Tunable Growth Factor Delivery from Injectable Hydrogels for Tissue Engineering

Current sustained delivery strategies of protein therapeutics are limited by the fragility of the protein, resulting in minimal quantities of bioactive protein delivered. In order to achieve prolonged release of bioactive protein, an affinity-based approach was designed which exploits the specific binding of the Src homology 3 (SH3) domain with short proline-rich peptides. Specifically, methyl cellulose was modified with SH3-binding peptides (MC-peptide) with either a weak affinity or strong affinity for SH3. The release profile of SH3-rhFGF2 fusion protein from hyaluronan MC-SH3 peptide (HAMC-peptide) hydrogels was investigated and compared to unmodified controls. SH3-rhFGF2 release from HAMC-peptide was extended to 10 days using peptides with different binding affinities compared to the 48 h release from unmodified HAMC. This system is capable of delivering additional proteins with tunable rates of release, while maintaining bioactivity, and thus is broadly applicable

Affinity-based Growth Factor Delivery from Injectable Hydrogels for Tissue Engineering

Due to the complexities of tissue repair or regeneration processes, effective clinical strategies have been impaired by both poor delivery of therapeutic agents to the site of injury and a lack of sustained release that is required for long-term efficacy. In this thesis, a strategy for delivering protein therapeutics in a localized and sustained fashion is presented within the context of these regenerative medicine challenges. An affinity-based system was developed whereby transient interactions between complementary binding partners were used to slow the diffusional release of a therapeutic from a polymeric delivery matrix. The Src homology 3 (SH3) domain, which binds a library of SH3-binding peptides, with varying affinity (10Ph.D

Integration and testing of readout L1DDC boards at BB5 laboratory for New Small Wheel Upgrade

In this project we focused mostly on configuring and testing readout boards called Level-1 Data Driver Cards (L1DDC). These electronic components, among with MMFE8 boards and Address Data Driver Cards (ADDC) are integrated into micromegas detectors and strip Thin Gas Chambers in the New Small Wheel Upgrade of ATLAS Experiment

From Candidate to Clinic: Strategies to Accelerate you Molecule's Development Path

The development of orally administered small molecules is becoming more challenging as an increasing number of molecules in pipelines have poor aqueous solubility and bioavailability. This article will introduce an efficient development process that can help deliver the right clinical candidate, optimal formulation strategy and the most appropriate dosage form to clinic. It will also review some established data-driven approaches to formulation development, focus on the value proposition for discovery biopharmaceutics and discuss a preformulation toolkit for drug discovery

Tunable Growth Factor Delivery from Injectable Hydrogels for Tissue Engineering

Current sustained delivery strategies of protein therapeutics are limited by the fragility of the protein, resulting in minimal quantities of bioactive protein delivered. In order to achieve prolonged release of bioactive protein, an affinity-based approach was designed which exploits the specific binding of the Src homology 3 (SH3) domain with short proline-rich peptides. Specifically, methyl cellulose was modified with SH3-binding peptides (MC-peptide) with either a weak affinity or strong affinity for SH3. The release profile of SH3-rhFGF2 fusion protein from hyaluronan MC-SH3 peptide (HAMC-peptide) hydrogels was investigated and compared to unmodified controls. SH3-rhFGF2 release from HAMC-peptide was extended to 10 days using peptides with different binding affinities compared to the 48 h release from unmodified HAMC. This system is capable of delivering additional proteins with tunable rates of release, while maintaining bioactivity, and thus is broadly applicable

Dielectric and ferroelectric properties of BST ceramics obtained by a hydrothermally assisted complex polymerization method

Ba0.8Sr0.2TiO3 (BST) powder, obtained by a hydrothermal treatment of precursor solution previously prepared by a complex polymerization method (HT-CPM), was uniaxially pressed and sintered at 1280 degrees C for 1-32 h. The sintering effect on structural parameters, phase composition, dielectric and ferroelectric properties was investigated. Rietveld refinement analysis of BST ceramics showed that predominant phase was tetragonal BST with monoclinic Ba6Ti17O40 (B6T17) as a secondary phase. Phase contents determined by Rietveld refinement match well with the results of energy dispersive X-ray analysis. Dielectric and ferroelectric properties of BST ceramics have been correlated with density of sintered compacts, phase composition, structural parameters and microstructure. The sample sintered for 16 h showed the highest density (93% rho(t)), as well as the highest value of dielectric constant (similar to 2300) and remanent polarization - Pr (2 mu C/cm(2)) among investigated samples

Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases