Materials Measurement Laboratory • Biosystems & Biomaterials Division • Biomaterials Group
Making Sense of Biomaterials An Update. DEFINITIONS Synthetic (man-made material) –Absorbable...
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Transcript of Making Sense of Biomaterials An Update. DEFINITIONS Synthetic (man-made material) –Absorbable...
Making Sense of Biomaterials
An Update
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
Acellularized Structural Tissue Matrix: (Dermis, SIS, Pericardium)
Based on successes of autologous grafts, like TFL or de-epithelialized dermis
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
Two VA NSQuIP database reviews concluded:
Ventral hernia patients with co-morbid conditions have a four-fold increase in wound-infection rates
COPD, 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
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-TermOutcomes after Colectomy for Cancer, JACS 208;(1):53-61, January 2009
Risk of Synthetic Mesh: Chronic Infection and Bowel Injury
Large area wounds
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
The Ideal Biological Prosthesis
Acellularized human dermal matrix3 years
10X 40X
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
Immune Response and Integration Data:Animal Models and Human Explants
• Host-cell repopulation• Angiogenesis• Immune cell infiltration• Foreign-body giant cells• Encapsulation• Contraction• Resorption
Host Tissue Incorporation
Incorporation
Incorporation
Resorption
1-Month 6-Months
Incapsulation
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
Primate Abdominal Wall3-Month Explants
Chr
onic
infl
amm
atio
n
Encapsulation
Resorption/ScarRegeneration ?
Host Inflammatory Response
Processing methods modify the ECM:The biological effect of cross-linking ?
Bellows CF, et al, Expert Rev. Med. Devices, 2006
Processing
Detergents
Acetone, NaOHGamma-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
“Biological Matrix” in vivo response:It’s measurable
Explant Assessment Implant Duration 1 month 3 months 6 monthsRepopulation (H&E) 0 0.8 0.0 2.0 0.0Revascularization (H&E) 0 1.0 0.0 2.0 0.0
T-cells (CD-3) 1.5 0.6 2.5 0.8 2.8 0.4
B-cells (CD-20) 1.8 0.9 3.0 0.9 2.3 1.0
Macrophages (CD-68) 2.7 0.8 2.8 0.8 2.3 0.5Foreign body response/ Inflammation/ (H&E)
2.8 0.0 2.5 ± 0.5 2.3 0.0
H&E
H&E
Explant Assessment Implant Duration 1 month 3 months 6 monthsRepopulation (H&E) 0 0.6 ± 0.2 1.1 0.0Revascularization (H&E) 0 0.3 ± 0.4 1.0 ± 0.7
T-cells (CD-3) 0.8 0.6 1.5 0.7 1.8 1.4
B-cells (CD-20) 1.3 1.2 1.1 0.6 1.9 1.7Macrophages (CD-68) 1.0 0.7 2.2 0.9 2.7 0.7Foreign body response/ Inflammation/ (H&E)
1.3 ± 0.3 2.2 ± 0.6 2.1 0.0
Product Manufacturer Properties Potential Advantages
Potential Disadvantages
Human DermisAlloderm Lifecell Non-cross-linked
Aseptic without irradiation
Preserved matrixLarge reported clinical experience
Freeze dried;Needs refrigeration;Small sizes
Flex HD Musculoskeletal Transplant Foundation (MTF)/Ethicon
Non-cross linkedAseptic
No refrigeration or rehydration
Small reported clinical experience
Allomax Bard/Davol Proprietary Tutoplast process to remove cells and preserve matrix
Low-dose gamma irradiation to sterilize
Small reported clinical experience;Requires hydration
Porcine DermisPermacol Covidien Chemically cross-
linkedLarge 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
Strattice LifeCell Non-cross-linkedTerminally sterilized
Large sheetsNo rehydration
Few clinical data
XenMatrix Bard/Davol Non-cross-linkedElectron beam sterilized
No rehydration; Large sheets
Few clinical data
Porcine IntestineSurgisis Cook Modified intestinal
submucosal matrix; Non-cross-linked
Long clinical experience; No refrigeration
Reports of enzymatic degradation; Requires rehydration
BovineVeritas Synovis Pericardium Small clinical
experience in ventral hernia
Tutopatch Tutogen Pericardium Little dataSurgiMend TEI Biosciences Fetal dermis
Non-cross-linkedFavorable fetal collagen content;Long shelf life
Requires rehydration;Very little data
?
Immunologically inert
Immunologically active
Extracellular matrix is preserved and intact
Heavily chemically cross-linked
Modified matrixForeign antigens
InflammationIncreased proteasesResorptionReplacement with scar
Normal fibroblastsRevascularizationRemodeling to normal tissue
Inflammation without infiltrationForeign body response (giant cell formation)EncapsulationContraction
Immunologic Response
Tissue Processing
Biologic Response
Mechanism of Action
Regeneration
Resorption/Scar plate
Encapsulation
Understand the Mechanism of Action