Biodegradable materials for bone defect repair.
Military Medical Research
Compared with non-degradable materials, biodegradable biomaterials play an increasingly important role in the repairing of severe bone defects, and have attracted extensive attention from researchers. In the treatment of bone defects, scaffolds made of biodegradable materials can provide a crawling bridge for new bone tissue in the gap and a platform for cells and growth factors to play a physiological role, which will eventually be degraded and absorbed in the body and be replaced by the new bone tissue. Traditional biodegradable materials include polymers, ceramics and metals, which have been used in bone defect repairing for many years. Although these materials have more or fewer shortcomings, they are still the cornerstone of our development of a new generation of degradable materials. With the rapid development of modern science and technology, in the twenty-first century, more and more kinds of new biodegradable materials emerge in endlessly, such as new intelligent micro-nano materials and cell-based products. At the same time, there are many new fabrication technologies of improving biodegradable materials, such as modular fabrication, 3D and 4D printing, interface reinforcement and nanotechnology. This review will introduce various kinds of biodegradable materials commonly used in bone defect repairing, especially the newly emerging materials and their fabrication technology in recent years, and look forward to the future research direction, hoping to provide researchers in the field with some inspiration and reference.
10.1186/s40779-020-00280-6
Engineering exosomes for bone defect repair.
Frontiers in bioengineering and biotechnology
Currently, bone defect repair is still an intractable clinical problem. Numerous treatments have been performed, but their clinical results are unsatisfactory. As a key element of cell-free therapy, exosome is becoming a promising tool of bone regeneration in recent decades, because of its promoting osteogenesis and osteogenic differentiation function and . However, low yield, weak activity, inefficient targeting ability, and unpredictable side effects of natural exosomes have limited the clinical application. To overcome the weakness, various approaches have been applied to produce engineering exosomes by regulating their production and function at present. In this review, we will focus on the engineering exosomes for bone defect repair. By summarizing the exosomal cargos affecting osteogenesis, the strategies of engineering exosomes and properties of exosome-integrated biomaterials, this work will provide novel insights into exploring advanced engineering exosome-based cell-free therapy for bone defect repair.
10.3389/fbioe.2022.1091360
A Biomimetic Fibrous Composite Scaffold with Nanotopography-Regulated Mineralization for Bone Defect Repair.
Biomacromolecules
The effective regeneration of large bone defects bone tissue engineering is challenging due to the difficulty in creating an osteogenic microenvironment. Inspired by the fibrillar architecture of the natural extracellular matrix, we developed a nanoscale bioengineering strategy to produce bone fibril-like composite scaffolds with enhanced osteogenic capability. To activate the surface for biofunctionalization, self-adaptive ridge-like nanolamellae were constructed on poly(ε-caprolactone) (PCL) electrospinning scaffolds surface-directed epitaxial crystallization. This unique nanotopography with a markedly increased specific surface area offered abundant nucleation sites for Ca recruitment, leading to a 5-fold greater deposition weight of hydroxyapatite than that of the pristine PCL scaffold under stimulated physiological conditions. Bone marrow mesenchymal stem cells (BMSCs) cultured on bone fibril-like scaffolds exhibited enhanced adhesion, proliferation, and osteogenic differentiation In a rat calvarial defect model, the bone fibril-like scaffold significantly accelerated bone regeneration, as evidenced by micro-CT, histological histological and immunofluorescence staining. This work provides the way for recapitulating the osteogenic microenvironment in tissue-engineered scaffolds for bone repair.
10.1021/acs.biomac.4c00378
Local FK506 delivery induces osteogenesis in rat bone defect and rabbit spine fusion models.
Bone
Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and increase surgical costs, adding to patients' already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 enhanced osteogenic differentiation and mineralization of hMSCs in vitro. Standalone treatment with FK506 delivered on a collagen sponge produced consistent bone bridging of a critically sized rat femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challenging in vivo models, and indicate FK506 can be utilized to treat a variety of spine disorders.
10.1016/j.bone.2024.117195
Bone Regenerative Effect of Injectable Hypoxia Preconditioned Serum-Fibrin (HPS-F) in an Ex Vivo Bone Defect Model.
International journal of molecular sciences
Biofunctionalized hydrogels are widely used in tissue engineering for bone repair. This study examines the bone regenerative effect of the blood-derived growth factor preparation of Hypoxia Preconditioned Serum (HPS) and its fibrin-hydrogel formulation (HPS-F) on drilled defects in embryonic day 19 chick femurs. Measurements of bone-related growth factors in HPS reveal significant elevations of Osteopontin, Osteoprotegerin, and soluble-RANKL compared with normal serum (NS) but no detection of BMP-2/7 or Osteocalcin. Growth factor releases from HPS-F are measurable for at least 7 days. Culturing drilled femurs organotypically on a liquid/gas interface with HPS media supplementation for 10 days demonstrates a 34.6% increase in bone volume and a 52.02% increase in bone mineral density (BMD) within the defect area, which are significantly higher than NS and a basal-media-control, as determined by microcomputed tomography. HPS-F-injected femur defects implanted on a chorioallantoic membrane (CAM) for 7 days exhibit an increase in bone mass of 123.5% and an increase in BMD of 215.2%, which are significantly higher than normal-serum-fibrin (NS-F) and no treatment. Histology reveals calcification, proteoglycan, and collagen fiber deposition in the defect area of HPS-F-treated femurs. Therefore, HPS-F may offer a promising and accessible therapeutic approach to accelerating bone regeneration by a single injection into the bone defect site.
10.3390/ijms25105315
Reconstruction of an Extensive Segmental Radial Shaft Bone Defect by Vascularized 3D-Printed Graft Cage.
Journal of personalized medicine
We report here a 46-year-old male patient with a 14 cm segmental bone defect of the radial shaft after third degree open infected fracture caused by a shrapnel injury. The patient underwent fixed-angle plate osteosynthesis and bone reconstruction of the radial shaft by a vascularized 3D-printed graft cage, including plastic coverage with a latissimus dorsi flap and an additional central vascular pedicle. Bony reconstruction of segmental defects still represents a major challenge in musculo-skeletal surgery. Thereby, 3D-printed scaffolds or graft cages display a new treatment option for bone restoration. As missing vascularization sets the limits for the treatment of large-volume bone defects by 3D-printed scaffolds, in the present case, we firstly describe the reconstruction of an extensive radial shaft bone defect by using a graft cage with additional vascularization.
10.3390/jpm14020178
Advancements in drug-loaded hydrogel systems for bone defect repair.
Regenerative therapy
Bone defects are primarily the result of high-energy trauma, pathological fractures, bone tumor resection, or infection debridement. The treatment of bone defects remains a huge clinical challenge. The current treatment options for bone defects include bone traction, autologous/allogeneic bone transplantation, gene therapy, and bone tissue engineering amongst others. With recent developments in the field, composite scaffolds prepared using tissue engineering techniques to repair bone defects are used more often. Among the various composite scaffolds, hydrogel exhibits the advantages of good biocompatibility, high water content, and degradability. Its three-dimensional structure is similar to that of the extracellular matrix, and as such it is possible to load stem cells, growth factors, metal ions, and small molecule drugs upon these scaffolds. Therefore, the hydrogel-loaded drug system has great potential in bone defect repair. This review summarizes the various natural and synthetic materials used in the preparation of hydrogels, in addition to the latest research status of hydrogel-loaded drug systems.
10.1016/j.reth.2023.12.010
Bone Marrow-Derived Mesenchymal Stem Cell-Laden Nanocomposite Scaffolds Enhance Bone Regeneration in Rabbit Critical-Size Segmental Bone Defect Model.
Journal of functional biomaterials
Bone regeneration poses a significant challenge in the field of tissue engineering, prompting ongoing research to explore innovative strategies for effective bone healing. The integration of stem cells and nanomaterial scaffolds has emerged as a promising approach, offering the potential to enhance regenerative outcomes. This study focuses on the application of a stem cell-laden nanomaterial scaffold designed for bone regeneration in rabbits. The in vivo study was conducted on thirty-six healthy skeletally mature New Zealand white rabbits that were randomly allocated into six groups. Group A was considered the control, wherein a 15 mm critical-sized defect was created and left as such without any treatment. In group B, this defect was filled with a polycaprolactone-hydroxyapatite (PCL + HAP) scaffold, whereas in group C, a PCL + HAP-carboxylated multiwalled carbon nanotube (PCL + HAP + MWCNT-COOH) scaffold was used. In group D, a PCL + HAP + MWCNT-COOH scaffold was used with local injection of bone morphogenetic protein-2 (BMP-2) on postoperative days 30, 45, and 60. The rabbit bone marrow-derived mesenchymal stem cells (rBMSCs) were seeded onto the PCL + HAP + MWCNT-COOH scaffold by the centrifugal method. In group E, an rBMSC-seeded PCL + HAP + MWCNT-COOH scaffold was used along with the local injection of rBMSC on postoperative days 7, 14, and 21. For group F, in addition to the treatment given to group E, BMP-2 was administered locally on postoperative days 30, 45, and 60. Gross observations, radiological observation, scanning electron microscopic assessment, and histological evaluation study showed that group F displayed the best healing properties, followed by group E, group D, group C, and B. Group A showed no healing with ends blunting minimal fibrous tissue. Incorporating growth factor BMP-2 in tissue-engineered rBMSC-loaded nanocomposite PCL + HAP + MWCNT-COOH construct can augment the osteoinductive and osteoconductive properties, thereby enhancing the healing in a critical-sized bone defect. This novel stem cell composite could prove worthy in the treatment of non-union and delayed union fractures in the near future.
10.3390/jfb15030066
Scaffold-Free Bone Marrow-Derived Mesenchymal Stem Cell Sheets Enhance Bone Formation in a Weight-Bearing Rat Critical Bone Defect Model.
Tissue engineering. Part A
Researchers have been exploring alternative methods for bone tissue engineering, as current management of critical bone defects may be a significant challenge for both patient and surgeon with conventional surgical treatments associated with several potential complications and drawbacks. Recent studies have shown mesenchymal stem cell sheets may enhance bone regeneration in different animal models. We investigated the efficacy of implanted scaffold-free bone marrow-derived mesenchymal stem cell (BMSC) sheets on bone regeneration of a critical bone defect in a weight-bearing rat model. BMSCs were isolated from the femora of male Sprague-Dawley rats 5-6 weeks of age and cell sheets were produced on temperature-responsive culture dishes. Nine male Sprague-Dawley rats 6-8 weeks of age were utilized. A bilateral femoral critical bone defect was created with a bridge plate serving as internal fixation. One side was randomly selected and BMSC sheets were implanted into the bone defect (BMSC group), with the contralateral side receiving no treatment (control). Rats were anesthetized and radiographs were performed at 2-week intervals. At the 8-week time point, rats were euthanized, femurs harvested, and microcomputed tomography and histological analysis was performed. We found a statistically significant increase in new bone formation and bone volume fraction compared with the control. Histomorphometry analysis revealed a larger percent of newly formed bone and a higher total histological score. Our results suggest that scaffold-free BMSC sheets may be used in the management of large weight-bearing bone defects to complement a different surgical technique or as a standalone approach followed by internal fixation. However, further research is still needed.
10.1089/ten.TEA.2023.0118
Self-healing hydrogels for bone defect repair.
RSC advances
Severe bone defects can be caused by various factors, such as tumor resection, severe trauma, and infection. However, bone regeneration capacity is limited up to a critical-size defect, and further intervention is required. Currently, the most common clinical method to repair bone defects is bone grafting, where autografts are the "gold standard." However, the disadvantages of autografts, including inflammation, secondary trauma and chronic disease, limit their application. Bone tissue engineering (BTE) is an attractive strategy for repairing bone defects and has been widely researched. In particular, hydrogels with a three-dimensional network can be used as scaffolds for BTE owing to their hydrophilicity, biocompatibility, and large porosity. Self-healing hydrogels respond rapidly, autonomously, and repeatedly to induced damage and can maintain their original properties (, mechanical properties, fluidity, and biocompatibility) following self-healing. This review focuses on self-healing hydrogels and their applications in bone defect repair. Moreover, we discussed the recent progress in this research field. Despite the significant existing research achievements, there are still challenges that need to be addressed to promote clinical research of self-healing hydrogels in bone defect repair and increase the market penetration.
10.1039/d3ra01700a
The Impact of Defect Size on Bone Healing in Critical-Size Bone Defects Investigated on a Rat Femur Defect Model Comparing Two Treatment Methods.
Bioengineering (Basel, Switzerland)
Critical-size bone defects up to 25 cm can be treated successfully using the induced membrane technique established by Masquelet. To shorten this procedure, human acellular dermis (HAD) has had success in replacing this membrane in rat models. The aim of this study was to compare bone healing for smaller and larger defects using an induced membrane and HAD in a rat model. Using our established femoral defect model in rats, the animals were placed into four groups and defects of 5 mm or 10 mm size were set, either filling them with autologous spongiosa and surrounding the defect with HAD or waiting for the induced membrane to form around a cement spacer and filling this cavity in a second operation with a cancellous bone graft. Healing was assessed eight weeks after the operation using µ-CT, histological staining, and an assessment of the progress of bone formation using an established bone healing score. The α-smooth muscle actin used as a signal of blood vessel formation was stained and counted. The 5 mm defects showed significantly better bone union and a higher bone healing score than the 10 mm defects. HAD being used for the smaller defects resulted in a significantly higher bone healing score even than for the induced membrane and significantly higher blood vessel formation, corroborating the good results achieved by using HAD in previous studies. In comparison, same-sized groups showed significant differences in bone healing as well as blood vessel formation, suggesting that 5 mm defects are large enough to show different results in healing depending on treatment; therefore, 5 mm is a viable size for further studies on bone healing.
10.3390/bioengineering11030287
Metal Ion-Doped Hydroxyapatite-Based Materials for Bone Defect Restoration.
Bioengineering (Basel, Switzerland)
Hydroxyapatite (HA)-based materials are widely used in the bone defect restoration field due to their stable physical properties, good biocompatibility, and bone induction potential. To further improve their performance with extra functions such as antibacterial activity, various kinds of metal ion-doped HA-based materials have been proposed and synthesized. This paper offered a comprehensive review of metal ion-doped HA-based materials for bone defect restoration based on the introduction of the physicochemical characteristics of HA followed by the synthesis methods, properties, and applications of different kinds of metal ion (Ag, Zn, Mg, Sr, Sm, and Ce)-doped HA-based materials. In addition, the underlying challenges for bone defect restoration using these materials and potential solutions were discussed.
10.3390/bioengineering10121367
Flavonoid-Loaded Biomaterials in Bone Defect Repair.
Molecules (Basel, Switzerland)
Skeletons play an important role in the human body, and can form gaps of varying sizes once damaged. Bone defect healing involves a series of complex physiological processes and requires ideal bone defect implants to accelerate bone defect healing. Traditional grafts are often accompanied by issues such as insufficient donors and disease transmission, while some bone defect implants are made of natural and synthetic polymers, which have characteristics such as good porosity, mechanical properties, high drug loading efficiency, biocompatibility and biodegradability. However, their antibacterial, antioxidant, anti-inflammatory and bone repair promoting abilities are limited. Flavonoids are natural compounds with various biological activities, such as antitumor, anti-inflammatory and analgesic. Their good anti-inflammatory, antibacterial and antioxidant activities make them beneficial for the treatment of bone defects. Several researchers have designed different types of flavonoid-loaded polymer implants for bone defects. These implants have good biocompatibility, and they can effectively promote the expression of angiogenesis factors such as VEGF and CD31, promote angiogenesis, regulate signaling pathways such as Wnt, p38, AKT, Erk and increase the levels of osteogenesis-related factors such as Runx-2, OCN, OPN significantly to accelerate the process of bone defect healing. This article reviews the effectiveness and mechanism of biomaterials loaded with flavonoids in the treatment of bone defects. Flavonoid-loaded biomaterials can effectively promote bone defect repair, but we still need to improve the overall performance of flavonoid-loaded bone repair biomaterials to improve the bioavailability of flavonoids and provide more possibilities for bone defect repair.
10.3390/molecules28196888
Tacrolimus, FK506, promotes bone formation in bone defect mouse model.
Journal of oral biosciences
OBJECTIVES:Some studies have reported that tacrolimus (FK506), an immunosuppressant, may have positive effects on bone formation. However, the precise effects of FK506 on bone repair or osteoblasts remain inadequately elucidated, and limited research has explored the outcomes of its use in an in vivo mouse model. This study aims to examine the effects of FK506 on bone repair and osteoblast functions using bone defect and BMP-2-induced ectopic ossification mouse models, as well as cultured primary mouse osteoblasts treated with FK506. METHODS:We established mouse models of femur bone defect and BMP-2-induced ectopic ossification to evaluate the effect of FK506 on new bone formation, respectively. Additionally, primary mouse osteoblasts were cultured with FK506 and examined for gene expressions related to osteoblast differentiation. RESULTS:While FK506 promoted the repair of bone defect areas in the femur of the bone defect mouse model, it also led to widespread abnormal bone formation outside the intended area. Additionally, following the implantation of a collagen sponge containing BMP-2 into mouse muscle tissue, FK506 was found to promote ectopic ossification and enhance BMP-2-induced osteoblast differentiation in vitro. Our findings also revealed that FK506 increased the number of immature osteoblasts in the absence of BMP-2 without affecting osteoblast differentiation. Furthermore, direct effects were observed, reducing the ability of osteoblasts to support osteoclastogenesis. CONCLUSIONS:These results indicate that FK506 increases new bone formation during bone repair and influences the proliferation of immature osteoblasts, as well as osteoblast-supported osteoclastogenesis.
10.1016/j.job.2024.02.003
Advances in the Application of Bone Transport Techniques in the Treatment of Bone Nonunion and Bone Defects.
Orthopaedic surgery
Bone nonunion and bone defects frequently occur following high-energy open injuries or debridement surgeries, presenting complex challenges to treatment and significantly affecting patients' quality of life. At present, there are three primary treatment options available for addressing bone nonunion and bone defects: vascularized bone grafts, the Masquelet technique, and the Ilizarov technique. The Ilizarov technique, also known as distraction osteogenesis, is widely favored by orthopedic surgeons because of several advantages, including minimal soft tissue requirements, low infection risk, and short consolidation time. However, in recent years, the application of the Masquelet technique has resulted in novel treatment methods for managing post-traumatic bone infections when bone defects are present. Although these new techniques do not constitute a panacea, they continue to be the most commonly employed options for treating complex large bone nonunion and bone defects. This review evaluates the currently available research on the Ilizarov and Masquelet bone transport techniques applied at various anatomical sites. Additionally, it explores treatment durations and associated complications to establish a theoretical foundation that can guide clinical treatment decisions and surgical procedures for the management of bone nonunion and bone defects.
10.1111/os.13936
Sudoku of porous, injectable calcium phosphate cements - Path to osteoinductivity.
Bioactive materials
With the increase of global population, people's life expectancy is growing as well. Humans tend to live more active lifestyles and, therefore, trauma generated large defects become more common. Instances of tumour resection or pathological conditions and complex orthopaedic issues occur more frequently increasing necessity for bone substitutes. Composition of calcium phosphate cements (CPCs) is comparable to the chemical structure of bone minerals. Their ability to self-set and resorb secures a variety of potential applications in bone regeneration. Despite the years-long research and several products already reaching the market, finding the right properties for calcium phosphate cement to be osteoinductive and both injectable and suitable for clinical use is still a sudoku. This article is focused on injectable, porous CPCs, reviewing the latest developments on the path toward finding osteoinductive material, which is suitable for injection.
10.1016/j.bioactmat.2022.01.001