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Knee osteoarthritis occurs predominately at the medial compartment. To unload the affected compartment, valgus braces are used which induce an additional valgus moment in order to shift the load more laterally. Until now the biomechanical effect of braces was mainly evaluated by measuring changes in external knee adduction moments. The aim of this study was to investigate if and to which extent the medial compartment load is reduced in vivo when wearing valgus braces. Six components of joint contact load were measured in vivo in three subjects, using instrumented, telemeterized knee implants. From the forces and moments the medio-lateral force distribution was calculated. Two braces, MOS Genu (Bauerfeind AG) and Genu Arthro (Otto Bock) were investigated in neutral, 4° and 8° valgus adjustment during walking, stair ascending and descending. During walking with the MOS brace in 4°/8° valgus adjustment, medial forces were reduced by 24%/30% on average at terminal stance. During walking with the GA in the 8° valgus position, medial forces were reduced by only 7%. During stair ascending/descending significant reductions of 26%/24% were only observed with the MOS (8°). The load reducing ability of the two investigated valgus braces was confirmed in three subjects. However, the load reduction depends on the brace stiffness and its valgus adjustment and varies strongly inter-individually. Valgus adjustments of 8° might, especially with the MOS brace, not be tolerated by patients for a long time. Medial load reductions of more than 25% can therefore probably not be expected in clinical practise.

An instrumented tibial tray was developed that enables the measurement of six load components in a total knee arthroplasty (TKA). The design is fully compatible with a commonly available knee arthroplasty product since it uses the original tibial insert and femoral component. Two plates with hollow stems made from titanium alloy are separated by a small gap. Six semiconductor strain gages are used for measuring the load-dependent deformation of the inner hollow stem. A 9-channel telemetry unit with a radio-frequency transmitter is encapsulated hermetically in the cavity of the prosthesis. The telemetry is powered inductively and strain gage signals are transmitted via a small antenna at the tip of the implant. The mean sampling rate is 125 Hz. The calibration of the prosthesis resulted in an accuracy better than 2% mean measuring error. Fatigue testing of the implant was performed up to 10 million loading cycles and showed no failure. The pending in vivo application will give further insight into the kinetics of TKA. The measured values will enhance the quality of future pre-clinical testing, numerical modeling in knee biomechanics and the patients’ physiotherapy and rehabilitation.

A preclinical analysis of novel implants used in shoulder surgery requires biomechanical testing conditions close to physiology. Existing shoulder experiments may only partially apply multiple cycles to simulate postoperative, repetitive loading tasks. The aim of the present study was therefore the development of an experimental shoulder simulator with rotating scapula able to perform multiple humeral movement cycles by simulating individual muscles attached to the rotator cuff. A free-hanging, metallic humerus pivoted in a polyethylene glenoid is activated by tension forces of linear electroactuators to simulate muscles of the deltoideus (DELT), supraspinatus (SSP), infraspinatus/teres minor and subscapularis. The abductors DELT and SSP apply forces with a ratio of 3:1 up to an abduction angle of 85°. The rotating scapular part driven by a rotative electro actuator provides one-third to the overall arm abduction. Resulting joint forces and moments are measured by a 6-axis load cell. A linear increase in the DELT and SSP motors is shown up to a maximum of 150 and 50 N for the DELT and SSP, respectively. The force vector in the glenoid resulted in 253 N at the maximum abduction. The present investigation shows the contribution of individual muscle forces attached to the moving humerus to perform active abduction in order to reproducibly test shoulder implants.

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5 , while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.

Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.

Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.

Patient derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases from primary patient samples. Organoids can be used as models for drug discovery and are being explored to guide clinical decision making. Patient derived organoids can have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we used high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with more than 500 small molecules. Integration of data using a joint multi-omics modelling framework identified organoid size and cystic vs. solid organoid architecture as axes of morphological variation across organoids. Mechanistically, we found that organoid size was linked to IGF1 receptor signaling, while a cystic organoid architecture was associated with an LGR5+ stemness program. Treatment-induced organoid morphology reflected organoid viability, drug mechanism of action, and was biologically interpretable using joint modelling. Inhibition of MEK led to cystic reorganization of organoids and increased expression of LGR5, while inhibition of mTOR induced IGF1 receptor signaling. In conclusion, we identified shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. Image-based profiling of patient derived organoids coupled with multi-omics integration facilitates drug discovery by linking drug responses with underlying biological mechanisms. Competing Interest Statement The authors declare no competing interests. M.B. and M.E. received a research grant within the Merck Heidelberg Innovation Program, which did not support this study. Footnotes * Updated several figures and new analysis was added to the new version of the manuscript. Supplemental files were updated.