Safety and feasibility of cell-based therapy of autologous bone marrow-derived mononuclear cells in plate-stabilized proximal humeral fractures in humans

Abstract

BackgroundLocal implantation of ex vivo concentrated, washed and filtrated human bone marrow-derived mononuclear cells (BMC) seeded onto β-tricalciumphosphate (TCP) significantly enhanced bone healing in a preclinical segmental defect model. Based on these results, we evaluated in a first clinical phase-I trial safety and feasibility of augmentation with preoperatively isolated autologous BMC seeded onto β-TCP in combination with angle stable plate fixation for the therapy of proximal humeral fractures as a potential alternative to autologous bone graft from the iliac crest.Methods10 patients were enrolled to assess whether cell therapy with 1.3 × 106 autologous BMC/ml/ml β-TCP, collected on the day preceding the definitive surgery, is safe and feasible when seeded onto β-TCP in patients with a proximal humeral fracture. 5 follow-up visits for clinical and radiological controls up to 12 weeks were performed.Resultsβ-tricalciumphosphate fortification with BMC was feasible and safe; specifically, neither morbidity at the harvest site nor at the surgical wound site were observed. Neither local nor systemic inflammation was noted. All fractures healed within the observation time without secondary dislocation. Three adverse events were reported: one case each of abdominal wall shingles, tendon loosening and initial screw perforation, none of which presumed related to the IND.ConclusionsCell therapy with autologous BMC for bone regeneration appeared to be safe and feasible with no drug-related adverse reactions being described to date. The impression of efficacy was given, although the study was not powered nor controlled to detect such. A clinical trial phase-II will be forthcoming in order to formally test the clinical benefit of BMC-laden β-TCP for PHF patients. Trial registration The study was registered in the European Clinical Trial Register as EudraCT No. 2012-004037-17. Date of registration 30th of August 2012. Informed consent was signed from all patients enrolled.

Comparison of three different types of scaffolds preseeded with human bone marrow mononuclear cells on the bone healing in a femoral critical size defect model of the athymic rat

“…The concentration of the putative MSC precursor in our BMC samples is between 0.02% and 0.04% of BMC. Similar concentrations were reported previously by our group and other research groups (Henrich et al, ; Seebach et al, ; Kuci et al, ).…”

“…So far, BMC has been tested clinically in several completed studies for safety, feasibility, and efficacy in cardiac and in peripheral vascular indications (Assmus et al, ; Assmus et al, ; Assmus et al, ; Assmus et al, ; Fischer‐Rasokat et al, ; Leistner et al, ; Walter et al, ). With regard to bone healing, we confirmed recently the safety of the BMC application for the treatment of proximal humerus fractures in a clinical phase I trial (Seebach et al, ). The effectivity of transplanted BMC seeded on an interconnected porous calcium hydroxyapatite scaffold for early bone healing was demonstrated in patients with osteonecrosis of the femoral head.…”

“…This assumption is supported by own previous results. We could clearly demonstrate that vitality and CFU‐F frequency of BMC are significantly attenuated after 72‐hr storage at room temperature, whereas the percentages of progenitor cell populations did not differ significantly (Seebach et al, ). Similar findings were reported by Gastens et al (); they observed a significant 15% reduction of CFU‐F in bone marrow after 24‐hr storage time compared to fresh bone marrow obtained from the same donors.…”

“…This decision was made on basis of own previous results, which demonstrate that the vitality and the percentages of stem cell populations as measured by fluorescence activated cell sorting (FACS) analysis remain stable for at least 48 hr. However, a significant decline of colony‐forming unit‐fibroblast (CFU‐F) concentration was seen after 48 hr compared to the 24‐hr values (Seebach et al, ). Hence, one might argue that a reduction of the MSC concentration leads to a loss of osteogenic functionality of the BMC preparation along with increasing storage time.…”

Size matters: Effect of granule size of the bone graft substitute (Herafill®) on bone healing using Masquelet's induced membrane in a critical size defect model in the rat's femur

“…In order to seed BMC onto Herafill®, scaffolds were placed in a monolayer in individual wells (area = 2 cm 2 ) and syngenic BMC in a volume of 350 μL PBS were dripped onto the scaffolds (concentration: 1.33 × 10 6 /cm 3 biomaterial) (Seebach et al, ; Seebach et al, ; Verboket et al, ). Afterwards an incubation at 37°C followed for 10 min.…”