In vitro characterization of self-assembled anterior cruciate ligament cell spheroids for ligament tissue engineering.

Tissue engineering of an anterior cruciate ligament (ACL) implant with functional enthesis requires site-directed seeding of different cell types on the same scaffold. Therefore, we studied the suitability of self-assembled three-dimensional spheroids generated by lapine ACL ligament fibroblasts for directed scaffold colonization. The spheroids were characterized in vitro during 14 days in static and 7 days in dynamic culture. Size maintenance of self-assembled spheroids, the vitality, the morphology and the expression pattern of the cells were monitored. Additionally, we analyzed the total sulfated glycosaminoglycan, collagen contents and the expression of the ligament components type I collagen, decorin and tenascin C on protein and for COL1A1, DCN and TNMD on gene level in the spheroids. Subsequently, the cell colonization of polylactide-co-caprolactone [P(LA-CL)] and polydioxanone (PDS) polymer scaffolds was assessed in response to a directed, spheroid-based seeding technique. ACL cells were able to self-assemble spheroids and survive over 14 days. The spheroids decreased in size but not in cellularity depending on the culture time and maintained or even increased their differentiation state. The area of P[LA-CL] scaffolds, colonized after 14 days by the cells of one spheroid, was in average 4.57 ± 2.3 mm(2). Scaffolds consisting of the polymer P[LA-CL] were more suitable for colonization by spheroids than PDS embroideries. We conclude that ACL cell spheroids are suitable as site-directed seeding strategy for scaffolds in ACL tissue engineering approaches and recommend the use of freshly assembled spheroids for scaffold colonization, due to their balanced proliferation and differentiation.

Embroidered polymer-collagen hybrid scaffold variants for ligament tissue engineering.

Embroidery techniques and patterns used for scaffold production allow the adaption of biomechanical scaffold properties. The integration of collagen into embroidered polylactide-co-caprolactone [P(LA-CL)] and polydioxanone (PDS) scaffolds could stimulate neo-tissue formation by anterior cruciate ligament (ACL) cells. Therefore, the aim of this study was to test embroidered P(LA-CL) and PDS scaffolds as hybrid scaffolds in combination with collagen hydrogel, sponge or foam for ligament tissue engineering. ACL cells were cultured on embroidered P(LA-CL) and PDS scaffolds without or with collagen supplementation. Cell adherence, vitality, morphology and ECM synthesis were analyzed. Irrespective of thread size, ACL cells seeded on P(LA-CL) scaffolds without collagen adhered and spread over the threads, whereas the cells formed clusters on PDS and larger areas remained cell-free. Using the collagen hydrogel, the scaffold colonization was limited by the gel instability. The collagen sponge layers integrated into the scaffolds were hardly penetrated by the cells. Collagen foams increased scaffold colonization in P(LA-CL) but did not facilitate direct cell-thread contacts in the PDS scaffolds. The results suggest embroidered P(LA-CL) scaffolds as a more promising basis for tissue engineering an ACL substitute than PDS due to superior cell attachment. Supplementation with a collagen foam presents a promising functionalization strategy.

Regulation of osteoarthritis-associated key mediators by TNFα and IL-10: effects of IL-10 overexpression in human synovial fibroblasts and a synovial cell line.

Synovial fibroblasts (SF) contribute to the pathogenesis of osteoarthritis (OA), but the effects of intra-articular cytokines on SF are not completely understood. The aim of this study was to characterize the interplay between tumor necrosis factor (TNF)α and the anti-inflammatory interleukin (IL)-10. Non-immortalized human SF and SF of the human cell line K4IM were stimulated with recombinant TNFα, IL-10, or TNFα + IL-10 (10 ng/ml each) for 24 h or transduced with an adenoviral vector overexpressing human IL-10 (hIL-10) and subsequently treated with 10 ng/ml TNFα for 24 h. Effects on the gene expression and protein synthesis of IL-6, IL-10, matrix metalloproteinases (MMP)-1, -3, type I collagen, ß1-integrin, and CD44 were investigated via real-time detection polymerase chain reaction, immunofluorescence labeling, flow cytometry, and Western blotting. IL-10 release by transduced SF was confirmed with enzyme-linked immunosorbent assay. Both cell populations were activated by TNFα and by TNFα + IL-10, increasing their gene expression and protein synthesis of IL-6, IL-10, MMP-1, and MMP-3 and altering the synthesis of type I collagen, ß1-integrin, and CD44. hIL-10 overexpression greatly elevated the gene expression and protein synthesis of IL-10. However, transduction did not significantly affect the gene expression of IL-6, MMP-1, and MMP-3 in SF. The increased expression of pro-inflammatory and catabolic mediators in TNFα-activated SF indicates their role in OA pathogenesis, suggesting they are a potential therapeutic target. Although the vigorousness of the responses of non-immortalized SF and K4IM clearly differ, the K4IM cell line seems to be a suitable model for non-immortalized human SF.

[Dislocation of the atlantoaxial joint]. / Die atlantoaxiale Dislokation.

Injuries of the cervical spine in adolescents only occur in 0.2 % of cases. Due to the mismatch of size of the head in comparison to the relatively weakly developed neck muscles at this age, the cranial section is more vulnerable to injuries of any kind compared to the lower sections of the cervical spine. In children isolated ligament trauma is more common than fractures due to the relatively good bone structure combined with a lower bone density but the risk for fractures increases with the age of the patient. Atlantoaxial dislocation (AAD) in children is a very rare mostly ligamentous injury. A differentiation is made between traumatic AAD and the much more common non-traumatic AAD described in the literature. Although the cause is still unknown different risk factors have been isolated that seem to increase the risk for non-traumatic AAD. The following article presents guidelines for the diagnosis and treatment of this rare type of injury and also describes the case of a 19-year-old female who presented at the emergency department with an AAD without a history of trauma. After successful closed repositioning the neck was stabilized in a semi-rigid cervical collar for 6 weeks.

In vitro and in vivo neo-cartilage formation by heterotopic chondrocytes seeded on PGA scaffolds.

Implantation of tissue-engineered heterotopic cartilage into joint cartilage defects might be an alternative approach to improve articular cartilage repair. Hence, the aim of this study was to characterize and compare the quality of tissue-engineered cartilage produced with heterotopic (auricular, nasoseptal and articular) chondrocytes seeded on polyglycolic acid (PGA) scaffolds in vitro and in vivo using the nude mice xenograft model. PGA scaffolds were seeded with porcine articular, auricular and nasoseptal chondrocytes using a dynamic culturing procedure. Constructs were pre-cultured 3 weeks in vitro before being implanted subcutaneously in nude mice for 1, 6 or 12 weeks, non-seeded scaffolds were implanted as controls. Heterotopic neo-cartilage quality was assessed using vitality assays, macroscopical and histological scoring systems. Neo-cartilage formation could be observed in vitro in all PGA associated heterotopic chondrocytes cultures and extracellular cartilage matrix (ECM) deposition increased in vivo. The 6 weeks in vivo incubation time point leads to more consistent results for all cartilage species, since at 12 weeks in vivo construct size reductions were higher compared with 6 weeks except for auricular chondrocytes PGA cultures. Some regressive histological changes could be observed in all constructs seeded with all chondrocytes subspecies such as cell-free ECM areas. Particularly, but not exclusively in nasoseptal chondrocytes PGA cultures, ossificated ECM areas appeared. Elastic fibers could not be detected within any neo-cartilage. The neo-cartilage quality did not significantly differ between articular and non-articular chondrocytes constructs. Whether tissue-engineered heterotopic neo-cartilage undergoes sufficient transformation, when implanted into joint cartilage defects requires further investigation.

The role of pro-inflammatory and immunoregulatory cytokines in tendon healing and rupture: new insights.

Owing to limited self-healing capacity, tendon ruptures and healing remain major orthopedic challenges. Increasing evidence suggests that post-traumatic inflammatory responses, and hence, cytokines are involved in both cases, and also in tendon exercise and homeostasis. This review summarizes interrelations known between the cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)α, IL-6 and vascular endothelial growth factor (VEGF) in tendon to assess their role in tendon damage and healing. Exogenic cytokine sources are blood-derived leukocytes that immigrate in damaged tendon. Endogenous expression of IL-1ß, TNFα, IL-6, IL-10 and VEGF was demonstrated in tendon-derived cells. As tendon is a highly mechanosensitive tissue, cytokine homeostasis and cell survival underlie an intimate balance between adequate biomechanical stimuli and disturbance through load deprivation and overload. Multiple interrelations between cytokines and tendon extracellular matrix (ECM) synthesis, catabolic mediators e.g. matrix-degrading enzymes, inflammatory and angiogenic factors (COX-2, PGE2, VEGF, NO) and cytoskeleton assembly are evident. Pro-inflammatory cytokines affect ECM homeostasis, accelerate remodeling, amplify biomechanical adaptiveness and promote tenocyte apoptosis. This multifaceted interplay might both contribute to and interfere with healing. Much work must be undertaken to understand the particular interrelation of these inflammatory and regulatory mediators in ruptured tendon and healing, which has relevance for the development of novel immunoregulatory therapeutic strategies.

Differing in vitro biology of equine, ovine, porcine and human articular chondrocytes derived from the knee joint: an immunomorphological study.

For lack of sufficient human cartilage donors, chondrocytes isolated from various animal species are used for cartilage tissue engineering. The present study was undertaken to compare key features of cultured large animal and human articular chondrocytes of the knee joint. Primary chondrocytes were isolated from human, porcine, ovine and equine full thickness knee joint cartilage and investigated flow cytometrically for their proliferation rate. Synthesis of extracellular matrix proteins collagen type II, cartilage proteoglycans, collagen type I, fibronectin and cytoskeletal organization were studied in freshly isolated or passaged chondrocytes using immunohistochemistry and western blotting. Chondrocytes morphology, proliferation, extracellular matrix synthesis and cytoskeleton assembly differed substantially between these species. Proliferation was higher in animal derived compared with human chondrocytes. All chondrocytes expressed a cartilage-specific extracellular matrix. However, after monolayer expansion, cartilage proteoglycan expression was barely detectable in equine chondrocytes whereby fibronectin and collagen type I deposition increased compared with porcine and human chondrocytes. Animal-derived chondrocytes developed more F-actin fibers during culturing than human chondrocytes. With respect to proliferation and extracellular matrix synthesis, human chondrocytes shared more similarity with porcine than with ovine or equine chondrocytes. These interspecies differences in chondrocytes in vitro biology should be considered when using animal models.

IL-10 overexpression differentially affects cartilage matrix gene expression in response to TNF-alpha in human articular chondrocytes in vitro.

Cartilage-specific extracellular matrix synthesis is the prerequisite for chondrocyte survival and cartilage function, but is affected by the pro-inflammatory cytokine TNF-alpha in arthritis. The aim of the present study was to characterize whether the immunoregulatory cytokine IL-10 might modulate cartilage matrix and cytokine expression in response to TNF-alpha. Primary human articular chondrocytes were treated with either recombinant IL-10, TNF-alpha or a combination of both (at 10ng/mL each) or transduced with an adenoviral vector overexpressing human IL-10 and subsequently stimulated with 10ng/ml TNF-alpha for 6 or 24h. The effects of IL-10 on the cartilage-specific matrix proteins collagen type II, aggrecan, matrix-metalloproteinases (MMP)-3, -13 and pro-inflammatory cytokines were evaluated by real-time RT-PCR and immunohistochemistry. Transduced chondrocytes overexpressed high levels of IL-10 which significantly up-regulated collagen type II expression. TNF-alpha suppressed collagen type II and aggrecan, but increased MMP and cytokine expression in chondrocytes compared to the non-stimulated controls. The TNF-alpha mediated down-regulation of aggrecan expression was significantly antagonized by IL-10 overexpression, whereas the suppression of collagen type II was barely affected. The MMP-13 and IL-1beta expression by TNF-alpha was slightly reduced by IL-10. These results suggest that IL-10 overexpression modulates some catabolic features of TNF-alpha in chondrocytes.

Impaired erythropoiesis after haemorrhagic shock in mice is associated with erythroid progenitor apoptosis in vivo.

OBJECTIVE: Multiply traumatised patients often suffer from blood loss and from subsequent therapy-resistant anaemia, possibly mediated by apoptosis, necrosis, or humoral factors. Therefore, the underlying mechanisms were investigated in bone marrow (BM) and peripheral blood in a murine resuscitated haemorrhagic shock (HS) model. METHODS: In healthy male mice, pressure-controlled HS was induced for 60 min. The BM was analysed for Annexin-V, 7-amino-actinomycin D, apoptotic enzymes (caspases-3/7, -8, and -9), expression of death receptors (CD120a, CD95), mitochondrial proteins (Bax, Bcl-2, Bcl-x), as well as erythropoietin (EPO) receptor (EPO-R). Blood cell count, peripheral EPO, and tumour necrosis factor-alpha response were additionally monitored. RESULTS: Twenty-four and 72 h after HS, EPO and EPO-R were strongly up-regulated in peripheral blood and BM, respectively. Decreasing numbers of erythroid progenitors in BM after HS correlated with significant apoptotic changes confirmed by increased caspases-3/7, -8, -9 activity in total BM, death receptor CD95 and CD120a expression on erythroid progenitors, and down-regulated mitochondrial Bcl-2 expression in total BM. Erythroid progenitors in peripheral blood were found to be increased after 72 h. CONCLUSION: Despite the massive EPO response and up-regulation of EPO-R, BM erythroblasts (EBs) decreased. This could be due to deficient maturation of erythroid progenitors. Furthermore, the increased intrinsic and extrinsic apoptosis activation suggests programmed death of erythroid progenitors. We propose that both apoptosis and negatively regulated erythropoiesis contribute to BM dysfunction, while erythroid progenitor egress plays an additional role.

Interleukin-10 modulates pro-apoptotic effects of TNF-alpha in human articular chondrocytes in vitro.

The aim of this study is to determine if there is an antagonistic effect between tumour necrosis factor (TNF)-alpha and the immunoregulatory interleukin (IL)-10 on chondrocytes survival. Serum-starved primary human articular chondrocytes were stimulated with either 10 ng/ml recombinant TNF-alpha, IL-10 or a combination of both (at 10 ng/ml each). Chondrocyte apoptosis was determined by measuring caspase-3/7, -8 and -9 activities using caspase assays. Mitochondrial apoptotic inducer bax, and the suppressor bcl-2 were evaluated using western blotting at 48 h. Results indicated that TNF-alpha increased caspase activities and resulted in a significant (p = 0.001) increase in bax/bcl-2 ratio. Stimulation with IL-10 did not alter caspase activities, while co-treatment with IL-10 and TNF-alpha inhibited TNF-alpha induced caspase activities and significantly (p > 0.004) impaired bax/bcl-2 ratio. At 24 h, mRNA levels for collagen type II, TNF-alpha and IL-10 were determined using real-time RT-PCR. Stimulation with TNF-alpha or TNF-alpha and IL-10 significantly inhibited collagen type II and increased IL-10 and TNF-alpha mRNA expression. IL-10 modulated the pro-apoptotic capacity of TNF-alpha in chondrocytes as shown by the decrease in caspase activities and bax/bcl-2 ratio compared to TNF-alpha stimulated chondrocytes, suggesting a mostly antagonistic interplay of IL-10 and TNF-alpha on mitochondrial apoptotic pathways.

Interleukin-18 induces apoptosis in human articular chondrocytes.

Elevated levels of the pro-inflammatory cytokine, interleukin-18 (IL-18) have recently been demonstrated in osteoarthritic cartilage. However, the effects of IL-18 on chondrocyte signalling and matrix biosynthesis are poorly understood. Therefore, the present study was undertaken to further characterize the impact of IL-18 on human articular chondrocyte in vitro. Human articular chondrocytes were stimulated with various concentrations of recombinant human IL-18 (1, 10, 100 ng/ml) for 0, 4, 8, 12, 24, 48, 72 h in vitro. The effects of IL-18 on the cartilage-specific matrix protein collagen type II, the cytoskeletal protein vinculin, the cell matrix signal transduction receptor beta-integrin, key signalling proteins of the MAPKinase pathway (such as SHC (Sarc Homology Collagen) and activated MAPKinase [ERK-1/-2]), the pro-inflammatory enzyme cyclo-oxygenase-2 (COX-2) and the apoptosis marker activated caspase-3 were evaluated by Western blot analysis and immunofluorescence labelling. Morphological features of IL-18 stimulated chondrocytes were estimated by transmission electron microscopy. IL-18 lead to inhibition of collagen type II-deposition, decreased beta-integrin receptor and vinculin synthesis, SHC and MAPKinase activation, increased COX-2 synthesis and activation of caspase-3 in chondrocytes in a time- and dose-dependent manner. Furthermore, chondrocytes treated with IL-18 exhibited typical morphological features of apoptosis as revealed by transmission electron microscopy. Taken together, the results of the present study underline key catabolic events mediated by IL-18 signalling in chondrocytes such as loss of cartilage-specific matrix and apoptosis. Inhibition of MAPKinase signalling is hypothesized to contribute to these features. Future therapeutics targeting IL-18 signalling pathways may be beneficial in rheumatoid arthritis and osteoarthritis therapy.

Adenoviral transduction is more efficient in alginate-derived chondrocytes than in monolayer chondrocytes.

Gene transfer into cultured chondrocytes by using adenoviral vectors has potential applications in treating cartilage disorders. The present study was undertaken to compare and optimize two chondrocyte culture conditions for adenoviral transduction efficacy by using primary human articular chondrocytes cultivated either directly in a monolayer condition or as outgrowths from alginate-stored chondrocyte cultures. Isolated primary chondrocytes from human articular cartilage were either immediately transduced with an EGFP (enhanced green fluorescent protein)-gene-bearing adenoviral vector (1,000 and 3,000 virus particles/cell) or cultured in alginate before transduction. Immunohistochemistry and flow cytometric analysis were employed to determine the expression of extracellular matrix proteins and of the alphavbeta5 integrin receptor involved in adenoviral cell entry. Monolayer chondrocytes exhibited moderate transduction rates (mean 22.2% and 46.9% EGFP-positive cells at 1,000 and 3,000 virus particles/cell by 72 h post-transduction), whereas alginate-derived chondrocytes revealed significantly higher transduction efficacies (95.7% and 99%). Both monolayer and alginate-derived chondrocytes expressed alphavbeta5 integrin, type II collagen and cartilage proteoglycans. The mean fluorescence intensity of type II collagen was significantly higher in the alginate-derived chondrocytes, whereas that of alphavbeta5 integrin was higher in the monolayer chondrocytes. Our results indicate that transduction efficacy is independent of alphavbeta5 integrin expression levels in chondrocytes. Moreover, adenoviral transduction of alginate-derived chondrocytes is more efficient than that for monolayer chondrocytes and may be a suitable tool to achieve sufficient numbers of transduced and differentiated chondrocytes for experimental applications and cartilage repair.

Brown-Séquard syndrome caused by a high velocity gunshot injury: a case report.

STUDY DESIGN: Case report. OBJECTIVE: To present an unusual traumatic neurologic pathology caused by gunshot injury. SETTING: Spine unit of Department of Trauma and Orthopaedic Surgery, University Medical School, Charité - Campus Benjamin Franklin, Berlin, Germany. METHOD AND RESULT: A 35-year-old male sustained a gunshot injury from a machine gun. The projectile caused a fracture of the left pedicle of Th10. The spinal cord was indirectly damaged by cavitation that caused a Brown-Séquard syndrome (BSS). After a microscopically assisted posterior revision at T9/10 with removal of bullet and bone fragments from the spinal canal and debridement of the bullet cavity via extended fenestrectomy the patient gained his motor function back. The sensory deficit remained unchanged. CONCLUSION: BSS can be caused by bullet-related injury of the spinal canal with no direct damage of neural structures. The initial treatment is always based on the total injury pattern. Possible spinal cord injuries are only clarified after restitution of vital functions. Decompression of neural structures in shotgun injury is indicated in incomplete paraplegia, injury of intra-abdominal hollow organs or high velocity bullet wounds. Through debridement and decompression of neural structures and chronic damage caused by foreign body granulomas can be prevented. Secondary destabilization of the spine should be avoided.

Systemic effects of severe trauma on the function and apoptosis of human skeletal cells.

Systemic factors are believed to be pivotal for the development of heterotopic ossification in severely-injured patients. In this study, cell cultures of putative target cells (human fibroblastic cells, osteoblastic cells (MG-63), and bone-marrow stromal cells (hBM)) were incubated with serum from ten consecutive polytraumatised patients taken from post-traumatic day 1 to day 21 and with serum from 12 healthy control subjects. The serum from the polytraumatised patients significantly stimulated the proliferation of fibroblasts, MG-63 and of hBM cells. The activity of alkaline phosphatase in MG-63 and hBM cells was significantly decreased when exposed to the serum of the severely-injured patient. After three weeks in 3D cell cultures, matrix production and osteogenic gene expression of hBM cells were equal in the patient and control groups. However, the serum from the polytraumatised patients significantly decreased apoptosis of hBM cells compared with the control serum (4.3% vs 19.1%, p = 0.031). Increased proliferation of osteoblastic cells and reduced apoptosis of osteoprogenitors may be responsible for increased osteogenesis in severely-injured patients.

[Role of gene therapy in trauma and orthopedic surgery]. / Stellenwert der Gentherapie in Unfallchirurgie und Orthopädie.

Modern molecular and genetic technologies enable the modification of a cellular genome through transfer of specific genes. The various procedures alter specific cell functions, which allow the transfected cell to produce any encoded transgene information. The transfected cell then synthesizes proteins that are normally not produced or only in very small amounts. Numerous animal studies have demonstrated that gene therapy may support and accelerate the healing and regeneration of specific tissues such as skin, tendons, cartilage, and bones. Currently, further animal studies are evaluating new vectors with reduced immunogenicity in the continuous effort to improve the efficacy and safety of gene transfer. In the forthcoming decade we expect gene therapy to have an important influence on the treatment of fractures, cartilage lesions, and infection.

Spinal extradural meningeal cyst with spinal stenosis.

STUDY DESIGN: Case report. OBJECTIVE: To present a rare pathology causing a common disease. SETTING: Spine unit of the orthopaedic surgery department of a university hospital in Berlin/Germany. CASE REPORT: A 39-year-old female with an intraspinal extradural arachnoid cyst of the lumbar spine presented with intermittent radiating lumbar pain. The magnetic resonance imaging (MRI) showed a dorsal spinal extradural arachnoid cyst at L3/4. After wide laminotomy L3, operative cyst resection and stabilisation at L3/4 by posterior lumbar interbody fusion (PLIF), major symptom relief occurred. CONCLUSION: Spinal extradural arachnoid cysts are a rare entity causing low back pain and intermittent radicular syndromes. They can be caused by arachnoid herniation through dural weak spots which are hereditary or occur after trauma. A ball-valve mechanism promotes growth. The main diagnostic tool for spinal extradural cysts is the MRI scan. Additionally, myelography is helpful to demonstrate fluid communication. Complete surgical removal of the cyst should be attempted to reduce risk of recurrence. If extensive decompression is needed for the surgical approach causing segmental instability, interbody fusion is recommended. The outcome depends on age, duration and degree of neurological damage.

[Pelvic injuries in the polytraumatized patient]. / Die Beckenringzerreissung beim polytraumatisierten Patienten.

Pelvic injuries represent a thorny and stubborn therapeutic challenge. Because major forces are required to fracture the pelvis, pelvic ring disruption, more than any other fracture, can lead to life-threatening associated injuries such as massive bleeding, organ injuries, and open fractures including hemipelvectomy. The rapid diagnosis and effective treatment ("damage control") of those injuries play the key role in the patient's survival, inasmuch as the mortality of multiply injured patients with pelvic ring disruption remains high with 20-35%. Exsanguinating hemorrhage represents the most dreaded acute complication of pelvic injuries. Therefore, diagnostic and therapeutic procedures have to be primarily adapted to the hemodynamics of the patient, secondarily to injuries of the brain and the torso. The time point and the techniques of definitive pelvic ring stabilization may be different in the patient with multiple injuries compared to isolated pelvic ring injuries.

[Traumatic brain injury: impact on timing and modality of fracture care]. / Einfluss des Schädel-Hirn-Traumas auf Zeitpunkt und Technik der Frakturversorgung.

Traumatic brain injury (TBI) represents the major "killing factor" after trauma in young individuals. Those patients who survive the initial injury are highly susceptible to secondary insults to the injured brain which are mainly caused by hypotension and/or hypoxia in the early resuscitative period. Furthermore, a potent inflammatory cascade is initiated within the injured brain which leads to the development of brain edema and delayed neuronal cell death. This profound endogenous neuroinflammatory response after TBI, which is phylogenetically aimed at repairing lesioned tissue and defending the brain from invading pathogens, is in large part responsible for the extent of secondary brain damage and adverse outcome. Thus, the optimal management of the multiply injured patient, based on a thorough understanding of the pathophysiological alterations after TBI, should avoid an iatrogenic "second hit" which may be devastating to the injured brain. The standard approach of "early total care" for isolated fractures should be strictly avoided in brain-injured patients in favor of an "orthopedic damage control" concept with temporary external fixation of long bone fractures and priority given to early transfer to intensive care. The present review provides an up-to-date overview on the neuroinflammatory pathophysiology of brain injury and its implications for an optimized concept of fracture care in TBI patients.

[Current concepts of polytrauma management: from ATLS to "damage control"]. / Aktuelle Konzepte des Polytraumamanagements: Von ATLS zu "Damage Control".

In recent years, the implementation of standardized protocols for polytrauma management has led to a significant improvement in trauma care as well as to a decrease in post-traumatic morbidity and mortality. As such, the "Advanced Trauma Life Support" (ATLS) protocol of the American College of Surgeons for the acute management of severely injured patients has been established as a gold standard in most European countries since the 1990s. Continuative concepts to the ATLS program include the "Definitive Surgical Trauma Care" (DSTC) algorithm and the concept of "damage control" surgery for polytraumatized patients with immediate life-threatening injuries. These phase-oriented therapeutic strategies appraise the injured patient of the whole extent of the sustained injuries and are in sharp contrast to previous modalities of "early total care" which advocate immediate definitive surgical intervention. The approach of "damage control" surgery takes into account the influence of systemic post-traumatic inflammatory and metabolic reactions of the organism and is aimed at reducing both the primary and the secondary, delayed, mortality in severely injured patients. The present paper provides an overview of the current state of management algorithms for polytrauma patients, with a focus on the standard concepts of ATLS and "damage control".