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Bone grafting in oral and maxillofacial surgery has evolved significantly due to developments in materials science, offering innovative alternatives for the repair of bone defects. A few grafts are currently used in clinical settings, including autografts, xenografts, and allografts. However, despite their benefits, they have some challenges, such as limited availability, the possibility of disease transmission, and lack of personalization for the defect. Synthetic bone grafts have gained attention since they have the potential to overcome these limitations. Moreover, new technologies like nanotechnology, 3D printing, and 3D bioprinting have allowed the incorporation of molecules or substances within grafts to aid in bone repair. The addition of different moieties, such as growth factors, stem cells, and nanomaterials, has been reported to help mimic the natural bone healing process more closely, promoting faster and more complete regeneration. In this regard, this review explores the currently available bone grafts, the possibility of incorporating substances and molecules into their composition to accelerate and improve bone regeneration, and advanced graft manufacturing techniques. Furthermore, the presented current clinical applications and success stories for novel bone grafts emphasize the future potential of synthetic grafts and biomaterial innovations in improving patient outcomes in oral and maxillofacial surgery.

The development of hydroxyapatite (HAp) and polyether ether ketone (PEEK) biocomposites has been extensively studied for bone repair applications due to the synergistic properties of the involved materials. In this study, we aimed to develop HAp/PEEK biocomposites using high-energy ball milling, with HAp concentrations (20%, 40%, and 60% w/v) in PEEK, to evaluate their physicochemical, mechanical, cytotoxicity, and antimicrobial properties for potential applications in Tissue Engineering (TE). The biocomposites were characterized by structure, morphology, apparent porosity, diametral compression strength, cytotoxicity, and antimicrobial activity. The study results demonstrated that the HAp/PEEK biocomposites were successfully synthesized. The C2 biocomposite, containing 40% HAp, stood out due to the optimal distribution of HAp particles in the PEEK matrix, resulting in higher compression strength (246 MPa) and a homogeneous microstructure. It exhibited antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, with no cytotoxicity observed. These properties make the C2 biocomposite promising for regenerative medicine applications, combining mechanical strength, bioactivity, and biocompatibility.

Bone regeneration and repair are complex processes with the potential of added complications, like delayed repair, fracture non-union, and post-surgical infections. These conditions remain a challenge globally, pressurizing the economy and patients suffering from these conditions. Applications of nanotechnology (NBT) in the field of medicine have provided a medium for several approaches to support these global challenges. Tissue engineering is one such field that has been on the rise in the last three decades through the utilization of NBT for addressing the challenges related to bone regeneration. First, NBT enables the formation of scaffolds at the nanoscale needed for bone tissue engineering (BTE) using natural and synthetic polymers, as well as with minerals and metals. Then, it aids the development of the nano-formulation strategized to deliver antimicrobial drugs and/or growth factors through various ways to enhance bone repair through the scaffold. Third, NBT facilitates the use of specialized nanoparticles to image and track cellular events in vitro as well as in vivo. This review is an effort to bring together the current knowledge in the field of BTE and present the scope of ever-evolving NBT, a contribution towards precision medicine.

The demand for novel tissue grafting and regenerative wound care biomaterials is growing as traditional options often fall short in biocompatibility, functional integration with human tissue, associated cost(s), and sustainability. Salmon aquaculture generates significant volumes of waste, offering a sustainable opportunity for biomaterial production, particularly in osteo-conduction/-induction, and de novo clinical/surgical bone regeneration. Henceforth, this study explores re-purposing salmon waste through a standardized pre-treatment process that minimizes the biological waste content, followed by a treatment stage to remove proteins, lipids, and other compounds, resulting in a mineral-rich substrate. Herein, we examined various methods—alkaline hydrolysis, calcination, and NaOH hydrolysis—to better identify and determine the most efficient and effective process for producing bio-functional nano-sized hydroxyapatite. Through comprehensive chemical, physical, and biological assessments, including Raman spectroscopy and X-ray diffraction, we also optimized the extraction process. Our modified and innovative alkaline hydrolysis–calcination method yielded salmon-derived hydroxyapatite with a highly crystalline structure, an optimal Ca/P ratio, and excellent biocompatibility. The attractive nano-scale cellular/tissular properties and favorable molecular characteristics, particularly well-suited for bone repair, are comparable to or even surpass those of synthetic, human, bovine, and porcine hydroxyapatite, positioning it as a promising candidate for use in tissue engineering, wound healing, and regenerative medicine indications.

Due to the limited supply of autologous bone grafts, there is a need to develop more bone matrix materials to repair bone defects. Xenograft bone is expected to be used for clinical treatment due to its exact structural similarity to natural bone and its high biocompatibility. In this study, decellularized antler cancellous bone matrix (DACB) was first prepared, and then the extent of decellularization of DACB was verified by histological staining, which demonstrated that it retained the extracellular matrix (ECM). The bioactivity of DACB was assessed using C3H10T1/2 cells, revealing that DACB enhanced cell proliferation and facilitated cell adhesion and osteogenic differentiation. When evaluated by implanting DACB into nude mice, there were no signs of necrosis or inflammation in the epidermal tissues. The bone repair effect of DACB was verified in vivo using sika deer during the antler growth period as an animal model, and the molecular mechanisms of bone repair were further evaluated by transcriptomic analysis of the regenerated tissues. Our findings suggest that the low immunogenicity of DACB enhances the production of bone extracellular matrix components, leading to effective osseointegration between bone and DACB. This study provides a new reference for solving bone defects.

Nano-hydroxyapatite (n-HA) is the main inorganic component of natural bone, which has been widely used as a reinforcing filler for polymers in bone materials, and it can promote cell adhesion, proliferation, and differentiation. It can also produce interactions between cells and material surfaces through selective protein adsorption and has therefore always been a research hotspot in orthopedic materials. However, n-HA nano-particles are inherently easy to agglomerate and difficult to disperse evenly in the polymer. In addition, there are differences in trace elements between n-HA nano-particles and biological apatite, so the biological activity needs to be improved, and the slow degradation in vivo, which has seriously hindered the application of n-HA in bone fields, is unacceptable. Therefore, the modification of n-HA has been extensively reported in the literature. This article reviewed the physical modification and various chemical modification methods of n-HA in recent years, as well as their modification effects. In particular, various chemical modification methods and their modification effects were reviewed in detail. Finally, a summary and suggestions for the modification of n-HA were proposed, which would provide significant reference for achieving high-performance n-HA in biomedical applications.

Implant therapy is a common treatment option in dentistry and orthopedics, but its application is often associated with an increased risk of microbial contamination of the implant surfaces that cause bone tissue impairment. This study aims to develop two silver-enriched platelet-rich plasma (PRP) multifunctional scaffolds active at the same time in preventing implant-associated infections and stimulating bone regeneration. Commercial silver lactate (L) and newly synthesized silver deoxycholate:β-Cyclodextrin (B), were studied in vitro. Initially, the antimicrobial activity of the two silver soluble forms and the PRP enriched with the two silver forms has been studied on microbial planktonic cells. At the same time, the biocompatibility of silver-enriched PRPs has been assessed by an MTT test on human primary osteoblasts (hOBs). Afterwards, an investigation was conducted to evaluate the activity of selected concentrations and forms of silver-enriched PRPs in inhibiting microbial biofilm formation and stimulating hOB differentiation. PRP-L (0.3 µg/mm2) and PRP-B (0.2 µg/mm2) counteract Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans planktonic cell growth and biofilm formation, preserving hOB viability without interfering with their differentiation capability. Overall, the results obtained suggest that L- and B-enriched PRPs represent a promising preventive strategy against biofilm-related implant infections and demonstrate a new silver formulation that, together with increasing fibrin binding protecting silver in truncated cone-shaped cyclic oligosaccharides, achieved comparable inhibitory results on prokaryotic cells at a lower concentration.

Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of studies have confirmed that deferoxamine can reduce inflammatory response and promote angiogenesis. Blood vessels play a crucial role in sustaining vital life by facilitating the delivery of immune cells, oxygen, and nutrients, as well as eliminating waste products generated during cellular metabolism. Dysfunction in blood vessels may contribute significantly to the development of life-threatening diseases. Anti-angiogenesis therapy and pro-angiogenesis/angiogenesis strategies have been frequently recommended for various diseases. Herein, we describe the mechanism by which deferoxamine promotes angiogenesis and summarize its application in chronic wounds, bone repair, and diseases of the respiratory system. Furthermore, we discuss the drug delivery system of deferoxamine for treating various diseases, providing constructive ideas and inspiration for the development of new treatment strategies.

Severe loss of bone mass may require grafting, and, among the alternatives available, there are natural biomaterials that can act as scaffolds for the cell growth necessary for tissue regeneration. Collagen and elastin polymers are a good alternative due to their biomimetic properties of bone tissue, and their characteristics can be improved with the addition of polysaccharides such as chitosan and bioactive compounds such as jatoba resin and pomegranate extract due to their antigenic actions. The aim of this experimental protocol was to evaluate bone neoformation in experimentally made defects in the mandible of rats using polymeric scaffolds with plant extracts added. Thirty rats were divided into group 1, with a mandibular defect filled with a clot from the lesion and no graft implant (G1-C, n = 10); group 2, filled with collagen/chitosan/jatoba resin scaffolds (G2-CCJ, n = 10); and group 3, with collagen/nanohydroxyapatite/elastin/pomegranate extract scaffolds (G3-CHER, n = 10). Six weeks after surgery, the animals were euthanized and samples from the surgical areas were submitted to macroscopic, radiological, histological, and morphometric analysis of the mandibular lesion repair process. The results showed no inflammatory infiltrates in the surgical area, indicating good acceptance of the scaffolds in the microenvironment of the host area. In the control group (G1), there was a predominance of reactive connective tissue, while in the grafted groups (G2 and G3), there was bone formation from the margins of the lesion, but it was still insufficient for total bone repair of the defect within the experimental period standardized in this study. The histomorphometric analysis showed that the mean percentage of bone volume formed in the surgical area of groups G1, G2, and G3 was 17.17 ± 2.68, 27.45 ± 1.65, and 34.07 ± 0.64 (mean ± standard deviation), respectively. It can be concluded that these scaffolds with plant extracts added can be a viable alternative for bone repair, as they are easily manipulated, have a low production cost, and stimulate the formation of new bone by osteoconduction.

Bone morphogenetic protein (BMP) and platelet-derived growth factor (PDGF) are known to regulate/stimulate osteogenesis, playing vital roles in bone homeostasis, rendering them strong candidates for osteoporosis treatment. We evaluated the effects of recombinant human BMP-7 (rhBMP7) and PDGF-BB (rhPDGF-BB) in an oophorectomy-induced osteoporosis rat model. Forty Sprague Dawley rats underwent oophorectomy surgery; treatments commenced on the 100th day post-surgery when all animals exhibited signs of osteoporosis. These peptide growth factors were administered intraocularly (iv) once or twice a week and the animals were monitored for a total of five weeks. Two weeks after the conclusion of the treatments, the animals were euthanized and tissues were collected for assessment of alkaline phosphatase, X-ray, micro-CT, and histology. The results indicate that the most promising treatments were 20 µg/kg rhPDGF-BB + 30 µg/kg rhBMP-7 twice a week and 30 µg/kg BMP-7 twice a week, showing significant increases of 15% (p < 0.05) and 13% (p < 0.05) in bone volume fraction and 21% (p < 0.05) and 23% (p < 0.05) in trabecular number, respectively. In conclusion, rhPDGF-BB and rhBMP-7 have demonstrated the ability to increase bone volume and density in this osteoporotic animal model, establishing them as potential candidates for osteoporosis treatment.

Promoting the efficiency of bone regeneration in bone loss diseases is a significant clinical challenge. Traditional therapies often fail to achieve better therapeutic outcomes and shorter treatment times. However, in recent years, extracellular vesicles (EVs) have gained significant attention due to their exceptional osteogenic function in bone regeneration and superior therapeutic effects compared to traditional cell therapy. EVs have emerged as a promising therapy for tissue defect regeneration due to their various physiological functions, such as regulating the immune response and promoting tissue repair and regeneration. Moreover, EVs have good biocompatibility, low immunogenicity, and long-term stability, and can be improved through pretreatment and other methods. Studies investigating the mechanisms by which extracellular vesicles promote bone regeneration and applying EVs from different sources using various methods to animal models of bone defects have increased. Therefore, this paper reviews the types of EVs used for bone regeneration, their sources, roles, delivery pathways, scaffold biomaterials, and applications.

Porosity is a key feature in dictating the overall performance of biomedical scaffolds, with special relevance to mechanical properties. Usually, compressive strength and elastic modulus are the main parameters used to determine the potential mechanical suitability of porous scaffolds for bone repair. However, their assessment may not be so easy from an experimental viewpoint and, especially if the porosity is high, so reliable for brittle bioceramic foams. Hence, assessing the relationship between porosity and mechanical properties based only on the constitutive parameters of the solid material is a challenging and important task to predict the scaffold performance for optimization during design. In this work, a set of equations was used to predict the compressive strength and elastic modulus of bone-like hydroxyapatite scaffolds produced by digital light processing-based vat photopolymerization (total porosity about 80 vol.%). The compressive strength was found to depend on total porosity, following a power-law approximation. The relationship between porosity and elastic modulus was well fitted by second-order power law, with relative density and computational models obtained by numerical simulations.

In orthopedics, the repair of bone defects remains challenging. In previous research reports, magnesium phosphate cements (MPCs) were widely used because of their excellent mechanical properties, which have been widely used in the field of orthopedic medicine. We built a new k-struvite (MPC) cement obtained from zinc oxide (ZnO) and assessed its osteogenic properties. Zinc-doped magnesium phosphate cement (ZMPC) is a novel material with good biocompatibility and degradability. This article summarizes the preparation method, physicochemical properties, and biological properties of ZMPC through research on this material. The results show that ZMPC has the same strength and toughness (25.3 ± 1.73 MPa to 20.18 ± 2.11 MPa), that meet the requirements of bone repair. Furthermore, the material can gradually degrade (12.27% ± 1.11% in 28 days) and promote osteogenic differentiation (relative protein expression level increased 2–3 times) of rat bone marrow mesenchymal stem cells (rBMSCs) in vitro. In addition, in vivo confirmation revealed increased bone regeneration in a rat calvarial defect model compared with MPC alone. Therefore, ZMPC has broad application prospects and is expected to be an important repair material in the field of orthopedic medicine.

Since their first description nearly 20 years ago, dense collagen hydrogels obtained by plastic compression have become popular scaffolds in tissue engineering. In particular, when seeded with dental pulp stem cells, they have demonstrated a great in vivo potential in cranial bone repair. Here, we investigated how physico-chemical and cell-seeding conditions could influence the formation and in vitro mineralization of these cellularized scaffolds. A qualitative assessment demonstrated that the gel stability before and after compression was highly sensitive to the conditions of fibrillogenesis, especially initial acid acetic and buffer concentrations. Gels with similar rheological properties but different fibrillar structures that exhibited different stabilities when used for the 3D culture of Stem cells from Human Exfoliated Deciduous teeth (SHEDs) could be prepared. Finally, in our optimal physico-chemical conditions, mineralization could be achieved only using human dental pulp stem cells (hDPSCs) at a high cell density. These results highlight the key role of fibrillogenic conditions and cell type/density on the bone repair potential of cell-laden plastically compressed collagen hydrogels.

Biomaterials are used extensively in graft procedures to correct bone defects, interacting with the body without causing adverse reactions. The aim of this pre-clinical study was to analyze the effects of photobiomodulation therapy (PBM) with the use of a low-level laser in the repair process of bone defects filled with inorganic matrix (IM) associated with heterologous fibrin biopolymer (FB). A circular osteotomy of 4 mm in the left tibia was performed in 30 Wistar male adult rats who were randomly divided into three groups: G1 = IM + PBM, G2 = IM + FB and G3 = IM + FB + PBM. PBM was applied at the time of the experimental surgery and three times a week, on alternate days, until euthanasia, with 830 nm wavelength, in two points of the operated site. Five animals from each group were euthanized 14 and 42 days after surgery. In the histomorphometric analysis, the percentage of neoformed bone tissue in G3 (28.4% ± 2.3%) was higher in relation to G1 (24.1% ± 2.91%) and G2 (22.2% ± 3.11%) at 14 days and at 42 days, the percentage in G3 (35.1% ± 2.55%) was also higher in relation to G1 (30.1% ± 2.9%) and G2 (31.8% ± 3.12%). In the analysis of the birefringence of collagen fibers, G3 showed a predominance of birefringence between greenish-yellow in the neoformed bone tissue after 42 days, differing from the other groups with a greater presence of red-orange fibers. Immunohistochemically, in all experimental groups, it was possible to observe immunostaining for osteocalcin (OCN) near the bone surface of the margins of the surgical defect and tartrate-resistant acid phosphatase (TRAP) bordering the newly formed bone tissue. Therefore, laser photobiomodulation therapy contributed to improving the bone repair process in tibial defects filled with bovine biomaterial associated with fibrin biopolymer derived from snake venom.

This study aimed to develop a novel culture method for rat adipose-derived stem cells (rADSC) and evaluate their osteogenic potential. The rADSC cultured in xeno-free culture medium (XF-rADSCs) or conventional culture medium containing fetal bovine serum (FBS-rADSCs) were combined with micropieces of xeno-free recombinant collagen peptide to form 3-dimensional aggregates (XF-rADSC-CellSaic or FBS-rADSC-CellSaic). Both FBS-rADSC and XF-ADSC in CellSaic exhibited multilineage differentiation potential. Compared to FBS-rADSC-CellSaic, XF-rADSC-CellSaic accelerated and promoted osteogenic differentiation in vitro. When transplanted into rat mandibular congenital bone defects, the osteogenically differentiated XF-rADSC-CellSaic induced regeneration of bone tissue with a highly maturated structure compared to FBS-rADSC-CellSaic. In conclusion, XF-rADSC-CellSaic is a feasible 3-dimensional platform for efficient bone formation.

Joint damage is a major symptom of osteoarthritis, a degenerative disease that worsens over time. The purpose of this review was to assess the effectiveness and safety of nanomaterials as an alternative to the widely used methods. Due to its poor regenerative and self-healing properties, cartilage repair after lesions or debilitating disease is a major clinical issue. Here, we use the organometallic chemistry identity of chondroitin sulphate to repair cartilage lesions by creating a nano-elemental particle through electrostatic interactions. As an integral part of the extracellular matrix, chondroitin sulphate (CS) is shown to improve osteogenesis in this review. The injectability of hydrated cement products was greatly improved by the addition of CS, but there was no discernible change in their phase, morphology, apparent porosity, or compressive strength. This review article provides a thorough analysis of the results from the use of nanocomposites in orthopaedic drug delivery and bone remodelling engineering.

Reactive oxygen species (ROS) has great influence in many physiological or pathological processes in organisms. In the site of bone defects, the overproduced ROS significantly affects the dynamic balance process of bone regeneration. Many antioxidative organic and inorganic antioxidants showed good osteogenic ability, which has been widely used for bone repair. It is of great significance to summarize the antioxidative bone repair materials (ABRMs) to provide guidance for the future design and preparation of osteogenic materials with antioxidative function. Here, this review introduced the major research direction of ABRM at present in nanoscale, 2-dimensional coating, and 3-dimensional scaffolds. Moreover, the referring main active substances and antioxidative properties were classified, and the positive roles of antioxidative materials for bone repair have also been clearly summarized in signaling pathways, antioxidant enzymes, cellular responses and animal levels.

The aim of this study was to conduct an integrative review of the biological and mechanical outcomes of porous zirconia structures for extensive bone repair. An electronic search was performed on the PubMed database using a combination of the following scientific terms: porous, scaffold, foam, zirconia, bone regeneration, bone repair, bone healing. Articles published in the English language up to December 2021 and related to porosity, pore interconnectivity, biocompatibility and strength of the material, and the manufacturing methods of zirconia porous structures were included. Randomized controlled trials and prospective cohort studies were also evaluated. The research identified 145 studies, of which 23 were considered relevant. A high percentage of pores and the size and interconnectivity of pores are key factors for cell migration, attachment, proliferation, and differentiation. In addition, pore interconnectivity allows for the exchange of nutrients between cells and formation of blood vessels. However, a decrease in strength of the porous structures was noted with an increase in the number and size of pores. Therefore, yttria-stabilized zirconia tetragonal polycrystal (Y-TZP) has mechanical properties that make it suitable for the manufacture of highly porous structures or implants for extensive bone repair. Additionally, the porous structures can be coated with bioactive ceramics to enhance the cell response and bone ingrowth without compromising pore networking. Porous structures and mesh implants composed of zirconia have become a strategy for extensive bone repair since the material and the pore network provide the desired biological response and bone volume maintenance.

Hydrogels are three-dimensional (3D) water-swellable polymeric matrices that are used extensively in tissue engineering and drug delivery. Hydrogels can be conformed into any desirable shape using 3D bio-printing, making them suitable for personalized treatment. Among the different 3D bio-printing techniques, digital light processing (DLP)-based printing offers the advantage of quickly fabricating high resolution structures, reducing the chances of cell damage during the printing process. Here, we have used DLP to 3D bio-print biocompatible gelatin methacrylate (GelMA) scaffolds intended for bone repair. GelMA is biocompatible, biodegradable, has integrin binding motifs that promote cell adhesion, and can be crosslinked easily to form hydrogels. However, GelMA on its own is incapable of promoting bone repair and must be supplemented with pharmaceutical molecules or growth factors, which can be toxic or expensive. To overcome this limitation, we introduced zinc-based metal-organic framework (MOF) nanoparticles into GelMA that can promote osteogenic differentiation, providing safer and more affordable alternatives to traditional methods. Incorporation of this nanoparticle into GelMA hydrogel has demonstrated significant improvement across multiple aspects, including bio-printability, and favorable mechanical properties (showing a significant increase in the compressive modulus from 52.14 ± 19.42 kPa to 128.13 ± 19.46 kPa with the addition of ZIF-8 nanoparticles). The designed nanocomposite hydrogels can also sustain drug (vancomycin) release (maximum 87.52 ± 1.6% cumulative amount) and exhibit a remarkable ability to differentiate human adipose-derived mesenchymal stem cells toward the osteogenic lineage. Furthermore, the formulated MOF-integrated nanocomposite hydrogel offers the unique capability to coat metallic implants intended for bone healing. Overall, the remarkable printability and coating ability displayed by the nanocomposite hydrogel presents itself as a promising candidate for drug delivery, cell delivery and bone tissue engineering applications.

Bone lesions have the capacity for regeneration under normal conditions of the bone metabolism process. However, due to the increasing incidence of major traumas and diseases that cause bone-mineral deficiency, such as osteoporosis, scaffolds are needed that can assist in the bone regeneration process. Currently, natural polymeric scaffolds and bioactive nanoparticles stand out. Therefore, the objective of the study was to evaluate the osteoregenerative potential in tibiae of healthy and ovariectomized rats using mineralized collagen and nanohydroxyapatite (nHA) scaffolds associated with elastin. The in-vivo experimental study was performed with 60 20-week-old Wistar rats, distributed into non-ovariectomized (NO) and ovariectomized (O) groups, as follows: Controls (G1-NO-C and G4-O-C); Collagen with nHA scaffold (G2-NO-MSH and G5-O-MSH); and Collagen with nHA and elastin scaffold (G3-NO-MSHC and G6-O-MSHC). The animals were euthanized 6 weeks after surgery and the samples were analyzed by macroscopy, radiology, and histomorphometry. ANOVA and Tukey tests were performed with a 95% CI and a significance index of p < 0.05. In the histological analyses, it was possible to observe new bone formed with an organized and compact morphology that was rich in osteocytes and with maturity characteristics. This is compatible with osteoconductivity in both matrices (MSH and MSHC) in rats with normal conditions of bone metabolism and with gonadal deficiency. Furthermore, they demonstrated superior osteogenic potential when compared to control groups. There was no significant difference in the rate of new bone formation between the scaffolds. Ovariectomy did not exacerbate the immune response but negatively influenced the bone-defect repair process.

Most electrospun scaffolds for bone tissue engineering typically use hydroxyapatite (HA) or beta tricalcium phosphate (β-TCP). However, the biological activity of these crystalline compounds can be limited due to their low solubility. Therefore, amorphous calcium phosphate (ACP) may be an alternative in bone repair scaffolds. This study analyzes the morphology, porosity, mechanical strength, and surface chemistry of electrospun scaffolds composed of polylactic acid and collagen integrated with hydroxyapatite (MHAP) or amorphous calcium phosphate (MACP). In addition, the in vitro biocompatibility, osteogenic differentiation, and growth factor production associated with bone repair using human Wharton’s jelly-derived mesenchymal stem cells (hWJ-MSCs) are evaluated. The results show that the electrospun MHAP and MACP scaffolds exhibit a fibrous morphology with interconnected pores. Both scaffolds exhibit favorable biocompatibility and stimulate the proliferation and osteogenesis of hWJ-MSCs. However, cell adhesion and osteocalcin production are greater in the MACP scaffold compared to the MHAP scaffold. In addition, the MACP scaffold shows significant production of bone-repair-related growth factors such as transforming growth factor-beta 1 (TGF-β1), providing a solid basis for its use in bone tissue engineering.

Large bone defects due to trauma, infections, and tumors are difficult to heal spontaneously by the body’s repair mechanisms and have become a major hindrance to people’s daily lives and economic development. However, autologous and allogeneic bone grafts, with their lack of donors, more invasive surgery, immune rejection, and potential viral transmission, hinder the development of bone repair. Hydrogel tissue bioengineered scaffolds have gained widespread attention in the field of bone repair due to their good biocompatibility and three-dimensional network structure that facilitates cell adhesion and proliferation. In addition, loading natural products with nanoparticles and incorporating them into hydrogel tissue bioengineered scaffolds is one of the most effective strategies to promote bone repair due to the good bioactivity and limitations of natural products. Therefore, this paper presents a brief review of the application of hydrogels with different gel-forming properties, hydrogels with different matrices, and nanoparticle-loaded natural products loaded and incorporated into hydrogels for bone defect repair in recent years.

Clinical biophysical stimulating strategies, which have significant effects on improving the function of organs or treating diseases by causing the salutary response of body, have shown many advantages, such as non-invasiveness, few side effects, and controllable treatment process. As a critical technique for stimulation, the low intensity pulsed ultrasound (LIPUS) has been explored in regulating osteogenesis, which has presented great promise in bone repair by delivering a combined effect with biomaterials. This review summarizes the musculoskeletal biomaterials that can be synergized with LIPUS for enhanced biomedical application, including bone regeneration, spinal fusion, osteonecrosis/osteolysis, cartilage repair, and nerve regeneration. Different types of biomaterials are categorized for summary and evaluation. In each subtype, the verified biological mechanisms are listed in a table or graphs to prove how LIPUS was effective in improving musculoskeletal tissue regeneration. Meanwhile, the acoustic excitation parameters of LIPUS that were promising to be effective for further musculoskeletal tissue engineering are discussed, as well as their limitations and some perspectives for future research. Overall, coupled with biomimetic scaffolds and platforms, LIPUS may be a powerful therapeutic approach to accelerate musculoskeletal tissue repair and even in other regenerative medicine applications.

Degenerative scoliosis (DS), encompassing conditions like spondylolisthesis and spinal stenosis, is a common type of spinal deformity. Lumbar interbody fusion (LIF) stands as a conventional surgical intervention for this ailment, aiming at decompression, restoration of intervertebral height, and stabilization of motion segments. Despite its widespread use, the precise mechanism underlying spinal fusion remains elusive. In this review, our focus lies on endochondral ossification for spinal fusion, a process involving vertebral development and bone healing. Endochondral ossification is the key step for the successful vertebral fusion. Endochondral ossification can persist in hypoxic conditions and promote the parallel development of angiogenesis and osteogenesis, which corresponds to the fusion process of new bone formation in the hypoxic region between the vertebrae. The ideal material for interbody fusion cages should have the following characteristics: (1) Good biocompatibility; (2) Stable chemical properties; (3) Biomechanical properties similar to bone tissue; (4) Promotion of bone fusion; (5) Favorable for imaging observation; (6) Biodegradability. Utilizing cartilage-derived bone-like constructs holds promise in promoting bony fusion post-operation, thus warranting exploration in the context of spinal fusion procedures.

The use of bioactive materials, such as Ximenia americana L., to stimulate the bone repair process has already been studied; however, the synergistic effects of its association with light emitting diode (LED) have not been reported. The present work aims to evaluate the effect of its stem bark extract incorporated into methacrylate gelatin hydrogel (GelMA) on the bone repair process using pure hydrogel and hydrogel associated with LED therapy. For this purpose, the GelMA hydrogel loaded with Ximenia americana L. extract (steam bark) was produced, characterized and applied in animal experiments. The tests were performed using 50 male Wistar rats (divided into 5 groups) submitted to an induced tibia diaphyseal fracture. The therapy effects were verified for a period of 15 and 30 days of treatment using histological analysis and Raman spectroscopy. After 15 days of induced lesion/treatment, the new bone formation was significantly higher in the GXG (GelMA + X. americana L.) group compared to the control group (p < 0.0001). After 30 days, a statistically significant difference was observed when comparing the GXLEDG (GelMA + X. americana L. + LED) and the control group (p < 0.0001), the GXG and the control group (p < 0.001), and when comparing the GG, GXG (p < 0.005) and GXLEDG (p < 0.001) groups. The results shows that the Ximenia americana L. stem extract incorporated into GelMA hydrogel associated with LED therapy is a potentiator for animal bone repair.

Periosteum is a highly vascularized membrane lining the surface of bones. It plays essential roles in bone repair following injury and reconstruction following invasive surgeries. To broaden the use of periosteum, including for augmenting in vitro bone engineering and/or in vivo bone repair, we have developed an ex vivo perfusion bioreactor system to maintain the cellular viability and metabolism of surgically resected periosteal flaps. Each specimen was placed in a 3D printed bioreactor connected to a peristaltic pump designed for the optimal flow rates of tissue perfusate. Nutrients and oxygen were perfused via the periosteal arteries to mimic physiological conditions. Biochemical assays and histological staining indicate component cell viability after perfusion for almost 4 weeks. Our work provides the proof-of-concept of ex vivo periosteum perfusion for long-term tissue preservation, paving the way for innovative bone engineering approaches that use autotransplanted periosteum to enhance in vivo bone repair.

Background: Tissue engineering and cell therapy have been the focus of investigations on how to treat challenging bone defects. This study aimed to produce and characterize a P(VDF-TrFE)/BaTiO3 scaffold and evaluate the effect of mesenchymal stem cells (MSCs) combined with this scaffold and photobiomodulation (PBM) on bone repair. Methods and results: P(VDF-TrFE)/BaTiO3 was synthesized using an electrospinning technique and presented physical and chemical properties suitable for bone tissue engineering. This scaffold was implanted in rat calvarial defects (unilateral, 5 mm in diameter) and, 2 weeks post-implantation, MSCs were locally injected into these defects (n = 12/group). Photobiomodulation was then applied immediately, and again 48 and 96 h post-injection. The μCT and histological analyses showed an increment in bone formation, which exhibited a positive correlation with the treatments combined with the scaffold, with MSCs and PBM inducing more bone repair, followed by the scaffold combined with PBM, the scaffold combined with MSCs, and finally the scaffold alone (ANOVA, p ≤ 0.05). Conclusions: The P(VDF-TrFE)/BaTiO3 scaffold acted synergistically with MSCs and PBM to induce bone repair in rat calvarial defects. These findings emphasize the need to combine a range of techniques to regenerate large bone defects and provide avenues for further investigations on innovative tissue engineering approaches.

The development of calcium phosphate cement (CaPC) has been regarded as a significant advance in the field of bone defect reconstruction. This patent analysis-based research concerns patent documents with an active legal status until 2022. The state of the art is reviewed by introducing what has been patented concerning CaPCs for bone repair. As a result, 740 active patent documents were found, and 51% of them were published during the last 7 years. According to the findings, the United States ranked as the first jurisdiction, with academic institutions from France and the United States leading the patenting way. The Cooperative Patent Classification reveals that most inventions are intended for materials or treatments for tissue regeneration, such as the reconstruction of bones with weight-bearing implants, as well as inorganic materials for grafts or prostheses, such as phosphorus-containing materials.

Bone fractures and bone defects affect millions of people every year. Metal implants for bone fracture fixation and autologous bone for defect reconstruction are used extensively in treatment of these pathologies. Simultaneously, alternative, sustainable, and biocompatible materials are being researched to improve existing practice. Wood as a biomaterial for bone repair has not been considered until the last 50 years. Even nowadays there is not much research on solid wood as a biomaterial in bone implants. A few species of wood have been investigated. Different techniques of wood preparation have been proposed. Simple pre-treatments such as boiling in water or preheating of ash, birch and juniper woods have been used initially. Later researchers have tried using carbonized wood and wood derived cellulose scaffold. Manufacturing implants from carbonized wood and cellulose requires more extensive wood processing—heat above 800 °C and chemicals to extract cellulose. Carbonized wood and cellulose scaffolds can be combined with other materials, such as silicon carbide, hydroxyapatite, and bioactive glass to improve biocompatibility and mechanical durability. Throughout the publications wood implants have provided good biocompatibility and osteoconductivity thanks to wood’s porous structure.

This study aims to critically analyse the workflow of the in situ bioprinting procedure, presenting a simulated neurosurgical case study, based on a real traumatic event, for collecting quantitative data in support of this innovative approach. After a traumatic event involving the head, bone fragments may have to be removed and a replacement implant placed through a highly demanding surgical procedure in terms of surgeon dexterity. A promising alternative to the current surgical technique is the use of a robotic arm to deposit the biomaterials directly onto the damaged site of the patient following a planned curved surface, which can be designed pre-operatively. Here we achieved an accurate planning-patient registration through pre-operative fiducial markers positioned around the surgical area, reconstructed starting from computed tomography images. Exploiting the availability of multiple degrees of freedom for the regeneration of complex and also overhanging parts typical of anatomical defects, in this work the robotic platform IMAGObot was used to regenerate a cranial defect on a patient-specific phantom. The in situ bioprinting process was then successfully performed showing the great potential of this innovative technology in the field of cranial surgery. In particular, the accuracy of the deposition process was quantified, as well as the duration of the whole procedure was compared to a standard surgical practice. Further investigations include a biological characterisation over time of the printed construct as well as an in vitro and in vivo analysis of the proposed approach, to better analyse the biomaterial performances in terms of osteo-integration with the native tissue.

Calcitonin gene-related peptide (CGRP) has 37 amino acids. Initially, CGRP had vasodilatory and nociceptive effects. As research progressed, evidence revealed that the peripheral nervous system is closely associated with bone metabolism, osteogenesis, and bone remodeling. Thus, CGRP is the bridge between the nervous system and the skeletal muscle system. CGRP can promote osteogenesis, inhibit bone resorption, promote vascular growth, and regulate the immune microenvironment. The G protein-coupled pathway is vital for its effects, while MAPK, Hippo, NF-κB, and other pathways have signal crosstalk, affecting cell proliferation and differentiation. The current review provides a detailed description of the bone repair effects of CGRP, subjected to several therapeutic studies, such as drug injection, gene editing, and novel bone repair materials.

The restoration of cartilage damage is a slow and not always successful process. Kartogenin (KGN) has significant potential in this space—it is able to induce the chondrogenic differentiation of stem cells and protect articular chondrocytes. In this work, a series of poly(lactic-co-glycolic acid) (PLGA)-based particles loaded with KGN were successfully electrosprayed. In this family of materials, PLGA was blended with a hydrophilic polymer (either polyethyleneglycol (PEG) or polyvinylpyrrolidone (PVP)) to control the release rate. Spherical particles with sizes in the range of 2.4–4.1 µm were fabricated. They were found to comprise amorphous solid dispersions, with high entrapment efficiencies of >93%. The various blends of polymers had a range of release profiles. The PLGA-KGN particles displayed the slowest release rate, and blending with PVP or PEG led to faster release profiles, with most systems giving a high burst release in the first 24 h. The range of release profiles observed offers the potential to provide a precisely tailored profile via preparing physical mixtures of the materials. The formulations are highly cytocompatible with primary human osteoblasts.

Superparamagnetic iron oxide nanoparticles (SPION) are widely used in bone tissue engineering because of their unique physical and chemical properties and their excellent biocompatibility. Under the action of a magnetic field, SPIONs loaded in a biological scaffold can effectively promote osteoblast proliferation, differentiation, angiogenesis, and so on. SPIONs have very broad application prospects in bone repair, bone reconstruction, bone regeneration, and other fields. In this paper, several methods for forming biological scaffolds via the biological assembly of SPIONs are reviewed, and the specific applications of these biological scaffolds in bone tissue engineering are discussed.

This study describes the surgical treatment of multiple humeral fractures in a Caretta caretta sea turtle referred by the ‘Centro Faunistico del Parco Regionale Bosco e Paludi di Rauccio’, in the area surrounding the city of Lecce, in southern Italy. Radiographs showed an evident detachment of the distal humeral epiphysis, compatible with a type II Salter-Harris fracture, as well as a transverse fracture of the diaphysis. After the surgical fracture reduction, radiographic follow-up was performed at 2, 4, 12, 16, and 24 months, showing a progressive healing and the formation of poorly mineralized callus tissue. Unfortunately, three months after his release at sea, the turtle was caught dead at a depth of 40 m. Histological and histomorphometric examinations of the surgically treated humerus were carried out on the corpse to collect further information about the bone tissue repair mechanisms in these animals.

Strategies for the production of new nanocomposites that promote bone tissue regeneration are important, particularly those that enhance the osteoinduction of hydroxyapatite in situ. Here, we studied and report the synthesis of nanohydroxyapatite and titanate nanotube (nHAp/TiNT) composites formulated at different concentrations (1, 2, 3, and 10 wt % TiNT) by means of a wet aqueous chemical reaction. The addition of TiNT affects the morphology of the nanocomposites, decreasing the average crystallite size from 54 nm (nHAp) to 34 nm (nHAp/TiNT10%), while confirming its interaction with the nanocomposite. The crystallinity index (CI) calculated by Raman spectroscopy and XRD showed that the values decreased according to the increase in TiNT concentration, which confirmed their addition to the structure of the nanocomposite. SEM images showed the presence of TiNTs in the nanocomposite. We further verified the potential cytotoxicity of murine fibroblast cell line L929, revealing that there was no remarkable cell death at any of the concentrations tested. In vivo regenerative activity was performed using oophorectomized animal (rat) models organized into seven groups containing five animals each over two experimental periods (15 and 30 days), with bone regeneration occurring in all groups tested within 30 days; however, the nHAp/TiNT10% group showed statistically greater tissue repair, compared to the untreated control group. Thus, the results of this study demonstrate that the presently formulated nHAp/TiNT nanocomposites are promising for numerous improved bone tissue regeneration applications.

Bone homeostasis (a healthy bone mass) is regulated by maintaining a delicate balance between bone resorption and bone formation. The regulation of physiological bone remodeling by a complex system that involves multiple cells in the skeleton is closely related to bone homeostasis. Loss of bone mass or repair of bone is always accompanied by changes in bone homeostasis. However, due to the complexity of bone homeostasis, we are currently unable to identify all the mechanisms that affect bone homeostasis. To date, bone macrophages have been considered a third cellular component in addition to osteogenic spectrum cells and osteoclasts. As confirmed by co-culture models or in vivo experiments, polarized or unpolarized macrophages interact with multiple components within the bone to ensure bone homeostasis. Different macrophage phenotypes are prone to resorption and formation of bone differently. This review comprehensively summarizes the mechanisms by which macrophages regulate bone homeostasis and concludes that macrophages can control bone homeostasis from osteoclasts, mesenchymal cells, osteoblasts, osteocytes, and the blood/vasculature system. The elaboration of these mechanisms in this narrative review facilitates the development of macrophage-based strategies for the treatment of bone metabolic diseases and bone defects.

Extensive bone defect healing is an important health issue not yet completely resolved. Different alternative treatments have been proposed but, in face of a critical bone defect, it is still very difficult to reach a complete regeneration, with the new-formed bone presenting all morphological and physiological characteristics of a normal, preinjury bone. Topical melatonin use has shown as a promising adjuvant for bone regeneration due to its positive effects on bone metabolism. Thus, to search for new, safe, biological techniques that promote bone repair and favor defect healing, we hypothesized that there is a synergistic effect of melatonin treatment associated with rhBMP-2 to guide bone regeneration. This study aimed to investigate bone repair effects of topical melatonin administration in different concentrations (1, 10, and 100 µg), associated or not with rhBMP-2. Surgical-induced bone defect healing was qualitatively evaluated through histopathological analysis by light microscopy. Additionally, quantitative stereology was performed in immunohistochemistry-prepared tissue to identify angiogenic, osteogenic, and osteoclastogenic factors. Quantification data were compared between groups by the ANOVA/Tukey test and differences were considered significant when p < 0.05. Our results showed that the presence of the scaffold in the bone defect hindered the process of bone repair because in the group treated with “blood clot + scaffold” the results of bone formation and immunolabeling were reduced in comparison with all other groups (treated with melatonin alone or in association with rhBMP-2). Statistical analysis revealed a significant difference between the control group (bone defect + blood clot), and groups treated with different concentrations of melatonin in association with rhBMP-2, indicating a positive effect of the association for bone repair. This treatment is promising once it becomes a new safe alternative technique for the clinical treatment of fractures, bone defects, and bone grafts. Our results support the hypothesis of the safe use of the association of melatonin and rhBMP-2 and have established a safe and effective dose for this experimental treatment.

Transfer of regenerative approaches into clinical practice is limited by strict legal regulation of in vitro expanded cells and risks associated with substantial manipulations. Isolation of cells for the enrichment of bone grafts directly in the Operating Room appears to be a promising solution for the translation of biomedical technologies into clinical practice. These intraoperative approaches could be generally characterized as a joint concept of tissue engineering in situ. Our review covers techniques of intraoperative cell isolation and seeding for the creation of tissue-engineered grafts in situ, that is, directly in the Operating Room. Up-to-date, the clinical use of tissue-engineered grafts created in vitro remains a highly inaccessible option. Fortunately, intraoperative tissue engineering in situ is already available for patients who need advanced treatment modalities.

Phosphate-based glasses (PBGs) are promising materials for bone repair and regeneration as they can be formulated to be compositionally similar to the inorganic components of bone. Alterations to the PBG formulation can be used to tailor their degradation rates and subsequent release of biotherapeutic ions to induce cellular responses, such as osteogenesis. In this work, novel invert-PBGs in the series xP2O5·(56 − x)CaO·24MgO·20Na2O (mol%), where x is 40, 35, 32.5 and 30 were formulated to contain pyro (Q1) and orthophosphate (Q0) species. These PBGs were processed into highly porous microspheres (PMS) via flame spheroidisation, with ~68% to 75% porosity levels. Compositional and structural analysis using EDX and 31P-MAS NMR revealed that significant depolymerisation occurred with reducing phosphate content which increased further when PBGs were processed into PMS. A decrease from 50% to 0% in Q2 species and an increase from 6% to 35% in Q0 species was observed for the PMS when the phosphate content decreased from 40 to 30 mol%. Ion release studies also revealed up to a four-fold decrease in cations and an eight-fold decrease in phosphate anions released with decreasing phosphate content. In vitro bioactivity studies revealed that the orthophosphate-rich PMS had favourable bioactivity responses after 28 days of immersion in simulated body fluid (SBF). Indirect and direct cell culture studies confirmed that the PMS were cytocompatible and supported cell growth and proliferation over 7 days of culture. The P30 PMS with ~65% pyro and ~35% ortho phosphate content revealed the most favourable properties and is suggested to be highly suitable for bone repair and regeneration, especially for orthobiologic applications owing to their highly porous morphology.

In this preclinical protocol, an adjunct method is used in an attempt to overcome the limitations of conventional therapeutic approaches applied to bone repair of large bone defects filled with scaffolds. Thus, we evaluate the effects of photobiomodulation therapy (PBMT) on the bone repair process on defects filled with demineralized bovine bone (B) and fibrin sealant (T). The groups were BC (blood clot), BT (B + T), BCP (BC + PBMT), and BTP (B + T + PBMT). Microtomographically, BC and BCP presented a hypodense cavity with hyperdense regions adjacent to the border of the wound, with a slight increase at 42 days. BT and BTP presented discrete hyperdensing areas at the border and around the B particles. Quantitatively, BCP and BTP (16.96 ± 4.38; 17.37 ± 4.38) showed higher mean bone density volume in relation to BC and BT (14.42 ± 3.66; 13.44 ± 3.88). Histologically, BC and BCP presented deposition of immature bone at the periphery and at 42 days new bone tissue became lamellar with organized total collagen fibers. BT and BTP showed inflammatory infiltrate along the particles, but at 42 days, it was resolved, mainly in BTP. In the birefringence analysis, BT and BTP, the percentage of red birefringence increased (9.14% to 20.98% and 7.21% to 27.57%, respectively), but green birefringence was similar in relation to 14 days (3.3% to 3.5% and 3.5% to 4.2%, respectively). The number of osteocytes in the neoformed bone matrix proportionally reduced in all evaluated groups. Immunostaining of bone morphogenetic protein (BMP—2/4), osteocalcin (OCN), and vascular endothelial growth factor (VEGF) were higher in BCP and BTP when compared to the BC and BT groups (p < 0.05). An increased number of TRAP positive cells (tartrate resistant acid phosphatase) was observed in BT and BTP. We conclude that PBMT positively influenced the repair of bone defects filled with B and T.

Facilitated endogenous tissue engineering, as a facile and effective strategy, is emerging for use in bone tissue regeneration. However, the development of bioactive scaffolds with excellent osteo-inductivity to recruit endogenous stem cells homing and differentiation towards lesion areas remains an urgent problem. Chitosan (CS), with versatile qualities including good biocompatibility, biodegradability, and tunable physicochemical and biological properties is undergoing vigorously development in the field of bone repair. Based on this, the review focus on recent advances in chitosan-based scaffolds for facilitated endogenous bone regeneration. Initially, we introduced and compared the facilitated endogenous tissue engineering with traditional tissue engineering. Subsequently, the various CS-based bone repair scaffolds and their fabrication methods were briefly explored. Furthermore, the functional design of CS-based scaffolds in bone endogenous regeneration including biomolecular loading, inorganic nanomaterials hybridization, and physical stimulation was highlighted and discussed. Finally, the major challenges and further research directions of CS-based scaffolds were also elaborated. We hope that this review will provide valuable reference for further bone repair research in the future.

In the present study, the structural, morphological, and in vivo biocompatibility of un-doped and boron (B)-doped strontium apatite (SrAp) nanoparticles were investigated. Biomaterials were fabricated using the hydrothermal process. The structural and morphological characterizations of the fabricated nanoparticles were performed by XRD, FT-IR, FE-SEM, and EDX. Their biocompatibility was investigated by placing them in defects in rat tibiae in vivo. The un-doped and B-doped SrAp nanoparticles were successfully fabricated. The produced nanoparticles were in the shape of nano-rods, and the dimensions of the nano-rods decreased as the B ratio increased. It was observed that the structural and morphological properties of strontium apatite nanoparticles were affected by the contribution of B. A stoichiometric Sr/P ratio of 1.67 was reached in the 5% B-doped sample (1.68). The average crystallite sizes were 34.94 nm, 39.70 nm, 44.93 nm, and 48.23 nm in un-doped, 1% B-doped, 5% B-doped, and 10% B-doped samples, respectively. The results of the in vivo experiment revealed that the new bone formation and osteoblast density were higher in the groups with SrAp nanoparticles doped with different concentrations of B than in the control group, in which the open defects were untreated. It was observed that this biocompatibility and the new bone formation were especially elevated in the B groups, which added high levels of strontium were added. The osteoblast density was higher in the group in which the strontium element was placed in the opened bone defect compared with the control group. However, although new bone formation was slightly higher in the strontium group than in the control group, the difference was not statistically significant. Furthermore, the strontium group had the highest amount of fibrotic tissue formation. The produced nanoparticles can be used in dental and orthopedic applications as biomaterials.

3D-printing technology can be used to construct personalized bone substitutes with customized shapes, but it cannot regulate the topological morphology of the scaffold surface, which plays a vital role in regulating the biological behaviors of stem cells. In addition, stem cells are able to sense the topographical and mechanical cues of surface of scaffolds by mechanosensing and mechanotransduction. In our study, we fabricated a 3D-printed poly(ε-caprolactone) (PCL) scaffold with a nanotopographical surface and loaded it with urine-derived stem cells (USCs) for application of bone regeneration. The topological 3D-printed PCL scaffolds (TPS) fabricated by surface epiphytic crystallization, possessed uniformly patterned nanoridges, of which the element composition and functional groups of nanoridges were the same as PCL. Compared with bare 3D-printed PCL scaffolds (BPS), TPS have a higher ability for protein adsorption and mineralization in vitro. The proliferation, cell length, and osteogenic gene expression of USCs on the surface of TPS were significantly higher than that of BPS. In addition, the TPS loaded with USCs exhibited a good ability for bone regeneration in cranial bone defects. Our study demonstrated that nanotopographical 3D-printed scaffolds loaded with USCs are a safe and effective therapeutic strategy for bone regeneration.

Osteoconductive silk fibroin (SF) binders were fabricated for the bone repair of an alveolar cleft defect. Binders were prefigureared by mixing different ratios of a mixture of random coils and SF aggregation with SF fibrils: 100:0 (SFB100), 75:25 (SFB75), 50:50 (SFB50), 25:75 (SFB25), and 0:100 (SFB0). The gelation, molecular organization, structures, topography, and morphology of the binders were characterized and observed. Their physical, mechanical, and biological properties were tested. The SF binders showed gelation via self-assembly of SF aggregation and fibrillation. SFB75, SFB50, and SFB25 had molecular formation via the amide groups and showed more structural stability than SFB100. The morphology of SFB0 demonstrated the largest pore size. SFB0 showed a lowest hydrophilicity. SFB100 showed the highest SF release. SFB25 had the highest maximum load. SFB50 exhibited the lowest elongation at break. Binders with SF fibrils showed more cell viability and higher cell proliferation, ALP activity, calcium deposition, and protein synthesis than without SF fibrils. Finally, the results were deduced: SFB25 demonstrated suitable performance that is promising for the bone repair of an alveolar cleft defect.

The repair of infected bone defects (IBDs) is still a great challenge in clinic. A successful treatment for IBDs should simultaneously resolve both infection control and bone defect repair. Hydrogels are water-swollen hydrophilic materials that maintain a distinct three-dimensional structure, helping load various antibacterial drugs and biomolecules. Hybrid hydrogels may potentially possess antibacterial ability and osteogenic activity. This review summarizes the recent progress of different kinds of antibacterial agents (including inorganic, organic, and natural) encapsulated in hydrogels. Several representative hydrogels of each category and their antibacterial mechanism and effect on bone repair are presented. Moreover, the advantages and disadvantages of antibacterial agent hybrid hydrogels are discussed. The challenge and future research directions are further prospected.

There are several treatment methods available for bone repair, although the effectiveness becomes limited in cases of large defects. The objective of this pre-clinical protocol was to evaluate the grafting of hydroxyapatite/tricalcium phosphate (BCP) ceramic biomaterial (B; QualyBone BCP®, QualyLive, Amadora, Portugal) together with the heterologous fibrin biopolymer (FB; CEVAP/UNESP Botucatu, Brazil) and with photobiomodulation (PBM; Laserpulse®, Ibramed, Amparo, Brazil) in the repair process of bone defects. Fifty-six rats were randomly divided into four groups of seven animals each: the biomaterial group (G1/B), the biomaterial plus FB group (G2/BFB); the biomaterial plus PBM group (G3/B + PBM), and the biomaterial plus FB plus PBM group (G4/BFB + PBM). After anesthesia, a critical defect was performed in the center of the rats’ parietal bones, then filled and treated according to their respective groups. The rats were euthanized at 14 and 42 postoperative days. Histomorphologically, at 42 days, the G4/BFB + PBM group showed a more advanced maturation transition, with more organized and mature bone areas forming concentric lamellae. A birefringence analysis of collagen fibers also showed a more advanced degree of maturation for the G4/BFB + PBM group. In the comparison between the groups, in the two experimental periods (14 and 42 days), in relation to the percentage of formation of new bone tissue, a significant difference was found between all groups (G1/B (5.42 ± 1.12; 21.49 ± 4.74), G2/BFB (5.00 ± 0.94; 21.77 ± 2.83), G3/B + PBM (12.65 ± 1.78; 29.29 ± 2.93), and G4/BFB + PBM (12.65 ± 2.32; 31.38 ± 2.89)). It was concluded that the use of PBM with low-level laser therapy (LLLT) positively interfered in the repair process of bone defects previously filled with the biocomplex formed by the heterologous fibrin biopolymer associated with the synthetic ceramic of hydroxyapatite and tricalcium phosphate.

Plasma electrolytic oxidation (PEO) is widely used as a surface modification method to enhance the corrosion resistance of Mg alloy, the most likely applied biodegradable material used in orthopedic implants. However, the pores and cracks easily formed on the PEO surface are unfavorable for long-term corrosion resistance. In this study, to solve this problem, we used simple immersion processes to construct Mn and Fe oxyhydroxide duplex layers on the PEO-treated AZ31 (PEO–Mn/Fe). As control groups, single Mn and Fe oxyhydroxide layers were also fabricated on PEO (denoted as PEO–Mn and PEO–Fe, respectively). PEO–Mn showed a similar porous morphology to the PEO sample. However, the PEO–Fe and PEO–Mn/Fe films completely sealed the pores on the PEO surfaces, and no cracks were observed even after the samples were immersed in water for 7 days. Compared with PEO, PEO–Mn, and PEO–Fe, PEO–Mn/Fe exhibited a significantly lower self-corrosion current, suggesting better corrosion resistance. In vitro C3H10T1/2 cell culture showed that PEO–Fe/Mn promoted the best cell growth, alkaline phosphatase activity, and bone-related gene expression. Furthermore, the rat femur implantation experiment showed that PEO–Fe/Mn–coated Mg showed the best bone regeneration and osteointegration abilities. Owing to enhanced corrosion resistance and osteogenesis, the PEO–Fe/Mn film on Mg alloy is promising for orthopedic applications.

Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in seeds, grains, tea, coffee, wine, chocolate, cocoa, vegetables and, mainly, in citrus fruits. Neohesperidin, hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory and antioxidant potential. Neohesperidin, in the form of neohesperidin dihydrochalcone (NHDC), also has dietary properties as a sweetener. In general, these flavanones have been investigated as a strategy to control bone diseases, such as osteoporosis and osteoarthritis. In this literature review, we compiled studies that investigated the effects of neohesperidin, hesperidin and its aglycone, hesperetin, on bone health. In vitro studies showed that these flavanones exerted an antiosteoclastic and anti- inflammatory effects, inhibiting the expression of osteoclastic markers and reducing the levels of reactive oxygen species, proinflammatory cytokines and matrix metalloproteinase levels. Similarly, such studies favored the osteogenic potential of preosteoblastic cells and induced the overexpression of osteogenic markers. In vivo, these flavanones favored the regeneration of bone defects and minimized inflammation in arthritis- and periodontitis-induced models. Additionally, they exerted a significant anticatabolic effect in ovariectomy models, reducing trabecular bone loss and increasing bone mineral density. Although research should advance to the clinical field, these flavanones may have therapeutic potential for controlling the progression of metabolic, autoimmune or inflammatory bone diseases.

DM has a high prevalence worldwide and exerts a negative influence on bone repair around dental implants. Modifications of the microgeometry of implants have been related to positive results in bone repair. This study assessed, for the first time, the influence of an implant with modified macrodesign based on the presence of a healing chamber in the pattern of peri-implant repair under diabetic conditions. Thirty Wistar rats were assigned to receive one titanium implant in each tibia (Control Implant (conventional macrogeometry) or Test Implant (modified macrogeometry)) according to the following groups: Non-DM + Control Implant; Non-DM + Test Implant; DM + Control Implant; DM + Test Implant. One month from the surgeries, the implants were removed for counter-torque, and the bone tissue surrounding the implants was stored for the mRNA quantification of bone-related markers. Implants located on DM animals presented lower counter-torque values in comparison with Non-DM ones, independently of macrodesign (p < 0.05). Besides, higher biomechanical retention levels were observed in implants with modified macrogeometry than in the controls in both Non-DM and DM groups (p < 0.05). Moreover, the modified macrogeometry upregulated OPN mRNA in comparison with the control group in Non-DM and DM rats (p < 0.05). Peri-implant bone repair may profit from the use of implants with modified macrogeometry in the presence of diabetes mellitus, as they offer higher biomechanical retention and positive modulation of important bone markers in peri-implant bone tissue.