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.     

Bone grafts,bone substitutes and orthobiologics

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.     

Platelet-rich plasma vs bone marrow aspirate concentrate: An overview of mechanisms of action and orthobiologic synergistic effects

The use of orthobiologics as a novel therapy for the treatment of numerous musculoskeletal disorders has increased considerably over the past decade.Currently,there are multiple alternatives available as suitable treatments;however,the use of autologous blood-derived products such as platelet-rich plasma(PRP),bone marrow aspirate(BMA)and BMA concentrate(BMAC),specifically,is expanding.Although many investigations attempted to demonstrate the effectiveness of these therapies,even with positive results,the literature lacks standardized protocols and overall accuracy in study designs,which leads to variance and difficulty in reproducibility of protocols.The efficacy of PRP for the treatment of cartilage,bone and muscle tissues is well known.Although BMAC has generated optimistic results for the same purposes,its applicability in clinical trials is still relatively recent when compared to PRP.Both products demonstrate the potential to set forth reparative processes,each in their own distinct mechanism.The combination of these biological products has been previously proposed,yet little is known about their synergism.Evidence indicates that growth factor,cytokine,and chemokine profiles seen in both PRP and BMAC vary but are likely to work synergistically to enhance musculoskeletal healing.BMAC products seem to work well without PRP;however,the addition of PRP to BMAC has been shown to act as a rich and natural source of culture medium for stem cells located either peripherally or in the bone marrow itself.Nevertheless,additional variables associated with the use of BMAC and PRP in orthopedics must be further evaluated in order to consolidate the efficacy of this therapeutic strategy.     

A novel surgical procedure for bridging of massive bone defects

BACKGROUND: Bony defects arising from tumor resection or debridement after infection, non-union or trauma present a challenging problem to orthopedic surgeons, as well as patients due to compliance issues. Current treatment options are time intensive, require more than one operation and are associated with high rate of complications. For this reason, we developed a new surgical procedure to bridge a massive long bone defect. METHODS: To bridge the gap, an in situ periosteal sleeve is elevated circumferentially off of healthy diaphyseal bone adjacent to the bone defect. Then, the adjacent bone is osteotomized and the transport segment is moved along an intramedullary nail, out of the periosteal sleeve and into the original diaphyseal defect, where it is docked. Vascularity is maintained through retention of the soft tissue attachments to the in situ periosteal sleeve. In addition, periosteal osteogenesis can be augmented through utilization of cancellous bone graft or in situ cortical bone adherent to the periosteal sleeve. RESULTS: The proposed procedure is novel in that it exploits the osteogenic potential of the periosteum by replacing the defect arising from resection of tissue out of a pathological area with a defect in a healthy area of tissue, through transport of the adjacent bone segment. Furthermore, the proposed procedure has several advantages over the current standard of care including ease of implementation, rapid patient mobilization, and no need for specialized implants (intramedullary nails are standard inventory for surgical oncology and trauma departments) or costly orthobiologics. CONCLUSIONS: The proposed procedure offers a viable and potentially preferable alternative to the current standard treatment modalities, particularly in areas of the world where few surgeons are trained for procedures such as distraction osteogenesis (e.g. the Ilizarov procedure) as well as areas of the world where surgeons have little access to expensive, complex devices and orthobiologics.     

Evaluation of biological protein-based collagen scaffolds in cartilage and musculoskeletal tissue engineering--a systematic review of the literature

The term tissue engineering is the technology that combines cells, engineering and biological/synthetic material in order to repair, replace or regenerate biological tissues such as bone, muscle, tendons and cartilage. The major human applications of tissue engineering are: skin, bone, cartilage, corneas, blood vessels, left mainstem bronchus and urinary structures. In this systematic review several criteria were identified as the most desirable characteristics of an ideal scaffold. These state that an ideal scaffolds needs to be biodegradable, possess mechanical strength, be highly porous, biocompatible, non-cytotoxic, non antigentic, stuitable for cell attachment, proliferation and differentiation, flexible and elastic, three dimensional, osteoconductive and support the transport of nutrients and metabolic waste. Subsequently, studies reporting on the various advantages and disadvantages of using collagen based scaffolds in musculoskeletal and cartilage tissue engineering were identified. The purpose of this review is to 1) provide a list of ideal characteristics of a scaffold as identified in the literature 2) identify different types of biological protein-based collagen scaffolds used in musculoskeletal and cartilage tissue engineering 3) assess how many of the criteria each scaffold type meets 4) weigh different scaffolds against each other according to their relative properties and shortcomings. The rationale behind this approach is that the ideal scaffold material has not yet been identified. Hence, this review will define how many of the identified ideal characteristics are fulfilled by natural collagen-based scaffolds and address the shortcomings of its use as found in the literature.     

Bone density and risk of hip fracture in men and women: cross sectional analysis.

OBJECTIVE: To determine the relative contribution of decline in bone density to the increase in risk of hip fracture with age in men and women. DESIGN: Incidence data of hip fracture from the general population were combined with the bone density distribution in a sample from the same population and with a risk estimate of low bone density known from literature. SETTING: The Netherlands. SUBJECTS: All people with a hospital admission for a hip fracture in 1993, and bone density measured in a sample of 581.4 men and women aged 55 years and over in a district of Rotterdam. MAIN OUTCOME MEASURE: One year cumulative risk of hip fracture by age, sex, and bone density measured at the femoral neck. RESULTS: A quarter of all hip fractures occurred in men. Men reached the same incidence as women at five years older. Controlled for age, the risk of hip fracture by bone density was similar in men and women. The risk of hip fracture increased 13-fold from age 60 to 80; decrease in bone density associated with age contributed 1.9 (95% confidence interval 1.5 to 2.4) in women and 1.6 (1.3 to 1.8) in men. CONCLUSIONS: The risk of hip fracture by age and bone density is similar in men and women. The decrease in bone density associated with age makes a limited contribution to the exponential increase of the risk of hip fracture with age.     

骨水泥型与生物型髋关节置换术治疗股骨颈骨折对术后关节疼痛的影响

目的:探讨骨水泥型与生物型髋关节置换术治疗股骨颈骨折对术后患者关节疼痛的影响。方法:回顾性分析2012年2月-2013年8月我院收治的股骨颈骨折患者的临床病历资料,按照假体类型将其分为骨水泥型髋关节置换术(A组)和生物型髋关节置换术(B组),通过Harris与分项百分制髋关节疼痛评分比较两组患者术后髋关节的疼痛情况。结果:两组患者的手术时间、术中出血量以及术后引流量比较,差异无统计学意义(P0.05),A组的住院时间短于B组,差异有统计学意义(P0.05)。A组术后3、6个月的髋关节疼痛率均低于B组,术后12、24个月则高于B组,差异有统计学意义(P0.05);经x2趋势分析,A组患者术后髋关节疼痛率随时间增加呈逐渐上升趋势,差异有统计学意义(x2=10.837,P=0.001),B组患者术后髋关节疼痛率随时间增加呈逐渐下降趋势,差异有统计学意义(x2=9.842,P=0.002)。A组患者术后3、6个月的髋关节疼痛评分高于B组,术后12、24个月则低于B组,差异有统计学意义(P0.05);A组术后3、6个月的髋关节疼痛评分高于术后12、24个月,B组3、6个月的髋关节疼痛评分低于术后12、24个月,差异有统计学意义(P0.05)。结论:骨水泥型假体缓解髋关节疼痛近期效果优于生物型假体,而生物型假体远期效果优于骨水泥型假体。     

Dietary boron: progress in establishing essential roles in human physiology

This review summarizes the progress made in establishing essential roles for boron in human physiology and assesses that progress in view of criteria for essentiality of elements. The evidence to date suggests that humans and at least some higher animals may use boron to support normal biological functions. These include roles in calcium metabolism, bone growth and maintenance, insulin metabolism, and completion of the life cycle. The biochemical mechanisms responsible for these effects are poorly understood but the nature of boron biochemistry suggests further characterization of the cell signaling molecules capable of complexing with boron. Such characterization may provide insights into the biochemical function(s) of boron in humans.     

Specimen-specific predictions of contact stress under physiological loading in the human hip: validation and sensitivity studies

Hip osteoarthritis may be initiated and advanced by abnormal cartilage contact mechanics, and finite element (FE) modeling provides an approach with the potential to allow the study of this process. Previous FE models of the human hip have been limited by single specimen validation and the use of quasi-linear or linear elastic constitutive models of articular cartilage. The effects of the latter assumptions on model predictions are unknown, partially because data for the instantaneous behavior of healthy human hip cartilage are unavailable. The aims of this study were to develop and validate a series of specimen-specific FE models, to characterize the regional instantaneous response of healthy human hip cartilage in compression, and to assess the effects of material nonlinearity, inhomogeneity and specimen-specific material coefficients on FE predictions of cartilage contact stress and contact area. Five cadaveric specimens underwent experimental loading, cartilage material characterization and specimen-specific FE modeling. Cartilage in the FE models was represented by average neo-Hookean, average Veronda Westmann and specimen- and region-specific Veronda Westmann hyperelastic constitutive models. Experimental measurements and FE predictions compared well for all three cartilage representations, which was reflected in average RMS errors in contact stress of less than 25 %. The instantaneous material behavior of healthy human hip cartilage varied spatially, with stiffer acetabular cartilage than femoral cartilage and stiffer cartilage in lateral regions than in medial regions. The Veronda Westmann constitutive model with average material coefficients accurately predicted peak contact stress, average contact stress, contact area and contact patterns. The use of subject- and region-specific material coefficients did not increase the accuracy of FE model predictions. The neo-Hookean constitutive model underpredicted peak contact stress in areas of high stress. The results of this study support the use of average cartilage material coefficients in predictions of cartilage contact stress and contact area in the normal hip. The regional characterization of cartilage material behavior provides the necessary inputs for future computational studies, to investigate other mechanical parameters that may be correlated with OA and cartilage damage in the human hip. In the future, the results of this study can be applied to subject-specific models to better understand how abnormal hip contact stress and contact area contribute to OA.     

On the optimal shape of hip implants

The success of a total hip arthroplasty is strongly related to the initial stability of the femoral component and to the stress shielding effect. In fact, for cementless stems, initial stability is essential to promote bone ingrowth into the stem coating. An inefficient primary stability is also a cause of thigh pain. In addition, the bone adaptation after the surgery can lead to an excessive bone loss and, consequently, can compromise the success of the implant. These factors depend on prosthesis design, namely on material, interface conditions and shape. Although, surgeons use stems with very different geometries, new computational tools using structural optimization methods have been used to achieve a better design in order to improve initial stability and therefore, the implant durability. In this work, a multi-criteria shape optimization process is developed to study the relationship between implants performance and geometry. The multi-criteria objective function takes into account the initial stability of the femoral stem and the effect of stress shielding on bone adaptation after the surgery. Then, the optimized stems are tested using a concurrent model for bone remodeling and osseointegration to evaluate long-term performance. Additionally, the sensitivity to misalignments is analyzed, since femoral stems are often placed in varus or valgus position. Results show that the different criteria are contradictory resulting in different characteristics for the hip stem. However, the multi-criteria formulation leads to compromise solutions, with a combination of the geometric characteristics obtained for each criterion separately.     

Evaluating a suitable level of model complexity for finite element analysis of the intact acetabulum

To enable large-scale multi-factorial finite element (FE) studies, the FE models used must be as computationally efficient as is feasible, while maintaining a suitable level of definition. The present study seeks to find an optimum level of model complexity for use in such large-scale studies by investigating which model attributes are most influential over the chosen model outputs of principal stress and strain in the intact acetabulum. A multi-factorial sensitivity study was carried out using 128 FE models, representing combinations of the following variables: bone stiffness distribution, imposed muscle loading, boundary condition location, hip joint contact conditions and patient's bone anatomy. The relative sensitivity of each input factor was analysed, and it was concluded that the optimum level of model definition must include CT-dependent trabecular bone properties and a sliding interface at the hip joint. It was found that it was not essential to describe the ligamentous sacroiliac and pubic symphysis joints; these could be rigidly fixed in space; and for the normal walking load case, muscle forces may be neglected. It was also concluded that a variety of bone anatomies should be included in a multi-factorial analysis if results are to be inferred for a wider population.     

A method for visual determination of sex, using the human hip bone

A new visual method for the determination of sex using the human hip bone (os coxae) is proposed, based on a revision of several previous approaches which scored isolated characters of this bone. The efficacy of the methodology is tested on a sample of 402 adults of known sex and age of French and Portuguese origins. With the simultaneous use of five characters of the hip bone, it is possible to provide a correct sexual diagnosis in 95% of all cases, with an error of 2% and an inability to identify sex in only 3%. The advantage of this new method is a reduction in observer subjectivity, since the evaluation procedure cannot involve any anticipation of the result. In addition, this method of sex determination increases the probability of a correct diagnosis with isolated fragments of the hip bone, provided that a combination of elements of one character is found to be typically male or female.     

Experimental method for the in vitro testing of the initial stability of cementless hip prostheses

Micromotions at the interface between bone and prosthesis are believed to induce bone resorption and ultimately lead to loosening of the implant. Thus the initial stability achieved by a hip prosthesis is an important factor for the long-term function of the implant. Knowing the biological consequences of the mechanical conditions, it appears to be mandatory to measure the extent of these three-dimensional movements. An in vitro dynamic method for measurement of the micromotion of the femoral component of hip prostheses has been developed. Tests in cemented prostheses have confirmed that the use of cement reduces sinkage and rotation manyfold and have yielded reference values for stability. Comparison with two types of cementless prostheses has shown that certain cementless implants may achieve stability comparable to cemented ones in some load directions.     

Calcitonin effects on cartilage and fracture healing

The literature about the effects of systemically administered calcitonin on fracture healing and in the prevention of disuse osteoporosis after fracture are reviewed in this study. Fracture healing is a biological process of great importance for the survival of the injured animal. Endochondral ossification is augmented in the fracture site followed by fast remodeling of the produced woven bone. There is strong evidence of the direct effects of calcitonin on cartilage proliferation as well as the vascularization of the callus. Calcitonin is found to promote the cartilaginous phase of fracture healing. On the other hand, the innervation of callus reveals an extensive distribution of sensory fibers containing a calcitonin gene-related peptide, a neuropeptide with potent vasodilatory actions. From several experimental studies, salmon calcitonin administration has been found to have a beneficial effect on fracture healing. Studies in humans also concur that calcitonin may speed up the time of fracture repair and facilitate early mobilization of the injured limb. Finally, calcitonin prevents post-fracture bone loss due to increased post-injury remodeling and lowers hydroxyproline and calcium excretion of patients who underwent internal fixation of fracture on the hip.     

Regeneration of the skeleton by recombinant human bone morphogenetic proteins

Recombinant human bone morphogenetic proteins (rhBMPs) have past a long journey in human orthopaedic surgery during the last 15 years. From the first reports of the use of rhBMPs in hostile environments such as critically-sized bone defects, avascular femoral head necrosis, unstable thoracolumbar vertebral fractures, instability between the atlas and axis due to rheumatoid arthritis; over the use for nonunions of long bones and the scaphoid, reconstructive and revision surgeries of the hip, acute fractures, allograft nonunions, congenital pseudarthrosis, and various approaches of lumbar and cervical spine fusions, rhBMPs overgrow to a safe and reliable device in the treatment of open tibial shaft fractures, nonunions of long bone fractures, anterior lumbar interbody fusion and revision posterolateral lumbar fusions. Systematic review of the published literature of rhBMPs is presented.     

Soluble factors differ in platelets derived from separate niches: a pilot study comparing the secretome of peripheral blood and bone marrow platelets

Background aimsPlatelet-rich plasma (PRP) and bone marrow aspirate are commonly used in orthobiologics for their anti-inflammatory, anabolic/regenerative and immunomodulatory characteristics via platelet degranulation and cell secretions. Although platelets are derived from megakaryocytes in the bone marrow, no attention has been paid to the potential benefits of bone marrow platelets and whether their contents differ from aging platelets in peripheral blood.MethodsIn the present study, leukocyte-poor peripheral blood-derived platelets in plasma (LPP) and leukocyte-poor bone marrow platelets in plasma (BMP) were prepared from six donors, activated with calcium chloride, incubated and sampled at day 0, day 3 and day 6. LPP and BMP are platelet preparations intended to evaluate the respective platelet secretomes but are not classified as conventional PRPs, as they are not concentrated to the extent necessary to meet the qualifying criteria. At each time point, 15 growth and immunomodulatory factors were quantitated in LPP and BMP: platelet-derived growth factor AA, basic fibroblast growth factor/fibroblast growth factor 2, granulocyte-macrophage colony-stimulating factor, hepatocyte growth factor, macrophage colony-stimulating factor, stem cell factor, vascular endothelial growth factor, tumor necrosis factor alpha, IL-1β, interferon gamma, IL-4, IL-10, IL-1 receptor antagonist protein, IL-12p40 and arginase-1.ResultsThe results illustrate that platelets derived from bone marrow have a unique secretome profile compared with those derived from peripheral blood, with significant differences in anti-inflammatory cytokines, which are associated with monocyte polarization.ConclusionsUltimately, bone marrow-derived platelets may be useful as a stand-alone orthobiologic or as an effective adjuvant to autologous cell therapies where anti-inflammatory and anabolic processes are desired, especially with respect to monocyte function.     

α2-HS 糖蛋白基因与中国人群的髋部骨大小的相关性研究

骨大小是一种独立于骨密度（BMD）的骨质疏松性骨折的重要风险因子。由于其高遗传率,充分了解控制骨大小的遗传因素有很重要的临床意义。文章研究目的为检测中国人群中α2-HS糖蛋白基因（AHSG）多态性和腰椎及髋部骨大小变异之间的关联。我们总共征集了来自中国401个核心家庭（包括父母亲及至少一个女儿）的1260个研究样本,并且分型了AHSG基因第7个外显子的Sac Ⅰ位点多态性。该位点核苷酸的替换（C→G）引起第238号丝氨酸被苏氨酸取代,因此可能对基因功能有影响。在任何骨骼位点,没有发现显著的群体分层。发现-HSG基因SacⅠ位点多态性和转子间（P=0．019）以及全髋的（P=0．035）骨大小呈显著性相关。该多态性位点能分别解释转子间和全髋3．74％和3．16％的骨大小变异。连锁分析没有检测到显著性结果,可能的主要原因是样本中同胞对的数目较少,统计效力较低,以及SacⅠ位点多态相对于微卫星标记对连锁分析提供的信息量少。结果表明,月HSG基因多态性可能和中国人群中髋部骨大小变异有关。     

Impacted bone stiffness measured during construction of morsellised bone samples

Impacted morsellised bone is widely used for filling bone deficiencies during revision of total hip arthroplasties. However, the physical properties and mechanical behaviour of this bone material are still not well understood. In this study we recorded the increase of stiffness in pellets of morsellised bone during their construction. The construction of bone pellets was measured stroke-by-stroke to ascertain optimal stiffness. We have derived an impact-constrained module of elasticity, which represents the dynamic resistance in the granulated bone mass to impaction. Drop level of the impaction slap hammer increases constrained bone stiffness during impaction and load. However, increasing the number of impaction strokes at the highest drop level does not improve stiffness properties; no significant increase in stiffness was achieved after five strokes on each layer of morsellised bone.     

Mechanical significance of femoral head trabecular bone structure in Loris and Galago evaluated using micromechanical finite element models

Work on the interspecific and intraspecific variation of trabecular bone in the proximal femur of primates demonstrates important architectural variation between animals with different locomotor behaviors. This variation is thought to be related to the processes of bone adaptation whereby bone structure is optimized to the mechanical environment. Micromechanical finite element models were created for the proximal femur of the leaping Galago senegalensis and the climbing and quadrupedal Loris tardigradus by converting bone voxels from high-resolution X-ray computed tomography scans of the femoral head to eight-noded brick elements. The resulting models had approximately 1.8 million elements each. Loading conditions representing takeoff phase of a leap and more generalized load orientations were applied to the models, and the models were solved using the iterative "row-by-row" matrix-vector multiplication algorithm. The principal strain and Von Mises stress results for the leaping model were similar for both species at each load orientation. Similar hip joint reaction forces in the range of 4.9 x to 12 x body weight were calculated for both species under each loading condition, but the hip reaction values estimated for Loris were higher than predicted based on locomotor behavior. These results suggest that functional adaptation to hip joint loading may not fully explain the differences in femoral head trabecular bone structure in Galago and Loris. The finite element method represents a unique and useful tool for analyzing the functional adaptation of trabecular bone in a diversity of animals and for reconstructing locomotor behavior in extinct taxa.