Healing of recalcitrant long bone fractures attributed to high-dose stem cell mixture

Study finds no stem cell-related complications and treatment is safe, effective for atrophic nonunions.

Issue: December 2007

Overall about 90% of patients’ recalcitrant long bone fractures showed bone bridging 1 year after treatment with an autologous stem cell mixture and allograft bone carrier.

The 36 patients (23 men, 13 women) enrolled in the prospective FDA-approved multicenter case series study underwent open reduction internal fixation in conjunction with the high-dose stem cell treatment, usually with intramedullary nails or plates. Patients ranged in age from 19 to 79 years and had previously failed a minimum of one previous attempt at fracture fixation (average, 1.75).

Matthew L. Jimenez, MD
Matthew L. Jimenez

The researchers treated fractures of the tibia, humerus or femur.

“Callus formation, an early sign of healing on plain radiographs, was observed in 97% at 6 months and 97% at 1 year,” Matthew L. Jimenez, MD, said. “The results of this study suggest that combining tissue repair cells (TRC) — stem cells expanded ex vivo — with allograft is safe and efficacious for recalcitrant long bone nonunions and further study regarding the application of novel cell-based therapies, such as TRCs, is warranted.”

Iliac crest harvest

Jimenez, an investigator at one of four U.S. centers that participated in the study, presented final results of the clinical phase I/II trial during the recent Orthopaedic Trauma Association 23rd Annual Meeting in Boston.

Patients enrolled in the study were treated from July 2004 to June 2006. They had normal marrow and organ function. Those with fractures closer than 4 cm to the joint, metabolic diseases, infections, immunodeficiencies and some other conditions were excluded.

Investigators harvested 30 ml to 50 ml bone marrow from the patients’ iliac crest, and shipped the bone marrow mononuclear cells (BMMNC) to the centralized production facility. The BMMNCs were separated, washed and suspended in 0.5% human serum/albumin. Next, the cells were placed in an automated cell production system to produce the TRCs (stem and early progenitor cells) over a 12-day period (Aastrom Biosciences; Ann Arbor, Mich.). On day 12, investigators implanted the cells at the nonunion site (figure 1).

Figure 1: Surgeons placed TRC at long bone nonunion sites
Surgeons placed tissue repair cells (TRC) at long bone nonunion sites. They consisted of autologous stem and early-stage progenitor cells.

Figure 2: TRCs were mixed with composite allograft particles
TRCs were mixed with composite allograft particles and implanted in patients exactly 12 days after harvesting and processing.

Images: Jimenez ML

Cell/allograft mixture

Prior to implantation, investigators gently mixed the cells with partially demineralized cortical cancellous bone allograft particles (0.5- to 2-mm particle size) for a ratio of 3 million TRCs to 1 cc allograft, Jimenez said. “We gave a fixed dose to each patient,” he explained (figure 2).

To get TRCs to adhere to the allograft, investigators placed the allograft into a filter flask on top of a semi-permeable membrane, mixed the cell suspension into the allograft and used a vacuum to remove excess liquid.

Independent, intervention-blinded radiologists assessed bone healing at 6 months and 12 months after treatment using computed tomography scans. “[Their] analysis showed 85% healing at 6 months and 91% healing at 12 months,” Jimenez said.

Fracture site healing at 1 year postop occurred in 91% of tibias, 100% of humeri and 86% of femurs based on CT scan analysis, he noted (figure 3).

Complete follow-up was only available for 33 patients. Two patients had signs of clinical healing but did not return for the 6-month follow-up visit, and one patient was lost to follow-up.

“There were no TRC-related adverse events and no morbidity associated with the aspiration,” Jimenez said.

Complications included three hardware problems, two wound infections and one wound hematoma, which he said were secondary and unrelated to the cells used.

$Figure 3a: Patient’s tibia fracture resulted in a nonunion$
This patient’s tibia fracture resulted in a nonunion, but was subsequently treated successfully with the high-dose stem cell treatment.

For more information:
Matthew L. Jimenez, MD, can be reached at Illinois Bone and Joint Institute, 9000 Waukegan Road, Suite 200, Morton Grove, IL 60053. 847-324-3965; e-mail: mljdoc@aol.com. He received research support from Aastrom Biosciences Inc.
Reference:
Jimenez ML, Lyon TR, Nowinski G, et al. High-dose stem and progenitor cell therapy for refractory long-bone nonunions: final results of a multicenter phase I/II clinical study. #17. Presented at the Orthopaedic Trauma Association 23rd Annual Meeting. Oct. 17-20, 2007. Boston.