Biomaterials 21 (2000) 2635}2652

Pre-clinical in vivo evaluation of orthopaedic bioabsorbable devices

Yuehuei H. An*, Shane K. Woolf, Richard J. Friedman
Musculoskeletal Research Laboratory, Department of Orthopaedic Surgery, Medical University of South Carolina, 96 Jonathan Lucas Street,
Suite 708, Charleston, SC 29425, USA

Abstract

The presence of bioabsorbable materials in orthopaedics has grown signi"cantly over the past two decades with applications in
fracture "xation, bone replacement, cartilage repair, meniscal repair, "xation of ligaments, and drug delivery. Numerous biocompat-
ible, biodegradable polymers are now available for both experimental and clinical use. Not surprisingly, there have been a wealth of
studies investigating the biomechanical properties, biocompatibility, degradation characteristics, osteoconductivity, potential toxic-
ity, and histologic e!ects of various materials. Promising results have been reported in the areas of fracture "xation, ligament repair,
and drug delivery. In this article we review the pre-clinical in vivo testing of bioabsorbable devices with particular emphasis on
implants used for these applications.  2000 Elsevier Science Ltd. All rights reserved.

Keywords: Bioabsorbable polymers; Orthopaedics; In vivo; Pre-clinical testing; Biocompatibility

1. Introduction Since Kulkarni et al. introduced the concept of bioab-

Over the past two decades, bioabsorbable devices have
been utilized and experimented in many aspects of ortho-
paedic surgery, including "xation of fractures, bone re-
placement, cartilage repair, meniscal repair, "xation of
ligaments, and drug delivery. Absorbable materials
have been used in the form of screws, pins, plugs,
and plates for orthopaedic, oral, and craniofacial
surgery. However, the major clinical orthopaedic
applications thus far are "xation of fractures and
osteotomies and interference screws for ligament repairs.
Depending upon their constituent polymers, these mater-
ials can be tailored to provide su$cient rigidity to
allow bone healing, retain mechanical strength for a
period of time, and then eventually begin to undergo
degradation. The material properties of the ideal polymer
are a delicate balance between mechanical, thermal, and
viscoelastic factors. The earliest and most commonly
used absorbable materials include polyglycolic acid
(PGA), polylactic acid (PLA), PGA}PLA copolymers,
and poly(ortho esters) [1,2]. Numerous other materials
have been developed and used experimentally in recent
years.
* Corresponding author. Tel.: #1-843-792-8169; fax: #1-843-792-0243.
E-mail address: any@musc.edu (Y.H. An).
sorbable materials in the 1960s [3,4], animal models have
contributed to the success of the clinical use of these
materials. Rabbits have been the standard for in vivo
modeling of biocompatibility, but rats, dogs, sheep, and
pigs have all been utilized to varying degrees. The typical
areas of study have included soft tissue and bone implant
compatibility, degradation properties, and mechanical
strength testing. The ultimate goal of this research is the
development of bioabsorbable, biocompatible materials
with the appropriate strength and degradation character-
istics to allow for regular clinical use for treating ortho-
paedic problems in human patients. This article reviews
basic concepts of bioabsorbable materials, pre-clinical
research, and evaluation techniques with emphasis on
researching devices potentially useful in orthopaedic
applications.
2. Basics of bioabsorbable materials
2.1. Common bioabsorbable materials
Numerous biodegradeable polymers are presently be-
ing used or have potential roles in medical applications.
The most common types, high molecular weight poly-
hydroxyacids, are formed by a ring-opening polymeriz-
ation of cyclic diesters (Fig. 1) [5]. The polymers most

0142-9612/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved.
PII: S 0 1 4 2 - 9 6 1 2 ( 0 0 ) 0 0 1 3 2 - 0
2636 Y.H. An et al. / Biomaterials 21 (2000) 2635}2652
Fig. 1. Ring-opening polymerization of cyclic diesters to create poly-
hydroxyacids.
widely used in medicine today are PGA, PLA, and their
copolymers [6,7], although various polyhydroxyacids
are increasingly available on the commercial market
[5,8}11]. Other materials more recently available include
poly(ortho esters), poly(glycolide-co-trimethylene car-
bonate), poly(p-dioxanone) [PDS], poly(e-caprolactone)
[PCL], poly(b-hydroxybutyrate) [PHB], and poly
(PHB-hydroxyvaleric acid) [1,7,12}15]. In addition,
pseudo-poly(aminoacids) or polyiminocarbonates, for-
med when amino acids are linked by nonamide bonds,
have shown promise for their biocompatibility and
mechanical properties. Poly(Dat-Tyr-Hex), for instance,
has potential as a high strength "xation material in
orthopaedics because of its stability and biocompatibility
[7,16,17].
2.2. Biodegradation
The rate of polymer biodegradation depends on many
factors, such as the size of the implant, the kind of
materials, the molecular weight of the material, the ma-
terial phase (crystalline versus amorphous), the racemic
mixture of the polymer, the presence of additives or
impurities, the mechanism of degradation (enzymatic
cleavage versus hydrolysis), the implantation sites (sub-
cutaneous tissue or bone), stress on the implant, and even
the age of the host animals [12,18,19]. Likewise, the
desired biodegradation properties of these materials vary
depending upon the intended orthopaedic use (e.g. frac-
ture "xation versus drug delivery).
Polyhydroxyacids are thought to degrade by stages in
vivo. The "rst stage is a nonspeci"c hydrolytic scission of
their ester bonds which begins upon contact with water
(Fig. 2). The carboxylic acid end groups of the polymers
autocatalyze this reaction. Through hydrolysis, PLA
molecules are degraded in vivo to lactic acid and PGA to
glycine which can enter the tricarboxylic acid cycle and
be excreted in the form of water and carbon dioxide
(Fig. 3). PGA and PDS degradation products are
Fig. 2. Nonspeci"c hydrolytic cleavage of ester bonds begins upon contact with water.
excreted by the kidneys as well [20]. It is known that
PGA is also broken down by enzymes like esterase [21],
and that breakdown of PLA may be in part mediated by
enzymes [5]. Hydroxyl radicals are thought to contribute
to the biodegradation of polycaprolactone (PCL) and
possibly other polyhydroxyacids [15]. The degradation
of bulky PGA, PLA and some poly(ortho ester) implants
releases acidic by-products via hydrolysis which can ac-
celerate the process over time. This is due to the slower
rate of outward di!usion of high molecular weight degra-
dation products from the inner portion of the material
compared to di!usion from the surface into surrounding
tissues. An acidic environment is created in this central
portion as the concentration of carboxylic end groups
increases relative to surrounding tissues, thus
autocatalyzing the hydrolytic reaction. Subsequently,
a heterogenous process ensues with resorption of the
surface and central material occurring before the implant
mantel [5,7,22]. With other more hydrophobic
poly(ortho esters), water is restricted to the surface of the
material where nonacidic degradation products are "rst
produced. Acidic degradation products slowly accumu-
late as surface hydrolysis predominates [18].
In addition, the molecular characteristics of R-groups
and degree of crystallinity of the polymer dictate hydro-
phobicity and thus in#uence the rate of hydrolysis by
a!ecting di!usion of water into the material. Hydrophilic
and amorphous regions of polymers allow better access
to water molecules. For example, PLA with a methyl
R-group degrades slower than PGA (R"hydrogen). The
L-isomer of PLA (PLLA) is much more crystalline than
its amorphic D-isomer (PDLA) and subsequently more
biostable. Copolymers of PLA}PGA or PDLA}PLLA
(PDLLA), however, are less crystalline, less hydrophobic,
and tend to have faster rates of hydrolysis [9,10,23].
The degradation of bioabsorbable polymers begins
upon contact with tissues in vivo. Some polymers de-
grade completely in about 5}8 weeks. SR-PGA exhibits
complete strength loss by one month and fully degrades
in about three months. Other polymers, such as pure
PLLA and SR-PLLA, may take years to break down
[20,23}25]. Depending upon the rate of polymer degra-
dation, mechanical strength may decline well before ad-
equate union of fractures or healing of tissues is achieved.
Thus, a race between biological repair and mechanical
strength of the implant ensues. Rate of absorption has
other important considerations. With some bulk mater-
ials, the degradation product load is either too great or is
too rapidly released for it to be completely absorbed and
 Y.H. An et al. / Biomaterials 21 (2000) 2635}2652
Fig. 3. Routes of elimination for commonly used polyhydroxyacids. Enzymes, free radicals, and immune cells are also thought to play various roles in
the degradation of bioabsorbable materials.
excreted. PGA implants have been found to produce
#uid-"lled sterile sinuses with subsequent drainage
[2,26]. Conversely, pure PLLA is highly crystalline and
resorbs slowly. SR-PLLA takes up to 5}6 years to resorb
completely. The somewhat more amorphous PDLLA
resorbs over 2}3 years, leaving behind crystallites that
can elicit an in#ammatory response. A PGA}PLA
copolymer will resorb di!erently depending upon the
copolymer ratios [20,23,25].
2.3. Mechanical properties of bioabsorbable materials
The requirements for polymer implants used to hold
fracture or osteotomy fragments together are that they
remain strong until bone union is achieved, normally
about 4}8 weeks, and yet degrade completely once their
mechanical strength is no longer needed. For drug deliv-
ery, a consistent, predictable rate of degradation and
drug release is desirable. Carriers for bone morphogenic
proteins should promote osteogenesis with concurrent
polymer degradation. Most of the polymer screws and
rods have been applied in areas of low stress [27]. Poly-
mer screws are not recommended for use without ex-
ternal support in sites of high mechanical stress [27,28].
Displacement of bone fragments has been reported,
ranging from minor (several millimeters) to severe
[29}31]. However, quality and strength of "xation is
a function of the type of polymer material. Self-reinforced
PGA (SR-PGA) has been reported to perform better
[32}35].
The tensile yield strength for PLLA has been reported
in the range of 11}72 MPa [18] and for PGA, 57 MPa
[36]. Tensile yield strength for PCL is 19}21 MPa
[37,38]. Flexural strengths for PLA are reported between
45 and 145 MPa [18]. POE has a tensile strength of
2637
about 30 MPa and #exural strength of 65}66 MPa
[39,40]. The greatest #exural strengths demonstrated in
fully biodegradable polymers are between 195 and
375 MPa for PGA-"ber-reinforced PGA composites
(SR-PGA) [8]. PGA reinforced with PLA "bers has
a #exural strength of 250 MPa [41]. These values com-
pare favorably with stainless steel at 280 MPa. Although
"ber reinforcement can improve the maximum strength
of the material, it does not always improve the #exural
modulus of the material, which remains very low
(1.6}27 GPa for various reinforced and non-reinforced
polymers compared to 200 GPa for stainless steel) [24].
Another advantage of bioabsorbable plates is that they
may be adapted to "t bone geometry in vivo by heating
above the glass transition temperature (¹ ). Pietrzak

et al. [6] heated plates made of PLLA/PGA copolymers
above their ¹ and found a transient 20% reduction in

the #exural modulus with an increase of approximately
50% in energy to failure. Upon cooling, the plates
demonstrated baseline mechanical properties and did
not appear to lose strength any faster than nonheated
plates [6].
3. Biocompatibility
3.1. Biocompatibility and biodegradation testing
in soft tissues
Subcutaneous or intramuscular implantation is the
"rst in vivo step of testing a bioabsorbable polymer for
its biocompatibility and degradation properties (Table 1).
Rats are suggested as the "rst choice for soft tissue
degradation studies because of their low cost and the
rich background data for the animal. In the rat, bone
 2638

Table 1
Degradation of bioabsorbable materials in vivo * subcutaneous and intramuscular implantation (Adapted from An and Friedman [115])

Animal References Implant site Material tested Period Mass/mol. weight In#ammatory Mechanical strength
(Wks) (MW) degradation reaction after implantation

Mouse Gogolewski [116] SC PLA, PHB
, PHB/VA 24 56}99%/24 weeks #or## N/A

Rat Schakenraad [117] SC Glycine/DL-lactic acid discs 10 100% ### N/A

Bos [118] SC PLA 143 14%/80 weeks #or## N/A
Gerlach [42] IM PLA rods 108 N/A # 50% of original at 4 weeks
Pistner [119] IMC PLA (crystalline; 429,000 Mvis) 116 No change #at "rst few weeks N/A
PLA (amorphous; 203,000 Mvis) 116 100% ### N/A
PLA (amorphous; 120,000 Mvis) 116 100% ## N/A

Rabbit Nakamura [120] IM PLA, puri"ed 52 No change/40 weeks N/A 50% decrease
Richards [121] IM 4 Poly (phosphoesters) 70 80%/70 weeks # N/A
TormaK laK [35] SC PGA 8 N/A N/A Lost mech. strength at 4}7 weeks
Kumta [43] SC PGA rods 21 N/A N/A 64% decrease at 2 weeks
Matsusue [44] SC PLA rods 78 91% (MW)/12 weeks # 100% decrease at 25 weeks
Bhatia [12] SC, IM, bone Absorbable pins (Orthosorb) 5 N/A N/A Decreased di!erently at each site
Tschakalo! [60] SC PLA plates 6 87% (MW) No N/A
Ertel [16] IM, bone Poly(DTH carbonate) 26 Started at 26 weeks No N/A
and PDS pins PDS partially absorbed ##, bone resorption N/A
Y.H. An et al. / Biomaterials 21 (2000) 2635}2652

Matsusue [45] SC PLA rods 276 100%/27 6 weeks No 100% decrease at 276 weeks

SC"subcutaneous; CIM"intramuscular.

PHB"poly (3-hydroxybutyrate).
PHB/VA"poly (3-hydroxybutyrate-co-3-hydroxyvalerate).
Note:#"slight; ##"moderate; ###"signi"cant.
 Y.H. An et al. / Biomaterials 21 (2000) 2635}2652 2639

elongation ceases by age 6}9 months, and the remaining by many investigators [35,42}45]. We recommend
lifespan of the animal after that time is about 12}15 a standard disc measuring 10 mm in diameter and 1 mm
months. If the observation period is planned to be longer in thickness be used for histological studies of mass
than 12}15 months, rabbit models should be considered degradation or molecular weight degradation studies us-
instead. ing a viscosimeter. A sample of this size is easy to make
Implants are inserted into pouches in the subcu- and readily implantable.
taneous tissue or into muscles. The exact site in the
subcutaneous tissue (back, inner aspect of the thighs, or 3.2. Biodegradation in bone tissue
abdominal wall) or into which muscle group (back
muscles, thigh muscles, or abdominal muscles) the im- If the material is to be used inside of or in contact with
plant is placed does not matter. However, most re- bone, testing of bioabsorbable implant degradation in
searchers use the back subcutaneous tissue or the back bone tissue should follow soft tissue implantation once
muscles for implantation simply because of the conveni- biocompatibility has been established. Although di!erent
ence reaching the samples and the large area and volume animal models have been used, the rabbit has been the
of these tissues. most popular model for testing these conditions
Up to six implants, discs 10 mm in diameter and 1 mm [16,43}45]. Implants in the forms of rods, plugs, pins, or
thick, can be implanted on the back of each rat (Fig. 4), screws are most often placed in the cancellous bone of the
while 8}10 implants can be inserted into the back of each distal femur in the rabbit through drill holes (Fig. 5A and
rabbit. Implantations can be performed either through B) [16,43}49]. Diaphyseal implantation has also been
one large midline incision or through multiple small ones. used in di!erent animals (Fig. 5C) [48}50]. Table 2
The key is that the sample is placed into the correct layer;
the loose subcutaneous tissue space or the paravertebral
muscles. For testing degradation of mechanical properties,
rod-shaped samples (3.2 mm in diameter and 50 mm long)
are often used. At least six rods can be implanted into the
back of an adult rabbit. The time duration used to observe
degradation ranges from 1 month to 5 years. As stated
above, for studies greater than 1.5 years, the use of rabbit
models should be considered.
Standardizing sample shape and size is very important
for comparing data between research groups. Soft tissue
implantation is suitable for standardized testing of mech-
anical and mass degradation because the implant is more
retrievable compared to bone implantations. An absorb-
able material sample measuring 3.2 mm in diameter and
50 mm in length is suggested for studying changes in the
mechanical properties of the material and has been used

Fig. 4. Schematic diagram showing soft tissue implantations inserted

subcutaneously or intramuscularly into the back of a rat. (Reprinted
with permission from Animal Models in Orthopaedic Research. Chap-
ter 12. Animal models for testing bioabsorbable materials. Yuehuei
H An, Richard J Friedman, editors. Boca Raton: CRC Press, 1999.
Copyright Lewis Publishers, an imprint of CRC Press, Boca Raton,
FL.)
Fig. 5. Schematic diagram showing di!erent in-bone implantation sites
useful for testing bioabsorbable materials. (Reprinted with permission
from Animal Models in Orthopaedic Research. Chapter 12. Animal
models for testing bioabsorbable materials. Yuehuei H An, Richard
J Friedman, editors. Boca Raton: CRC Press, 1999. Copyright Lewis
Publishers, an imprint of CRC Press, Boca Raton, FL.)
 2640

Table 2
Animal models of bioabsorbable implant degradation in bone tissues (updated from An and Friedman [115])

Animal Bone References Site Material tested Period Degradation In#ammatory Mechanical property of
(weeks) reaction materials

Rat Femur Cutright 1974 [25] Upper femur drill hole PGA, PLA, copolymers 31 100% in 14}31 weeks No N/A

Rabbit Femur VainionpaK aK 1986 [122] Intercondylar area PGA rods 12 Started in 6 weeks No N/A
MaK kelaK 1989 [123] Intercondylar area PDS rods 36 Nearly 100% in 36 weeks N/A N/A
Knowles 1992 [48] Diaphyseal drill holes PHB plugs 19 - N/A N/A for the material
Kumta 1992 [43] Medullary canal PGA rods 3 Broken down in 3 weeks N/A 73% bending strength
Matsusue 1992 [44] Intercondylar area PLA rods 70 22%52 weeks,70%78 weeks # 100% loss at 25 weeks
BoK stman 1994 [46] Intercondylar area PGA pins and screws 48 100% in 36 weeks ? N/A
Fini 1995 [47] Medullary canal PLA (high MW) rods 64 0% No Flexural sti!ness
Matsusue 1995 [45] Intercondylar area PLA rods 248 100%/24 in 8 weeks No N/A
Voche 1995 [124] Medullary canal PLA rods 156 100% macroscopically No N/A
Tibia VainionpaK aK 1986 [49] Diaphyseal drill holes PGA rods 12 Started in 6 weeks No N/A
Ertel 1995 [16] Medial tibial plateau Poly(DTH carbonate) 26 Started at 26 weeks No
and PDS pins PDS partially absorbed ##, osteolysis N/A
Peri-orbital Kellman 1994 [125] 1.5 mm drill holes PLA, PLA/TMC , PGA 32 N/A ## No strength at 32 weeks
screws

Dog Femur Miettinen 1992 [126] Intramedullary implant SR-PGA implant 24 Started in 3}6 weeks No N/A
Suganuma 1993 [127] Distal metaphysis PLA in a bone chamber 24 20% in 24 weeks ## N/A
Andriano 1999 [114] Intramedullary implant SR-PGA pin 12 Pasty at 3 months N/A not tested
Y.H. An et al. / Biomaterials 21 (2000) 2635}2652

POE pin 78 Some internal resorption N/A '99% strength loss

Goat Femur Verheyen 1993 [50] Diaphysis drill holes PLA, PLA/HA plugs 104 Obvious for pure PLA Lymph nodes N/A

Pig Femur van der Elst 1996 [128] Medullary cavity PLLA powder 8 - # N/A
Mandible Schliephake 1993 [129] Hole below the mandibular PDS pins 26 100% in 22}26 weeks N/A N/A
canal

PLA/TMC"polylactic acid/trimethylene carbonate copolymer.

Note: #"slight; ##"moderate.
 Y.H. An et al. / Biomaterials 21 (2000) 2635}2652 2641

demonstrates the biocompatibility and degradation pat-
terns of various materials when implanted into living
bone.
4. Experimental applications
4.1. Fixation of fractures and osteotomies
The representative models of epiphysometaphyseal os-
teotomies (Table 3) include the osteotomy of medial tibial
plateau in the rabbit (Fig. 6A) [51], Salter}Harris type IV
fracture in the dog (Fig. 6B) [52], the femoral transcon-
dylar osteotomy in the rabbit (Fig. 6C) [49,53], and the
lateral femoral condyle osteotomy in the dog (Fig. 6D)
[54].
Femoral transcondylar osteotomy in rabbits is a well-
established model [49,53]. Salter}Harris type IV fracture
in the dog femur or a similar osteotomy created at the
medial tibial plateau by Matsusue et al. [51] are other
excellent models for the epiphysometaphyseal area. The
forces that the absorbable screw is subjected to are
simple, either on the lateral or the medial side of the knee
joint. The proximal-to-distal shearing force is sustained
by the transverse portion of the osteotomy. Another
interesting model is the subcapital femoral neck os-
teotomy in sheep, which is a more demanding site for
"xation because of weight bearing [55].
For the lateral femoral condyle osteotomy in dogs,
a unilateral model is recommended because of the
amount of surgical injury created [54]. Through a lateral
approach, an osteotomy from the superolateral aspect of
the condyle to the intercondylar notch in the knee joint is
made and the osteotomy is secured with two screws. The
advantage of this model is the instability of the os-
teotomy (high shear force to the screws), which chal-
lenges the e$cacy of the "xation devices. The e!ect of
bioabsorbable screws on the cancellous bone healing can
be evaluated with a trephined plug model in the canine
distal femur (Fig. 7) [54].
Very few diaphyseal models are available (Table 4).
The "rst diaphyseal model was reported by VainionpaK aK
et al. [56], in which a tibial osteotomy was "xed with
a T-shaped PGA/PLA copolymer implant (Fig. 8A). Ob-
lique fractures of metacarpal bones in calves were also
"xed with PLA tension screws (Fig. 8B) [57]. Models of
femoral osteotomy "xed with PLA, SR-PLA, or SR-PGA
intramedullary rods have been reported in the dog, rab-
bit, and cat (Fig. 8C and D) [52,58,59]. The intramedul-
lary rod can be inserted through the greater trochanter or
retrograde through the intercondylar notch. These stud-
ies showed that the bioabsorbable rods were strong
enough to be used for intramedullary nailing of femoral
diaphyseal osteotomies in the three animal species
tested. In the authors' laboratory, healing of a trephined
femoral diaphyseal osteotomy in the dog has been used
to observe the e!ect of "xation using a PGA/PLA (80/20
ratio) screw (Fig. 7) [54]. In most of the reports, bone
consolidation normally occurred in 6}8 weeks
[54,56,59].
Models of mandibular osteotomies are most popular
and well established in dogs and sheep (Fig. 9A). Rabbits
are not suitable for mandibular models because they do
not have a long enough mandible for "xation with im-
plants. Few models using zygomatic or nasal bones have
been reported using rabbits (Fig. 9B and C) [60,61].
Based on anatomical features, dogs can be used for these
two models. The most common form of bioabsorbable
"xation devices for these models are mini plate and
screws although the use of absorbable suture and screws
only has also been reported (Table 5). More recently,
bioabsorbable materials have seen some application in
"xation of fractures and osteotomies in human patients
(Table 6).

Fig. 6. Schematic diagrams showing di!erent epiphysometaphyseal implantation models: (A) osteotomy of medial tibial plateau in the rabbit; (B)
Salter}Harris type IV fracture in the dog; (C) the femoral transcondylar osteotomy in the rabbit; and (D) the lateral femoral condyle osteotomy in the
dog. (Reprinted with permission from Animal Models in Orthopaedic Research. Chapter 12. Animal models for testing bioabsorbable materials.
Yuehuei H An, Richard J Friedman, editors. Boca Raton: CRC Press, 1999. Copyright Lewis Publishers, an imprint of CRC Press, Boca Raton, FL.)
 2642

Table 3
Animal models of "xation of epiphysometaphyseal osteotomies of long bones and irregular bones of the limbs using bioabsorbable materials (Adapted from An and Friedman [115])

Animal Bone Reference Osteotomy or fracture Material Period Degradation In#ammatory Fracture healing
(Weeks) reaction

Rat Femur Majola [130] Transcondylar SR-PLA, SR-PDLA/PLLA 48 Started at 12 Weeks No 95% healed (48 weeks)

Rabbit Femur VainionpaK aK [49] Transcondylar PGA thread and rods 24 Started at 6 weeks N/A Healed (6 weeks)
Vihtonen [131] Transcondylar PGA thread (Dexon) 24 N/A N/A 79% healed (6 weeks)
Vihtonen [132] Transcondylar Bone cement, PGA thread 48 N/A N/A 65% healed
Vasenius [133] Transcondylar SR-PGA rods 48 100% in 24-36 weeks No 99% healed
Plaga [134] Oblique medial condyle PDS pins 6 N/A N/A 86% healed
BoK stman [135] Transcondylar PGA screws 36 100%/36 weeks ## Healed
Otsuka [136] Transphyseal PDS pins 16 100%/16 weeks No Physes intact
PaK ivaK rinta [137] Transcondylar PGA screws 48 100%/36 weeks # or ## Healed
PLA screws 48 0%/48 weeks # or ## Healed
PihlajamaK ki [53] Transcondylar PLA expansion plug 24 N/A No Healed
PihlajamaK ki [138] Transcondylar SR-PLA expansion plug 24 N/A No 75% Healed (24 weeks)
Cady [13] Transphyseal PDS pins 12 Started at 3 weeks 0%/12 weeks Physes intact
Tibia Matsusue [51] Prox. tibial osteotomy PLA or stainless steel screws 16 N/A # Healed

Dog Femur An [54] Lateral condyle osteotomy PGA/PLA screws 68 '95%/68 weeks No Healed at 8 weeks
Total hip Otsuka [139] Fixing acetabular component PLA screws 14 N/A N/A Healed
Y.H. An et al. / Biomaterials 21 (2000) 2635}2652

Sheep Femur Jukkala-Partio [55] Subcapital osteotomy SR-PLA lag-screws 12 N/A ? 86% healed
Tibia Weiler [140] Medial condyle PGA rods (Bio"x) 12 N/A ### Healed
Ulnae Manninen [28] Transverse olecranon PLA screws 12 N/A N/A Healed

Goat Femur Donigian [30] Salter}Harris IV fracture PLA, polydioxanone pins 8 N/A No Healed

PHBA"poly-b-hydroxy butyric acid.

Note: #"slight; ##"moderate; ###"signi"cant.
 Y.H. An et al. / Biomaterials 21 (2000) 2635}2652
Fig. 7. Schematic diagrams showing trephine osteotomies made at
both diaphyseal and epiphysometaphyseal areas in the dog. (Reprinted
with permission from Animal Models in Orthopaedic Research. Chap-
ter 12. Animal models for testing bioabsorbable materials. Yuehuei
H An, Richard J Friedman, editors Boca Raton: CRC Press, 1999.
Copyright Lewis Publishers, an imprint of CRC Press, Boca Raton,
FL.)
Fig. 8. Schematic diagrams showing di!erent diaphyseal fracture mod-
els: (A) An oblique fracture of metacarpal bone in calves "xed with
polymer screws (lateral view); [57]; (B) a femoral osteotomy "xed with
a bioabsorbable intramedullary rod inserted through greater trochan-
ter in the dog [59]; (C) a femoral osteotomy "xed with a bioabsorbable
intramedullary rod inserted through intercondylar notch in the rabbit
[58]; and (D) a potential fracture "xation model using a intramedullary
rod in the rabbit. (Reprinted with permission from Animal Models in
Orthopaedic Research. Chapter 12. Animal models for testing bioab-
sorbable materials. Yuehuei H An, Richard J Friedman, editors. Boca
Raton: CRC Press, 1999. Copyright Lewis Publishers, an imprint of
CRC Press, Boca Raton, FL.)
4.2. Bone replacement
In the case of repairing bone defects, bioabsorbable
materials are used independently for bone conduction
2643
Fig. 9. Schematic diagrams showing maxillofacial bone osteotomy and
"xation with bioabsorbable plate and screws: (A) a mandibular os-
teotomy in the goat, (B) and (C) a zygomatic bone and nasal bone
osteotomies in the rabbit. (Reprinted with permission from Animal
Models in Orthopaedic Research. Chapter 12. Animal models for
testing bioabsorbable materials. Yuehuei H An, Richard J Friedman,
editors. Boca Raton: CRC Press, 1999. Copyright Lewis Publishers, an
imprint of CRC Press, Boca Raton, FL.)
[62,63], as a part of the substitute (with hydroxyapatite
[64,65], or proteolipid [66]), or as carriers for growth
factors [67,68], bone morphogenic proteins (BMPs)
[69}72] and other bone elements [73}76]. Another func-
tion of bioabsorbable materials may be as a sca!olding
for bone conduction [65,77] or guided bone regeneration
[78]. Racemic D,L-PLA implants with pore sizes in the
300}350 lm range and 60% void volume were found to
be capable of promoting osteoconduction in calvarial
defects [79]. A porous PDLLA-PGA copolymer matrix
was found to induce bone formation in rat calvarial
defects via a mechanism based on hematoma stabiliz-
ation [80]. Table 6 lists studies in which bioabsorbable
materials have been used as bone "llers or as carriers for
osteogenic substances.
4.3. Repair of cartilage defects and meniscal lesions
With variable results, the typical studies of repairing
cartilage defect using bioabsorbable materials include the
use of PGA rods [46], PGA or PLA combined with
perichondrium in the rabbit [81,82] and PLA/PGA im-
plants impregnated with demineralized bone powder
[83] or TGF-b [84,85]. Seeding cells onto porous PLA
polymers is a new approach. Freed et al. studied neocar-
tilage formation in vitro and in vivo using porous PGA
and PLA sca!olds [86]. Chondrocyte-seeded absorbable
devices have also been implanted to attempt repair of
cartilage defects with promising results [87]. In recent
years, more investigations have been reported on the
repair of cartilage defects using cell-seeded absorbable
implants (Table 6) [88,89].
 2644

Table 4
Animal models of "xation of diaphyseal osteotomy using bioabsorbable materials (Adapted from An and Friedman [115])

Animal Bone Reference Osteotomy or Fixation method Period Degradation In#ammatory Fracture healing
fracture (Weeks) reaction

Rabbit Femur Manninen [58] T SR-PLA intramedullary rods 48 N/A No Healed

Humerus Lowry [14] T PCL pin 12 N/A Minimal Healed &38% malunion
(6 weeks)
Tibia VainionpaK aK [56] T Carbon "ber-reinforced 24 Started at 6 weeks N/A Healed at 6 weeks
PGA/PLA and PHB implant

Dog Femur Miettinen [59] T SR-PLA or SR-PGA 48 Disappeared at 24 weeks No Healed/6 weeks
An [54] Trephined PGA/PLA screws 68 '95%/68 weeks No Healed/8 weeks

Cat Femur Hara [52] T PLA intramedullary rods 16 N/A No Healed/Large callus

Calf Metacarpal Illi [57] 453 PLA or AO metallic screws 6 0% or N/A No Healed

Table 5
Animal models of "xation of maxillofacial bone osteotomies using bioabsorbable materials (Adapted from An and Friedman [115])

Animal Bone Reference Osteotomy or fracture Fixation method Period Degradation In#ammation Fracture healing
(Weeks) reaction

Rabbit Calvarial bone Eppley [141] Circular defect PLA/PGA plate/screws 52 100%/52 weeks No Healed/24 weeks
Y.H. An et al. / Biomaterials 21 (2000) 2635}2652

Nasal bone Tschakalo! [60] Transverse osteotomy PLA plate and screws 6 75% Mol. Weight No N/A
Zygomatic Thaller [61] Saw osteotomy PGA plate and screws 16 N/A N/A Healed
Dog Mandible Getter [142] Transverse osteotomy PLA plate and screws 32 100%/32 weeks # Healed
Leenslag [143] Transverse osteotomy PLA plate and screws 11 Some at 11 weeks No Healed
Gerlach [42] Transverse osteotomy PLA plate and screws 100 N/A # Healed/8 weeks
Hara [144] Salter-Harris IV fracture PLA screws 24 Started/24 weeks No Healed/4}8
weeks
Tams [145] Transverse osteotomy PLA plate and screws 18 Not much/18 weeks No Healed/12 weeks
Sheep Mandible Leenslag [143] Transverse osteotomy PLA plate and screws 11 Some at 11 weeks No Healed
Bos [146] Transverse osteotomy PLA plate and screws 11 Not much/11 weeks No Healed
Suuronen [34] Neck of condylar process SR-PLA screws 24 N/A N/A Healed

#"slight reaction.
Table 6
Compilation of use of bioabsorbable materials in animal models for orthopaedic research and in human subjects clinically (Adapted from An and Friedman [115])

Application Subject Location Materials References

Fixation of fracture or osteotomy Animals Various Various (see Tables 3}5)

Human Thumb arthrodesis PLA pins Voche [124]
Human Maxillofacial fractures PLLA miniplate and screws Bessho [147]
Human Fixation of chevron bunionectomy PDS pins Gill [97]
Human Ankle fracture "xation PGA, PLLA screws George [77]

Bone "ller or substitute Rat Tibia and humerus drill holes PLA/PGA Hollinger [62]
Rat Femur, drill hole PLA/HA composite Higashi [65]
Dog Mandibular discontinuities PLA/PGA and proteolipid Hollinger [66]
Rabbit Calvarial defects PLA/PGA/HA Antikainen [64]
Rat Critical size defect (5 mm) in mandible PLA/PGA membranes Sanberg [148]
Rat Femur/around metaphyseal bone SR-PGA membranes Ashammakhi [149]
Rat Femur/around bone surfaces SR-PGA membranes Ashammakhi [78]
Rabbit Augmenting distal femoral drill holes SR-PGA membranes Ashammakhi [63]
Rabbit Calvarial defects Porous PDLLA Robinson [79]
Rat Calvarial defects Porous PDLLA-coPGA matrix Whang [80]

Carriers for osteogenic substances Human Femoral nonunion h-BMP in PLA/PGA copolymer Johnson [150]
Rabbit Calvarial defect DFDB in PLA/PGA Schmitz [73]
Rat Osteogenesis in muscles DBM
in POE Pinholt [74]
Rabbit Calvarial defect Osteoinductive protein in PLA/PGA Turk [68]
Y.H. An et al. / Biomaterials 21 (2000) 2635}2652

Dog Osteogenesis in SC tissue PCBM in PLA mesh Kinoshita [75]

Rat Osteogenesis in SC tissue DBM in PLA Saitoh [76]
Rat Calvarial defect BMP in PLA disc Miki [69]
Rat Calvarial defect BMP in PLA/PGA microparticles Kenley [70]
Rat Osteogenesis in calvarial defect IGF-I in POE Busch [67]
Rat Osteogenesis in SC tissue BMP in PLA/PGA/blood clot Alpaslan [72]
Mouse Osteogenesis in muscles BMP in PLG/PEG reservoirs Yamazaki [71]
Rat Mandibular defects rhBMP-2 in PDLLA-coPGA beads Zellin [151]

*continued
2645
 2646

Table 6*continued

Application Subject Location Materials References

Repair of cartilage defect Goat Defect on medial femoral condyle PDLLA-PGA # TGF-b Athanasiou [84]
Rabbit Defect in distal femoral joint PLA/periosteum von Schroeder [81]
Rabbit Defect in distal femoral joint PGA sca!old # chondrocytes Freed [87]
Rabbit Defect in distal femoral joint PLA sca!old # chondrocytes Vacanti [88]
Rabbit Defect on medial femoral condyle Porous PLA # perichondrocytes Chu [89]
Human Osteochondritis/osteochondral fracture PLLA pin Matsusue [98]

Repair of meniscus Dog Lateral menisci Porous PLA implant Klompmaker [90]
Dog Lateral menisci PLLA/PCL copolymer de Groot [91]
Dog Medial menisci peripheral 1/3 incision PGA/PLA staples or 3-0 PDS suture Koukoubis [92]

Repair or replacement of ligament and tendon Dog/rabbit Patellar/achilles/MCL PLA-carbon sca!olding ribbons Parsons [93]
Sheep ACL reconstruction Braided PLA augmentation Laitinen [95]
Sheep PDS-augmented patellar tendon PDS cords Holzmuller [96]
Rabbit Achilles tendon laceration or defect PGA/Dacron device Rodkey [94]

Fixation of ligament and tendon Human Arthroscopic patellar tendon graft PLA interference screws Barber [99]
Human Ulnar collateral ligament of the SR-PLA mini tack "xation Juutilainen [100]
1st metacarpophalangeal joint
Human Arthroscopic bone-patellar tendon-bone graft PLLA, PDLLA-coPGA, PDLLA interference StaK helin [103]
screws
Cow/sheep Patellar tendon graft Interference screws Pellacci [152]

Drug delivery Rabbit Implanted into distal femur PLA/kanamycin Wei [104]
Rabbit Tibial fracture, infection PLA/cefazolin microspheres Jacob [153]
Dog Tibia osteomyelitis PLA/PGA implant plus gentamicin Garvin [105]
Rabbit Inserted into proximal femur PGA/cipro#oxacin cylinder Overbeck [106]
Y.H. An et al. / Biomaterials 21 (2000) 2635}2652

Rabbit Tibial osteomyelitis PLA, PLA/PGA plus vancomycin Calhoun [154]

Conduits for nerve repair Human Digital nerve defect PGA tube Mackinnon [110]
Primate Median nerve defect PGA tube Hentz [111]
Rat Ischiatic nerve defect PLA/6-caprolactone conduit Nicoli Aldini [112]

Sca!old for vessel regeneration Rat Abdominal aorta graft Microporous polyurethane/PLA van der Lei [109]
Rabbit Infrarenal aorta Woven PDS graft Greisler [155]

DFDB"demineralized freeze-dried bone

DBM"demineralized bone matrix
SC"subcutaneous tissue
PCBM"particulate cancellous bone and marrow
PLG/PEG"poly(lactide-co-glycolide)/poly(ethylene glycol)
 Y.H. An et al. / Biomaterials 21 (2000) 2635}2652
A porous PLA sca!old was used by Klompmaker et al.
to repair meniscal lesions [90]. It was found that biode-
gradable implants with a porous structure (100}300 lm
pores) could provide guidance for vascular ingrowth into
the defect. Recently, the same investigators reconstructed
canine menisci using a porous copolymer material
(L-lactide/e-caprolactone) and found gap formation be-
tween implant sides and meniscal tissue could be pre-
vented, but the adherence of implant to the underlying
meniscal tissue seemed to be a problem [91]. More
recently, a new PGA/PLA staple has been tested for
meniscal repair [92]. The results showed that the staple
provided greater tensile strength than PDS suture to the
repaired meniscus. There is no doubt that tissue engin-
eering principles for cartilage and meniscal repair will be
a major direction of research in the future (Table 6).
4.4. Repair of tendons and ligaments
The replacement of tendons and ligaments with bioab-
sorbable materials is still in the early stages of research.
The concept was introduced in 1983 when Parsons et al.
reported the use of a PLA-"lamentous carbon "ber to
replace tendons and ligaments [93]. Rodkey et al. found
that a PGA/Dacron material had adequate strength and
physical properties to be used both for primary tenorrha-
phy and bridging tendon defects in a rabbit Achilles
tendon model [94]. Braided PLA and PDS cords have
been used to augment fascia lata and patellar tendon in
sheep for ACL reconstruction with promising results
[95,96].
Although few animal models have been reported, "x-
ation of tendon, ligament, and cartilage to bone by ab-
sorbable interference screws, staples, pins, and mini tacks
clinically in humans has become well established (Table
6) [97}103].
4.5. Carriers for drug delivery
Typical bioabsorbable drug delivery systems are de-
signed to introduce antibiotics for local use in tissues
(Table 6). PLA with oligomer dideoxykanamycin B was
used as a delivery system to treat osteomyelitis in the
rabbit femur [104]. Garvin et al. reported the use of
a PLA/PGA-gentamicin implant in the treatment of os-
teomyelitis in a canine model [105]. Overbeck et al. later
implanted a novel cipro#oxacin-containing PGA cylin-
der into the medullary canal of the proximal femur in
rabbits and showed that a signi"cantly greater concen-
tration of cipro#oxacin was obtained in bone than that
reported for gentamicin cement beads [106]. Langer re-
viewed drug delivery systems made from bioabsorbable
materials [107]. Biodegradable polymers have also been
used for the controlled release of insulin-like growth
factors, indomethacin, and angiogenesis inhibitors
[67,71,108].
2647
4.6. Small blood vessel and nerve regeneration
Absorbable materials have been used for small vessel
and nerve regeneration (Table 6). Animal studies of vessel
regeneration using absorbable materials were reported
by van der Lei et al. [109]. Microporous, compliant
vascular grafts made from a mixture of polyurethane
(95%) and PLA (5%) can function as a sca!old for the
regeneration of small-caliber arteries [109]. Common
models for studying small vessel graft include rat abdom-
inal aorta, rabbit carotid artery and infrarenal aorta, and
canine femoral artery, carotid artery, and aorta.
For nerve regeneration, several materials, such as PGA
tubes [110,111], PLA/PCL conduits [112], and other
forms of absorbable guides [113] have been investigated
with controversial results. The common model for ex-
perimental nerve regeneration is an ischiatic nerve defect
in the rat [112].
5. Evaluation methods
Methods for evaluating the in vivo performance of
bioabsorbable polymers consist of physical examination,
radiography, histology, and biomechanical testing. Re-
gardless of the tissue being studied, live animals should
be inspected daily for evidence of foreign-body reactions
(sterile sepsis) and sinus drainage. Radiographs are used
for determining the location of an osteotomy, the quality
of the "xation, the existence of osteolysis, and the pro-
gress of bone healing.
After sacri"cing the animal, histological analysis is
used to evaluate bone healing, bone and soft tissue re-
sponse to bioabsorbable devices, and the mass degrada-
tion of the polymer. Lymph nodes are also examined
histologically. Ground sectioning can be useful for its
advantages that the residues of polymer may be preser-
ved during specimen processing.
A materials testing device is used to analyze bio-
mechanical aspects of implant}bone complexes. To
evaluate bone ingrowth, shear strength is tested by
pin/screw pull-out or push-out studies [114]. Bending
and tensile tests are commonly performed to evaluate the
strength of absorbable devices before and after implanta-
tion. A three-point bending apparatus, similar to that
used in the testing of metals, is the typical method used to
assess the implant device itself. However, when an os-
teotomy or fracture model is being evaluated, a four-
point bending test is more appropriate. In this case, the
actuator is centered over the osteotomy or fracture site
with equal distance between contact points on either side
(Fig. 10). An indentation test can be performed to study
the compressive strength and sti!ness of bone around
a bioabsorbable screw or rod [54,114]. The "xation
strength at osteotomy sites in the diaphysis of long bones
can be assessed under simulated physiologic stresses by
2648 Y.H. An et al. / Biomaterials 21 (2000) 2635}2652
Fig. 10. Schematic of 4-point bending apparatus for use with a mater-
ials testing device. Note the load is not applied directly over the fracture
or osteotomy site (midline), and the contact points of the device are
adjusted to be equidistant from midline (d).
using cyclic, bending, and torsional tests, depending
upon the capabilities of the testing device.
6. Conclusion
The use of bioabsorbable devices represents the state
of the art in managing orthopaedic problems. Whether
implants are intended for fracture "xation, drug delivery,
or ligament repair, clinical use of biodegradable poly-
mers will undoubtedly become even more common in the
next century of orthopaedic care. With new and promis-
ing polymers becoming increasingly available, pre-clini-
cal in vivo biocompatibility and biomechanical testing
methods are available and necessary to evaluate these
materials for potential clinical applicability.
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