MedicalDeviceTechnologyGroupProject

3DPrintedChitosan/PLAScaffoldforArticularCartilageRepair

CarolineBannon 15200136

StephHastings 11301611

PhilipHenry 15203444

MarthaGoodwin 11415732

RachaelFagan 15203209

TableofContents

1.0ExecutiveSummary................................................................................................................1

2.0ProductandSurgeryProcess.................................................................................................2

3.0Introduction............................................................................................................................3

3.1Whatis/arethecoretechnologiesintheapplicationspacebeingtargeted?..................4

3.2ACI.......................................................................................................................................4

3.3MACI...................................................................................................................................4

4.0NewProductTechnology.......................................................................................................6

4.1Advantages.........................................................................................................................7

5.0CurrentUsers..........................................................................................................................7

5.2CausesofArticularCartilageDamage................................................................................8

5.3InfluenceofGenderonCoreUsers....................................................................................8

5.4SurgeonsasCoreUsers......................................................................................................9

5.5SurgicalTreatmentsforArticularCartilageDamage.........................................................9

6.0Whatadditionaltechnologiesand/orfunctionalitycouldbeincorporated?.....................10

7.0CoreUserNeeds...................................................................................................................12

7.1Current..............................................................................................................................12

7.3Market..............................................................................................................................14

7.4Increasedcosteffectiveness............................................................................................15

8.0RegulatoryPathwayandIntellectualProperty....................................................................15

9.0Pre-clinical&ClinicalValidation...........................................................................................17

9.1Overview...........................................................................................................................17

9.2Pre-ClinicalValidation.......................................................................................................18

9.3ClinicalValidation.............................................................................................................19

10.Conclusion............................................................................................................................20

11.References............................................................................................................................21

SectionsCompletedbyPerson:..................................................................................................27

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1.0ExecutiveSummary

The following report details a new product development project proposal within the

orthopaedicmedicaldevice space. Theproposedmedicaldevice is specificallydesigned in

addressingarticularcartilagedamageofthekneeandutilizesnoveltechnologies,suchas3D

printingandbio-absorbentmaterials.Thereportexaminesindetailthecoreusers,product

design, potential market, regulatory pathway, intellectual property capture and validation

requirements.Thekeypointsandfindingsaresummarizedbelow:

KeyPoints:

1. Cartilageisfoundinmanypartsofthebodyandcanbedamagedfromanumberof

causes.Damagedcartilagecanleadtoseverepain,swellingandlossoffunction.

2. Autologous Chondrocyte Implantation (ACI) and Matrix-assisted Autologous

Chondrocyte Implantation (MACI) are two commonly used surgical procedures to

assistinarticularcartilageregeneration.

3. Themainissueassociatedwiththeseproceduresistheneedforsurgeonstomanually

manipulatescaffoldstosize.Thisisatimeconsumingprocessandthecauseofmost

ACIandMACIcomplications.

4. Theproposedproduct isa3Dprinted,chitosan-polylacticacidbased,bio-absorbent

scaffolddevelopedformoreaccuratefittings.Thescaffoldmeasureswillbeobtained

usinginformationfromanMRIscan.

5. Theproductconcept (3Dprintedscaffolding)couldbeused inanexpanded fieldof

applications including; volumetric muscle loss surgery, talus repair surgery and

vertebraecartilageregeneration.

6. A sizeable market exists for cartilage repair, particularly as the number of trauma

relatedsportsinjuries,obesityandpatientssufferingfromosteoarthritiscontinueto

grow.

7. MACIcontinuestogrowinpopularityasanarticularcartilagerepairsurgeryduetoits

regenerativeadvantagesovertraditionaltechniques.

8. As a bio-absorbable device with a lifetime longer than three months, the product

wouldbeclassifiedasaclassIIIdevice.However,similarbiomaterialsproductsinthe

orthopaedicspacehavealreadybeengrantedFDA-approvalandpatented.

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9. Clinical validation studies will be required using the Knee Injury and Osteoarthritis

outcome score (KOOS) over a long-term study. MACI has been a long approved

procedurewhichwilllikelysimplifyvalidationprocedures.

2.0ProductandSurgeryProcess

Figure2.1:Processflowofsurgeryincorporatingnew3Dprintedscaffoldproduct.

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3.0Introduction

Cartilageisaflexibleconnectivetissuethatisfoundinmanyareasofthebodyincluding;the

jointsbetweenbones,theendsofribs,betweenthevertebraeinthespine,intheairwaysof

the upper respiratory tract and external structure of the ears and nose. Cartilage is

composedofchondrocytesembeddedwithinanextracellularmatrixconsistingofcollagen,

elastinfibersandproteoglycan.Nutrientsaresuppliedtothecartilagethroughdiffusionfrom

theperichondriumintothecartilagecore.Cartilageregenerationfollowingtraumaorinjuryis

limited due to a lack of vascularity and nerve supply, immobility of chondrocytes and a

restricted capacity of mature chondrocytes to proliferate, making it more difficult for

surgeonstorepair(Newman,1998).

Figure3.1:Left:Articularcartilageinahealthyknee.Right:Defectivearticularcartilageofadamagedknee

(eorthopod.com).

Articularcartilageisathin layeroftissueinvolvedinthelubricationof joints,preventionof

bone-to-bone friction and the transmission of loads to the subchondral bone. This can be

seen in figure3.1 above. The resident cell type is the chondrocyte. If damaged, thebone

endsbecomeexposedandrubagainsteachothercausingpainandswelling.Preventionof

chondral defects is paramount to the health of the joint in order to maintain flexible

movement(Foxetal.,2009).

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3.1Whatis/arethecoretechnologiesintheapplicationspacebeingtargeted?

Autologous Chondrocyte Implantation (ACI) surgery andmore recentlymatrix-assisted ACI

(MACI)arerestorativetreatmentsusedtomanageisolatedarticularcartilagedefectsofthe

knee. The objective of these treatments is to regenerate a hyaline-like tissue and restore

functionandmovementtothearticularsurface.

3.2ACI

Thefirstsurgicalprocedureisaminimallyinvasivearthroscopywherethepatient’sowncells

areharvestedfromthenon-weightbearingareaoftheknee.Afterthecellsareculturedfor

4-6weeks,opensurgery isperformedwherebya small incision ismadeover thedamaged

cartilage.Thechondrocyteculturesuspensionisimplantedintothedefectunderaperiosteal

patch.Thepatch issuturedoverthedamagedareaandmustbewater-tighttocontainthe

suspension. The cells adhere to the patient’s knee to form a hyaline-like cartilage that

resemblesthenativejointcartilage.

Issues commonly associated with this procedure include uneven cell distribution and

potential cell leakage. The periosteal harvest can also be technically challenging and can

increaseoperativetimes,particularlywithlesionsthataresituatedinaposteriorlocation.A

new technique using chondrocytes attached to a scaffold was subsequently developed to

overcometheseproblems(DunkinandLattermann,2013).

3.3MACI

Similar toACI, cellsare firstharvested fromthe joint.Cellsare thencultivatedandseeded

onto a sterile collagen membrane (porcine type I/type III collagen bilayer) biodegradable

scaffold. One side of the scaffold hosts a rough surface, due to the chondrocytes being

seeded between widely-spaced collagen fibers. The other side is smooth as the collagen

fibersaretightlypackedandthereisalargerdensity.Thescaffoldisthenimplantedintothe

defectedareaandovertime,restoresthecartilageandflexibilityoftheknee.Fibringluecan

be used to secure the scaffold to the base of the defect. This technique does not require

sutures or periosteal harvesting. There is less exposure compared to ACI and the

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implantationandfixationarefacilitated,thusitcanbeperformedmorequicklyandmayalso

beperformedalongsideligamentousreconstructionandbonegrafting(Bartlettetal.,2005).

Currently the surgeon debrides the calcified cartilage layer without disrupting the

subchondral boneusing a round-eye sharp curette. The area ismeasuredwith a template

andthescaffoldissizedtofitthetemplate.Thescaffoldmustnotriseovertheborderofthe

articularmargins.ThisdiffersfromtheoriginalACImethodwherethemembranehastospan

thedefect.Thedeviceisinsertedintothelesionwiththeroughsidefacedownandsecured

withglueoradditionallywithsuturesandanchorstoavoiddelamination.Digitalpressureis

used to confirm fixation to the subchondral bone and adjacent cartilage (Dunkin and

Lattermann 2013). For some lesions the MACI implant can be delivered arthroscopically,

however,long-termstudiesarerequiredtoassesstheefficacyandsafetyofthismethodas

analternativetomini-arthrotomy(Corteseetal.,2012).

3.4NewProduct

Whenascaffoldispresentedtothesurgeon,he/shemusttrimitaccordingtothetemplate

measurements. It must match the size of the defect and not extend over the rim of the

margins.Itisthenfittedintothelesion.Thisistimeconsumingandcumbersomeforboththe

patientandsurgeon.Thishasprovidedtherationaleforthedevelopmentofanewmedical

device.

The company aims to improve the MACI technique by utilizing 3D printing to create a

customizedimplantoftheexactsizeandshapeofthepatient’sdefect.

AnMRIscanwouldidentifythecartilageloss.A3Dprinterwouldthengenerateascaffoldof

the exact size and depth indicated by the scan thatwould be needed by the patient. The

patientcellswouldbeseededontothescaffoldtoproduceacartilagemodelreplicatethat

wouldinsertintothelesion.Theaccuratelysizedscaffoldwouldnotneedtobemanipulated

bythesurgeonandso,couldbedirectlyplacedintothedamagedarea.Itwouldbelesstime-

consumingforthesurgeon,decreaseoperativetime, improveoverallsafetyforthepatient

andpotentiallyreducefailurerates.Therewouldalsobelesschanceofthescaffoldmoving

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andapotentialdecreaseinpossiblesideeffectsincludingtissuehypertrophy,infectionsand

theneedforadditionalsurgery(Jacobietal.,2011).

4.0NewProductTechnology

Solid freeform fabrication enables the manufacture of personalized 3D constructs. The

implantswouldbebuiltlayerbylayer.Theapproachwouldinvolve:

1. Generatinga3Dcomputermodele.g.fromanMRI.

2. Slicingofthemodelinto2Dimages.

3. Manufacturingthemodelthroughalayer-by-layerprocedure.

4. Adjusting the devicewith post-procedures including surface adjustments (Chia and

Wu,2015).

A chitosan-polylactic acid (PLA) blend would be utilized to produce the 3D scaffold. The

structurewouldbegeneratedvialayer-by-layerdeposition.

Partialdeacetylationofthenaturalpolysaccharidechitingeneratestheformationofchitosan.

Chitosan is a desirable contender for cartilage regeneration due to its biocompatibility,

biodegradability,hydrophilicity, resorbability,plasticityand its architectural resemblance to

theglycosaminoglycanslocatedintheextracellularmatrix.Chitosanalsohasanantibacterial

propertywiththepotential toreduce infectionrates.The3Dporousscaffoldenhancescell

adherence, growth and migration. Chitosan however, also has a number of limitations

includingitslackofmechanicalstrengthanditsunstablenature(Lietal.,2015).

PLAisasyntheticpolymerthatdemonstratespredictablemechanicalfeaturessuchastensile

strength, elasticity and a controllable degradation rate. These characteristics are both

predictableandreproducibleandhavecontributedtoitsriseinpopularityasacomponentin

tissueengineering(Dhandayuthapanietal.,2011).

This hybrid scaffold would ensure that the natural chitosan component would provide

favourable biological functions while the synthetic polymer would augment mechanical

strengths, increase processabilitywhilemaintaining regulated degradation rates (Doet al.,

2015).

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4.1Advantages

The primary advantage of 3D printed scaffolds is that they can bettermimic native tissue

structure, function and biomechanics. The scaffoldwould aim to cover larger pore size to

produce sufficientmatrix components. It would take into account pore size, surface area,

protein coating, movement, diffusion and flow rates, which can have an impact on cell

seeding, adherence and proliferation (Rosenzweig et al., 2015). As previously mentioned,

bothchitosanandPLAattaindesirablepropertieswithintheapplicationoftissueengineering

(Lietal.,2015).

The3Dprinterwouldallowrapidarchitecturedesign,producingtheproductinanumberof

hourscomparedtotraditionalmethodsofproducingitemsthatrequireshapingandforging

fromanywherebetween4-6weeks.Thisapproachproduceshighlyreproducibleconstructs

with optimal geometry for maximizing the cell proliferation and matrix formation in the

tissue of choice. The flexibility, elastic properties and resorbability of the material would

provide the implant with the correct structure and function required for cartilage repair

(Rosenzweigetal.,2015).

Duetothegeneralconsensusthatlocationofthelesionhasnosignificanteffectonrecovery,

this3Dprintingscaffoldcanthereforebeappliedtoanysizedefectandisnotlimitedtothe

knee(Basadetal.2014)

5.0CurrentUsers

5.1TypesofCartilageDamage

Patientssufferingfromarticularcartilagelesionsanddamagewouldbetheprimaryusersof

this technology. Two chondral phenotypes of articular cartilage lesions exist, classified by

their attributing factors (Chubinskaya et al., 2015). The first are focal articular cartilage

lesions,whichoccurasa resultof trauma,osteochondritisdissecansorosteonecrosis from

excessive alcohol consumption. Degenerative articular lesions on the other hand usually

developovertimeasaresultofligamentinstability,minusculetearsandosteoarthritis.

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5.2CausesofArticularCartilageDamage

Trauma is the most common cause of articular cartilage damage from sports, falls and

accidents. The shearing forces from trauma cause stress fractures through the cartilage

matrixwhich canbecome further damaged. Trauma induced articular cartilagedamage is

most commonly found in patients between the ages of 20 – 40 as a result of sporting

activities(McCormicketal.,2014).FurtherriskfactorsincludeaBodyMassIndex(BMI)over

30andatotalbodyweightinexcessof225lbs.

After theageof 40, osteoarthritis is theprimary causeof cartilagedamageand can cause

chondral lesions of varying depths and shapes. Thirty million people in the USA are

estimated to suffer from osteoarthritis, with approximately one-hundred million suffering

globally.TheannualfinancialcostofosteoarthritisintheUSAisinexcessof$15.5billionUSD

(Bhatia et al., 2013). Ageing populations, combinedwithwith growing levels of obesity in

westernsocietiesareexpectedtosignificantlyincreasethenumberofpersonssufferingfrom

osteoarthritis. Consequently, joint inflammationandcartilagedamageareexpectedtorise

accordinglywiththenumberofosteoarthritissuffers(Bhatiaetal.,2013).If leftuntreated,

either formof cartilage damage leads to stiffening of the subchondral bonewhich in turn

resultsinreducedshockabsorptionandmatrixdegradation.Lesionsinweightbearingjoints,

such as the kneebecomeabradedover time, leading to further pain, loss of function and

potentialmeniscusandligamentdamage(Willersetal.,2003).

5.3InfluenceofGenderonCoreUsers

Studies have demonstrated ACI andMACI to be an effective treatment in bothmale and

females for full thickness cartilage repair (Zhengetal., 2007,Gilleetal., 2013). However,

somestudieshighlightdiscrepancies in recovery timeofpatientsofdifferentgenders. For

example, one study conducted in 2013 found that following ACI surgery, males achieved

significantly better results in the Lysholm score (a scale used to evaluate the success of a

knee surgery) after six-twelvemonths recovery, compared to females (Kreuzet al., 2013).

Similarly,Filardo (etal.,2013) foundbettercartilageandkneehealth inmen ina five-year

postoperativestudy,comparedtowomen.Itishighlightedhowever,thatingeneralwomen

moreoftenhavehadmoreunfavorableconditionsrelatingtothecauseandsiteofinjuries.

Both studies conclude in detail that while these operations have proven generally more

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effective formen, women still have high probabilities of successful cartilage regeneration

(Filardoetal.,2013).

5.4SurgeonsasCoreUsers

While patients are the core users and beneficiaries of this novel MACI technique, the

surgeonsperformingtheoperationcanalsobeconsideredcoreusers. Oneissueidentified

by orthopaedic surgeons regardingMACI operations was the need tomanually shape the

insertedstructuralimplant(Basadetal.,2015).Thishasbeenidentifiedastimeconsuming

duringoperationsandanareaofpotentialerror,withincorrectlyshapedimplantspotentially

leading to loosening, infectionand ineffectivecellular integration (Basadetal.,2015). It is

hopedthatusinga3Dprinted3Dstructurewillreducetheserisks, improveintegrationand

benefitsurgeonsbyallowingforasimplerprocedure.Indoingso,peripheraluserswillalso

benefit,withreducedpressuresonhospitalstaffandsupportingfamilymembers.

5.5SurgicalTreatmentsforArticularCartilageDamage

Treatment of articular cartilage lesions still remains challenging for orthopaedic surgeons.

Currently, a range of treatments exist including; palliative treatments (chondroplasty)

arthroscopic lavage, microfracture and osteochondral grafting (McCormick et al., 2014).

However, as articular cartilage does not possess a blood supply, the cartilage has a highly

limited ability to regenerate. As a result, these procedures usually result in fibrous

regeneration (fibrocartilage), which fails to provide the same biomechanical support of

hyalinecartilageneededtowithstandthepressuresplacedontheknee(Chubinskayaetal.,

2015).McCormicketal.examinedtrendsinsurgicaltreatmentsforarticularcartilagelesions.

Itwasfoundbetweentheyearsof2004-2011,1,959,007operationswereperformedtotreat

cartilage lesions. While palliative treatments were used inmany cases,McCormick et al.

discusses the growing trends of regenerative treatments, such as matrix autologous

chondrocyte implantation (MACI),and their improved role inpain reliefandability toalter

the progression of degenerative cartilage damage. While McCormick does highlight

consistent five percent annual increases in use ofMACI since 2004, bothMcCormick and

D’Anchise(2005)argueaworryinglevelofroutineapplicationofchondroplastyexistsinthe

surgicalcommunity,despitetheabsenceofsuperiorityasatechnique.Severalstudieshave

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in fact foundMACItobethetreatmentofchoiceforarticularcartilage lesion,withgreater

painreductionandtheapparentcapabilitytoregeneratehyalinecartilagecells(D’Anchiseet

al., 2005, Behrens et al., 2006). Additionally, MACI proves a more attractive procedure

compared to total knee replacement in patients under the age of thirty-five who have

developedcartilagedamageasaresultoftrauma.This isduetotherisksof looseningand

theneedforfurtheroperationsafterten-fifteenyearsofwear(Weinsteinetal.,2013).

6.0Whatadditionaltechnologiesand/orfunctionalitycouldbeincorporated?

Scaffolds are playing an increasingly important role in tissue regeneration solutions.While

differenttissuetypeshavedifferentrequirementsforregenerationsuccess,strongsupport,

biocompatibilityandenhancementofbiomechanicalfunctionarethemaincharacteristicsof

a useful tissue repair scaffold (Charge and Rudnicki, 2004; Smith and Grande, 2015). As

previously discussed, the application of 3D printing in scaffold development could offer

improved personalisation, facilitating enhanced fixation, integration, and ease of surgical

procedure.However,3DprintedscaffoldsarenotlimitedtoMACIsurgery.

MusculoskeletalproblemsarehighlyprevalentintheU.S,with>50%oftheadultpopulation

reportingsomeformofmusculoskeletalissuee.g.acutetendon,bone,ligament,cartilageor

meniscus damage (Smith andGrande, 2015).While a host of surgical procedures exist for

musculoskeletal issues, the field of tissue engineering is growing rapidly, with particular

interestintissueregeneration.

One recent study details the use of scaffolds in a number of patients suffering from

volumetricmuscleloss(Sicarietal.,2014).Inmostcases,humanskeletalmuscleiscapableof

regeneratingfollowinginjury.However,followingserioustraumaorsurgery,weakenedscar

tissueiscommonlyformedinstead(ChargeandRudnicki,2004).Scaffoldswereemployedto

aid surgeons in the ease of handling and precise placement of cells and growth factors

(Figure6.1). Asaresult, thebiologicscaffolds,composedofmammalianECM,promoteda

constructive,functionalskeletalmuscleresponse.Sixmonthsfollowingsurgery,allpatients

showed abundant small blood vessel vascularization, improved muscle density and

moderately well developed connective tissues. Additionally, subjects demonstrated 25%

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improvements in force production in the damaged limb six months after scaffold

implantationsurgery(Sicarietal.,2014)

Figure6.1:Theuseofscaffoldsinvolumetricmusclelosssurgery.

3D printed scaffolds could also be utilized for intervertebral disc degeneration. In theU.S,

treatmentofbackandneckproblemsincursaneconomicannualcostof$90billion(Hudson

et al., 2013). Intervertebral disc degeneration is the driver of back pain with 4/5 people

enduringthepainduringtheirlifetime(Hudsonetal.,2013).Adegenerativediscoccursdue

to aberrant structural failure, in concurrence with the aging process, though this may be

accelerated. Excessivemechanical loading interrupts the structure of the disc, triggering a

signalingcascadeleadingtofurtherdisorder.Similartothearticularcartilageintheknee,the

discisalsoavascularwithlimitedself-regenerationcapacity(AdamsandRoughley,2006).

Intervertebraldiscs(IVDs)compriseoftwosections,thecentralgelatinousnucleuspulposus

and the outer fibrocartilaginous annulus fibrosus (AF). Scaffolds made of biodegradable

syntheticsorbiologicmaterialsthatmimicthetworegionsareshowingencouragingresults

in early clinical trials (Hudsonet al., 2013).A recent studybyXuet al., (2015)used tissue

engineering toproduceabiphasicscaffoldusingbonematrixgelatin (BMG) to replicateAF

andacellularcartilageECM(ACECM) for theNPsection.Thescaffoldswere implanted into

mice and monitored over a period of 6 weeks. A microenvironment was created that

sustainedcell adhesionandgrowth.However, further research surroundingECMsecretion

andmechanicalstabilityofthe implantneedstobeconducted.3Dprintingofthescaffolds

wouldenhanceconstructfixationandpotentiallycontributetothetherapeuticprospectfor

degenerativedisctreatment.

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These cases have been presented as examples demonstrating the host of applications 3D

printing could be used for in the future, particularly in the areas of implantology and

regenerativemedicine.

7.0CoreUserNeeds

7.1Current

The primary goal of the matrix-induced autologous chondrocyte implantation (MACI)

procedureistorepairthedamagedarticularcartilagewithinajointinsuchawaythatitwill

berestoredto itsnormalfunction,causing less irritationandpainforthepatient. Indoing

so, it is possible toprevent furtherdamagewhich could lead to severe conditions such as

osteoarthritis, osteochondral injuries and patellofemoral syndrome etc. By re-creating a

hyaline-tissue cartilage structure, compatible with the body, it is possible to regenerate

damagedcartilage.Anothercoreaspectoftheimplantationisensuringareasonablesurvival

timethatcanbeseenwithmonthly followups.Followingany implantationprocedure, it is

important that full integration of the surrounding tissue is obtained, lowering the rate of

rejectionontheimplant(Konetal.2012)(Zhouetal.,2014).

7.2UnmetNeeds

The popular method of matrix-induced autologous chondrocyte implantation (MACI) has

beenvery successfulover thepast fewyears for repairingdamagedarticularcartilageasa

result of injury or trauma etc. Although MACI has been able to overcome some of the

challengesassociatedwitharticularcartilagerepairtherearestillsomeunderlyingissuesand

disadvantagesthatsuggestthepotentialgapinthemarket. Oneofthemainstagesofthis

procedureasmentionedpreviouslyinvolvescuttingaroundthecollagenmembraneinorder

tofittheimplantintothecorrectshape.Itiscrucialthatthatthemembranedoesnotextend

overtherimofthemargins.Unfortunately,thismanipulationcanleadtolossofimportant

chondrocyteswhichmaybeneededforcartilageregeneration(Gilleetal.,2010). Thiscan

alsobeaverytime-consumingprocessforthesurgeonandincreasepossibilityoferrors.The

new3Dscaffoldwillbeabletoalleviatethisproblemandminimizefurtherrisks.

During a study carried out onMACI in a cohort of patients between 18-50 years of age,

significantresultswerefound.18.5%ofpatientsexperiencedsymptomssuchaspain,knee

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locking,crepitusandcontinuousswellingaroundthesiteofimplant.Furthertreatmenthad

tobecarriedoutsuchasmicrofractureduringthe6 -36month follow-upperiod. Another

studypresentedresultsshowingthat implantswerenotfully integratedbythesurrounding

tissue inasmallnumberofpatientsat the2yearpostoperative follow-upstage. Similarly,

thesepatientsalsohadtoundergofurthertreatmentasaresult(Basadetal.,2014).

Subchondral cysts have also been experienced by patients following the MACI procedure

whichmayalsobeasaresultofnon-regenerativetissuearoundthesubjectarea.Cellshave

the ability to become abnormal and group together forming a lump due as a result of an

implant that isnot fully compatiblewith the surrounding cells (Konetal. 2012). Theseall

could be a result of cells not being able to differentiate properly into the chondroctyes,

unsuccessful adherence to the collagen scaffold, therefore creating a larger immune

response.

Previous studies have shown that only 58% of patients were successful in a 5 year

implantationproceduresowearehopingtoincreasethispercentagedramaticallytoensure

ahigherlevelofoperationalsuccess.Thecompanyhopestoreduceoralleviatesomeorallof

thesenegativeeffectsbyuseof this 3D scaffold. Since the scaffoldwill containnotonly a

polymer base but also a natural polysaccharide chitosan, this will help to enhance the

biomaterials efficacy within the body. This natural material maintains lower rate of

immunogenicity, antibacterial properties along with the presence of glycosaminoglycans.

Eachof thesecharacteristicswill in turnhelp to reduce immune responses to the implant,

reduce infectionand inflammationandalsohelp increase further chondrocyte growthand

differentiation.

TheMACIprocedurenormallyworkswith implantsmeasuringapproximately3cm. Studies

have suggested that they can be larger but evidence still remains a question (Basadet al.

2014). With the new product the company hopes that the 3D printing scaffold could

potentially create a larger dimension scaffold for greater sized lesions. In previous cases

therehavebeen results showinggraftdetachment from the sub-chondralboneduring the

followupperiod(Marlovitsetal.2004).Duetothepreviousscaffoldonlybeingmadeupofa

collagenmembrane,thenewmaterialcombinedwithbothchitosanandPLAshouldallowfor

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stronger tissue integration around the site of implantation, leaving a tighter fit and less

chance fordetachment. Other reportshave found that there is a lower success ratewith

MACIinpatientsover40yearsofagewhichwehopetoalsoovercome(Konetal.,2012).The

improvedqualityprovidedbythe3Dscaffoldshouldaltersomeofthesedisadvantagesand

increasethesuccessratewithinallcohorts.

7.3Market

3Dprinterswithhigh-resolutionandseveralprintmaterialsaredecreasingthetimeofwhich

innovativeideasfortissueengineering,regenerativemedicineandorgantransplantationcan

be prototyped and analyzed. Prototyping is the prime reason why manufacturers are

pursuing this concept. It allows thecreator tomakeadjustmentsand improve theproduct

duringproductionallowingmoreflexibilityduringthemanufacturingphase.

Theabilityof3Dprintingtocreateproductsthatmayhaveonlybeenvisibleonascreenor

throughmolecularmanipulationmakesitmucheasiertosolvemedicalissuesinreality.Due

to its high efficiency, increased accuracy and reduced number of errors the use of this

process isestimatedto increasedramaticallyoverthenextdecade.Withintheorthopaedic

market,theprocessofcartilagerepairisaverypopularprocedurethatcouldbenefitfrom3D

printingacrossdifferentpartsoftheglobe(PersonandPhalke,2015).Ithasbeensuggested

that thekneecartilagerepairmarket isestimatedtoreachnearly$3Billiongloballybythe

year 2023. The market is separated into categories comprising of each of the continents

(Transparencymarketresearch.com, 2016). It is growing at a significant rate due to many

reasonsandoneofthemostpopularbeingtheriseinobesity.Recently,itwasproposedthat

abodyweightofgreaterthan222.5lbsputsindividualsatanincreasedriskofcartilageinjury

(SportsMedicineSimplified,2015).

Thefigurebelowshowspredictivedataforthegrowthofthe3Dprintingmarket.Alongwith

thesefiguresanotherreporthasalsosuggestedthatthetotal3Dprintingmarketissettorise

to$20billionby2025(Idtechex.com,2015).

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Figure7.1:Predictiveforecastsofglobal3Dprintingmarkets(Forbes.com,2014).

Sufficientevidenceexistsinsupportofapotentialmarketfor3Dprintingintheorthopaedic

sector.Ithasthepotentialtosolvemanychallengesfacedbycurrentmedicalresearchers.

Theglobalinstrumentationmarketisestimatedtoriseover$56billionbytheyear2017.The

global aging population is a huge driving force for this market and also the need for

developmentoflonger-lasting, improvedimplants(BioMedTrends). CompanieslikeStryker,

JRI Orthopaedics are only some of many that are now incorporating this type of medical

deviceintotheirownresearchtocreateinnovativeproducts.

7.4Increasedcosteffectiveness

The cost of production is relatively cheap, especially for small-sized constructs. This is

particularlybeneficialforcompanieswithsmallproductionvolumes,onesthatmanufacture

complex implants or for those that need regular adjustments. Additionally, 3D printed

scaffolds produce less wastematerial, as in the past surgeons would have to trim excess

material.

8.0RegulatoryPathwayandIntellectualProperty

Numerous MACI scaffolds are currently on the market in various locations or are in

development. These include Cartipatch (TBF Tissue Engineering, France), NovoCart (Tetec,

Germany), NeoCart (Histogenics, USA), the MACI method by Genzyme, USA, CaReS (Ars

Arthro, Germany), Chondron (Sewon Cellontech Co. Ltd, South Korea), Atelocollagen gel

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(Koken,Japan),andBioSeed-C(BioTissueTechnologies,Germany)(Konetal.,2013;Jacobiet

al., 2011).BioSeed-C,whichhasbeen in clinicaluse since2001, is a resorbable scaffoldof

fibrin,polydioxanoneandpolyglycolic/polylacticacid.Itdegradesinthebodyover6months

and is made using a patented technology. BioSeed-C comprises rectangular, porous 3D

cartilagegrafts(20x30x1.1mm)whichmustbecuttosizetofittheaffectedarea(BioSeed-C

Product Features at biotissue.ch; Kon et al., 2013; Jacobi et al., 2011; Kaps and Tanczos,

2009).

As the scaffold proposed in this casewould also be bioresorbable, alternative component

materialswouldbeused;apolylacticacid(PLA)andchitosanblend.Aspreviouslymentioned

in the ‘New Product Technology’ section of this report, this blend of materials would be

suitableforemploymentinahybridscaffold.Moreover,3D-printingwouldbeutilizedinthe

productionofthisscaffoldwhichwouldgivetheadvantageofcustomizablescaffoldsmadeto

fiteachpatient’sknee.Thus,thesurgicalprocedurewouldbesimplifiedastheimplantwould

nothavetobecuttofitthedebridedarea.

Intermsofintellectualproperty,asearchwasconductedutilizingEspacenetforpatentswith

the keywords “PLA” and “chitosan” in their title or abstract (Advanced Search at

Espacenet.com). Hence, relevant patents filed concerning the use of similar biomaterials

appeartoonlybevalidinSouthKoreaandChina(Kimetal.,2003;Kwonetal.,2013;KimSH,

2013;LiaoandXu,2012;Kimetal.,2011;Yeong,2007).Thus,licensesmayneedtobesought

fromtherelevantbodiesfortheremainderoftheperiodofthesepatentsiftheproductwere

to bemarketed in these territories. Another patentwas filed in South Korea andmultiple

other jurisdictions through theWorld IntellectualPropertyOrganization (WIPO) (Leeet al.,

2007).WIPOdirect thePatentCooperationTreaty (PCT),whichallows formultiplepatents

for a single invention to be filed in many of its member states at the same time. An

InternationalSearchiscarriedouttoseeifandwheretheinventioncouldbepatentedand

then an International Publication is released. However, the applicant is not automatically

grantedpatentprotectioninanymemberstatetheywish.Theapplicationmustreviewedby

eachcountry inwhichpatentprotection isbeingsought.This isreferredtoasenteringthe

NationalPhase,whereeachpatentofficeforthememberstatesinquestiondecidewhether

theywill grant the patent. The patent filed throughWIPO in this case has since lapsed in

17

SouthKoreaandonlyenteredtheNationalPhaseinCanadaandtheUS;itwasnotgrantedin

Europe (Lee et al., 2007; World Intellectual Property Organization at wipo.int). Another

patentfiledthroughWIPOisvalidonlyinSouthKoreaanddidnotentertheEuropeanPhase

(Kimetal.,2011)

Furthermore, themajority of the valid patents found through this search do not explicitly

mentionPLAandchitosanascompositematerials in their inventions,but rather ina listof

possiblecomponentsamongotherpolymersorbiomaterials.OnepatentvalidinChinadoes

listPLAandchitosaninthecompositionofamicroballoonforcellandtissueengineering,but

thisisalongsidehydroxyapatite(LiaoandXu,2012).Moreover,noneoftheaforementioned

patents state that theuseof theirbiomaterial isonly forcartilage repair.Cartilagemaybe

mentionedintheclaims,butitisamongotherusesorapplications.OnepatentfiledinChina

did state that the scaffoldwould be used for cartilage tissue engineering, but it has been

withdrawn(Sunetal.,2013).

Therefore, it appears that a patent could be filed for the current product in Europe and

certainotherterritoriesasa“3D-printedchitosan/PLAcompositeMACIscaffoldforarticular

cartilageregeneration”withouttheneedfor licensing.Apatent licencemayberequired in

certaincountries,particularlyChinaorSouthKorea,butthiscouldbereviewedfurtherifthe

decision were made to include these regions in the product market. According to the

EuropeanCommission,asanimplantabledeviceintendedforuseformorethan30days,this

scaffold would fall into Class IIb. Nonetheless, the use of an absorbable material instead

makesthisaClassIIImedicaldevice(EuropeanCommission,2010).

9.0Pre-clinical&ClinicalValidation

9.1Overview

Theintegrationof3Dprintingtechnologiesintohealthcareisgrowingrapidlyandpredicted

to revolutionizemodernmedicine. This is undoubtedly associated with the ability of such

technologies to produce custom-made, personalised prosthetics and implants. This device

makesuseof3Dprintingtechnologiesinordertocreateapatient-uniquescaffoldformatrix-

induced autologous chondrocyte implantation (MACI) in the knee. In order to clinically

18

validatethedevice,aseriesofpre-clinicalandclinicalstudiesareadvisedinordertoconfirm

the safety and efficacy of the product. MACI is already well-established and approved

treatment forcartilagedefects in theknee.Therefore,data fromphase Iand II studiesare

alreadyavailable, this includeswell-defined safetyandefficacyparameters associatedwith

theuseofculturedautologouschondrocytes.HoweversignificantphaseIIIstudiesarecrucial

toestablishthebenefitsof3DprintingaccompaniedMACIovertraditionalMACIinpatients

withcartilagedefects. It ishopedthis largescalestudywilldemonstratetheadvantagesof

thepersonalisedscaffoldovertraditionalMACI,andthusthemarketviabilityoftheproduct.

A PLA-chitosan blend material is proposed as a scaffold for chondrocyte seeding and

implantationinthebody.Thereissignificantclinicalevidenceavailableconfirmingthesafety

of PLA-chitosanmembranes for implantation into the human body (Khor and Lim., 2003),

however a number of further pre-clinical and clinical trials are warranted in order to

determinethesafetyandfunctionalityofthebiomaterialforuseasacartilagescaffold.

9.2Pre-ClinicalValidation

Pre-clinical validation isproposed inorder todetermine the safetyandefficacyofMACI in

animalmodels.Pre-clinicalvalidationinvolvingonerodentandonenon-rodentspeciessuch

as rabbits is recommended. Previous pre-clinical studies carried out in rabbits showed

minimal immunogenic response three months post-implantation, with a mild lymphocyte

accumulationobserved(Willersetal.2005).This immunecellaccumulationhaddiminished

significantly at six months post-implantation indicating that the implanted cells had

successfully integratedwith the host cells. Post-implantationmonitoring over a 24month

periodisadvisedinordertodeterminethelong-termeffectsofimplantation,carriedoutin

both rodent and non-rodent species. It is also important to study the integration and

compatibilityoftheanimalchondrocyteswiththecollagenmembrane.Invitrostudieswould

alsobebeneficial inordertoensurethePLA-chitosanscaffolddoesnotcauseanycytotoxic

effectstothechondrocytesfollowingcellseedingontothescaffold.Itisimportanttoensure

chondrocytesseedandintegratesuccessfullyonthePLA-chitosanmembranepriortoclinical

studies. It isexpectedthatchitosanwillsupportthegrowthofthechondrocytes,dueto its

biocompatible properties (Li et al., 2016). Mutagenic studies are advised to ensure cell

seedingofchondrocytesontothemembranedoesnotpromotemutagenesisoruncontrolled

cellgrowth.

19

9.3ClinicalValidation

In order to determine the safety of the membrane as a scaffold for the chondrocyte

monolayer, a small scale phase II trial is proposed. Approximately 10-20 patients with

cartilage defects in the knee should undergo the novel personalised MACI treatment

involving the PLA-chitosan scaffold. Following implantation, patients should be closely

monitored for adverse effects in response to the implant. The main adverse effects

associatedwith traditionalMACIaregrafthypertrophyandgraftdelamination (Dunkinand

Lattermann., 2013). Any other unexpected adverse effects observed should be carefully

recordedandwarrantfurtherinvestigation.

ShouldtheproductprogressthroughphaseIItrials,alargescale,randomisedphaseIIItrialis

crucialtodeterminetheclinicalviabilityofourproduct.Itisrecommendedthatatleast200

subjects enroll in the trial between the ages of 18-65, with at least one existing cartilage

defectintheknee.AsubsetofpatientsshouldundergotraditionalMACI,where3Dprinting

technologies arenotutilized, such that the chondrocyte implant is trimmed to the correct

sizeandshapebythesurgeonatthetimeofimplantation.Analternativesubsetofpatients

shouldundergoacomparativetreatmentsuchasmicrofracture.

ThecohortreceivingpersonalisedMACIwouldundergoanMRIscanofthekneeinorderto

determinetheshapeandsizeofrequiredcartilage.Thesedimensionswillthenbethebasis

forapersonalisedscaffold,producedby3Dprinting.Acartilagebiopsyshouldbetakenfrom

patients in advance, and the isolated chondrocytes then seeded in amonolayer onto the

personalisedscaffold.Itisexpectedthatthechondrocyteculturewillrequireapproximately4

weeks expansion time, beforebeing surgically implantedback into thepatient, and sealed

withfibringlue.Patientswouldbemonitoredupto60monthsfollowingsurgeryinorderto

determine the long-term effects of personalised MACI versus traditional MACI and

microfracturemethods.Previousstudiescarriedout(Sarisetal.,2014)comparingtraditional

MACIwithmicrofracturereportedsignificantlyhigherclinicalscoresinpatientswhoreceived

MACI treatment versus the microfracture cohort. The proposed clinical trial aims to

supplement these studies with further evidence of the benefits of MACI over alternative

approaches,andfurthermoredemonstratethebenefitsofpersonalisedMACIovertraditional

MACI.

20

The recommended primary endpoint of the study is the Knee Injury and Osteoarthritis

outcomescore(KOOS)(Collinsetal.,2011).KOOSisanestablishedmeasureoftheshort-and

long-termconsequencesofkneeinjuryandosteoarthritisandscorespatientsbasedonfive

separatelyscoredsubscales;KOOSpain,KOOSsymptoms,KOOSADL(functionindailyliving),

KOOS Sport/Rec (Function in sport and recreation) andKOOSQOL (knee-relatedquality of

life).Secondaryendpointsshouldincluderevisionrate,MRIandbiopsies.Treatmentfailures

shouldalsobereportedandsafetyassessmentsperformed.

10.Conclusion

There is an existing and growing market for cartilage regeneration within the tissue

engineering field. ACI andMACI have proven effective for treatment of chondral injuries,

howevertheyarenotwithouttheircaveats.Adoptionof3Dprintingtechnologiesisexpected

to revolutionize the orthopaedic sector. The integration of such a platformwill facilitate a

personalisedapproachtotheMACIprocedureandameliorateassociated limitations. A3D

printed scaffold comprising a chitosan-PLA blendwill offer advantages of enhanced tissue

integration, decreased operative time and overall improved patient quality of life. The

proposedproduct represents an attractivebusiness venturewith relatively lowproduction

costs,significantscaleuppotentialandtheopportunityformarketexpansion.Personalised

scaffoldingpresentsnewopportunitiesandsolutionsintissueregenerationandrepair.

21

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27

SectionsCompletedbyPerson:

1) ExecutiveSummary&Processsummary–Philip

2) Introduction–Stephanie

3) NewProductTechnology–Stephanie

4) CurrentUsers–Philip

5) ExpandedFunctionalities–Stephanie&Philip

6) CoreUserNeedsandUnmetNeeds–Caroline

7) Market–Caroline&Stephanie

8) RegulatoryPathway–Rachael

9) IntellectualProperty–Rachael

10) PreclinicalandClinicalValidation-Martha

11) Conclusion–Collectivelywritten

12) References–Caroline

13) Editing–Collectivelyedited

14) Formatting–Philip&Racheal