2Arizona Center for Integrative Medicine (Department of Medicine), University of Arizona College of Medicine, Tucson, AZ, USA
3University of Arizona College of Nursing, University of Arizona, Tucson, AZ, USA
4Bastyr Integrative Oncology Research Center, Bastyr University, Kenmore, WA 98028, USA
5Department of Psychology, University of Arizona, Tucson, AZ, USA
6Fusion Medicine Collaborative, Philadelphia, PA, USA
7Bastyr University -San Diego, CA, USA
Keywords: Homeopathy; Nanoparticles; Silica; Adsorption; Surface chemistry; Protein corona; Cell danger response; Danger- Associated Molecular Patterns (DAMP); Biological signaling; Adaptation; Hormesis; Inflammasome; Heat shock proteins; Oxidative stress; Cell stress; Cell signaling; Cytokines; Gene expression
Homeopathy is a traditional, albeit controversial, system of Complementary and Alternative Medicine (CAM) used worldwide, notably in India, Latin America, the United Kingdom, and Europe. The nature and mechanisms of action of HMs have stirred intense debate throughout the more than 200-year history of homeopathy's existence as a natural product-based system of CAM . Preparation of HMs involves serial steps of dilution of plant, animal, or mineral source materials in dry lactose, ethanol/ water, or water using ratios of 1:10 (X potency series) or 1:100 (C potency series). Each dilution step is followed by extensive mechanical grinding in dry materials or "succussions" in liquid dilutions (i.e., 10 or more agitations/step via manual pounding on a hard but elastic surface or vortexing). For diagnosis and treatment, practitioners of individualized homeopathy obtain detailed clinical and personal/social histories to match a single HM's potential multi-system effects to a given patient's complex symptom and behavioral state or presentation pattern .
A number of homeopathic investigators continue to study basic science models involving structured water, but, with only rare exceptions , overlook the fact that (a) very low potency insoluble HMs are never diluted in any water at all and that (b) after preparation, even high potency HMs are often dried onto lactose sugar pellets for storage and administration. Nonetheless, data suggest that in liquid solution, the original solutes may induce nanostructure formation of the ethanol-water or water solvent [15-17]. Skeptics continue to insist (incorrectly) that the serial dilution processes of homeopathic manufacturing must theoretically remove any trace of the original source material by the 12C and 24X or higher potencies (i.e., bulk dilution to 10012 or 10,24 where Avogadro's number of molecules is 6 x 1023), thus rendering all HMs as presumptive biologically inert placebos .
Empirical data, however, only document removal of the bulk forms of the source material during homeopathic manufacturing at higher potencies . Evidence for the persistence of nanoscale forms of the source material by itself and/or the more abundant nanosilica and/or other materials from the agitation of liquid solutions in their containers (typically, but not always glassware) via multiple succussions is growing for both low (e.g., 1X, 2X, 3X, up to 6X, 12X or 6C) and higher (e.g., above 12C or 24X) homeopathic potencies (Tables 2 and 3).
The ability of the HM NPs to survive serial dilutions likely depends upon the multiple succussions (agitation in liquid) that follow every dilution step. Studies demonstrate that succussions induce heterogeneous layering of source NPs in solution for collection in the "dilution" steps, perhaps via air bubble formation of various sizes . No studies have yet examined the impact of different sampling procedures for transferring a measured 1/10 or 1/100 portion of the solution from one preparation step to the next. However, variability in materials and methods is one of multiple potential factors contributing to variability of the final product HMs . Evidence also indicates that agitation of solutions can also embed source NPs into glassware, from which they can leach back into solution over time . To make higher potency HMs, manufacturers usually resort to Korsakovian methods by re-using the same piece of glassware for every serial dilution/succussion step beyond certain potency, e.g., 15C-25C. Agitation per se also releases silicates and generates potentially bioactive silica NPs throughout the manufacturing process [21,22]. In contrast, the larger bulk form source materials are removed over serial dilutions and succussions .
In recent years, the empirical data on HMs support a testable, hypothesis-driven model based on the generation of source and silica and/or other container- and reagent-derived nanoparticles (NPs) in HMs during the manufacturing process [1,2,23,24]. In nanotechnology, grinding or ball milling of materials (comparable to the initial homeopathic manufacturing steps of trituration in dry lactose for very low potencies) as well as sonication and/or water jet treatment (comparable to homeopathic manufacturing steps of repeated succussions in water or water-ethanol diluents at room temperature for higher potencies), generate micro- and nano-sized particles of the original source material [20,25-29] (Table 3). Once generated, NPs in HMs could provide the forms capable of generating the unique electromagnetic, optical, thermal, and quantum mechanical phenomena previously reported in HMs [30-33].
silica and/or other container- and reagent-derived nanoparticles (NPs) in HMs during the manufacturing process [1,2,23,24]. In nanotechnology, grinding or ball milling of materials (comparable to the initial homeopathic manufacturing steps of trituration in dry lactose for very low potencies) as well as sonication and/or water jet treatment (comparable to homeopathic manufacturing steps of repeated succussions in water or water-ethanol diluents at room temperature for higher potencies), generate micro- and nano-sized particles of the original source material [20,25-29] (Table 3). Once generated, NPs in HMs could provide the forms capable of generating the unique electromagnetic, optical, thermal, and quantum mechanical phenomena previously reported in HMs [30-33].
In solution, silica NPs can both (a) adsorb trace amounts of other source materials such as plant, animal, and human proteins, minerals or metal NPs onto their large surface area [41- 44] and (b) use other materials, e.g., viruses, plant constituents, or chemical agents, as templates to imprint their structural and chemical information onto surfaces of silica nanostructures [45-48]. Surface-adsorbed materials modify silica NP bioreactivity , potentially carry the source material "fingerprint" [41,50-52], and could amplify the information of the original source [53-56] into higher potencies. Plant extracts can also biosynthesize silica or metal NPs from respective precursors in water , leaving trace bioactive specific plant materials on the resultant NP surfaces [58-60]. One study that needs independent replication reported that increasing the numbers of succussions will reduce the particle size of plant source materials into the nanoscale range .
The present paper proposes that the nanoscale versus bulk form of HMs makes a critical difference in understanding how these agents can interact with living systems. By their nature, nanoscale forms differ from bulk (conventional macro scale) forms of any given material with size- and shape-dependent immune, biochemical, electromagnetic, optical, and quantum properties [62-66]. At the nanoscale, particle size, shape, and surface charge as well as ionic constituents, temperature, and pH of the surrounding medium can markedly change the properties and effects of a given type of NP [17,43,62,67-69]. The factors that could particularly foster host adaptive responses encompass virus-like properties of certain NPs  and their ability to trigger the cell danger response pathways of the body as exogenous stressors or stimuli . Some larger NPs can exert bacteria-like effects on living systems as well .
In nanotoxicology, despite the same "doses" (e.g., in vitro 1 ug/ml, 10 ug/ml), a specific size range (60-120 nm) and zeta potential value (surface charge/stability, e.g., -37 to -41 millivolts) of diesel exhaust nanoparticles are more likely to trigger cytokine activation and protein expression in human immune cells whereas NPs of other sizes and zeta potentials do not trigger bioreactivity . Finally, different surface coatings of zinc oxide NPs (e.g., triethoxycaprylylsilane or dimethoxydiphenylsilane/ triethoxycaprylylsilane cross polymer or uncoated) modify the adaptive responses of human olfactory cells by modulating manifestations of cell stress, inflammatory response (cytokine patterns), and apoptotic cell death .
The usual assumptions premised on composition (source material) and dose that are the primary factors for evaluating bulk form conventional pharmaceutical drugs are not sufficient and sometimes not readily applicable at the nanoscale for the "same" source material, including HMs. For instance, simply diluting a stock solution of fullerite carbon-based NPs will produce NPs with morphological properties different from those of the more concentrated stock solution . One size NP of a given source material can exert different effects from another size NP of the same source material, e.g., 80 nm engineered calcium phosphate/ hydroxyapatite NPs are more effective at killing osteosarcoma cells than are 2 0 nm NPs of the "same" source material .
In triggering adaptive responses, nanoparticles are known to act on gene expression, cytokine release, and signaling pathways or networks as cell danger signals for the body, in part by activating Danger-Associated Molecular Pattern (DAMP) recognition receptors [79,80]. Endogenous response amplification to NPs is nonlinear and potentially multi-factorial , including but not limited to immune/inflammatory/metabolic mediator modulation , nervous system cross-sensitization , and adaptive changes of hormesis . Nanomaterials are often inherently more potent than their bulk form counterparts [63,83], lowering doses needed for direct effects by orders of magnitude , and even lower for adaptive phenomena like vaccine immune responses [53,54,56,85] and hormesis [1,7,8,82].
Other research groups followed with both electron microscopic and Dynamic Light Scattering (DLS) data showing the formation of nanostructures during homeopathic potentization procedures and/or using homeopathic mother tinctures (herbal extract concentrates) (Table 2). Consistent with a large body of non-homeopathic research in nanotechnology e.g., , one study of homeopathically-prepared test materials specifically reported that increasing the number of succussions produced progressively smaller and smaller sizes of nanoparticles of source plant extract materials down to approximately 14 nanometers (nm) .
Particle sizes in the range of viruses [36,70]
10-150 nm size range 
Virus-like particle surface defects from mechanical grinding (top-down processes ) or other manufacturing procedures increase bio-molecular binding and cell uptake [74,75]
Defects include cracks, fissures, roughness, folds, and pores [44,72,86]
Virus-like activation of cell defense response (CDR) mediator pathways/networks [36,81]
CDR changes involve cell metabolism; cell membrane stiffness; antiviral chemical release; autophagy; DNA methylation and histones to alter gene expression, endogenous nucleic-acid-related protection mobilization to produce genetic variants; cell-to-cell signaling mediator release including cytokines and eicosanoids; host behavioral changes 
Meanwhile, other homeopathic investigators repeatedly found that agitation per se releases variable but readily measurable amounts of elemental silicon (which quickly generates silicon dioxide or silica on contact with oxygen) into solution from the inner walls of the glassware in the parts per million ranges (Table 3). The silica appears to be in the form of both larger sized and nanoscale particles with the capacity to interact with proteins and cause inflammatory and/or immune system activation [22,34,92]. Ives et al.  originally proposed a silica-based model for HMs. The latter group demonstrated that the homeopathic succussion-released silica stabilized acetylcholine esterase enzyme activity, similar to a finding recently replicated for modern engineered silica nanoparticles coated on their surfaces with polyethyleneimine .
Thus, whether or not source NPs make their way into a given dose of a homeopathic medicine, it is highly likely that biologicallyactive nanosilica and even larger silicate aggregates and/or other nanostructures will occur with each succussion step and persist in HMs at higher potencies during classical homeopathic manufacturing. The silicates are known to interact with salts, amino acids, and proteins, e.g., from plant extracts or animal fluids, to form aggregates of 3D gel networks . Depending on pH and amounts of other materials in solution, various sizes of nanosilica can also form . Apart from manufactured forms, biosilica with unique physical properties is well-known to form in the natural environment within single-celled organisms, higher plants , and primitive animals such as sponges , all of which are commonly-used source materials in homeopathic manufacturing.
Ives, et al.  also showed that repeated succussions will gradually lower the pH of a homeopathically-prepared solution from alkaline toward a more neutral buffered pH near 7. In turn, this group noted, studies show that this drift of pH values fosters conversion of precursor monomer silicates in a solution into nanoparticles forms of silica . Thus, nanosilica is highly likely to be a key constituent of any homeopathicallyprepared potency in liquid solutions made in glass. At the same time, studies have demonstrated that silicates in water can shift between uncondensed monomers to colloidal nanoscale particle forms larger 3-dimensional silicate structures, depending on conditions in the medium . Both doped nanosilica and the smallest sizes of silicon NPs, e.g., silicon quantum dots (e.g., NPs < 10 nm sizes) per se, offer potentially size-tunable semiconductor nanocrystals with (a) nontoxic delivery vehicle properties for
Chikramane et al. 
Transmission electron microscopy, ICP-AES
Gold, silver, copper, zinc, platinum, tin up to 200C
Chikramane et al. 
Transmission electron microscopy
Gold up to 15C
Upadhyay and Nayak 
Scanning electron microscopy
Pulsatilla, Belladonna, Colchicum (plants) up to 15C
Nuclear magnetic resonance
Silica/lactose up to 21C
Das et al. 
Transmission electron microscopy, zeta potential
Silver NPs biosynthesized by Thuja, Hydrastis, Phytolacca, Gelsemium plant mother tincture extracts
Barve and Chaughule 
Dynamic light scattering
Terminalia arjuna, Holarrhena plant mother tinctures
Stovbun et al. 
Dynamic light scattering
Phenazepam, Panavir (synthetic drugs)
Elia et al. [14,98]
Atomic force microscopy, fluorescence microscopy, FT-IR and UV-vis spectroscopy
Water in glassware up to 200C
Konovalov and Ryzhkina 
Dynamic light scattering, zeta potential, atomic force microscopy, microelectophoresis, conductivity, ultraviolet and EPR spectroscopy
Nanostructures triggered by highly diluted solutes (alpha tocopherol, ichfan C-10, potassium phenosan) interacting with external physical fields (geomagnetic, low frequency electromagnetic) and solution preparation procedures
Field emission scanning electron microscopy and energy dispersive spectroscopy
Nanoparticles detected at all potencies evaluated, including plant derived Lycopodium 6C, 30C, 200C, 1M, 10M, 50M, and CM potencies but not in 90% ethanol (alcohol) controls. NP sizes ranged from 12 nm to 832 nm with varying observations of agglomerates at 6C potency vs. many clusters at extremely high potencies. All verum samples were sonicated prior to evaluation.
Notably, silica precursors can self-assemble around a virus, plant constituent, chemical toxicant, protein or other templates and/or form a stabilizing shell on the outside of core NPs in solution to form silica shell-source core nanocomposite [45,48,102-105]. Other constituents in the solution such as ethanol or salt concentrations and pH will modify the thickness and/or surface properties of the silica shell [69,103,106-109]. In homeopathy research, Elia et al.  have repeatedly demonstrated that raising the pH of homeopathically-prepared solutions to a highly alkaline level will increase the release of heat and specific conductivity significantly more than those of unsuccussed dilute control solutions. Investigators of the latter studies interpreted the heat release as an indication of disrupted order of the materials in solution. Cartwright [51,111] recently reported an essential role for silanol (Si-O-H) groups on the quartz glass surfaces and ions in solution rather than water in carrying the specific information of a given HM. As noted above, plant extracts can also biosynthesize silica NPs, leaving trace amounts of their plant material proteins, nucleic acids and other organic constituents on the surfaces of the resultant silica NPs [57,94].
Is there evidence for biological effects of remedy source-free HMs, but homeopathically–prepared control solutions containing only the silicates from the glassware (i.e. succussed)? In an in vitro cell culture wound injury/repair model for experimental wound closure healing, Hostanska et al.  recently showed that succussed "controls" were indeed biologically active, though less active than the plant source HM verum compared with unsuccussed solvent controls (Figure 1). Such data are consistent with the presence of bioactivity in the silica previously reported in the succussed "controls."
Homeopaths use silica and each of the four different plantderived HMs (Arnica montana 3X, Hypericum perforatum [St. John's Wort] 3X, Calendula officinalis [Marigold] 3X, Symphytum [Comfrey] 5X) in the verum combination homeopathic product studied by Hostanska et al.  for various clinical indications related to injuries and wound healing. Consistent with the homeopathic succussed control findings, a separate nanomedicine study recently demonstrated that silica NPs alone can significantly boost immunogenicity of a protein antigen in a combination formulation even when the silica NPs are not physically attached to the antigen . The silica NP effects occurred only if the NPs were virus-sized (i.e., 50 nm rather than 1000 nm in size).
Independent of homeopathic research, conventional pharmaceutical investigators have replicated the observation that not only glassware, but also plastic, and stainless steel containers and tubing can all release larger and smaller particles into solutions that they contain, especially upon agitation, e.g., end-over-end rotation of a syringe with an air-water and silicone-oil-water interface or unsiliconized syringe with proteins in solution, vortexing or sonication [22,34,92,113,114]. In the case of borosilicate or soda lime glass, such particles include silica micro- and nanoparticles. In turn, any proteins or other substances in the solution form immunogenic complexes with the adjuvant particles. These complexes trigger immune reactions, even after filtering, at concentrations below the limits of detection with available instruments .
Waterjet abrasion per se, which is similar to homeopathic manufacturing methods such as succussion and/or fluxion (see Table 4), can break down contaminants in water samples into micro- and nanoscale structures [28,115,116]. Moreover, nanocontaminants in extremely low concentrations in stock reagent supplies can also serve as chemical catalysts for certain reactions [117,118].
The data imply that it should be possible to make HMs in plastic  or stainless steel containers, but their physical chemistry and biological properties would vary from those made with classical materials and methods in glass. Table 4 illustrates overlaps between homeopathic manufacturing and nanotechnology methods.
Nanosilica is an excellent drug delivery vehicle and serves as an immune stimulating adjuvant in oral vaccines [53,56,120-122]. Nanoscale forms of not only silica, but also conventional drugs, biologics, minerals, herbal extracts, and animal products are known for their small size-related enhanced bioavailability and bioactivity [38,123-126]. Common nanotechnology strategies for tuning the electromagnetic, optical and biochemical properties of NPs include coating the outer surface of a given NP with a
Elemental Silicon Concentrations Measured (ppm)
Witt et al. 2006 (Germany)
Ives et al. 2010 (USA)
Up to 30C
Demangeat 2010 (France)
Upadhyay and Nayak 2011 (India)
Nonetheless, skeptics could argue that (a) human beings regularly encounter nanoparticles of various natural and manmade sources in the environment without obvious therapeutic benefit; (b) the amounts of source material nanoparticles reported to date are extremely low and unlikely to exert conventional pharmacological effects. In short, what does finding nanostructures in HMs add to the field of homeopathy? In the present model, the answer relates to the HM providing a salient, individualized low intensity stress or danger signal to the recipient organism as a complex adaptive system [1,2].
Nanoscience research offers a helpful direction for addressing these objections. Recent nanomedicine and nanotoxicology studies indicate that the source and/or silica NPs in a given HM would be most likely to produce significant biological effects if the sizes fall into the range of viruses or smaller [36,70,71] (viruses range in size from 10-150 nm ). In addition, bioactive NPs may exhibit relative stability as indicated by certain zeta potential values on their surfaces . Therefore, if NPs play a role in biological actions of HMs, testable hypotheses are that (a) their sizes would need to fall into the nanoscale range for viruses and (b) their surface zeta potentials would need to be sufficiently stable to convey their specific information in a low dose, viruslike manner.|
Sizes of NPs of conventional synthetic drugs are often somewhat larger than viruses (> 150 nm), though often smaller than 1000 nm [25,130,131]. Even micro-sized forms of drugs or natural products are known to exhibit greater bioavailability [63,132-134]. However, the nano-drug mechanisms of action are typically more pharmacological (relatively higher dose, direct ligand-receptor effects) than homeopathic (pulsed lower dose, stress adaptive signaling stimulus effects) in nature.
Are there virus-triggered biological mechanisms that nanoparticles are known to mobilize? Do those mechanisms map onto the repeatedly demonstrated ability of HMs to modulate gene expression patterns and release biological mediators such as cytokines and other endogenous signaling mediators in the body? To answer these questions, it is important to understand
Homeopathic Manufacturing Method
Parallel Nanotechnology Methods
Underlying Effects on NP Formation
Trituration of source material in dry lactose (manual grinding or ball milling)-very low potencies
Mechanical grinding of smaller and smaller particles off starting bulk source materials [27,29,135]
Serial dilutions and succussions in water or ethanol-water within glass containers – higher potencies in liquid
Dilution physically separates NPs as they form to protect reactive surfaces from inactivation by agglomeration , but leads to variability in UV-visible spectroscopic properties between batches [77,137]
Mechanical shearing of smaller and smaller particles off the starting bulk source materials 
Embedding formed source nanoparticles into inner walls of glassware via turbulence of liquid 
Release of silica micro- and nanoparticles from inner walls of glassware by agitation [22,34]
Fluxion (rarely used older method for continuous strong flow of water into the same glass container with the starting source material) – alternative manufacturing method for very high potencies in liquid
Water jet abrasion 
Mechanical shearing of smaller and smaller particles off the starting bulk source materials 
Embedding formed source nanoparticles into inner walls of glassware via turbulence of liquid 
Release of silica micro- and nanoparticles from inner walls of glassware by agitation [22,34]
• First, nano-forms are biologically more bioavailable and potent than bulk forms for direct pharmacological actions by orders of magnitude (10-1000x) [63,83,84,123,138].
o Silica and silica NPs from glassware or plant extracts could exert immunomodulating and immune adjuvant effects [53,120,139] as well as demonstrate the capacity for self assembly into stable nanostructures around viruses  or plant constituents  as templates. In addition, dozens of studies have shown that many different ethanolic plant extracts (e.g., Equisetum, Quercus, Salvia, Hydrastis, Thuja, Gelsemium, Phytolacca - source materials also used for making homeopathic plant-derived medicines) can biosynthesize nanoparticles from precursors in solution, including but not limited to silica, gold, silver, and platinum NPs [57,59,60,93,140,141].
• Second, unique to their small size, nanoparticles sizes, shapes, surface areas, surface charges and surface chemistry play a major role in determining the nature of particle interactions with cells and resultant biological activity [133,142-144].
o For some NPs, a factor as simple as coating the surface with lactose leads to improved uptake into cancer cells, but not normal cells [145,146]. Both lactose and silica nano coatings and shells can stabilize the reactive surfaces of NPs [102,145,147,148]. Lactose is a standard material used during dry trituration or grinding/milling of insoluble source materials in homeopathic manufacturing.
• Third, dilution from stock solutions in the laboratory or in the environment has unpredictable effects on NP properties .
o NPs are so reactive on their surfaces that they adsorb onto each other and other materials that they encounter. These adsorbed materials can dope and tune the properties of the nanostructure by altering its size and shape, decrease or increase its toxicity, and/or decrease or increase its surface reactivity and biological identity for a living cell [44,133,144]. In many cases, dilution increases available surface area on NPs by avoiding particle agglomeration and leaving smaller but more reactive particles. As a result, some diluted NPs can potentially be even more toxic than a more concentrated solution of the same NPs [77,136,137]. Smaller particles translate into much larger surface area available for adsorbing other materials .
• Fourth, key to the effects of higher potency HMs, nanoparticles can exert not only direct pharmacological effects, but also induce indirect, biological adaptive processes via modulation of gene expression and cell-signaling pathways [70, 71,81,76,79].
o Nanoparticles are known to activate the pathogenand danger-associated molecular pattern (DAMP) receptor recognition and mediator network [81,87,79,150]. The adaptive changes manifest via modulation of gene expression patterns, cytokine and inflammatory mediator release, immune system activation, neuronal effects , and biological signaling at the cell-to-cell level [81,76,80]. Cell uptake of silica NPs in the parts per billion (ppb) and parts per million (ppm) ranges occurs , and concentrations of various NPs in the ppb to ppm range can exert toxic effects on small organisms in the environment [153,154].
• Fifth, in contrast with ordinary bulk pharmaceutical drugs, NPs are uniquely able to generate aging , pH sensitivity [109,156], electromagnetic , photoluminescence [158-161], and quantum mechanical effects [162-165].
o These types of phenomena overlap a number of the seemingly unrelated basic science findings previously reported for HMs [30,32,33,50,98]. Even the variations in modern nanotechnology using mechanical manufacturing processes from ball milling and vortexing or sonication to water jet treatment of liquids are empirically shown to generate nanoparticles from larger bulk forms in a top-down manner [20,25,116,166]. Ethanol, the solvent used in a range of concentrations for some HM manufacturing processes, can modify the sizes and surface properties of resultant nanotechnology-generated silica and other NPs [67,166]. Lactose is one of a variety of sugars that act as reducing and/or capping agents to make and stabilize nanoparticles, thereby modifying their biological activity [145,167].
Finally, it is essential to distinguish four interconnected, but separate issues in this area. That is, (i) what is HMs; (ii) what emergent properties of HMs capture and carry the unique information; (iii) how does the specific salient HM/information interact with a specific living system for which it is well-matched or resonant; (iv)how does the body's response evolve over time after the initiating event of interacting with a salient HM? Logically, the nature of the homeopathic information from a given HM, if any, must arise from the nature of manufacturing process and its products.
Nanoparticles are far more than conventional biochemical or pharmaceutical agents in living systems [65,168,169]. A common misunderstanding of the nature of NPs is that the dose or concentration must still fall into range for direct pharmacological effects. On the contrary, identifying a nanoscale structure in HMs does not mean that the reported therapeutic effects arise from structural properties of NPs as simple end-organ ligand-receptor effects per se in the conventional pharmaceutical sense. Even in mainstream cancer nanopharmacology, for instance, ultrasound, magnetic fields, and light stimuli can activate certain nano-drugs to release their contents only after they migrate into the target tissue by passive uptake afforded by their small size [170,171].
NPs can also modulate immune activity. For instance, nanoscale vaccines are much more effective than conventional vaccines at triggering immune system responses against infection or cancer, typically at much lower antigen doses [172-175]. Biosynthesized nanosilver can induce neuronal differentiation by modulating oxidative stress and cell signaling pathways . Notably, to modulate bio-reactivity of the host, biosynthesized NPs can carry trace residual components of the original plant or other biological material that generated the silica or metal NP into the interaction with the body.
Thus, nanomaterials act as stressors for cells and can affect biological systems across the adaptive networks of the body [176-179]. NPs can trigger systemic effects by (a) inducing release of nanoscale vesicles (Exosomes) from cells to initiate immune system reactions [168,169]; (b) activating intracellular inflammasome protein cascade and cytokine release ; (c) mobilizing interferon release . Overall, these networks involve modulation of gene expression patterns, cytokine release, cell signaling mediator release, cell and mitochondrial stress responses [77,81]. The effects can cascade into nonlinear amplified responses .
A number of studies from independent laboratories support the hypothesis of homeopathic NPs as salient mild systemic stressors. As Khuda-Bukhsh et al.  have previously proposed and demonstrated in experimental skin cancer, HMs can modulate gene expression and signaling proteins in the body without needing to rely on pharmacological tissue-based end organ ligand-receptor effects per se. Others have also demonstrated complex gene expression patterns in response to specific HMs in potency such as Apis , Gelsemium , Arsenicum Album , or a combination of multiple common HMs (commercial product Canova™ ).
Wiegant and van Wijk  demonstrated hormesis, i.e., low dose reversal in direction of effects using a toxicity model system. The model evoked intracellular heat shock protein (chaperone proteins) stress responses to higher toxic levels of bulk form arsenic or cadmium. The biological stress response reversed towards normal by administering homeopathically-prepared forms of the "same" source materials. They also showed crosssensitization in which one agent could induce an effect, and the other, chemically unrelated material could modify the observed response [182,185,186]. In biology, cross-sensitization occurs via not only immune, but also non-immune processes [2,193- 197]. Separately, other homeopathic investigators have observed that various HMs can modulate cytokine release [187,198-200].
In short, understanding HMs as discrete, pulsed sub toxic doses of natural product nanomedicines  helps integrate seemingly diverse empirical observations into a cohesive understanding. That is, NPs in HMs modulate adaptive biological pathways to generate state-dependent bidirectional changes in living systems [183,201].
Low potency homeopathy is likely dominated by a role for the HM source material micro-sized and nanosized particles with greater bioavailability than their respective bulk forms . However, high potency homeopathy is likely dominated by the amplified role of silica NPs modified by trace amounts of the source material NPs and/or, based on prior studies , any other materials used during manufacturing [21,51]. The other materials involved in making higher potency HMs can include specific borosilicate or soda lime glassware (or plastic) containers of various sizes and constituents, pipettes for dilution, distilled water, ethanol at various concentrations, and container stoppers (phenol caps, synthetics, rubber, natural cork) .
Furthermore, nanoparticles size and surface-related zeta potential can determine whether or not and to what extent a given NP exerts biological effects . From nanoscale forms, homeopathic information for the organism could arise from a unique cell signaling effect , electromagnetic  and/or optical signal, and/or quantum mechanical effect (for very small NPs < 10 nm in size) on the interconnected, nonlinear dynamic networks of the body . The specific objective correlates in the properties of NPs in HMs for the biological activity of those HMs remain an important and as yet unstudied question.
Despite the claims of skeptics, there is a substantial basic science and preclinical literature demonstrating that HMs at low and high potencies exerts biological effects different from placebos on cells, plants, animals, and human subjects [112,188- 190,192,198,200,203-215]. Multiple studies have demonstrated the ability of various nanomaterials to trigger the adaptive nonlinear dose-response phenomenon of hormesis at low doses . Hormetic mechanisms also encompass both receptor and/ or cell signaling pathways .
Table 5 summarizes the variety of overlapping features of nanomaterials and HMs discussed above. Whatever the nature of the homeopathic signal from the HM NPs, Bell et al.  have elsewhere discussed multiple endogenous nonlinear amplification mechanisms by which complex adaptive systems such as human beings or animals can respond to a small, pulsed but salient signal , especially from a nanomaterial. Such processes include not only hormesis, but also stochastic resonance and time-dependent sensitization/cross-sensitization . Other papers have outlined the evolving and self-organized nature of the reported changes in the recipient organism after an effective HM treatment using discrete intermittent doses, i.e., pulsed or spaced over time from one another [202,216-218].
Given the properties of nanomaterials, it is possible that the salient information conveyed from the HM to the individual organism sets the healing response in motion in multiple ways. Based on the evidence, the communication of the information could derive from the HM NP-generated biochemical, immunomodulatory, electromagnetic, magnetic, or optical/photon-based signals and/or from quantum mechanical phenomena .
HMs and NPs in sub toxic doses both show ability to modulate biological activity through changes in gene expression, signaling protein release, cytokine release, and/or oxidative stress patterns
Variability in physical chemistry, ultraviolet visible spectroscopy and bioactivity findings is common in both HMs and NPs as an inherent function of properties of the form rather than composition of the agent
HMs and modern NPs both exhibit susceptibility to aging in solution with resultant changes in properties; pH, temperature, salt and ethanol concentration-dependent effects occur
The indirect biological pathways of adaptation and crossadaptation in the body, rather than direct local end organ ligandreceptor pharmacological mechanisms would better account for the clinical phenomenology of homeopathic treatment (Figure 2). In specific, independent laboratories have found that different HMs play an immuno-modulatory role in specific biological models [187,224-226].
To maintain a focus on theory-driven testable hypotheses that arise from the present model, the remainder of the discussion will address potential biological mediation of the observed changes in living systems. One convergent conclusion from several different laboratories [187,192,211,227] is that HMs act by modulation of immune, inflammatory, and biological signaling, including
The diffuse network nature of the Cell Danger Response (CDR) system of the body provides a rational foundation for understanding the individual clinical response to an HM. Nanomaterials are one form of emerging exogenous danger signal for types of the endogenous Pattern Recognition Receptors (PRRs). PRRs initiate a dynamic and diffuse cascade of subsequent biological signaling events across the body . Other types of PRRs include those that recognize Pathogen-Associated Molecular Patterns (PAMPs, e.g., viruses and bacteria), damageassociated molecular patterns (DAMPs or "alarmins," e.g., heat shock proteins - HSPs) and related nanoparticle-associated molecular patterns [81,87,79,179,229]. Nanoparticles tend to trigger responses related to viruses, whereas larger micro-sized particles affect responses related to bacteria .
The cell danger response is implicated in a wide range of acute and chronic diseases , including many conditions that homeopaths sometimes report treating successfully, e.g., viral and bacterial infections [210,227,230] and sepsis , tissue injury [183,232], various allergies [233-238], autoimmune diseases , fibromyalgia , traumatic brain injury , attention deficit disorder , autism , and cancer [244,245]. The body has evolved mechanisms involving endogenous DAMPs as biological signals that detect and signify nano- and micro-scale and molecular threats to its survival [79,81]. The threats can be microbial pathogens, tissue damage, certain endogenous mediators, nanomaterials, or endogenous homeostatic disturbances (e.g., inflammation, hypoxia, acidity, metabolic stress)  (Figure 3).
Immune and/or non-immune (metabolic, inflammatory, nervous system, hormonal) adaptive pathways participate in biological stress responses. One immunological example is IgEbased allergic adjuvant reactions to nanoparticles such as carbon nanotubes . Apart from immune hyper reactivity, however, the threat does not have to be so intense as to kill the cell or individual organism . Rather, even low dose, sub toxic levels of NPs can still elicit cell oxidative stress responses [80,248] and thus activate a cascade of endogenous "alarmin" signaling events throughout the body [71,249] (see also Figure 4).
Nanomaterials are among the types of exogenous stimuli that act as danger signals for dendritic cells in the immune system to respond with release of endogenous biological danger signals . Furthermore, silica NPs can activate the intracellular inflammasome protein cascade, another component of the diffuse danger sensing and signaling biochemical network of the body . Inflammasome activation induces cytokine release, e.g., interleukin 1b . Other endogenous alarmins lead to purinergic signaling . These extracellular signals are mediated by purine nucleotides such as ATP (adenosine triphosphate) and are also associated with intracellular inflammasome activation followed by extracellular cytokine release .
Endogenous mediators such as ATP can play one metabolic role when inside an intact cell, but an alarmin role when released outside a damaged cell . Heat shock proteins, other mediators within the cell danger response network, are among the endogenous molecular alarmin signaling structures in response to cell damage or other types of biological threat. A series of previous studies by van Wijk and Wiegant [182,185,186,254] have repeatedly demonstrated that homeopathically-prepared materials can modulate heat shock protein activation patterns.
The important point in the current model for homeopathic medicines is that the danger signal triggers a complex nonlinear, self-regulatory cascade of endogenous mediator and modulator activation events [188,255]. These events constitute an adaptive response that tries to strengthen the organism against the danger . It is the cross-adaptive or cross-sensitized  nature of the HM as an individual danger signal to the pre-existing pattern of maladaptation and dysfunction in the individual that leads to the actual reversal in direction of the response back towards the health [1,2,23,220]. Such a nonlinear process would be a type of individualized cross-sensitization (between the original large magnitude biological stressors causing disease and the small HM NP discrete pulsed signal), post conditioning hormesis [182,185,258], or oscillation from cross-sensitization
(A) Exogenous danger signals include pathogen-associated molecular patterns, as well as exogenous particulate matter. Exogenous danger signals activate DCs (dendritic cells) directly via pattern recognition receptors, or indirectly though tissue damage (B) and homeostatic perturbations (C). (B) Inflammatory cell death as a result of tissue injury or programmed necrosis causes the release of endogenous danger signals (D) which also activate DCs. (C) Homeostatic perturbations such as those found in inflamed tissue (e.g., decreased pH, hypoxia) may also act as endogenous danger signals, influencing DC immune functions. (E) DCs integrate both exogenous and endogenous danger signals in order to orchestrate the appropriate immune response.
The acute CDR includes 8 functional changes in cell structure, physiology, metabolism, and gene expression. These are: 1) shift cellular metabolism from polymer to monomer synthesis to prevent the hijacking and assembly of cellular resources by intracellular pathogens, 2) stiffen the cell membranes to limit superinfection and pathogen egress, 3) release antiviral and antimicrobial chemicals into the pericellular environment, 4) increase autophagy, mitochondrial fission, and mitophagy to facilitate removal of intracellular pathogens and biogenesis centers,5) change DNA methylation and histone modification to alter gene expression, 6) mobilize endogenous retroviruses and LINEs to produce genetic variations, 7) warn neighboring cells and distant effectors cells of the danger with extracellular nucleotides, H2O2, eicosanoids, metabolites, and cytokines, and 8) alter the behavior of the host to prevent the spread of infection to kin, and sleep patterns to facilitate healing.
In turn, endogenous biological danger signals such as cytokines then carry and potentiate the message concerning existence of a salient threat danger to the rest of the body's defense systems, including the brain. Researchers now consider the pro-inflammatory cytokine interleukin 1a, for example, as an alarmin or marker of oxidative stress for various chronic conditions associated with inflammation . The selfregulatory results of defense system pathway activation include complex modulation of inflammatory and anti-inflammatory events [228,264,265].
Notably, ingredients of several different single and combination homeopathic medicines increase and/or decrease certain pro-inflammatory and anti-inflammatory cytokines under specific conditions [192,198-200,266]. Determining the potential role of homeopathic medicine NPs as modulators of cytokine release, heat shock protein activation patterns and other components of the danger signal pathways is one of several appropriate experimental directions to pursue.
Immune/inflammatory and brain/neural pathways also communicate with one another bidirectional concerning exogenous threats [228,267]. Bell et al. have repeatedly demonstrated that sniffing individually-salient HMs versus double-blind placebos significantly changes quantitative Electroencephalographic (EEG) responses acutely and induces sensitization over time [205,206]. Thus, data indicate that sensory signaling and central nervous system sensitization can play a role in HM effects.
Taken together, the evidence indicates that when an HM dose at a given higher potency contains source material NPs in very small sizes  and adjuvant (amplifying) silica NPs from the glassware, it will be biologically more potent than (a) an HM dose at a low potency, i.e., higher concentration of larger sized, less reactive particles and residual bulk material; or (b) the same dose of source NPs lacking nanosilica as adsorbent, stabilizer and amplifier. Biologically, small NPs have extremely high bioavailability and unimpeded capacity to cross cell membranes [62,63].
Once in contact with physiological fluids, serum proteins will adsorb onto the HM nanoparticles surfaces and create a unique biological signature for the composite nanomaterial in the body per se (protein corona) [49,79,130,142,144]. Shape and surface chemistry variations of nanoparticles such as silica NPs modulate the nature of the unique protein corona that adsorbs to the NPs [142,269,270]. According to Walkey and Chan , it is necessary to characterize not only the NPs, but also the unique pattern of adsorbed proteins, i.e., the protein corona "adsorbome" that immediately attaches to the NPs on introduction to biological fluids, especially serum proteins [133,144]. This enables researchers to know the "biological identity" of the proteinnanocomposite structures that will develop on interaction with the body [269,271,272]. They propose that it is the biological identity, not the manufactured synthetic nanoparticle identity, which leads to the physiological response.
Considering homeopathy as a form of adaptive network nanomedicine  rather than conventional pharmacology leads to predictions consistent with clinical observations. For example, activating the CDR excessively with disease-fostering high intensity stressors overwhelms homeostatic/allostatic dynamics [228,264,265,273] and fosters the emergence of disease and sickness behavior (including fatigue) (Figure 4). Conversely, successful homeopathic treatment with individually chosen low dose, i.e., sub toxic levels of, NPs should reverse this process. HMs would achieve their effects by modulating the adaptive dynamics of the same pre-sensitized metabolic, immune, and neural CDR pathways back toward resilience and health (including the emergent effect of greater global sense of energy and well-being) [1,2,23,188]. Modulating the plasticity of the nervous system pathways per se may reflect quantum mechanical dynamics [274,275].
Figure 4 shows the putative components of the acute cell danger response and pathways to sickness or to healing. Like NPs, (a) homeopathic medicines can modulate reactive oxygen species [278-281], heat shock proteins [185,254,282], and cytokine release [187,192,198,199,266] and trigger biological signaling cascades in cancer cells [187,188]; and (b) nanoparticles constitute an emerging type of danger signal for cells . Consequently, further systematic examination of the effects of low dose HMs and their constituent NPs on the cell danger response pathway network is likely to be productive [257,282].
Understanding low and high potency homeopathic medicines as various types of nanomedicine opens the door to studying potential mechanisms of action . Very low potencies would exert direct pharmacological and/or hypersensitivity effects related to enhanced bioavailability, drug delivery capacity and duration of action of natural source nanomaterials . Higher potencies in water would bring about their effects as virus-like systemic stressors (i.e., indirectly), based mainly on source-modified silica nanomaterial properties. As salient nanoenhanced signals at higher potencies, the concentrations of the pulsed doses of a well-chosen HM can be very low and still trigger individual bio-reactivity in a state-dependent, nonlinear manner (cf., ).
In addition to small amounts of source material NPs, the more prevalent silica NPs would include source-doped nanosilica or silica-shell/source-core NPs, together acting as nanosilica-amplified immune adjuvant [36,53,55,56,121], sub toxic metabolic stressors [80,285], nanocatalysts [117,286], and/ or nanomaterial-induced exogenous danger signals triggering a cell danger response . The clinically reported extended duration of evolving responses to a given HM dose  in multiple bodily systems across the organism  would reflect the interconnected self-organizing state of the organism and capacity for nonlinear amplification and change .
The nature of the specific signal from the homeopathic nanomaterial may emerge from the biochemical , electromagnetic [33,98,288], magnetic , photon [32,50], and/or quantum mechanical [30,290,291] properties of nanomaterials at different potencies and in various contexts [30,292]. Available evidence suggests that the nature of homeopathic medicines and their mechanisms of action on living systems are complex and multivariate. While any given study may have its limitations and flaws, the convergence of evidence surrounding the major observations on which this model is based is extensive.
Now the biological effects of homeopathic medicines are accessible for objective quantitative study with the sophisticated and highly sensitive tools and technologies of nanobiology. Examining whether or not the specific physical properties of the nanomaterials in HMs, e.g., certain sizes, shapes, surface areas, surface charges (zeta potentials), and/or adsorbents/ dopants, correlate with their effects in vitro and in vivo on subsystems involved in biological adaptation (cf. [49,65,70,76] ) is the next major empirical question for the present hypothesis-driven research model.
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