Recent Advances in Design of Functional Biocompatible Hydrogels for Bone Tissue Engineering

Bone related diseases have caused serious threats to human health owing to their complexity and specificity. Fortunately, owing to the unique 3D network structure with high aqueous content and functional properties, emerging hydrogels are regarded as one of the most promising candidates for bone tissue engineering, such as repairing cartilage injury, skull defect, and arthritis. Herein, various design strategies and synthesis methods (e.g., 3D-printing technology and nanoparticle composite strategy) are introduced to prepare implanted hydrogel scaffolds with tunable mechanical strength, favorable biocompatibility, and excellent bioactivity for applying in bone regeneration. Injectable hydrogels based on biocompatible materials (e.g., collagen, hyaluronic acid, chitosan, polyethylene glycol, etc.) possess many advantages in minimally invasive surgery, including adjustable physicochemical properties, filling irregular shapes of defect sites, and on-demand release drugs or growth factors in response to different stimuli (e.g., pH, temperature, redox, enzyme, light, magnetic, etc.). In addition, drug delivery systems based on micro/nanogels are discussed, and its numerous promising designs used in the application of bone diseases (e.g., rheumatoid arthritis, osteoarthritis, cartilage defect) are also briefed in this review. Particularly, several key factors of hydrogel scaffolds (e.g., mechanical property, pore size, and release behavior of active factors) that can induce bone tissue regeneration are also summarized in this review. It is anticipated that advanced approaches and innovative ideas of bioactive hydrogels will be exploited in the clinical field and increase the life quality of patients with the bone injury.     

Tissue-Engineered Vascular Grafts: Emerging Trends and Technologies

Vascular tissue engineering has made prodigious progress in recent years by converging multidisciplinary approaches. Latest technological advancements foster the development of next-generation tissue-engineered vascular grafts (TEVGs) for treating various vasculopathies. While traditional therapeutic methods rely on bypassing the severely damaged vessels with synthetic counterparts with no growth potential, contemporary perspectives focus on biodegradable conduits bestowing an inherent remodeling capability. This review highlights emerging innovative trends and technologies adopted to pragmatically fulfill current scientific needs while improving overall TEVG performance in pre-clinical and clinical settings. A comprehensive overview of various milestones achieved in the past few decades is first summarized, followed by an appraisal of the significant hurdles for clinical translation. The latest techniques to rationally address critical challenges, viz., intimal hyperplasia, thrombosis, constructive graft remodeling, and adequate neo-tissue formation are discussed. Finally, an update on ongoing clinical trials is provided and future perspectives required to persuade TEVGs to become a clinical reality are delineated.     

Current advances concerning the most cited metal ions doped bioceramics and silicate-based bioactive glasses for bone tissue engineering

Studies related to biomaterials that stimulate the repair of living tissue have increased considerably, improving the quality of many people's lives that require surgery due to traumatic accidents, bone diseases, bone defects, and reconstructions. Among these biomaterials, bioceramics and bioactive glasses (BGs) have proved to be suitable for coating materials, cement, scaffolds, and nanoparticles, once they present good biocompatibility and degradability, able to generate osteoconduction on the surrounding tissue. However, the role of biomaterials in hard tissue engineering is not restricted to a structural replacement or for guiding tissue regeneration. Nowadays, it is expected that biomaterials develop a multifunctional role when implanted, orchestrating the process of tissue regeneration and providing to the body the capacity to heal itself. In this way, the incorporation of specific metal ions in bioceramics and BGs structure, including magnesium, silver, strontium, lithium, copper, iron, zinc, cobalt, and manganese are currently receiving enhanced interest as biomaterials for biomedical applications. When an ion is incorporated into the bioceramic structure, a new category of material is created, which has several unique properties that overcome the disadvantages of primitive material and favors its use in different biomedical applications. The doping can enhance handling properties, angiogenic and osteogenic performance, and antimicrobial activity. Therefore, this review aims to summarize the effect of selected metal ion dopants into bioceramics and silicate-based BGs in bone tissue engineering. Furthermore, new applications for doped bioceramics and BGs are highlighted, including cancer treatment and drug delivery.     

Single Cell Bioprinting with Ultrashort Laser Pulses

Tissue engineering requires the precise positioning of mammalian cells and biomaterials on substrate surfaces or in preprocessed scaffolds. Although the development of 2D and 3D bioprinting technologies has made substantial progress in recent years, precise, cell-friendly, easy to use, and fast technologies for selecting and positioning mammalian cells with single cell precision are still in need. A new laser-based bioprinting approach is therefore presented, which allows the selection of individual cells from complex cell mixtures based on morphology or fluorescence and their transfer onto a 2D target substrate or a preprocessed 3D scaffold with single cell precision and high cell viability (93–99% cell survival, depending on cell type and substrate). In addition to precise cell positioning, this approach can also be used for the generation of 3D structures by transferring and depositing multiple hydrogel droplets. By further automating and combining this approach with other 3D printing technologies, such as two-photon stereolithography, it has a high potential of becoming a fast and versatile technology for the 2D and 3D bioprinting of mammalian cells with single cell resolution.     

Spatiotemporal Magnetocaloric Microenvironment for Guiding the Fate of Biodegradable Polymer Implants

The degradation behavior of implants is significantly important for bone repair. However, it is still unprocurable to spatiotemporally regulate the degradation of the implants to match bone ingrowth. In this paper, a magneto-controlled biodegradation model is established to explore the degradation behavior of magnetic scaffolds in a magnetothermal microenvironment generated by an alternating magnetic field (AMF). The results demonstrate that the scaffolds can be heated by magnetic nanoparticles (NPs) under AMF, which dramatically accelerated scaffold degradation. Especially, magnetic NPs modified by oleic acid with a better interface compatibility exhibit a greater heating efficiency to further facilitate the degradation. Furthermore, the molecular dynamics simulations reveal that the enhanced motion correlation between magnetic NPs and polymer matrix can accelerate the energy transfer. As a proof-of-concept, the feasibility of magneto-controlled degradation for implants is demonstrated, and an optimizing strategy for better heating efficiency of nanomaterials is provided, which may have great instructive significance for clinical medicine.     

Pulsed Electromagnetic Field Stimulation in Osteogenesis and Chondrogenesis: Signaling Pathways and Therapeutic Implications

Mesenchymal stem cells (MSCs) are the main cell players in tissue repair and thanks to their self-renewal and multi-lineage differentiation capabilities, they gained significant attention as cell source for tissue engineering (TE) approaches aimed at restoring bone and cartilage defects. Despite significant progress, their therapeutic application remains debated: the TE construct often fails to completely restore the biomechanical properties of the native tissue, leading to poor clinical outcomes in the long term. Pulsed electromagnetic fields (PEMFs) are currently used as a safe and non-invasive treatment to enhance bone healing and to provide joint protection. PEMFs enhance both osteogenic and chondrogenic differentiation of MSCs. Here, we provide extensive review of the signaling pathways modulated by PEMFs during MSCs osteogenic and chondrogenic differentiation. Particular attention has been given to the PEMF-mediated activation of the adenosine signaling and their regulation of the inflammatory response as key player in TE approaches. Overall, the application of PEMFs in tissue repair is foreseen: (1) in vitro: to improve the functional and mechanical properties of the engineered construct; (2) in vivo: (i) to favor graft integration, (ii) to control the local inflammatory response, and (iii) to foster tissue repair from both implanted and resident MSCs cells.     

A Distinct Cytokine Profile and Stromal Vascular Fraction Metabolic Status without Significant Changes in the Lipid Composition Characterizes Lipedema

Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction.     

Amyloid-Beta Induces Different Expression Pattern of Tissue Transglutaminase and Its Isoforms on Olfactory Ensheathing Cells: Modulatory Effect of Indicaxanthin

Herein, we assessed the effect of full native peptide of amyloid-beta (Aβ) (1-42) and its fragments (25-35 and 35-25) on tissue transglutaminase (TG2) and its isoforms (TG2-Long and TG2-Short) expression levels on olfactory ensheathing cells (OECs). Vimentin and glial fibrillary acid protein (GFAP) were also studied. The effect of the pre-treatment with indicaxanthin from Opuntia ficus-indica fruit on TG2 expression levels and its isoforms, cell viability, total reactive oxygen species (ROS), superoxide anion (O₂⁻), and apoptotic pathway activation was assessed. The levels of Nestin and cyclin D1 were also evaluated. Our findings highlight that OECs exposure to Aβ(1-42) and its fragments induced an increase in TG2 expression levels and a different expression pattern of its isoforms. Indicaxanthin pre-treatment reduced TG2 overexpression, modulating the expression of TG2 isoforms. It reduced total ROS and O₂⁻ production, GFAP and Vimentin levels, inhibiting apoptotic pathway activation. It also induced an increase in the Nestin and cyclin D1 expression levels. Our data demonstrated that indicaxanthin pre-treatment stimulated OECs self-renewal through the reparative activity played by TG2. They also suggest that Aβ might modify TG2 conformation in OECs and that indicaxanthin pre-treatment might modulate TG2 conformation, stimulating neural regeneration in Alzheimer’s disease.     

Inorganic Nanoparticles Applied as Functional Therapeutics

Inorganic nanoparticles (NPs) offer significant advantages to the biomedical field owing to their large surface area, controllable structures, diverse surface chemistry, and unique optical and physical properties. Researchers worldwide have shown that inorganic NPs and the released metal ions can act as therapeutic agents in targeted tissues or to cure various diseases without acute toxicity. In this progress report, the recent developments in inorganic NPs with different compositions directly used as therapeutics are discussed. First, the recent convergence of nanotechnology and biotechnology in biomedical applications as well as the unique functions, features, and advantages of inorganic NPs in biomedical applications are summarized. Thereafter, the biological effects of inorganic compositions in NPs which include balancing the intracellular redox environment, regulating the specific cellular signaling and cellular behaviors, and apoptosis are explained. In addition, the emerging therapeutic applications of inorganic NPs in various diseases are exemplified. Finally, the perspectives and challenges for overcoming the weaknesses of inorganic NPs as therapeutics are discussed. By carefully considering and investigating the biological effects of inorganic NPs and metal ions released from NPs, more promising inorganic NPs based therapeutic agents can be developed.