A single-center, open-labeled, randomized, 6-month, parallel-group study to assess the safety and efficacy of allogeneic cultured keratinocyte sheet transplantation for deep second-degree burn wounds: rationale and design of phase I/II clinical trial.

BACKGROUND: Burn-related injuries are a major global health issue, causing 180,000 deaths per year. Early debridement of necrotic tissue in association with a split-thickness skin graft is usually administered for some of the 2nd- and 3rd-degree injuries. However, this approach can be complicated by factors such as a lack of proper donor sites. Artificial skin substitutes have attracted much attention for burn-related injuries. Keratinocyte sheets are one of the skin substitutes that their safety and efficacy have been reported by previous studies. METHODS: Two consecutive clinical trials were designed, one of them is phase I, a non-randomized, open-label trial with 5 patients, and phase II is a randomized and open-label trial with 35 patients. A total number of 40 patients diagnosed with 2nd-degree burn injury will receive allogenic keratinocyte sheet transplantation. The safety and efficacy of allogeneic skin graft with autograft skin transplantation and conventional treatments, including Vaseline dressing and topical antibiotic, will be compared in different wounds of a single patient in phase II. After the transplantation, patients will be followed up on days 3, 7, 10, 14, 21, and 28. In the 3rd and 6th months after the transplantation scar, a wound closure assessment will be conducted based on the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale. DISCUSSION: This study will explain the design and rationale of a cellular-based skin substitute for the first time in Iran. In addition, this work proposes this product being registered as an off-the-shelf product for burn wound management in the country. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT) IRCT20080728001031N31, 2022-04-23 for phase I and IRCT20080728001031N36, 2024-03-15 for phase II.

2023, A Landmark Year in Biomedical Research; A Turning Point in Medical History.

The rapid development of knowledge on healthy nutrition, and hygiene practices, as well as the advent of antibiotics and vaccines, has led to increased life expectancy in the recent century. The extended lifespan has brought new challenges for healthcare professionals, including the management of chronic degenerative diseases, malignancies, and autoimmune disorders. Advanced therapeutic medicinal products (ATMPs) have emerged as a promising frontier alongside conventional therapeutic modalities, offering innovative solutions through cell-based therapies, gene therapy, and tissue engineering. Recent years have witnessed remarkable advancements in regenerative medicine and the launching of innovative ATMPs. Numerous ATMPs have been registered and approved by regulatory agencies for the management of different diseases in 2023. The approval of groundbreaking therapies around the world has made 2023 an exceptional year. Novel ATMPs and the development of artificial intelligence (AI) in 2023 will pave the way for the integration of ATMPs and advanced technologies in personalized medicine, early diagnosis and targeted treatments.

Advanced Therapeutic Medicinal Products in Bone and Cartilage Defects.

The number of patients with functional loss of bone and cartilage tissue has shown an increasing trend. Insufficient or inappropriate conventional treatments applied for trauma, orthopedic diseases, or other bone and cartilage-related disorders can lead to bone and cartilage damage. This represents a worldwide public health issue and a significant economic burden. Advanced therapeutic medicinal products (ATMPs) proposed promising alternative therapeutic modalities by application of cell-based and tissue engineering approaches. Recently, several ATMPs have been developed to promote bone and cartilage tissue regeneration. Fifteen ATMPs, two related to bone and 13 related to cartilage, have received regulatory approval and marketing authorization. However, four ATMPs were withdrawn from the market for various reasons. However, ATMPs that are still on the market have demonstrated positive results, their broad application faced limitations. The development and standardization of methodologies will be a major challenge in the coming decades. Currently, the number of ATMPs in clinical trials using mesenchymal stromal cells or chondrocytes indicates a growing recognition that current ATMPs can be improved. Research on bone and cartilage tissue regeneration continues to expand. Cell-based therapies are likely to be clinically supported by the new ATMPs, innovative fabrication processes, and enhanced surgical approaches. In this study, we highlighted the available ATMPs that have been used in bone and cartilage defects and discussed their advantages and disadvantages in clinical applications.

Prevalence of Hepatobiliary Manifestations in Inflammatory Bowel Disease: A GRADE Assessed Systematic Review and Meta-Analysis of more than 1.7 Million Patients.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] comprises an immune-mediated group of chronic gastrointestinal disorders. Patients with IBD may experience extraintestinal manifestations, such as hepatobiliary complications. This meta-analysis aims to assess the prevalence of different hepatic manifestations in IBD patients. METHODS: For this systematic review and meta-analysis, PubMed, Scopus, Web of Science, and Embase were searched until July 20, 2022, by specifying keywords for IBD, hepatic manifestations, and study type. Full texts of cohort studies in English that examined the prevalence of different hepatic manifestations were included in this study. The primary outcome was the overall prevalence of hepatic manifestations in IBD patients. For the statistical analysis, a proportion by random effect model meta-analysis was performed. The registration number for the protocol of this study in PROSPERO is CRD42022369595. RESULTS: From the 4421 articles retrieved from the primary search, 118 met the inclusion criteria and were included in the final analysis. After a pooled analysis of 1 729 128 patients, the overall prevalence of hepatic manifestations was 3.49% (95% confidence interval [CI]: 3.31-3.68%; I2: 99.55%). The pooled prevalence of non-alcoholic fatty liver disease in 228 216 patients was 26.1% [95% CI: 22.1-30.2%; I2: 99.018%]. After pooled analysis of 9642 patients, the prevalence of primary sclerosing cholangitis was 1.67% [95% CI: 1.47-1.88%; I2: 99.10%]. The pooled prevalence of biliary stones was 4.1% [95% CI: 3.6-4.7%; I2: 97.43%]. Autoimmune hepatitis (0.51% [95% CI: 0.26-0.75%]; I2: 85.36%) and portal vein thrombosis (0.21% [95% CI: 0.08-0.33%]; I2: 97.95%) are considered as rare manifestations. CONCLUSION: This study summarizes the prevalence and importance of different hepatic manifestations in IBD patients. These findings are crucial for the management of extraintestinal manifestations, especially hepatic manifestations, in IBD patients.

Recent advances and future directions of 3D to 6D printing in brain cancer treatment and neural tissue engineering.

The field of neural tissue engineering has undergone a revolution due to advancements in three-dimensional (3D) printing technology. This technology now enables the creation of intricate neural tissue constructs with precise geometries, topologies, and mechanical properties. Currently, there are various 3D printing techniques available, such as stereolithography and digital light processing, and a wide range of materials can be utilized, including hydrogels, biopolymers, and synthetic materials. Furthermore, the development of four-dimensional (4D) printing has gained traction, allowing for the fabrication of structures that can change shape over time using techniques such as shape-memory polymers. These innovations have the potential to facilitate neural regeneration, drug screening, disease modeling, and hold tremendous promise for personalized diagnostics, precise therapeutic strategies against brain cancers. This review paper provides a comprehensive overview of the current state-of-the-art techniques and materials for 3D printing in neural tissue engineering and brain cancer. It focuses on the exciting possibilities that lie ahead, including the emerging field of 4D printing. Additionally, the paper discusses the potential applications of five-dimensional and six-dimensional printing, which integrate time and biological functions into the printing process, in the fields of neuroscience.

Cartilage regeneration and inflammation modulation in knee osteoarthritis following injection of allogeneic adipose-derived mesenchymal stromal cells: a phase II, triple-blinded, placebo controlled, randomized trial.

BACKGROUND: Intra-articular injection of mesenchymal stromal cells (MSCs) with immunomodulatory features and their paracrine secretion of regenerative factors proposed a noninvasive therapeutic modality for cartilage regeneration in knee osteoarthritis (KOA). METHODS: Total number of 40 patients with KOA enrolled in two groups. Twenty patients received intra-articular injection of 100 × 106 allogeneic adipose-derived mesenchymal stromal cells (AD-MSCs), and 20 patients as control group received placebo (normal saline). Questionnaire-based measurements, certain serum biomarkers, and some cell surface markers were evaluated for 1 year. Magnetic resonance imaging (MRI) before and 1 year after injection was performed to measure possible changes in the articular cartilage. RESULTS: Forty patients allocated including 4 men (10%) and 36 women (90%) with average age of 56.1 ± 7.2 years in control group and 52.8 ± 7.5 years in AD-MSCs group. Four patients (two patients from AD-MSCs group and two patients from the control group) excluded during the study. Clinical outcome measures showed improvement in AD-MSCs group. Hyaluronic acid and cartilage oligomeric matrix protein levels in blood serum decreased significantly in patients who received AD-MSCs (P < 0.05). Although IL-10 level significantly increased after 1 week (P < 0.05), the serum level of inflammatory markers dramatically decreased after 3 months (P < 0.001). Expressions of CD3, CD4, and CD8 have a decreasing trend during 6-month follow-up (P < 0.05), (P < 0.001), and (P < 0.001), respectively. However, the number of CD25+ cells increased remarkably in the treatment group 3 months after intervention (P < 0.005). MRI findings showed a slight increase in the thickness of tibial and femoral articular cartilages in AD-MSCs group. The changes were significant in the medial posterior and medial anterior areas of ​​the tibia with P < 0.01 and P < 0.05, respectively. CONCLUSION: Inter-articular injection of AD-MSCs in patients with KOA is safe. Laboratory data, MRI findings, and clinical examination of patients at different time points showed notable articular cartilage regeneration and significant improvement in the treatment group. TRIAL REGISTRATION: Iranian registry of clinical trials (IRCT, https://en.irct.ir/trial/46 ), IRCT20080728001031N23. Registered 24 April 2018.

Clinical and laboratory findings following transplantation of allogeneic adipose-derived mesenchymal stromal cells in knee osteoarthritis, a brief report.

BACKGROUND: Mesenchymal stromal cells (MSCs) injection has been proposed as an innovative treatment for knee osteoarthritis (KOA). Since, allogeneic MSCs can be available as off-the-shelf products, they are preferable in regenerative medicine. Among different sources for MSCs, adipose-derived MSCs (AD-MSCs) appear to be more available. METHODS: Three patients with KOA were enrolled in this study. A total number of 100 × 106 AD-MSCs was injected intra-articularly, per affected knee. They were followed up for 6 months by the assessment of clinical outcomes, magnetic resonance imaging (MRI), and serum inflammatory biomarkers. RESULTS: The primary outcome of this study was safety and feasibility of allogeneic AD-MSCs injection during the 6 months follow-up. Fortunately, no serious adverse events (SAEs) were reported. Assessment of secondary outcomes of visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and knee osteoarthritis outcome score (KOOS) indicated improvement in all patients. Comparison between baseline and endpoint findings of MRI demonstrated a slight improvement in two patients. In addition, decrease in serum cartilage oligomeric matrix protein (COMP) and hyaluronic acid (HA) indicated the possibility of reduced cartilage degeneration. Moreover, quantification of serum interleukin-10 (IL-10) and interleukin-6 (IL-6) levels indicated that the host immune system immunomodulated after infusion of AD-MSCs. CONCLUSION: Intra-articular injection of AD-MSCs is safe and could be effective in cartilage regeneration in KOA. Preliminary assessment after six-month follow-up suggests the potential efficacy of this intervention which would need to be confirmed in randomized controlled trials on a larger population. TRIAL REGISTRATION: This study was registered in the Iranian registry of clinical trials (https://en.irct.ir/trial/46) in 24 April 2018 with identifier IRCT20080728001031N23.

Mesenchymal Stromal Cell Therapy Improves Refractory Perianal Fistula in Crohn's Disease: Case Series Clinical Interventional Study.

Objective: Perianal fistulas in Crohn's disease (CD) are the main challenges in inflammatory bowel diseases (IBDs). Some of the fistulas are refractory to any therapeutic strategy. The aim of this study was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) as a novel promising modality for the treatment of fistulizing CD. Materials and Methods: This case series clinical interventional study was conducted from 2014 to 2017 at Shariati Hospital, an IBD referral center in Tehran, Iran. Refractory adult patients with CD who had draining perianal fistulas were enrolled in this study. All patients were examined by a colorectal surgeon and the fistula imaging studies were performed by pelvic magnetic resonance imaging (MRI). After autologous bone marrow (BM) aspiration and MSCs isolation, the cells were cultured and passaged under current good manufacturing practice (cGMP) conditions. Four intra-fistula injections of cells, each containing 40×106 MSCs suspended in fibrin glue, were administered by an expert surgeon every 4 weeks. Procedure safety, feasibility and closure of the perianal fistulas at week 24 were assessed. Clinical examination and MRI findings were considered as the primary end points. Results: In total, 5 patients (2 males and 3 females) were enrolled in this study. No adverse events were observed during the six-month follow-up in these patients. Both the Crohn's Disease Activity Index (CDAI) and Perianal Disease Activity Index (PDAI) scores decreased in all patients after cell injections and one patient achieved complete remission with closure of fistulas, discontinuation of fistula discharge, and closure of the external opening. Conclusion: Local injection of MSCs combined with fibrin glue is potentially a safe and effective therapeutic approach for complex perianal fistulas in patients with CD.

Investigating the Microstructure and Mechanical Properties of Aluminum-Matrix Reinforced-Graphene Nanosheet Composites Fabricated by Mechanical Milling and Equal-Channel Angular Pressing.

Layered-graphene reinforced-metal matrix nanocomposites with excellent mechanical properties and low density are a new class of advanced materials for a broad range of applications. A facile three-step approach based on ultra-sonication for dispersion of graphene nanosheets (GNSs), ball milling for Al-powder mixing with different weight percentages of GNSs, and equal-channel angular pressing for powders' consolidation at 200 °C was applied for nanocomposite fabrication. The Raman analysis revealed that the GNSs in the sample with 0.25 wt.% GNSs were exfoliated by the creation of some defects and disordering. X-ray diffraction and microstructural analysis confirmed that the interaction of the GNSs and the matrix was almost mechanical, interfacial bonding. The density test demonstrated that all samples except the 1 wt.% GNSs were fully densified due to the formation of microvoids, which were observed in the scanning electron microscope analysis. Investigation of the mechanical properties showed that by using Al powders with commercial purity, the 0.25 wt.% GNS sample possessed the maximum hardness, ultimate shear strength, and uniform normal displacement in comparison with the other samples. The highest mechanical properties were observed in the 0.25 wt.% GNSs composite, resulting from the embedding of exfoliated GNSs between Al powders, excellent mechanical bonding, and grain refinement. In contrast, agglomerated GNSs and the existence of microvoids caused deterioration of the mechanical properties in the 1 wt.% GNSs sample.