Activating extraction of demineralized bone matrix
Inventors
Behnam, Keyvan • Brochmann-Murray, Elsa J. • Murray, Samuel S.
Assignees
US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-8753660-B2
Publication Date
2014-06-17
Expiration Date
2025-11-29
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Abstract
Demineralized bone matric (DBM) and native bone morphogenetic protein (nBMP) are complex mixtures of non-collagenous bone proteins. These mixtures contain many of the BMPs that are available as recombinant molecules. Information regarding the presence in these materials of molecules that may affect the availability and activity of the BMPs is very limited. A chemical extraction of DBM, such as using alkali-urea produces a water soluble extractate which inhibits the osteogenic activity of DBM. Noggin, an extracellular BMP ligand antagonist is found in the water soluble extractate from DBM. Differential chemical extraction is a useful means of removing non-osteogenic, or osteogenic inhibitory molecules from DBM and nBMP.
Core Innovation
The invention relates to osteogenic factors, more specifically to demineralized bone matrix (DBM) and native bone morphogenetic protein (nBMP). It involves compositions including DBM and/or nBMP from which at least one endogenous inhibitor of osteogenic activity, such as noggin, is removed. This removal enhances osteogenesis by reducing inhibitory proteins that affect the availability and activity of BMPs. The method includes chemical extraction using an alkali-urea solution to produce a water soluble extractate that contains inhibitory molecules.
The problem being addressed is that DBM and nBMP are complex mixtures containing both osteogenic proteins (BMPs) and inhibitors that reduce their osteogenic potential. Noggin, a known extracellular BMP ligand antagonist, is present in DBM and inhibits BMP activity, thereby diminishing bone formation and repair. There is limited information on molecules in these materials affecting BMP availability, and the presence of inhibitors prevents DBM and nBMP from achieving optimal osteogenic efficacy. Recombinant BMPs are costly, and improved DBM and nBMP compositions with enhanced osteogenic activity are desired to allow effective treatment with lower doses.
The invention provides methods and compositions to increase the osteogenic activity of DBM and nBMP by removing or reducing osteogenic inhibitory proteins, specifically noggin, through chemical extraction with chaotropic solvents such as alkali-urea at an alkaline pH (about 10.5). The extracted DBM retains osteoinductive activity and contains reduced levels of non-osteogenic proteins. Additional embodiments include systemic or localized delivery of these compositions, the use of implants coated or seeded with the extracted material, and combining with other osteogenic agents for enhanced bone formation and repair.
Claims Coverage
The patent includes two independent claims that define the composition and method for producing the extracted demineralized bone matrix with improved osteogenic properties.
Composition of extracted demineralized bone matrix with reduced inhibitors
A composition comprising demineralized bone matrix extracted with a chaotropic solvent at an alkaline pH, retaining osteoinductive activity and bone morphogenetic proteins, but containing fewer non-osteogenic proteins than native DBM.
Method for producing extracted demineralized bone matrix with reduced inhibitors
A method comprising obtaining DBM from bone tissue, extracting the DBM with a chaotropic solvent at an alkaline pH, and isolating the resulting DBM which contains BMPs and has reduced levels of osteogenic inhibitory factors.
The independent claims cover both the composition of DBM after chaotropic solvent extraction at alkaline pH resulting in reduced non-osteogenic proteins and retained osteoinductive activity, and the method of producing such DBM. The key inventive features focus on reducing osteogenic inhibitors such as noggin from DBM using alkali-urea extraction at about pH 10.5.
Stated Advantages
The invention enhances osteogenesis by removing inhibitors such as noggin, increasing the osteogenic activity of DBM and nBMP.
It enables the use of lower doses of osteogenic materials for clinical applications, making treatments more affordable.
The extracted DBM and nBMP compositions can enhance the activity of other osteogenic agents like BMP-2, BMP-4, and BMP-7.
Documented Applications
Use in clinical situations to enhance bone healing, including fracture healing of flat and long bones, non-union fractures, and reconstructive surgery.
Treatment of bone disorders such as osteoporosis.
Applications in knee, hip and joint repair or replacement surgery, periodontitis treatment, periodontal regeneration, alveolar ridge augmentation for tooth implant reconstruction.
Use in implants such as pins, screws, plates or prosthetic joints to stabilize fractures or prosthetic implants by stimulating bone formation or repair.
Systemic or localized delivery of agents or cells to maintain bone homeostasis, enhance bone formation, or enhance bone repair.
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