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Diblock Copolypeptide Hydrogels for Drug Delivery and Stem Cell Grafting

  • Author(s): Wollenberg, Alexander Lee
  • Advisor(s): Deming, Timothy J.
  • et al.

Grafting of stem cells into the central nervous system (CNS) for regeneration of damaged or degrading neural tissue has shown promise. Unfortunately, this approach is hampered by poor grafted cell survivability, uncontrollable differentiation, and limited integration with host tissue. Many of these problems have been eliminated by using a cell delivery vehicle, such as a hydrogel, which mimics extra cellular matrix (ECM). ECM is densely populated with proteins and proteoglycans that provide a scaffold to support cellular interactions and has therefore driven many researchers to develop novel protein and polysaccharide based hydrogels to replicate this environment.

This dissertation encompasses the synthesis and characterization of novel L-methionine (Met) based diblock copolypeptide hydrogels (DCH) for use in drug delivery and stem cell grafting in the central nervous system (CNS). Met is a naturally occurring amino acid that has rich biochemistry and can be either alkylated or oxidized to form cationic sulfonium or non-ionic sulfoxide functionalities, respectively. We took advantage of Met reactivity to synthesize a library of chemically diverse DCH using ring opening polymerizations of N-carboxyanhydrides (NCA) monomers. These DCH were found to have tunable physical properties and underwent sheer-thinning when large amounts of strain were applied, which is an important feature for non-invasive injectable hydrogels. This DCH library consisted of cationic Met sulfonium based hydrogels (DCHMM) and non-ionic Met sulfoxide based hydrogels (DCHMO).

In vitro encapsulation of neural stem/progenitor cells (NSPC) within DCHMO gave comparable cell viability to culture media alone, and cell culture studies show minimal cell attachment to these scaffolds, which preserved NSPC stemness and multipotency compared to other materials. NSPC in DCHMO injected into uninjured forebrain remained localized to the grafted deposit and, after 4 weeks, exhibited an immature astroglial phenotype that integrated with host neural tissue and acted as cellular substrates that supported growth of host-derived axons.

ECM is filled with complex proteoglycans which are involved in many biological functions and provide structural and physical cellular support, all of which are desirable properties for regenerative medicine biomaterials. By utilizing polypeptides possessing N-methylaminooxy side-chain functionality, the direct functionalization of reducing saccharides to give neoglycopolypeptides was accomplished in high yields. Different side chain functionalities generated tunable chain conformation, hydrophobicity, and charge. These polypeptides were found to be stable at pH 7 for 1 week. This approach will prove useful for easy conjugation of complex saccharides and will further advance the function of future hydrogels toward regenerative medicine applications.

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