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Regenerative Robotics This is a repository copy of Regenerative robotics. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/147130/ Version: Published Version Article: Damian, D. orcid.org/0000-0002-0595-0182 (2019) Regenerative robotics. Birth Defects Research. ISSN 2472-1727 https://doi.org/10.1002/bdr2.1533 Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Received: 15 May 2019 Accepted: 19 May 2019 DOI: 10.1002/bdr2.1533 REVIEW ARTICLE Regenerative robotics Dana D. Damian Department of Automatic Control and Systems Engineering, University of Abstract Sheffield, Sheffield, United Kingdom Congenital diseases requiring reconstruction of parts of the gastrointestinal tract, skin, or bone are a challenge to alleviate especially in rapidly growing children. Correspondence Dana D. Damian, Department of Automatic Novel technologies may be the answer. This article presents the state-of-art in regen- Control and Systems Engineering, erative robotic technologies, which are technologies that assist tissues and organs to University of Sheffield, Sheffield, United regenerate using sensing and mechanotherapeutical capabilities. It addresses the chal- Kingdom. Email: [email protected] lenges in the development of such technologies, among which are autonomy and fault-tolerance for long-term therapy as well as morphological conformations and Funding information compliance of such devices to adapt to gradual changes of the tissues in vivo. The Engineering and Physical Sciences Research Council, Grant/Award Number: potential as medical devices for delivering therapies for tissue growth and as tools EP/S021035/1 for scientific exploration of regenerative mechanisms is also discussed. KEYWORDS mechanotherapy, robotic implants, soft robots, tissue growth, tissue regeneration 1 | TISSUE REPAIR organ. Yet, the child is dependent on parenteral nutrition (PN, i.e., intravenous feeding) for months to years (Spencer Tissue repair is a complex, long term, and physiologically et al., 2008) which can lead to morbidities like bloodstream demanding process requiring dynamic and optimal therapies infections and liver disease. These heroic surgeries per- (Eming, Wynn, & Martin, 2017). Patients suffering from formed by a few world experts are sadly primitive and conditions such as long-gap esophageal atresia (LGEA), a morbid. congenital disease in which a section of the esophagus of 3 cm or more is missing, or short bowel syndrome (SBS), 2 | MECHANOTHERAPY a devastating condition associated with massive loss or resection of the small intestine, skin burns, or bone deformi- For a long time now, mechanotherapy—a form of physio- ties, are just a few examples of dramatic cases of tissue therapy using mechanical equipment to manipulate parts of reconstruction that challenge patients and surgeons alike. the body, along with other exercises, massage, and so Currently, the only effective treatment for LGEA consists of forth—has been recognized as effective for tissue repair, attaching sutures to the end of the esophageal ends, tying with treatments spanning months or years. Recent studies them off at the child's back and tightening them daily for show that tissues grow in response to stimulative strain weeks to encourage the tissue to elongate. During this (mechanostimulation; Cezar et al., 2016; Folkman & treatment, the baby is sedated, and assessed with X-rays Moscona, 1978)—this is nowhere seen more readily than (Foker, Kendall Krosch, Catton, Munro, & Khan, 2009). in the growing child, in adults where exercise develops In SBS, because the child's remaining bowel length is muscle mass and in pregnant women where skin expands insufficient to absorb nutrients and maintain health and to accommodate the growing fetus. It has been shown growth, the treatments often target the dilation of the in vitro that this stimulation applied to cells can change This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Author. Birth Defects Research published by Wiley Periodicals, Inc. Birth Defects Research. 2019;1–6. wileyonlinelibrary.com/journal/bdr2 1 2 DAMIAN their developmental trajectory toward death (necrosis), pro- animal studies (Roche et al., 2017; Xu et al., 2014), there is liferation or differentiation (Folkman & Moscona, 1978). no robot that has operated in vivo long term. The possibility Clinically, the principle has been applied to induce bone to combine chemical, physical and electronic properties in growth, for skin grafts (Chua et al., 2016), wound healing soft-matter substrates brings unprecedented flexibility in (Huang, Holfeld, Schaden, Orgill, & Ogawa, 2013), growth medical device customization, complexity, and mechanical of arteries (Kim et al., 2012) and esophagus expansion and compatibility for in vivo environments. elongation (Foker et al., 2009). However, the treatments rely on the surgeon's on-site tactile perception or visual 5 | REGENERATIVE ROBOTIC assessment, and empirical training, and thus are inconsis- TECHNOLOGIES tent. When much of the information about diseases is derived from advanced imaging technology (e.g., X-rays, Future tissue therapy should allow sustained, noninvasive, ultrasound) the importance of real-time interaction with tis- tissue-responsive repair through autonomous, in-situ, sue in understanding immediate and long-term effects of a feedback-controlled robotic implant technologies that regu- therapy seems to be overlooked. With the knowledge of late tissue growth by mechanostimulation (Damian et al., complex living tissues being at an early stage, inquiries on 2018; Miyashita et al., 2016). The realization of such the optimal regimens of force application for tissue growth devices would enable onboard clinical expertise and deliv- are needed. Presently, there are no studies about how tissue ery of effective therapy at all times, as well as the acquisi- regeneration unfolds or is controlled during long-term tion of in vivo tissue data to research growth mechanisms, mechanostimulation. An in vivo device that enables which is impossible in current clinical and research prac- informed and automated therapy would thus be extremely tice. This technology could customize treatments by exploi- useful. ting natural growth capabilities of the remaining tissue. Novel regenerative technologies are emerging and combine 3 | MEDICAL TECHNOLOGIES FOR the interdisciplinary knowledge from these fields in order TISSUE REPAIR AND GROWTH to provide more reliable, controlled, on-demand tissue ther- apies for wound healing and tissue growth. Two examples are given below: Surgery-assistive robotic devices have been shown to pro- duce consistent outcomes in tissue repair, albeit their use, as 1. Therapeutic hydrogel substrates: Cezar et al. developed a tool for surgeons (Shademan et al., 2016), is limited to an actuated biologic-free ferrogel able to apply, under a manually-operated, daily interventions (Sajadi & Goldman, magnetic field, mechanical compression to damaged 2015). Medical implants, such as the pacemaker, usually skeletal muscle (Cezar et al., 2016). Their results showed operate according to preprogrammed regimens (Copeland that this mechanical intervention positively affected the et al., 2004). Tissue engineering, on another front, uses host inflammatory response, by significantly reducing the engineered biomaterials (scaffolds) and growth factors to fibrotic capsule around the gel after 2 weeks of implanta- encourage host or donor cells to proliferate and grow new tion in mice hind limb. Furthermore, the cyclic application tissue. Despite successes in this field, challenges of cell of the mechanical compression led to enhanced muscle death before vascularization of the scaffold, and patient- regeneration compared to no-treatment controls, indicat- specific factors affecting the tissue remodeling potential ing the potential of regenerative therapies through mecha- remain (Atala, Kasper, & Mikos, 2012). notherapy. The hydrogel substrate allowed a profile of mechanical compression that produced a better outcome 4 | SOFT ROBOTICS than the acute compression profile of inflating balloon cuffs around the mouse limb (Figure 1). In the reported Soft robots take advantage of both soft material engineering work the mechanotherapy regimens were predefined, thus and robotic control to mimic natural properties, such as further envisaged improvement could be sensing incorpo- viscoelasticity, smooth motion, deformations, and self-healing ration to adapt these regimens to changes of the tissue in (Rus & Tolley, 2015). Soft robotic growth has also been time, such as stiffness. investigated by a few studies for even search and rescue 2. Robotic implants: Damian et al. developed robotic (Hawkes, Blumenschein, Greer, & Okamura, 2017; Rieffel & implants that show capabilities to regulate and enhance Smith, 2014; Sadeghi,
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