Browsing by Subject "Growth factor"

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    Development of multifunctional electrospun wraps for bone healing
    (2020-11-17) Buie, Taneidra Walker; Cosgriff-Hernandez, Elizabeth; Suggs, Laura; Zoldan, Janeta; Laverty, David
    The Masquelet technique is a two-staged procedure that uses an induced biological membrane and bone graft to reconstruct critical-sized bone defects. However, unpredictable clinical outcomes result due to the variable durability and the transient vascular network of the induced membrane, as well as high incidences of osteomyelitis. To this end, we have engineered a resorbable multifunctional electrospun wrap that guides formation of the induced membrane with improved durability and enhanced angiogenesis while simultaneously preventing infection. We achieve this by developing and combining an antimicrobial poly(lactic-co-glycolic) acid (PLGA) mesh and an angiogenic crosslinked gelatin mesh. We first confirmed the ability of electrospun PLGA to provide sustained release of gentamicin sulfate or gallium maltolate above its minimum inhibitory concentration (MIC). Studies that evaluated antimicrobial activity indicated that osteomyelitis-derived bacteria was not susceptible to released gallium maltolate at the hypothesized MIC and further established the accurate gallium maltolate MIC. The inhibitory concentration of each antimicrobial on osteoblasts was compared to the respective MIC to determine if they were safe and effective at released concentrations. Results concluded that the gentamicin sulfate-loaded PLGA mesh is safer and more effective mesh. Next, the bioactivity retention of vascular endothelial growth factor (VEGF) released from electrospun photo-crosslinked gelatin-methacrylate was confirmed. Subcutaneous implantation of the VEGF-loaded mesh in a rat corroborated resorption and the capacity for sustained release. A multifunctional electrospun wrap was then engineered to prevent osteomyelitis and guide formation of the induced membrane by combining the antimicrobial and angiogenic platforms with co-electrospinning. The combination of the two fiber populations was confirmed microscopically and offered independently tuned bimodal release of gentamicin sulfate and VEGF. Overall, this work provides the fundamentals to advance the development of a multifunctional electrospun wrap that can guide formation of the induced membrane and prevent osteomyelitis for improved clinical outcomes with the Masquelet technique. This work offers a substrate that can recruit and support cellular adhesion, provide a template for matrix deposition and tissue remodeling, and enable bimodal release of bioactive agents. These studies also enhance the capacity of electrospun platforms to serve as stand-alone therapies or combinatorial therapies in various bone regeneration applications.
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    Glypican-1 proteoliposomes enhance growth factor activity for therapeutic angiogenesis
    (2016-05) Monteforte, Anthony Joseph, IV; Baker, Aaron Blair; Dunn, Andrew K; Mukhopadhyay, Somshuvra; Stachowiak, Jeanne; Suggs, Laura
    Peripheral arterial disease affects more than 27 million patients in the United States. PAD can lead to peripheral limb ischemia and result in non-healing foot ulcers. Currently, surgical therapies such a stenting, grafting, and bypass, exist for treatment of ischemia, but these treatments are prone to long-term failure. These treatments also only successfully yield beneficial results about 25% of the time. Alternatively, regenerative therapies that stimulate the growth of new vasculature have great potential for treating peripheral and myocardial ischemia. Growth factor based therapies that induce neovascularization have shown promising results in animal models, but have limited success in clinical trials. This discrepancy is most likely a result of growth factor resistance brought on by diseases that lead to peripheral vascular disease. Here, we have developed a new method for enhancing the activity of growth factors in growth factor resistant disease states such as diabetes and hyperlipidemia. Our novel method delivers the growth factor co-receptor glypican-1 embedded in a liposomal carrier to create a glypican-1 proteoliposome (a “glypisome”). By co-delivering the co-receptor glypican-1 along with the growth factor, we hope to overcome growth factor resistance associated with long-term disease. Here we optimize glypisome composition to maximize angiogenic response when co-delivered with growth factors, through the use of in vitro endothelial assays and explore what mechanisms bring about this change in activity. Then we determine therapeutic potential of co-delivering glypisomes with growth factors in vivo by assessing neovascularization in healthy and disease mouse models of ischemia. We also explore overcoming disease mediated growth factor resistance by delivering glioblastoma-derived exosomes as a naturally occurring alternative to the glypisomes that we have developed. We test these exosomes in both in vitro endothelial assays and in vivo with a mouse hind limb ischemia model. We demonstrate that delivering these co-receptors in conjunction with the growth factor will allow us to overcome the disease phenotype and lead to a viable growth factor therapy for peripheral arterial disease.