Bone development, maintenance, and regeneration are remarkably sensitive to mechanical cues. Consequently, mechanical stimulation has long been sought as a putative target to promote endogenous healing after fracture. Given the transient nature of bone repair, tissue-level mechanical cues evolve rapidly over time after injury and are challenging to measure noninvasively. The objective of this work was to develop and characterize an implantable strain sensor for noninvasive monitoring of axial strain across a rodent femoral defect during functional activity. Herein, we present the design, characterization, and in vivo demonstration of the device's capabilities for quantitatively interrogating physiological dynamic strains during bone regeneration. Ex vivo experimental characterization of the device showed that it possessed promising sensitivity, signal resolution, and electromechanical stability for in vivo applications. The digital telemetry minimized power consumption, enabling extended intermittent data collection. Devices were implanted in a rat 6 mm femoral segmental defect model, and after three days, data were acquired wirelessly during ambulation and synchronized to corresponding radiographic videos, validating the ability of the sensor to noninvasively measure strain in real-time. Together, these data indicate the sensor is a promising technology to quantify tissue mechanics in a specimen specific manner, facilitating more detailed investigations into the role of the mechanical environment in dynamic bone healing and remodeling processes.

Objective: This study examined the effects of reduced and elevated weight bearing on post-traumatic osteoarthritis (PTOA) development, locomotor joint kinematics, and degree of voluntary activity in rats following medial meniscal transection (MMT). Design: Twenty-one adult rats were subjected to MMT surgery of the left hindlimb and then assigned to one of three groups: (1) regular (i.e., no intervention), (2) hindlimb immobilization, or (3) treadmill running. Sham surgery was performed in four additional rats. Voluntary wheel run time/distance was measured, and 3D hindlimb kinematics were quantified during treadmill locomotion using biplanar radiography. Rats were euthanized 8 weeks after MMT or sham surgery, and the microstructure of the tibial cartilage and subchondral bone was quantified using contrast enhanced micro-CT. Results: All three MMT groups showed signs of PTOA (full-thickness lesions and/or increased cartilage volume) compared to the sham group, however the regular and treadmill-running groups had greater osteophyte formation than the immobilization group. For the immobilization group, increased volume was only observed in the anterior region of the cartilage. The treadmill-running group demonstrated a greater knee varus angle at mid-stance than the sham group, while the immobilization group demonstrated greater reduction in voluntary running than all the other groups at 2 weeks post-surgery. Conclusions: Elevated weight-bearing via treadmill running at a slow/moderate speed did not accelerate PTOA in MMT rats when compared to regular weight-bearing. Reduced weight-bearing via immobilization may attenuate overall PTOA but still resulted in regional cartilage degeneration. Overall, there were minimal differences in hindlimb kinematics and voluntary running between MMT and sham rats.

Bone development, maintenance, and regeneration are remarkably sensitive to mechanical cues.Consequently, mechanical stimulation has long been sought as a putative target to promote endogenous healing after fracture. Given the transient nature of bone repair, tissue-level mechanical cues evolve rapidly over time after injury and are challenging to measure non-invasively. The objective of this work was to develop and characterize an implantable strain sensor for non-invasive monitoring of axial strain across a rodent femoral defect during functional activity. Herein, we present the design, characterization, and in vivo demonstration of the device's capabilities for quantitatively interrogating physiological dynamic strains during bone regeneration. Ex vivo experimental characterization of the device showed that it exceeded the technical requirements for sensitivity, signal resolution, and electromechanical stability. The digital telemetry minimized power consumption, enabling long-term intermittent data collection. Devices were implanted in a rat 6 mm femoral segmental defect model and after three days, data were acquired wirelessly during ambulation and synchronized to corresponding radiographic videos, validating the ability of the sensor to non-invasively measure strain in real-time. Lastly, in vivo strain peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/142778 doi: bioRxiv preprint first posted online Page 2 of 24 measurements were utilized in a finite element model to estimate the strain distribution within the defect region. Together, these data indicate the sensor is a promising technology to quantify local tissue mechanics in a specimen specific manner, facilitating more detailed investigations into the role of the mechanical environment in dynamic skeletal healing and remodeling.

cartilage loss results in pain, the main symptoms of OA patients. OA pain involves a complex integration of sensory, affective, and cognitive processes. The correlation between structural damage of the joint and pain is weak, the prevalence of knee pain in patients with radiographic knee OA ranges from 15%e81% in different studies. Still, gradual increase of pain seems to be connected with OA progression and therefore pain is discussed as an indicator of disease activity. Recent MRI studies further revealed a positive relationship between inflammatory changes in the joint and pain raising the intriguing question of which inflammatory mechanisms and mediators might be involved in pain generation. Nociceptors are located throughout the joint in tissues peripheral to cartilage but not in cartilage itself. Increased nociceptive inputs from the joints cause complex changes in the central nervous system. In the state of central sensitization, nociceptive neurons at different levels of the neuraxis are hyperexcitable, and hence, the nociceptive processing is amplified. Peripheral nociceptors are important targets in analgesic therapy due to the fact that many pathological conditions such as inflammation induce receptor excitation and sensitization. Numerous ion channels and receptors take part in nociception and might function as targets in pain therapy. Therefore, we analyzed electrophysiological properties of neuronal cells under the influence of conditioned medium derived from chondrocytes and synoviocytes from OA patients. Methods: Neuroblastoma cells (MHH) were grown in the presence of conditioned medium (CM) derived from chondrocytes (CM-c) and synoviocytes (CM-s) isolated from OA patients. After 5 days of treatment MHH cells were tested for their electrophysiological behavior by the patch clamp technique. Expression of ion channels including the peripheral Na þ channels Nav1.6e1.9 and the K þ channels KCNQ2 and KCNQ3 respectively was assessed by qPCR. Both types of CM from all five patients were tested for the content of thirteen cytokines including MCP1, Il-6 and IL-8 via the human inflammation panel (Legendplex). Results: Whole cell Na þ current measurements revealed, in four out of five samples, a reduction of the maximal conductance (g max ) of MHH cells under CM-c, CM-s reduced g max in three out of five cases. The steady state activation in all cases was shifted to a more positive membrane potential (E m ), the inactivation and recovery kinetics were unchanged. For the K þ current a reduction in I max was observed in four out of five samples under both treatment conditions (CM-c and CM-s), the steady state activation was unchanged. Expression studies showed changes of voltage dependent Na þ channels with the most prominent effect for Nav1.7, the expression of the two K þ channels KCNQ2, 3 was down regulated. Results from the inflammation panel showed IL-6, IL-8 and MCP1 to be present in the CM-c and CM-s. Conclusions: Treatment with conditioned medium changes the electrophysiological behavior of neuroblasto...

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