Slide 1 Enhancing the Fixation

of Orthopaedic Implants

engineering solutions and making science work for people

Dr Melanie CoathupProfessor, Director of Biionix™

College of MedicineUniversity of Central Florida

Orlando, USA

Inter-Disciplinary Translational Innovation for NeuroMusculoSkeletal Challenges

Pioneer Biomedical Discovery Improve and Advance Patient Care

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Slide 2 Changing Demographics

✓ Increased life expectancy

✓ Change in activity profile

✓ Implants into younger patients

❖Advanced “Smart” Materials❖ Implantable & Wearable Devices❖ Innovative Strategies for Tissue Repair & Implant Integration❖ Intelligent Rehabilitation and Assistive Technology

The Future….

To understand the problems of disease, trauma, pain and

ageing and develop innovative therapies to deliver an

increasingly technology-driven standard of care

engineering solutions and making science work for people

Cluster Research Themes:

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Slide 3 Design of massive bone tumor implantsAseptic Loosening

Patient

Age 6y

✔ Stanmore Implants Worldwide (Spin out)✔ 14,000 implants inserted worldwide

✔World leading Centre of Excellence

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Slide 4 Telemetry of Implants to measure strain distribution Proximal femoral

replacement in a patient

instrumented with strain

gauges in the shaft and

in the stem tip

Taylor, Perry, Meswania, Donaldson, Walker, Cannon. J Biomech, 1997

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Slide 5 Fibrous tissue

No Collar = Fibrous Tissue Interface

Sintered Bead Coated Collar = Fibrous Tissue Interface

ExtracorticalBone

FibrousTissue

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Slide 6 Cortical bony bridging to enhance fixation of cemented intramedullary stemmed segmental replacements using hydroxyapatite coated collars . Implant shaft

HA collar

Bone

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Slide 7 ✔ 61 patients at RNOH

✔ Cemented DFR’s

✔ Mean follow-up 8.5 years (2 – 18 years)

Bone in direct contact Study 1: Bone ingrowth to HA collar reduces aseptic loosening

Coathup et al. JBJS Am 2013

98.0%

75.0%

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Slide 8 ⦿ 22 pair-matched adult patients with

cemented DFRs

11 with HA collar : 11 with no collar

⦿ Match - Age; Resection Length; Follow-up

Study 2: Bone ingrowth to HA collar reduces aseptic loosening

P < 0.05

Coathup et al. CORR 2015

HA Collar

✔ 9/11 Osteointegrated

RLL Score (p = 0.001)

Cortical Bone loss (p < 0.001)

No Collar HA Collar

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Slide 9 HA Collar Osteointegration

p = 0.017

HA Collar Incorporated

HA Collar Not Incorporated

Survival – Aseptic Loosening

Duration:

12 years 3 month

Age

19 years

Coathup and Blunn 2015

At 5 years follow-up:✔87.5% survival with incorporation✔48.0% without incorporation

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Slide 10

High stresses (grey) in the stem at the

shoulder with no osteointegration of the collar.

Lower stresses in the stem (no grey)

with 75% of the collar integrated.

Methods:❖ Maximum forces recorded during a gait cycle applied to the implant shaft. ❖ Stress distribution investigated at five different growth stages

(i) 0% (ii) 25%, (iii) 50%, (iv) 75% and (v) 100%

Results:

❖ Least amount of integration (25%) caused a reduction in stress (approx. 800 MPa).

❖ Removes risk of implant fracture, yield or fatigue.

❖ Loads transmitted within bone were reduced when implant was osteointegrated.

Fromme, Blunn, Aston, Briggs, Koris, Coathup. Med Eng Phys, 2017

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Slide 11 Additive manufacturing• Selective laser sintering (SLS) can produce novel titanium

porous components• varying pore (1500 and 750µm)

• varying degrees of structural stiffness

• Coated with electrochemically deposited coatings

Mummith, Coathup, Aston, Briggs, Blunn, BJJ 2017

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Slide 12 Intramedullary stem

Extracortical bone

Grooved (control) Porous Collar

sizes (Ø1500µm, LP), small pore (Ø750µm, SP)

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Slide 13 Patient Study at the Royal National Orthopaedic Hospital, Stanmore, UK- 2019

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Slide 14 A stem cell is an unspecialized cell

capable of replicating or self renewing and developing into a variety of specialised cell types.

(eg. fibroblasts, osteoblasts, chondrocytes, smooth muscle cells, endothelial cells, adipocytes, myocytes, tendinocytes etc).

Embryonic or Adult

Bone marrow, umbilical cord, peripheral blood, amniotic fluid, adipose tissue.

1 – 10 in every 100,000 cells.

Easily defined in culture –adherent cell component.

Easily expanded in culture.

High proliferative capacity - attractive cell source for the regeneration of damaged tissues in orthopedic clinical applications.

Many in vitro and in vivo studies have demonstrated bone formation.

Mesenchymal Stem Cells and Bone Regeneration

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Slide 15

Chemotherapy is commonly used and has significantly improved survival rates of bone

tumour patients. However, chemotherapeutic agents are known to inhibit bone formation and turnover.

The aim of this study was to investigate the hypothesis that the administration of isogenic MSCs

within fibrin glue will increase bone regeneration within a femoral defect in chemotherapy-treated rats when

compared with controls.

Lee O, Coathup M, Goodship A, Blunn G. Tissue Eng. 2005 Nov;11(11-12):1727-35.

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Slide 16 Do MSCs Remain Viable in Tisseel® Fibrin glue?Alamar Blue (cell activity): No significant difference in cell activity at various time points. The level of cell viability was 80% of control values.

Dividing cells observed

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Slide 17

Three experimental groups:

Osteotomy only (n=6)

• Osteotomy + fibrin glue (n=6)

• Osteotomy+cells (100,000)+fibrin glue (n=6)

1.5mm gap in femoral shaft of 36 adult male Wistar rats,

18 received chemotherapy, 18 no chemo treatment.

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Slide 18 Percentage bone formation in the gap at 5 weeks

0

10

20

30

40

50

60

Perc

enta

ge b

one form

atio

n (

%)

bb

c

aa

c

Control

Fibrin + MSCs

NCcontrol

NCfibrin

NCfibrin

+

MSCsC

control

Cfibrin

Cfibrin

+

MSCs

1 2 3 4 5 6

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Slide 19 Conclusions

• Fibrin glue is a suitable material for delivery of MSCs.

• Cells remain viable (and divide) in the fibrin glue for up to 96 hours in tissue culture

In an animal model where regeneration of bone was adversely affected by chemotherapy, use of

fibrin glue combined with isogenic MSCs significantly increased bone formation.

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Slide 20 Enhance bony bridging?

Further improve fixation using tissue engineering techniques

using spray technique?

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Slide 21 Spraying BMSCs at 1 atm

Spraying of ovine MSCs at 1 atm does not affect cell viability and proliferation.

0

5

10

15

20

25

Day 0 Day 1 Day 2 Day 4 Day 7

Day

Ab

so

rb

an

ce

Canula 1.0 Atm

Alamar Blue Assay

Day

Ab

sorb

ance

0

10

20

30

40

50

60

70

80

Canula 1.0 atm Spray

Type of Fibrin Application Method

% L

ive B

MS

Cs/

To

tal

BM

SC

s

Live/Dead Assay

0

10

20

30

40

50

60

70

80

90

100

24 Hours 48 Hours 72 Hours

Time

Bq

/u

g D

NA

/h

ou

r

Canula Spray (1 Atm)

3H-Thymidine Assay

Time (hours)

Bq

/g

DN

A/h

ou

r

1 x 106 cells/mL

1 Atm

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Slide 22

12 implants

Ovine Model Materials and Methods

MSC Spray treatment(2 x 106 MSCs/collar)

Control (No treatment)

HA-Coated CollarProximal Stem

Kalia et al. Tissue Eng. 2006 Jun;12(6):1617-26.

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Slide 23 Tibial Mid-Shaft Replacement

6 months

Radiography and undecalcified histology

1 2 3

4 5

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Slide 24

Bone a

rea (

mm

2)

Results - Radiography

At each time point, there is significantly more bone growth

around MSC-treated implants than around controls.

Bone Area in Lateral X-Rays

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Slide 25

0

10

20

30

40

50

60

70

GroupB

on

e A

rea (

sq

uare m

m)

Control MSC-Treated

Results - Bone Area

Significantly more bone in MSC-treated samples

than control (p = 0.02)

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Slide 26

Control MSC-Treated

% B

on

e-I

mp

lan

t C

on

tact

Bone-Implant Contact

Increased bone-implant contact

(+) Cells

(-) CellsExperimental Groups

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Slide 27

A B C

Effect of Dose, Osteoblasts and Donor Cells

✓ Uncoated collar

✓ Fibrin Glue Only

✓ 2 million autogenic MSCs

✓ 10 million autogenic MSCs

✓ 2 million osteoblasts

✓ 10 million osteoblasts

✓ 10 million allogenic MSCs

Groups (n = 6):

A = Fibrin Only Implant

B = 2 million MSCs

Coathup M et al. JBMR-A 2013

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Slide 28

✓ Significantly increased bone in all cell given groups compared with controls.

✓ No significant differences in cell given groups.

OsteoblastsOsteoblastsMSCsMSCs

Spraying MSCs in fibrin glue onto the HA collars of massive implants significantly increased bone formation adjacent to implant, and improved

bone-implant contact.

Donor cells should not be used.

Coathup M et al. JBMR-A. 2012.

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Slide 29 •Integrating the bone implant interface is important

•Which surface give the best seal?

A comparison of bone remodelling around

hydroxyapatite-coated, porous coated and grit- blasted

hip replacements retrieved at post-mortem.

Coathup M et al. JBJS 2001

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Slide 30

Stem coatings

✓ Plasma sprayed titanium,

✓ Plasma sprayed titanium with plasma sprayed hydroxyapatite.

✓ Interlok grit blasted surface.

❖ One surgical team (North Hampshire Surgical Trust)

❖ Insertion of 160 hemiarthroplasty stems for fracture

neck of femur.

✓ Single design, uncemented

✓ 3 surface finishes

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Slide 31 ✓ 58 autopsy specimens.

✓ 2 days - 5 years.

✓ 15 Interlok specimens.

✓ 24 porous titanium specimens.

✓ 19 hydroxyapatite specimens.

❖ Specimens fixed, embedded and sectioned.

❖ Level F1, F2 and F3 in the porous coated region.

❖ Histological analysis of bone ingrowth into the porous structure and bone attachment

F2

F1

F3

Level of sections

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Slide 32 POROUS COATING 19 days duration

Interlok 20 days duration

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Slide 33

Porous coating 100 days duration

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Slide 34 Female 91 years old duration 4y 10m HA

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Slide 35

**

Porous coating + HA

Porous coating

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Slide 36

Porous Coating

243D

Porous Coating + HA

216D

Time matched F1 (proximal Level)

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Slide 37

Can we modify the implant surface and prevent

implant failure due to aseptic loosening?

QUESTION?

Human autopsy retrieval study demonstrated that an implant surface can be modified to provide more even bone distribution

and seals the implant interface

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Slide 38 Total Hip Replacement Surgery• 70% of failures are due to aseptic

loosening related to wear particle-induced osteolysis.

• Particles travel from the rim towards the dome of the cup along the bone cement interface inducing the formation of a fibrous tissue membrane

Radiolucent Line

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Slide 39 • Ovine Model• 36 sheep were randomly assigned into

groups: all animals had a roughened femoral head

- Cemented; (3, 6mm holes)

- Grit blasted;

- Plasma Sprayed Ti Porous Coating

- HA Plasma Sprayed Ti Porous Coating

- HA Grit Blasted

- Sintered beads

Cartilage removed andimplant press fit/cemented onto

bleeding subchondral bone.

Coathup M et al. Biomaterials 2005

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Slide 40 • Implants remained in vivo for 12 months

(1) Ground Reaction Force (GRF) 12 readings of maximum force (Fmax, Nm-2)

Pre-op, 12, 24, 36 and 52 weeks post op.

(2) Radiographic Analysis Zone 1Zone 2

Zone 3

(3) Wear Particle Analysis: Capsule biopsies digested

Wear particle area and aspect ratio measured.

(4)Thin sections prepared (

Slide 43 • In all groups, majority of

• particles 0 - 1µm (av. 0.736µm)

• Aspect Ratio similar (av. 0.600)

Particle Area

14.0013.00

12.0011.00

10.009.00

8.007.00

6.005.00

4.003.00

2.001.00

0.00

300

200

100

0

Std. Dev = 1.35

Mean = .65

N = 583.00

Particle Area

14.0

13.0

12.0

11.0

10.0

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0

500

400

300

200

100

0

Std. Dev = 1.23

Mean = .5

N = 538.00

Particle Area

12.0011.00

10.009.00

8.007.00

6.005.00

4.003.00

2.001.00

0.00

160

140

120

100

80

60

40

20

0

Std. Dev = 1.79

Mean = .97

N = 368.00

CEMENTED GROUP

GRIT BLASTED GROUP

PLAIN POROUS GROUP

0.75mm average linear penetration measured by shadow graph technique

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Slide 44 Grit Blasted Cup

Fibrous tissue

Bone

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Slide 45 CONTROL SPECIMEN

1b

Wear particlesobserved under semi-

polarised light in the interface

PLAIN POROUS SPECIMEN

2b

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Slide 46 A Comparison Of Bone Contact to the Acetabular Component

0

10

20

30

40

50

60

70

80

90

% B

ON

E C

ON

TAC

T

Control

Grit Blasted

Plain Porous

Sin Beads

HA GB

HA Porous

HA

Po

rous

HA

GB

Sin

Bea

ds

Pla

in P

oro

us

Gri

t B

last

ed

Cem

ent

HA Porous significantly greater (

Slide 49

6 - BMSC Spray treatment

(10 x 106 BMSCs/cup)

6 - Control (fibrin only)

12 implants

Experimental Groups

Kalia P et al. Tiss Eng Part A 2008

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Slide 50

Implants remained in situ for 6 months.

Surgical Procedure

Post-operative

Radiograph

1 2 3

4 5

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Slide 51 %New Bone Area

No significant difference between groups.

0

10

20

30

40

50

60

70

80

90

%B

ON

E A

RE

A

GROUPS

CONTROL

BMSC

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Slide 52

Bone-implant contact was significantly improved around BMSC-treated cups.

Bone-Implant Contact

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Slide 53

0

200

400

600

800

1000

1200

1400

1600

1800

2000

0 5 10 15 20 25 30 35 40

Point Along Acetabular Cup (1 mm intervals)

Fib

ro

us T

issu

e L

en

gth

(m

m)

Control Group BMSC Group

A decrease in fibrous tissue was observed towards the cup

periphery of BMSC-treated implants.

Control

BMSC

Point Along Acetabular Cup

Fib

rou

s T

issu

e L

en

gth

(m

m)

Fibrous Tissue Thickness

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Slide 54 Conclusion

Spraying BMSCs in fibrin glue onto HA-coated, press-fit acetabular cups

significantly increased bone-implant contact around the implants, increased bone area, and reduced fibrous tissue adjacent to the

cup.

In primary THAs procedures, this technique may reduce the number

of revision THAs.

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Slide 55 Revision Hip Procedures

• In the UK the revision THR 9,000/50,000 ops/yr(18%)

• NHS spends £59.1 million on costs/year.

• Mean operative time;

• Estimated blood loss; Complication rate;

• Mean hospital stay all increased in revision surgery.

• 25% - 50% of revision hips will fail. Survivorship is reduced with each operation and bone loss is further increased.

If applied during revision THAs, may be beneficial in cases

of poor bone stock.

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Slide 56 Bone RestorationAllograft impaction

Exeter exchange system (Gie and Ling)

For continued support and implant stability the graft must allow

for bone growth - even with HA coatings and allograft

impaction bone regeneration is limited – graft failure.

Femoral

cortex

allograft

stem

Pre

op

Post

op

4

years

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Slide 57

Will the administration of autologous

mesenchymal stem cells within impacted

allograft significantly increase bone formation

in revision hip surgery?

Korda M, Blunn G, Goodship A, Hua J. J Orthop Res. 2008 Jun;26(6):880-5.

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Slide 58 Ovine hemi-arthroplasty

In vivo 6 months, undecalcified histology, sections in proximal,

mid and tip regions and image analysis used: new bone area, bone-implant contact.

10x106/cm3

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Slide 59 Results: New BoneT0 T 6 months control T 6 months MSC

1

2

3

% new bone

0

10

20

30

40

50

60

ctrl MSC

% N

ew

Bo

ne

*p

Slide 61 Conclusion

Integration of the implant surface is essential

and the choice of surface important.

MSCs may be used to enhance

osteointegration in the clinical situation.

✔Massive bone tumour implants

✔ THR

✔ Impaction allografting

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Slide 62

Dr Paul Fromme (Mechanical Engineer)Prof Oscar Lee (Orthopedic Surgeon)Dr Vee San Cheong (Mechanical Engineer)Dr Aadil Mummith (Orthopedic Surgeon)Dr Priya Kalia (Biomedical Scientist)Dr Sujith Konan (Orthopedic Surgeon)Dr Vineet Batta (Orthopedic Surgeon), Dr Sara Ajami (Biomedical Scientist),

Samee Ahmad (Medical Student)Jacob Koris (Medical Student)Karen Erskine (Medical Student)Jemima Miller (Medical Student)James Blackburn (Medical Student)Dr Robyn Brown

Professor Gordon Blunn

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