The current need for organ and tissue replacement, repair, and regeneration for patients is continually growing such that supply is not meeting demand primarily due to a paucity of donors as well as ...biocompatibility issues leading to immune rejection of the transplant. In order to overcome these drawbacks, scientists have investigated the use of scaffolds as an alternative to transplantation. These scaffolds are designed to mimic the extracellular matrix (ECM) by providing structural support as well as promoting attachment, proliferation, and differentiation with the ultimate goal of yielding functional tissues or organs. Initial attempts at developing scaffolds were problematic and subsequently inspired an interest in 3D printing as a mode for generating scaffolds. Utilizing three‐dimensional printing (3DP) technologies, ECM‐like scaffolds can be produced with a high degree of complexity, where fine details can be included at a micrometer level. In this Review, the criteria for printing viable and functional scaffolds, scaffolding materials, and 3DP technologies used to print scaffolds for tissue engineering are discussed. Creating biofunctional scaffolds could potentially help to meet the demand by patients for tissues and organs without having to wait or rely on donors for transplantation.
The generation of scaffolds using 3D printing technologies is set to become a tangible option for a broad spectrum of patients in need of new tissues or organs. Bioengineers and clinicians are collaborating to create 3D printed scaffolds to mimic the local architecture of specific tissues at an intricate level. This Review gives an overview of the advancements made in 3D printing for tissue regeneration and compares the advantages and disadvantages of the different printing technologies and materials used.
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Large bone defects are usually managed by replacing lost bone with non-biological prostheses or with bone grafts that come from the patient or a donor. Bone tissue engineering, as a ...field, offers the potential to regenerate bone within these large defects without the need for grafts or prosthetics. Such therapies could provide improved long- and short-term outcomes in patients with critical-sized bone defects. Bone tissue engineering has long relied on the administration of growth factors in protein form to stimulate bone regeneration, though clinical applications have shown that using such proteins as therapeutics can lead to concerning off-target effects due to the large amounts required for prolonged therapeutic action. Gene-based therapies offer an alternative to protein-based therapeutics where the genetic material encoding the desired protein is used and thus loading large doses of protein into the scaffolds is avoided. Gene- and RNAi-activated scaffolds are tissue engineering devices loaded with nucleic acids aimed at promoting local tissue repair. A variety of different approaches to formulating gene- and RNAi-activated scaffolds for bone tissue engineering have been explored, and include the activation of scaffolds with plasmid DNA, viruses, RNA transcripts, or interfering RNAs. This review will discuss recent progress in the field of bone tissue engineering, with specific focus on the different approaches employed by researchers to implement gene-activated scaffolds as a means of facilitating bone tissue repair.
Development of synthetic biomaterials imbued with inorganic and organic characteristics of natural bone that are capable of promoting effective bone tissue regeneration is an ongoing goal of ...regenerative medicine. Calcium phosphate (CaP) has been predominantly utilized to mimic the inorganic components of bone, such as calcium hydroxyapatite, due to its intrinsic bioactivity and osteoconductivity. CaP-based materials can be further engineered to promote osteoinductivity through the incorporation of osteogenic biomolecules. In this study, we briefly describe the microstructure and the process of natural bone mineralization and introduce various methods for coating CaP onto biomaterial surfaces. In particular, we summarize the advantages and current progress of biomimetic surface-mineralizing processes using simulated body fluids for coating bone-like carbonated apatite onto various material surfaces such as metals, ceramics, and polymers. The osteoinductive effects of integrating biomolecules such as proteins, growth factors, and genes into the mineral coatings are also discussed.
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•Progress of preclinical and clinical research into engineered nanomedicine is helping to bring new effective diagnostic and therapeutic approaches to cancer ...patients.•Biomarker-driven engineered nanoparticles offer enhanced cancer-specific and personalized therapy.•Engineered nanoparticles represent an efficient tool to deliver different types of treatments for patients with difficult-to-treat cancers.•Surface-engineered nanoparticles have the potential to overcome the physical and biological barriers that are known to limit the effectiveness of unmodified or unfunctionalized nanoparticles.
Over the past two decades, multidisciplinary investigations into the development of nanoparticles for medical applications have continually increased. However, nanoparticles are still subject to biological barriers and biodistribution challenges, which limit their overall clinical potential. This has motivated the implementation of innovational modifications to a range of nanoparticle formulations designed for cancer imaging and/or cancer treatment to overcome specific barriers and shift the accumulation of payloads toward the diseased tissues. In recent years, novel technological and chemical approaches have been employed to modify or functionalize the surface of nanoparticles or manipulate the characteristics of nanoparticles. Combining these approaches with the identification of critical biomarkers provides new strategies for enhancing nanoparticle specificity for both cancer diagnostic and therapeutic applications. This review discusses the most recent advances in the design and engineering of nanoparticles as well as future directions for developing the next generation of nanomedicines.
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In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems associated with ...this type of delivery is that the drug concentration is controlled by first pass metabolism, and therefore may not always remain within the therapeutic window. Implantable drug delivery systems (IDDSs) are an excellent alternative to traditional delivery because they offer the ability to precisely control the drug release, deliver drugs locally to the target tissue, and avoid the toxic side effects often experienced with systemic administration. Since the creation of the first FDA-approved IDDS in 1990, there has been a surge in research devoted to fabricating and testing novel IDDS formulations. The versatility of these systems is evident when looking at the various biomedical applications that utilize IDDSs. This review provides an overview of the history of IDDSs, with examples of the different types of IDDS formulations, as well as looking at current and future biomedical applications for such systems. Though there are still obstacles that need to be overcome, ever-emerging new technologies are making the manufacturing of IDDSs a rewarding therapeutic endeavor with potential for further improvements.
Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the ...tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45
lymphoid and myeloid cells in matched tumor and blood from three patients with ccRCC. We also included 11,367 immune cells from four other individuals derived from the kidney and peripheral blood to facilitate the identification and assessment of ccRCC-specific differences. There is an overall increase in CD8
T-cell and macrophage populations in tumor-infiltrated immune cells compared to normal renal tissue. We further demonstrate the divergent cell transcriptional states for tumor-infiltrating CD8
T cells and identify a MKI67 + proliferative subpopulation being a potential culprit for the progression of ccRCC. Using the SCRS gene expression, we found preferential prediction of clinical outcomes and pathological diseases by subcluster assignment. With further characterization and functional validation, our findings may reveal certain subpopulations of immune cells amenable to therapeutic intervention.
Selenium has been extensively evaluated clinically as a chemopreventive agent with variable results depending on the type and dose of selenium used. Selenium species are now being therapeutically ...evaluated as modulators of drug responses rather than as directly cytotoxic agents. In addition, recent data suggest an association between selenium base-line levels in blood and survival of patients with COVID-19. The major focus of this mini review was to summarize: the pathways of selenium metabolism; the results of selenium-based chemopreventive clinical trials; the potential for using selenium metabolites as therapeutic modulators of drug responses in cancer (clear-cell renal-cell carcinoma (ccRCC) in particular); and selenium usage alone or in combination with vaccines in the treatment of patients with COVID-19. Critical therapeutic targets and the potential role of different selenium species, doses, and schedules are discussed.
Objectives
To evaluate the effect of non-viral gene therapy on human dental pulp stem cells (DPSCs) in an in vitro and an ex vivo model.
Materials and methods
Nanoplexes comprising polyethyleneimine ...(PEI) and plasmid DNA (pDNA) encoding for fibroblast growth factor-2 (p
FGF-2
) and bone morphogenic protein-2 (p
BMP-2
) were cultured with DPSCs to evaluate cytotoxicity, protein expression, and mineralization activity. Collagen scaffolds loaded with these nanoplexes or mineral trioxide aggregate (MTA) were utilized in an ex vivo tooth culture model to assess pulp response, over a period of 14 days. All nanoplex formulations were characterized for size and zeta potential by measuring dynamic light scattering and electrophoretic mobility, respectively.
Results
DPSCs treated with the nanoplexes showed increased cell proliferation and enhanced expression of BMP-2 and FGF-2 proteins. Collagen scaffolds containing PEI-p
BMP-2
and/or p
FGF-2
nanoplexes significantly increased cell proliferation, BMP-2 and FGF-2 expression, and mineralization when compared to MTA. Ex vivo histology showed a well-preserved pulp and healthy tissue in both the MTA and scaffold groups. Connective tissue in contact with the scaffold was dense and homogeneous, with some cells present in contact and within the scaffold.
Conclusion
Transfection of DPSCs with p
BMP-2
/p
FGF-2
nanoplexes resulted in increased expression of BMP-2 and FGF-2, enhanced proliferation, and mineralization properties compared to MTA. These findings were supported by the ex vivo observations.
Clinical relevance
This biological approach in pulp capping brings new insights into the effective management of engineered pulp tissues, mainly those generated by the transplantation of DPSCs in empty root canals.
Cytosine–phosphorothioate–guanine oligodeoxynucleotides (CpG ODN) is a recent class of immunostimulatory adjuvants that includes unmethylated CpG dinucleotide sequences similar to those commonly ...found in bacterial DNA. CpG ODN specifically triggers toll like receptor 9 (TLR9), which is found within phagoendosomes of antigen presenting cells (APCs) such as dendritic cells (DCs). CpG ODN triggers activation and maturation of DCs and helps to increase expression of antigens. CpG ODN can be used to induce polarized Th1 type immune responses. Several studies have shown that antigens and CpG ODN must be co-localized in the same APC to generate the most potent therapeutic antigen-specific immune responses. Delivery vehicles can be utilized to ensure co-delivery of antigens and CpG ODN to the same APCs and to significantly increase uptake by APCs. These strategies can result in antigen-specific immune responses that are 5 to 500-fold greater than administration of antigen alone. In this review, we discuss several recent and innovative strategies to co-delivering antigens and CpG ODN adjuvants to APCs. These approaches include the utilization of conjugate molecules, multi-component nanorods, liposomes, biodegradable microparticles, pulsatile release chips and cell-microparticle hybrids.
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