Clinical Evaluation of BMPs and Bone Marrow Stromal Cells in Orthopedic Surgery - Engineered Bone: Tissue Engineering Intelligence Unit - page 199

will be deflated. Although no major systemic effects were reported in the different clinical
trials, an immune response was observed in 38% of the patients treated with OP-1 thus pre-
venting from the implantation of another dose of OP-1 in the future. 20
Another reason for the need in human of high dose of BMPs is probably related to the
under-performance of BMPs in higher species as opposed to rodents, 34 and the fact that BMP2
and BMP7 are physiologically part of a complex cascade involving a number of molecules to
achieve bone repair. Such a mixture of osteoinductive proteins can be found in the demineral-
ized bone matrix (DBM) that is currently in use in clinical practice. It is noteworthy that the
inductive potential of rh-BMP2 or OP-1 is 1 million times that of the DBM, while DBM has
given similar results than the application of a high-dose of a single BMP. 19 The use of a high
dose of a recombinant molecule raises also the acute problem of the cost of this new technol-
ogy. This cost, although excessive (approximately 4500 euros per dose), should be balanced by
the potential reduction of failure rate of currently available techniques, their morbidity, and the
resulting disability. As for any new therapeutic procedure, the cost-benefit of BMPs should be
carefully evaluated before they can be routinely applied in clinical practice. The comparison of
BMPs to the standard of care in prospective clinical trials is of paramount importance, but the
design of the study itself, the choice of outcome parameters, the analysis and interpretation of
the data are critical to provide clear and non-ambiguous information to the medical commu-
nity. 35 In this respect, several parameters might have been considered in previous reported
trials:
1. stating that a fracture is healed should be based on both clinical parameters and several
x-rays views taken at different time points, given the fact that interpretation of x-rays is very
subjective and cannot be blind, as bone grafting is easily recognizable;
2. The effect of BMPs should be easily quantified and distinguished from the action of other
potential procedures: tibial reaming and nailing, autologous bone grafting are by them-
selves effective treatments of bone nonunions and should ideally not be combined with the
use of BMPs in randomized trials, because they make the interpretation more difficult;
3. With regards to long bone nonunions, the patients should be at least stratified by the sever-
ity of open wound, the presence of infection or not, the length of the bone defect, as the
results might considerably vary from one group to another.
Clinical Experience with Bone Marrow Stromal Cells
The efficiency of osteoinductive biomaterials relies on the recruitment of osteocompetent
cells from the surrounding tissues. Therefore, their use will be limited to clinical cases where
the wound bed can provide these cells, excluding clinical situations involving necrotic areas
and large bone defects. To overcome this problem, the use of osteogenic material composed of
a scaffold loaded with osteocompetent cells has been proposed. 13
There are a number of possible sources of bone progenitor cells, each with its own advan-
tages and drawbacks. The osteogenic potential of fresh bone marrow has long been recognised
and a number of investigators have experienced some success using autologous fresh bone
marrow to augment bone formation in experimental studies. Connoly, 36 Healey 37 and Garg 38
have documented the use of fresh bone marrow in the treatment of ununited fractures. How-
ever, no prospective randomized clinical trial has been carried out to definitely demonstrate the
efficacy of this practice. In addition, the quantity of newly formed bone is directly dependent
on the number of osteocompetent cells implanted, prompting the use of techniques allowing
the isolation and amplification of the osteocompetent cell pool. Once the expansion of BMSCs
is achieved, the next step in the process of building an osteogenic material is to load BMSCs
onto a scaffold. There is general agreement that the scaffold should favor BMSCs adhesion,
proliferation and differentiation as well as encourage rapid vascular invasion. Ideally, the new
extra-cellular matrix should take on the mechanical function of the template as bone forms,
implying that the scaffold should disappear at a rate commensurate with new bone forma-
tion. 13 A number of carriers have been evaluated for delivering BMSCs including collagen,