Multipotent Mesenchymal Cells Homing and Differentiation on Poly(ε-caprolactone) Blended with 20% Tricalcium Phosphate and Polylactic Acid Incorporating 10% Hydroxyapatite 3D-Printed Scaffolds via a Commercial Fused Deposition Modeling 3D Device.

As highlighted by the 'Global Burden of Disease Study 2019' conducted by the World Health Organization, ensuring fair access to medical care through affordable and targeted treatments remains crucial for an ethical global healthcare system. Given the escalating demand for advanced and urgently needed solutions in regenerative bone procedures, the critical role of biopolymers emerges as a paramount necessity, offering a groundbreaking avenue to address pressing medical needs and revolutionize the landscape of bone regeneration therapies. Polymers emerge as excellent solutions due to their versatility, making them reliable materials for 3D printing.

Tackling Inequalities in Oral Health: Bone Augmentation in Dental Surgery through the 3D Printing of Poly(ε-caprolactone) Combined with 20% Tricalcium Phosphate.

The concept of personalized medicine and overcoming healthcare inequalities have become extremely popular in recent decades. Polymers can support cost reductions, the simplicity of customized printing processes, and possible future wide-scale expansion. Polymers with β-tricalcium phosphate (TCP) are well known for their synergy with oral tissues and their ability to induce osteoconductivity.

p62/SQSTM1 indirectly mediates remote multipotent mesenchymal cells and rescues bone loss and bone marrow integrity in ovariectomized rats.

Intramuscular administration of p62/SQSTM1 (sequestosome1)-encoding plasmid demonstrated an anticancer effect in rodent models and dogs as well as a high safety profile and the first evidence of clinical benefits in humans. Also, an anti-inflammatory effect of the plasmid was reported in several rodent disease models. Yet, the mechanisms of action for the p62 plasmid remain unknown.

P62/SQSTM1 beyond Autophagy: Physiological Role and Therapeutic Applications in Laboratory and Domestic Animals.

Inflammation is the preceding condition for the development of mild and severe pathological conditions, including various forms of osteopenia, cancer, metabolic syndromes, neurological disorders, atherosclerosis, cardiovascular, lung diseases, etc., in human and animals. The inflammatory status is induced by multifarious intracellular signaling cascades, where cytokines, chemokines, arachidonic acid metabolites, adhesion molecules, immune cells and other components foster a "slow burn" at a local or systemic level.

P62/SQSTM1 enhances osteogenesis and attenuates inflammatory signals in bone marrow microenvironment.

Bone marrow-derived mesenchymal/stromal stem cells (MSCs) became a major focus of research since the anti-inflammatory features and the osteogenic commitment of these cells can prevent the inflamm-aging and various form of osteopenia in humans and animals. We previously showed that p62/SQSTM1 plasmid can prompt release of anti-inflammatory cytokines/chemokines by MSC when injected in adult mice. Furthermore, it can enhance osteoblastogenesis at the expense of adipogenesis and ameliorate bone density and bone remodeling.

Autophagic Mediators in Bone Marrow Niche Homeostasis.

The bone marrow serves as a reservoir for a multifunctional assortment of stem, progenitor, and mature cells, located in functional anatomical micro-areas termed niches. Within the niche, hematopoietic and mesenchymal progenies establish a symbiotic relationship characterized by interdependency and interconnectedness. The fine-tuned physical and molecular interactions that occur in the niches guarantee physiological bone turnover, blood cell maturation and egression, and moderation of inflammatory and oxidative intramural stressful conditions.

Photobiomodulation by Near-Infrared 980-nm Wavelengths Regulates Pre-Osteoblast Proliferation and Viability through the PI3K/Akt/Bcl-2 Pathway.

Background: bone tissue regeneration remains a current challenge. A growing body of evidence shows that mitochondrial dysfunction impairs osteogenesis and that this organelle may be the target for new therapeutic options. Current literature illustrates that red and near-infrared light can affect the key cellular pathways of all life forms through interactions with photoacceptors within the cells' mitochondria.

Archetypal autophagic players through new lenses for bone marrow stem/mature cells regulation.

The bone marrow landscape consists of specialized and stem/progenitor cells, which coordinate important tissue-related and systemic physiological features. Within the marrow cavity, stem/progenitor and differentiated hematopoietic and skeletal cells congregate into dynamic functional assemblies throughout specific anatomical regions, termed niches. There is a need for better understanding of the bone marrow microareas, through exploration of the intramural physical and molecular interactions of the distinctive cell populations.

The effects of 808-nm near-infrared laser light irradiation on actin cytoskeleton reorganization in bone marrow mesenchymal stem cells.

Tailoring the cell organelles and thus changing cell homeostatic behavior has permitted the discovery of fascinating metabolic features enabling enhanced viability, differentiation, or quenching inflammation. Recently, photobiomodulation (PBM) has been accredited as an effective cell manipulation technique with promising therapeutic potential. In this prospective, in vitro results revealed that 808-nm laser light emitted by a hand-piece with a flat-top profile at an irradiation set up of 60 J/cm2 (1 W, 1 W/cm; 60 s, continuous wave) regulates bone marrow stromal cell (BMSC) differentiation toward osteogenesis.

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus.

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist was synthesized and studied for their affinity at M-M mAChRs. The 6-cyclohexyl-6-phenyl derivative , with a configuration between the CHN(CH) chain in the 2-position and the cyclohexyl moiety in the 6-position, showed p values for mAChRs higher than those of and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of and the corresponding tertiary amine revealed that the eutomers are (2,6)-(-)- and (2,6)-(-)-, respectively.

Loss of p62 impairs bone turnover and inhibits PTH-induced osteogenesis.

The p62 (also named sequestosome1/SQSTM1) is multidomain and multifunctional protein associated with several physiological and pathological conditions. A number of studies evidenced an involvement of p62 on the disruptive bone scenarios due to its participation in the inflammatory/osteoclastogenic pathways. However, so far, information regarding the function of p62 in the fine-tuned processes underpinning the bone physiology are not well-defined and are sometime discordant.

Interpenetrating Hydrogel Networks Enhance Mechanical Stability, Rheological Properties, Release Behavior and Adhesiveness of Platelet-Rich Plasma.

Platelet-rich plasma (PRP) has attracted much attention for the treatment of articular cartilage defects or wounds due to its intrinsic content of growth factors relevant for tissue repair. However, the short residence time of PRP in vivo, due to the action of lytic enzymes, its weak mechanical properties and the consequent short-term release of bioactive factors has restricted its application and efficacy. The present work aimed at designing new formulation strategies for PRP, based on the use of platelet concentrate (PC)-loaded hydrogels or interpenetrating polymer networks, directed at improving mechanical stability and sustaining the release of bioactive growth factors over a prolonged time-span.

The 808 nm and 980 nm infrared laser irradiation affects spore germination and stored calcium homeostasis: A comparative study using delivery hand-pieces with standard (Gaussian) or flat-top profile.

Photobiomodulation relies on the transfer of energy from incident photons to a cell photoacceptor. For many years the concept of photobiomodulation and its outcome has been based upon a belief that the sole receptor within the cell was the mitochondrion. Recently, it has become apparent that there are other photoacceptors operating in different regions of the electromagnetic spectrum.

Thermosensitive hybrid hydrogels for the controlled release of bioactive vancomycin in the treatment of orthopaedic implant infections.

The purpose of this work was the development of antibacterial delivery systems for vancomycin, with potential application in the prevention or treatment of orthopedic implant infections. Previous studies have shown tandem thermal gelling and Michael addition cross-linking of hydrogels based on methacrylate, acrylate or vinylsulfone triblock copolymers of PEG-p(HPMAm-lac) and thiolated hyaluronic acid. In this work we exploited these α-β unsaturated derivatives of PEG-p(HPMAm-lac) triblock copolymers and used them in combination with thiolated hyaluronic acid as controlled delivery systems for vancomycin.

Thermosensitive hybrid hyaluronan/p(HPMAm-lac)-PEG hydrogels enhance cartilage regeneration in a mouse model of osteoarthritis.

Osteoarthritis (OA), due to cartilage degeneration, is one of the leading causes of disability worldwide. Currently, there are not efficacious therapies to reverse cartilage degeneration. In this study we evaluated the potential of hybrid hydrogels, composed of a biodegradable and thermosensitive triblock copolymer cross-linked via Michael addition to thiolated hyaluronic acid, in contrasting inflammatory processes underlying OA.

A Comparative Study Between the Effectiveness of 980 nm Photobiomodulation Delivered by Hand-Piece With Gaussian vs. Flat-Top Profiles on Osteoblasts Maturation.

Photobiomodulation (PBM) is a clinically accepted tool in regenerative medicine and dentistry to improve tissue healing and repair and to restore the functional disability. The current study aimed to investigate the photobiomodulatory effects of 980 nm wavelength (the real energy at the target: ~0.9 W, ~0.

P62 deficiency shifts mesenchymal/stromal stem cell commitment toward adipogenesis and disrupts bone marrow homeostasis in aged mice.

With advancing age have been observed bone and bone marrow phenotypic alterations due to the impaired bone tissue homeostatic features, involving bone remodeling, and bone marrow niche ontogeny. The complex "inflamm-aging" pathological scenario that culminates with osteopenia and mesenchymal/stromal and hematopoietic stem cell commitment breakdown, is controlled by cellular and molecular intramural components comprising adapter proteins such as the sequestosome 1 (p62/SQSTM1). p62, a "multiway function" protein, has been reported as an effective anti-inflammatory, bone-building factor.

Bone and bone marrow disruption by endocrine-active substances.

Bone is a multifaceted dynamic tissue, involved in mobility, mineral metabolism, and mesenchymal or stromal and hematopoietic progenitor or stem cells breading. Recently, an endocrine role has been attributed to bone due to its ability to produce at least two hormones (osteocalcin and fibroblast growth factor 23) and to participate directly or indirectly in leptin, insulin, estrogens, and serotonin signaling; regulation; and action. Also, bearing in mind the enormous amounts of substances secreted by the different bone marrow cell types, it becomes understandable the contribution of bone tissue to systemic homeostasis.

The Effects of Photobiomodulation of 808 nm Diode Laser Therapy at Higher Fluence on the Osteogenic Differentiation of Bone Marrow Stromal Cells.

The literature has supported the concept of mesenchymal stromal cells (MSCs) in bone regeneration as one of the most important applications in oro-maxillofacial reconstructions. However, the fate of the transplanted cells and their effects on the clinical outcome is still uncertain. Photobiomodulation (PBM) plays an important role in the acceleration of tissue regeneration and potential repair.

Molecular Adjuvants Based on Plasmids Encoding Protein Aggregation Domains Affect Bone Marrow Niche Homeostasis.

Background: During last years, DNA vaccine immunogenicity has been optimized by the employment of co-stimulatory molecules and molecular adjuvants. It has been reported that plasmid (pATRex), encompassing the DNA sequence for the von Willebrand A (vWA/A) domain of the Anthrax Toxin Receptor-1 (ANTXR-1, alias TEM8, Tumor Endothelial Marker 8), acts as strong immune adjuvant by inducing formation of insoluble intracellular aggregates. Markedly, we faced with upsetting findings regarding the safety of pATRex as adjuvant since the aggregosome formation prompted to osteopenia in mice.

INF-γ encoding plasmid administration triggers bone loss and disrupts bone marrow microenvironment.

IFN-γ is a pleotropic cytokine produced in the bone microenvironment. Although IFN-γ is known to play a critical role on bone remodeling, its function is not fully elucidated. Consistently, outcomes on the effects of IFN-γ recombinant protein on bone loss are contradictory among reports.

In vivo biocompatibility of p(HPMAm-lac)-PEG hydrogels hybridized with hyaluronan.

The present study reports on the biocompatibility in vivo after intramuscular and subcutaneous administration in Balb/c mice of vinyl sulphone bearing p(HPMAm-lac1-2)-PEG-p(HPMAm-lac1-2)/thiolated hyaluronic acid hydrogels, designed as novel injectable biomaterials for potential application in the fields of tissue engineering and regenerative medicine. Ultrasonography, used as a method to study hydrogel gelation and residence time in vivo, showed that, upon injection, the biomaterial efficiently formed a hydrogel by simultaneous thermal gelation and Michael Addition cross-linking forming a viscoelastic spherical depot at the injection site. The residence time in vivo (20 days) was found to be shorter than that observed in vitro (32 days), indicating that the injected hydrogel was resorbed not only by chemical hydrolysis but also by cellular metabolism and/or enzymatic activity.

Administration of DNA Plasmid Coding Protein Aggregating Domain Induces Inflammatory Bone Loss.

Background: Plasmids coding protein aggregation polypeptides from different sources have been proposed as genetic adjuvants for DNA vaccines. We reported that a plasmid (pATRex), encompassing the DNA sequence for the von Willebrand A (vWA/A) domain of the Anthrax Toxin Receptor-1 (ANTXR-1, alias TEM8, Tumor Endothelial Marker 8), acts as strong immune adjuvant by inducing formation of insoluble intracellular aggregates and subsequent cell death.

Objective: In the present study we addressed the question of whether there is any substantial immunotoxicity associated with the use of self-aggregating proteins as genetic adjuvants.