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Novel Use of Biomimetic Proteoglycans to Molecularly Engineer the Extracellular Matrix of Damaged Skin
- 1. Jessica Gidzinski, David Pearson, Travis Weiss Advisor: Dr. Michele Marcolongo Mentors: Alicia Kriete, Evan Phillips, Dr. Katsiaryna Prudnikova Novel Use of Biomimetic Proteoglycans to Molecularly Engineer the Extracellular Matrix of Damaged Skin 1
- 2. Problem Statement Problem: As skin ages, it dehydrates and loses compliance. • Vulnerability to wounds/infection o 92% of institutionalized elderly sustain at least 1 skin tear every year • Wrinkles 2MALONE, ML, et al. "the Epidemiology of Skin Tears in the Institutionalized Elderly."JOURNAL OF THE AMERICAN GERIATRICS SOCIETY 39.6 (1991): 591-5. Web. and proteoglycans (ECM molecules)
- 3. Skin Layers and Molecular Composition ● Epidermis ● Dermis ● Hypodermis ● ECM: offers structural and biochemical support ○ Structural proteins ○ Glycoproteins ○ Proteoglycans (PGs): embed structural proteins & are critical for wound healing ■ PG breakdown over time causes dehydration and reduced compliance ECM 3reading.ac.uk headandneckcancerguide.org
- 4. Proteoglycans Protein core with covalently attached glycosaminoglycan (GAG) chains Functions: • Mechanical: o Increased water uptake (hydration)→ negatively charged GAG chains • Biological: ○ PGs aid in last 2 stages of wound healing 1. Cell migration/proliferation (fibroblasts) 2. Remodelling: bind to type I collagen fibers in skin to align them in organized fashion 4sci.utah.edu
- 5. Proposed Solution - Biomimetic Proteoglycans (BPGs) • Increased hydration & compliance • Restored PG content could potentially enhance wound healing o PGs align collagen fibers during wound healing o High PG content→less scarring 5 Degenerated Tissue Restored Tissue (Hydration/Swelling) Marcolongo, M. "Matrix Molecular Engineering Using Biomimetic Proteoglycans." 26 Oct. 2015. Lecture. Lightfoot Vidal, Sarah Eugenia, Michele S. Marcolongo and Drexel University. College of Engineering. "Novel Biomimetic Aggrecan for the Acellular Regeneration of the Intervertebral Disc: Synthesis, Enzymatic Stability and Molecular Engineering." 2013. Web. PAA
- 6. Objectives and Methods Objective 1: Determine if BPGs have a statistically significant effect on skin compliance Method: Employ piezoelectric finger (PEF) method to measure elastic modulus of BPG-injected porcine skin samples Objective 2: Evaluate the diffusion behavior of BPGs in skin Method: Cryosection samples thin enough to view under confocal microscope; quantify percent area fluorescence of tagged BPGs at varying distances from injection site 6
- 7. Piezoelectric Finger (PEF) Method Xu, Xin, Cynthia Gifford-Hollingsworth, Richard Sensenig, Wei-Heng Shih, Wan Shih, and Ari D. Brooks. "Breast Tumor Detection Using Piezoelectric Fingers: First Clinical Report." Vol. 216, No. 6. Drexel University, June 2013. 7 Exceeded target of 25% reduction in modulus (increased compliance)
- 8. Confocal Microscopy Embedding Mold Leica 1850 Cryostat 8
- 10. Confocal Microscopy Results 10 ● Decrease in amount of molecule near injection sites over 24 hr period ● Overall, molecular level integration with existing extracellular matrix and diffusion around injection site is shown over a 24 hr period.
- 11. Overall Conclusions and Design Considerations • For the first time, demonstrated molecular engineering of the ECM of porcine skin using biomimetic proteoglycans. • The skin hydration and increased compliance caused by injectable BPGs offers potential for treatment of diseased and aged skin against tearing and subsequent infection. o An injection of natural PGs can cost $300/mg while an injection of BPGs typically costs $0.06/mg. 11
Editor's Notes
- Images: http://remeka.hu/index.php/magazinxmszakmai-frissxm/single-column-blog-190/kozmetikus-szemmel/805-az-antiaging, http://www.isaywhatever.com/handling-elderly-skin-needs One study at a long-term care facility of approximately 1800 patients showed that 92% of institutionalized elderly sustain at least 1 skin tear every year; these wounds increase the risk of infection
- To gain insight into the problem, here’s some background on the composition of the skin
- Image: http://www.lookfordiagnosis.com/mesh_info.php?term=Prot%C3%A9oglycanes&lang=4
- Injection of BA-10 at 50 mg/mL resulted in a 32% reduction of tissue modulus over non-injected control specimens and 48% reduction of tissue modulus compared to commercially available hyaluronic acid (Restylane) 24 hours after injection. This exceeded the target of 25% reduction in tissue modulus (increased compliance).
- BA-10 molecules diffused over a 4 mm area, which could be beneficial for treating the entire area of a wound. The molecules integrated with the ECM, molecularly engineering the tissue. This is the first time this approach has been demonstrated in skin.
- Hydrating molecules could be delivered to skin through injections (including through small gage microneedles (ref) which has been demonstrated in the lab. Image: https://aswomenage.wordpress.com/ Injection of BA-10 at 50 mg/mL resulted in a 32% reduction of tissue modulus over non-injected control specimens 24 hours after injection. In addition, the BA-10 at 50 mg/mL resulted in a 48% reduction of tissue modulus compared to commercially available hyaluronic acid (Restylane). This exceeded the target of 25% reduction in tissue modulus (increased compliance). In addition, it was demonstrated that BA-10 molecules diffused over a 4 mm area, which could be beneficial for treating the entire area of a wound. The molecules integrated with the ECM, molecularly engineering the tissue. This is the first time this approach has been demonstrated in skin. Because BA-10 can be injected via microneedles to allow for application throughout the wound area, minimally invasive delivery of the molecule over the skin surface is possible. Microneedle application is less painful than standard needle application, which could potentially increase patient compliance. The feasibility of modulating tissue mechanics for the dermis to increase compliance by molecularly engineering the ECM of the tissue was demonstrated. This approach could be used to treat wounds, skin tears, and promote efficient healing, limiting scar formation. Synthetic biomimetic aggrecan is much cheaper and can be synthesized easily. An injection of natural aggrecan can cost $300 while an injection of BA typically costs $0.06. Two to three cubic centimeters (cc’s) are the typical injection volumes for these types of applications, meaning that an injection of BA-10 at 10 and 50 mg/mL would cost approximately $0.60 and $3.00, respectively, in material.