Method Weight-bearing implants with a 0.75-mm surrounding gap were inserted bilaterally in the knees of 10 dogs. Growth factors were incorporated in a biodegradable poly(D,L-lactide) coating on porous coated titanium implants. Plasma-sprayed HA implants served as controls. The dogs were killed at 4 weeks and the implants were evaluated by mechanical push-out test and by histomorphometry.

Results There was no difference in any of the mechanical parameters. Bone ongrowth was 3-fold higher for HA-coated implants (p < 0.001). For growth factor-coated implants, bone volume was 26% higher in the inner half of the gap and 28% higher in the outer half compared to HA (p < 0.03).

Implants with a hydroxyapatite (HA) coating stimulate bone ingrowth to implants. The highly osteoconductive nature of HA coatings has been demonstrated experimentally (Soballe et al. 1990, 1992), and superior longevity has been demonstrated clinically (Soballe et al. 1993, Capello et al. 2006, Kelly et al. 2006). Recently, new adjuvant therapies using osteogenic growth factors have been introduced. Experimental studies have shown that local growth factor treatment can stimulate osseointegration and gap healing of orthopedic implants (Lamberg et al. 2006, Sumner et al. 2006). Some of these treatments have also proven useful in fracture healing and spinal fusion (Schmidmaier et al. 2001a, Kandziora et al. 2002).

We have previously shown that the combination of transforming growth factor β1 (TGF-β1) and insulin-like growth factor 1 (IGF-1) in a biodegradable poly(D,L-lactide) coating markedly increases the fixation and osseointegration of porous coated titanium implants in an unloaded 1-mm gap model (Lamberg et al. 2006). To follow up on the comparison with the negative control group (Ti), we next compared local growth factor treatment pairwise with HA coating, a known effective stimulator of osseointegration.

The mechanical push-out test found all implants to be well fixed, with shear strength ranging from 2.5 to 5 MPa. There were no statistically significant differences in any of the 3 mechanical parameters (Figure 3 and Table 1).

In contrast to the push-out test, the histomorphometric analysis showed differences in tissue distribution around the implants. Bone ongrowth to the implants was 3-fold higher for HA-coated implants (p < 0.001) (Table 2). There was ongrowth of fibrous tissue in 4 of the 10 HA-coated implants (up to 8%), and no fibrous tissue on the growth factor-coated implants (p = 0.05) (Figure 4). In the inner half of the gap, the bone volume fraction was 26% higher in the growth factor-coated implant group (p = 0.01) (Table 2). In the outer half of the gap, the bone volume fraction was 28% higher in the growth factor-coated implant group (p = 0.03) (Figure 5). There were no signs of residual polymer on the implant surfaces.

We used an experimental animal model that attempts to mimic the cancellous bone fixation of clinical implants. The implants are weight-bearing and their intraarticular location results in a flow of synovial fluid along the implant interface. The main idea of this model is to test whether a treatment will enhance the initial implant fixation, and thus prevent early loosening. The observation period of 4 weeks has been shown to detect differences in early fixation in this model (Soballe et al. 2003, 2004). We used a paired design, thus eliminating the inter-individual variation between animals.

As with all other experimental models, this model also has limitations. The loading is mainly in shear and does not include the rotational forces that also apply to human implants. The dog has a bone turnover which is 2–3 times higher than that in humans. This may influence the effect of certain treatments. Moreover, the implants are simplified in shape and size and do not include fixation points of both cancellous and cortical bone. However, this allows implantation in a highly controlled environment and permits unbiased histological evaluation.

The histological analysis showed that the solid fixation in both groups was obtained in a different way for each group: the HA-coated implants had a greater surface bone ongrowth, whereas the growth factor-coated Ti implants had greater new bone formation in the surrounding gap.

The effect of local release of TGF-β1 and IGF-1 on the tissue response was different than for HA. In accordance with previous studies (Lamberg et al. 2006), no fibrous tissue ongrowth was found on any implant with TGF-β1 and IGF-1. Without adjuvant therapy, a high degree of fibrous tissue anchorage would be expected on titanium implants in this implant model (Soballe et al. 1992, Elmengaard et al. 2005). We believe that the elimination of fibrous tissue on the interface is not an effect related to the poly(D,L-lactide) scaffold. A parallel study has shown no difference in fibrous tissue ongrowth between poly(D,L-lactide)-coated and control titanium implants (unpublished data). To our knowledge, no other adjuvant treatment has been shown experimentally to stimulate gap healing around titanium implants better than HA.

Applications combining 2 or more growth factors may be more favorable due to additive or synergistic effects on bone formation. TGF-β1 and IGF-1 are both highly expressed during bone growth (Dequeker et al. 1993, Nicolas et al. 1994, Lammens et al. 1998, Eingartner et al. 1999, Pfeilschifter et al. 1999, Kveiborg et al. 2001). A synergistic effect of TGF-β1 and IGF-1 on bone healing has been reported (Schmidmaier et al. 2003). Our study does not allow us to make conclusions on the contribution of each component to the result. However, the overall effect of the combined growth factors was higher compared to historic data from studies using the same model and single administration of TGF-β1 (Lind et al. 1996a, b).

We used a polymer for controlled release of the growth factors. The poly(D,L-lactide) has been used successfully as a drug carrier (Schmidmaier et al. 2001b, Rose et al. 2004). Polylactides are also used to make screws and plates for fracture treatment, and are generally considered safe. This delivery system has advantages over other methods such as simple surface adsorption of growth factors and collagen sponges, as it has been documented to be mechanically stable (Schmidmaier et al. 2001b) and thereby able to resist the forces of implantation. In addition, it is generally accepted that the majority of the growth factors most likely remain in the scaffold until the bleeding from the bone has ceased. Elution studies have shown a release profile of 50% release within 48 h, with growth factors detectable for several weeks thereafter. In contrast to the studies of fracture healing in a rat model (Schmidmaier et al. 2001b), there was no polymer left on our implants at the end of the observation period. The amount of growth factor used depends on the size of the implants, as the growth factors are administered in a specific w/w ratio to the poly(D,L-lactide) scaffold. The w/w ratio that we used was based on previous experience (Kandziora et al. 2003, Lamberg et al. 2006). It is possible that even better results would be obtained with different ratios, and this is the subject of further investigation.