understanding the biological outcomes and responses to ... · total hip replacement (thr) is a...

Bladen 2012, Understanding the biological outcomes and responses to orthopaedic surgical implants.

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Understanding the biological outcomesand responses to orthopaedic surgicalimplants.

Dr Catherine Bladen, University of Leeds,UK

A report for the Winston Churchill Memorial Trust,2012


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Acknowledgements:

Firstly, I would like to thank the Winston Churchill Memorial Trust for

believing in my fellowship idea. Their support and encouragement has

allowed me to undertake a truly life changing trip. Dr Marshall and I

have made a significant and ongoing professional relationship that will

facilitate cutting edge research in the field of orthopaedics.

Secondly, I would like to thank Dr Marshall and her surgical and

research teams. Her work ethic and “can do” attitude has been truly

inspirational.

Thirdly, I must say a big thank you to my parents, who looked after my

children while I was away. Without them, this trip simply would not have

been possible.


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Overview:

The use of artificial materials in the treatment of arthritis over the past

few decades has increased dramatically. It is important that we

understand the biological responses to the materials used (metal,

polymers, ceramic) and determine their effectiveness and suitability. It is

important to understand the local and systemic effects of these

implanted materials both at the time of implantation and indeed over the

lifetime of the implant.

Total hip replacement (THR) is a surgical intervention eliminating pain

and increasing mobility. Ultra High Molecular Weight Polyethylene

(UHMWPE) prostheses are still the most frequently used worldwide.

Most THR's will fail (10-15 years) particularly in younger patients (<65

years) who often outlive the life of the implant. The major cause of failure

is osteolysis and aseptic loosening due to the biological response to

UHMWPE wear particles (i.e.) the activation of inflammatory cytokines

including tumour necrosis factor-alpha. This fellowship brought together

Dr Catherine Bladen (molecular biologist) at the University of Leeds and

Dr Amanda Marshall (orthopaedic surgeon) at the University of Texas

(San Antonio) who both have a primary research interests in the

biological responses to wear particles from UHMWPE implants and in

the development of novel bearing materials. Bringing together scientists

from different disciplines has allowed for meaningful intellectual

exchange and highlight possible future collaborations within this area of

research.


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Fellowship Itinerary:

Four incredible weeks were spent with Dr Marshall in the research

laboratory and in surgery. Specifically the first week was spent with Dr

Marshall in surgery observing hip and knee replacements. The second

week was spent with Dr Marshall's collegue Dr Anil Dutta observing

shoulder implant surgeries and techniques. The third week was spent

with another of Dr Marshall's collegues, Dr Raj Rajani observing the

removal of tumours and pseudotumors associated with metal hip

implants. The final week was spent in the laboratory with Dr Marshall

where I taught her how to assay the periprosthetic tissue (removed after

an implant fails) to look for cell death and DNA damage.

An introduction to Joint replacement:

Total Joint replacement (TJR) is a successful surgical intervention,

eliminating pain, increasing mobility and restoring quality of life. Hip

replacement is the most common joint replacement procedure

comprising almost 80% of total joint surgeries [1]. There are several

bearing material choices available (metal-on-polyethylene (MPE), metal-

on-metal (MOM), metal-on-ceramic, ceramic-on-ceramic). Prostheses

comprising an acetabular component of highly cross-linked UHMWPE

(MPE) are the most frequently used worldwide. However, over a period

of 10-15 years, a proportion (10-20%) will fail particularly in younger

patients (<65 years old), who will often outlive the working life of the

implant. This is generally due to patient specific factors, e.g., age at

implantation, activity level [2, 3], surgical technique, fixation of the implant

to the bone, osteolysis and long-term bone remodelling, with 75% of


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failures being attributable to aseptic loosening due to osteolysis. With

conventional MPE, it is believed that the major cause of osteolysis and

subsequent aseptic loosening is due to the biological response to

UHMWPE wear debris generated at the articulating interface, mainly by

the interaction of macrophages with these particles [1]. Highly cross-

linked UHMWPE offers significant advantages over conventional

UHMWPE in terms of reduced osteolytic potential [4]. However, failure

does still occur in highly cross-linked UHMWPE, in particular there is an

increase in rim fracture due to a decrease in fatigue resistance [5, 6].

The size range of UHMWPE wear particles can vary from nanometers

up to several millimetres [7] . It is now clear that particles in the size range

of 0.1-1 μm are the most biologically reactive [8, 9]. In addition to the size,

the volume of wear debris plays an important role in the biological

reactivity of the particles [8, 9].

The biological response to UHMWPE wear debris is dependent on the

volume of particles within a critical size range. It has been found that

only particle volume to cell number ratios of ≥10 μm3/ cell are capable of

eliciting a significant biological response to UHMWPE particles, in terms

of osteolytic cytokine release [9]. Analysis of periprosthetic tissues

retrieved from revision surgeries has demonstrated the presence of

biochemical mediators of inflammation that are associated with

macrophage activation. Cytokines that have been detected in the

periprosthetic tissues include TNF-α (tumor necrosis factor-alpha), IL-1β

(interleukin 1β), and IL-6, IL-8, IL-11, macrophage-colony stimulating

factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-

CSF), transforming growth factor-α and -β (TGF-α, TGF-β) and

prostaglandin E2 (PGE2), TNF-α is the most abundantly produced

cytokine and has become a widely accepted marker for inflammation[10].


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MOM bearings were once considered to be the future of modern joint

replacement due to their low wear rates and improved strength [11].

However, as the MOM bearing wears, metal ions are released into the

local tissue and eventually make their way into the blood stream of the

patient where they can travel; to distant sites in the body causing organ

damage [12]. Hypersensitivity reactions also occur with MOM bearings

leading to significant tissue loss around the prosthesis and to the

incidence of pseudotumours. It is now generally accepted that MOM

prosthesis should be removed and replaced with either MPE or ceramic

components.

My Fellowship:

On arriving in San Antonio on the Sunday evening I had to hit the ground

running. 7am Monday morning I gave my first talk. I spoke to the entire

orthopedic department, outlining my research ideas and explaining my

fellowship. Then I did some paperwork, got my ID badge and was in the

OR all before 9am!


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Dr Bladen getting ready for surgery.

Dr Marshall had really given some thought as to the different types of

surgery I would get to scrub in on during my fellowship and I was

extremely lucky to see a mixture of straight forward primary joint

replacement surgeries and complex and challenging revision surgeries.

My first case was a primary hip. Hip replacement surgery becomes

necessary when the hip joint has been badly damaged (often from

osteoarthritis) and the resulting pain cannot be satisfactorily controlled

by analgesia. Dr Marshall carries out both anterior (front) and posterior

(rear) approaches for primary hip replacement. Generally, slightly built

or very active people are offered the anterior approach since it involves

less damage to the abductor muscles. Less active or more heavily built

people will have a posterior approach. This first case was a posterior

approach, primary hip in a 62 year old female with advanced

osteoarthritis. A, MPE prosthesis was selected. Dr Marshall does not

use MOM implants and generally selects MPE prostheses unless the

http://catherinebladen.files.wordpress.com/2012/07/scrubs1.jpg


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patient is young and very active in which case a ceramic-on-

polyethylene component would be used.

A posterior approach primary hip replacement.

My first exposure to hip revision surgery was a 70 year old male patient

who required revision surgery due to pain and chronic dislocation. Lab

results indicated that this patient’s pain was likely due to infection arising

from the primary surgery. Revision surgeries are very different

depending on the presence or absence of infection, amount of bone

loss, abductor muscle strength etc. In this case, it was decided to

remove both the femoral (ball joint) and acetabular (cup) components

from the primary surgery. An antibiotic spacer was then added (bone

cement impregnated with antibiotics). This spacer would stay in place

for six to eight weeks to allow the infection to subside. Then the spacer

would be removed and replaced with new hip replacement components.


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An example of the femoral component of antibiotic spacer used to treat infection

prior to revision surgery.

Dr Marshall also carries out primary and revision knee surgeries.

My first exposure to a primary knee replacement was a 64 year old

morbidly obese female with osteoarthritis in both knees. This patient

had been on a weight loss program prior to surgery. With knees, if the

patient is very obese then surgical access can be impaired resulting in

less than perfect alignment and potential problems later on. 6 weeks

after the first surgery, this patient was scheduled to have her other knee

replaced.

http://www.bing.com/images/search?q=antibiotic+spacer&view=detail&id=AB0291E44548F474B71C710F215B8468C3575B69&first=1


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Primary knee replacement, opening up the knee.

Drilling the holes in order to fit the femoral component of a primary knee

replacement.

That same day I scrubbed in on a complex knee revision surgery where

the original implant needed to be revised due to fracture. This case was

a 93 year old female who had simply knelt down from a chair and

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fractured the femoral component of the knee replacement. The tibial

component was also loose and therefore required replacement.

Fractured femoral component from knee replacement.


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Primary knee replacements are minimally invasive to the femoral and

tibial bone (A). Revision components are more invastive resulting in

more bone loss (B). This patient needed a complex type of revision

arthroplasty often used in cases of bone cancer (C).

A. B. C.

Primary and revision knee components.

Dr Bladen with patient after knee revision surgery.

http://www.bing.com/images/search?q=revision+arthroplasty&view=detail&id=2DFE652D56390586D7DD81D8B654CB5F9A4252EF&first=1

http://www.bing.com/images/search?q=revision+arthroplasty&view=detail&id=1958D3DECBDFC71E589C03AC45A2F88DC6A478A3&first=1

http://www.bing.com/images/search?q=revision+knee+arthroplasty&view=detail&id=444892FD83C6D8AB8FDAA8C9AAA76D27F4B9980A&first=99

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Dr Marshall and Dr Bladen during knee revision arthroplasty.

I was lucky enough to see a wide variety of primary and revision hip and

knee surgeries but want to take this opportunity to highlight some of the

more extraordinary cases.

I got to scrub in on a hip revision where the acetabulum (cup) had

migrated into the pelvic cavity. The whole pelvis had to be reconstructed

before a new acetabular component could be fitted.


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Migration of acetabular component into pelvic cavity.

Opening up the hip ready for removal of damaged acetabulum and reconstruction of

pelvis.

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The acetabular shell (Smith and Nephew USA) used to reconstruct the acetabulum

prior to fitting new acetabular component.

This was an extremely complex surgery and involved significant physio-

therapy afterwards but this patient is now able to walk unaided.

Metal-on-metal (MOM) hip replacements can cause catastrophic bone

and soft tissue damage. This case is a 54 year old male physician. He

is an active cyclist and in 2006 was hit by a car whilst out on his bike

resulting in a femoral fracture. The fracture was fixed but two years later

he developed avascular necrosis (bone death) in his femoral head. He

was given a MOM primary hip replacement by a surgeon in Dallas and

came to Dr Marshall in July 2011 complaining of severe pain, chronic

dislocation and a significant limp. Dr Marshall tested his metal ion levels

and found that he had elevated levels suggesting that his MOM

prosthesis was breaking down. X-ray indicated a well fixed prosthesis

but MRI showed significant soft tissue loss in the area surrounding the

metal components. Upon revision surgery, he was found to have

significant necrosis of the soft tissue surrounding his hip and significant

loss of abductor muscle tissue (causing him to dislocate). The dead

tissue had to be completely removed and the metal components were

replaced with a ceramic femoral head (active patient) and a polyethylene

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acetabular cup. His abductor defect was then corrected using buttock

muscle. Prior to me leaving Texas, this patient was back on his bike.

MRI showing soft tissue loss around MOM components.

Opening up the hip – note the significant loss of abductor muscle.


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Necrotic (dead) soft tissue surrounding the MOM components.

Repair of damaged abductor muscles using buttock muscle.


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I then spent a week with Dr Anil Dutta observing shoulder replacement

surgeries. This is a very interesting and technically demanding

procedure. I saw one conventional and one reverse (19 year old kid-

trauma). I was surprised how delicate these procedures were in

comparison with hip and knee surgeries, due in part to the smaller size

and complex vasculature of the upper arm and shoulder. Dr Dutta didn’t

allow me to take as many photographs as Dr Marshall but the science

behind the implants is much the same as hip replacement. Wear and

wear debris is not as big an issue in shoulder replacements simply

because the shoulder is not a load bearing joint the way the hip is. MPE

components are used most frequently with a polyethylene cup (glenoid)

and a metal humeral head or the reverse.

http://www.rosemed.com/dotAsset/310201.jpg


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I then spent a fascinating week with Dr Raj Rajani (orthopaedic

oncologist) observing tumour resections and amputations. The

amputations were quite harrowing especially one patient who was only

28 years old and had a long history of osteosarcoma. He had been

through many different surgeries including removal of some of his femur

and most of his tibia followed by specialist revision arthroplasty so that

he could walk. Unfortunately his tumour was particularly aggressive

resulting in him having an above knee, mid thigh amputation. His

prognosis is poor and he is likely to die in the nest 12 to 24 months. Out

of respect for this patient I have not included and images of his

amputation.

I also got to see how different surgeons often need to work together to

solve complex cases. An example was a 62 year old male patient with

metastatic osteosarcoma. He had tumour masses in the majority of his

left leg above and including the knee joint. He had further tumour

masses in his groin, abdomen and up his left side under his arm. This

surgery was carried out in three stages over 9 hours. Firstly, Dr Rajani

removed the cancerous bone and tissue from his leg before assisting Dr

Marshall in fitting a specialist total knee replacement. Then urology

surgeon Dr Catravas, removed the tumour mass from his groin along

with one of his testicles. Finally, general surgeon Dr Hahn removed the

abdominal tumour mass. This was a grueling but fascinating surgery. I

was actually surprised to hear that this patient had an excellent

prognosis. It’s incredible that we can overcome such significant surgery.

My final week was spent with Dr Marshall both in the lab and in surgery.

We developed a method for assaying the periprosthetic tissue (tissue

surrounding the implant) for hxpoxia (lack of oxygen), oxidative stress


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and DNA-damage induced cell death. Dr Marshall and I have set up a

tissue transfer agreement which will allow me to access tissue from all

her patients in order to set up a research program for determining how

different bearing materials damage their surrounding tissues. We are

particularly interested in comparing MOM versus MPE bearings. We

have already seen that both materials can cause hypoxia and oxidative

stress but that DNA damage is elevated in MOM cases only not MPE

cases. Our focus, therefore is to understand the mechanisms by which

polyethylene causes hypoxia and oxidative stress in addition to further

understanding the way in which polyethylene induces chronic

inflammation in its surrounding tissues.

Outreach:

The main beneficiaries of this research will be the NHS and ultimately

the patients who will receive more appropriately selected hip prostheses.

This research will also benefit the UK prosthesis manufacturing industry.

The results of this collaboration will be disseminated through

presentations at national and international conferences (specifically the

British Orthopaedic Society [BORS], and the International Orthopaedic

Society [ORS]). Results will be disseminated directly to the collaborators,

and a wider audience of academics and industry specialists through

inclusion in the University of Leeds Institute of Medical and Biological

Engineering [IMBE] research group annual report.


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It wasn’t all work:

Now when Dr Marshall suggested we take a trip out on her boat I didn’t

realise that what she actually had planned was to pull me behind it on a

blow up rubber ring!!!! Of course me being me …I loved it!

We also took a trip to the Alamo.

http://catherinebladen.files.wordpress.com/2012/08/tubing.jpg

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References:

1. Ingham, E. and J. Fisher, The role of macrophages in osteolysis oftotal joint replacement. Biomaterials, 2005. 26(11): p. 1271-86.

2. Heisel, C., M. Silva, and T.P. Schmalzried, Bearing surface optionsfor total hip replacement in young patients. Instr Course Lect,2004. 53: p. 49-65.

3. Kim, Y.H., S.H. Oh, and J.S. Kim, Primary total hip arthroplastywith a second-generation cementless total hip prosthesis inpatients younger than fifty years of age. J Bone Joint Surg Am,2003. 85-A(1): p. 109-14.

4. Besong, A.A., et al., Quantitative comparison of wear debris fromUHMWPE that has and has not been sterilised by gammairradiation. The Journal of bone and joint surgery. British volume,1998. 80(2): p. 340-4.

5. Jasty, M., H.E. Rubash, and O. Muratoglu, Highly cross-linkedpolyethylene: the debate is over--in the affirmative. The Journal ofarthroplasty, 2005. 20(4 Suppl 2): p. 55-8.

6. Ries, M.D., Highly cross-linked polyethylene: the debate is over--inopposition. The Journal of arthroplasty, 2005. 20(4 Suppl 2): p. 59-62.

7. Richards, L., et al., Identification of nanometre-sized ultra-highmolecular weight polyethylene wear particles in samples retrievedin vivo. J Bone Joint Surg Br, 2008. 90(8): p. 1106-13.

8. Green, T.R., et al., Polyethylene particles of a 'critical size' arenecessary for the induction of cytokines by macrophages in vitro.Biomaterials, 1998. 19(24): p. 2297-302.

9. Matthews, J.B., et al., Comparison of the response of primarymurine peritoneal macrophages and the U937 human histiocyticcell line to challenge with in vitro generated clinically relevantUHMWPE particles. Biomed Mater Eng, 2000. 10(3-4): p. 229-40.

10. Xu, J.W., et al., Tumor necrosis factor-alpha (TNF-alpha) inloosening of total hip replacement (THR). Clin Exp Rheumatol,1996. 14(6): p. 643-8.33.

11. Fisher J, Jin Z, Tipper J, Stone M, Ingham E.Tribology of alternative bearingsClin Orthop Relat Res. 2006 Dec;(4)53:25-34

12. Leslie I, Williams S, Brown C, Isaac G, Jin Z, Ingham E, Fisher J.Effect of bearing size on the long-term wear, wear debris, and ionlevels of large diameter metal-on-metal hip replacements-An invitro study.J Biomed Mater Res B Appl Biomater. 2008 Oct;87(1):163-72

http://www.ncbi.nlm.nih.gov/pubmed/18386846




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