

BACKGROUND: The application of radiofrequency energy (RFE) has become widespread for surgical performed chondroplasty especially due to the anticipated sealing effect, however the safety of this procedure in the wrist remains unclear. The purpose of this study was to investigate the subchondral temperature during radiofrequency energy (RFE) application simulating chondroplasty in an arthroscopic setting of the wrist. METHODS: A chondroplasty of the lunate fossa was performed during an arthroscopy setting on 14 cadaver arms using monopolar or bipolar RFE. The temperature was recorded simultaneously from 7 predefined anatomical landmarks. RESULTS: The mean temperature for both application modes did not exceed more than 30°C at all measured points, except for the lunate fossa. The highest subchondral measured peak temperature was 49.35°C (monopolar) and 69.21°C (bipolar) in the lunate fossa. In addition, the temperature decreased for both radiofrequency (RF) devices depending on the distance of the sensors to the RF-probe. CONCLUSION: It remains to be questionable how safe RFE can be used for chondroplasty in wrist arthroscopy under continuous irrigation and constant movement to obtain the desired sealing effect. However, the bipolar device should be applied with more caution since peak temperature in the lunate fossa almost reached 70°C even under continuous irrigation.

Temperature in and around the scapholunate ligament during radiofrequency shrinkage: a cadaver study.

PURPOSE: To investigate whether applied radiofrequency energy (RFE) for shrinkage of the scapholunate interosseus ligament reaches temperatures required for ligament shrinkage while leaving adjacent structures unaffected. METHODS: Standard wrist arthroscopy was performed on 7 pairs of cadaveric limbs with continuous saline irrigation and gravity-assisted outflow through an 18-gauge needle. We subjected 14 scapholunate ligaments to treatment with monopolar (n = 7) or bipolar (n = 7) RFE for ligament shrinkage. Temperature was recorded simultaneously inside the dorsal part of the scapholunate interosseus ligament at a depth of 0.9 ± 0.1 mm and at 6 other sites in and around the wrist because thermal shrinkage starts at 60°C to 65°C. RESULTS: We observed an increase in temperature corresponding to the time of energy application. The highest measured peak temperatures at the scapholunate ligament were 43°C (monopolar) and 32°C (bipolar). Mean temperatures at 30 seconds of application were 29°C ± 7°C (monopolar) and 28°C ± 3°C (bipolar). CONCLUSIONS: Temperatures sufficiently high to induce ligament shrinkage were not reached with either monopolar or bipolar RFE. We did not monitor temperature levels responsible for damage on adjacent cartilage or immediately adjacent capsular tissue in this setting. CLINICAL RELEVANCE: This study suggests that RFE for capsular shrinkage in the wrist is safe but ineffective.

Genome-wide profiling of Hfq-bound RNAs reveals the iron-responsive small RNA RusT in Caulobacter crescentus.

The alphaproteobacterium Caulobacter crescentus thrives in oligotrophic environments and is able to optimally exploit minimal resources by entertaining an intricate network of gene expression control mechanisms. Numerous transcriptional activators and repressors have been reported to contribute to these processes, but only few studies have focused on regulation at the post-transcriptional level in C. crescentus. Small RNAs (sRNAs) are a prominent class of regulators of bacterial gene expression, and most sRNAs characterized today engage in direct base-pairing interactions to modulate the translation and/or stability of target mRNAs. In many cases, the ubiquitous RNA chaperone, Hfq, contributes to the establishment of RNA-RNA interactions. Although the deletion of the hfq gene is associated with a severe loss of fitness in C. crescentus, the RNA ligands of the chaperone have remained largely unexplored. Here we report on the identification of coding and non-coding transcripts associated with Hfq in C. crescentus and demonstrate Hfq-dependent post-transcriptional regulation in this organism. We show that the Hfq-bound sRNA RusT is transcriptionally controlled by the NtrYX two-component system and induced in response to iron starvation. By combining RusT pulse expression with whole-genome transcriptome analysis, we determine 16 candidate target transcripts that are deregulated, many of which encode outer membrane transporters. We hence suggest RusT to support remodeling of the C. crescentus cell surface when iron supplies are limited.IMPORTANCEThe conserved RNA-binding protein Hfq contributes significantly to the adaptation of bacteria to different environmental conditions. Hfq not only stabilizes associated sRNAs but also promotes inter-molecular base-pairing interactions with target transcripts. Hfq plays a pivotal role for growth and survival, controlling central metabolism and cell wall synthesis in the oligotroph Caulobacter crescentus. However, direct evidence for Hfq-dependent post-transcriptional regulation and potential oligotrophy in C. crescentus has been lacking. Here, we identified sRNAs and mRNAs associated with Hfq in vivo, and demonstrated the requirement of Hfq for sRNA-mediated regulation, particularly of outer membrane transporters in C. crescentus.

Temperature profile of radiofrequency probe application in wrist arthroscopy: monopolar versus bipolar.

PURPOSE: The purpose of this study was to investigate the changes in temperature during wrist arthroscopy comparing monopolar and bipolar radiofrequency energy (RFE). METHODS: A standard wrist arthroscopy was performed on 14 arms of 7 cadavers without irrigation or with continuous irrigation with 0.9% saline solution and gravity-assisted outflow through an 18-gauge needle. We treated 7 wrists with a bipolar device (VAPR II with 2.3-mm side effect electrodes; DePuy Mitek, Westwood, MA) and 7 wrists with a monopolar device (OPES Ablator for small joints, 45°; Arthrex, Naples, FL). The temperature was recorded simultaneously from 7 predefined anatomic landmarks. RESULTS: We observed an increase in the temperature corresponding to the time of energy application. The highest measured peak temperatures were 52°C (monopolar) and 49.5°C (bipolar) without irrigation. Continuous irrigation led to a significant reduction in the temperature at the site of the energy application. The mean temperature decreased by 7°C for the monopolar system and 5°C for the bipolar system when irrigation was used. For both radiofrequency devices, we found a decrease in the temperature proportional to the distance of the sensors to the radiofrequency probe. CONCLUSIONS: Monopolar and bipolar RFE can be safely used in wrist arthroscopy if a continuous irrigation system is applied and the energy impulse does not exceed 5 to 10 seconds. However, it should be used with great care to avoid local heat damage especially at the cartilage. CLINICAL RELEVANCE: This basic science study was performed to gain data concerning the temperature in wrist arthroscopy and to broaden the knowledge about the risks when using RFE. Furthermore, we sought to control side effects of RFE by finding the best applied form of RFE regarding duration and pulsation (monopolar/bipolar).

An RNA sponge controls quorum sensing dynamics and biofilm formation in Vibrio cholerae.

Small regulatory RNAs (sRNAs) acting in concert with the RNA chaperone Hfq are prevalent in many bacteria and typically act by base-pairing with multiple target transcripts. In the human pathogen Vibrio cholerae, sRNAs play roles in various processes including antibiotic tolerance, competence, and quorum sensing (QS). Here, we use RIL-seq (RNA-interaction-by-ligation-and-sequencing) to identify Hfq-interacting sRNAs and their targets in V. cholerae. We find hundreds of sRNA-mRNA interactions, as well as RNA duplexes formed between two sRNA regulators. Further analysis of these duplexes identifies an RNA sponge, termed QrrX, that base-pairs with and inactivates the Qrr1-4 sRNAs, which are known to modulate the QS pathway. Transcription of qrrX is activated by QrrT, a previously uncharacterized LysR-type transcriptional regulator. Our results indicate that QrrX and QrrT are required for rapid conversion from individual to community behaviours in V. cholerae.

Towards maximum acceleration of monoclonal antibody development: Leveraging transposase-mediated cell line generation to enable GMP manufacturing within 3 months using a stable pool.

In recent years, acceleration of development timelines has become a major focus within the biopharmaceutical industry to bring innovative therapies faster to patients. However, in order to address a high unmet medical need even faster further acceleration potential has to be identified to transform "speed-to-clinic" concepts into "warp-speed" development programs. Recombinant Chinese hamster ovary (CHO) cell lines are the predominant expression system for monoclonal antibodies (mAbs) and are routinely generated by random transgene integration (RTI) of the genetic information into the host cell genome. This process, however, exhibits considerable challenges such as the requirement for a time-consuming clone screening process to identify a suitable clonally derived manufacturing cell line. Hence, RTI represents an error prone and tedious method leading to long development timelines until availability of Good Manufacturing Practice (GMP)-grade drug substance (DS). Transposase-mediated semi-targeted transgene integration (STI) has been recently identified as a promising alternative to RTI as it allows for a more rapid generation of high-performing and stable production cell lines. In this report, we demonstrate how a STI technology was leveraged to develop a very robust DS manufacturing process based on a stable pool cell line at unprecedented pace. Application of the novel strategy resulted in the manufacturing of GMP-grade DS at 2,000 L scale in less than three months paving the way for a start of Phase I clinical trials only six months after transfection. Finally, using a clonally derived production cell line, which was established from the parental stable pool, we were able to successfully implement a process with an increased mAb titer of up to 5 g per liter at the envisioned commercial scale (12,000 L) within eight months.

[Tumors and tumor-like lesions of the foot and ankle - a retrospective analysis of 22 years]. / Tumore und tumorsimulierende Läsionen am Fuss und Sprunggelenk - eine retrospektive Analyse aus 22 Jahren.

Musculoskeletal tumors are rare, with approximately 1% of all malignancies. Only 4% are localized at the foot and ankle. Because of this fact, tumors are often overlooked or even misdiagnosed. During a period of 22 years, 75 tumors (from a total of 1452) were localized at the foot and ankle. Retrospectively, we analyzed the anatomic location of the tumors, the patient's age at the date of diagnosis, and the therapy. Eighteen of 75 tumor cases were malignant, seven cases were with a malignant bone tumor, and 11 cases were with a malignant soft tissue tumor. The most important precondition is a faithful implementation of diagnostic and therapeutic guidelines when treating musculoskeletal tumors. Primary malignant tumors require a wide or radical surgical resection. Whether limb-keeping or ablative procedures should be used also depends on the anatomic location of the tumor, the expectations of the patient, and the functional demands of patients.

Optically tracked and 3D printed haptic phantom hand for surgical training system.

BACKGROUND: For surgical fixation of bone fractures of the human hand, so-called Kirschner-wires (K-wires) are drilled through bone fragments. Due to the minimally invasive drilling procedures without a view of risk structures like vessels and nerves, a thorough training of young surgeons is necessary. For the development of a virtual reality (VR) based training system, a three-dimensional (3D) printed phantom hand is required. To ensure an intuitive operation, this phantom hand has to be realistic in both, its position relative to the driller as well as in its haptic features. The softest 3D printing material available on the market, however, is too hard to imitate human soft tissue. Therefore, a support-material (SUP) filled metamaterial is used to soften the raw material. Realistic haptic features are important to palpate protrusions of the bone to determine the drilling starting point and angle. An optical real-time tracking is used to transfer position and rotation to the training system. METHODS: A metamaterial already developed in previous work is further improved by use of a new unit cell. Thus, the amount of SUP within the volume can be increased and the tissue is softened further. In addition, the human anatomy is transferred to the entire hand model. A subcutaneous fat layer and penetration of air through pores into the volume simulate shiftability of skin layers. For optical tracking, a rotationally symmetrical marker attached to the phantom hand with corresponding reference marker is developed. In order to ensure trouble-free position transmission, various types of marker point applications are tested. RESULTS: Several cuboid and forearm sample prints lead to a final 30 centimeter long hand model. The whole haptic phantom could be printed faultless within about 17 hours. The metamaterial consisting of the new unit cell results in an increased SUP share of 4.32%. Validated by an expert surgeon study, this allows in combination with a displacement of the uppermost skin layer a good palpability of the bones. Tracking of the hand marker in dodecahedron design works trouble-free in conjunction with a reference marker attached to the worktop of the training system. CONCLUSIONS: In this work, an optically tracked and haptically correct phantom hand was developed using dual-material 3D printing, which can be easily integrated into a surgical training system.

Gene autoregulation by 3' UTR-derived bacterial small RNAs.

Negative feedback regulation, that is the ability of a gene to repress its own synthesis, is the most abundant regulatory motif known to biology. Frequently reported for transcriptional regulators, negative feedback control relies on binding of a transcription factor to its own promoter. Here, we report a novel mechanism for gene autoregulation in bacteria relying on small regulatory RNA (sRNA) and the major endoribonuclease, RNase E. TIER-seq analysis (transiently-inactivating-an-endoribonuclease-followed-by-RNA-seq) revealed ~25,000 RNase E-dependent cleavage sites in Vibrio cholerae, several of which resulted in the accumulation of stable sRNAs. Focusing on two examples, OppZ and CarZ, we discovered that these sRNAs are processed from the 3' untranslated region (3' UTR) of the oppABCDF and carAB operons, respectively, and base-pair with their own transcripts to inhibit translation. For OppZ, this process also triggers Rho-dependent transcription termination. Our data show that sRNAs from 3' UTRs serve as autoregulatory elements allowing negative feedback control at the post-transcriptional level.

Quantitative Analysis of Surface Contouring with Pulsed Bipolar Radiofrequency on Thin Chondromalacic Cartilage.

The purpose of this study was to evaluate the quality of surface contouring of chondromalacic cartilage by bipolar radio frequency energy using different treatment patterns in an animal model, as well as examining the impact of the treatment onto chondrocyte viability by two different methods. Our experiments were conducted on 36 fresh osteochondral sections from the tibia plateau of slaughtered 6-month-old pigs, where the thickness of the cartilage is similar to that of human wrist cartilage. An area of 1 cm2 was first treated with emery paper to simulate the chondromalacic cartilage. Then, the treatment with RFE followed in 6 different patterns. The osteochondral sections were assessed for cellular viability (live/dead assay, caspase (cell apoptosis marker) staining, and quantitative analysed images obtained by fluorescent microscopy). For a quantitative characterization of none or treated cartilage surfaces, various roughness parameters were measured using confocal laser scanning microscopy (Olympus LEXT OLS 4000 3D). To describe the roughness, the Root-Mean-Square parameter (Sq) was calculated. A smoothing effect of the cartilage surface was detectable upon each pattern of RFE treatment. The Sq for native cartilage was Sq = 3.8 ± 1.1 µm. The best smoothing pattern was seen for two RFE passes and a 2-second pulsed mode (B2p2) with an Sq = 27.3 ± 4.9 µm. However, with increased smoothing, an augmentation in chondrocyte death up to 95% was detected. Using bipolar RFE treatment in arthroscopy for small joints like the wrist or MCP joints should be used with caution. In the case of chondroplasty, there is a high chance to destroy the joint cartilage.

Symbiosis, virulence and natural-product biosynthesis in entomopathogenic bacteria are regulated by a small RNA.

Photorhabdus and Xenorhabdus species have mutualistic associations with nematodes and an entomopathogenic stage1,2 in their life cycles. In both stages, numerous specialized metabolites are produced that have roles in symbiosis and virulence3,4. Although regulators have been implicated in the regulation of these specialized metabolites3,4, how small regulatory RNAs (sRNAs) are involved in this process is not clear. Here, we show that the Hfq-dependent sRNA, ArcZ, is required for specialized metabolite production in Photorhabdus and Xenorhabdus. We discovered that ArcZ directly base-pairs with the mRNA encoding HexA, which represses the expression of specialized metabolite gene clusters. In addition to specialized metabolite genes, we show that the ArcZ regulon affects approximately 15% of all transcripts in Photorhabdus and Xenorhabdus. Thus, the ArcZ sRNA is crucial for specialized metabolite production in Photorhabdus and Xenorhabdus species and could become a useful tool for metabolic engineering and identification of commercially relevant natural products.

Immediacy bias in emotion perception: current emotions seem more intense than previous emotions.

People tend to perceive immediate emotions as more intense than previous emotions. This immediacy bias in emotion perception occurred for exposure to emotional but not neutral stimuli (Study 1), when emotional stimuli were separated by both shorter (2 s; Studies 1 and 2) and longer (20 min; Studies 3, 4, and 5) delays, and for emotional reactions to pictures (Studies 1 and 2), films (Studies 3 and 4), and descriptions of terrorist threats (Study 5). The immediacy bias may be partly caused by immediate emotion's salience, and by the greater availability of information about immediate compared with previous emotion. Consistent with emotional salience, when people experienced new emotions, they perceived previous emotions as less intense than they did initially (Studies 3 and 5)-a change in perception that did not occur when people did not experience a new immediate emotion (Study 2). Consistent with emotional availability, reminding people that information about emotions naturally decays from memory reduced the immediacy bias by making previous emotions seem more intense (Study 4). Discussed are implications for psychological theory and other judgments and behaviors.

Imitating human soft tissue on basis of a dual-material 3D print using a support-filled metamaterial to provide bimanual haptic for a hand surgery training system.

BACKGROUND: Currently, it is common practice to use three-dimensional (3D) printers not only for rapid prototyping in the industry, but also in the medical area to create medical applications for training inexperienced surgeons. In a clinical training simulator for minimally invasive bone drilling to fix hand fractures with Kirschner-wires (K-wires), a 3D-printed hand phantom must not only be geometrically but also haptically correct. Due to a limited view during an operation, surgeons need to perfectly localize underlying risk structures only by feeling of specific bony protrusions of the human hand. METHODS: The goal of this experiment is to imitate human soft tissue with its haptic and elasticity for a realistic hand phantom fabrication, using only a dual-material 3D printer and support-material-filled metamaterial between skin and bone. We present our workflow to generate lattice structures between hard bone and soft skin with iterative cube edge (CE) or cube face (CF) unit cells. Cuboid and finger shaped sample prints with and without inner hard bone in different lattice thickness are constructed and 3D printed. RESULTS: The most elastic available rubber-like material is too firm to imitate soft tissue. By reducing the amount of rubber in the inner volume through support material (SUP), objects become significantly softer. Without metamaterial, after disintegration, the SUP can be shifted through the volume and thus the body loses its original shape. Although the CE design increases the elasticity, it cannot restore the fabric form. In contrast to CE, the CF design increases not only the elasticity but also guarantees a local limitation of the SUP. Therefore, the body retains its shape and internal bones remain in its intended place. Various unit cell sizes, lattice thickening and skin thickness regulate the rubber material and SUP ratio. Test prints with higher SUP and lower rubber material percentage appear softer and vice versa. This was confirmed by an expert surgeon evaluation. Subjects adjudged pure rubber-like material as too firm and samples only filled with SUP or lattice structure in CE design as not suitable for imitating tissue. 3D-printed finger samples in CF design were rated as realistic compared to the haptic of human tissue with a good palpable bone structure. CONCLUSIONS: We developed a new dual-material 3D print technique to imitate soft tissue of the human hand with its haptic properties. Blowy SUP is trapped within a lattice structure to soften rubber-like 3D print material, which makes it possible to reproduce a realistic replica of human hand soft tissue.

Force-feedback assisted and virtual fixtures based K-wire drilling simulation.

One common method to fix fractures of the human hand after an accident is an osteosynthesis with Kirschner wires (K-wires) to stabilize the bone fragments. The insertion of K-wires is a delicate minimally invasive surgery, because surgeons operate almost without a sight. Since realistic training methods are time consuming, costly and insufficient, a virtual-reality (VR) based training system for the placement of K-wires was developed. As part of this, the current work deals with the real-time bone drilling simulation using a haptic force-feedback device. To simulate the drilling, we introduce a virtual fixture based force-feedback drilling approach. By decomposition of the drilling task into individual phases, each phase can be handled individually to perfectly control the drilling procedure. We report about the related finite state machine (FSM), describe the haptic feedback of each state and explain, how to avoid jerking of the haptic force-feedback during state transition. The usage of the virtual fixture approach results in a good haptic performance and a stable drilling behavior. This was confirmed by 26 expert surgeons, who evaluated the virtual drilling on the simulator and rated it as very realistic. To make the system even more convincing, we determined real drilling feed rates through experimental pig bone drilling and transferred them to our system. Due to a constant simulation thread we can guarantee a precise drilling motion. Virtual fixtures based force-feedback calculation is able to simulate force-feedback assisted bone drilling with high quality and, thus, will have a great potential in developing medical applications.