Jeffrey A. Ross, DPM, MD, FACFAS Associate Professor Baylor College of Medicine Houston, Texas DFCon 2018 Houston, Texas

Jeffrey A. Ross, DPM, MD, FACFAS Associate Professor Baylor College of Medicine Houston, Texas DFCon 2018 Houston, Texas

A Bridge to Healing S.T.E.P Save The Extremity Program Brooklyn Bridge

Abnormal Wound Repair Diabetes mellitus and wound healing 7 Affects the acute inflammatory response Defective phagocytosis Insufficient cellular response Poor vasodilation Inadequate granulation response Dysfunctional fibroblasts due to low intracellular glucose Poor deposition of extracellular matrix Collagen synthesis dependent on oxygen 7. Carson SN. Diabetes mellitus and wound healing. 8. http://www.woundhealer.com/diabetes_mellitus_and_wound_heal.htm

Repair Process is Based on Inflammation Leads to Scar Formation Fibrin scaffold Inflammation and proliferation Fibrosis and remodeling to scar Repair DSL #11.0697

Algorithm for Application of Acellular Matrices Previous studies have shown that reduction in the area of chronic wound during the first four weeks of treatment is a predictor of complete healing at 12 weeks. 9. If no improvement is seen at this time, there should be further evaluation of the patient and current treatment strategy. 9. Sheehan P., Jones P. Caselli A et al. Percent change in wound area of diabetic foot ulcers over a 4 week period is a robust predictor of complete healing in a 12 week prospective trial. Diabetes Care 2003; 26 (6); 1879 82.

Extracellular Matrix Products A variety of extracellular matrix products (ECM) available in the treatment of diabetic wounds. These products act as a scaffold to allow wound closure to occur using the body s natural healing response. The EMC collagen reduces elastase levels in the wound environment and this subsequently decreases matrix metalloproteinase (MMP) production. 10. Extracellular matrices also rely on collagen component to allow for more efficient angiogenesis and greater fibroblast chemotaxis. 11. 10.Khurram K, Harkless L., Extracellular Matrices : Are They Worth It? Podiatry Today, July, 2008 11.Fleck CA, Understanding the mechanism of collagen dressings, Advances in Skin & Wound Care,2005

Ideal Properties of an Acellular Matrix for hard to Heal Wounds Structural Closely resembles native ECM (i.e. retains natural architecture and key components for wound healing. Minimal storage/preparation needed and long shelf life. Terminally sterile (i.e. cannot transmit viral or other agents)

Biological Provides barrier to infection (i.e. innate immunity) Resistant to proteolytic enzyme degradation Promotes optimal cell activity for rapid revascularization and tissue regeneration.

Clinical Process Single or infrequent application Easy to handle/apply and secure Cost effective/reimburseable Consistent with standard of care Outcome No host immune response Improves patient comfort/reduces pain Reduction in wound size/complete closure Reduced or no scarring and good skin durability Low complication rate

Acellular Matrices and Wound Healing Wound healing is a dynamic process involving interactions between cells, extracellular matrix (ECM) and growth factors that reconstitutes tissue following injury. 12. The extracellular matrix (ECM) plays an important role in tissue regeneration and is the major component of the dermal skin layer. Provides a structural support for cells. Some components of the ECM bind to growth factors to stimulate cell proliferation and migration. 13. 12.Clark, RA, Ghosh K, Tonnesen MG, Tissue engineering for cutaneous wounds. J. Invest Dermatol 2007; 127 (5);1018 29. 13.Schultz GS, Wysocki A. Interactions between extracellular matrix and growth factors in wound Healing. Wound Repair Regen 2009; 17 (2) 153 62.

Features of Dermal Matrix Scaffold Key technology features Supports revascularization and cellular repopulation by host tissue Facilitates tissue regeneration capability which converts to functional host tissue 12, 13. Excellent mechanical properties for ease of handling and grafting 12.Snyder, SJ., Arnoczky SP., Bond JL, Dopirak R., Histologic Evaluation of a Biopsy Specimen 3 Months After Rotator Cuff Augmentation With GraftJacket Matrix Arthroscopy, Vol 25, No 3 (March), 2009: pp 329 333. 13. Linden BA., Simmons M., Histologic Evaluation of a 6 month GraftJacket Matrix Biopsy Used for Achilles Tendon Augmentation, J. American Podiatric Medical Association, March/April 2009, Vol. 99 No 2, pp 104 107.

Extracellular Matrix Contains Complex Three Dimensional Information Regenerative Tissue Matrix Native collagen and natural matrix components Matrix capable of supporting cellular repopulation and revascularization into host tissue Fibrillar collagens and Collagen VI Elastin Hyaluronan Large and small Proteoglycans Fibronectin Vascular Channels 11.0697

Benefits of Dermal Matrix Scaffold in Chronic Wound Repair

Unique Dermal Matrix Features: Contains intact vascular channels for revascularization Preserved extracellular matrix for rapid cell repopulation Supports regeneration of host tissue More of a like for like replacement Preserved vascular channels provide a pipeline for cellular repopulation. 400x Dermal Matrix 21 days post implantation in the athymic nude rat intramuscular model demonstrating extensive cellular infiltration.

Clinical Data Studied in the treatment of deep, chronic diabetic foot ulcers This body of evidence demonstrates that the Acellular Dermal Matrix, in conjunction with good standard wound care, demonstrates that the body can heal challenging chronic diabetic foot ulcers faster than standard wound care alone

Current ECM Products Porcine derived acellular small intestine submucosa Cross linked porcine collagen Human dermal membrane Unite horse pericardium Acellular dermal matrix from human skin tissue.

Current ECM Products Bilayer Matrix Wound Dressing non living extracellular matrix of bovine tendon collagen and chondroitin 6 sulfate with silicone backing. Fetal bovine dermis Restore orthobiologic implant porcine small intestine submucosa Graftskin and Dermagraft are considered living tissue

Advanced Approaches to Wound Care Extracellular matrix scaffolds organize the healing process GRAFTJACKET Regenerative Tissue Matrix OASIS Non cross linked xenograft GAMMAGRAFT Irradiated cadaver skin INTEGRA BMD and PRIMATRIX DERMACELL Regenerative Tissue matrix Cell based technology delivers exogenous growth factors to the wound bed APLIGRAF DERMAGRAFT Isolated recombinant growth factors REGRANEX Hydrolized Collagen CELLERATE Biomechanical action NPWT Sonic

Acellular Dermal Matrix: Level 1 DFU Clinical Study Results 12 week prospective, randomized, controlled, multi center Double the Chance of Healing Faster Healing Rate Wounds treated with one Acellular Matrix are approximately twice as likely to heal at 12 weeks vs standard moist dressing (p 0 023 Complete healing Mean Healing Time Study 69.6% 5.7 weeks

12 week prospective, randomized, controlled, multi center UT Grade 1 or 2 1 cm 2 < wound size < 25 cm 2 86 patients: Study group = 47 patients Control group = 39 patients Study group treated with Dermal Matrix Control group treated with standard moist dressing Primary objective: Healing rates through 12 weeks Secondary objective: Mean time to healing Published: International Wound Journal, June 2009

Out of clutter, find simplicity. From discord, find harmony. In the middle of difficulty, lies opportunity. Albert Einstein

Dakin s Solution Dakin's solution is used to prevent and treat skin and tissue infections.it is also used before and after surgery to prevent surgical wound infections. Dakin's solution is a type of hypochlorite solution. It is made from bleach that has been diluted and treated to decrease irritation. Chlorine, the active ingredient in Dakin's solution, is a strong antiseptic that kills most forms of bacteria and viruses. When used on wounds, Dakin's solution can be poured on to the affected area as an irrigation or cleanser. It is also used to wet certain types of wound dressings (e.g., wet to moist dressing). The body's own wound healing tissues and fluids can decrease the antibacterial effect of Dakin's solution. Therefore, this solution is often used only once daily for minor wounds and twice daily for heavily draining or contaminated wounds. Protect the surrounding healthy skin with a moisture barrier ointment (e.g., petroleum jelly) or skin sealant as needed to prevent irritation.

Dakin s Solution Dakin's solution containing hypochlorite (dilute bleach) has a broad antibacterial activity but is toxic to fibroblasts and it has been found that wound treated with Dakin's solution were significantly slower to epithelize and neovascularize [23], [24], [25] It also retards collagen synthesis and delays epithelization, and also inhibits migration of neutrophils in a wound bed, thus undermining the body's natural defense system [22]. They are toxic to tissues because they oxidize tissue enzymes [26].

Case Presentation 76y.o female DM Type II, PAD, occluded P.T. AT. And peroneal arterie

PriMatrix Dermal Repair Scaffold Description PriMatrix is an acellular dermal tissue matrix derived from fetal bovine dermis PriMatrix Dermal Repair Scaffold PriMatrix Ag Antimicrobial Dermal Repair Scaffold

INTEGRA Bilayer Matrix INTEGRA Bilayer Matrix Wound Dressing is an advanced wound care device comprised of a porous matrix of cross linked bovine tendon collagen and glycosaminoglycan and a semipermeable polysiloxane (silicone layer). The semi permeable silicone membrane controls water vapor loss, provides a flexible adherent covering for the wound surface and adds increased tear strength to the device. The collagen glycosaminoglycan biodegradable matrix provides a scaffold for cellular invasion and capillary growth. Wound Dressing

Case Presentation

4x8cm 4x4cm Product Characteristics: Donated allograft human dermis Single application use in most cases Conforms to the wound bed Fenestrated to allow for wound fluid to escape Thin (0.38.mm 1.02mm Thickness) conforms and maintains surface area contact when sutured/stapled in place Distinct basement membrane and dermal surface White to buff colored, uniform in appearance Indications: Repair or replacement of damaged or inadequate integumental tissue, such as diabetic foot ulcers, venous leg ulcers, pressure ulcers, surgical wounds, traumatic wounds Common uses: Wound applications to include Diabetic Foot Ulcers 49

.25% Acetic Acid Solution Acetic acid is to be kept in mind as one of the alternatives when infection is caused by multiple antibiotic resistant strains of P. aeruginosa. At a time when bacterial resistance to antibiotics is a matter of increasing concern, the value of topical agents such as acetic acid should not be forgotten. Acetic acid treatment of pseudomonal wound infections A review: Author links open overlay panel B.S.Nagoba a S.P.Selkar b B.J.Wadher c R.C.Gandhi a Journal of Infection and Public Health Volume 6, Issue 6 December 2013, Pages 410 415

Case Presentation 1 week post debridement

Case History Acellular Dermal Matrix and Wound VAC 5 days post application RTM

44 weeks post application 46 weeks post application

.25% Acetic Acid Dilute acetic acid though successfully used by many workers for the treatment of wound infections caused by P. aeruginosa, Lineaweaver et al. showed that a 0.25% acetic acid solution killed 100% of exposed fibroblasts in an in vitro model so that impaired wound healing would be expected at any clinically effective concentration. Acetic acid has also been shown to slow down the wound epithelization and to limit polymorphonuclear neutrophilfunction[29].

Pre Op Angio

Post op Angio

Dermacell Acellular Dermal Matrix

The DermACELL RCT Wound Repair & Regeneration (2017)Cazzell et al.

% of Wounds Healed: Week 16 Walters J, Cazzell S, Pham H, Vayser D, Reyzelman A. Healing rates in a multicenter assessment of a sterile, room temperature, acellular dermal matrix versus conventional care wound management and an active comparator in the treatment of full-thickness diabetic foot ulcers. eplasty. 2016;16:73-86.

Excellence

References 1. Guyton GP, et al. The diabetic foot. 70 th Annual Meeting of the American academy of Orthopaedic Surgeons. February 2003. 2. Sanders LJ, Reiber GE. Diabetic foot ulcers and amputations. American Diabetes Association, Inc., 2001. 3. Med Market Diligence. Report #M450, April 2003. 4. Watson T. Soft tissue wound healing review. http://www.electrotherapy.org/electro/downloads/healing%2 0july%2003.pdf 5. Cytokines in wound healing. http://www.rndsystems.com/asp/g_sitebuilder.asp?bodyid=41 5. 6. Moore K. The scientific basis of wound healing. Advances in Tissue Banking 2001; 5: 379 397. 7. Carson SN. Diabetes mellitus and wound healing. http://www.woundhealer.com/diabetes_mellitus_and_wound _heal.htm. 8. Lavery LA, Armstrong DG, Harkless LB. Classification of diabetic foot wounds. http://woundcare.org/newsvol2n2/ulcer2.htm.

References 9. Karr, JC, Retrospective Comparison of Diabetic Foot Ulcer and Venous Stasis Ulcer Healing Outcome Between a dermal Repair Scaffold (Prematrix) and a Bilayered Living Cell Therapy (Apligraf), Advances in Skin and Wound Care, March 2011, Volume 24, Number 3, P. 119 125.11 10. Khurran K, Harkless L, Kravitz, S. Extracellular Matrices: Are they worth It? Podiatry Today, July, 2008, P. 56 63. 11. Fleck CA, Understanding the mechanism of collagen dressings. Advances in Skin and Wound Care 20 (5), 2007. 12.. Snyder, SJ., Arnoczky SP., Bond JL, Dopirak R., Histologic Evaluation of a Biopsy Specimen Obtained 3 Months After Rotator Cuff Augmentation With GraftJacket Matrix Arthroscopy, Vol 25, No 3 (March), 2009: pp 329 333. 13. Linden BA., Simmons M., Histologic Evaluation of a 6 month GraftJacket Matrix Biopsy Used for Achilles Tendon Augmentation, J. American Podiatric Medical Association, March/April 2009, Vol. 99 No 2, pp 104 107. 15. Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomized, multicentre study. International Wound Journal. 2009 Jun;6 (3):196 208. 15. Ichioka, S. et al. Wound Rep and Reg 16:460 465, 2008 16. Xu H, et al. Host response to human acellular dermal matrix transplantation in a primate model of abdominal wall repair. Tissue Eng Part A. 2008; 14(12):2009 2019

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