"Long before it's in the papers"
August 31, 2012

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“Cyborg” tissues may become reality, Harvard scientists say

Aug. 31, 2012
Courtesy of Harvard University
and World Science staff

In the fu­ture, if you re­ceive an im­planted or­gan, it might be threaded through with ex­tremely fi­ne wires that serve to mon­i­tor it, stim­u­late it or de­liv­er tar­geted drugs in­to it.

Har­vard Uni­vers­ity sci­en­tists are work­ing to­ward such a fu­ture, and as an in­i­tial step have cre­at­ed a type of “cy­borg” tis­sue by em­bed­ding a three-di­men­sion­al net­work of func­tion­al wires in­to en­gi­neered hu­man tis­sues. The wires, of sub-microscopic width, are de­signed to be com­pat­ible with bi­o­log­i­cal tis­sue.

Led by Harvard researchers Charles M. Lieber and Dan­iel Ko­hane, the sci­ent­ists de­vel­oped a sys­tem for cre­at­ing tiny “s­caf­folds” that can be seeded with cells that grow in­to tis­sue. The work is de­scribed in a pa­per pub­lished Aug. 26 in the jour­nal Na­ture Ma­te­ri­als.

“The cur­rent meth­ods we have for mon­i­toring or in­ter­act­ing with liv­ing sys­tems are lim­it­ed,” said Lieber. “We can use elec­trodes to meas­ure ac­ti­vity in cells or tis­sue, but that dam­ag­es them. With this tech­nol­o­gy, for the first time, we can work at the same scale as the un­it of bi­o­log­i­cal sys­tem with­out in­ter­rupt­ing it. Ul­ti­mate­ly, this is about merg­ing tis­sue with elec­tron­ics in a way that it be­comes dif­fi­cult to de­ter­mine where the tis­sue ends and the elec­tron­ics be­gin.”

Sci­en­tists have been work­ing for years on grow­ing new or­gans from scratch, and have met with some suc­cess, but some would like to cre­ate sys­tems ca­pa­ble of sens­ing chem­i­cal or elec­tri­cal changes in the tis­sue af­ter it has been grown and im­planted.

“In the body, the au­to­nom­ic nerv­ous sys­tem keeps track of pH [ac­id­ity], chem­istry, ox­y­gen, and oth­er fac­tors, and trig­gers re­sponses as need­ed,” Ko­hane said. “We need to be able to mim­ic the kind of in­trin­sic feed­back loops the body has evolved.”

The pro­cess of build­ing the net­works, Lieber said, is si­m­i­lar to that used to etch mi­crochips.

Be­gin­ning with a two-di­men­sion­al sur­face, re­search­ers laid out a mesh of or­ganic pol­y­mer, or plastic-like sub­stances, around molecular-scale wires. Mi­nus­cule elec­trodes, to con­nect the wires, were built with­in the mesh to ena­ble tran­sis­tors to meas­ure the ac­ti­vity in cells. Once com­plet­ed, the un­der­ly­ing sur­face was dis­solved, leav­ing a net­like sponge, or a mesh, that could be folded or rolled in­to var­i­ous shapes.

Once com­plete, the net­works were po­rous enough to al­low the team to seed them with cells and en­cour­age those cells to grow in 3-D cul­tures, the re­search­ers said.

“Pre­vi­ous ef­forts to cre­ate bioen­gi­neered sens­ing net­works have fo­cused on two-di­men­sion­al lay­outs, where cul­ture cells grow on top of elec­tron­ic com­po­nents, or on con­for­mal lay­outs, where probes are placed on tis­sue sur­faces,” said Bozhi Tian, a form­er doc­tor­al stu­dent un­der Lieber, who helped build the struc­tures. “It is desira­ble to have an ac­cu­rate pic­ture of cel­lu­lar be­hav­ior with­in the 3-D struc­ture of a tis­sue, and it is al­so im­por­tant to have nano­scale [mole­cu­lar-scale] probes to avoid dis­rup­tion of ei­ther cel­lu­lar or tis­sue ar­chi­tec­ture.”

Us­ing heart and nerve cells, the team said it suc­cessfully en­gi­neered tis­sues con­tain­ing em­bed­ded nanoscale net­works with­out af­fect­ing the cells’ vi­a­bil­ity or ac­ti­vity. Us­ing the em­bed­ded de­vices, the re­search­ers re­ported they were then able to de­tect elec­tri­cal sig­nals gen­er­at­ed by cells deep with­in the tis­sue, and to meas­ure changes in those sig­nals in re­sponse to var­i­ous drugs.

They re­ported that they were al­so able to build bioen­gi­neered blood ves­sels, and use the em­bed­ded tech­nol­o­gy to meas­ure ac­id­ity changes — as would be seen in re­sponse to in­flamma­t­ion, heart at­tacks, and oth­er bio­chem­i­cal or cel­lu­lar en­vi­ron­ments — in­side and out­side the ves­sels.

Though a num­ber of po­ten­tial ap­plica­t­ions ex­ist for the tech­nol­o­gy, the most near-term use, Lieber said, may come from the drug in­dus­try, where re­search­ers could use it to more pre­cisely study how newly de­vel­oped drugs act in three-di­men­sion­ tis­sues, rath­er than thin lay­ers of cul­tured cells.

* * *

In the future, if you receive an implanted organ, it might be threaded through with extremely fine wires that serve to monitor it, stimulate it or deliver targeted drugs into it. Harvard University scientists are working toward such a future, and as an initial step have created a type of “cyborg” tissue by embedding a three-dimensional network of functional wires into engineered human tissues. The wires, of sub-microscopic width, are designed to be compatible with biological tissue. Led by chemist Charles M. Lieber and anesthesiologist Daniel Kohane at Harvard Medical School, the researchers developed a system for creating nanoscale “scaffolds” that can be seeded with cells that grow into tissue. The work is described in a paper published Aug. 26 in the journal Nature Materials. “The current methods we have for monitoring or interacting with living systems are limited,” said Lieber. “We can use electrodes to measure activity in cells or tissue, but that damages them. With this technology, for the first time, we can work at the same scale as the unit of biological system without interrupting it. Ultimately, this is about merging tissue with electronics in a way that it becomes difficult to determine where the tissue ends and the electronics begin.” Scientists have been working for years on growing new organs from scratch, and have met with some success, but some would like to create systems capable of sensing chemical or electrical changes in the tissue after it has been grown and implanted. “In the body, the autonomic nervous system keeps track of pH [acidity], chemistry, oxygen, and other factors, and triggers responses as needed,” Kohane said. “We need to be able to mimic the kind of intrinsic feedback loops the body has evolved in order to maintain fine control at the cellular and tissue level.” The process of building the networks, Lieber said, is similar to that used to etch microchips. Beginning with a two-dimensional surface, researchers laid out a mesh of organic polymer, or plastic-like substances, around molecular-scale wires. Minuscule electrodes, to connect the wires, were built within the mesh to enable transistors to measure the activity in cells. Once completed, the underlying surface was dissolved, leaving researchers with a netlike sponge, or a mesh, that could be folded or rolled into various shapes. Once complete, the networks were porous enough to allow the team to seed them with cells and encourage those cells to grow in 3-D cultures, the researchers said. “Previous efforts to create bioengineered sensing networks have focused on two-dimensional layouts, where culture cells grow on top of electronic components, or on conformal layouts, where probes are placed on tissue surfaces,” said Bozhi Tian, a former doctoral student under Lieber, who helped build the structures. “It is desirable to have an accurate picture of cellular behavior within the 3-D structure of a tissue, and it is also important to have nanoscale probes to avoid disruption of either cellular or tissue architecture.” Using heart and nerve cells, the team said it successfully engineered tissues containing embedded nanoscale networks without affecting the cells’ viability or activity. Using the embedded devices, the researchers reported they were then able to detect electrical signals generated by cells deep within the tissue, and to measure changes in those signals in response to various drugs. They reported that they were also able to build bioengineered blood vessels, and use the embedded technology to measure acidity changes — as would be seen in response to inflammation, heart attacks, and other biochemical or cellular environments — inside and outside the vessels. Though a number of potential applications exist for the technology, the most near-term use, Lieber said, may come from the pharmaceutical industry, where researchers could use it to more precisely study how newly developed drugs act in three-dimensional tissues, rather than thin layers of cultured cells. The system might also one day be used to monitor changes inside the body and react accordingly, whether through electrical stimulation or the release of a drug.