Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Compositions to be polymerized by wave energy wherein said...
Reexamination Certificate
2002-06-28
2004-06-22
Wilson, D. R. (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Compositions to be polymerized by wave energy wherein said...
C522S107000, C525S444000, C525S445000, C521S052000
Reexamination Certificate
active
06753358
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to a compound for replacing or reconstructing bone. More particularly, the present invention relates to compositions comprising poly(propylene fumarate) cross linked with diethyl fumarate and methods for making these compositions.
BACKGROUND OF THE INVENTION
In the field of tissue engineering, degradable biomaterials can serve as a scaffold to provide mechanical support and a matrix for the ingrowth of new tissue. As new tissue forms on the scaffold, the biomaterial degrades until it is entirely dissolved. The degradation products are eliminated through the body's natural pathways, such as metabolic processes.
One example of the use of such biomaterials is as a temporary bone replacement. It is often desired to replace or reconstruct all or a portion of a living bone, such as when a bone has been broken or has been resected as a result of a bone tumor. In these instances, the missing bone can be replaced with a mechanical device, such as a pin, plate or the like, or it can be replaced with an implant that is designed to more closely resemble the original bone itself. Often these implants comprise biodegradable polymeric compounds or parts made from such compounds. It is contemplated that bone tissue will grow back into the pores of the implant and will gradually replace the entire implant as the implant itself is gradually degraded in the in vivo environment. Thus it is desirable that such implants be biocompatible and non-toxic.
Poly(propylene fumarate) is one such polymer. Poly(propylene fumarate) (hereinafter “PPF”) is an unsaturated linear polyester that degrades in the presence of water into propylene glycol and fumaric acid, degradation products that are easily cleared from the human body by normal metabolic processes. Because the fumarate double bonds in PPF are reactive and cross link at low temperatures, PPF has potential to be an effective in situ polymerizable biomaterial. The high mechanical strength of cured PPF matrices and their ability to be cross linked in situ makes them especially suitable for orthopedic applications, including bone cement, orthopaedic scaffolding for bone tissue regeneration, and drug delivery systems.
In particular, an injectable matrix is desired. A principle advantage of injectable biomaterials lies in their ability to completely fill the irregularly shaped bone defects that often arise clinically. Other advantages include their ease of use, allowance of minimally invasive surgical procedures, and ability to act as a carrier of cells or bioactive agents. The development of an injectable, in situ polymerizable biomaterial, however, requires the consideration of a number of material characteristics that are not often evaluated for other biomaterials, including uncured solution viscosity and heat evolution during curing. Hence, despite advances in the technology, there remains a need for an effective, injectable, in situ polymerizable biomaterial. The development of tissue engineered materials for the treatment of large bone defects would provide attractive alternatives to the autografts, allografts, non-degradable polymers, ceramics, and metals that are currently used in clinical settings.
PPF has been investigated as a bone graft/bone scaffolding material. PPF contains a repeating fumarate unit that is comprised of one carbon—carbon double bond and two ester groups. The carbon—carbon double bond allows the viscous PPF polymer to be crosslinked into a solid, while each ester group allows PPF to degrade, via ester hydrolysis, into biocompatible fragments [6]. Photocrosslinked PPF has been formed into scaffolds, shown to elicit a mild tissue response, and, when loaded with transforming growth factor beta 1 (TGF-
1), shown to promote the formation of bone in a rabbit cranial defect model [7-9]. A photocrosslinkable biomaterial such as this PPF-based system may be suitable both for treatments that prefer a prefabricated implant and treatments that prefer an injectable biomaterial that is cured by light, either during or after its injection.
At high PPF molecular weights, however, the polymer becomes quite viscous, inhibiting its handling properties and, by definition, markedly reduces its ability to flow. This viscous nature of PPF has repercussions for both injectable and prefabrication processes. Hence, it is desired to create a PPF system that possesses a significantly reduced viscosity, while still retaining the advantageous characteristics of fumarate-based biomaterials.
SUMMARY OF THE INVENTION
The present invention comprises new, injectable biodegradable polymer composites based on PPF cross linked with a fumarate derivative, and in particular with diethyl fumarate. According to the present invention, poly(propylene fumarate) (PPF), a viscous polyester synthesized from a fumarate precursor such as diethyl fumarate (DEF), is use as an engineered bone graft. More specifically, the photocrosslinking of PPF dissolved in a fumarate precursor such as DEF, using a photoinitiator such as bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and low levels of ultraviolet light exposure, is disclosed.
In order to investigate the various characteristics of the present fumarate polymers, a three-factor, 2×2×4 factorial design was applied to the composition, so that the effects of PPF number average molecular weight, BAPO initiator content, and DEF content upon photocrosslinking characteristics and mechanical properties could be studied.
It was discovered that for uncured DEF/PPF solution viscosity fell over three orders of magnitude as DEF content was increased from 0 to 75%. The exothermic photocrosslinking reaction releases low levels of heat, with no more than 160 J/g released from any formulation tested. As a result, the maximum photocrosslinking temperature remained below 47° C. for all samples. Sol fraction varied from 26 to 65%, with composites of high PPF molecular weight and high BAPO content containing the smallest sol fraction. Compressive mechanical properties were within the range of trabecular bone, with the strongest samples possessing an elastic modulus of 195.3±17.5 MPa and a fracture strength of 68.8±9.4 MPa. Finally, the results indicated that PPF crosslinking was facilitated at low DEF precursor concentrations, but hindered at higher precursor concentrations.
The invention comprises the compositions formed by dissolving PPF in a fumarate solvent, the polymeric networks formed by crosslinking those compositions, and to methods for making items comprised of the polymer networks. These novel DEF/PPF solutions may be preferred over pure PPF as the basis for an engineered bone graft as they: (1) exhibit reduced viscosity and thus are easily handled, (2) form polymer networks with compressive strengths at fracture that are suitable for consideration for trabecular bone replacement, and (3) may be readily fabricated into solids with a wide range of structures.
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Alger, “Polymer Science Dictionary”, 2nd ed., Chapman & Hall, New York, p. 374 (1997).
Fisher John P.
Mikos Antonios G.
William Marsh Rice University
Wilson D. R.
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