In situ Porous Structures: A Unique Polymer Erosion Mechanism in Biodegradable Dipeptide‐Based Polyphosphazene and Polyester Blends Producing Matrices for Regenerative Engineering

Synthetic biodegradable polymers serve as temporary substrates that accommodate cell infiltration and tissue in‐growth in regenerative medicine. To allow tissue in‐growth and nutrient transport, traditional three‐dimensional (3D) scaffolds must be prefabricated with an interconnected porous structure. Here a unique polymer erosion process through which polymer matrices evolve from a solid coherent film to an assemblage of microspheres with an interconnected 3D porous structure is demonstrated for the first time. This polymer system is developed on the highly versatile platform of polyphosphazene‐polyester blends. Co‐substituting a polyphosphazene backbone with both hydrophilic glycylglycine dipeptide and hydrophobic 4‐phenylphenoxy group generates a polymer with strong hydrogen bonding capacity. Rapid hydrolysis of the polyester component permits the formation of 3D void space filled with self‐assembled polyphosphazene spheres. Characterization of such self‐assembled porous structures reveals macropores (10–100 μm) between spheres as well as micro‐ and nanopores on the sphere surface. A similar degradation pattern is confirmed In vivo using a rat subcutaneous implantation model. 12 weeks of implantation results in an interconnected porous structure with 82–87% porosity. Cell infiltration and collagen tissue in‐growth between microspheres observed by histology confirms the formation of an in situ 3D interconnected porous structure. It is determined that the in situ porous structure results from unique hydrogen bonding in the blend promoting a three‐stage degradation mechanism. The robust tissue in‐growth of this dynamic pore forming scaffold attests to the utility of this system as a new strategy in regenerative medicine for developing solid matrices that balance degradation with tissue formation.

[1]  C. Laurencin,et al.  Dipeptide-based polyphosphazene and polyester blends for bone tissue engineering. , 2010, Biomaterials.

[2]  A. Andrianov.  Polyphosphazenes for Biomedical Applications , 2009 .

[3]  Cato T. Laurencin,et al.  The Implications of Polymer Selection in Regenerative Medicine: A Comparison of Amorphous and Semi‐Crystalline Polymer for Tissue Regeneration , 2009 .

[4]  E. W. Meijer,et al.  Metastable supramolecular polymer nanoparticles via intramolecular collapse of single polymer chains. , 2009, Journal of the American Chemical Society.

[5]  C. Laurencin,et al.  Biodegradable Polyphosphazene Blends for Biomedical Applications , 2008 .

[6]  C. Hawker,et al.  Polymeric Nanoparticles via Noncovalent Cross-Linking of Linear Chains , 2008 .

[7]  Cato T Laurencin,et al.  Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: A combined gene therapy–cell transplantation approach , 2008, Proceedings of the National Academy of Sciences.

[8]  C. Laurencin,et al.  Biodegradable polymers as biomaterials , 2007 .

[9]  Andrew J. Wilson.  Non-covalent polymer assembly using arrays of hydrogen-bonds. , 2007, Soft matter.

[10]  C. Laurencin,et al.  Miscibility of bioerodible polyphosphazene/poly(lactide-co-glycolide) blends. , 2007, Biomacromolecules.

[11]  C. Laurencin,et al.  The Biocompatibility of Biodegradable Glycine Containing Polyphosphazenes: A Comparative study in Bone , 2007 .

[12]  C. Laurencin,et al.  In vivo biodegradability and biocompatibility evaluation of novel alanine ester based polyphosphazenes in a rat model. , 2006, Journal of biomedical materials research. Part A.

[13]  Cato T Laurencin,et al.  Effect of side group chemistry on the properties of biodegradable L-alanine cosubstituted polyphosphazenes. , 2006, Biomacromolecules.

[14]  S. Hodgson.  Proximal Humerus Fracture Rehabilitation , 2006, Clinical orthopaedics and related research.

[15]  D. Kaplan,et al.  Porosity of 3D biomaterial scaffolds and osteogenesis. , 2005, Biomaterials.

[16]  C T Laurencin,et al.  Tissue-engineered bone formation in vivo using a novel sintered polymeric microsphere matrix. , 2004, The Journal of bone and joint surgery. British volume.

[17]  Chad Johnson,et al.  The effect of scaffold degradation rate on three-dimensional cell growth and angiogenesis. , 2004, Biomaterials.

[18]  Cato T Laurencin,et al.  Bioreactor-based bone tissue engineering: the influence of dynamic flow on osteoblast phenotypic expression and matrix mineralization. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  C. Laurencin,et al.  Structural and human cellular assessment of a novel microsphere-based tissue engineered scaffold for bone repair. , 2003, Biomaterials.

[20]  H. Allcock.  Chemistry and applications of polyphosphazenes , 2002 .

[21]  L. Qiu.  In vitro and in vivo degradation study on novel blends composed of polyphosphazene and polyester or polyanhydride , 2002 .

[22]  S. Mann,et al.  The potential of biomimesis in bone tissue engineering: lessons from the design and synthesis of invertebrate skeletons. , 2002, Bone.

[23]  R. Langer,et al.  A tough biodegradable elastomer , 2002, Nature Biotechnology.

[24]  D. Katti,et al.  Degradable polyphosphazene/poly(α-hydroxyester) blends: degradation studies , 2002 .

[25]  K. Leong,et al.  The design of scaffolds for use in tissue engineering. Part I. Traditional factors. , 2001, Tissue engineering.

[26]  Y. Inoue,et al.  Studies on Poly(«-caprolactone)/Thiodiphenol Blends: The Specific Interaction and the Thermal and Dynamic Mechanical Properties , 2000 .

[27]  T. Park,et al.  Porous biodegradable polymeric scaffolds prepared by thermally induced phase separation. , 1999, Journal of biomedical materials research.

[28]  H R Allcock,et al.  Novel polyphosphazene/poly(lactide-co-glycolide) blends: miscibility and degradation studies. , 1997, Biomaterials.

[29]  S. Gogolewski,et al.  Long-term soft tissue reaction to various polylactides and their in vivo degradation , 1996 .

[30]  R Langer,et al.  Novel approach to fabricate porous sponges of poly(D,L-lactic-co-glycolic acid) without the use of organic solvents. , 1996, Biomaterials.

[31]  Harry R. Allcock,et al.  Poly[(amino acid ester)phosphazenes]: Synthesis, Crystallinity, and Hydrolytic Sensitivity in Solution and the Solid State , 1994 .

[32]  Robert Langer,et al.  Preparation and characterization of poly(l-lactic acid) foams , 1994 .

[33]  Adibi Sa.  Glycyl-dipeptides: new substrates for protein nutrition. , 1989 .

[34]  S F Hulbert,et al.  Potential of ceramic materials as permanently implantable skeletal prostheses. , 1970, Journal of biomedical materials research.

[35]  L. Wood.  Glass transition temperatures of copolymers , 1958 .

[36]  Justin L. Brown,et al.  Biomimetic, bioactive etheric polyphosphazene-poly(lactide-co-glycolide) blends for bone tissue engineering. , 2010, Journal of biomedical materials research. Part A.

[37]  Cato T Laurencin,et al.  Miscibility and in vitro osteocompatibility of biodegradable blends of poly[(ethyl alanato) (p-phenyl phenoxy) phosphazene] and poly(lactic acid-glycolic acid). , 2008, Biomaterials.

[38]  Cato T Laurencin,et al.  Tissue engineered microsphere-based matrices for bone repair: design and evaluation. , 2002, Biomaterials.

[39]  J. A. Cooper,et al.  Tissue engineering: orthopedic applications. , 1999, Annual review of biomedical engineering.

[40]  Xiaoqing Zhang,et al.  Phase separation and thermal degradation of poly(vinyl alcohol)/poly(methacrylic acid) and poly(vinyl alcohol)/poly(acrylic acid) systems by 13C c.p./m.a.s. n.m.r. , 1992 .