1. Making Sense of Biomaterials An Update

2. DEFINITIONS Synthetic (man-made material) –Absorbable Rapidly absorbed “Long-term” absorbable –Permanent (non-absorbable) PRIMARY FUNCTION IS MECHANICAL STABILITY Biological is one-time living material (collagen based) PRIMARY FUNCTION IS REGENERATIVE POTENTIAL (Angiogenesis / Vasculogenesis) Bio-material –A biomaterial is any material, natural or synthetic, that augments, or replaces a normal biological function

3. Acellularized Structural Tissue Matrix: (Dermis, SIS, Pericardium) Based on successes of autologous grafts, like TFL or de-epithelialized dermis

4. Why the introduction of biologicals? Complications… Risk of infection with synthetics Risk of recurrence with synthetics –Flum and others –Synthetics “shrink” Risk of bowel injury with synthetics Evolution of abdominal wall reconstruction –Component separation –Large wounds with tenuous skin coverage

5. Two VA NSQuIP database reviews concluded: nVentral hernia patients with co-morbid conditions have a four-fold increase in wound-infection rates nCOPD, steroid use, smoking, and low pre-op serum albumin were independent risk factors for increased post-op infection in ventral hernia patients Dunne JR, Malone DL, Tracy JK, Napolitano LM. Abdominal wall hernias: risk factors for infection and resource utilization. J Surg Res. 2003 May 1;111(1):78-84. Finan KR, Vick CC, Kiefe CI, Neumayer L, Hawn MT. Predictors of wound infection in ventral hernia repair. Am J Surg. 2005 Nov;190(5):676-81. Co-morbid conditions increase wound infection rates in ventral hernias 5

6. Jan. 2009 review of ACS-NSQuIP database concluded: Patients with BMI greater than 35 have relative risk of wound disruption / dehiscence 3.50 X wound infection 2.66 X Obesity increases laparotomy wound failure and infection rates 6 Ryan P Merkow, Karl Y Bilimoria, Martin D McCarter, David J Bentrem, Effect of Body Mass Index on Short-Term Outcomes after Colectomy for Cancer, JACS 208;(1):53-61, January 2009

7. Risk of Synthetic Mesh: Chronic Infection and Bowel Injury

8. Large area wounds

9. Major Biological Matrix Functional Determinants Collagen isoforms Elastin –Human dermis more than porcine Vascular channels –Preserved in unmodified matrices –Lost in stripped or laminated matrices ECM immunogenic epitopes –Alpha-gal best understood –Xenograft / Allograft trade-offs

10. The Ideal Biological Prosthesis

11. Acellularized human dermal matrix 3 years 10X40X

12. Modification of the Biological Matrix Allograft or Xenograft immune response should be mitigated –Acellularized –Removal or blockade of the alpha-gal ECM epitope in porcine xenografts Processing should maintain extra-cellular matrix (ECM) function –The amount of “cross-linking” debate Is there an optimum? Normal tropocollagen has hydrogen bond “cross-linking” Protects against collagenase activity –Sterilization can modify the ECM too –Strike a balance between durability and tissue in-growth

13. Immune Response and Integration Data: Animal Models and Human Explants Host-cell repopulation Angiogenesis Immune cell infiltration Foreign-body giant cells Encapsulation Contraction Resorption

14. Host Tissue Incorporation Incorporation Resorption 1-Month6-Months Incapsulation

15. 6-months FB Giant Cells H&E 200x “Good” integration Minimal inflammation Evidence of transition to fascia-like tissue Classic foreign body response TRAM donor site (12-month) Bacteria; liitle or no recellularization (1 month) Primate model Human explants Immune Response and Integration Data: Animal Models and Human Explants

16. Primate Abdominal Wall 3-Month Explants Chronic inflammation Encapsulation Resorption/Scar Regeneration ? Host Inflammatory Response

17. Processing methods modify the ECM: The biological effect of cross-linking ? Bellows CF, et al, Expert Rev. Med. Devices, 2006 Processing Detergents Acetone, NaOH Gamma-irrad Disinfection soln Enzymes Organic Solvents Alcohol; HCl Bleach Other Chemical Treatments Propylene Oxide IN VITRO CHANGES Biomechanical properties Ultrastructure (histology, scanning & transmission EM) Biochemical composition (collagens, PGs) MMP sensitivity (collagenase) Thermal stability (DCS) IN VIVO CHANGES Repopulation and re-vascularization Remodeling and Transition Immune Response (T- and B-cells, Macrophages) FBGC, capsule formation

18. “Biological Matrix” in vivo response: It’s measurable Explant Assessment Implant Duration1 month3 months6 months Repopulation (H&E) 0 0.8  0.02.0  0.0 Revascularization (H&E) 0 1.0  0.02.0  0.0 T-cells (CD-3) 1.5  0.62.5  0.82.8  0.4 B-cells (CD-20) 1.8  0.93.0  0.92.3  1.0 Macrophages (CD-68) 2.7  0.82.8  0.82.3  0.5 Foreign body response/ Inflammation/ (H&E) 2.8  0.0 2.5 ± 0.5 2.3  0.0 H&E Explant Assessment Implant Duration1 month3 months6 months Repopulation (H&E) 00.6 ± 0.2 1.1  0.0 Revascularization (H&E) 00.3 ± 0.41.0 ± 0.7 T-cells (CD-3) 0.8  0.61.5  0.71.8  1.4 B-cells (CD-20) 1.3  1.21.1  0.61.9  1.7 Macrophages (CD-68) 1.0  0.72.2  0.92.7  0.7 Foreign body response/ Inflammation/ (H&E) 1.3 ± 0.32.2 ± 0.6 2.1  0.0

19. ProductManufacturerProperties Potential Advantages Potential Disadvantages Human Dermis AllodermLifecell Non-cross-linked Aseptic without irradiation Preserved matrix Large reported clinical experience Freeze dried; Needs refrigeration; Small sizes Flex HD Musculoskeletal Transplant Foundation (MTF)/Ethicon Non-cross linked Aseptic No refrigeration or rehydration Small reported clinical experience AllomaxBard/Davol Proprietary Tutoplast process to remove cells and preserve matrix Low-dose gamma irradiation to sterilize Small reported clinical experience; Requires hydration Porcine Dermis PermacolCovidien Chemically cross- linked Large sizes; No refrigeration or rehydration; Large reported clinical experience Concern for increased foreign body reaction due to heavy cross- linking; Chemical odor and concern for inflammation StratticeLifeCell Non-cross-linked Terminally sterilized Large sheets No rehydration Few clinical data XenMatrixBard/Davol Non-cross-linked Electron beam sterilized No rehydration; Large sheets Few clinical data Porcine Intestine SurgisisCook Modified intestinal submucosal matrix; Non-cross-linked Long clinical experience; No refrigeration Reports of enzymatic degradation; Requires rehydration Bovine VeritasSynovisPericardium Small clinical experience in ventral hernia TutopatchTutogenPericardiumLittle data SurgiMendTEI BiosciencesFetal dermis Non-cross-linked Favorable fetal collagen content; Long shelf life Requires rehydration; Very little data ?

20. Immunologically inert Immunologically active Extracellular matrix is preserved and intact Heavily chemically cross- linked Modified matrix Foreign antigens Inflammation Increased proteases Resorption Replacement with scar Normal fibroblasts Revascularization Remodeling to normal tissue Inflammation without infiltration Foreign body response (giant cell formation) Encapsulation Contraction Immunologic Response Tissue Processing Biologic Response Mechanism of Action Regeneration Resorption/Scar plate Encapsulation Understand the Mechanism of Action