Bone grafts,bone substitutes and orthobiologics: The bridge between basic science and clinical advancements in fracture healing

The biology of fracture healing is better understood than ever before, with advancements such as the locking screw leading to more predictable and less eventful osseous healing. However, at times one’s intrinsic biological response, and even concurrent surgical stabilization, is inadequate. In hopes of facilitating osseous union, bone grafts, bone substitutes and orthobiologics are being relied on more than ever before. The osteoinductive, osteoconductive and osteogenic properties of these substrates have been elucidated in the basic science literature and validated in clinical orthopaedic practice. Furthermore, an industry built around these items is more successful and in demand than ever before. This review provides a comprehensive overview of the basic science, clinical utility and economics of bone grafts, bone substitutes and orthobiologics.     

Free bone graft reconstruction of irradiated facial tissue: experimental effects of basic fibroblast growth factor stimulation

A study was undertaken to evaluate the potential utility of basic fibroblast growth factor in the induction of angiogenesis and osseous healing in bone previously exposed to high doses of irradiation. Thirty New Zealand rabbits were evaluated by introducing basic fibroblast growth factor into irradiated mandibular resection sites either prior to or simultaneous with reconstruction by corticocancellous autografts harvested from the ilium. The fate of the free bone grafts was then evaluated at 90 days postoperatively by microangiographic, histologic, and fluorochrome bone-labeling techniques. Sequestration, necrosis, and failure to heal to recipient osseous margins was observed both clinically and histologically in all nontreated irradiated graft sites as well as those receiving simultaneous angiogenic stimulation at the time of graft placement. No fluorescent activity was seen in these graft groups. In the recipient sites pretreated with basic fibroblast growth factor prior to placement of the graft, healing and reestablishment of mandibular contour occurred in nearly 50 percent of the animals. Active bone formation was evident at cortical margins adjacent to the recipient sites but was absent in the more central cancellous regions of the grafts.     

Tissue engineering of bone: the reconstructive surgeon's point of view

Bone defects represent a medical and socioeconomic challenge. Different types of biomaterials are applied for reconstructive indications and receive rising interest. However, autologous bone grafts are still considered as the gold standard for reconstruction of extended bone defects. The generation of bioartificial bone tissues may help to overcome the problems related to donor site morbidity and size limitations. Tissue engineering is, according to its historic definition, an "interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function". It is based on the understanding of tissue formation and regeneration and aims to rather grow new functional tissues than to build new spare parts. While reconstruction of small to moderate sized bone defects using engineered bone tissues is technically feasible, and some of the currently developed concepts may represent alternatives to autologous bone grafts for certain clinical conditions, the reconstruction of large-volume defects remains challenging. Therefore vascularization concepts gain on interest and the combination of tissue engineering approaches with flap prefabrication techniques may eventually allow application of bone-tissue substitutes grown in vivo with the advantage of minimal donor site morbidity as compared to conventional vascularized bone grafts. The scope of this review is the introduction of basic principles and different components of engineered bioartificial bone tissues with a strong focus on clinical applications in reconstructive surgery. Concepts for the induction of axial vascularization in engineered bone tissues as well as potential clinical applications are discussed in detail.     

Comparison of frozen and freeze-dried particulate bone allografts

Freeze-dried and frozen particulate bone allografts are used interchangeably on the assumption that the biologic behavior of these grafts is similar. Dissimilarities in biologic behavior and differences in the rate and extent of bone incorporation of freeze-dried and frozen particulate grafts were demonstrated in a comparative study using a non-human primate model. Freeze-dried particulate allografts induced new bone formation and healing of the osseous defects much faster than the frozen allografts.     

Very long-term radiographic and bone scan results of frozen autograft and allograft bone grafting in 17 patients (20 grafts) a 30- to 35-year follow-up

In the early 1950s, 48 patients received bone implants from a bone bank in Tel-Hashomer Hospital that stored frozen autograft and allograft bones at temperatures less than -17 degrees C. Seventeen (35%) of these patients (20 implants), 10 men and 7 women, with a mean age of 52.4 (34-69) years were available for follow-up after a mean period of 32.5 (30-35) years. They underwent clinical examination, radiographs and bone scans to evaluate their surgical results. Fracture healing, non-union, graft resorption, osteoporosis and bone sclerosis were used as radiographic criteria for bone incorporation, and normal, increased and decreased uptake served to assess the bone scan. Based on the above criteria, the results were satisfactory in 17 (85%) and poor in 3 (15%). The three failures were after shelf operation for hip dysplasia that used two allografts and one autograft. Allogenous or a combination of allogenous with autogenous frozen bone grafts proved to be a satisfactory and durable method for filling bone defects.     

Fresh frozen homologous bone in oral surgery: case reports

Intraoral bone defects may be treated using autologous grafts, homologous grafts, heterologous grafts or synthetic products. Autologous bone is now considered the gold standard for bone grafting procedures. Homologous fresh frozen bone, provided by bone banks, is frequently utilized by orthopaedic surgeons because it is considered a safe material from immunological and viral points of view.In the cases reported here, homologous bone was used to repair some osseous defects without changing the surgical protocol utilized for autologous bone procedures. The main advantages of this strategy are low morbidity, shorter surgical times, more comfort and less risk of infection for the patient as well as the greater availability of bone.     

Orthobiologics in the treatment of hip disorders

Orthobiologics are biological materials that are intended for the regeneration or healing of bone,cartilage and soft tissues.In this review we discuss the use of orthobiologics for hip disorders providing an update.The orthobiologics included in this article are hyaluronic acid,platelet rich plasma,bone marrow,adipose tissue and expanded mesenchymal stem cells.We explain the concepts and definitions of each orthobiological product,and the literature regarding its use in the hip joint.The paucity of guidelines for the production and characterization of the biological products leads to uneven results across the literature.Each biologic therapy has indications and benefits;however,noteworthy are the characterization of the orthobiologics,the application method and outcome analysis for further improvement of each technique.     

Therapeutic effects of electromagnetic fields in the stimulation of connective tissue repair

The therapeutic effects of electric and magnetic fields have been studied largely for their promotion of connective tissue repair. The most widely studied application concerns bone repair and deals with acceleration of the healing of fresh fractures, delayed and non-unions, incorporation of bone grafts, osteoporosis, and osteonecrosis. More recently the effects of these fields upon the repair of cartilage and soft fibrous tissues have been described. In all these experimental systems and clinical applications an acceleration of extracellular matrix synthesis and tissue healing has been observed. A degree of specificity, in terms of the parameters of applied energy and biological response, is hypothesized.     

Bone regeneration at the expense of Bioceramic/Hydrogel composite: Clinical evidence

It is often necessary to restore bone structure following the loss of osseous substance. Therefore, the use of bone substitutes made of synthetic calcium phosphate (CaP) ceramics has become more widespread. Granular forms of these biomaterials have demonstrated osteogenic capacities within various sites. Recently, a combination of CaP microporous granules and hydrosoluble polymers was developed (In’Oss?). This composite material is non-self-hardening, injectable, and moldable. The purpose of this non-interventional clinical study was to demonstrate the safety and efficacy of these bioceramic/hydrogel bone substitutes in bone regeneration following maxillofacial surgery. In’Oss? biomaterial was injected into bone defects created by tooth removal in 78 patients. Notably, no infectious or foreign body reactions were reported during at least 17 months of follow up for the study. Regeneration of bone architecture was observed by histomorphometry.     

Taking cues from the extracellular matrix to design bone-mimetic regenerative scaffolds

There is an ongoing need for effective materials that can replace autologous bone grafts in the clinical treatment of bone injuries and deficiencies. In recent years, research efforts have shifted away from a focus on inert biomaterials to favor scaffolds that mimic the biochemistry and structure of the native bone extracellular matrix (ECM). The expectation is that such scaffolds will integrate with host tissue and actively promote osseous healing. To further enhance the osteoinductivity of bone graft substitutes, ECM-mimetic scaffolds are being engineered with a range of growth factors (GFs). The technologies used to generate GF-modified scaffolds are often inspired by natural processes that regulate the association between endogenous ECMs and GFs. The purpose of this review is to summarize research centered on the development of regenerative scaffolds that replicate the fundamental collagen-hydroxyapatite structure of native bone ECM, and the functionalization of these scaffolds with GFs that stimulate critical events in osteogenesis.     

Spatial and temporal patterns of bone formation in ectopically pre-fabricated, autologous cell-based engineered bone flaps in rabbits

Biological substitutes for autologous bone flaps could be generated by combining flap pre-fabrication and bone tissue engineering concepts. Here, we investigated the pattern of neotissue formation within large pre-fabricated engineered bone flaps in rabbits. Bone marrow stromal cells from 12 New Zealand White rabbits were expanded and uniformly seeded in porous hydroxyapatite scaffolds (tapered cylinders, 10-20 mm diameter, 30 mm height) using a perfusion bioreactor. Autologous cell-scaffold constructs were wrapped in a panniculus carnosus flap, covered by a semipermeable membrane and ectopically implanted. Histological analysis, substantiated by magnetic resonance imaging (MRI) and micro-computerized tomography scans, indicated three distinct zones: an outer one, including bone tissue; a middle zone, formed by fibrous connective tissue; and a central zone, essentially necrotic. The depths of connective tissue and of bone ingrowth were consistent at different construct diameters and significantly increased from respectively 3.1 +/- 0.7 mm and 1.0 +/- 0.4 mm at 8 weeks to 3.7+/- 0.6 mm and 1.4 +/- 0.6 mm at 12 weeks. Bone formation was found at a maximum depth of 1.8 mm after 12 weeks. Our findings indicate the feasibility of ectopic pre-fabrication of large cell-based engineered bone flaps and prompt for the implementation of strategies to improve construct vascularization, in order to possibly accelerate bone formation towards the core of the grafts.     

Tissue engineering of cultured skin substitutes

Skin replacement has been a challenging task for surgeons ever since the introduction of skin grafts by Reverdin in 1871. Recently, skin grafting has evolved from the initial autograft and allograft preparations to biosynthetic and tissue-engineered living skin replacements. This has been fostered by the dramatically improved survival rates of major burns where the availability of autologous normal skin for grafting has become one of the limiting factors. The ideal properties of a temporary and a permanent skin substitute have been well defined. Tissue-engineered skin replacements: cultured autologous keratinocyte grafts, cultured allogeneic keratinocyte grafts, autologous/allogeneic composites, acellular biological matrices, and cellular matrices including such biological substances as fibrin sealant and various types of collagen, hyaluronic acid etc. have opened new horizons to deal with such massive skin loss. In extensive burns it has been shown that skin substitution with cultured grafts can be a life-saving measure where few alternatives exist. Future research will aim to create skin substitutes with cultured epidermis that under appropriate circumstances may provide a wound cover that could be just as durable and esthetically acceptable as conventional split-thickness skin grafts. Genetic manipulation may in addition enhance the performance of such cultured skin substitutes. If cell science, molecular biology, genetic engineering, material science and clinical expertise join their efforts to develop optimized cell culture techniques and synthetic or biological matrices then further technical advances might well lead to the production of almost skin like new tissue-engineered human skin products resembling natural human skin.     

Segmental bone replacement via patient‐specific,three‐dimensional printed bioresorbable graft substitutes and their use as templates for the culture of mesenchymal stem cells under mechanical stimulation at various frequencies

The treatment of large segmental bone defects remains a challenge as infection, delayed union, and nonunion are common postoperative complications. A three‐dimensional printed bioresorbable and physiologically load‐sustaining graft substitute was developed to mimic native bone tissue for segmental bone repair. Fabricated from polylactic acid, this graft substitute is novel as it is readily customizable to accommodate the particular size and location of the segmental bone of the patient to be replaced. Inspired by the structure of the native bone tissue, the graft substitute exhibits a gradient in porosity and pore size in the radial direction and exhibit mechanical properties similar to those of the native bone tissue. The graft substitute can serve as a template for tissue constructs via seeding with stem cells. The biocompatibility of such templates was tested under in vitro conditions using a dynamic culture of human mesenchymal stem cells. The effects of the mechanical loading of cell‐seeded templates under in vitro conditions were assessed via subjecting the tissue constructs to 28 days of daily mechanical stimulation. The frequency of loading was found to have a significant effect on the rate of mineralization, as the alkaline phosphatase activity and calcium deposition were determined to be particularly high at the typical walking frequency of 2 Hz, suggesting that mechanical stimulation plays a significant role in facilitating the healing process of bone defects. Utilization of such patient‐specific and biocompatible graft substitutes, coupled with patient’s bone marrow cells seeded and exposed to mechanical stimulation of 2 Hz have the potential of reducing significant volumes of cadaveric tissue required, improving long‐term graft stability and incorporation, and alleviating financial burdens associated with delayed or failed fusions of long bone defects.     

MACROSCOPIC, MICROSCOPIC, AND MECHANICAL ANALYSES OF PROTOTYPE DOUBLE VELOUR VASCULAR GRAFTS

In-vivo and ex-vivo evaluations of two prototype double velour tube grafts have been conducted. The experimental grafts were fabricated from terry cloth derivatives of the Dacron polyester material that is used in the construction of presently available Microvel(R) Double Velour and Cooley Double Velour Guideline(R) grafts.(*) The use of terry cloth derivatives in the experimental grafts provides a velour pile that is more uniform in height and density than current clinical grafts. The hypothesis examined by these studies was whether the utilization of terry cloth derivatives provides a more perfect capsular and luminal surface for fibrous tissue attachment and ingrowth, thereby enhancing neointimal formation at the blood contacting surface. Using standard techniques, prototype grafts were implanted in the abdominal aortas of dogs for test periods of 1 to 6 months. All grafts remained patent throughout the healing period. At explantation, the macroscopic and microscopic properties of the grafts were examined and characterized. Neointimal analysis demonstrated that the lighter denier, higher porosity prototype consistently produced more homogeneous blood-contacting surfaces with smoother contours and more complete endothelialization than the heavier denier, lower porosity prototype. From these analyses, we can conclude that both prototype grafts possess the basic properties of useful arterial prostheses. They are not prone to early thrombosis, and exhibit rapid healing properties. This study indicates that the use of terry cloth derivatives provides a more uniform, less random velour pile and that arterial grafts constructed from such materials produce more uniform and biologically stable neointimas.     

Reconstruction of mandibular defects with revascularized free rib grafts.

Two cases of hemimandibular reconstructions with revascularized free rib grafts are presented. The viability of the transplants was confirmed by bone scans and biopsy, even though the main nutrient vessels providing the intramedullary blood flow were not included in these grafts (and only the periosteal circulation was utilized). The removal of a rib graft without the nutrient vessel eliminates the need for a complicated posterior dissection, close to the costovertebral joint. Revascularized free bone grafts have a greater chance of survival, provide more rapid healing, offer less risk of absorption, and are more resistant to infection than conventional bone grafts.     

Validation of Bone Conversion in Osteoconductive and Osteoinductive Bone Substitutes

Bone reconstruction can be performed with an autogeneic graft from various donor regions. Osteoconductive and osteoinductive bone substitutes originate from substances of diverse chemical and morphological types and can have a synthetic or a biological derivation. Alongside autogeneic bone transplants and allogenic and xenogeneic bone implants, alloplastic bone replacements of synthetic or semi-synthetic origin are being used for defect reconstruction. In an animal model in rabbits five bone substitutes and one autogeneic graft were surgically incorporated into identical bone defects (10times 10 mm in size) in six anatomically defined regions of the skull. With scintigraphic and histological methods, the metabolic dynamics of the bone is examined as it reacts to the transplantation of autogeneic bone or to implanted bone replacement material. The different autogeneic, xenogeneic and alloplastic bone replacement materials can be differentiated according to the functional quality of the new tissue and the dynamics of the bone conversion thus induced. In the comparison of mineralized, osteoconductive bone subsitutes (TCP, HA, calcium carbonate ceramics) with demineralized, osteoinductive implants (DBM new, DBM old) and autogeneic bone grafts, the bone inducing matrices show the largest quantity of new bone formation, making possible a volume-constant reconstruction. This revised version was published online in July 2006 with corrections to the Cover Date.     

椎间植骨粒体积对腰椎滑脱融合内固定术融合效果的影响

目的:探讨在腰椎后路植骨融合手术中,椎间植骨粒的体积对手术效果的影响。方法:回顾性分析我院2012年5月-2013年9月采用腰椎后路植骨融合术的75例患者的临床资料,根据患者手术中椎间植骨粒体积不同分为A组(小体积组,5粒/cm3)、B组(中体积组,11粒/cm3)以及C组(大体积组,23粒/cm3)。分析三组患者的植骨粒体积、植骨融合率以及手术效果。结果:三组患者植骨粒体积比较,差异具有统计学意义(P0.05);椎间植骨总体积比较,差异无统计学意义(P0.05)。与术前比较,三组术后ODI指数及VAS评分明显下降,差异具有统计学意义(P0.05);但三组间比较,差异无统计学意义(P0.05)。B组植骨融合率高于A组及C组,而A组高于C组,组间比较,差异均具有统计学意义(P0.05)。手术后各组椎体滑脱程度与术前相比得到明显改善(P0.05)。结论:腰椎滑脱内固定术中应用中等体积植骨粒可明显提高椎体间融合率。     

Treatment of peri-implantitis with deproteinised bovine bone and tetracycline: a case report

doi: 10.1111/j.1741‐2358.2011.00470.x
Treatment of peri‐implantitis with deproteinised bovine bone and tetracycline: a case report Objective: The objective of this study is to evaluate the use of tetracycline in a patient with peri‐implantitis. Background: Tetracycline is widely used in regeneration procedures owing to its positive effect with bone graft material, regeneration of extraction socket bone and its traditional antibacterial effect. However, there have been limited reports on bone graft procedures combined with tetracycline application in peri‐implantitis. Materials and methods: The detoxification procedure was performed with chlorhexidine and tetracycline, and the defect area was grafted with a 4:1 volume ratio combination of deproteinised bovine bone mixed with tetracycline. Results: Soft tissue healing was uneventful, and the treatment yielded improved clinical results with a reduced probing depth. Conclusions: Tetracycline was used in the treatment of peri‐implantitis by burnishing the implant surface and applying tetracycline in conjunction with an osseous graft to the defect area. The treatment of peri‐implantitis with tetracycline seemed to show improved clinical results up to the follow‐up period.     

Segmental bone defects: from cellular and molecular pathways to the development of novel biological treatments

Several conditions in clinical orthopaedic practice can lead to the development of a diaphyseal segmental bone defect, which cannot heal without intervention. Segmental bone defects have been traditionally treated with bone grafting and/or distraction osteogenesis, methods that have many advantages, but also major drawbacks, such as limited availability, risk of disease transmission and prolonged treatment. In order to overcome such limitations, biological treatments have been developed based on specific pathways of bone physiology and healing. Bone tissue engineering is a dynamic field of research, combining osteogenic cells, osteoinductive factors, such as bone morphogenetic proteins, and scaffolds with osteoconductive and osteoinductive attributes, to produce constructs that could be used as bone graft substitutes for the treatment of segmental bone defects. Scaffolds are usually made of ceramic or polymeric biomaterials, or combinations of both in composite materials. The purpose of the present review is to discuss in detail the molecular and cellular basis for the development of bone tissue engineering constructs.     

强骨胶囊对老年股骨头近段骨折延迟愈合患者血清BMP-2 及IGF-1水平的影响

目的:探究强骨胶囊对老年股骨头近段骨折延迟愈合患者血清骨形态发生蛋白-2(BMP-2)及胰岛素生长因子-1(IGF-1)水平的影响。方法:选择我院收治的股骨近端骨折延迟愈合的老年患者41例,随机分为实验组及对照组。对照组19例予钙片;实验组22例予强骨胶囊。对比两组的临床疗效及治疗前后血清BMP-2及IGF-1水平的改变。结果:实验组总有效率(95.5%)高于对照组(78.9%),差异具备统计学意义(P0.05)。两组血清BMP-2及IGF-1水平均较治疗前显著升高(P0.05),且实验组血清BMP-2和IGF-1水平较对照组高(P0.05)。治疗后,两组血浆粘度均下降、骨密度值(BMD)均升高(P0.05);与对照组相较,实验组血浆粘度降低、BMD较高(P0.05)。结论:强骨胶囊能够有效改善老年股骨头近段骨折延迟愈合,促进骨折断端的愈合,推测其机制与增加患者血清BMP-2及IGF-1水平有关。