The optimal treatment for complex fractures and large bone defects is an important unsolved issue in orthopedics and related specialties. Approximately 5-10% of fractures fail to heal and develop non-unions. Bone healing can be characterized by three partially overlapping phases: the inflammatory phase, the repair phase, and the remodeling phase. Eventual healing is highly dependent on the initial inflammatory phase, which is affected by both the local and systemic responses to the injurious stimulus. Furthermore, immune cells and mesenchymal stromal cells (MSCs) participate in critical inter-cellular communication or crosstalk to modulate bone healing. Deficiencies in this inter-cellular exchange, inhibition of the natural processes of acute inflammation, and its resolution, or chronic inflammation due to a persistent adverse stimulus can lead to impaired fracture healing. Thus, an initial and optimal transient stage of acute inflammation is one of the key factors for successful, robust bone healing. Recent studies demonstrated the therapeutic potential of immunomodulation for bone healing by the preconditioning of MSCs to empower their immunosuppressive properties. Preconditioned MSCs (also known as "primed/ licensed/ activated" MSCs) are cultured first with pro-inflammatory cytokines (e.g., TNFα and IL17A) or exposed to hypoxic conditions to mimic the inflammatory environment prior to their intended application. Another approach of immunomodulation for bone healing is the resolution of inflammation with anti-inflammatory cytokines such as IL4, IL10, and IL13. In this review, we summarize the principles of inflammation and bone healing and provide an update on cellular interactions and immunomodulation for optimal bone healing.

/pdf/modulation-of-the-inflammatory-response-and-bone-healing-1xx1cdik3c.pdf

Modulation of the Inflammatory Response and Bone Healing.

As important players in cell-to-cell communication, exosomes (exo) are believed to play a similar role in promoting fracture healing. This study investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exos) could improve fracture healing of nonunion. BMMSC-Exos were isolated and transplanted into the fracture site in a rat model of femoral nonunion (Exo group) every week. Moreover, equal volumes of phosphate-buffered saline (PBS) and exosome-depleted conditioned medium (CM-Exo) were injected into the femoral fracture sites of the rats in the control and CM-Exo groups. Bone healing processes were recorded and evaluated by radiographic methods on weeks 8, 14 and 20 after surgery. Osteogenesis and angiogenesis at the fracture sites were evaluated by radiographic and histological methods on postoperative week 20. The expression levels of osteogenesis- or angiogenesis-related genes were evaluated in vitro by western blotting and immunohistochemistry. The ability to internalize exosomes was assessed using the PKH26 assay. Altered proliferation and migration of human umbilical vein endothelial cells (HUVECs) and mouse embryo osteoblast precursor cells (MC3TE-E1s) treated with BMMSC-Exos were determined by utilizing EdU incorporation, immunofluorescence staining, and scratch wound assay. The angiogenesis ability of HUVECs was evaluated through tube formation assays. Finally, to explore the effect of exosomes in osteogenesis via the BMP-2/Smad1/RUNX2 signalling pathway, the BMP-2 inhibitors noggin and LDN193189 were utilized, and their subsequent effects were observed. BMMSC-Exos were observed to be spherical with a diameter of approximately 122 nm. CD9, CD63 and CD81 were expressed. Transplantation of BMMSC-Exos obviously enhanced osteogenesis, angiogenesis and bone healing processes in a rat model of femoral nonunion. BMMSC-Exos were taken up by HUVECs and MC3T3-E1 in vitro, and their proliferation and migration were also improved. Finally, experiments with BMP2 inhibitors confirmed that the BMP-2/Smad1/RUNX2 signalling pathway played an important role in the pro-osteogenesis induced by BMMSC-Exos and enhanced fracture healing of nonunion. Our findings suggest that transplantation of BMMSC-Exos exerts a critical effect on the treatment of nonunion by promoting osteogenesis and angiogenesis. This promoting effect might be ascribed to the activation of the BMP-2/Smad1/RUNX2 and the HIF-1α/VEGF signalling pathways.

/pdf/exosomes-from-bone-marrow-mesenchymal-stem-cells-enhance-1bnr5zha3a.pdf

Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion

Traditional treatment approaches for cancer involve intravenous chemotherapy or other forms of drug delivery. These therapeutic measures suffer from several limitations such as nonspecific targeting, poor biodistribution, and buildup of drug resistances. However, significant technological advancements have been made in terms of superior modes of drug delivery over the last few decades. Technical capability in analyzing the molecular mechanisms of tumor biology, nanotechnology─particularly the development of biocompatible nanoparticles, surface modification techniques, microelectronics, and material sciences─has increased. As a result, a significant number of nanostructured carriers that can deliver drugs to specific cancerous sites with high efficiency have been developed. This particular maneuver that enables the introduction of a therapeutic nanostructured substance in the body by controlling the rate, time, and place is defined as the nanostructured drug delivery system (NDDS). Because of their versatility and ability to incorporate features such as specific targeting, water solubility, stability, biocompatibility, degradability, and ability to reverse drug resistance, they have attracted the interest of the scientific community, in general, and nanotechnologists as well as biomedical scientists. To keep pace with the rapid advancement of nanotechnology, specific technical aspects of the recent NDDSs and their prospects need to be reported coherently. To address these ongoing issues, this review article provides an overview of different NDDSs such as lipids, polymers, and inorganic nanoparticles. In addition, this review also reports the challenges of current NDDSs and points out the prospective research directions of these nanocarriers. From our focused review, we conclude that still now the most advanced and potent field of application for NDDSs is lipid-based, while other significantly potential fields include polymer-based and inorganic NDDSs. However, despite the promises, challenges remain in practical implementations of such NDDSs in terms of dosage and stability, and caution should be exercised regarding biocompatibility of materials. Considering these aspects objectively, this review on NDDSs will be particularly of interest for small-to-large scale industrial researchers and academicians with expertise in drug delivery, cancer research, and nanotechnology.

Recent Progress in Nanostructured Smart Drug Delivery Systems for Cancer Therapy: A Review.

Bacteriophages, or phages, are viruses that specifically infect bacteria and coopt the cellular machinery to create more phage proteins, eventually resulting in the release of new phage particles. Phages are heavily utilized in bioengineering for applications ranging from tissue engineering scaffolds to immune signal delivery. Of specific interest to vaccines and immunotherapies, phages have demonstrated an ability to activate both the innate and adaptive immune systems. The genome of these viral particles can be harnessed for DNA vaccination, or the surface proteins can be exploited for antigen display. More specifically, genes that encode an antigen of interest can be spliced into the phage genome, allowing antigenic proteins or peptides to be displayed by fusion to phage capsid proteins. Phages therefore present antigens to immune cells in a highly ordered and repetitive manner. This review discusses the use of phage with adjuvanting activity as antigen delivery vehicles for vaccination against infectious disease and cancer.

Phage display as a tool for vaccine and immunotherapy development

Bone is one of the most frequently transplanted tissues. The bone structure and its physiological function and stem cells biology were known to be closely related to each other for many years. Bone is considered a home to the well-known systems of postnatal mesenchymal stem cells (MSCs). These bone resident MSCs provide a range of growth factors (GF) and cytokines to support cell growth following injury. These GFs include a group of proteins and peptides produced by different cells which are regulators of important cell functions such as division, migration, and differentiation. GF signaling controls the formation and development of the MSCs condensation and plays a critical role in regulating osteogenesis, chondrogenesis, and bone/mineral homeostasis. Thus, a combination of both MSCs and GFs receives high expectations in regenerative medicine, particularly in bone repair applications. It is known that the delivery of exogenous GFs to the non-union bone fracture site remarkably improves healing results. Here we present updated information on bone tissue engineering with a specific focus on GF characteristics and their application in cellular functions and tissue healing. Moreover, the interrelation of GFs with the damaged bone microenvironment and their mechanistic functions are discussed.

Osteogenesis and bone remodeling: A focus on growth factors and bioactive peptides

Despite years of intensive research, breast cancer remains the leading cause of death in women worldwide New technologies including oncolytic virus therapies, virus, and phage display are among the most powerful and advanced methods that have emerged in recent years with potential applications in cancer prevention and treatment Oncolytic virus therapy is an interesting strategy for cancer treatment Presently, a number of viruses from different virus families are under laboratory and clinical investigation as oncolytic therapeutics Oncolytic viruses (OVs) have been shown to be able to induce and initiate a systemic antitumor immune response The possibility of application of a multimodal therapy using a combination of the OV therapy with immune checkpoint inhibitors and cancer antigen vaccination holds a great promise in the future of cancer immunotherapy Display of immunologic peptides on bacterial viruses (bacteriophages) is also increasingly being considered as a new and strong cancer vaccine delivery strategy In phage display immunotherapy, a peptide or protein antigen is presented by genetic fusions to the phage coat proteins, and the phage construct formulation acts as a protective or preventive vaccine against cancer In our laboratory, we have recently tested a few peptides (E75, AE37, and GP2) derived from HER2/neu proto-oncogene as vaccine delivery modalities for the treatment of TUBO breast cancer xenograft tumors of BALB/c mice Here, in this paper, we discuss the latest advancements in the applications of OVs and bacterial viruses display systems as new and advanced modalities in cancer immune therapeutics

The viral approach to breast cancer immunotherapy.

Lipid-based nanoparticulate delivery platforms such as liposomes help overcome cell and tissue barriers and allow prolonged therapeutic plasma drug concentrations, simultaneous targeting of tumor tissue, and increased bioavailability of numerous drugs used for treatment of cancer. The human epidermal growth factor receptor, HER2, is an important player in the pathogenesis of breast cancer and is considered a potential cancer biomarker for the design of immunotherapeutics. HER2-positive breast cancer is found in up to 30% of breast cancer patients. Currently, a variety of lipid nanoparticulate systems are being evaluated in preclinical settings and in clinical trials for targeting HER2-positive breast cancer. Advances in functionalized anti-HER2 lipid nanoparticulates have demonstrated promise and may lead to the development of new nano-immunotherapy protocols against HER2 positive breast cancer. Here we present a review of the most up-to-date literature, including our own research, on the use of lipid nanoparticulate carriers in immunotherapy of HER2-positive breast cancer. 

Lipid-based nanoparticulate delivery systems for HER2-positive breast cancer immunotherapy

Depending on the duration of healing process, 5-10% of bone fractures may result in either nonunion or delayed union. Because nonunions remain a clinically important problem, there is interest in the utilization of tissue engineering strategies to augment bone fracture repair. Three basic biologic elements that are required for bone regeneration include cells, extracellular matrix scaffolds and biological adjuvants for growth, differentiation and angiogenesis. Mesenchymal stem cells (MSCs) are capable to differentiate into various types of the cells including chondrocytes, myoblasts, osteoblasts, and adipocytes. Due to their potential for multilineage differentiation, MSCs are considered important contributors in bone tissue engineering research. In this review we highlight the progress in the application of biomaterials, stem cells and tissue engineering in promoting nonunion bone fracture healing. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2551-2561, 2018.

Nonunion fractures, mesenchymal stem cells and bone tissue engineering.

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The viral approach to breast cancer immunotherapy.

Lipid-based nanoparticulate delivery systems for HER2-positive breast cancer immunotherapy

Nonunion fractures, mesenchymal stem cells and bone tissue engineering.