Hydrogels in the treatment of rheumatoid arthritis: drug delivery systems and artificial matrices for dynamic in vitro models.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disorder that mostly affects the synovial joints and can promote both cartilage and bone tissue destruction. Several conservative treatments are available to relieve pain and control the inflammation; however, traditional drugs administration are not fully effective and present severe undesired side effects. Hydrogels are a very attractive platform as a drug delivery system to guarantee these handicaps are reduced, and the therapeutic effect from the drugs is maximized. Furthermore, hydrogels can mimic the physiological microenvironment and have the mechanical behavior needed for use as cartilage in vitro model. The testing of these advanced delivery systems is still bound to animal disease models that have shown low predictability. Alternatively, hydrogel-based human dynamic in vitro systems can be used to model diseases, bypassing some of the animal testing problems. RA dynamic disease models are still in an embryonary stage since advances regarding healthy and inflamed cartilage models are currently giving the first steps regarding complexity increase. Herein, recent studies using hydrogels in the treatment of RA, featuring different hydrogel formulations are discussed. Besides, their use as artificial extracellular matrices in dynamic in vitro articular cartilage is also reviewed.

Microfluidics for Angiogenesis Research.

Angiogenesis is a natural and vital phenomenon of neovascularization that occurs from pre-existing vasculature, being present in many physiological processes, namely in development, reproduction and regeneration. Being a highly dynamic and tightly regulated process, its abnormal expression can be on the basis of several pathologies. For that reason, angiogenesis has been a subject of major interest among the scientific community, being transverse to different areas and founding particular attention in tissue engineering and cancer research fields. Microfluidics has emerged as a powerful tool for modelling this phenomenon, thereby surpassing the limitations associated to conventional angiogenic models. Holding a tremendous flexibility in terms of experimental design towards a specific goal, microfluidic systems can offer an unlimited number of opportunities for investigating angiogenesis in many relevant scenarios, namely from its fundamental comprehension in normal physiological processes to the identification and testing of new therapeutic targets involved on pathological angiogenesis. Additionally, microvascular 3D in vitro models are now opening up new prospects in different fields, being used for investigating and establishing guidelines for the development of next generation of 3D functional vascularized grafts. The promising applications of this emerging technology in angiogenesis studies are herein overviewed, encompassing fundamental and applied research.

Biomaterials and Microfluidics for Drug Discovery and Development.

Microfluidic devices are now one of the most promising tools to mimic in vivo like conditions, either in normal or disease scenarios, such as tumorigenesis or pathogenesis. Together with the potential of biomaterials, its combination with microfluidics represents the ability to more closely mimic cells' natural microenvironment concerning its three-dimensional (3D) nature and continuous perfusion with nutrients and cells' crosstalk. Due to miniaturization and increased experimental throughput, microfluidics have generated significant interest in the drug discovery and development domain. Herein, the most recent advances in the field of microfluidics for drug discovery are overviewed, and the role of biomaterials in 3D in vitro models and the contribution of organ-on-a-chip technologies highlighted.

Scaffolds and coatings for bone regeneration.

Bone tissue has an astonishing self-healing capacity yet only for non-critical size defects (<6 mm) and clinical intervention is needed for critical-size defects and beyond that along with non-union bone fractures and bone defects larger than critical size represent a major healthcare problem. Autografts are, still, being used as preferred to treat large bone defects. Mostly, due to the presence of living differentiated and progenitor cells, its osteogenic, osteoinductive and osteoconductive properties that allow osteogenesis, vascularization, and provide structural support. Bone tissue engineering strategies have been proposed to overcome the limited supply of grafts. Complete and successful bone regeneration can be influenced by several factors namely: the age of the patient, health, gender and is expected that the ideal scaffold for bone regeneration combines factors such as bioactivity and osteoinductivity. The commercially available products have as their main function the replacement of bone. Moreover, scaffolds still present limitations including poor osteointegration and limited vascularization. The introduction of pores in scaffolds are being used to promote the osteointegration as it allows cell and vessel infiltration. Moreover, combinations with growth factors or coatings have been explored as they can improve the osteoconductive and osteoinductive properties of the scaffold. This review focuses on the bone defects treatments and on the research of scaffolds for bone regeneration. Moreover, it summarizes the latest progress in the development of coatings used in bone tissue engineering. Despite the interesting advances which include the development of hybrid scaffolds, there are still important challenges that need to be addressed in order to fasten translation of scaffolds into the clinical scenario. Finally, we must reflect on the main challenges for bone tissue regeneration. There is a need to achieve a proper mechanical properties to bear the load of movements; have a scaffolds with a structure that fit the bone anatomy.

Silk Fibroin-Based Scaffold for Bone Tissue Engineering.

Regeneration of diseased or damaged skeletal tissues is one of the challenge that needs to be solved. Although there have been many bone tissue engineering developed, scaffold-based tissue engineering complement the conventional treatment for large bone by completing biological and functional environment. Among many materials, silk fibroin (SF) is one of the favorable material for applications in bone tissue engineering scaffolding. SF is a fibrous protein mainly extracted from Bombyx mori. and spiders. SF has been used as a biomaterial for bone graft by its unique mechanical properties, controllable biodegradation rate and high biocompatibility. Moreover, SF can be processed using conventional and advanced biofabrication methods to form various scaffold types such as sponges, mats, hydrogels and films. This review discusses about recent application and advancement of SF as a biomaterial.

Seaweed polysaccharide-based hydrogels used for the regeneration of articular cartilage.

This manuscript provides an overview of the in vitro and in vivo studies reported in the literature focusing on seaweed polysaccharides based hydrogels that have been proposed for applications in regenerative medicine, particularly, in the field of cartilage tissue engineering. For a better understanding of the main requisites for these specific applications, the main aspects of the native cartilage structure, as well as recognized diseases that affect this tissue are briefly described. Current available treatments are also presented to emphasize the need for alternative techniques. The following part of this review is centered on the description of the general characteristics of algae polysaccharides, as well as relevant properties required for designing hydrogels for cartilage tissue engineering purposes. An in-depth overview of the most well known seaweed polysaccharide, namely agarose, alginate, carrageenan and ulvan biopolymeric gels, that have been proposed for engineering cartilage is also provided. Finally, this review describes and summarizes the translational aspect for the clinical application of alternative systems emphasizing the importance of cryopreservation and the commercial products currently available for cartilage treatment.

In vivo biofunctional evaluation of hydrogels for disc regeneration.

PURPOSE: Regenerative strategies aim to restore the original biofunctionality of the intervertebral disc. Different biomaterials are available, which might support disc regeneration. In the present study, the prospects of success of two hydrogels functionalized with anti-angiogenic peptides and seeded with bone marrow derived mononuclear cells (BMC), respectively, were investigated in an ovine nucleotomy model. METHODS: In a one-step procedure iliac crest aspirates were harvested and, subsequently, separated BMC were seeded on hydrogels and implanted into the ovine disc. For the cell-seeded approach a hyaluronic acid-based hydrogel was used. The anti-angiogenic potential of newly developed VEGF-blockers was investigated on ionically crosslinked metacrylated gellan gum hydrogels. Untreated discs served as nucleotomy controls. 24 adult merino sheep were used. After 6 weeks histological, after 12 weeks histological and biomechanical analyses were conducted. RESULTS: Biomechanical tests revealed no differences between any of the implanted and nucleotomized discs. All implanted discs significantly degenerated compared to intact discs. In contrast, there was no marked difference between implanted and nucleotomized discs. In tendency, albeit not significant, degeneration score and disc height index deteriorated for all but not for the cell-seeded hydrogels from 6 to 12 weeks. Cell-seeded hydrogels slightly decelerated degeneration. CONCLUSIONS: None of the hydrogel configurations was able to regenerate biofunctionality of the intervertebral disc. This might presumably be caused by hydrogel extrusion. Great importance should be given to the development of annulus sealants, which effectively exploit the potential of (cell-seeded) hydrogels for biological disc regeneration and restoration of intervertebral disc functioning.

Hydroxyapatite/alginate/gellan gum inks with osteoconduction and osteogenic potential for bioprinting bone tissue analogues.

There is a growing demand for engineered bone tissues custom-designed to match the patient-specific defect size and in vitro models for studying bone diseases and/or drug screening. Herein, we propose a bioprinted bone tissue construct using SaOs-2 cells within alginate/gellan gum/hydroxyapatite inks. Different ink formulations were developed with varying hydroxyapatite content and then evaluated for viscoelasticity, printability, biomineralization properties, post-printing viability, proliferation, metabolic activity, and osteogenic phenotype of SaOs-2-encapsulated cells. Results indicate that ink formulations exhibit non-Newtonian shear-thinning behaviour, maintaining shape integrity and structural stability post-printing. Ink mineralization rates increase with the hydroxyapatite content, rendering them suitable for bone defect strategies. Post-printed cells in the developed constructs remain live, spreading, and metabolically active but do not proliferate. Osteogenic gene and protein expression, both early and late, show upregulation at day 7 relative to day 1, followed by downregulation at day 14. Lower hydroxyapatite content inks demonstrate up to fourfold upregulation in genes and proteins at most time points. Additionally, these constructs release calcium and phosphate at levels conducive to mineralization. Overall, the tissue-engineered miniaturized constructs not only meet the criteria for early-stage bone defect/fracture regeneration but also serve as a promising platform for drug screening and evaluating potential therapeutic treatments.

Innovative nanotheranostics: Smart nanoparticles based approach to overcome breast cancer stem cells mediated chemo- and radioresistances.

The alarming increase in the number of breast cancer patients worldwide and the increasing death rate indicate that the traditional and current medicines are insufficient to fight against it. The onset of chemo- and radioresistances and cancer stem cell-based recurrence make this problem harder, and this hour needs a novel treatment approach. Competent nanoparticle-based accurate drug delivery and cancer nanotheranostics like photothermal therapy, photodynamic therapy, chemodynamic therapy, and sonodynamic therapy can be the key to solving this problem due to their unique characteristics. These innovative formulations can be a better cargo with fewer side effects than the standard chemotherapy and can eliminate the stability problems associated with cancer immunotherapy. The nanotheranostic systems can kill the tumor cells and the resistant breast cancer stem cells by novel mechanisms like local hyperthermia and reactive oxygen species and prevent tumor recurrence. These theranostic systems can also combine with chemotherapy or immunotherapy approaches. These combining approaches can be the future of anticancer therapy, especially to overcome the breast cancer stem cells mediated chemo- and radioresistances. This review paper discusses several novel theranostic systems and smart nanoparticles, their mechanism of action, and their modifications with time. It explains their relevance and market scope in the current era. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Biocomposite Macrospheres Based on Strontium-Bioactive Glass for Application as Bone Fillers.

Traditional bioactive glass powders are typically composed of irregular particles that can be packed into dense configurations presenting low interconnectivity, which can limit bone ingrowth. The use of novel biocomposite sphere formulations comprising bioactive factors as bone fillers are most advantageous, as it simultaneously allows for packing the particles in a 3-dimensional manner to achieve an adequate interconnected porosity, enhanced biological performance, and ultimately a superior new bone formation. In this work, we develop and characterize novel biocomposite macrospheres of Sr-bioactive glass using sodium alginate, polylactic acid (PLA), and chitosan (CH) as encapsulating materials for finding applications as bone fillers. The biocomposite macrospheres that were obtained using PLA have a larger size distribution and higher porosity and an interconnectivity of 99.7%. Loose apatite particles were observed on the surface of macrospheres prepared with alginate and CH by means of soaking into a simulated body fluid (SBF) for 7 days. A dense apatite layer was formed on the biocomposite macrospheres' surface produced with PLA, which served to protect PLA from degradation. In vitro investigations demonstrated that biocomposite macrospheres had minimal cytotoxic effects on a human osteosarcoma cell line (SaOS-2 cells). However, the accelerated degradation of PLA due to the degradation of bioactive glass may account for the observed decrease in SaOS-2 cells viability. Among the biocomposite macrospheres, those composed of PLA exhibited the most promising characteristics for their potential use as fillers in bone tissue repair applications.