Prevention of osteoporotic fracture:from skeletal and non-skeletal perspectives

With the global population aging,especially in China,the prevention and management of osteoporotic fragility fractures has become increasingly important.Bone mineral density(BMD)is an important index of osteoporotic fracture risk,which has become aroutine measurement inclinical practice and thus formed the cornerstone in monitoring treatment efficacy of osteoporosis.In the past 30 years,several pharmacologic therapies have been developed to increase BMD and reduce osteoporotic fractures,especially vertebral fractures.However,the management of nonvertebral fractures and hip fractures remains challenging as low BMD is only one of the multi-factors for these conditions.Hip fractures mainly result from a fall and its incidence is higher in the frigid zone due to low temperature affecting neuromuscular function and high latitude with less sunlight,the conditions rendering less active vitamin D conversion,apart from increased falling.In this paper,we focus on two therapeutic strategies targeting both skeletal and non-skeletal factors,that is,Tai Chi(TC)exercise for improving balance and"kidney-tonifying"traditional Chinese medicine(TCM)against muscle atrophy.TC is a mind-body exercise that has the potential as an effective and safe intervention for preventing fall-related fractures in the elderly.This makes it a promising and feasible physical activity for the elderly in frigid zone to prevent osteoporotic fractures.Several TCM formula popular in northeast of China within frigid zone are also introduced.They are reportedly effective in maintaining or improving BMD and muscle strength with the potential of reducing osteoporotic fracture.However,more rationally designed vigorous basic investigations and prospective clinical trials are highly desired to validate and consolidate the preliminary observations in the future.

Nanoengineered hydrogels as 3D biomimetic extracellular matrix with injectable and sustained delivery capability for cartilage regeneration

The regeneration of articular cartilage remains a great challenge due to the difficulty in effectively enhancing spontaneous healing.Recently,the combination of implanted stem cells,suitable biomaterials and bioactive molecules has attracted attention for tissue regeneration.In this study,a novel injectable nanocomposite was rationally designed as a sustained release platform for enhanced cartilage regeneration through integration of a chitosan-based hydrogel,articular cartilage stem cells(ACSCs)and mesoporous SiO_(2)nanoparticles loaded with anhydroicaritin(AHI).The biocompatible engineered nanocomposite acting as a novel 3D biomimetic extracellular matrix exhibited a remarkable sustained release effect due to the synergistic regulation of the organic hydrogel framework and mesopore channels of inorganic mSiO_(2)nanoparticles(mSiO_(2)NPs).Histological assessment and biomechanical tests showed that the nanocomposites exhibited superior performance in inducing ACSCs proliferation and differentiation in vitro and promoting extracellular matrix(ECM)production and cartilage regeneration in vivo.Such a novel multifunctional biocompatible platform was demonstrated to significantly enhance cartilage regeneration based on the sustained release of AHI,an efficient bioactive natural small molecule for ACSCs chondrogenesis,within the hybrid matrix of hydrogel and mSiO_(2)NPs.Hence,the injectable nanocomposite holds great promise for use as a 3D biomimetic extracellular matrix for tissue regeneration in clinical diagnostics.

Anti-inflammatory and anabolic biphasic scaffold facilitates osteochondral tissue regeneration in osteoarthritic joints

Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair as both cartilage and subchondral bone regeneration are further impaired due to the arthritic environment. Numerous biomaterials have been developed and tested in osteochondral defects while ignoring the inflammatory environment. To target this challenging underlying pathophysiology, we designed and fabricated a biphasic porous and degradable scaffold incorporating anti-inflammatory and anabolic molecules by low-temperature rapid prototyping technology, and its effects on promoting osteochondral regeneration were evaluated using our well-established OA-OCD rabbit model. The biphasic porous scaffolds consisted of poly lactic-co-glycolic acid (PLGA) with kartogenin (KGN) for cartilage repair and PLGA and β-calcium phosphate (PLGA/β-TCP) with cinnamaldehyde (CIN) for subchondral bone repair. KGN is a molecule for promoting chondrogenesis and CIN is a phytomolecule for enhancing osteogenesis and alleviating inflammation. The biphasic scaffolds PLGA/KGN-PLGA/β-TCP/CIN (PK/PTC) with bio-mimic structure provided stable mechanical properties and exhibited excellent biocompatibility to support cell adhesion, proliferation, migration, and distribution. Furthermore, KGN and CIN within biphasic scaffolds could be released in a controlled and sustained mode, and the biphasic scaffold degraded slowly in vitro . Evaluating the repair of 16-weeks post-implantation into critically sized OA-OCD rabbit models revealed that the biphasic scaffold could promote subchondral bone and cartilage regeneration, as well as reverse subchondral osteosclerosis caused by inflammation in vivo . These findings support the utilization of the PK/PTC scaffold for osteochondral regeneration and provide a promising potential strategy for clinical application for the treatment of patients with OA-OCD.

Anti-infection mechanism of a novel dental implant made of titanium-copper(TiCu)alloy and its mechanism associated with oral microbiology

This work was focused on study of anti-infection ability and its underlying mechanism of a novel dental implant made of titanium-copper(TiCu)alloy.In general,most studies on antibacterial implants have used a single pathogen to test their anti-infection ability using infectious animal models.However,dental implant-associated infections are polymicrobial diseases.We innovatively combine the classic ligature model in dogs with sucrose-rich diets to induce oral infections via the canine native oral bacteria.The anti-infection ability,biocompatibility and underlying mechanism of TiCu implant were systematically investigated in comparison with pure Ti implant via general inspection,hematology,imageology(micro-CT),microbiology(16S rDNA and metagenome),histology,and Cu ion detections.Compared with Ti implant,TiCu implant demonstrated remarkable anti-infection potentials with excellent biocompatibility.Additionally,the underlying anti-infection mechanism of TiCu implant was considered to involve maintaining the oral microbiota homeostasis.It was found that the carbohydrates in the plaques formed on the surface of TiCu implant were metabolized through the tricarboxylic acid cycle(TCA)cycles,which prevented the formation of an acidic microenvironment and inhibited the accumulation of acidogens and pathogens,thereby maintaining the microflora balance between aerobic and anaerobic bacteria.

Article Preclinical evaluation of acute systemic toxicity of magnesium incorporated poly(lactic-co-glycolic acid)porous scaffolds by three-dimensional printing Jing

Biodegradable polymer scaffolds combined with bioactive components which accelerate osteogenesis and angiogenesis have promise for use in clinical bone defect repair.The preclinical acute toxicity evaluation is an essential assay of implantable biomaterials to assess the biosafety for accelerating clinical translation.We have successfully developed magnesium(Mg)particles and beta-tricalcium phosphate(β-TCP)for incorporation into poly(lactic-co-glycolic acid)(PLGA)porous composite scaffolds(PTM)using low-temperature rapid prototyping three-dimensional-printing technology.The PTM scaffolds have been fully evaluated and found to exhibit excellent osteogenic capacity for bone defect repair.The preclinical evaluation of acute systemic toxicities is essential and important for development of porous scaffolds to facilitate their clinical translation.In this study,acute systemic toxicity of the PTM scaffolds was evaluated in mice by intraperitoneal injection of the extract solutions of the scaffolds.PTM composite scaffolds with different Mg andβ-TCP content(denoted as PT5M,PT10M,and PT15M)were extracted with different tissue culture media,including normal saline,phosphate-buffered saline,and serum-free minimum essential medium,to create the extract solutions.The evaluation was carried out following the National Standard.The acute toxicity was fully evaluated through the collection of extensive data,including serum/organs ion concentration,fluorescence staining,and in vivo median lethal dose measurement.Mg in major organs(heart,liver,and lung),and Mg ion concentrations in serum of mice,after intraperitoneal injection of the extract solutions,were measured and showed that the extract solutions of PT15M caused significant elevation of serum Mg ion concentrations,which exceeded the safety threshold and led to the death of the mice.In contrast,the extract solutions of PT5M and PT10M scaffolds did not cause the death of the injected mice.The median lethal dose of Mg ions in vivo for mice was determined for the first time in this study to be 110.66 mg/kg,and the safety level of serum magnesium toxicity in mice is 5.4 mM,while the calcium serum safety level is determined as 3.4 mM.The study was approved by the Animal Care and Use Committee of Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences(approval No.SIAT-IRB-170401-YGS-LYX-A0346)on April 5,2017.All these results showed that the Mg ion concentration of intraperitoneally-injected extract solutions was a determinant of mouse survival,and a high Mg ion concentration(more than 240 mM)was the pivotal factor contributing to the death of the mice,while changes in pH value showed a negligible effect.The comprehensive acute systemic toxicity evaluation for PTM porous composite scaffolds in this study provided a reference to guide the design and optimization of this composite scaffold and the results demonstrated the preclinical safety of the as-fabricated PTM scaffold with appropriate Mg content,strongly supporting the official registration process of the PTM scaffold as a medical device for clinical translation.

Promoting osteointegration effect of Cu-alloyed titanium in ovariectomized rats

Osteoporosis is a common skeletal disease making patients be prone to the osteoporotic fracture.However,the clinical implants made of titanium and its alloys with a poor osseointegration need a long time for healing and easily to loosening.Thus,a new class of Cu-alloyed titanium(TiCu)alloys with excellent mechanical properties and bio-functionalization has been developed.In this study,the osteoporosis modeled rats were used to study the osteointegration effect and underlying mechanism of TiCu.The results showed that after implantation for 4 weeks,TiCu alloy could promote the reconstruction of vascular network around the implant by up-regulating vascular endothelial growth factor expression.After 8weeks,it could further promote the proliferation and differentiation of osteoblasts,mineralization and deposition of collagens,and then significantly increasing bone mineral density around the implant.In conclusion,TiCu alloy would enhance the fixation stability,accelerate the osteointegration,and thus reduce the risk of aseptic loosening during the long-term implantation in the osteoporosis environment.This study was the first to report the role and mechanism of a Cu-alloyed metal in promoting osteointegration in osteoporosis environment,which provides a new attractive support for the improvement of future clinical applications of Cu-alloyed antibacterial titanium alloys.