Characterization of 3D printed biodegradable piezoelectric scaffolds for bone regeneration.

Objective: The primary objective of this research was to develop a poly(l-lactic acid) (PLLA) scaffold and evaluate critical characteristics essential for its biologic use as a craniofacial implant.

Materials And Methods: PLLA scaffolds were designed and fabricated using fused deposition modeling technology. The surface morphology and microarchitecture were analyzed using scanning electron microscopy (SEM) and microCT, respectively.

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively.

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities.

Interval delivery of 5HT agonists using multilayered polymer films.

There is an urgent unmet medical need to develop therapeutic options for the ~50% of depression patients suffering from treatment-resistant depression, which is difficult to treat with existing psycho- and pharmaco-therapeutic options. Classical psychedelics, such as the 5HT agonists, have re-emerged as a treatment paradigm for depression. Recent clinical trials highlight the potential effectiveness of 5HT agonists to improve mood and psychotherapeutic growth in treatment-resistant depression patients, even in those who have failed a median of four previous medications in their lifetime.

Indoloxytriazines as binding molecules for the JAK2 JH2 pseudokinase domain and its V617F variant.

Small molecules that selectively bind to the pseudokinase JH2 domain over the JH1 kinase domain of JAK2 kinase are sought. Virtual screening led to the purchase of 17 compounds among which 9 were found to bind to V617F JAK2 JH2 with affinities of 40 - 300 μM in a fluorogenic assay. Ten analogues were then purchased yielding 9 additional active compounds.

Systems for local, sustained release of zoledronic acid as a potential treatment for metastatic bone disease.

Bone pain is the leading cause of morbidity in patients with metastatic cancer. Systemic administration of zoledronic acid (ZA) decreases skeletally-related events in bone cancer patients but is associated with major side effects. This project investigated two biomaterials, poly(methyl methacrylate) (PMMA) bone cement and poly(lactic-co-glycolic acid) (PLGA), for local ZA delivery.

Selective Janus Kinase 2 (JAK2) Pseudokinase Ligands with a Diaminotriazole Core.

Janus kinases (JAKs) are non-receptor tyrosine kinases that are essential components of the JAK-STAT signaling pathway. Associated aberrant signaling is responsible for many forms of cancer and disorders of the immune system. The present focus is on the discovery of molecules that may regulate the activity of JAK2 by selective binding to the JAK2 pseudokinase domain, JH2.

Topical vancomycin for treatment of methicillin-resistant Staphylococcus epidermidis infection in a rat spinal implant model.

Study Design: Basic science.

Objective: Investigate the ability of local applicaiton of vancomycin, either in powder form or suspended within poly(lactic-co-glycolic acid) microspheres (MS), to treat infection using a rat spinal model. Surgical site infections (SSIs) are a serious complication after spine surgery and are associated with high morbidity and mortality and often caused my coagulase negative staphylococci.

Vancomycin- and Poly(simvastatin)-Loaded Scaffolds with Time-Dependent Development of Porosity.

Biodegradable scaffolds are widely use in drug delivery and tissue engineering applications. The scaffolds can be modified to provide the necessary mechanical support for tissue formation and to deliver one or more drugs to stimulate tissue formation or for the treatment of a specific condition. In the current study, we developed biodegradable scaffolds that have the potential for dual drug delivery.

A rodent model using skeletal anchorage and low forces for orthodontic tooth movement.

Introduction: Nonhuman animal models have been used extensively to study orthodontic tooth movement (OTM). However, rodent models have disadvantages, including a reported reduction in bone volume during OTM. The purpose of this study was to determine the viability of a skeletal anchorage and the effect of low force (∼3 cN) on interradicular bone volume during OTM.

Highly Thiolated Poly (Beta-Amino Ester) Nanoparticles for Acute Redox Applications.

Disulfides are used extensively in reversible cross-linking because of the ease of reduction into click-reactive thiols. However, the free-radical scavenging properties upon reduction are often under-considered. The free thiols produced upon reduction of this disulfide material mimic the cellular reducing chemistry (glutathione) that serves as a buffer against acute oxidative stress.

Biodegradable Simvastatin-Containing Polymeric Prodrugs with Improved Drug Release.

Simvastatin was previously converted to a polymeric prodrug with higher drug loading, but the hydrophobic nature of the poly(simvastatin) component of the block copolymer led to slow release of the drug . In this study, we hypothesized that degradation could be accelerated by chemically modifying the polymer backbone by introducing glycolide and lactide comonomers. Copolymers were formed by ring-opening polymerization using 5 kDa monomethyl ether poly(ethylene glycol) as the microinitiator in presence of triazabicyclodecene catalyst.

Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α).

Elucidating the physiological roles and modes of action of the recently discovered ligands (designated ALKAL1,2 or AUG-α,β) of the receptor tyrosine kinases Anaplastic Lymphoma Kinase (ALK) and Leukocyte Tyrosine Kinase (LTK) has been limited by difficulties in producing sufficient amounts of the two ligands and their poor stability. Here we describe procedures for expression and purification of AUG-α and a deletion mutant lacking the N-terminal variable region. Detailed biochemical characterization of AUG-α by mass spectrometry shows that the four conserved cysteines located in the augmentor domain (AD) form two intramolecular disulfide bridges while a fifth, primate-specific cysteine located in the N-terminal variable region mediates dimerization through formation of a disulfide bridge between two AUG-α molecules.

Reducible disulfide poly(beta-amino ester) hydrogels for antioxidant delivery.

Unlabelled: Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g.

Tuning Properties of Poly(ethylene glycol)--poly(simvastatin) Copolymers Synthesized via Triazabicyclodecene.

Simvastatin was polymerized into copolymers to better control drug loading and release for therapeutic delivery. When using the conventional stannous octoate catalyst in ring-opening polymerization (ROP), reaction temperatures ≥200 °C were required, which promoted uncontrollable and undesirable side reactions. Triazabicyclodecene (TBD), a highly reactive guanidine base organocatalyst, was used as an alternative to polymerize simvastatin.

Testing of a bioactive, moldable bone graft substitute in an infected, critically sized segmental defect model.

Large infected bone defects, often resulting from high energy traumas, are difficult to treat due to their variability in complexity and location. Standard treatment for infected bone defects begins with a protocol that includes a series of debridements in conjunction with an extended course of systemic antibiotics. Only after the infection has been eliminated will repair of the defect commence, typically with implantation of autologous bone.

Sequential Release of Multiple Drugs from Flexible Drug Delivery Films.

Sequential release of drugs aligned with the phases of tissue healing could reduce scarring. To achieve this aim, layered film devices comprising cellulose acetate phthalate (CAP) and Pluronic F-127 (Pluronic) were loaded with ketoprofen, quercetin, and pirfenidone. Citrate plasticizers were added to impart flexibility.

Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders.

Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT signaling pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity.

JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules.

A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent and used in the assay are reported as well as results for 10 compounds, including JNJ7706621, NVP-BSK805, and filgotinib (GLPG0634). X-ray crystal structures of JAK2 JH2 in complex with NVP-BSK805, filgotinib, and diaminopyrimidine elucidate the binding poses.

Resistance of Mandibular Polyurethane Replicas to Fracture After Removal of Blocks From the Symphysis and Ramus.

Background: When block grafts are harvested intraorally, the donor sites may act as stress concentrators and alter the structural integrity of the mandible.

Purpose: The study aimed to compare displacement and load failure between intact polyurethane mandibular replicas and similar replicas from which blocks were taken at the symphysis or the ramus. It also aimed to identify trends of load failure.

Combined Effects of Drugs and Plasticizers on the Properties of Drug Delivery Films.

Formation of scar tissue may be reduced or prevented if wounds were locally treated with a combination of molecules tuned to the different healing phases, guiding tissue regeneration along a scar free path. To this end, drug delivery devices made of cellulose acetate phthalate and Pluronic F-127 were loaded with either quercetin or pirfenidone and plasticized with either triethyl citrate (TEC) or tributyl citrate (TBC). Quercetin inhibits oxidative stress, and pirfenidone has been shown to reduce production of pro-inflammatory and fibrogenic molecules.

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight.

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models.

Multifunctional poly(β-amino ester) hydrogel microparticles in periodontal in situ forming drug delivery systems.

In situ forming implants (ISIs) formed from poly(lactic-co-glycolic acid) (PLGA) have been commercialized for local drug delivery to treat periodontitis, but drug release from these bulk materials is typically subject to an initial burst. In addition, PLGA has inferior material properties for the dynamic mechanical environment of gingival tissue. In this work, poly(β-amino ester) (PBAE) hydrogel microparticles were incorporated into a PLGA matrix to provide several new functions: mechanical support, porosity, space-filling, and controlled co-delivery of antimicrobial and osteogenic drugs.