Biodegradable Screw Fixation of Rabbit Tibia Proximal Osteotomies

Yoshitaka Matsusue,* Takao Yamamuro,* Satoru Yoshii,* Masanori Oka,** Yoshito Ikada,** Suong-Hyu Hyon,** and Yasuo Shikinami**

*Department of Orthopaedic Surgery, Faculty of Medicine, Kyoto University, and **Research Center for Medical Polymers and Biomaterials, Kyoto University.

The purpose of this study was to evaluate a biodegradable poly(l-lactide) (P-L-LA) screw for osteosynthesis under a load-bearing condition. A proximal tibial osteotomy on 25 rabbits was fixed with a biodegradable screw made of P-L-LA. A follow-up study was done at 1, 2,4, 8, and 16 weeks. In another 25 rabbits, the tibial osteotomy was fixed with stainless steel (SUS) screws of the same size as the P-L-LA screws with a similar follow-up period. Radiographic, histological, microradiographic, and oxytetracycline-labeling studies showed healing of the osteotomy within 4 to 8 weeks. The displacement of frag- ments and the mass of newly formed bone around the screws were measured by histo- morphometric analysis. There was no significant difference in the displacement of the fragments in these two groups and new bone was more abundantly detected in the P-L-LA group than in the SUS group. Histologically, no inflammatory lesion was detected in either group. All osteotomies united without delay and the displacement was minimal, although no external support was applied and the rabbits were allowed to move freely after the opera- tion. The results of this study suggest a possible use for a P-L-LA screw in the clinical treatment of human bone fractures.

INTRODUCTION

Biodegradable polymers are of increasing interest for sur- gical applications. Therefore, biodegradable synthetic polymers have been widely investigated in recent years.’-’’ Absorbable suture materials, such as polyglycolide (PGA), have been commercially available since 1970,’ and today Dexon (Davis and Geck, Danbury, CT) a PGA, and Vi- cry1 (Ethicon, Somerville, NJ) a copolymer of glycolide and lactide, are commonly used as sutures in many kinds of surgery.

Several have been made to use bio- degradable polymers, which lose their strength gradually, for fixation of fractures during healing. Cutright and Hunsuck” showed that poly(1actic acid) sutures resulted in successful bone healing in mandibular fractures, and also discussed tissue reaction to the biodegradable poly- lactic acid suture.” Getter et a].’* also reported success- ful results from the use of polylactic acid screws and plates in the experimental treatment of fractures in six dogs. Several authors in Gerrnanyl3-l5 have used poly- dioxanone rods or screws for fixing osteochondral frag- ments of the knee in dogs or sheep. Recently other

have reported on the use of PGA sutures and rods in fractures of the distal femur in rabbits. Successful

Requests for reprints should be sent to Yoshitaka Matsusue, Depart- ment of Orthopaedic Surgery, Faculty of Medicine, Kyoto University, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606, Japan.

Journal of Applied Biomaterials, Vol. 2, 1-12 (1991) 0 1991 John Wiley & Sons, Inc. CCC 1045-4861/91/010001-12$4.00

degradable fixation by PGA rods in human ankle frac- tures has also been rep~rted.”-’~ HirvensaloZ3 found 2 cases of failure of fixation and 3 cases of moderate displacement in 41 cases of severe ankle fracture. Daniel et reviewed papers and abstracts published in En- glish from 1980 through 1988 concerning biodegradable polymers and composites proposed for internal fixation of bone, and concluded that the key to successful clinical use has been careful selection of applications, designs used, and fixation method. However, there are no de- tailed experimental or clinical reports on the use of biodegradable screws in the fixation of fractures or os- teotomies of the metaphysis of long bones.

The purpose of this study was to evaluate the useful- ness of biodegradable poly(l4actide) (P-L-LA) screws for the fixation of osteotomies in the metaphysics of a long bone model in rabbits.

MATERIALS AND METHODS

P-L-LA Screws

P-L-LA was synthesized according to a previously re- ported method.25 The optical purity of L-lactide was 98% and the optical rotation, [abZ, of P-L-LA was +150”. The initial viscosity-average molecular weight (Mw) of P-L-LA was 4 x lo5 daltons with a bending strength of 160 MPa and bending modulus of 9.8 GPa. The P-L-LA was dried in a vacuum at 140°C for 2 h. Then, this polymer was extruded at 200°C with a pressure of

2 MATSUSUE ET AL.

30 MPa. After a subsequent drawing at 100°C to a uniaxial direction by 2.5 times, the P-L-LA rod exhibited Mw of 2 x lo5 daltons with the bending strength of 220 MPa and bending modulus of 13 GPa. No solvent was used in the molding process. The reduction of molecular weight might be due to thermal degradation of the polymer dur- ing molding?6 The mechanical testing was carried out by the three-point bending method at 23°C and 55% RH according to Japanese Industrial Standard (JIS) using Autograph SD-100-C (Shimadzu Co., Kyoto, Japan). The cross head speed was 10 mm/min.

For fabrication of the P-L-LA screws, a metal die was first made from a stainless steel screw (SUS 304, M-3 type, Okiturasen Co., Kobe, Japan) that was used in this study. Then, the P-L-LA rod was inserted into the die and shaved into the shape of the screw so as to have a shape identical to that of the stainless steel screws used in this study. There was no reduction of the mechanical strength due to this machining. The thread and root di- ameter were 3.0 and 2.5 mm, respectively, and the length was 20 mm (Fig. 1). The screws to be implanted were sterilized with ethylene oxide (EOG 20 wt%, COz 80 wt%) at 40°C for 5 h and without vapor. An out-gas period of at least 48 h at 50°C was allowed for before use.

Degradation of Drawn P-L-LA Rod in vitro

Biodegradable rods of 3.2 mm diameter and 5 cm length were fabricated using the same P-L-LA as this screw. After molding, the rods were drawn to 2.5 times. An in vitro degradation test was carried out for the rods at 37°C in phosphate buffered saline (PBS) of pH 7.4 under stir-

ring. In Figure 2, the change of bending strength of the P-L-LA rods with time is shown. Each datum is the mean value of five samples. The initial bending strength of 220 MPa maintained for about 8 weeks, decreased to 60% of that value at 12 weeks, and degraded to zero at 25 weeks, However, there was no appreciable change in mass at 25 weeks.

Surgical Technique

Fifty-six Japanese male rabbits, weighing 3-3..5 kg each, were included in this study. Rearing of these rabbits and the animal experiments were carried out at the Institute of Laboratory Animals, Faculty of Medicine, Kyoto Wni- versity. The rabbits were anesthetized by intravenous injection of 0.5 mL/kg of nembutal (Abott, North Chicago, U.S.A.). Under standard aseptic conditions, a skin incision was made 4 cm long along the anteromedial aspect of the right tibia1 proximal metaphysis, and the skin and periosteum were retracted.

A hole of 2.5 mm diameter was drilled and tapped with its center 7 mm distally from the epiphyseal plate. The hole was drilled from the medial to lateral direction, penetrating the lateral wall. The vertical osteotomy of the proximal tibia was made using a bone saw and the distal transverse osteotomy was made with a micro-drill (Fig. 3). The capsule and medial collateral ligament were completely severed from their insertion to the osteoto- mized bone. The fragment was then reduced and fixed with a screw made of P-L-LA or SUS at a torque of 0.12 N . m using a KANON 5 DPSK torque driver (Naka- mura Mfg. Co., Ltd., Nagoya, Japan). After confirmation

Figure 1. P-L-LA screw used in this study.

OSTEOSYNTHESIS WITH BIODEGRADABLE SCREW 3

0 5 10 15 20 Weeks

Figure 2. Degradation of drawn P-L-LA rod in vitro. Change of bending strength of P-L-LA rod of 3.2 mm diameter and 5 cm length with time in phosphate buffered saline (PBS)(pH 24 at 37°C). The vertical bar represents the mean plus or minus one standard deviation.

of the sufficient reduction of the fragment, the fascia and skin were closed in layers. During the follow-up study, the rabbits were reared in cages and allowed to move freely without any external support.

Experimental Groups

In the SUS group, the osteotomy was fixed with a stain- less steel (SUS 304) screw of the same size as the P-L- LA screw using the method described above. In the preliminary group, the osteotomy was not fixed with a screw. Rabbits from the groups with the P-L-LA and the SUS screws were sacrificed 1, 2, 4, 8, and 16 weeks

after operation. Each group consisted of five rabbits. In the preliminary group, rabbits were sacrificed in groups of two at 1, 2, and 4 weeks after operation. However, no rabbits without screw fixation loaded on the operated limb, and all of the animals were severely emaciated. Two of these were also infected due to fracture of the operated limb. Therefore, the preliminary group could not be used for a control. During the follow-up study, attention was directed to wound healing and to the load- ing which the rabbit could tolerate on the operated limb. No rabbits with the P-L-LA or SUS screws were in- fected and all loaded on the operated limb.

Three days before sacrifice, the rabbits received oxy- tetracycline (teramycin 50 mg/kg, Taito Pfizer, Tokyo, Japan) for labeling studies. The rabbits were sacrificed with an overdose of nembutal.

Figure 3. A hole was drilled at the frontal level from the medial to lateral direction. The vertical osteotomy (a) was done using a bone saw and the distal osteotomy (b) was accomplished with a micro- drill. The capsule and medial collateral ligament were completely severed. The medial fragment was fixed with a P-L-LA screw (c) at 0.12N . m of torque using a torque driver.

Method of Examination

X-ray photographs in the anteroposterior and lateral pro- jections were taken of the tibiae after excision of the proximal half segments. The distance between the roent- gen tube and the film was 50 cm, and the exposure fac- tors used were 35 kV, 5 mA, and 1.0 min. The proximal portions of each tibia, free of the soft tissues, were fixed in phosphate-buffered formalin solution. The fixed seg- ments were dehydrated with an ethanol-water mixture in serial concentrations and embedded in polyester resin. Histological sections were cut on a milling machine with a diamond disc (Crystal Cutter, Maruto Ltd., Tokyo, Japan) at 300 pm parallel to the axis of the tibia. The sections were ground on a grinding machine with a dia- mond lap disc (Speed Lap, Maruto, Tokyo, Japan) to 80 pm.

After contact microradiography (CMR), all sections were stained with the Giemsa surface staining tech-

4 MATSUSUE ET AL.

n i q ~ e ~ ~ and histologically evaluated under light and f luo- rescence microscopes. In CMR, a Kodak high resolution film (649-0) was used. The technical factors were 10 kV, 4 mA, and 12 min. Fluorescence microscopy was per- formed using a HBO-l000W/2 ultraviolet (UV) lamp and a BA 420 primary filter.

Quantitative Evaluation

The evaluation of the displacement of fragments was per- formed using a semiautomatic histo-morphometric method (Digigrammer 1 Model-G/A, Mutoh, Tokyo, Japan). The system consisted of a microscope with cross polarizing filters, a digitizing platen, a digitizer (Model ID-24, Mutoh, Tokyo, Japan) a printer (A-1200 Can- non, Inc., Tokyo, Japan), and a microcomputer (AS- 100M, Cannon, Tokyo, Japan) with a minifloppy disc drive (A-1300, Cannon, Tokyo, Japan). The microscope was equipped with a drawing tube (Nikon, Tokyo, Japan) through which the image of the digitizing platen was pro- jected over the optimal field. A cursor was projected over the histologic field where the X-ray film was set. By moving this cursor on the digitizing platen, the horizontal osteotomy displacement distance (a), the vertical os- teotomy displacement distance (b), and the horizontal width of the proximal tibia (c) were measured by the microcomputer using the method of 8 points-average- measurement (Fig. 4). The displacement ratio, defined as {(a) + (b)/(c) - (a)} x 100, was calculated for each specimen.

The newly formed bone around the screw and near the cortex was assessed by measuring bone growth in the three indentations of the screw closest to the lateral cor-

I I

I

I $ I

I ! I

Figure 4. Schematic representation of horizontal displacement (a), vertical displacement (b), and horizontal width of the proximal tibia (c).

tex. The newly formed bone in these indentations was traced by moving a cursor on the digitizing platen and its area was calculated by the minicomputer. One section from one leg (50 sections for 50 animals) were examined. The area of newly formed bone in each section was cal- culated and expressed as a percentage of the area of the indentations of the screw threads (Fig. 5) .

RESULTS

Radiographic Results

The osteotomy lines were clearly detected in their radio- graphs up to 2 weeks. The external callus was noted from 2 weeks at the medial and posterior walls of the cortex, and its thickness decreased at 16 weeks. There was no significant decrease in the size of the screw hole in the P-L-LA group at 16 weeks (Fig. 6).

The displacement ratio showed no significant differ- ence at any point in time between the P-L-LA and the SUS groups (Fig. 7). In the SUS group, the maximum of 9.26% was observed at one week, and the minimum of 0% at 8 and 16 weeks. In the P-L-LA group, the maxi- mum of 9.12% was observed at 4 weeks, and the mini- mum of 0% at 8 and 16 weeks.

In the preliminary group, the fragment was severely displaced (Fig. 8) and the union was markedly delayed as compared to the other groups. The displacement ratios of the preliminary group were 28.6% on average, with a 60% maximum and a 9% minimum.

Microradiographic Evaluation

The microradiography at 1 week showed partial union of two osteotomies in the SUS group and one in the P- L-LA group. Immature bone was observed around the screw in three cases for the P-L-LA group and two cases for the SUS group.

At 2 weeks, partial union was noted in four cases of both groups and immature new bone at the osteotomy site was noticed in all cases.

At 4 weeks, complete union was noticed in two ani- mals of the P-L-LA group and in three animals of the SUS group. In the preliminary group, immature bone was abundantly noted at the osteotomy site. The new bone that formed around the screw showed no signifi- cant difference between the P-L-LA and SUS groups.

At 8 weeks, all cases in both groups showed complete union and regeneration occurring in the cancellous bone of the proximal tibia. New mature bone around the screw near the cortex was much more evident in the P- L-LA group than the SUS group (Fig. 9).

At 16 weeks, all osteotomies were completely united and remodeling of the trabeculae in the epiphysis was advanced in both groups. New mature bone was less evi- dent in the SUS group than the P-L-LA group.

OSTEOSY NTHESIS WITH BIODEGRADABLE SCREW 5

I n I

Lateral cortex

Screw

Figure 5. Area surrounded by thick line ( 0 ) was evaluated for quantitative study (left schematic). The mass of newly formed bone was measured in the three upper and lower indentations of the screw on the inner side of the lateral cortex. The dotted area shows newly formed bone and the broken line shows indentations of screw-threads which were calculated by histo-morphometric analysis (right schematic).

Quantitative Assessment

Area of newly formed bone around the screw. The newly formed bone mass was expressed as a percentage of the area of the new bone to the area of the three indentations of the screw threads near the lateral cortex (Fig. 5). Figure 10 illustrates its change with the implan- tation time, and each datum is the mean value of five sections. In the two groups, mature bone increased up to 16 weeks, but the new bone mass was more abundant in the P-L-LA group than in the SUS group at 8 and 16 weeks. There was a significant difference between the

two groups both at 8 and 16 weeks (Student’s t-test, N = 5 , p < 0.05). However, there was no significant dif- ference between the groups at 1, 2, and 4 weeks. There was much less new bone in the marrow cavity than near the cortex in both groups.

Histological Evaluation

Histological studies at 1 week showed hematoma, a small amount of connective tissue ingrowth in the marrow cavity, and a small quantity of woven cartilaginous tissue

Figure 6. X-ray picture at 16 weeks in the P-L-LA group. Fracture has completely healed and the osteotomy line (arrow) has diminished. There is no significant decrease in the size of the screw hole.

MATSUSUE ET AL.

T T T

0 PLLA group at the osteotomy site. No inflammatory cells were seen in either group.

At 2 weeks, abundant cartilaginous tissue and woven sus group

bone were noticed at the osteotomy site. The woven bone around the screw was moderately formed in both groups. A slight infiltration of inflammatory cells, such as lym- phocytes, was seen in the marrow cavity in both groups.

At 4 weeks, the volume of woven bone decreased at the osteotomy site, and complete union was found in two of the P-L-LA group and in three of the SUS group. However, more abundant woven bone was formed at the osteotomy site in the preliminary group without fixa- tion and consolidation was markedly delayed as compared

1 2 4 8 16 (Weeks) to other groups. A slight infiltration of inflammatory cells was detected in the vicinity of the marrow cavity and around the implant material in some cases of both groups. bone had been absorbed in the marrow cavity, and the cavity now contained mostly

Figure 7. Time course of displacement ratio. The displacement ratio shows no significant difference at each week between the P-L-LA and SUS groups. The vertical bar represents the mean plus one standard deviation.

all

Figure 8. X-ray at 4 weeks in the preliminary group (without screw fixation). The fragment is severely displaced.

OSTEOSYNTHESIS WITH BIODEGRADABLE SCREW

100.

50.

7

0 PLA Screw * sus Screw n

Figure 9. Contact microradiograph at 8 weeks in the SUS group (left photograph) and P-L-LA group (right photograph). New mature bone around the screw near the cortex is more evident in the P-L-LA group than in the SUS group.

fatty marrow. A moderate amount of new mature bone was observed in the vicinity of the cortex between the screw threads in both groups.

At 8 weeks, all osteotomies were completely consoli- dated in both groups and remodeling of the trabecu- lae began in most of the cases. Inflammatory cells were hardly noticed in the marrow cavity in either group. The interface between the screw thread and bone for the P-

i 6 (Weeks)

* p<0.05

Figure 10. Time course of newly formed bone mass, expressed as a percentage of the area of the new bone relative to indentations of screw-threads, in the SUS group and P-L-LA group. The vertical bar represents the mean plus one standard deviation. The bone mass at 8 and 16 weeks shows a significant difference at p c 0.05 between the two groups.

L-LA group showed a thin fibrous tissue layer, which was thicker than the layer observed for the SUS group, and no inflammatory cells. The volume of new bone be- tween the screw threads near the cortex showed a ten- dency to be more abundant in the P-L-LA group than the SUS group (Fig. 11).

At 16 weeks, complete union of osteotomies and re- modeling of trabeculae were accomplished in all cases of both groups. No inflammatory cells were noted in the marrow cavity and around the screw. The mass of the new bone formed between the screw threads was the same as that at 8 weeks and continued to be larger in the P-L- LA group than the SUS group.

OTC-Labeling Evaluation

At 1 week, OTC-fluorescence showed weak uptake in the osteotomy site of three animals of the P-L-LA group and two animals of the SUS group. At 2 weeks, moderate uptake of OTC-fluorescence was observed at the oste- otomy site and near the implant materials in three ani- mals of both groups. At 4 weeks, strong uptake of OTC- fluorescence was noticed at the osteotomy site and moderate uptake was seen near the materials in all cases of both groups. At 8 weeks, moderate uptake was ob- served at the osteotomy site and in the vicinity of the materials in both groups. At 16 weeks, slight uptake was seen in the osteotomy line and vicinity of the materials near the cortex in both groups.

8 MATSUSUE ET AL.

Figure 11. Photomicrographs of a section of the SUS group near the cortex at 8 weeks (a) and of the P-L-LA group at 8 weeks after the operation (b and c). No inflammatory cells are seen in both groups. The volume of new bone (arrow) between the screw-threads is more abundant in the P-L-LA group than in the SUS group. Giemsa stain, SUS (a) and P-L-LA group (b)(original magnifi- cation x40), P-L-LA group (c) (original magnification x200).

OSTEOSYNTHESIS WITH BIODEGRADABLE SCREW 9

(c)

Figure 11. (continued)

DISCUSSION

Metal implants made of stainless steel and cobalt based alloys (Vitallium) have several disadvantages: they cor- rode slightly2’ and in very rare cases may produce a ma- lignant t ~ m o r . ’ ~ - ~ ~ The bone tends to be more atrophic and easily broken due to the stress shielding effect under the plate34 and in some cases a second operation for re- moval is necessary or preferred. There have been several reports on biodegradable materials used for osteosynthe- sis in recent However, there is no detailed report on biodegradable screws to rigidly fix the bone under an in-vivo loading condition. This present study sug- gests the possible efficacy of using biodegradable screws for osteosynthesis.

A fracture of human cancellous bone usually unites in 3 to 4 weeks and consolidates in 6 to 8 weeks. However, a fracture of human cortical bone needs a longer time for consolidation, depending on the site and type of frac- ture. It is necessary in the treatment of a fracture of hu- man bone that the bending strength of the absorbable fixation material exceeds that of the human cortical bone and should maintain its strength for at least 8 weeks. The bending strength of human cortical bone varies from 120 to 200 MPa.3S The initial bending strength of this P-L-LA screw, 220 MPa, decreases by 10% after 8 weeks, by 40% during 8 to 16 weeks, and falls to zero at 25 weeks by hydrolysis in vitro. This P-L- LA screw has the highest values for bending strength and

modulus among the nonreinforced P-L-LA described in the l i t e r a t ~ r e . ~ ” ’ ~ ~ ~ A screw of this strength may not be necessary for fixing a fracture of rabbit bone, but may be necessary for the treatment of a fracture of human bone.

Cutright and Hunsuck” successfully repaired the ex- perimental mandibular fractures in five rhesus monkeys using biodegradable polylactic acid sutures. Recently, Vih- tonen et aI.l7 used PGA sutures in the fixation of the experimental fractures of the distal part of the rabbit fe- mur, but delayed union or nonunion occurred in three of 14 cases. Vainionpaa et a1.16 successfully repaired all of the same osteotomies using a PGA suture in combination with a PGA rod. Gay et al.I4 used absorbable osteosyn- thesis screws made of polydioxanone (PDS) for the osteo- chondral fragments of the medial femoral condyle in dogs. They concluded that the screws were too soft as traction screws and the PDS-screws were suitable for fractures with low mechanical loads and a fast healing tendency. However, there has been no detailed study about the rigid fixation of experimental osteotomies us- ing biodegradable screws. In the present study using the P-L-LA screws, all osteotomies healed completely with a minimum displacement in spite of no external support. The displacement of fragments at the osteotomy site showed no significant difference between the P-L-LA group and the SUS group under a load-bearing condi- tion. This result encourages clinical applications of the biodegradable P-L-LA screws in the treatment of hu- man small bone fractures without any external support.

10 MATSUSUE ET AL.

Figure 12. Photomicrographs of a section of the same implanted P-L-LA screw as was used in this study at 2 years after operation. The P-L-LA screw (M) degraded and about half of the material was replaced by bone and tissue (a). Hematoxylin-Eosin stain, (original magnification x20). Bone in- growth (B) and phagocytosis by histiocytes (H) were found (b) (original magnification x200).

OSTEOSY NTHESIS WITH BIODEGRADABLE SCREW 11

The P-L-LA screw used in this study did not show any evidence of absorption at 16 weeks. The authors found in long term in-vivo experiments in three rabbits that about half of the same implanted material as was used in this study was replaced by bone and tissue at 2 years after operation (Fig. 12). Therefore, it may be expected to be absorbed completely within a few more years.

Hollinger’s report’ on the osteogenic potential of a biodegradable copolymer of PLA and PGA showed an accelerated rate of healing when treated with biodegrad- able copolymer implant. In the present study, the P-L- LA screw resulted in formation of significantly more abundant bone than the SUS screw. The probable reason is the lower elastic modulus of the P-L-LA screw than the SUS screw. Histologically, there was almost no in- flammatory or foreign body reaction for 16 weeks.

We have already successfully used P-L-LA pins for the attachment of ribs to the sternum after chest sur- g e r ~ . ~ ~ , ~ ’ On the basis of this study, the highly drawn P- L-LA screw is considered promising for osteosynthesis in the field of orthopaedic surgery.

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Received February 27, 1990 Accepted October 26, 1990