Biocompatibility and Characterization of a Peptide Amphiphile Hydrogel for Applications in Peripheral Nerve Regeneration

Peripheral nerve injury is a debilitating condition for which new bioengineering solutions are needed. Autografting, the gold standard in treatment, involves sacrifice of a healthy nerve and results in loss of sensation or function at the donor site. One alternative solution to autografting is to use a nerve guide conduit designed to physically guide the nerve as it regenerates across the injury gap. Such conduits are effective for short gap injuries, but fail to surpass autografting in long gap injuries. One strategy to enhance regeneration inside conduits in long gap injuries is to fill the guide conduits with a hydrogel to mimic the native extracellular matrix found in peripheral nerves. In this work, a peptide amphiphile (PA)-based hydrogel was optimized for peripheral nerve repair. Hydrogels consisting of the PA C16GSH were compared with a commercially available collagen gel. Schwann cells, a cell type important in the peripheral nerve regenerative cascade, were able to spread, proliferate, and migrate better on C16GSH gels in vitro when compared with cells seeded on collagen gels. Moreover, C16GSH gels were implanted subcutaneously in a murine model and were found to be biocompatible, degrade over time, and support angiogenesis without causing inflammation or a foreign body immune response. Taken together, these results help optimize and instruct the development of a new synthetic hydrogel as a luminal filler for conduit-mediated peripheral nerve repair.

[1]  D. Boyd,et al.  FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy. , 2012, Injury.

[2]  R. Bitton,et al.  Cooperative DNA binding and assembly by a bZip peptide-amphiphile , 2010 .

[3]  S. Stupp,et al.  Induction of cancer cell death by self-assembling nanostructures incorporating a cytotoxic peptide. , 2010, Cancer research.

[4]  J. Triffitt,et al.  A review on macrophage responses to biomaterials , 2006, Biomedical Materials.

[5]  G. Koenderink,et al.  Rheology of heterotypic collagen networks. , 2011, Biomacromolecules.

[6]  S. Mackinnon New directions in peripheral nerve surgery. , 1989, Annals of plastic surgery.

[7]  James M. Anderson,et al.  Chapter 4 Mechanisms of inflammation and infection with implanted devices , 1993 .

[8]  T. Meade,et al.  Self-assembled peptide amphiphile nanofibers conjugated to MRI contrast agents. , 2005, Nano letters.

[9]  Richard L. Sidman,et al.  Increased rate of peripheral nerve regeneration using bioresorbable nerve guides and a laminin-containing gel , 1985, Experimental Neurology.

[10]  Yi-Cheng Huang,et al.  Biomaterials and strategies for nerve regeneration. , 2006, Artificial organs.

[11]  C James Kirkpatrick,et al.  Dynamic in vivo biocompatibility of angiogenic peptide amphiphile nanofibers. , 2009, Biomaterials.

[12]  H. Teng,et al.  Intrinsic Migratory Properties of Cultured Schwann Cells Based on Single-Cell Migration Assay , 2012, PloS one.

[13]  R. Tranquillo,et al.  Guided Neurite Elongation and Schwann Cell Invasion into Magnetically Aligned Collagen in Simulated Peripheral Nerve Regeneration , 1999, Experimental Neurology.

[14]  S. Mackinnon,et al.  Management of nerve gaps: Autografts, allografts, nerve transfers, and end-to-side neurorrhaphy , 2010, Experimental Neurology.

[15]  S. Stupp,et al.  Tunable mechanics of peptide nanofiber gels. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[16]  H. Gruppen,et al.  Prediction of molar extinction coefficients of proteins and peptides using UV absorption of the constituent amino acids at 214 nm to enable quantitative reverse phase high-performance liquid chromatography-mass spectrometry analysis. , 2007, Journal of agricultural and food chemistry.

[17]  John B. Matson,et al.  Controlled release of dexamethasone from peptide nanofiber gels to modulate inflammatory response. , 2012, Biomaterials.

[18]  B. Seckel,et al.  Enhancement of peripheral nerve regeneration , 1990, Muscle & nerve.

[19]  Michael G. Fehlings,et al.  Self-Assembling Nanofibers Inhibit Glial Scar Formation and Promote Axon Elongation after Spinal Cord Injury , 2008, The Journal of Neuroscience.

[20]  John W Haycock,et al.  Next generation nerve guides: materials, fabrication, growth factors, and cell delivery. , 2012, Tissue engineering. Part B, Reviews.

[21]  S. Stupp,et al.  Supramolecular Nanofibers of Peptide Amphiphiles for Medicine. , 2013, Israel journal of chemistry.

[22]  S. Stupp,et al.  Peptide amphiphile nanofiber delivery of sonic hedgehog protein to reduce smooth muscle apoptosis in the penis after cavernous nerve resection. , 2011, The journal of sexual medicine.

[23]  K. Marra,et al.  Injectable systems and implantable conduits for peripheral nerve repair , 2012, Biomedical materials.

[24]  S. Stupp,et al.  Self‐assembling peptide amphiphile promotes plasticity of serotonergic fibers following spinal cord injury , 2010, Journal of neuroscience research.

[25]  M. Spector,et al.  Near‐terminus axonal structure and function following rat sciatic nerve regeneration through a collagen‐GAG matrix in a ten‐millimeter gap , 2000, Journal of neuroscience research.

[26]  C T Chalfoun,et al.  Tissue engineered nerve constructs:where do we stand? , 2006, Journal of cellular and molecular medicine.

[27]  E. Biazar,et al.  Types of neural guides and using nanotechnology for peripheral nerve reconstruction , 2010, International journal of nanomedicine.

[28]  Matthew Tirrell,et al.  Self‐Assembled Peptide Amphiphile Micelles Containing a Cytotoxic T‐Cell Epitope Promote a Protective Immune Response In Vivo , 2012, Advanced materials.

[29]  Anderson,et al.  Host response to tissue engineered devices. , 1998, Advanced drug delivery reviews.

[30]  R. Midha,et al.  Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. , 1998, The Journal of trauma.

[31]  G. Charriere,et al.  Reactions to a bovine collagen implant. Clinical and immunologic study in 705 patients. , 1989, Journal of the American Academy of Dermatology.

[32]  T. Satou,et al.  A MORPHOLOGICAL STUDY ON THE EFFECTS OF COLLAGEN GEL MATRIX ON REGENERATION OF SEVERED RAT SCIATIC NERVE IN SILICONE TUBES , 1986, Acta pathologica japonica.

[33]  Xavier Navarro,et al.  Magnetically Aligned Collagen Gel Filling a Collagen Nerve Guide Improves Peripheral Nerve Regeneration , 1999, Experimental Neurology.

[34]  P. Patel,et al.  Comparative analysis of Schwann cell lines as model systems for myelin gene transcription studies , 2002, Journal of neuroscience research.

[35]  M. Meek,et al.  US Food and Drug Administration/Conformit Europe-Approved Absorbable Nerve Conduits for Clinical Repair of Peripheral and Cranial Nerves , 2008, Annals of plastic surgery.

[36]  M. Shoichet,et al.  Peripheral nerve regeneration through guidance tubes , 2004, Neurological research.

[37]  Ashish Garg,et al.  Targeting colon cancer cells using PEGylated liposomes modified with a fibronectin-mimetic peptide. , 2008, International journal of pharmaceutics.

[38]  J. Schneider,et al.  Self-assembling materials for therapeutic delivery. , 2009, Acta biomaterialia.

[39]  Long Wang,et al.  Win-Stay-Lose-Learn Promotes Cooperation in the Spatial Prisoner's Dilemma Game , 2012, PloS one.

[40]  M. Tirrell,et al.  pH-responsive branched peptide amphiphile hydrogel designed for applications in regenerative medicine with potential as injectable tissue scaffolds , 2012 .

[41]  R. Bitton,et al.  Self-assembly of model DNA-binding peptide amphiphiles. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[42]  S. Stupp,et al.  Enzyme Directed Templating of Artificial Bone Mineral , 2009, Advanced materials.

[43]  A. Seifalian,et al.  Biochemical engineering nerve conduits using peptide amphiphiles. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[44]  G. Terenghi,et al.  VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy , 2000, Journal of anatomy.

[45]  Matthew Tirrell,et al.  Structural properties of soluble peptide amphiphile micelles , 2011 .

[46]  S. Stupp,et al.  Self-Assembly and Mineralization of Peptide-Amphiphile Nanofibers , 2001, Science.

[47]  G. Morelli,et al.  Micelles derivatized with octreotide as potential target‐selective contrast agents in MRI , 2009, Journal of peptide science : an official publication of the European Peptide Society.

[48]  M. Yaszemski,et al.  A systematic review of animal models used to study nerve regeneration in tissue-engineered scaffolds. , 2012, Biomaterials.