Advances in 3D bioprinting to enhance translational applications in bone tissue engineering and regenerative medicine.

Bone defects are due to trauma, infections, tumors, or aging, including bone fractures, bone metastases, osteoporosis, or osteoarthritis. The global burden of these demands research into innovative strategies that overcome the limitations of conventional autografts. In this sense, the development of three-dimensional (3D) bioprinting has emerged as a promising approach in the field of tissue engineering and regenerative medicine (TERM) for the on-demand generation and transplantation of tissues and organs, including bone. It combines biological materials and living cells, which are precisely positioned layer by layer. Despite obtaining some promising results, 3D bioprinting of bone tissue still faces several challenges, such as generating an effective vascular network to increase tissue viability. In this review, we aim to collect the main knowledge on methods and techniques of 3D bioprinting. Then, we will review the main biomaterials, their composition, and the rationale for their application in 3D bioprinting for the TERM of bone.

Artificial Intelligence Used for Diagnosis in Facial Deformities: A Systematic Review.

AI is included in a lot of different systems. In facial surgery, there are some AI-based software programs oriented to diagnosis in facial surgery. This study aims to evaluate the capacity and training of models for diagnosis of dentofacial deformities in class II and class III patients using artificial intelligence and the potential use for indicating orthognathic surgery. The search strategy is from 1943 to April 2024 in PubMed, Embase, Scopus, Lilacs, and Web of Science. Studies that used imaging to assess anatomical structures, airway volume, and craniofacial positions using the AI algorithm in the human population were included. The methodological quality of the studies was assessed using the Effective Public Health Practice Project instrument. The systematic search identified 697 articles. Eight studies were obtained for descriptive analysis after exclusion according to our inclusion and exclusion criteria. All studies were retrospective in design. A total of 5552 subjects with an age range between 14.7 and 56 years were obtained; 2474 (44.56%) subjects were male, and 3078 (55.43%) were female. Six studies were analyzed using 2D imaging and obtained highly accurate results in diagnosing skeletal features and determining the need for orthognathic surgery, and two studies used 3D imaging for measurement and diagnosis. Limitations of the studies such as age, diagnosis in facial deformity, and the included variables were observed. Concerning the overall analysis bias, six studies were at moderate risk due to weak study designs, while two were at high risk of bias. We can conclude that, with the few articles included, using AI-based software allows for some craniometric recognition and measurements to determine the diagnosis of facial deformities using mainly 2D analysis. However, it is necessary to perform studies based on three-dimensional images, increase the sample size, and train models in different populations to ensure accuracy of AI applications in this field. After that, the models can be trained for dentofacial diagnosis.

Emerging histological and serological biomarkers in oral squamous cell carcinoma: Applications in diagnosis, prognosis evaluation and personalized therapeutics (Review).

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and accounts for >90% of all oral cancers. Despite advances in diagnostic procedures and therapeutic interventions, overall survival has not improved significantly in recent decades, primarily due to late diagnosis, locoregional recurrence and treatment resistance. Identifying reliable biomarkers for early detection, prognosis evaluation and treatment response prediction is critical for improving clinical outcomes in patients with OSCC. In the present review, the prognostic and predictive utility of circulating biomarkers, such as circulating tumour cells, serological biomarkers and histological and genetic biomarkers, were explored in the context of OSCC. In addition, the potential role of immune checkpoints in the treatment of OSCC was highlighted and the rapidly evolving field of liquid biopsy and its potential to revolutionize diagnosis, prognosis evaluation and treatment were examined. The existing evidence for the clinical utility of these biomarkers was critically evaluated and the challenges and limitations associated with their introduction into routine clinical practice were addressed. In conclusion, the present review highlights the promising role of biomarkers in improving the current understanding of the pathogenesis of OSCC and offers potential avenues for improving patient care through personalized medicine approaches.

Orthognathic surgery and aligners. A comparative assessment of periodontal health and quality of life in postsurgical orthodontic treatment with aligners versus traditional fixed appliances: a randomized controlled trial

Background: Removable clear aligners have become very popular in the last few decades, but they are still little used in the field of orthognathic surgery (OS). The objective of this study was to compare periodontal health and quality of life (QoL) associated to postsurgical orthodontic treatment. Material and methods: Patients with dentofacial deformities undergoing OS were randomly allocated to receive postsurgical orthodontic treatment with either fixed orthodontic appliances or Invisalign. The main outcomes were periodontal health and QoL. Plaque index, probing depth and bleeding on probing were assessed as periodontal health indicators. QoL was assessed through the Orthognathic Quality of Life Questionnaire (OQLQ-22) and the Oral Health Impact Profile (OHIP-14). Data were analyzed before surgery and end of treatment. Total duration of treatment was also recorded. Results: Twenty-eight patients were randomized, (16 women, 12 men). Periodontal assessment showed better outcomes for the Invisalign group: bleeding on probing (p=0.013), plaque index (p=0.001) and probing depth (p<0.001). The QoL questionnaires showed significant differences in favor of the Invisalign group: OHIP-14 (p=0.004) and OQLQ-22 (p=0.002). Total duration of treatment was similar in both groups (p=0.575). Conclusions: Compared to traditional orthodontics with fixed appliances, patients managed with clear aligners after OS (surgery-first approach) had better periodontal health and QoL outcomes. (AU)

Medication-Related Osteonecrosis of the Jaws (MRONJ) in Children and Young Patients-A Systematic Review.

Medication-related osteonecrosis of the jaw (MRONJ) is defined by the American Association of Oral and Maxillofacial Surgeons (AAOMS) as the presence of an exposed bone area in the maxillofacial region, present for more than eight weeks in patients treated with the use of antiresorptive or antiangiogenic agents, with no history of radiation or metastatic disease. Bisphosphonates (BF) and denosumab (DS) are widely used in adults for the management of patients with cancer and osteoporosis, and recently there has been an increase in their use in child and young patients for the management of disorders such as osteogenesis imperfecta (OI), glucocorticoid-induced osteoporosis, McCune-Albright syndrome (MAS), malignant hypercalcemia, and others. There are differences between case reports in adults compared to child and young patients related to the use of antiresorptive/antiangiogenic drugs and the development of MRONJ. The aim was to analyze the presence of MRONJ in children and young patients, and the relation with oral surgery. A systematic review, following the PRISMA search matrix based on the PICO question, was conducted in PubMed, Embase, ScienceDirect, Cochrane, Google Scholar, and manual search in high-impact journals between 1960 and 2022, publications in English or Spanish, including randomized and non-randomized clinical trials, prospective and retrospective cohort studies, cases and controls studies, and series and case reports. A total of 2792 articles were identified and 29 were included; all of them published between 2007 and 2022, identifying 1192 patients, 39.68% male and 36.24% female, aged 11.56 years old on average, using these drugs mainly for OI (60.15%); 4.21 years on average was the therapy time and 10.18 drug doses administered on average; oral surgery was observed in 216 subjects, reporting 14 cases of MRONJ. We concluded that there is a low presence of MRONJ in the child and youth population treated with antiresorptive drugs. Data collection is weak, and details of therapy are not clear in some cases. Deficiencies in protocols and pharmacological characterization were observed in most of the included articles.

SARS-CoV-2 Virus in Cancer Patients: A New Unknown in an Unsolved Equation.

INTRODUCTION: Cancer patients are more susceptible to infections, and infection can be more severe than in patients without cancer diagnosis. We conducted this retrospective study in patients admitted for SARS-CoV-2 infection in order to find differences in inflammatory markers and mortality in cancer patients compared to others. METHODS: We reviewed the electronic records of patients admitted for SARS-CoV-2 infection confirmed by PCR from March to September 2020. Data on socio-demographics, comorbidities, inflammatory makers, and cancer-related features were analyzed. RESULTS: 2,772 patients were admitted for SARS-CoV-2, to the Hospital Universitario Ramón y Cajal in Madrid during this period. Of these, 2,527 (91%) had no history of neoplastic disease, 164 (5.9%) patients had a prior history of cancer but were not undergoing oncological treatment at the time of infection, and 81 (2.9%) were in active treatment. Mortality in patients without a history of cancer was 19.5%, 28.6% for patients with a prior history of cancer, and 34% in patients with active cancer treatment. Patients in active oncology treatment with the highest mortality rate were those diagnosed with lung cancer (OR 5.6 95% CI: 2.2-14.1). In the multivariate study, active oncological treatment (OR 2.259 95% CI: 1.35-3.77) and chemotherapy treatment (OR 3.624 95% CI: 1.17-11.17), were statistically significant factors for the risk of death for the whole group and for the group with active oncological treatment, respectively. CONCLUSION: Cancer patients on active systemic treatment have an increased risk of mortality after SARS-CoV-2 infection, especially with lung cancer or chemotherapy treatment.

Lost in Translation: Evaluation of Subcutaneous Interferon-ß Treatment for SARS-CoV-2 Infection in Real Life.

Despite in vitro activity of interferon-ß (IFN-ß) against SARS-CoV-2 infection, its clinical efficacy remains controversial. We evaluated the impact of IFN-ß treatment in a cohort of 3590 patients hospitalized with COVID-19 during March−April 2020. The primary endpoint was a composed variable of admission to intensive care unit (ICU)/death. Overall, 153 patients (4%) received IFN-ß. They were significantly more severely ill, with a worse clinical and analytical situation, explaining a higher ICU admission (30% vs. 17%; p < 0.01), and a shorter time to the composed variable. In a Cox regression analysis, older age, lymphopenia, renal failure, or increased neutrophil-to-lymphocyte ratio were associated with a greater hazard ratio (HR) of admission at ICU/death. Notably, the HR of IFN-ß for the outcome variable was no longer significant after adjustment (HR, 1.03; 95% CI, 0.82−1.30), and different sensitivity analysis (early IFN use, ICU admission) showed no changes in the estimates. A propensity score matching analysis showed no association of IFN-ß therapy and outcome. In conclusion, in this large cohort of hospitalized COVID-19 patients, IFN-ß was used mainly in patients with advanced disease, reflecting an important bias of selection. After adjusting by severity, IFN-ß was not associated with a higher rate of ICU admission or mortality.

Bemiparin vs enoxaparin in the prevention of thrombosis in microvascular head and neck reconstruction.

This study aims to compare the use of Bemiparin vs Enoxaparin in patients undergoing microvascular head and neck reconstruction, analyzing the incidence of flap thrombotic complications and local bleeding that could compromise the flap survival. This is an observational study on a group of 204 patients who underwent a microvascular flap for head and neck reconstruction at the Oral and Maxillofacial Surgery Department of Ramon y Cajal Hospital in Madrid, Spain. A group of 67 patients was treated according to a protocol for postoperative prophylaxis of thromboembolism with Bemiparin, which was compared with data collected retrospectively from a group of 137 patients treated with Enoxaparin. We evaluated the incidence of thrombotic complications in the microvascular anastomoses and the incidence of postoperative bleeding events. The flap success rate was 91% in patients treated with Bemiparin, and 91,2% in the group of Enoxaparin (p = 0.963). One major bleeding event was recorded in the Bemiparin group, while 18 events were observed in the Enoxaparin group (p=0.008). Only the type of thromboprophylactic treatment (Bemiparin vs Enoxaparin) was related to presenting major bleeding (p = 0.007). Therefore, Bemiparin is useful in the thromboembolic prophylaxis in patients with microvascular head and neck reconstructions, providing a lower risk of major bleeding than Enoxaparin.

Applications of Polymeric Composites in Bone Tissue Engineering and Jawbone Regeneration.

Polymer-based composites are a group of biomaterials that exert synergic and combined activity. There are multiple reported uses of these composites in multiple biomedical areas, such as drug carriers, in wound dressings, and, more prominently, in tissue engineering and regenerative medicine. Bone grafting is a promising field in the use of polymeric composites, as this is the second most frequently transplanted organ in the United States. Advances in novel biomaterials, such as polymeric composites, will undoubtedly be of great aid in bone tissue engineering and regeneration. In this paper, a general view of bone structure and polymeric composites will be given, discussing the potential role of these components in bone tissue. Moreover, the most relevant jawbone and maxillofacial applications of polymeric composites will be revised in this article, collecting the main knowledge about this topic and emphasizing the need of further clinical studies in humans.

Towards an updated view on the clinical management of pancreatic adenocarcinoma: Current and future perspectives.

Pancreatic cancer has a dire prognosis and will represent the second leading cause of cancer death in the next 10 years. The multifactorial approach represents one of the main issues in controlling the extension of this neoplasm. In recent years, the characteristics of the tumor microenvironment, metastasis mechanisms and the relationship between immune system and neoplastic cells have been described, which has made it possible to understand the pathophysiology of pancreatic adenocarcinoma. Currently, there is a failure to provide an effective preventive method or early detection, so patients present with an advanced stage at the time of diagnosis. Despite numerous efforts, little progress has been made in clinical outcome and in improving survival in long term. Therefore, in the recent years, diverse diagnostic tests, treatments and possible approaches have been developed in the fields of radiotherapy, chemotherapy and surgery to find a combination of them that improves life expectancy in patients diagnosed with pancreatic cancer. At the moment, numerous clinical trials are being conducted to evaluate preventive diagnostic procedures such as serological markers or perfecting available imaging tests. On the other hand, implementation of immunotherapy is being studied in a neoplasm that has lagged in the application of this procedure since present possible treatments do not substantially improve quality of life. Therefore, the purpose of our study is to summarize the main progresses that have been made in the diagnosis, treatment and screening of this disease, explaining the limitations that have been observed and analyzing future prospects in the management of this illness.

International transfer of knowledge: Training and education in craniomaxillofacial surgery. Contributing to humanitarian aid by teaching the teachers.

The development of multiple international aid programs aims to offer health care according to basic quality standards to the global population. In many fields of Oral and Maxillofacial Surgery such as the treatment of head and neck tumours, complex or acquired malformations and craniomaxillofacial trauma, aid programs contribute to solve urgent needs although in the long term only the establishment at local or subregional levels of stable specialized healthcare networks including training of specialized health personnel will be able to contribute to achieving an adequate standard of care. In this paper we review our experience regarding the different efforts made to enhance education and training in the specialty at the European level by the EACMFS and at the global level by the IAOMS.

Chronic venous disease patients show increased IRS-4 expression in the great saphenous vein wall.

OBJECTIVES: Chronic venous disease (CVeD) is a multifactorial and debilitating condition that has a high prevalence in Western countries and an important associated socioeconomic burden. Varicose veins (VVs) are the most common manifestations of CVeD. Pathologically, many morphological and functional changes have been described in VVs, which most notably affect venous wall integrity. Previous studies have found several molecular alterations that negatively affect normal cell signaling pathways. Insulin receptor substrate (IRS)-4 is a central adaptor protein that is closely related to insulin/insulin-like growth factor-1 signaling upstream, phosphatidylinositol 3-kinase/Akt or mitogen-activated protein kinases downstream, and other proteins. These molecular pathways have been implicated in CVeD pathogenesis. Thus, the aim of our study was to identify the role of IRS-4 in VV tissue. METHODS: We conducted a histopathological study to analyze IRS-4 protein expression in CVeD patients compared with healthy controls. RESULTS: Our results demonstrate a significant increase in IRS-4 expression in VV tissue. CONCLUSIONS: IRS-4 may be implicated in CVeD development and progression. Therefore, IRS-4 could be a potential diagnostic or therapeutic target for patients with this condition.

Mesenchymal adipose stem cells maintain the capacity for differentiation and survival in culture beyond the long term.

Mesenchymal cells (MSCs) are considered to be cellular populations of common embryological origin. For clinical research applications, MSCs are expanded and increased with cells obtained from a primary culture. By extracting cells from tissue and encouraging them to reproduce, the stem cell population ends up dominating the culture due to a high proliferation rate and self-renewal. The first subcultures between the third and sixth are chosen in order to obtain the maximum number of cells with optimal differentiation capacity. However, few studies have reported long-term cultivation of MSCs. The objective of this study was to advance the knowledge on the characteristics of MSCs by assessing their capacity for self-renewal and phenotypic maintenance beyond 50 cell subcultures, which is defined as the normal limit for cellular survival. Rat subcutaneous adipose tissue was the source of mesenchymal adipose stem cells (MASCs) cultured over 175 subcultures. Early 1 to 5 and late 25 to 30 subcultures were used to induce cellular differentiation to become adipogenic, chondrogenic and osteogenic connective tissue cells. MASCs characteristics were studied using flow cytometry, transmission electron microscopy (TEM), and immunohistochemical and reverse transcription polymerase chain reaction (RT-qPCR) assays. The MASCs maintained cell differentiation capacity for more than 30 subcultures but lost potentiality starting at 60 up to 175 subcultures. MASCs showed the embryonic phenotypes OCT3/4 and Nanog indefinitely, and developed compensatory mechanisms, such as autophagy, to achieve cell survival over a long time period. Therefore, long-term subcultures showed that MASCs could maintain their potential for clinical research use.

The Impact of Healthcare-Associated Infections in Patients Undergoing Oncological Microvascular Head and Neck Reconstruction: A Prospective Multicentre Study.

(1) Background: Healthcare-associated infections (HAIs) after head and neck free-flap reconstruction are a common postoperative complication. Risk factors for HAIs in this context and their consequences have not been adequately described. (2) Methods: Ongoing prospective multicentre study between 02/2019 and 12/2020. Demographic characteristics and outcomes were analysed, focusing on infections. (3) Results: Forty out of 65 patients (61.54%) suffered HAIs (surgical site infection: 52.18%, nosocomial pneumonia: 23.20%, bloodstream infection: 13% and urinary tract infection: 5.80%). Methicillin-resistant Staphylococcus aureus (MRSA) and resistant Pseudomonas aeruginosa, Klebsiella pneumoniae and Enterobacter cloacae were the most frequently implicated. The significant risk factors for infection were: previous radiotherapy (Odds ratio (OR): 5.42; 95% confidence interval (CI), 1.39-21.10), anaemia (OR: 8.00; 95% CI, 0.96-66.95), salvage surgery (eight out of eight patients), tracheostomy (OR: 2.86; 95% CI, 1.01-8.14), surgery duration (OR: 1.01; 95% CI, 1.00-1.02), microvascular reoperation <72 h (eight/eight) and flap loss (eight/eight). The major surgical complications were: a need to reoperate (OR: 6.89; 95% CI, 1.42-33.51), prolonged hospital admission (OR: 1.16; 95% CI, 1.06-1.27) and delay in the initiation of postoperative radiotherapy (OR: 9.07; 95% CI, 1.72-47.67). The sixth month mortality rate in patients with HAIs was 7.69% vs. 0% in patients without HAIs (p = 0.50). (4) Conclusions: HAIs were common after this type of surgery, many of them caused by resistant microorganisms. Some modifiable risk factors were identified. Infections played a role in cancer prognosis by delaying adjuvant therapy.

Influence of Genetic Polymorphisms on the Response to Tramadol, Ibuprofen, and the Combination in Patients With Moderate to Severe Pain After Dental Surgery.

PURPOSE: We aimed to elucidate the influence on analgesic effect of genetic polymorphisms in enzymes responsible for biotransformation of tramadol and ibuprofen or other possible genes involved in their mechanism of action. METHODS: The study population comprised 118 patients from a multicenter, randomized, double-blind, placebo-controlled, Phase III clinical trial that assessed the analgesic efficacy and tolerability of a single dose of ibuprofen (arginine)/tramadol 400/37.5 mg compared with ibuprofen arginine 400 mg alone, tramadol 50 mg alone, and placebo in patients with moderate to severe pain after dental surgery. We analyzed 32 polymorphisms in the cytochrome P450 (CYP) enzymes COMT, ABCB1, SLC22A1, OPRM1, and SLC22A1. FINDINGS: We did not find any statistically significant difference among CYP2C9 phenotypes related to ibuprofen response, although CYP2C9 poor metabolizers had a longer effect (higher pain relief at 6 hours). Likewise, we did not find any statistically significant difference among PTGS2 genotypes, contradicting previously publications. IMPLICATIONS: There was not a clear effect of CYP2D6 phenotype on tramadol response, although CYP2D6 poor metabolizers had a slower analgesic effect. Concerning the transport of CYP2D6, we observed a better response in individuals carrying ABCB1 mutated alleles, which might correlate with higher tramadol plasma levels. Finally, we found a statistically significant better response in patients carrying the OPRM1 A118G G allele, which contradicts the previous reports. Measuring the active metabolite O-desmethyl-tramadol formation would be of great importance to better evaluate this association because O-desmethyl-tramadol has a higher µ-opioid receptor affinity compared with the parent drug. EudraCT.ema.europa.eu identifier: 2013-004637-33.

Management of the clinically N0 neck in early-stage oral squamous cell carcinoma (OSCC). An EACMFS position paper.

Metastasis of oral squamous cell carcinoma (OSCC) to the cervical lymph nodes has a significant impact on prognosis. Accurate staging of the neck is important in order to deliver appropriate treatment for locoregional control of the disease and for prognosis. The management of the neck in early, low volume disease (clinically T1/T2 oral cavity tumours) has long been debated. The risk of occult nodal involvement in cT1/T2 OSCC is estimated around 20-30%. We describe the natural evolutionary history of OSCC and its patterns of spread and metastasis to the local lymphatic basins. We discuss most published literature and studies on management of the clinically negative neck (cN0). Particular focus is given to prospective randomized trials comparing the outcomes of upfront elective neck dissection against the observational stance, and we summarize the results of the sentinel node biopsy studies. The paper discusses the significance of the primary tumour histological characteristics and specifically the tumour's depth of invasion (DOI) and its impact on predicting nodal metastasis. The DOI has been incorporated in the TNM staging highlighting its significance in aiding the treatment decision making and this is reflected in world-wide oncological guidelines. The critical analysis of all available literature amalgamates the existing evidence in early OSCC and provides recommendations in the management of the clinically N0 neck.

Vascular clinical anatomy of the submandibular gland.

OBJECTIVE: The aim of this study is to describe in depth the precise anatomy of the vascular supply of the submandibular gland, trying to determine the existence of patterns of glandular vascularization. Knowledge of these patterns could facilitate surgical management of the gland and the submandibular gland flap. MATERIAL AND METHODS: Neck dissections of formaldehyde preserved human cadavers were performed. Submandibular and transmandibular approaches were used during the dissections. All the vascular branches found were registered and classified into 2groups: main or accessory branches. The anatomical data analyzed was: The diameter and length of the main and accessory branches, as well as the most important measurements of the submandibular gland flap pedicle. RESULTS: 33 glands were dissected to study the arterial supply of the submandibular gland (17 right, 16 left; 17 males, 16 females) and 29 were dissected to study the venous supply (15 left, 14 right; 15 males,14 females). A total of 123 arterial branches were found reaching the 33 submandibular glands (47 main and 76 accessories) and 116 venous branches were found draining the 29 submandibular glands (47 main branches and 69 accessory branches). A constant main venous branch that ran parallel to the Wharton duct and drained in the sublingual vein was found in all of cases (Concomitant Wharton Duct Vein or CWDV). CONCLUSION: The CWDV is a constant venous branch for the drainage of the gland and should be considered as venous pedicle during the dissection of submandibular gland flaps.

A worldwide comparison of the management of surgical treatment of advanced oral cancer.

INTRODUCTION: Microvascular surgery following tumor resection has become an important field of oral and maxillofacial surgery (OMFS). Following the results from management of T1/T2 floor-of-mouth and tongue squamous cell carcinoma (SCC) in German-speaking countries, Europe, and worldwide, this paper presents specific concepts for the management of resection and reconstruction of T3/T4 SCC of the maxillary and mandibular alveolar process and tongue. METHODS: The DÖSAK questionnaire was distributed in three different phases to a growing number of maxillofacial units worldwide. Within this survey, clinical patient settings were presented to participants and center-specific treatment strategies were evaluated. RESULTS: A total of 188 OMFS units from 36 different countries documented their treatment strategies for T3/T4 maxillary and mandibular alveolar process and tongue SCC. The extent of surgical resections and subsequent reconstructions is more consistent than with T1/T2 tumors, although the controversy surrounding continuity resections and mandible-sparing procedures remains. For continuity resection of the mandible the fibula free flap is the most frequently used bone replacement, whereas maxilla reconstruction concepts are less consistent, ranging from locoregional coverage concepts and different microvascular reconstruction options to treatment via obturator prosthesis. CONCLUSION: Results from treatment strategies for T3/T4 tumors underline the limited evidence for the appropriate amount of resection and subsequent reconstruction process, especially in cases involving the mandible. Prospective randomized trials will be necessary in the long term to establish valid treatment guidelines.