Discussion
A paramount requirement for healing of critical-sized defects is the establishment of an osteogenetically inductive and conductive environment paired with mechanical stability (diamond concept) [
9]. Autologous grafts, like vascularized fibula transfer or iliac crest, offer a satisfying combination of above-mentioned biological and mechanical properties and are therefore still considered the gold standard [
10]. However, its use is limited by several factors, including limited bone graft size and volume and donor-site morbidity with persistent pain at the iliac crest after bone graft harvesting in up 30% [
11‐
13]. Further, critical-sized defects filled with a fibula or iliac crest graft are usually stabilized either with a plate or an external fixation because they are not accessible for a biomechanically superior nail osteosynthesis due to a missing canal. Nail osteosynthesis may be performed in combination with the Masquelet technique [
14]: after induction of the Masquelet membrane the void is filled with RIA bone grafting. Despite several reported excellent results in the literature as well as in our hands [
4,
15,
16], extensive graft resorption and weakness of the reconstructed segment, probably due to a missing osteoconduction, is a major drawback of this technique. The problem of RIA bone graft resorption despite insertion into a vascularized membrane can be seen in the above illustrated case. The failure of the tricortical iliac crest graft in our presented case may be due to two factors: first, this type of graft is difficult to insert press fit into a larger three-dimensional complex defect, especially in case of an already inserted nail, and secondly only partly addresses the volume of the circumferential defect.
In the past decades, scaffold-guided bone tissue engineering has emerged as a promising strategy to overcome the shortcomings associated with established techniques [
17‐
19]. The ability of 3D-printing allows the design and manufacture of osteoconductive scaffolds which are optimized for clinical translation in terms of pore size, layering, and degradation [
20]. Equipping the scaffolds with osteogenic as well as osteoinductive properties is a condition sine qua non; yet this is a highly demanding process with several challenges. For example, the seeding of the scaffold with mesenchymal precursor cells in order to gain osteogenetic properties is possible; however, several drawbacks have to be kept in mind. First, this requires a harvesting surgical procedure and an ex vivo cultivation of the cells, which has been shown to reduce the osteogenetic potential as well as affect phenotype and behavior of these cells [
21,
22]. Secondly, sterilization of the seeded scaffolds is difficult and may further reduce the biological potential. Thirdly, new biodegradable material directly coupled with a biologic may face the most difficult FDA class 3 regulatory approval [
23]. So overall, this is an extremely demanding and expensive process reducing the suitability for routine clinical use.
Our approach, illustrated in the above presented case, separates the diamond concept into three independent workflows, which are easily merged during surgery: 3D-printing of a well-designed biodegradable scaffold with osteoconductive properties, which is intraoperatively packed with osteogenetic and osteoinductive highly potent RIA bone grafting [
24‐
26]. Mechanical stability is achieved with an intramedullary nail on which the customized RIA bone graft filled scaffold is circumferentially clipped.
There are various advantages of this clinically driven methodology. First of all, this approach allows usage of an intramedullary nail as the mechanically most robust implant for long bone stabilization with critical-sized defects. Secondly, customized printing according to a CT-scan allows for an individualized and optimal fit of the scaffold in the defect and around the nail. Further, the 3D-printing in layering technique allows creation of a high porosity (70%) with interconnected pores of 800–2000 µm, which is reported to be a design requirement for large-volume segmental tibia and femur defect in a preclinical model [
27,
28]. The usage of medical-grade PCL and ß-TCP in an 80:20 ratio further offers the suitable mechanical properties and degradation kinetics by hydrolysis as compared to unpredictable resorption of fast degrading natural and synthetic polymers. Briefly, PCL is a biopolymer with excellent biocompatibility and biodegradability [
29] causing no local inflammation [
30] and no accumulation in organs [
31]. The pore geometry of a scaffold with collagen fiber network eventually functions as a cell-deposit template. Thereby, it fosters vascular ingrowth which builds a proper microenvironment facilitating oxygen and nutrient transport to the inner part of the scaffold essential for bone repair and crucial for avoiding premature bone graft resorption [
18,
32]. By inclusion of TCP and manufacturing of the mPCL–TCP composites osteoconductivity of scaffolds further increases resulting in the production of a scaffold providing structural support for cell attachment and tissue development suitable for clinical application in combination with autologous bone grafting [
6,
33].
Thus, the intraoperative packing of the mPCL–TCP scaffold with RIA bone grafting adds excellent osteogenic as well as osteoinductive properties without ex vivo cultivation and minimal reported donor-site morbidity [
34].
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