Bioactive Glass in Tissue Regeneration: Unveiling Recent Advances in Regenerative Strategies and Applications.

Bioactive glass (BG) is a class of biocompatible, biodegradable, multifunctional inorganic glass materials, which is successfully used for orthopedic and dental applications, with several products already approved for clinical use. Apart from exhibiting osteogenic properties, BG is also known to be angiogenic and antibacterial. Recently, BG's role in immunomodulation has been gradually revealed. While the therapeutic effect of BG is mostly reported in the context of bone and skin-related regeneration, its application in regenerating other tissues/organs, such as muscle, cartilage, and gastrointestinal tissue, has also been explored recently. The strategies of applying BG have also expanded from powder or cement form to more advanced strategies such as fabrication of composite polymer-BG scaffold, 3D printing of BG-loaded scaffold, and BG-induced extracellular vesicle production. This review presents a concise overview of the recent applications of BG in regenerative medicine. Various regenerative strategies of BG will be first introduced. Next, the applications of BG in regenerating various tissues/organs, such as bone, cartilage, muscle, tendon, skin, and gastrointestinal tissue, will be discussed. Finally, summarizing clinical applications of BG for tissue regeneration will conclude, and outline future challenges and directions for the clinical translation of BG.

Intra-articular sustained-release of pirfenidone as a disease-modifying treatment for early osteoarthritis.

Osteoarthritis (OA) is a major clinical challenge, and effective disease-modifying drugs for OA are still lacking due to the complicated pathology and scattered treatment targets. Effective early treatments are urgently needed to prevent OA progression. The excessive amount of transforming growth factor ß (TGFß) is one of the major causes of synovial fibrosis and subchondral bone sclerosis, and such pathogenic changes in early OA precede cartilage damage. Herein we report a novel strategy of intra-articular sustained-release of pirfenidone (PFD), a clinically-approved TGFß inhibitor, to achieve disease-modifying effects on early OA joints. We found that PFD effectively restored the mineralization in the presence of excessive amount of TGFß1 (as those levels found in patients' synovial fluid). A monthly injection strategy was then designed of using poly lactic-co-glycolic acid (PLGA) microparticles and hyaluronic acid (HA) solution to enable a sustained release of PFD (the "PLGA-PFD + HA" strategy). This strategy effectively regulated OA progression in destabilization of the medial meniscus (DMM)- induced OA mice model, including preventing subchondral bone loss in early OA and subchondral bone sclerosis in late OA, and reduced synovitis and pain with cartilage preservation effects. This finding suggests the promising clinical application of PFD as a novel disease-modifying OA drug.

Enhanced photoelectrochemical water splitting by a 3D hierarchical sea urchin-like structure: ZnO nanorod arrays on TiO2hollow hemisphere.

A hierarchical sea urchin-like hybrid metal oxide nanostructure of ZnO nanorods deposited on TiO2porous hollow hemispheres with a thin zinc titanate interface layer is specifically designed and synthesized to form a combined type I straddling and type II staggered junctions. The HHSs, synthesized by electrospinning, facilitate light trapping and scattering. The ZnO nanorods offer a large surface area for improved surface oxidation kinetics. The interface layer of zinc titanate (ZnTiO3) between the TiO2HHSs and ZnO nanorods regulates the charge separation in a closely coupled hierarchy structure of ZnO/ZnTiO3/TiO2. The synergistic effects of the improved light trapping, charge separation, and fast surface reaction kinetics result in a superior photoconversion efficiency of 1.07% for the photoelectrochemical water splitting with an outstanding photocurrent density of 2.8 mA cm-2at 1.23 V versus RHE.

Clomiphene Citrate Administered in Periconception Phase Causes Fetal Loss and Developmental Impairment in Mice.

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated the consequences in mice for fetal development and pregnancy outcome of periconception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 hours after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in 3 independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30-hour average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed postweaning growth and development similar to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can compromise implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the periconception phase unless its use is well-supervised.

International Society of Paediatric Surgical Oncology (IPSO): A Short History, Developments, and Current Status.

The International Society of Paediatric Surgical Oncology (IPSO) was officially inaugurated in 1991 through the creativeness and inspiration of a collective dynamic group of paediatric surgeons committed to advancing childhood cancer. This article traces the origins and birth of IPSO tracking its modern day development to a growing world community of paediatric surgeon oncology members. LEVEL OF EVIDENCE: 5.

Recent advances in reproductive research in Australia and New Zealand: highlights from the Annual Meeting of the Society for Reproductive Biology, 2022.

In 2022, the Society for Reproductive Biology came together in Christchurch New Zealand (NZ), for its first face-to-face meeting since the global COVID-19 pandemic. The meeting showcased recent advancements in reproductive research across a diverse range of themes relevant to human health and fertility, exotic species conservation, and agricultural breeding practices. Here, we highlight the key advances presented across the main themes of the meeting, including advances in addressing opportunities and challenges in reproductive health related to First Nations people in Australia and NZ; increasing conservation success of exotic species, including ethical management of invasive species; improvements in our understanding of developmental biology, specifically seminal fluid signalling, ovarian development and effects of environmental impacts such as endocrine-disrupting chemicals; and leveraging scientific breakthroughs in reproductive engineering to drive solutions for fertility, including in assisted reproductive technologies in humans and agricultural industries, and for regenerative medicine.

Effect of Valproic Acid on Promoting the Differentiation of Human Embryonic Stem Cells Into Cholangiocyte-Like Cells.

Cholangiocytes form a complex 3D network of bile ducts in the liver and contribute to liver function. The damage or destruction of cholangiocytes can lead to biliary diseases, and the shortage of cholangiocytes remains an obstacle for drug development targeting biliary diseases. Valproic acid (VPA) is a potent activator of Notch signaling pathway that is essential for cholangiocyte differentiation. Here, we report a VPA-based approach for cholangiocyte differentiation of human pluripotent stem cells. VPA activated Notch2 expression and upregulated HES-1, HEY-1, and Sox9 gene expression in hESC-derived hepatoblast. After 7 days treatment, VPA promoted successful differentiation of hepatoblast into cholangiocytes expressing cholangiocyte marker genes (AE2, AQP1, CFTR) and proteins (CK19 and CK7). In addition, the differentiated cholangiocytes formed bile duct-like structures after implantation into the spleen of NOD/SCID mice. Our results suggested that VPA can promote hESC differentiation to cholangiocyte-like cells. The induced cholangiocytes may serve as a potential cell source for both in vitro modeling and regenerative therapy of cholangiopathies. The findings can also support further development of small-molecule based differentiation protocols for cholangiocyte production.

The endometrial transcriptome transition preceding receptivity to embryo implantation in mice.

BACKGROUND: Receptivity of the uterus is essential for embryo implantation and progression of mammalian pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from a non-receptive state at ovulation, to a receptive state several days later. The precise molecular mechanisms underlying this transition and their upstream regulators remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the endometrial transcriptome in the peri-ovulatory and peri-implantation states, to define the genes and gene pathways that are different between these states, and to identify new candidate upstream regulators of this transition, in the mouse. RESULTS: High throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of female C57Bl/6 mice at estrus and on day 3.5 post-coitum (pc) after mating with BALB/c males (n = 3-4 biological replicates). Compared to the endometrium at estrus, 388 genes were considered differentially expressed in the endometrium on day 3.5 post-coitum. The transcriptional changes indicated substantial modulation of uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. Ingenuity Pathway Analysis software predicted the activation of several upstream regulators previously shown to be involved in the transition to receptivity including various cytokines, ovarian steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. Our analysis also revealed four candidate upstream regulators that have not previously been implicated in the acquisition of uterine receptivity, with growth differentiation factor 2, lysine acetyltransferase 6 A, and N-6 adenine-specific DNA methyltransferase 1 predicted to be activated, and peptidylprolyl isomerase F predicted to be inhibited. CONCLUSIONS: This study confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes, regulatory pathways, and upstream drivers not previously associated with implantation. The findings will inform further research to investigate the molecular mechanisms of uterine receptivity.

Fenestrated Physician-Modified Endografts for Preservation of Main and Accessory Renal Arteries in Juxtarenal Aortic Aneurysms.

BACKGROUND: There is a paucity of reporting outcomes of complex aortic aneurysm treatment such as juxtarenal abdominal aortic aneurysms, where additional techniques to preserve renal artery perfusion are required. METHODS: Retrospective analysis of consecutive patients who underwent emergent and elective aortic repair with fenestrated PMEGs between March 2019 and January 2023. Endpoints were technical success, reinterventions, secondary reinterventions and target vessel patency. RESULTS: Forty-seven target vessels in 37 patients (23 male, median age 75 years) were targeted, of which 44 were renal arteries (RAs) with a mean diameter of 5.4 ± 1.0 mm. Thirteen were accessory RAs and six had a diameter ≤ 4 mm. Technical success rate was 87% overall; 97% for main and 62% for accessory RAs respectively. Target vessel patency and freedom from secondary reintervention was 100% and 97% at 30 days and 96% and 91% at one year, respectively. There was no 30-day mortality. CONCLUSION: Fenestrated physician-modified endografts are safe and effective for the treatment of patients with juxtarenal abdominal aortic aneurysms when incorporating main renal arteries. Limited technical success may be expected when targeting accessory renal arteries, especially when small in diameter. Long-term follow-up is needed to confirm durability of PMEGs for renal artery preservation.

The identity of Tokays (Squamata: Gekkonidae: Gekko) from Hong Kong.

The Tokay gecko (Gekko gecko), found throughout Southeast Asia and India, is a heavily harvested species of high commercial value. Recent studies have supported the elevation of the black morph of Tokay gecko, found only in southern China and northern Vietnam, to the species Gekko reevesii. Previous genetic studies focused on specimens of G. reevesii from southwestern populations. Hong Kong, in southeastern China, has native populations of G. reevesii. To verify the identity of G. reevesii in Hong Kong, we employed three mitochondrial genes (COI, Cytb & ND2) and constructed a matrilineal genealogy using other specimens from Guangxi (southwestern China) and northern Vietnam, as well as G. gecko from a wide range of Southeast Asian countries. Our study confirmed that G. reevesii occurs naturally in Hong Kong, but one exotic population of G. gecko, likely a translocation from international trade, was also revealed. Our study did not reject the species ranking of G. reevesii. Moreover, like previous studies, we recovered a paraphyletic G. gecko, which may reflect a species complex, hybridization or incomplete lineage sorting. More extensive sampling of the two species over a broader range of their asserted distribution together with the use of both mitochondrial and nuclear DNA are required to better investigate their biogeography.

Microneedle system for tissue engineering and regenerative medicine.

Global increasing demand for high life quality and length facilitates the development of tissue engineering and regenerative medicine, which apply multidisciplinary theories and techniques to achieve the structural reconstruction and functional recovery of disordered or damaged tissues and organs. However, the clinical performances of adopted drugs, materials, and powerful cells in the laboratory are inescapably limited by the currently available technologies. To tackle the problems, versatile microneedles are developed as the new platform for local delivery of diverse cargos with minimal invasion. The efficient delivery, as well as painless and convenient procedure endow microneedles with good patient compliance in clinic. In this review, we first categorize different microneedle systems and delivery models, and then summarize their applications in tissue engineering and regenerative medicine mainly involving maintenance and rehabilitation of damaged tissues and organs. In the end, we discuss the advantages, challenges, and prospects of microneedles in depth for future clinical translations.

Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure.

Reactive oxygen species (ROS)-associated oxidative stress, inflammation storm, and massive hepatocyte necrosis are the typical manifestations of acute liver failure (ALF), therefore specific therapeutic interventions are essential for the devastating disease. Here, we developed a platform consisting of versatile biomimetic copper oxide nanozymes (Cu NZs)-loaded PLGA nanofibers (Cu NZs@PLGA nanofibers) and decellularized extracellular matrix (dECM) hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells (hADMSCs-derived HLCs) (HLCs/Cu NZs@fiber/dECM). Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF, and reduce the massive accumulation of pro-inflammatory cytokines, herein efficiently preventing the deterioration of hepatocytes necrosis. Moreover, Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted HLCs. Meanwhile, HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF therapy. The dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of HLCs. In addition, the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host liver. Hence, HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF mice. This strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.

Novel Surgeon-Modified Fenestrated Iliac Stent Graft.

PURPOSE: We describe the feasibility and early results of a novel endovascular approach with a surgeon-modified fenestrated iliac stent graft to preserve pelvic perfusion in patients with iliac aneurysms not suitable for iliac branch devices (IBDs). TECHNIQUE: Seven high-risk patients, median age 76 years (range 63-83), with a complex aortoiliac anatomy with contraindications for commercially available IBDs were treated with a novel surgeon-modified fenestrated iliac stent graft between August 2020 and November 2021. The modified device was built using an iliac limb stent graft (Endurant II Stent Graft; Medtronic), which was partially deployed, surgically fenestrated with a scalpel, reinforced, re-sheathed, and inserted via femoral access. The internal iliac artery was cannulated and bridged with a covered stent. Technical success rate was 100%. After a median follow-up period of 10 months, there was 1 type II endoleak and no migrations, stent fractures, or loss of device integrity. One iliac limb occlusion occurred after 7 months, which needed a secondary endovascular intervention, restoring patency. CONCLUSION: Surgeon-modified fenestrated iliac stent graft is feasible and might be used as an alternative in patients with a complex iliac anatomy not suitable to commercially available IBDs. Long-term follow-up is needed to evaluate stent graft patency and potential complications. CLINICAL IMPACT: Surgeon modified fenetrated iliac stent grafts might be a promising alternative to iliac branch devices, extending endovascular solutions to a broader patient population with complex aorto-iliac anatomies preserving antegrade internal iliac artery perfusion. It is possible to treat small iliac bifurcations and large angulations of the iliac bifurcation safely and there is no need for a contralateral or upper-extremity access.

Oral Delivery of Bioactive Glass-Loaded Core-Shell Hydrogel Microspheres for Effective Treatment of Inflammatory Bowel Disease.

Resolving inflammation and promoting intestinal tissue regeneration are critical for inflammatory bowel disease (IBD) treatment. Bioactive glass (BG) is a clinically approved bone graft material and has been shown to modulate inflammatory response, but it is unknown whether BG can be applied to treat IBD. Here, it is reported that BG attenuates pro-inflammatory response of lipopolysaccharide (LPS)-stimulated macrophages and hence reduces inflammatory damage to intestinal organoids in vitro. In addition, zein/sodium alginate-based core-shell microspheres (Zein/SA/BG) are developed for oral delivery of BG, which helps prevent premature dissolution of BG in the stomach. The results show that Zein/SA/BG protects BG from a gastric-simulated environment while dissolved in an intestinal-simulated environment. When administered to acute and chronic colitis mice model, Zein/SA/BG significantly reduces intestinal inflammation, promotes epithelial tissue regeneration, and partially restores microbiota homeostasis. These findings are the first to reveal the therapeutic efficacy of BG against IBD, which may provide a new therapeutic approach at low cost for effective IBD treatment.

Light trapping by porous TiO2 hollow hemispheres for high efficiency photoelectrochemical water splitting.

Photocatalytic water splitting has recently received increasing attention as a green fuel source. The controlled nano-geometry of the photocatalytic material can improve light harvesting. In this study, as a proof of concept, hollow hemisphere (HHS)-based films of TiO2 material were created by a conventional electrospray method and subsequently applied for photoelectrochemical (PEC) water splitting. To preserve the morphology of the HHS structure, a hydrolysis precipitation phase separation method (HPPS) was developed. As a result, the TiO2 HHS-based thin films presented a maximum PEC water splitting efficiency of ca. 0.31%, almost two times that of the photoanode formed by TiO2 nanoparticle-based films (P25). The unique morphology and porous structure of the TiO2 HHSs with reduced charge recombination and improved light absorption are responsible for the enhanced PEC performance. Light scattering by the HHS was demonstrated with total reflection internal fluorescence microscopy (TRIFM), revealing the unique light trapping phenomenon within the HHS cavity. This work paves the way for the rational design of nanostructures for photocatalysis in fields including energy, environment, and organosynthesis.

Establishment of iPS cell line (KLRMMEi003-A) from a patient with Usher syndrome due to USH2A mutation.

We generated an induced pluripotent stem (iPS) cell line by reprogramming peripheral blood mononuclear cells of a patient with Usher syndrome type II carrying USH2A gene mutation (c.8559-2A > G). The iPS cell line with confirmed patient-specific point mutation exhibited typical iPS cell characteristics and maintained a normal karyotype. It can be used as 2D and 3D models to investigate the underlying pathogenic mechanism and lay a solid foundation for future personalized therapy.

One-stop assembly of adherent 3D retinal organoids from hiPSCs based on 3D-printed derived PDMS microwell platform.

The three-dimensional (3D) retinal organoids (ROs) derived from human induced pluripotent stem cells (hiPSCs), mimicking the growth and development of the human retina, is a promising model for investigating inherited retinal diseasesin vitro. However, the efficient generation of homogenous ROs remains a challenge. Here we introduce a novel polydimethylsiloxane (PDMS) microwell platform containing 62 V-bottom micro-cavities for the ROs differentiation from hiPSCs. The uniform adherent 3D ROs could spontaneously form using neural retina (NR) induction. Our results showed that the complex of NR (expressing VSX2), ciliary margin (CM) (expressing RDH10), and retinal pigment epithelium (RPE) (expressing ZO-1, MITF, and RPE65) developed in the PDMS microwell after the differentiation. It is important to note that ROs in PDMS microwell platforms not only enable one-stop assembly but also maintain homogeneity and mature differentiation over a period of more than 25 weeks without the use of BMP4 and Matrigel. Retinal ganglion cells (expressing BRN3a), amacrine cells (expressing AP2a), horizontal cells (expressing PROX1 and AP2α), photoreceptor cells for cone (expressing S-opsin and L/M-opsin) and rod (expressing Rod opsin), bipolar cells (expressing VSX2 and PKCα), and Müller glial cells (expressing GS and Sox9) gradually emerged. Furthermore, we replaced fetal bovine serum with human platelet lysate and established a xeno-free culture workflow that facilitates clinical application. Thus, our PDMS microwell platform for one-stop assembly and long-term culture of ROs using a xeno-free workflow is favorable for retinal disease modeling, drug screening, and manufacturing ROs for clinical translation.

Highly efficient fabrication of functional hepatocyte spheroids by a magnetic system for the rescue of acute liver failure.

Engineering hepatocytes as multicellular cell spheroids can improve their viability after implantation in vivo for effective rescue of the devastating acute liver failure (ALF). However, there is still a lack of straightforward methods for efficient generation of functional hepatocyte spheroids. In this study, a magnetic system, consisting of magnetic microwell arrays and magnet blocks, is developed to realize magnetically controlled 3D cell capture and spatial confinement-mediated cell aggregation. The cell spheroids with smaller size show superior hepatic functions than the larger-sized counterparts. Notably, the intrinsic magnetism of magnetic microwell arrays can regulate superoxide anions in hepatocyte spheroids and herein promote various biological processes, including antioxidation, hepatocyte-related functions, and pro-angiogenic potential. Ectopic implantation of the functional cell spheroids in ALF-challenged mice significantly prolongs the animal survival, ameliorates inflammation, and promotes liver regeneration. Hence, application of the magnetic system for generation of functionally enhanced hepatocyte spheroids holds great potential for clinical translation in the future.

Injectable bioactive glass/sodium alginate hydrogel with immunomodulatory and angiogenic properties for enhanced tendon healing.

Tendon healing is a complex process involving inflammation, proliferation, and remodeling, eventually achieving a state of hypocellularity and hypovascularity. Currently, few treatments can satisfactorily restore the structure and function of native tendon. Bioactive glass (BG) has been shown to possess immunomodulatory and angiogenic properties. In this study, we investigated whether an injectable hydrogel fabricated of BG and sodium alginate (SA) could be applied to enhance tenogenesis following suture repair of injured tendon. We demonstrated that BG/SA hydrogel significantly accelerated tenogenesis without inducing heterotopic ossification based on histological analysis. The therapeutic effect could attribute to increased angiogenesis and M1 to M2 phenotypic switch of macrophages within 7 days post-surgery. Morphological characterization demonstrated that BG/SA hydrogel partially reverted the pathological changes of Achilles tendon, including increased length and cross-sectional area (CSA). Finally, biomechanical test showed that BG/SA hydrogel significantly improved ultimate load, failure stress, and tensile modulus of the repaired tendon. In conclusion, administration of an injectable BG/SA hydrogel can be a novel and promising therapeutic approach to augment Achilles tendon healing in conjunction with surgical intervention.