Materials Used in Bone Repair

A Look at the History of Technology and Methods Used

By Halley McLaren and Leonardo Larocca

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In this presentation we will discuss:

An overview of the material and structural properties of bone

Types of bone breaks and traditional ways to mend bone

How new materials including ceramics and polymers are breaking through the limitations of traditional bone healing practices

How stem cells and biomaterials are being used to build bone from scratch

Developing methods of the future

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Bone composition (1)

Composite phase

Organic & inorganic

Living, vascular

Composition changes over location & time

3 parts: matrix, cells, marrow

Dense cortical bone & cancellous/trabecular bone (has spaces)

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The Three Functional Divisions (1)(11)(12)

MatrixStrength/elasticity & mineral storeCollagen (protein) 70-90% of non-mineralized ECM &hydroxyapatite (HA) Ca10(PO4)6(OH)2 70% of boneNon-collagenous proteins -made by bone cells & regulate bone mineralization and remodelling

Bone CellsOsteoblasts – productionOsteocytes – maintenanceOsteoclasts – reabsorbtion of bone

MarrowOsteogenic stem cells originate here

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Structure (1) (2)

Strongest along axis which is parallel to the collagen fiber mineral crystal axes (anisotropic)

Almost as strong as steel, but lighter and more elastic

Cortical bone found on bone’s exterior & is stiff

Cancellous bone provides network of spaces for marrow

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Understanding Bone Fractures

Main categories are:CompleteIncompleteSimple (closed)Compound (open)

[22]

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Understanding Bone Fractures

[23]

Some types of bone fractures

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Problems associated with bone fractures

Blood lossVeins or arteries damaged

Injury to organs, tissues or surrounding structuresStunted growth of the bone

injury to the lining of the bone (periosteum)Specialized connective tissueBone-forming potentialities

[24]

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Traditional methods used to solve fractures

Plaster of ParisExternal fixationInternal fixation [28]

[28]

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Complications of methods

Poor alignment of the limbIncorrectly fitted plaster castInfectionInadequate stabilization after the break/fractureInadequate blood flow

These complications may not permita proper bone healing

[24]

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More susceptible areas

[26] [27]

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Biocompatibility: Titanium

Excellent corrosion resistanceWhich limits ions released into the tissue

Poor tribological propertiesInteracting with surfaces that are in relative motionSignificant release rates when sliding against another material

Production of pigmentation on the skintoxicological and clinical significance of this is not clear

[33]

[33]

[33]

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Titanium is still an intrinsically safe biomaterialMay be used with minimal risk under many well-defined conditionsIf large amounts of titanium are released as a result of enhanced wear critical level of reactivity may be reached

Biocompatibility: Titanium

[33]

[33]

[33]

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Ti-based amorphous alloysThey do not contain Al and Ni elementsExcellent potentiality of corrosion resistanceHigher strength and lower Young's modulus than pure Ti and Ti–6Al–4V (Titanium-Aluminum-Vanadium) alloy

Ex: (TixZryTaz)85Si15

Biocompatibility: Titanium Alloy

[34]

[34]

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Problems with traditional materials for bone implants (13)

E.g. plastics & stainless steel have different properties than bone (3)

May have to be replaced after a few years because of absorption (3) (5)

Invasive (3)

Surrounding real bone atrophies from not bearing weight (3)

Suppress osteogenicdifferentiation (4)

Immune response (4)

Inflammation (5)

Chronic soreness (10)

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Problems with Traditional Implants (8)(14)

The “glue” that attaches solid metal & ceramic joint replacements to bone usually wears out

Solid ceramic bone implants are made of the same materials as real bones, but real bone is hard on the outside and porous on the inside

Porous scaffolds allow real bone to grow into holes so the glue is trivial

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Grafting Versus BGSs (1)

Grafts useful for severe & large breaks with a stabilization apparatusBone grafting ideal – bone renews naturallyProblems with Grafting

Not enough supply for demande.g. hip repair may take 4-6 femoral heads

Auto graft risks weakening another boneRisk of disease & ethical issues

Bone graft requirementsOsseointegrationBe osteoconductiveBe osteoinductive

Many synthetic bone-graft substitutes (BGSs) can fit all these requirements and be produced limitlessly

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What is required of a material for use in bone repair? (1) (3)

2 Main Design Consideration Groups:

Chemistry & BiocompatibilityThe scaffold either needs to be biodegradable for new bone to take its place, or remain in the bodyBe active in promoting the differentiation of stem cells

Specific Mechanical PropertiesThe scaffold has to have a porous network to encourage bone and vascular growthHave enough strength to bear appropriate weight

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Analysis of a few bone graft substitutes:

Synthetic polymers

Collagen-hydroxyapatite composite (both naturally occurring in bone)

Nano bones

Stem Cells

Bones created from sea-water-frozen scaffolds

Biomaterial ink jet printer

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Synthetic Polymer Scaffolds (4)(15)

AdvantagePore size can be easily controlled Some patented compositions claim to be non-toxic

DisadvantagesChemicals such as additives or traces of catalysts may be released from the polymer & cause adverse reactions Polymeric scaffolds can often take a few years to degrade whereas collagen-HA composites may only take a few months to a year Osteogenic cells fuse better to collagen surfaces than polymers

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Collagen (4)(16)

StrengthsCollagen is naturally occurring in bone and thus is biocompatibleIt is easily broken down and reabsorbed within the body

WeaknessHas low mechanical properties (E ~100 MPa) compared to bone (E ~2-50GPa)

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Hydroxyapatite (HA) (7)(19)

HA is classified as a ceramicSynthetic HA has a similar composition to HA found in boneStrengths

BiocompatibleOsteoconductive

Weaknessfragile and weaker than cortical bone

Useful for dental fillings or coatings on implanted bones where there is not a lot of stress

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Collagen & HA Composite (4)(1)

Extra-cellular matrix is 95% collagen and HATogether they have better mechanical properties than one material alone

Collagen is ductileHydroxyapatite is brittle

Individually, they influence osteoblast differentiation Together they enhance:

osteogenesisosteoconductive properties

Many different patents on this composite material

Different size/number of poresDifferent ratio of materialsSource of collagenDensityDefect chemistry of HAParticle size

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Three Methods of Fabrication (4)(17)

Method 1: Collagen-HA Heat Gels

Liposomes have a polar phospholipid layer Can deliver water-soluble drugs & materialsCalcium and phosphate ions can be held in liposomes & added to collagen acidic gel suspensionGel inserted into skeletal defectBody heat initiates gel formation A collagen fibrous network forms & minerals start to deposit

Method 2: Water/Oil Suspension

Collagen-HA gel beads are used as injection bone fillersA collagen suspension is mixed with powdered HAWhen heated & mixed in olive oil, collagen fused & remodeled shapeDisadvantages:

Cannot remove all the oil when doneViscosity of injection mixture too low when in contact with body fluids –not stable

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Method of Fabrication 3 (4)

Critical Point ScaffoldsForms porous matrixIce crystals form between collagen fibresAt CP liquid & vapour appear identicalUnique pressure & temperature Above CP surface tension is small - minute matrix collapseCO2 (31.1°C, 7.3MPa) has lower CP than H2O (364°C, 22.1MPa) –preferredBenefits:

Low residueEasy ice removalPore size determined by:

• Freezing rate• Solubility of the

suspension• Collagen concentration

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NanoBones (5)(18)

Main material is calcium phosphorus on the scale of 30 nm x 60 nm

The key is that:On a large scale calcium phosphorus will not degradeOn a nanoscale calcium phosphorus does degrade

Nanoscale material degrades after 6 months and natural bone fills gaps

Successful trials & approved by China's & Germany’s FDA & has a good chance to be approved by U.S. FDA

Experimenting being done with nanotechnology for repair of brain and the liver

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NanoBones (5)(18)

AdvantagesRemain in body for a relatively short period of time Lowered risk of infectionNo operation for removalLowered risk of breakage of new boneLess pain

DisadvantagesHas only been proven effective on small bones less than 2 cm

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Ceramics and Stem Cells

Technology that combine cells capable of osteogenic activity with an appropriate scaffolding material

Human mesenchymal stem cells (hMSCs) combined with hydroxyapatite/b-tricalciumphosphate (HA/TCP) ceramic scaffolds20%HA / 80%TCP induce bone formation in large, long bone defects

[35]

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Stem Cells

OverviewEmbryonic stem cells

Can differentiate into all of the 220 types of cells found in the human body

Adult stem cellsLimited in flexibilityResearch using adult stem cells has a two decade head start on embryonic stem cells

[29]

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Bone healing with Mesenchymal Stem Cells (MSC)

The MSC is the basic cellular unitBone regeneration mimics bone healing and can be achieved with MSC combined with strategies of:

OsteogenesisOsteoinductionOsteoconductionOsteopromotion

[32]

[32]

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MSC and their progeny respond aggressively to local mechanical forces:

low-to-moderate magnitudes of tensile strain and hydrostatic tensile stress may stimulate new bone formationThis occurs because of deformation or elongation of cellsCellular deformation results in intracellular signals, which in turn encourage regenerating cells to proliferate and follow an osteoblastic lineage

Bone healing with MSC [32]

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The effect of the mechanical environment on bone regeneration

Compressive forces: chondrogenesis is favoredTensile forces: osteogenesis is favored

[32]

Bone healing with MSC

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The effect of the mechanical environment on bone regeneration:

distractive forces: osteogenesis is favored

[32]

Bone healing with MSC

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The effect of the mechanical environment on bone regeneration:

Several strategies have been employed to impart an optimal mechanical environment for osteopromotionOrthopedic fixation devices [32]

Bone healing with MSC

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Bone healing with MSC [32]

[32]

Immunologically privilegedThese techniques utilize osteoconductive and osteoinductive carriersMSC can be manipulated and combined with carriers that will result in bone regeneration of critically sized bone defects

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Improving on Stem Cell Implantation

Bone marrow is taken from the patient, processed, & stem cells are transplanted into fracture site

At least 40,000 people have already been treated by this method

Method can be improved by increasing survival and creation of transplanted cells – just about 1 in 20,000 bone-marrow cells is a bone-producing stem cell

Comb scaffolds containing epidermal growth factor (EGF) help survival rate

A goal is to be able to remove bone marrow from a patient & immediately separate the stem cells in a scaffold enhance their growth & survival, then implant the cells into the patient.

[36]

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Sea Water Scaffolds (6) (10)

Seawater freezes to make a porous framework with wafer-like layers

Mirrors intricate structure of nacre (mother of pearl-CaCO3)-finely layered, found in mollusk shells

Nacre’s construction in the mm scale differs from its’ nm scale

Freezing a watery suspension of HA concentrates the HA in the spaces between the ice crystals which makes nacre-like layers

Increasing the rate freezing reduces the size of the layers

Smallest size developed so far is 1 micron, whereas nacre is ½ a micron

Nature’s architecture with scientists selection of materials

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Sea Water Formed Bones (6)

StrengthMechanical strength is 4 times stronger than traditional HA scaffoldsLightweightRough layers help adhesionSpace between layers can be filled with organic polymer that degrades over weeks to release antibiotics & bone growth stimulating compoundsBone fills pores

WeaknessCurrently in experimental stage

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Biomaterials Ink Jet Printer - Background (9)

Exact shapes of gaps in bone are printed and inserted into body

Grafts are printed layer by layer to mock real bone structure

“Paper” = thin bed of cement-like powder

“Ink” = acid and more cement powder

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Ink Jet Printer (9)(20)

Advantages

Takes around 10 minutes to print

Printer is only around 1-2 sq m in size

Graft is biocompatible (made of similar materials to real bone) , will dissolve & be replaced by new bone

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Ink Jet Printer (9)(21)

Daily Mail Very big advantageHoles in graft can be precisely deignedBone can be channeled to grow in a specific direction

cosmetic surgeryreconstructive surgery Spinal surgery

DisadvantageThis technology is still far from being an established method

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Summing up the materials

There is no definitive material or method used for bone repair that will always yield the best results. The size and the severity of the damage are factors will influence the type of bone repair implemented. The technology is continuously changing.

The movement away from old bone repair techniques to dissolving scaffolds is promising because:

Biocompatible materials and scaffolds that mimic natural bone structure will integrate better with bone & support new growthNo need for replacement Less invasiveReal bone is strengthenedReal bone eventually replaces scaffoldLess chance of a negative immune responseNot as painful

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References(1) Hing, Karin A. (2004). Bone repair in the twenty-first century: biology, chemistry or engineering? The Royal Society(2) Florence Barrère, Clemens A van Blitterswijk, and Klaas de Groot. (2006). Bone regeneration: molecular and cellular interactions with calcium phosphate ceramics. Int J Nanomedicine.(3) Cambridge-MIT Institute funds artificial bone research 2002 [online] Available: http://www.admin.cam.ac.uk/news/dp/2002020401(4) Wahl DA and Czernuszka JT. 2006 Collagen-HydroxyapatiteComposites For Hard Tissue Repair. European Cells and Materials Vol. 11. (pages 43-56)(5) Chinese researcher ready to 'bring nano bones to the world. 2003. [online] Available: http://www.smalltimes.com/Articles/Article_Display.cfm?ARTICLE_ID=268840&p=109(6) Krotz, D. Secrets of the Sea Yield Stronger Artificial Bone. 2006. Research News Berkley Lab. [online] Available: http://www.bio-medicine.org/biology-news/Secrets-of-the-sea-yield-stronger-artificial-bone-2859-3/

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(7) Schenberger, D. (2008) Bioceramics: The Future of Joint Healing. Med-Tech Precision [online] Available: http://www.devicelink.com/mtprecision/archive/08/04/008.html(8) Knee bone connected to the … artificial bone. Texas A&M Engineering ~ Engineering Works. 2008. [online] Available: http://engineeringworks.tamu.edu/?p=93(9) Mayne, Eleanor. The artificial bones made from an inkjet. Daily Mail.Apr. 14, 2007.http://www.dailymail.co.uk/pages/live/articles/news/news.html?in_article_id=448654 (10) Deville, S., Saiz, E., Nalla, R.K., Tomsia A. P. Freezing as a Path to Build Complex Composites. January 27, 2006 Science.(11) www.virtualmedicalcentre.com (no date) [online] Available: www.virtualcancercentre.com/Treatments.asp?sid=22(12) National Institutes of Health Cells 1/STS-59 (no date) [online] Available: lis.arc.nasa.gov/.../NIH_C/NIH_C1.html

References

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(13) Computer Aided(Assisted) Knee Replacement Surgery - Why India Hospitals & Surgeons. Wednesday, January 30th, 2008. [online] Available: http://www.medicaltourismco.com/medical-tourism/tag/computer-aided-total-knee-arthroplasty/(14) OsseoTech Weekly Update. Tuesday September 26th, 2006 [online] Available: www.osseotech.com/?tid=5(15) Biodegradable porous polymer scaffolds for tissue engineering prepared from an effervescent mixture and its preparation. 05/13/2003 [online] Available: http://www.freepatentsonline.com/6562374.html(16) Elmer,P. (5 November, 2001) Bath leads research into new knees. [online] Available: www.bath.ac.uk/pr/releases/newknees.htm(17) Biological membranes [online] Available: scienceinyoureyes.memphys.sdu.dk/liposome.gif

References

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(18) NanoBone® remodelling : Bone Grafting Material Nanotechnology for strong bones. (06/2005) [online] Available: www.artoss.com/redaktion/download.php?id=10&type=file(19) Hydroxyapatite. (28 August 2008 )[online] Available: http://en.wikipedia.org/wiki/Hydroxyapatite(20) Bioprinters vs. the Meatrix. (2006). [online] Available: www.boingboing.net/2006/12/19/index.html(21) Erin McCarthy E. (December 12, 2006) Bio-Inkjet Printer Draws Muscle and Bone. Popular Mechanics.

References

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[22] Understanding Fractures – Basic, Available: http://www.webmd.com/osteoporosis/ [June 01st, 2007][23] Classification of Broken Bones and Fractures, Available: http://pain.health-info.org/Pain%20Pages/fractures.htm [1996][24] Bone Fractures, Available: http://www.betterhealth.vic.gov.au/ [June 2008][25] Dorland's Medical Dictionary for Health Consumers[26] Image: http://apps.uwhealth.org/health/adam/graphics/images/en/19625.jpg[27] Images: http://www.fotosearch.com/photos-images/tibia.html[28] Treatment of Infection Following Bone Fractures or Trauma at Our Southern California Practice, Available: http://www.osteomyelitis.com/html/trauma-infection.html [2007][29] Stem cell research: All viewpoints, Available: religioustolerance.org/res_stem.htm[30] Stem Cells, Available: http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/ [December 30th, 2007]

References

48

[31] Gladstone scientist's Japan lab reprograms human adult stem cells, Available: http://www.bizjournals.com/sanfrancisco/stories/2007/11/19/daily12.html?page=1 [November 20th, 2007][32] Karl H. Kraus, Carl Kirker-Head, Mesenchymal Stem Cells and Bone Regeneration, Veterinary Surgery[33] Williams, D. F. (1994). Titanium: epitome of biocompatibility or cause for concern. Journal Bone Joint Surgery, 76-B, 348-9[34] Oak, Jeong-Jung and Inoue, Akihisa (2006). Attempt to develop Ti-based amorphous alloys for biomaterials. Materials Science and Engineering: A, 449-451, 220-224[35] Arinzeh, T. Livingston (2004). A comparative study of biphasic calcium phosphate ceramics for human mesenchymal stem-cell-induced bone formation. Biomaterials, 26, 3631–3638[36] Healing Bone with Stem Cells, Available: http://www.technologyreview.com/Biotech/18274/ [March 07th, 2007]

References