Hagen Schmal

Characteristic Complications After Autologous Chondrocyte Implantation for Cartilage Defects of the Knee Joint

Background Although autologous chondrocyte implantation (ACI) is a well-established therapy for the treatment of isolated cartilage defects of the knee joint, little is known about typical complications and their treatment after ACI. Hypothesis Unsatisfactory outcome after ACI is associated with technique-related typical complications. Study Design Case series; Level of evidence, 4. Methods A total of 309 consecutive patients with 349 ACI procedures of the knee joint were analyzed. Three different ACI techniques were used: periosteum-covered ACI in 52 cases (14.9%), Chondrogide (Geistlich Biomaterials, Wolhusen, Switzerland) membrane-covered ACI in 215 cases (61.6%), and a 3-dimensional matrix-associated ACI (BioSeed-C, Biotissue Technologies, Freiburg, Germany) in 82 cases (23.5%). In 52 patients, revision surgery was performed for persistent clinical problems. These patients were analyzed for defect size and location, technique of ACI, and intraoperative findings during revision surgery. The mean time of follow-up for patients after ACI was 4.5 years (standard deviation, ±1.5). Results Four typical major complications were identified: hypertrophy of the transplant, disturbed fusion of the regenerative cartilage and the healthy surrounding cartilage, insufficient regenerative cartilage, and delamination. These diagnoses covered a total of 88.5% of the patients who underwent revision surgery. The overall complication rate was highest in the group of patients treated with periosteum-covered ACI (P = .008). The incidence of symptomatic hypertrophy was 5.2% for all techniques and defect locations; the highest incidence was in patients treated with periosteum-covered ACI (15.4%) (P = .001). The incidence of disturbed fusion was highest in the Chondrogide-covered ACI (3.7%) and the matrix-associated ACI group (4.8%). Concerning the incidence of complications by defect location, there was a tendency for increased complications in patellar defects (P = .095). Within the patellar defects group, no correlation was found for the occurrence of delamination, insufficient regeneration, and disturbed fusion. As a statistical trend, an increased rate of hypertrophy was found for patellar defects (P = .091). Conclusion A major proportion of complications after ACI can be summarized by 4 major diagnoses (symptomatic hypertrophy, disturbed fusion, delamination, and graft failure). Among those, the overall complication rate and incidence of hypertrophy of the transplant were higher for periosteum-covered ACI. Furthermore, an increased rate of symptomatic hypertrophy was found for patellar defects. Therapeutic concepts need to be developed to treat these typical complications of ACI.

Role of CC Chemokines (Macrophage Inflammatory Protein-1β, Monocyte Chemoattractant Protein-1, RANTES) in Acute Lung Injury in Rats

The role of the CC chemokines, macrophage inflammatory protein-1β (MIP-1β), monocyte chemotactic peptide-1 (MCP-1), and RANTES, in acute lung inflammatory injury induced by intrapulmonary deposition of IgG immune complexes injury in rats was determined. Rat MIP-1β, MCP-1, and RANTES were cloned, the proteins were expressed, and neutralizing Abs were developed. mRNA and protein expression for MIP-1β and MCP-1 were up-regulated during the inflammatory response, while mRNA and protein expression for RANTES were constitutive and unchanged during the inflammatory response. Treatment of rats with anti-MIP-1β Ab significantly decreased vascular permeability by 37% (p = 0.012), reduced neutrophil recruitment into lung by 65% (p = 0.047), and suppressed levels of TNF-α in bronchoalveolar lavage fluids by 61% (p = 0.008). Treatment of rats with anti-rat MCP-1 or anti-rat RANTES had no effect on the development of lung injury. In animals pretreated intratracheally with blocking Abs to MCP-1, RANTES, or MIP-1β, significant reductions in the bronchoalveolar lavage content of these chemokines occurred, suggesting that these Abs had reached their targets. Conversely, exogenously MIP-1β, but not RANTES or MCP-1, caused enhancement of the lung vascular leak. These data indicate that MIP-1β, but not MCP-1 or RANTES, plays an important role in intrapulmonary recruitment of neutrophils and development of lung injury in the model employed. The findings suggest that in chemokine-dependent inflammatory responses in lung CC chemokines do not necessarily demonstrate redundant function.

Open-wedge osteotomy using an internal plate fixator in patients with medial-compartment gonarthritis and varus malalignment: 3-year results with regard to preoperative arthroscopic and radiographic findings.

PURPOSE Our purpose was to evaluate the 3-year clinical results of patients with medial-compartment osteoarthritis of the knee and varus malalignment who underwent open-wedge high tibial osteotomy (HTO) with an internal plate fixator (TomoFix; Synthes, Solothurn, Switzerland). Clinical results are correlated with arthroscopic and radiographic findings at the time of surgery. METHODS This study included 69 patients with a minimum follow-up of 36 months who underwent open-wedge HTO for medial-compartment osteoarthritis of the knee. Knee function was assessed before surgery and at 6, 12, 24, and 36 months after HTO by use of subjective International Knee Documentation Committee and Lysholm scores. Arthroscopic findings before HTO and radiographic assessment of the metaphyseal deformity of the proximal tibia (tibial bone varus angle) were correlated with clinical outcome. RESULTS A significant continuous increase in International Knee Documentation Committee score from 47.25 ± 18.71 points before surgery to 72.72 ± 17.15 points at 36 months after HTO was found (P < .001). Grade of cartilage damage of the medial compartment and partial-thickness defects of the lateral compartment did not significantly influence clinical outcome (P > .05 at all time points). The tibial bone varus angle was correlated significantly with greater improvement and better clinical outcome after HTO (P < .01). The overall complication rate of 8.6% was mostly related to surgical causes; nevertheless, a high proportion of patients reported discomfort related to the implant at some point during the follow-up period (40.6%). CONCLUSIONS Open-wedge osteotomy by use of the TomoFix system leads to reliable 3-year results. Results do not depend on the severity of medial cartilage defects, whereas partial-thickness defects of the lateral compartment seem to be well tolerated. The prognostic relevance of patellofemoral cartilage defects remains unclear. Local irritation of the implant was observed in a significant number of patients. LEVEL OF EVIDENCE Level IV, therapeutic case series.

Survival trends and predictors of mortality in severe pelvic trauma: Estimates from the German Pelvic Trauma Registry Initiative

STUDY OBJECTIVE To determine longitudinal trends in mortality, and the contribution of specific injury characteristics and treatment modalities to the risk of a fatal outcome after severe and complex pelvic trauma. METHODS We studied 5048 patients with pelvic ring fractures enrolled in the German Pelvic Trauma Registry Initiative between 1991 and 1993, 1998 and 2000, and 2004 and 2006. Complete datasets were available for 5014 cases, including 508 complex injuries, defined as unstable fractures with severe peri-pelvic soft tissue and organ laceration. Multivariable mixed-effects logistic regression analysis was employed to evaluate the impact of demographic, injury- and treatment-associated variables on all-cause in-hospital mortality. RESULTS All-cause in-hospital mortality declined from 8% (39/466) in 1991 to 5% (33/638) in 2006. Controlling for age, Injury Severity Score, pelvic vessel injury, the need for emergency laparotomy, and application of a pelvic clamp, the odds ratio (OR) per annum was 0.94 (95% confidence interval [CI] 0.91-0.96). However, the risk of death did not decrease significantly in patients with complex injuries (OR 0.98, 95% CI 0.93-1.03). Raw mortality associated with this type of injury was 18% (95% CI 9-32%) in 2006. CONCLUSION In contrast to an overall decline in trauma mortality, complex pelvic ring injuries remain associated with a significant risk of death. Awareness of this potentially life-threatening condition should be increased amongst trauma care professionals, and early management protocols need to be implemented to improve the survival prognosis.

Long-term Outcomes After First-Generation Autologous Chondrocyte Implantation for Cartilage Defects of the Knee

Background: Autologous chondrocyte implantation (ACI) represents an established surgical therapy for large cartilage defects of the knee joint. Although various studies report satisfying midterm results, little is known about long-term outcomes. Purpose: To evaluate long-term clinical and magnetic resonance imaging (MRI) outcomes after ACI. Study Design: Case series; Level of evidence, 4. Methods: Between January 1997 and June 2001, a total of 86 patients were treated with ACI for isolated cartilage defects of the knee. The mean patient age at the time of surgery was 33.3 ± 10.2 years, and the mean defect size was 6.5 ± 4.0 cm2. Thirty-four defects were located on the medial femoral condyle and 13 on the lateral femoral condyle, while 6 patients were treated for cartilage defects of the trochlear groove and 17 for patellar lesions. At a mean follow-up of 10.9 ± 1.1 years, 70 patients (follow-up rate, 82%) treated for 82 full-thickness cartilage defects of the knee were available for an evaluation of knee function using standard instruments, while 59 of these patients were additionally evaluated by 1.5-T MRI to quantify the magnetic resonance observation of cartilage repair tissue (MOCART) score. Clinical function at follow-up was assessed by means of the Lysholm score, the International Knee Documentation Committee (IKDC) score, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Patient activity was assessed by the Tegner score. In addition, pain on a visual analog scale (VAS) and patient satisfaction were evaluated separately. Results: At follow-up, 77% reported being “satisfied” or “very satisfied.” The mean IKDC score at follow-up was 74.0 ± 17.3. The mean Lysholm score improved from 42.0 ± 22.5 before surgery to 71.0 ± 17.4 at follow-up (P < .01). The mean pain score on the VAS decreased from 7.2 ± 1.9 preoperatively to 2.1 ± 2.1 postoperatively. The mean MOCART score was 44.9 ± 23.6. Defect-associated bone marrow edema was found in 78% of the cases. Nevertheless, no correlation between the MOCART score and clinical outcome (IKDC score) could be found (Pearson coefficient, r = 0.173). Conclusion: First-generation ACI leads to satisfying clinical results in terms of patient satisfaction, reduction of pain, and improvement in knee function. Nevertheless, full restoration of knee function cannot be achieved. Although MRI reveals lesions in the majority of the cases and the overall MOCART score seems moderate, this could not be correlated with long-term clinical outcomes.

Autologous Chondrocyte Implantation for Treatment of Cartilage Defects of the Knee: What Predicts the Need for Reintervention?

Background: Autologous chondrocyte implantation (ACI) is a well-established treatment option for isolated cartilage defects of the knee joint, providing satisfying outcome. However, cases of treatment failure with the need for surgical reintervention are reported; typical patient’s individual and environmental risk factors have previously not been described. Hypothesis: The need for reintervention after ACI is associated with specific preoperative detectable individual risk factors. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 413 patients following ACI (first, second, and third generation) were filtered for those who required revision surgery during their follow-up time (2-11.8 years). Factors were analyzed that might have significant effects on increased revision rate. Using preoperatively collected data, all patients were grouped according to 12 standard prognostic factors. Apart from odds ratio and Pearson χ2 test, statistical analysis of risk factors was performed with multivariate binary logistic regression models and Cox regression, the method of choice for survival time data. Results: After a follow-up of 4.4 ± 0.9 years (limited to 5 years), a total of 88 patients (21.3%) had undergone surgical revision. The time to revision surgery was 1.8 ± 1.1 years. Four prognostic factors associated with a significantly higher risk for reintervention were detected: (1) female gender (Cox survival fit: P = .033), (2) previous surgeries of the affected joint (P = .002), (3) previous bone marrow stimulation (P = .041), and (4) periosteum patch–covered ACI (P = .028). An influence of patient age, body mass index (BMI), defect number, defect size, lesion origin, lesion location, parallel treatment, or smoking on the risk for reintervention could not be observed. Conclusion: The study identifies clear facts that significantly increase the risk of revision surgery. These facts can be easily obtained preoperatively and may be taken into consideration when indicating ACI.

Survival of human mesenchymal stromal cells from bone marrow and adipose tissue after xenogenic transplantation in immunocompetent mice

INTRODUCTION Mesenchymal stromal cells (MSC) represent an attractive cell population for tissue engineering purposes. As MSC are described as immunoprivileged, non-autologous applications seem possible. A basic requirement is the survival of MSC after transplantation in the host. The purpose of the current paper was to evaluate the survival of undifferentiated and osteogenically induced human MSC from different origins after transplantation in immunocompetent mice. METHODS Human MSC were isolated from bone marrow (BMSC) and adipose tissue (ASC). After cultivation on mineralized collagen, MSC were transplanted subcutaneously into immunocompetent mice (n=12). Undifferentiated MSC (group A) were compared with osteogenic-induced MSC (group B). Human-specific in situ hybridization and anti-vimentin staining was used to follow MSC after transplantation. Quantitative evaluation of lymphocytes and macrophages was performed as a measure of immunologic rejection. Unloaded scaffolds served as controls (group C). Specimens were harvested at 4 and 8 weeks. RESULTS Undifferentiated BMSC and ASC were detected in the majority of cases after xenogenic transplantation (group A, a total of 22 out of 24 cases), while osteogenic-induced MSC (group B) could be detected in only three of 24 cases. Quantification of lymphocytes and macrophages revealed significantly higher cell numbers in group B compared with group A (P<0.05). DISCUSSION Our results suggest that undifferentiated MSC are candidates for non-autologous cell transplantation, while osteogenic-induced MSC seem to be eliminated by the hosts immune system. This observation seems independent of the origin of MSC and applies to BMSC and ASC.

Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion

We evaluated the roles of the C-X-C chemokines cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) as well as the complement activation product C5a in development of lung injury after hindlimb ischemia-reperfusion in rats. During reperfusion, CD11b and CD18, but not CD11a, were upregulated on neutrophils [bronchoalveolar lavage (BAL) and blood] and lung macrophages. BAL levels of CINC and MIP-2 were increased during the ischemic and reperfusion periods. Treatment with either anti-CINC or anti-MIP-2 IgG significantly reduced lung vascular permeability and decreased lung myeloperoxidase content by 93 and 68%, respectively (P < 0.05). During the same period, there were significant increases in serum C5a-related neutrophil chemotactic activity. Treatment with anti-C5a decreased lung vascular permeability, lung myeloperoxidase, and BAL CINC by 51, 58, and 23%, respectively (P < 0.05). The data suggest that the C-X-C chemokines CINC and MIP-2 as well as the complement activation product C5a are required for lung neutrophil recruitment and full induction of lung injury after hindlimb ischemia-reperfusion in rats.We evaluated the roles of the C-X-C chemokines cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) as well as the complement activation product C5a in development of lung injury after hindlimb ischemia-reperfusion in rats. During reperfusion, CD11b and CD18, but not CD11a, were upregulated on neutrophils [bronchoalveolar lavage (BAL) and blood] and lung macrophages. BAL levels of CINC and MIP-2 were increased during the ischemic and reperfusion periods. Treatment with either anti-CINC or anti-MIP-2 IgG significantly reduced lung vascular permeability and decreased lung myeloperoxidase content by 93 and 68%, respectively ( P < 0.05). During the same period, there were significant increases in serum C5a-related neutrophil chemotactic activity. Treatment with anti-C5a decreased lung vascular permeability, lung myeloperoxidase, and BAL CINC by 51, 58, and 23%, respectively ( P < 0.05). The data suggest that the C-X-C chemokines CINC and MIP-2 as well as the complement activation product C5a are required for lung neutrophil recruitment and full induction of lung injury after hindlimb ischemia-reperfusion in rats.

Role of complement in in vitro and in vivo lung inflammatory reactions

Complement is one of the integral buttresses of the inflammatory response. In addition to host defense activities, proinflammatory properties of several complement components are described. This overview elucidates the role of complement in inflammatory reactions in vitro and in vivo, focusing on the complement activation products, C5a, and the membrane attack complex, C5b‐9. Using several approaches, the impact of these complement components in mechanisms relevant to neutrophil recruitment is emphasized. In addition, the participation of complement in endothelial superoxide generation and its essential requirement for full expression of lung injury is demonstrated, as are the involved intracellular signal transduction pathways. Understanding the mechanisms of complement‐induced proinflammatory effects may provide a basis for future therapeutic blockade of complement and/or its activation products. J. Leukoc. Biol. 64: 40–48; 1998.

Chondrogenesis of Adipose-Derived Adult Stem Cells in a Poly-Lactide-Co-Glycolide Scaffold

Adult adipose-derived stem cells (ASCs) are considered to be an alternative cell source for cell-based cartilage repair because of their multiple differentiation potentials. This article addresses the chondrogenic differentiation of ASCs seeded into poly-lactide-co-glycolide (PLGA) scaffolds after implantation in a subcutaneous pocket of nude mice. Human ASCs were seeded into PLGA (polylactic acid:polyglycolic acid = 90:10) scaffolds and cultured in transforming growth factor beta 1 (TGF-beta1)-containing medium for 3 weeks in vitro. Then specimens were implanted into a subcutaneous pocket of severe combined immunodeficiency mice and harvested after 8 weeks. Chondrospecific messenger RNA (mRNA) expression was analyzed using reverse transcriptase polymerase chain reaction. Corresponding extracellular matrix (ECM) synthesis was demonstrated using immunohistochemical staining. Chondrospecific marker molecules such as collagen type II and type X, cartilage oligomeric matrix protein, and aggrecan subsequently increased during the 3 weeks period in vitro. After a further 8 weeks, in vivo samples pretreated with TGF-beta1 continued expressing collagen type II and aggrecan mRNA, and collagen type II was found within the ECM using immunohistochemistry. Chondrospecific mRNA was not detected in control samples. ASC-seeded PLGA scaffolds express a stable chondrogenic phenotype in a heterotopic model of cartilage transplantation and represent a suitable tool for tissue engineering of cartilage.