View source for Biohybrid microswimmer

{{microbial and microbot movement|biohybrid}}
A '''biohybrid microswimmer''' also known as '''biohybrid nanorobot''',<ref>{{cite journal | doi=10.1186/s13045-023-01463-z | doi-access=free | title=Advances of medical nanorobots for future cancer treatments | date=2023 | last1=Kong | first1=Xiangyi | last2=Gao | first2=Peng | last3=Wang | first3=Jing | last4=Fang | first4=Yi | last5=Hwang | first5=Kuo Chu | journal=Journal of Hematology & Oncology | volume=16 | issue=1 | page=74 | pmid=37452423 | pmc=10347767 }}</ref> can be defined as a [[microswimmer]] that consist of both biological and artificial constituents, for instance, one or several living microorganisms attached to one or various synthetic parts.

In recent years [[nanoscopic]] and [[Wiktionary:mesoscopic|mesoscopic]] objects have been designed to collectively move through direct inspiration from nature or by harnessing its existing tools. Small mesoscopic to nanoscopic systems typically operate at low [[Reynolds number]]s (Re ≪ 1), and understanding their motion becomes challenging. For locomotion to occur, the symmetry of the system must be broken.

In addition, collective motion requires a coupling mechanism between the entities that make up the collective. To develop mesoscopic to nanoscopic entities capable of swarming behaviour, it has been hypothesised that the entities are characterised by broken symmetry with a well-defined morphology, and are powered with some material capable of harvesting energy. If the harvested energy results in a field surrounding the object, then this field can couple with the field of a neighbouring object and bring some coordination to the collective behaviour. Such [[robotic swarm]]s have been categorised by an online expert panel as among the 10 great unresolved group challenges in the area of [[robotic]]s. Although investigation of their underlying mechanism of action is still in its infancy, various systems have been developed that are capable of undergoing controlled and uncontrolled swarming motion by harvesting energy (e.g., light, thermal, etc.).
 
Over the past decade, biohybrid microrobots, in which living mobile microorganisms are physically integrated with untethered artificial structures, have gained growing interest to enable the active locomotion and cargo delivery to a target destination. In addition to the motility, the intrinsic capabilities of sensing and eliciting an appropriate response to artificial and environmental changes make cell-based biohybrid microrobots appealing for transportation of cargo to the inaccessible cavities of the human body for local active delivery of diagnostic and therapeutic agents.

==Background==
[[File:Basic features of an in vivo microrobot.jpg|thumb|upright=1.7| {{center|'''Basic features of an ''in vivo'' microrobot'''{{hsp}}<ref name=Schwarz2017 />}} In a biohybrid approach, all three of these  basic features can be realised either biologically by a microorganism, or artificially by synthetic attachments. Blue indicates biological entities (flagellated or target cells), red indicates artificial structures (attached tubes, helices, particles, or external devices). Arrows in the upper left panel indicate the motile actor, wave lines in the upper right panel indicate signal pathways. The lower panel shows how functionalities can be carried out based on cell-cell interactions or by synthetic cargo (red particles).]]

Biohybrid microswimmers can be defined as microswimmers that consist of both biological and artificial constituents, for instance, one or several living microorganisms attached to one or various synthetic parts.<ref name=Schwarz2017>{{cite journal |doi = 10.1063/1.4993441|title = Hybrid Bio ''Micromotors''|year = 2017|last1 = Schwarz|first1 = Lukas|last2 = Medina-Sánchez|first2 = Mariana|last3 = Schmidt|first3 = Oliver G.|journal = Applied Physics Reviews|volume = 4|issue = 3|page = 031301|bibcode = 2017ApPRv...4c1301S|doi-access = free}}</ref><ref name=BastosArrieta2018>{{cite journal |doi = 10.3389/frobt.2018.00097|title = Bacterial Biohybrid Microswimmers|year = 2018|last1 = Bastos-Arrieta|first1 = Julio|last2 = Revilla-Guarinos|first2 = Ainhoa|last3 = Uspal|first3 = William E.|last4 = Simmchen|first4 = Juliane|journal = Frontiers in Robotics and AI|volume = 5|page = 97|pmid = 33500976|pmc = 7805739|doi-access = free}} [[File:CC-BY icon.svg|50px]] Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref> The pioneers of this field, ahead of their time, were Montemagno and Bachand with a 1999 work regarding specific attachment strategies of biological molecules to nanofabricated substrates enabling the preparation of hybrid inorganic/organic [[nanoelectromechanical systems]], so called NEMS.<ref>{{cite journal |doi = 10.1088/0957-4484/10/3/301|title = Constructing nanomechanical devices powered by biomolecular motors|year = 1999|last1 = Montemagno|first1 = Carlo|last2 = Bachand|first2 = George|journal = Nanotechnology|volume = 10|issue = 3|pages = 225–231|bibcode = 1999Nanot..10..225M| s2cid=250910730 }}</ref> They described the production of large amounts of [[F-ATPase|F1-ATPase]] from the thermophilic bacteria ''[[AGCS family|Bacillus PS3]]'' for the preparation of F1-ATPase bio[[molecular motor]]s immobilized on a nanoarray pattern of gold, copper or nickel produced by [[electron beam lithography]]. These proteins were attached to one [[micron]] [[microsphere]]s tagged with a synthetic [[peptide]]. Consequently, they accomplished the preparation of a platform with chemically active sites and the development of biohybrid devices capable of converting energy of biomolecular motors into useful work.<ref name=BastosArrieta2018 />

One of the most fundamental questions in science is what defines life.<ref>{{cite journal |doi = 10.1088/0031-8949/92/1/012501|title = Life, the Universe, and everything—42 fundamental questions|year = 2017|last1 = Allen|first1 = Roland E.|last2 = Lidström|first2 = Suzy|journal = Physica Scripta|volume = 92|issue = 1|page = 012501|arxiv = 1804.08730|bibcode = 2017PhyS...92a2501A|s2cid = 119444389}}</ref> [[Collective motion]] is one of the hallmarks of life.<ref name=Vicsek2012>{{cite journal |doi = 10.1016/j.physrep.2012.03.004|title = Collective motion|year = 2012|last1 = Vicsek|first1 = Tamás|last2 = Zafeiris|first2 = Anna|journal = Physics Reports|volume = 517|issue = 3–4|pages = 71–140|arxiv = 1010.5017|bibcode = 2012PhR...517...71V|s2cid = 119109873}}</ref> This is commonly observed in nature at various dimensional levels as energized entities gather, in a concerted effort, into motile aggregated patterns. These motile aggregated events can be noticed, among many others, as [[Swarm behaviour|dynamic swarms]]; e.g., unicellular organisms such as bacteria, locust swarms, or the flocking behaviour of birds.<ref>{{cite journal |doi = 10.1016/j.bpj.2010.01.053|title = Dynamics of Bacterial Swarming|year = 2010|last1 = Darnton|first1 = Nicholas C.|last2 = Turner|first2 = Linda|last3 = Rojevsky|first3 = Svetlana|last4 = Berg|first4 = Howard C.|journal = Biophysical Journal|volume = 98|issue = 10|pages = 2082–2090|pmid = 20483315|pmc = 2872219|bibcode = 2010BpJ....98.2082D}}</ref><ref>{{cite journal |doi = 10.1371/journal.pcbi.1002642|title = Locust Dynamics: Behavioral Phase Change and Swarming|year = 2012|last1 = Topaz|first1 = Chad M.|last2 = d'Orsogna|first2 = Maria R.|author2-link=Maria Rita D'Orsogna|last3 = Edelstein-Keshet|first3 = Leah|last4 = Bernoff|first4 = Andrew J.|journal = PLOS Computational Biology|volume = 8|issue = 8|pages = e1002642|pmid = 22916003|pmc = 3420939|arxiv = 1207.4968|bibcode = 2012PLSCB...8E2642T | doi-access=free }}</ref><ref>{{cite journal |doi = 10.7554/eLife.45071|title = Compound-V formations in shorebird flocks|year = 2019|last1 = Corcoran|first1 = Aaron J.|last2 = Hedrick|first2 = Tyson L.|journal = eLife|volume = 8|pmid = 31162047|pmc = 6548498 | doi-access=free }}</ref>

Ever since Newton established his equations of motion, the mystery of motion on the microscale has emerged frequently in scientific history, as famously demonstrated by a couple of articles that should be discussed briefly. First, an essential concept, popularized by [[Osborne Reynolds]], is that the relative importance of [[inertia]] and [[viscosity]] for the motion of a fluid depends on certain details of the system under consideration.<ref name=BastosArrieta2018 /> The [[Reynolds number]] {{math|''Re''}}, named in his honor, quantifies this comparison as a [[dimensionless ratio]] of characteristic inertial and viscous forces:

:<math>\mathrm{Re} = \frac{\rho u l}{\mu}</math>

Here, {{math|''ρ''}} represents the density of the fluid; {{math|''u''}} is a characteristic velocity of the system (for instance, the velocity of a swimming particle); {{math|''l''}} is a characteristic length scale (e.g., the swimmer size); and {{math|''μ''}} is the viscosity of the fluid. Taking the suspending fluid to be water, and using experimentally observed values for {{math|''u''}}, one can determine that inertia is important for macroscopic swimmers like fish ({{math|''Re''}} = 100), while viscosity dominates the motion of microscale swimmers like bacteria ({{math|''Re''}} = 10<sup>−4</sup>).<ref name=BastosArrieta2018 />

The overwhelming importance of viscosity for swimming at the micrometer scale has profound implications for swimming strategy. This has been discussed memorably by [[E. M. Purcell]], who invited the reader into the world of microorganisms and theoretically studied the conditions of their motion.<ref name=Purcell1977>{{cite journal |doi = 10.1119/1.10903|title = Life at low Reynolds number|year = 1977|last1 = Purcell|first1 = E. M.|journal = American Journal of Physics|volume = 45|issue = 1|pages = 3–11|bibcode = 1977AmJPh..45....3P}}</ref> In the first place, propulsion strategies of large scale swimmers often involve imparting [[momentum]] to the surrounding fluid in periodic [[Wiktionary:discrete|discrete events]], such as [[vortex shedding]], and coasting between these events through [[inertia]]. This cannot be effective for microscale swimmers like bacteria: due to the large [[viscous damping]], the inertial coasting time of a micron-sized object is on the order of 1 μs. The coasting distance of a microorganism moving at a typical speed is about 0.1 [[angstrom]]s (Å). Purcell concluded that only forces that are exerted in the present moment on a microscale body contribute to its propulsion, so a constant energy conversion method is essential.<ref name=Purcell1977 /><ref name=BastosArrieta2018 />

Microorganisms have optimized their [[Microbial metabolism|metabolism]] for continuous energy production, while purely artificial microswimmers (microrobots) must obtain energy from the environment, since their on-board-storage-capacity is very limited. As a further consequence of the continuous dissipation of energy, biological and artificial microswimmers do not obey the laws of equilibrium statistical physics, and need to be described by non-equilibrium dynamics.<ref name=BastosArrieta2018 /> Mathematically, Purcell explored the implications of low Reynolds number by taking the [[Navier-Stokes equation]] and eliminating the inertial terms:

:<math> \begin{align} \mu \nabla^2 \mathbf{u} -\boldsymbol{\nabla}p &= \boldsymbol{0} \\ \end{align}</math>

where <math>\mathbf{u}</math> is the [[velocity]] of the fluid and <math>\boldsymbol{\nabla} p</math> is the gradient of the [[pressure]]. As Purcell noted, the resulting equation — the [[Stokes flow|Stokes equation]] — contains no explicit time dependence.<ref name=Purcell1977 /> This has some important consequences for how a suspended body (e.g., a bacterium) can swim through periodic mechanical motions or deformations (e.g., of a [[flagellum]]). First, the rate of motion is practically irrelevant for the motion of the microswimmer and of the surrounding fluid: changing the rate of motion will change the scale of the velocities of the fluid and of the microswimmer, but it will not change the pattern of fluid flow. Secondly, reversing the direction of mechanical motion will simply reverse all velocities in the system. These properties of the Stokes equation severely restrict the range of feasible swimming strategies.<ref name=Purcell1977 /><ref name=BastosArrieta2018 />

Recent publications of biohybrid microswimmers include the use of sperm cells, contractive [[muscle cell]]s, and bacteria as biological components, as they can efficiently convert chemical energy into movement, and additionally are capable of performing complicated motion depending on environmental conditions. In this sense, biohybrid microswimmer systems can be described as the combination of different functional components: cargo and carrier. The cargo is an element of interest to be moved (and possibly released) in a customized way. The carrier is the component responsible for the movement of the biohybrid, transporting the desired cargo, which is linked to its surface. The great majority of these systems rely on biological motile propulsion for the transportation of synthetic cargo for targeted drug delivery/<ref name=Schwarz2017 /> There are also examples of the opposite case: artificial microswimmers with biological cargo systems.<ref name="Wu2014"/><ref name="Wang2015"/><ref name=BastosArrieta2018 />

Over the past decade, biohybrid microrobots, in which living mobile microorganisms are physically integrated with untethered artificial structures, have gained growing interest to enable the active locomotion and cargo delivery to a target destination.<ref>{{cite journal |doi = 10.1126/scirobotics.aaq0495|title = Biohybrid actuators for robotics: A review of devices actuated by living cells|year = 2017|last1 = Ricotti|first1 = Leonardo|last2 = Trimmer|first2 = Barry|last3 = Feinberg|first3 = Adam W.|last4 = Raman|first4 = Ritu|last5 = Parker|first5 = Kevin K.|last6 = Bashir|first6 = Rashid|last7 = Sitti|first7 = Metin|last8 = Martel|first8 = Sylvain|last9 = Dario|first9 = Paolo|last10 = Menciassi|first10 = Arianna|journal = Science Robotics|volume = 2|issue = 12|pages = eaaq0495|pmid = 33157905|s2cid = 29776467|doi-access = free}}</ref><ref>{{cite journal |doi = 10.1146/annurev-control-053018-023803|title = Microrobotics and Microorganisms: Biohybrid Autonomous Cellular Robots|year = 2019|last1 = Alapan|first1 = Yunus|last2 = Yasa|first2 = Oncay|last3 = Yigit|first3 = Berk|last4 = Yasa|first4 = I. Ceren|last5 = Erkoc|first5 = Pelin|last6 = Sitti|first6 = Metin|journal = Annual Review of Control, Robotics, and Autonomous Systems|volume = 2|pages = 205–230| s2cid=139819519 }}</ref><ref>{{cite journal |doi = 10.1002/adma.201706245|title = Neutrophil-Based Drug Delivery Systems|year = 2018|last1 = Chu|first1 = Dafeng|last2 = Dong|first2 = Xinyue|last3 = Shi|first3 = Xutong|last4 = Zhang|first4 = Canyang|last5 = Wang|first5 = Zhenjia|journal = Advanced Materials|volume = 30|issue = 22|pages = e1706245|pmid = 29577477|pmc = 6161715| bibcode=2018AdM....3006245C }}</ref><ref>{{cite journal |doi = 10.1002/smll.201400384|title = Bio-Hybrid Cell-Based Actuators for Microsystems|year = 2014|last1 = Carlsen|first1 = Rika Wright|last2 = Sitti|first2 = Metin|journal = Small|volume = 10|issue = 19|pages = 3831–3851|pmid = 24895215}}</ref> In addition to the motility, the intrinsic capabilities of sensing and eliciting an appropriate response to artificial and environmental changes make cell-based biohybrid microrobots appealing for transportation of cargo to the inaccessible cavities of the human body for local active delivery of diagnostic and therapeutic agents.<ref>{{cite journal |doi = 10.1016/j.snb.2015.09.034|title = Active tumor-therapeutic liposomal bacteriobot combining a drug (Paclitaxel)-encapsulated liposome with targeting bacteria (Salmonella Typhimurium)|year = 2016|last1 = Nguyen|first1 = Van Du|last2 = Han|first2 = Ji-Won|last3 = Choi|first3 = Young Jin|last4 = Cho|first4 = Sunghoon|last5 = Zheng|first5 = Shaohui|last6 = Ko|first6 = Seong Young|last7 = Park|first7 = Jong-Oh|last8 = Park|first8 = Sukho|journal = Sensors and Actuators B: Chemical|volume = 224|pages = 217–224| bibcode=2016SeAcB.224..217N }}</ref><ref name="Magneto-aerotactic bacteria deliver">{{cite journal |doi = 10.1038/nnano.2016.137|title = Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions|year = 2016|last1 = Felfoul|first1 = Ouajdi|last2 = Mohammadi|first2 = Mahmood|last3 = Taherkhani|first3 = Samira|last4 = De Lanauze|first4 = Dominic|last5 = Zhong Xu|first5 = Yong|last6 = Loghin|first6 = Dumitru|last7 = Essa|first7 = Sherief|last8 = Jancik|first8 = Sylwia|last9 = Houle|first9 = Daniel|last10 = Lafleur|first10 = Michel|last11 = Gaboury|first11 = Louis|last12 = Tabrizian|first12 = Maryam|last13 = Kaou|first13 = Neila|last14 = Atkin|first14 = Michael|last15 = Vuong|first15 = Té|last16 = Batist|first16 = Gerald|last17 = Beauchemin|first17 = Nicole|last18 = Radzioch|first18 = Danuta|last19 = Martel|first19 = Sylvain|journal = Nature Nanotechnology|volume = 11|issue = 11|pages = 941–947|pmid = 27525475|pmc = 6094936|bibcode = 2016NatNa..11..941F}}</ref><ref name=Yasa2018>{{cite journal |doi = 10.1002/adma.201804130|title = Microalga-Powered Microswimmers toward Active Cargo Delivery|year = 2018|last1 = Yasa|first1 = Oncay|last2 = Erkoc|first2 = Pelin|last3 = Alapan|first3 = Yunus|last4 = Sitti|first4 = Metin|journal = Advanced Materials|volume = 30|issue = 45|pages = e1804130|pmid = 30252963| bibcode=2018AdM....3004130Y | s2cid=52823884 }}</ref> Active locomotion, targeting and steering of concentrated therapeutic and diagnostic agents embedded in mobile microrobots to the site of action can overcome the existing challenges of conventional therapies.<ref>{{cite journal |doi = 10.1039/C7LC00064B|title = Mobile microrobots for bioengineering applications|year = 2017|last1 = Ceylan|first1 = Hakan|last2 = Giltinan|first2 = Joshua|last3 = Kozielski|first3 = Kristen|last4 = Sitti|first4 = Metin|journal = Lab on a Chip|volume = 17|issue = 10|pages = 1705–1724|pmid = 28480466|doi-access = free}}</ref><ref>{{cite journal |doi = 10.1126/scirobotics.aam6431|title = Micro/Nanorobots for biomedicine: Delivery, surgery, sensing, and detoxification|year = 2017|last1 = Li|first1 = Jinxing|last2 = Esteban-Fernández De Ávila|first2 = Berta|last3 = Gao|first3 = Wei|last4 = Zhang|first4 = Liangfang|last5 = Wang|first5 = Joseph|journal = Science Robotics|volume = 2|issue = 4|pages = eaam6431|pmid = 31552379|pmc = 6759331}}</ref><ref name="Mobile Microrobots for Active Thera">{{cite journal |doi = 10.1002/adtp.201800064|title = Mobile Microrobots for Active Therapeutic Delivery|year = 2019|last1 = Erkoc|first1 = Pelin|last2 = Yasa|first2 = Immihan C.|last3 = Ceylan|first3 = Hakan|last4 = Yasa|first4 = Oncay|last5 = Alapan|first5 = Yunus|last6 = Sitti|first6 = Metin|journal = Advanced Therapeutics|volume = 2|s2cid = 88204894|doi-access = free}}</ref> To this end, bacteria have been commonly used with attached beads and ghost cell bodies.<ref name="Park2017"/><ref>{{cite journal |doi = 10.1063/1.2431454|title = Bacterial flagella-based propulsion and on/Off motion control of microscale objects|year = 2007|last1 = Behkam|first1 = Bahareh|last2 = Sitti|first2 = Metin|journal = Applied Physics Letters|volume = 90|issue = 2|page = 023902|bibcode = 2007ApPhL..90b3902B}}</ref><ref>{{cite journal |doi = 10.1063/1.3040318|title = Effect of quantity and configuration of attached bacteria on bacterial propulsion of microbeads|year = 2008|last1 = Behkam|first1 = Bahareh|last2 = Sitti|first2 = Metin|journal = Applied Physics Letters|volume = 93|issue = 22|page = 223901|bibcode = 2008ApPhL..93v3901B}}</ref><ref>{{cite journal |doi = 10.1002/advs.201700058|title = Bioadhesive Bacterial Microswimmers for Targeted Drug Delivery in the Urinary and Gastrointestinal Tracts|year = 2017|last1 = Mostaghaci|first1 = Babak|last2 = Yasa|first2 = Oncay|last3 = Zhuang|first3 = Jiang|last4 = Sitti|first4 = Metin|journal = Advanced Science|volume = 4|issue = 6|pmid = 28638787|pmc = 5473323}}</ref><ref>{{cite journal |doi = 10.1038/s41598-018-28102-9|title = Motility and chemotaxis of bacteria-driven microswimmers fabricated using antigen 43-mediated biotin display|year = 2018|last1 = Schauer|first1 = Oliver|last2 = Mostaghaci|first2 = Babak|last3 = Colin|first3 = Remy|last4 = Hürtgen|first4 = Daniel|last5 = Kraus|first5 = David|last6 = Sitti|first6 = Metin|last7 = Sourjik|first7 = Victor|journal = Scientific Reports|volume = 8|issue = 1|page = 9801|pmid = 29955099|pmc = 6023875|bibcode = 2018NatSR...8.9801S}}</ref><ref name="Microemulsion-Based Soft Bacteria-D">{{cite journal |doi = 10.1021/acsnano.7b02082|title = Microemulsion-Based Soft Bacteria-Driven Microswimmers for Active Cargo Delivery|year = 2017|last1 = Singh|first1 = Ajay Vikram|last2 = Hosseinidoust|first2 = Zeinab|last3 = Park|first3 = Byung-Wook|last4 = Yasa|first4 = Oncay|last5 = Sitti|first5 = Metin|journal = ACS Nano|volume = 11|issue = 10|pages = 9759–9769|pmid = 28858477}}</ref><ref>{{cite journal |doi = 10.1002/smll.201603679|title = Biohybrid Microtube Swimmers Driven by Single Captured Bacteria|year = 2017|last1 = Stanton|first1 = Morgan M.|last2 = Park|first2 = Byung-Wook|last3 = Miguel-López|first3 = Albert|last4 = Ma|first4 = Xing|last5 = Sitti|first5 = Metin|last6 = Sánchez|first6 = Samuel|journal = Small|volume = 13|issue = 19|pmid = 28299891|hdl = 2445/123481|hdl-access = free}}</ref><ref>{{cite journal |doi = 10.1021/acsnano.7b04128|title = Magnetotactic Bacteria Powered Biohybrids TargetE. Coli ''Biofilms''|year = 2017|last1 = Stanton|first1 = Morgan M.|last2 = Park|first2 = Byung-Wook|last3 = Vilela|first3 = Diana|last4 = Bente|first4 = Klaas|last5 = Faivre|first5 = Damien|last6 = Sitti|first6 = Metin|last7 = Sánchez|first7 = Samuel|journal = ACS Nano|volume = 11|issue = 10|pages = 9968–9978|pmid = 28933815|hdl = 2445/123493|hdl-access = free}}</ref><ref name=Akolpoglu2020 />

==Bacterial biohybrids==
{{see also|Bacterial motility}}
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 | footer            = {{center|'''Bacteria-driven biohybrid microswimmers with a spherical body'''{{hsp}}<ref name=Zhuang2017>{{cite journal |doi = 10.1002/advs.201700109|title = Propulsion and Chemotaxis in Bacteria-Driven Microswimmers|year = 2017|last1 = Zhuang|first1 = Jiang|last2 = Park|first2 = Byung-Wook|last3 = Sitti|first3 = Metin|journal = Advanced Science|volume = 4|issue = 9|pmid = 28932674|pmc = 5604384}} [[File:CC-BY icon.svg|50px]] Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref>}} (a) SEM images showing 2 μm diameter polystyrene microbeads, each attached by a few ''E. coli'' bacteria<br />
(b) An illustration of the forces and torques exerted on the spherical microbead by its attached bacteria, where the force and the motor reaction torque of each bacterium are state dependent.
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Artificial micro and nanoswimmers are small scale devices that convert energy into movement.<ref>{{cite journal |doi = 10.1002/adma.200501767|title = Dream Nanomachines|year = 2005|last1 = Ozin|first1 = G. A.|last2 = Manners|first2 = I.|last3 = Fournier-Bidoz|first3 = S.|last4 = Arsenault|first4 = A.|journal = Advanced Materials|volume = 17|issue = 24|pages = 3011–3018| bibcode=2005AdM....17.3011O | s2cid=55293424 }}</ref><ref name=Wang2015>{{cite journal |doi = 10.1021/acs.chemrev.5b00047|title = Fabrication of Micro/Nanoscale Motors|year = 2015|last1 = Wang|first1 = Hong|last2 = Pumera|first2 = Martin|journal = Chemical Reviews|volume = 115|issue = 16|pages = 8704–8735|pmid = 26234432|doi-access = free}}</ref> Since the first demonstration of their performance in 2002, the field has developed rapidly in terms of new preparation methodologies, propulsion strategies, motion control, and envisioned functionality.<ref>{{cite journal |doi = 10.1002/1521-3773(20020215)41:4<652::AID-ANIE652>3.0.CO;2-U|title = Autonomous Movement and Self-Assembly|year = 2002|last1 = Ismagilov|first1 = Rustem F.|last2 = Schwartz|first2 = Alexander|last3 = Bowden|first3 = Ned|last4 = Whitesides|first4 = George M.|journal = Angewandte Chemie International Edition|volume = 41|issue = 4|pages = 652–654|doi-access = free}}</ref><ref>{{cite journal |doi = 10.1021/acs.accounts.6b00386|title = Designing Micro- and Nanoswimmers for Specific Applications|year = 2017|last1 = Katuri|first1 = Jaideep|last2 = Ma|first2 = Xing|last3 = Stanton|first3 = Morgan M.|last4 = Sánchez|first4 = Samuel|journal = Accounts of Chemical Research|volume = 50|issue = 1|pages = 2–11|pmid = 27809479|pmc = 5244436}}</ref> The field holds promise for applications such as drug delivery, [[environmental remediation]] and sensing. The initial focus of the field was largely on artificial systems, but an increasing number of "biohybrids" are appearing in the literature. Combining artificial and biological components is a promising strategy to obtain new, well-controlled microswimmer functionalities, since essential functions of living organisms are intrinsically related to the capability to move.<ref>{{cite journal |doi = 10.1126/science.288.5463.88|title = The Way Things Move: Looking Under the Hood of Molecular Motor Proteins|year = 2000|last1 = Vale|first1 = R. D.|last2 = Milligan|first2 = R. A.|journal = Science|volume = 288|issue = 5463|pages = 88–95|pmid = 10753125|bibcode = 2000Sci...288...88V}}</ref> Living beings of all scales move in response to environmental stimuli (e.g., temperature or pH), to look for food sources, to reproduce, or to escape from predators. One of the more well-known living microsystems are swimming bacteria, but directed motion occurs even at the molecular scale, where enzymes and proteins undergo conformational changes in order to carry out biological tasks.<ref>{{cite journal |doi = 10.1016/j.ejpb.2004.10.007|title = Nature's design of nanomotors|year = 2005|last1 = Vogel|first1 = Pia D.|journal = European Journal of Pharmaceutics and Biopharmaceutics|volume = 60|issue = 2|pages = 267–277|pmid = 15939237}}</ref><ref name=BastosArrieta2018 />

Swimming bacterial cells have been used in the development of hybrid microswimmers.<ref name=DiLeonardo2010>{{cite journal |doi = 10.1073/pnas.0910426107|title = Bacterial ratchet motors|year = 2010|last1 = Di Leonardo|first1 = R.|last2 = Angelani|first2 = L.|last3 = Dell'Arciprete|first3 = D.|last4 = Ruocco|first4 = G.|last5 = Iebba|first5 = V.|last6 = Schippa|first6 = S.|last7 = Conte|first7 = M. P.|last8 = Mecarini|first8 = F.|last9 = De Angelis|first9 = F.|last10 = Di Fabrizio|first10 = E.|journal = Proceedings of the National Academy of Sciences|volume = 107|issue = 21|pages = 9541–9545|pmid = 20457936|pmc = 2906854|arxiv = 0910.2899|bibcode = 2010PNAS..107.9541D|doi-access = free}}</ref><ref name=Zhang2013>{{cite journal |doi = 10.1088/0957-4484/24/18/185103|title = Propulsion of liposomes using bacterial motors|year = 2013|last1 = Zhang|first1 = Zhenhai|last2 = Li|first2 = Zhifei|last3 = Yu|first3 = Wei|last4 = Li|first4 = Kejie|last5 = Xie|first5 = Zhihong|last6 = Shi|first6 = Zhiguo|journal = Nanotechnology|volume = 24|issue = 18|page = 185103|pmid = 23579252|bibcode = 2013Nanot..24r5103Z| s2cid=40359976 }}</ref><ref name=Stanton2016>{{cite journal |doi = 10.1002/admi.201500505|title = Biohybrid Janus Motors Driven by ''Escherichia'' coli|year = 2016|last1 = Stanton|first1 = Morgan M.|last2 = Simmchen|first2 = Juliane|last3 = Ma|first3 = Xing|last4 = Miguel-López|first4 = Albert|last5 = Sánchez|first5 = Samuel|journal = Advanced Materials Interfaces|volume = 3|issue = 2| s2cid=138755512 }}</ref><ref name=Suh2016>{{cite journal |doi = 10.1039/C6LC00059B|title = Bacterial chemotaxis-enabled autonomous sorting of nanoparticles of comparable sizes|year = 2016|last1 = Suh|first1 = Seungbeum|last2 = Traore|first2 = Mahama A.|last3 = Behkam|first3 = Bahareh|journal = Lab on a Chip|volume = 16|issue = 7|pages = 1254–1260|pmid = 26940033|hdl = 10919/77561|hdl-access = free}}</ref> Cargo attachment to the bacterial cells might influence their swimming behavior.<ref name=BastosArrieta2018 /> Bacterial cells in the swarming state have also been used in the development of hybrid microswimmers. Swarming ''[[Serratia marcescens]]'' cells were transferred to PDMS-coated coverslips, resulting in a structure referred to as a "bacterial carpet" by the authors. Differently shaped flat fragments of this bacterial carpets, termed "auto-mobile chips", moved above the surface of the microscope slide in two dimensions.<ref name=Darnton2004>{{cite journal |doi = 10.1016/S0006-3495(04)74253-8|title = Moving Fluid with Bacterial Carpets|year = 2004|last1 = Darnton|first1 = Nicholas|last2 = Turner|first2 = Linda|last3 = Breuer|first3 = Kenneth|last4 = Berg|first4 = Howard C.|journal = Biophysical Journal|volume = 86|issue = 3|pages = 1863–1870|pmid = 14990512|pmc = 1304020|bibcode = 2004BpJ....86.1863D}}</ref> Many other works have used ''[[Serratia marcescens]]'' swarming cells,<ref>{{cite book |doi = 10.1109/IEMBS.2006.259841|chapter = Towards Hybrid Swimming Microrobots: Bacteria Assisted Propulsion of Polystyrene Beads|title = 2006 International Conference of the IEEE Engineering in Medicine and Biology Society|year = 2006|last1 = Behkam|first1 = Bahareh|last2 = Sitti|first2 = Metin|volume = 2006|pages = 2421–2424|pmid = 17946113|isbn = 1-4244-0032-5|s2cid = 6409992}}</ref><ref>{{cite journal |doi = 10.1063/1.2752721|title = Control of microfabricated structures powered by flagellated bacteria using phototaxis|year = 2007|last1 = Steager|first1 = Edward|last2 = Kim|first2 = Chang-Beom|last3 = Patel|first3 = Jigarkumar|last4 = Bith|first4 = Socheth|last5 = Naik|first5 = Chandan|last6 = Reber|first6 = Lindsay|last7 = Kim|first7 = Min Jun|journal = Applied Physics Letters|volume = 90|issue = 26|page = 263901|bibcode = 2007ApPhL..90z3901S}}</ref><ref>{{cite journal |doi = 10.1177/0278364910394227|title = Modeling, control and experimental characterization of microbiorobots|year = 2011|last1 = Mahmut Selman Sakar|last2 = Steager|first2 = Edward B.|last3 = Dal Hyung Kim|last4 = Agung Julius|first4 = A.|last5 = Kim|first5 = Minjun|last6 = Kumar|first6 = Vijay|last7 = Pappas|first7 = George J.|journal = The International Journal of Robotics Research|volume = 30|issue = 6|pages = 647–658|s2cid = 36806}}</ref><ref>{{cite journal |doi = 10.1039/c000463d|title = Motility enhancement of bacteria actuated microstructures using selective bacteria adhesion|year = 2010|last1 = Park|first1 = Sung Jun|last2 = Bae|first2 = Hyeoni|last3 = Kim|first3 = Joonhwuy|last4 = Lim|first4 = Byungjik|last5 = Park|first5 = Jongoh|last6 = Park|first6 = Sukho|journal = Lab on a Chip|volume = 10|issue = 13|pages = 1706–1711|pmid = 20422075}}</ref><ref>{{cite journal |doi =  10.1103/PhysRevE.84.061908|title = Computational and experimental study of chemotaxis of an ensemble of bacteria attached to a microbead|year = 2011|last1 = Traoré|first1 = Mahama A.|last2 = Sahari|first2 = Ali|last3 = Behkam|first3 = Bahareh|journal = Physical Review E|volume = 84|issue = 6|page = 061908|pmid = 22304117|bibcode = 2011PhRvE..84f1908T|hdl = 10919/24901|hdl-access = free}}</ref><ref>{{cite journal |doi = 10.1109/TRO.2015.2504370|title = Electric Field Control of Bacteria-Powered Microrobots Using a Static Obstacle Avoidance Algorithm|year = 2016|last1 = Kim|first1 = Hoyeon|last2 = Kim|first2 = Min Jun|journal = IEEE Transactions on Robotics|volume = 32|pages = 125–137|s2cid = 15062290}}</ref> as well as ''E. coli'' swarming cells{{hsp}}<ref>{{cite journal |doi = 10.1002/adhm.201670097|title = Bacteria-Driven Particles: Patterned and Specific Attachment of Bacteria on Biohybrid Bacteria-Driven Microswimmers (Adv. Healthcare Mater. 18/2016)|year = 2016|last1 = Singh|first1 = Ajay Vikram|last2 = Sitti|first2 = Metin|journal = Advanced Healthcare Materials|volume = 5|issue = 18|page = 2306|doi-access = free}}</ref><ref name=Park2017>{{cite journal |doi = 10.1021/acsnano.7b03207|title = Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery|year = 2017|last1 = Park|first1 = Byung-Wook|last2 = Zhuang|first2 = Jiang|last3 = Yasa|first3 = Oncay|last4 = Sitti|first4 = Metin|journal = ACS Nano|volume = 11|issue = 9|pages = 8910–8923|pmid = 28873304}}</ref> for the development of hybrid microswimmers.<ref name=BastosArrieta2018 /> [[Magnetotactic bacteria]] have been the focus of different studies due to their versatile uses in biohybrid motion systems.<ref>Lu, Z., and Martel, S. (2006). "Preliminary investigation of bio-carriers using magnetotactic bacteria". In: ''Engineering in Medicine and Biology Society'', 2006. EMBS'06. 28th Annual International Conference of the IEEE (New York, NY: IEEE), 3415–3418.</ref><ref>{{cite journal |doi = 10.1021/cr078258w|title = Magnetotactic Bacteria and Magnetosomes|year = 2008|last1 = Faivre|first1 = Damien|last2 = Schüler|first2 = Dirk|journal = Chemical Reviews|volume = 108|issue = 11|pages = 4875–4898|pmid = 18855486}}</ref><ref>{{cite journal |doi = 10.1007/s10544-012-9696-x|title = Bacterial microsystems and microrobots|year = 2012|last1 = Martel|first1 = Sylvain|journal = Biomedical Microdevices|volume = 14|issue = 6|pages = 1033–1045|pmid = 22960952|s2cid = 2894776}}</ref><ref>{{cite journal |doi = 10.1021/nn5011304|title = Covalent Binding of Nanoliposomes to the Surface of Magnetotactic Bacteria for the Synthesis of Self-Propelled Therapeutic Agents|year = 2014|last1 = Taherkhani|first1 = Samira|last2 = Mohammadi|first2 = Mahmood|last3 = Daoud|first3 = Jamal|last4 = Martel|first4 = Sylvain|last5 = Tabrizian|first5 = Maryam|journal = ACS Nano|volume = 8|issue = 5|pages = 5049–5060|pmid = 24684397}}</ref><ref>{{cite journal |doi = 10.1016/j.bpj.2016.11.3052|title = Magneto-Aerotaxis: Bacterial Motility in Magnetic Fields|year = 2017|last1 = Klumpp|first1 = Stefan|last2 = Lefevre|first2 = Christopher|last3 = Landau|first3 = Livnat|last4 = Codutti|first4 = Agnese|last5 = Bennet|first5 = Mathieu|last6 = Faivre|first6 = Damien|journal = Biophysical Journal|volume = 112|issue = 3|pages = 567a|bibcode = 2017BpJ...112..567K|doi-access = free}}</ref><ref name=BastosArrieta2018 />

{{clear}}

==Protist biohybrids==
{{see also|Protist locomotion}}

===Algal===
[[File:Biohybrid Chlamydomonas reinhardtii microswimmers 2.jpg|thumb|upright=2| {{center|'''Biohybrid ''[[Chlamydomonas reinhardtii]]'' microswimmers'''{{hsp}}<ref name=Akolpoglu2020>{{cite journal |doi = 10.1002/advs.202001256|title = High-Yield Production of Biohybrid Microalgae for On-Demand Cargo Delivery|year = 2020|last1 = Akolpoglu|first1 = Mukrime Birgul|last2 = Dogan|first2 = Nihal Olcay|last3 = Bozuyuk|first3 = Ugur|last4 = Ceylan|first4 = Hakan|last5 = Kizilel|first5 = Seda|last6 = Sitti|first6 = Metin|journal = Advanced Science|volume = 7|issue = 16|pmid = 32832367|pmc = 7435244}} [[File:CC-BY icon.svg|50px]] Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref>}} Top: Schematics of production steps for biohybrid ''C. reinhardtii''.<br />Bottom: SEM images of bare microalgae (left) and biohybrid microalgae (right) coated with chitosan-coated iron oxide nanoparticles (CSIONPs). Images were pseudocolored. A darker green color on the right SEM image represents chitosan coating on microalgae cell wall. Orange-colored particles represents CSIONPs.]]

''[[Chlamydomonas reinhardtii]]'' is a unicellular green [[microalga]]. The wild-type ''C. reinhardtii'' has a spherical shape that averages about 10&nbsp;μm in diameter.<ref name=Harris2001>{{cite journal |doi = 10.1146/annurev.arplant.52.1.363|title = Chlamydomonasas Amodelorganism|year = 2001|last1 = Harris|first1 = Elizabeth H.|journal = Annual Review of Plant Physiology and Plant Molecular Biology|volume = 52|pages = 363–406|pmid = 11337403}}</ref> This microorganism can perceive the visible light and be steered by it (i.e., [[phototaxis]]) with high swimming speeds in the range of 100–200&nbsp;μm s<sup>−1</sup>.<ref name=Yasa2018 /> It has natural [[autofluorescence]] that permits label-free fluorescent imaging.<ref name=Harris2001 /> ''C. reinhardtii'' has been actively explored as the live component of biohybrid microrobots for the active delivery of therapeutics.<ref name=Yasa2018 /> They are biocompatible with healthy mammalian cells, leave no known toxins, mobile in the physiologically relevant media, and allow for surface modification to carry cargo on the cell wall.<ref name=Yasa2018 /><ref name=Weibel2005>{{cite journal |doi = 10.1073/pnas.0505481102|title = Microoxen: Microorganisms to move microscale loads|year = 2005|last1 = Weibel|first1 = D. B.|last2 = Garstecki|first2 = P.|last3 = Ryan|first3 = D.|last4 = Diluzio|first4 = W. R.|last5 = Mayer|first5 = M.|last6 = Seto|first6 = J. E.|last7 = Whitesides|first7 = G. M.|journal = Proceedings of the National Academy of Sciences|volume = 102|issue = 34|pages = 11963–11967|pmid = 16103369|pmc = 1189341|bibcode = 2005PNAS..10211963W| doi-access=free }}</ref><ref>{{cite journal |doi = 10.1016/j.actbio.2013.12.055|title = Development of photosynthetic biomaterials for in vitro tissue engineering|year = 2014|last1 = Hopfner|first1 = Ursula|last2 = Schenck|first2 = Thilo-Ludwig|last3 = Chávez|first3 = Myra-Noemi|last4 = Machens|first4 = Hans-Günther|last5 = Bohne|first5 = Alexandra-Viola|last6 = Nickelsen|first6 = Jörg|last7 = Giunta|first7 = Riccardo-Enzo|last8 = Egaña|first8 = José-Tomás|journal = Acta Biomaterialia|volume = 10|issue = 6|pages = 2712–2717|pmid = 24406198}}</ref><ref>{{cite journal |doi = 10.1016/j.actbio.2018.09.060|title = Development of photosynthetic sutures for the local delivery of oxygen and recombinant growth factors in wounds|year = 2018|last1 = Centeno-Cerdas|first1 = Carolina|last2 = Jarquín-Cordero|first2 = Montserrat|last3 = Chávez|first3 = Myra Noemi|last4 = Hopfner|first4 = Ursula|last5 = Holmes|first5 = Christopher|last6 = Schmauss|first6 = Daniel|last7 = Machens|first7 = Hans-Günther|last8 = Nickelsen|first8 = Jörg|last9 = Egaña|first9 = José Tomás|journal = Acta Biomaterialia|volume = 81|pages = 184–194|pmid = 30287280| s2cid=52922420 }}</ref><ref>{{cite journal |doi = 10.1016/j.actbio.2014.12.012|title = Photosynthetic biomaterials: A pathway towards autotrophic tissue engineering|year = 2015|last1 = Schenck|first1 = Thilo Ludwig|last2 = Hopfner|first2 = Ursula|last3 = Chávez|first3 = Myra Noemi|last4 = Machens|first4 = Hans-Günther|last5 = Somlai-Schweiger|first5 = Ian|last6 = Giunta|first6 = Riccardo Enzo|last7 = Bohne|first7 = Alexandra Viola|last8 = Nickelsen|first8 = Jörg|last9 = Allende|first9 = Miguel L.|last10 = Egaña|first10 = José Tomás|journal = Acta Biomaterialia|volume = 15|pages = 39–47|pmid = 25536030}}</ref> Alternative attachment strategies for ''C. reinhardtii'' have been proposed for the assembly through modifying the interacting surfaces by electrostatic interactions<ref name=Yasa2018 /><ref name=Weibel2005 /> and covalent bonding.<ref>{{cite journal |doi = 10.1021/acs.langmuir.8b01210|title = Artificial Magnetotaxis of Microbot: Magnetophoresis versus Self-Swimming|year = 2018|last1 = Ng|first1 = Wei Ming|last2 = Che|first2 = Hui Xin|last3 = Guo|first3 = Chen|last4 = Liu|first4 = Chunzhao|last5 = Low|first5 = Siew Chun|last6 = Chieh Chan|first6 = Derek Juinn|last7 = Mohamud|first7 = Rohimah|last8 = Lim|first8 = Jitkang|journal = Langmuir|volume = 34|issue = 27|pages = 7971–7980|pmid = 29882671| s2cid=46953567 }}</ref>
<ref name=Akolpoglu2020 />

===Robocoliths===
[[File:Robocolith hybrids combining polydopamine and coccoliths.jpg|thumb|upright=2| {{center|'''Robocolith hybrids combining polydopamine and coccoliths'''{{hsp}}<ref name=Lomora2010 />}}  EHUX coccolithophores are cultivated for isolation of coccoliths. When coccoliths (asymmetric morphology) are exposed to light, no collective motion is observed. Coccoliths are then mixed gently with dopamine solutions. Thus, polydopamine-coated coccoliths hybrids are obtained as a basis for design of Robocoliths. Light excitation and the asymmetry of Robocoliths generates a thermal flux of heat because of polydopamine's photothermal properties. Coupling of convection from neighboring Robocoliths transforms their movement into an aggregated collective motion. Robocolith functionalization is also proposed to prevent and control nonspecific attachment of biomacromolecules and possible diminution of the aggregation.]]

[[File:Asymmetric architecture of coccolith morphology.jpg|thumb|upright=2| {{center|'''Asymmetric architecture of coccolith morphology'''{{hsp}}<ref name=Lomora2010>{{cite journal |doi = 10.1016/j.xcrp.2021.100373|title = An engineered coccolith-based hybrid that transforms light into swarming motion|year = 2021|last1 = Lomora|first1 = Mihai|last2 = Larrañaga|first2 = Aitor|last3 = Rodriguez-Emmenegger|first3 = Cesar|last4 = Rodriguez|first4 = Brian|last5 = Dinu|first5 = Ionel Adrian|last6 = Sarasua|first6 = Jose-Ramon|last7 = Pandit|first7 = Abhay|journal = Cell Reports Physical Science|volume = 2|issue = 3|page = 100373|bibcode = 2021CRPS....200373L|s2cid = 233687429|hdl = 10810/52638|hdl-access = free}} [[File:CC-BY icon.svg|50px]] Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref>}} (A) EHUX coccolithophores were cultivated successfully and visualized by SEM (scale bar, 4 μm).
<br />(B) Following this, we broke and removed the cellular material from EHUX coccolithophores to isolate multiple (top; scale bar, 20 μm) and individual (bottom; scale bar, 1 μm) coccoliths, as visualized by SEM.
<br />(C) AFM image of an individual coccolith. Micrograph size, 4 × 4 μm.
<br />(D) AFM magnification the micrograph of an individual coccolith. Scale bar, 400&nbsp;nm.
<br />(E) Illustration of a coccolith, depicting its specific morphological parameters.
<br />(F) Typical plotted values of the specific morphological parameters. Data are represented as mean ± SD (n = 55), where n is the number of coccoliths visualized by TEM.]]

[[Collective motion]] is one of the hallmarks of life.<ref name=Vicsek2012 /> In contrast to what is accomplished individually, multiple entities enable local interactions between each participant to occur in proximity. If we consider each participant in the collective behaviour as a (bio)physical [[transducer]], then the energy will be converted from one type into another. The [[proxemic]]s will then favour enhanced communication between neighbouring individuals via transduction of energy, leading to dynamic and complex [[synergetic]] behaviours of the composite powered structure.<ref>{{cite journal |doi = 10.1103/PhysRevX.8.031056|title = Collective Power: Minimal Model for Thermodynamics of Nonequilibrium Phase Transitions|year = 2018|last1 = Herpich|first1 = Tim|last2 = Thingna|first2 = Juzar|last3 = Esposito|first3 = Massimiliano|journal = Physical Review X|volume = 8|issue = 3|page = 031056|arxiv = 1802.00461|bibcode = 2018PhRvX...8c1056H|s2cid = 89610765}}</ref><ref name=Lomora2010 />

In recent years [[nanoscopic]] and [[Wiktionary:mesoscopic|mesoscopic]] objects have been designed to collectively move through direct inspiration from nature or by harnessing its existing tools.<ref>{{cite journal |doi = 10.1021/acsnano.5b03367|title = Controlling Motion at the Nanoscale: Rise of the Molecular Machines|year = 2015|last1 = Abendroth|first1 = John M.|last2 = Bushuyev|first2 = Oleksandr S.|last3 = Weiss|first3 = Paul S.|last4 = Barrett|first4 = Christopher J.|journal = ACS Nano|volume = 9|issue = 8|pages = 7746–7768|pmid = 26172380|doi-access = free}}</ref><ref>{{cite journal |doi = 10.1016/j.nantod.2013.08.009|title = Small power: Autonomous nano- and micromotors propelled by self-generated gradients|year = 2013|last1 = Wang|first1 = Wei|last2 = Duan|first2 = Wentao|last3 = Ahmed|first3 = Suzanne|last4 = Mallouk|first4 = Thomas E.|last5 = Sen|first5 = Ayusman|journal = Nano Today|volume = 8|issue = 5|pages = 531–554}}</ref><ref>{{cite journal |doi = 10.3390/mi9020088|doi-access = free|title = Light-Controlled Swarming and Assembly of Colloidal Particles|year = 2018|last1 = Zhang|first1 = Jianhua|last2 = Guo|first2 = Jingjing|last3 = Mou|first3 = Fangzhi|last4 = Guan|first4 = Jianguo|journal = Micromachines|volume = 9|issue = 2|page = 88|pmid = 30393364|pmc = 6187466}}</ref><ref>{{cite journal |doi = 10.1038/nmat4761|title = Controlled collective motions|year = 2016|last1 = Di Leonardo|first1 = Roberto|journal = Nature Materials|volume = 15|issue = 10|pages = 1057–1058|pmid = 27658450}}</ref> Such [[robotic swarm]]s were categorised by an online expert panel as among the 10 great unresolved group challenges in the area of [[robotic]]s.<ref>{{cite journal |doi = 10.1126/scirobotics.aar7650|title = The grand challenges of ''Science'' Robotics|year = 2018|last1 = Yang|first1 = Guang-Zhong|last2 = Bellingham|first2 = Jim|last3 = Dupont|first3 = Pierre E.|last4 = Fischer|first4 = Peer|last5 = Floridi|first5 = Luciano|last6 = Full|first6 = Robert|last7 = Jacobstein|first7 = Neil|last8 = Kumar|first8 = Vijay|last9 = McNutt|first9 = Marcia|last10 = Merrifield|first10 = Robert|last11 = Nelson|first11 = Bradley J.|last12 = Scassellati|first12 = Brian|last13 = Taddeo|first13 = Mariarosaria|last14 = Taylor|first14 = Russell|last15 = Veloso|first15 = Manuela|last16 = Wang|first16 = Zhong Lin|last17 = Wood|first17 = Robert|journal = Science Robotics|volume = 3|issue = 14|pages = eaar7650|pmid = 33141701|s2cid = 3800579|doi-access = free}}</ref> Although investigation of their underlying mechanism of action is still in its infancy, various systems have been developed that are capable of undergoing controlled and uncontrolled swarming motion by harvesting energy (e.g., light, thermal, etc.).<ref>{{cite journal |doi = 10.1021/acs.accounts.5b00025|title = From One to Many: Dynamic Assembly and Collective Behavior of Self-Propelled Colloidal Motors|year = 2015|last1 = Wang|first1 = Wei|last2 = Duan|first2 = Wentao|last3 = Ahmed|first3 = Suzanne|last4 = Sen|first4 = Ayusman|last5 = Mallouk|first5 = Thomas E.|journal = Accounts of Chemical Research|volume = 48|issue = 7|pages = 1938–1946|pmid = 26057233}}</ref> Importantly, this energy should be transformed into a net force for the system to move.<ref name=Lomora2010 />

Small mesoscopic to nanoscopic systems typically operate at low [[Reynolds number]]s (Re ≪ 1), and understanding their motion becomes challenging.<ref>Nelson P.C. (2003) "Life in the slow lane: The low Reynolds-number world", In: ''Biological Physics: Energy, Information, Life,'' by W.H. Freeman, pages 158–194.</ref> For locomotion to occur, the symmetry of the system must be broken.14 In addition, collective motion requires a coupling mechanism between the entities that make up the collective.<ref name=Lomora2010 />

To develop mesoscopic to nanoscopic entities capable of swarming behaviour, it has been hypothesised that the entities are characterised by broken symmetry with a well-defined morphology, and are powered with some material capable of harvesting energy. If the harvested energy results in a field surrounding the object, then this field can couple with the field of a neighbouring object and bring some coordination to the collective behaviour.<ref name=Lomora2010 />

''[[Emiliania huxleyi]]'' (EHUX) [[coccolithophore]]-derived asymmetric [[coccolith]]s stand out as candidates for the choice of a nano/mesoscopic object with broken symmetry and well-defined morphology. Besides the thermodynamical stability because of their [[calcite]] composition,<ref>Karunadasa K.S.P., C.H. Manoratne, H.M.T.G.A. Pitawala and R.M.G. Rajapakse (2019) "Thermal decomposition of calcium carbonate (calcite polymorph) as examined by in-situ high-temperature X-ray powder diffraction", ''J. Phys. Chem. Solids'', '''134''': 21–28.</ref> the critical advantage of EHUX coccoliths is their distinctive and sophisticated asymmetric morphology. EHUX coccoliths are characterised by several hammer-headed ribs placed to form a proximal and distal disc connected by a central ring. These discs have different sizes but also allow the coccolith to have a curvature, partly resembling a wagon wheel.<ref>{{cite journal |doi = 10.1364/OE.21.017625|title = Inherent optical properties of the coccolithophore: Emiliania huxleyi|year = 2013|last1 = Zhai|first1 = Peng-Wang|last2 = Hu|first2 = Yongxiang|last3 = Trepte|first3 = Charles R.|last4 = Winker|first4 = David M.|last5 = Josset|first5 = Damien B.|last6 = Lucker|first6 = Patricia L.|last7 = Kattawar|first7 = George W.|journal = Optics Express|volume = 21|issue = 15|pages = 17625–17638|pmid = 23938635|bibcode = 2013OExpr..2117625Z|doi-access = free|hdl = 11603/24962|hdl-access = free}}</ref> EHUX coccoliths can be isolated from EHUX coccolithophores, a unique group of unicellular [[marine algae]] that are the primary producers of [[biogenic]] calcite in the ocean.<ref>{{cite journal |doi = 10.1038/ncomms10284|title = Decrease in coccolithophore calcification and CO2 since the middle Miocene|year = 2016|last1 = Bolton|first1 = Clara T.|last2 = Hernández-Sánchez|first2 = María T.|last3 = Fuertes|first3 = Miguel-Ángel|last4 = González-Lemos|first4 = Saúl|last5 = Abrevaya|first5 = Lorena|last6 = Mendez-Vicente|first6 = Ana|last7 = Flores|first7 = José-Abel|last8 = Probert|first8 = Ian|last9 = Giosan|first9 = Liviu|last10 = Johnson|first10 = Joel|last11 = Stoll|first11 = Heather M.|journal = Nature Communications|volume = 7|page = 10284|pmid = 26762469|pmc = 4735581|bibcode = 2016NatCo...710284B}}</ref> Coccolithophores can intracellularly produce intricate three-dimensional mineral structures, such as calcium carbonate scales (i.e., coccoliths), in a process that is driven continuously by a specialized vesicle.<ref>{{cite journal |doi = 10.1021/cr8002856|title = Controlling Mineral Morphologies and Structures in Biological and Synthetic Systems|year = 2008|last1 = Meldrum|first1 = Fiona C.|last2 = Cölfen|first2 = Helmut|journal = Chemical Reviews|volume = 108|issue = 11|pages = 4332–4432|pmid = 19006397}}</ref>

[[File:Emiliania huxleyi.jpg|thumb|left| {{center|''[[Emiliania huxleyi]]'' protected with asymmetric [[coccolith]]s}}]]

After the process is finished, the formed coccoliths are secreted to the cell surface, where they form the exoskeleton (i.e., [[coccosphere]]). The broad diversity of coccolith architecture results in further possibilities for specific applications in nanotechnology{{hsp}}<ref>{{cite journal |doi = 10.1016/j.copbio.2017.07.013|title = Exploiting algal mineralization for nanotechnology: Bringing coccoliths to the fore|year = 2018|last1 = Skeffington|first1 = Alastair W.|last2 = Scheffel|first2 = André|journal = Current Opinion in Biotechnology|volume = 49|pages = 57–63|pmid = 28822276|doi-access = free}}</ref> or biomedicine.<ref>{{cite journal |doi = 10.1002/adtp.201800099|title = Therapeutic Applications of Phytoplankton, with an Emphasis on Diatoms and Coccolithophores|year = 2019|last1 = Lomora|first1 = Mihai|last2 = Shumate|first2 = David|last3 = Rahman|first3 = Asrizal Abdul|last4 = Pandit|first4 = Abhay|journal = Advanced Therapeutics|volume = 2|issue = 2|s2cid = 139596031}}</ref> Inanimate coccoliths from EHUX live coccolithophores, in particular, can be isolated easily in the laboratory with a low culture cost and fast reproductive rate and have a reasonably moderate surface area (~20 m<sup>2</sup>/g) exhibiting a mesoporous structure (pore size in the range of 4&nbsp;nm).<ref>{{cite journal |doi = 10.1002/elsc.201600183|title = Biogenic calcite particles from microalgae-Coccoliths as a potential raw material|year = 2017|last1 = Jakob|first1 = Ioanna|last2 = Chairopoulou|first2 = Makrina Artemis|last3 = Vučak|first3 = Marijan|last4 = Posten|first4 = Clemens|last5 = Teipel|first5 = Ulrich|journal = Engineering in Life Sciences|volume = 17|issue = 6|pages = 605–612|pmid = 28701909|pmc = 5484330| bibcode=2017EngLS..17..605J }}</ref><ref name=Lomora2010 />

Presumably, if harvesting of energy is done on both sides of the EHUX coccolith, then it will allow generation of a net force, which means movement in a directional manner. Coccoliths have immense potential for a multitude of applications, but to enable harvesting of energy, their surface properties must be finely tuned.<ref>{{cite journal |doi = 10.1016/j.bios.2018.08.021|title = A new coccolith modified electrode-based biosensor using a cognate pair of aptamers with sandwich-type binding|year = 2019|last1 = Kim|first1 = Sang Hoon|last2 = Nam|first2 = Onyou|last3 = Jin|first3 = Eonseon|last4 = Gu|first4 = Man Bock|journal = Biosensors and Bioelectronics|volume = 123|pages = 160–166|pmid = 30139622| s2cid=206176301 }}</ref> Inspired by the composition of adhesive proteins in mussels, dopamine self-polymerization into polydopamine is currently the most versatile functionalization strategy for virtually all types of materials.<ref>{{cite journal |doi = 10.1126/science.1147241|title = Mussel-Inspired Surface Chemistry for Multifunctional Coatings|year = 2007|last1 = Lee|first1 = H.|last2 = Dellatore|first2 = S. M.|last3 = Miller|first3 = W. M.|last4 = Messersmith|first4 = P. B.|journal = Science|volume = 318|issue = 5849|pages = 426–430|pmid = 17947576|pmc = 2601629|bibcode = 2007Sci...318..426L}}</ref> Because of its surface chemistry and wide range of light absorption properties, polydopamine is an ideal choice for aided energy harvesting function on inert substrates.<ref>{{cite journal |doi = 10.1021/acsami.7b19865|title = Polydopamine Surface Chemistry: A Decade of Discovery|year = 2018|last1 = Ryu|first1 = Ji Hyun|last2 = Messersmith|first2 = Phillip B.|last3 = Lee|first3 = Haeshin|journal = ACS Applied Materials & Interfaces|volume = 10|issue = 9|pages = 7523–7540|pmid = 29465221|pmc = 6320233}}</ref><ref>{{cite journal |doi = 10.1021/acsami.8b02929|title = Ten Years of Polydopamine: Current Status and Future Directions|year = 2018|last1 = Schanze|first1 = Kirk S.|last2 = Lee|first2 = Haeshin|last3 = Messersmith|first3 = Phillip B.|journal = ACS Applied Materials & Interfaces|volume = 10|issue = 9|pages = 7521–7522|pmid = 29510631|doi-access = free}}</ref><ref>{{cite journal |doi = 10.1021/cr400407a|title = Polydopamine and Its Derivative Materials: Synthesis and Promising Applications in Energy, Environmental, and Biomedical Fields|year = 2014|last1 = Liu|first1 = Yanlan|last2 = Ai|first2 = Kelong|last3 = Lu|first3 = Lehui|journal = Chemical Reviews|volume = 114|issue = 9|pages = 5057–5115|pmid = 24517847}}</ref> In this work, we aim to exploit the benefits of polydopamine coating to provide advanced energy harvesting functionalities to the otherwise inert and inanimate coccoliths. Polydopamine (PDA has already been shown to induce movement of polystyrene beads because of thermal diffusion effects between the object and the surrounding aqueous solution of up to 2&nbsp;°C under near-infrared (NIR) light excitation.<ref>{{cite journal |doi = 10.1021/acsami.9b14402|title = Calligraphy/Painting Based on a Bioinspired Light-Driven Micromotor with Concentration-Dependent Motion Direction Reversal and Dynamic Swarming Behavior|year = 2019|last1 = Sun|first1 = Yunyu|last2 = Liu|first2 = Ye|last3 = Zhang|first3 = Dongmei|last4 = Zhang|first4 = Hui|last5 = Jiang|first5 = Jiwei|last6 = Duan|first6 = Ruomeng|last7 = Xiao|first7 = Jie|last8 = Xing|first8 = Jingjing|last9 = Zhang|first9 = Dafeng|last10 = Dong|first10 = Bin|journal = ACS Applied Materials & Interfaces|volume = 11|issue = 43|pages = 40533–40542|pmid = 31577118| s2cid=203638540 }}</ref> However, no collective behavior has been reported. Here, we prove, for the first time, that polydopamine can act as an active component to induce, under visible light (300–600&nbsp;nm), collective behavior of a structurally complex, natural, and challenging-to-control architecture such as coccoliths. As a result, the organic-inorganic hybrid combination (coccolith-polydopamine) would enable design of Robocoliths.<ref name=Lomora2010 />

Dopamine polymerization proceeds in a solution, where it forms small colloidal aggregates that adsorb on the surface of the coccoliths, forming a confluent film. This film is characterized by high roughness, which translates into a high specific surface area and enhanced harvesting of energy. Because of the conjugated nature of the polymer backbone, polydopamine can absorb light over a broad electromagnetic spectrum, including the visible region.<ref name=Lomora2010 />

As a result, the surface of coccoliths is endowed with a photothermal effect, locally heating and creating convection induced by the presence of PDA. This local convection is coupled with another nearby local convection, which allows coupling between individual Robocoliths, enabling their collective motion (Figure 1).<ref name=Lomora2010 />

Therefore, when the light encounters the anisometric Robocoliths, they heat locally because of the photothermal conversion induced by the presence of PDA on their surface. The intense local heating produces convection that is different on either side of the Robocolith, causing its observed movement. Such convection can couple with the convection of a neighboring Robocolith, resulting in a "swarming" motion. In addition, the surface of Robocoliths is engineered to accommodate antifouling polymer brushes and potentially prevent their aggregation. Although a primary light-activated convective approach is taken as a first step to understand the motion of Robocoliths, a multitude of mechanistic approaches are currently being developed to pave the way for the next generation of multifunctional Robocoliths as swarming bio-micromachines.<ref name=Lomora2010 />
{{clear}}

==Biomedical applications==
[[File:Biohybrid bacterial microswimmers.jpg|thumb|upright=2| {{center|'''Biohybrid bacterial microswimmers'''{{hsp}}<ref name= Buss2020>{{cite journal |doi = 10.1063/1.5130670|title = Nanoerythrosome-functionalized biohybrid microswimmers|year = 2020|last1 = Buss|first1 = Nicole|last2 = Yasa|first2 = Oncay|last3 = Alapan|first3 = Yunus|last4 = Akolpoglu|first4 = Mukrime Birgul|last5 = Sitti|first5 = Metin|journal = APL Bioengineering|volume = 4|issue = 2|page = 026103|pmid = 32548539|pmc = 7141839}} [[File:CC-BY icon.svg|50px]] Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref>}}]]

[[File:Bio-inspired hybrid multifunctional drug delivery system (cropped).png|thumb|upright=2| {{center|'''Biohybrid diatomite microswimmer drug delivery system'''}} Diatom frustule surface functionalised with photoactivable molecules (orange spheres) linked to vitamin B-12 (red sphere) acting as a tumor-targeting tag. The system can be loaded with chemotherapeutic drugs (light blue spheres), which can be selectively delivered to colorectal cancer cells. In addition, diatomite microparticles can be photoactivated to generate carbon monoxide or free radicals inducing tumor cell apoptosis.<ref name=Delasoie2020>{{cite journal | last1=Delasoie | first1=Joachim | last2=Schiel | first2=Philippe | last3=Vojnovic | first3=Sandra | last4=Nikodinovic-Runic | first4=Jasmina | last5=Zobi | first5=Fabio | title=Photoactivatable Surface-Functionalized Diatom Microalgae for Colorectal Cancer Targeted Delivery and Enhanced Cytotoxicity of Anticancer Complexes | journal=Pharmaceutics | publisher=MDPI AG | volume=12 | issue=5 | date=25 May 2020 | issn=1999-4923 | doi=10.3390/pharmaceutics12050480|pmc=7285135 | page=480| pmid=32466116 | doi-access=free }} [[File:CC-BY icon.svg|50px]] Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref><ref name=Tramontano2020>{{cite journal | last1=Tramontano | first1=Chiara | last2=Chianese | first2=Giovanna | last3=Terracciano | first3=Monica | last4=de Stefano | first4=Luca | last5=Rea | first5=Ilaria | title=Nanostructured Biosilica of Diatoms: From Water World to Biomedical Applications | journal=Applied Sciences | publisher=MDPI AG | volume=10 | issue=19 | date=2020-09-28 | issn=2076-3417 | doi=10.3390/app10196811 | page=6811| doi-access=free }} [[File:CC-BY icon.svg|50px]] Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref>]]

Biohybrid microswimmers, mainly composed of integrated biological actuators and synthetic cargo carriers, have recently shown promise toward minimally invasive [[Theranostics|theranostic applications]].<ref>{{cite journal |doi = 10.1016/j.addr.2016.09.007|title = Bioengineered and biohybrid bacteria-based systems for drug delivery|year = 2016|last1 = Hosseinidoust|first1 = Zeinab|last2 = Mostaghaci|first2 = Babak|last3 = Yasa|first3 = Oncay|last4 = Park|first4 = Byung-Wook|last5 = Singh|first5 = Ajay Vikram|last6 = Sitti|first6 = Metin|journal = Advanced Drug Delivery Reviews|volume = 106|issue = Pt A|pages = 27–44|pmid = 27641944}}</ref><ref>{{cite journal |doi = 10.1063/1.4993441|title = Hybrid Bio ''Micromotors''|year = 2017|last1 = Schwarz|first1 = Lukas|last2 = Medina-Sánchez|first2 = Mariana|last3 = Schmidt|first3 = Oliver G.|journal = Applied Physics Reviews|volume = 4|issue = 3|page = 031301|bibcode = 2017ApPRv...4c1301S|doi-access = free}}</ref><ref>{{cite journal |doi = 10.3389/frobt.2018.00097|doi-access = free|title = Bacterial Biohybrid Microswimmers|year = 2018|last1 = Bastos-Arrieta|first1 = Julio|last2 = Revilla-Guarinos|first2 = Ainhoa|last3 = Uspal|first3 = William E.|last4 = Simmchen|first4 = Juliane|journal = Frontiers in Robotics and AI|volume = 5|page = 97|pmid = 33500976|pmc = 7805739}}</ref><ref name="Mobile Microrobots for Active Thera"/> Various microorganisms, including bacteria,<ref name="Park2017"/><ref name="Microemulsion-Based Soft Bacteria-D"/> [[microalgae]],<ref>{{cite journal |doi = 10.1073/pnas.0505481102|title = Microoxen: Microorganisms to move microscale loads|year = 2005|last1 = Weibel|first1 = D. B.|last2 = Garstecki|first2 = P.|last3 = Ryan|first3 = D.|last4 = Diluzio|first4 = W. R.|last5 = Mayer|first5 = M.|last6 = Seto|first6 = J. E.|last7 = Whitesides|first7 = G. M.|journal = Proceedings of the National Academy of Sciences|volume = 102|issue = 34|pages = 11963–11967|pmid = 16103369|pmc = 1189341|bibcode = 2005PNAS..10211963W|doi-access = free}}</ref><ref name="Yasa2018"/> and [[spermatozoid]]s,<ref>{{cite journal |doi = 10.1021/acsnano.7b06398|title = Sperm-Hybrid Micromotor for Targeted Drug Delivery|year = 2018|last1 = Xu|first1 = Haifeng|last2 = Medina-Sánchez|first2 = Mariana|last3 = Magdanz|first3 = Veronika|last4 = Schwarz|first4 = Lukas|last5 = Hebenstreit|first5 = Franziska|last6 = Schmidt|first6 = Oliver G.|journal = ACS Nano|volume = 12|issue = 1|pages = 327–337|pmid = 29202221|doi-access = free|arxiv = 1703.08510}}</ref><ref>{{cite journal |doi = 10.1002/adbi.201700160|title = Chemotactic Guidance of Synthetic Organic/Inorganic Payloads Functionalized Sperm Micromotors|year = 2018|last1 = Chen|first1 = Chuanrui|last2 = Chang|first2 = Xiaocong|last3 = Angsantikul|first3 = Pavimol|last4 = Li|first4 = Jinxing|last5 = Esteban-Fernández De Ávila|first5 = Berta|last6 = Karshalev|first6 = Emil|last7 = Liu|first7 = Wenjuan|last8 = Mou|first8 = Fangzhi|last9 = He|first9 = Sha|last10 = Castillo|first10 = Roxanne|last11 = Liang|first11 = Yuyan|last12 = Guan|first12 = Jianguo|last13 = Zhang|first13 = Liangfang|last14 = Wang|first14 = Joseph|journal = Advanced Biosystems|volume = 2|s2cid = 103392074|doi-access = free}}</ref> have been utilised to fabricate different biohybrid microswimmers with advanced medical functionalities, such as autonomous control with environmental stimuli for targeting, navigation through narrow gaps, and accumulation to necrotic regions of tumor environments.<ref name=Alapan2019>{{cite journal |doi = 10.1146/annurev-control-053018-023803|title = Microrobotics and Microorganisms: Biohybrid Autonomous Cellular Robots|year = 2019|last1 = Alapan|first1 = Yunus|last2 = Yasa|first2 = Oncay|last3 = Yigit|first3 = Berk|last4 = Yasa|first4 = I. Ceren|last5 = Erkoc|first5 = Pelin|last6 = Sitti|first6 = Metin|journal = Annual Review of Control, Robotics, and Autonomous Systems|volume = 2|pages = 205–230|s2cid = 139819519}}</ref> Steerability of the synthetic cargo carriers with long-range applied external fields, such as acoustic or magnetic fields,<ref name=Wu2014>{{cite journal |doi = 10.1021/nn506200x|title = Turning Erythrocytes into Functional Micromotors|year = 2014|last1 = Wu|first1 = Zhiguang|last2 = Li|first2 = Tianlong|last3 = Li|first3 = Jinxing|last4 = Gao|first4 = Wei|last5 = Xu|first5 = Tailin|last6 = Christianson|first6 = Caleb|last7 = Gao|first7 = Weiwei|last8 = Galarnyk|first8 = Michael|last9 = He|first9 = Qiang|last10 = Zhang|first10 = Liangfang|last11 = Wang|first11 = Joseph|journal = ACS Nano|volume = 8|issue = 12|pages = 12041–12048|pmid = 25415461|pmc = 4386663}}</ref><ref name=Alapan2018>{{cite journal |doi = 10.1126/scirobotics.aar4423|title = Soft erythrocyte-based bacterial microswimmers for cargo delivery|year = 2018|last1 = Alapan|first1 = Yunus|last2 = Yasa|first2 = Oncay|last3 = Schauer|first3 = Oliver|last4 = Giltinan|first4 = Joshua|last5 = Tabak|first5 = Ahmet F.|last6 = Sourjik|first6 = Victor|last7 = Sitti|first7 = Metin|journal = Science Robotics|volume = 3|issue = 17|pmid = 33141741|s2cid = 14003685|doi-access = free}}</ref> and intrinsic [[taxis|taxis behaviours]] of the biological actuators toward various environmental stimuli, such as [[chemoattractant]]s,<ref>{{cite journal |doi = 10.1038/srep32135|title = Chemotaxis of bio-hybrid multiple bacteria-driven microswimmers|year = 2016|last1 = Zhuang|first1 = Jiang|last2 = Sitti|first2 = Metin|journal = Scientific Reports|volume = 6|page = 32135|pmid = 27555465|pmc = 4995368|bibcode = 2016NatSR...632135Z}}</ref> [[pH]], and oxygen,<ref>{{cite journal |doi = 10.1038/srep11403|title = PH-Taxis of Biohybrid Microsystems|year = 2015|last1 = Zhuang|first1 = Jiang|last2 = Wright Carlsen|first2 = Rika|last3 = Sitti|first3 = Metin|journal = Scientific Reports|volume = 5|page = 11403|pmid = 26073316|pmc = 4466791|bibcode = 2015NatSR...511403Z}}</ref><ref name="Magneto-aerotactic bacteria deliver"/> make biohybrid microswimmers a promising candidate for a broad range of medical active cargo delivery applications.<ref name=Alapan2019 /><ref name= Buss2020 />

Bacteria have a high swimming speed and efficiency in the low Reynolds (Re) number flow regime, are capable of sensing and responding to external environmental signals, and could be externally detected via fluorescence or ultrasound imaging techniques.<ref>{{cite journal |doi = 10.1038/nrc2934|title = Engineering the perfect (Bacterial) cancer therapy|year = 2010|last1 = Forbes|first1 = Neil S.|journal = Nature Reviews Cancer|volume = 10|issue = 11|pages = 785–794|pmid = 20944664|pmc = 3756932}}</ref><ref>{{cite journal |doi = 10.1016/j.tibtech.2017.04.008|title = Pushing Bacterial Biohybrids to in Vivo Applications|year = 2017|last1 = Stanton|first1 = Morgan M.|last2 = Sánchez|first2 = Samuel|journal = Trends in Biotechnology|volume = 35|issue = 10|pages = 910–913|pmid = 28501457|hdl = 2445/123484|hdl-access = free}}</ref><ref>{{cite journal |doi = 10.1038/nature25021|title = Acoustic reporter genes for noninvasive imaging of microorganisms in mammalian hosts|year = 2018|last1 = Bourdeau|first1 = Raymond W.|last2 = Lee-Gosselin|first2 = Audrey|last3 = Lakshmanan|first3 = Anupama|last4 = Farhadi|first4 = Arash|last5 = Kumar|first5 = Sripriya Ravindra|last6 = Nety|first6 = Suchita P.|last7 = Shapiro|first7 = Mikhail G.|journal = Nature|volume = 553|issue = 7686|pages = 86–90|pmid = 29300010|pmc = 5920530|bibcode = 2018Natur.553...86B}}</ref> Due to their inherent sensing capabilities, various bacteria species have been investigated as potential anti-tumor agents and have been the subject of preclinical and clinical trials.<ref>Cann, S.H., Van Netten, J.P. and Van Netten, C. (2003) [https://pmj.bmj.com/content/79/938/672.short "Dr William Coley and tumour regression: a place in history or in the future"], ''Postgraduate Medical Journal'', '''79'''(938): 672-680.</ref><ref>{{cite journal |doi = 10.1111/1751-7915.12787|title = Tumour-targeting bacteria-based cancer therapies for increased specificity and improved outcome|year = 2017|last1 = Felgner|first1 = Sebastian|last2 = Pawar|first2 = Vinay|last3 = Kocijancic|first3 = Dino|last4 = Erhardt|first4 = Marc|last5 = Weiss|first5 = Siegfried|journal = Microbial Biotechnology|volume = 10|issue = 5|pages = 1074–1078|pmid = 28771926|pmc = 5609243}}</ref><ref>{{cite journal |doi = 10.1016/S0022-5347(17)58737-6|title = Intracavitary Bacillus Calmette-guerin in the Treatment of Superficial Bladder Tumors|year = 1976|last1 = Morales|first1 = A.|last2 = Eidinger|first2 = D.|last3 = Bruce|first3 = A.W.|journal = Journal of Urology|volume = 116|issue = 2|pages = 180–182|pmid = 820877}}</ref><ref>{{cite journal |doi = 10.1016/j.smim.2010.02.002|title = Listeria and Salmonella bacterial vectors of tumor-associated antigens for cancer immunotherapy|year = 2010|last1 = Paterson|first1 = Yvonne|last2 = Guirnalda|first2 = Patrick D.|last3 = Wood|first3 = Laurence M.|journal = Seminars in Immunology|volume = 22|issue = 3|pages = 183–189|pmid = 20299242|pmc = 4411241}}</ref><ref>{{cite journal |doi = 10.1155/2016/8451728|doi-access = free|title = Bacteria in Cancer Therapy: Renaissance of an Old Concept|year = 2016|last1 = Felgner|first1 = Sebastian|last2 = Kocijancic|first2 = Dino|last3 = Frahm|first3 = Michael|last4 = Weiss|first4 = Siegfried|journal = International Journal of Microbiology|volume = 2016|pages = 1–14|pmid = 27051423|pmc = 4802035}}</ref><ref>{{cite journal |doi = 10.18632/oncotarget.18392|title = Local application of bacteria improves safety of Salmonella-mediated tumor therapy and retains advantages of systemic infection|year = 2017|last1 = Kocijancic|first1 = Dino|last2 = Felgner|first2 = Sebastian|last3 = Schauer|first3 = Tim|last4 = Frahm|first4 = Michael|last5 = Heise|first5 = Ulrike|last6 = Zimmermann|first6 = Kurt|last7 = Erhardt|first7 = Marc|last8 = Weiss|first8 = Siegfried|journal = Oncotarget|volume = 8|issue = 30|pages = 49988–50001|pmid = 28637010|pmc = 5564822}}</ref> The presence of different bacteria species in the human body, such as on the skin and the [[gut microbiome|gut microenvironment]], has promoted their use as potential theranostic agents or carriers in several medical applications.<ref>{{cite journal |doi = 10.1038/nm0117-5|title = Living therapeutics: Scientists genetically modify bacteria to deliver drugs|year = 2017|last1 = Maxmen|first1 = Amy|journal = Nature Medicine|volume = 23|issue = 1|pages = 5–7|pmid = 28060795|s2cid = 3989795}}</ref><ref name=Buss2020 />

On the other hand, specialised [[eukaryotic]] cells, such as [[red blood cell]]s (RBCs), are one of the nature's most efficient passive carriers with high payload efficiency, deformability, degradability, and biocompatibility, and have also been used in various medical applications.<ref>{{cite journal |doi = 10.1016/j.addr.2007.08.029|title = Cell-based drug delivery|year = 2008|last1 = Pierigè|first1 = F.|last2 = Serafini|first2 = S.|last3 = Rossi|first3 = L.|last4 = Magnani|first4 = M.|journal = Advanced Drug Delivery Reviews|volume = 60|issue = 2|pages = 286–295|pmid = 17997501}}</ref><ref>{{cite journal |doi = 10.1039/C6BM00072J|title = Erythrocytes in nanomedicine: An optimal blend of natural and synthetic materials|year = 2016|last1 = Zhang|first1 = Haijun|journal = Biomater. Sci.|volume = 4|issue = 7|pages = 1024–1031|pmid = 27090487}}</ref><ref>{{cite journal |doi = 10.1016/j.addr.2016.02.007|title = Red blood cells: Supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems|year = 2016|last1 = Villa|first1 = Carlos H.|last2 = Anselmo|first2 = Aaron C.|last3 = Mitragotri|first3 = Samir|last4 = Muzykantov|first4 = Vladimir|journal = Advanced Drug Delivery Reviews|volume = 106|issue = Pt A|pages = 88–103|pmid = 26941164|pmc = 5424548}}</ref> RBCs and RBC-derived [[Wiktionary:nanovesicle|nanovesicle]], such as nanoerythrosomes,<ref>{{cite journal |doi = 10.3390/app11052173|doi-access = free|title = Erythrocytes and Nanoparticles: New Therapeutic Systems|year = 2021|last1 = Guido|first1 = Clara|last2 = Maiorano|first2 = Gabriele|last3 = Gutiérrez-Millán|first3 = Carmen|last4 = Cortese|first4 = Barbara|last5 = Trapani|first5 = Adriana|last6 = d'Amone|first6 = Stefania|last7 = Gigli|first7 = Giuseppe|last8 = Palamà|first8 = Ilaria Elena|journal = Applied Sciences|volume = 11|issue = 5|page = 2173}}</ref> have been successfully adopted as passive cargo carriers to enhance the circulation time of the applied substances in the body,<ref>{{cite journal |doi = 10.1002/adhm.201200138|title = Erythrocyte-Inspired Delivery Systems|year = 2012|last1 = Hu|first1 = Che-Ming J.|last2 = Fang|first2 = Ronnie H.|last3 = Zhang|first3 = Liangfang|journal = Advanced Healthcare Materials|volume = 1|issue = 5|pages = 537–547|pmid = 23184788| s2cid=205229117 }}</ref> and to deliver different bioactive substances for the treatment of various diseases observed in the liver, spleen and lymph nodes, and also cancer via administrating through intravenous, intraperitoneal, subcutaneous, and inhalational routes.<ref>{{cite journal |doi = 10.1016/j.biomaterials.2008.10.031|title = Opsonized erythrocyte ghosts for liver-targeted delivery of antisense oligodeoxynucleotides|year = 2009|last1 = Kim|first1 = Sang-Hee|last2 = Kim|first2 = Eun-Joong|last3 = Hou|first3 = Joon-Hyuk|last4 = Kim|first4 = Jung-Mogg|last5 = Choi|first5 = Han-Gon|last6 = Shim|first6 = Chang-Koo|last7 = Oh|first7 = Yu-Kyoung|journal = Biomaterials|volume = 30|issue = 5|pages = 959–967|pmid = 19027156}}</ref><ref>{{cite journal |doi = 10.1039/c3nr00015j|title = 'Marker-of-self' functionalization of nanoscale particles through a top-down cellular membrane coating approach|year = 2013|last1 = Hu|first1 = Che-Ming J.|last2 = Fang|first2 = Ronnie H.|last3 = Luk|first3 = Brian T.|last4 = Chen|first4 = Kevin N. H.|last5 = Carpenter|first5 = Cody|last6 = Gao|first6 = Weiwei|last7 = Zhang|first7 = Kang|last8 = Zhang|first8 = Liangfang|journal = Nanoscale|volume = 5|issue = 7|pages = 2664–2668|pmid = 23462967|pmc = 3667603|bibcode = 2013Nanos...5.2664H}}</ref><ref>{{cite journal |doi = 10.1038/nnano.2013.54|title = A biomimetic nanosponge that absorbs pore-forming toxins|year = 2013|last1 = Hu|first1 = Che-Ming J.|last2 = Fang|first2 = Ronnie H.|last3 = Copp|first3 = Jonathan|last4 = Luk|first4 = Brian T.|last5 = Zhang|first5 = Liangfang|journal = Nature Nanotechnology|volume = 8|issue = 5|pages = 336–340|pmid = 23584215|pmc = 3648601|bibcode = 2013NatNa...8..336H}}</ref><ref>{{cite journal |doi = 10.3109/21691401.2012.743901|title = Biodegradable long circulating cellular carrier for antimalarial drug pyrimethamine|year = 2013|last1 = Agnihotri|first1 = Jaya|last2 = Jain|first2 = Narendra Kumar|journal = Artificial Cells, Nanomedicine, and Biotechnology|volume = 41|issue = 5|pages = 309–314|pmid = 23305602|s2cid = 22401350|doi-access = free}}</ref><ref name=Gupta2014>{{cite journal |doi = 10.1007/s11095-013-1261-7|title = Nano-Engineered Erythrocyte Ghosts as Inhalational Carriers for Delivery of Fasudil: Preparation and Characterization|year = 2014|last1 = Gupta|first1 = Nilesh|last2 = Patel|first2 = Brijeshkumar|last3 = Ahsan|first3 = Fakhrul|journal = Pharmaceutical Research|volume = 31|issue = 6|pages = 1553–1565|pmid = 24449438|pmc = 5322565}}</ref> For instance, decreased recognition of drug-loaded particles by immune cells was shown when attached to membranes of the RBCs prior to intravenous injection into mice.<ref>{{cite journal |doi = 10.1038/nnano.2017.47|title = Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes|year = 2017|last1 = Wibroe|first1 = Peter Popp|last2 = Anselmo|first2 = Aaron C.|last3 = Nilsson|first3 = Per H.|last4 = Sarode|first4 = Apoorva|last5 = Gupta|first5 = Vivek|last6 = Urbanics|first6 = Rudolf|last7 = Szebeni|first7 = Janos|last8 = Hunter|first8 = Alan Christy|last9 = Mitragotri|first9 = Samir|last10 = Mollnes|first10 = Tom Eirik|last11 = Moghimi|first11 = Seyed Moein|author-link11=Moein Moghimi|journal = Nature Nanotechnology|volume = 12|issue = 6|pages = 589–594|pmid = 28396605|bibcode = 2017NatNa..12..589W|url = https://eprint.ncl.ac.uk/271821|hdl = 10037/13642|hdl-access = free}}</ref> Additionally, the altered bioaccumulation profile of nanocarriers was shown when conjugated onto the RBCs, boosting the delivery of nanocarriers to the target organs.<ref>{{cite journal |doi = 10.1038/s41467-018-05079-7|title = Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude|year = 2018|last1 = Brenner|first1 = Jacob S.|last2 = Pan|first2 = Daniel C.|last3 = Myerson|first3 = Jacob W.|last4 = Marcos-Contreras|first4 = Oscar A.|last5 = Villa|first5 = Carlos H.|last6 = Patel|first6 = Priyal|last7 = Hekierski|first7 = Hugh|last8 = Chatterjee|first8 = Shampa|last9 = Tao|first9 = Jian-Qin|last10 = Parhiz|first10 = Hamideh|last11 = Bhamidipati|first11 = Kartik|last12 = Uhler|first12 = Thomas G.|last13 = Hood|first13 = Elizabeth D.|last14 = Kiseleva|first14 = Raisa Yu.|last15 = Shuvaev|first15 = Vladimir S.|last16 = Shuvaeva|first16 = Tea|last17 = Khoshnejad|first17 = Makan|last18 = Johnston|first18 = Ian|last19 = Gregory|first19 = Jason V.|last20 = Lahann|first20 = Joerg|last21 = Wang|first21 = Tao|last22 = Cantu|first22 = Edward|last23 = Armstead|first23 = William M.|last24 = Mitragotri|first24 = Samir|last25 = Muzykantov|first25 = Vladimir|journal = Nature Communications|volume = 9|issue = 1|page = 2684|pmid = 29992966|pmc = 6041332|bibcode = 2018NatCo...9.2684B}}</ref> It was also reported that the half-life of Fasudil, a drug for pulmonary arterial hypertension, inside the body increased approximately sixfold to eightfold when it was loaded into nanoerythrosomes.<ref name=Gupta2014 /><ref name=Buss2020 />

Superior cargo-carrying properties of the RBCs have also generated increased interest for their use in biohybrid microswimmer designs. Recently, active navigation and control of drug and [[superparamagnetic]] [[nanoparticle]] ([[SPION]])-loaded RBCs were presented using sound waves and magnetic fields.<ref name=Wu2014 /> RBCs were further utilized in the fabrication of soft biohybrid microswimmers powered by motile bacteria for active cargo delivery applications.<ref name=Alapan2018 /> RBCs, loaded with drug molecules and SPIONs, were propelled by bacteria and steered via magnetic fields, which were also capable of traveling through gaps smaller than their size due to the inherent high deformability of the RBCs.<ref name= Buss2020 />

{{clear}}

==References==
{{reflist}}

[[Category:Microswimmers]]
[[Category:Microorganisms]]
[[Category:Robotics]]
[[Category:Nanomedicine]]
[[Category:Drug delivery devices]]