Biomaterials 21 (2000) 2615}2621

Clinical biocompatibility of biodegradable orthopaedic implants

for internal "xation: a review
O. BoK stman*, H. PihlajamaK ki
Department of Orthopaedic and Trauma Surgery, Helsinki University Hospital, Topeliuksenkatu 5, FIN-00260 Helsinki, Finland

Abstract

When the polymeric material reaches the "nal stages of its degradation process, biodegradable orthopaedic "xation devices elicit
a local foreign-body reaction. In most cases, the symptoms of this tissue response are subclinical and pass unnoticed, but in some
patients a clinically manifest in#ammatory foreign-body reaction ensues. Mild clinical reactions consist of a painful erythematous
papule, those of medium severity show a sinus discharging polymeric debris for up to 6 months, and in the patients a!ected by a severe
reaction, extensive osteolytic lesions may develop at the implant tracks. The histopathologic picture is that of a non-speci"c
foreign-body reaction. For implants made of polyglycolide, the average incidence of the manifest reactions is 5%. When slow-
degrading polymers are used, the incidence is lower. The tissue responses to polyglycolide manifest themselves 11 weeks after surgery,
on an average, whereas foreign-body reactions to devices made of poly-L-lactide can emerge as late as 4 or 5 yr after the original
fracture "xation operation. A poorly vascularized bone section, use of a quinone dye as an additive in the polymer, and an implant
geometry with large surface area each seems to be associated with an increased risk of the occurrence of a foreign-body reaction. Yet in
majority of the patients a!ected, no known individual marker of high risk is present. Some recent laboratory experiments indicate that
it may be possible to diminish the risk of an adverse tissue response by incorporating alkaline salts or antibodies to in#ammatory
mediators in the implants. The results of in vitro and animal experiments, however, cannot always be directly extrapolated to humans.
Only large-scale long-term clinical research will ultimately show which physico-chemical characteristics of a biodegradable ortho-
paedic implant provide the optimal clinical biocompatibility.  2000 Elsevier Science Ltd. All rights reserved.

Keywords: Biodegradable; Biocompatibility; Internal "xation; Review

1. Introduction The biocompatibility of a degradable internal "xation

The internal "xation devices used in orthopaedic sur-
gery serve no purpose as soon as they have ful"lled their
mission of securing the healing and union of the tissues
concerned. Biodegradable implants for internal "xation
were developed to eliminate the need for a second surgi-
cal intervention for removal of the devices. In addition,
the possible risks of retained metallic implants, such as
corrosion and stress-protection weakening of bone, can
be avoided. However, the advantages of biodegradable
devices are of little value, if the biocompatibility of the
materials is questionable. Besides su$cient mechanical
strength retention properties, an acceptable biocompati-
bility is a sine qua non when large-scale clinical introduc-
tion of biodegradable implants is considered.
* Correspondence address: Tiirasaarentie 24 C, FIN-00200 Helsinki,
Finland. Fax: #358 9 4718 7481.
E-mail address: Ole.bostman@Helsinki." (O. BoK stman).
device is strongly in#uenced by the degradation behavior
of the material utilized. The degradation of synthetic
biodegradable polyesters suited for manufacturing of
orthopaedic implants occurs principally by simple
hydrolytic scission and, to a lesser extent, through non-
speci"c enzymatic action, the main route of "nal elimina-
tion being respiration [1,2]. Despite the similarities in
metabolism, the rates of degradation between di!erent
polymers vary greatly, from a few months for polyglycol-
ide to "ve years or more for poly-L-lactide [3}6]. The
chemical composition of the polymer does not as such
determine the degradation characteristics of a "xation
device, but also the molecular weight, crystallinity,
thermal history and geometry of the implant are of
importance, as well as the tissue milieu surrounding the
implant. A porous thin sheet degrades more rapidly than
a compact block made of the same polymer. Likewise,
an implant is more e$ciently depolymerized by richly
vascularized cancellous bone than by dense avascular
connective tissue. In this review, the biocompatibility of

0142-9612/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved.
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2616 O. Bo( stman, H. Pihlajama( ki / Biomaterials 21 (2000) 2615}2621
biodegradable orthopaedic "xation devices is discussed
mainly from a clinical point of view.
2. Findings in pre-clinical and in vitro studies
The potential hazards of biodegradable materials are
numerous (Table 1). As with any other medical implant,
a degradable fracture "xation device must be free of toxic
and mutagenic e!ects, in particular. As long as the mater-
ials used are puri"ed synthetic polymers, with the con-
stituent monomeric units having a well-known and
simple structure, the theoretical risks of serious hazards
are small.
Histopathologic "ndings, typical of a non-speci"c
foreign-body reaction on microscopic examination, have
been reported in many experimental studies on synthetic
biodegradable materials [7}15]. The di!erent polymers
investigated in these studies included polylactide, poly-
glycolide, lactide}glycolide copolymers in various ratios,
and polydioxanone. Also, osteolytic changes around the
implants have been observed in test animals [4,13], but
no macroscopically evident in#ammatory foreign-body
reactions similar to those encountered in clinical practice.
Indeed, especially with regard to biocompatibility, it has
to be recognized that the results of animal experiments
cannot be directly extrapolated to humans.
Sarcomatous changes have been seen to develop at
polylactide implants placed in the soft tissues of rats [16].
In another study, however, no di!erence in the
tumorigenicity was found between implants made of
poly-L-lactide and those of polyethylene [17]. It seems
likely that such tumors merely represent the non-speci"c
tissue response to any foreign material, well-known in
rodents [18].
As for immunogenicity, polyglycolide was found to be
an inert compound, when studied in vitro using human
lymphocyte cultures [19]. In another in vitro study on
Table 1
Potential hazards of biodegradable orthopaedic implants
References
Toxicity
Cytotoxicity [4,12,18,75]
Tissue toxicity [5,11,13,15,25,27,35,
43,54,56}62,64}67]
Immunogenicity
Allergic reactions [20,21]
Other immunologically mediated reactions [19,20]
Mutagenicity
Teratogenicity [18]
Tumorigenicity
Cancerogenicity [17,18]
Sarcomatous tumors [16,17]
Favoring of infections [72]
serum derived from patients treated for osteochondritis
dissecans in the knee joint using polylactide pins, adverse
activation of the complement system was reported [20],
but the data on this issue still appear to be controversial
[21].
3. Clinical observations
3.1. General incidence of adverse tissue reactions
Soon after the clinical introduction of biodegradable
fracture "xation devices in the mid-1980s, it became
obvious that these materials sometimes provoke an ad-
verse tissue response that has the characteristics of an
in#ammatory, abacterial foreign-body reaction [22}27].
The "rst biodegradable synthetic polymers clinically
used in orthopaedic surgery on a larger scale, were based
on polyglycolide. Adverse tissue responses to "xation
implants made of polyglycolide have been reported in
more than 15 clinical studies, the incidence varying from
2.0 to 46.7% [28}43]. The highest reaction rates have
been observed in fractures of the distal radius and the
scaphoid bone [28,30,38]. In a recent survey, a clinically
signi"cant foreign-body reaction occurred in 107 patients
(5.3%) among 2037 patients who were treated using
polyglycolide implants, and in one (0.2%) among those
491 treated with polylactide implants [43]. The incidence
varied from 1.8%, in fractures at the elbow joint, to 25%,
in nonunited fractures of the scaphoid. In malleolar frac-
tures, the most common indication for the use of biode-
gradable implants in that series, the 95% con"dence
interval calculated for the reaction rate was from 4.9 to
7.8% when using "xation devices made of polyglycolide.
In studies concerned with polylactide implants, the
reaction rate has usually been lower than that with poly-
glycolide. In many clinical series, no adverse tissue
responses were reported [44}53]. However, in one study
on fractures of the ankle, the reaction rate to polylactide
plates was 47.4% [54]. Later on, the same research group
was able to eliminate the delayed local swelling kind of
tissue responses by changing their plate design into a less
bulky one [55]. The interval between the "xation opera-
tion and the clinical signs of a reaction to polylactide
implants is, as a rule, considerably longer than with
polyglycolide. A foreign-body reaction to biodegradable
implants made of poly-L-lactide can manifest itself as late
as 4 or 5 yr after the original operation [5,56,57]. Accord-
ingly, in clinical reports with maximum follow-up times
less than 4 yr, no foreign-body reactions to poly-L-lactide
may be encountered, regardless of how high the ultimate
true incidence of such late reactions might be. Because
relevant long-term clinical data on the slow-degrading
polymers are so far limited, the incidence of late foreign-
body reactions to poly-L-lactide devices cannot be deter-
mined yet.
 O. Bo( stman, H. Pihlajama( ki / Biomaterials 21 (2000) 2615}2621 2617

The clinical use of implants made of other biodegrad-

able polymers, e.g. polydioxanone and polyglycolide-
CO-trimethylene-carbonate, has been less frequent than
that of polyglycolide and polylactide, but sporadic
foreign-body reactions have been reported for these
materials, too [58,59].

3.2. Clinical characteristics of the reactions

Among the patients treated with polyglycolide devices,

the average interval between the operation and the "rst
clinical signs of an in#ammatory foreign-body reaction is
from 10}12 weeks [25,31,43]. The clinical spectrum of the
tissue responses is broad (Table 2). Mild reactions may Fig. 1. A foreign-body reaction to biodegradable "xation devices made
pass unnoticed. The typical foreign-body reaction ini- of polyglycolide often results in a sinus discharging polymeric debris.
tially presents as a suddenly emerging painful, The typical appearance of such a persistent sinus is seen here on the
erythematous, #uctuating papule over the implant track. lateral side of the left ankle of a 43-yr-old man with a bimalleolar
Unless immediately aspirated or incised, the papule usu- fracture that was treated by open reduction and internal "xation using
polyglycolide screws. The sinus emerged 11 weeks after the operation.
ally bursts within a few days and reveals a sinus discharg- Despite surgical debridement procedures, it continued to discharge for
ing liquid remnants of the disintegrated implant (Fig. 1). 10 weeks.
The average duration of the discharge is 6 weeks, but it
may continue for up to 6 months. Bacterial cultures do
not grow anything, unless a secondary infection ensues.
Surgical debridement under local or general anesthesia is
often required. In intra-articular "xations at large joints,
such as knee and elbow, sterile synovitis is often a con-
spicuous clinical feature of an acute tissue reaction to
biodegradable implants [60}64].
Radiographs obtained at the time of the clinical mani-
festation of the adverse tissue responses show osteolysis
along the implant tracks (Fig. 2) in approximately one-
half of the patients [65,66]. The bony architecture at the
osteolytic foci is radiographically restored within 1 yr,
but irreversible articular damage may occur already dur-
ing the acute phase of the reaction [67].
Biopsy specimens show a rather uniform his-
topathologic picture of a non-speci"c in#ammatory
foreign-body reaction with abundant polymeric particles,
birefringent under polarized light (Fig. 3), being sur-

Table 2
Adverse tissue response patterns to biodegradable "xation devices

References

Mechanical irritation at protruding
subcutaneous implants
In#ammatory foreign-body reactions
Sterile sinuses discharging polymeric
debris
Secondary bacterial infection and
sloughing of skin
Intra-articular synovial in#ammation
Osteolytic lesions around implant
tracks
Late osteoarthritic changes after earlier
foreign-body reactions
[54,68,69] Fig. 2. Osteolytic lesions (asterisks) at the implant tracks in a 45-yr-old
woman with a trimalleolar fracture of the right ankle that was treated
[5,25,28,30,35,43,54,56}59] by open reduction and internal "xation using polyglycolide screws.
[25,27,29,39,43] This anteroposterior radiograph was obtained 9 weeks after the opera-
tion. Discharging sinuses developed on both the medial and lateral
[27,67] sides of the ankle. Severe osteoarthritis later developed.
[43,60,61,64]
[62,65}67] rounded by mononuclear phagocytes and multinucleated
foreign-body giant cells [25,27,28,39,60,62]. No signs of
[67] malignancy have been reported in humans. The clinical
features and the histologic "ndings of the adverse tissue
2618 O. Bo( stman, H. Pihlajama( ki / Biomaterials 21 (2000) 2615}2621
Fig. 3. The characteristic histopathological picture of a non-speci"c
foreign-body reaction to biodegradable implants. This specimen was
taken from the ankle of a 33-yr-old woman 4.8 yrs after the "xation of
a bimalleolar fracture with poly-L-lactide screws. Five months earlier,
a clinically manifest in#ammatory foreign-body reaction had emerged.
Polymeric particles of various sizes (asterisks) are seen surrounded by
foreign-body giant cells. Masson-Goldner stain, original magni"cation
350;.
responses to polylactide implants seem to be quite similar
to the reactions reported when using polyglycolide devi-
ces, although discharging sinuses are rare in foreign-body
reactions to polylactide. On microscopic examination,
large amounts of polymeric debris were still seen in the
tissues when a biopsy specimen was obtained 57 months
after the "xation of an ankle fracture with poly-L-lactide
screws [57]. Immunohistochemically, T lymphocytes
were found to be present in that case. In addition to the
frank foreign-body reactions, persisting subcutaneous
poly-L-lactide screw heads in the ankle have necessitated
surgical removal of the protruding parts of the implant in
a few patients [68,69]. The mildest reactions lack clinical
signi"cance as they do not increase the morbidity of the
patients. The average total costs for a foreign-body reac-
tion per patient a!ected have been estimated at $1218
[70,71].
3.3. Markers of high risk
The foreign-body reaction rate seems to be indepen-
dent of the age and gender of the patients. In the two
largest clinical series, the polymer volume implanted did
not signi"cantly di!er between the patients with and
those without a foreign-body reaction [25,43]. In con-
trast, a correlation has been reported between the poly-
mer volume and the frequency of bacterial infections
[72].
The presence of a quinone dye as an additive in poly-
glycolide clearly increased the risk of a reaction, the odds
ratio being 2.1 [27,43]. Also, the geometry of the implant
appears to in#uence the reaction rate, screws showing
a higher incidence of adverse tissue responses than cylin-
drical pins and rods. There seems to be an inverse associ-
ation between vascularity of the tissues concerned and
the reaction rate. Bone sections with a recognizably poor
vascularity by nature, such as the scaphoid, show an
over-representation of adverse tissue responses [38].
A su$cient debris-clearing capacity of the tissues is prob-
ably essential to prevent the accumulation of a local
overload of polymeric degradation particles.
4. Conclusions
The foreign-body reactions to biodegradable polymers
obviously represent an inherent biologic tissue response
to the degradation and absorption processes of these
materials. To our knowledge, no mutagenic e!ects of
these materials have been recorded in humans. Also, the
toxic and immunogenic hazards seem to be of minor
clinical signi"cance. Instead of indicating a direct toxic
in#uence, the osteolytic response seen to accompany the
foreign-body reactions is likely to be the result of non-
speci"c activation of the bone-resorbing mechanisms by
the hydrolyzed polymeric debris. Also, non-degradable
polymeric particles are known to activate macrophages
and cause osteolysis [73].
Although the reaction rate for the slow-degrading
stereoisomeric forms of polylactide is so far unsettled, the
fast-degrading polymers such as polyglycolide are prob-
ably associated with a higher incidence of adverse tissue
responses than the slower ones. A meaningful compari-
son of the complication rate between implants made of
the same polymer but by di!erent manufacturers is ren-
dered di$cult by the fact that raw materials from di!er-
ent sources often considerably di!er from each other in
their physico-chemical characteristics [3,8,10,74}80],
which, in turn, may a!ect the biocompatibility of the
implants. Such characteristics include molecular weight,
inherent viscosity, thermal history, residual monomer
content, degree of crystallinity and porosity of the
implant as well as the presence of additives and
impurities in the polymer, and the method of fabrication
and sterilization of the implants.
Polyglycolide also di!ers from polylactide in that poly-
glycolide is a stronger acid and behaves more hydrophili-
cally than polylactide, which is more hydrophobic
because of its methyl groups. The decrease of pH values
in the tissues adjacent to degrading biodegradable poly-
esters may contribute to adverse e!ects. Consequently,
one of the methods to diminish the adverse e!ects (Table
3) could be to incorporate basic salts within the polymer.
Promising results have already been presented in an in
vitro study [81]. Recently, it has also been shown that
foreign-body reactions to biodegradable biomaterials in
rat can be modulated by impregnating the implant with
an antibody against a macrophage-activating T-cell-
derived cytokine [82].
 O. Bo( stman, H. Pihlajama( ki / Biomaterials 21 (2000) 2615}2621
Table 3
Possible methods of diminishing the incidence and intensity of adverse
tissue e!ects of biodegradable orthopaedic implants
Modifying the geometry of the devices into a less-bulky
design with a small surface-area, i.e. reactive tissue}
implant interface
Modifying the operative technique by avoiding poorly
vascularized regions and direct synovial contact with
the implant
Incorporation of alkaline salts within the implant to
diminish the pH decrease in adjacent tissues during
degradation
Impregnating the implant with antibodies against
recipient-tissue in#ammatory mediators
A very long degradation time of several years,
although advantageous from a biocompatibility point of
view, may be a disadvantage in some clinical situations,
as the implant then behaves much like a metallic one. The
long degradation time of implants made of poly-L-lactic
acid homopolymer has led to a search for suitable biode-
gradable macromolecular compounds with depolymeriz-
ation times of intermediate length, to degrade more in
concert with the fracture repair dynamics. Much interest
has been focused on stereocopolymers of lactic acid
[83,84]. In its amorphousness, racemic polylactide is
unsuited for the purpose, but the combination of repeat-
ing units of L- and D-opposite chiral con"gurations in
di!erent enantiomeric ratios provides a means of adjust-
ing the degradation rate of polylactide stereoforms. The
clinical experience of implants made of D,L-
stereocopolymers of lactic acid is so far limited.
To avoid the diagnostic confusion that can result from
the "nding of an unexpected in#ammatory lesion, ortho-
paedic and trauma surgeons should be aware of the
possibility of very late foreign-body reactions to biode-
gradable implants with a long degradation time. This is
of increasing importance, as the clinical use of devices
made of polylactide is expanding in new applications
such as arrow repair of meniscal lesions and interference
screw "xation in reconstruction of the anterior cruciate
ligament of the knee [50,64,78,80,85,86].
The results of current and future research may be able
to provide means to diminish the incidence and intensity
of the adverse tissue reactions, but today, it seems that
the unpredictable foreign-body reactions constitute the
price that the patients and surgeons are obliged to pay
for the indisputable advantages of biodegradable
implants. Also a low reaction rate is of clinical import-
ance when common fractures are to be treated. The
increasing clinical use of biodegradable implants within
vascular, urologic and abdominal surgery will, in due
time, produce supplementary data on the biocompatibil-
2619
ity of these polymers. Scrupulous large-scale, long-term
clinical follow-up studies are necessary to verify the ulti-
mate biocompatibility of biodegradable orthopaedic im-
References plant and to establish scienti"cally proven treatment
methods.
[3,43,55]
Acknowledgements
[43,67]
This study was supported by grants from the Research
[81] Funds of Helsinki University Hospital, and the Funds of
the Scienti"c Advisory Board for Defence.
[82]
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