Tissue Engineering of Bone by Osteoinductive Biomaterials
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resides in the solubilized component but needs to be reconstituted with an appropriate carrier to restore the osteoinductive activity.5 In this case, the carrier is the insoluble collagenous bone matrix— mainly crosslinked type I collagen. Nature had a lesson to teach. Bone formation requires three key components: the osteoinductive signal, a suitable substratum with which this signal is to be delivered and that acts as a scaffold for the new bone to form, and responding host cells capable of differentiation into bone cells. All three components are amenable to manipulation: the signal (or signals) to be delivered and the nature of the substratum, which additionally may be loaded with responding cells or tissues.6
The Signals The molecular dissection of the extracellular matrix of bone has permitted the identification of an entirely new family of protein initiators that regulate differentiation of cartilage and bone in vivo. The signals responsible for osteoinduction are a family of proteins collectively called the bone morphogenetic proteins (BMPs).7"11 Bone morphogenetic proteins are members of a superfamily of growth and differentiation factors that includes the activins and inhibins, the transforming growth factor /3s (TGF-/3s), growth and differentiation factors (GDFs), and cartilage-derived morphogenetic proteins.12-15 Members of the BMP family are factors that have potent and diverse effects on cell migration, proliferation, differentiation, and matrix synthesis. To date, 13 BMP sequences have been cloned. With the exception of BMP-1,
which is a misnamed type I procollagen proteinase,16 recombinant human BMP-2 through BMP-6 and osteogenic protein-1 and 2 (OP-1 and OP-2, also known as BMP-7 and BMP-8, respectively), in conjunction with the collagenous matrix, singly induce de novo bone formation when implanted in extraskeletal sites in a variety of animal models.12-15 The bone tissue induced by BMPs is organized into an ossicle comprising an outer cortical shell and inner trabecular bone permeated by marrow. As for intact demineralized bone matrix, the tissue response elicited by implantation of recombinant human BMPs under the skin, combined with the collagenous matrix, is reminiscent of embryonic bone development.1314 Thus BMPs are the common molecular initiators deployed for embryonic development and induction of bone formation and regeneration in postnatal osteogenesis. Ample evidence is accruing on the efficacy and safety of native and recombinant human BMPs, in conjunction with the collagenous carrier, for the regeneration of orthopedic and craniofacial bone defects in animal models including primates.17"19 Preclinical studies on nonhuman primates are critical to test the efficacy of recombinant molecules under evaluation for therapeutic osteogenesis. The possibility of fabricating osteoinductive biomaterials by combining recombinant human BMPs with a plethora of synthetic biomaterials other than the insoluble collagenous matrix is a fertile area of research for tissue engineering of bone.
The Subs
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