Treatment Of Critical Bone Defects Research Articles

Periodic static compression of micro-strain pattern regulates endochondral bone formation.

Introduction: Developmental engineering based on endochondral ossification has been proposed as a potential strategy for repairing of critical bone defects. Bone development is driven by growth plate-mediated endochondral ossification. Under physiological conditions, growth plate chondrocytes undergo compressive forces characterized by micro-mechanics, but the regulatory effect of micro-mechanical loading on endochondral bone formation has not been investigated. Methods: In this study, a periodic static compression (PSC) model characterized by micro-strain (with 0.5% strain) was designed to clarify the effects of biochemical/mechanical cues on endochondral bone formation. Hydrogel scaffolds loaded with bone marrow mesenchymal stem cells (BMSCs) were incubated in proliferation medium or chondrogenic medium, and PSC was performed continuously for 14 or 28days. Subsequently, the scaffold pretreated for 28days was implanted into rat femoral muscle pouches and femoral condylar defect sites. The chondrogenesis and bone defect repair were evaluated 4 or 10weeks post-operation. Results: The results showed that PSC stimulation for 14days significantly increased the number of COL II positive cells in proliferation medium. However, the chondrogenic efficiency of BMSCs was significantly improved in chondrogenic medium, with or without PSC application. The induced chondrocytes (ichondrocytes) spontaneously underwent hypertrophy and maturation, but long-term mechanical stimulation (loading for 28days) significantly inhibited hypertrophy and mineralization in ichondrocytes. In the heterotopic ossification model, no chondrocytes were found and no significant difference in terms of mineral deposition in each group; However, 4weeks after implantation into the femoral defect site, all scaffolds that were subjected to biochemical/mechanical cues, either solely or synergistically, showed typical chondrocytes and endochondral bone formation. In addition, simultaneous biochemical induction/mechanical loading significantly accelerated the bone regeneration. Discussion: Our findings suggest that microstrain mechanics, biochemical cues, and in vivo microenvironment synergistically regulate the differentiation fate of BMSCs. Meanwhile, this study shows the potential of micro-strain mechanics in the treatment of critical bone defects.

Ligand-Selective Targeting of Macrophage Hydrogel Elicits Bone Immune-Stem Cell Endogenous Self-Healing Program to Promote Bone Regeneration.

Targeting macrophages can facilitate the site-specific repair of critical bone defects. Herein, a composite hydrogel, gelatin-Bletilla striata polysaccharide-mesoporous bioactive glass hydrogel (GBMgel), is constructed via the self-assembly of mesoporous bioactive glass on polysaccharide structures, through the Schiff base reaction. GBMgel can efficiently capture macrophages and drive the recruitment of seed stem cells and vascular budding required for regeneration in the early stages of bone injury, and the observed sustained release of inorganic silicon ions further enhances bone matrix deposition, mineralization, and vascular maturation. Moreover, the use of macrophage-depleted rat calvarial defect models further confirms that GBMgel, with ligand-selective macrophage targeting, increases the bone regeneration area and the proportion of mature bone. Mechanistic studies reveal that GBMgel upregulates the TLR4/NF-κB and MAPK macrophage pathways in the early stages and the JAK/STAT3 pathway in the later stages; thus initiating macrophage polarization at different time points. In conclusion, this study is based on the endogenous self-healing properties of bone macrophages, which enhances stem cell homing, and provides a research and theoretical basis upon which bone tissue can be reshaped and regenerated using the body's immune power, providing a new strategy for the treatment of critical bone defects.

The bio-functionalized membrane loaded with Ta/WH nanoparticles promote bone regeneration through neurovascular coupling.

Electrospinning technology, as a novel approach, has been extensively applied in the field of tissue engineering. Nanofiber membranes prepared by electrospinning can effectively mimic the structure and function of natural bone matrix, providing an ideal scaffold for attachment, proliferation, and differentiation of bone cells while inducing osteogenic differentiation and new bone formation. However, it lacks bioactivities such as osteoinduction, angiogenesis and the ability to promote nerve regeneration. In the presence of complex critical bone defects, a single component electrospun membrane often fails to suffice for bone repair needs. Based on this, we prepared a biofunctionalized membrane loaded with Tantalum(Ta)/Whitlockite(WH) nanoparticles (poly-ε-caprolactone (PCL)/Ta/WH) in order to promote high-quality bone defect repair through neurovascular coupling effect. According to the results of in vitro and in vivo experiments, the early Mg2+ release of WH can effectively increase the local nerve and vascular density, and synergize with Tantalum nanoparticles (TaNPs) to create a rich nerve-vascular microenvironment. This allows the PCL/Ta/WH membrane to repair bone defects in multiple dimensions and achieve high-quality repair of bone tissue, providing new solutions for the treatment of critical bone defects in clinical.

Orthopaedic Advances: Use of Three-Dimensional Metallic Implants for Reconstruction of Critical Bone Defects After Trauma.

Multiple successful strategies exist for the management of critical-sized bone defects. Depending on the location and etiology of an osseous defect, there are nuances that must be considered by the treating surgeon. The induced membrane technique and various modifications of the Ilizarov method (bone transport by distraction osteogenesis) have been the most common methods for biologic reconstruction. Despite the versatility and high union rates reported, they may not be practical for every patient. The rapid expansion of three-dimensional printing of medical devices has led to an increase in their use within orthopaedic surgery, specifically in the definitive treatment of critical bone defects. This article proposes indications and contraindications for implementation of this technology and reviews the available clinical evidence on the use of custom nonresorbable implants for the treatment of traumatic bone loss. Clinical cases are presented to illustrate the scenarios in which this approach is viable.

Hydrogenated silicene nanosheet functionalized scaffold enables immuno-bone remodeling.

An ideal implant needs to have the ability to coordinate the foreign body response and tissue regeneration. Here, Hydrogenated-silicon nanosheets (H-Si NSs) with favorable biodegradability are integrated and functionalized into a β-tricalcium phosphate scaffold (H-Si TCP) for bone defect healing. H-Si TCP can greatly improve bone regeneration through osteoimmunomodulation-guided biodegradation in vivo. The spatiotemporal regulation of degradation products replenishes sufficient nutrients step by step for the entire process of bone repair. Extracellular and intracellular reactive oxygen species (ROS) are first downregulated by reaction with H-Si NSs, followed by marked M2 polarization, remodeling the micro-environment timely for immune-bone regeneration. The release of primary reaction products awakened bone marrow mesenchymal stem cells (BMSCs), which are converted into osteoblasts anchored on scaffolds. Subsequently, biomineralization is promoted by the final degradation products. The intrinsic ROS-responsive, immunoregulatory, and osteo-promotive capability of 2D H-Si NSs makes such composite H-Si TCP scaffold a highly potential alternative for the treatment of critical bone defect.

The Gradual Release of Alendronate for the Treatment of Critical Bone Defects in Osteoporotic and Control Rats.

Osteoporosis is a severe health problem with social and economic impacts on society. The standard treatment consists of the systemic administration of drugs such as bisphosphonates, with alendronate (ALN) being one of the most common. Nevertheless, complications of systemic administration occur with this drug. Therefore, it is necessary to develop new strategies, such as local administration. In this study, emulsion/dispersion scaffolds based on W/O emulsion of PCL and PF68 with ALN, containing hydroxyapatite (HA) nanoparticles as the dispersion phase were prepared using electrospinning. Scaffolds with different release kinetics were tested in vitro on the co-cultures of osteoblasts and osteoclast-like cells, isolated from adult osteoporotic and control rats. Cell viability, proliferation, ALP, TRAP and CA II activity were examined. A scaffold with a gradual release of ALN was tested in vivo in the bone defects of osteoporotic and control rats. The release kinetics were dependent on the scaffold composition and the used system of the poloxamers. The ALN was released from the scaffolds for more than 22 days. The behavior of cells cultured in vitro on scaffolds with different release kinetics was comparable. The difference was evident between cell co-cultures isolated from osteoporotic and control animals. The PCL/HA scaffold show slow degradation in vivo and residual scaffold limited new bone formation inside the defects. Nevertheless, the released ALN supported bone formation in the areas surrounding the residual scaffold. Interestingly, a positive effect of systemic administration of ALN was not proved. The prepared scaffolds enabled tunable control release of ALN. The effect of ALN was proved in vitro and in in vivo study supported peri-implant bone formation.

Patient-Specific 3D-Printed Titanium Implant for Distal Tibial Critical Bone Defect

Aim: Post-traumatic large critical bone defects remain a challenge for today’s orthopedist. Despite multiple available options for treatment including autograft, massive allograft and various methods of bone transport, no strategy has shown itself to be free of significant complications or discouraging rates of nonunion and other mechanisms of failure. Case presentation: Here, we present a patient example of successful treatment of critical bone defect of the distal tibia utilizing the novel technology of a 3D-printed titanium cage coupled with a combination of autologous and allogenic bone graft in a 26-year-old male injured in motor vehicle collision. Conclusion: This case provides further evidence of a successful and promising new treatment to address these challenging injuries.

Risk factors of ankle osteoarthritis in the treatment of critical bone defects using ilizarov technique

BackgroundDistraction osteogenesis using the Ilizarov external circular fixator has been applied in lower limb reconstructive surgery widely. The increasing ankle osteoarthritis (OA) progression and severity are often associated with the period of external fixator and the greater relative instability of the ankle joint, but few studies have quantified risk factors directly during this technique.MethodsThe study was conducted on 236 patients who underwent bone transport surgery for tibias using the Ilizarov external circular fixator from 2008 to 2018. The cumulative incidence of ankle OA diagnoses in patients after the Ilizarov technique treatment was calculated and stratified by risk factors from preoperative and postoperative management. After the data were significant through the Mann-Whitney U test analyzed, odds ratios were calculated using logistic regression to describe factors associated with the OA diagnosis including gender, age, BMI, location of bone defect, diabetes, hypertension, osteoporosis, the history of metal allergy and glucocorticoid intake, the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-HF scale scores, defect size (DS), the type of bone transport, the bone union time, external fixator time (EFT), and external fixator index (EFI).ResultsThere were 199 males and 37 females with a mean age of 47 years (range 28–59 years). Out of 236 patients, 49 had an additional treatment for ankle OA after the Ilizarov technique treatment of bone defects (average follow-up time 2.1 years, range 1.6–4.2 years). The incidence of postoperative ankle OA was 20.8 %, with 19 patients classified as K&L grade 3 and seven patients as grade 4. The top five risk factors included double-level bone transport (OR3.79, P = 0.005), EFI > 50days/cm (OR3.17, P = 0.015), age > 45years (OR2.29, P = 0.032), osteoporosis (OR1.58, P < 0.001), BMI > 25 (OR1.34, P < 0.001). Male, BMI > 25, diabetes, osteoporosis, and AOFAS ankle-HF scale scores are the independent risk factors.ConclusionsIlizarov external circular fixator is a safe and effective method of treatment for critical bone defects. The double level bone transport, EFI > 50days/cm, age > 45years, osteoporosis, BMI > 25 are the top five relevant risk factors of ankle OA. The probability of developing ankle OA among patients having three or more risk factors is 50–70 %.

Adipose-derived stem cell sheets combined with β-tricalcium phosphate/collagen-I fiber scaffold improve cell osteogenesis.

Transplantation of cell-based material is a promising approach for the treatment of critical bone defects. However, it is still limited by the lack of suitable scaffold material or abundant seeding cell sources. The present study aimed to establish a novel composite of an adipose-derived stem cell (ADSC) sheet and a synthetic porous β-tricalcium phosphate/collagen-I fiber (β-TCP/COL-I) scaffold to enhance osteogenic activity. ADSCs were isolated from 3-week-old female Sprague Dawley rats and the ADSC sheets were prepared in an osteoinductive medium. The study groups included the ADSC sheets/scaffold, scattered ADSCs/scaffold, ADSC sheet alone and scaffold alone. Scanning electron microscopy and energy-dispersive spectrometry were used to observe cell-scaffold interactions and analyze the relative calcium content on the composites' surface. Alizarin red S staining was used to examine the calcium deposition. ELISA and reverse transcription-quantitative PCR were used to detect the expression levels of alkaline phosphatase (ALP), osteocalcin (OCN) and osteopontin (OPN). The results revealed that ADSCs were able to tightly adhere to the β-TCP/COL-I scaffold with no cytotoxicity. The calcifying nodules reaction was positive on ADSC sheets and gradually increased after osteogenic induction. In addition, the β-TCP/COL-I scaffold combined with ADSC sheets was able to significantly enhance the expression levels of ALP, OCN and OPN and increase the superficial relative calcium content compared to scattered ADSCs/scaffold or the ADSC sheet alone (P<0.05). The results indicated that ADSCs possess a strong osteogenic potential, particularly in the cell-sheet form and when compounded with the β-TCP/COL-I scaffold, compared to scattered ADSCs with a β-TCP/COL-I scaffold or an ADSC sheet alone. This novel composite may be a promising candidate for bone engineering.

A facile one-stage treatment of critical bone defects using a calcium sulfate/hydroxyapatite biomaterial providing spatiotemporal delivery of bone morphogenic protein-2 and zoledronic acid.

Bone morphogenic proteins (BMPs) are the only true osteoinductive molecules. Despite being tremendously potent, their clinical use has been limited for reasons including supraphysiological doses, suboptimal delivery systems, and the pro-osteoclast effect of BMPs. Efforts to achieve spatially controlled bone formation using BMPs are being made. We demonstrate that a carrier consisting of a powder of calcium sulfate/hydroxyapatite (CaS/HA) mixed with bone active molecules provides an efficient drug delivery platform for critical femoral defect healing in rats. The bone-active molecules were composed of osteoinductive rhBMP-2 and the bisphosphonate, and zoledronic acid (ZA) was chosen to overcome BMP-2-induced bone resorption. It was demonstrated that delivery of rhBMP-2 was necessary for critical defect healing and restoration of mechanical properties, but codelivery of BMP-2 and ZA led to denser and stronger fracture calluses. Together, the CaS/HA biomaterial with rhBMP-2 and/or ZA can potentially be used as an off-the-shelf alternative to autograft bone.

A novel experimental approach to evaluate guided bone regeneration (GBR) in the rat femur using a 3D-printed CAD/CAM zirconia space-maintaining barrier

IntroductionObtaining a certain bone volume is an important goal in implantology or orthopedics. Thus, after tooth extraction, quite a lot of horizontal and vertical alveolar bone is lost in time and can be detrimental to the implant treatment outcome, while the treatment of critical bone defects is a considerable challenge for surgery. ObjectivesIn this study we designed a new in vivo model as an useful experimental tool to assess guided bone regeneration (GBR) using a computer-aided design/manufacturing (CAD-CAM) space-maintaining barrier. MethodsThe barrier was 3D printed with three progressive heights, surgically placed on rat femur, and GBR results were analyzed at 2, 4, and 8 weeks by X-ray and bone mineral density analysis, histology/morphometry and by immunofluorescence and immunohistochemistry for osteogenesis and angiogenesis evaluation. ResultsThe obtained results show that the proposed experimental model provides a real-time useful information on progressive bone tissue formation, which depends on the volume of isolated space created for GBR and on molecular events that lead to satisfactory vertical and horizontal bone augmentation and osteointegration. ConclusionIn conclusion, the proposed customized three-dome space-maintaining barrier is suitable as an experimental tool to assess the potential of using the designed barriers in dentistry and orthopedics to promote the formation of new bone and determine their space- and time-dependent limitations. Meanwhile, guided bone augmentation for dentistry requires subsequent evaluation on an alveolar bone preclinical model followed by clinical implementation.

Challenges and Opportunities in the Selective Laser Melting of Biodegradable Metals for Load-Bearing Bone Scaffold Applications

The aim of this paper is to assess the current status of processing biodegradable metals (BDM) via selective laser melting (SLM), with particular emphasis on bone scaffold applications, and provide a meta-analysis on the effect of processing parameters on relative density to better direct recommendations for the future of this growing field. Synthetic bone scaffolds are becoming a popular alternative for the treatment of critical bone defects that cannot heal without surgical intervention. These scaffolds act as a bridge allowing bone to grow across the gap. Selective laser melting can achieve bone scaffolds with complex hierarchical architecture tailored specifically to the patient. SLM-manufactured titanium scaffolds have already been clinically tested with some success. Permanent titanium alloys have a higher chance of implant rejection from the innate immune reaction, coupled with complications linked to the high mismatch in stiffness between the implant and the bone. Biodegradable metals can overcome these problems by maintaining sufficient mechanical properties for load-bearing applications during healing and eventually degrade away completely. Currently, however, the use of SLM for the manufacturing of BDM scaffolds is still in its infancy as only a few peer-reviewed studies are published, with the majority of these published in the last couple of years. Literature was systematically reviewed to critically analyze and synthesize the data in the form of a meta-analysis. Only studies that included the processing parameters used for volumetric energy density (namely the laser power, scan speed, hatch spacing, and energy density) and provided as built relative densities were used. SLM of biodegradable metals is an exciting research area that requires further exploration. Apart from overcoming the problems unique to each major biodegradable metal family, the meta-analysis showed that the vast majority of studies regard the optimization of SLM processing parameters. However, these studies are specific to the powder and machine used. Rather, broader guidelines need to be developed for modern SLM machines to allow for quicker optimization for future SLM-manufactured BDM.

Additively manufactured iron-manganese for biodegradable porous load-bearing bone scaffold applications

Selective laser melting (SLM) can produce complex hierarchical architectures paving the way for highly customisable biodegradable load-bearing bone scaffolds. For the first time, an in-depth analysis on the performance of SLM-manufactured iron-manganese bone scaffolds suitable for load-bearing applications is presented. Microstructural, mechanical, corrosion and biological characterisations were performed on SLM-manufactured iron-manganese scaffolds. The microstructure of the scaffold consisted primarily of γ-austenite, leading to high ductility. The mechanical properties of the scaffold were sufficient for load-bearing applications even after 28 days immersion in simulated body fluids. Corrosion tests showed that the corrosion rate was much higher than bulk pure iron, attributed to a combination of the manufacturing method, the addition of Mn to the alloy and the design of the scaffold. In vitro cell testing showed that the scaffold had good biocompatibility and viability towards mammalian cells. Furthermore, the presence of filopodia showed good osteoblast adhesion. In vivo analysis showed successful bone integration with the scaffold, with new bone formation observed after 4 weeks of implantation. Overall the SLM manufactured porous Fe-35Mn implants showed promise for biodegradable load-bearing bone scaffold applications. Statement of significanceBiodegradable iron scaffolds are emerging as a promising treatment for critical bone defects. Within this field, selective laser melting (SLM) has become a popular method of manufacturing bespoke scaffolds. There is limited knowledge on SLM-manufactured iron bone scaffolds, and no knowledge on their application for load-bearing situations. The current manuscript is the first study to characterise SLM manufactured iron-manganese bone scaffolds for load-bearing applications and also the first study to perform In vivo testing on SLM produced biodegradable iron scaffolds. In this study, for the first time, the mechanical, corrosion and biological properties of an iron-manganese scaffold manufactured using SLM were investigated. In summary the SLM-manufactured porous iron-manganese implants displayed great potential for biodegradable load-bearing bone scaffolds.

Osteoprogenitor cells can enhance early bone formation in critical bone defects in dogs

ABSTRACT: The aim of this study was to evaluate the effect of osteoprogenitor cells derived from mesenchymal stem cells from adipose tissue (OC-AD-MSCs), and differentiated into osteoblasts, in the treatment of critical bone defects in dogs. Adipose tissue derived mesenchymal stem cells (AD-MSCs) were subjected to osteogenic differentiation for 21 days and used in the treatment of bone defects in dogs radius. Either three experimental groups were bone defects treated with OC-AD-MSCs (OC), defects filled with autogenous bone (Control- C +), or empty defects (Control- C -). Bone regeneration was assessed by radiology, densitometry, and histomorphometry. The area of new bone formation was higher in the OC group compared to the control group (C-) on postoperative day 15. Defects treated with OC-AD-MSCs showed greater neovascularization than the other two groups at 90 days. We concluded that treatment with OC-AD-MSCs increased the area of new bone formation 15 days after surgery; however, it didn’t complete the bone union in critical bone defects in the radius of dogs at 90 days.

Matriz porosa do BV60S no tratamento de defeitos ósseos críticosem rádios de cães

O objetivo deste estudo foi avaliar o efeito da matriz porosa do biovidro de composição molar 60% SiO2 - 36% CaO - 4% P2O5 (BV60S) no tratamento de defeitos ósseos críticos de cães. Foram utilizados 20 cães, machos, sem raça definida, com dois anos e massa corporal média de 25kg. Foram constituídos três grupos experimentais: defeitos ósseos preenchidos com BV60S (BV), com osso autógeno (C+) e defeitos não preenchidos (C-). A regeneração óssea foi avaliada por meio de exames radiográficos, densitométricos e histomorfométricos ao longo de 90 dias. A matriz do BV60S mostrou rápida reabsorção com redução média de 12,62% a cada 15 dias. A regeneração foi completa no grupo C+ e incompleta nos grupos BV e C-, aos 90 dias. A área de neoformação óssea foi semelhante entre os grupos BV e C-, em todos os tempos estudados. Conclui-se que a matriz porosa do BV60S possui rápida reabsorção, não sendo eficiente no tratamento de defeitos ósseos críticos em rádios de cães.

Optimized bone regeneration based on sustained release from three‐dimensional fibrous PLGA/HAp composite scaffolds loaded with BMP‐2

Contemporary treatment of critical bone defect remains a significant challenge in the field of orthopedic surgery. Engineered biomaterials combined with growth factors have emerged as a new treatment alternative in bone repair and regeneration. Our approach is to encapsulate bone morphogenetic protein-2 (BMP-2) into a polymeric matrix in different ways and characterize their individual performance in a nude mouse model. The main objective of this study is to examine whether the PLGA/HAp composite fibrous scaffolds loaded with BMP-2 through electrospinning can improve bone regeneration. The hypothesis is that different loading methods of BMP-2 and different HAp contents in scaffolds can alternate the release profiles of BMP-2 in vivo, therefore modify the performance of scaffolds in bone regeneration. Firstly, mechanical strength of scaffolds and HAp nanoparticles distribution in scaffolds were investigated. Secondly, nude mice experiments extended to 6 weeks were carried out to test the in vivo performance of these scaffolds, in which measurements, like serum BMP-2 concentration, ALP activity, X-ray qualification, and H&E/IHC tissue staining were utilized to monitor the growth of new bone and the changes of the corresponding biochemical parameters. The results showed that the PLGA/HAp composite scaffolds developed in this study exhibited good morphology/mechanical strength and HAp nanoparticles were homogeneously dispersed inside PLGA matrix. Results from the animal experiments indicate that the bioactivity of BMP-2 released from the fibrous PLGA/HAp composite scaffolds is well maintained, which further improves the formation of new bone and the healing of segmental defects in vivo. It is concluded that BMP-2 loaded PLGA/HAp composite scaffolds are promising for bone healing.