Our goal is to develop an in vitro experimental model to study skin tissue changes that lead to impaired healing and pressure ulcers in elderly. This study will determine the age-related changes in the extracellular matrix (ECM composition, organization and turnover) in human skin and how these changes contribute to its altered mechanical, cellular and molecular properties. Furthermore, we will determine how compressive stress (pressure) affects these mechanical, cellular and molecular properties. A pressure ulcer is defined as a break in the integument usually caused by continuous pressure to the skin. It is estimated that 2.5 million pressure ulcers require treatment annually in the hospital setting, primarily targeting the elderly population, with total annual costs estimated at $2.2 to $3.6 billion. This does not include pain, suffering and other morbidities associated with pressure ulcers. Currently, there is no FDA approved therapy determined in randomized clinical trials for efficacy for pressure ulcers and no experimental model. Therefore, we aim to develop an experimental model to study changes that lead to development and impaired healing in pressure ulcers. In this proposal, we will use our Mechanical Explant Test System (METS) to compressively load (stress) human skin explants and determine time and load magnitude that generates pathogenic changes in the ECM, mechanical properties, cellular processes that will contribute to impaired wound healing and development of pressure ulcers. Furthermore, we will determine age related changes that will contribute to development of pressure ulcers using skin of young (25-35 years old), middle aged (40-55 years old) and elderly individuals (60-75 years old).The following parameters will be measured in skin specimens in the absence or presence of compressive load: 1) extra cellular matrix (ECM) properties (tenascin, fibronectin, elastin, procollagen, collagen, matrix metalloproteinases (MMP)) and its signaling (integrins, FAK and MAPK);2) mechanical properties of the skin (tensile strength);3) cellular morphology/biology (proliferation, apoptosis, and growth factor/cytokine production) using biomechanical testing and standard molecular biology techniques (immunohistochemistry, Western blots, real-time PCR). Our long-term goal is to eliminate stage IV pressure ulcers and decrease morbidity, mortality and suffering related to pressure ulcers among the elderly population. The experimental approach proposed in this application will provide us with the opportunity to identify changes that lead to pressure ulcers in elderly, an ultimate first step towards the development of novel therapeutic modalities. Developing an experimental model to study mechanisms that lead to bed sores (pressure ulcers) in elderly human skin is the first step towards identification of the cause (pathogenesis) of pressure ulcers. Currently, there is neither an adequate experimental model nor an FDA approved therapy for these ulcers, thus our research proposed will have a high impact in future development of potential therapy for treatment of this devastating disease. An experimental model for pressure ulcers will not only provide an understanding of the underlying mechanisms of pathogenesis, but also allow for pre- clinical testing of potential therapeutic modalities.
| Stojadinovic, Olivera; Minkiewicz, Julia; Sawaya, Andrew et al. (2013) Deep tissue injury in development of pressure ulcers: a decrease of inflammasome activation and changes in human skin morphology in response to aging and mechanical load. PLoS One 8:e69223 |
| Vukelic, Sasa; Stojadinovic, Olivera; Pastar, Irena et al. (2010) Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. J Biol Chem 285:1980-8 |
| Schiffman, Jessica; Golinko, Michael S; Yan, Alan et al. (2009) Operative debridement of pressure ulcers. World J Surg 33:1396-402 |
| Lee, Ding-Dar; Stojadinovic, Olivera; Krzyzanowska, Agata et al. (2009) Retinoid-responsive transcriptional changes in epidermal keratinocytes. J Cell Physiol 220:427-439 |
| Golinko, Michael S; Joffe, Renata; de Vinck, David et al. (2009) Surgical pathology to describe the clinical margin of debridement of chronic wounds using a wound electronic medical record. J Am Coll Surg 209:254-260.e1 |
| Brem, Harold; Golinko, Michael S; Stojadinovic, Olivera et al. (2008) Primary cultured fibroblasts derived from patients with chronic wounds: a methodology to produce human cell lines and test putative growth factor therapy such as GMCSF. J Transl Med 6:75 |
| Charles, Carlos A; Tomic-Canic, Marjana; Vincek, Vladimir et al. (2008) A gene signature of nonhealing venous ulcers: potential diagnostic markers. J Am Acad Dermatol 59:758-71 |
| Andrew Chan, K L; Zhang, Guojin; Tomic-Canic, Marjana et al. (2008) A coordinated approach to cutaneous wound healing: vibrational microscopy and molecular biology. J Cell Mol Med 12:2145-54 |
| Barrientos, Stephan; Stojadinovic, Olivera; Golinko, Michael S et al. (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16:585-601 |
| Pastar, Irena; Stojadinovic, Olivera; Tomic-Canic, Marjana (2008) Role of keratinocytes in healing of chronic wounds. Surg Technol Int 17:105-12 |
