Advancing Cancer Research: Current Knowledge on Cutaneous Neoplasia.

Skin cancers require a multidisciplinary approach. The updated guidelines introduce new insights into the management of these diseases. Melanoma (MM), the third most common skin cancer, a malignant melanocytic tumor, which is classified into four major histological subtypes, continues to have the potential to be a lethal disease. The mortality-incidence ratio is higher in Eastern European countries compared to Western European countries, which shows the need for better prevention and early detection in Eastern European countries. Basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC) remain the top two skin cancers, and their incidence continues to grow. The gold standard in establishing the diagnosis and establishing the histopathological subtype in BCC and SCC is a skin biopsy. Sebaceous carcinoma (SeC) is an uncommon and potentially aggressive cutaneous malignancy showing sebaceous differentiation. It accounts for 0.7% of skin cancers and 3-6.7% of cancer-related deaths. Due to the rapid extension to the regional lymph nodes, SeC requires early treatment. The main treatment for sebaceous carcinoma is surgical treatment, including Mohs micrographic surgery, which has the advantage of complete margin evaluation and low recurrence rates. Primary cutaneous lymphomas (PCLs) are a heterogeneous group of lymphoproliferative diseases, with no evidence of extracutaneous determination at the moment of the diagnosis. PCLs have usually a very different evolution, prognosis, and treatment compared to the lymphomas that may secondarily involve the skin. The aim of our review is to summarize the important changes in the approach to treating melanoma, non-melanoma skin, cutaneous T and B cell lymphomas, and other types of skin cancers. For all skin cancers, optimal patient management requires a multidisciplinary approach including dermatology, medical oncology, and radiation oncology.

The Overlap of Kidney Failure in Extrapulmonary Sarcoidosis in Children-Case Report and Review of Literature.

Sarcoidosis is a non-necrotizing granulomatous inflammatory multisystemic disorder of unknown etiology. In children, as in adults, it can involve a few or all organ systems to a varying extent and degree, entailing multisystemic manifestations. Kidney involvement in pediatric-onset adult-type sarcoidosis is rare, with a wide range of renal manifestations, most of them related to calcium metabolism. Children with renal sarcoidosis tend to be more symptomatic than adults, although male patients have a higher prevalence. We present the case of a 10-year-old boy who presented with advanced renal failure with nephrocalcinosis and important hepatosplenomegaly. The diagnosis was established by histopathological examination, with consequent cortisone therapy and hemodialysis. This review emphasizes that sarcoidosis should be considered in the differential diagnosis of pediatric patients with acute kidney insufficiency or chronic kidney disease of an unknown etiology. As far as we know, this is the first study regarding extrapulmonary sarcoidosis in children from Romania.

The Role of the Gut Microbiota in Anorexia Nervosa in Children and Adults-Systematic Review.

Among the factors incriminated in the appearance of eating disorders, intestinal microbiota has recently been implicated. Now there is evidence that the composition of gut microbiota is different in anorexia nervosa. We gathered many surveys on the changes in the profile of gut microbiota in patients with anorexia nervosa. This review comprehensively examines the contemporary experimental evidence concerning the bidirectional communication between gut microbiota and the brain. Drawing from recent breakthroughs in this area of research, we propose that the gut microbiota significantly contributes to the intricate interplay between the body and the brain, thereby contributing to overall healthy homeostasis while concurrently impacting disease risk, including anxiety and mood disorders. Particular attention is devoted to elucidating the structure and functional relevance of the gut microbiota in the context of Anorexia Nervosa.

KIT-Associated Familial GIST Syndrome: Response to Tyrosine Kinase Inhibitors and Implications for Risk Management.

Sporadic gastrointestinal stromal tumors (GIST) are rare tumors, with a median age at diagnosis of 60 years. Familial GISTs are very rare and typically associated with earlier onset, with an average age at diagnosis of 48 years. To date, just over 50 familial cases associated with a germline variant KIT or PDGFRa genes have been published. Therefore, there are many challenges in managing these patients, including the timing of starting systemic treatment, considering that most patients have been asymptomatic for a long period before being diagnosed, as well as the choice of tyrosine kinase inhibitor and the plan for surveillance. It is uncertain if early diagnosis through screening of asymptomatic individuals improves overall survival. Screening could start from the age of 18 years but may be considered at earlier ages depending on the underlying genotype and family history. The long-term benefit of early diagnosis or palliative/prophylactic treatment with tyrosine kinase inhibitors is unknown as there are no data available. Long-term side effects of treatment with imatinib are rare but well documented and could be damaging in patients who have no or minimal disease. We present the case of a 53-year-old Caucasian patient who was diagnosed with multifocal GIST and subsequently found to be a carrier of a pathogenic germline KIT variant in exon 11. We discuss the implication of treatment and genetic testing in this case and in familial KIT associated GISTs.

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms.

Vascular anomalies (VAs) are morphogenesis defects of the vascular system (arteries, capillaries, veins, lymphatic vessels) singularly or in complex combinations, sometimes with a severe impact on the quality of life. The progress made in recent years with the identification of the key molecular pathways (PI3K/AKT/mTOR and RAS/BRAF/MAPK/ERK) and the gene mutations that lead to the appearance of VAs has allowed the deciphering of their complex genetic architecture. Understanding these mechanisms is critical both for the correct definition of the phenotype and classification of VAs, as well as for the initiation of an optimal therapy and the development of new targeted therapies. The purpose of this review is to present in synthesis the current data related to the genetic factors involved in the etiology of VAs, as well as the possible directions for future research. We analyzed the data from the literature related to VAs, using databases (Google Scholar, PubMed, MEDLINE, OMIM, MedGen, Orphanet) and ClinicalTrials.gov. The obtained results revealed that the phenotypic variability of VAs is correlated with genetic heterogeneity. The identification of new genetic factors and the molecular mechanisms in which they intervene, will allow the development of modern therapies that act targeted as a personalized therapy. We emphasize the importance of the geneticist in the diagnosis and treatment of VAs, as part of a multidisciplinary team involved in the management of VAs.

The Genetic Architecture of the Etiology of Lower Extremity Peripheral Artery Disease: Current Knowledge and Future Challenges in the Era of Genomic Medicine.

Lower extremity artery disease (LEAD), caused by atherosclerotic obstruction of the arteries of the lower limb extremities, has exhibited an increase in mortality and morbidity worldwide. The phenotypic variability of LEAD is correlated with its complex, multifactorial etiology. In addition to traditional risk factors, it has been shown that the interaction between genetic factors (epistasis) or between genes and the environment potentially have an independent role in the development and progression of LEAD. In recent years, progress has been made in identifying genetic variants associated with LEAD, by Genome-Wide Association Studies (GWAS), Whole Exome Sequencing (WES) studies, and epigenetic profiling. The aim of this review is to present the current knowledge about the genetic factors involved in the etiopathogenic mechanisms of LEAD, as well as possible directions for future research. We analyzed data from the literature, starting with candidate gene-based association studies, and then continuing with extensive association studies, such as GWAS and WES. The results of these studies showed that the genetic architecture of LEAD is extremely heterogeneous. In the future, the identification of new genetic factors will allow for the development of targeted molecular therapies, and the use of polygenic risk scores (PRS) to identify individuals at an increased risk of LEAD will allow for early prophylactic measures and personalized therapy to improve their prognosis.

Pain Intensity and Degree of Disability after Fragility Fractures of the Pelvis.

Background and objectives: Fragility fractures of the pelvis (FFP) are of increasing interest lately, being associated with a loss of mobility and affecting the quality of life. The aim of our study was to investigate the effect of FFP on disability and pain in patients, after one year since injury. Materials and Methods: In the study, we included 76 patients diagnosed with FFP, who were admitted to our trauma department between January 2016 and January 2019, and were above 65 years of age. The Von Korff pain intensity and disability scores were calculated in the hospital at 6 months and after 1 year. Results: Fifty-four patients were female (71%), with an average age of 75.9 ± 7.19 years. Twenty-two patients were male (29%) and had a mean age of 77.22 ± 7.33 years. We did not record significant differences regarding age between the men and women (p > 0.05). Significant improvements appeared between the baseline and the 6 month follow-up; the average pain intensity score at 6 months was 44.94 (SD 21.20) (p < 0.001), and the disability score was 54.30 (SD 21.62). The following average pain intensity and disability scores after 12 months were similar to the values at6 months: 44.48 (SD 21.74) for pain intensity and 52.36 (SD 24.53) for disability. The Von Korff pain score at 6 months and after 1 year depends on gender and on the initial Von Korff pain score (p = 0.02). The Von Korff disability score at 6 months depends on gender, the baseline pain score and the baseline disability score (p = 0.001). Conclusions: our patients reported long-lasting pain that had a severe effect on their daily routines, and they could not return to their normal status prior to injury.

Uncommon Metastasis of Ovarian Dysgerminoma: A Case Report and Review of the Literature.

Ovarian malignant germ cell tumors (OMGCT) represent less than 10% of all ovarian tumors. Dysgerminoma is the most common malignant primitive germ cell tumor in young women, known for its curability and low propensity to invade and metastasize when diagnosed early. Herein, we report an unusual type of ovarian dysgerminoma (OD) metastasis with a brief review of the literature, lacking similar reported cases. To our knowledge, although there are several case reports of dysgerminoma metastases with variable anatomic location and presentation, vaginal metastasis has not been previously described. The local or systemic relapse together with local and distant metastasis is considered as an independent predictor of poor survival in patients with OD. In light of the absence of mutations status, our patient successfully responded to therapy. Currently, the patient remains in clinical remission. A specific follow-up plan is ongoing knowing that ovarian dysgerminomas tend to recur most often in the first 2-3 years after treatment.

Hypolipemiant Actions and Possible Cardioprotective Effects of Valine and Leucine: An Experimental Study.

Background and Objectives: Considering atherosclerosis as one of the more challenging threats to healthcare worldwide, any novel therapy that counteracts the risks for developing it, provides new opportunities for the management of this process. Material and methods: We performed an experimental research in which we induced a hypercholesterolemia via a cholesterol-rich diet. Our aim was to demonstrate the antiatherogenic potential of two essential amino acids (valine and leucine). The experimental study was carried out over a period of 60 days. Male Wistar rats weighing between 250-280 g were used and divided into 4 groups, each group including 8 animals. Group I-control was fed with a standard diet. Group II received cholesterol, group III cholesterol and valine and group IV cholesterol and leucine. Blood samples were collected from the retro-orbital plexus, under anesthesia with 75 mg/kg of intraperitoneal ketamine, in three different moments (R0-1st day, R1-the 30th day, R2-the 60th day) in order to measure the levels of triglycerides. Results: In R0, there were no significant differences between the average levels of triglycerides across all the groups (p < 0.05). Compared to the group I, in R1 and R2, the average levels of triglycerides were significantly higher in all groups (p < 0.001). Also, in R1 and R2, the average triglycerides in group II receiving cholesterol (C) were significantly higher than those in group III receiving valine (C + V) as well as in group IV receiving leucine (C + L) (p < 0.001; p < 0.05). In R2, the average triglycerides in group III were significantly lower than in group IV (p < 0.001). Conclusions: Our data provides evidence that valine and leucine have a direct impact on the lipid metabolism parameters by lowering the level of triglycerides. The comparison of the two essential amino acids indicates that valine acts more promptly and rapidly than leucine.

The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis.

BACKGROUND: This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers. MATERIALS AND METHODS: Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method. RESULTS: Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine. CONCLUSION: Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules. IMPLICATIONS FOR PRACTICE: Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.

Vitamin D in kidney transplant recipients
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Kidney transplant recipients (KTRs) are susceptible to low levels of vitamin D, which may be responsible for mineral and bone metabolism disorders and play some role in the occurrence of cardiovascular, metabolic, immunologic, neoplastic, and infectious complications after kidney transplant. Kidney Disease Improving Global Outcomes (KDIGO) guidelines of the year 2017 recommended vitamin D supplementation in the first 12 months after transplant using the same treatment strategies for the general population. However, no recommendations are provided after the first 12 months due to a lack of sufficient data. This review analyses some studies that assessed the vitamin D status of KTRs and the effects of nutritional and active vitamin D supplementation on bone mineral density, cardiovascular disease, proteinuria, and graft function in KTRs.

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy.

Cannabis has been used in pain management since 2900 BC. In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs. Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed. In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography-mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed. In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.

Radiation-induced angiosarcoma of the breast: retrospective analysis at a regional treatment centre.

BACKGROUND: Radiation-induced angiosarcoma (RIA) is an uncommon but morbid complication after radiotherapy for breast cancer. METHODS: Retrospective analysis of breast RIA patients at Cambridge University Hospital (CUH), a regional treatment centre in the East of England. RESULTS: 22 patients were identified between 2010 and 2022. Median age of diagnosis was 65 years (range 41-78). Median time from breast radiotherapy to RIA diagnosis was 6.5 years (range 2.4-16.0)-this interval has decreased over the last 24 years (r2 = 0.6601). 9% had metastasis at presentation. All patients underwent surgery (55% at CUH, 45% at local hospitals). 27% received peri-operative pegylated liposomal doxorubicin in the first-line setting. 62% relapsed following their primary curative-intent treatments after a median of 28 months. Metastases occurred in 36%, the commonest sites being lung (100%) and lymph node (50%). 2-year and 5-year overall survival (OS) rates for all patients were 73% and 60%, respectively. No correlation between progression-free survival (PFS) and OS was found with tumour size, margin, peri-operative chemotherapy, and whether surgery was performed at CUH. Patients with multifocal disease on their breasts had shorter PFS following surgery compared to single-lesion disease (median 10 vs 65 months; HR = 4.359 [95% CI 1.342-14.16]; P = 0.0143). Patients aged > 72 years had a median OS of 45 months vs 102 months for those ≤ 72 years (HR = 7.129 [95% CI 1.646-30.88]; P = 0.0086). CONCLUSION: RIA has high rates of recurrence and mortality and appears to be occurring sooner after breast radiotherapy. Further studies on its pathogenesis and effective treatment are warranted.

Impact of COVID-19 on Pediatric Inflammatory Bowel Diseases-From Expectations to Reality.

Viral infections have always been considered a threat to global health, with numerous outbreaks across time. Despite the relative recent experience with coronavirus-associated diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), severe acute respiratory syndrome-2's (SARS-CoV-2) continuous evolution displays a different behavior. With a tropism for both respiratory and digestive mucosa, coronavirus disease 2019 (COVID-19) and inflammatory bowel disease (IBD) seem to share a particular common background. Current literature offers evidence that viral alteration of the immune system, inflammatory intestinal tissue damage, increased intestinal permeability, incomplete viral clearance with viral antigen persistence, and intestinal dysbiosis, might explain SARS-CoV-2-IBD relationship in terms of etiopathogenesis and evolution. The hyperinflammatory state that both entities have in common explains the lack of success of current IBD therapy, raising the need for new personalized therapeutic options, with better outcomes for IBD and COVID-19 as well. This review aims to summarize the current available data on pediatric IBD evolution, management, and outcomes in the post-COVID period, with an emphasis on the particular aspects of the SARS-CoV-2-IBD relationship in children.

Lidocaine-Liposomes-A Promising Frontier for Transdermal Pain Management.

(1) Background: We aim to develop novel gel formulations for transdermal drug delivery systems in acute and inflammatory pain therapy. (2) Methods: We induced inflammation by the injection of λ-carrageenan on the hind paw of 80 Wistar male rats. The animals were randomized into eight groups of 10 rats each: C (placebo gel), E (EMLATM), L (lidocaine 2%), L-CD (lidocaine + cyclodextrin 2.5%), L-LP (lidocaine + liposomes 1.7%), L-CS (lidocaine + chitosan 4%), L-CSh (lidocaine + chitosan hydrochloride), and L-CS-LP (lidocaine + chitosan + liposomes). The behavior response was determined with a hot plate, cold plate, and algesimeter, each being performed at 30, 60, 120, 180, and 240 min after pain induction. At the end of the experiment, tissue samples were collected for histological assessment. (3) Results: L-LP had the greatest anesthetic effects, which was proven on the cold plate test compared to placebo and EMLATM (all p ≤ 0.001). L-CS-LP had a significant effect on cold plate evaluation compared to placebo (p ≤ 0.001) and on hot plate evaluation compared to EMLATM (p = 0.018). (4) Conclusions: L-LP is a new substance with a substantial analgesic effect demonstrated by the cold plate in the first 120 min. Further studies with more animals are needed to determine the maximum doses that can be applied for a better analgesia with minimum side effects.

The Role of Natural Extracts in the Management of Infantile Hemangiomas and Vascular Tumors.

Hemangiomas are vascular tumors resulting from the proliferation of endothelial-like cells; they are the most common childhood tumors, affecting approximately 5-10% of newborns and infants. Besides hemangiomas, which are definitely benign tumors despite their overgrowth potential, there are other vascular tumors like hemangioendotheliomas, which may display intermediate characteristics between benign hemangiomas and highly malignant angiosarcomas. Standard therapy may be constricted by serious adverse effects, high cost, or traumatic influence. Diet is a major resource for health preservation, disease prevention, and treatment. The therapeutic property of edible berries, marine products, or medicinal plants have long been known and used in traditional medicine; a plant-based nutrition can prevent the development and progression of diseases associated with extensive neo-vascularization. The purpose of our review is to highlight those natural treatments that hemangioma and vascular tumor patients can receive in the future, both for their benefit and that of their families. We performed the review according to the Preferred Reporting Items for Systematic Reviews and Metanalysis Statement. We used the Web of Science, PubMed, and EMBASE engines for the study, and searched for the association of hemangioma with naturopathic treatment/plant extract/plants in published articles. We found that natural extracts from plants and fruits are cost-effective and safe treatments for hemangiomas and vascular tumors, as well as for other forms of cancer. In any case, more in vitro and in vivo studies are needed to confirm the proposed signaling pathways in tumors and validate the improvement parameters after natural products administration. The era of molecularly targeted therapy and personalized medicine is approaching and naturally occurring substances are very useful tools for tumor treatment and prevention. Plant extract substances have strong specificity and pertinence, are non- toxic and have few side effects, and may become an emerging cancer treatment.

Diagnosis and Management of Simple and Complicated Meconium Ileus in Cystic Fibrosis, a Systematic Review.

The early management of neonates with meconium ileus (MI) and cystic fibrosis (CF) is highly variable across countries and is not standardized. We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The protocol was registered in PROSPERO (CRD42024522838). Studies from three providers of academic search engines were checked for inclusion criteria, using the following search terms: meconium ileus AND cystic fibrosis OR mucoviscidosis. Regarding the patient population studied, the inclusion criteria were defined using our predefined PICOT framework: studies on neonates with simple or complicated meconium which were confirmed to have cystic fibrosis and were conservatively managed or surgically treated. Results: A total of 566 publications from the last 10 years were verified by the authors of this review to find the most recent and relevant data, and only 8 met the inclusion criteria. Prenatally diagnosed meconium pseudocysts, bowel dilation, and ascites on ultrasound are predictors of neonatal surgery and risk factor for negative 12-month clinical outcomes in MI-CF newborns. For simple MI, conservative treatment with hypertonic solutions enemas can be effective in more than 25% of cases. If repeated enemas fail to disimpact the bowels, the Bishop-Koop stoma is a safe option. No comprehensive research has been conducted so far to determine the ideal surgical protocol for complicated MI. We only found three studies that reported the types of stomas performed and another study comparing the outcomes of patients depending on the surgical management; the conclusions are contradictory especially since the number of cases analyzed in each study was small. Between 18% and 38% of patients with complicated MI will require reoperation for various complications and the mortality rate varies between 0% and 8%. Conclusion: This study reveals a lack of strong data to support management decisions, unequivocally shows that the care of infants with MI is not standardized, and suggests a great need for international collaborative studies.

Role of the Renin-Angiotensin System in Long COVID's Cardiovascular Injuries.

The renin-angiotensin system (RAS) is one of the biggest challenges of cardiovascular medicine. The significance of the RAS in the chronic progression of SARS-CoV-2 infection and its consequences is one of the topics that are currently being mostly discussed. SARS-CoV-2 undermines the balance between beneficial and harmful RAS pathways. The level of soluble ACE2 and membrane-bound ACE2 are both upregulated by the endocytosis of the SARS-CoV-2/ACE2 complex and the tumor necrosis factor (TNF)-α-converting enzyme (ADAM17)-induced cleavage. Through the link between RAS and the processes of proliferation, the processes of fibrous remodelling of the myocardium are initiated from the acute phase of the disease, continuing into the long COVID stage. In the long term, RAS dysfunction may cause an impairment of its beneficial effects leading to thromboembolic processes and a reduction in perfusion of target organs. The main aspects of ACE2-a key pathogenic role in COVID-19 as well as the mechanisms of RAS involvement in COVID cardiovascular injuries are studied. Therapeutic directions that can be currently anticipated in relation to the various pathogenic pathways of progression of cardiovascular damage in patients with longCOVID have also been outlined.

Electrospun/3D-Printed Bicomponent Scaffold Co-Loaded with a Prodrug and a Drug with Antibacterial and Immunomodulatory Properties.

This work reports the construction of a bicomponent scaffold co-loaded with both a prodrug and a drug (BiFp@Ht) as an efficient platform for wound dressing, by combining the electrospinning and 3D-printing technologies. The outer component consisted of a chitosan/polyethylene oxide-electrospun membrane loaded with the indomethacin-polyethylene glycol-indomethacin prodrug (Fp) and served as a support for printing the inner component, a gelatin methacryloyl/sodium alginate hydrogel loaded with tetracycline hydrochloride (Ht). The different architectural characteristics of the electrospun and 3D-printed layers were very well highlighted in a morphological analysis performed by Scanning Electron Microscopy (SEM). In vitro release profile studies demonstrated that both Fp and Ht layers were capable to release the loaded therapeutics in a controlled and sustained manner. According to a quantitative in vitro biological assessment, the bicomponent BiFp@Ht scaffold showed a good biocompatibility and no cytotoxic effect on HeLa cell cultures, while the highest proliferation level was noted in the case of HeLa cells seeded onto an Fp nanofibrous membrane. Furthermore, the BiFp@Ht scaffold presented an excellent antimicrobial activity against the E. coli and S. aureus bacterial strains, along with promising anti-inflammatory and proangiogenic activities, proving its potential to be used for wound dressing.