Activation of CGRP receptor-mediated signaling promotes tendon-bone healing.

Calcitonin gene-related peptide (CGRP), an osteopromotive neurotransmitter with a short half-life, shows increase while calcitonin receptor-like (CALCRL) level is decreased at the early stage in bone fractures. Therefore, the activation of CALCRL-mediated signaling may be more critical to promote the tendon-bone healing. We found CGRP enhanced osteogenic differentiation of BMSCs through PKA/CREB/JUNB pathway, contributing to improved sonic hedgehog (SHH) expression, which was verified at the tendon-bone interface (TBI) in the mice with Calcrl overexpression. The osteoblast-derived SHH and slit guidance ligand 3 were reported to favor nerve regeneration and type H (CD31hiEMCNhi) vessel formation, respectively. Encouragingly, the activation or inactivation of CALCRL-mediated signaling significantly increased or decreased intensity of type H vessel and nerve fiber at the TBI, respectively. Simultaneously, improved gait characteristics and biomechanical performance were observed in the Calcrl overexpression group. Together, the gene therapy targeting CGRP receptor may be a therapeutic strategy in sports medicine.

MRI-visible mesoporous polydopamine nanoparticles with enhanced antioxidant capacity for osteoarthritis therapy.

Since the progression of osteoarthritis (OA) is closely associated with synovitis and cartilage destruction, the inhibition of inflammatory responses in synovial macrophages and reactive oxygen species (ROS) induced apoptosis in chondrocytes is crucial for OA amelioration. However, most of the current anti-inflammatory and antioxidant drugs are small molecules apt to be eliminated in vivo. Herein, mesoporous polydopamine nanoparticles (DAMM NPs) doped with arginine and manganese (Mn) ions were prepared to load dexamethasone (DEX) for OA intervention. A series of in vitro studies showed that the sustained release of DEX from DAMM NPs suppressed synovial inflammation and simultaneously inhibited toll-like receptor 3 (TLR-3) production in chondrocytes, contributing to prevention of chondrocyte apoptosis through the inflammatory factor-dependent TLR-3/NF-κB signaling pathway via modulation of macrophage-chondrocyte crosstalk. In addition, DAMM NPs exerted a predominant role in removal of ROS generated in chondrocytes. Therefore, the DEX-loaded DAMM NPs significantly attenuated OA development in mice model. Importantly, the T1-T2 magnetic contrast capabilities of DAMM NPs allowed an MRI-trackable delivery, manifesting a distinct feature widely regarded to boost the potential of nanomedicines for clinical applications. Together, our developed antioxidant-enhanced DAMM NPs with MRI-visible signals may serve as a novel multifunctional nanocarriers for prevention of OA progression.

Opportunities and challenges of hydrogel microspheres for tendon-bone healing after anterior cruciate ligament reconstruction.

Poor angiogenesis and bony ingrowth are the major factors causing unsatisfactory healing between the tendon graft and the bone tunnel surface. Exogenous biological factors, biomaterials, and cells have been considered as new strategies to promote healing quality in recent years. However, it remains challenging for their clinical use because of insufficient in-situ retention time and release efficiency. Increasing attention has been paid to the hydrogel microspheres (HMPs) as potential drug-loading deliveries in biomedicine due to their minimally invasive manner, extended drug retention time, and high loading efficiency. In this review, the healing mechanism between the tendon graft and the bone tunnel is introduced, which is followed by a brief summarization of current methods applied for enhancement of the healing quality. Then, the preclinical studies focusing on HMPs as novel drug carriers are summarized to address the aforementioned concerns in the treatment of tendon-bone healing. Of note, the challenges and perspectives of HMPs in clinical conversion are also outlooked. Collectively, this review may inspire researchers and clinicians to develop clinical available HMPs in orthopedics such as sports medicine from both material and biomedical aspects.