This renewal proposal builds on our successes in developing a nanostructured material we call ?MultiDomain Peptides? or MDPs. Amongst the many discoveries during our first funding period, we found that these hydrogels have remarkable properties in vivo, in particular: 1) The MDP amino acid sequence can be tailored for rapid or slow degradation. 2) The hydrogel is entirely infiltrated by host cells within 7 days where the large number of cells interacting with the MDP matrix provides for powerful and rapid response to the matrix. 3) No fibrous encapsulation is observed up to 42 days in vivo allowing for good communication between our nanostructured matrix and the biological system. 4) Biomimetic amino acid sequences can be added to the base MDP structure allowing it to provoke desired biological responses such as angiogenesis and neurogenesis. Published data from our previous funding period and unpublished preliminary data presented here demonstrate the extremely powerful angiogenic and neurogenic properties of carefully designed MDPs which is unprecedented elsewhere in the literature and is the basis for the current proposal. A key feature of our approach is that the MDP hydrogel is composed of just a single designed, synthetic peptide. There is no need for additional growth factors or cells, either of which increases the challenge of clinical translation due to unforeseen and undesirable biological responses such as immune reaction, host rejection or tumor formation. The current proposal has four aims which can be summarized as follows.
In aim 1 we prepare a new series of nanofibrous MDP hydrogels each containing a unique mimic of a growth factor or extracellular matrix protein. The chemistry, nanostructure and materials properties are characterized in this aim.
In aim 2 we test the the MDP?s ability to activate expected cellular receptors. We also assess their performance in subcutaneous injections in healthy mice. We assess inflammatory response, cellular infiltration, cytokine expression, angiogenesis and neurogenesis. Based on these results antibody depletion studies will allow us to dissect the mechanism of action.
Aim 3 moves our study of tissue regeneration in the specific context of neural regeneration. Two major sets of experiments are proposed. The first utilizes a cell culture model of neurite sprouting to allow rapid screening of candidate MDPs. The second is a sciatic nerve injury model in rats. This in vivo test of neuroregeneration allows more rapid and economical assessment of regeneration before moving the more clinically relevant rabbit model.
In aim 4 we examine nerve regeneration of the inferior alveolar nerve of the rabbit. MDP hydrogels with demonstrated angiogenic and neurogenic properties will be used to accelerate regeneration. Our interdisciplinary team combines expertise in chemistry, materials science, nanotechnology, neuroscience and clinical medicine. We will generate data that will provide the framework for further advances in nanostructured tissue engineering generally as well as advances specific to neural regeneration.
One of the most exciting areas of medical research is tissue engineering which promises to supplement our own regenerative ability allowing us to replace or re-grow damaged and diseased tissues and organs. In this proposal we describe an interdisciplinary approach to the design and optimization of a nanostructured matrix made from synthetic peptides which can be delivered by syringe and act to direct the body?s regenerative ability to accelerate the production of blood vessels and neurons. This proposal utilizes these exciting properties to for the regeneration of the peripheral nervous system.
|Moore, Amanda N; Lopez Silva, Tania L; Carrejo, Nicole C et al. (2018) Nanofibrous peptide hydrogel elicits angiogenesis and neurogenesis without drugs, proteins, or cells. Biomaterials 161:154-163|
|Leach, David G; Dharmaraj, Neeraja; Piotrowski, Stacey L et al. (2018) STINGel: Controlled release of a cyclic dinucleotide for enhanced cancer immunotherapy. Biomaterials 163:67-75|
|Carrejo, Nicole C; Moore, Amanda N; Lopez Silva, Tania L et al. (2018) Multidomain Peptide Hydrogel Accelerates Healing of Full-Thickness Wounds in Diabetic Mice. ACS Biomater Sci Eng 4:1386-1396|
|Li, I-Che; Hartgerink, Jeffrey D (2017) Covalent Capture of Aligned Self-Assembling Nanofibers. J Am Chem Soc 139:8044-8050|
|Moore, Amanda N; Hartgerink, Jeffrey D (2017) Self-Assembling Multidomain Peptide Nanofibers for Delivery of Bioactive Molecules and Tissue Regeneration. Acc Chem Res 50:714-722|
|Kumar, Vivek A; Liu, Qi; Wickremasinghe, Navindee C et al. (2016) Treatment of hind limb ischemia using angiogenic peptide nanofibers. Biomaterials 98:113-9|
|Kumar, Vivek A; Shi, Siyu; Wang, Benjamin K et al. (2015) Drug-triggered and cross-linked self-assembling nanofibrous hydrogels. J Am Chem Soc 137:4823-30|
|Kumar, Vivek A; Taylor, Nichole L; Shi, Siyu et al. (2015) Self-assembling multidomain peptides tailor biological responses through biphasic release. Biomaterials 52:71-8|
|Wickremasinghe, Navindee C; Kumar, Vivek A; Shi, Siyu et al. (2015) Controlled Angiogenesis in Peptide Nanofiber Composite Hydrogels. ACS Biomater Sci Eng 1:845-854|
|Kumar, Vivek A; Wickremasinghe, Navindee C; Shi, Siyu et al. (2015) Nanofibrous Snake Venom Hemostat. ACS Biomater Sci Eng 1:1300-1305|
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