Biomineralized matrix and small molecule for bone tissue engineering

2.2 million surgical procedures for bone grafting are performed annually worldwide. While natural bones, such as autografts and allografts, and growth factors are commonly utilized in the procedures, they suffer from various shortcomings, such as high cost, donor site morbidity, and potential side effects. Alternatively, inspired by mineralized, dynamic environment of native bone, we developed biomineralized matrix recapitulating calcium phosphate (CaP)-rich mineral microenvironment that undergoes dynamic dissolution and reprecipitation. In this dissertation, we focus on the application of biomineralized matrix to induce osteogenesis of human pluripotent stem cells (hPSCs) for bone formation.Chapter 1 describes the progress in the development of CaP-based biomaterials and their applications in directing stem cell differentiation and supporting bone tissue formation. It includes our prior findings of biomineralized matrix-mediated osteogenesis of human mesenchymal stem cells (hMSCs) and bone formation in vivo. Chapter 2 demonstrates that biomineralized matrix can direct osteogenic differentiation of human embryonic stem cells (hESCs) by matrix-based cues alone, both in vitro and in vivo. Chapter 3 shows that the biomineralized matrix can solely induce osteogenic commitment of human induced pluripotent stem cells (hiPSCs) that can offer clinical benefits of autologous therapy. In chapter 4, we employ biomineralized matrix to study the effect of mineralized microenvironment on fate decision of hMSCs in presence of adipogenic-inducing medium. We show that biomineralized matrix dominates adipogenic soluble cues to direct osteogenic differentiation of hMSCs through adenosine A2b receptor (A2bR) signaling. Chapter 5 demonstrates utilization of adenosine, naturally small molecule to induce direct conversion of both hESCs and hiPSCs into osteoblasts. The osteoblasts derived from hiPSCs through adenosine treatment were found to contribute to the healing of critical-sized bone defects. Chapter 6 shows the application of biomineralized trilayered scaffold to induce subchondral bone formation for osteochondral tissue engineering in vivo. Chapter 7 concludes the dissertation and presents future directions, including functional bone tissue engineering and mechanistic studies of biomineralized matrix- and small molecule-driven osteogenic differentiation of hPSCs

Fast Numerical Reconstruction of Integral Imaging Based on a Determined Interval Mapping

In this paper, a fast numerical reconstruction of the integral imaging based on a determined interval mapping is proposed. To reduce the computation time, the proposed method employs the determined interval mapping instead of the use of magnification. In the numerical reconstruction procedure, the acquired elemental image array (EIA) from the 3D object is displayed. The flipped elemental image (EI)s are numerically formed by the virtual pinhole array. Then, the determined interval depending on the reconstruction plane is calculated and applied to each flipped EI. These flipped EIs are shifted to match the determined interval at the reconstruction plane and superimposed together. After this superimposed image is divided by the number of the superposition, the position error between the location of the shifted EI and the pixel position of the reconstruction plane is corrected by interpolation. As a result, the refocused image depending on the reconstruction plane can be reconstructed rapidly. From the experimental result, we confirmed that the proposed method largely decreased the computation time compared with the conventional method. In addition, we verified that the quality of the reconstruction by the proposed method is higher than the conventional method by the use of the structural similarity index method

Functionalized Nanomaterials as Tailored Theranostic Agents in Brain Imaging

Functionalized nanomaterials of various categories are essential for developing cancer nano-theranostics for brain diseases; however, some limitations exist in their effectiveness and clinical translation, such as toxicity, limited tumor penetration, and inability to cross blood–brain and blood-tumor barriers. Metal nanomaterials with functional fluorescent tags possess unique properties in improving their functional properties, including surface plasmon resonance (SPR), superparamagnetism, and photo/bioluminescence, which facilitates imaging applications in addition to their deliveries. Moreover, these multifunctional nanomaterials could be synthesized through various chemical modifications on their physical surfaces via attaching targeting peptides, fluorophores, and quantum dots (QD), which could improve the application of these nanomaterials by facilitating theranostic modalities. In addition to their inherent CT (Computed Tomography), MRI (Magnetic Resonance Imaging), PAI (Photo-acoustic imaging), and X-ray contrast imaging, various multifunctional nanoparticles with imaging probes serve as brain-targeted imaging candidates in several imaging modalities. The primary criteria of these functional nanomaterials for translational application to the brain must be zero toxicity. Moreover, the beneficial aspects of nano-theranostics of nanoparticles are their multifunctional systems proportioned towards personalized disease management via comprising diagnostic and therapeutic abilities in a single biodegradable nanomaterial. This review highlights the emerging aspects of engineered nanomaterials to reach and deliver therapeutics to the brain and how to improve this by adopting the imaging modalities for theranostic applications

The association between personality traits and placebo effects: A preregistered systematic review and meta-analysis

Placebo effects are ubiquitous yet highly variable between individuals, and therefore strongly impact clinical trial outcomes. It is unclear whether dispositional psychological traits influence responsiveness to placebo. This preregistered meta-analysis and systematic review synthesized the literature investigating the association between personality traits and placebo effects. Based on 19 studies with 712 participants, we performed formal meta-analyses for 10 different personality traits. We did not find evidence of associations between any of these traits and magnitude of placebo effects, which was supported by equivalence tests. Furthermore, we did not find evidence for moderating factors such as placebo manipulation type (Conditioning, non-conditioning) or condition (pain, non-pain). However, the current synthesis was not statistically powered for full inquiry into potential conditional or interactive associations between personality and situational variables. These findings challenge the notion that personality influences responsiveness to placebos and contradict its utility for identifying placebo “responders” and “non-responders”

Natural Products as New Approaches for Treating Bladder Cancer: From Traditional Medicine to Novel Drug Discovery

Bladder cancer (BC) is a heterogeneous disease that a tumor develops in the bladder lining and in some cases, the bladder muscle. Chemotherapy and immunotherapy are commonly used to treat bladder cancer. However, chemotherapy can cause burning and irritation in the bladder while BCG immunotherapy, which is the main type of intravesical immunotherapy for bladder cancer, can also cause burning in the bladder and flu-like symptoms. Thus, drugs originating from natural products have attracted much attention due to the reports that they have anti-cancer properties with low adverse effects. In this study, eighty-seven papers that dealt with natural products preventing or treating bladder cancer were reviewed. The studies were classified into the following mechanism: 71 papers on cell death, 5 papers on anti-metastasis, 3 papers on anti-angiogenesis, 1 paper on anti-resistance, and 7 papers on clinical trials. Most of the natural products that induced apoptosis up-regulated proteins such as caspase-3 and caspase-9. Regarding anti-metastasis, MMP-2 and MMP-9 are regulated frequently. Regarding anti-angiogenesis, HIF-1α and VEGF-A are down-regulated frequently. Nevertheless, the number of papers regarding anti-resistance and clinical trial are too few, so more studies are needed. In conclusion, this database will be useful for future in vivo studies of the anti-bladder cancer effect of natural products, in the process of selecting materials used for the experiment

Advances in Engineered Polymer Nanoparticle Tracking Platforms towards Cancer Immunotherapy—Current Status and Future Perspectives

Engineering polymeric nanoparticles for their shape, size, surface chemistry, and functionalization using various targeting molecules has shown improved biomedical applications for nanoparticles. Polymeric nanoparticles have created tremendous therapeutic platforms, particularly applications related to chemo- and immunotherapies in cancer. Recently advancements in immunotherapies have broadened this field in immunology and biomedical engineering, where “immunoengineering” creates solutions to target translational science. In this regard, the nanoengineering field has offered the various techniques necessary to manufacture and assemble multifunctional polymeric nanomaterial systems. These include nanoparticles functionalized using antibodies, small molecule ligands, targeted peptides, proteins, and other novel agents that trigger and encourage biological systems to accept the engineered materials as immune enhancers or as vaccines to elevate therapeutic functions. Strategies to engineer polymeric nanoparticles with therapeutic and targeting molecules can provide solutions for developing immune vaccines via maintaining the receptor storage in T- and B cells. Furthermore, cancer immunotherapy using polymeric nanomaterials can serve as a gold standard approach for treating primary and metastasized tumors. The current status of the limited availability of immuno-therapeutic drugs highlights the importance of polymeric nanomaterial platforms to improve the outcomes via delivering anticancer agents at localized sites, thereby enhancing the host immune response in cancer therapy. This review mainly focuses on the potential scientific enhancements and recent developments in cancer immunotherapies by explicitly discussing the role of polymeric nanocarriers as nano-vaccines. We also briefly discuss the role of multifunctional nanomaterials for their therapeutic impacts on translational clinical applications

Biomineralized Matrices Dominate Soluble Cues To Direct Osteogenic Differentiation of Human Mesenchymal Stem Cells through Adenosine Signaling

Stem cell differentiation is determined by a repertoire of signals from its microenvironment, which includes the extracellular matrix (ECM) and soluble cues. The ability of mesenchymal stem cells (MSCs), a common precursor for the skeletal system, to differentiate into osteoblasts and adipocytes in response to their local cues plays an important role in skeletal tissue regeneration and homeostasis. In this study, we investigated whether a bone-specific calcium phosphate (CaP) mineral environment could induce osteogenic differentiation of human MSCs, while inhibiting their adipogenic differentiation, in the presence of adipogenic-inducing medium. We also examined the mechanism through which the mineralized matrix suppresses adipogenesis of hMSCs to promote their osteogenic differentiation. Our results show that hMSCs cultured on mineralized matrices underwent osteogenic differentiation despite being cultured in the presence of adipogenic medium, which indicates the dominance of matrix-based cues of the mineralized matrix in directing osteogenic commitment of stem cells. Furthermore, the mineralized matrix-driven attenuation of adipogenesis was reversed with the inhibition of A2b adenosine receptor (A2bR), implicating a role of adenosine signaling in mineralized environment-mediated inhibition of adipogenesis. Such synthetic matrices with an intrinsic ability to direct differentiation of multipotent adult stem cells toward a targeted phenotype while inhibiting their differentiation into other lineages not only will be a powerful tool in delineating the role of complex microenvironmental cues on stem cell commitment but also will contribute to functional tissue engineering and their translational applications