Subhamoy Das

Biomaterials and Nanotherapeutics for Enhancing Skin Wound Healing

Wound healing is an intricate process that requires complex coordination between many cell types and an appropriate extracellular microenvironment. Chronic wounds often suffer from high protease activity, persistent infection, excess inflammation, and hypoxia. While there has been intense investigation to find new methods to improve cutaneous wound care, the management of chronic wounds, burns, and skin wound infection remain challenging clinical problems. Ideally, advanced wound dressings can provide enhanced healing and bridge the gaps in the healing processes that prevent chronic wounds from healing. These technologies have great potential for improving outcomes in patients with poorly healing wounds but face significant barriers in addressing the heterogeneity and clinical complexity of chronic or severe wounds. Active wound dressings aim to enhance the natural healing process and work to counter many aspects that plague poorly healing wounds, including excessive inflammation, ischemia, scarring, and wound infection. This review paper discusses recent advances in the development of biomaterials and nanoparticle therapeutics to enhance wound healing. In particular, this review focuses on the novel cutaneous wound treatments that have undergone significant preclinical development or are currently used in clinical practice.

Overcoming Disease-Induced Growth Factor Resistance in Therapeutic Angiogenesis Using Recombinant Co-Receptors Delivered by a Liposomal System

Current treatment options for ischemia include percutaneous interventions, surgical bypass or pharmacological interventions aimed at slowing the progression of vascular disease. Unfortunately, while each of these treatment modalities provides some benefit for patients in the short-term, many patients have resistant or recurrent disease that is poorly managed by these therapies. A highly appealing strategy for treating ischemic disease is to stimulate the revascularization of the tissue to restore blood flow. While many techniques have been explored in this regard, clinically effective angiogenic therapies remain elusive. Here, we hypothesized that the presence of co-morbid disease states inherently alters the ability of the body to respond to angiogenic therapies. Using a mouse model of diabetes and obesity, we examined alterations in the major components for the signaling pathways for FGF-2, VEGF-A and PDGF under normal and high fat dietary conditions. In skeletal muscle, a high fat diet increased levels of growth factor receptors and co-receptors including syndecan-1, syndecan-4 and PDGFR-α in wild-type mice. These increases did not occur in Ob/Ob mice on a high fat diet and there was a significant decrease in protein levels for neuropilin-1 and heparanase in these mice. With the aim of increasing growth factor effectiveness in the context of disease, we examined whether local treatment with alginate gel-delivered FGF-2 and syndecan-4 proteoliposomes could overcome the growth factor resistance in these mice. This treatment enhanced the formation of new blood vessels in Ob/Ob mice by 6 fold in comparison to FGF-2 delivered alone. Our studies support that disease states cause a profound shift in growth factor signaling pathways and that co-receptor-based therapies have potential to overcome growth factor resistance in the context of disease.

Nanoscale strategies: treatment for peripheral vascular disease and critical limb ischemia.

Peripheral vascular disease (PVD) is one of the most prevalent vascular diseases in the U.S. afflicting an estimated 8 million people. Obstruction of peripheral arteries leads to insufficient nutrients and oxygen supply to extremities, which, if not treated properly, can potentially give rise to a severe condition called critical limb ischemia (CLI). CLI is associated with extremely high morbidities and mortalities. Conventional treatments such as angioplasty, atherectomy, stent implantation and bypass surgery have achieved some success in treating localized macrovascular disease but are limited by their invasiveness. An emerging alternative is the use of growth factor (delivered as genes or proteins) and cell therapy for PVD treatment. By delivering growth factors or cells to the ischemic tissue, one can stimulate the regeneration of functional vasculature network locally, re-perfuse the ischemic tissue, and thus salvage the limb. Here we review recent advance in nanomaterials, and discuss how their application can improve and facilitate growth factor or cell therapies. Specifically, nanoparticles (NPs) can serve as drug carrier and target to ischemic tissues and achieve localized and sustained release of pro-angiogenic proteins. As nonviral vectors, NPs can greatly enhance the transfection of target cells with pro-angiogenic genes with relatively fewer safety concern. Further, NPs may also be used in combination with cell therapy to enhance cell retention, cell survival and secretion of angiogenic factors. Lastly, nano/micro fibrous vascular grafts can be engineered to better mimic the structure and composition of native vessels, and hopefully overcome many complications/limitations associated with conventional synthetic grafts.

Syndecan-4 Enhances Therapeutic Angiogenesis after Hind Limb Ischemia in Mice with Type 2 Diabetes.

Delivering syndecan-4 with FGF-2 improves the effectiveness of FGF-2 therapy for ischemia in the diabetic disease state. The syndecan-4 proteoliposomes significantly enhance in vitro tubule formation as well as blood perfusion and vessel density in the ischemic hind limbs of diseased ob/ob mice. Syndecan-4 therapy also induces a marked immunomodulation in the tissues, increasing the polarization of macrophages toward the M2 phenotype.

Syndecan-4 enhances PDGF-BB activity in diabetic wound healing

UNLABELLED Non-healing ulcers are a common consequence of long-term diabetes and severe peripheral vascular disease. These non-healing wounds are a major source of morbidity in patients with diabetes and place a heavy financial burden on the healthcare system. Growth factor therapies are an attractive strategy for enhancing wound closure in non-healing wounds but have only achieved mixed results in clinical trials. Platelet derived growth factor-BB (PDGF-BB) is the only currently approved growth factor therapy for non-healing wounds. However, PDGF-BB therapy is not effective in many patients and requires high doses that increase the potential for side effects. In this work, we demonstrate that syndecan-4 delivered in a proteoliposomal formulation enhances PDGF-BB activity in diabetic wound healing. In particular, syndecan-4 proteoliposomes enhance the migration of keratinocytes derived from patients with diabetes. In addition, syndecan-4 proteoliposomes sensitize keratinocytes to PDGF-BB stimulation, enhancing the intracellular signaling response to PDGF-BB. We further demonstrated that co-therapy with syndecan-4 proteoliposomes enhanced wound closure in diabetic, hyperlipidemic ob/ob mice. Wounds treated with both syndecan-4 proteoliposomes and PDGF-BB had increased re-epithelization and angiogenesis in comparison to wounds treated with PDGF-BB alone. Moreover, the wounds treated with syndecan-4 proteoliposomes and PDGF-BB also had increased M2 macrophages and reduced M1 macrophages, suggesting syndecan-4 delivery induces immunomodulation within the healing wounds. Together our findings support that syndecan-4 proteoliposomes markedly improve PDGF-BB efficacy for wound healing and may be useful in enhancing treatments for non-healing wounds. STATEMENT OF SIGNIFICANCE Non-healing wounds are major healthcare issue for patients with diabetes and peripheral vascular disease. Growth factor therapies have potential for healing chronic wounds but have not been effective for many patients. PDGF-BB is currently the only approved growth factor for enhancing wound healing. However, it has not seen widespread adoption due to limited efficacy and high cost. In this work, we have developed an enhancing agent that improves the activity of PDGF-BB in promoting wound healing in animals with diabetes. This co-therapy may be useful in improving the efficacy of PDGFBB and enhance its safety through lowering the dose of growth factor needed to improve wound healing.

Nitro sulfonyl fluorides are a new pharmacophore for the development of antibiotics

The development of antibiotics against Gram-negative bacteria is a central problem in drug discovery. In this report, we demonstrate that aromatic sulfonyl fluorides with a nitro group in their ortho position have remarkable antibacterial activity and are active against drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), multidrug resistant Acinetobacter baumannii, and Pseudomonas aeruginosa.