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Recent Advances in Bone Graft Technologies
Abstract
Bone is a living, dynamic, vascular, mineralized, connective tissue, characterized by its hardness, resistance and ability to remodel and repair itself. It provides structural support and protection for the bone and vital organs and it serves as a mineral (calcium) and blood cell reservoir for the body. Bone loss and skeletal deficiencies due to traumatic injury, abnormal development, or cancer are major problems worldwide, frequently requiring surgical intervention. Current treatments have achieved a level of success, but still have limitations. Researchers have begun to enhance current treatments and develop novel bone grafts from biological or synthetic materials. These options include the use of biocompatible polymers to mimic trabecular and cortical bone, hormones or growth factors, and bioactive ceramic glass. This patent review presents backgrounds on bone biology and structure, current treatments for damaged bone and bone defects, and new bone grafting technologies in hopes of creating an optimal bone graft substitute.
... Structurally, bone is organized into two distinct types based on its density and location, cortical bone and trabecular bone [1][2][3]. Cortical bone, or compact bone, has a highly dense organized structure composed of tightly packed osteons [4]. Trabecular bone, or spongy bone, is 90% porous with lower mechanical strength than cortical bone and is a meshwork of collagenous tissue filled with bone marrow [3,4]. ...
... Cortical bone, or compact bone, has a highly dense organized structure composed of tightly packed osteons [4]. Trabecular bone, or spongy bone, is 90% porous with lower mechanical strength than cortical bone and is a meshwork of collagenous tissue filled with bone marrow [3,4]. The main components of bone, collagen type I, hydroxyapatite (HAp) and water, contribute to the toughness, stiffness and viscoelastic properties of bone [1,2,5]. ...
In the USA, approximately 500,000 bone grafting procedures are performed annually to treat injured or diseased bone. Autografts and allografts are the most common treatment options but can lead to adverse outcomes such as donor site morbidity and mechanical failure within 10 years. Due to this, tissue engineered replacements have emerged as a promising alternative to the biological options. In this study, we characterize an electrospun porous composite scaffold as a potential bone substitute. Various mineralization techniques including electrodeposition were explored to determine the optimal method to integrate mineral content throughout the scaffold. In vitro studies were performed to determine the biocompatibility and osteogenic potential of the nanofibrous scaffolds. The presence of hydroxyapatite (HAp) and brushite throughout the scaffold was confirmed using energy dispersive X-ray fluorescence, scanning electron microscopy, and ash weight analysis. The active flow of ions via electrodeposition mineralization led to a threefold increase in mineral content throughout the scaffold in comparison to static and flow mineralization. Additionally, a ten-layer scaffold was successfully mineralized and confirmed with an alizarin red assay. In vitro studies confirmed the mineralized scaffold was biocompatible with human bone marrow derived stromal cells. Additionally, bone marrow derived stromal cells seeded on the mineralized scaffold with embedded HAp expressed 30% more osteocalcin, a primary bone protein, than these cells seeded on non-mineralized scaffolds and only 9% less osteocalcin than mature pre-osteoblasts on tissue culture polystyrene. This work aims to confirm the potential of a biomimetic mineralized scaffold for full-thickness trabecular bone replacement.
... Bioglasses are a class of ceramics containing a bioactive component (CaO, Na 2 O, SiO 2 , or P 2 O 5 ) that generates a calcium-phosphorous layer on its surface upon contacting to body fluid [228]. This layer is highly osteoinductive, osteoconductive and osteointegrative [229], and supports new bone formation [230]. Bioglasses also have good antimicrobial properties [231]. ...
Osteochondral (OC) repair is an extremely challenging topic due to the complex biphasic structure and poor intrinsic regenerative capability of natural osteochondral tissue. In contrast to the current surgical approaches which yield only short-term relief of symptoms, tissue engineering strategy has been shown more promising outcomes in treating OC defects since its emergence in the 1990s. In particular, the use of multizonal scaffolds (MZSs) that mimic the gradient transitions, from cartilage surface to the subchondral bone with either continuous or discontinuous compositions, structures, and properties of natural OC tissue, has been gaining momentum in recent years. Scrutinizing the latest developments in the field, this review offers a comprehensive summary of recent advances, current hurdles, and future perspectives of OC repair, particularly the use of MZSs including bilayered, trilayered, multilayered, and gradient scaffolds, by bringing together onerous demands of architecture designs, material selections, manufacturing techniques as well as the choices of growth factors and cells, each of which possesses its unique challenges and opportunities.
... En este contexto, estructuras perfectamente mineralizadas de animales marinos, tales como erizos de mar, esponjas naturales, moluscos cefalópodos, algas rojas mineralizadas, coral, entre otros, son modelos ideales de soportes para la regeneración de tejidos óseos [6]. Esto se debe a las interesantes ventajas que ofrecen en la configuración de la microestructura, siendo similar a los huesos, así como también dispone de una alta macroporosidad para la vascularización, la proliferación de células óseas, y la angiogénesis [8]. Dadas las consideraciones anteriores, los materiales de origen biológico, han tenido un gran interés médico, especialmente por los buenos resultados en sus aplicaciones [6]. ...
Recent progresses in orthopedic medicine, traumatology and odontology have created a great requirement for biomaterials, especially those products having a composition based on calcium orthophosphate, which is similar to inorganic bone structure. Given this situation, there has been an intense search for new origins and resources of biomaterials. The natural occurring materials have been a focus of important studies because they can satisfy the great demand of biomaterials. Studies on these natural materials have reported interesting progresses in relation to the biological tissue regeneration for reparative medicine. In this research work, samples of minerals of a geological hydrothermal deposit were analyzed and this material has been proposed as an important resource of biomaterials. The minerals extracted were disaggregated, transformed into cylindrical specimens by Arc Plasma Sintering, and tested for biological compatibility. The mineralogy of the extracted material revealed a high content of phosphates in the form of apatite, followed by small amounts of other associated mineralogical species such as quartz and gypsum. Under these characteristics, the mineral powder showed a good disposition to sintering; being able to densify at temperatures above 1000 degrees C. The results of sintering were correlated with the different phase evolutions with the process temperatures; with apatite showing very good thermochemistry stability. Preliminary, biological "in vitro" tests of cells attachment and proliferation of human osteoblasts, MG63, indicated that, the prepared specimen sintered at 1200 degrees C appear to be quite promising, as it showed the best cell activation similar to the biological behavior of the reported commercial hydroxyapatite.
... En este contexto, estructuras perfectamente mineralizadas de animales marinos, tales como erizos de mar, esponjas naturales, moluscos cefalópodos, algas rojas mineralizadas, coral, entre otros, son modelos ideales de soportes para la regeneración de tejidos óseos [6]. Esto se debe a las interesantes ventajas que ofrecen en la configuración de la microestructura, siendo similar a los huesos, así como también dispone de una alta macroporosidad para la vascularización, la proliferación de células óseas, y la angiogénesis [8]. Dadas las consideraciones anteriores, los materiales de origen biológico, han tenido un gran interés médico, especialmente por los buenos resultados en sus aplicaciones [6]. ...
Actualmente los grandes progresos en la medicina ortopédica, traumatológica y odontológica, han originado una gran necesidad por biomateriales, especialmente por aquellos productos que tienen una composición en base de ortofosfato de calcio, el cual es similar a la estructura inorgánica de los huesos. Ante este escenario, se ha generado una intensa búsqueda de nuevos orígenes y recursos, siendo los materiales naturales un foco de importantes estudios, debido a que estos pueden abastecer plenamente la gran demanda por biomateriales. Los estudios de estos materiales naturales han reportado interesantes avances, especialmente en lo que respecta a la regeneración de tejidos biológicos en medicina reparativa. De manera de seguir contribuyendo con este desafío, se analizaron muestras de minerales provenientes de un extenso depósito geológico hidrotermal, para proponer estos materiales como posible fuente de recursos. Los minerales extraídos fueron disgregados, para posteriormente fabricar probetas cilíndricas mediante Sinterización por Arco de Plasma, para luego ser biológicamente testeadas. La caracterización mineralógica del material extraído, reveló altos contenidos de fosfatos en forma de apatita, seguidas de pequeñas cantidades de otras especies mineralógicas asociadas, como el cuarzo y yeso. Dadas estas características, el polvo de mineral presentó una buena disposición a la sinterización, siendo capaz de densificar completamente a temperatura sobre los 1000ºC. Los resultados de la sinterización fueron correlacionados con las fases obtenidas con las diferentes temperaturas de proceso, presentando la apatita muy buena estabilidad termoquímica. Pruebas preliminares in vitro de proliferación y adhesión celular de osteoblastos humanos, MG63, en las muestras preparadas, parecen ser bastantes prometedoras, siendo la probeta sinterizada a 1200ºC la que presentó la mejor activación celular, semejante al comportamiento biológico de las hidroxiapatitas comerciales reportadas.
... The autograft is the gold standard, but there are only a few bones that can be used as donor tissue and frequently result in donor site morbidity. Allografts have a high risk of tissue rejection and potential viral or bacterial transmission; moreover, poor tissue integration with host tissue causes the grafting failure rate of 15 to 25% [6][7][8]. Since both options are highly limited by the age of the donors/recipients and their availability, the demand for synthetic bone substitutes has been increasing as an alternative source for bone regeneration. ...
Our laboratory utilized biomimicry to develop a synthetic bone scaffold based on hydroxyapatite-gelatin-calcium silicate (HGCS). Here, we evaluated the potential of HGCS scaffold in bone formation in vivo using the rat calvarial critical-sized defect (CSD). Twelve Sprague-Dawley rats were randomized to four groups: control (defect only), decellularized bone matrix (DECBM), and HGCS with and without multipotent adult progenitor cells (MAPCs). DECBM was prepared by removing all the cells using SDS and NH4OH. After 12 weeks, the CSD specimens were harvested to evaluate radiographical, histological, and histomorphometrical outcomes. The in vitro osteogenic effects of the materials were studied by focal adhesion, MTS, and alizarin red. Micro-CT analysis indicated that the DECBM and the HGCS scaffold groups developed greater radiopaque areas than the other groups. Bone regeneration, assessed using histological analysis and fluorochrome labeling, was the highest in the HGCS scaffold seeded with MAPCs. The DECBM group showed limited osteoinductivity, causing a gap between the implant and host tissue. The group grafted with HGCS+MAPCs resulting in twice as much new bone formation seems to indicate a role for effective bone regeneration. In conclusion, the novel HGCS scaffold could improve bone regeneration and is a promising carrier for stem cell-mediated bone regeneration.
Global increases in life expectancy drive increasing demands for bone regeneration. The gold standard for surgical bone repair is autografting, which enjoys excellent clinical outcomes; however, it possesses significant drawbacks including donor site morbidity and limited availability. Although collagen sponges delivered with bone morphogenetic protein, type 2 (BMP2) are a common alternative or supplement, they do not efficiently retain BMP2, necessitating extremely high doses to elicit bone formation. Hence, reports of BMP2 complications are rising, including cancer promotion and ectopic bone formation, the latter inducing complications such as breathing difficulties and neurologic impairments. Thus, efforts to exert spatial control over bone formation are increasing. Several tissue engineering approaches have demonstrated the potential for targeted and controlled bone formation. These approaches include biomaterial scaffolds derived from synthetic sources, e.g., calcium phosphates or polymers; natural sources, e.g., bone or seashell; and immobilized biofactors, e.g., BMP2. Although BMP2 is the only protein clinically approved for use in a surgical device, there are several proteins, small molecules, and growth factors that show promise in tissue engineering applications. This review profiles the tissue engineering advances in achieving control over the location and onset of bone formation (spatiotemporal control) toward avoiding the complications associated with BMP2.
Xenogenic bone substitutes are commonly used during orthopedic reconstructive procedures to assist bone regeneration. However, huge amounts of blood accompanied with massive bone loss usually increase the difficulty of placing the xenograft into the bony defect. Additionally, the lack of an organic matrix leads to a decrease in the mechanical strength of the bone-grafted site. For effective bone grafting, this study aims at developing a mussel adhesion-employed bone graft binder with great blood-resistance and enhanced mechanical properties. The distinguishing water (or blood) resistance of the binder originates from sandcastle worm-inspired complex coacervation using negatively charged hyaluronic acid (HA) and a positively charged recombinant mussel adhesive protein (rMAP) containing tyrosine residues. The rMAP/HA coacervate stabilizes the agglomerated bone graft in the presence of blood. Moreover, the rMAP/HA composite binder enhances the mechanical and hemostatic properties of the bone graft agglomerate. These outstanding features improve the osteoconductivity of the agglomerate and subsequently promote in vivo bone regeneration. Thus, the blood-resistant coacervated mussel protein glue is a promising binding material for effective bone grafting and can be successfully expanded to general bone tissue engineering.
Tissue engineering has emerged as a promising solution to tissue regeneration in the case of significant bone loss due to disease or injury. The ability to promote cellular attachment, migration, and differentiation into tissue is dependent on the scaffold's surface properties and composition. Bovine gelatin is a natural polymer commonly used as a scaffolding material for tissue engineering applications. Nonetheless, due to the hydrophilic behavior of gelatin, cross-linking and additives are necessary to maintain the scaffold's structure and overall strength in vivo. In this article, we discuss various processing techniques to determine the optimal electrospinning, cross-linking, sintering, and mineralization parameters necessary to yield a porous, mechanically enhanced scaffold. The scaffolds were evaluated quantitatively using compressive mechanical testing, and qualitatively using scanning electron microscopy (SEM). Mechanical data concluded the use of biocompatible microbial transglutaminase (mTG) as a cross-linking agent, led to increased compressive strength. SEM images confirmed the presence of individual gelatin and polymeric nanofibers woven into one scaffold. Sintering before leaching the scaffold yielded structured pores throughout the three-dimensional scaffold when compared to the scaffolds that were leached prior to sintering. The results presented in this article will provide novel information about processing techniques that can be utilized to develop a hybrid synthetic and biological based biomimetic mineralized scaffold for trabecular bone tissue regeneration. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.
The invention relates to biocompatible bone graft materials for repairing bone defects and the application of such bone grafts. The devices of the invention comprise resorbable calcium phosphate, resorbable collagen and bioactive glasses.
In the literature there are conflicting reports on the optimal scaffold mean pore size required for successful bone tissue engineering. This study set out to investigate the effect of mean pore size, in a series of collagen–glycosaminoglycan (CG) scaffolds with mean pore sizes ranging from 85 μm to 325 μm, on osteoblast adhesion and early stage proliferation up to 7 days post-seeding. The results show that cell number was highest in scaffolds with the largest pore size of 325 μm. However, an early additional peak in cell number was also seen in scaffolds with a mean pore size of 120 μm at time points up to 48 h post-seeding. This is consistent with previous studies from our laboratory which suggest that scaffold specific surface area plays an important role on initial cell adhesion. This early peak disappears following cell proliferation indicating that while specific surface area may be important for initial cell adhesion, improved cell migration provided by scaffolds with pores above 300 μm overcomes this effect. An added advantage of the larger pores is a reduction in cell aggregations that develop along the edges of the scaffolds. Ultimately scaffolds with a mean pore size of 325 μm were deemed optimal for bone tissue engineering.
Increases in reconstructive orthopaedic surgery, such as total hip replacement and spinal fusion, resulting from advances in surgical practice and the ageing population, have lead to a demand for bone graft that far exceeds supply. Consequently, a number of synthetic bone-graft substitutes (BGSs) have been developed with mixed success and surgical acceptance. Skeletal tissue regeneration requires the interaction of three basic elements: cells, growth factors (GFs) and a permissive scaffold. This can be achieved by pre-loading a synthetic scaffold with GFs or pre-expanded cells; however, a 'simpler' approach is to design intrinsic 'osteoinductivity' into your BGS, i.e. the capability to recruit and stimulate the patient's own GFs and stem cells. Through investigation of the mechanisms controlling bone repair in BGSs, linking interactions between the local chemical and physical environment, scientists are currently developing osteoinductive materials that can stimulate bone regeneration through control of the scaffold chemistry and structure. Moreover, this body of research is providing the foundations for future generations of BGSs and bone-repair therapies and may ultimately contribute towards improving the quality of life through maintenance of the skeleton and reversal of disease states, as opposed to the mending of broken bones that we currently practice. Will we be able to grow our own bones in a bioreactor for use as autologous graft materials in the future? Could surgery be limited to accidental trauma cases, with greater restoration of function through biochemical or gene therapies? The technology and research probes necessary to this task are currently being developed with the advent of nanotechnology, genomics and proteomics: are we about to embark on a chemical revolution in medicine? This paper aims to discuss some of the current thinking on the mechanisms behind bioactivity and biocompatibility in bone and how a fuller understanding of the interactions between cells and the materials used today could bring about completely new approaches for the treatment of bone fracture and disease tomorrow.
Many organisms incorporate inorganic solids in their tissues to enhance their functional, primarily mechanical, properties. These mineralized tissues, also called biominerals, are unique organo-mineral nanocomposites, organized at several hierarchical levels, from nano- to macroscale. Unlike man-made composite materials, which often are simple physical blends of their components, the organic and inorganic phases in biominerals interface at the molecular level. Although these tissues are made of relatively weak components under ambient conditions, their hierarchical structural organization and intimate interactions between different elements lead to superior mechanical properties. Understanding basic principles of formation, structure, and functional properties of these tissues might lead to novel bioinspired strategies for material design and better treatments for diseases of the mineralized tissues. This review focuses on general principles of structural organization, formation, and functional properties of biominerals on the example the bone tissues. WIREs Nanomed Nanobiotechnol 2011 3 47–69 DOI: 10.1002/wnan.105
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The tremendous need for bone tissue in numerous clinical situations and the limited availability of suitable bone grafts are driving the development of tissue engineering approaches to bone repair. In order to engineer viable bone grafts, one needs to understand the mechanisms of native bone development and fracture healing, as these processes should ideally guide the selection of optimal conditions for tissue culture and implantation. Engineered bone grafts have been shown to have capacity for osteogenesis, osteoconduction, osteoinduction and osteointegration - functional connection between the host bone and the graft. Cells from various anatomical sources in conjunction with scaffolds and osteogenic factors have been shown to form bone tissue in vitro. The use of bioreactor systems to culture cells on scaffolds before implantation further improved the quality of the resulting bone grafts. Animal studies confirmed the capability of engineered grafts to form bone and integrate with the host tissues. However, the vascularization of bone remains one of the hurdles that need to be overcome if clinically sized, fully viable bone grafts are to be engineered and implanted. We discuss here the biological guidelines for tissue engineering of bone, the bioreactor cultivation of human mesenchymal stem cells on three-dimensional scaffolds, and the need for vascularization and functional integration of bone grafts following implantation.
To determine prospectively the rates of change in bone mineral density in elderly people and to examine the relation between lifestyle and demographic factors and these rates of change.
Longitudinal population based study.
Dubbo, New South Wales, Australia.
Representative sample (n = 769) of residents aged > or = 60 on 1 January 1989.
Rates of change in bone mineral density measured prospectively (mean scan interval 2.5 years) at the femoral neck and lumbar spine by dual energy x ray absorptiometry.
Summary rates of loss in the femoral neck were 0.96% per year (95% confidence interval 0.64% to 1.28%) in women and 0.82% per year (0.52% to 1.12%) in men. Importantly, rates of loss at the femoral neck (both percentage and absolute) increased in both sexes with advancing age. No significant loss was evident in either sex at the lumbar spine, probably because of coexistent osteoarthritis. Lifestyle factors had only modest effects on rates of loss at either site.
These data show that bone density of the femoral neck declines at an increasing rate in elderly people, and as this site is predictive of fracture suggest that treatment to minimise bone loss may be important even in very elderly people.
Detailed descriptions of the structural features of bone abound in the literature; however, the mechanical properties of bone, in particular those at the micro- and nano-structural level, remain poorly understood. This paper surveys the mechanical data that are available, with an emphasis on the relationship between the complex hierarchical structure of bone and its mechanical properties. Attempts to predict the mechanical properties of bone by applying composite rule of mixtures formulae have been only moderately successful, making it clear that an accurate model should include the molecular interactions or physical mechanisms involved in transfer of load across the bone material subunits. Models of this sort cannot be constructed before more information is available about the interactions between the various organic and inorganic components. Therefore, further investigations of mechanical properties at the 'materials level', in addition to the studies at the 'structural level' are needed to fill the gap in our present knowledge and to achieve a complete understanding of the mechanical properties of bone.
Bioabsorbable implants are widely used in orthopedic surgery today and the worldwide market is expanding rapidly. Despite the popularity of these implants, reports of complications continue to appear in the literature. Although the complications rarely have an adverse affect on long-term outcomes, the reports are too numerous to be mere isolated incidents related to one specific implant. Complications have been reported with most of the commercially available implant materials with varying incidence rates and severities of reactions to the implants. The purpose of this review is to summarize the adverse events that have been reported in clinical trials of bioabsorbable implants in orthopedic surgery.
GENERAL CONSIDERATIONS Basic Composition and Structure of Bone -E. Bonucci Basic Concepts of Mechanical Property Measurement and Bone Biomechanics -Y. H. An and W. R. Barfield and R. A. Draughn Mechanical Properties of Bone -Y.H. An Factors Affecting Mechanical Properties of Bone -P. Zioupos, C. W. Smith, and Y. H. An Basic Facilities and Instruments for Mechanical Testing of Bone -C.V. Bensen and Y.H. An Methods of Evaluation for Bone Dimensions, Densities, , Morphology, and Structures -Y.H. An, W. R. Barfield and I. Knets General Considerations of Mechanical Testing -Y.H. An and C.V. Bensen A Hierarchical Approach to Exploring Bone Mechanical Properties -C. E. Hoffler, B. R. McCreadie, E. A. Smith, and S. A. Goldstein Nondestructive Mechanical Testing of Cancellous Bone -F. Linde and I. Hvid Synthetic Materials and Structures Used as Models for Bone -J. A. Szivek METHODS OF MECHANICAL TESTING OF BONE Tensile and Compression Testing of Bone -T. S. Keller and M. A. Liebschner Bending Tests of Bone -M. J. Lopez and M. D. Markel Torsional Testing of Bone -B. Furman and S. Saha Indentation Testing of Bone -B. E. McKoy, Q. Kang and Y. H. An Penetration Testing of Bone Using an Osteopenetrometer -I. Hvid and F. Linde Microhardness Testing of Bone -S. S. Huja, T. R. Katona, and W. E. Roberts Nanoindentation Testing of Bone -J. Y. Rho and G. M. Pharr Single Osteon Micromechanical Testing -M. G. Ascenzi, A. Benvenuti, and A. Ascenzi Micromechanical Testing of Single Trabeculae -P. L. Mente Strain Gauge Measurements from Bone Surfaces -J. A. Szivek and V. M. Gharpuray Screw Pullout Test for Evaluating Mechanical Properties of Bone -M. S. Crum, F. A. Young, Jr., and Y. H. An Viscoelastic Properties of Bone and Testing Methods -N. Sasaki Observation of Material Failure Mode Using a SEM with a Built-in Mechanical Testing Device -R. M. Wang and Y. H. An Ultrasonic Methods for Evaluating Mechanical Properties of Bone -J. Y. Rho Evaluating Mechanical Properties of Bone Using Scanning Acoustic Microscopy -C. H. Turner and J. L. Katz Peripheral Quantitative Computed Tomography for Evaluating Structural and Mechanical Properties of Small Bone -J. L. Ferretti Computer Modeling for Evaluating Trabecular Bone Mechanics -R. Saxena and T. S. Keller METHODS OF MECHANICAL TESTING OF THE BONE-IMPLANT INTERFACE Factors Affecting the Strength of the Bone-Implant Interface -B. E. McKoy, Y. H. An and R. J. Friedman Implant Pushout and Pullout Test -A. Berzins and D. R. Sumner The Validity of a Single Pushout Test -W. J. A. Dhert and J. A. Jansen Tensile Testing of Bone-Implant Interface -T. Nakamura and S. Nishiguchi Fracture Toughness Tests of the Bone-Implant Interface -X. Wang, K. A. Athanasiou, and C. M. Agrawal In Vitro Measurements of Implant Stability -A. Berzins and D. Sumner In Vitro Testing of the Stability of Acetabular Components -J. R. Davis, R. A. Lofthouse, and R. H. Jinnah In Vitro Testing of the Stability of Femoral Components -S. H. Naidu, F. M. Khoury and J. M. Cuckler Screw Pullout Test -L. A. Ferrara and T. C. Ryken Finite Element Analysis for Evaluating Mechanical Properties of the Bone-Implant Interface -K. R. Williams Fatigue Testing of Bioabsorbable Screws in a Synthetic Bone Substrate -W. S. Pietrzak, D. R. Sarver, and D. H. Kohn Testing Intervertebral Stability after Spinal Fixation -K. S. James and A. U. Daniels
During the past two decades significant advances have been made in the development of biodegradable polymeric materials for biomedical applications. Degradable polymeric biomaterials are preferred candidates for developing therapeutic devices such as temporary prostheses, three-dimensional porous structures as scaffolds for tissue engineering and as controlled/sustained release drug delivery vehicles. Each of these applications demands materials with specific physical, chemical, biological, biomechanical and degradation properties to provide efficient therapy. Consequently, a wide range of natural or synthetic polymers capable of undergoing degradation by hydrolytic or enzymatic route are being investigated for biomedical applications. This review summarizes the main advances published over the last 15 years, outlining the synthesis, biodegradability and biomedical applications of biodegradable synthetic and natural polymers.
Repair of load-bearing defects resulting from disease or trauma remains a critical barrier for bone tissue engineering. Calcium phosphate (CaP) scaffolds are among the most extensively studied for this application. However, CaPs are reportedly too weak for use in such defects and, therefore, have been limited to non-load-bearing applications. This paper reviews the compression, flexural and tensile properties of CaPs and CaP/polymer composites for applications in bone replacement and repair. This review reveals interesting trends that have not, to our knowledge, previously been reported. Data are classified as bulk, scaffolds, and composites, then organized in order of decreasing strength. This allows for general comparisons of magnitudes of strength both within and across classifications. Bulk and scaffold strength and porosity overlap significantly and scaffold data are comparable to bone both in strength and porosity. Further, for compression, all composite data fall below those of the bulk and most of the scaffold. Another interesting trend revealed is that strength decreases with increasing β-tricalcium phosphate (β-TCP) content for CaP scaffolds and with increasing CaP content for CaP/polymer composites. The real limitation for CaPs appears not to be strength necessarily, but toughness and reliability, which are rarely characterized. We propose that research should focus on novel ways of toughening CaPs and discuss several potential strategies.
Autograft and allograft, the standard approaches for lumbar fusion procedures, have important disadvantages. Bone graft substitutes such as recombinant human bone morphogenetic proteins (rhBMP-2 and rhBMP-7) have emerged as viable alternatives. The authors conducted a systematic review to compare the efficacy and safety of osteoinductive bone graft substitutes using autografts and allografts in lumbar fusion.
A search for prospective controlled trials was conducted on MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases. Data were extracted for key outcomes including radiographically demonstrated nonunion, Oswestry Disability Index, operating time, blood loss, and length of hospital stay. The quality of randomized controlled trials was assessed using the Jadad scale. Meta-analyses were performed when feasible, and heterogeneity was assessed using the Q statistic and the I(2) statistic.
Seventeen of 732 potential studies met the inclusion criteria, with 9 examining rhBMP-2, 3 examining rhBMP-7, 3 examining demineralized bone matrix, and 2 examining autologous growth factor. Recombinant human BMP-2 significantly decreased radiographic nonunion when compared with autologous iliac crest bone graft (AIBG) in a meta-analysis (relative risk 0.27, 95% CI 0.16-0.46). Stratification of meta-analyses by the type of surgical procedure performed yielded similar results. Funnel plots suggested publication bias. Trials of rhBMP-2 suggested reductions in the operating time and surgical blood loss, with less effect on the length of hospital stay. There was no difference in radiographic nonunion with the use of rhBMP-7 when compared with AIBG (relative risk 1.02, 95% CI 0.52-1.98). Neither rhBMP-2 nor rhBMP-7 demonstrated a significant improvement on the Oswestry Disability Index when compared with AIBG. The limited data on demineralized bone matrix and autologous growth factor showed no significant improvement in radiographic outcomes.
Recombinant human BMP-2 may be an effective alternative to AIBG in lumbar fusion. Data are limited for other bone graft substitutes.
Bone grafting is frequently used to augment bone healing with the numerous approaches to reconstructing or replacing skeletal defects. Autologous cancellous bone graft remains the most effective grafting material because it provides the three elements required for bone regeneration: osteoconduction, osteoinduction, and osteogenic cells. Autologous cortical bone graft provides these three components to a limited extent as well and also provides the structural integrity important in reconstruction of larger defects. However, because autogenous grafting is associated with several shortcomings and complications, including limited quantities of bone for harvest and donor-site morbidity, alternatives have been used in a wide range of orthopaedic pathologic conditions. Grafting substitutes currently available include cancellous and cortical allograft bone, ceramics, demineralized bone matrix, bone marrow, and composite grafts. No single alternative graft material provides all three components for bone regeneration. The clinical applications for each type of material are dictated by its particular structural and biochemical properties. Composite grafts consisting of several materials are often used to maximize bone healing, especially where the grafting site is compromised.
Platelet-rich plasma contains autologous thrombocyte growth factors and might be promising for acceleration of dentoalveolar bone regeneration. In this study, it was analysed for platelet counts and growth factor concentrations.
Platelet-rich plasma was isolated by discontinuous cell separation from 158 healthy men and 55 women aged 17-62 years. One hundred and fifteen specimens (stratified for age and gender of the donor) were analysed for growth factor concentrations and platelet count.
The platelet count in platelet-rich plasma (1,407,640+/-320,100/microl) was 5 times higher than in donor blood (266,040+/-60,530/microl). Platelet-derived growth factor AB (117+/-63 ng/ml), transforming growth factor (TGF) beta -1 (169+/-84 ng/ml), and insulin-like growth factor (IGF) I (84+/-23 ng/ml) were found in large amounts, while platelet-derived growth factor (PDGF) BB (10+/-8 ng/ml) and transforming growth factor beta -2 (0.4+/-0.3 ng/ml) were found in small amounts only. The growth factor content was not well correlated with the platelet count in whole blood nor with the platelet-rich plasma (r(p)=0.35). No influence of gender or age on platelet count or growth factor concentrations was discovered (except IGF-I).
While there was substantial variation in the growth factor content of platelet-rich plasma, the factors influencing this are still worthy of further investigation. Furthermore, a technique whereby the growth factor content could be rapidly assessed in platelet-rich plasma may be of therapeutic benefit.
In bone tissue engineering, poly(DL-lactic-co-glycolic acid) (PLGA) microparticles are frequently used as a delivery vehicle for bioactive molecules. Calcium phosphate cement is an injectable, osteoconductive, and degradable bone cement that sets in situ. The objective of this study was to create an injectable composite based on calcium phosphate cement embedded with PLGA microparticles for sustained delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2).
(125) I-labeled rhBMP-2 was incorporated in PLGA microparticles. PLGA microparticle/calcium-phosphate cement composites were prepared in a ratio of 30:70 by weight. Material properties were evaluated by scanning electron microscopy, microcomputed tomography, and mechanical testing. Release kinetics of rhBMP-2 from PLGA/calcium-phosphate cement disks and PLGA microparticles alone were determined in vitro in two buffer solutions (pH 7.4 and pH 4.0) for up to twenty-eight days.
The entrapment yield of rhBMP-2 in PLGA microparticles was a mean (and standard deviation) of 79% +/- 8%. Analysis showed spherical PLGA microparticles (average size, 17.2 +/-1.3 micro m) distributed homogeneously throughout the nanoporous disks. The average compressive strength was significantly lower (p < 0.001) for PLGA and calcium-phosphate cement composite scaffolds than for calcium-phosphate cement scaffolds alone (6.4 +/- 0.6 MPa compared with 38.6 +/- 2.6 MPa, respectively). Average rhBMP-2 loading was 5.0 +/- 0.4 micro g per 75-mm (3) disk. Release of rhBMP-2 was limited for all formulations. At pH 7.4, 3.1% +/- 0.1% of the rhBMP-2 was released from the PLGA/calcium-phosphate cement disks and 18.0% +/- 1.9% was released from the PLGA microparticles alone after twenty-eight days. At pH 4.0, PLGA/calcium-phosphate cement disks revealed more release of rhBMP-2 than did PLGA microparticles alone (14.5% +/- 6.3% compared with 5.4% +/- 0.7%) by day 28.
These results indicate that preparation of a PLGA/calcium-phosphate cement composite for the delivery of rhBMP-2 is feasible and that the release of rhBMP-2 is dependent on the composite composition and nanostructure as well as the pH of the release medium.
Toughness is a quantitative measure of bone quality in terms of its susceptibility to fracture. Thus, to elucidate the underlying mechanisms of age-related bone fractures, it is necessary to understand age-related changes in the toughness of bone. The objective of this review is to provide current understanding on the structure-function relationships of cortical bone and its correlation with the toughness of the tissue from the perspective of basic engineering principles. The review is written for the readers in the musculoskeletal research field, who may not have a strong engineering background. For better understanding of toughening mechanisms, this review intends to focus on correlations of the toughness of cortical bone with its constituents and microstructural characteristics. In addition, a special emphasis is placed on age-related changes in the toughness of bone.
"Osteobiologics" is the term that has been introduced to refer to the class of engineered materials that have been created and which promote healing of fractures and bone defects. The list of osteobiologics is rapidly expanding as new products incorporating osteoconductive materials are mixed with a variety of osteoinductive proteins, demineralized bone, and preparations of osteogenic cells. The growth in osteobiologics has been stimulated by the early success of osteoconductive materials as graft substitutes in the repair of fractures and by the increasing demand for grafts in all areas of orthopaedics. Although allografts have historically been employed with success, the number of donors has grown much slower than demand leading to the development of artificial materials. Manufactured bone graft substitutes, or osteobiologics, attempt to mimic the components of an autogeneous bone graft by reproducing the bone matrix, which is osteoconductive and osteoinductive. Other products aim to introduce osteogenic cells by concentrating bone marrow while others introduce differing growth factors from platelets in peripheral blood. Very few of these products have been supported by appropriate clinical studies and as such their value is unknown. Orthopaedic surgeons employing these products must understand the basic science principles behind their development in order to understand the indications and limitations of their application. Properly designed clinical studies should be performed to determine the usefulness and cost-effectiveness of both current and future products.
Allograft bone is the primary source of graft material for structural oncological limb salvage procedures. Failure rates after massive allograft reconstructions have been reported as high as 60% at 10 years, which are associated with a multitude of biologic processes influencing the graft incorporation and functional capacity. It is unknown if mechanical failure is associated with a gradual loss of bulk material properties of the bone (strength and modulus), loss of bone mineral density, osteoclastic resorption of the allograft, unrepaired allograft microfractures or microcracks, and/or local stress concentration within the tissue. Allograft material properties, bone mineral density, microcrack prevalence, and cortical porosity were quantified in 13 failed human allograft retrievals ranging in longevity from 1 to 13 years in vivo. Nonimplanted allograft tissue (n = 27) served as the baseline for comparison. A 50% loss in strength of allograft tissue was noted after 10 years in vivo. Loss of strength was correlated with an increase in microfracture prevalence and decrease in bone mineral density within the retrieved allograft cortex. This study suggests functional failure of allograft limb salvage procedures may, in part, be attributed to degradation of the tissue's material properties, bone mineral density and prevalence of microcracks.
Carriers for bone morphogenetic proteins (BMPs) are used to increase retention of these factors at orthopedic treatment sites for a sufficient period of time to allow regenerative tissue forming cells to migrate to the area of injury and to proliferate and differentiate. Carriers can also serve as a matrix for cell infiltration while maintaining the volume in which repair tissue can form. Carriers have to be biocompatible and are often required to be bioresorbable. Carriers also have to be easily, and cost-effectively, manufactured for large-scale production, conveniently sterilized and have appropriate storage requirements and stability. All of these processes have to be approvable by regulatory agencies. The four major categories of BMP carrier materials include natural polymers, inorganic materials, synthetic polymers, composites of these materials. Autograft or allograft carriers have also used. Carrier configurations range from simple depot delivery systems to more complex systems mimicking the extracellular matrix structure and function. Bone regenerative carriers include depot delivery systems for fracture repair, three-dimensional polymer or ceramic composites for segmental repairs and spine fusion and metal or metal/ceramic composites for augmenting implant integration. Tendon/ligament regenerative carriers range from depot delivery systems to three-dimensional carriers that are either randomly oriented or linearly oriented to improve regenerative tissue alignment. Cartilage regenerative systems generally require three-dimensional matrices and often incorporate cells in addition to factors to augment the repair. Alternative BMP delivery systems include viral vectors, genetically altered cells, conjugated factors and small molecules.
Autograft is considered ideal for grafting procedures, providing osteoinductive growth factors, osteogenic cells, and an osteoconductive scaffold. Limitations, however, exist regarding donor site morbidity and graft availability. Allograft on the other hand, posses the risk of disease transmission. Synthetic graft substitutes lack osteoinductive or osteogenic properties. Composite grafts combine scaffolding properties with biological elements to stimulate cell proliferation and differentiation and eventually osteogenesis. We present here an overview of bone grafts and graft substitutes available for clinical applications.
Several bone graft substitutes are now available for use in augmenting bone healing following trauma. Many of these products are osteoconductive and are indicated for filling bone defects in conjunction with standard methods of internal and external fixation. Osteoconduction refers to a process in which the three-dimensional structure of a substance is conducive for the ongrowth and/or ingrowth of newly formed bone. Currently used bone graft substitutes that primarily offer osteoconductive properties include coralline hydroxyapatite, collagen-based matrices, calcium phosphate, calcium sulfate, and tricalcium phosphate. These products vary considerably in chemical composition, structural strength, and resorption or remodeling rates. Understanding these differences is important in selecting a bone graft substitute with the properties desired for a specific clinical situation. The limited number of clinical studies and lack of direct-comparison studies between these products require the surgeon to fully understand the properties of each product when choosing a bone graft substitute.
Since the identification of the osteogenic protein-1 (OP-1) gene, also called bone morphogenetic protein-7 (BMP-7), almost 20 years ago, OP-1 has become one of the most characteristic members of the BMP family. The biological activity of recombinant human OP-1 has been defined using a variety of animal models. These studies have demonstrated that local implantation of OP-1 in combination with a collagen matrix results in the repair of critical size defects in long bones and in craniofacial bones and the formation of bony fusion masses in spinal fusions. Clinical trials investigating long bone applications have provided supportive evidence for the use of OP-1 in the treatment of open tibial fractures, distal tibial fractures, tibial nonunions, scaphoid nonunions and atrophic long bone nonunions. Clinical studies investigating spinal fusion applications have provided supportive evidence for the use of OP-1 in posterolateral lumbar models and compromised patients as an adjunct or as a replacement for autograft. Both long bone repair and spinal fusion studies have demonstrated the efficacy and safety of OP-1 by clinical outcomes and radiographic measures. Future clinical investigations will be needed to better define variables, such as dose, scaffold and route of administration. Clearly the use of BMPs in orthopaedics is still in its formative stage, but the data suggest an exciting and promising future for the development of new therapeutic applications.
Bone morphogenetic proteins (BMPs) are multi-functional growth factors belonging to the transforming growth factor beta superfamily, especially BMP-2, induce bone formation in vivo, and clinical application in repair of bone fractures and defects is expected. However, appropriate systems to delivery BMPs for practical use need to be developed with the objective to heal cartilage and bone-related diseases in medical, dental and veterinary practice. Thus, the aim of this article was to present an overview of the principals carriers used to delivery BMPs and alternative delivery systems for these proteins.
When the normal physiologic reaction to fracture does not occur, such as in fracture nonunions or large-scale traumatic bone injury, surgical intervention is warranted. Autografts and allografts represent current strategies for surgical intervention and subsequent bone repair, but each possesses limitations, such as donor-site morbidity with the use of autograft and the risk of disease transmission with the use of allograft. Synthetic bone-graft substitutes, developed in an effort to overcome the inherent limitations of autograft and allograft, represent an alternative strategy. These synthetic graft substitutes, or matrices, are formed from a variety of materials, including natural and synthetic polymers, ceramics, and composites, that are designed to mimic the three-dimensional characteristics of autograft tissue while maintaining viable cell populations. Matrices also act as delivery vehicles for factors, antibiotics, and chemotherapeutic agents, depending on the nature of the injury to be repaired. This intersection of matrices, cells, and therapeutic molecules has collectively been termed tissue engineering. Depending on the specific application of the matrix, certain materials may be more or less well suited to the final structure; these include polymers, ceramics, and composites of the two. Each category is represented by matrices that can form either solid preformed structures or injectable forms that harden in situ. This article discusses the myriad design considerations that are relevant to successful bone repair with tissue-engineered matrices and provides an overview of several manufacturing techniques that allow for the actualization of critical design parameters.
Discovered in 1965, bone morphogenetic proteins (BMPs) are a group of cytokines from the transforming growth factor-beta (TGFbeta) superfamily with significant roles in bone and cartilage formation. BMPs are used as powerful osteoinductive components of diverse tissue-engineering products for the healing of bone. Several BMPs with different physiological roles have been identified in humans. The purpose of this review is to cover the biological function of the main members of BMP family, the latest research on BMPs signalling pathways and advances in the production of recombinant BMPs for tissue engineering purposes.
Bone morphogenetic proteins (BMPs) are cytokines with a strong effect on bone and cartilage growth and with important roles during embryonic patterning and early skeletal formation. BMPs have promising potential for clinical bone and cartilage repair, working as powerful bone-inducing components in diverse tissue-engineering products. Synthetic polymers, natural origin polymers, inorganic materials and composites may be used as carriers for the delivery of BMPs. Carriers range from nanoparticles to complex three-dimensional (3D) scaffolds, membranes for tissue-guided regeneration, biomimetic surfaces and smart thermosensitive hydrogels. Current clinical uses include spinal fusion, healing of long bone defects and craniofacial and periodontal applications, amongst others. BMP-2 and BMP-7 have recently received approval by the US Food and Drug Administration (FDA) for specific clinical cases, delivered in absorbable collagen sponges. Considering the expanding number of publications in the field of BMPs, there are prospects of a brilliant future in the field of regenerative medicine of bone and cartilage with the use of BMPs.
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