Specialized pro-resolving mediator Maresin 1 attenuates pain in a mouse model of osteoarthritis.

Objective: We test whether the specialized pro-resolving molecule Maresin 1 (MaR1) attenuates nociceptive behaviors in mice with osteoarthritis-like pain.

Design: Osteoarthritis (OA)-like pain behavior was induced by intra-articular injection of monosodium iodoacetate (MIA) and treated with MaR1 (N=6) or vehicle (N=5) by intraperitoneal injection 8 weeks after injury. Mice without MIA injection were used as control (N=6).

Multi-Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing.

Bone injuries such as fractures are one major cause of morbidities worldwide. A considerable number of fractures suffer from delayed healing, and the unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids with substantial adverse effects.

General versus Neuraxial Anesthesia on Clinical Outcomes in Patients Receiving Hip Fracture Surgery: An Analysis of the ACS NSQIP Database.

Whether the use of neuraxial anesthesia or general anesthesia leads to more favorable postoperative outcomes in patients receiving hip fracture surgery remains unclear. We used data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Data Files between 2016 and 2020 to investigate the association of neuraxial anesthesia and general anesthesia with morbidity and mortality after hip fracture surgery. Inverse probability of treatment weighting (IPTW) was used to balance the baseline characteristics, and multivariable Cox regression models were used to estimate the hazard ratio (HR) with a 95% confidence interval (CI) for postoperative morbidity and mortality among the different anesthesia groups.

Preoperative renal insufficiency predicts postoperative adverse outcomes in a mixed surgical population: a retrospective matched cohort study using the NSQIP database.

Background: The incidence of chronic kidney disease is increasing, but most cases are not diagnosed until the accidental finding of abnormal laboratory data or the presentation of severe symptoms. Patients with chronic kidney disease are reported to have an increased risk of postoperative mortality and morbidities, but previous studies mainly targeted populations undergoing cardiovascular surgery. The authors aimed to evaluate the risk of postoperative mortality and complications in a surgical population with preoperative renal insufficiency (RI).

pH-Sensitive nanocarrier assisted delivery of adenosine to treat osteoporotic bone loss.

Bone tissue undergoes continuous remodeling osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An imbalance in this process with enhanced osteoclastic activity can lead to excessive bone resorption, resulting in bone thinning. Once activated, osteoclasts bind to the bone surface and acidify the local niche.

Bone targeting nanocarrier-assisted delivery of adenosine to combat osteoporotic bone loss.

Extracellular adenosine has been shown to play a key role in maintaining bone health and could potentially be used to treat bone loss. However, systemic administration of exogenous adenosine to treat bone disorders remains a challenge due to the ubiquitous presence of adenosine receptors in different organs and the short half-life of adenosine in circulation. Towards this, we have developed a bone-targeting nanocarrier and determined its potential for systemic administration of adenosine.

In Vivo Sequestration of Innate Small Molecules to Promote Bone Healing.

Approaches that enable innate repair mechanisms hold great potential for tissue repair. Herein, biomaterial-assisted sequestration of small molecules is described to localize pro-regenerative signaling at the injury site. Specifically, a synthetic biomaterial containing boronate molecules is designed to sequester adenosine, a small molecule ubiquitously present in the human body.

Dysregulation of ectonucleotidase-mediated extracellular adenosine during postmenopausal bone loss.

Adenosine and its receptors play a key role in bone homeostasis and regeneration. Extracellular adenosine is generated from CD39 and CD73 activity in the cell membrane, through conversion of adenosine triphosphate to adenosine monophosphate (AMP) and AMP to adenosine, respectively. Despite the relevance of CD39/CD73 to bone health, the roles of these enzymes in bona fide skeletal disorders remain unknown.

Phenylboronic Acid-polymers for Biomedical Applications.

Background: Phenylboronic acid-polymers (PBA-polymers) have attracted tremendous attention as potential stimuli-responsive materials with applications in drug-delivery depots, scaffolds for tissue engineering, HIV barriers, and biomolecule-detecting/sensing platforms. The unique aspect of PBA-polymers is their interactions with diols, which result in reversible, covalent bond formation. This very nature of reversible bonding between boronic acids and diols has been fundamental to their applications in the biomedical area.

Effect of age on biomaterial-mediated in situ bone tissue regeneration.

Unlabelled: Emerging studies show the potential application of synthetic biomaterials that are intrinsically osteoconductive and osteoinductive as bone grafts to treat critical bone defects. Here, the biomaterial not only assists recruitment of endogenous cells, but also supports cellular activities relevant to bone tissue formation and function. While such biomaterial-mediated in situ tissue engineering is highly attractive, success of such an approach relies largely on the regenerative potential of the recruited cells, which is anticipated to vary with age.

In Situ Gene Therapy via AAV-CRISPR-Cas9-Mediated Targeted Gene Regulation.

Development of efficacious in vivo delivery platforms for CRISPR-Cas9-based epigenome engineering will be critical to enable the ability to target human diseases without permanent modification of the genome. Toward this, we utilized split-Cas9 systems to develop a modular adeno-associated viral (AAV) vector platform for CRISPR-Cas9 delivery to enable the full spectrum of targeted in situ gene regulation functionalities, demonstrating robust transcriptional repression (up to 80%) and activation (up to 6-fold) of target genes in cell culture and mice. We also applied our platform for targeted in vivo gene-repression-mediated gene therapy for retinitis pigmentosa.

Direct Conversion of Human Pluripotent Stem Cells to Osteoblasts With a Small Molecule.

Human pluripotent stem cells (hPSCs), which exhibit unlimited self-renewal ability and can differentiate into all cell types in the human body, are a promising cell source for cell-based therapies and regenerative medicine. Small molecules hold great potential in the derivation of tissue-specific cells from hPSCs owing to their cost-effectiveness and scalability. Here, we describe a protocol for deriving osteoblasts from hPSCs by using a single, natural small molecule: adenosine.

Mineralized Biomaterials Mediated Repair of Bone Defects Through Endogenous Cells.

Synthetic biomaterials that create a dynamic calcium (Ca)-, phosphate (PO) ion-, and calcium phosphate (CaP)-rich microenvironment, similar to that found in native bone tissue, have been shown to promote osteogenic commitment of stem cells in vitro and in vivo. The intrinsic osteoconductivity and osteoinductivity of such biomaterials make them promising bone grafts for the treatment of bone defects. We thus aimed to evaluate the potential of mineralized biomaterials to induce bone repair of a critical-sized cranial defect in the absence of exogenous cells and growth factors.

Small molecule-driven direct conversion of human pluripotent stem cells into functional osteoblasts.

The abilities of human pluripotent stem cells (hPSCs) to proliferate without phenotypic alteration and to differentiate into tissue-specific progeny make them a promising cell source for regenerative medicine and development of physiologically relevant in vitro platforms. Despite this potential, efficient conversion of hPSCs into tissue-specific cells still remains a challenge. Herein, we report direct conversion of hPSCs into functional osteoblasts through the use of adenosine, a naturally occurring nucleoside in the human body.

A Single-Cell Assay for Time Lapse Studies of Exosome Secretion and Cell Behaviors.

To understand the inhomogeneity of cells in biological systems, there is a growing demand on the capability of characterizing the properties of individual single cells. Since single-cell studies require continuous monitoring of the cell behaviors, an effective single-cell assay that can support time lapsed studies in a high throughput manner is desired. Most currently available single-cell technologies cannot provide proper environments to sustain cell growth and, proliferation of single cells and convenient, noninvasive tests of single-cell behaviors from molecular markers.

Adenosine Signaling Mediates Osteogenic Differentiation of Human Embryonic Stem Cells on Mineralized Matrices.

Human embryonic stem cells (hESCs) are attractive cell sources for tissue engineering and regenerative medicine due to their self-renewal and differentiation ability. Design of biomaterials with an intrinsic ability that promotes hESC differentiation to the targeted cell type boasts significant advantages for tissue regeneration. We have previously developed biomineralized calcium phosphate (CaP) matrices that inherently direct osteogenic differentiation of hESCs without the need of osteogenic-inducing chemicals or growth factors.

In vivo comparison of biomineralized scaffold-directed osteogenic differentiation of human embryonic and mesenchymal stem cells.

Human pluripotent stem cells such as embryonic stem cells (hESCs) and multipotent stem cells like mesenchymal stem cells (hMSCs) hold great promise as potential cell sources for bone tissue regeneration. Comparing the in vivo osteogenesis of hESCs and hMSCs by biomaterial-based cues provides insight into the differentiation kinetics of these cells as well as their potential to contribute to bone tissue repair in vivo. Here, we compared in vivo osteogenic differentiation of hESCs and hMSCs within osteoinductive calcium phosphate (CaP)-bearing biomineralized scaffolds that recapitulate a bone-specific mineral microenvironment.

Biomineralized matrices dominate soluble cues to direct osteogenic differentiation of human mesenchymal stem cells through adenosine signaling.

Stem cell differentiation is determined by a repertoire of signals from its microenvironment, which includes the extracellular matrix (ECM) and soluble cues. The ability of mesenchymal stem cells (MSCs), a common precursor for the skeletal system, to differentiate into osteoblasts and adipocytes in response to their local cues plays an important role in skeletal tissue regeneration and homeostasis. In this study, we investigated whether a bone-specific calcium phosphate (CaP) mineral environment could induce osteogenic differentiation of human MSCs, while inhibiting their adipogenic differentiation, in the presence of adipogenic-inducing medium.

Mineralized gelatin methacrylate-based matrices induce osteogenic differentiation of human induced pluripotent stem cells.

Human induced pluripotent stem cells (hiPSC) are a promising cell source with pluripotency and self-renewal properties. Design of simple and robust biomaterials with an innate ability to induce lineage-specificity of hiPSC is desirable to realize their application in regenerative medicine. In this study, the potential of biomaterials containing calcium phosphate minerals to induce osteogenic differentiation of hiPSC was investigated.

Biomineralized matrix-assisted osteogenic differentiation of human embryonic stem cells.

The physical and chemical properties of a matrix play an important role in determining various cellular behaviors, including lineage specificity. We demonstrate that the differentiation commitment of human embryonic stem cells (hESCs), both and can be solely achieved through synthetic biomaterials. hESCs were cultured using mineralized synthetic matrices mimicking a calcium phosphate (CaP)-rich bone environment differentiated into osteoblasts in the absence of any osteogenic inducing supplements.

Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling.

Synthetic matrices emulating the physicochemical properties of tissue-specific ECMs are being developed at a rapid pace to regulate stem cell fate. Biomaterials containing calcium phosphate (CaP) moieties have been shown to support osteogenic differentiation of stem and progenitor cells and bone tissue formation. By using a mineralized synthetic matrix mimicking a CaP-rich bone microenvironment, we examine a molecular mechanism through which CaP minerals induce osteogenesis of human mesenchymal stem cells with an emphasis on phosphate metabolism.

Mineralized synthetic matrices as an instructive microenvironment for osteogenic differentiation of human mesenchymal stem cells.

The effect of substrate-mediated signals on osteogenic differentiation of hMSCs is studied using a synthetic bone-like material comprising both organic and inorganic components that supports adhesion, spreading, and proliferation of hMSCs. hMSCs undergo osteogenic differentiation even in the absence of osteogenesis-inducing supplements. They exhibit higher expressions of Runx2, BSP, and OCN compared to their matrix-rigidity-matched, non-mineralized hydrogel counterparts.

Regulation of the fate of human mesenchymal stem cells by mechanical and stereo-topographical cues provided by silicon nanowires.

Extracellular stimuli imposed on stem cells enable efficient initiation of mechanotransductive signaling to regulate stem cell fates; however, how such physical cues conferred by the stereo-topographical matrix govern the fate of stem cells still remains unknown. The purpose of this study is to delineate the effects of stereotopography and its various relevant physical properties on the fate regulation of human mesenchymal stem cells (hMSCs). Stereo-topographical silicon nanowires (SiNWs) that were precisely controlled with respect to their various dimensions and their growth orientation were used in this study.

Phosphoproteomic analysis of human mesenchymal stromal cells during osteogenic differentiation.

Human mesenchymal stromal cells (hMSCs) are promising candidates for cell therapy and tissue regeneration. Knowledge of the molecular mechanisms governing hMSC commitment into osteoblasts is critical to the development of therapeutic applications for human bone diseases. Because protein phosphorylation plays a critical role in signaling transduction network, the purpose of this study is to elucidate the phosphoproteomic changes in hMSCs during early osteogenic lineage commitment.