Biomaterials For Bone Regeneration Research Articles

Model-Based Design to Enhance Neotissue Formation in Additively Manufactured Calcium-Phosphate-Based Scaffolds.

In biomaterial-based bone tissue engineering, optimizing scaffold structure and composition remains an active field of research. Additive manufacturing has enabled the production of custom designs in a variety of materials. This study aims to improve the design of calcium-phosphate-based additively manufactured scaffolds, the material of choice in oral bone regeneration, by using a combination of in silico and in vitro tools. Computer models are increasingly used to assist in design optimization by providing a rational way of merging different requirements into a single design. The starting point for this study was an in-house developed in silico model describing the in vitro formation of neotissue, i.e., cells and the extracellular matrix they produced. The level set method was applied to simulate the interface between the neotissue and the void space inside the scaffold pores. In order to calibrate the model, a custom disk-shaped scaffold was produced with prismatic canals of different geometries (circle, hexagon, square, triangle) and inner diameters (0.5 mm, 0.7 mm, 1 mm, 2 mm). The disks were produced with three biomaterials (hydroxyapatite, tricalcium phosphate, and a blend of both). After seeding with skeletal progenitor cells and a cell culture for up to 21 days, the extent of neotissue growth in the disks' canals was analyzed using fluorescence microscopy. The results clearly demonstrated that in the presence of calcium-phosphate-based materials, the curvature-based growth principle was maintained. Bayesian optimization was used to determine the model parameters for the different biomaterials used. Subsequently, the calibrated model was used to predict neotissue growth in a 3D gyroid structure. The predicted results were in line with the experimentally obtained ones, demonstrating the potential of the calibrated model to be used as a tool in the design and optimization of 3D-printed calcium-phosphate-based biomaterials for bone regeneration.

Osseointegration of photodynamic active biomaterials for bone regeneration in an animal bone model over a period of 12 months.

Previous efforts led to the development of two different polymeric biomaterials for periodontal regeneration with antibacterial photodynamic surface activity. The present study aimed to investigate osseointegration and bone formation of both materials in an ovine model. Both biomaterials: 1) urethane dimethacrylate-based Biomaterial 1 (BioM1) and 2) tri-armed oligoester-urethane methacrylate-based Biomaterial 2 (BioM2) are enriched with beta-tri-calcium phosphate and the photosensitizer meso-tetra(hydroxyphenyl)chlorin (mTHPC). These materials were implanted in non-critical size bone defects in the sheep femur (n=16) and tibia (n=8). Empty defects served as controls (n=16). Polyfluorochrome sequential bone labeling was carried out at baseline and after 3, 6, and 12 months. Animals were sacrificed after 12 months. Bone specimens (n=40) were fixed and subjected to microtomographic analysis (µCT) for the evaluation of the bone-volume-fraction (BV/TV), trabecular number and trabecular thickness. Subsequently, histological sections were arranged and polyfluorochrome sequential bone labeling was analyzed by confocal laser scanning microscopy (cLSM). cLSM analysis revealed that highest remodeling and bone formation activity occurred during the second half of the study period (6-12 months). Bone formation in the tibia was significantly lower for the control (2.71±1.26%) as compared to BioM1 (6.01±2.99%) and BioM2 (6.45±2.12%); (p=0.006, p=0004). Micro-computed tomography revealed a BV/TV volume fraction of 44.72±9.01% in femur defects filled with BioM1 which was significantly higher compared to the control (32.27±7.02%; p=0.01). Bone architecture (trabecular number, trabecular thickness) did not significantly differ from the self-healed defects. Both biomaterials, especially BioM1 showed good osseointegration and bone formation characteristics and can be recommended for further examination in periodontal regeneration studies.

Biofabricated poly (γ-glutamic acid) bio-ink reinforced with calcium silicate exhibiting superior mechanical properties and biocompatibility for bone regeneration

Background/purposeThe modification in 3D hydrogels, tissue engineering, and biomaterials science has enabled us to fabricate novel substitutes for bone regeneration. This study aimed to combine different biomaterials by 3D technique to fabricate a promising all-rounded hydrogel for bone regeneration. Materials and methodsIn this study, glycidyl methacrylate (GMA)-modified poly γ-glutamic acid (γ-PGA-GMA) hydrogels with calcium silicate (CS) hydrogel of different concentrations were fabricated by a 3D printing technique, and their biocompatibility and capability in bone regeneration were also evaluated. ResultsThe results showed that CS γ-PGA-GMA could be successfully fabricated, and the presence of CS enhanced the rheological and mechanical properties of γ-PGA-GMA hydrogels, thus making them more adept at 3D printing and implantations. SEM images of the surface structure showed that higher CS concentrations (5% and 10%) contributed to denser surface architectures, thus achieving improved cellular adhesion and stem cell proliferation. Furthermore, higher concentrations of CS resulted in elevated expressions of osteogenic-related markers such as alkaline phosphatase (ALP) and osteocalcin (OC), as well as enhanced calcium deposition represented by the increased Alizarin Red S staining. In vivo studies referring to critical defects of rabbit femur further showed that the existence of hydrogels alone was able to induce partial bone regeneration, demonstrated by the results from quantitative and qualitative analysis of micro-CT scans. However, CS alterations caused significant increases in bone regeneration, as indicated by micro-CT and histological staining. ConclusionThese results robustly suggest combining different biomaterials is crucial to producing a well-rounded hydrogel for tissue regeneration. We hope this study could be applied as a platform for others to brainstorm potential out-of-the-box solutions, contributing to developing high-potential biomaterials for bone regeneration.

The Influence of Chitosan on Water Absorption and Solubility of Calcium Phosphate Cement

Calcium phosphate cements are widely used biomaterials for bone regeneration due to their biological properties, such as biocompatibility, biodegradability, and bioactivity. The presence of chitosan in cement composition influences the resorption rate of the material and its mechanical properties. In the present work, the water absorption and solubility of a tricalcium phosphate bone cement, prepared with and without chitosan addition, was comparatively evaluated. The absorption and solubility properties were monitored for 21 days by immersing the samples in water at room temperature and then weighing them. A morphological analysis of the samples was carried out via scanning electron microscopy (SEM). The absorption dynamics and pore evolution were investigated with low-field nuclear magnetic resonance (NMR) relaxometry. It was demonstrated that the presence of chitosan accelerates the hardening dynamics, reduces water absorption, and influences the solubility and degradation behavior of the cement. It was also observed that, independent of the presence of chitosan, the polymerization process is not completed even after one hour, which influences the solubility process. It was also shown that the presence of chitosan reduces the amount of microcracks and improves the functional properties of the hardened cement.

3D interconnected porous PMMA scaffold integrating with advanced nanostructured CaP-based biomaterials for rapid bone repair and regeneration

Bioactive scaffolds with polymer and nanostructured bioactive glass-based composites are promising materials for regenerative applications in consequence of close mimics of natural bone composition. Poly methyl methacrylate (PMMA) is a highly preferred thermoplastic polymer for orthopedic applications as it has good biocompatibility. Different kinds of bioactive, biodegradable as well as biocompatible biomaterial composites such as Bioglass (BG), Hydroxyapatite (Hap), and Tricalcium phosphate (TCP) can be integrated with PMMA, so as to augment the bioactivity, porosity as well as regeneration of hard tissues in human body. Among the bioactive glass, 60S BG (Bioactive glass with 60 percentage of Silica without Sodium ions) is better materials among aforementioned systems owning to mechanical stability as well as controlled bioactive material. In this work, the fabrication of PMMA-CaP (calcium phosphate)-based scaffolds were carried out by Thermal Induced Phase Separation method (TIPS). X-ray diffractogram analysis (XRD) is used to examine the physiochemical properties of the scaffolds that evidently reveal the presence of calcium phosphate besides calcium phosphate silicate phases. The Field Emission Scanning Electron Microscopy (FESEM) studies obviously exhibited the microstructure of the scaffolds as well as their interconnected porous morphology. The PMMA/60S BG/TCP (C50) scaffold has the maximum pore size, measuring 77 ± 23 μm, while the average pore size ranges from 50 ± 20 to 80 ± 23 μm. By performing a liquid displacement method, the C50 scaffold is found to have the largest porosity of 50%, high hydrophilicity of 118.16°, and a compression test reveals the scaffolds to have a maximum compressive strength of 0.16 MPa. The emergence of bone-like apatite on the scaffold surface after 1st and 21st days of SBF immersion is further supported by in vitro bioactivity studies. Cytocompatibility and hemocompatibility analyses undoubtedly confirmed the biocompatibility behavior of PMMA-based bioactive scaffolds. Nano-CT investigation demonstrates that PMMA-CaP scaffolds provide more or less alike morphologies of composites that resemble the natural bone. Therefore, this combination of scaffolds could be considered as potential biomaterials for bone regeneration application. This detailed study promisingly demonstrates the eminence of the unique scaffolds in the direction of regenerative medicines.

Development of a Novel Marine-Derived Tricomposite Biomaterial for Bone Regeneration.

Bone tissue engineering is a promising treatment for bone loss that requires a combination of porous scaffold and osteogenic cells. The aim of this study was to evaluate and develop a tricomposite, biomimetic scaffold consisting of marine-derived biomaterials, namely, chitosan and fucoidan with hydroxyapatite (HA). The effects of chitosan, fucoidan and HA individually and in combination on the proliferation and differentiation of human mesenchymal stem cells (MSCs) were investigated. According to the SEM results, the tricomposite scaffold had a uniform porous structure, which is a key requirement for cell migration, proliferation and vascularisation. The presence of HA and fucoidan in the chitosan tricomposite scaffold was confirmed using FTIR, which showed a slight decrease in porosity and an increase in the density of the tricomposite scaffold compared to other formulations. Fucoidan was found to inhibit cell proliferation at higher concentrations and at earlier time points when applied as a single treatment, but this effect was lost at later time points. Similar results were observed with HA alone. However, both HA and fucoidan increased MSC mineralisation as measured by calcium deposition. Differentiation was significantly enhanced in MSCs cultured on the tricomposite, with increased alkaline phosphatase activity on days 17 and 25. In conclusion, the tricomposite is biocompatible, promotes osteogenesis, and has the structural and compositional properties required of a scaffold for bone tissue engineering. This biomaterial could provide an effective treatment for small bone defects as an alternative to autografts or be the basis for cell attachment and differentiation in ex vivo bone tissue engineering.

SiO2/SiC Nanowire Surfaces as a Candidate Biomaterial for Bone Regeneration

Tissue engineering (TE) and nanomedicine require devices with hydrophilic surfaces to better interact with the biological environment. This work presents a study on the wettability of cubic silicon-carbide-based (SiC) surfaces. We developed four cubic silicon-carbide-based epitaxial layers and three nanowire (NW) substrates. Sample morphologies were analyzed, and their wettabilities were quantified before and after a hydrogen plasma treatment to remove impurities due to growth residues and enhance hydrophilicity. Moreover, sample biocompatibility has been assessed with regard to L929 cells. Our results showed that core–shell nanowires (SiO2/SiC NWs), with and without hydrogen plasma treatment, are the most suitable candidate material for biological applications due to their high wettability that is not influenced by specific treatments. Biological tests underlined the non-toxicity of the developed biomaterials with regard to murine fibroblasts, and the proliferation assay highlighted the efficacy of all the surfaces with regard to murine osteoblasts. In conclusion, SiO2/SiC NWs offer a suitable substrate to develop platforms and membranes useful for biomedical applications in tissue engineering due to their peculiar characteristics.

The role of smart polymeric biomaterials in bone regeneration: a review.

Addressing critical bone defects necessitates innovative solutions beyond traditional methods, which are constrained by issues such as immune rejection and donor scarcity. Smart polymeric biomaterials that respond to external stimuli have emerged as a promising alternative, fostering endogenous bone regeneration. Light-responsive polymers, employed in 3D-printed scaffolds and photothermal therapies, enhance antibacterial efficiency and bone repair. Thermo-responsive biomaterials show promise in controlled bioactive agent release, stimulating osteocyte differentiation and bone regeneration. Further, the integration of conductive elements into polymers improves electrical signal transmission, influencing cellular behavior positively. Innovations include advanced 3D-printed poly (l-lactic acid) scaffolds, polyurethane foam scaffolds promoting cell differentiation, and responsive polymeric biomaterials for osteogenic and antibacterial drug delivery. Other developments focus on enzyme-responsive and redox-responsive polymers, which offer potential for bone regeneration and combat infection. Biomaterials responsive to mechanical, magnetic, and acoustic stimuli also show potential in bone regeneration, including mechanically-responsive polymers, magnetic-responsive biomaterials with superparamagnetic iron oxide nanoparticles, and acoustic-responsive biomaterials. In conclusion, smart biopolymers are reshaping scaffold design and bone regeneration strategies. However, understanding their advantages and limitations is vital, indicating the need for continued exploratory research.

Osteogenic stimulation of osteoprogenitors by putamen ovi peptides and hyaluronic acid

Eggshell peptides (EP) majorly contribute to rapid bone building in chicks, wherefore this paper investigated their potential for stimulating osteogenesis in vitro. In this study, the effects of EP, also called putamen ovi peptides and a combination of hyaluronic acid with EP in cell culture medium were tested towards proliferation, differentiation, gene expression and mineralization of bovine osteoprogenitors and primary human osteoblasts. The influence of EP at concentrations of 0.005 g/L, 0.5 g/L and 0.5 g/L with 0.25% hyaluronic acid was analyzed using immunocytochemical staining of bone-specific matrix proteins, namely collagen type I, osteonectin, osteopontin and osteocalcin, to prove osteoblastic differentiation. Additionally, Richardson-staining was performed. All tests revealed a superior osteoblastic differentiation with EP at 0.5 g/L after 5 days of cultivation. Hyaluronic acid alone showed controversial results and partially constrained osteoblastic differentiation in combination with EP to a level as low as for pure EP at 0.005 g/L. Of particular interest is the osteoblast-typical mineralization, as an important indicator of bone formation, which was measured indirectly via the calcium concentration after cultivation over 4 weeks. The mineralization showed an increase by a factor of 286 during the cultivation of primary human osteoblasts with hyaluronic acid and EP. Meanwhile, cell cultures treated with EP (0.5 g/L) only showed an 80-fold increase in calcium concentration.The influence of EP (0.5 g/L) on primary human osteoblasts was investigated by gene expression after 2 weeks of cultivation. Microarray and qRT-PCR analysis showed a strongly increased expression of main important genes in bone formation, bone regeneration and the physiological bone remodelling processes. Namely, BMP 2, osteopontin and the matrix metalloproteinases 1 and 9, were present during in vitro osteoprogenitor culture with EP. By explicitly underlining the potential of eggshell peptides for stimulating osteogenesis, as well as emphasizing complex and controversial interaction with hyaluronan, this manuscript is relevant for developing new functionalized biomaterials for bone regeneration.

Bioinspired self-healing injectable nanocomposite hydrogels based on oxidized dextran and gelatin for growth-factor-free bone regeneration

Hydrogels with great biocompatibility, biodegradability, and mechanical properties, combined with osteoconductivity, osteoinductivity, and osteointegration as biomaterials for bone regeneration without adding exogenous growth factors and cells are highly appealing but challenging. Here, inspired by organic-inorganic analogues of natural bone tissue and the adhesion chemistry of mussels, nanocomposite hydrogels with self-healing, injectable, adhesive, antioxidant, and osteoinductive properties (termed GO-PHA-CPs) were constructed by Schiff base cross-linking between dopamine-modified gelatin (Gel-DA) and oxidized dextran (ODex). Furthermore, the hydrogel network was enhanced by the introduction of polydopamine-functionalized nanohydroxyapatite (PHA) by improving the interfacial compatibility between the rigid inorganic particles and the flexible hydrogel matrix. Bioactive cod peptides (CPs) with osteogenic activity from Atlantic cod were further incorporated into the nanocomposite hydrogel. As a result, the multicomponent nanocomposite hydrogel favored the adhesion and spreading of MC3T3-E1 cells. The increased ALP activity suggested that GO-PHA-CPs hydrogels contributed to the osteogenic differentiation of MC3T3-E1 cells. The suitability of GO-PHA-CPs hydrogels for enhancing bone regeneration in vivo was further confirmed by the rat femoral defect model. Our results indicate that the multifunctional GO-PHA-CPs nanocomposite hydrogels without growth factors are a promising and effective candidate material for bone regeneration.

Selenium-Doped Mesoporous Bioactive Glass Regulates Macrophage Metabolism and Polarization by Scavenging ROS and Promotes Bone Regeneration In Vivo.

Bone regeneration is complex and involves multiple cells and systems, with macrophage-mediated immune regulation being critical for the development and regulation of inflammation, angiogenesis, and osteogenesis. Biomaterials with modified physical and chemical properties (e.g., modified wettability and morphology) effectively regulate macrophage polarization. This study proposes a novel approach to macrophage-polarization induction and -metabolism regulation through selenium (Se) doping. We synthesized Se-doped mesoporous bioactive glass (Se-MBG) and demonstrated its macrophage-polarization regulation toward M2 and its enhancement of the macrophage oxidative phosphorylation metabolism. The underlying mechanism is the effective scavenging of excessive intracellular reactive oxygen species (ROS) by the Se-MBG extracts through the promotion of peroxide-scavenging enzyme glutathione peroxidase 4 expression in the macrophages; this, in turn, improves the mitochondrial function. Printed Se-MBG scaffolds were implanted into rats with critical-sized skull defects to evaluate their immunomodulatory and bone regeneration capacity in vivo. The Se-MBG scaffolds demonstrated excellent immunomodulatory function and robust bone regeneration capacity. Macrophage depletion with clodronate liposomes impaired the Se-MBG-scaffold bone regeneration effect. Se-mediated immunomodulation, which targets ROS scavenging to regulate macrophage metabolic profiles and mitochondrial function, is a promising concept for future effective biomaterials for bone regeneration and immunomodulation.

Extrusion-based 3D printing of biodegradable, osteogenic, paramagnetic, and porous FeMn-akermanite bone substitutes.

The development of biodegradable Fe-based bone implants has rapidly progressed in recent years. Most of the challenges encountered in developing such implants have been tackled individually or in combination using additive manufacturing technologies. Yet not all the challenges have been overcome. Herein, we present porous FeMn-akermanite composite scaffolds fabricated by extrusion-based 3D printing to address the unmet clinical needs associated with Fe-based biomaterials for bone regeneration, including low biodegradation rate, MRI-incompatibility, mechanical properties, and limited bioactivity. In this research, we developed inks containing Fe, 35 wt% Mn, and 20 or 30 vol% akermanite powder mixtures. 3D printing was optimized together with the debinding and sintering steps to obtain scaffolds with interconnected porosity of 69%. The Fe-matrix in the composites contained the γ-FeMn phase as well as nesosilicate phases. The former made the composites paramagnetic and, thus, MRI-friendly. The in vitro biodegradation rates of the composites with 20 and 30 vol% akermanite were respectively 0.24 and 0.27mm/y, falling within the ideal range of biodegradation rates for bone substitution. The yield strengths of the porous composites stayed within the range of the values of the trabecular bone, despite in vitro biodegradation for 28 d. All the composite scaffolds favored the adhesion, proliferation, and osteogenic differentiation of preosteoblasts, as revealed by Runx2 assay. Moreover, osteopontin was detected in the extracellular matrix of cells on the scaffolds. Altogether, these results demonstrate the remarkable potential of these composites in fulfilling the requirements of porous biodegradable bone substitutes, motivating future in vivo research. STATEMENT OF SIGNIFICANCE: We developed FeMn-akermanite composite scaffolds by taking advantage of the multi-material capacity of extrusion-based 3D printing. Our results demonstrated that the FeMn-akermanite scaffolds showed an exceptional performance in fulfilling all the requirements for bone substitution in vitro, i.e., a sufficient biodegradation rate, having mechanical properties in the range of trabecular bone even after 4 weeks biodegradation, paramagnetic, cytocompatible and most importantly osteogenic. Our results encourage further research on Fe-based bone implants in in vivo.

The immunomodulatory effects of RNA-based biomaterials on bone regeneration.

The use of RNA as therapeutic agents is a visionary idea in contemporary medicine. Some forms of RNA can modulate the immune response of the host to enhance tissue regeneration events such as osteogenesis. Herein, RNA molecules commercially available for immunomodulatory applications (imRNA) were used to prepare biomaterials for bone regeneration. The polyanionic imRNA stabilized calcium phosphate ionic clusters to produce imRNA-ACP that had the capacity to mineralize the intrafibrillar compartments of collagen fibrils. For the first time, it was shown that incorporating imRNA-ACP into collagen scaffolds resulted in rapid new bone formation in cranial defects of mice. Both in vivo and in vitro results demonstrated that macrophage polarization was highly-sensitive to the imRNA-ACP containing collagen scaffolds. Macrophages were polarized into the anti-inflammatory M2 phenotype that produced anti-inflammation cytokines and growth factors. The favorable osteoimmunological microenvironment created by the scaffolds prevented their immunorejection and facilitated osteogenesis. The potential of RNA in creating immunomodulatory biomaterials has been underestimated in the past. The overall aim of this study was to explore the potential application of imRNA-based biomaterials in bone tissue engineering, with the competitive edge of facile synthesis and excellent biocompatibility. STATEMENT OF SIGNIFICANCE: : In this work, commercially available RNA extracted from bovine spleens for immunomodulatory applications (imRNA) were used to stabilize amorphous calcium phosphate (ACP) and induce mineralization within collagen fibrils. Incorporation of imRNA-ACP into collagen scaffolds regenerated new bone in-situ. Because of its immunomodulatory effects, the imRNA-ACP that was incorporated into collagen scaffolds modulated the local immune environment of murine cranial defects by altering the macrophage phenotype through JAK2/STAT3 signaling pathway. The novelty of this work exists in the discovery of RNA's potential in creating immunomodulatory biomaterials. With the competitive edge of facile synthesis and excellent biocompatibility, the imRNA-based biomaterials are potentially useful for future bone tissue engineering applications.

Extrafibrillarly Demineralized Dentin Matrix for Bone Regeneration (Adv. Healthcare Mater. 12/2023)

Extrafibrillar Demineralization In article 2202611 by Cui Huang, Hongye Yang, and co-workers, the extrafibrillar demineralization concept is introduced into the construction of tissue engineering scaffolds. The extrafibrillarly demineralized dentin facilitated mechanotransduction and osteogenic differentiation of stem cells, eventually brings about new ideas to develop hierarchical collagen-based biomaterials for bone regeneration.

Slipper Limpet (Crepidula fornicata) Shells Support In Vitro Osteogenesis of Human Adipose-Derived Stem Cells.

This study aimed to investigate a cost-effective alternative to man-made calcium phosphate ceramics for treating bone defects. The slipper limpet is an invasive species in European coastal waters, and its shells composed of calcium carbonate could potentially be a cost-effective source of bone graft substitutes. This research analyzed the mantle of the slipper limpet (Crepidula fornicata) shells to enhance in vitro bone formation. Discs machined from the mantle of C. fornicata were analyzed using scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS), X-ray crystallography (XRD), Fourier-transform infrared spectroscopy (FT-IR) and profilometry. Calcium release and bioactivity were also studied. Cell attachment, proliferation, and osteoblastic differentiation (RT-qPCR and alkaline phosphatase activity) were measured in human adipose-derived stem cells grown on the mantle surface. The mantle material was mainly composed of aragonite and showed a sustained Ca2+ release at physiological pH. In addition, apatite formation was observed in simulated body fluid after three weeks, and the materials supported osteoblastic differentiation. Overall, our findings suggest the mantle of C. fornicata shows potential as a material for fabricating bone graft substitutes and structural biomaterials for bone regeneration.

Recent Advance of Strontium Functionalized in Biomaterials for Bone Regeneration.

Bone defect disease causes damage to people's lives and property, and how to effectively promote bone regeneration is still a big clinical challenge. Most of the current repair methods focus on filling the defects, which has a poor effect on bone regeneration. Therefore, how to effectively promote bone regeneration while repairing the defects at the same time has become a challenge for clinicians and researchers. Strontium (Sr) is a trace element required by the human body, which mainly exists in human bones. Due to its unique dual properties of promoting the proliferation and differentiation of osteoblasts and inhibiting osteoclast activity, it has attracted extensive research on bone defect repair in recent years. With the deep development of research, the mechanisms of Sr in the process of bone regeneration in the human body have been clarified, and the effects of Sr on osteoblasts, osteoclasts, mesenchymal stem cells (MSCs), and the inflammatory microenvironment in the process of bone regeneration have been widely recognized. Based on the development of technology such as bioengineering, it is possible that Sr can be better loaded onto biomaterials. Even though the clinical application of Sr is currently limited and relevant clinical research still needs to be developed, Sr-composited bone tissue engineering biomaterials have achieved satisfactory results in vitro and in vivo studies. The Sr compound together with biomaterials to promote bone regeneration will be a development direction in the future. This review will present a brief overview of the relevant mechanisms of Sr in the process of bone regeneration and the related latest studies of Sr combined with biomaterials. The aim of this paper is to highlight the potential prospects of Sr functionalized in biomaterials.

The effects of BaTiO3 on the handleability and mechanical strength of the prepared piezoelectric calcium phosphate silicate for bone tissue engineering

Natural bone is a piezoelectric material that can generate electrical signals when subjected to an external force. Although many studies have attempted to develop piezoelectric biomaterials for bone regeneration, post-treatment steps, such as sintering, are always needed. In this study, we prepared an injectable and piezoelectric bone substitute based on nanosized BaTiO3 (nBT)-added calcium phosphate silicate (CPS). The impacts of nBT on the CPS handleability and mechanical strength were characterized, and show that adding nBT could improve the CPS handleability but affect the CPS mechanical strength in a concentration-dependent manner (from 25.3 ± 1.0 MPa for 10BC to 13.5 ± 1.0 MPa for 40BC). In addition, our approach could fabricate a piezoelectric bone substitute with comparable piezoelectricity to the native bone without any post-treatment. The in vitro analyses demonstrated that nBT/CPS was biocompatible and could promote osteoblast differentiation. In conclusion, our results strongly indicate that the injectable formulation based on nBT/CPS can be a promising candidate in bone tissue engineering, and further research is needed to investigate the biomaterial's performance in bone defect animal models.

Eggshell Membrane as a Biomaterial for Bone Regeneration.

The physicochemical features of the avian eggshell membrane play an essential role in the process of calcium carbonate deposition during shell mineralization, giving rise to a porous mineralized tissue with remarkable mechanical properties and biological functions. The membrane could be useful by itself or as a bi-dimensional scaffold to build future bone-regenerative materials. This review focuses on the biological, physical, and mechanical properties of the eggshell membrane that could be useful for that purpose. Due to its low cost and wide availability as a waste byproduct of the egg processing industry, repurposing the eggshell membrane for bone bio-material manufacturing fulfills the principles of a circular economy. In addition, eggshell membrane particles have has the potential to be used as bio-ink for 3D printing of tailored implantable scaffolds. Herein, a literature review was conducted to ascertain the degree to which the properties of the eggshell membrane satisfy the requirements for the development of bone scaffolds. In principle, it is biocompatible and non-cytotoxic, and induces proliferation and differentiation of different cell types. Moreover, when implanted in animal models, it elicits a mild inflammatory response and displays characteristics of stability and biodegradability. Furthermore, the eggshell membrane possesses a mechanical viscoelastic behavior comparable to other collagen-based systems. Overall, the biological, physical, and mechanical features of the eggshell membrane, which can be further tuned and improved, make this natural polymer suitable as a basic component for developing new bone graft materials.

Dynamic degradation patterns of porous polycaprolactone/β-tricalcium phosphate composites orchestrate macrophage responses and immunoregulatory bone regeneration.

Biodegradable polycaprolactone/β-tricalcium phosphate (PT) composites are desirable candidates for bone tissue engineering applications. A higher β-tricalcium phosphate (TCP) ceramic content improves the mechanical, hydrophilic and osteogenic properties of PT scaffolds in vitro. Using a dynamic degradation reactor, we established a steady in vitro degradation model to investigate the changes in the physio-chemical and biological properties of PT scaffolds during degradation.PT46 and PT37 scaffolds underwent degradation more rapidly than PT scaffolds with lower TCP contents. In vivo studies revealed the rapid degradation of PT (PT46 and PT37) scaffolds disturbed macrophage responses and lead to bone healing failure. Macrophage co-culture assays and a subcutaneous implantation model indicated that the scaffold degradation process dynamically affected macrophage responses, especially polarization. RNA-Seq analysis indicated phagocytosis of the degradation products of PT37 scaffolds induces oxidative stress and inflammatory M1 polarization in macrophages. Overall, this study reveals that the dynamic patterns of biodegradation of degradable bone scaffolds highly orchestrate immune responses and thus determine the success of bone regeneration. Therefore, through evaluation of the biological effects of biomaterials during the entire process of degradation on immune responses and bone regeneration are necessary in order to develop more promising biomaterials for bone regeneration.

3D Printed Composite Structures for Bone Repair and Drug Delivery Application

Due to the increase in traffic accidents, industrial contingencies, and natural disasters, there is a high demand for bone regeneration biomaterials. Although bone can regenerate and self-repair, it is difficult to do so when the defect area exceeds the critical repair area due to trauma, tumour resection, or congenital diseases. The traditional methods for bone repair are autograft, allograft, and xenograft. However, these methods have flaws and limitations, such as complications in the donor bone area, a limited number of donors, rejection, and infectious diseases. However, in recent years, the use of additive manufacturing technologies in bone tissue engineering has increased. Three-dimensional printing (3DP) is gaining popularity among the various technology options due to its ability to directly print porous composite with designed shape, controlled chemistry, and interconnected porosity. Some of these inorganic composites are biodegradable and have proven ideal for bone tissue engineering, with the ability to deliver growth factors or drugs to specific sites. The purpose of this study is to discuss recent advancements in 3D printed bone tissue engineering composite, as well as current challenges and future directions.