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