Anchor-based minimal important difference values are often sensitive to the distribution of the change score.

PURPOSE: Anchor-based studies are today the most popular approach to determine a minimal important difference value for an outcome variable. However, a variety of construction methods for such values do exist. This constitutes a challenge to the field. In order to distinguish between more or less adequate construction methods, meaningful minimal requirements can be helpful. For example, minimal important difference values should not reflect the intervention(s) the patients are exposed to in the study used for construction, as they should later allow to compare interventions. This requires that they are not sensitive to the distribution of the change score observed. This study aims at investigating to which degree established construction methods fulfil this minimal requirement. METHODS: Six constructions methods were considered, covering very popular and recently suggested methods. The sensitivity of MID values to the distribution of the change score was investigated in a simulation study for these six construction methods. RESULTS: Five out of six construction methods turned out to yield MID values which are sensitive to the distribution of the change score to a degree that questions their usefulness. Insensitivity can be obtained by using construction methods based solely on an estimate of the conditional distribution of the anchor variable given the change score. CONCLUSION: In future the computation of MID values should be based on construction methods avoiding sensitivity to the distribution of the change score.

Unsupervised machine-learning algorithms for the identification of clinical phenotypes in the osteoarthritis initiative database.

OBJECTIVES: Osteoarthritis (OA) is a complex disease comprising diverse underlying patho-mechanisms. To enable the development of effective therapies, segmentation of the heterogenous patient population is critical. This study aimed at identifying such patient clusters using two different machine learning algorithms. METHODS: Using the progression and incident cohorts of the Osteoarthritis Initiative (OAI) dataset, deep embedded clustering (DEC) and multiple factor analysis with clustering (MFAC) approaches, including 157 input-variables at baseline, were employed to differentiate specific patient profiles. RESULTS: DEC resulted in 5 and MFAC in 3 distinct patient phenotypes. Both identified a "comorbid" cluster with higher body mass index (BMI), relevant burden of comorbidity and low levels of physical activity. Both methods also identified a younger and physically more active cluster and an elderly cluster with functional limitations, but low disease impact. The additional two clusters identified with DEC were subgroups of the young/physically active and the elderly/physically inactive clusters. Overall pain trajectories over 9 years were stable, only the numeric rating scale (NRS) for pain showed distinct increase, while physical activity decreased in all clusters. Clusters showed different (though non-significant) trajectories of joint space changes over the follow-up period of 8 years. CONCLUSION: Two different clustering approaches yielded similar patient allocations primarily separating complex "comorbid" patients from healthier subjects, the latter divided in young/physically active vs elderly/physically inactive subjects. The observed association to clinical (pain/physical activity) and structural progression could be helpful for early trial design as strategy to enrich for patients who may specifically benefit from disease-modifying treatments.

The impact of specific fracture characteristics of low-energy fractures of the pelvis on mortality.

BACKGROUND: Pelvic fractures in older patients are associated with relevant morbidity and mortality. Both might be determined by fracture morphology and/or patient characteristics. The aim of this project is to investigate the prognostic value of specific fracture characteristics with respect to overall survival and to compare it with an established classification system. METHODS: Retrospective analysis of patients ≥ 60 years, treated conservatively for a CT-scan verified, low-energy pelvic ring fracture between August 2006 and December 2018. Survival data was available from patients' charts and cantonal or national registries. The prognostic value of fracture characteristic describing the anterior and posterior involvement of the pelvic ring was investigated. This analysis was repeated after patients were stratified into a high-risk vs a low-risk group according to patient characteristic (age, gender, comorbidities, mobility, living situation). This allowed to assess the impact of the different fracture morphologies on mortality in fit vs. frail senior patients separately. RESULTS: Overall, 428 patients (83.4% female) with a mean age of 83.7 years were included. Two thirds of patients were still living in their home and mobile without walking aid at baseline. In-hospital mortality was 0.7%, overall, one-year mortality 16.9%. An independent and significant association of age, gender and comorbidities to overall survival was found. Further, the occurrence of a horizontal sacral fracture as well as a ventral comminution or dislocation was associated with an increased mortality. The effect of a horizontal sacral fracture was more accentuated in low-risk patients while the ventral fracture components showed a larger effect on survival in high-risk patients. CONCLUSION: Specific fracture characteristics may indicate a higher risk of mortality in conservatively treated patients with a low-energy pelvic ring fracture. Hence, they should be taken into account in future treatment algorithms and decisions on patient management.

Focusing on individual morphological fracture characteristics of pelvic ring fractures in elderly patients can support clinical decision making.

INTRODUCTION: Pelvic ring fractures in the elderly are often caused by minor trauma. Treatment of these patients is currently based on fracture classification, clinical course, and ability to mobilize. Our aim was to identify morphological fracture characteristics with potential prognostic relevance and evaluate their association with clinical decision making and outcome, as well as their interobserver reliability. METHODS: Five fracture characteristics were investigated as potential variables: 1. Extent of the dorsal pelvic ring fracture (absent, unilateral, bilateral); 2. Extent of the ventral pelvic ring fracture (absent, unilateral, bilateral); 3. Presence of a horizontal sacral fracture; 4. Ventral dislocation; 5. Ventral comminution. These characteristics were assessed retrospectively in a series of 548 patients. The association of their presence with the decision to perform surgery, failure of conservative treatment and the length of hospital stay (LOS) was determined. Further, the inter-observer reliability for the specific characteristics was calculated and the relation with survival assessed. RESULTS: Four of the five evaluated characteristics showed an association with clinical decision making and patient management. In particular the extent of the dorsal fractures (absent vs. unilateral vs. bilateral) (OR = 7.0; p < 00.1) and the presence of ventral comminution/dislocation (OR = 2.4; p = 0.004) were independent factors for the decision to perform surgery. Both the extent of the dorsal fracture (OR = 1.8; p < 0.001) and the presence of ventral dislocation (OR = 1.7; p = 0.003) were independently associated with a prolonged overall LOS. The inter-observer agreement for the fracture characteristics ranged from moderate to substantial. A relevant association with increased mortality was shown for horizontal sacral and comminuted ventral fractures with hazard ratios (HR) of 1.7 (95% CI: 1.1, 2.5; p = 0.008) and HR = 1.5 (95% CI: 1.0, 2.2; p = 0.048). CONCLUSION: In the elderly, the extent of the dorsal fractures and the presence of ventral comminution/dislocation were associated to the decision to undergo surgery, failure of conservative treatment and length of stay. Survival was related to horizontal sacral fractures and ventrally comminuted fractures. These characteristics thus represent a simplified but highly informative approach for the evaluation of pelvic ring fractures in the elderly. This approach can support clinical decision making, promote patient-centred treatment algorithms and thus improve the outcome of individualized care.

Case Report: Reconstruction of a Large Maxillary Defect With an Engineered, Vascularized, Prefabricated Bone Graft.

The reconstruction of complex midface defects is a challenging clinical scenario considering the high anatomical, functional, and aesthetic requirements. In this study, we proposed a surgical treatment to achieve improved oral rehabilitation and anatomical and functional reconstruction of a complex defect of the maxilla with a vascularized, engineered composite graft. The patient was a 39-year-old female, postoperative after left hemimaxillectomy for ameloblastic carcinoma in 2010 and tumor-free at the 5-year oncological follow-up. The left hemimaxillary defect was restored in a two-step approach. First, a composite graft was ectopically engineered using autologous stromal vascular fraction (SVF) cells seeded on an allogenic devitalized bone matrix. The resulting construct was further loaded with bone morphogenic protein-2 (BMP-2), wrapped within the latissimus dorsi muscle, and pedicled with an arteriovenous (AV) bundle. Subsequently, the prefabricated graft was orthotopically transferred into the defect site and revascularized through microvascular surgical techniques. The prefabricated graft contained vascularized bone tissue embedded within muscular tissue. Despite unexpected resorption, its orthotopic transfer enabled restoration of the orbital floor, separation of the oral and nasal cavities, and midface symmetry and allowed the patient to return to normal diet as well as to restore normal speech and swallowing function. These results remained stable for the entire follow-up period of 2 years. This clinical case demonstrates the safety and the feasibility of composite graft engineering for the treatment of complex maxillary defects. As compared to the current gold standard of autologous tissue transfer, this patient's benefits included decreased donor site morbidity and improved oral rehabilitation. Bone resorption of the construct at the ectopic prefabrication site still needs to be further addressed to preserve the designed graft size and shape.

Kinesiotaping for postoperative oedema - what is the evidence? A systematic review.

BACKGROUND: Postoperative oedema is a common condition affecting wound healing and function. Traditionally, manual lymphatic drainage is employed to reduce swelling. Kinesiotaping might be an alternative resource-sparing approach. This article explores current evidence for the effectiveness of kinesiotaping for the reduction of oedema in the postoperative setting. METHODS: A systematic literature search was performed on the basis of five databases (Pubmed, CINAHL, Embase, Cochrane Library, and Clinicaltrials.gov) for studies published between January 2000 and October 2019.Only prospective controlled trials were included. Case studies, uncontrolled case series, studies on oedema caused by other etiologies than by surgery, as well as studies on malignant disease related oedema (especially breast cancer related oedema) were excluded.Articles were screened by title, abstract, and full text and the references were searched for further publications on the topic. A narrative and quantitative (using STATA) analysis was performed. RESULTS: One thousand two hundred sixty-three articles were screened, twelve were included in the analysis. All studies evaluated either oedema after extremity surgery or maxillofacial interventions, and showed relevant methodological flaws. Only three studies employed an active comparator. Of the twelve included studies ten found positive evidence for kinesiotape application for the reduction of swelling and beneficial effects on secondary outcome parameters such as pain and patient satisfaction. The available trials were heterogenic in pathology and all were compromised by a high risk of bias. CONCLUSION: There is some evidence for the efficacy of kinesiotaping for the treatment of postoperative oedema. This evidence is, however, not yet convincing given the limitations of the published trials. Methodologically sound comparison to standard of care or an active comparator is indispensable for an evaluation of effectiveness. In addition, assessments of patient comfort and cost-benefit analyses are necessary to evaluate the potential relevance of this novel technique in daily practice. SYSTEMATIC REVIEW REGISTRATION NUMBER: International prospective register of systematic reviews (PROSPERO) ID 114129).

The Masquelet technique in traumatic loss of the talus after open lateral subtalar dislocation-A case report.

INTRODUCTION: Subtalar dislocations are rare injuries and treatment recommendations missing. Gross contamination and devascularisation are aspects supporting talectomy as potential treatment choice. Reconstruction in these cases can be challenging. The Masquelet technique presents one viable option. PRESENTATION OF CASE: A carpenter sustained a high energy chrush injury with traumatic open lateral talar dislocation qualifying as Gustillo Anderson type IIIc injury, a mangeled extremity index of 7 and gross contamination. The severity of soft tissue damage and contamination prompted the decision for talectomy before plastic coverage with a gracilis flap. Additionally a Masquelet procedure with cement spacer was initiated. After consolidation of the soft tissues a hindfoot arthrodesis with approximate preservation of leg length could be performed. In the course of treatment, the patient suffered no infection and could resume full weight bearing after nine months. The patient resumed his previous occupation with adapted workload and is satisfied with the treatment result. DISCUSSION: In the present case the principle options were talus preservation or talectomy with reconstruction. Talus preservation in the presence of gross contamination can be associated with the risk of infection, in addition there is a risk to develop secondary arthritis. For this individual patient the a fast and definite solution was important at this point in life. Surgeons therefore opted for talectomy. To optimally reconstruct leg length and optimize for arthrodesis the Masquelet technique was employed. CONCLUSION: The Masquelet technique is a viable option also in the emergency situation to preserve extremity length and optimize tissue viability.

Routine patient surveys: Patients' preferences and information gained by healthcare providers.

BACKGROUND: Patient feedback after contact with a hospital is regarded as an important source of information for the improvement of local healthcare services. Routine patient surveys are in widespread use to obtain such feedback. While general principles for the composition of this kind of surveys have been described in the literature, it is unknown which method of contact and topics of feedback are important to patients in postcontact healthcare surveys. MATERIAL AND METHODS: We invited 2931 consecutive patients who had in- or outpatient contact with the Department of Orthopaedics and Traumatology at the University Hospital Basel to an anonymous survey. They were asked whether they were generally in favor of feedback surveys. They also had the opportunity to state their preferred form of contact (text message, app, email, online or letter) and provide up to three topics that they regarded as specifically important in patient surveys. RESULTS: A total of 745 patients participated in the survey (25.4%), of these 61.9% expressed the preference to be surveyed, and 69.1% selected `letter' as one of the preferred forms of contact. Favoring only `letter' contact increased substantially with age. Overall 54.6% of patients stated at least one topic that they wished to give feedback on. The most frequent topics were related to treatment and rather general aspects regarding staff and overall impression. The wish to include suggestions for improvements was rarely mentioned as specific topic. CONCLUSIONS: The majority of patients seem to be rather indifferent to the existence and content of patient surveys. They mention a wide range of topics from general to specific ones, but do not express interest in the opportunity to suggest changes. There is a need to effectively engage patients in healthcare planning using new approaches to obtain valuable feedback on patients' hospital stay and contact experiences. These new approaches should ideally be more informative and cost-effective than the current practice.

Tissue engineering for paediatric patients.

The effects of oncological treatment, congenital anomalies, traumatic injuries and post-infection damage critically require sufficient amounts of tissue for structural and functional surgical reconstructions. The patient’s own body is typically the gold standard source of transplant material, but in children autologous tissue is available only in small quantities and with severe morbidity at donor sites. Engineering of tissue grafts starting from a small amount of autologous material, combined with suitable surgical manipulation of the recipient site, is expected to enhance child and adolescent health, and to offer functional restoration for long-term wellbeing. Moreover, engineered tissues based on patient-derived cells represent invaluable models to investigate mechanisms of disease and to develop/test novel therapeutic approaches. In view of these great opportunities, here we introduce the currently limited successful implementation of tissue engineering in paediatric settings and discuss the open challenges in the field. A particular focus is on the specific needs and envisioned strategies in the areas of bone and osteochondral regeneration in children.

Handling of informed consent and patient inclusion in research with geriatric trauma patients - a matter of protection or disrespect?

BACKGROUND: Despite the aging of numerous societies and future health care challenges, clinical research in the elderly is underrepresented. The aim of this review was to analyze the current practice exemplary in gerontotraumatology and to discuss potential improvements. MATERIALS AND METHODS: A literature review was performed in 2016 based on a PubMed search for gerontotraumatologic studies published between 2005 and 2015. Trials were evaluated for methodology and ethical and age-related aspects. RESULTS: The search revealed 649 articles, 183 of which met the inclusion criteria. The age range for inclusion was heterogeneous; one-third of trials included patients <65 years and only 11% excluded very elderly. Seventy-four trials excluded patients with typical comorbidities, with 55% of these without stating scientific reasons. Frailty was assessed in 94 trials and defined as the exclusion criterion in 66 of them. Informed consent (IC) was reportedly obtained in 144 trials; descriptions of the IC process mostly remained vague. Substitute decision making was described in 19 trials; the consenting party remained unclear in 45 articles. Diagnosed dementia was a primary exclusion criterion in 31% of the trials. Seventeen trials assessed decisional capacity before inclusion, with six using specific assessments. CONCLUSION: Many trials in gerontotraumatology exclude relevant subgroups of patients, and thus risk presenting biased estimates of the relevant treatment effects. Exclusion based on age, cognitive impairment, or other exhaustive exclusion criteria impedes specific scientific progress in the treatment of elderly patients. Meaningful trials could profit from a staged, transparent approach that fosters shared decision making. Rethinking current policies is indispensable to improve treatment and care of elderly trauma patients and to protect study participants and researchers alike.

The association of surgical drains with surgical site infections - A prospective observational study.

BACKGROUND: Surgical drains are widely used despite limited evidence in their favor. This study describes the associations between drains and surgical site infections (SSI). METHODS: This prospective observational double center study was performed in Switzerland between February 2013 and August 2015. RESULTS: The odds of SSI in the presence of drains were increased in general (OR 2.41, 95%CI 1.32-4.30, p = 0.004), but less in vascular and not in orthopedic trauma surgery. In addition to the surgical division, the association between drains and SSI depended significantly on the duration of surgery (p = 0.01) and wound class (p = 0.034). Furthermore, the duration of drainage (OR 1.24, 95%CI 1.15-1.35, p < 0.001), the number (OR 1.74, 95%CI 1.09-2.74, p = 0.019) and type of drains (open versus closed: OR 3.68, 95%CI 1.88, 6.89, p < 0.001) as well as their location (overall p = 0.002) were significantly associated with SSI. CONCLUSIONS: The general use of drains is discouraged. However, drains may be beneficial in specific surgical procedures.

Rationale and methods of an observational study to support the design of a nationwide surgical registry: the MIDAS study.

BACKGROUND Surgical registries are becoming increasingly popular. In addition, Swiss legislation requires data on therapeutic outcome quality. The Swiss Association of Surgeons (Schweizerische Gesellschaft Chirurgie, SGC-SCC) has already agreed on a first minimum data set. However, in the long run the scope and content of the registry should be evidence-based and not only accepted by professional stakeholders. The MIDAS study aims at providing such evidence for the example population of patients undergoing emergency or elective hip surgery. Five relevant aspects are considered: (1) choice of instruments for assessing health related quality of life (HRQoL); (2) optimal time-point for assessment; (3) use of proxy assessments; (4) choice of pre-surgery risk factors; and (5) assessment of peri- and postoperative variables. METHODS MIDAS is a longitudinal observational multicentre study. All patients suffering from a femoral neck fracture or from arthritis of the hip joint with an indication for prosthetic joint replacement surgery will be offered participation. The study is based on a combination of routine data from clinical standard practice with specifically documented data to be reported by the treating clinician and data to be collected in cooperation with the patient ­ in particular patient-reported outcome measures (PROMs). The latter include the Health Utility Index Mark 3 (HUI3) and Euro-Qol-5D (EQ-5D) as generic instruments, Hip Disability and Osteoarthritis Outcome Score (HOOS) as a disease specific instrument for the assessment of HRQoL, and two performance-based functional tests. Data will be collected at baseline, during hospitalisation/at discharge and at three routine follow-up visits. All patients will be asked to name a person for assessing proxy-perceived HRQoL. DISCUSSION To the best of our knowledge, this is the first study explicitly addressing questions about the design of a national surgical registry in an empirical manner. The study aims at providing a scientific base for decisions regarding scope and content of a potential national Swiss surgical registry. We designed a pragmatic study to envision data collection in a national registry with the option of specifying isolated research questions of interest. One focus of the study is the use of PROMs, and we hope that our study and their results will inspire also other surgical registries to take this important step forward. Trial registration Registered at the "Deutsches Register Klinischer Studien (DRKS)", the German Clinical Trials Registry, since this registry meets the scope and methodology of the proposed study. Registration no.: DRKS00012991

Minimally invasive anterior muscle-sparing versus a transgluteal approach for hemiarthroplasty in femoral neck fractures-a prospective randomised controlled trial including 190 elderly patients.

BACKGROUND: The relevance of femoral neck fractures (FNFs) increases with the ageing of numerous societies, injury-related decline is observed in many patients. Treatment strategies have evolved towards primary joint replacement, but the impact of different approaches remains a matter of debate. The aim of this trial was to evaluate the benefit of an anterior minimally-invasive (AMIS) compared to a lateral Hardinge (LAT) approach for hemiarthroplasty in these oftentimes frail patients. METHODS: Four hundred thirty-nine patients were screened during the 44-months trial, aiming at the evaluation of 150 patients > 60 yrs. of age. Eligible patients were randomised using an online-tool with completely random assignment. As primary endpoint, early mobility, a predictor for long-term outcomes, was evaluated at 3 weeks via the "Timed up and go" test (TUG). Secondary endpoints included the Functional Independence Measure (FIM), pain, complications, one-year mobility and mortality. RESULTS: A total of 190 patients were randomised; both groups were comparable at baseline, with a predominance for frailty-associated factors in the AMIS-group. At 3 weeks, 146 patients were assessed for the primary outcome. There was a reduction in the median duration of TUG performance of 21.5% (CI [- 41.2,4.7], p = 0.104) in the AMIS-arm (i.e., improved mobility). This reduction was more pronounced in patients with signs of frailty or cognitive impairment. FIM scores increased on average by 6.7 points (CI [0.5-12.8], p = 0.037), pain measured on a 10-point visual analogue scale decreased on average by 0.7 points (CI: [- 1.4,0.0], p = 0.064). The requirement for blood transfusion was lower in the AMIS- group, the rate of complications comparable, with a higher rate of soft tissue complications in the LAT-group. The mortality was higher in the AMIS-group. CONCLUSION: These results, similar to previous reports, support the concept that in elderly patients at risk of frailty, the AMIS approach for hemiarthroplasty can be beneficial, since early mobilisation and pain reduction potentially reduce deconditioning, morbidity and loss of independence. The results are, however, influenced by a plethora of factors. Only improvements in every aspect of the therapeutic chain can lead to optimisation of treatment and improve outcomes in this growing patient population. TRIAL REGISTRATION: www.clinicaltrials.gov : NCT01408693 (registered August 3rd 2011).

Associations of Hospital Length of Stay with Surgical Site Infections.

BACKGROUND: Surgical site infections (SSI) are a major cause of morbidity and mortality in surgical patients. Postoperative and total hospital length of stay (LOS) are known to be prolonged by the occurrence of SSI. Preoperative LOS may increase the risk of SSI. This study aims at identifying the associations of pre- and postoperative LOS in hospital and intensive care with the occurrence of SSI. METHODS: This observational cohort study includes general, orthopedic trauma and vascular surgery patients at two tertiary referral centers in Switzerland between February 2013 and August 2015. The outcome of interest was the 30-day SSI rate. RESULTS: We included 4596 patients, 234 of whom (5.1%) experienced SSI. Being admitted at least 1 day before surgery compared to same-day surgery was associated with a significant increase in the odds of SSI in univariate analysis (OR 1.65, 95% CI 1.25-2.21, p < 0.001). More than 1 day compared to 1 day of preoperative hospital stay did not further increase the odds of SSI (OR 1.08, 95% CI 0.77-1.50, p = 0.658). Preoperative admission to an intensive care unit (ICU) increased the odds of SSI as compared to hospital admission outside of an ICU (OR 2.19, 95% CI 0.89-4.59, p = 0.057). Adjusting for potential confounders in multivariable analysis weakened the effects of both preoperative admission to hospital (OR 1.38, 95% CI 0.99-1.93, p = 0.061) and to the ICU (OR 1.89, 95% CI 0.73-4.24, p = 0.149). CONCLUSION: There was no significant independent association between preoperative length of stay and risk of SSI while SSI and postoperative LOS were significantly associated.

Good functional outcome in patients suffering fragility fractures of the pelvis treated with percutaneous screw stabilisation: Assessment of complications and factors influencing failure.

BACKGROUND: Low energy pelvic ring fractures in the elderly have traditionally been treated conservatively, a treatment with potential long-term complications and loss of self-independence. Percutaneous screw stabilisation of the posterior pelvic ring is a new treatment modality that enables immediate mobilisation. The aim of this study was to assess the functional outcome after sacroiliac stabilisation in the elderly. METHODS: All elderly patients with a surgically stabilised low energy pelvic fracture between 2010 and 2015 were included. In 2016 a radiographic follow up and functional test was performed at least one year postoperative. RESULTS: The 50 operated patients had a mean age of 79 years and a one-year mortality of 10% (5/50). Only six patients lost independency after the pelvic fracture and moved to nursing home. The mean Timed Up and Go test was 16s at follow-up. The operation of the posterior pelvic ring averaged 63min with a radiation equal to a diagnostic pelvic CT. One intra-foraminally placed screw was immediately removed and 9 patients were later re-operated on due to symptomatic loosening of one or more screws. No loosening of screws was seen in 11 patients where both S1 and S2 were stabilised and out of 23 trans-sacral screws (crossing both sacroiliac joints) only two loosened. DISCUSSION: CT guided stabilisation of the posterior pelvis is safe and most patients resumed good function and independent living. The risk of a revision operation was 20%, but trans-sacral screw stabilisation in both S1 and S2 could reduce the risk of implant loosening.

Implantation of Stromal Vascular Fraction Progenitors at Bone Fracture Sites: From a Rat Model to a First-in-Man Study.

Stromal Vascular Fraction (SVF) cells freshly isolated from adipose tissue include osteogenic- and vascular-progenitors, yet their relevance in bone fracture healing is currently unknown. Here, we investigated whether human SVF cells directly contribute to the repair of experimental fractures in nude rats, and explored the feasibility/safety of their clinical use for augmentation of upper arm fractures in elderly individuals. Human SVF cells were loaded onto ceramic granules within fibrin gel and implanted in critical nude rat femoral fractures after locking-plate osteosynthesis, with cell-free grafts as control. After 8 weeks, only SVF-treated fractures did not fail mechanically and displayed formation of ossicles at the repair site, with vascular and bone structures formed by human cells. The same materials combined with autologous SVF cells were then used to treat low-energy proximal humeral fractures in 8 patients (64-84 years old) along with standard open reduction and internal fixation. Graft manufacturing and implantation were compatible with intraoperative settings and led to no adverse reactions, thereby verifying feasibility/safety. Biopsies of the repair tissue after up to 12 months, upon plate revision or removal, demonstrated formation of bone ossicles, structurally disconnected and morphologically distinct from osteoconducted bone, suggesting the osteogenic nature of implanted SVF cells. We demonstrate that SVF cells, without expansion or exogenous priming, can spontaneously form bone tissue and vessel structures within a fracture-microenvironment. The gained clinical insights into the biological functionality of the grafts, combined with their facile, intra-operative manufacturing modality, warrant further tests of effectiveness in larger, controlled trials. Stem Cells 2016;34:2956-2966.

Intraoperative engineering of osteogenic grafts combining freshly harvested, human adipose-derived cells and physiological doses of bone morphogenetic protein-2.

Engineered osteogenic constructs for bone repair typically involve complex and costly processes for cell expansion. Adipose tissue includes mesenchymal precursors in large amounts, in principle allowing for an intraoperative production of osteogenic grafts and their immediate implantation. However, stromal vascular fraction (SVF) cells from adipose tissue were reported to require a molecular trigger to differentiate into functional osteoblasts. The present study tested whether physiological doses of recombinant human BMP-2 (rhBMP-2) could induce freshly harvested human SVF cells to generate ectopic bone tissue. Enzymatically dissociated SVF cells from 7 healthy donors (1 x 10(6) or 4 x 10(6)) were immediately embedded in a fibrin gel with or without 250 ng rhBMP-2, mixed with porous silicated calcium-phosphate granules (Actifuse(®), Apatech) (final construct size: 0.1 cm(3)) and implanted ectopically for eight weeks in nude mice. In the presence of rhBMP-2, SVF cells not only supported but directly contributed to the formation of bone ossicles, which were not observed in control cell-free, rhBMP-2 loaded implants. In vitro analysis indicated that rhBMP-2 did not involve an increase in the percentage of SVF cells recruited to the osteogenic lineage, but rather induced a stimulation of the osteoblastic differentiation of the committed progenitors. These findings confirm the feasibility of generating fully osteogenic grafts using an easily accessible autologous cell source and low amounts of rhBMP-2, in a timing compatible with an intraoperative schedule. The study warrants further investigation at an orthotopic site of implantation, where the delivery of rhBMP-2 could be bypassed thanks to the properties of the local milieu.