Extensive Vascularization Research Articles

Advantages of Nasal Drug Delivery System

The nasal drug delivery system has received a lot of interest as a non-invasive and effective way to provide medications. Its distinct benefits include quick absorption due to the nasal mucosa's extensive vascularization, bypassing first-pass metabolism, and increased bioavailability when compared to oral administration. This approach is especially useful for administering medications that have little gastrointestinal stability or are destroyed by hepatic enzymes. The nasal route offers an alternative to systemic medication administration, particularly for individuals who have difficulties swallowing pills or injections. Furthermore, the nasal cavity's closeness to the brain makes it an appealing alternative for treating central nervous system problems, as medications can traverse the blood-brain barrier via the olfactory and trigeminal pathways. Nasal administration is also simple, patient-friendly, and inexpensive, with minimum pain. Advances in formulation technology, such as nanoparticles and mucoadhesive compounds, have improved medication retention and effectiveness. Despite its potential, issues including mucosal irritation and low medication volume must be addressed. Overall, the nasal medication delivery system is a potential tool for increasing treatment results and patient compliance.

Beta-Cell-Derived Extracellular Vesicles: Mediators of Intercellular Communication in the Islet Microenvironment in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterised by an autoimmune response specifically mounted against the insulin-producing beta cells. Within the islet, high cellular connectivity and extensive vascularisation facilitate intra-islet communication and direct crosstalk with the surrounding tissues and the immune system. During the development of T1D, cytokines and extracellular vesicles released by beta cells can contribute to the recruitment of immune cells, further amplifying autoimmunity and aggravating beta cell damage and dysfunction. In this review, we will evaluate the role of beta-cell-derived extracellular vesicles as mediators of the autoimmune response and discuss their potential for early diagnosis and new therapeutic strategies in T1D.

LncRNA SLNCR1 facilitates angiogenesis and tumor growth in melanoma via DNMT1‐mediated epigenetically silencing SPRY2

AbstractBackgroundThe malignancy of melanoma is attributed to its pronounced invasiveness, extensive vascularization, and rapid tumor cell growth and metastasis. LncRNA SLNCR1 is closely associated with a variety of aggressive tumors. However, our understanding of SLNCR1 influences on malignant melanoma growth metastasis mechanism especially proangiogenic mechanism remains unclear.MethodsThe expression of SLNCR1 was evaluated in melanoma tissues, adjacent tissues, melanoma cell lines. The abilities of SLNCR1 on proliferation, migration, and angiogenesis of HUVECs were detected by CCK‐8, flow cytometry, and Western blot assays. The association between SLNCR1, DNMT1, and SPRY2 was assessed by ChIP, RIP, and Western blot assays. The effect of SLNCR1 on tumor growth was determined using a xenograft model in nude mice.ResultsSLNCR1 was confirmed to be highly expressed in melanoma tissues and cells. CM from melanoma cells transfected with sh‐SLNCR1 attenuated proliferation, migration, and angiogenesis of HUVECs. Moreover, loss of SLNCR1 hindered tumor growth and metastasis, as evidenced by reduced tumor size and weight, as well as angiogenesis. Mechanistic studies revealed that SLNCR1 silenced SPRY2 expression, likely through enhancing DNMT1‐mediated DNA methylation of SPRY2 promoter.ConclusionSLNCR1 is an oncogene that interacts with DNMT1 to mediate SPRY2 methylation, thereby suppressing SPRY2 expression and promoting the angiogenesis and tumor growth in melanoma. SLNCR1 may serve as a potential target for melanoma treatment.

Vascularization of the menisci: a descriptive study of the peri-meniscal archs.

The meniscal vascularization remains poorly documented, particularly its origin. The aim of this cadaveric study was to describe the origin of the arterial vascularization of the menisci. This is an anatomical study on human specimens. Twenty knees were used. The average age of the subjects was 82.7 years old (56-97). Ten knees were injected with latex-neoprene and ten knees were injected with colored gelatin mixed with India ink. The same protocol for dissection was used in all cases. The meniscal vascularization is provided by the genicular arteries of the knee originating from the popliteal artery. The superior medial, superior lateral, inferior medial, inferior lateral, and middle genicular arteries had constant pathways. A second middle genicular artery was found in 55% of cases. The inferior lateral genicular artery ran alongside the meniscal's periphery. The inferior medial genicular artery followed the proximal tibial metaphysis. In all dissections, a previously undocumented small artery originated from under the middle genicular arteries. This artery remained extracapsular and followed the medial meniscal periphery. This artery has been named the "medial capsulo-meniscal artery". The genicular arteries formed an extensive peri-articular anastomotic vascularization for the menisci and thus referred to the "peri-meniscal arterial archs". The lateral peri-meniscal arch was predominantly supplied by the inferior lateral genicular artery, while the medial peri-meniscal arch was mainly supplied by the medial capsulo-meniscal artery. The peri-meniscal arterial archs are a vascular complex formed by the genicular arteries of the knee and an artery not previously described: the "capsulo-meniscal artery". These archs have a constant presence but their formation and distribution is different between the medial and lateral menisci.

Success and safety of endoscopic versus microscopic resection of temporal bone paraganglioma: a meta-analysis.

Temporal bone paraganglioma (TBP) are the most common tumors of the middle ear. They pose a challenge in otologic surgery due to their extensive vascularity and intricate location within the middle ear. This meta-analysis aimed to compare the safety and efficacy of two surgical approaches, microscopic middle ear surgery (MMES) and endoscopic middle ear surgery (EMES), in the resection of TBP. Eligible studies published after 1988 were identified through systematic searches of "PubMed", "Scopus" and "Google Scholar". Retrospective studies and randomized/non-randomized control trials reporting on surgical approaches for TBP with a minimum of five adult patients were included. A total of 595 records were initially identified. After removing 229 duplicates, 349 articles were excluded based upon article subject, title and abstract. Following the review of full texts, 13 articles were assessed for eligibility. The pooled analysis included a total of 529 ears, with a complication rate of 7.8% for EMES and 14.2% for MMES. Subgroup differences indicated no significant variation between the two methods (p = 0.2945). Both EMES and MMES demonstrated favorable surgical outcomes with low complication rates for TBP resection. These findings suggest that EMES is a safe and effective method for TBP resection and one that is comparable to MMES. Since the risk of bleeding is significant in these tumors, a third-hand technique, endoscopic bipolar cautery or laser-assisted hemostasis should be considered. Conversion to MMES is another option when visibility is critically affected by bleeding.

The effect of traction force on eyelid blood perfusion during closure of defects

ABSTRACT Purpose In oculoplastic surgery the eyelid tissue is frequently stretched in order to repair defects after tumor surgery. However, there is a paucity of research regarding how stretching affects eyelids. The purpose of this study was to gain insight into how traction force affects eyelid stretch as well as tissue perfusion, using a laser-based in vivo monitoring technique. Method Lower-lid pentagonal resections were performed in eight patients and a total of nine eyelids. The medial section of the eyelid was then stretched using a dynamometer up to a force of 2.3 Newtons (N), and eyelid stretching and blood perfusion were continuously measured using laser speckle contrast imaging. Results Tissue perfusion decreased exponentially when eyelid tissue was stretched, with an initial sharp decline followed by a more gradual reduction. Perfusion approached zero at a force of approximately 2.0 N. The length of the eyelid increased with increasing force up to 1.5 N, after which there was only a very slight increase in length. Conclusions Eyelid tissue seems to respond to traction in a non-linear fashion, where the initial force results in the greatest eyelid stretching and reduction in blood perfusion. The results provide information on the effects of a large force for direct closure of large eyelid defects. Considering how quickly perfusion approaches zero, the high success rate of eyelid reconstruction surgery is likely a testament to the extensive vascularization of the periocular region.

Abstract 5490: Spatial profiling of inflamed tumor microenvironment of clear cell renal cell carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) presents a distinctive tumor microenvironment (TME) characterized by extensive vascularization and immune infiltration. This unique TME makes ccRCC an attractive target for anti-angiogenesis and immune checkpoint blockade (ICB). To better understand the complexity of ccRCC and the associated cell types and states involved in disease progression, we conducted high-throughput single-cell immunofluorescence imaging on tissue sections from 437 localized tumors that were surgically resected. These samples included regions from the tumor center, tumor edge, and adjacent benign areas (TMA cores, n=1859). Our primary focus was on tumors with elevated immune cell enrichment (CD45high), as these tumors are known to be aggressive and may respond well to immunotherapy. Our study reveals the intricate interactions between tumor, vascular, stromal, and immune cells within ccRCC. We find that CD45high tumors, upon losing epithelial marker expression, acquire tumor cell PD-L1 and mesenchymal markers such as Fibroblast activation protein (FAP). This shift is indicative of the epithelial-mesenchymal transition (EMT) process. These CD45high and EMThigh tumors are enriched with changes in TME, including elevated FAP+ cancer-associated fibroblasts (CAFs) and subsets of immune suppressive T cells and macrophages. We report that ccRCC patients with high tumor PD-L1 expression or abundant FAP+ CAFs are associated with earlier metastasis and, in sunitinib-treated patients, shorter progression-free survival. This study illuminates the intricate connection between immune cell infiltration, stromal biology, and EMT in ccRCC, offering a deeper understanding of the disease's complex biology and potentially guiding future therapeutic approaches and strategies. Citation Format: Teijo Pellinen, Lassi Luomala, Kalle Mattila, Jenni Säilä, Annabrita Hemmes, Katja Valimaki, Oscar Bruck, Lassi Paavolainen, Harry Nisen, Petrus Järvinen, Olli Kallioniemi, Paula Vainio, Panu Jaakkola, Tuomas Mirtti. Spatial profiling of inflamed tumor microenvironment of clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5490.

The Adrenal Gland and Pancreatic Islets - A Beneficial Endocrine Alliance.

Intraportal islet transplantation in patients with type 1 diabetes enables restoration of glucose-regulated insulin secretion. However, several factors hamper a widespread application and long-term success: chronic hypoxia, an inappropriate microenvironment and suppression of regenerative and proliferative potential by high local levels of immunosuppressive agents. Therefore, the identification of alternative and superior transplant sites is of major scientific and clinical interest. Here, we aim to evaluate the adrenal as an alternative transplantation site. The adrenal features a particular microenvironment with extensive vascularization, anti-apoptotic and pro-proliferative, anti-inflammatory and immunosuppressive effects. To validate this novel transplantation site, an in vitro co-culture system of adrenal cells and pancreatic islets was established and viability, islet survival, functional potency and antioxidative defense capacity were evaluated. For in vivo validation, an immune-deficient diabetic mouse model for intra-adrenal islet transplantation was applied. The functional capacity of intra-adrenally grafted islets to reverse diabetes was compared to a standard islet transplant model and measures of engraftment such as vascular integration were evaluated. The presence of adrenal cells positively impacted on cell metabolism and oxidative stress. Following transplantation, we could demonstrate enhanced islet function in comparison to standard models with improved engraftment and superior re-vascularization. This experimental approach allows for novel insights into the interaction of endocrine systems and may open up novel strategies for islet transplantation augmented through the bystander effect of other endocrine cells or the active factors secreted by adrenal cells modulating the microenvironment.

Nose-to-Heart Approach: Unveiling an Alternative Route of Acute Treatment.

Intranasal (IN) administration has emerged as a novel approach for rapid systemic absorption, with potential applicability in the management of acute cardiovascular events. This review explores the evolution of IN cardiovascular pharmacotherapy, emphasizing its potential in achieving systemic effects and bypassing the first-pass metabolism associated with oral administration. The extensive vascularization of nasal mucosa and a porous endothelial basement membrane facilitate efficient drug absorption into the bloodstream. The IN route ensures a critical swift onset of action, which allows self-administration in at-home settings. For instance, etripamil nasal spray, a first-in-class formulation, exemplifies the therapeutic potential of this approach in the treatment of spontaneous supraventricular tachycardia. The review critically assesses studies on IN formulations for angina, acute myocardial infarction, hypertensive episodes, and cardiac arrhythmias. Preclinical evaluations of beta-blockers, calcium-channel blockers, and antianginal drugs demonstrate the feasibility of IN administration for acute cardiovascular events. A small number of clinical trials have revealed promising results, emphasizing the superiority of IN drug delivery over oral administration in terms of bioavailability and onset of action. Unambiguously, the limited clinical trials and patient enrollment pose challenges in generalizing experimental outcomes. However, the nose-to-heart approach has clinical potential.

The ‘barcode sign’ seen on optical coherence tomography of extensive corneal vascularization

The ‘barcode sign’ seen on optical coherence tomography of extensive corneal vascularization

Stacking thick perfusable human microvascular grafts enables dense vascularity and rapid integration into infarcted rat hearts

Fabrication of large-scale engineered tissues requires extensive vascularization to support tissue survival and function. Here, we report a modular fabrication approach, by stacking of patterned collagen membranes, to generate thick (2 mm and beyond), large, three-dimensional, perfusable networks of endothelialized vasculature. In vitro, these perfusable vascular networks exhibit remodeling and evenly distributed perfusion among layers, while maintaining their patterned, open-lumen architecture. Compared to non-perfusable, self-assembled vasculature, constructs with perfusable vasculature demonstrated increased gene expression indicative of vascular development and angiogenesis. Upon implantation onto infarcted rat hearts, perfusable vascular networks attain greater host vascular integration than self-assembled controls, indicated by 2.5-fold greater perfused vascular density measured by histological analysis and 5-fold greater perfusion rate measured by optical microangiography. Together, the success of fabricating thick, perfusable tissues with dense vascularity and rapid anastomoses represents an important step forward for vascular bioengineering, and paves the way towards more complex, large scale, highly metabolic engineered tissues.

Glioma-derived small extracellular vesicles induce pericyte-phenotype transition of glioma stem cells under hypoxic conditions

BackgroundGlioblastoma (GBM) is the most common and lethal primary brain tumor characterized by extensive vascularization. Anti-angiogenic therapy for this cancer offers the possibility of universal efficacy. However, preclinical and clinical studies suggest that anti-VEGF drugs, such as Bevacizumab, actively promote tumor invasion, which ultimately leads to a therapy-resistant and recurrent phenotype of GBMs. Whether Bevacizumab can improve survival over chemotherapy alone remains debated. Herein, we emphasize the importance of small extracellular vesicles (sEVs) internalization by glioma stem cells (GSCs) in giving rise to the failure of anti-angiogenic therapy in the treatment of GBMs and discover a specific therapeutic target for this damaging disease. MethodsTo experimentally prove that hypoxia conditions promote the release of GBM cells-derived sEVs, which could be taken up by the surrounding GSCs, we used an ultracentrifugation strategy to isolate GBM-derived sEVs under hypoxic or normoxic conditions, performed bioinformatics analysis and multidimensional molecular biology experiments, and established a xenograft mouse model. ResultsThe internalization of sEVs by GSCs was proven to promote tumor growth and angiogenesis through the pericyte-phenotype transition. Hypoxia-derived sEVs could efficiently deliver TGF-β1 to GSCs, thus resulting in the activation of the TGF-β signaling pathway and the consequent pericyte-phenotype transition. Specifically targeting GSC-derived pericytes using Ibrutinib can reverse the effects of GBM-derived sEVs and enhance the tumor-eradicating effects when combined with Bevacizumab. ConclusionThis present study provides a new interpretation of the failure of anti-angiogenic therapy in the non-operative treatment of GBMs and discovers a promising therapeutic target for this intractable disease.

Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy.

Glioblastoma is characterized by extensive vascularization and is highly resistant to current therapy. Identification of drugs that target tumor directly and angiogenesis processes present an effective therapeutic strategy for glioblastoma. Mnk kinase is required for the activation of eukaryotic initiation factor 4E (eIF4E), which mediates translation of oncogenic proteins. We investigated the effects of tomivosertib, a novel MAPK-interacting kinase (MNK) inhibitor, on glioblastoma angiogenesis, growth, and survival. We found that tomivosertib inhibited growth and induced caspase-dependent apoptosis in various glioblastoma cell lines. Tomivosertib disrupted glioblastoma endothelial cell capillary network formation, growth, and survival. Mechanistically, tomivosertib acted on glioblastoma via suppressing MNK-dependent eIF4E phosphorylation and activation in tumor and endothelial cells. We further found that temozolomide activated eIF4E and this was reversed by tomivosertib. Using glioblastoma xenograft mouse model, we demonstrated that temozolomide and tomivosertib combination had higher efficacy than tomivosertib alone. Of note, tomivosertib inhibited glioblastoma angiogenesis and decreased p-eIF4E level in mice. We finally showed that p-eIF4E activation was a common molecular feature in glioblastoma patients. Our pre-clinical findings suggest that tomivosertib is a useful addition to the treatment armamentarium for glioblastoma and that targeting MNK-eIF4E pathway represents a therapeutic strategy to overcome glioblastoma chemoresistance.

The immunosuppressive microenvironment and immunotherapy in human glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor in adults, characterized by extensive infiltrative growth, high vascularization, and resistance to multiple therapeutic approaches. Among the many factors affecting the therapeutic effect, the immunosuppressive GBM microenvironment that is created by cells and associated molecules via complex mechanisms plays a particularly important role in facilitating evasion of the tumor from the immune response. Accumulating evidence is also revealing a close association of the gut microbiota with the challenges in the treatment of GBM. The gut microbiota establishes a connection with the central nervous system through bidirectional signals of the gut-brain axis, thus affecting the occurrence and development of GBM. In this review, we discuss the key immunosuppressive components in the tumor microenvironment, along with the regulatory mechanism of the gut microbiota involved in immunity and metabolism in the GBM microenvironment. Lastly, we concentrate on the immunotherapeutic strategies currently under investigation, which hold promise to overcome the hurdles of the immunosuppressive tumor microenvironment and improve the therapeutic outcome for patients with GBM.

Challenges and Strategies to Enhance the Systemic Absorption of Inhaled Peptides and Proteins.

Proteins and peptides-based therapeutics are making substantial access to the market due to their obvious advantages of strong potency, high specificity and desirable safety profile. However, most clinical products are mainly delivered via parenteral route with inferior convenience. Lung is an attractive non-invasive alternative passage for systemic administration of biologics with numerous outstanding features, as examples of large absorptive surface area, extensive vascularization and mild local microenvironment. Even so, mucociliary clearance, alveolar macrophage phagocytosis, enzymatic metabolism, pulmonary surfactant adsorption and limited epithelium permeability constitute major obstacles affecting the systemic absorption of inhaled proteins and peptides. This article begins by giving a brief overview of challenges for the systemic absorption of inhaled proteins and peptides, and then goes on to a comprehensive review of possible strategies for enhanced pulmonary absorption, including chemical modification, addition of protease inhibitors, incorporation of absorption enhancers, modification with fusion proteins and development of particulate-based drug delivery systems. These strategies can provide enhanced transmembrane absorption capacity while avoiding pulmonary clearance, offering a valuable reference for designing pulmonary delivery systems of protein and peptide drugs.

Salzmann’s Nodular Degeneration

Saltzman’s nodular degeneration is a rare, non-inflammatory, slowly progressive degenerative disease of the cornea characterized by bluish-white nodules elevated above the surface of the cornea. More often nodules are located in the mid periphery of the cornea, they can spread into the optical zone. Sometimes localize along the limbus. They consist of dense heterogeneous collagen tissue with hyalinization, localized between the epithelium and Bowman’s layer. Can penetrate deeper into the stroma. The exact pathophysiological mechanism of the lesion is unclear. It is considered that this condition is associated with a violation of the structural relationship of epithelial cells against the background of chronic inflammation of the ocular surface, which leads to the destruction of the Bowman’s layer, the activation and migration of fibroblasts anteriorly, and the deposition of a disorganized extracellular matrix in subepithelial nodules. Clinically, the disease can be manifested by irritation and inflammation of the ocular surface, dryness or decreased vision, more often due to flattening of the cornea and astigmatism. In some cases, the formed tissue can be easily separated from the corneal surface, leaving Bowman’s layer almost intact. In this case, a subsequent phototherapeutic keratectomy may be required to “smooth” the surface. Relapses in these eyes are rare. In other situations (often with extensive peripheral vascularization), the lesions involve the anterior stroma, making it more difficult to remove them while maintaining the smoothness of the cornea. Several laser ablation procedures may be required, but there is a high risk of recurrence with this approach. It may be necessary to treat the meibomian gland’ dysfunction and dry eye syndrome that often accompanies Saltzman’s degeneration to reduce the risk of disease progression.

Dynamic Interactions between Tumor Cells and Brain Microvascular Endothelial Cells in Glioblastoma.

Simple SummaryIn glioblastoma (GBM), tumor cells develop a symbiotic relation with brain microvascular endothelial cells (BMECs) to shift tissue homeostasis toward a tumor-supporting context. Disentangling the molecular mechanisms that govern this dynamic interaction in the context of GBM represents an exciting challenge for the update of conventional treatment and for the development of novel therapeutic targets for this aggressive and lethal brain tumor.GBM is the most aggressive brain tumor among adults. It is characterized by extensive vascularization, and its further growth and recurrence depend on the formation of new blood vessels. In GBM, tumor angiogenesis is a multi-step process involving the proliferation, migration and differentiation of BMECs under the stimulation of specific signals derived from the cancer cells through a wide variety of communication routes. In this review, we discuss the dynamic interaction between BMECs and tumor cells by providing evidence of how tumor cells hijack the BMECs for the formation of new vessels. Tumor cell–BMECs interplay involves multiple routes of communication, including soluble factors, such as chemokines and cytokines, direct cell–cell contact and extracellular vesicles that participate in and fuel this cooperation. We also describe how this interaction is able to modify the BMECs structure, metabolism and physiology in a way that favors tumor growth and invasiveness. Finally, we briefly reviewed the recent advances and the potential future implications of some high-throughput 3D models to better understanding the complexity of BMECs–tumor cell interaction.

CT Visualization of Vasculature Channels in Modern and Fossil Sloth Ungual Claws

One of the interesting features of modern sloths is the vasculature patterns of their upper and lower limbs. Even though sloths are endothermic like other mammals, their mean body temperature tends to be lower, more variable, and more linked to the ambient temperature than other placental mammals. Like some other mammals from environments with temperature extremes, they possess rete arteriovenous bundles, which work as an effective heat exchange mechanism, where heat from distally flowing arterial blood is transferred to proximally flowing venous blood. This minimizes the heat loss from the extremities while still maintaining blood flow. The temperature gradient increases in the rete system when the animal’s core temperature decreases, which cools the limbs and preserves core body heat. When the body temperature rises the flow through the superficial venous system increases, which promotes heat loss and body cooling.This begs the question of how this complex vasculature system may or may not extend to the distal phalanges and claws of the sloth, perhaps their most distinctive feature. One possibility could be that to work with the limb cooling function of the rete system, the distal phalanx and claw may be poorly vascularized so as not to increase chances for heat loss. However, considering the extensive and important use of their claws, they may require extensive vascularization to withstand the large amount of stress they are often under. This study uses Micro CT scans of sloth ungual phalanges to visualize their vascular channels. In both modern and extinct giant ground sloths, vascular networks through the bone of the ungual phalanx are quite extensive, and are very clearly linked to externally visible channels and impressions left by the proper digital arteries. In ground sloths these internal vascular channels quickly branch on either side and continue distally, letting off smaller branches as they go. These channels are rather large, even appearing to be artificial drill holes on one specimen that has the distal end broken off. Modern sloths show a similar pattern, but their vascular channels take up proportionally less space in the bone than in the giant ground sloths. This difference may be due extinct giant ground sloths’ more varied use of their claws. These complex patterns show that sloth claws require a significant blood supply, and may indicate that the rete system is effective enough that by the time the arterial blood gets to the distal phalanx it has been sufficiently cooled to not be a significant source of heat loss.

Inorganic Nanoparticles in Bone Healing Applications.

Modern biomedicine aims to develop integrated solutions that use medical, biotechnological, materials science, and engineering concepts to create functional alternatives for the specific, selective, and accurate management of medical conditions. In the particular case of tissue engineering, designing a model that simulates all tissue qualities and fulfills all tissue requirements is a continuous challenge in the field of bone regeneration. The therapeutic protocols used for bone healing applications are limited by the hierarchical nature and extensive vascularization of osseous tissue, especially in large bone lesions. In this regard, nanotechnology paves the way for a new era in bone treatment, repair and regeneration, by enabling the fabrication of complex nanostructures that are similar to those found in the natural bone and which exhibit multifunctional bioactivity. This review aims to lay out the tremendous outcomes of using inorganic nanoparticles in bone healing applications, including bone repair and regeneration, and modern therapeutic strategies for bone-related pathologies.

Kidney Decellularized Extracellular Matrix Enhanced the Vascularization and Maturation of Human Kidney Organoids.

Kidney organoids derived from human pluripotent stem cells (hPSCs) have extensive potential for disease modelling and regenerative medicine. However, the limited vascularization and immaturity of kidney organoids have been still remained to overcome. Extracellular matrix (ECM) can provide mechanical support and a biochemical microenvironment for cell growth and differentiation. Here in vitro methods using a kidney decellularized extracellular matrix (dECM) hydrogel to culture hPSC‐derived kidney organoids, which have extensive vascular network and their own endothelial cells, are reported. Single‐cell transcriptomics reveal that the vascularized kidney organoids cultured using the kidney dECM have more mature patterns of glomerular development and higher similarity to human kidney than those cultured without the kidney dECM. Differentiation of α‐galactosidase A (GLA)‐knock‐out hPSCs generated using CRISPR/Cas9 into kidney organoids by the culture method using kidney dECM efficiently recapitulate Fabry nephropathy with vasculopathy. Transplantation of kidney organoids with kidney dECM into kidney of mouse accelerates the recruitment of endothelial cells from the host mouse kidney and maintains vascular integrity with the more organized slit diaphragm‐like structures than those without kidney dECM. The kidney dECM methodology for inducing extensive vascularization and maturation of kidney organoids can be applied to studies for kidney development, disease modeling, and regenerative medicine.