Bioengineering at the tissue level

Specialized organization of cells

Learning Objectives

Define the term biomaterial Explain biocompatibility Discuss applications and requirements of materials for medical applications List the requirements for tissue engineering

Reading assignment

Chpt 23, 29 in the Hoefnagels Text

Bioengineers and Materials

Bioengineers use materials to make things!

Cardiovascular/thoracic devices Orthopedic devices Dentistry devices and materials Environmental remediation Characterization of biologic tissue

Engineering Materials Classes

A material class is a set of materials with similar microstructural organization, and/or performance i.e. electronic configuration, bonding, structure, function, etc.

M aterial Classes

Metals Ceramics Polymers Semiconductors Composites Biomaterials

Engineering Materials Classes

Material classes may include elements of other material classes. For example

A certain metal may be a biomaterial However, not all biomaterials are metals And not all metals are biomaterials

Material Properties

A material property is an intrinsic characteristic that can be used to describe a material behavior
M aterial P roperty
Elastic Modulus Tensile Yield Fracture Toughness Hardness Resistivity

Quality
Stiffness Strength Fracture Resistance Wear Resistance Conductance

Sym bol
E Sy K Rc (example)

Stress
Tensile stress, : Shear stress, :

Ft Ao

original area before loading

Stress has units: N/m2 or lb/in2

Strain
Tensile strain:
wo
L/2 /2

Lateral strain:

Lo
/2 L/2

Shear strain:
/2

= tan

/2 - /2

Strain is always dimensionless.

/2

Simple Tensile Mechanical Properties

Obtained by a tensile test

Stress-Strain Testing
Typical tensile specimen Typical tensile test machine
Adapted from Fig. 6.2,

Callister 6e.

gauge (portion of sample with = length reduced cross section)

Other types of tests:

--compression: brittle
materials (e.g., concrete) --torsion: cylindrical tubes, shafts.

Modulus of Elasticity, E

Slope of the linear portion of the stress-strain graph

Hooke's Law =E
Units: E: [GPa] or [psi]

Poisson's ratio,

metals: ~ 0.33 ceramics: ~0.25 polymers: ~0.40

Units: : dimensionless

Elastic Shear modulus, G

Slope of the linear portion Pressurevolume change curve =G

simple torsion test

Special relations for isotropic materials

E G= 2(1 + )

Yield Strength, y
Stress at which noticeable plastic deformation has occurred. when p = 0.002
tensile stress,

engineering strain,

p = 0.002

Tensile Strength, TS

Maximum possible engineering stress in tension

Metals: occurs when noticeable necking starts. Ceramics: occurs when crack propagation starts. Polymers: occurs when polymer backbones are aligned and about to break. Other symbols UTS, UTS

Biomaterials

Biomaterials Experts?

Overview

Background Traditional biomaterials New generation biomaterials The Future Conclusions

Historical Uses of Biomaterials

Earliest examples are sutures. Circa 4000 BC. Linen and adhesive plaster Horse hair, cotton, leather (600 BC) Catgut (2nd century) Silk (11th century) Wire (16th century) Violin strings (19th century)

Biomaterials?

What are they living, dead, animate, both, neither, something else??? Is a biomaterial biological? Is a biomaterial organic? Could a biomaterial be inorganic?

Biomaterials: Definition

YES! A biomaterial is any non-native substance -- typically man-made, but can be derived from living tissue -- that is systemically and pharmacologically inert and designed for implantation or incorporation with the living system.

Clemson University Biomaterials Symposia Definition.

Biomaterial

A biomaterial is a nonviable material used in a medical device intended to interact with biologic systems

Biomaterials. Proceedings of a Consensus Conference of the European Society of Biomaterials, Chester, England, Mar 3-5,
1986, Vol 4, Elsevier, NY

Williams, D.F. (1987) Definitions in

Biomaterial (Most General)

A material intended to interface with biological systems to evaluate, treat, augment, or replace any tissue, organ, or function of the body.

ESB Consensus Conference II

Biomaterials Requirements

Must not evoke adverse reactions (toxic, carcinogenic) or worse (death) The material must not interfere with, or modify (in a negative fashion), life processes such as wound healing. The material must not be damaged by being in the bodily environment (such as corrosion). The purpose is generally for functional replacement or interventional devices

Uses of Biomaterials

Biomaterials usage constitutes approximately $100 billion per year from medical device industry Medical uses (partial list from A to Z):

Arterial graft Heart valves Joint replacement Pacemakers Stents Zirconium knee joint

Interdisciplinary Field

Materials Science Surface chemistry Biochemists Biology Medicine Ethicists Lawyers

What is Biocompatibility?

Materials that are biocompatible evoke minimal (at best no) adverse responses while in contact with the host, as well as maintaining material integrity over the intended service life.

Host

Human or animal Local tissue and distant systems/organs Dies, heals, carcinogenic, thrombogenic, etc. Brief, <24 hours, <30 days, >30 days Implant, mucous membrane, skin, eye, etc.

Response

Contact

Soft Tissue Response to Implanted Biomaterials

Non-toxic reactionEssence of Biocompatibility

Typical Biological Response to Non-Toxic Implanted Materials (Cardiovascular or Soft Tissue)

1. 2. 3.

4. 5. 6.

Implant Protein Adsorption (seconds) Thrombosis and Complement Activation (seconds to hours) Cellular Recognition (minutes to hours) Inflammation (days) Resolution (weeks/months)

Foreign Body Reaction

Giant cell formation & cytokine release
1 sec to 1 hr 2 10 days

Protein adsorption

Cellular attack/recognition
30 min 2 days

Fibrous Capsule

3+ weeks

Time Course of Inflammation

Thrombosis, Complement Activation

Protein Adsorption
J. Anderson, Inflammation and the Foreign Body Response, Problems in General Surgery, 11, 147-160 (1994).

Foreign Body Reaction

Histology Slides of Silicone Implanted in SVC for 6 months
50 m 50 m

Macrophages and FBGCs

Acellular Fibrous Capsule

Silicone Implant Haematoxylin and Eosin

Nuclei - Purple/Black

Massons Trichrome
Collagen - Blue Cytoplasm - Red

Blood Responses Foreign Body

Clotting system pathways activated Thrombus formation (clot)

Restricting flow Strokes, heart attacks

Thrombus embolization

Blood cells damage (hemolysis) Surrounding tissues damage Bacterial colonization

Foreign Body Reaction

Summary

The body is designed to detect foreign materials The basic strategy is to either digest, or encapsulate the foreign body if removal is not possible While there are some similarities, the Foreign Body Reaction is not the same thing as Rejection

Typical Implantable Materials

Metals Ceramics Polymers

Bioabsorbable

Metals

Strong (good) Wear resistant (good) Formable (good) Stiff (may not be so good) Chemically active (not so good)

Stainless Steel (316LV) Titanium and titanium alloys Zirconium Nitinol Tantalum MP35N Co-Cr-(Mo) Alloys Gold Platinum and Pt-Ir

Ceramics

Most biocompatible class of materials Chemically inert due to atomic bonding Easily sterilized (good) Generally brittle (bad) Generally hard (good) Some ceramic materials are naturally degraded by the body Some ceramic coatings may enhance device biocompatibility

Zirconia Alumina Graphite Diamond Hydroxyapatite Bioglass

Polymeric Materials

Polymers represent a class of materials that are generally biocompatable Due primarily to atomic bonding stability Most biocompatable polymers are in pure form Generally polymers must be highly polymerized (mers may be carcinogenic) Polymers must not leach substances

Fillers, plasticizers, colorants, etc.

Biodegradation & Erosion

Bio-as a prefix will be used to indicate processes that are influenced by biological agents

Cells Enzymes Microorganisms

Emphasizes the process is facilitated by biologic agents or physiologic conditions

Biodegradation

Breakdown of a substance by biological means (cellular activity, biologic environment, etc) Chemical structure is broken down into smaller components Cleavage of covalent bonds Cannot strictly be considered as hydrolysis, such as poly(lactic acid) Sometimes called bioresorption or bioabsorption

Bioerodable Polymers

A water-insoluble polymer that is converted under physiologic conditions into water-soluble materials without regard to the specific mechanism involved in the erosion process The polymer backbone is not broken down

Degradable Materials

Variable life materials, may be short-, mid-, or long-life A degradable material is designed to function as a biomaterial for a pre-defined life, then be digested by the body, which evokes minimal foreign body reactions at any stage

The by-products must be inert The rate of decomposition must be sufficiently slow to allow the device to function Some by-products can be metabolized

Biodegradable Materials

Most commonly composed of polymers Often times are formed from block copolymers Degradation typically involves hydrolysable bonds

Esters Carbonyls Amides

Some Degradable Polys

O

Poly(glycolic acid)

O C C H2
O

Poly(lactic acid)

H O C C CH3

O
Poly(-caprolactone)

CH2 5 O

Inert Polymers

These polymers are intended for longterm use Highly stable Do not leach Few (if any) additives

Some Stable (Inert) Polys

CH3
Silicone Rubber

Si O CH3
F F
n

Teflon

C C F
H H

Polyethylene

C C H H

Biomaterials: Some Common Sterilization Methods

Ethylene oxide

Lethal Can be problematic for polymers Effective Simple, inexpensive Many polymers cannot be treated Lethal Possibly the best method, but very expensive Can damage polymers

Pressure and Steam (Autoclave)

Gamma irradiation

Polymers

Any polymer must be able to be sterilized Typical sterilization techniques

Exposure to ethylene oxide Gamma irradiation Autoclave (pressure and steam)

Polymers can be designed to selectively degrade with time

Infection: Possible Mitigating Strategies

Surface coatings

Hydroxyapatite Silver Gentimicin Endothelialization

Antibiotic coatings

Cell seeding

Surface modified materials to prevent colonization of materials

Cellular response to force

Tissues grow and adapt in response to mechanical loading Engineers have developed a means to quantify cellular response by culturing cells in the presence of a flow field Can lead to better engineered tissue replacements

Langers Lines

Collagen, the reinforcing fiber of tissue, is organized in the direction of applied tensile stress Langers lines are a map of collagen fiber orientation for the skin Think of it as lines of principal tensile stress

Skin

An example of epithelial tissue Skin is one of the largest structures of the body Replacement necessitated by

Sensory Protective

tramatic injury burn (12000 fatalities / year) cosmetic/vanity Microbe/disease Radiation (Sun/UV) Chemical

Thermoregulation Secretion

http://www.agen.ufl.edu/~chyn/age2062/lect/lect_19/lect_19.htm

Tissue Engineering

Engineered tissue can be used in patients who are in need of transplantation, eliminating problems such as shortage of donors and immune rejection. Several tissue types are in the process of being engineered:

Pancreas Liver Skin Nerves Cornea Breast Bone Blood Muscle Cartilage Blood vessels

Artificial Skin

Scaffold

Artificial Allograft derived

Culture cells the

scaffold Usually cultured in the presence of loads

Current Bioengineered Skin Substitutes

Autologous Graft: Dermatome and Skin Mesher

Cultured Keratinocytes

Dermagraft

Dermagraft is a cryopreserved human fibroblast-derived dermal substitute Diabetic Foot Ulcers Composion:

Fibroblasts Extracellular matrix Bioabsorbable scaffold.

Dermal Grafts for Burn Victims

Implant tissue

The circulating stem cells target damaged tissue Cells deposit and adhere to the matrix Cells differentiate into tissue-specific cell types Differentiated cells elaborate the new matrix to regenerate tissue Over time, autologous graft is applied

www.bvmed.de/bilderpool/Bilder_Medizinprodukt...

New Directions

Electrospinning of fibers to form a matrix for cell seeding Solid Freeform Fabrication (3D printing)

Can include ECM, Cells, supporting structures Experimental for now

Questions to address

What are desirable properties for materials? Is mimicking the mature skin optimal?

Quote to consider

many tissue-engineering papers consider the fact that the scaffolds resemble native ECM a great benefit to their wound-healing potential. This may seem plausible, but is still only a hypothesis. There are indications that the structure of normal skin is not exactly what is needed to produce optimal wound-healing results.

van der Veen, VC et al. New dermal substitutes. Wound Rep Reg (2011) 19 S59S65