Advanced therapies in orthopaedics.

Advanced therapies are expected to play a crucial role in supporting repair after injury, halting the degeneration of musculoskeletal tissue to enable and promote physical activity. Despite advancements, the progress in developing advanced therapies in orthopaedics lags behind specialties like oncology, since innovative regenerative treatment strategies fall short of their expectations in musculoskeletal clinical trials. Researchers should focus on understanding the mechanism of action behind the investigated target before conducting clinical trials. Strategic research networks are needed that not only enhance scientific exchange among like-minded researchers but need to include early on commercial views, companies and venture perspectives, regulatory insights and reimbursement perspectives. Only in such collaborations essential roadblocks towards clinical trials and go-to-patients be overcome.

Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice.

Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin (PCT/CT) or a calcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP-/- and CALCA-/- mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA-/- mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP-/- and WT mice. Osteophyte formation is reduced to the same extent in CALCA-/- and αCGRP-/- mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA-encoded peptides may represent novel targets for the treatment of ptOA.

Loading of the Hip and Knee During Swimming: An in Vivo Load Study.

BACKGROUND: Swimming is commonly recommended as postoperative rehabilitation following total hip arthroplasty (THA) and total knee arthroplasty (TKA). So far, in vivo hip and knee joint loads during swimming remain undescribed. METHODS: In vivo hip and knee joint loads were measured in 6 patients who underwent THA and 5 patients who underwent TKA with instrumented joint implants. Joint loads, including the resultant joint contact force (F Res ), torsional moment around the femoral shaft axis or the tibial axis (M Tors ), bending moment at the middle of the femoral neck (M Bend ), torsional moment around the femoral neck axis (M Tne ), and medial force ratio (MFR) in the knee, were measured during breaststroke swimming at 0.5, 0.6, and 0.7 m/s and the breaststroke and crawl kicks at 0.5 and 1.0 m/s. RESULTS: The ranges of the median maximal F Res were 157% to 193% of body weight for the hip and 93% to 145% of body weight for the knee during breaststroke swimming. Greater maxima of F Res (hip and knee), M Tors (hip and knee), M Bend (hip), and M Tne (hip) were observed with higher breaststroke swimming velocities, but significance was only identified between 0.5 and 0.6 m/s in F Res (p = 0.028), M Tors (p = 0.028), and M Bend (p = 0.028) and between 0.5 and 0.7 m/s in F Res (p = 0.045) in hips. No difference was found in maximal MFR between different breaststroke swimming velocities. The maximal F Res was significantly positively correlated with the breaststroke swimming velocity (hip: r = 0.541; p < 0.05; and knee: r = 0.414; p < 0.001). The maximal F Res (hip and knee) and moments (hip) were higher in the crawl kick than in the breaststroke kick, and a significant difference was recognized in F Res Max for the hip: median, 179% versus 118% of body weight (p = 0.028) for 0.5 m/s and 166% versus 133% of body weight (p = 0.028) for 1.0 m/s. CONCLUSIONS: Swimming is a safe and low-impact activity, particularly recommended for patients who undergo THA or TKA. Hip and knee joint loads are greater with higher swimming velocities and can be influenced by swimming styles. Nevertheless, concrete suggestions to patients who undergo arthroplasty on swimming should involve individual considerations. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Restoration of Hip Geometry after Femoral Neck Fracture: A Comparison of the Femoral Neck System (FNS) and the Dynamic Hip Screw (DHS).

BACKGROUND: The femoral neck system (FNS) was introduced as a minimally invasive fixation device for managing femoral neck fractures. OBJECTIVE: To compare radiographic, clinical, and patient-reported outcome measures (PROMs) of femoral neck fracture patients following FNS compared to dynamic hip screw (DHS) implantation combined with an anti-rotational screw. METHODS: Patients who underwent closed reduction and internal fixation of a femoral neck fracture between 2020 and 2022 were retrospectively included. We measured leg length, femoral offset, and centrum-collum-diaphyseal (CCD) angle in plain radiographs. Scar length, Harris Hip Score, short-form health survey 36-item score (SF-36), and Numeric Rating Scale (NRS) were assessed during follow-up visits. RESULTS: We included 43 patients (22 females) with a median age of 66 (IQR 57, 75). In both groups, leg length differences between the injured and the contralateral side increased, and femoral offset and CCD angle differences were maintained over time. FNS patients had shorter scars and reported fewer emotional problems and more energy. There were no differences between groups regarding the remaining SF-36 sub-scores, Harris Hip Score, and NRS. CONCLUSIONS: The FNS allows for a comparable leg length, femoral offset, and CCD angle reconstruction while achieving similarly high functional and global health scores to the DHS.

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

Emergency thoracotomies in traumatic cardiac arrests following blunt trauma - experiences from a German level I trauma center.

PURPOSE: Resuscitative thoracotomies (RT) are the last resort to reduce mortality in patients suffering severe trauma. In recent years, indications for RT have been extended from penetrating to blunt trauma. However, discussions on efficacy are still ongoing, as data on this rarely performed procedure are often scarce. Therefore, this study analyzed RT approaches, intraoperative findings, and clinical outcome measures following RT in patients with cardiac arrest following blunt trauma. METHODS: All patients admitted to our level I trauma center's emergency room (ER) who underwent RT between 2010 and 2021 were retrospectively analyzed. Retrospective chart reviews were performed for clinical data, laboratory values, injuries observed during RT, and surgical procedures. Additionally, autopsy protocols were assessed to describe injury patterns accurately. RESULTS: Fifteen patients were included in this study with a median ISS of 57 (IQR 41-75). The 24-h survival rate was 20%, and the total survival rate was 7%. Three approaches were used to expose the thorax: Anterolateral thoracotomy, clamshell thoracotomy, and sternotomy. A wide variety of injuries were detected, which required complex surgical interventions. These included aortic cross-clamping, myocardial suture repairs, and pulmonary lobe resections. CONCLUSION: Blunt trauma often results in severe injuries in various body regions. Therefore, potential injuries and corresponding surgical interventions must be known when performing RT. However, the chances of survival following RT in traumatic cardiac arrest cases following blunt trauma are small.

Inactivation of the gene encoding procalcitonin prevents antibody-mediated arthritis.

BACKGROUND: Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA. METHODS: Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca-/-), lacking PCT (n = 15), and wild-type (WT) mice (n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48 days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography. RESULTS: Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, while Calca-deficiency preserved bone integrity. CONCLUSION: The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA.

Individual immune cell and cytokine profiles determine platelet-rich plasma composition.

OBJECTIVE: Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. DESIGN: For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. RESULTS: All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 (COL1A1), COL2A1, and aggrecan (ACAN) as well as reduced proteoglycan content. CONCLUSIONS: Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual's immune profile and the concentration method appear to impact the final PRP product. TRIAL REGISTRATION: This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).

Intramuscular and intratendinous placenta-derived mesenchymal stromal-like cell treatment of a chronic quadriceps tendon rupture.

BACKGROUND: Quadriceps tendon ruptures (QTRs) are rare but debilitating injuries, often associated with chronic metabolic conditions or long-term steroid treatment. While the surgical treatment for acute QTRs is described thoroughly, no common strategy exists for the often frustrating treatment of chronic, reoccurring QTRs. The pro-angiogenic and immunomodulatory properties of placenta-derived adherent mesenchymal stromal-like (PLX-PAD) cells have been described to protect musculoskeletal tissues from inflammation and catabolic cytokine migration, yet little is known about the regenerative potential of PLX-PAD cells in repetitively damaged tendon tissue. CASE: We report the case of an 80-year-old male patient with a chronic three-time QTR of his right knee. The quadriceps tendon was reconstructed applying a conventional suture anchor repair procedure combined with a synthetic mesh augmentation and additional intramuscular and intratendineous PLX-PAD cell injections as an individualized treatment approach. No adverse events were reported, and excellent radiological and functional outcomes with a passive range of motion of 0/0/120° knee extension-flexion were observed at the 12 month follow-up. Gait analysis confirmed restoration of joint motion, including gait speed, deficit in step length, and knee extensor muscle strength (pre-surgery: 0.98 m/s, 40 cm, 42.4 ± 12.4 N; 9 months post-surgery: 1.07 m/s, 0 cm, 10.4 ± 18.9 N) as well as hyperextension throughout stance and late swing phases (pre-surgery: -11.2 ± 0.9°; 9 months post-surgery: -2.7 ± 1.6°). Postoperative lymphocyte and cytokine analyses from the patient's peripheral blood serum suggested a systemic short-term immunoregulatory reaction with postoperatively increased interleukin (IL)-6 (pre-surgery: 0.79 pg/mL; day 1: 139.97 pg/mL; day 5: 5.58 pg/mL; 9 months: 1.76 pg/mL) and IL-10 (pre-surgery: 0.9 pg/mL; day 1: 1.21 pg/ mL; day 5: 0.3 pg/mL; 9 months: 0.34 pg/mL) levels that decreased again over time. CONCLUSIONS: Herein, we demonstrate a successfully treated chronic QTR with a synergistic surgical and biological reconstructive treatment approach. This local add-on treatment with PLX-PAD cells may be considered in specific cases of chronic QTRs, not susceptible to traditional suture anchor procedures and which exhibit a high risk of treatment failure. Further scientific engagement is warranted to explore underlying immunomodulatory mechanisms of action behind PLX-PAD cell treatment for tendon injuries.

Decreased Medical Care During the COVID-19 Pandemic - A Comprehensive Analysis of Radiological Examinations.

OBJECTIVES: As a cross-section discipline within the hospital infrastructure, radiological departments might be able to provide important information regarding the impact of the COVID-19 pandemic on healthcare. The goal of this study was to quantify changes in medical care during the first wave of the pandemic using radiological examinations as a comprehensive surrogate marker and to determine potential future workload. METHODS: A retrospective analysis of all radiological examinations during the first wave of the pandemic was performed. The number of examinations was compared to time-matched control periods. Furthermore, an in-depth analysis of radiological examinations attributed to various medical specialties was conducted and postponed examinations were extrapolated to calculate additional workload in the near future. RESULTS: A total of 596,760 examinations were analyzed. Overall case volumes decreased by an average of 41 % during the shutdown compared to the control period. The most affected radiological modalities were sonography (-54 %), X-ray (-47 %) followed by MRI (-42 %). The most affected medical specialty was trauma and orthopedics (-60 % case volume) followed by general surgery (-49 %). Examination numbers increased during the post-shutdown period leading to a predicted additional workload of up to 22 %. CONCLUSION: This study shows a marked decrease in radiological examinations in total and among several core medical specialties, indicating a significant reduction in medical care during the first COVID-19 shutdown. KEY POINTS: · Number of radiological examinations decreased by 41 % during the first wave of the COVID-19 pandemic.. · Several core medical specialties were heavily affected with a reduction of case volumes up to 60 %.. · When extrapolating postponed examinations to the near future, the overall workload for radiological departments might increase up to 22 %.. CITATION FORMAT: · Fleckenstein FN, Maleitzke T, Böning G et al. Decreased Medical Care During the COVID-19 Pandemic - A Comprehensive Analysis of Radiological Examinations. Fortschr Röntgenstr 2021; 193: 937 - 946.

Combining Transarterial Radioembolization (TARE) and CT-Guided High-Dose-Rate Interstitial Brachytherapy (CT-HDRBT): A Retrospective Analysis of Advanced Primary and Secondary Liver Tumor Treatment.

PURPOSE: Treatment of patients with primary and secondary liver tumors remains challenging. This study analyzes the efficacy and safety of transarterial radioembolization (TARE) combined with CT-guided high-dose-rate interstitial brachytherapy (CT-HDRBT) for the treatment of primary and secondary liver tumors. PATIENTS AND METHODS: A total of 77 patients (30 female) with various liver malignancies were treated. Primary endpoints were median overall survival (OS) and time to untreatable progression (TTUP). Additionally, subgroup analyses were performed in consideration of diagnosis and procedure sequence. Median OS and TTUP prediction were estimated using Kaplan-Meier analysis and hazard ratios (HR) were calculated using a multivariate Cox proportional hazard model. RESULTS: A total of 115 CT-HDRBT and 96 TARE procedures were performed with no significant complications recorded. Median OS and TTUP were 29.8 (95% CI 18.1-41.4) and 23.8 (95% CI 9.6-37.9) months. Median OS for hepatocellular carcinoma (HCC)-, cholangiocarcinoma carcinoma (CCA) and colorectal cancer (CRC) patients was 29.8, 29.6 and 34.4 months. Patients starting with TARE had a median OS of 26.0 (95% CI 14.5-37.5) compared to 33.7 (95% CI 21.6-45.8) months for patients starting with CT-HDRBT. Hazard ratio of 1.094 per month was shown for patients starting with CT-HDRBT. CONCLUSION: Combining TARE and CT-HDRBT is effective and safe for the treatment of advanced stage primary and secondary liver tumors. Our data indicate that early TARE during the disease progression may have a positive effect on survival.

Can an acute high-grade acromioclavicular joint separation be reduced and stabilized without surgery? A surgeon's experience.

INTRODUCTION: While the management of Rockwood type III injuries is still a topic of debate, high-grade Rockwood type V injuries are mostly treated surgically, to anatomically reduce the acromioclavicular (AC) joint and to restore functionality. In this case report, we present a method for non-operative reduction and stabilization of a high-grade AC joint injury. CASE: A 31-year-old male orthopaedic resident sustained a Rockwood type V injury during a snowboarding accident. His AC joint was reduced and stabilized with an AC joint brace for six weeks. The brace provided active clavicle depression and humeral elevation. After removal of the brace the AC joint showed a nearly anatomic reduction. Six-month follow-up weighted X-ray views showed an AC joint which had healed in a Rockwood type II position and the patient returned to full pre-injury function with a satisfying cosmetic appearance. CONCLUSION: Non-operative reduction and stabilization of high-grade AC joint separations seems to be a valuable treatment option. A "closed reduction and external fixation" approach with the aid of a dedicated AC joint brace can reduce the AC joint and keep it in place until ligamentous consolidation occurs, thus improving AC joint stability and cosmetic appearance without surgical intervention.

Haematoma block: a safe method for pre-surgical reduction of distal radius fractures.

BACKGROUND: The haematoma block (HB) has been successfully used to minimise pain prior to otherwise painful closed reduction manoeuvres for distal radius fractures. However, the invasive manner of the procedure, which technically produces an open fracture, still raises the question, whether HBs increase the risk of infection compared to conventional intravenous analgesia (IA). The purpose of this study was to assess complication rates and safety of the HB procedure for the closed reduction of surgically treated distal radius fractures. METHODS: We included 176 distal radius fractures in 170 patients in a retrospective mono-centric study, who underwent closed reduction and casting followed by definitive surgical care over a period of two years. Patients either received a HB or IA before closed reduction and were evaluated for minor and major complications over a follow-up period of four years. RESULTS: Overall, 42 distal radius fractures were treated with a HB (23.9%) and 134 with IA (76.1%) before closed reduction. There were a single major (2.3%) and eight minor (19%) complications observed in the HB group compared to two major (1.4%) and 24 minor (17.9%) complications in the IA group. No significant differences were identified between the two groups. Sex and type of fracture had no effect on complication rates, however, younger patients experienced higher complication rates in comparison to older ones (p = 0.035). CONCLUSION: According to our data, the apprehensions that clinicians may have of creating open fractures through HB procedures, are unnecessary and may be abandoned confidently.

Mesenchymal stromal cell and bone marrow concentrate therapies for musculoskeletal indications: a concise review of current literature.

The interest on applying mesenchymal stromal cells (MSCs) in orthopedic disorders has risen tremendously in the last years due to scientific successes in preclinical in vitro and animal model studies. In a wide range of diseases and injuries of the musculoskeletal system, MSCs are currently under evaluation, but so far have found access to clinical use only in few cases. The current assignment is to translate the acquired knowledge into clinical practice. Therefore, this review aims at presenting a synopsis of the up-to-date status of the use of MSCs and MSC related cell products in musculoskeletal indications. Clinical studies were included, whereas preclinical and animal study data not have been considered. Most studies published so far investigate the final outcome applying bone marrow derived MSCs. In fewer trials the use of adipose tissue derived MSCs and allogenic MSCs was investigated in different applications. Although the reported results are equivocal in the current literature, the vast majority of the studies shows a benefit of MSC based therapies depending on the cell sources and the indication in clinical use. In summary, the clinical use of MSCs in patients in orthopedic indications has been found to be safe. Standardized protocols and clear definitions of the mechanisms of action and the mode and timing of application as well as further coordinated research efforts will be necessary for finally adding MSC based therapies in standard operating procedures and guidelines for the clinicians treating orthopedic disorders.

A case report of cutaneous mucormycosis of the hand after minor trauma in a patient with acute myeloid leukaemia.

BACKGROUND: Mucormycosis is a rare but life-threatening infection, caused by fungi of the Mucorales order, which can be found in soil, rotting leaves or on animals. Through characteristic angioinvasive growth, infections with mucor spores can occur as a pulmonary, rhinocerebral or cutaneous form. Infections mainly affect immunosuppressed patients with a history of uncontrolled diabetes or haematological malignancies, among others. Treatment is multimodal and requires an immediate combination of intravenous amphotericin B therapy and serial surgical debridements. Only a limited number of cases of cutaneous mucormycosis of the hand have been documented and described previously. CASE PRESENTATION: We report a cutaneous mucormycosis in an elderly patient with a therapy-resistant acute myeloid leukaemia after a minor trauma on his right hand, sustained whilst gardening. The fungal infection was treated with serial radical debridements, vacuum-assisted negative-pressure wound closure technique and intravenous antifungals. Despite successful eradication of the fungal infection, a palliative open wound care concept was implemented during the terminal course of the patient's leukaemia. CONCLUSIONS: Cutaneous mucormycosis is a rare but fulminant fungal infection mostly affecting immunosuppressed patients. Survival is possible when diagnosed and treated early, yet mortality rates remain high.

Tocilizumab: a novel humanized anti-interleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic, inflammatory rheumatic diseases.

Tocilizumab is a highly effective therapeutic agent for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. Furthermore, a large amount of case study data reveals that tocilizumab can be an effective therapy for not only rheumatoid arthritis but also for other mostly rare inflammatory rheumatic diseases. By blocking the interleukin-6 pathway tocilizumab can be a useful therapeutic alternative when conventional treatment fails. It is successful in treating diseases such as the adult-onset Still's disease, amyloidosis, giant cell arteritis, multiple myeloma, polymyalgia rheumatica, relapsing polychondritis, remitting seronegative symmetrical synovitis with pitting edema-syndrome, systemic lupus erythematosus, systemic sclerosis, and Takayasu arteritis. Studies underway are now recruiting patients to acquire further data on treating patients with non-rheumatic arthritis, inflammatory diseases. This review focuses on tocilizumab as a promising agent for treating rare and orphan diseases in rheumatology for which no satisfactory treatment is yet available.