Application of Human Adipose-Derived Stem cells for Bone Regeneration of the Skull in Humans.

BACKGROUND: Archeological archives report cranioplasty as 1 of the oldest surgical procedures; however, it was not until the last century that true advances have been made. Alternative approaches are necessary to achieve optimal closure of the defect with fewer adverse effects. We aim to evaluate the use of human adipose-derived stem cells (hADSCs) alone or seeded in scaffolds as the main treatment for cranial bone defects and to assess human patient outcomes. METHODS: A systematic review was performed by querying PubMed, Ovid MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature databases with the MeSH terms: "adipose-derived stem cells," "cranial bone defect," "stromal vascular factor," "fat grafting," as well as synonyms in combinations determined by our search strategy. We included human models that used hADSCs as primary therapy. We excluded studies in languages other than English. RESULTS: One hundred ninety-four studies were identified after removal of duplicates. Four articles that used hADSCs as the main therapy to treat calvarial defects in humans were included. One article applied the cell therapy alone, and 3 used ß-tricalcium phosphate granules as a scaffold to seed the hADSCs. CONCLUSIONS: Bone regeneration was reached in a short and intermediate period using autologous hADSCs in humans with no major adverse effects in all 4 articles included. A long-term follow-up study (6 years) exhibited late infections and reabsorption of the ß-tricalcium phosphate scaffold seeded with hADSCs.

Adipose-Derived Stem Cells Therapy for Radiation-Induced Skin Injury.

BACKGROUND: Radiation-induced skin injuries have been treated with different medical therapies and have shown diverse outcomes. We aim to evaluate the effect of adipose-derived stem cells (ADSCs) therapy on radiation-induced skin injury. METHODS: We performed a review by querying PubMed, Ovid MEDLINE, and EMBASE databases from inception to April 2020 following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The MeSH terms "adipose-derived stem cells," "wound healing," "radiation," and synonyms in combinations determined our search strategy. Experimental peer-reviewed articles describing the protocol and comparing the results with controls were included. Non-English studies were excluded. RESULTS: Our search recorded a total of 137 articles. Only 8 studies met our inclusion criteria and were included in this review. Five studies evaluated the use of ADSC alone, whereas the others evaluated the efficacy of ADSC seeded in scaffolds. Adipose-derived stem cell-based therapies, either alone or seeded in scaffolds, were shown to improve wound healing in most studies when compared with controls. CONCLUSIONS: There is evidence supporting the positive benefits from ADSC-based therapies in radiation-induced skin injury. However, further studies are needed to standardize the method of ADSC extraction, radiation-induced skin injury experimental model, and increase the time of follow-up to evaluate the results accurately.

Materiales sensibles a biomarcadores y apósitos inteligentes: revisión sistemática.

OBJECTIVE: Evaluate a number of biomarkers that can objectively measure the wound healing process, and identify the materials that could replicate this in smart wound dressings. METHOD: A systematic review was conducted to establish the use of materials sensitive to biomarkers. Publications in English were included. Review articles and abstracts presented at conferences were excluded. RESULTS: A total of 296 studies were identified, of which 19 were included. All of these were experimental studies. The articles evaluated pH, temperature, blood pressure, uric acid, and glucose. The materials used were hydrogels, fibres and conductive inks. CONCLUSION: The most cited biomarker was pH. Materials that evaluate biomarkers via colorimetric methods could be the most suitable to incorporate into smart wound dressings.

OBJETIVO: Evaluar una serie de biomarcadores que permiten medir el proceso de cicatrización de las heridas e identificar los materiales que fueron utilizados para realizar dicha medición, teniendo en cuenta su incorporación en apósitos inteligentes. MÉTODO: Se realizó una revisión sistemática a partir de PubMed, Medline, CINAHL y Embase, sobre estudios que evaluaran el uso de materiales sensibles a biomarcadores. Se incluyeron estudios en inglés, sin tomar en cuenta el estado o fecha de publicación. No se incluyeron artículos de revisión ni sinopsis de conferencias. RESULTADOS: La búsqueda mostró 296 estudios. Un investigador seleccionó 19 artículos para su inclusión. Todos los estudios fueron experimentales. Se encontraron artículos que evaluaron pH, tensión de oxígeno, temperatura, presión, ácido úrico, y glucosa. Los materiales utilizados fueron hidrogeles, fibras y tintas conductivas. CONCLUSIÓN: El biomarcador más estudiado fue el pH. Los materiales que evalúan biomarcadores por medio de métodos colorimétricos podrían ser los más adecuados para su incorporación en apósitos inteligentes. CONFLICTO DE INTERÉS: Este estudio fue respaldado, en parte, por el centro de Medicina Individualizada de Mayo Clinic, y por la Fundación de Cirugía Plástica (Plastic Surgery Foundation).

Chronic Tenosynovitis of the Upper Extremities Caused by Mycobacterium kansasii : A Clinical Case and Systematic Review of Literature.

Background Chronic tenosynovitis of the upper extremities caused by Mycobacterium kansasii ( M. kansasii ) is uncommon, but symptoms may overlap with other more common diseases. Late diagnosis and treatment can lead to disfiguration of structures and rupture of tendons, resulting in worse cosmetic outcomes after reconstruction. Methods We present a clinical case and literature review of M. kansasii in patients with chronic tenosynovitis of upper extremities. PubMed was queried for cases of upper extremities tenosynovitis caused by M. kansasii . The keywords " M. kansasii ," "tenosynovitis" and synonyms were used for search in different combinations. Manuscripts, with no specific data or another condition, where the infection was not located in the upper extremities, were reviews, or not in English, were excluded from the study. Results We described 23 reported cases of tenosynovitis of the upper extremity caused by M. kansasii . An immunosuppressed state was present in eight (34.8%) cases, and 12 (52.2%) patients received immunosuppressive treatment. A long-time period between the first appearance of symptoms and the definitive diagnosis was identified (median: 7 months, interquartile range: 9). The most frequent symptoms were local swelling (65.2%), pain (56.5%), mass effect (26%), and stiffness (13%). Tendon rupture was found in three (13%) patients as a complication of the disease. Moreover, seven (30.4%) patients underwent previous surgeries to try to relieve the symptoms before definitive diagnosis was achieved. Conclusion M. kansasii is an important differential causal pathogen for tenosynovitis of the upper extremities. Although rare, raising awareness about this infectious disease is imperative to avoid inadequate management and hazardous aesthetic sequelae.

Propensity for different vascular distributions and cerebral edema of intraparenchymal brain metastases from different primary cancers.

PURPOSE: This study seeks to ascertain whether different primary tumor types have a propensity for brain metastases (BMs) in different cerebral vascular territories and cerebral edema. METHODS: Consecutive adult patients who underwent surgical resection of a BM at a tertiary care institution between 2001 and 2011 were retrospectively reviewed. Only patients with the most common primary cancers (lung, breast, skin-melanoma, colon, and kidney) were included. Preoperative MRIs were reviewed to classify all tumors by cerebral vascular territory (anterior cerebral artery-ACA, lenticulostriate, middle cerebral artery-MCA, posterior cerebral artery-PCA, posterior fossa, and watershed), and T2-weighted FLAIR widths were measured. Chi square analyses were performed to determine differences in cerebral vascular distribution by primary tumor type, and one-way ANOVA analyses were performed to determine FLAIR signal differences. RESULTS: 669 tumors from 388 patients were classified from lung (n = 316 BMs), breast (n = 144), melanoma (n = 119), renal (n = 47), and colon (n = 43). BMs from breast cancer were less likely to be located in PCA territory (n = 18 [13%]; χ2 = 6.10, p = 0.01). BMs from melanoma were less likely to be located in cerebellar territory (n = 11 [9%]; χ2 = 14.1, p < 0.001), and more likely to be located in lateral (n = 5 [4%]; χ2 = 4.56, p = 0.03) and medial lenticulostriate territories (n = 2 [2%]; χ2 = 6.93, p = 0.009). BMs from breast and melanoma had shorter T2-FLAIR widths, with an average [IQR] of 47.2 [19.6-69.2] mm (p = 0.01) and 41.2 [14.4-62.7] mm (p = 0.002) respectively. Conversely, BMs from renal cancer had longer T2-FLAIR widths (64.2 [43.6-80.8] mm, p = 0.002). CONCLUSIONS: These findings suggest that different primary tumor types could have propensities for different cerebral vascular territories and cerebral edema.

Tokuhashi score is predictive of survival in a cohort of patients undergoing surgery for renal cell carcinoma spinal metastases.

PURPOSE: Renal cell carcinoma (RCC) is an aggressive disease that metastasizes to the spine often requiring surgery. However, selecting the appropriate surgical intervention can be challenging. The Tokuhashi scoring system can be used to predict survival and inform the surgical strategy. We set out to determine the Tokuhashi score for patients with RCC spine metastases and compare expected and observed survival. METHODS: Records were reviewed for all patients who underwent surgery for spinal metastases at a single institution from January 2000 to December 2011 to determine the Tokuhashi score and survival. Kaplan-Meier estimates and log-rank test for univariate analysis were performed with R version 2.15.12 (R Foundation, 2012). RESULTS: Thirty patients underwent 40 spinal operations for metastatic RCC. Median survival was 11.4 months. Preoperative Tokuhashi scores were: 12-15, 15 patients; 9-11, seven patients; 0-8, eight patients. Median survival was 32.9, 11.7, and 5.4 months, respectively. Bone (p=0.01) and visceral metastases (p=0.005), and KPS (p=0.002) significantly affected survival. Tokuhashi score predicted survival (p=0.016); survival differed between the high and low score groups (p=0.006). CONCLUSIONS: RCC is an aggressive disease with short life expectancy when metastatic to the spine. However, patients with low systemic disease burden and solitary spinal metastases can have long survival and benefit from excisional surgery. Tokuhashi score can be useful in selecting surgical intervention in patients with RCC spinal metastases, and may be more relevant than in other cancers with spinal metastases.

In Vitro Enhanced Osteogenic Potential of Human Mesenchymal Stem Cells Seeded in a Poly (Lactic-co-Glycolic) Acid Scaffold: A Systematic Review.

Study Design: Human bone marrow stem cells (hBMSCs) and human adipose-derived stem cells (hADSCs) have demonstrated the capability to regenerate bone once they have differentiated into osteoblasts. Objective: This systematic review aimed to evaluate the in vitro osteogenic differentiation potential of these cells when seeded in a poly (lactic-co-glycolic) acid (PLGA) scaffold. Methods: A literature search of 4 databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted in January 2021 for studies evaluating the osteogenic differentiation potential of hBMSCs and hADSCs seeded in a PLGA scaffold. Only in vitro models were included. Studies in languages other than English were excluded. Results: A total of 257 studies were identified after the removal of duplicates. Seven articles fulfilled our inclusion and exclusion criteria. Four of these reviews used hADSCs and three used hBMSCs in the scaffold. Upregulation in osteogenic gene expression was seen in all the cells seeded in a 3-dimensional scaffold compared with 2-dimensional films. High angiogenic gene expression was found in hADSCs. Addition of inorganic material to the scaffold material affected cell performance. Conclusions: Viability, proliferation, and differentiation of cells strongly depend on the environment where they grow. There are several factors that can enhance the differentiation capacity of stem cells. A PLGA scaffold proved to be a biocompatible material capable of boosting the osteogenic differentiation potential and mineralization capacity in hBMSCs and hADSCs.

Verteporfin-loaded microparticles for radiosensitization of preclinical lung and breast metastatic spine cancer.

OBJECTIVE: The vertebral column is the most common site for skeletal metastasis, often leading to debilitating pain and weakness. Metastatic cancer has unique genetic drivers that potentiate tumorigenicity. There is an unmet need for novel targeted therapy in patients with spinal metastatic disease. METHODS: The authors assessed the effect of verteporfin-induced yes-associated protein (YAP) inhibition on spine metastatic cell tumorigenicity and radiation sensitivity in vitro. Animal studies used a subcutaneous xenograft mouse model to assess the use of systemic intraperitoneal verteporfin (IP-VP) and intratumoral verteporfin microparticles (IT-VP) to inhibit the tumorigenicity of lung and breast spinal metastatic tumors from primary patient-derived tissue. RESULTS: Verteporfin led to a dose-dependent decrease in migration, clonogenicity, and cell viability via inhibition of YAP and downstream effectors cyclin D1, CTGF, TOP2A, ANDRD1, MCL-1, FOSL2, KIF14, and KIF23. This was confirmed with knockdown of YAP. Verteporfin has an additive response when combined with radiation, and knockdown of YAP rendered cells more sensitive to radiation. The addition of verteporfin to YAP knockdown cells did not significantly alter migration, clonogenicity, or cell viability. IP-VP and IT-VP led to diminished tumor growth (p < 0.0001), especially when combined with radiation (p < 0.0001). Tissue analysis revealed diminished expression of YAP (p < 0.0001), MCL-1 (p < 0.0001), and Ki-67 (p < 0.0001) in tissue from verteporfin-treated tumors compared with vehicle-treated tumors. CONCLUSIONS: This is the first study to demonstrate that verteporfin-mediated inhibition of YAP leads to diminished tumorigenicity in lung and breast spinal metastatic cancer cells. Targeting of YAP with verteporfin offers promising results that could be translated to human clinical trials.

Human stem cells prevent flap necrosis in preclinical animal models: A systematic review.

Background and Aim: Adipose-derived mesenchymal stem cells (ADSCs) have been proven effective to prevent distal skin flap necrosis in preclinical models. However, to appropriately translate these findings to clinical trials, the effect of ADSC of human origin (hADSC) needs to be evaluated. We hypothesize that hADSC treatment is as effective as animal ADSC treatment at preventing distal skin flap necrosis in animal flap models. Methods: Three databases were inquired on August 17, 2020, to evaluate the necrotic flap area after using hADSCs in animal models of ischemic flaps. No publication status or dates were considered. Studies were included if they used hADSCs, measured the surviving or necrotic skin area of flaps, used animal models, and were in English. Studies were excluded if they did not use cells of human origin. The flap survival or necrotic area, perfusion, capillary density, vascular endothelial growth factor secretion and HIF-1α expression were extracted. Results: Ten studies met inclusion criteria. The mean absolute risk reduction (ARR) in necrotic skin area was 22.37% (95% confidence interval [CI] 16.98-27.76%, P<0.05) for flaps treated with animal ADSCs and 18.04% (95% CI 2.74-33.33%, P<0.05) for flaps treated with hADSCs. The difference between mean ARRs was not statistically significant (4.33%, 95% CI - 34.47-43.13%, P>0.05). Conclusion: Human ADSCs prevent skin flap necrosis to the same degree as animal ADSCs in rodent and rabbit flap models. Relevance for Patients: This review found that adipose-derived stem cells of human origin are equally effective at reducing the risk of surgical flap necrosis in preclinical models of small animals as autologous animal cells. The findings in this review should encourage researchers to use human adipose-derived stem cells in animal models of ischemic flaps to accelerate their translation into clinical trials and, eventually, surgical practice. The low immunogenicity of these cells should be leveraged to gain insight into the effects of the products that will be ultimately administered to patients. Furthermore, human adipose-derived stem cells' pro-angiogenic mechanism of action sets this therapy as a promising preventive measure for flap necrosis.

Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma.

Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin's functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin's cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.

Hypoxia-preconditioning of human adipose-derived stem cells enhances cellular proliferation and angiogenesis: A systematic review.

BACKGROUND: Human adipose-derived stem cells (hADSCs) have gained attention lately because of their ease of harvesting and ability to be substantially multiplied in laboratory cultures. Stem cells are usually cultured under atmospheric conditions; however, preconditioning stem cells under hypoxic conditions seems beneficial. AIM: This systematic review aims to investigate the effect of hypoxia preconditioning and its impact on the proliferation and angiogenic capacity of the hADSCs. METHODS: We performed a systematic review by searching PubMed, Scopus, Embase, and Google Scholar databases from all years through March 22, 2021, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Medical Subject Headings terms "adipose-derived stem cell," "Hypoxia," "cell proliferation," and "angiogenesis" guided our search. Only articles written in English using experimental models comparing a preconditioned group against a control group of hADSCs with data on proliferation and angiogenic capacity were included. RESULTS: Our search yielded a total of 321 articles. 11 articles met our inclusion criteria and were ultimately included in this review. Two studies induced hypoxia using hypoxia-inducible factor-1 alpha stabilizing agents, while nine reached hypoxia by changing oxygen tension conditions around the cells. Four articles conducted in-vivo studies to correlate their in-vitro findings, which proved to be consistent. Although 1 article indicated cell proliferation inhibition with hypoxia preconditioning, the remaining 10 found enhanced proliferation in preconditioned groups compared to controls. All articles showed an enhanced angiogenic capacity of hADSCs after hypoxia preconditioning. CONCLUSION: In this review, we found evidence to support hypoxia preconditioning of hADSCs before implantation. Benefits include enhanced cell proliferation with a faster population doubling rate and increased secretion of multiple angiogenic growth factors, enhancing angiogenesis capacity. RELEVANCE FOR PATIENTS: Although regenerative therapy is a promising field of study and treatment in medicine, much is still unknown. The potential for angiogenic therapeutics with stem cells is high, but more so, if we discover ways to enhance their natural angiogenic properties. Procedures and pathologies alike require the assistance of angiogenic treatments to improve outcome, such is the case with skin grafts, muscle flaps, skin flaps, or myocardial infarction to mention a few. Enhanced angiogenic properties of stem cells may pave the way for better outcomes and results for patients.

Targeted Therapy for Chordoma: Key Molecular Signaling Pathways and the Role of Multimodal Therapy.

BACKGROUND: Chordoma is a rare but devastating tumor that arises in the cranial skull base or spine. There are currently no US Food and Drug Administration-approved targeted therapies for chordoma, and little understanding of whether using more than one therapy has benefit over monotherapy. OBJECTIVE: The objective of this study was to systematically review the current status of clinical trials completed for patients with chordoma to determine if multimodal therapy offers a benefit in progression-free survival over monomodal therapy. METHODS: We performed a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to review the available clinical trials of targeted therapy for chordoma. We compiled the clinical data to determine if there is a benefit of multimodal therapy over monotherapy. RESULTS: Our search resulted in 11 clinical trials including 270 patients with advanced chordoma who were treated with targeted therapies. The most commonly employed targeted therapies acted within the following pathways: platelet-derived growth factor receptor (187 patients), vascular endothelial growth factor (66 patients), and mammalian target of rapamycin (43 patients). Reported progression-free survival for included studies ranged from 2.5 to 58 months, with the longest progression-free survival in a trial that included a platelet-derived growth factor receptor inhibitor, nilotinib, and concurrent radiotherapy (58.2 months). There was a higher range of progression-free survival for trials treating patients with multimodal therapy (10.2-14 months vs 2.5-9.2 months, except for a monotherapy trial published in 2020 with a progression-free survival of 18 months), and those published in 2018 or later (14-58.2 months vs 2.5-10.2 months). Only 23% of patients with chordoma in published clinical trials have been treated with multimodal therapy. CONCLUSIONS: Progression-free survival may be enhanced by the use of targeted therapy with concurrent radiotherapy, use of multimodal therapy, and use of newer targeted therapy. Future clinical trials should consider use of concurrent radiotherapy and multimodal therapy for patients with advanced chordoma.

Use of adipose-derived stem cells in lymphatic tissue engineering and regeneration.

The potential to differentiate into different cell lines, added to the easy and cost-effective method of extraction, makes adipose-derived stem cells (ADSCs) an object of interest in lymphedema treatment. Our study's goal was to conduct a comprehensive systematic review of the use of ADSCs in lymphatic tissue engineering and regeneration. On July 23, 2019, using PubMed/MEDLINE, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, and Embase databases, we conducted a systematic review of published literature on the use of ADSCs in lymphatic tissue engineering and regeneration. There were no language or time frame limitations, and the following search strategy was applied: ((Adipose stem cell) OR Adipose-derived stem cell)) AND ((Lymphedema) OR Breast Cancer Lymphedema). Only original research manuscripts were included. Fourteen studies fulfilled the inclusion criteria. Eleven studies were experimental (in vitro or in vivo in animals), and only three were clinical. Publications on the topic demonstrated that ADSCs promote lymphangiogenesis, and its effect could be enhanced by modulation of vascular endothelial growth factor-C, interleukin-7, prospero homeobox protein 1, and transforming growth factor-ß1. Pilot clinical studies included 11 patients with breast cancer-related lymphedema, and no significant side effects were present at 12-month follow-up. Literature on the use of ADSCs in lymphatic tissue engineering and regeneration demonstrated promising data. Clinical evidence is still in its infancy, but the scientific community agrees that ADSCs can be useful in regenerative lymphangiogenesis. Data collected in this review indicate that unprecedented advances in lymphedema treatment can be anticipated in the upcoming years.

Circulatory shear stress induces molecular changes and side population enrichment in primary tumor-derived lung cancer cells with higher metastatic potential.

Cancer is a leading cause of death and disease worldwide. However, while the survival for patients with primary cancers is improving, the ability to prevent metastatic cancer has not. Once patients develop metastases, their prognosis is dismal. A critical step in metastasis is the transit of cancer cells in the circulatory system. In this hostile microenvironment, variations in pressure and flow can change cellular behavior. However, the effects that circulation has on cancer cells and the metastatic process remain unclear. To further understand this process, we engineered a closed-loop fluidic system to analyze molecular changes induced by variations in flow rate and pressure on primary tumor-derived lung adenocarcinoma cells. We found that cancer cells overexpress epithelial-to-mesenchymal transition markers TWIST1 and SNAI2, as well as stem-like marker CD44 (but not CD133, SOX2 and/or NANOG). Moreover, these cells display a fourfold increased percentage of side population cells and have an increased propensity for migration. In vivo, surviving circulatory cells lead to decreased survival in rodents. These results suggest that cancer cells that express a specific circulatory transition phenotype and are enriched in side population cells are able to survive prolonged circulatory stress and lead to increased metastatic disease and shorter survival.

Functional Characterization of Brain Tumor-Initiating Cells and Establishment of GBM Preclinical Models that Incorporate Heterogeneity, Therapy, and Sex Differences.

Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4 All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

Theranostic OCT microneedle for fast ultrahigh-resolution deep-brain imaging and efficient laser ablation in vivo.

Current minimally invasive optical techniques for in vivo deep-brain imaging provide a limited resolution, field of view, and speed. These limitations prohibit direct assessment of detailed histomorphology of various deep-seated brain diseases at their native state and therefore hinder the potential clinical utilities of those techniques. Here, we report an ultracompact (580 µm in outer diameter) theranostic deep-brain microneedle combining 800-nm optical coherence tomography imaging with laser ablation. Its performance was demonstrated by in vivo ultrahigh-resolution (1.7 µm axial and 5.7 µm transverse), high-speed (20 frames per second) volumetric imaging of mouse brain microstructures and optical attenuation coefficients. Its translational potential was further demonstrated by in vivo cancer visualization (with an imaging depth of 1.23 mm) and efficient tissue ablation (with a 1448-nm continuous-wave laser at a 350-mW power) in a deep mouse brain (with an ablation depth of about 600 µm).

Adipose-derived stem cells in wound healing of full-thickness skin defects: a review of the literature.

The complex process of wound healing can be delayed in circumstances when the natural niche is extremely altered. Adipose-derived stem cells (ADSC) seem to be a promising therapy for these type of wounds. We aim to describe the studies that used ADSC for wound healing after a full-thickness skin defect, the ADSC mechanisms of action, and the outcomes of the different ADSC therapies applied to date. We performed a review by querying PubMed database for studies that evaluated the use of ADSC for wound healing. The Mesh terms, adipose stem cells AND (skin injury OR wound healing) and synonyms were used for the search. Our search recorded 312 articles. A total of 30 articles met the inclusion criteria. All were experimental in nature. ADSC was applied directly (5 [16.7%]), in sheets (2 [6.7%]), scaffolds (14 [46.7%]), skin grafts (3 [10%]), skin flaps (1 [3.3%]), as microvesicles or exosomes (4 [13.3%]), with adhesives for wound closure (1 [3.3%]), and in a concentrated conditioned hypoxia-preconditioned medium (1 [3.3%]). Most of the studies reported a benefit of ADSC and improvement of wound healing with all types of ADSC therapy. ADSC applied along with extracellular matrix, stromal cell-derived factor (SDF-1) or keratinocytes, or ADSC seeded in scaffolds showed better outcomes in wound healing than ADSC alone. ADSC have shown to promote angiogenesis, fibroblast migration, and up-regulation of macrophages chemotaxis to enhance the wound healing process. Further studies should be conducted to assure the efficacy and safety of the different ADSC therapies.

Chitosan-Based Non-viral Gene and Drug Delivery Systems for Brain Cancer.

Central nervous system (CNS) tumors are a leading source of morbidity and mortality worldwide. Today, different strategies have been developed to allow targeted and controlled drug delivery into the brain. Gene therapy is a system based on the modification of patient's cells through the introduction of genetic material to exert a specific action. Administration of the foreign genetic material can be done through viral-mediated delivery or non-viral delivery via physical or mechanical systems. For brain cancer specifically, gene therapy can overcome the actual challenge of blood brain barrier penetration, the main reason for therapeutic failure. Chitosan (CS), a natural based biodegradable polymer obtained from the exoskeleton of crustaceans such as crab, shrimp, and lobster, has been used as a delivery vehicle in several non-viral modification strategies. This cationic polysaccharide is highly suitable for gene delivery mainly due to its chemical properties, its non-toxic nature, its capacity to protect nucleic acids through the formation of complexes with the genetic material, and its ease of degradation in organic environments. Recent evidence supports the use of CS as an alternative gene delivery system for cancer treatment. This review will describe multiple studies highlighting the advantages and challenges of CS-based delivery structures for the treatment of brain tumors. Furthermore, this review will provide insight on the translational potential of various CS based-strategies in current clinical cancer studies. Specifically, CS-based nanostructures including nanocapsules, nanospheres, solid-gel formulations, and nanoemulsions, also microshperes and micelles will be evaluated.

Ablation of neuropilin-1 improves the therapeutic response in conventional drug-resistant glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly proliferative and locally invasive cancer with poor prognosis and a high recurrence rate. Although anti-VEGF (vascular endothelial growth factor) therapy offers short-term benefit to GBM patients, this approach fails as the tumor develops into a more invasive and drug-resistant phenotype and ultimately recurs. Recently, both glioma stemlike cells (GSCs) and brain tumor-initiating cells (BTICs) have been implicated in GBM recurrence and its resistance to therapy. We observed that patient-derived GBM cells expressing shRNAs of VEGF or neuropilin-1 (NRP-1) attenuate cancer stem cell markers, inhibit the tumor-initiating cell's neurosphere-forming capacity, and migration. Furthermore, both VEGF and NRP-1 knockdown inhibit the growth of patient-derived GBM xenografts in both zebrafish and mouse models. Interestingly, NRP-1-depleted patient-derived GBM xenografts substantially prolonged survival in mice compared to that of VEGF depletion. Our results also demonstrate that NRP-1 ablation of patient-derived GBM cells improves the sensitivity of TMZ and enhances the overall survival of the respective tumor-bearing mice. This improved outcome may provide insight into the inhibition of GBM progression and effective treatment strategies by targeting NRP-1 in addition to chemotherapy and radiotherapy.

The Study of Brain Tumor Stem Cell Invasion.

Ninety percent of deaths from solid tumors have been ascribed to the invasion and metastatic dissemination of cancer cells. One of the most fundamental prerequisites of brain tumor stem cell invasion is their ability to penetrate and traverse through the basement membrane and stromal compartments displacing from their original point of origin and repopulating at a distant site and adjacent tissue. In order to propose a successful clinical strategy, the investigation of the molecular determinants of invasion must factor in measurements and predictors of the complexity of brain tumor invasion potential accounting for the physiological scenarios encountered in the tumor niche. This chapter will highlight some laboratory approaches such as: spot assay, 3D chemogradient chambers, Fluoroblok™ tumor invasion, organotypics, and 3D tumor spheroid assays that could help mitigate the investigation of a tumor stem cell's invasion capacity through restrictive 3D environments otherwise seen in vivo.