Biomaterials and osseous regeneration

The autologous bone graft is commonly used for the repair of bony defects, but its resorption is unpredictable, and there is an inherent morbidity of the donor site. There is a wide range of biomaterials that could be used as bone substitutes, depending on their bioactivity. Among bioactive materials, bioglasses present a linkage between their reactive surface and the adjacent bone although they cannot be colonized by bony ingrowth, moreover their fragility and resorption as particles limit their use. The osteoconductive biomaterials are either represented by the synthetized ceramics, such as hydroxyapatite (HA) or tricalcium phosphate (TCP), or either natural coral and the derived biomaterials of bony matrix. Coral exoskeleton or TCP are highly resorbable, but pure HA is only slightly. Bony ingrowth in osteoconductive materials is limited to the periphery of the implant which does not make it suitable for the repair of large defects. Research is focused on the adjunction of a biologically active substance to the osteoconductive matrix in order to enhance bony ingrowth. Osteoinductive materials such as bone growth factors in combination with a carrier can promote bone healing, especially when bone morphogenetic protein (BMP) is used. Nevertheless, even if their efficacy is demonstrated, their inocuity has not been totally confirmed. Furthermore, the dose used are far superior than in the physiological pathways. Hybrid biomaterials combine an osteoconductive carrier with bone marrow cells. Bone cell cultures could amplify to almost any extent the number of osteogenic cells for such a biomaterial. Bone substitutes will certainly be used in the future to repair bony defects.     

Bioactive materials in orthopaedic surgery: overview and regulatory considerations

Although bone graft continues to be the standard against which other skeletal substitutes are measured, orthopaedic surgeons soon will have various new tools available for skeletal reconstruction. With these tools, the distinctions between inert materials, resorbables, bioactive materials, transplantable tissues, engineered tissues, drugs, and composites become indistinct. Although almost any implanted material evokes some type of host reaction, in the context of reconstructive orthopaedic surgery, bioactive materials can be considered osteogenic, osteoconductive, osteoinductive, or a combination thereof. In the United States, the regulatory control of a new skeletal substitute material is complex, and is based in part on whether the material is considered primarily a biologic, a drug, or a medical device. Different agencies within the Food and Drug Administration have responsibility for regulatory control of different types of products. Although some new materials can be approved by a Premarket Notification (510(K)), others require a Premarket Approval Application. Regulations are being developed that affect the extent of regulatory influence over minimally manipulated tissues for transplantation.     

RETRACTED: Bone graft substitutes: What are the options?

Currently, a number of bone grafting materials are available in the clinical setting to enhance bone regeneration, varying from autologous bone to several bone graft substitutes. Although autologous bone remains the "gold standard" for stimulating bone repair and regeneration, the morbidity from its harvesting and its restricted availability generated the need for the development of other materials or strategies either to substitute autologous bone graft or expand its limited supply. Bone graft substitutes can possess one or more components: an osteoconductive matrix, acting as a scaffold; osteoinductive proteins and other growth factors to induce differentiation and proliferation of bone-forming cells; and osteogenic cells for bone formation. Based on their distinct properties, all these bone grafting alternatives have specific indications, and can be used either alone or in combination. In this review, we summarise the available bone grafting materials, focussing mainly on the various bone substitutes and their characteristics, in an effort to specify the indications for their use.     

Molecular basis for action of bioactive glasses as bone graft substitute.

Bone grafting procedures are undergoing a major shift from autologous and allogeneic bone grafts to synthetic bone graft substitutes. Bioactive glasses are a group of synthetic silica-based bioactive materials with bone bonding properties first discovered by Larry Hench. They have several unique properties compared with other synthetic bioresorbable bioactive ceramics, such as calcium phosphates, hydroxyapatite (HA) and tricalcium phosphate (TCP). Bioactive glasses have different rates of bioactivity and resorption rates depending on their chemical compositions. The critical feature for the rate of bioactivity is a SiO2 content < 60% in weight. In vivo, the material is highly osteoconductive and it seems to promote the growth of new bone on its surface. In a recent study, the activity of the material was found even to overshadow the effect of BMP-2 gene therapy. In vivo, there is a dynamic balance between intramedullary bone formation and bioactive glass resorption. Recent studies of molecular biology have shown that bioactive glass induces a high local turnover of bone formation and resorption. Many osteoporotic fracture patients are candidates for concurrent treatment with bisphosphonates and bioceramic bone graft substitutes. Since osteopromotive silica-based bioactive glasses induce accelerated local bone turnover, adjunct antiresorptive agents may affect the process. However, a recent study showed that an adjunct antiresorptive therapy (zoledronic acid) is even beneficial for bone incorporation of bioactive glass. Based on these observations, bioactive glasses are a promising group of unique biomaterials to act as bone graft substitutes.     

Current approaches to experimental bone grafting

A number of osteogenic, osteoinductive, and osteoconductive substances currently are being investigated for use in bone repair. It is conceivable that a selected combination of osteogenic cells, osteoinductive factors, and osteoconductive matrices can be combined and fabricated into an implantable material custom-suited to particular clinical demands. Consequently, it is crucial that potential graft substances be experimentally characterized in terms of their precise contribution to the bone-forming mechanisms. In this article, the authors review current areas of research in the realm of experimental grafting, including the current understanding of materials that manifest osteogenic, osteoinductive, or osteoconductive properties.     

What should be the characteristics of the ideal bone graft substitute? Combining scaffolds with growth factors and/or stem cells

Reconstruction of large bone defects or non-unions resulting from biochemical disorders, tumour resections or complicated fractures is still a challenge for orthopaedic and trauma surgery. On the one hand, autografts harbour most features of ideal bone graft substitutes but on the other hand, they have a lot insurmountable disadvantages. An ideal bone graft substitute should be biomechanically stable, able to degrade within an appropriate time frame, exhibit osteoconductive, osteogenic and osteoinductive properties and provide a favourable environment for invading blood vessels and bone forming cells. Whilst osteoconductivity of biomaterials for bone tissue engineering strategies can be directed by their composition, surface character and internal structure, osteoinductive and osteogenic features can be provided by growth factors originally participating in fracture healing and/or multipotent mesenchymal stromal/stem cells (MSC) capable of rebuilding bone and marrow structures. In this review, aspects of the clinical application of the most commonly used growth factors for bone repair, the bone morphogenetic proteins (BMPs), and the potential use of human MSC for clinical application will be discussed.     

Bioresorbability, porosity and mechanical strength of bone substitutes: what is optimal for bone regeneration?

Bone repair is a multi-dimensional process that requires osteogenic cells, an osteoconductive matrix, osteoinductive signalling, mechanical stability and vascularization. In clinical practice, bone substitute materials are being used for reconstructive purposes, bone stock augmentation, and bone repair. Over the last decade, the use of calcium phosphate (CaP) based bone substitute materials has increased exponentially. These bone substitute materials vary in composition, mechanical strength and biological mechanism of function, each having their own advantages and disadvantages. It is known that intrinsic material properties of CaP bone substitutes have a profound effect on their mechanical and biological behaviour and associated biodegradation. These material properties of bone substitutes, such as porosity, composition and geometry change the trade-off between mechanical and biological performance. The choice of the optimal bone substitutes is therefore not always an easy one, and largely depends on the clinical application and its associated biological and mechanical needs. Not all bone graft substitutes will perform the same way, and their performance in one clinical site may not necessarily predict their performance in another site. CaP bone substitutes unfortunately have yet to achieve optimal mechanical and biological performance and to date each material has its own trade-off between mechanical and biological performance. This review describes the effect of intrinsic material properties on biological performance, mechanical strength and biodegradability of CaP bone substitutes.     

Osteobiologics

"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.     

The use of bone graft substitutes in large cancellous voids: any specific needs?

Bone graft is the second most common transplantation tissue, with blood being by far the commonest. 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 poses 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 graft substitutes available for clinical application in large cancellous voids.     

The efficacy of autologous laminectomy bone combined with bone graft extenders in posterolateral lumbar instrumented fusion

Iliac crest autograft has been used successfully for many years in spinal fusion operations. The main advantages to iliac crest autograft are the easy accessibility, the robust combination of osteogenic, osteoinductive, and osteoconductive properties, and the resultant efficacy. However, autograft iliac crest bone graft has fallen out of favor in spinal fusion operations due to the morbidity associated with harvest. Various bone graft substitutes have become commercially available that provide similar fusion rates when compared to iliac crest autograft. None of the bone graft substitutes can match iliac crest bone graft in all 3 osteogenic, osteoinductive, and osteoconductive parameters, but when combined with local autologous laminectomy bone and, therefore, used as a bone graft extender, may very well come close. This article reviews the main categories of bone graft substitutes and extenders and the role of these substances when combined with local autologous laminectomy bone in posterolateral lumbar instrumented fusion operations.     

Bone substitutes: new concepts

Summary The filling of bone defects resulting from trauma or surgical resections of tumors requires bone grafts or bone substitutes. Bone substitute must be biocompatible, osteoconductive, and must present good mechanical properties. Among biomaterials classicaly used, calcium phosphate ceramic appear to be suitable alternatives to bone grafts. Calcium phosphate are known able to promote new bone formation on contact and have been already used for the repair of periodontal defects, orthopaedic and maxillofacial applications. However, if these ceramics possess osteoconductive characteristics, they do not have no intrinsic osteinductive capability. They were unable to induce new bone formation in extraosseous site. Therefore they are inadapted to fill large bone defects or lesions, especially since they have little contact with bone. Thus, clinical applications may have to be restricted. Two main concepts have been envisaged to develop bone substitutes with osteogenic capacity. The first concern the combination of biomaterials with osteoprogenitors. These osteoprogenitors can be obtained from total bone marrow, mononuclear cell fraction of bone marrow, clone of bone marrow osteoblastic progenitors or bone explants. The second concept concern the association of biomaterials with osteogenic factors or plasmid DNA to develop a drug delivery system. Thus, growth hormone, transforming growth factor, bone morphogentetic protein, antibiotics, anti-cancer drugs or antiosteoporotic agents have been used to improve the osteoinduction of calcium phosphate ceramic. These types of new hybrid material appear as materials of the future.     

Bone substitutes: an update

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.     

Thiol-ene Hydrogels for Local Delivery of PTH for Bone Regeneration in Critical Size defects

Neither allograft nor commercially available bone graft substitutes provide the same quality of bone healing as autograft. Incorporation of bioactive molecules like parathyroid hormone (PTH) within bone graft substitute materials may provide similar, if not better treatment options to grafting. The goal of this work was to develop a biomaterial system for the local delivery of PTH to large bone defects for promoting bone regeneration. PTH was loaded in a thiol-ene hydrogel at several concentrations and polymerized in and around an osteoconductive poly(propylene fumarate) (PPF) scaffold. PTH was shown to be bioactive when released from the hydrogel for up to 21 days. Eighty percent of the PTH was released by day 3 with the remaining 20% released by day 14. Bone healing was quantified in rat critical size femoral defects that were treated with hydrogel/PPF and 0, 1, 3, 10, or 30 µg of PTH. Although complete osseous healing was not observed in all samples in any one treatment group, all samples in the 10 µg PTH group were bridged fully by bone or a combination of bone and cartilage containing hypertrophic chondrocytes and endochondral ossification. Outcome measures indicated improved defect bridging by a combination of bony and cartilaginous tissue in the 10 μg treatment group compared with empty bone defects and defects treated with only hydrogel/PPF (i.e., without PTH). Given the tailorability of the hydrogel, future studies will investigate the effects of prolonged gradual PTH release on bone healing. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:536–544, 2020     

Zellbasierte Therapie der Femurkopfnekrose

The goal of the therapy for necrosis of the femoral head in adults is the preservation of the femoral head and, therefore, avoidance of total joint replacement. Core decompression is known to reduce the intraosseous pressure and additionally provides the opportunity to introduce bioactive materials, substances and cells into the core tract. These include vascularized and non-vascularized bone grafts, allogenic and synthetic bone substitutes, osteogenic and angiogenic growth factors, as well as different progenitor cells. In particular, the use of cell-based strategies has great therapeutic potential and could play an important role in the treatment of femoral head necrosis in adults in the future. In this article, we summarize the existing clinical experience of current cell-based strategies for the treatment of femoral head necrosis in adults, and present a therapeutic approach using bone marrow stem cells (TRCs: tissue repair cells). in combination with a beta-TCP matrix.     

Major bone defect treatment with an osteoconductive bone substitute

A bone defect can be provoked by several pathological conditions (e.g. bone tumours, infections, major trauma with bone stock loss) or by surgical procedures, required for the appropriate treatment. Surgical techniques currently used for treating bone defects may count on different alternatives, including autologous vascularized bone grafts, homologous bone graft provided by musculoskeletal tissue bank, heterologous bone graft (xenograft), or prostheses, each one of them dealing with both specific advantages and complications and drawbacks. The main concerns related to these techniques respectively are: donor site morbidity and limited available amount; possible immune response and viral transmission; possible animal-derived pathogen transmission and risk of immunogenic rejection; high invasiveness and surgery-related systemic risks, long post-operative. physical recovery and prostheses revision need. Nowadays, an ideal alternative is the use of osteoconductive synthetic bone substitutes. Many synthetic substitutes are available, used either alone or in combination with other bone graft. Synthetic bone graft materials available as alternatives to autogeneous bone include calcium sulphates, special glass ceramics (bioactive glasses) and calcium phosphates (calcium hydroxyapatite, HA; tricalcium phosphate, TCP; and biphasic calcium phosphate, BCP). These materials differ in composition and physical properties fro each other and from bone (De Groot in Bioceramics of calcium phosphate, pp 100–114, 1983; Hench in J Am Ceram Soc 74:1487–1510, 1994; Jarcho in Clin Orthop 157:259–278, 1981; Daculsi et al. in Int Rev Cytol 172:129–191, 1996). Both stoichiometric and non-stoichiometric HA-based substitutes represent the current first choice in orthopedic surgery, in that they provide an osteoconductive scaffold to which chemotactic, circulating proteins and cells (e.g. mesenchymal stem cells, osteoinductive growth factors) can migrate and adhere, and within which progenitor cells can differentiate into functioning osteoblasts (Szpalski and Gunzburg in Orthopedics 25S:601–609, 2002). Indeed, HA may be extemporarily combined either with whole autologous bone marrow or PRP (platelet rich plasma) gel inside surgical theatre in order to favour and accelerate bone regeneration. A case of bifocal ulnar bone defect treated with stoichiometric HA-based bone substitute combined with PRP is reported in here, with a 12-month-radiographic follow-up.     

Coral grafting supplemented with bone marrow.

Limited success in regenerating large bone defects has been achieved by bridging them with osteoconductive materials. These substitutes lack the osteogenic and osteoinductive properties of bone autograft. A direct approach would be to stimulate osteogenesis in these biomaterials by the addition of fresh bone-marrow cells (BMC). We therefore created osteoperiosteal gaps 2 cm wide in the ulna of adult rabbits and either bridged them with coral alone (CC), coral supplemented with BMC, or left them empty. Coral was chosen as a scaffold because of its good biocompatibility and resorbability. In osteoperiosteal gaps bridged with coral only, the coral was invaded chiefly by fibrous tissue. It was insufficient to produce union after two months. In defects filled with coral and BMC an increase in osteogenesis was observed and the bone surface area was significantly higher compared with defects filled with coral alone. Bony union occurred in six out of six defects filled with coral and BMC after two months. An increase in the resorption of coral was also observed, suggesting that resorbing cells or their progenitors were present in bone marrow and survived the grafting procedure. Our findings have shown that supplementation of coral with BMC increased both the resorption of material and osteogenesis in defects of a clinical significance.     

Spinal Fusion of an Unstable Atlantoaxial Fracture in a Completely Tetraplegic Patient Using Silicate-Substituted Calcium Phosphate

Bone graft harvesting from the iliac crest constitutes the gold standard in spinal surgery due to its osteogenic, osteoconductive and osteoinductive properties. Large amounts of autograft can provoke complications like donor site morbidity, pain and the need for a second operation. Therefore, research into bone graft substitutes is of great interest. Silicate-substituted calcium phosphate (Actifuse^TM Synthetic Bone Graft, ApaTech Ltd, London) was used in combination with morselized corticocancellous graft in a transarticular stabilization (modified Magerl) of a completely tetraplegic patient with an unstable atlantoaxial fracture. Computed tomography showed bone bridging between the segment C1/C2, the surface of the implant and the remodeled bone at follow-up at 8 months. The use of silicate-substituted calcium phosphate as a bone graft extender in spinal surgery could be an alternative to autografting from the iliac crest. Vegetative symptoms are often underestimated but can be triggered by donor site morbidity or pain in patients after spinal cord injury.     

Ingénierie tissulaire et maladies du squelette

Tissue engineering, a cross between the science of living organism and that of engineering, aims to replace, maintain or improve human tissue functions, by means of tissue substitutes containing living elements. Thus, it is about production of artificial tissue, using (alone or in combination) cells, matrix or bioactive factors. Their association gives rise to a hybrid biomaterial combining biological components (cells, growth factors or adhesion proteins) and materials (polymers, ceramics). The applications are wide-ranging, from the skin to the liver, or to the cornea as well as to the locomotor system. Bone tissue engineering has advanced the most in this field, partly because of the progress made by research into bone substitutes, although cartilage and tendons are also concerned. This technology requires cell culture (committed cells or more often bone marrow stem cells), biomaterials (porous materials with controlled architecture and cements), growth factors (such as « Bone Morphogenetic Proteins »), the proteins implicated in cell adhesion (such as fibronectin or the aminoacid sequences specifically recognised by integrin sub-units) or gene therapy (notably using transfected stem cells). Tissue engineering and regenerative stimulation of tissue are now booming on experimental and industrial levels and clinical applications are increasingly numerous. Considering the potential of these technologies, they should continue to develop widely.     

Cellular strategies in bone tissue engineering: a review

The objective of bone tissue engineering is to reconstruct bone stock using matrix structures, osteoinductor factors and osteogenic cells. Different types of natural or synthetic biomaterials are available or under development. The objective of recent work is to optimize matrix materials, particularly with better cell adhesion to the surface and better osteoconduction. For osteoinductors, most research is currently focused on bone morphogenetic protein (BMP) and angiogenic factors such as vascular endothelial growth factor (VEGF). Concerning the nature of the cells to be implanted, there is a clear dissociation between fundamental and clinical studies. Many clinical studies have demonstrated the strong osteogenic potential of fresh harvested total bone marrow. There has been nevertheless little fundamental work on the use of total bone marrow as a source of cells for bone tissue engineering. Most of the fundamental work has been focused on the use of mesenchymatous stromal cells selected from bone marrow and cultivated ex vivo. This approach which was first developed more than fifteen years ago has shown that the adjunction of these cells can improve the osteoformative capacity of bone substitutes. This strategy has, however, had almost no clinical impact to date since only two studies involving four patients have been reported. The purpose of this article is to review current research concerning bone tissue engineering using total bone marrow and mesenchymatous stromal cells.