Daily low-intensity pulsed ultrasound stimulation mitigates joint degradation and pain in a post-traumatic osteoarthritis rat model.

Objectives: The aim of this study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) in a post-traumatic osteoarthritis (OA) rat model and in vitro. Methods: Thirty-eight male, four-month-old Sprague Dawley rats were randomly assigned to Sham, Sham â€‹+ â€‹US, OA, and OA â€‹+ â€‹US. Sham surgery was performed to serve as a negative control, and anterior cruciate ligament transection was used to induce OA. Three days after the surgical procedures, Sham â€‹+ â€‹US and OA â€‹+ â€‹US animals received daily LIPUS treatment, while the rest of the groups received sham ultrasound (US) signals. Behavioral pain tests were performed at baseline and every week thereafter. After 31 days, the tissues were collected, and histological analyses were performed on knees and innervated dorsal root ganglia (DRG) neurons traced by retrograde labeling. Furthermore, to assess the activation of osteoclasts by LIPUS treatment, RAW264.7 â€‹cells were differentiated into osteoclasts and treated with LIPUS. Results: Joint degradation in cartilage and bone microarchitecture were mitigated in OA â€‹+ â€‹US compared to OA. OA â€‹+ â€‹US showed improvements in behavioral pain tests. A significant increase of large soma-sized DRG neurons was located in OA compared to Sham. In addition, a greater percentage of large soma-sized innervated neurons were calcitonin gene-related peptide-positive. Daily LIPUS treatment suppressed osteoclastogenesis in vitro, which was confirmed via histological analyses and mRNA expression. Finally, lower expression of netrin-1, a sensory innervation-related protein, was found in the LIPUS treated cells. Conclusion: Our findings demonstrate that early intervention using LIPUS treatment has protective effects from the progression of knee OA, including reduced tissue degradation, mitigated pain characteristics, improved subchondral bone microarchitecture, and less sensory innervation. Furthermore, daily LIPUS treatment has a suppressive effect on osteoclastogenesis, which may be linked to the suppression of sensory innervation in OA. The translational potential of this article: This study presents a new potential for early intervention in treating OA symptoms through the use of LIPUS, which involves the suppression of osteoclastogenesis and the alteration of DRG profiles. This intervention aims to delay joint degradation and reduce pain.

Improved mechanical, degradation, and biological performances of Zn-Fe alloys as bioresorbable implants.

Zinc (Zn) is a promising bioresorbable implant material with more moderate degradation rate compared to magnesium (Mg) and iron (Fe). However, the low mechanical strength and localized degradation behavior of pure Zn limit its clinical applications. Alloying is one of the most effective ways to overcome these limitations. After screening the alloying element candidates regarding their potentials for improvement on the degradation and biocompatibility, we proposed Fe as the alloying element for Zn, and investigated the in vitro and in vivo performances of these alloys in both subcutaneous and femoral tissues. Results showed that the uniformly distributed secondary phase in Zn-Fe alloys significantly improved the mechanical property and facilitated uniform degradation, which thus enhanced their biocompatibility, especially the Zn-0.4Fe alloy. Moreover, these Zn-Fe alloys showed outstanding antibacterial property. Taken together, Zn-Fe alloys could be promising candidates as bioresorbable medical implants for various cardiovascular, wound closure, and orthopedic applications.

Short Cyclic Regimen With Parathyroid Hormone (PTH) Results in Prolonged Anabolic Effect Relative to Continuous Treatment Followed by Discontinuation in Ovariectomized Rats.

Despite the potent effect of intermittent parathyroid hormone (PTH) treatment on promoting new bone formation, bone mineral density (BMD) rapidly decreases upon discontinuation of PTH administration. To uncover the mechanisms behind this adverse phenomenon, we investigated the immediate responses in bone microstructure and bone cell activities to PTH treatment withdrawal and the associated long-term consequences. Unexpectedly, intact female and estrogen-deficient female rats had distinct responses to the discontinuation of PTH treatment. Significant tibial bone loss and bone microarchitecture deterioration occurred in estrogen-deficient rats, with the treatment benefits of PTH completely lost 9 weeks after discontinuation. In contrast, no adverse effect was observed in intact rats, with sustained treatment benefit 9 weeks after discontinuation. Intriguingly, there is an extended anabolic period during the first week of treatment withdrawal in estrogen-deficient rats, during which no significant change occurred in the number of osteoclasts, whereas the number of osteoblasts remained elevated compared with vehicle-treated rats. However, increases in number of osteoclasts and decreases in number of osteoblasts occurred 2 weeks after discontinuation of PTH treatment, leading to significant reduction in bone mass and bone microarchitecture. To leverage the extended anabolic period upon early withdrawal from PTH, a cyclic administration regimen with repeated cycles of on and off PTH treatment was explored. We demonstrated that the cyclic treatment regimen efficiently alleviated the PTH withdrawal-induced bone loss, improved bone mass, bone microarchitecture, and whole-bone mechanical properties, and extended the treatment duration. © 2021 American Society for Bone and Mineral Research (ASBMR).

A Novel Modified-Curcumin Promotes Resolvin-Like Activity and Reduces Bone Loss in Diabetes-Induced Experimental Periodontitis.

PURPOSE: Clinically, it is challenging to manage diabetic patients with periodontitis. Biochemically, both involve a wide range of inflammatory/collagenolytic conditions which exacerbate each other in a "bi-directional manner." However, standard treatments for this type of periodontitis rely on reducing the bacterial burden and less on controlling hyper-inflammation/excessive-collagenolysis. Thus, there is a crucial need for new therapeutic strategies to modulate this excessive host response and to promote enhanced resolution of inflammation. The aim of the current study is to evaluate the impact of a novel chemically-modified curcumin 2.24 (CMC2.24) on host inflammatory response in diabetic rats. METHODS: Type I diabetes was induced by streptozotocin injection; periodontal breakdown then results as a complication of uncontrolled hyperglycemia. Non-diabetic rats served as controls. CMC2.24, or the vehicle-alone, was administered by oral gavage daily for 3 weeks to the diabetics. Micro-CT was used to analyze morphometric changes and quantify bone loss. MMPs were analyzed by gelatin zymography. Cell function was examined by cell migration assay, and cytokines and resolvins were measured by ELISA. RESULTS: In this severe inflammatory disease model, administration of the pleiotropic CMC2.24 was found to normalize the excessive accumulation and impaired chemotactic activity of macrophages in peritoneal exudates, significantly decrease MMP-9 and pro-inflammatory cytokines to near normal levels, and markedly increase resolvin D1 (RvD1) levels in the thioglycolate-elicited peritoneal exudates (tPE). Similar effects on MMPs and RvD1 were observed in the non-elicited resident peritoneal washes (rPW). Regarding clinical relevance, CMC2.24 significantly inhibited the loss of alveolar bone height, volume and mineral density (ie, diabetes-induced periodontitis and osteoporosis). CONCLUSION: In conclusion, treating hyperglycemic diabetic rats with CMC2.24 (a tri-ketonic phenylaminocarbonyl curcumin) promotes the resolution of local and systemic inflammation, reduces bone loss, in addition to suppressing collagenolytic MMPs and pro-inflammatory cytokines, suggesting a novel therapeutic strategy for treating periodontitis complicated by other chronic diseases.

Evaluation of nucleus pulposus fluid velocity and pressure alteration induced by cartilage endplate sclerosis using a poro-elastic finite element analysis.

The nucleus pulposus (NP) in the intervertebral disk (IVD) depends on diffusive fluid transport for nutrients through the cartilage endplate (CEP). Disruption in fluid exchange of the NP is considered a cause of IVD degeneration. Furthermore, CEP calcification and sclerosis are hypothesized to restrict fluid flow between the NP and CEP by decreasing permeability and porosity of the CEP matrix. We performed a finite element analysis of an L3-L4 lumbar functional spine unit with poro-elastic constitutive equations. The aim of the study was to predict changes in the solid and fluid parameters of the IVD and CEP under structural changes in CEP. A compressive load of 500 N was applied followed by a 10 Nm moment in extension, flexion, lateral bending, and axial rotation to the L3-L4 model with fully saturated IVD, CEP, and cancellous bone. A healthy case of L3-L4 physiology was then compared to two cases of CEP sclerosis: a calcified cartilage endplate and a fluid constricted sclerotic cartilage endplate. Predicted NP fluid velocity increased for the calcified CEP and decreased for the calcified + less permeable CEP. Decreased NP fluid velocity was prominent in the axial direction through the CEP due to a less permeable path available for fluid flux. Fluid pressure and maximum principal stress in the NP were predicted to increase in both cases of CEP sclerosis compared to the healthy case. The porous medium predictions of this analysis agree with the hypothesis that CEP sclerosis decreases fluid flow out of the NP, builds up fluid pressure in the NP, and increases the stress concentrations in the NP solid matrix.

Mechanobiological modulation of in situ and in vivo osteocyte calcium oscillation by acoustic radiation force.

The biological effect of ultrasound on bone regeneration has been well documented, yet the underlying mechanotransduction mechanism is largely unknown. In relation to the mechanobiological modulation of the cytoskeleton and Ca2+ influx by short-term focused acoustic radiation force (FARF), the current study aimed to visualize and quantify Ca2+ oscillations in real-time of in situ and in vivo osteocytes in response to focused low-intensity pulsed ultrasound (FLIPUS). For in situ studies, fresh mice calvaria were subjected to FLIPUS stimulation at 0.05, 0.2, 0.3, and 0.7 W. For the in vivo study, 3-month-old C57BL/6J Ai38/Dmp1-Cre mice were subjected to FLIPUS at 0.15, 1, and 1.5 W. As observed via real-time confocal imaging, in situ FLIPUS led to more than 80% of cells exhibiting Ca2+ oscillations at 0.3-0.7 W and led to a higher number of Ca2+ spikes with larger values at >0.3 W. In vivo FLIPUS at 1-1.5 W led to more than 90% of cells exhibiting Ca2+ oscillations. Higher FLIPUS energies led to larger Ca2+ spike magnitudes. In conclusion, this study provided a pilot study of both in situ and in vivo osteocytic Ca2+ oscillations under noninvasive FARF, which aids further exploration of the mechanosensing mechanism of the controlled bone cell motility response to the stimulus.