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Orthoregeneration is defined as a solution for orthopaedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and, optimally, provide an environment for tissue regeneration. Options include drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electromagnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the hip, including osteonecrosis (aseptic necrosis) involving bone marrow, bone, and cartilage, and chondral injuries involving articular cartilage, synovium, and bone marrow. Promising and established treatment modalities for osteonecrosis include nonweightbearing; pharmacological treatments including low molecular-weight heparin, prostacyclin, statins, bisphosphonates, and denosumab, a receptor activator of nuclear factor-kB ligand inhibitor; extracorporeal shock wave therapy; pulsed electromagnetic fields; core decompression surgery; cellular therapies including bone marrow aspirate comprising mesenchymal stromal cells (MSCs aka mesenchymal stem cells) and bone marrow autologous concentrate, with or without expanded or cultured cells, and possible addition of bone morphogenetic protein-2, vascular endothelial growth factor, and basic fibroblast growth factor; and arterial perfusion of MSCs that may be combined with addition of carriers or scaffolds including autologous MSCs cultured with beta-tricalcium phosphate ceramics associated with a free vascularized fibula. Promising and established treatment modalities for chondral lesions include autologous platelet-rich plasma; hyaluronic acid; MSCs (in expanded or nonexpanded form) derived from bone marrow or other sources such as fat, placenta, umbilical cord blood, synovial membrane, and cartilage; microfracture or microfracture augmented with membrane containing MSCs, collagen, HA, or synthetic polymer; mosaicplasty; 1-stage autologous cartilage translation (ACT) or 2-stage ACT using 3-dimensional spheroids; and autologous cartilage grafting; chondral flap repair, or flap fixation with fibrin glue. Hip pain is catastrophic in young patients, and promising therapies offer an alternative to premature arthroplasty. This may address both physical and psychological components of pain; the goal is to avoid or postpone an artificial joint. Level of Evidence Level V, expert opinion.

Purpose Based on the recent literature, chest computed tomography (CT) examination could aid for management of patients during COVID-19 pandemic. However, the role of chest CT in management of COVID-19 patients is not exactly the same for medical or surgical specialties. In orthopaedic or trauma emergency, abdomen, pelvis, cervical, dorsal, and lumbar spine CT are performed to investigate patients; the result is a thoracic CT scan incorporating usually the thorax; however, information about lung parenchyma can be obtained on this thorax CT, and manifestations of COVID-19 can be diagnosed. The objective of our study was to evaluate this role in orthopedic patients to familiarize orthopaedists with the value and limits of thoracic CT in orthopaedic surgery. Materials and methods Among the 1397 chest CT scans performed during the pandemic period from 1 March 2020 to 10 May 2020, in two centres with orthopaedic surgery, we selected all the 118 thoracic or chest CT performed for patients who presented to the Emergency Department of the hospital with a diagnosis of trauma for orthopaedic surgical treatment. Thirty-nine of these 118 patients were tested with PCR for the diagnosis of COVID-19 infection. Depending on clinical status (symptomatic or non-symptomatic), the information useful for the orthopaedist surgeon and obtained from the Chest CT scan according to the result of the PCR (gold standard) was graded from 0 (no or low value) to 3 (high value). The potential risks of chest CT as exposure to radiation, and specific pathway were analyzed and discussed. A group of patients treated during a previous similar period (1 March 2018 to 15 April 2018) was used as control for evaluation of the increase of CT scanning during the COVID-19 pandemic. Results Among the 118 patients with chest CT, there were 16 patients with positive COVID-19 chest CT findings, and 102 patients with negative chest CT scan. With PCR results as reference, the sensitivity, specificity, positive predictive value of chest CT in indicating COVID-19 infection were 81%, 93%, and 86%, respectively (p = 0.001). A useful information for the orthopaedic surgeon (graded as 1 for 71 cases, as 2 for 5 cases, and as 3 for 11 cases) was obtained from 118 chest CT scans for 87 (74%) patients, while the CT was no value in 30 (25%) cases, and negative value in one (1%) case. Roughly 20% of the total number of CT scanner performed over the pandemic period was dedicated to COVID-19, but only 2% were for orthopaedic or trauma patients. However, this was ten times higher than during the previous control period of comparison. Conclusion Although extremely valuable for surgery management, these results should not be overstated. The CT findings studied are not specific for COVID-19, and the positive predictive value of CT will be low unless disease prevalence is high, which was the case during this period.

Artículo con numerosos autores, sólo se recogen el primero y los pertenecientes a la UAM, Background and study aim: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture. Patients and methods: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ±13 years, 57% were males, and mean Body Mass Index 27 ±7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ±SD of 27.9 ±31.2 months before recruit- ment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological con- solidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni). Results: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioce- ramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consoli- dation scale values were seen in non-smoking patients at 6 ( p = 0.012, t -test) and 12 months ( p = 0.011, t -test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation. Conclusion: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs com- bined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers, This research received funding from the European Union’s Sev- enth Framework Programme ( FP7/FP7-HEALTH-2009 ) with the RE- BORNE Project (under G.A. 241876), and the European Union’s Horizon 2020 Programme ( H2020-SC1 2016-2017 ), with the OR- THOUNION Project (under G.A. 7333288)

Objectives Chest CT has been widely used to screen and to evaluate the severity of COVID-19 disease in the early stages of infection without severe acute respiratory syndrome, but no prospective data are available to study the relationship between extent of lung damage and short-term mortality. The objective was to evaluate association between standardized simple visual lung damage CT score (vldCTs) at admission, which does not require any software, and 30-day mortality. Methods In a single-center prospective cohort of COVID-19 patients included during 4 weeks, the presence and extent of ground glass opacities(GGO), consolidation opacities, or both of them were visually assessed in each of the 5 lung lobes (score from 0 to 4 per lobe depending on the percentage and out of 20 per patient = vldCTs) after the first chest CT performed to detect COVID-19 pneumonia. Results Among 210 confirmed COVID-19 patients, the number of survivors and non-survivors was 162 (77%) and 48 (23%), respectively at 30 days. vldCTs was significantly higher in non-survivors, and the AUC of vldCTs to distinguish survivors and non-survivors was 0.72 (95%CI 0.628–0.807, p < 0.001); the best cut-off vldCTs value was 7. During follow-up, significant differences in discharges and 30-day mortality were observed between patients with vldCTs ≥ 7 versus vldCTs < 7: (98 [85.2%] vs 49 [51.6%]; p < 0.001 and 36 [37.9%] vs 12 [12.4%]; p < 0.001, respectively. The 30-day mortality increased if vldCTs ≥ 7 (HR, 3.16 (1.50–6.43); p = 0.001), independent of age, respiratory rate and oxygen saturation levels, and comorbidities at admission. Conclusions By using chest CT in COVID-19 patients, extensive lung damage can be visually assessed with a score related to 30-day mortality independent of conventional risk factors of the disease. Key Points • In non-selected COVID-19 patients included prospectively during 4 weeks, the extent of ground glass opacities(GGO) and consolidation opacities evaluated by a simple visual score was related to 30-day mortality independent of age, respiratory rate, oxygen saturation levels, comorbidities, and hs-troponin I level at admission. • This severity score should be incorporated into risk stratification algorithms and in structured chest CT reports requiring a standardized reading by radiologists in case of COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-021-07938-2.

Purpose Three hundred seventy million years ago, bone marrow appeared in skeleton of a fish. More than one hundred years ago, the concept of bone marrow transplantation was proposed to treat human diseases. During the last five decades, this concept became a reality first in hematology and later for orthopaedic diseases. Material and methods These advances were possible due to the comprehension of the three major components of bone marrow: the fat part, the haematologic part, and the stroma part. Each part has a different history, but the three parts are linked in physiology as in history. Results During many centuries, bone marrow was considered just as food; however, one hundred years ago, the concept of bone marrow transplantation to treat humans was proposed by the French physician Brown-Séquard. During the last five decades, this concept became a reality first in haematology and later for orthopaedic diseases. Transferring what was known from experimental animal models to humans was met with many challenges, the atomic bomb research, and many deaths. Yet through the recognition and subsequent understanding of fundamental processes, medical resiliency, and the determination of a few pioneers, local bone marrow transplantation in orthopaedic surgery became a therapeutic option first for a limited number of diseases and patients. Over the last two decades, mesenchymal stromal cells (MSCs) have been the focus of intense research by acadaemia and industry due to their unique features. MSCs can be easily isolated and expanded through in vitro culture by taking full advantage of their self-renewing capacity. In addition, MSCs exert immunomodulatory effects and can be differentiated into various lineages, which makes them highly attractive for clinical applications in cell-based therapies. Conclusion In this review, we attempted to provide a historical overview of bone marrow history, MSC discovery, characterization, and the first clinical studies conducted.

The prognosis of sickle cell disease (SCD) has greatly improved in recent years, resulting in an increased number of patients reporting musculoskeletal complications such as osteonecrosis of the femoral head. Total hip arthroplasty (THA) can be utilized to alleviate the pain associated with this disease. Although it is well known that hip arthroplasty for avascular necrosis (AVN) in SCD may represent a challenge for the surgeon, complications are frequent, and no guidelines exist to prevent these complications. Because patients with SCD will frequently undergo THA, we thought it necessary to fulfil the need for guidance recommendations based on experience, evidence and agreement from the literature. For all these reasons this review proposes guidelines that provide clinicians with a document regarding management of patients with SCD in the period of time leading up to primary THA. The recommendations provide guidance that has been informed by the clinical expertise and experience of the authors and available literature. Although this is not a systematic review since some papers may have been published in languages other than English, our study population consisted of 5,868 patients, including 2,126 patients with SCD operated on for THA by the senior author in the same hospital during 40 years and 3,742 patients reported in the literature. Cite this article: EFORT Open Rev 2020;5:641-651. DOI: 10.1302/2058-5241.5.190073

Short and long-term stabilities of cementless implants are strongly determined by the interfacial load transfer between implants and bone tissue. Stress-shielding effects arise from shear stresses due to the difference of material properties between bone and the implant. It remains difficult to measure the stress field in periprosthetic bone tissue. This study proposes to investigate the dependence of the stress field in periprosthetic bone tissue on i) the implant surface roughness, ii) material properties of bone and of the implant, iii) the bone-implant contact ratio. To do so, a microscale 2-D finite element model of an osseointegrated boneimplant interface was developed where the surface roughness was modeled by a sinusoidal surface. The results show that the isostatic pressure is not affected by the presence of the bone-implant interface while shear stresses arise due to the combined effects of a geometrical singularity (for low surface roughness) and of shear stresses at the bone-implant interface (for high surface roughness). Stress-shielding effects are likely to be more important when the bone-implant contact ratio value is low, which corresponds to a case of relatively low implant stability. Shear stress reach a maximum value at a distance from the interface comprised between 0 and 0.1 time roughness wavelength $\lambda$ and tend to 0 at a distance from the implant surface higher than $\lambda$, independently from bone-implant contact ratio and waviness ratio. A comparison with an analytical model allows validating the numerical results. Future work should use the present approach to model osseointegration phenomena., Comment: Journal of Orthopaedic Research, Wiley, In press

BACKGROUND The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. OBJECTIVES The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. METHODS The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. CONCLUSIONS Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. KEY WORDS Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.

Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in orthopaedic clinics. The number of patients with ONFH is increasing worldwide every year. There are an estimated 8.12 million patients with nontraumatic osteonecrosis in China alone. Treatment of nontraumatic osteonecrosis has always been a clinical challenge for orthopaedic surgeons. To further standardize diagnosis and treatment of ONFH, these guidelines provide not only basic diagnosis, treatment, and evaluation systems for ONFH but also expert advice and standards in many aspects, including epidemiology, aetiology, diagnostic criteria, pathological staging, prevention and treatment options, and postoperative rehabilitation. The aetiological factors of ONFH can currently be divided into two major categories: traumatic and nontraumatic; however, the specific pathological mechanism of ONFH is not completely clear. Currently, the staging system of ONFH formulated by the Association Research Circulation Osseous is widely used in clinical practice. Based on the changes in the intraosseous blood supply at different stages, the corresponding nonsurgical and surgical treatments are recommended, and when there are risk factors for possible ONFH, certain preventive measures to avoid the occurrence of osteonecrosis are recommended. These guidelines provide brief classification criteria and treatment regimen for osteonecrosis. Specification of the aetiology, treatment plan based on comprehensive consideration of the different stages of osteonecrosis, hip function, age, and occupation of the patients are important steps in diagnosis and developing treatment strategies. Translational potential of this article: New advances in the epidemiology, etiology, pathophysiology, imaging, diagnosis and treatment of ONFH have been renewed in this revision. This guideline can be used for reference by orthopedic professionals and researchers, and for standardized diagnosis and treatment management under the clinical guidance, which is conducive to the prevention, treatment and further research of ONFH, improving the diagnosis and treatment level, making patients' symptoms under good control, and improving their quality of life. Keywords: Diagnosis, Guideline, Osteonecrosis of the femoral head (ONFH), Treatment