Given the progressive ageing of Western populations, the fragility fractures market has a growing socioeconomic impact. Fragility fractures are common in the elderly, negatively impacting their quality of life, limiting autonomy, increasing disability, and decreasing life expectancy. Different causes contribute to the development of a fractures in frail individuals. Among all, targeting fragile patients before the development of a fracture may represent the greatest challenge, and current diagnostic tools suffer from limitations. This study summarizes the current evidence on the management of fragility fractures, discussing risk factors, prevention, diagnosis, and actual limitations of the clinical therapeutic options, putting forward new ideas for further scientific investigation.

The treatment of bone defects remains a challenging clinical problem with high reintervention rates, morbidity, and resulting significant healthcare costs. Surgical techniques are constantly evolving, but outcomes can be influenced by several parameters, including the patient’s age, comorbidities, systemic disorders, the anatomical location of the defect, and the surgeon’s preference and experience. The most used therapeutic modalities for the regeneration of long bone defects include distraction osteogenesis (bone transport), free vascularized fibular grafts, the Masquelet technique, allograft, and (arthroplasty with) mega-prostheses. Over the past 25 years, three-dimensional (3D) printing, a breakthrough layer-by-layer manufacturing technology that produces final parts directly from 3D model data, has taken off and transformed the treatment of bone defects by enabling personalized therapies with highly porous 3D-printed implants tailored to the patient. Therefore, to reduce the morbidities and complications associated with current treatment regimens, efforts have been made in translational research toward 3D-printed scaffolds to facilitate bone regeneration. Three-dimensional printed scaffolds should not only provide osteoconductive surfaces for cell attachment and subsequent bone formation but also provide physical support and containment of bone graft material during the regeneration process, enhancing bone ingrowth, while simultaneously, orthopaedic implants supply mechanical strength with rigid, stable external and/or internal fixation. In this perspective review, we focus on elaborating on the history of bone defect treatment methods and assessing current treatment approaches as well as recent developments, including existing evidence on the advantages and disadvantages of 3D-printed scaffolds for bone defect regeneration. Furthermore, it is evident that the regulatory framework and organization and financing of evidence-based clinical trials remains very complex, and new challenges for non-biodegradable and biodegradable 3D-printed scaffolds for bone regeneration are emerging that have not yet been sufficiently addressed, such as guideline development for specific surgical indications, clinically feasible design concepts for needed multicentre international preclinical and clinical trials, the current medico-legal status, and reimbursement. These challenges underscore the need for intensive exchange and open and honest debate among leaders in the field. This goal can be addressed in a well-planned and focused stakeholder workshop on the topic of patient-specific 3D-printed scaffolds for long bone defect regeneration, as proposed in this perspective review.

Introduction: Physician-staffed helicopter emergency medical services (HEMS) are a well-established component of prehospital trauma care in Germany. Reduced rescue times and increased catchment area represent presumable specific advantages of HEMS. In contrast, the availability of HEMS is connected to a high financial burden and depends on the weather, day time and controlled visual flight rules. To date, clear evidence regarding the beneficial effects of HEMS in terms of improved clinical outcome has remained elusive. Methods: Traumatized patients (Injury Severity Score; ISS ≥9) primarily treated by HEMS or ground emergency medical services (GEMS) between 2007 and 2009 were analyzed using the TraumaRegister DGU^® of the German Society for Trauma Surgery. Only patients treated in German level I and II trauma centers with complete data referring to the transportation mode were included. Complications during hospital treatment included sepsis and organ failure according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) consensus conference committee and the Sequential Organ Failure Assessment (SOFA) score. Results: A total of 13,220 patients with traumatic injuries were included in the present study. Of these, 62.3% (n = 8,231) were transported by GEMS and 37.7% (n = 4,989) by HEMS. Patients treated by HEMS were more seriously injured compared to GEMS (ISS 26.0 vs. 23.7, P < 0.001) with more severe chest and abdominal injuries. The extent of medical treatment on-scene, which involved intubation, chest and treatment with vasopressors, was more extensive in HEMS (P < 0.001) resulting in prolonged on-scene time (39.5 vs. 28.9 minutes, P < 0.001). During their clinical course, HEMS patients more frequently developed multiple organ dysfunction syndrome (MODS) (HEMS: 33.4% vs. GEMS: 25.0%; P < 0.001) and sepsis (HEMS: 8.9% vs. GEMS: 6.6%, P < 0.001) resulting in an increased length of ICU treatment and in-hospital time (P < 0.001). Multivariate logistic regression analysis found that after adjustment by 11 other variables the odds ratio for mortality in HEMS was 0.75 (95% CI: 0.636 to 862). Afterwards, a subgroup analysis was performed on patients transported to level I trauma centers during daytime with the intent of investigating a possible correlation between the level of the treating trauma center and posttraumatic outcome. According to this analysis, the Standardized Mortality Ratio, SMR, was significantly decreased following the Trauma Score and the Injury Severity Score (TRISS) method (HEMS: 0.647 vs. GEMS: 0.815; P = 0.002) as well as the Revised Injury Severity Classification (RISC) score (HEMS: 0.772 vs. GEMS: 0.864; P = 0.045) in the HEMS group. Conclusions: Although HEMS patients were more seriously injured and had a significantly higher incidence of MODS and sepsis, these patients demonstrated a survival benefit compared to GEMS.

Although therapeutic concepts of patients with major trauma have improved during recent years, organ dysfunction still remains a frequent complication during clinical course in intensive care units. It has previously been shown that cytokines are upregulated under stress conditions such as trauma or sepsis. However, it is still debatable if cytokines are adequate parameters to describe the current state of trauma patients. To elucidate the relevance of cytokines, we investigated if cytokines predict development of multiple organ dysfunction syndrome (MODS) or outcome. A total of 143 patients with an injury severity score ≥ 16, between 16 and 65 years, admitted to the Hannover Medical School Level 1 Trauma Center between January 1997 and December 2001 were prospectively included in this study. Marshall Score for MODS was calculated for at least 14 days and plasma levels of TNF-α, IL-1β, IL-6, IL-8 and IL-10 were measured. To determine the association between cytokine levels and development of MODS the Spearman rank correlation coefficient was calculated and logistic regression and analysis were performed. Patients with MODS had increased plasma levels of IL-6, IL-8 and IL-10. IL-6 predicted development of MODS with an overall accuracy of 84.7% (specificity: 98.3%, sensitivity: 16.7%). The threshold value for development of MODS was 761.7 pg/ml and 2176.0 pg/ml for mortality during the in patient time. We conclude that plasma IL-6 levels predict mortality and that they are a useful tool to identify patients who are at risk for development of MODS.

Bone defects after trauma, infection, or tumour resection present a challenge for patients and clinicians. To date, autologous bone graft (ABG) is the gold standard for bone regeneration. To address the limitations of ABG such as limited harvest volume as well as overly fast remodelling and resorption, a new treatment strategy of scaffold-guided bone regeneration (SGBR) was developed. In a well-characterized sheep model of large to extra-large tibial segmental defects, three-dimensional (3D) printed composite scaffolds have shown clinically relevant biocompatibility and osteoconductive capacity in SGBR strategies. Here, we report four challenging clinical cases with large complex posttraumatic long bone defects using patient-specific SGBR as a successful treatment. After giving informed consent computed tomography (CT) images were used to design patient-specific biodegradable medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP, 80:20 ​wt%) scaffolds. The CT scans were segmented using Materialise Mimics to produce a defect model and the scaffold parts were designed with Autodesk Meshmixer. Scaffold prototypes were 3D-printed to validate robust clinical handling and bone defect fit. The final scaffold design was additively manufactured under Food and Drug Administration (FDA) guidelines for patient-specific and custom-made implants by Osteopore International Pte Ltd. Four patients (age: 23–42 years) with posttraumatic lower extremity large long bone defects (case 1: 4 ​cm distal femur, case 2: 10 ​cm tibia shaft, case 3: complex malunion femur, case 4: irregularly shaped defect distal tibia) are presented. After giving informed consent, the patients were treated surgically by implanting a custom-made mPCL-TCP scaffold loaded with ABG (case 2: additional application of recombinant human bone morphogenetic protein-2) harvested with the Reamer-Irrigator-Aspirator system (RIA, Synthes®). In all cases, the scaffolds matched the actual anatomical defect well and no perioperative adverse events were observed. Cases 1, 3 and 4 showed evidence of bony ingrowth into the large honeycomb pores (pores >2 ​mm) and fully interconnected scaffold architecture with indicative osseous bridges at the bony ends on the last radiographic follow-up (8–9 months after implantation). Comprehensive bone regeneration and full weight bearing were achieved in case 2 ​at follow-up 23 months after implantation. This study shows the bench to bedside translation of guided bone regeneration principles into scaffold-based bone tissue engineering. The scaffold design in SGBR should have a tissue-specific morphological signature which stimulates and directs the stages from the initial host response towards the full regeneration. Thereby, the scaffolds provide a physical niche with morphology and biomaterial properties that allow cell migration, proliferation, and formation of vascularized tissue in the first one to two months, followed by functional bone formation and the capacity for physiological bone remodelling. Great design flexibility of composite scaffolds to support the one to three-year bone regeneration was observed in four patients with complex long bone defects. This study reports on the clinical efficacy of SGBR in the treatment of long bone defects. Moreover, it presents a comprehensive narrative of the rationale of this technology, highlighting its potential for bone regeneration treatment regimens in patients with any type of large and complex osseous defects.