Fracture healing in paraplegic rats

In paraplegic rats, histomorphometric and chemical methods were used to evaluate callus production in tibial fractures stabilized by intramedullary nails. There were no differences in the mean sizes of fracture callus between paraplegic rats and their non-weight-bearing and weight-bearing controls. However, the variance of callus size was large in paraplegic rats. The concentration of nitrogen was high in calluses of paraplegic rats during the cartilaginous stage of healing. The hydroxyproline concentration did not differ between the groups. The rate of callus ossification was more rapid in paraplegic rats than in controls, but fracture calluses of paraplegic rats showed delayed accumulation of calcium and incomplete maturation of woven new bone. The results suggest that there are both mechanical and non-mechanical factors affecting callus formation in fractures below a spinal lesion.     

An experimental study on fracture healing in paraplegic rats

Fracture healing in denervated limbs was studied using paraplegic rats of Wistar stain. Femoral fractures were made at the same time as spinal cord injury or at regular intervals after spinal cord injury, for roentgenological and histological observation. In the former, proliferation and differentiation of osteogenic cells derived from the periosteum was almost the same as controls, with earlier bone union than controls. In the latter, with longer intervals between spinal cord injury and fracture, osteogenic cells were less proliferated and differentiated resulting in scant callus or delayed union. The environment of paralytic limbs was evidently altered substantially from 2 to 3 weeks after spinal cord injury, because thereafter fracture healing seemed to become poor. Circulatory disturbance plays a major role in fracture healing in paralytic limbs. Although healing is accelerated by increased circulatory volume at the acute phase of spinal cord injury, this potentiality is gradually decreased because of the regressive degeneration of long-term vasomotor nerve insufficiency.     

Fracture healing in rats treated with diphenylhydantoin (Dilantin).

Fibula fractures were surgically made in mature male rats. Experimental animals received 4 mg/kg body weight of DPH (Dilantin) injected intraperitoneally, and equivalent volumes of sterile saline were injected intraperitoneally in controls. Fracture healing was assessed by a histologic method 5, 10, 15, 20, 25, and 30 days following the fracture. Thirty days following the injury, the DPH-treated animals showed a statistically significant increased rate of union. A comparison in trends of fracture healing for experimental and control animals showed similar enhancement of fracture healing in the experimental animals throughout the entire observation period.     

Fracture healing in rats inhibited by locally administered indomethacin.

We studied the inhibitory effect of indomethacin on fracture healing in 135 young, male rats after oral administration compared with local application into the fracture. A closed mid-diaphyseal fracture of the left femur was performed in all the rats. The fractures were not immobilized. In one experiment, half of the animals received indomethacin via a stomach tube (2 mg/kg/day) for 10 days; the controls received only the vehicle. In another experiment, 0.5 mg of indomethacin, contained in a bioerodible polyorthoester gel, was injected into the fracture area in half the rats; in the controls, only the gel was injected. In both experiments, random animals were killed on Days 0, 5, 10, and 20. As assessed by radiographs and manual testing, the same inhibition of fracture healing was found regardless of whether indomethacin was given orally or locally. However, the amount of indomethacin that was applied locally was only one fourth of the total dose given orally; no indomethacin was detected in the serum.     

Fracture healing.

The sequence of events occurring after fracture is now relatively well understood. Healing takes place in three phases--inflammatory, reparative and remodelling. In each phase certain cells predominate and specific histologic and biochemical events are characteristic. Factors that influence fracture healing are both local and systemic; the former include particularly the degree of local trauma and bone loss, the type of bone affected, the degree of immobilization and local pathologic conditions; the latter include age, hormones, local stress and electric currents. Natural processes of healing should be allowed to take their usual course and interference should be attempted only when there is demonstrable need or substantial advantages for the patient.     

Fracture healing in HIV-positive populations

Highly active anti-retroviral therapy has transformed HIV into a chronic disease with a long-term asymptomatic phase. As a result, emphasis is shifting to other effects of the virus, aside from immunosuppression and mortality. We have reviewed the current evidence for an association between HIV infection and poor fracture healing. The increased prevalence of osteoporosis and fragility fractures in HIV patients is well recognised. The suggestion that this may be purely as a result of highly active anti-retroviral therapy has been largely rejected. Apart from directly impeding cellular function in bone remodelling, HIV infection is known to cause derangement in the levels of those cytokines involved in fracture healing (particularly tumour necrosis factor-alpha) and appears to impair the blood supply of bone. Many other factors complicate this issue, including a reduced body mass index, suboptimal nutrition, the effects of anti-retroviral drugs and the avoidance of operative intervention because of high rates of wound infection. However, there are sound molecular and biochemical hypotheses for a direct relationship between HIV infection and impaired fracture healing, and the rewards for further knowledge in this area are extensive in terms of optimised fracture management, reduced patient morbidity and educated resource allocation. Further investigation in this area is overdue.     

Demineralization and pathological physiology of the skeleton in paraplegic rats

Summary The mechanism of bone loss after a spinal cord section with paraplegia is still largely unknown. The purpose of this study was to investigate in paraplegic rats the rate and distribution of bone loss, changes in bone calcium metabolism, and bone blood flow. Female Sprague-Dawley rats aged 100–120 days were rendered paraplegic by sectioning the spinal cord at the 11th dorsal vertebra. By comparison with their sham-operated controls (SO controls), we found a diminished bone calcium content in the tibia and femur (paralyzed region) and in the humerus (supralesional region) of the paraplegic animals. In the femur bone calcium loss was present within a week and at 12 weeks had reached 22%; in the tibia it started at about 2 weeks and at 12 weeks had reached 15%; in the humerus it started at about 5 weeks and reached 7.5%. It was not uniform and was greatest in the metaphyseal-epiphyseal regions on either side of the femorotibial joint. The blood flow in femur and tibia was measured by the technique of arteriolar blockade of 15 μm microspheres. It was continuously higher in the paraplegic animals than in the SO controls, from 1 to 12 weeks. In both groups, paraplegics and controls, the bone blood flow was unequally distributed in the two bones; it was greatest in the same metaphyseal-epiphyseal regions contiguous to the femorotibial joint. The 72 h⁴⁵Ca clearance by the femur and tibia was lower in the paraplegic animals, indicating that bone deposition had slowed down and perhaps that resorption had occurred. The fact that the site of maximum bone calcium loss and the site where the blood flow was greatest are the same suggests a close relationship between the increased blood flow and demineralization, whether it be causal or not.     

Fracture healing monitored with strain gauges

We measured healing in 7 cases of surgical neck fracture of the humerus by applying a strain gauge measuring bar between the external fixation pins. Repeated measurements provided a healing curve for the individual cases. The gradual decrease in deflection of the fracture zone reached a plateau of about 50 percent after 2 to 4 weeks in 6 cases. Removal of the frame at this time proved safe, as solid healing occurred. In one fracture no such decrease was seen and nonunion developed.     

Fracture healing under factor XIII medication

Summary Following application of factor XIII for 3 weeks bone healing was studied in Sprague-Dawley rats on the 20th postoperative day qualitatively (radiographs, scintigraphy) and quantitatively (determination of callus thickness, of bone mineral content, and scintillation counting). No significant difference could be detected between animals treated with factor XIII and animals which served as controls. Therefore, a stimulating effect of factor XIII upon bone healing can not be expected in case of a normal factor XIII serum-level. The application of factor XIII is indicated only in high risk patients with a low factor XIII serum-level.Prof. Dr. A. N. Witt, to his 65th birthday     

Fracture healing: the diamond concept

Fracture healing is a complex physiological process. With the latest advances made in molecular biology and genetics it is now known that it involves the spatial and temporal coordinated action of several different cell types, proteins and the expression of hundreds of genes working towards restoring its structural integrity without scar formation. The standard tissue engineering approach to provide solutions for impaired fracture healing, bone restoration and regeneration includes the utilisation of growth factors, scaffolds and mesenchymal stem cells (triangular concept). However, although the mechanical environment is discussed and is considered as an important element in bone regeneration, its importance is often underestimated and it is not always given the necessary attention. The available scientific evidence supports the view that all the 4 known factors contributing to bone restoration should be given an equal acknowledgment and recognition. The traditional discussed triangular concept therefore should be reconsidered and be accepted as the 'diamond concept'.     

Low-intensity pulsed ultrasound: Fracture healing

Annually, millions of people across the world are inflicted with bone fracture injuries. Untimely healing is a significant burden in terms of socioeconomic costs, personal costs, and patients'' quality of life. Low-intensity pulsed ultrasound (LIPUS) has gained much attention as a potential adjunctive therapy for accelerating fresh fracture healing, but its efficacy remains controversial. This paper is presented in two parts a literature review followed by a systematic review. The literature review highlights the physiology of fracture healing and the influence LIPUS exerts on cells and molecules involved in this healing process. In part two, we present a systematic review of randomized controlled trials (RCTs) assessing the clinical effectiveness of LIPUS in accelerating the time to fracture healing. The electronic databases we searched for the systematic review are as follows: MEDLINE (from 1996 to November 2008), EMBASE (from 1996 to November 2008), and Healthstar (from 1966 to October 2008). A two-step screening process was used to assess the eligibility of studies yielded by our search. The first step was a review of titles and abstracts for the selection of studies that met the following criteria: (i) inclusion of skeletally mature patients with a fresh fracture, (ii) a minimum of two treatment arms with at least one arm receiving LIPUS treatment and another arm receiving placebo, (iii) random allocation of patients to the different treatment arms, (iv) radiological assessment of time to fracture healing, and (v) publication in the English language. In the second step, selected articles were reviewed in full text. Eligible trials were all scored independently by two reviewers for methodological reporting quality using the 15-item CLEAR NPT checklist (Checklist to Evaluate the Report of a Nonpharmacological Trial). We identified a total of seventy seven studies, nine of which met our inclusion criteria after the initial screening. Of these nine trials, seven were included for the final review. The types of fractures studied among these seven trials included lateral malleolar, radial, and tibial fractures. Three of the seven trials found that LIPUS significantly reduces healing time compared to placebo, whereas the other four did not find a statistically significant difference. There is a substantial level of inconsistency in the findings of several RCTs evaluating the efficacy of LIPUS as an adjunct for fracture healing. Although LIPUS has proven to be effective in certain trials for accelerating fracture healing, no definitive statement can be made regarding its universal use for all fracture types and methods of fracture care. Future high-quality RCTs with larger sample sizes may help to elucidate the specific indications that warrant or dismiss the need for LIPUS therapy.