Bone Repair Biomaterials

485 Pages·2009·17.41 MB·English

by  J. A. Planell, S. M. Best, D. Lacroix, A. Merolli

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Bone repair biomaterials
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Challenges of bone repair
J. A. PlAnell and M. nAvArro,
Institute for Bioengineering of Catalonia (IBeC), Spain
Abstract: Musculoskeletal problems, including bone and joint pathologies
are among the main causes of chronic pain, physical disability, and work
absenteeism in both developed and developing countries, and they affect
millions of people worldwide. This is the reason why biomaterials play a
key role in bone repair and regeneration. In this chapter, the societal impact
of musculoskeletal diseases, as well as other bone problems is discussed in
terms of their costs and the degree of physical disability that they generate.
In addition, some of the most relevant clinical challenges in bone repair are
presented.
Key words: musculoskeletal diseases, societal impact, economical impact,
quality of life, bone diseases, clinical challenges in bone repair.
1.1 Introduction
Musculoskeletal problems, including bone and joint pathologies that lead
to tissue degeneration and infammation, are among the main causes of
chronic pain, physical disability and work absenteeism in both developed
and developing countries and they affect millions of people worldwide,
especially those aged over 50 years. Present forecasts state that the percentage
of target population affected by these diseases will double by 2020. Thus, it
is expected that the demand and development of new caring techniques and
treatments for these problems will also largely increase in these next few
years. Musculoskeletal ailments frequently require surgery, including bone
substitution and total joint replacement. Furthermore, the treatment of most
bone traumatisms and malfunctions require the use of different devices. This
is the reason why biomaterials play a key role in bone repair and regeneration.
In this chapter, the societal impact of musculoskeletal diseases as well as
other bone problems are discussed in terms of their costs and the degree of
physical disability that they generate. In addition, some of the most relevant
clinical challenges in bone repair are presented.
1.2 Social and economical impact of
musculoskeletal disease
Bone and joint degenerative and infammatory problems affect millions of
people across the world. In fact, musculoskeletal conditions, namely joint
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pathologies, fractures related to osteoporosis, back pain, serious injuries and
different sorts of bone diseases and disabilities are among the most common
causes of hundreds of millions of people worldwide suffering severe long-
term pain and becoming physically handicapped or crippled.
It has been reported that over 100 million europeans suffer chronic
musculoskeletal pain, while in the USA musculoskeletal problems affect
over 40 million people aged 45 years or older and are projected to affect
more than 60 million persons, or 22% of the population, by the year 2030.
While mortality from these conditions is low, they have a major effect on
disability, medical costs and patient quality of life (Murray and lopez, 1996;
White and Harth, 1999).
The two most commonly reported causes of pain worldwide are back pain
and arthritis. These two conditions represent a third of all reported causes.
low-back pain is the most common problem, affecting approximately 4–33%
of the population. Although back pain affects almost everyone at some
point in life, it seems to be more prevalent in men and in younger people.
Arthritis, a pathology that involves damage to and infammation of the joints,
is the most frequent cause of pain in women and in older people. In fact, it
has been estimated that osteoarthritis affects nearly 10% of men and 18%
of women aged over 60 years, while rheumatoid arthritis, which is a more
severe disease, affects 0.3–1% of the general population and is more prevalent
among women and in developed countries (elliott et al., 1999; Woolf and
Pfeger, 2003). Moreover, it has been estimated that approximately 40% of
arthritic adults suffer from osteoarthritis of the knee, 80% of people with
osteoarthritis have limitation of movement and 25% cannot perform their
major daily activities (Brooks, 2002).
osteoporosis and, particularly, fractures caused by this illness are another
of the most common problems affecting contemporary society. osteoporosis
has been defned as a condition in which BMD (bone mass density) is 2.5
standard deviations or more below the mean seen in young healthy subjects
(WHO, 1994). Osteoporotic fractures primarily result from low BMD.
However, microstructural changes in bone, especially of trabecular bone,
also contribute signifcantly by increasing trabecular brittleness. This fragility
is translated in an increase of vertebra, wrist and hip fractures (Kanis and
Melton, 1994; Bonjour et al., 1996).
The prevalence of osteoporosis in the USA only is estimated to increase
from ten million to more than 14 million people by 2020. This is a signifcant
increase in population with a high risk of falls and fractures (national
osteoporosis Foundation, 2002). Indeed, fractures related to osteoporosis
have almost doubled in number in the last decade and it is foreseen that 40%
of all women over 50 years will suffer from an osteoporotic fracture (Bone
and Joint Decade’s Musculoskeletal Portal, 2001). Although osteoporosis
is less prevalent in men than in women, it is estimated that 30% of all hip
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Challenges of bone repair 5
fractures occur in men (Campion and Maricic, 2003). In addition, studies
have shown that the fracture-related morbidity rate is higher in men than
in women (olszynski et al., 2004). As in the case of arthritis and other
musculoskeletal diseases, osteoporosis is a functional abnormality and an
important clinical syndrome leading to many problems with respect to quality
of life (Yilmaz et al., 2008).
Hip and vertebral fractures are the most common fractures among individuals
suffering osteoporosis. In osteoporotic women, low BMD particularly at the
femoral neck, increases the risk of hip fractures two- to-threefold (Cummings
et al., 1985).
Hip fractures constitute a major and growing health care problem in
the Western world and an emerging problem in the developing countries
(Cummings et al., 1985; WHo, 1994). It has been estimated that the
worldwide annual number of hip fractures in 1990 was 1.66 million (Cooper
et al., 1992b). If current demographic and incidence trends continue, the
worldwide annual number of hip fractures will increase to 6.26 million by
year 2050 (Cooper et al., 1992b; Melton, 1993). They are associated with
considerable disability, loss of independence and diminished quality of life,
but more importantly with a 20% reduction in expected survival (Cummings
et al., 1990; Kannus et al., 1996; Melton, 1993; richmond et al., 2003).
Additionally, hip fractures constitute a signifcant economic burden for
modern medical care, both directly during fracture treatment and indirectly
particularly during the frst year after the fracture (Lauritzen, 1996; Sernbo
and Johnell, 1993). Thus, as measured by their frequency, infuence on
quality of life and economic cost, hip fractures are a public health problem
of crisis proportions.
vertebral fractures and deformities affect approximately 20% of
postmenopausal women and are the hallmark of osteoporosis (O’Neill et al.,
1996; Fechtenbaum et al., 2005). Postmenopausal women with previous or
incident vertebral fractures are at higher risk of both vertebral and non-vertebral
fractures than women without previous vertebral fractures, independent of
bone density (Klotzbuecher et al., 2000; Kotowicz et al., 1994; Burger et
al., 1994). In contrast to other major osteoporotic fractures, the majority of
vertebral deformities do not come to clinical attention (Kanis and McCloskey,
1992; Cooper et al., 1992a; Cooper and Melton, 1992).
vertebral fractures may cause local pain for three years or more, although
they may be presented asymptomatically (ross, 1997). Clinical vertebral
fractures are associated with increased back pain, kyphosis, height loss,
impaired functional capacity in daily life, sleep problems, mood changes
and reduced general health, with recent fractures having the greatest impact
and causing greater health care utilization, including increased numbers of
physician visits (Armstrong et al., 1992; Cooper and Melton, 1992; ettinger
et al., 1992; leidig et al., 1990; Huang et al., 1996). Social isolation and
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depression have been also reported in patients with vertebral fractures. All
together, these factors have an important impact on patients’ health-related
quality of life (Qol) (Kanis et al., 1992).
Severe trauma caused by accidents is also noteworthy among the most
important musculoskeletal conditions that affect contemporary society. The
severe injuries caused by traffc accidents and war produce a tremendous
demand for preventive and restorative help. It is anticipated that 25% of the
health expenditure of developing countries will be spent on trauma-related
care by the year 2010. recent world health statistics from the WHo revealed
that road traffc accidents will emerge as the ffth leading cause of death by
the year 2030 (WHo, 2008). Thus, it is expected that severe bone trauma
related to this cause will also increase during this period of time.
1.3 Economic burden of musculoskeletal
disease
The costs of illness are generally divided into three categories: direct costs,
indirect costs and intangible costs. Direct costs include expenditure for
medical care and related items. These include expenditure for physician
visits, diagnostic tests, prescription and over-the-counter medications, hospital
stays, aids and devices, and outpatient surgical procedures.
Indirect costs are those resulting from lost function in one’s usual activity,
including work disability, sick leave or reduced productivity associated with
a reduction in work hours or a need to change the nature of one’s work
to reduce pain and improve physical function. A number of studies have
shown the signifcant effect of musculoskeletal conditions on employment
(Blyth et al., 2001). Depending on the specifc condition, the indirect costs
of musculoskeletal conditions may equal, or even exceed, the direct costs.
Intangible costs are those associated with loss of function, increased pain
and reduced quality of life. As observed, disability is a signifcant outcome
of musculoskeletal diseases. The limitations associated with these conditions
include limitations of the activities of daily living, reduction in leisure and
community activities, chronic pain and psychological problems, including
depression and anxiety, and reduced general health.
1.3.1 Direct costs of musculoskeletal conditions
The direct costs associated with musculoskeletal conditions are substantial,
especially among persons with arthritis. The reason behind these increased
direct medical costs is mainly due to the increasing number of higher cost
drug therapies. other medical treatment with attendant high costs include
total joint replacement surgery, which is common among persons with
rheumatoid arthritis and osteoarthritis, and it is expected to increase over
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the coming decades with the growing prevalence of musculoskeletal disease
in an ageing population.
The specifc musculoskeletal condition results in different direct costs. In
the USA and europe, rheumatoid arthritis alone is estimated to cost US$1–2
billion per year (Yelin, 1996; Allaire et al., 1994; Yelin and Wanke, 1999;
Fautrel and Guillemin, 2002; reginster, 2002).
Several studies on rheumatoid arthritis carried out in the USA revealed
that the average direct costs ranged from US$2299–8500 (Yelin et al.,
1999; Yelin and Callahan, 1995). Total annual costs were US$8500, with
hospitalizations accounting for between 55 and 62–68% of all expenditure.
In Canada, it has been reported that total costs for patients with rheumatoid
arthritis averaged US$2299 (lubeck, 2003).
For osteoarthritis, a less severe arthritic condition, total costs ranging
from US$3.4–13.2 billion per year, with almost half associated with direct
medical expenditure, have been reported (leigh et al., 2001). The total
medical costs for people under 65 years of age were found to be twice as
high when compared with similar individuals without the condition. Among
those individuals with osteoarthritis over the age of 65 years, expenditure was
50% higher than for those without the condition. Much of the difference was
due to the costs of hospitalization (Maclean et al., 1998). osteoarthritis and
related conditions accounted for more than half of all total hip replacements
and 85% of all total knee replacements a decade ago and the cost for these
replacements was over $300 million (Praemer et al., 1992).
The economic impact of musculoskeletal diseases and chronic pain
associated with them not only involves the direct, indirect and intangible
costs previously mentioned, they also have a deep effect on the economic
burden related with work absenteeism and lower performance. It has been
estimated that the impact of arthritis on lost productive work time amounted
to US$7.11 billion, but with 66% if this attributed to the 38% of workers
with pain-related disabilities (ricci et al., 2005).
Furthermore, musculoskeletal conditions are the most common medical
cause of long-term sickness absence (Woolf and Pfeger, 2003). In the UK,
for instance, 3000 people go on to the incapacity beneft scheme every week
and approximately 300 never return to work (Frank and Chamberlain, 2001).
In Germany, musculoskeletal conditions cost employers US$30.8 million
and are considered to be the largest single contributor to lost productivity
(Phillips, 2006). In France, a study of nearly 2000 professionals suffering from
acute pain showed that approximately 50% of them suffered musculoskeletal
related pain; the average number of sick days resulting from their disability
was 9 days/year (Autret-leca et al., 2001).
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1.3.2 Economic impact of osteoporosis and
related fractures
Current direct medical costs of osteoporosis in the USA have been estimated
at US$13.7–20.3 billion. This burden is projected to grow by approximately
50% by 2025. A similar situation is expected to take place in other developed
countries (Day, 1996; Ray et al., 1997; Hoerger et al., 1999; Chrischilles
et al., 1994).
In the USA, it has been estimated that total cost of incident fractures will
rise from US$209 billion during 2006–2015 to US$228 billion for 2016–2025.
Some interesting predictions about fracture sites and race/ethnicity of the
affected population in USA have been reported. Across fracture types, the
largest changes are predicted for pelvic fractures, where incidence increases
by 56% and costs are predicted to rise by 60% between 2005 and 2025. By
race/ethnicity, the proportion of fractures and costs among the non-white
population will increase from 14% and 12% in 2005, respectively, to 21% and
19% in 2025. The most rapid increase is projected to occur in the Hispanic
and other subpopulations. The annual costs for Hispanics are estimated to
grow from US$754 million in 2005 to over US$2 billion per year by 2025
for an increase of 175%. Similarly, the other population shows cost increases
of 175%, starting from a smaller 2005 total of US$502 million and rising
to more than US$1.38 billion per year in 2025 (Burge et al., 2007).
1.3.3 Costs of cancellous bone grafting versus
alternative methods in trauma surgery
At present, one of the most popular and used techniques for substituting
bone in those conditions where bone replacement is required is the use of
autologous bone. Autologous bone grafts are prescribed in numerous cases such
as defect pilon tibial, osteomyelitis, arthodesis, juvenile bone cysts, fracture,
ventral spondylodesis, tibial plateau fractures and non-unions (lohmann et
al., 2007). The main advantages of autologous bone are its biological nature
which avoids possible disease transmission or host rejection and also its
osteoconductive, osteoinductive and osteogenetic properties.
Cancellous bone grafting is currently the most frequent method for
replacement of bone tissue. Worldwide, in 10% of all orthopaedic operations,
a bone substitute is necessary. In Germany, 125 000 bone grafts are harvested
per year (Bischo, 1995). owing to the easy access and high transplant quantity,
autogenous bone is predominantly taken from the iliac crest. However, the
use of autologous bone as a bone graft or replacement also presents several
disadvantages, such as deep infection, prolonged wound drainage, nerve
injuries and chronic pain.
Allogenic bone material has been predominantly taken from the femoral
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Challenges of bone repair 9
head during hip arthroplasty. The harvested bone material had to be processed
and stored in expensive bone banks. The allogenic bone is osteoconductive
but has only reduced osteostimulative affectivity owing to the production
process. owing to the remaining high risk of disease transmission, this method
is disregarded. In recent years, several alternative therapeutic approaches
such as synthetic bone substitutes, local growth factors and composites have
been developed.
It has been calculated from clinical data that, in the USA, the average direct
costs relating to the use of cancellous bone grafts account for approximately
US$4000 (St John et al., 2003). The use of synthetic materials and growth
factors is usually considered as rather expensive alternatives in comparison
with autologous bone; however, according to a study performed by lohmann
et al. (2007), the costs of alternative methods are comparable and even
cheaper than using cancellous bone grafts for bone replacement. Furthermore,
given the complications associated with harvesting bone tissue, total costs,
especially follow-up costs, increase when using cancellous bone grafts in
comparison to bone replacement biomaterials.
Although autogenic bone grafting is associated with a considerable
complication rate and secondary morbidity (Younger and Chapman, 1989;
Arrington et al., 1996), it is still the gold standard for bone replacement.
Introduction of synthetic materials has opened up a wider range of available
material during the last 10 years. nonetheless, the question of an optimal
bone substitute is still unsolved.
Given the numerous complications caused by bone harvesting at the donor
site, follow-up costs play a key role in medical decision making. Thus, since
the direct costs for alternative bone materials are comparable to the costs
for autologous bone grafting, surgeons are urged to take these materials into
account for the beneft of their patients and the health care system.
1.4 Social aspects of dental and maxillofacial
conditions
oral diseases such as dental caries, periodontal disease, tooth loss,
oropharyngeal cancers and orodental trauma are major public problems
worldwide. The experience of pain, problems with eating, chewing, smiling
and communication caused by missing, discoloured or damaged teeth have
a major impact on people’s daily lives and well-being. Furthermore, oral
diseases restrict activities at school, at work and at home, causing millions of
school and work hours to be lost each year throughout the world (Petersen et
al., 2005). Because the nature of most dental problems is not life-threatening,
but acute and normally are easily managable, their impact on well-being
is not obvious and is often minimized in the context of other more serious
chronic conditions (reisine, 1998).
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Within oral conditions, those involving tooth loss are among the ones with
a greater impact in society. Tooth loss in adult life may also be attributable to
poor periodontal health and more specifcally to the presence of periodontitis
and gingivitis conditions. Severe periodontitis is found in 5–20% of most
adult populations worldwide, especially adults between 35–44 years old,
whereas most children and adolescents present signs of gingivitis (WHo,
2004).
Dental erosion which consists of a progressive, irreversible loss of dental
hard tissue owing to chemical etching of its surface is a growing problem
among the population of several countries, affecting 8–13% of adults (Cate
and Imfeld, 1996). other oral conditions affecting people worldwide are
related to developmental disorders such as congenital diseases of the enamel
or dentine of teeth namely amelogenesis imperfecta, problems related to the
number, size and shape of teeth, and craniofacial birth defects such as cleft
lip and palate (Poulsen et al., 2008; WHo, 2004).
The current global distribution of oral disease is very variable and highly
dependent on the living conditions, lifestyles and the implementation of
preventive oral health systems in different countries. However, it is expected
that with the growing consumption of tobacco in developing countries, the
risk of periodontal disease and tooth loss is likely to increase. Periodontal
disease and tooth loss are also linked to chronic diseases such as diabetes
mellitus; the growing incidence of diabetes may have a negative impact on
the oral health of people in several countries. Thus, public health problems
related to tooth loss and weakened oral function are expected to increase,
particularly in many developing countries (Petersen et al., 2005)
one of the most important developmental disorders involving both dental
and craniomaxillofacial problems is the cleft lip and palate. The medical
condition of patients with cleft lip and palate problems is very complex as
it involves hearing, speech, learning, nutrition and socialization problems
as well as frequent surgery and prolonged diffcult dental care (Waite and
Waite, 1996). The incidence of cleft lip and palate varies enormously from
one country to another. native Americans show the highest incidences at
3.74 per 1000 live births, whereas a uniform incidence of 1:600 to 1:700
live births is reported among europeans. The incidences appear high among
Asians (0.82–4.04 per 1000 live births), intermediate in Caucasians (0.9–2.69
per 1000 live births) and low in Africans (0.18–1.67 per 1000 live births)
(WHo, 2002).
orodental trauma is another source of dental problems. Although there is
a lack of reliable data about the distribution and severity of this condition,
there are some studies reporting that most dental trauma relates to sports,
unsafe playgrounds or schools, traffc accidents or violence. Some studies have
reported dental trauma in about 15% of school children in latin American
countries and around 5–12% in some Middle east countries. Moreover, it
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