Exploring In Vivo Models of Musculoskeletal Frailty: A Comprehensive Systematic Review.

Musculoskeletal frailty-a common and debilitating condition linked to aging and chronic diseases-presents a major public health issue. In vivo models have become a key tool for researchers as they investigate the condition's underlying mechanisms and develop effective interventions. This systematic review examines the current body of research on in vivo models of musculoskeletal frailty, without any time constraints. To achieve this aim, we utilized three electronic databases and incorporated a total of 11 studies. Our investigation delves into varied animal models that simulate specific features of musculoskeletal frailty, including muscle loss, bone density reduction, and functional decline. Furthermore, we examine the translational prospects of these models in augmenting our comprehension of musculoskeletal frailty and streamlining the production of groundbreaking therapeutic approaches. This review provides significant insights and guidance for healthcare researchers and practitioners who aim to combat musculoskeletal frailty, ultimately enhancing the quality of life for older adults and individuals affected by this condition.

In Vitro Models of Cell Senescence: A Systematic Review on Musculoskeletal Tissues and Cells.

Ageing is an irreversible and inevitable biological process and a significant risk factor for the development of various diseases, also affecting the musculoskeletal system, resulting from the accumulation of cell senescence. The aim of this systematic review was to collect the in vitro studies conducted over the past decade in which cell senescence was induced through various methods, with the purpose of evaluating the molecular and cellular mechanisms underlying senescence and to identify treatments capable of delaying senescence. Through three electronic databases, 22 in vitro studies were identified and included in this systematic review. Disc, cartilage, or muscle cells or tissues and mesenchymal stem cells were employed to set-up in vitro models of senescence. The most common technique used to induce cell senescence was the addition to the culture medium of tumor necrosis factor (TNF)α and/or interleukin (IL)1ß, followed by irradiation, compression, hydrogen peroxide (H2O2), microgravity, in vitro expansion up to passage 10, and cells harvested from damaged areas of explants. Few studies evaluated possible treatments to anti-senescence effects. The included studies used in vitro models of senescence in musculoskeletal tissues, providing powerful tools to evaluate age-related changes and pathologies, also contributing to the development of new therapeutic approaches.

Gender-Specific Differences in Human Vertebral Bone Marrow Clot.

Recently, our group described the application of vertebral bone marrow (vBMA) clot as a cell therapy strategy for spinal fusion. Its beneficial effects were confirmed in aging-associated processes, but the influence of gender is unknown. In this study, we compared the biological properties of vBMA clots and derived vertebral mesenchymal stem cells (MSCs) from female and male patients undergoing spinal fusion procedures and treated with vBMA clot. We analyzed the expression of growth factors (GFs) in vBMA clots and MSCs as well as morphology, viability, doubling time, markers expression, clonogenicity, differentiation ability, senescence factors, Klotho expression, and HOX and TALE gene profiles from female and male donors. Our findings indicate that vBMA clots and derived MSCs from males had higher expression of GFs and greater osteogenic and chondrogenic potential compared to female patients. Additionally, vBMA-clot-derived MSCs from female and male donors exhibited distinct levels of HOX and TALE gene expression. Specifically, HOXA1, HOXB8, HOXD9, HOXA11, and PBX1 genes were upregulated in MSCs derived from clotted vBMA from male donors. These results demonstrate that vBMA clots can be effectively used for spinal fusion procedures; however, gender-related differences should be taken into consideration when utilizing vBMA-clot-based studies to optimize the design and implementation of this cell therapy strategy in clinical trials.

Sharing Circulating Micro-RNAs between Osteoporosis and Sarcopenia: A Systematic Review.

BACKGROUND: Osteosarcopenia, a combination of osteopenia/osteoporosis and sarcopenia, is a common condition among older adults. While numerous studies and meta-analyses have been conducted on osteoporosis biomarkers, biomarker utility in osteosarcopenia still lacks evidence. Here, we carried out a systematic review to explore and analyze the potential clinical of circulating microRNAs (miRs) shared between osteoporosis/osteopenia and sarcopenia. METHODS: We performed a systematic review on PubMed, Scopus, and Embase for differentially expressed miRs (p-value < 0.05) in (i) osteoporosis and (ii) sarcopenia. Following screening for title and abstract and deduplication, 83 studies on osteoporosis and 11 on sarcopenia were identified for full-text screening. Full-text screening identified 54 studies on osteoporosis, 4 on sarcopenia, and 1 on both osteoporosis and sarcopenia. RESULTS: A total of 69 miRs were identified for osteoporosis and 14 for sarcopenia. There were 9 shared miRs, with evidence of dysregulation (up- or down-regulation), in both osteoporosis and sarcopenia: miR-23a-3p, miR-29a, miR-93, miR-133a and b, miR-155, miR-206, miR-208, miR-222, and miR-328, with functions and targets implicated in the pathogenesis of osteosarcopenia. However, there was little agreement in the results across studies and insufficient data for miRs in sarcopenia, and only three miRs, miR-155, miR-206, and miR-328, showed the same direction of dysregulation (down-regulation) in both osteoporosis and sarcopenia. Additionally, for most identified miRs there has been no replication by more than one study, and this is particularly true for all miRs analyzed in sarcopenia. The study quality was typically rated intermediate/high risk of bias. The large heterogeneity of the studies made it impossible to perform a meta-analysis. CONCLUSIONS: The findings of this review are particularly novel, as miRs have not yet been explored in the context of osteosarcopenia. The dysregulation of miRs identified in this review may provide important clues to better understand the pathogenesis of osteosarcopenia, while also laying the foundations for further studies to lead to effective screening, monitoring, or treatment strategies.

Complications after Posterior Lumbar Fusion for Degenerative Disc Disease: Sarcopenia and Osteopenia as Independent Risk Factors for Infection and Proximal Junctional Disease.

Proximal Junctional Disease (PJD) and Surgical Site Infection (SSI) are among the most common complications following spine surgery. Their risk factors are not fully understood. Among them, sarcopenia and osteopenia have recently been attracting interest. The aim of this study is to evaluate their influence on mechanical or infective complications after lumbar spine fusion. Patients who underwent open posterior lumbar fusion were analyzed. Through preoperative MRI, central sarcopenia and osteopenia were measured with the Psoas Lumbar Vertebral Index (PLVI) and the M-Score, respectively. Patients were stratified by low vs. high PLVI and M-Score and then by postoperative complications. Multivariate analysis for independent risk factors was performed. A total of 392 patients (mean age 62.6 years, mean follow up 42.4 months) were included. Multivariate linear regression identified comorbidity Index (p = 0.006), and dural tear (p = 0.016) as independent risk factors for SSI, and age (p = 0.014) and diabetes (p = 0.43) for PJD. Low M-score and PLVI were not correlated to a higher complications rate. Age, comorbidity index, diabetes, dural tear and length of stay are independent risk factors for infection and/or proximal junctional disease in patients who undergo lumbar arthrodesis for degenerative disc disease, while central sarcopenia and osteopenia (as measured by PLVI and M-score) are not.

Vertebral Bone Marrow Clot towards the Routine Clinical Scenario in Spine Surgeries: What about the Antimicrobial Properties?

Exploring innovative techniques and treatments to improve spinal fusion procedures is a global challenge. Here, we provide a scientific opinion on the ability of a vertebral bone marrow (vBM) clot to provide a local combined delivery system not only of stem cells, signaling biomolecules and anti-inflammatory factors but also of molecules and proteins endowed with antimicrobial properties. This opinion is based on the evaluation of the intrinsic basic properties of the vBM, that contains mesenchymal stem cells (MSCs), and on the coagulation process that led to the conversion of fibrinogen into fibrin fibers that enmesh cells, plasma but above all platelets, to form the clot. We emphasize that vBM clot, being a powerful source of MSCs and platelets, would allow the release of antimicrobial proteins and molecules, mainly cathelicidin LL- 37, hepcidin, kinocidins and cationic host defense peptides, that are per se gifted with direct and/or indirect antimicrobial effects. We additionally highlight that further studies are needed to deepen this knowledge and to propose vBM clot as multifunctional bioscaffold able to target all the main key challenges for spinal fusion surgery.

Fast-track protocols for patients undergoing spine surgery: a systematic review.

BACKGROUND CONTEXT: Fast-track is an evidence-based multidisciplinary strategy for pre-, intra-, and postoperative management of patients during major surgery. To date, fast-track has not been recognized or accepted in all surgical areas, particularly in orthopedic spine surgery where it still represents a relatively new paradigm. PURPOSE: The aim of this review was provided an evidenced-based assessment of specific interventions, measurement, and associated outcomes linked to enhanced recovery pathways in spine surgery field. METHODS: We conducted a systematic review in three databases from February 2012 to August 2022 to assess the pre-, intra-, and postoperative key elements and the clinical evidence of fast-track protocols as well as specific interventions and associated outcomes, in patients undergoing to spine surgery. RESULTS: We included 57 full-text articles of which most were retrospective. Most common fast-track elements included patient's education, multimodal analgesia, thrombo- and antibiotic prophylaxis, tranexamic acid use, urinary catheter and drainage removal within 24 hours after surgery, and early mobilization and nutrition. All studies demonstrated that these interventions were able to reduce patients' length of stay (LOS) and opioid use. Comparative studies between fast-track and non-fast-track protocols also showed improved pain scores without increasing complication or readmission rates, thus improving patient's satisfaction and functional recovery. CONCLUSIONS: According to the review results, fast-track seems to be a successful tool to reduce LOS, accelerate return of function, minimize postoperative pain, and save costs in spine surgery. However, current studies are mainly on degenerative spine diseases and largely restricted to retrospective studies with non-randomized data, thus multicenter randomized trials comparing fast-track outcomes and implementation are mandatory to confirm its benefit in spine surgery.

The Complex Interplay between the Gut Microbiome and Osteoarthritis: A Systematic Review on Potential Correlations and Therapeutic Approaches.

The objective of this review is to systematically analyze the potential correlation between gut microbiota and osteoarthritis (OA) as well as to evaluate the feasibility of microbiota-targeted therapies for treating OA. Studies conducted from October 2013 to October 2023 were identified via a search on electronic databases such as PubMed, Web of Science, and Scopus, following established PRISMA statement standards. Two reviewers independently screened, assessed, and extracted relevant data, and then they graded the studies using the ROBINS I tool for non-randomized interventions studies and SYRCLE's risk-of-bias tool for animal studies. A search through 370 studies yielded 38 studies (24 preclinical and 14 clinical) that were included. In vivo research has predominantly concentrated on modifying the gut microbiota microenvironment, using dietary supplements, probiotics, and prebiotics to modify the OA status. Lactobacilli are the most thoroughly examined with Lactobacillus acidophilus found to effectively reduce cartilage damage, inflammatory factors, and pain. Additionally, Lactobacillus M5 inhibits the development of OA by preventing high-fat diet (HFD)-induced obesity and protecting cartilage from damage. Although there are limited clinical studies, certain compositions of intestinal microbiota may be associated with onset and progression of OA, while others are linked to pain reduction in OA patients. Based on preclinical studies, there is evidence to suggest that the gut microbiota could play a significant role in the development and progression of OA. However, due to the scarcity of clinical studies, the exact mechanism linking the gut microbiota and OA remains unclear. Further research is necessary to evaluate specific gut microbiota compositions, potential pathogens, and their corresponding signaling pathways that contribute to the onset and progression of OA. This will help to validate the potential of targeting gut microbiota for treating OA patients.

Ageing and Osteoarthritis Synergically Affect Human Synoviocyte Cells: An In Vitro Study on Sex Differences.

Osteoarthritis is a chronic inflammatory disease that affects all of the joints, especially those of the elderly. Aging is a natural and irreversible biological process implicated in the pathophysiology of many chronic diseases, such as osteoarthritis. Inflammation and oxidative stress are the main factors involved in osteoarthritis and aging, respectively, with the production of several pro-inflammatory cytokines such as Interleukin 1ß (IL1ß) and reactive oxygen species. The aim of the study was to set-up an in vitro model of osteoarthritis and aging, focusing on the sex differences by culturing male and female fibroblast-like synoviocytes (FLSs) with IL1ß, hydrogen peroxide (H2O2), IL1ß+H2O2 or a growth medium (control). IL1ß+H2O2 reduced the cell viability and microwound healing potential, increased Caspase-3 expression and reactive oxygen species and IL6 production; IL1ß increased IL6 production more than the other conditions did; H2O2 increased Caspase-3 expression and reactive oxygen species production; Klotho expression showed no differences among the treatments. The FLSs from female donors demonstrated a better response capacity in unfavorable conditions of inflammation and oxidative stress than those from the male donors did. This study developed culture conditions to mimic the aging and osteoarthritis microenvironment to evaluate the behavior of the FLSs which play a fundamental role in joint homeostasis, focusing on the sex-related aspects that are relevant in the osteoarthritis pathophysiology.

Clinical and Pathological Profiles of Vertebral Bone Metastases from Endometrial Cancers: Evidence from a Twenty-Year Case Series.

Patients with endometrial cancer (EC) frequently have metastases to lungs, extra-pelvic nodes, and liver. Although an uncommon occurrence, cases of EC metastasis to bone, prevalently in vertebral bone, have also been reported. The objective of this study was to analyze clinical and pathological profiles of patients with EC metastatic to vertebral bone. We carried out a retrospective case series on surgically treated patients for this pathology. From 2001 to 2021, out of 775 patients with bone metastasis, 1.6% had bone metastasis from EC. The median time between the diagnosis of primary tumor and that of bone metastases was 31.5 months. Solitary bone lesion was present in 7 patients and lumbar vertebrae were the segments most affected. Pathological fractures in 46.2% of patients and spinal pain in all were present. In terms of location, 46.2% of bone metastases resided within the anterior section of the vertebra, while the remaining presented an extension within the anterior and posterior sections, with 46.1% of cases showing an extradural extra-osseous extension and paraspinous envelope. Median survival after diagnosis of bone metastasis was 11.5 months. Vertebral bone metastasis in EC is a rare phenomenon, with severe prognosis. An in-depth understanding of this topic may guide future management and treatment decisions, thus improving life expectancy and quality.

Sex and gender determinants following spinal fusion surgery: A systematic review of clinical data.

In the last decade, numerous studies analyzed and described the surgical outcomes in male and female patients submitted to orthopedic surgery. Although this, the impact of sex/gender on spinal fusion surgery clinical outcomes is still poorly defined. This review systematically maps and synthesizes the scientific literature on sex/gender differences in postoperative outcomes for patients undergoing spinal fusion surgery. The search was performed in PubMed, Scopus, and Web of Science in the last 22 years. Clinical studies evaluating potential sex/gender differences in postoperative outcomes and/or complications, as primary or secondary aim, were included and analyzed. Out of the 1,885 records screened, 47 studies were included. These studies comprised a total of 1,158,555 patients (51.31% female; 48.69% male). About 77% of the analyzed studies reported sex/gender-related differences in postoperative outcomes. Most studies treated patients for lumbar degenerative diseases and more than 55% of them reported a worse postoperative outcome in female patients in terms of pain, disability, health-related quality of life questionnaires, and complications. Differently, a significant heterogeneity across studies on patients treated for cervical and sacral degenerative diseases as well as for spinal deformity and traumatic spinal fracture prevented the understanding of specific sex/gender differences after spinal fusion surgery. Despite this, the present review highlighted those female patients treated for lumbar degenerative spine diseases could require more clinical awareness during postoperative care. The understanding of how sex/gender differences can really affect clinical outcomes after spinal fusion surgeries is mandatory for all spinal pathological conditions to drive clinical research toward oriented and personalized protocols.

Speculation on the pathophysiology of musculoskeletal injury with COVID-19 infection.

Coronavirus disease 2019 (COVID-19) primarily affects the respiratory tract, but also many other organs and tissues, leading to different pathological pictures, such as those of the musculoskeletal tissues. The present study should be considered as a speculation on the relationship between COVID-19 infection and some frequent musculoskeletal pathologies, in particular sarcopenia, bone loss/osteoporosis (OP) and fracture risk and osteoarthritis (OA), to hypothesize how the virus acts on these pathologies and consequently on the tissue regeneration/healing potential. The study focuses in particular on the modalities of interaction of COVID-19 with Angiotensin-Converting Enzyme 2 (ACE2) and on the "cytokine storm." Knowing the effects of COVID-19 on musculoskeletal tissues could be important also to understand if tissue regenerative/reparative capacity is compromised, especially in elderly and frail patients. We speculate that ACE2 and serine proteases together with an intense inflammation, immobilization and malnutrition could be the responsible for muscle weakness, altered bone remodeling, increase in bone fracture risk and inflammatory joint pathologies. Future preclinical and clinical studies may focus on the regenerative/reparative properties of the musculoskeletal tissues after COVID-19 infection, toward a personalized treatment usually based on scaffolds, cells, and growth factors.

Osteoporosis Preclinical Research: A Systematic Review on Comparative Studies Using Ovariectomized Sheep.

Sheep ovariectomy (OVX) alone or associated to steroid therapy, deficient diet, or hypothalamic-pituitary disconnection has proven to be of critical importance for osteoporosis research in orthopedics. However, the impact of specific variables, such as breed, age, diet, time after OVX, and other variables, should be monitored. Thus, the design of comparative studies is mandatory to minimize the impact of these variables or to recognize the presence of unwanted variables as well as to better characterize bone remodeling in this model. Herein, we conducted a systematic review of the last 10 years on PubMed, Scopus, and Web of Knowledge considering only studies on OVX sheep where a control group was present. Of the 123 records screened, 18 studies were included and analyzed. Results showed that (i) Merino sheep are the most exploited breed; (ii) 5-6 years of age is the most used time for inducing OVX; (iii) ventral midline laparotomy is the most common approach to induce OVX; (iv) OVX associated to steroid therapy is the most widely used osteoporosis model; and (v) success of OVX was mostly verified 12 months after surgery. In detail, starting from 12 months after OVX a significant decline in bone mineral density and in microarchitectural bone parameters as well as in biochemical markers were detected in all studies in comparison to control groups. Bone alteration was also site-specific on a pattern as follows: lumbar vertebra, femoral neck, and ribs. Before 12 months from OVX and starting from 3-5 months, microarchitectural bone changes and biochemical marker alterations were present when osteoporosis was induced by OVX associated to steroid therapy. In conclusion, OVX in sheep influence bone metabolism causing pronounced systemic bone loss and structural deterioration comparable to the situation found in osteoporosis patients. Data for treating osteoporosis patients are based not only on good planning and study design but also on a correct animal use that, as suggested by 3Rs principles and by ARRIVE guidelines, includes the use of control groups to be directly contrasted with the experimental group.

Key Components, Current Practice and Clinical Outcomes of ERAS Programs in Patients Undergoing Orthopedic Surgery: A Systematic Review.

Enhanced recovery after surgery (ERAS) protocols have led to improvements in outcomes in several surgical fields, through multimodal optimization of patient pathways, reductions in complications, improved patient experiences and reductions in the length of stay. However, their use has not been uniformly recognized in all orthopedic fields, and there is still no consensus on the best implementation process. Here, we evaluated pre-, peri-, and post-operative key elements and clinical evidence of ERAS protocols, measurements, and associated outcomes in patients undergoing different orthopedic surgical procedures. A systematic literature search on PubMed, Scopus, and Web of Science Core Collection databases was conducted to identify clinical studies, from 2012 to 2022. Out of the 1154 studies retrieved, 174 (25 on spine surgery, 4 on thorax surgery, 2 on elbow surgery and 143 on hip and/or knee surgery) were considered eligible for this review. Results showed that ERAS protocols improve the recovery from orthopedic surgery, decreasing the length of hospital stays (LOS) and the readmission rates. Comparative studies between ERAS and non-ERAS protocols also showed improvement in patient pain scores, satisfaction, and range of motion. Although ERAS protocols in orthopedic surgery are safe and effective, future studies focusing on specific ERAS elements, in particular for elbow, thorax and spine, are mandatory to optimize the protocols.

Postoperative Survival and Clinical Outcomes for Uterine Leiomyosarcoma Spinal Bone Metastasis: A Case Series and Systematic Literature Review.

Spinal bone metastases from uterine leiomyosarcoma (LMS) are relatively uncommon and few data are present in the literature. In this study, cases of nine consecutive patients who underwent spinal surgery for metastatic uterine LMS between 2012 and 2022 at a single institution were retrospectively reviewed. The recorded demographic, operative, and postoperative factors were reviewed, and the functional outcomes were determined by changes in Frankel grade classification during follow-up. A systematic review of the literature was also performed to evaluate operative and postoperative factors and outcomes for patients with the same gynecological metastases to the spine. For our cases, the mean time between primary tumors to bone metastases diagnosis was 5.2 years, and the thoracic vertebrae were the most affected segment. Overall, median survival after diagnosis of metastatic spine lesions was 46 months. For the systematic review, the mean time between primary tumors to bone metastases was 4.9 years, with the lumbar spine as the most involved site of metastasis. Overall, median survival after diagnosis was 102 months. Once a spinal bone lesion from LMS is identified, surgical treatment can be beneficial and successful in alleviating symptoms. Further efforts will be crucial to identify prognostic markers as well as therapeutic targets to improve survival in these patients.

Clinical Characteristics, Treatment Modalities, and Potential Contributing and Prognostic Factors in Patients with Bone Metastases from Gynecological Cancers: A Systematic Review.

The purpose of this study is to review the clinical characteristics, treatment modalities, and potential contributing and prognostic factors of bone metastases from gynecological cancers (GCs). A systematic literature search on PubMed, Scopus, Web of Science Core Collection and Cochrane Central Register of Controlled Trials databases was conducted. Thirty-one studies, all retrospective, were included in this review, for a total of 2880 patients with GC bone metastases. Primary tumors leading to bone metastases included endometrial cancer (EC), cervical cancer (CC), ovarian cancer (OC), uterine sarcoma (US) and vulvar cancer (VuC), mainly with an International Federation of Gynecology and Obstetrics (FIGO) Stage of III and IV. The main bone metastatic lesion site was the vertebral column, followed by the pelvic bone and lower extremity bones. The median survival rate after bone metastases diagnosis ranged from 3.0 to 45 months. The most frequent treatments were palliative and included radiotherapy and chemotherapy, followed by surgery. The findings of this review give a first dataset for a greater understanding of GC bone metastases that could help clinicians move toward a more "personalized" and thus more effective patient management.

Gender and Sex Are Key Determinants in Osteoarthritis Not Only Confounding Variables. A Systematic Review of Clinical Data.

Many risk factors for osteoarthritis (OA) have been noted, while gender/sex differences have been understated. The work aimed to systematically review literature investigating as primary aim the relationship between gender/sex related discriminants and OA. The search was performed in PubMed, Science Direct and Web of Knowledge in the last 10 years. Inclusion criteria were limited to clinical studies of patients affected by OA in any joints, analyzing as primary aim gender/sex differences. Exclusion criteria were review articles, in vitro, in vivo and ex vivo studies, case series studies and papers in which gender/sex differences were adjusted as confounding variable. Of the 120 records screened, 42 studies were included. Different clinical outcomes were analyzed: morphometric differences, followed by kinematics, pain, functional outcomes after arthroplasty and health care needs of patients. Women appear to use more health care, have higher OA prevalence, clinical pain and inflammation, decreased cartilage volume, physical difficulty, and smaller joint parameters and dimensions, as compared to men. No in-depth studies or mechanistic studies analyzing biomarker differential expressions, molecular pathways and omic profiles were found that might drive preclinical and clinical research towards sex-/gender-oriented protocols.

Stromal Vascular Fraction and Amniotic Epithelial Cells: Preclinical and Clinical Relevance in Musculoskeletal Regenerative Medicine.

Musculoskeletal regenerative medicine is mainly based on the use of cell therapy to heal damaged tissues such as bone, cartilage, and tendons. Throughout the years, different cell types have been employed for the treatment of musculoskeletal diseases, in particular, mesenchymal stem cells (MSCs) derived from bone marrow (BMSCs) and adipose tissue (ADSCs). Though the results of these literature studies have been encouraging, there are some limitations, especially on long-term results. Recently, some interest has shifted towards new cell types such as the stromal vascular fraction (SVF) and amniotic endothelial cells (AECs). The aim of the present literature review is to evaluate preclinical and clinical studies that used SVF and AECs for musculoskeletal tissue regeneration. Forty-eight preclinical and clinical studies, performed in the last 10 years, were identified. Both SVF and AECs, injected or implanted with or without scaffolds, were shown to be valid alternatives, and in some ways superior, to ADSCs and BMSCs, being able to differentiate towards osteogenic, chondrogenic, and tenogenic lineages, and to promote cell and tissue regenerative potential. The use of SVF and AECs could represent a new regenerative treatment in several musculoskeletal pathologies, solving the problem of cell expansion in vitro.

Nano-Based Biomaterials as Drug Delivery Systems Against Osteoporosis: A Systematic Review of Preclinical and Clinical Evidence.

Osteoporosis (OP) is one of the most significant causes of morbidity, particularly in post-menopausal women and older men. Despite its remarkable occurrence, the search for an effective treatment is still an open challenge. Here, we systematically reviewed the preclinical and clinical progress in the development of nano-based materials as drug delivery systems against OP, considering the effects on bone healing and regeneration, the more promising composition and manufacturing methods, and the more hopeful drugs and delivery methods. The results showed that almost all the innovative nano-based delivery systems developed in the last ten years have been assessed by preclinical investigations and are still in the preliminary/early research stages. Our search strategy retrieved only one non-randomized controlled trial (RCT) on oligosaccharide nanomedicine of alginate sodium used for degenerative lumbar diseases in OP patients. Further investigations are mandatory for assessing the clinical translation and commercial purposes of these materials. To date, the main limits for the clinical translation of nano-based materials as drug delivery systems against OP are probably due to the low reproducibility of the manufacturing processes, whose specificity and complexity relies on an adequate chemical, structural, and biomechanical characterization, as the necessary prerequisite before assessing the efficacy of a given treatment or process. Finally, an unsatisfactory drug-loading capacity, an uncontrollable release kinetic, and a low delivery efficiency also limit the clinical application.

Two Hits for Bone Regeneration in Aged Patients: Vertebral Bone Marrow Clot as a Biological Scaffold and Powerful Source of Mesenchymal Stem Cells.

Recently, the use of a new formulation of bone marrow aspirate (BMA), the BMA clot, has been described. This product entails a naturally formed clot from the harvested bone marrow, which retains all the BMA components preserved in a matrix biologically molded by the clot. Even though its beneficial effects were demonstrated by some studies, the impact of aging and aging-associated processes on biological properties and the effect of BMA cell-based therapy are currently unknown. The purpose of our study was to compare selected parameters and properties of clotted BMA and BMA-derived mesenchymal stem cells (MSCs) from younger (<45 years) and older (>65 years) female donors. Clotted BMA growth factors (GFs) expression, MSCs morphology and viability, doubling time, surface marker expression, clonogenic potential, three-lineage differentiation, senescence-associated factors, and Klotho synthesis from younger and older donors were analyzed. Results indicated that donor age does not affect tissue-specific BMA clot regenerative properties such as GFs expression and MSCs morphology, viability, doubling time, surface antigens expression, colony-forming units, osteogenic and adipogenic differentiation, and Klotho and senescence-associated gene expression. Only few differences, i.e., increased platelet-derived growth factor-AB (PDGF-AB) synthesis and MSCs Aggrecan (ACAN) expression, were detected in younger donors in comparison with older ones. However, these differences do not interfere with all the other BMA clot biological properties. These results demonstrated that BMA clot can be applied easily, without any sample processing and avoiding potential contamination risks as well as losing cell viability, proliferation, and differentiation ability, for autologous transplantation in aged patients. The vertebral BMA clot showed two successful hits since it works as a biological scaffold and as a powerful source of mesenchymal stem cells, thus representing a novel and advanced therapeutic alternative for the treatment of orthopedic injuries.