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Distant metastasis is the most lethal hallmark of cancer. Nevertheless, due to a lack of suitable markers, the emerging motility of cancer cells only has a negligible impact on current diagnosis and prognosis. In cancer clusters of solid tumours, cooperative unjamming transitions generate regions of unjammed motile cells, as we could show by vital cancer cell tracking in patient-derived tumour explants. Thereby, cancer cells and their nuclei collectively deform/elongate to squeeze past each other. The cells' differing shapes and densities, and nuclei of jammed and unjammed cancer cells can serve as the first reliable motility marker in static images such as histopathological slides. A retrospective clinical study that strongly correlates unjamming with distant metastasis demonstrates that unjamming within primary tumours is part of the metastatic cascade. With the histological slides of two independent breast cancer patient collectives, we train (N=688) and validate (N=692) our quantitative prognostic index based on unjamming regarding metastatic risk. Our index corrects for false high- and low-risk predictions based on nodal status. Combining information derived from the nodal status with unjamming may reduce over- and under-treatment and significantly improve the understanding of the metastatic cascade.

Granular hydrogels have evolved into an innovative technology for biomedicine. Unlike conventional hydrogels, granular hydrogels display dynamic properties like injectability and porosity, making them feasible for applications in 3D bioprinting and tissue engineering. High-energy electron irradiation combines sterilization and tuning of hydrogel properties without adding potentially cytotoxic chemicals. In this study, granular agarose/alginate hydrogels are prepared by electrospraying. Utilizing 10 MeV electron irradiation, the granular hydrogels are treated in a dose range of 0 kGy-30 kGy relevant for sterilization. Herein, a size reduction of the microparticles is observed. Mechanical properties of individual agarose/alginate beads are examined using AFM measurements revealing a gel softening attributed to radiation induced chain scission. Shear-thinning and self-healing characteristics of the entire granular hydrogel are studied employing rheology. Although viscoelasticity changes under irradiation, shear-thinning and self-healing prevails. These dynamic properties enable injection, which is demonstrated for 27 G needles. This study presents a mechanical characterization of high-energy electron irradiated granular agarose/alginate hydrogels that extends the diversity of available injectable hydrogels and provides a basis for biomedical applications of this scaffold.

We present a novel technique to noninvasively control the growth and turning behavior of an extending neurite. A highly focused infrared laser, positioned at the leading edge of a neurite, has been found to induce extension/turning toward the beam's center. This technique has been used successfully to guide NG108-15 and PC12 cell lines [Ehrlicher, A., Betz, T., Stuhrmann, B., Koch, D. Milner, V. Raizen, M. G., and Kas, J. (2002). Guiding neuronal growth with light. Proc. Natl. Acad. Sci. USA 99, 16024-16028], as well as primary rat and mouse cortical neurons [Stuhrmann, B., Goegler, M., Betz, T., Ehrlicher, A., Koch, D., and Kas, J. (2005). Automated tracking and laser micromanipulation of cells. Rev. Sci. Instr. 76, 035105]. Optical guidance may eventually be used alone or with other methods for controlling neurite extension in both research and clinical applications.

The presented work is concerned with the development and application of an ultrasonic detection scheme suitable for the monitoring of muscle dynamics with high temporal - down to 5 µs - and spatial resolution - down to 0.78 µm. A differential detection scheme has been developed to monitor the variations of the velocity of longitudinal polarized ultrasound waves travelling in contracting and relaxing muscle, compensating for variations of the path length by referencing to a frame. The observed time dependent variations of the time-of-flight of the ultrasonic waves caused by variations in the muscle and in addition by minor deformations of the enclosure are detected each separately and synchronously and are evaluated differentially. Beside of the detected increase of the speed of sound observed for contracted muscle with respect to the relaxed state of about 0.6%, the recovery time from maximum isometric contraction is quantified and relaxation processes are observed for the recovery phase following the isometric contraction. The developed ultrasonic calliper was employed to monitor both, the brain controlled and externally excited muscle dynamics with sampling intervals down to 10 ms synchronously with signals relating to the excitation. Monitored are the activation, hold, and relaxation phase for maximum voluntary isometric contraction of the gastrocnemius muscle. A so far not reported post tetanus overshoot and subsequent exponential recovery are observed. Both are attributed to the muscle as suggested by combined monitoring with EMG and are modelled with a lumped mechanical circuit containing an idealized bidirectional linear motor unit, ratchet, damper, and springs. Both, the rapid contraction and relaxation phases require a high order filter or alternatively a kernel filter, attributed to the nerve system as suggested by external electric stimulation. The respective response function is modelled by an electrical lumped circuit. Together with a reaction time and occasionally observed droops in the hold phase, both adjusted empirically, the monitored response is represented in close approximation by the combined electrical and mechanical lumped circuits. The respectively determined model parameters provide a refined evaluation scheme for the performance of monitored athletes. Valuable parameters relate to the latent period, the muscle response time, the activation and deactivation dynamics, a possible droop and other instabilities of the hold phase, and parameters characterizing the relaxation phase including the observed post tetanus overshoot and subsequent contraction. Monitored and modelled are also the different processes involved in active muscle dynamics including isotonic, isometric, and eccentric contraction or stretching. The developed technology provides time sequential observation of these processes and registration of their path in the extension and force parameter space. Under suitable conditions the closed-loop cycles of mind controlled human muscle movements proceed along characteristic lines coinciding with well identifiable elementary processes. The presentation of the monitored processes in the extension and force parameter space allows the determination of the mechanical energy expenditure for the observed different muscle actions. An elementary macroscopic mechanical model has been developed, suitable to express the basic features of the monitored muscle dynamics.:Table of Contents Chapter 1 1. Introduction 1 1.1 Monitoring of muscle biomechanics 1 1.2 Detection methods in biomechanics 2 1.3 Ultrasound in biomechanical application 5 1.4 Skeletal muscle 6 1.5 Activation of skeletal muscle 8 1.6 Catatonus effect 10 Chapter 2 2. Concepts and methods in ultrasonic motion monitoring 12 2.1 Ultrasound 12 2.2 Specific concepts of the developed ultrasonic detection scheme 16 2.2.1 Time-of-flight 17 2.2.2 Cross correlation 18 2.2.3 Concepts of cross correlation 19 2.2.4 Chirp technique 19 Chapter 3 3. Ultrasonic monitoring of the muscle extension 21 3.1 Data analysis 21 3.2 Application of the developed monitoring scheme 23 3.2.1 Fast signal and data acquisition mode 23 3.2.2 Monitoring with off-line evaluation 24 3.2.3 Method 26 3.2.4 Data evaluation 27 3.3 Quasi-continuous monitoring scheme 28 3.3.1 Slow with on-line data processing and display 29 3.3.2 Fast with data storage only 30 3.4 Monitoring with on-line evaluation 34 3.4.1 Application involving monitoring of athletic performance 36 3.4.2 Data evaluation 37 3.4.3 Summary 42 3.5 Comparative study of pre and post physical loading session 43 3.5.1 Method 43 3.5.2 Results 44 3.5.3 Summary 45 Chapter 4 4. High resolution monitoring of the velocity of ultrasound in contracting and relaxing muscle 47 4.1 Methods 49 4.2 Results and evaluation 51 4.2.1 Poission’s ratio for isometrically contracted muscle 52 4.3 Summary 53 Chapter 5 5. Monitoring of muscle dynamics, muscle force, and EMG 56 5.1 Synchronous monitoring of muscle dynamics with muscle force 56 5.1.1 Force-length dynamics under all-out isometric contraction 56 5.1.1.1 Method 56 5.1.1.2 Result and evaluation 58 5.1.2 Force-length dynamics of equal holding monitoring 62 5.1.2.1 Method 62 5.1.2.2 Results and evaluation 63 5.1.3 Summary 67 5.2 Synchronous monitoring of muscle movement with EMG 69 5.2.1 Method 69 5.2.2 Results and evaluation 70 5.3 Synchronous monitoring of muscle movement, EMG and muscle force 73 5.3.1 Method 73 5.3.2 Results and evaluation 74 5.3.3 Summary 77 Chapter 6 6. Monitoring of skeletal muscle dynamics under isometric contraction and modelling of the non-linear response including post tetanus effects 80 6.1 Method 82 6.2 Data analysis 82 6.3 Results and evaluation 82 6.3.1 Mechanical model 83 6.3.2 Equations relating to modelling 85 6.3.3 Comparison of experimental results and modelling 91 6.3.4 Electrical lumped circuit 93 6.4 Summary 100 Chapter 7 7. Lumped Circuit Model and Energy Transfer for quasi-static approximation 101 7.1 Basic muscle model and biomechanical processes 102 7.1.1 Muscle model 102 7.1.2 Force in the muscular motoric processes 104 7.2 Method 104 7.3 Results of experimental observations of muscle action 106 7.3.1 Muscle force and closed-loop contraction dynamics 106 7.3.2 Muscle work considerations 109 7.4 Summary 110 Chapter 8 8.1 Ultrasonic calliper 112 8.2 Interpretation of sound velocity variation in muscle 114 8.3 Monitored muscle dynamics 118 8.4 Isometric muscle action and tetanus effect 121 8.5 Quasi-static muscle action 125 8.6 Summarizing statement with a moderate outlook 126 References 128 Acknowledgements 140 Selbständigkeitserklärung 141