Bone Biomaterials Research Articles

Feature Papers in Bone Biomaterials

Bone biomaterials have garnered significant attention in the field of regenerative medicine due to their application in a wide range of clinical scenarios [...]

Three-Dimensional Scaffolds Designed and Printed Using CAD/CAM Technology: A Systematic Review

The objective of this work is to review the literature on the use of three-dimensional scaffolds obtained by printing for the regeneration of bone defects in the maxillofacial area. The research question asked was: what clinical experiences exist on the use of bone biomaterials manufactured by CAD/CAM in the maxillofacial area? Prospective and retrospective studies and randomized clinical trials in humans with reconstruction area in the maxillofacial and intraoral area were included. The articles had to obtain scaffolds for bone reconstruction that were designed by computer processing and printed in different materials. Clinical cases, case series, in vitro studies and those that were not performed in humans were excluded. Six clinical studies were selected that met the established inclusion criteria. The selected studies showed heterogeneity in their objectives, materials used and types of regenerated bone defects. A high survival rate was found for dental implants placed on 3D-printed scaffolds, with rates ranging from 94.3% to 98%. The materials used included polycaprolactone, coral-derived hydroxyapatite, biphasic calcium phosphate (BCP) and bioceramics. The use of CAD/CAM technology is seen as key for satisfying variations in the shapes and requirements of different fabrics and size variations between different individuals. Furthermore, the possibility of using the patient’s own stem cells could revolutionize the way bone defects are currently treated in oral surgery. The results indicate a high survival rate of dental implants placed on 3D-printed scaffolds, suggesting the potential of this technology for bone regeneration in the maxillofacial mass.

Interleukin-4-Loaded Heparin Hydrogel Regulates Macrophage Polarization to Promote Osteogenic Differentiation.

In bone tissue engineering, biological scaffolds are designed with structural and functional properties that closely resemble the extracellular environment, aiming to establish a microenvironment conducive to osteogenesis. Macrophages hold significant potential for promoting osteogenesis and modulating the biological behavior of tumor cells. Multiple coculture experiments of macrophages and osteoblasts have demonstrated that macrophage polarization significantly impacts osteogenesis. Therefore, exploring bone biomaterials that can modulate macrophage polarization holds great clinical significance. In this study, heparin was modified with maleimide and was used as a raw material to form a hydrogel with 4-am-PEG-SH. The compound was used to polarize macrophages and promote osteogenesis after combining with interleukin 4 (IL-4) by taking advantage of the electronegativity of heparin. The results revealed overexpressed M2 macrophage-related phenotypic genes and cocultivation with MC3T3-E1 cells demonstrated the osteogenesis-promoting effect of the loaded IL-4 heparin hydrogel. Previous research reported that hydrogel loaded with IL-4 can be used as a biomaterial for osteogenesis promotion. Heparin materials used in this paper are derived from clinically anticoagulant drugs and feature a simple operation. The synthesized hydrogel effectively binds cytokines, regulates macrophages to induce osteogenesis and has many potential clinical applications.

Polysaccharide-Based Composite Systems in Bone Tissue Engineering: A Review.

In recent years, a growing demand for biomaterials has been observed, particularly for applications in bone regenerative medicine. Bone tissue engineering (BTE) aims to develop innovative materials and strategies for repairing and regenerating bone defects and injuries. Polysaccharides, due to their biocompatibility, biodegradability as well as bioactivity, have emerged as promising candidates for scaffolds or composite systems in BTE. Polymers combined with bioactive ceramics can support osteointegration. Calcium phosphate (CaP) ceramics can be a broad choice as an inorganic phase that stimulates the formation of new apatite layers. This review provides a comprehensive analysis of composite systems based on selected polysaccharides used in bone tissue engineering, highlighting their synthesis, properties and applications. Moreover, the applicability of the produced biocomposites has been analyzed, as well as new trends in modifying biomaterials and endowing them with new functionalizations. The effects of these composites on the mechanical properties, biocompatibility and osteoconductivity were critically analyzed. This article summarizes the latest manufacturing methods as well as new developments in polysaccharide-based biomaterials for bone and cartilage regeneration applications.

Preparation of composite calcium phosphate cement scaffold loaded with Hedysarum polysaccharides and its efficacy in repairing bone defects

It’s imperative to create a more ideal biological scaffold for bone defect repair. Calcium phosphate bone cements (CPC) could be used as a scaffold. Some ingredients and osteogenic factors could be added to improve its poor mechanical properties and biological activity. As a macromolecule extracted from traditional Chinese medicine, Hedysarum polysaccharides (HPS) would significantly promote the osteogenic activity of bone biomaterials. Zirconium oxide and starch were added to the solid phase and citric acid was added to the liquid phase to optimize CPC. HPS was loaded onto the scaffold as an osteogenic factor, and the prepared CPS + HPS was characterized. Further, the cytocompatibility of CPS + HPS was assessed according to activity, differentiation, and calcification in neonatal rat calvarial osteoblasts, and the biosafety of CPS + HPS was evaluated according to acute toxicity, pyrogen, sensitization, and hemolysis. The success of CPS + HPS in repairing bone defects was evaluated by using a rabbit femur implantation experiment. After optimization, CPS-20-CA-5 containing 10% starch and 5% citric acid displayed the highest mechanical strength of 28.96 ± 0.03 MPa. HPS-50 was demonstrated to exert the best osteogenic effect. The combination of CPS + HPS achieved HPS-loaded CPC. Material characterization, cytocompatibility, biosafety, and femoral implantation experiments indicated that CPS + HPS possessed better pressure resistance and improved osteogenic ability in bone defect repair.CPS + HPS demonstrated effective pressure resistance and superior osteogenic ability, which may be of great significance for bone defects and bone tissue engineering to promote bone regeneration and repair.Graphical The composite CPS loaded with HPS-50 is an excellent scaffold with fine load-bearing ability and sustained release of osteogenic factors to repair bone defects.

Electromechanical coupling in polyetheretherketone through flexoelectricity

The electrical signals generated by an electromechanical coupling mechanism in biomaterials have significant potential applications in the field of biomedical engineering. For example, the piezoelectric- or flexoelectric-induced electrical signals in bone biomaterials play an important role in facilitating self-repair, remodeling, and reshaping processes. Polyetheretherketone (PEEK) has been found to possess excellent mechanical properties and biocompatibility with bone, making it an outstanding choice as an implantable polymer material. It is particularly important to investigate the electromechanical response performance of PEEK materials. In this study, we experimentally examine the flexoelectricity of PEEK and evaluate its effective out-of-plane direct and converse flexoelectric coefficients. Using the piezoresponse force microscopy module of atomic force microscopy, we observe a clear converse flexoelectric effect in a PEEK disk-shaped sample. The effective out-of-plane converse flexoelectric coefficient of the PEEK disk-shaped sample is about μ3333eff=0.21 ± 0.02 nN/V. The effective out-of-plane direct flexoelectric coefficient, determined through the bending experiment of a PEEK cantilever, is f3113eff = 17.61 nC/m, which is larger than that of polyvinylidene fluoride and is nearly two orders of magnitude superior over other biomaterials such as bone and hydroxyapatite. This indicates that PEEK materials have even greater potential for development and research in biomedical engineering applications such as intervertebral fusion, bone joint replacement, bone rehabilitation and regeneration, etc.

Experimental long bone fracture healing in goats with cockle shell-based calcium carbonate bone paste

Long bone fractures are common orthopedic conditions. There are numerous ways to repair these fractures. Bone grafting becomes necessary when a broken bone has a significant gap. However, due to insufficient donor volume and donor site morbidity, substitutes are required. In veterinary orthopaedics, calcium carbonate from cockle shells could be used as a bone biomaterial. We investigated its efficacy as a bone biomaterial repair for goat femoral fractures. The study included 10 healthy adult male Black Bengal goats weighing 8 kg and aged 12–13 months. The study includes control and treatment groups. Intramedullary pinning stabilized an 8-mm right femur diaphyseal fracture in the treatment and control groups. The treated group received 2 ml of bone paste in the fractured gap, whereas the control group left it empty. We examined all goats with X-rays on the 7th, 45th, and 60th days, followed by gross and histological findings. Due to callus bridging, radiographs revealed faster bone growth in the treated group than in the control group. Gross examination demonstrates the treated group had a larger fracture callus than the control group. Histopathology showed that bone formed faster and included more osteocytes, osteoblasts, osteoclasts, and bony spicules than in the control group. The treated group had more periosteum osteoblasts, while the control group had fibroblasts. These results showed that the treated group had more osteogenic activity than the control group. This study demonstrates the potential of cockle shell-based calcium carbonate bone paste as a synthetic biomaterial for healing long bone fractures in goats.

Osteogenic Differentiation Potential of iMSCs on GelMA-BG-MWCNT Nanocomposite Hydrogels.

The ability of bone biomaterials to promote osteogenic differentiation is crucial for the repair and regeneration of osseous tissue. The development of a temporary bone substitute is of major importance in enhancing the growth and differentiation of human-derived stem cells into an osteogenic lineage. In this study, nanocomposite hydrogels composed of gelatin methacryloyl (GelMA), bioactive glass (BG), and multiwall carbon nanotubes (MWCNT) were developed to create a bone biomaterial that mimics the structural and electrically conductive nature of bone that can promote the differentiation of human-derived stem cells. GelMA-BG-MWCNT nanocomposite hydrogels supported mesenchymal stem cells derived from human induced pluripotent stem cells, hereinafter named iMSCs. Cell adhesion was improved upon coating nanocomposite hydrogels with fibronectin and was further enhanced when seeding pre-differentiated iMSCs. Osteogenic differentiation and mature mineralization were promoted in GelMA-BG-MWCNT nanocomposite hydrogels and were most evidently observed in the 70-30-2 hydrogels, which could be due to the stiff topography characteristic from the addition of MWCNT. Overall, the results of this study showed that GelMA-BG-MWCNT nanocomposite hydrogels coated with fibronectin possessed a favorable environment in which pre-differentiated iMSCs could better attach, proliferate, and further mature into an osteogenic lineage, which was crucial for the repair and regeneration of bone.

Sr-Incorporated Bioactive Glass Remodels the Immunological Microenvironment by Enhancing the Mitochondrial Function of Macrophage via the PI3K/AKT/mTOR Signaling Pathway.

The repair of critical-sized bone defects continues to pose a challenge in clinics. Strontium (Sr), recognized for its function in bone metabolism regulation, has shown potential in bone repair. However, the underlying mechanism through which Sr2+ guided favorable osteogenesis by modulating macrophages remains unclear, limiting their application in the design of bone biomaterials. Herein, Sr-incorporated bioactive glass (SrBG) was synthesized for further investigation. The release of Sr ions enhanced the immunomodulatory properties and osteogenic potential by modulating the polarization of macrophages toward the M2 phenotype. In vivo, a 3D-printed SrBG scaffold was fabricated and showed consistently improved bone regeneration by creating a prohealing immunological microenvironment. RNA sequencing was performed to explore the underlying mechanisms. It was found that Sr ions might enhance the mitochondrial function of macrophage by activating PI3K/AKT/mTOR signaling, thereby favoring osteogenesis. Our findings demonstrate the relationship between the immunomodulatory role of Sr ions and the mitochondrial function of macrophages. By focusing on the mitochondrial function of macrophages, Sr2+-mediated immunomodulation sheds light on the future design of biomaterials for tissue regenerative engineering.

Enhanced osteogenesis and physicochemical properties of PMMA bone cement with SrBG/HA porous core-shell microspheres

Artificial bone graft with osteoconductivity, angiogenesis, and immunomodulation is promising clinical therapeutics for the reluctant healing process of bone defects. Among various osteogenic substitutes, polymethyl methacrylate (PMMA) bone cement is a quit competitive platform due to its easy deployment to the bone defects with irregular shape and biomimetic mechanical properties. However, the biologically inert essence of PMMA is reliant on the passive osseointegration and cannot provide sufficient biologic cues to induce fast bone repair. Bioactive glass could serve as an efficient platform for the active osteogenesis of PMMA via ionic therapy and construction of alkaline microenvironment. However, the direct of deployment of bioactive glass into PMMA may trigger additional cytotoxicity and hinder cell growth on its surface. Hence we incorporated ionic therapy as osteogenic cue into the PMMA to enhance the biomedical properties. Specifically, we synthesized core-shell microspheres with a strontium-doped bioactive glass (SrBG) core and hydroxyapatite (HA) shell, and then composited them with PMMA to introduce multifunctional effects of HA incorporation, alkaline microenvironment construction, and functional ion release by adding microsphere. We prepared xSrBG@HA/PMMA cements (x = 30, 40, 50) with varied microsphere content and evaluated impacts on mechanical/handling properties, ion release, and investigated the impacts of different composite cements on proliferation, osteogenic differentiation, angiogenic potential, and macrophage polarization. These findings provide new perspectives and methodologies for developing advanced bone biomaterials to promote tissue regeneration.

Optimized DLP 3D-printed high-resolution nano zirconia-hydroxyapatite scaffold with craniomaxillofacial soft tissue invasion resistance and pro-osteogenic properties via dectin-1/syk inflammatory axis

One major challenge of craniomaxillofacial bone regeneration is the direct contact of subcutaneous fibrous tissue towards bone regenerative region, which results in fast fibroblast invasion and suppression of bone regeneration. Dectin-1, a pattern recognition receptor expressed on activated macrophages, is crucial for directing fibrous invasion. Targeting Dectin-1 and its downstream signaling cascade could be an effective strategy to resist “craniomaxillofacial soft tissue invasion”. Nano zirconia can shelter the essential amino acids of Dectin-1 and was reported to deactivate the inflammation signals. Herein, we succeeded in incorporating nano zirconia into high-resolution 3D hydroxyapatite (HA) scaffolds via modified digital light processing (DLP) technique system. The incorporation of nano zirconia can endow high-resolution HA scaffolds with the capacity of regulating the key structure of extracellular C-type lectin-like domain (CTLD) of dectin-1, proved by computational simulation. This results in inhibiting the dectin-1/syk axis and pro-soft tissue proliferation cytokines production. In vivo experiments further validated the effects of HA/nano zirconia resisting craniomaxillofacial soft tissue invasion and promoting bone regeneration. Our work practices the concept of “soft tissue invasion resisting capacity” via targeting in manipulating dectin-1, which succeeds in attenuating fibrous invasion and craniomaxillofacial bone regeneration. The “soft tissue invasion resisting capacity” could become a valuable biological paradigm of craniomaxillofacial bone biomaterials.

Zinc-energized dynamic hydrogel accelerates bone regeneration via potentiating the coupling of angiogenesis and osteogenesis.

Insufficient initial vascularization plays a pivotal role in the ineffectiveness of bone biomaterials for treating bone defects. Consequently, enhancing the angiogenic properties of bone repair biomaterials holds immense importance in augmenting the efficacy of bone regeneration. In this context, we have successfully engineered a composite hydrogel capable of promoting vascularization in the process of bone regeneration. To achieve this, the researchers first prepared an aminated bioactive glass containing zinc ions (AZnBg), and hyaluronic acid contains aldehyde groups (HA-CHO). The composite hydrogel was formed by combining AZnBg with gelatin methacryloyl (GelMA) and HA-CHO through Schiff base bonding. This composite hydrogel has good biocompatibility. In addition, the composite hydrogel exhibited significant osteoinductive activity, promoting the activity of ALP, the formation of calcium nodules, and the expression of osteogenic genes. Notably, the hydrogel also promoted umbilical vein endothelial cell migration as well as tube formation by releasing zinc ions. The results of in vivo study demonstrated that implantation of the composite hydrogel in the bone defect of the distal femur of rats could effectively stimulate bone generation and the development of new blood vessels, thus accelerating the bone healing process. In conclusion, the combining zinc-containing bioactive glass with hydrogels can effectively promote bone growth and angiogenesis, making it a viable option for the repair of critical-sized bone defects.

Sol-Gel Derived Gelatin-Bioactive Glass Nanocomposite Biomaterials Incorporating Calcium Chloride and Calcium Ethoxide.

Calcium-containing organic-inorganic nanocomposites play an essential role in developing bioactive bone biomaterials. Ideally, bone substitute materials should mimic the organic-inorganic composition of bone. In this study, the roles of calcium chloride (CaCl2) and calcium ethoxide (Ca(OEt)2) were evaluated for the development of sol-gel-derived organic-inorganic biomaterials composed of gelatin, bioactive glass (BG) and multiwall carbon nanotubes (MWCNTs) to create nanocomposites that mimic the elemental composition of bone. Nanocomposites composed of either CaCl2 or Ca(OEt)2 were chemically different but presented uniform elemental distribution. The role of calcium sources in the matrix of the nanocomposites played a major role in the swelling and degradation properties of biomaterials as a function of time, as well as the resulting porous properties of the nanocomposites. Regardless of the calcium source type, biomineralization in simulated body fluid and favorable cell attachment were promoted on the nanocomposites. 10T1/2 cell viability studies using standard media (DMEM with 5% FBS) and conditioned media showed that Ca(OEt)2-based nanocomposites seemed more favorable biomaterials. Collectively, our study demonstrated that CaCl2 and Ca(OEt)2 could be used to prepare sol-gel-derived gelatin-BG-MWCNT nanocomposites, which have the potential to function as bone biomaterials.

In vitro biocompatibility of polycaprolactone/hydroxyapatite nanocomposite membranes modified by oleic acid for bone regeneration

The bone defect is common in the orthopedic clinic, possibly due to trauma, tumor, or congenital diseases. Also, some patients with alveolar bone defects in the dental clinic result from the different proliferation speeds between soft and hard tissue. Biomaterials made of polymers and bioceramics have been developed to deal with these problems but mixing them directly can result in a low-mechanical strength complex. To solve this, we used oleic acid (C18) as a surfactant to improve the dispersity of hydroxyapatite (HA) in the polycaprolactone (PCL) matrix, and then immerse the material in a simulated biomineralization process. The results showed that the low crystallinity PCL formed an evenly distributed mineralized layer that had phosphate ions signal and a hydroxyapatite peak. The biocompatibility of the material was assessed using MC3T3 cells, and found that the PCL-HA membrane and PCL-C18-HA membranes had significant cell filopodia and lamellipodia. Additionally, the polycaprolactone/oleic acid/hydroxyapatite (PCL-C18-HA) membrane had the highest cell viability among all groups. The addition of C18 also decreased the platelets activation degree but had a significant difference in the reactive oxygen species (ROS) amount compared to the control, which requires further investigation. Overall, this study successfully fabricated a safe and promising polycaprolactone/hydroxyapatite/oleic acid nanocomposite membrane as a potential solution for bone biomaterials.

Comparative study of demineralized freeze-dried bone allograft and its combination with platelet-rich fibrin in the treatment of intrabony defects: A randomized clinical trial.

The clinical and radiographic efficacy of bone grafts and biomaterials, such as platelet-rich plasma and platelet-rich fibrin (PRF), for reconstructing lost periodontal structures has been well documented. However, there is limited data regarding the presence of demineralized freeze-dried bone allograft (DFDBA) in an environment with abundant growth factors provided by platelet concentrates. The aim of the study was to compare the clinical and radiographic effectiveness of DFDBA with PRF versus DFDBA alone in the treatment of intrabony defects. Twenty-four intrabony defects in contralateral sites were randomly assigned to either the DFDBA group or the DFDBA combined with PRF group. Clinical parameters, including the plaque index (PI), the gingival index (GI), probing pocket depth (PPD), relative attachment level (RAL), and radiographic bone fill (RBF), were measured at baseline, and at 6 and 9 months. Paired and unpaired t-tests were used for intraand intergroup comparisons. Both the PI and the GI showed statistically significant improvements from baseline to 9 months. However, the intergroup comparisons did not reveal any significant differences (p < 0.05) between the groups with regard to clinical and radiographic measurements from baseline to 9 months. Platelet-rich fibrin in combination with DFDBA did not show any additional benefit in terms of reconstructive output in the treatment of intrabony defects compared to the use of DFDBA alone.

Peptide-Based Biomaterials for Bone and Cartilage Regeneration.

The healing of osteochondral defects (OCDs) that result from injury, osteochondritis, or osteoarthritis and bear lesions in the cartilage and bone, pain, and loss of joint function in middle- and old-age individuals presents challenges to clinical practitioners because of non-regenerative cartilage and the limitations of current therapies. Bioactive peptide-based osteochondral (OC) tissue regeneration is becoming more popular because it does not have the immunogenicity, misfolding, or denaturation problems associated with original proteins. Periodically, reviews are published on the regeneration of bone and cartilage separately; however, none of them addressed the simultaneous healing of these tissues in the complicated heterogeneous environment of the osteochondral (OC) interface. As regulators of cell adhesion, proliferation, differentiation, angiogenesis, immunomodulation, and antibacterial activity, potential therapeutic strategies for OCDs utilizing bone and cartilage-specific peptides should be examined and investigated. The main goal of this review was to study how they contribute to the healing of OCDs, either alone or in conjunction with other peptides and biomaterials.

Electroactive Biomaterials Regulate the Electrophysiological Microenvironment to Promote Bone and Cartilage Tissue Regeneration

AbstractThe incidence of large bone and articular cartilage defects caused by traumatic injury is increasing worldwide; the tissue regeneration process for these injuries is lengthy due to limited self‐healing ability. Endogenous bioelectrical phenomenon has been well recognized to play an important role in bone and cartilage homeostasis and regeneration. Studies have reported that electrical stimulation (ES) can effectively regulate various biological processes and holds promise as an external intervention to enhance the synthesis of the extracellular matrix, thereby accelerating the process of bone and cartilage regeneration. Hence, electroactive biomaterials have been considered a biomimetic approach to ensure functional recovery by integrating various physiological signals, including electrical, biochemical, and mechanical signals. This review will discuss the role of endogenous bioelectricity in bone and cartilage tissue, as well as the effects of ES on cellular behaviors. Then, recent advances in electroactive materials and their applications in bone and cartilage tissue regeneration are systematically overviewed, with a focus on their advantages and disadvantages as tissue repair materials and performances in the modulation of cell fate. Finally, the significance of mimicking the electrophysiological microenvironment of target tissue is emphasized and future development challenges of electroactive biomaterials for bone and cartilage repair strategies are proposed.

Biomaterials for bone defect repair: Types, mechanisms and effects.

Bone defects or bone discontinuities caused by trauma, infection, tumours and other diseases have led to an increasing demand for bone grafts and biomaterials. Autologous bone grafts, bone grafts with vascular tips, anastomosed vascular bone grafts and autologous bone marrow components are all commonly used in clinical practice, while oversized bone defects require the use of bone tissue engineering-related biomaterials to repair bone defects and promote bone regeneration. Currently, inorganic components such as polysaccharides and bioceramics, as well as a variety of bioactive proteins, metal ions and stem cells can be loaded into hydrogels or 3D printed scaffold materials to achieve better therapeutic results. In this review, we provide an overview of the types of materials, applications, potential mechanisms and current developments in the repair of bone defects.

Breaking the hydrophilic limitation of polyphenylene sulfide through the introduction of bulky polar monomers

Polyphenylene sulfide (PPS) is widely used in electrical accessories, instrument parts, dust filter materials, and separation membranes, but its hydrophobicity restricts its applications, especially in biomaterials and medical devices. To endow PPS with hydrophilicity from molecular structure, here a strategy is proposed of linking bulky polar monomers to the main chain of the PPS by copolymerization. Although the polarity and bulkiness of the monomers can collaboratively promote the hydrophilicity of PPS, they have opposite effects on improving the thermal properties of PPS. Meanwhile, these monomers did not alter the semi-crystalline nature of PPS. The synthesized PPS copolymers have water contact angles ranging from 68 to 86° (Neat-PPS, ∼100°). The greater the polarity and bulkiness of the monomers, the lower the water contact angle of the copolymers. Moreover, the best hydrophilic copolymer combines structural stability and cytocompatibility. Importantly, it is more conducive to cell adhesion than Neat-PPS. The improved hydrophilicity of PPS copolymers can be harvested for bone scaffold materials and broaden the application of PPS in bone biomaterials.

From Its Nature to Its Function: Marine-Collagen-Based-Biomaterials for Hard Tissue Applications.

Impact statement This review discusses the research done using marine collagens (MCs) on biomaterials for bone, cartilage, and osteochondral tissue regenerative applications with the underlying technologies that enable their development, and explains the methodologies used to characterize MCs highlighting their importance, namely regarding the performance of derived biomaterials, and the inherent properties of such collagens. In the second part, the applicability of MCs as biomaterials for hard tissue applications was studied, focusing on the mostly applied fabrication techniques. In conclusion, this review describes the major challenges to be overcome and the forecast for the upcoming years concerning the use of MCs.