Migrating Myeloid Cells Sense Temporal Dynamics of Chemoattractant Concentrations.

Chemoattractant-mediated recruitment of hematopoietic cells to sites of pathogen growth or tissue damage is critical to host defense and organ homeostasis. Chemotaxis is typically considered to rely on spatial sensing, with cells following concentration gradients as long as these are present. Utilizing a microfluidic approach, we found that stable gradients of intermediate chemokines (CCL19 and CXCL12) failed to promote persistent directional migration of dendritic cells or neutrophils.

Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes.

Antibodies are critical for defense against a variety of microbes, but they may also be pathogenic in some autoimmune diseases. Many effector functions of antibodies are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs)-important antigen-presenting cells that play a central role in inducing antigen-specific tolerance or immunity. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via the lymphatics to present antigen to T cells.

Selective activation of sphingosine 1-phosphate receptors 1 and 3 promotes local microvascular network growth.

Proper spatial and temporal regulation of microvascular remodeling is critical to the formation of functional vascular networks, spanning the various arterial, venous, capillary, and collateral vessel systems. Recently, our group has demonstrated that sustained release of sphingosine 1-phosphate (S1P) from biodegradable polymers promotes microvascular network growth and arteriolar expansion. In this study, we employed S1P receptor-specific compounds to activate and antagonize different combinations of S1P receptors to elucidate those receptors most critical for promotion of pharmacologically induced microvascular network growth.

The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720.

Poor vascularization coupled with mechanical instability is the leading cause of post-operative complications and poor functional prognosis of massive bone allografts. To address this limitation, we designed a novel continuous polymer coating system to provide sustained localized delivery of pharmacological agent, FTY720, a selective agonist for sphingosine 1-phosphate receptors, within massive tibial defects. In vitro drug release studies validated 64% loading efficiency with complete release of compound following 14 days.

Injectable tissue-engineered bone repair of a rat calvarial defect.

Objectives/hypothesis: Advances in bone repair have focused on the minimally-invasive delivery of tissue-engineered bone (TEB). A promising injectable biopolymer of chitosan and inorganic phosphates was seeded with mesenchymal stem cells (MSCs) and a bone growth factor (BMP-2), and evaluated in a rat calvarial critical size defect (CSD). Green fluorescent protein (GFP)-labeled MSCs are used to evaluate patterns of cell viability and proliferation.

Therapeutic potential of the immunomodulatory activities of adult mesenchymal stem cells.

Adult mesenchymal stem cells (MSCs) include a select population of resident cells within adult tissues, which retain the ability to differentiate along several tissue-specific lineages under defined media conditions and have finite expansion potential in vitro. These adult progenitor populations have been identified in various tissues, but it remains unclear exactly what role both transplanted and native MSCs play in processes of disease and regeneration. Interestingly, increasing evidence reveals a unique antiinflammatory immunomodulatory phenotype shared among this population, lending support to the idea that MSCs play a central role in early tissue remodeling responses where a controlled inflammatory response is required.

FTY720 promotes local microvascular network formation and regeneration of cranial bone defects.

The calvarial bone microenvironment contains a unique progenitor niche that should be considered for therapeutic manipulation when designing regeneration strategies. Recently, our group demonstrated that cells isolated from the dura are multipotent and exhibit expansion potential and robust mineralization on biodegradable constructs in vitro. In this study, we evaluate the effectiveness of healing critical-sized cranial bone defects by enhancing microvascular network growth and host dura progenitor trafficking to the defect space pharmacologically by delivering drugs targeted to sphingosine 1-phosphate (S1P) receptors.

Engineering vascularized tissues using natural and synthetic small molecules.

Vascular growth and remodeling are complex processes that depend on the proper spatial and temporal regulation of many different signaling molecules to form functional vascular networks. The ability to understand and regulate these signals is an important clinical need with the potential to treat a wide variety of disease pathologies. Current approaches have focused largely on the delivery of proteins to promote neovascularization of ischemic tissues, most notably VEGF and FGF.

Expansion of microvascular networks in vivo by phthalimide neovascular factor 1 (PNF1).

Phthalimide neovascular factor (PNF1, formerly SC-3-149) is a potent stimulator of proangiogenic signaling pathways in endothelial cells. In this study, we evaluated the in vivo effects of sustained PNF1 release to promote ingrowth and expansion of microvascular networks surrounding biomaterial implants. The dorsal skinfold window chamber was used to evaluate the structural remodeling response of the local microvasculature.

Comparative effects of scaffold pore size, pore volume, and total void volume on cranial bone healing patterns using microsphere-based scaffolds.

Bony craniofacial deficits resulting from injury, disease, or birth defects remain a considerable clinical challenge. In this study, microsphere-based scaffold fabrication methods were use to study the respective effects of scaffold pore size, open pore volume, and total void volume fraction on osseous tissue infiltration and bone regeneration in a critical size rat cranial defect. To compare the healing effects of these parameters, three different scaffolds types were fabricated: solid 100 microm spheres, solid 500 microm spheres, and hollow 500 microm spheres.

Sustained release of sphingosine 1-phosphate for therapeutic arteriogenesis and bone tissue engineering.

Sphingosine 1-phosphate (S1P) is a bioactive phospholipid that impacts migration, proliferation, and survival in diverse cell types, including endothelial cells, smooth muscle cells, and osteoblast-like cells. In this study, we investigated the effects of sustained release of S1P on microvascular remodeling and associated bone defect healing in vivo. The murine dorsal skinfold window chamber model was used to evaluate the structural remodeling response of the microvasculature.