Advances in cell membrane-coated nanoparticles and their applications for bone therapy.

Due to the specific structure of natural bone, most of the therapeutics are incapable to be delivered into the targeted site with effective concentrations. Nanotechnology has provided a good way to improve this issue, cell membrane mimetic nanoparticles (NPs) have been emerging as an ideal nanomaterial which integrates the advantages of natural cell membranes with synthetic NPs to significantly improve the biocompatibility as well as achieving long-lasting circulation and targeted delivery. In addition, functionalized modifications of the cell membrane facilitate more precise targeting and therapy. Here, an overview of the preparation of cell membrane-coated NPs and the properties of cell membranes from different cell sources has been given to expatiate their function and potential applications. Strategies for functionalized modification of cell membranes are also briefly described. The application of cell membrane-coated NPs for bone therapy is then presented according to the function of cell membranes. Moreover, the prospects and challenges of cell membrane-coated NPs for translational medicine have also been discussed.

Organoid extracellular vesicle-based therapeutic strategies for bone therapy.

With the rapid development of population ageing, bone-related diseases seriously affecting the life of the elderly. Over the past few years, organoids, cell clusters with specific functions and structures that are self-induced from stem cells after three-dimensional culture in vitro, have been widely used for bone therapy. Moreover, organoid extracellular vesicles (OEVs) have emerging as promising cell-free nanocarriers due to their vigoroso physiological effects, significant biological functions, stable loading capacity, and great biocompatibility. In this review, we first provide a comprehensive overview of biogenesis, internalisation, isolation, and characterisation of OEVs. We then comprehensively highlight the differences between OEVs and traditional EVs. Subsequently, we present the applications of natural OEVs in disease treatment. We also summarise the engineering modifications of OEVs, including engineering parental cells and engineering OEVs after isolation. Moreover, we provide an outlook on the potential of natural and engineered OEVs in bone-related diseases. Finally, we critically discuss the advantages and challenges of OEVs in the treatment of bone diseases. We believe that a comprehensive discussion of OEVs will provide more innovative and efficient solutions for complex bone diseases.

On-Target Side Effects of Targeted Therapeutics of Cancer.

The concept of precision medicine is based on the identification of hallmarks of cancer to exploit them as drug targets. The basic idea was that in this way the therapeutic modalities will be more effective and the side effects will be less. Since the majority of these novel modalities are not specific for a cancer-related biological process or a cancer-specific (mutant) target protein, it is not a surprise that we had to learn new type of side effects, because these therapeutics also affect physiological or pathological processes. Even more, in cases of some of these novel therapies we were able to discover new molecular mechanisms of physiological and pathological processes. Identification of the on-target side effects of targeted drugs can help to prevent the development of them or better manage the patients when emerge during cancer therapy.

Role of Phosphorus-Containing Molecules on the Formation of Nano-Sized Calcium Phosphate for Bone Therapy.

Calcium phosphate (CaP) is the principal inorganic constituent of bone and teeth in vertebrates and has various applications in biomedical areas. Among various types of CaPs, amorphous calcium phosphate (ACP) is considered to have superior bioactivity and biodegradability. With regard to the instability of ACP, the phosphorus-containing molecules are usually adopted to solve this issue, but the specific roles of the molecules in the formation of nano-sized CaP have not been clearly clarified yet. Herein, alendronate, cyclophosphamide, zoledronate, and foscarnet are selected as the model molecules, and theoretical calculations were performed to elucidate the interaction between calcium ions and different model molecules. Subsequently, CaPs were prepared with the addition of the phosphorus-containing molecules. It is found that cyclophosphamide has limited influence on the generation of CaPs due to their weak interaction. During the co-precipitation process of Ca2+ and PO4 3-, the competitive relation among alendronate, zoledronate, and foscarnet plays critical roles in the produced inorganic-organic complex. Moreover, the biocompatibility of CaPs was also systematically evaluated. The DFT calculation provides a convincing strategy for predicting the structure of CaPs with various additives. This work is promising for designing CaP-based multifunctional drug delivery systems and tissue engineering materials.

Black phosphorus-based 2D materials for bone therapy.

Since their discovery, Black Phosphorus (BP)-based nanomaterials have received extensive attentions in the fields of electromechanics, optics and biomedicine, due to their remarkable properties and excellent biocompatibility. The most essential feature of BP is that it is composed of a single phosphorus element, which has a high degree of homology with the inorganic components of natural bone, therefore it has a full advantage in the treatment of bone defects. This review will first introduce the source, physicochemical properties, and degradation products of BP, then introduce the remodeling process of bone, and comprehensively summarize the progress of BP-based materials for bone therapy in the form of hydrogels, polymer membranes, microspheres, and three-dimensional (3D) printed scaffolds. Finally, we discuss the challenges and prospects of BP-based implant materials in bone immune regulation and outlook the future clinical application.

Preferences of orthopedic surgeons for treating midshaft clavicle fracture in adults / Preferências dos cirurgiões ortopédicos para o tratamento da fratura do terço médio da clavícula em adultos

ABSTRACT Objective To determine the current clinical practice in Latin America for treating midshaft clavicle fractures, including surgical and non-surgical approaches. Methods A cross-sectional study using a descriptive questionnaire. Shoulder and elbow surgeons from the Brazilian Society of Shoulder and Elbow Surgery and from the Latin American Society of Shoulder and Elbow were contacted and asked to complete a short questionnaire (SurveyMonkey®) on the management of midshaft fractures of the clavicle. Incomplete or inconsistent answers were excluded. Results The type of radiographic classification preferably used was related to description of fracture morphology, according to 41% of participants. Allman classification ranked second and was used by 24.1% of participants. As to indications for surgical treatment, only the indications with shortening and imminence of skin exposure were statistically significant. Conservative treatment was chosen in cortical contact. Regarding immobilization method, the simple sling was preferred, and treatment lasted from 4 to 6 weeks. Although the result was not statistically significant, the blocked plate was the preferred option in surgical cases. Conclusion The treatment of midshaft clavicle fractures in Latin America is in accordance with the current literature.

RESUMO Objetivo Determinar a prática clínica atual na América Latina para o tratamento das fraturas do terço médio da clavícula, incluindo abordagens cirúrgicas e não cirúrgicas. Métodos Estudo transversal com aplicação de questionário descritivo. Cirurgiões de ombro e cotovelo da Sociedade Brasileira de Cirurgia do Ombro e Cotovelo e da Sociedade Latino-Americana de Ombro e Cotovelo foram contatados e convidados a completar um breve questionário (SurveyMonkey®) sobre o manejo das fraturas do terço médio da clavícula. Foram excluídas as respostas incompletas ou inconsistentes. Resultados O tipo de classificação radiográfica utilizada de preferência esteve de acordo com a descrição da morfologia da fratura, representando 41% do total dos participantes. Em segundo lugar, apareceu a classificação de Allman, que foi utilizada por 24,1% dos participantes. Nas indicações de tratamento cirúrgico, as indicações com encurtamento e iminência de exposição da pele foram estatisticamente significativas. Tratamento conservador foi prescrito em caso de contato entre as corticais. Como método de imobilização, a tipoia simples foi a preferência, e o tempo de tratamento foi de 4 a 6 semanas. Apesar do resultado sem significância estatística, a placa bloqueada foi a opção preferencial nos casos cirúrgicos. Conclusão A metodologia de tratamento das fraturas do terço médio da clavícula nos países da América Latina é semelhante, assim como com a literatura atual.

Bone-specific poly(ethylene sodium phosphate)-bearing biodegradable nanoparticles.

Chemotherapy is the most reliable treatment for osteoporosis and osseous metastases. To facilitate better drug delivery for bone treatments, a novel preparation of polymeric nanoparticles with high affinity to bone has been prepared. Two-step synthesis of cholesteryl-functionalized poly(ethylene sodium phosphate) (Ch-PEPn·Na) was performed via ring-opening polymerization of cyclic phosphoesters and the demethylation. The molecular weight of Ch-PEPn·Na could be well controlled by changing the ratio of cholesterol and cyclic phosphoesters. Because Ch-PEPn·Na exhibits an amphiphilic nature in aqueous media, Ch-PEPn·Na-bearing nanoparticles (PEPn·Na NPs) were prepared by a solvent evaporation technique. The size of the nanoparticles investigated in the current study is approximately 100nm, which was determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Due to the presence of highly water-soluble polymer chains, dispersion of PEPn·Na NPs in aqueous media was stable for at least 1 week. Hemolytic activity of PEPn·Na NPs was found to be low and PEPn·Na NPs did not disintegrate mammalian cell membranes. Additionally, cytotoxicity of PEPn·Na NPs was not observed at concentrations below 100µg/mL. The adsorption of PEPn·Na NPs on hydroxyapatite (HAp) microparticles was studied in comparison with poly(ethylene glycol) nanoparticles (PEG NPs). Both PEPn·Na NPs and PEG NPs adsorbed well onto HAp microparticles in distilled water with binding equilibrium constants (KHAp) for PEPn·Na NPs and PEG NPs of 3.6×106 and 7.9×106, respectively. In contrast, only PEPn·Na NPs adsorbed onto HAp microparticles in a saline phosphate buffer. Moreover, the adsorption of PEPn·Na NPs onto HAp microparticles occurred even in the presence of 1.2mM calcium ions or low-pH media. The affinity of the nanoparticles to bovine bone slices was also studied, with the result that large quantities of adsorbed PEPn·Na NPs were observed on the slices by scanning electron microscope.

Titania nanotubes for orchestrating osteogenesis at the bone-implant interface.

Titanium implants can fail due to inappropriate biomechanics at the bone-implant interface that leads to suboptimal osseointegration. Titania nanotubes (TNTs) fabricated on Ti implants by the electrochemical process have emerged as a promising modification strategy to facilitate osseointegration. TNTs enable augmentation of bone cell functions at the bone-implant interface and can be tailored to incorporate multiple functionalities including the loading of active biomolecules into the nanotubes to target anabolic processes in bone conditions such as osteoporotic fractures. Advanced functions can be introduced, including biopolymers, nanoparticles and electrical stimulation to release growth factors in a desired manner. This review describes the application of TNTs for enhancing osteogenesis at the bone-implant interface, as an alternative approach to systemic delivery of therapeutic agents.

Drug diffusion, integration, and stability of nanoengineered drug-releasing implants in bone ex-vivo.

To treat skeletal conditions such as bone infections, osteoporotic fractures, and osteosarcoma, it would be ideal to introduce drugs directly to the affected site. Localized drug delivery from the bone implants is a promising alternative to systemic drug administration. In this study we investigated electrochemically nanoengineered Ti wire implants with titania nanotubes (TNTs), as minimally invasive drug-releasing implants for the delivery of drugs directly into the bone tissue. Since trabecular bone in vivo contains a highly interconnected bone marrow, we sought to determine the influence of marrow on drug release and diffusion. Electrochemical anodization of Ti wires (length 10 mm) was performed to create an oxide layer with TNTs on the surface, followed by loading with a fluorescent model drug, Rhodamine B (RhB). Cores of bovine trabecular bone were generated from the sternum of a young steer, and were processed to have an intact bone marrow, or the marrow was removed. RhB-loaded TNTs/Ti wires were inserted into the bone cores, which were then cultured ex vivo using the ZetOS™ bioreactor system to maintain bone viability. Release and diffusion of RhB inside the bone was monitored using fluorescence imaging and different patterns of drug transport in the presence or absence of marrow were observed. Scanning electron microscopy of the implants after retrieval from bone cores confirmed survival of the TNTs structures. Histological investigation showed the presence of bone cells adherent on the implants. This study shows a potential of Ti drug-releasing implants based on TNTs technology towards localized bone therapy. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 714-725, 2016.

Anti-Resorptive Functions of Poly(ethylene sodium phosphate) on Human Osteoclasts.

Osteoporosis involves hyperactive osteoclasts. A large number of current drugs result in side effects affecting their efficacy in the clinic. Polyphosphoesters are unique polymeric biomaterials because of their biocompatibility, biodegradability, and bone affinity. We studied the viability and ability of human osteoclasts to resorb bone when dosed with poly(ethylene sodium phosphate) (PEP·Na). This did not trigger any change in osteoblast cell viability, however the polymer diminished human osteoclasts and their ability to resorb bone at concentrations as low as 10(-4) m · mL(-1). This is the first report to validate the possibility of using polyphosphoesters for selective inhibition of human osteoclast functions, indicating its potential to be used as an effective polymer prodrug for treatment of osteoporosis.