ABSTRACT
Keywords: nanomedicine, bio-nanomaterials, nanodevices, future studies, drug delivery, regenerative medicine, stem cells, DNA nanotechnology, synthetic biology, optogenetics, transcranial magnetic stimulation, stapled peptides, nanoparticles, microneedle arrays, neural stem cells 4.1 IntroductionThis chapter provides a summary of recent research advances as of 2011 in the top 10 areas of nanomedicine, bio-nanomaterials, and nanodevices from a future studies perspective. A summary of the advances is provided in Table 4.1, which organizes the 10 areas into categories and highlighting the key findings in each area. The first category, Drug Delivery, includes nanoparticles, stapled peptides, and microneedle arrays. Next, Organ Repair subsumes regenerative medicine and stem cell research. The category Fundamental Nanomedical Technologies includes the integration of organic and inorganic matter and DNA nanotechnology. Engineering
of biology includes synthetic biology and biomimetic synthesis. Working with the Brain includes a review of contemporary neural research findings. Results from approximately fifty different research projects are discussed in this chapter. Table 4.1 Summary of key research results by nanomedicine category A. Drug delivery 1. Nanoparticles: cytosolic drug delivery, cell therapies, and peptoids • Cytosolic drug delivery with light activation and peptide conjugates • Improved cell therapy viability using integrated nanoparticles • Drug development via synthesis of alkylated antimicrobial peptoids
2. New class of drugs: stapled peptides • Stapled peptide formation through hydrocarbon bonds and chemical reactions • Stapled peptide-generated oncogene MCL-1 inhibitor (BCL-2 family protein) in clinical trials 3. Drug delivery and biomonitoring: microneedle array • Transdermal delivery and controlled material release via thin films • Silicon pancreas system mimics normal insulin function
B. Organ repair 4. Regenerative medicine: conduits, augments, blood-vessel and skin printing • Hollow organs: lab-generated bladders
• Solid organs: conduits and augments • Solid organs: vascularization • Skin regeneration: portable skin printing system
5. Stem cells: heart, spinal cord, adipose-derived, neural • Heart: cardioprotection via DRRSAb (sodium potassium ATPase antibody), improved stem cell viability by seeding microthread
sutures with human mesenchymal stem cells (hMSCs) • Adipose-derived stem cells: easily harvestable alternative for heart and kidney injury treatment and breast reconstruction • Spinal cord injury: human embryonic stem cell (hESC)-derived
oligodendrocyte progenitor cell, GRNOPC1, in clinical trials • Neural stem cells: tested for stroke recovery in a UK-based clinical trial • Process innovation: bio-mimicking soft substrates superior to conventional rigid substrates in culturing and direct conversion of skin cells to functional neurons
C. Fundamental nanomedical technologies 6. Integration of organic and inorganic materials • Biomolecular interface: genetically engineered peptides (GEPIs) used to improve surface chemistry between implants and human tissue • Organic-inorganic hybrids: engineered fusion proteins, graphene sheets sandwiched in phospholipid bilayers, catenanes and rotaxanes 7. DNA nanotechnology • Structures: molecular calipers, 11-state nanomachine, tensegrity nanostructures, improved control circuitry via compiled chemical
equations, microfluidic channel control through torque and temperature • Transport systems: DNA walkers in the form of molecular spiders and light-driven motors, demonstration of a molecular assembly line D. The engineering of biology 8. Synthetic biology: genetic engineering and assembly • DNA assembly: synthetic chromosome, improved throughout via DNA microchips and robotic sequencing • Parts Registry: in vivo reference standards, restriction enzyme-constructed protein fusions, BioScaffolds for rapid circuit generation • Nanomedical applications: tunable extracellular matrices and DNA damage sensors 9. Bio-nanomaterials characterization and biomimetic synthesis • Metabolic engineering: RNA scaffolds organize in vivo enzymatic pathways to amp hydrogen production, cyanobacteria as a feedstock alternative for biochemicals production • Biomineralization: crystal nucleation and bifacially differentiated interstitial composites • Systems-level cooperation: multi-organism signaling networks
E. Working with the Brain 10. Intelligence: brain coprocessors, brain-computer interfaces, transcranial magnetic stimulation • Optogenetics: activating and silencing specific neurons, distributed neural targeting via multi-waveguide probe, brain coprocessor • Brain-computer interfaces (BCIs): improved control through fatigue reduction and motor imagery training • Transcranial magnetic stimulation (TMS): clinical treatment of depression, motor learning enhancement, visual system elucidation
A future studies methodology was employed to select the advances on the basis of three criteria. First, findings were identified from research published in the last one to two years (i.e., from mid-2009 to mid-2011) from established leaders in different nanomedical fields, in some cases follow-on work in areas of previous achievement. Second, research advances were selected based on their stage of maturity such that they could possibly have a bench to bedside translational impact within the next decade, ideally within the next five years. Advances in regenerative medicine are particularly exemplary of meeting this requirement. Third, research results were selected on the basis of being fundamental technologies that could address whole new classes of problems in nanomedicine and beyond. Strong examples of these fundamental technologies are achievements in molecular programming, synthetic biology, and the integration of organic and inorganic matter. The scope of this analysis was necessarily limited and certain key research may have been unintentionally omitted. 4.2 Top 10 Areas of Recent Advance in
• Cytosolic drug delivery with light activation and peptide conjugates •Improved cell therapy viability using integrated nanoparticles • Drug development via synthesis of alkylated antimicrobial peptoidsOne of the most established applications in nanomedicine is using nanoparticles for drug delivery. A contemporary challenge is conveying drug molecules through the cell wall to the interior of the cell. Two recent advances in intracellular drug delivery pass nanoparticles into cells and then burst their membranes to disgorge the cargo. The membrane-bursting, or endosomal breakage, is conducted using light activation and peptide conjugation. In lightmediated endosomal breakage (Fig. 4.1), nanoparticles have been developed that can be loaded with a variety of compounds, targeted
to specific cells (e.g., cancer cells), and released into the cytosol [1]. These nanoparticles are highly monodispersed mesoporous silica nanoparticles that are size-tunable in the range of 30-200 nm. Endosomal breakage for intracellular drug delivery has also been achieved through peptide conjugates. A peptide that mimics viral fusion protein sequences, GALA (repeating Glu-Ala-Leu-Alaamino acid sequences), is attached to nanoparticles. GALA helps nanoparticle cargo to escape by imitating the process of virus gene release from endosomes into the cell [2].
