Oliver P. Gautschi

BONE MORPHOGENETIC PROTEINS IN CLINICAL APPLICATIONS

The role of bone morphogenetic proteins (BMPs) in bone healing has been shown in numerous animal models. To date, at least 20 BMPs have been identified, some of which have been shown in vitro to stimulate the process of stem cell differentiation into osteoblasts in human and animal models. Having realized the osteoinductive properties of BMPs and having identified their genetic sequences, recombinant gene technology has been used to produce BMPs for clinical application – most commonly, as alternatives or adjuncts in the treatment of cases in which fracture healing is compromised. BMP‐2 and BMP‐7 are approved for clinical use in open fractures of long bones, non‐unions and spinal fusion. However, despite significant evidence of their potential benefit to bone repair and regeneration in animal and preclinical studies, there is, to date, a dearth of convincing clinical trials. The purpose of this paper is to give a brief overview of BMPs and to critically review the clinical data currently available on the use of BMP‐2 and BMP‐7 in fracture healing.

Metal is not inert: Role of metal ions released by biocorrosion in aseptic loosening—Current concepts

Metal implants are essential therapeutic tools for the treatment of bone fractures and joint replacements. The metals and metal alloys used in contemporary orthopedic and trauma surgery are well tolerated by the majority of patients. However, complications resulting from inflammatory and immune reactions to metal implants have been well documented. This review briefly discusses the different mechanisms of metal implant corrosion in the human body, which lead to the release of significant levels of metal ions into the peri-implant tissues and the systemic blood circulation. Additionally, this article reviews the effects of the released ions on bone metabolism and the immune system and discusses their involvement in the pathophysiological mechanisms of aseptic loosening and metal hypersensitivity in patients with metal implants.

Bio-corrosion of stainless steel by osteoclasts—in vitro evidence

Most metals in contact with biological systems undergo corrosion by an electrochemical process. This study investigated whether human osteoclasts (OC) are able to grow on stainless steel (SS) and directly corrode the metal alloy leading to the formation of corresponding metal ions, which may cause inflammatory reactions and activate the immune system. Scanning electron microscopy analysis demonstrated long‐term viable OC cultures and evident resorption features on the surface of SS discs on which OC were cultured for 21 days. The findings were confirmed by atomic emission spectrometry investigations showing significantly increased levels of chromium, nickel, and manganese in the supernatant of OC cultures. Furthermore, significant levels of pro‐inflammatory cytokines IL‐1β, IL‐6, and TNF‐α, which are considered to be major mediators of osteolysis, were revealed in the same cultures by cytometric bead array analysis. Within the present study, it was shown that human osteoclast precursors are able to grow and differentiate towards mature OC on SS. The mature cells are able to directly corrode the metal surface and release corresponding metal ions, which induce the secretion of pro‐inflammatory cytokines that are known to enhance osteoclast differentiation, activation, and survival. Enhanced corrosion and the subsequently released metal ions may therefore result in enhanced osteolytic lesions in the peri‐prosthetic bone, contributing to the aseptic loosening of the implant.

Biocorrosion and uptake of titanium by human osteoclasts

All metals in contact with a biological system undergo corrosion through an electrochemical redox reaction. This study investigated whether human osteoclasts (OC) are able to grow on titanium and aluminum, and directly corrode the metals leading to the release of corresponding metal ions, which are believed to cause inflammatory reactions and activate osteoclastic differentiation. Scanning electron microscopy analysis demonstrated long-term viable OC cultures on the surface of titanium and aluminum foils. Atomic emission spectrometry investigations showed significantly increased levels of aluminum in the supernatant of OC cultured on aluminum; however, all measurements in the supernatants of cell cultures on titanium were below detection limits. Despite this, confocal microscopy analysis with Newport Green DCF diacetate ester staining depicted intense fluorescence throughout the cytoplasm and nucleolus of OC cultured on titanium foils. Comparable fluorescence intensities were not observed in monocytes and control cells cultured on glass. The present study demonstrated that human osteoclast precursors are able to grow and differentiate toward mature OC on titanium and aluminum. Furthermore, it established that the mature cells are able to directly corrode the metal surface and take up corresponding metal ions, which subsequently may be released and thereby induce the formation of osteolytic lesions in the periprosthetic bone, contributing to the loosening of the implant.

Humoral Factors Enhance Fracture-Healing and Callus Formation in Patients with Traumatic Brain Injury

BACKGROUNDnScientific evidence is mounting for an association between traumatic brain injury and enhanced osteogenesis. The aim of this study was to correlate the in vitro osteoinductive potential of serum with the features of fracture-healing and the extent of brain damage in patients with severe traumatic brain injury and bone fracture.nnnMETHODSnPatients with a long-bone fracture and a traumatic brain injury (seventeen patients) or without a brain injury (twenty-four patients) were recruited. The Glasgow Coma Scale score was determined on admission. Radiographs of the fracture were made before surgery, at six weeks, and at three, six, and twelve months after surgery. The time to union was estimated clinically and radiographically, and the callus ratio to shaft diameter was calculated. Serum samples were collected at six, twenty-four, seventy-two, and 168 hours after injury, and their osteogenic potential was determined by measurement of the in vitro proliferation rate of the human fetal osteoblastic cell line hFOB1.19.nnnRESULTSnPatients with a traumatic brain injury had a twofold shorter time to union (p = 0.01), a 37% to 50% increased callus ratio (p < 0.01), and their sera induced a higher proliferation rate in hFOB cells (p < 0.05). A linear relationship was revealed between hFOB cell proliferation rates and the amount of callus formed (p < 0.05). The Glasgow Coma Scale score was correlated with the callus ratio on both radiographic projections (p < 0.05), time to union (p = 0.04), and the proliferation rate of hFOB cells at six hours after injury (p = 0.03).nnnCONCLUSIONSnPatients with a severe brain injury release unknown humoral factors into the blood circulation that enhance and accelerate fracture-healing.

Serum-mediated osteogenic effect in traumatic brain-injured patients

Background:u2002 Patients with a traumatic brain injury (TBI) and bone fractures often show an enhanced fracture healing, as well as an increased incidence of heterotopic ossifications (HO). It has been suggested that unknown osteoinductive factors may be released by the injured brain into the systemic blood circulation and act peripherally on the affected tissues. The aim of this study was to investigate whether serum from TBI patients is osteoinductive.

Titanium induced production of chemokines CCL17/TARC and CCL22/MDC in human osteoclasts and osteoblasts

There is increasing evidence that titanium (Ti(IV)) ions are released from orthopedic implants and play a role in aseptic loosening. This study aimed to investigate whether titanium induces expression of chemokines and cytokines that are important in osteoclastogenesis in human osteoclasts and osteoblasts. Incubation of those cells with 1 muM Ti(IV) significantly upregulated expression of CCL17/TARC and CCL22/MDC, RANK-L, M-CSF and pro-inflammatory cytokines as determined by quantitative real-time PCR and ELISA assays. Additionally, flow cytometry was used to show Ti(IV) related increased expression of CCR4, the cognate receptor for CCL17 and CCL22 in challenged osteoclast precursors. These results strongly suggest that Ti(IV) ions play a role in the recruitment of osteoclast precursors to the bone-implant interface by increasing CCL17 and CCL22 expression and by upregulating their cognate receptor. Moreover the increased expression of RANK-L and M-CSF by osteoblasts together with increased levels of pro-inflammatory cytokines may enhance osteoclast differentiation and activity, and subsequently contribute to the pathomechanism of aseptic loosening.

Serum After Traumatic Brain Injury Increases Proliferation and Supports Expression of Osteoblast Markers in Muscle Cells

BACKGROUNDnTraumatic brain injury is associated with an increased rate of heterotopic ossification within skeletal muscle, possibly as a result of humoral factors. In this study, we investigated whether cells from skeletal muscle adopt an osteoblastic phenotype in response to serum from patients with traumatic brain injury.nnnMETHODSnSerum was collected from thirteen patients with severe traumatic brain injury, fourteen patients with a long-bone fracture, and ten control subjects. Primary cultures of skeletal muscle cells isolated from patients undergoing orthopaedic surgery were performed and characterized with use of immunofluorescence microscopy, reverse transcription-polymerase chain reaction, and Western blot analysis. Proliferation and osteoblastic differentiation were assessed with use of commercial cell assays, Western blot analysis (for Osterix protein), and the Villanueva bone stain.nnnRESULTSnAll serum-treated cell populations expressed the osteoblast marker Osterix after one week in culture. Cells treated with serum from all study groups in mineralization medium had increased alkaline phosphatase activity and mineralized nodules within the mesenchymal cell subpopulation after three weeks in culture. Serum from patients with traumatic brain injury induced a significant increase (p = 0.02) in the rate of proliferation of primary skeletal muscle cells (1.87 [95% confidence interval, 1.66 to 2.09]) compared with the rate induced by serum from patients with a fracture (1.42 [95% confidence interval, 1.21 to 1.58]) or by serum from controls (1.35 [95% confidence interval, 1.15 to 1.54]).nnnCONCLUSIONSnHuman serum supports the osteoblastic differentiation of cells derived from human skeletal muscle, and serum from patients with severe traumatic brain injury accelerates proliferation of these cells. These findings suggest the early presence of humoral factors following traumatic brain injury that stimulate the expansion of mesenchymal cells and osteoprogenitors within skeletal muscle.

Titanium IV ions induced human osteoclast differentiation and enhanced bone resorption in vitro.

There is increasing evidence that titanium (Ti) ions are released from orthopedic implants, with concentrations in the range of 1 microM in tissue and blood, and may play a role in aseptic loosening of orthopedic implants. This study investigated whether Ti(IV) ions induce differentiation of monocytic osteoclast precursors into osteo-resorptive multinucleated cells and influence the activation and function of in vitro generated osteoclasts. Human monocytes and in vitro generated osteoclasts were exposed to 1 microM Ti(IV) ions for 10 days. Thereafter, osteoclast differentiation, activation, and function were evaluated. Transcription of specific osteoclastic genes was measured using quantitative reverse transcription polymerase chain reactions, which showed increased expression of tartrate-resistant acid phosphatase (TRAP) in approximately 20% of Ti(IV)-treated monocytes. Detection and quantification of intracellular TRAP activity using ELF97 as a fluorescent substrate revealed a significant increase of TRAP-positive cells in Ti(IV)-treated monocytes. Additionally, as demonstrated on dentin slide cultures, Ti(IV)-treated monocytes became functional bone resorbing cells, significantly increasing their osteo-resorptive activity to similar levels as osteoclasts in vitro. These results suggest that Ti(IV) ions released by biocorrosion from orthopedic implants induce differentiation of monocytes toward mature, functional osteoclasts, which may well contribute the pathomechanism of aseptic loosening.

Earthquakes and trauma: review of triage and injury-specific, immediate care.

Earthquakes present a major threat to mankind. Increasing knowledge about geophysical interactions, progressing architectural technology, and improved disaster management algorithms have rendered modern populations less susceptible to earthquakes. Nevertheless, the mass casualties resulting from earthquakes in Great Kanto (Japan), Ancash (Peru), Tangshan (China), Guatemala, Armenia, and Izmit (Turkey) or the recent earthquakes in Bhuj (India), Bam (Iran), Sumatra (Indonesia) and Kashmir (Pakistan) indicate the devastating effect earthquakes can have on both individual and population health. Appropriate preparation and implementation of crisis management algorithms are of utmost importance to ensure a large-scale medical-aid response is readily available following a devastating event. In particular, efficient triage is vital to optimize the use of limited medical resources and to effectively mobilize these resources so as to maximize patient salvage. However, the main priorities of disaster rescue teams are the rescue and provision of emergency care for physical trauma. Furthermore, the establishment of transport evacuation corridors, a feature often neglected, is essential in order to provide the casualties with a chance for survival. The optimal management of victims under such settings is discussed, addressing injuries of the body and psyche by means of simple diagnostic and therapeutic procedures globally applicable and available.