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Structural muscle changes, including muscle atrophy and fatty infiltration, follow rotator cuff tendon tear and are associated with a high repair failure rate. Despite extensive research efforts, no pharmacological therapy is available to successfully prevent both muscle atrophy and fatty infiltration after tenotomy of tendomuscular unit without surgical repair. Poly(ADP-ribose) polymerases (PARPs) are identified as a key transcription factors involved in the maintenance of cellular homeostasis. PARP inhibitors have been shown to influence muscle degeneration, including mitochondrial hemostasis, oxidative stress, inflammation and metabolic activity, and reduced degenerative changes in a knockout mouse model. Tenotomized infraspinatus were assessed for muscle degeneration for 16 weeks using a Swiss Alpine sheep model (n = 6). All sheep received daily oral administration of 0.5 mg Talazoparib. Due to animal ethics, the treatment group was compared with three different controls from prior studies of our institution. To mitigate potential batch heterogeneity, PARP-I was evaluated in comparison with three distinct control groups (n = 6 per control group) using the same protocol without treatment. The control sheep were treated with an identical study protocol without Talazoparib treatment. Muscle atrophy and fatty infiltration were evaluated at 0, 6 and 16 weeks post-tenotomy using DIXON-MRI. The controls and PARP-I showed a significant (control p < 0.001, PARP-I p = 0.01) decrease in muscle volume after 6 weeks. However, significantly less (p = 0.01) atrophy was observed in PARP-I after 6 weeks (control 1: 76.6 ± 8.7%; control 2: 80.3 ± 9.3%, control 3: 73.8 ± 6.7% vs. PARP-I: 90.8 ± 5.1% of the original volume) and 16 weeks (control 1: 75.7 ± 9.9; control 2: 74.2 ± 5.6%; control 3: 75.3 ± 7.4% vs. PARP-I 93.3 ± 10.6% of the original volume). All experimental groups exhibited a statistically significant (p < 0.001) augmentation in fatty infiltration following a 16-week period when compared to the initial timepoint. However, the PARP-I showed significantly less fatty infiltration (p < 0.003) compared to all controls (control 1: 55.6 ± 6.7%, control 2: 53.4 ± 9.4%, control 3: 52.0 ± 12.8% vs. PARP-I: 33.5 ± 8.4%). Finally, a significantly (p < 0.04) higher proportion and size of fast myosin heavy chain-II fiber type was observed in the treatment group. This study shows that PARP-inhibition with Talazoparib inhibits the progression of both muscle atrophy and fatty infiltration over 16 weeks in retracted sheep musculotendinous units.

Computer aided orthopedic surgery suffers from low clinical adoption, despite increased accuracy and patient safety. This can partly be attributed to cumbersome and often radiation intensive registration methods. Emerging RGB-D sensors combined with artificial intelligence data-driven methods have the potential to streamline these procedures. However, developing such methods requires vast amount of data. To this end, a multi-modal approach that enables acquisition of large clinical data, tailored to pedicle screw placement, using RGB-D sensors and a co-calibrated high-end optical tracking system was developed. The resulting dataset comprises RGB-D recordings of pedicle screw placement along with individually tracked ground truth poses and shapes of spine levels L1–L5 from ten cadaveric specimens. Besides a detailed description of our setup, quantitative and qualitative outcome measures are provided. We found a mean target registration error of 1.5 mm. The median deviation between measured and ground truth bone surface was 2.4 mm. In addition, a surgeon rated the overall alignment based on 10% random samples as 5.8 on a scale from 1 to 6. Generation of labeled RGB-D data for orthopedic interventions with satisfactory accuracy is feasible, and its publication shall promote future development of data-driven artificial intelligence methods for fast and reliable intraoperative registration.

Ultrasound-based shear wave elastography (SWE) provides the means to quantify tissue mechanical properties in vivo and has proven valuable in detecting degenerative processes in tendons. Its current mode of use is for two-dimensional rendering measurements, which are highly position-dependent. We therefore propose an approach to create a volumetric reconstruction of the mechano-acoustic properties of a structure of interest based on optically tracking the ultrasound probe during free-hand measurement sweeps. In the current work, we aimed (1) to assess the technical feasibility of the three-dimensional mapping of unidirectional shear wave velocity (SWV), (2) to evaluate the possible artefacts associated with hand-held image acquisition, (3) to investigate the reproducibility of the proposed technique, and (4) to study the potential of this method in detecting local adaptations in a longitudinal study setting. Operative and technical feasibility as well as potential artefacts associated with hand-held image acquisition were studied on a synthetic phantom containing discrete targets of known mechanical properties. Measurement reproducibility was assessed based on inter-day and inter-reader scans of the patellar, Achilles, and supraspinatus tendon of ten healthy volunteers and was compared to traditional two-dimensional image acquisition. The potential of this method in detecting local adaptations was studied by testing the effect of short-term voluntary isometric loading history on SWV along the tendon long axis. The suggested approach was technically feasible and reproducible, with a moderate to very good reliability and a standard error of measurement in the range of 0.300–0.591 m/s for the three assessed tendons at the two test-retest modalities. We found a consistent variation in SWV along the longitudinal axis of each tendon, and isometric loading resulted in regional increases in SWV in the patellar and Achilles tendons. The proposed method outperforms traditional two-dimensional measurement with regards to reproducibility and may prove valuable in the objective assessment of pathological tendon changes.

Augmented reality (AR)-based surgical navigation may offer new possibilities for safe and accurate surgical execution of complex osteotomies. In this study we investigated the feasibility of navigating the periacetabular osteotomy of Ganz (PAO), known as one of the most complex orthopedic interventions, on two cadaveric pelves under realistic operating room conditions. Preoperative planning was conducted on computed tomography (CT)-reconstructed 3D models using an in-house developed software, which allowed creating cutting plane objects for planning of the osteotomies and reorientation of the acetabular fragment. An AR application was developed comprising point-based registration, motion compensation and guidance for osteotomies as well as fragment reorientation. Navigation accuracy was evaluated on CT-reconstructed 3D models, resulting in an error of 10.8 mm for osteotomy starting points and 5.4° for osteotomy directions. The reorientation errors were 6.7°, 7.0° and 0.9° for the x-, y- and z-axis, respectively. Average postoperative error of LCE angle was 4.5°. Our study demonstrated that the AR-based execution of complex osteotomies is feasible. Fragment realignment navigation needs further improvement, although it is more accurate than the state of the art in PAO surgery.

Mechanical loading and inflammation interact to cause degenerative disc disease and low back pain (LBP). However, the underlying mechanosensing and mechanotransductive pathways are poorly understood. This results in untargeted pharmacological treatments that do not take the mechanical aspect of LBP into account. We investigated the role of the mechanosensitive ion channel TRPV4 in stretch-induced inflammation in human annulus fibrosus (AF) cells. The cells were cyclically stretched to 20% hyperphysiological strain. TRPV4 was either inhibited with the selective TRPV4 antagonist GSK2193874 or knocked out (KO) via CRISPR-Cas9 gene editing. The gene expression, inflammatory mediator release and MAPK pathway activation were analyzed. Hyperphysiological cyclic stretching significantly increased the IL6, IL8, and COX2 mRNA, PGE2 release, and activated p38 MAPK. The TRPV4 pharmacological inhibition significantly attenuated these effects. TRPV4 KO further prevented the stretch-induced upregulation of IL8 mRNA and reduced IL6 and IL8 release, thus supporting the inhibition data. We provide novel evidence that TRPV4 transduces hyperphysiological mechanical signals into inflammatory responses in human AF cells, possibly via p38. Additionally, we show for the first time the successful gene editing of human AF cells via CRISPR-Cas9. The pharmacological inhibition or CRISPR-based targeting of TRPV4 may constitute a potential therapeutic strategy to tackle discogenic LBP in patients with AF injury.