Publication: Smart Engineered Soft Biomaterials as Advanced Healthcare Therapeutics
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Date
2025-03-25
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Indian Institute of Technology, Jodhpur
Abstract
Soft biomaterials play a pivotal role in various biomedical application domains. Materials with dynamic properties, such as the ability to expand and contract, change stiffness, self- heal, or dissolve in response to environmental changes, are highly sought after for various applications including biosensing, drug delivery, soft robotics, and tissue engineering. In the last thirty years, the creation and use of biomaterials has emerged as a highly active and promising field of study, situated at the crossroads of chemistry, materials science, bioengineering, and medicine. Utilizing self-assembly in the development of functional biomaterials is a highly promising and stimulating field of study, offering significant potential for the treatment of injury or disease. Peptide self-assembly is becoming a promising method for creating sophisticated biomaterials that possess exceptional physicochemical and biological characteristics. In this regard peptide sequences with inherent self-assembly capabilities have been intentionally engineered to give rise to diverse structural aggregates, including nanofibers, nanovesicles, nanobelts, and nanotubes. Over the course of the past few decades, a number of methodologies have been devised with the purpose of designing self- assembling peptides. Various supramolecular nanostructures have been created using synthetic peptides that possess beta sheet, alpha helix, triple helix, ELP-like, or amphiphile structures. These nanostructures were specifically designed to undergo self-assembly, resulting in the acquisition of specific properties and functionalities. This study investigates the use of bioinspired self-assembly to create a variety of supramolecular healthcare materials that can be used in drug delivery as well as antibacterial regenerative medicine purposes. First of all, we fabricated peptide based nanovesicles crafted from the “Hotspot” region of alpha beta tubulin heterodimer interface for the targeted delivery of a tubulin targeted drug in combination with an mTOR inhibitor. By in vitro assessment we found that such a tubulin targeted peptide nanovesicle mediated targeted delivery can increase the therapeutic potential of both docetaxel and everolimus significantly and can be employed as anticancer nanotherapeutic. In our next research work, we have constructed a Substance P mimicking supramolecular hydrogelator octapeptide by fusing truncated C-terminus peptide sequence “FFGLM” derived from Substance P along with an integrin-binding “RGD” motif. This designed octapeptide under the influence of its N-terminus aromatic capping group together with its uniquely balanced hydrophobic and hydrophilic residues undergoes quick self- assembly at biological pH (pH 7.4) to give rise to a soft yet thixotropic hydrogel matrix with superior thermal and pH responsive property. From experimental analysis, we envisioned this designed hydrogel as a futuristic cytocompatible matrix having both wound healing and pH responsive drug releasing therapeutic effectivity. Next in an endeavour to find new synthetic AMP, we have designed and constructed a few amyloid-inspired multi-domain peptide amphiphiles comprising N-terminus lipid chain succeeded by a core hydrophobic zone in combination with a C-terminus cationic heparin-binding motif. These synthesized peptide amphiphiles differ only by their aggregation propensity of the core hydrophobic zone. Interestingly, all the synthesized peptide amphiphiles were found to exert their antibacterial effectivity above their critical aggregation constant. However, our study reveals that the extent of antibacterial effectivity is guided by both hydrophobic core zone in combination with C-terminus positively charged heparin-binding motifs derived and modified from the Aβ42 peptide core. The lead peptide by its more aggregation-prone core region undergoes rapid self-assembly at lower CAC and shows higher LPS binding affinity with superior antibacterial effectivity against multi-drug resistant staphylococcus aureus in comparison with other analogues. The lead multidomain LVK-PA peptide under its self- assembly propensity gives rise to the formation of the thixotropic hydrogel with significant antibacterial wound healing property. Experimental data including wound closure ratio, % collagen deposition, and expression of various pro-inflammatory cytokines like IL-6, TGF-β along with CD-31/α-SMA revealed that the designed hydrogel promotes the healing of both gram-negative P. aeruginosa and gram-positive MRSA-infected diabetic wounds through reduced nflammatory repercussions and enhanced angiogenesis. In our final study, we have developed an extracellular matrix mimicking, wound-microenvironment responsive multi- component hybrid hydrogel scaffold composed of lysozyme-derived amyloid fibril (LZ) co- assembled with heparin Sulfate (HS) by mere utilization of their inherent favourable non- covalent interactions. Heparin Sulfate was employed to construct this amyloid-sugar co- assembled extracellular matrix (ECM)-mimetic scaffold due to its striking resemblance to heparan sulfate. Further to increase its conductivity at physiological pH and simultaneous antibacterial efficacy in an acidic chronic wound microenvironment we have incorporated tannic acid-functionalized silver nanoparticle into the hydrogel composite. The enhanced antimicrobial efficacy of this composite hydrogel is likely linked to the pH responsive disassembly of the supramolecular hydrogel matrix when exposed to chronic diabetic wound conditions. Apart from its antibacterial effectivity the at pH~5.5 the designed hydrogel can potentially eradicate bacterial biofilm formation providing a promising strategy for the management of clinical chronic wounds. These multifaceted synergistic effects significantly expedite the process of wound healing and enhance the overall quality of wound repair.
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ODONTOLOGY::Biomaterials
Citation
Mukherjee, Nabanita(2019).Smart Engineered Soft Biomaterials as Advanced Healthcare Therapeutics (Doctor's thesis). Indian Institute of Technology Jodhpur