Synthetic helical peptides on nanofibers to activate cell-surface receptors and synergistically enhance critical-sized bone defect regeneration.

More than 500,000 bone grafting procedures are performed annually in the USA. Considering the significant limitations of available bone grafts, we previously invented a phase-separation technology to generate nanofibrous poly(l-lactic acid) (PLLA) scaffolds that mimic the bone matrix collagen in nanofiber geometry and enhance bone regeneration. Here we report the development of nanofibrous scaffolds with covalently attached synthetic peptides that mimic native collagen peptides to activate the two main collagen receptors in bone cells, discoidin domain receptor 2 (DDR2) and ß1 integrins. We synthesized a PLLA-based graft-copolymer to enable covalent peptide conjugation via a click reaction. Using PLLA and the graft-copolymer, we developed 3D scaffolds with interconnected pores and peptides-containing nanofibers to activate DDR2 and ß1 integrins of osteogenic cells. The degradation rate and mechanical properties of the scaffolds are tunable. The peptides-decorated nanofibrous scaffolds demonstrated 7.8 times more mineralized bone regeneration over the control scaffolds without the peptides in a critical-sized bone defect regeneration model after 8 weeks of implantation, showing a synergistic effect of the two peptides. This study demonstrates the power of scaffolds to mimic ECM at both nanometer and molecular levels, activating cell surface receptors to liberate the innate regenerative potential of host stem/progenitor cells.

Role of NEL­like molecule­1 in osteogenesis/chondrogenesis (Review).

A dynamic balance exists between osteogenesis and osteoclastogenesis in bone tissue, which can lead to several bone diseases, such as osteoporosis, osteoarthritis, bone necrosis and bone defects, in cases of insufficient osteogenesis or excessive osteoclastogenesis. NEL­like molecule­1 (NELL­1) was first discovered in 1999 as an osteogenic factor that can prevent or treat bone diseases by increasing osteogenic levels. To date, research has identified multiple signaling pathways involved in improving osteogenic levels. Furthermore, to apply NELL­1 in clinical practice, researchers have optimized its osteogenic effect by combining it with other molecules, changing its molecular structure and performing bone tissue engineering. Currently, research on NELL­1 is gaining increasing attention. In the near future, it will definitely be applied in clinical practice to eliminate diseases. Thus, the present study provides a comprehensive review of NELL­1 in enhancing osteogenic levels from the perspectives of the molecular mechanism, interactions with other molecules/cells, molecular­level changes, applications in bone tissue engineering and its expression in tumors, providing a solid theoretical basis for its clinical application.

Unleashing the Potential of Electroactive Hybrid Biomaterials and Self-Powered Systems for Bone Therapeutics.

The incidence of large bone defects caused by traumatic injury is increasing worldwide, and the tissue regeneration process requires a long recovery time due to limited self-healing capability. Endogenous bioelectrical phenomena have been well recognized as critical biophysical factors in bone remodeling and regeneration. Inspired by bioelectricity, electrical stimulation has been widely considered an external intervention to induce the osteogenic lineage of cells and enhance the synthesis of the extracellular matrix, thereby accelerating bone regeneration. With ongoing advances in biomaterials and energy-harvesting techniques, electroactive biomaterials and self-powered systems have been considered biomimetic approaches to ensure functional recovery by recapitulating the natural electrophysiological microenvironment of healthy bone tissue. In this review, we first introduce the role of bioelectricity and the endogenous electric field in bone tissue and summarize different techniques to electrically stimulate cells and tissue. Next, we highlight the latest progress in exploring electroactive hybrid biomaterials as well as self-powered systems such as triboelectric and piezoelectric-based nanogenerators and photovoltaic cell-based devices and their implementation in bone tissue engineering. Finally, we emphasize the significance of simulating the target tissue's electrophysiological microenvironment and propose the opportunities and challenges faced by electroactive hybrid biomaterials and self-powered bioelectronics for bone repair strategies.

Piezoelectric Scaffolds as Smart Materials for Bone Tissue Engineering.

Bone repair and regeneration require physiological cues, including mechanical, electrical, and biochemical activity. Many biomaterials have been investigated as bioactive scaffolds with excellent electrical properties. Amongst biomaterials, piezoelectric materials (PMs) are gaining attention in biomedicine, power harvesting, biomedical devices, and structural health monitoring. PMs have unique properties, such as the ability to affect physiological movements and deliver electrical stimuli to damaged bone or cells without an external power source. The crucial bone property is its piezoelectricity. Bones can generate electrical charges and potential in response to mechanical stimuli, as they influence bone growth and regeneration. Piezoelectric materials respond to human microenvironment stimuli and are an important factor in bone regeneration and repair. This manuscript is an overview of the fundamentals of the materials generating the piezoelectric effect and their influence on bone repair and regeneration. This paper focuses on the state of the art of piezoelectric materials, such as polymers, ceramics, and composites, and their application in bone tissue engineering. We present important information from the point of view of bone tissue engineering. We highlight promising upcoming approaches and new generations of piezoelectric materials.

Cryogels Composites: Recent Improvement in Bone Tissue Engineering.

Autogenous bone grafts have long been considered the optimal choice for bone reconstruction due to their excellent biocompatibility and osteogenic properties. However, their limited availability and associated donor site morbidity have led to exploration of alternative bone substitutes. Cryogels, with their interconnected porosity, shape recovery, and enhanced mass transport capabilities, have emerged as a promising polymer-based solution. By incorporating bioactive glasses and nanofillers, cryogel composites offer bioactivity, cost-efficiency, and easy cell integration. This approach not only enhances bone regeneration but also underscores the broader role of nanotechnology in regenerative medicine. This mini-review discusses the advancement of organic-inorganic composites, focusing on biopolymeric cryogels and inorganic elements for reinforcement. We highlight how cryogels can be integrated into minimally invasive procedures, reducing patient distress and complications, and advanced 3D-printing techniques that enable further customization of these materials to mimic bone tissue architecture, offering potential for patient-specific treatments.

Synergetic effect of bioglass and nano montmorillonite on 3D printed nanocomposite of polycaprolactone/gelatin in the fabrication of bone scaffolds.

Nowadays, bone injuries and disorders have increased all over the world and can reduce the quality of human life. Bone tissue engineering repair approaches require new biomaterials and methods to construct scaffolds with the required structural properties as well as improved performance. As potential therapeutic strategies in bone tissue engineering, 3D printed scaffolds have been developed. Polycaprolactone/Ceramic composites have attracted considerable attention due to their cytocompatibility, biodegradability, and physical properties. In this study, a 3D printing process was used to create polycaprolactone (PCL)-Gelatin (GEL) scaffolds containing varying concentrations of Bioglass (BG) and Nano Montmorillonite (MMT). This mixture was then loaded into a 3D printer, and the scaffolds were printed layer by layer. After constructing the scaffolds, they were then examined for their physical, chemical, and biological characteristics. Surface appearance was analyzed with a scanning electron microscope (SEM), which revealed that NC increased the diameter of pores from 465 to 480 µm. The elements in the scaffolds were evaluated by EDX analysis, and a uniform dispersion of nano montmorillonite particles was observed. The compressive strength reached 76.43 MPa for PCL/G/35 %MMT/15 %BG scaffold. Also, the rate of water absorption, biodegradability and bioactivity of PCL-GEL scaffolds increased significantly in the presence of NC. According to the MTT cell test results, adding BG and NC increased cell proliferation, adhesion and cell viability to 127.7 %. These findings indicated that the 3D printed PCL/G/35 %MMT/15 %BG scaffold has promising strategies for bone repair applications. Also, polynomial curve fitting shows that scaffold degradability after soaking in PBS can be predicted using the initial weight and soaking time. Adding more variables and data could improve prediction accuracy, reducing the need for experiments and conserving resources.

The landscape of Functional Outcome Measures Used in Patients with Bone Sarcoma of the Lower Extremity or Pelvis: A Systematic Review.

This systematic review provides a structured overview of the measurement instruments of functional outcome used in lower extremity and pelvic bone sarcoma patients. We identified 42 unique instruments covering 18 distinct functional outcome constructs with most studies measuring constructs within the activity domain of the International Classification of Functioning, disability, and health. The MusculoSkeletal Tumor Society 1993 and 1987 score, Toronto Extremity Salvage Score, and range of motion instruments were the measurement instruments most commonly used.

Metal-organic frameworks (MOFs) and their derivatives as emerging biomaterials for the treatment of osteoarthritis.

As a novel class of smart biomaterials with promising potentials, metal-organic frameworks (MOFs) are widely utilized in the field of biomedicine. Current researches indicate that the therapeutic strategies for osteoarthritis (OA) are highly limited to achieving symptom improvement and reducing both pain and inflammation. Together, the introduction of MOFs into the treatment of OA holds the potential to offer significant benefits. This is because MOFs not only have intrinsic biological activities, but also act as carriers to facilitate controlled drug delivery and prolong the duration in the management of OA. This paper presents a review of the recent studies that have explored the potential usage of MOFs as drugs or carriers in the treatment of OA, which also examines the progress of MOFs in tissue engineering for the treatment of OA. These studies are anticipated to not only enhance the comprehension of MOFs but also provide strong evidence in favor of their utilization in the treatment of OA.

3D printed polylactic acid/polyethylene glycol/bredigite nanocomposite scaffold enhances bone tissue regeneration via promoting osteogenesis and angiogenesis.

Recently, the fabrication of personalized scaffolds with high accuracy has been developed through 3D printing technology. In the current study, polylactic acid/polyethylene glycol (PLA/PEG) composite scaffolds with varied weight percentages (0, 5, 10, 20 and 30 %) of bredigite nanoparticles (B) were fabricated using the 3D printing and then characterized through scanning electron microscopy and Fourier transform infra-red spectroscopy. The addition of B nanoparticles up to 20 wt% to PLA/PEG scaffold increased the compressive strength (from 7.59 to 13.84 MPa) and elastic modulus (from 142.42 to 268.33 MPa). The apatite formation ability as well as inorganic ion release in simulated body fluid were investigated for 28 days. The MG-63 cells viability and adhesion were enhanced by increasing the amount of B in the PLA/PEG scaffold and the osteogenic differentiation of the rat bone marrow mesenchymal stem cells was confirmed by alkaline phosphatase activity test and alizarin red staining. According to chorioallantoic membrane assay, the highest angiogenesis occurred around the PLA/PEG/B30 scaffold. In vivo experiments on a rat calvarial defect model demonstrated an almost complete recovery in the PLA/PEG/B30 group within 8 weeks. Based on the results, the PLA/PEG/B30 composite scaffold is proposed as an optimal scaffold to repair bone defects.

Determination of the Optimum Architecture of Additively Manufactured Magnetic Bioactive Glass Scaffolds for Bone Tissue Engineering and Drug-Delivery Applications.

For better bone regeneration, precise control over the architecture of the scaffolds is necessary. Because the shape of the pore may affect the bone regeneration, therefore, additive manufacturing has been used in this study to fabricate magnetic bioactive glass (MBG) scaffolds with three different architectures, namely, grid, gyroid, and Schwarz D surface with 15 × 15 × 15 mm3 dimensions and 70% porosity. These scaffolds have been fabricated using an in-house-developed material-extrusion-based additive manufacturing system. The composition of bioactive glass was selected as 45% SiO2, 20% Na2O, 23% CaO, 6% P2O5, 2.5% B2O3, 1% ZnO, 2% MgO, and 0.5% CaF2 (wt %), and additionally 0.4 wt % of iron carbide nanoparticles were incorporated. Afterward, MBG powder was mixed with a 25% (w/v) Pluronic F-127 solution to prepare a slurry for fabricating scaffolds at 23% relative humidity. The morphological characterization using microcomputed tomography revealed the appropriate pore size distribution and interconnectivity of the scaffolds. The compressive strengths of the fabricated grid, gyroid, and Schwarz D scaffolds were found to be 14.01 ± 1.01, 10.78 ± 1.5, and 12.57 ± 1.2 MPa, respectively. The in vitro study was done by immersing the MBG scaffolds in simulated body fluid for 1, 3, 7, and 14 days. Darcy's law, which describes the flow through porous media, was used to evaluate the permeability of the scaffolds. Furthermore, an anticancer drug (Mitomycin C) was loaded onto these scaffolds, wherein these scaffolds depicted good release behavior. Overall, gyroid-structured scaffolds were found to be the most suitable among the three scaffolds considered in this study for bone tissue engineering and drug-delivery applications.

One-step synthesis of a piezoelectric hybrid BNNT/BaTiO3 composite and its application in bone tissue engineering.

Nanomaterials with piezoelectric properties can significantly improve the applicability of polymers used in tissue engineering applications. In this study, we report the one-step synthesis of a novel hybrid piezoelectric composite comprising barium titanates and boron nitride nanotubes. This composite is distinguished by its unique microstructures, including nanoflakes, triangular boron nitride structures, and fiber-like boron nitride nanotube configurations, which contribute to its enhanced piezoelectric properties. The composite was incorporated into a chitosan-based tissue scaffold and evaluated in vitro. Electric-responsive Human Osteoblast cells cultured on the scaffolds are exposed to low-frequency ultrasound stimulation during cell growth. The biocompatibility, cell adhesion, alkaline phosphatase activities, and mineralization of osteoblast cells on the piezo-composite scaffolds were evaluated. The results show that the hybrid piezoelectric composite significantly enhances the properties of chitosan-based scaffold.

Role and mechanism of histone demethylase PHF8 in weightlessness osteoporosis.

Weightlessness osteoporosis, which progresses continuously and has limited protective effects, has become one of the major problems that need to be solved in manned spaceflight. Our study aims to investigate the regulatory role of PHF8 in disuse osteoporosis by observing the expression of PHF8 in bone marrow mesenchymal stem cells (BMSCs) under simulated weightlessness conditions. Therefore, we used the model of ground-based microgravity simulated by disuse osteoporosis patients and tail suspension in mice to simulate microgravity in vivo, and measured the expression of PHF8 in bone tissue. Subsequently, we used the 2D gyroscope to simulate the weightless effect on bone marrow mesenchymal stem cells. In the weightless condition, we detected the proliferation, apoptosis, osteogenesis, and osteogenic differentiation functions of BMSCs. We also detected the expression of osteogenic-related transcription factors after knocking down and overexpressing PHF8. Our results show that the weightless effect can inhibit the proliferation, osteogenesis, and osteogenic differentiation functions of BMSCs, while enhancing their apoptosis; and overexpression of PHF8 can partially alleviate the osteoporosis caused by simulated weightlessness, providing new ideas and clues for potential drug targets to prevent weightlessness and disuse osteoporosis.

Chitosan-based electrospun fibers for bone-tissue engineering: Recent research advancements.

Chitosan, a sustainable and highly abundant animal-derived biopolymer, possesses versatile properties, such as solubility, film-forming ability, viscosity, ion binding, and antimicrobial qualities, which are suitable for biomedical applications. Due to its charged nature, chitosan is a lucrative biopolymer for scaffold fabrication, especially for bone-tissue engineering applications, using the electrospinning method, which is an industrially suitable, scalable, and swift method for fabricating porous nanocomposite structures. Despite a lot of research being conducted on chitosan-based electrospun materials for bone tissue engineering, the research on this topic has not been thoroughly reviewed. This review article aims to fill this knowledge gap and provides an in-depth discussion of the research on this topic. To start with, a brief overview of bone tissue engineering has been provided, followed by the properties of chitosan, which make it an important biopolymer for this application. Also, the important factors that must be considered while electrospinning chitosan, especially considering its application in bone tissue engineering, have been debated. Further, the type of chitosan-based electrospun material has been discussed along with the recent advancements in this research area. Finally, a brief perspective on the future of this technology has been provided.

Direct MultiSearch optimization of TPMS scaffolds for bone tissue engineering.

BACKGROUND: Scaffolds designed for tissue engineering must consider multiple parameters, namely the permeability of the design and the wall shear stress experienced by the cells on the scaffold surface. However, these parameters are not independent from each other, with changes that improve wall shear stress, negatively impacting permeability and vice versa. This study introduces a novel multi-objective optimization framework using Direct MultiSearch (DMS) to design triply periodic minimal surface (TPMS) scaffolds for bone tissue engineering. METHOD: The optimization algorithm focused on maximizing the permeability of the scaffolds and obtaining a desired value of average wall shear stress (which ranges between the values that promote osteogenic differentiation of 0.1 mPa and 10 mPa). Multiple fluid inlet velocities and target wall shear stress were analyzed. The DMS method successfully generated Pareto fronts for each configuration, enabling the selection of optimized scaffolds based on specific structural requirements. RESULTS: The findings reveal that increasing the target wall shear stress results in a greater number of non-dominated points on the Pareto front, highlighting a more robust optimization process. Additionally, it was also demonstrated that the tested Schwartz diamond scaffolds had a better permeability-wall shear stress relation when compared to Schoen gyroid geometries. CONCLUSIONS: Direct MultiSearch was proven as an effective tool to aid in the design of tissue engineering scaffolds. This adaptable optimization framework has potential applications beyond bone tissue engineering, including cartilage tissue differentiation.

Comparative Histological Analysis of Dentine-Derived Tooth Grafts in Maxillary vs Mandibular Socket Preservation: A Retrospective Study of 178 Cases.

(1) Background: In recent years, there has been a growing interest in tooth-derived materials as valuable alternatives to synthetic biomaterials for preventing alveolar ridge dimensional changes. This study aimed to evaluate the histological and clinical differences between alveolar ridge preservation procedures in the maxilla and mandible using demineralized dentin treated with Tooth Transformer®. (2) Methods: A total of 178 patients in good general health were enrolled, with 187 post-extractive sockets lacking buccal and/or palatal bone walls. Alveolar socket preservation procedures and histological evaluations were performed. The sites were divided into two groups: Group A (99 mandibular samples) and Group B (108 maxillary samples). After 5 months (±1 month), single bone biopsies were performed for histologic and histomorphometric analysis. (3) Results: Clinical outcomes demonstrated a good healing of hard and soft tissues with an effective maintenance of bone architecture in both groups. Histomorphometric analysis revealed a total bone volume of 50.33% (±14.86) in Group A compared to 43.53% (±12.73) in Group B. The vital new bone volume was 40.59% (±19.90) in Group A versus 29.70% (±17.68) in Group B, with residual graft dentin material volume at 7.95% (±9.85) in Group A compared to 6.75% (±9.62) in Group B. (4) Conclusions: These results indicate that tooth-derived material supports hard tissue reconstruction by following the structure of the surrounding bone tissue. A 6.8% difference observed between the maxilla and mandible reflects the inherent disparities in natural bone structures in these regions. This suggests that the bone regeneration process after tooth extraction adheres to an anatomical functional pattern that reflects the specific bone characteristics of each area, thus contributing to the preservation of the morphology and functionality of the surrounding bone tissue.

Functional Scaffolds for Bone Tissue Regeneration: A Comprehensive Review of Materials, Methods, and Future Directions.

Bone tissue regeneration is a rapidly evolving field aimed at the development of biocompatible materials and devices, such as scaffolds, to treat diseased and damaged osseous tissue. Functional scaffolds maintain structural integrity and provide mechanical support at the defect site during the healing process, while simultaneously enabling or improving regeneration through amplified cellular cues between the scaffold and native tissues. Ample research on functionalization has been conducted to improve scaffold-host tissue interaction, including fabrication techniques, biomaterial selection, scaffold surface modifications, integration of bioactive molecular additives, and post-processing modifications. Each of these methods plays a crucial role in enabling scaffolds to not only support but actively participate in the healing and regeneration process in bone and joint surgery. This review provides a state-of-the-art, comprehensive overview of the functionalization of scaffold-based strategies used in tissue engineering, specifically for bone regeneration. Critical issues and obstacles are highlighted, applications and advances are described, and future directions are identified.

In Vivo Evaluation of Demineralized Bone Matrix with Cancellous Bone Putty Formed Using Hydroxyethyl Cellulose as an Allograft Material in a Canine Tibial Defect Model.

Demineralized bone matrix (DBM) is a widely used allograft material for bone repair, but its handling properties and retention at defect sites can be challenging. Hydroxyethyl cellulose (HEC) has shown promise as a biocompatible carrier for bone graft materials. This study aimed to evaluate the efficacy of DBM combined with cancellous bone putty formed using HEC as an allograft material for bone regeneration in a canine tibial defect model. Experiments were conducted using dogs with proximal tibial defects. Four groups were compared: empty (control group), DBM + HEC (DH), DBM + cancellous bone + HEC (DCH), and DBM + cancellous bone + calcium phosphate + HEC (DCCH). Radiographic, micro-computed tomography (CT), and histomorphometric evaluations were performed 4 and 8 weeks postoperatively to assess bone regeneration. The Empty group consistently exhibited the lowest levels of bone regeneration throughout the study period, indicating that DBM and cancellous bone with HEC significantly enhanced bone regeneration. At week 4, the DCCH group showed the fastest bone regeneration on radiography and micro-computed tomography. By week 8, the DCH group showed the highest area ratio of new bone among all experimental areas, followed by the DH and DCCH groups. This study demonstrated that HEC significantly enhances the handling, mechanical properties, and osteogenic potential of DBM and cancellous bone grafts, making it a promising carrier for clinical applications in canine allograft models. When mixed with allograft cancellous bone, which has high porosity and mechanical strength, it becomes a promising material offering a more effective and reliable option for bone repair and regeneration.

Bone Healing via Carvacrol and Curcumin Nanoparticle on 3D Printed Scaffolds.

Carvacrol is a potent antimicrobial and anti-inflammatory agent, while curcumin possesses antioxidant, anti-inflammatory, and anticancer properties. These phytochemicals have poor solubility, bioavailability, and stability in their free form. Nanoencapsulation can reduce these limitations with enhanced translational capability. Integrating nanocarriers with 3D-printed calcium phosphate (CaP) scaffolds presents a novel strategy for bone regeneration. Carvacrol and curcumin-loaded nanoparticles (CC-NP) synthesized with melt emulsification produced negatively charged, monodispersed particles with a hydrodynamic diameter of ≈127 nm. Their release from the scaffold shows a biphasic release under physiological and acidic conditions. At pH 5.0, the CC-NP exhibits a 53% release of curcumin and nearly 100% release of carvacrol, compared to 19% and 36% from their respective drug solutions. At pH 7.4, ≈40% of curcumin and 76% of carvacrol releases, highlighting their pH-sensitive release mechanism. In vitro studies demonstrate a 1.4-fold increase in osteoblast cell viability with CC-NP treatment. CC-NP exhibit cytotoxic effects against osteosarcoma cells, reducing cell viability by ≈2.9-fold. The antibacterial efficacy of CC-NP evaluated against Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) exhibiting 98% antibacterial efficacy. This approach enhances therapeutic outcomes and minimizes the potential side effects associated with conventional treatments, paving the way for innovative applications in regenerative medicine.

Humanized In Vivo Bone Tissue Engineering: In Vitro Preculture Conditions Control the Structural, Cellular, and Matrix Composition of Humanized Bone Organs.

Bone tissue engineering (BTE) has long sought to elucidate the key factors controlling human/humanized bone formation for regenerative medicine and disease modeling applications, yet with no definitive answers due to the high number and co-dependency of parameters. This study aims to clarify the relative impacts of in vitro biomimetic 'preculture composition' and 'preculture duration' before in vivo implantation as key criteria for the optimization of BTE design. These parameters are directly related to in vitro osteogenic differentiation (OD) and mineralization and are being investigated across different osteoprogenitor-loaded biomaterials, specifically fibrous calcium phosphate-polycaprolactone (CaP-mPCL) scaffolds and gelatin methacryloyl (GelMA) hydrogels. The results show that OD and mineralization levels prior to implantation, enhanced by a mineralization medium supplement to the osteogenic medium (OM), significantly improve ectopic BTE outcomes, regardless of the biomaterial type. Specifically, preculture conditions are pivotal in achieving more faithful mimicry of human bone structure, cellular and extracellular matrix composition and organization, and provide control over bone marrow composition. This work emphasizes the potential of using biomimetic culture compositions, specifically the addition of a mineralization medium as a cost-effective and straightforward approach to enhance BTE outcomes, facilitating rapid development of bone models with superior quality and resemblance to native bone.