Enhancement of bone growth into porous intramedullary implants using non-invasive low intensity ultrasound

ELSEVIER Journal of Orthopaedic Research 19 (2001) 195-199 Journal of Orthopaedic Research www.elsevier.nl/locate/orthres Enhancement of bone growth into porous intramedullary implants using non-invasive low intensity ultrasound M. Tanzer *, S. Kantor, J.D. Bobyn Diiiision qf Orthopaedic Surgery. McGill University and the Jo Miller Orthopaedic Research Laboratory, 1650 Cedar Avenue, # A2144, Montreal, Que, Canada H3G IA4 Received 17 December 1999; accepted 22 May 2000 Abstract An in vivo study was designed to determine if non-invasive low intensity ultrasound could enhance bone growth into porous intramedullary implants. Fully porous intramedullary rods were implanted bilaterally into the ulnae of six dogs. In each dog, one ulna served as a control and the other was treated with 20 min of daily ultrasound stimulation for 6 consecutive weeks. Analysis of serial transverse sections indicated an average of 119% more bone growth into the ultrasound-treated implants compared with the contralateral controls (P < 0.001). In each of the 6 dogs, there was a significantly greater amount of bone ingrowth on the ultrasound-stimulated side. These data indicate a clear potential for externally applied ultrasound therapy to augment biological fixation. 0 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. Introduction Total joint replacement is a highly successful treatment for arthritis and as follow up studies demonstrate excellent long-term results, the number of procedures and indications for total joint arthroplasty continues to increase. Porous-coated implants that enable direct skeletal attachment by bone ingrowth continue to play an important role in the armementarium of the arthroplasty surgeon. They are the current gold standard for acetabular fixation, frequently used for femoral fixation in primary total hips, are the most common implant used for femoral hip revision and are extensively used in total knee arthroplasty. Although, porous-coated implants have evolved in an attempt to optimize immediate and long-term fixation, there are persistent concerns regarding the reliability and extent of bone ingrowth. As a result, various invasive and non-invasive modalities have been investigated to enhance bone growth into porous-coated implants. Non-invasive low intensity ultrasound, which was initially developed to accelerate fracture healing, has subsequently been shown to be capable of increasing the amount of bone growth into porous-coated implants. In a previous in vivo study, 22 pairs of fully porous *Corresponding author. Tel.: +1-514-937-6011; ext. 2260; fax: +1-5 14-934-8283. transcortical implants were inserted bilaterally into the femora of 12 dogs [21]. In each dog, one femur was subjected to daily ultrasound stimulation while the other femur served as a control. The 20 minute ultrasound signal was produced by an external transducer and consisted of a 200 ps burst of 1.5 MHz sine waves repeating at 1 khz that delivered 30 mw/cm' incident intensity. After 2, 3, and 4 weeks the ultrasound-stimulated implants demonstrated an 18% increase in bone ingrowth as compared with the contralateral controls (P = 0.02). Additional ultrasound studies with transcortical implants indicated that extending the daily treatment time to 40 consecutive minutes did not have a beneficial effect on bone ingrowth [ 1 11. For ultrasound stimulation to be of practical use in all types of cementless arthroplasties, it would have to be effective both if the implant were subcutaneous, such as in total knee arthroplasty, or intramedullary, such as in total hip arthroplasty. The purpose of this study was to determine if non-invasive low intensity ultrasound could enhance bone growth into porous-coated intramedullary implants. Methods Porous tantalum intramedullary implants were inserted bilaterally into the ulnae of six skeletally mature mongrel dogs (weighing between 15-30 kg) (Fig. 1 ). Each implant was a fully porous cylinder measuring 0736-0266/01/$ - see front matter 0 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved PII: S 0 7 3 6-0 2 6 6 ( 0 0 ) 0 0 0 3 4-6

196 M. Tanzer et ul. I Journal of Orthopedic Research 19 (2001) IY5-199 Fig. I. Postoperative lateral radiograph of a canine ulna with the intramedullary tantalum implant in situ. 5.0 cm long and 5.0 mm wide (Implex, Allendale, NJ). Porous tantalum has been described in the literature and previously shown to be conducive to bone ingrowth [6,7]. It is manufactured by the chemical vapor deposition of commercially pure tantalum onto a vitreous carbon scaffold to create a regularly repeating array of pores interconnected by smaller openings or portals. The cylindrical implants had a pore size of 430 pm (95%) C1 413447) and a volume porosity ranging from 75% to 80% The surgical procedure involved anesthetizing the dog with a general anesthesia and exposing the proximal ulna with a two-centimeter incision over the olecranon process. The triceps tendon was split by sharp dissection down to bone. Under fluoroscopic guidance, a 5.0 mm drill was oriented along the long axis of the ulna and in line with the medullary canal. A 5.5 cm long hole was drilled under fluoroscopy to ensure the proper orientation of the drill hole and to prevent cortical penetration. The porous implant was tapped down the medullary canal of the ulna with a punch and mallet. The implant was slightly countersunk to ensure stimulation would occur at the central portion of the implant and to avoid postoperative irritation of the overlying triceps tendon. The implant s position was verified using fluoroscopy (Fig. 1). The wound was irrigated and closed with resorbable sutures. The identical procedure was subsequently carried out on the contralateral ulna. For each dog, one ulna served as a control and received no treatment. The contralateral ulna underwent daily 20 min ultrasound treatments. The ultrasound protocol was similar to that described previously for bone ingrowth and fracture healing [lo, 13,211. The nltrasound treatment started on the first postoperative day and was given daily for the entire treatment protocol. The ultrasound signal was produced by an external 2.5 cm lead zirconate-titanate transducer placed along the subcutaneous border of the ulna and directly over the center of the implant. This central location was determined intraoperatively by fluoroscopy and corresponded to the region where a palpable notch occurred between the straight subcutaneous border of the canine ulna and the flare of the olecranon process. This location was reconfirmed postoperatively with fluoroscopy at the first ultrasound treatment. The ultrasound signal consisted of a 200 ps burst of 1.5 MHz sine waves repeating at 1 khz that delivered 250 mw/cm incident intensity (Exogen, Piscataway, NJ). Ultrasound gel and a gel pad were used as a coupling medium and to prevent excessive heat formation from any ultrasound waves reflecting off the bone. Based on the manufacturer s testing and specifications, the ultrasound signal affected an area of 5.4 cm and therefore the entire implant was stimulated by the ultrasound signal. Previous canine ingrowth studies have demonstrated bone growth into porous-coated implants to maximize at 6 8 weeks [5,12,17,20]. As well, patients are usually kept non-weight bearing for six weeks following cementless total joint arthroplasty in order to avoid micromotion with ambulation and allow sufficient ingrowth to stabilize the prosthesis. Since the purpose of the study was to determine if noninvasive low intensity ultrasound could increase the absolute amount of bone growth into intramedullary porous implants, the treatment protocol was carried out for 6 weeks. After sacrifice, the ulnae were harvested, stripped of soft tissue, radiographed and processed for undecalcified hard-section histology. This involved dehydration in ascending solutions of ethanol, defatting in ether and acetone. and embedding in methylmethacrylate. Each implant was then sectioned transversely. The first section corresponded to the midpoint of the implant. Additional sections were made at one centimeter intervals proximally and distally from this point. This resulted in a total of five sections per implant. The sections were radiographed and then polished and prepared for backscattered electron microscopy. Computerized image analysis based on gray level discrimination was used to identify any bone, implant and void space. The computer was then able to generate quantitative information on the percentage of the available porosity that was filled with new bone (volume fraction of bone ingrowth). The volume fraction of bone ingrowth was also determined for each region of the sections, to determine if there was increased bone ingrowth directly adjacent to the ultrasound signal. As well, the volume fraction of bone ingrowth for the five sections of each ulna was summated to give a mean and S.D. for each ulna. Six matched pairs of implants or 30 matched sections were available for analysis. Statistical comparison of the amount of bone ingrowth in the ultrasound stimulated and non-stimulated implants was done using the Wilcoxon rank sum test and Student f-test. The level of significance was P < 0.05. Results All the dogs tolerated the operation and daily ultrasound treatments without complication. The dogs were ambulating on the first postoperative day and were full weight bearing over the next three days. Varying degrees of bone ingrowth occurred in the 12 implants, but there was consistently more bone growth into the ultrasound-stimulated porous intramedullary rods than in the non-stimulated implants (Fig. 2). Bone growth into the ultrasound-stimulated implants ranged from 8.0% to 18.1% compared with 2.7% to 8.5% in the control implants. Overall, the average volume fraction of bone ingrowth was 14.2% in the ultrasound-stimulated implants and 6.5% in the non-stimulated implants, a relative difference of 119% (P < 0.001). In each of the 6 dogs, the ultrasound-stimulated implant had significantly more ingrowth than its contralateral control (P < 0.001) (Table 1). As well, each of

M. Taxer rt u1. I Journul of' Orthopaedic Resrcrrch 19 (2001) 195 199 197 Both stimulated and non-stimulated implants had varying degrees of bone ingrowth throughout the depth of the implant. In the ultrasound-stimulated implants, the bone ingrowth was evenly distributed around the entire porous intramedullary rod. There was no preferential or increased ingrowth on the side of the implant directly adjacent to the ultrasound signal. Discussion Fig. 2. (A) Backscattered scanning electron micrograph of a 6-week non-stimulated implant cut transversely. Bone growth into the cylindrical porous implant is 8%. (B) Backscattered scanning electron micrograph of the contralateral 6-week stimulated implant cut transversely. Bone growth into the cylindrical porous implant is 24%. the five transverse sections of the stimulated implant had more ingrowth than its contralateral matched section. On average, the ultrasound-stimulated intramedullary rods had 950/, 104%,, 105%, 1 13940, 150% and 198% more ingrowth than the non-stimulated porous-coated rods. The results of this experimental study demonstrate that non-invasive low intensity ultrasound can significantly enhance bone ingrowth into porous intramedullary implants. Overall, ultrasound stimulation more than doubled the amount of bone that grew into the porous tantalum intramedullary rods. This enhancement of bone ingrowth was observed in every dog and every matched histologic section. In the only previous study assessing the role of ultrasound on bone ingrowth, ultrasound was also found to have a significant effect [21]. However, in that study, ultrasound stimulation of transcortical femoral implants made of titanium beads demonstrated only a modest 18% increase in bone ingrowth over the non-stimulated control, as compared to the 119% increase that occurred in this study. The large difference in bone ingrowth response to ultrasound in these two studies could be explained by the different implant types used or by a difference in the amount of ultrasound energy actually reaching the implant region. It is unlikely that the implant materials, titanium and tantalum, were responsible for the differences found in the degree of ingrowth enhancement that occurred in these two ultrasound studies. Since both studies involved bilateral models, one would expect that the relative difference in ingrowth between the ultrasoundstimulated and non-stimulated implants would be similar. Furthermore, separate studies have confirmed that both titanium and porous tantalum allow bone growth [6,7,15,20]. Porosity differences between the implants might have influenced the results. Porous tantalum has a Table 1 Percent bone growth into the non-stimulated and ultrasound stimulated implants at 6 weeks time" Non-stimulated implant Ultrasound stimulated implant P value % Bone ingrowth '%I Bone ingrowth Mean (S.D.) Mean (S.D.) Dog #I 6.25(2.59) 12.81(1.91) 0.005 Dog #2 2.68(0.60) 7.99( 1.73) 0.002 Dog #3 6.14( 1.36) 15.35( 5.89) 0.01 Dog #4 8.50( 1.72) 18.11(4.02) 0.002 Dog #5 7.31(1.77) 14.92( 1.90) 0.001 Dog #6 8.230.4 I ) 16.10(2.46) 0.002 Overall 6.46(2.48) 14.16(4.58) <0.001 a S.D. - standard deviation.

198 hf. Tanzer rt al. I Journal of' Orthopaedic Research IY (2001 1 195-199 porosity of 75-80% while the porosity of sintered beads is typically only 30-35%. Perhaps the increased porosity of the tantalum implants in some way facilitated access of the ultrasound signal to peri-implant tissue and osteogenic tissue within the pores, It is most likely that the substantially greater enhancement of bone growth with ultrasound in this study, as compared to our previous study, resulted from a difference in the amount of ultrasound energy delivered to the implant region. When passing through tissues, ultrasonic energy is absorbed at a rate proportional to the density of the tissue. This differential absorption may be critical in targeting the ultrasound to a fracture gap since the high density of bone and the surrounding tissues relative to a fracture gap facilitates the localization of the ultrasound wave to a fracture site. Unfortunately, this differential absorption also decreases the amount of energy capable of reaching the medullary canal. As well, at interfaces such as the bonemuscle surface, much of the incident radiation is reflected. Therefore, stimulation of the medullary canal requires a greater amount of ultrasonic energy. However, excessive energy, will result in tissue cavitation and injury. At the frequency used in this study, tissue cavitation occurs with an incident intensity greater than 300-350 mw/cm'. As a result, we used the same ultrasound stimulation as previously reported for bone ingrowth and fracture healing, but increased the incident intensity from 30 to 250 niw/cm'. The two prospective randomized placebo-controlled clinical trials that definitively demonstrated that noninvasive low intensity ultrasound-accelerated fracture healing were performed on the tibia and radius [10,13]. Both these bones are subcutaneous and therefore have little or no intervening tissue that could interfere with the ultrasound signal. The ulna was intentionally chosen for this intramedullary study since it was felt that its subcutaneous position would maximize the ultrasound signal reaching the implant. The decreased incident intensity of the ultrasound signal, combined with the partial absorption of the signal by the surrounding thigh musculature, are most likely responsible for the more modest response of bone ingrowth to ultrasound demonstrated in the previous transcortical femoral study. Although non-invasive low intensity ultrasound was able to substantially influence the bone ingrowth response, the mechanism by which this occurs remains unknown. Various thermal and non-thermal effects of ultrasound have been identified in fracture repair. Low intensity ultrasound has been shown to induce conformational changes in the cell membrane thereby altering ionic permeability [8,18], increase intracellular calcium [ 14,16,18,19], upregulate aggregan gene expression [24,25] and increase osseous blood flow [16]. Whether these or other factors are responsible for ultrasound's ability to enhance bone ingrowth has not yet been investigated. Bone ingrowth enhancement is needed to improve the reliability and longevity of cementless arthroplasties. Failure to achieve fixation after primary or revision cementless total joint arthroplasty remains a serious clinical problem. This results in the need for a reoperation, with its associated morbidity and cost. Even when bone ingrowth does occur, the bony attachment is patchy and incomplete. This allows for potential pathways for particulate debris from the articulating surface to migrate along the bone-implant interface. It is now known that this particulate debris can cause osteolysis, bone loss and implant loosening [1,4,9,21,23]. Any increase in the extent of bone ingrowth could only improve the reliability of cementless arthroplasty surgery. This is particularly the case in revision surgery or any surgery in which the host bone stock and healing potential are compromised. A non-invasive means of enhancing bone growth into porous implants would be a desirable adjuvant for arthroplasty surgeons. Invasive techniques, such as implant coatings, may enhance bone ingrowth but are not feasible for all implant designs, have been associated with complications and substantially increase the implant cost [2,3]. This study's findings that low intensity ultrasound can substantially increase bone growth into porous intramedullary implants establishes the potential clinical value of this modality clinically. Non-invasive low intensity ultrasound may provide a reliable, safe and inexpensive modality to augment bone ingrowth into cementless arthroplasties of all designs. However, further studies to optimize the ultrasound signal and assess its effects in an arthroplasty model are warranted prior to clinical use. Acknowledgements The authors thank Exogen Inc. (Piscataway, NJ) for providing the ultrasound transducers and Implex Corporation (Allendale, NJ) for providing the tantalum implants. References [I] Amstutz HC, Campbell P, Kossovsky N, Clarke I. Mechanism and clinical significance of wear debris-induced osteolysis. Clin Orthop 1992;276:7. [2] Bloebaum RD, Beeks D, Dorr L, Savory CG, Dupont JA, Hoffman AA. Complications with hydroxyapatite particulate separation in total hip arthroplasty. Clin Orthop 1994;298: 19. [3] Bloebaum RD, Dupont JA. Osteolysis from a press-fit hydroxyapatite-coated implant. A case study. J Arthroplasty 1993;8: 195. [4] Bobyn JD, Jacobs JJ, Tanzer M, et a]. The susceptibility of smooth implant surfaces to peri-implant fibrosis and migration of polyethylene wear debris. Clin Orthop 199531 121.

M. Tunzer er al. I Journal of Orthopaedic Research 19 (2001 i 19.5-199 199 [5] Bobyn JD, Pilliar RM, Cameron HU, Weatherly GC. The optimum pore size for the fixation of porous-surfaced metal implants by the ingrowth of bone. Clin Orthop 1980;150:263. [6] Bobyn JD, Stackpool GJ, Hacking AS, Tanzer M, Krygier JJ. Characteristics of bone ingrowth and interface mechanics of a new porous tantalum biomaterial. J Bone Joint Surg 1999;81B:907. [7] Bobyn JD, Toh KK, Hacking AS, Tanzer M, Krygier JJ. Tissue response to porous tantalum acetabular cups. J Arthroplasty 1999; 14:347. [8] Chapman I, MacNally NA, Tucker S. Ultrasound-induced changes in rates of influx and erux of potassium ions in rat thymocytes in vitro. Ultrasound Med Biol 1980;6:47. [9] Goldring S, Schiller A, Roelke M. The synovial-like membrane at the bone-cement interface in loose total hip replacements and its proposed role in bone lysis. J Bone Joint Surg 1983;65A:575. [lo] Heckman JD, Ryaby JP, McCabe J, Frey JJ, Kilcoyne RF. Acceleration of tibia1 fratlure healing by non-invasivejow-intensity pulsed ultrasound. J Bone Joint Surg 1994;76:26. [1 I] Kay A, Harvey E, Tanzer M, Stackpool GJ, Bobyn JD. The effect of prolonged ultrasound stimulation on bone growth into porous tantalum transcortical implants. Trans Orthop Res SOC 1996. p. 523. [12] Kienapfel H, Sumner DR, Turner TM, et al. Efficacy of autograft, freeze dried allograft and fibrin glue to enhance fixation of porouscoated implants in the presence of interface gaps. J Orthop Res 1992; 10:423-33. [I31 Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Roe LR. Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. J Bone Joint Surg 1997; 79A:961. [14] Otter M, McLeod BC, Rubin C. Electromagnetic fields in experimental fracture healing. Clin Orthop 1998;355:90. [15] Pidhorz LE, Urban RM, Jacobs JJ, Sumner DR, Galante JO. A quantitative study of bone and soft tissues in cementless porous- coated acetabular components retrieved at autopsy. J Arthroplasty 1993;8:213. [16] Rawool D, Goldberg B, Forsberg F. Power doppler assessment of vascular changes during fracture treatment with low intensity ultrasound. Trans Radio1 SOC North Am 1997;83:421. [17] Rivero DP, Fox J, Skipor AK, Urban RM, Galante JO. Calciumphosphate-coated titanium implants for enhanced skeletal fixation. J Biomed Mater Res 1988;22:191. [18] Ryaby JP, Bachner EJ, Bendo J. Low intensity pulsed ultrasound increases calcium incorporation in both differentiating cartilage and bone cell cultures. Trans Orthop Res SOC 1989:14:15. [I91 Ryaby JP, Matthews J, Pilla AA, Duarte-Alves P. Low intensity pulsed ultrasound affects adenylate cyclase activity and TGF-0 synthesis in osteoblastic cells. Trans Orthop Res Soc 1992; 17590. [20] Stein T, Armand C, Bobyn JD, Krygier JJ, Miller JE, Brooks CE. Quantitative histological comparison of bone growth into titanium and cobalt-chromium porous coated canine implants. Orthop Trans 1991; 15: 178. [21] Tanzer M, Harvey E, Kay A, Morton P, Bobyn JD. Effect of noninvasive low intensity ultrasound on bone growth into porouscoated implants. J Orthop Res 1996;14:901. [22] Tanzer M, Maloney WJ, Jasty M, Harris WH. The progression of femoral cortical osteolysis in association with total hip arthroplasty without cement. J Bone Joint Surg I992;74A:404. [23] Willert HG, Semlitsch M. Reactions of the articular capsule to wear products of artificial joint prosthesis. J Biomed Mater Res 1977; II:157. [24] Wu CC, Parvizi J, Lewallen DG, Greenleaf JF, Bolander ME. Exposure to low intensity ultrasound stimulates aggregan gene expression by cultured chondrocytes. Trans Orthop Res Soc 1996;21:622. [25] Yang KH, Parvizi J, Wang SJ. Exposure to low density ultrasound increases aggrecan gene expression in a rat femur fracture model. J Orthop Res 1996;14:802.