Early Stem Research Articles

A Pilot Study of Aptamer-Conjugated Silk Ligament with MSCs Recruitment Ability for ACL Reconstruction

ABSTRACT Anterior cruciate ligament (ACL) rupture is one of the most common knee injuries. Due to the limited self-healing capacity, complex structure, and mechanical environment, the regeneration of ACL remains a challenge. To achieve fast recovery and long-term ACL regeneration, biodegradable scaffolds with excellent initial mechanical support and cell recruitment ability have gained increasing research interest. The aptamer-functionalized silk fiber was fabricated by embedding silk fiber into morpholinoethanesulfonic/1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride, N-hydroxysuccinimide buffer with aptamer 19s (Apt19s) and characterized in vitro. The clinically size-matched silk ligament was braided utilizing commercial methodology (polyethylene terephthalate ligament), and the tensile strength was analyzed. A total of 18 rabbits were used to test the early mesenchymal stem cell (MSC) recruitment of Apt19s-functionalized silk ligaments. Macroscopic analysis and hematoxylin and eosin and immunohistochemistry stainings were applied at 3, 5, and 7 days post-implantation. The ultimate strength of silk fiber was lower than that of PET fibers. However, the prepared silk ligament had comparable mechanical strength to the native ACL. In vitro, the Apt19s-functionalized fiber recruited bone marrow-derived MSCs. In vivo, Apt19s-functionalized silk ligament enhanced early MSCs recruitment after implantation in comparison with the aptamer-free ligament. The Apt19s-functionalized scaffold silk ligament exhibited comparable mechanical strength with native ACL and enhanced endogenous MSC homing.

The effects of an early childhood-elementary teacher preparation program in STEM on pre-service teachers

The increasing interest in early and elementary STEM education comes with a need to increase training and support for teachers of children in the early grades. Early and elementary pre-service teacher preparation in science, math, and integrated STEM can play a critical role in enhancing teachers’ self-efficacy and pedagogical content knowledge in these areas. However, few quantitative research studies have been published on this topic, especially involving early childhood and elementary programs. Because few STEM courses are typically offered in these programs, we need courses and experiences that can be transformational. This study evaluates the short- and long-term impacts on pre-service teachers who participated in our STEM Collaboration approach (n=164), which was created to meet this goal through an innovative early childhood and elementary collaboration. Analyses of mixed methods data collected from surveys, tests, open-ended feedback, and a focus group revealed immediate, long-term, and positive impacts on science, math, and integrated STEM self-efficacy and pedagogical content knowledge. Participation in STEM education experiences in pre-service programs that include innovations such as collaboration across colleges and professionalization opportunities made a difference, and one that persisted.

Measuring the impact of student success retention initiatives for engineering students at a private research university

IntroductionStudent success in Science, Technology, Engineering, and Mathematics (STEM) is a national concern. To increase engineering retention and graduation rates at a small private institution, a university council developed a binary classifier to identify high-risk students and proposed interventions that included decoupling first-year Physics and Calculus courses, support in introductory Calculus, and Spatial Visualization (SV) training. This paper aims to validate the binary classifier used to identify the under-prepared students entering their first year and assess the impact of the interventions. We provide a comparative analysis of student success metrics for high-risk engineering students across a decade of cohorts, including 5 years before (2006–2010) and 5 years after (2011–2015) implementation of intentional strategies.MethodsWe validated the binary classifier using an accuracy measure and Matthews Correlation Coefficient (MCC). We used the 2-population proportion test to compare STEM retention and 4- and 6-year graduation rates of High-Risk engineering students before and after interventions and compare student performance in early foundation STEM courses across the same time frame.ResultsThe binary classification model identified High-Risk students with an accuracy of 63–70% and an MCC of +0.28 to +0.30. In addition, we found statistically significant improvement (p < 0.001) in the STEM retention rates, 6-year graduation rates, and first part of Physics, Calculus, and Chemistry sequences after the interventions.DiscussionThe methodology and strategies presented may provide effective guidance for institutions seeking to improve the overall performance of undergraduate students who otherwise might struggle in their first-year engineering curriculum.

Long term follow-up after haematopoietic stem cell transplantation for mucopolysaccharidosis type I-H: a retrospective study of 51 patients

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8–16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.

Early fate bias in neuroepithelial progenitors of hippocampal neurogenesis.

Hippocampal adult neural stem cells emerge from progeny of the neuroepithelial lineage during murine brain development. Hippocampus development is increasingly well understood. However, the clonal relationships between early neuroepithelial stem cells and postnatal neurogenic cells remain unclear, especially at the single-cell level. Here we report fate bias and gene expression programs in thousands of clonally related cells in the juvenile hippocampus based on single-cell RNA-seq of barcoded clones. We find evidence for early fate restriction of neuroepithelial stem cells to either neurogenic progenitor cells of the dentate gyrus region or oligodendrogenic, non-neurogenic fate supplying cells for other hippocampal regions including gray matter areas and the Cornu ammonis region 1/3. Our study provides new insights into the phenomenon of early fate restriction guiding the development of postnatal hippocampal neurogenesis.

CO134 Systematic Review of the Impact of Early Versus Late Diagnosis and/or Hematopoietic Stem Cell Transplantation (HSCT) for Severe Combined Immunodeficiency (SCID)

HSCT is considered the gold standard treatment for infants with SCID. This study aimed to determine whether or not age at diagnosis and or HSCT may impact clinical outcomes.

Exploring the foundations of early scientific literacy: Children's causal stance.

From an early age, children show a keen interest in discovering the causal structure of the world around them. Given how fundamental causal information is to scientific inquiry and knowledge, this early emerging "causal stance" might be important in propelling the development of scientific literacy. However, currently little is known about the development of children's causal stance, or how it might relate to concurrent or subsequent scientific literacy. In this study, 153 children from diverse backgrounds were evaluated at 3, 4, 5, and 6 years of age. Results demonstrate that causal stance at 3 years of age consistently predicted scientific literacy at each wave of data collection, extending through preschool, kindergarten, and into first grade. This relation was particularly pronounced across the earliest 2 measurement time-points, when children's causal stance predicted growth in scientific literacy above and beyond initial scores. The reciprocal relation did not hold: scientific literacy did not predict future causal stance. Implications for school readiness and early STEM engagement are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Nitrogen fertilization levels and timing affect the plasticity of yield components in bread wheat (Triticum aestivum L.)

The plasticity of grain yield components typically follows a hierarchy, with early-forming components having greater plasticity than late components (tiller number > spike number > grain number > grain weight). The first aim of this study was to assess the plasticity of two previously unexplored yield sub-components in wheat, i.e. spikelets per spike and grains per spikelet, and of other yield-related variables, i.e. straw mass, plant height, ovary mass and harvest index. The second aim was to test the potential limits of the phenotypic plasticity of yield components, and the relationships between them, by applying sudden strong changes in resource availability (via nitrogen fertilization)at different times during the crop cycle. Nitrogen (N) fertilization was applied only early (60 kg ha-1 of N, early tillering) or only late (120 kg ha-1, early stem elongation), very late (120 kg ha-1, late stem elongation) or extremely late (120 kg ha-1, pollination), never (N0) or multiple times (total of 300 kg ha-1) during the growth cycle of both a small-fruited (Bologna) and a large-fruited (Bora) bread wheat (Triticum aestivum L.) cultivar. Yield and grain number increased with fertilization levels in both cultivars, with the 300 kg N ha-1 treatment having the highest yield. Grain weight also increased with fertilization levels, but only when considering different N levels applied early.Delaying fertilization reduced yield, but increased grain weight, creating a tradeoff between yield (and grain number) and grain weight. Similarly, the relationships between other yield components and variables varied when considering N timing or levels. The plasticity of yield components, expressed as total variation of the trait over the trait value for the N0 (i.e. control) treatment, was 26.5%, 30.5%, 61%, 75% and 22%, respectively for tiller number, spike number, spikelets/spike, grains/spikelet and grain weight. The plasticity of grains/spike, grain number, yield, straw biomass, plant height, ovary mass and harvest index, was 174%, 236% and 268%, 417%, 54%, 54% and 36.5%, respectively. The results show that the plasticity of yield components (and other variables) may differ with different sources of environmental variation, explaining why, in the literature, two traits may be found to correlate both positively, negatively (tradeoff) or not at all. These results further our knowledge on the plasticity of, and the relationships among, yield components, and may be useful for further improvements of yield with agronomic intervention or breeding.

Potentials of synthetic hexaploid wheats to improve drought tolerance

Synthetic hexaploid wheat-derived lines (SHW-DL) offers new hope for breeders to restore genes lost during the evolutionary bottleneck. The study of adaptability, variation, and the possibility of selection in SHW-DL for drought tolerance is poorly understood in arid environments. The potential of 184 SHW-DL and their variation for agro-morphological traits were assessed under normal and water stress conditions for 2 years. The mean values of grain yield (YLD) varied from 683.9 g/m2 (water stress) to 992.1 g/m2 (normal conditions). Grain yield decreased by 64 and 71% under water stress in the two growing seasons. High genotypic variation was found for measured traits and drought tolerance. Heritability ranged from 19 (harvest index) to 47% (spike length), whereas grain yield indicated a moderate heritability (32%). Using the assessment of the interrelationship of traits, hectoliter (a quality trait) was correlated with drought tolerance and stability indices. Therefore, it can be considered as an important trait to select drought tolerant genotypes. In the following, the priority of yield components entering the regression model was different in two moisture conditions suggesting different strategies in indirect selection programs to improve yield. Spike m−2 and grain spike−1 indirectly and negatively affected yield through thousand-grain weight (TGW) under normal and water stress conditions, respectively. Furthermore, SHW-DL compared to ordinary wheat were significantly superior in terms of early maturity, dwarfing, yield, TGW, stem diameter, and harvest index. Overall, our findings suggest that SHW-DL are a valuable source for improving wheat yield and drought tolerance, and indirect selection might be possible to improve these complex traits.

Fossil bone histology reveals ancient origins for rapid juvenile growth in tetrapods

Patterns of growth throughout the lifetime of an animal reflect critical life history traits such as reproductive timing, physiology, and ecological interactions. The ancestral growth pattern for tetrapods has traditionally been described as slow-to-moderately paced, akin to modern amphibians, with fast growth and high metabolic rates considered a specialized physiological trait of amniotes. Here, we present bone histology from an ontogenetic series of the Early Carboniferous stem tetrapod Whatcheeria deltae, and document evidence of fibrolamellar bone—primary bone tissue associated with fast growth. Our data indicate that Whatcheeria juveniles grew rapidly and reached skeletal maturity quickly, allowing them to occupy a large-bodied predator niche in their paleoenvironment. This life history strategy contrasts with those described for other stem tetrapods and indicates that a diversity of growth patterns existed at the origins of tetrapod diversification. Importantly, Whatcheeria marks an unexpectedly early occurrence of fibrolamellar bone in Tetrapoda, both temporally and phylogenetically. These findings reveal that elevated juvenile growth is not limited to amniotes, but has a deep history in the tetrapod clade and may have played a previously unrecognized role in the tetrapod invasion of land.

Prognostic value of pretreatment diffusion-weighted imaging score for acute basilar artery occlusion with successful endovascular recanalization.

The aim of this study is to test the prognostic value of a diffusion-weighted imaging (DWI) score in acute basilar artery occlusion (ABAO) with successful recanalization. The DWI-based pons-midbrain and thalamus (PMT) score was developed to assess posterior circulation infarcts. We test its prognostic value and compare it with other two established scales, the DWI-based posterior circulation acute stroke prognosis Early CT score (PC-ASPECTS) and brain stem score (BSS). A retrospective cohort of consecutive ABAO patients with pretreatment magnetic resonance imaging and successful recanalization (defined as modified Thrombolysis in Cerebral Infarction 2b-3) were analyzed. A favorable outcome was defined as a 90-day modified Rankin Scale (mRS) score of 2 or less. The prognostic performance of three scales was estimated by receiver operating characteristic (ROC) curve analyses. One hundred and sixteen eligible patients (mean age, 59.1 ± 11.7 [standard deviation]; 96 [82.8%] man) were included and evaluated. Between favorable (mRS ≤ 2) and unfavorable groups, the baseline PMT score (median [interquartile range], 3 [1-4] versus 6 [5-8]; P < 0.001) differs significantly. ROC curve analyses showed the PMT score had the best prognostic value for favorable outcome (area under the curve, PMT versus BSS versus PC-ASPECTS = 0.80 versus 0.72 versus 0.68, P = 0.010). Multivariate logistic regression analyses showed baseline National Institute of Health stroke scale (OR, 0.90 [95%CI, 0.86-0.95], P = 0.004) and PMT score < 5 (OR, 17.83 [95%CI, 3.91-81.19], P < 0.001) were independent prognostic factors of favorable outcome. The PMT score seems to predict clinical outcome of ABAO patients with successful recanalization.

MODL-32. IMPACT OF PRDM6 ON CHROMATIN ACCESSIBILITY, GENE EXPRESSION, AND MEDULLOBLASTOMA FORMATION

Abstract Group 4 medulloblastoma (MB) is the most common medulloblastoma subgroup and shows high incidence of metastasis and late-onset relapse. Group 4 MBs lack a unifying oncogenic driver and treatment targets, despite extensive genomic characterization. Group 4 MBs are characterized by recurrent genetic alterations in chromatin modifiers, amplification of stemness genes, and putative enhancer "hijacking" events. A substantial fraction of Group 4 MBs are characterized by enhancer hijacking through tandem duplication of SNCAIP, resulting in high expression of PRDM6, a putative transcriptional repressor and histone methyltransferase. Some PRDM6-overexpressing MBs show additional mutations in chromatin regulators and high MYCN expression. We set out to elucidate the impact and oncogenic potential of sustained PRDM6 expression in early neural stem cell populations and patient-derived medulloblastoma cells. We find that PRDM6 expression in human iPSC-derived neuroepithelial stem cells (NESCs) results in tumor growth in mice, albeit at low penetrance. Moreover, we find that PRDM6 expression in MYCN-overexpressing NESCs does not further alter tumor aggressiveness or survival in vivo. Notably, PRDM6 overexpression in the patient-derived Group 3 MYC-amplified D283-Med cell line causes significantly increased aggressiveness of tumor growth and shorter survival in mice. At the cellular level, PRDM6 localizes to the nucleus, suggesting a role in gene expression regulation. Consistent with this notion, ATAC-seq and RNA-seq analysis of PRDM6-NESCs and PRDM6-D283-Med cells reveals major changes in chromatin accessibility and gene expression, including upregulation of integrin family members and genes related to focal adhesion and extracellular matrix-receptor interaction pathways. We conclude that PRDM6 promotes tumor growth in NESCs and may play a role in tumor maintenance through interactions with the extracellular matrix and tumor microenvironment.

Regulation of myeloid and lymphoid cell development by O-glycans on Notch.

Notch signaling via NOTCH1 stimulated by Delta-like ligand 4 (DLL4) is required for the development of T cells in thymus, and NOTCH2 stimulated by Notch ligand DLL1 is required for the development of marginal zone (MZ) B cells in spleen. Notch signaling also regulates myeloid cell production in bone marrow and is an essential contributor to the generation of early hematopoietic stem cells (HSC). The differentiation program in each of these cellular contexts is optimized by the regulation of Notch signaling strength by O-glycans attached to epidermal growth factor-like (EGF) repeats in the extracellular domain of Notch receptors. There are three major types of O-glycan on NOTCH1 and NOTCH2 - O-fucose, O-glucose and O-GlcNAc. The initiating sugar of each O-glycan is added in the endoplasmic reticulum (ER) by glycosyltransferases POFUT1 (fucose), POGLUT1/2/3 (glucose) or EOGT (GlcNAc), respectively. Additional sugars are added in the Golgi compartment during passage through the secretory pathway to the plasma membrane. Of particular significance for Notch signaling is the addition of GlcNAc to O-fucose on an EGF repeat by the Fringe GlcNAc-transferases LFNG, MFNG or RFNG. Canonical Notch ligands (DLL1, DLL4, JAG1, JAG2) expressed in stromal cells bind to the extracellular domain of Notch receptors expressed in hematopoietic stem cells and myeloid and lymphoid progenitors to activate Notch signaling. Ligand-receptor binding is differentially regulated by the O-glycans on Notch. This review will summarize our understanding of the regulation of Notch signaling in myeloid and lymphoid cell development by specific O-glycans in mice with dysregulated expression of a particular glycosyltransferase and discuss how this may impact immune system development and malignancy in general, and in individuals with a congenital defect in the synthesis of the O-glycans attached to EGF repeats.

Natural Killer Cells Are Key Host Immune Effector Cells Affecting Survival in Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation.

The infusion of autograft immune effector cells directly impacts the clinical outcomes of patients treated with autologous peripheral blood hematopoietic stem cell transplantation, suggesting the possibility of an autologous graft-versus tumor cells. Furthermore, the early recovery of immune effector cells also affects survival post-autologous peripheral blood hematopoietic stem cell transplantation. Natural killer cells are among the immune effector cells reported to be collected, infused, and recovered early post-autologous peripheral blood hematopoietic stem cell transplantation. In this review, I attempt to give an update on the role of natural killer cells regarding improving survival outcomes on patients treated with autologous peripheral blood hematopoietic stem cell transplantation.

The protocol of CUT&Tag for metabolic tissue cells.

Cleavage under target and tagment (CUT&Tag) is a technology that utilizes the fusion protein of Tn5 transposase and protein A/G which can guide Tn5 enzyme to the antibody bound to target protein and cleave the chromatin regions adjacent to target protein. Chromatin libraries are then tagged and sequenced by the high-throughput sequencing to obtain chromatin information at specific sites or protein binding locations. CUT&Tag technology plays an important role in the research of DNA and protein interactions. It can be used to understand the modifications of histone and the bindings of transcription factors. Compared with the traditional chromatin immunoprecipitation-sequencing (ChIP-seq) technology, the CUT&Tag has the strengths of high signal-to-noise ratio, good repeatability, short experimental period, and low cell input. It shows great advantages in early embryonic development, stem cells, cancer, epigenetics and other research fields. In this article, we described the protocol of CUT&Tag for metabolic tissue cells (mouse primary islet cells), to provide an epigenetic method for studying metabolic cells.

Single Cell in a Gravity Field.

The exploration of deep space or other bodies of the solar system, associated with a long stay in microgravity or altered gravity, requires the development of fundamentally new methods of protecting the human body. Most of the negative changes in micro- or hypergravity occur at the cellular level; however, the mechanism of reception of the altered gravity and transduction of this signal, leading to the formation of an adaptive pattern of the cell, is still poorly understood. At the same time, most of the negative changes that occur in early embryos when the force of gravity changes almost disappear by the time the new organism is born. This review is devoted to the responses of early embryos and stem cells, as well as terminally differentiated germ cells, to changes in gravity. An attempt was made to generalize the data presented in the literature and propose a possible unified mechanism for the reception by a single cell of an increase and decrease in gravity based on various deformations of the cortical cytoskeleton.

Gastrointestinal manifestations in children with primary immune deficiencies: A case series.

Gastrointestinal (GI) manifestations are the second most common complications of primary immune deficiencies (PIDs) after pulmonary disease, affecting up to one-half of children with PIDs. Non-infectious GI manifestations such as allergic, autoimmune, and inflammatory disorders can be the predominant manifestations of PIDs. We present a series of five children who presented predominantly with these GI manifestations of PID, not attributable to infections. Very early age of onset (infancy), parental consanguinity, and failure to respond to hypoallergenic formula led to strong suspicion for underlying PIDs. Next-generation sequencing led to the underlying genetic diagnosis. Early diagnosis and hematopoietic stem cell transplantation could be life-saving in these children.

MDS-014 Case Report: Woman With Myelodysplastic Syndrome and Complex Karyotype, Unusual Presentation in Age, and Unfavorable Clinical Behavior

Myelodysplastic syndromes (MDS) are a group of heterogeneous pathologies that are characterized by clonal alterations in hematopoietic stem cells (HSC). MDS are usually seen in patients over 60 years of age and are accompanied by decreased ability of HSC to differentiate and enter apoptosis, producing bone marrow with increased cellularity conditioned by ineffective hematopoiesis and a degree of peripheral cytopenia. Approximately 30% of de novo MDS are associated with a complex karyotype, defined as the existence of 3 or more chromosomal abnormalities in the same karyotype. We present the case of a 27-year-old woman referred for pancytopenia, who has a son with aplastic anemia. The patient presented a 6-month evolution picture characterized by asthenia and adynamia. She presented with pale integuments and without clinical bleeding. Initial laboratories showed hemoglobin 4.9 g/dL, hematocrit 14%, mean corpuscular volume 96.6 fL, mean cell hemoglobin 33 pg, white blood cells 2,000 cells/mL, neutrophils 900 cells/mL, lymphocytes 900 cells/mL, monocytes 100 cells/mL, platelets 36,000, lactate dehydrogenase 357 U/L. Bone marrow aspirate was performed, reporting hypercellularity for age, heterogeneous cellularity, dyspoiesis in the red series, and blasts <5%. Flow cytometry reported 11% of total cells with CD2+, CD33+, CD34+, CD38+, CD45+, CD117+, and HLA+ phenotypic expression and changes in the maturation pattern of the granulocytic series. Karyotyping showed 348-73,XXX,sl,t(4:10)(q35;q11.2) x(2),add(12)(q24)x(2),1+2+3+4+5+6+7+8+9+10+11+12+13+14+15+16+17+18+19+20+21+22 (26)/46,XX(2)(28). The double cell line predominated over the one that contains polyploidies, involving translocation between the long arms of chromosomes 4 and 10 and adhesion in the long arms of chromosome 12 of indeterminate origin on the normal line. Myelodysplastic syndrome with excess blasts was diagnosed, and IPSS-2 high risk was concluded. During the patient's evolution, she presented a high transfusion requirement and recurrent infections, dying due to an infectious process. The age of the patient contrasts with reports in the literature that MDS tend to be more aggressive at a younger age. The complex karyotype in MDS predisposes patients to clonal evolution; despite this, it is not considered a separate prognostic factor by the IPSS-R. Ideally, this group of young patients should seek early hematopoietic stem cell transplantation with curative intent.

A multimethod examination of hope and adolescent STEM career expectancies.

Science, technology, engineering, and mathematics (STEM) fields are growing rapidly and understanding adolescent's interest and hope for pursuing a STEM career is essential for additional growth and opportunity collectively and individually. Hope is a cognitive-motivational construct that includes three components: hopeful future expectations (HFEs), intentional self-regulation (ISR), and connection, and is associated with academic achievement and career pursuit; it has not been examined in relation to STEM. This study fills a gap in the literature by taking a multimethod approach to understanding the association between adolescents' hope and STEM career interests. Participants were 639 middle- and high-school adolescents in the southwestern United States who quantitatively reported their hope and STEM career interests and provided qualitative descriptions of reasons for wanting to pursue a STEM career. Quantitatively, HFEs significantly and positively predicted STEM career interest. Relations were examined by gender and school level. For middle-school girls, ISR significantly predicted STEM career interest, for middle-school boys and high-school girls, HFEs positively significantly predicted STEM career interest, but results of high-school boys were nonsignificant. Qualitatively, adolescents mentioned reasons aligning with HFEs and ISR as motivations for pursuing a STEM career, as well as prosocial motivations. Additionally, they discussed their interest in a STEM career as a way to pursue other goals such as financial stability. Findings highlight the possibility of hope as a malleable motivation for STEM career pursuit. Our findings support the components of hope as a salient associate of early STEM career interest, with adolescents who have high HFEs and ISR being particularly apt to say they would like to pursue a STEM career. Our results support the active development of hope among USadolescents as a catalyst toward personal and global success.

Bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration.

Diabetes mellitus (DM) aggravates periodontitis, resulting in accelerated periodontal bone resorption. Disordered glucose metabolism in DM causes reactive oxygen species (ROS) overproduction resulting in compromised bone healing, which makes diabetic periodontal bone regeneration a major challenge. Inspired by the natural bone healing cascade, a mesoporous silica nanoparticle (MSN)-incorporated PDLLA (poly(dl-lactide))-PEG-PDLLA (PPP) thermosensitive hydrogel with stepwise cargo release is designed to emulate the mesenchymal stem cell “recruitment-osteogenesis” cascade for diabetic periodontal bone regeneration. During therapy, SDF-1 quickly escapes from the hydrogel due to diffusion for early rat bone marrow stem cell (rBMSC) recruitment. Simultaneously, slow degradation of the hydrogel starts to gradually expose the MSNs for sustained release of metformin, which can scavenge the overproduced ROS under high glucose conditions to reverse the inhibited osteogenesis of rBMSCs by reactivating the AMPK/β-catenin pathway, resulting in regulation of the diabetic microenvironment and facilitation of osteogenesis. In vitro experiments indicate that the hydrogel markedly restores the inhibited migration and osteogenic capacities of rBMSCs under high glucose conditions. In vivo results suggest that it can effectively recruit rBMSCs to the periodontal defect and significantly promote periodontal bone regeneration under type 2 DM. In conclusion, our work provides a novel therapeutic strategy of a bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration.