Bone Morphogenetic Proteins and Tissue Engineering of Bone - Engineered Bone: Tissue Engineering Intelligence Unit - page 25

hyaluronan. Adhesive proteins fibronectin and laminin are critical in attachment of cells to ECM.
Hydroxyapatite in the mineral phase of bone is a natural biomimetic biomaterial. BMPs bind to
collagens I and IV, heparan sulfate, heparin and hydroxyapatite. 22,27 The geometry of the hy-
droxyapatite is critical for delivery of BMPs for bone induction. Consistently, optimal bone
morphogenesis was observed by hydroxyapatic discs compared to beads. This profound differ-
ence is independent of the pore size in the range from 200 to 500 µ m. The chemical composition
of the two hydroxyapatites were identical illustrating the key role of three-dimensional architec-
ture of the substratum the geometry for tissue engineering. 12,27,32,33 The role of Bioceramics in
medical applciations is well known. 10 In subhuman primates hydroxyapatite appears to be
“osteoinductive”. 31 It is likely that BMPs in circulation in the vascular system may bind to hy-
droxyapatite and secondarily induce bone formation. Thus, an osteoconductive biomaterial such
as hydroxyapatitte progressively becomes an osteoinductive substratum.
The controlled release of morphogenes and growth factors from biodegradable polymers of
poly (DL-lactic-co glycolyic acid, PLGA) and polyethylene glycol (PEG) is a critical area for
tissue engineering. 14 Biodegradable block copolymers of PLGA and PEG are optimal delivery
systems for BMP2. 34 Recombinant BMP4 and purified BMP3 bind to types I and IV collagen
and heparin. 22 A comparison of several delivery systems indicated collagen is the most optimal
delivery system for bone induction. 17 It is likely in the native demineralized bone matrix BMPs
are bound to collagenous extracellular matrix scaffolding. The role of the biomimetic biomate-
rial in the delivery of recombinant BMPs for bone tissue engineering is critically dependent on
the pharmacokinetic of release of BMPs. 39 The local retention of BMPs by the biomimetic
biomaterial such as collagen sponge as hydroxyapatite as composites of collagen and hydroxya-
patite may have profound influence on the osteoinduction by a tissue engineering device. Cells
may be transplanted in various matrices. 41
Clinical Applications of BMPs
The proof of concept that an osteoinductive composite of BMPs and scaffolding can be used
to fabricate a tissue engineered bone was demonstrated. 11 In this experiment a vascularized muscle
flap was placed in a mold mimicking the head of the femur of rat and was injected with BMPs
and collagenous matrix. It is noteworthy that a true transformation of muscle into bone mirror-
ing the shape of the femur was accomplished demonstrating the proof of principle for tissue
engineering of bone. 11 The outstanding regenerative potential of bone is common knowledge.
However, in the repair of massive segmental bone loss due to tumors, trauma or fractures due to
metabolic diseases such as diabetes and osteoporosis, it is common orthopaedic practice to aid
and abet the healing site with autogenous bone graft. The limited supply of autograft bone, the
associated donor site morbidity 46 including infections and pain is a major challenge. The avail-
ability of recombinant BMPs and biomimetic biomaterials and stem cells has set the optimal
stage for tissue engineering to enter the operating suites in orthopaedic surgery.
An auspicious beginning was made by the use of BMP 7 in treatment of tibial nonunions. 6,7
In addition to orthopaedics BMPs have been used in clinical dentistry in the realms of maxillo-
facial, surgery bone augmentation and integration of dental implants. 1,44 Despite these posi-
tive advances, many clinical challenges remain. In addition to optimization of the dose of
BMPs, pharmacokinetics of release, the optimal delivery from biomimetic biomaterials and the
optimal sterilization including irradiation. 42,43 The recent approval of recombinant BMP2 for
spine fusion appears to be the first use of a recombinant morphogen in orthopaedic surgery
and tissue engineering of bone.
Acknowledgements
I thank Rita Rowlands for outstanding help in the preparation of this article. This work is
supported by grant from Shriners Hospitals and the Department of Defense, Prostate Cancer
Research Program, DAMD17-02-1-0021, which is managed by the U.S. Army Medical Re-
search and Materiel Command.