Enhance Bone Regeneration Research Articles

A photothermal responsive system accelerating nitric oxide release to enhance bone repair by promoting osteogenesis and angiogenesis

Managing bone defects remains a formidable clinical hurdle, primarily attributed to the inadequate orchestration of vascular reconstruction and osteogenic differentiation in both spatial and temporal dimensions. This challenge persists due to the constrained availability of autogenous grafts and the limited regenerative capacity of allogeneic or synthetic bone substitutes, thus necessitating continual exploration and innovation in the realm of functional and bioactive bone graft materials. While synthetic scaffolds have emerged as promising carriers for bone grafts, their efficacy is curtailed by deficiencies in vascularization and osteoinductive potential. Nitric oxide (NO) plays a key role in revascularization and bone tissue regeneration, yet studies related to the use of NO for the treatment of bone defects remain scarce. Herein, we present a pioneering approach leveraging a photothermal-responsive system to augment NO release. This system comprises macromolecular mPEG-P nanoparticles encapsulating indocyanine green (ICG) (NO-NPs@ICG) and a mPEG-PA-PP injectable thermosensitive hydrogel carrier. By harnessing the synergistic photothermal effects of near-infrared radiation and ICG, the system achieves sustained NO release, thereby activating the soluble guanylate cyclase (SGC)-cyclic guanosine monophosphate (cGMP) signaling pathway both in vitro and in vivo. This orchestrated cascade culminates in the facilitation of angiogenesis and osteogenesis, thus expediting the reparative processes in bone defects. In a nutshell, the NO release-responsive system elucidated in this study presents a pioneering avenue for refining the bone tissue microenvironment and fostering enhanced bone regeneration.

Biomaterials Designed to Modulate Reactive Oxygen Species for Enhanced Bone Regeneration in Diabetic Conditions.

Diabetes mellitus, characterized by enduring hyperglycemia, precipitates oxidative stress, engendering a spectrum of complications, notably increased bone vulnerability. The genesis of reactive oxygen species (ROS), a byproduct of oxygen metabolism, instigates oxidative detriment and impairs bone metabolism in diabetic conditions. This review delves into the mechanisms of ROS generation and its impact on bone homeostasis within the context of diabetes. Furthermore, the review summarizes the cutting-edge progress in the development of ROS-neutralizing biomaterials tailored for the amelioration of diabetic osteopathy. These biomaterials are engineered to modulate ROS dynamics, thereby mitigating inflammatory responses and facilitating bone repair. Additionally, the challenges and therapeutic prospects of ROS-targeted biomaterials in clinical application of diabetic bone disease treatment is addressed.

Bioactive poly(ethylene glycol)-chondroitin sulfate-triple helical recombinant collagen hydrogel for enhanced cranial defect repair

The reconstruction of critical-size calvarial defects remains a fundamental challenge. Recombinant collagen has gained significant attention in bone tissue engineering owing to its remarkable bioactivity and non-immunogenicity. Herein, we have for the first time developed a bioactive poly(ethylene glycol)-chondroitin sulfate-triple helical recombinant collagen (PEG-ChS-THRC) hydrogel for enhanced bone regeneration in cranial defects. A simple and mild crosslinking reaction of two-arm polyethylene glycol active ester (NHS-PEG-NHS), adipic dihydrazide modified chondroitin sulfate (ChS-ADH) and triple helical recombinant collagen (THRC) leads to the formation of the PEG-ChS-THRC hydrogel. The hydrogel demonstrates interconnected porous structures, enhanced mechanical strength, diminished swelling ratios and adjustable biodegradability. It possesses exceptional biocompatibility and bioactivity, significantly facilitating cell proliferation, adhesion, migration, and osteogenic differentiation of BMSCs. Micro-computed tomography (micro-CT), magnetic resonance imaging (MRI) and histological characterization of rat models with critical-size cranial defects have consistently demonstrated that the PEG-ChS-THRC hydrogel significantly promotes bone tissues regeneration. The innovative bioactive scaffold provides a remarkably improved remedy for critical-size cranial defects, holding greatly promising applications in the fields of bone tissue regeneration.Graphical

Synergistic effect of electrophysiological microenvironment and bioactive ions for enhancing bone regeneration

Bone traumatic defects, requiring a long-term healing procedure cause the destruction of physical microenvironment, remain a critical challenge in orthopedic care. Given the electrical properties and bioactive elemental composition of natural bone, electrophysical microenvironment and bioactive ions play crucial roles in regulating bone metabolism. Our study constructs an implantable electret scaffold based on coaxial electrospinning technology. The core-shell electrospun fibrous membrane (PSPC) comprising shell structure of polycaprolactone (PCL)/calcium silicate nanowires (CSNs) loading with a core of polycaprolactone/silicon dioxide (SiO2) electret. In which, the sheath of the core-shell fibers is designed to continuously release bioactive ions to stimulate osteogenesis after the fiber degrades, while the core layer is intended to provide consistent endogenous electrical stimulation for osteogenic differentiation. This battery-free and biocompatible scaffold utilizes the synergistic outcome of electrical stimulation and bioactive ions and shows the most satisfactory osteogenic efficiency both in vitro and in vivo. Moreover, the underlying mechanism was interpreted that electrical stimulation-driven osteogenesis was driven by the activation of Calmodulin (CaM) / Calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signaling pathway. This work proposes a potential strategy to improve bone regeneration by developing a coaxial electrospun fibrous membrane that combines the synergistic benefits of electrophysical microenvironment restoration and bioactive ions.

Production of platelet-rich plasma (PRP)-enriched scaffolds for bone tissue regeneration with 3D printing technology

Bone disorders signify diverse abnormalities in the structure, development, and functions of bone tissue in the human body, with a significant correlation to ageing, insufficient physical activity, and escalating obesity. Recent advancements in bone tissue engineering aim to enhance bone tissue formation through the use of biomaterials, growth factors, and cells. The present study focuses on the fabrication and characterisation of scaffolds with a composition of gelatin (GEL) / sodium alginate (SA) / hydroxyapatite (HA) / platelet-rich plasma (PRP) using the 3D printing process. The inclusion of PRP, derived from blood, is of particular interest due to its potential to enhance bone regeneration through various growth factors. Scanning electron microscope (SEM) analysis revealed average pore sizes ranging from 481.50 ± 7.65 to 623.96 ± 11.54 µm. SEM images also showed that scaffold surfaces became smooth as the concentration of PRP increased. The mechanical test results demonstrated that as the PRP increased, the compressive strength decreased. When the swelling and degradation behaviours of scaffolds were examined, it was observed that GEL/SA/HA/3PRP scaffolds exhibited approximately 200 % swelling capability until the 4th day. GEL/SA/HA scaffolds showed a degradation behaviour about 70 % higher compared to other groups. A controlled release profile of PRP was maintained up to the 144th, 216th, and 240th hours from the scaffolds. According to the highest correlation coefficients (R2) in the release kinetics of scaffolds, GEL/SA/HA/0.5PRP and GEL/SA/HA/1PRP scaffolds were explained by the first-order model. In contrast, the GEL/SA/HA/3PRP scaffold was described using the Korsmeyer–Peppas model. The MTT analysis conducted with osteoblast cells showed that scaffolds did not demonstrate any toxic effects and facilitated cell adhesion by inducing the formation of extensions. These findings underscore the potential of PRP-incorporated GEL/SA/HA composites as a promising approach for bone tissue engineering, offering significant advancements in the treatment of bone disorders. This could lead to more effective treatments for bone disorders and injuries, reducing the need for more invasive procedures and improving patient recovery times.

Implantable Triboelectric Nanogenerators in the Biomedical Field

Implantable Triboelectric Nanogenerators (TENGs) have revolutionized the biomedical field by providing innovative power solutions for medical devices and enhancing diagnostic and therapeutic applications. Internally implanted TENG transforms kinetic energy from the body into electrical power, providing a constant energy supply for Implantable Medical Devices (IMD). Their ability to generate high voltage and low current makes them particularly effective for applications in biosensing, patient monitoring, and therapeutic interventions. Therapeutically, TENGs power cardiac pacemakers, promote wound healing, enhance bone regeneration, and support muscle and nerve stimulation. They also enable controlled drug release, particularly in targeted cancer treatments.

Biodegradable magnesium and zinc composite microspheres with synergistic osteogenic effect for enhanced bone regeneration

Biodegradable polymer microspheres in bone tissue engineering have become appealing as their non-invasive advantages in irregular damage bone repair. However, current microspheres used in BTE still lack sufficient osteogenic capacity to induce effective bone regeneration. In this study, we developed osteogenic composite microspheres concurrently loaded with magnesium oxide (MgO) and zinc oxide (ZnO), both of which are osteogenic active substances, using a facile and scalable emulsification method. The osteogenic composite microspheres exhibited a sequential yet complementary release profile characterized by a rapid release of Mg2+ and a gradual release of Zn2+ in a physiological environment, thereby maintaining the concentration of bioactive ions at a sustained high level. As a result, the combination of Mg2+ and Zn2+ in the composite microspheres led to a synergistic enhancement in biomimetic mineralization and the upregulation in the expression of osteogenic-related genes and proteins at the cellular level. Through a critical-sized calvarial rate defect model, the osteogenic composite microspheres were demonstrated to have strong osteogenic ability to promote new bone formation via ultrasonic imaging, histological and immunohistochemical evaluations. In sum, these osteogenic composite microspheres as microcarriers of Mg2+ and Zn2+ have great potential in the delivery of therapeutic ions for treating bone defects.

In-situ electret scaffolds with controllable electric fields printed by MEW for bone tissue regeneration

Physiologically relevant electrical microenvironments play an integral role in manipulating bone metabolism. Although implanted biomaterials using conductive or piezoelectric materials to mimic natural tissue electrical properties have been introduced into the field of bone regeneration, the use of electret materials to provide stable and durable electrical stimulation has rarely been studied in biomaterial design. In this study, the ZnO/PCL composite scaffolds with in-situ electret were fabricated using melt electro-writing to explore its efficacy in bone regeneration. By adjusting the electret concentration, the surface potential of the composite scaffolds could be tuned to the biopotential for promoting bone regeneration, and the prepared scaffolds exhibited good electrical stability over an observation period of up to 42 days. In vitro biological experiments showed that the in-situ electret scaffolds promoted the cell viability and osteogenic differentiation of mesenchymal stem cells. At the same time, the in-situ electret composite scaffolds can induce the phenotype transformation of RAW 264.7 cells from M1 to M2, creating a favorable microenvironment for bone tissue regeneration. The composite scaffolds significantly promoted bone regeneration in vivo through sustained endogenous electrical stimulation. These findings suggest that the in-situ electret scaffolds that maintain a stable and physiological electrical microenvironment are promising candidates for enhanced bone regeneration.

Sinus Floor Augmentation with Synthetic Hydroxyapatite (NanoBone®) in Combination with Platelet-Rich Fibrin: A Case Series.

Several techniques have been described for maxillary sinus graft augmentation, including the lateral window technique and crestal approach with osteotomes or osseodensification. Platelet-rich fibrin has been used in maxillary sinus lift procedures due to its ability to accelerate soft and hard tissue healing. The aim of this study was to evaluate the potential of PRF in combination with the synthetic hydroxyapatite NanoBone® to enhance bone regeneration in sinus floor elevation with the lateral window technique. Out of the 50 individuals screened in a preoperative assessment visit from the CESPU-Famalicão clinical unit and intervened upon between January 2023 and December 2023, only 6 patients who met the study's inclusion criteria consented to participate. In a split-mouth study, twelve sinus graft surgeries were carried out. Our observations reveal that for the test group (NanoBone®/PRF), there is a 27.5 ± 4.9% increase new vital bone, 23.0 ± 3.7% increase in inert bone particles, and 49.4 ± 2.8% increase in connective tissue. Meanwhile, for the control group (NanoBone®), there is a 19.5 ± 3.0% increase in new vital bone, 23.4 ± 5.7% increase in inert bone particles, and 57.0 ± 3.5% increase in connective tissue. The results strongly indicate that mixing liquid PRF with NanoBone® does not have a negative influence on the amount of viable bone formation, and it seems to slightly increase the amount of new bone formation and revascularization in sinus bone graft procedures with the lateral window technique compared to the single use of NanoBone®.

Emerging Roles of Natural Compounds in Osteoporosis: Regulation, Molecular Mechanisms and Bone Regeneration.

Bone health is a critical aspect of overall well-being, and disorders such as osteoporosis pose significant challenges worldwide. East Asian Herbal Medicine (EAHM), with its rich history and holistic approach, offers promising avenues for enhancing bone regeneration. In this critical review article, we analyze the intricate mechanisms through which EAHM compounds modulate bone health. We explore the interplay between osteogenesis and osteoclastogenesis, dissect signaling pathways crucial for bone remodeling and highlight EAHM anti-inflammatory effects within the bone microenvironment. Additionally, we emphasize the promotion of osteoblast viability and regulation of bone turnover markers by EAHM compounds. Epigenetic modifications emerge as a fascinating frontier where EAHM influences DNA methylation and histone modifications to orchestrate bone regeneration. Furthermore, we highlight EAHM effects on osteocytes, mesenchymal stem cells and immune cells, unraveling the holistic impact in bone tissue. Finally, we discuss future directions, including personalized medicine, combinatorial approaches with modern therapies and the integration of EAHM into evidence-based practice.

Amine plasma polymers deposited on porous hydroxyapatite artificial bone with bipolar pulsed discharges

A recent in vivo study [Kodama et al., Sci. Rep. 11, 1 (2021)] showed that porous artificial bones coated with amine-containing polymers deposited by plasma-enhanced chemical vapor deposition (PECVD) significantly enhanced bone regeneration. This article reports the chemical and physical properties of amine plasma polymers (PPs) formed under the same deposition conditions, including the film stability for up to two months, the effects of sterilization on the chemical compositions of the films, and the penetration of amine PPs into the inner surfaces of interconnected microscopic pores of the amine PP-coated porous artificial bone. It was found that, immediately after the plasma polymerization process, approximately 20% of nitrogen atoms on the surface of the deposited amine PP formed primary amines. However, the value decreased to approximately 5% over one month if the sample was exposed to ambient air. The relative concentration of primary amines also decreased to a similar value after the sample was sterilized by autoclaving or ethylene oxide gas. Molecular dynamics simulations were used to examine possible formation mechanisms of nitriles in deposit films under the PECVD conditions and found that ion impact can significantly reduce the nitrile content.

Lactate promotes bone healing by regulating the osteogenesis of bone marrow mesenchymal stem cells through activating Olfr1440

Bone malunion or nonunion leads to functional and esthetic problems and is a major healthcare burden. Activation of bone marrow mesenchymal stem cells (BMSCs) and subsequent induction of osteogenic differentiation by local metabolites are crucial steps for bone healing, which has not yet been completely investigated. Here, we found that lactate levels are rapidly increased at the local injury site during the early phase of bone defect healing, which facilitates the healing process by enhancing BMSCs regenerative capacity. Mechanistically, lactate serves as a ligand for the Olfr1440 olfactory receptor, to trigger an intracellular calcium influx that in turn activates osteogenic phenotype transition of BMSCs. Conversely, ablation of Olfr1440 delays skeletal repair and remodelling, as evidenced by thinner cortical bone and less woven bone formation in vivo. Administration of lactate in the defect area enhanced bone regeneration. These findings thus revealed the key roles of lactate in the osteogenic differentiation of BMSCs, which deepened our understanding of the bone healing process, as well as provided cues for a potential therapeutic option that might greatly improve bone defect treatment.

Anti-Microbial Drug Metronidazole Promotes Fracture Healing: Enhancement in the Bone Regenerative Efficacy of the Drug by a Biodegradable Sustained-Release In Situ Gel Formulation.

Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures.

In vivo experimental study comparing alveolar ridge preservation versus guided bone regeneration after unassisted socket healing at intact and damaged sites in narrow alveolar ridges.

To compare bone regeneration and dimensional alteration of alveolar ridge at intact and damaged extraction sockets after alveolar ridge preservation (ARP) and implant placement versus unassisted socket healing followed by guided bone regeneration (GBR) with simultaneous implant placement. In 6 beagle dogs, 3 types of extraction sockets in the mandible were created: (1) intact sockets, (2) 1-wall defect sockets and (3) 2-wall defect sockets. The sockets were allocated to undergo either (1) ARP and implant placement 8weeks later (ARP group) or (2) GBR with simultaneous implant placement after 8weeks of unassisted socket healing (GBR group). After an additional healing period of 8weeks, bone regeneration and dimensional changes were evaluated radiographically and histologically. GBR showed superior bone formation and greater bone gains compared to ARP, regardless of the initial extraction-socket configuration. Although ARP maintained the preexisting alveolar ridge dimensions, peri-implant bone defects were still detected at 8weeks of follow-up. Histomorphometric analyses confirmed that GBR increased dimensions of the alveolar ridge compared to baseline, and the augmentation and bone regeneration were greater with GBR than with ARP. Early implant placement with ARP can mitigate alveolar ridge changes in the narrow alveolar ridge. However, early implant placement with simultaneous GBR creates the conditions for enhanced bone regeneration around the implant and greater ridge augmentation compared to ARP, irrespective of the extraction-socket configuration.

Utilization of Additive Manufacturing Techniques for the Development of a Novel Scaffolds with Magnetic Properties for Potential Application in Enhanced Bone Regeneration.

This study focuses on designing and evaluating scaffolds with essential properties for bone regeneration, such as biocompatibility, macroporous geometry, mechanical strength, and magnetic responsiveness. The scaffolds are made using 3D printing with acrylic resin and iron oxides synthesized through solution combustion. Utilizing triply periodic minimal surfaces (TPMS) geometry and mask stereolithography (MSLA) printing, the scaffolds achieve precise geometrical features. The mechanical properties are enhanced through resin curing, and magnetite particles from synthesized nanoparticles and alluvial magnetite are added for magnetic properties. The scaffolds show a balance between stiffness, porosity, and magnetic responsiveness, with maximum compression strength between 4.8 and 9.2 MPa and Young's modulus between 58 and 174 MPa. Magnetic properties such as magnetic coercivity, remanence, and saturation are measured, with the best results from scaffolds containing synthetic iron oxides at 1% weight. The viscosity of the mixtures used for printing is between 350 and 380 mPas, and contact angles between 90° and 110° are achieved. Biocompatibility tests indicate the potential for clinical trials, though further research is needed to understand the impact of magnetic properties on cellular interactions and optimize scaffold design for specific applications. This integrated approach offers a promising avenue for the development of advanced materials capable of promoting enhanced bone regeneration.

Ti3C2Tx MXene-Decorated 3D-Printed Ceramic Scaffolds for Enhancing Osteogenesis by Spatiotemporally Orchestrating Inflammatory and Bone Repair Responses.

Inflammatory responses play a central role in coordinating biomaterial-mediated tissue regeneration. However, precise modulation of dynamic variations in microenvironmental inflammation post-implantation remains challenging. In this study, the traditional β-tricalcium phosphate-based scaffold is remodeled via ultrathin MXene-Ti3C2 decoration and Zn2+/Sr2+ ion-substitution, endowing the scaffold with excellent reactive oxygen species-scavenging ability, near-infrared responsivity, and enhanced mechanical properties. The induction of mild hyperthermia around the implant via periodic near-infrared irradiation facilitates spatiotemporal regulation of inflammatory cytokines secreted by a spectrum of macrophage phenotypes. The process initially amplifies the pro-inflammatory response, then accelerates M1-to-M2 macrophage polarization transition, yielding a satisfactory pattern of osteo-immunomodulation during the natural bone healing process. Later, sustained release of Zn2+/Sr2+ ions with gradual degradation of the 3D scaffold maintains the favorable reparative M2-dominated immunological microenvironment that supports new bone mineralization. Precise temporal immunoregulation of the bone healing process by the intelligent 3D scaffold enhances bone regeneration in a rat cranial defect model. This strategy paves the way for the application of β-tricalcium phosphate-based materials to guide the dynamic inflammatory and bone tissue responses toward a favorable outcome, making clinical treatment more predictable and durable. The findings also demonstrate that near-infrared irradiation-derived mild hyperthermia is a promising method of immunomodulation.

Synergistic effect of ultrasound and reinforced electrical environment by bioinspired periosteum for enhanced osteogenesis via immunomodulation of macrophage polarization through Piezo1

The periosteum plays a vital role in repairing bone defects. Researchers have demonstrated the existence of electrical potential in the periosteum and native bone, indicating that electrical signals are essential for functional bone regeneration. However, the clinical use of external electrical treatments has been limited due to their inconvenience and inefficacy. As an alternative, low-intensity pulsed ultrasound (LIPUS) is a noninvasive form of physical therapy that enhances bone regeneration. Furthermore, the wireless activation of piezoelectric biomaterials through ultrasound stimulation would generate electric charges precisely at the defect area, compensating for the insufficiency of external electrical stimulation and potentially promoting bone regeneration through the synergistic effect of mechanical and electrical stimulation. However, the optimal integration of LIPUS with an appropriate piezoelectric periosteum is yet to be explored. Herein, the BaTiO3/multiwalled-carbon nanotubes/collagen (BMC) membranes have been fabricated, possessing physicochemical properties including improved surface hydrophilicity, enhanced mechanical performance, ideal piezoelectricity, and outstanding biocompatibility, all of which are conducive to bone regeneration. When combined with LIPUS, the endogenous electrical microenvironment of native bone was recreated. After that, the wireless-generated electrical signals, along with the mechanical signals induced by LIPUS, were transferred to macrophages and activated Ca2+ influx through Piezo1. Ultimately, the regenerative effect of the BMC membrane with LIPUS stimulation (BMC + L) was confirmed in a mouse cranial defect model. Together, this research presents a co-engineering strategy that involves fabricating a novel biomimetic periosteum and utilizing the synergistic effect of ultrasound to enhance bone regeneration, which is achieved through the reinforcement of the electrical environment and the immunomodulation of macrophage polarization.

Harnessing extracellular vesicles-mediated signaling for enhanced bone regeneration: novel insights into scaffold design

The increasing prevalence of bone replacements and complications associated with bone replacement procedures underscores the need for innovative tissue restoration approaches. Existing synthetic grafts cannot fully replicate bone vascularization and mechanical characteristics. This study introduces a novel strategy utilizing pectin, chitosan, and polyvinyl alcohol to create interpenetrating polymeric network (IPN) scaffolds incorporated with extracellular vesicles (EVs) isolated from human mesenchymal stem cells (hMSCs). We assess the osteointegration and osteoconduction abilities of these models in vitro using hMSCs and MG-63 osteosarcoma cells. Additionally, we confirm exosome properties through Transmission Electron Microscopy (TEM), immunoblotting, and Dynamic Light Scattering (DLS). In vivo, chick allantoic membrane assay investigates vascularization characteristics. The study did not include in vivo animal experiments. Our results demonstrate that the IPN scaffold is highly porous and interconnected, potentially suitable for bone implants. EVs, approximately 100 nm in size, enhance cell survival, proliferation, alkaline phosphatase activity, and the expression of osteogenic genes. EVs-mediated IPN scaffolds demonstrate promise as precise drug carriers, enabling customized treatments for bone-related conditions and regeneration efforts. Therefore, the EVs-mediated IPN scaffolds demonstrate promise as precise carriers for the transport of drugs, allowing for customized treatments for conditions connected to bone and efforts in regeneration.

3D Printed Calcium Phosphate Physiochemically Dual-Regulating Pro-Osteogenesis and Antiosteolysis for Enhancing Bone Tissue Regeneration.

Osteoblasts and osteoclasts are two of the most important types of cells in bone repair, and their bone-forming and bone-resorbing activities influence the process of bone repair. In this study, we proposed a physicochemical bidirectional regulation strategy via ration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The fabrication of a hydroxyapatite/zoledronic acid composite biomaterial. This biomaterial promotes bone tissue regeneration by physically utilizing hydroxyapatite nanopatterning to recruit and induce MSCs osteogenic differentiation and by chemically inhibiting osteolysis activity through the loaded zoledronate. The nanorod-like hydroxyapatite coating was fabricated via a modified hydrothermal process while the zoledronic acid was loaded through the chelation within the calcium ions. The in vitro results tested on MSCs and RAW 246.7 indicated that the hydroxyapatite enhanced cells' physical sensing system, therefore enhancing the osteogenesis. At the same time the zoledronic acid inhibited osteolysis by downregulating the RANK-related genes. This research provides a promising strategy for enhancing bone regeneration and contributes to the field of orthopedic implants.

Localized delivery of metformin via 3D printed GelMA-Nanoclay hydrogel scaffold for enhanced treatment of diabetic bone defects

BackgroundDiabetic bone defects present significant challenges for individuals with diabetes. While metformin has been explored for bone regeneration via local delivery, its application in treating diabetic bone defects remains under-explored. In this study, we aim to leverage 3D printing technology to fabricate a GelMA-Nanoclay hydrogel scaffold loaded with metformin specifically for this purpose. The objective is to assess whether the in situ release of metformin can effectively enhance osteogenesis, angiogenesis, and immunomodulation in the context of diabetic bone defects. Materials and methodsUtilizing 3D printing technology, we constructed a GelMA-Nanoclay-Metformin hydrogel scaffold with optimal physical properties and biocompatibility. The osteogenic, angiogenic, and immunomodulatory characteristics of the hydrogel scaffold were thoroughly investigated through both in vitro and in vivo experiments. ResultsGelMA10%-Nanoclay8%-Metformin5mg/mL was selected as the bioink for 3D printing due to its favorable swelling rate, degradation rate, mechanical strength, and drug release rate. Through in vitro investigations, the hydrogel scaffold extract, enriched with metformin, demonstrated a substantial enhancement in the proliferation and migration of BMSCs within a high-glucose microenvironment. It effectively enhances osteogenesis, angiogenesis, and immunomodulation. In vivo experimental outcomes further underscored the efficacy of the metformin-loaded GelMA-Nanoclay hydrogel scaffold in promoting superior bone regeneration within diabetic bone defects. ConclusionsIn conclusion, while previous studies have explored local delivery of metformin for bone regeneration, our research is pioneering in its application to diabetic bone defects using a 3D printed GelMA-Nanoclay hydrogel scaffold. This localized delivery approach demonstrates significant potential for enhancing bone regeneration in diabetic patients, offering a novel approach for treating diabetic bone defects. The translational potential of this articleOur study demonstrates, for the first time, the successful loading of the systemic antidiabetic drug metformin onto a hydrogel scaffold for localized delivery. This approach exhibits significant efficacy in mending diabetic bone defects, presenting a promising new avenue for the treatment of such conditions.