Experimental graft arteriosclerosis. I. The Lewis-to-F-344 allograft model.

Progressive graft arteriosclerosis is responsible for the majority of late deaths occurring in cardiac transplant recipients. In order to define a model of this disease in the rat, we exchanged heterotopic cardiac allografts between MHC-compatible inbred strains. Lewis rats served as donors and F-344 rats as recipients. Twenty allografts were followed by daily palpation and removed at the time of terminal rejection or on the 120th postoperative day for pathologic study. Sixteen allografts (80%) survived at least three weeks, and five allografts (25%) survived indefinitely. The majority of arteries (greater than 90%) examined demonstrated significant intimal disease; histologic findings in lesions in allografts rejecting at early time points included intense mononuclear cell infiltration of the intima, while lesions in long-term-surviving allografts demonstrated fibrous intimal thickening, which is characteristic of graft arteriosclerosis seen clinically. A limited course of cyclosporine therapy in F-344 recipients increased the incidence of indefinite allograft survival from 25% to 86%, and was associated with a modest reduction in the amount of intimal disease observed. These results suggest that this model should be useful in future studies regarding the pathogenesis and therapy of cardiac graft arteriosclerosis.     

The biology of allograft incorporation

Musculoskeletal allografts remain an important, and are sometimes the only, treatment option for the reconstruction and replacement of damaged or absent musculoskeletal tissues. Understanding the biologic factors that affect the donor-host interactions and ultimate incorporation and remodeling of various allograft tissues is an essential prerequisite for their successful clinical use.     

Experimental model for internal repair of arteriovenous fistulas

An artificial arteriovenous fistula was created by performing an end-to-side anastomosis between the anterior facial vein and carotid artery of the rat. An intraarterial venous graft was then used to seal the fistula. In 8 of 10 rats, carotid artery flow was found to be maintained as judged by angiography, carried out 14 days after the operation. The fistula remained closed in each case. The vessels were also examined with a scanning electron microscope.     

The use of heparan sulfate to augment fracture repair in a rat fracture model.

Fracture healing is a complex process regulated by numerous growth and adhesive factors expressed at specific stages during healing. The naturally occurring, cell surface-expressed sugar, heparan sulfate (HS), is known to bind to and potentiate the effects of many classes of growth factors, and as such, may be a potential candidate therapy for enhancing bone repair. This study investigated the local application of bone-derived HS in the repair of rat femoral fractures. After 2 weeks, there was a significant increase in the callus size of rats administered with 5 microg HS compared to the control and 50 microg HS groups, presumably due to increased trabecular bone volume rather than increased cartilage production. In addition, 5 microg HS increased the expression of ALP, Runx2, FGF-1, IGF-II, TGF-beta1, and VEGF. It is hypothesized that these increases resulted from changes in HS-mediated receptor/ligand interactions that increase local growth factor production to augment bone formation. The findings of this study demonstrate the anabolic potential of HS in bone repair by recruiting and enhancing the production of endogenous growth factors at the site of injury.     

Experimental mandibular fracture: studies on bone repair and remodellation

An experimental mandibular fracture model was developed in Sprague-Dawley rats. Healing and remodellation were studied using routine histology, microradiography and incorporation of tetracycline and lead acetate. Bone healing after fracture started by outgrowth of bone trabeculae from the periosteum and from marrow spaces in the mandibular corpus and coronoid process. Stabile fracture healing was seen after 14-16 days, which correlated to the time when bone trabeculae were seen to cross the fracture diastasis morphologically. Formation of reparative bone was produced by direct formation of bone trabeculae but also via formation of a chondroid tissue which was later resorbed and replaced by bone.     

Mathematical model for repair of fatigue damage and stress fracture in osteonal bone

This paper assembles current concepts about bone fatigue and osteonal remodeling into a mathematical theory of the repair of fatigue damage and the etiology of stress fracture. The model was used to address three questions. (a) How does the half-life of fatigue damage compare with the duration of the remodeling cycle? (b) Does the porosity associated with the remodeling response contribute to stress fracture? (c) To what extent is a periosteal callus response necessary to augment repair by remodeling? To develop the theory, existing experimental data were used to formulate mathematical relationships between loading, damage, periosteal bone formation, osteonal remodeling, porosity, and elastic modulus. The resulting nonlinear relationships were numerically solved in an iterative fashion using a computer, and the behavior of the model was studied for various loading conditions and values of system parameters. The model adapted to increased loading by increasing remodeling to repair the additional damage and by adding new bone periosteally to reduce strain. However, if too much loading was encountered, the porosity associated with increased remodeling caused the system to become unstable: i.e., damage, porosity, and strain increased at a very high rate and without limit. It is proposed that this phenomenon is the equivalent of a stress fracture and that its biological and mechanical elements are significant in the etiology of stress fractures. Additional experiments must be done to test the model and provide better values for its parameters. However, the instability characteristic is relatively insensitive to changes in model parameters.     

Percutaneous electrical stimulation for clinical tibial fracture repair.

Observations on stress generated electrical currents in bone have stimulated interest in the possible osteogenetic effect of externally applied electrical energy to establish diaphyseal bone defects in animals and man. This report records the observed effects of pulsed electrical energy directed through a metal (Riordan pin) electrode placed in a large proximal tibial shaft dedect in a young man who sustained loss of bone from a gunshot wound. The fixation pin placed directly into the defect provided the cathode (-) electrode. The anode (+) electrode consisted of an aluminum foil band placed on the skin adjacent to the leg. The tibia had 282 consecutive days of electrical stimulation and provided X-ray and clinical evidence of enhanced osteogenetic activity. The degree of osteogenetic response attributable to the electrical stimulation is undetermined because other factors, including cast immobilization, time and minimal touchdown (25 pounds) weight-bearing in the cast during the period of observation, may also have had some influence on the healing response. Circumstantial clinical evidence indicates that the applied electrical energy was of primary importance in the healing process. This theoretically and technically acceptable source of osteogenetic activity merits continued, intensive investigation.     

Bone fracture and bone fracture repair

Fracture healing is a multistage repair process that involves complex, well-orchestrated steps initiated in response to tissue injury. The early upregulation of IL-6, osteoprotegerin (OPG), VEGF, and BMPs indicates a central role for these factors in the initiation of cartilage and periosteal woven bone formation. In both callus fracture repair and stress fracture repair, the RANKL/OPG ratio is initially reduced, but peaks earlier in stress fracture healing than callus fracture healing. Though the understanding of the biological processes and molecular signals that coordinate fracture repair has advanced, the cause of variability observed in fracture repair is poorly understood.     

Role of local insulin augmentation upon allograft incorporation in a rat femoral defect model

Each year, over one million orthopedic operations are performed which a bony defect is presence, requiring the use of further augmentation in addition to bony fixation. Application of autogenous bone graft is the standard of care to promote healing of these defects, but several determents exist in using autogenous bone graft exist including limited supply and donor site morbidity. Prior work has demonstrated that local insulin application to fracture sites promote fracture healing, but no work has been performed to date in its effects upon defect healing/allograft incorporation. The goal of this study was to examine the potential role of local insulin application upon allograft incorporation. Microradiographic, histologic, and histomorphometric analysis outcome parameters showed that local insulin significantly accelerated new bone formation. Histological comparisons using predetermined scoring systems demonstrated significantly greater healing in femora treated with insulin compared to control femora (p < 0.001). Quantitatively more bone production was also observed, specifically in areas of endosteal (p = 0.010) and defect (p = 0.041) bone in femora treated with local insulin, compared to control femora, 6 weeks after implantation. This study demonstrates the potential of local insulin as an adjunct for the treatment of segmental defect and allograft incorporation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:92–99, 2011     

Mechanotransduction and fracture repair

Fracture-healing is regulated in part by mechanical factors. Study of the processes by which the mechanical environment of a fracture modulates healing can yield new strategies for the treatment of bone injuries. This article focuses on several key unanswered questions in the study of mechanotransduction and fracture repair. These questions concern identifying the mechanical stimuli that promote bone-healing, defining the mechanisms that are involved in this process, and examining the potential for cross-talk between investigations of mechanotransduction in bone-healing and in healing of other mesenchymally derived tissues. Several approaches to obtain accurate estimates of the mechanical stimuli present within a fracture callus are proposed, and our current understanding of the mechanotransduction processes involved in bone-healing is reviewed. Further study of mechanotransduction mechanisms is needed in order to identify those that are most critical and active during the various phases of fracture repair. A better understanding of the effect of mechanical factors on bone-healing will also benefit the study of healing, regeneration, and engineering of other skeletal tissues.     

Cryopreserved allograft repair of aortic hypoplasia and interrupted aortic arch.

Mortality for interruption of the aortic arch approaches 100% within the first year of life if untreated. Prostaglandin E1 can stabilize the patient's condition in anticipation of surgical palliation, but total repair is required for long-term survival. Successful complete repair of type B interrupted aortic arch, hypoplasia of the left ventricular outflow tract, and ventricular septal defect was possible using a cryopreserved allograft in a child who previously had undergone unusual palliation.     

胫骨平台骨折对半月板愈合影响的实验研究

[目的]胫骨平台骨折常可合并包括半月板在内的膝关节软组织损伤,而骨折的发生对半月板愈合会产生何种影响尚未见报道。本文通过建立胫骨平台骨折合并半月板损伤的动物模型,试图观察骨折引起的膝关节改变对半月板修复产生的影响。[方法]建立12只新西兰兔外侧胫骨平台骨折,以及半月板非全层撕裂伤和打孔缺损模型,设立无骨折对照,12周后通过大体与光镜观察两组半月板损伤模型修复的差异。[结果]在无血运区,无论有无合并平台骨折,半月板损伤均未见任何修复迹象;两组有血运区的半月板撕裂伤均已修复裂隙,与正常组织难以区分;而在半月板外1/3区的打孔缺损模型,仅胫骨平台骨折组可见部分蛋白凝块的填充。[结论]胫骨平台骨折同时合并半月板损伤时,未见骨折阻碍半月板愈合的证据,相反,骨折能促使缺损区域的组织填充,但是否有益于半月板愈合尚有待进一步研究。     

Effect of osteoporosis on bone mineral density and fracture repair in a rat femoral fracture model

Osteoporosis (OP) is one of the most prevalent bone diseases worldwide with bone fracture the major clinical consequence. The effect of OP on fracture repair is disputed and although it might be expected for fracture repair to be delayed in osteoporotic individuals, a definitive answer to this question still eludes us. The aim of this study was to clarify the effect of osteoporosis in a rodent fracture model. OP was induced in 3‐month‐old rats (n = 53) by ovariectomy (OVX) followed by an externally fixated, mid‐diaphyseal femoral osteotomy at 6 months (OVX group). A further 40 animals underwent a fracture at 6 months (control group). Animals were sacrificed at 1, 2, 4, 6, and 8 weeks postfracture with outcome measures of histology, biomechanical strength testing, pQCT, relative BMD, and motion detection. OVX animals had significantly lower BMD, slower fracture repair (histologically), reduced stiffness in the fractured femora (8 weeks) and strength in the contralateral femora (6 and 8 weeks), increased body weight, and decreased motion. This study has demonstrated that OVX is associated with decrease in BMD (particularly in trabecular bone) and a reduction in the mechanical properties of intact bone and healing fractures. The histological, biomechanical, and radiological measures of union suggest that OVX delayed fracture healing. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:384–393, 2008     

冻干同种异体骨与冻干异种骨移植治疗骨缺损的比较实验研究

目的：对比观察冻干同种异体骨和冻干异种骨骨移植治疗骨缺损的效果。方法：48只中国大白兔一侧桡骨造成1cm骨缺损，随机分为同种异体骨组和异种骨组，每组24只，分别植入两种移植骨，术后4、8、12周分批取材，进行X线片和组织学检查，然后做对比分析。结果：术后4周异种骨组的X线片，Gary X线评分与同种异体骨组有统计学差异，而术后8周同种异体骨组组织学检查以及组织学评分与异种骨组有统计学差异，在其他时期两组比较无统计学差异。结论：冻干异种骨具有很好的成骨效果，可以作为修复骨缺损的移植材料。