Biomedical Polymers (Biomaterials) & Biocompatibility

Professors Kinam Park & Luis Solorio

Purdue UniversityBiomedical Engineering

Biomaterials

Biomaterials are basically any non-viable materials which become a part of the body either temporarily or permanently to restore, augment, or replace the natural functions of the living tissues or organs in the body.

They are intended to interact with biological systems.

Applications: prosthetic, diagnostic, and therapeutic.

Drug-Device Combination Products

Ex. antibiotics or growth hormone incorporated into implantable biomaterials for delivery at the implant interface to prevent deep-wound sepsis or to improve wound healing and tissue repair.

Biomaterials

Application of Biomaterials

I. Blood-contacting soft tissue replacements

Heart valve prosthesesMechanical heart valves:

Caged ball or caged disc type: polished CoCr alloy cage and silicone rubber ball, valve sewing ring made of knitted composite of PTFE and polypropylene cloth.Tilting disc type: Pyrolytic carbon disc, guiding struts made of titanium or CoCr.

Bileaflet type: Pyrolytic carbon valvesVascular prostheses: Dacron, PTFE, Silicone rubber

Cardiac pacemakers

Blood oxygenator

Extracorporeal dialysis

Blood circulation tubing

Intravascular catheter

Total artificial heart

http://www.nostalgiacentral.com/tv/drama/sixmillion.htm

Artificial Heart Valves

Examples

Total Artificial Heart

Scientific American

Left Ventricular Assist Device

Artificial Organs

Percutaneous Access Device

Polycarbonate device that allows access to the blood.

Devices are intended for short-term use while on waiting list.

Often on list for extremely long time.

The air port is the main route of infection.

Improved integration with tissue is anticipated to reduce infection.

Material/tissue mechanical property mismatch.

Immortal Human

Transition from Silk to Nylon

Get Your Polymers Here!

1950s: Polymeric Vascular Prostheses-Nylon, Orlon, and Dacron -Orlon and Dacron found to be superiorBoth had high patency rates in large arteries

Bio-glass

One of the first completely synthetic materials used to bind with bone.

Developed in 1967 by Professor Larry Hench.

Was focusing on interactions of glass with radiation.

U.S. Army challenged him to create a material that wouldn’t be rejected by the body, which was costing hundreds of limbs a week in Vietnam.

Created glass with elevated Ca and P ions.

The Filter that Fights Ebola

HemopurifierDeveloped by Aethlon Medical

What makes the Ebola virus so frightening is its speed. In a matter of days, it can pump out enough copies of itself to overtake the immune system. But the Hemopurifier, a specially designed cartridge that attaches to a dialysis machine, can tip the balance back in the body’s favor: its lectin filter attracts Ebola viruses and sucks them from the blood as it flows through. It’s been used only once, on a patient in Germany, but it did the trick—effectively curing his Ebola infection. In the future, doctors hope similar tech could be used on viruses like hepatitis.

http://time.com/3594971/the-25-best-inventions-of-2014/?xid=newsletter-brief

Fast Swelling Hydrogels for Aneurysm Treatment

HydroCoil Embolic System: MicroVention (www.microvent.com/Home/hydrocoil/index.html)

Adhesive Hydrogels as Gastric Bandage

Mucoadhesive hydrogel films to cover the ulcer area.Delivery of blood clotting agents.

CH2 CHC OOH n

http://www.nlm.nih.gov/medlineplus/ency/imagepages/19243.htm

The procedure called gastroscopy involves the placing of an endoscope (a small flexible tube with a camera and light) into the stomach and duodenum to search for abnormalities. Tissue samples may be obtained to check for H. pylori bacteria, a cause of many peptic ulcers. An actively bleeding ulcer may also be cauterized (blood vessels are sealed with a burning tool) during a gastroscopy procedure

Application of Biomaterials

II. Non-blood-contacting soft tissue replacements

Sutures and allied augmentation devicesSutures, Clips, staples, and pins, Surgical tapes, Tissue adhesives

Percutaneous and skin implants: Artificial skin, Burn dressing

Maxillofacial implantsReconstructive surgery: Copolymers of vinyl chloride and vinyl acetate, PMMA, silicone rubber, polyurethane

Ear and eye implants: Contact lens, Intraocular lens

Space-filling implants: Silicone gel breast implants, tissue expanders

Fluid transfer implants: Cerebrospinal fluid shunts, Endotracheal tubes, Urinary catheter, Peritoneal dialysis catheters

Prosthetic joints

Implantable drug delivery devices

Tissue Expander

Manual delayed expansion.Predefined size and shape.No ability to reshape by surgeons.

Current Tissue Expanders: Hydrogels

Copolymers of methylmethacrylate and N-vinylpyrrolidone

Predefined size and shape.No ability to reshape by surgeons.

C C

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The volume increase of 3-12 folds.

Hydrogel in silicone shell to reduce the swelling speed.

http://www.osmed.biz/html_e/produkte/produkte.html

New Hydrogel Tissue Expanders

A hydrogel expander normal and beingflexed between fingers. Note its elasticity.

http://polyscitech.com/currentResearch/restiex/ Restiex®

Re-Shapable Tissue Expanding Hydrogel

Application of Biomaterials

III. Hard tissue replacements

Bone repair and joint implantsMetallic alloys, biodegradable polymers (PLA, PGA) for treating minimally loaded fractures.

Surgical wiresUsed to reattach large fragments of bone, to provide additional stability in long-oblique or spiral fractures of long bones.

PinsUsed primarily to hold fragments of bones together and to guide large screws during insertion.

ScrewsMost widely used devices for fixation of bone fragments and to attach a metallic plate to bone.

PlatesUsed to facilitate fixation of bone fragment

Intramedullary nailsUsed as internal struts to stabilize long bone fractures.

Joint replacementsHip joint replacements

Dental implants

Polycaprolactone

Approved the use of the device under the emergency-use exemption

written informed consent was provided by the patient’s parents

The splint was manufactured from polycaprolactone

N Engl J Med 368: 21

Tracheal Brace

http://www.engin.umich.edu/college/about/news/stories/2013/may/3d-printed-splint-saves-life#inline_content_2164816

Commonly Found Degradable Biomaterials in FDA Approved Devices

Devices are approved by the FDA

Polymers are not approved by the FDA

Polydioxanone: suture clips and bone pins poly(caprolactone): contraceptives and as a suture Poly(PCPP-SA anhydride): Gliadel Wafer

poly(glycolic acid) (PGA)poly(lactic acid) (PLA)copolymer (PLGA) degradable sutures, bone pins, and drug delivery vehicles

PCL Case Study

PCL can be used for 3D printing to fill in bone defects of the face using 3D images obtained from CT scans to reconstruct a damaged area.

Would PCL be approved to fill in bone defects found in a critical defect of the femur?

Biocompatibility

Biocompatibility

The appropriate biological performance, either local or systemic, of a given implant in a specific application.

Desirable host response depends on the type of materials implanted and their intended use. It may be total inertness and no interaction with tissues surrounding the implanted materials or positive interaction resulting in active participation of the cells surrounding the materials.

Biocompatibility is a dynamic two-way process that involves the time-dependent effects of the host on the material and the material on the host. The performance of a biomaterial should not be affected by the host and the host should not be negatively affected by the implanted biomaterials.

No clear, absolute definition of biocompatibility exists yet mainly due to the fact that the biomaterials area is still evolving.

Potential side effect: Toxic, carcinogenic, immunogenic, and inflammatory responses.

Failure of Biomaterials and Biomedical Devices

1. Tissue Biocompatibility (Inflammation and Wound Healing)

2. Thrombosis (Blood Clotting)

3. Infections

Failure of Biomaterials and Biomedical Devices

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Biomaterials-Tissue Interactions

Local Interactions(at biomaterial-tissue interface)

Effect of material on host tissues

• Blood material interactions• Modification of healing• Inflammation• Infection• Tumorigenesis

Effect of environment on materialsPhysical-mechanical effects• Wear• Fatigue• Corrosion• Stress-corrosion cracking

Biological Effects• Adsorption of tissue constituents

by implant• Enzymatic degradation• Calcification

Systemic Interactions• Embolization• Hypersensitivity (itchy/redness)• Elevation of implant elements in blood• Particle transport to distal tissues

Device Associated Complications• Thrombosis/thromboembolism• Infection• Exuberant or poor healing• Biomaterial failure• Adverse local tissue reaction• Adverse systemic effect

Host Response to Injury

Placement of a biomaterial in a body requires injuring the host tissues or organs.

Mechanisms are activated to maintain homeostasis.

Injury/Implantation

Blood Material Interactions

Closely linked with inflammation.

Initial response mainly involves blood and vasculature.

Vroman effect-Proteins initially rapidly adsorb onto the surface ~10 μsec.

-Then competitive displacement of earlier adsorbed proteins with a higher affinity for the surface occurs.

-Protein adsorption can alter the protein conformation and overall function.

Blood clot formation and/or thrombus occurs.

Blood/protein deposition on the material constitutes the provisional matrix. http://andrew-white.com/research

Provisional Matrix

Blood/protein deposition on the material constitutes the provisional matrix

Consists of fibrinInflammatory products released by the complement systemActivated plateletsInflammatory cellsEndothelial Cells

Occurs within minutes to hours after implantation

Provides both structural and biochemical components during wound healing

Naturally derived biodegradable controlled release system

Components drive the repair process-inflammatory cell and fibroblast recruitment

Physiological Reviews 2003 Vol. 83 no. 3, 835-870

Inflammation

5 Cardinal Signs of Inflammation During Injury

• Heat

• Redness

• Swelling

• Pain

• Loss of function

Inflammation

The reaction of vascularized living tissue to local injury

• Contain

• Neutralize

• Dilute

• Wall Off Injurious Agent

Changes in the vascular flow and permeability

Exudation-Fluid, proteins, and blood cells escape from the vasculature system into the injured tissue

Followed by cellular events that characterized the inflammatory response

Acute and Chronic Inflammation

Annu. Rev. Mater. Res. 2001. 31:81–110

Acute and Chronic Inflammation

Fig. 8. A typical implanted cage retrieved after 21 days implantation The cage has been cut open and the inner surface is shown. Connective tissue was observed to cover the entire surface area of the mesh cage.

Fundam Appl Toxicol. 1989 Aug;13(2):217-227

Acute and Chronic Inflammation

Fundam Appl Toxicol. 1989 Aug;13(2):217-227

Acute Inflammation

Acute inflammation is of relatively short duration

The main characteristics of acute inflammation are-build up of fluid and proteins-emigration of leukocytes from blood to the injury

Opsonins (IgG) plasma derived proteins that adsorb to biomaterials

The accumulation of leukocytes is the most important feature of the inflammatory reaction

The major role of the neutrophils in acute inflammation is to phagocytose microorganisms and foreign materials

Phagocytosis is a three-step process:-recognition and neutrophil attachment-engulfment-killing or degradation

Biomaterials are not generally phagocytosed by neutrophils or macrophages because of the size disparity

Frustrated phagocytosis- release of leukocyte to degrade the biomaterial without engulfing

The amount of enzyme released depends on the size of the device. Larger particles inducing greater amounts of enzyme release.

Acute and Chronic Inflammation

Annu. Rev. Mater. Res. 2001. 31:81–110

Chronic Inflammation

Chronic inflammation is characterized by the presence of macrophages, monocytes, and lymphocytes, with the proliferation of blood vessels and connective tissue.

Persistent inflammatory stimuli: Chemical, physical, motion.

Confined to the implant site.

Macrophages process and present the antigen to immunocompetent cells and thus are key mediators in the development of immune reactions.

The macrophage is probably the most important cell in chronic inflammation because of the great number of biologically active products it produces.

Growth factors such as PDGF, FGF, TFG-β, TGF-α/EGF, and IL-1 or TNF are important to the growth of fibroblasts and blood vessels and the regeneration of epithelial cells.

Granulation Tissue

Proliferation of fibroblasts and vascular endothelial cells at the implant site, leading to the formation of granulation tissue, the hallmark of healing inflammation.

Pink, soft granular appearance on the surface of healing woundsHistological features include the proliferation of new small blood vessels and fibroblasts.

Fibroblasts synthesize collagen and proteoglycans.Early stages of granulation tissue development, proteoglycans predominate.Later collagen dominates and forms the fibrous capsule.

Observed as early as three to five days following implantation.

Primary Intention-is the healing of a clean, surgical incisions, with a minimal loss of tissue.

Second Intention- occurs when there is a large tissue defect, cannot reconstitute the original architecture (Big Scar).

Histology

Hemotoxylin & Eosin (H&E)

Hemotoxylin: basic dye that stains acidic structures blue

Eosin: acidic dye and stains basic structures red

Most proteins stain pinkNuclei stain purple

Granulation Tissue

Foreign Body Reaction

Composed of foreign body giant cells, macrophages, fibroblasts and capillaries

Surface topography will dictate the extent of the foreign body reaction-smooth surfaces have a foreign body reaction composed of macrophages and foreign body giant cells at the surface.-rough surfaces have foreign body giant cells, macrophages, and granulation tissue sub-adjacent to the surface response.

High surface-to-volume implants have a higher ratio of macrophages and foreign body giant cells at the implant sight, increasing fibrosis.

The foreign body reaction may persist for the entire life of the implant.

Foreign Body Reaction

Fibrosis/Fibrous Encapsulation

Fibrosis surrounds the biomaterial with an interfacial foreign body reaction

Consists of connective tissue

Isolates the biomaterial from the local tissue environment

End stage healing response

Exceptions to the ruleImplant site repair involves 2 processes:

-regeneration, replacement of injured tissue by parenchymal cells of the same type-replacement by connective tissue (fibrous capsule)

Extent of the injury and framework of the tissue (bone vs nervous system) determines process-cells are labile (stem cells), stable (can replicate, but not typical), or permanent (static)-all injuries to permanent cells give rise to fibrosis/loss of tissue function

Fibrosis

Tissue Reaction

Description of fibrous capsule formation around the implanted biomaterial. Activated polymorphonuclearleukocytes (PMN) release enzymes to remove dead cells, and macrophages (Mϕ) participate in the phagocytosis of foreign and cellular debris, Mϕ also stimulate fibroblasts (FB) to secrete collagen and other extracellular matrix components to form a fibrous capsule around the implanted biomaterial.

Discussion

How does the wound healing cascade effect the development of medical devices?

How does it affect the development of controlled release systems?

Thrombosis

Protein Adsorption

Hydrophobic materials:Fast adsorption which is largely irreversibleMost change in protein conformation (reduced bioactivity)

Hydrophilic materials:Slower adsorption, with significant desorption

-Protein exchange Least change in protein conformation (maintains bioactivity)

Proteins with a high surface activity will replace the protein with lower surface activity

Ex: Fibrinogen will replace albumin

Problems Associated With Biomaterials

Surface-induced thrombosis with blood-contacting biomaterials

Blood

Exposure of biomaterial to blood

Protein adsorption

Platelet adhesion: Type of blood proteins

Platelet spreading and platelet activation

Thrombus formation

Thrombus aging and embolization

Short-term surface passivation

Surface-Induced Thrombosis

Platelet adhesion Platelet spreading and platelet activation

Thrombus formation Short-term surface passivation

Glycocalyx

Cells interact with blood constantly, yet do not typically induce a thrombotic event unless there is an injury

Glycocalyx- Glycoprotein, glycolipid, and proteoglycan based covering an one side of the epithelium

Helps to mitigate non-specific protein adsorption

Inhibits cell adhesion

Also found in bacteria, and helps to shield bacteria from the immune response

Prevention of (platelet-activating) protein adsorption

Schematic description of steric repulsion exered by the surface-grafted linear polymers such as poly(ethylene oxide) or heparin (A) and globular proteins such as albumin (B).

Steric repulsion by surface-grafted PEO chains

Fibrinogen adsorption to glass surfaces grafted with various Pluronic® surfactants (L, P, and F series). The control surface was trichlorovinylsilane-modified glass. The three numbers in parentheses indicate the numbers of repeating units of ethylene oxide (EO) and propylene oxide (PO) in the poly(EO)/poly(PO)/poly(EO).

Pluronics®: PEO-PPO-PEO triblock copolymersPEO: poly(ethylene oxide)

PPO: poly(propylene oxide)

Glycocalyx Mimics

Can bind carbohydrates which are found in the glycocalyx to the surface of a material

Can reduce protein binding

Dextran and Maltose among others have been used

Low density coverage- PEG is superior because the conformational variability allows it to spread and cover more defect areas

High density coverage- Carbohydrates are theoretically better, because PEG tends to aggregate at higher concentrations

Challenges and Opportunities

Successful long-term applications of implantable materials requires prevention or minimization of surface-induced thrombosis and/or fibrous encapsulation (or isolation) of implants by the body.

While the surface modification of biomaterials with PEO, heparin, albumin, and other hydrophilic polymers appears to be promising, further systematic studies on the long-term effects of surface modification of biomaterials are necessary for the development of truly biocompatible materials.

Infection

Sterilization vs Sanitation vs Disinfection

Sterilization kills all forms of microbial life (bacteria, spores, fungi, viruses)

Disinfection destroys organisms in a non-sporing vegetative state

Sanitizing reduces organisms on a surface to make them safe for contact

Medical devices need to be sterilized before implantation into human hosts1. Steam (autoclave)2. Ethylene Oxide Vapor3. Gamma Irradiation4. Surface Methods: Ozone, formaldehyde, dry heat, electron radiation

Steam Sterilization

Process: Steam at 125°C at 3 atmospheres

Advantages: Simple and quick (~20 min)EffectiveGreat to use with non-organics, metals, glass

Disadvantages: Not for use with all polymers (can melt or soften them)Poor penetration throughout the polymerMay potentially lead to degradation of the polymer

Ethylene Oxide Sterilziation

Process: Pre-conditioning of sampleGassing/exposureEvacuationAeration (air wash)

Advantages: Can be used with many polymersMany places provide the service

Disadvantages: Ethylene Oxide is toxic and potentially explosiveCan react with carboxylic acids, alcohols, and aminesNeed to ensure complete removal of the residual gasNeed to optimize the conditions

Gamma Radiation

Process: Transmission of energy by EM waves that breaks DNA strandsSterilization is proportional to the amount of radiation absorbed1 Rad= 100 erg= 1x105 Joules absorbed energy/ gram of materialγ rays have the highest penetration in air

Advantages: No residual radiationCan use the sample immediatelyLow temperatures can be usedHigh penetration of the device

Disadvantages: Often times initiates degradation of polymer (changes the molecular weight)Can initiate crosslinkingsNeed special equipment and safety precautions

Cyclodextrin Coated Materials

Creates a pocket for hydrophobic drugs or antibiotics

Drug is not bound to the pocket and can be replaced by another hydrophobic molecule or another drug molecule

Hydrophobic compounds can hop from pocket to pocket

Cyclodextrin Coated Materials

http://dx.doi.org/10.1016/j.jss.2010.03.065

Cyclodextrin Coated Materials

Biomaterials 31 (8) 2010: 2335–2347

Commonly Found Degradable Biomaterials in FDA Approved Devices

Devices are approved by the FDA

Polymers are not approved by the FDA Polydioxanone: suture clips and bone pins poly(caprolactone): contraceptives and as a suture Poly(PCPP-SA anhydride): Gliadel Wafer

poly(glycolic acid) (PGA)poly(lactic acid) (PLA)copolymer (PLGA) degradable sutures, bone pins, and drug delivery vehicles

Rates of Degradation

Polyanhydrides degrade very quickly and are typically in surface eroding materials .

Polyesters degrade slower than polyanhydrides and the rate of water uptake is faster than the rate of polymer degradation so these devices tend to be bulk eroding devices.

Polyamides degrade even slower and are bulk eroding.

In order to create a device that was surface eroding for a polyester it would have to be 7.4 cm thick and a polyamide would need to be 13.4 m thick.

Polymer Degradation Products

PLGA degrades into both lactic and/or glycolic acid.

In healthy tissues with high clearance, these intermediates are metabolized by the body into carbon dioxide and water and show no adverse effects upon introduction of the material to the body.

If the clearance is low, elevated levels of acidic byproducts can accumulate in the tissue space.

It is important to make sure that the degradation products are not toxic.

Additives

Additives are used to modify an implant’s properties and to reduce manufacturing cost.

fillers and plasticizers are typically used to alter the mechanical properties.

Plasticizer di(2-ethylhexyl)phthalate (DEHP) has been used to soften the poly(vinyl chloride) used in blood storage bags.

-DEHP can damage the liver, kidneys, lungs, and reproductive system, particularly the developing testes of prenatal and neonatal males.

Plasticizers typically increase the flexibility of the plastic by disrupting the crystallinity.

However the effect of additives used must be carefully evaluated to insure that the additive does not induce a negative effect.

ISO10993

The ISO 10,993 standard and the FDA guidance document present a structured program for biocompatibility evaluation in which matrices are presented that indicate required tests according to specific types of tissue contact and contact duration.

CytotoxicitySensitizationHemocompatibilityPyrogenicityImplantationGenotoxicityCarcinogenicityReproductive and Developmental ToxicityDegradation Assessments