Clinical translation of a patient-specific scaffold-guided bone regeneration concept in four cases with large long bone defects

Abstract

Background: Bone defects after trauma, infection, or tumour resection present a challenge for patients and clinicians. To date, autologous bone graft (ABG) is the gold standard for bone regeneration. To address the limitations of ABG such as limited harvest volume as well as overly fast remodelling and resorption, a new treatment strategy of scaffold-guided bone regeneration (SGBR) was developed. In a well-characterized sheep model of large to extra-large tibial segmental defects, three-dimensional (3D) printed composite scaffolds have shown clinically relevant biocompatibility and osteoconductive capacity in SGBR strategies. Here, we report four challenging clinical cases with large complex posttraumatic long bone defects using patient-specific SGBR as a successful treatment.

Methods: After giving informed consent computed tomography (CT) images were used to design patient-specific biodegradable medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP, 80:20 ​wt%) scaffolds. The CT scans were segmented using Materialise Mimics to produce a defect model and the scaffold parts were designed with Autodesk Meshmixer. Scaffold prototypes were 3D-printed to validate robust clinical handling and bone defect fit. The final scaffold design was additively manufactured under Food and Drug Administration (FDA) guidelines for patient-specific and custom-made implants by Osteopore International Pte Ltd.

Results: Four patients (age: 23-42 years) with posttraumatic lower extremity large long bone defects (case 1: 4 ​cm distal femur, case 2: 10 ​cm tibia shaft, case 3: complex malunion femur, case 4: irregularly shaped defect distal tibia) are presented. After giving informed consent, the patients were treated surgically by implanting a custom-made mPCL-TCP scaffold loaded with ABG (case 2: additional application of recombinant human bone morphogenetic protein-2) harvested with the Reamer-Irrigator-Aspirator system (RIA, Synthes®). In all cases, the scaffolds matched the actual anatomical defect well and no perioperative adverse events were observed. Cases 1, 3 and 4 showed evidence of bony ingrowth into the large honeycomb pores (pores >2 ​mm) and fully interconnected scaffold architecture with indicative osseous bridges at the bony ends on the last radiographic follow-up (8-9 months after implantation). Comprehensive bone regeneration and full weight bearing were achieved in case 2 ​at follow-up 23 months after implantation.

Conclusion: This study shows the bench to bedside translation of guided bone regeneration principles into scaffold-based bone tissue engineering. The scaffold design in SGBR should have a tissue-specific morphological signature which stimulates and directs the stages from the initial host response towards the full regeneration. Thereby, the scaffolds provide a physical niche with morphology and biomaterial properties that allow cell migration, proliferation, and formation of vascularized tissue in the first one to two months, followed by functional bone formation and the capacity for physiological bone remodelling. Great design flexibility of composite scaffolds to support the one to three-year bone regeneration was observed in four patients with complex long bone defects.

The translational potential of this article: This study reports on the clinical efficacy of SGBR in the treatment of long bone defects. Moreover, it presents a comprehensive narrative of the rationale of this technology, highlighting its potential for bone regeneration treatment regimens in patients with any type of large and complex osseous defects.

Keywords: additive manufacturing; bone; defect; non-union; polycaprolactone; scaffold.

Fig. 1

Workflow of the interdisciplinary process for the development and manufacturing of the patient-specific biodegradable scaffolds.

Fig. 2

Schematic depiction of the development steps towards the optimized design of patient-specific biodegradable scaffolds for use in complex large bone defects. Typically, the hospital undertakes a CT scan and provides the team designing the scaffold with the acquired image data. Cross-sectional images of the CT scan (A) are segmented and converted into STL files. Based on the information stored in the STL file, the surface geometry of the 3D model (B) and the defect-fitting scaffolds are 3D-printed (C, exemplary prototypes of the modular, two-part mPCL-TCP scaffold of case 3 fitting the complex femoral bone defect). Modular design, with large pore sizes of 0.8–3 ​mm for incorporation of bone graft (see magnification in C), allowed for unilateral surgical access with placement of lateral scaffold first followed by the medial scaffold (black dashed line indicates the contact point of the two scaffolds).

Fig. 3

An mPCL-TCP scaffold loaded with ABG was used to treat femoral non-union and leg length discrepancy (- 4 ​cm) in a 23-year-old patient. The implanted LISS plate (Synthes®, A) was removed, and the patient received re-osteosynthesis using an NCB plate (nine holes, Zimmer®) laterally and LCP (eight-hole large fragment system, Synthes®) medially (B). At the short-term follow-up, delicate but adequate bone formation with full scaffold integration (C).

Fig. 4

Treatment of extra-large tibial segmental (10 ​cm) defect with mPCL-TCP scaffold loaded with ABG and supplemented with rhBMP-2 (INFUSE® Bone Graft, Medtronic). An Orthofix® (TrueLok™ Ring Fixation System) was implanted to allow for full weight bearing, while an inserted antibiotic-impregnated PMMA spacer was used to initiate the IMT (A). In the second surgery of the two-stage IMT, the PMMA spacer (white triangle) is carefully removed after Masquelet-membrane (asterisks) incision (B). The RIA system (Synthes®) was used to harvest the ABG (C), which was then carefully inserted into the large-pored scaffold (D). After insertion of the scaffold loaded with ABG (white triangles) and supplemented with rhBMP-2 and Cerament G® in the segmental defect, the Masquelet-membrane (asterisk) was closed (E).

Fig. 5

Complete bone regeneration achieved in an extra-large tibial segmental (10 ​cm) defect after implantation of an mPCL-TCP scaffold loaded with ABG and supplemented with rhBMP-2 (INFUSE® Bone Graft, Medtronic). Scaffold integration at the proximal and distal defect ends after one year (A) was observed, and an external fixator was exchanged with plate fixation. At 19 months after scaffold implantation, x-ray (B) and 3D reconstruction of the CT scan (C) showed bony fusion. At 23 months after scaffold implantation, functional reconstruction of the extra-large segmental defect was achieved and the osteosynthesis implants were removed (D).

Fig. 6

Treatment of large bone defect with complex malunion of the right femoral shaft with modular (two parts) 3D-printed mPCL-TCP scaffolds. Following comprehensive treatment of a posttraumatic septic defect pseudarthrosis, including implantation of a hybrid fixator (Orthofix®) to support stability during infect consolidation (A), 3D reconstruction of CT imaging data showed two distinguished femoral bone defects located antero-lateral and antero-medial and also the preferred plate osteosynthesis was integrated at an early stage in the surgical planning (B). Two geometrically matched 3D-printed mPCL-TCP scaffolds loaded with ABG (C) were implanted and combined with plate osteosynthesis. Proper fit of the modular two-part scaffold of the bone defect as per the pre-operative planning (see inset in D), was confirmed intra-operatively (D).

Fig. 7

Early radiological confirmation of correct fit of patient-specific mPCL-TCP scaffolds secured with stainless steel cerclage wire. 3D reconstruction of the CT imaging seven months after scaffold implantation with early mineralisation of the fully interconnected large pore architecture (A). Further, progressing osseous consolidation five (B) and nine months (C) after implantation are shown radiographically.

Fig. 8

Complex course of treatment after polytrauma with distal lower leg fracture and recurrent MRSA-induced osteomyelitis. Initial treatment included open biopsy (test result: MRSA), removal of the implants (A), and implantation of an Orthofix® ring fixator (TrueLok™ Ring Fixation System) along with Cerament V® insertion in the medullary cavity of the right tibia (B). After treatment of the MRSA osteomyelitis, the procedure was changed 12 months after application of the ring fixator to a Stryker® T2 tibia nail (C). During short-term follow-up, removal of the intramedullary nail and multiple debridement due to a recurrent MRSA infection were indicated (D).

Fig. 9

Implantation of 3D-printed patient-specific bioresorbable two-part composite scaffold in complex bone defect right distal tibia dorso-medially 22 months after index trauma. In a comprehensive course of treatment, a recurrent infected posttraumatic non-union was eventually stabilized with an external fixator with PMMA spacer (induced-membrane technique, IMT) application (A) in the defect (see inset in A for defect visualization). After persistent MRSA-induced osteomyelitis had been ruled out in an open biopsy following antibiotic therapy, a two-part mPCL-TCP scaffold fitting the irregularly shaped defect was loaded with ABG during the second stage of the IMT (B). Proper fit of the modular scaffold of the defect, as observed during pre-operative planning (see inset in C), was confirmed intra-operatively (C). The scaffold (white triangles) was additionally secured with plate osteosynthesis (D). Eight months after implantation, there was bone formation inside and outside the fully interconnected scaffold architecture (E, triangles indicate the outer border of the scaffold).