![\"\"](\"https:\/\/engineering.jhu.edu\/magazine-archive\/wp-content\/uploads\/2022\/01\/Feature-Sprd_FINAL-1024x670.jpg\")
\nIn the roundup that follows, we highlight some of the most promising projects now underway at Johns Hopkins.<\/p>\n
Jump to a Section<\/strong><\/p>\n <\/p>\n Enter Warren Grayson<\/a>. The professor of biomedical engineering has been leading efforts to regenerate bonelike tissue with natural anatomical structure: living tissue that grows and changes with the patient and is made from a patient\u2019s own genetic material so it won\u2019t be rejected.<\/p>\n In studies in mice and pigs, Grayson\u2019s lab has used 3D printers to create scaffolds made from biodegradable polymers combined with other natural materials in the exact shape of the facial defects. Then, they take stem cells derived from fat tissue and apply them to the scaffold in a liquid solution. The idea is the cells will grow throughout the porous scaffold, which provides instructive cues so the cells form bone. The scaffold then degrades, leaving new, vibrant bone tissue.<\/p>\n Over the years, the Grayson lab has tinkered with various scaffold materials, methods to stimulate stem cells, and recipes for optimal bone growth. Animal studies have demonstrated that some bone can be regrown in this manner. \u201cThere\u2019s definitely room for improvement,\u201d Grayson says, \u201cbut the results have been extremely promising. The data tell you that you can induce the body to go beyond its normal healing capacity.\u201d<\/p>\n In related work, Grayson and colleagues are applying similar processes to regenerate skeletal muscle and are developing new imaging tools to better study how these materials work once transplanted into the body. Grayson\u2019s group is applying for funding to conduct pilot clinical studies in humans. How quickly things move from there will depend on results and larger-scale clinical trials.<\/p>\n <\/p>\n Green\u2019s lab has taken a cue from viruses \u2014 which trick cells into letting them enter and then use this space to replicate \u2014 to develop novel biodegradable nanobiomaterials that can deliver medications or genetic material in miniature packages (1\/1,000th the size of a human hair) directly to specific types of cells, thereby reprogramming them from the inside out.<\/p>\n The process could be used to deliver DNA and RNA to cells to turn genes on or off individually or in combination. This holds potential for common genetic conditions, such as cystic fibrosis or hemophilia, as well as more complicated diseases, like cancer or diabetes, Green says. It even can help hit targets traditionally seen by pharmaceutical companies as \u201cundruggable.\u201d<\/p>\n Green and colleagues also are working on developing different sizes and shapes of artificial immune cells to mimic biological cells, with proteins added to the surface that teach native immune cells what to do, such as attack cancers or promote tissue repair. A recent study demonstrated that lab-developed nanoparticles using molecules called poly(beta-amino ester)s, along with an engineered sequence of DNA, could reprogram liver cancer cells to secrete a protein called TRAIL that initiates cancer cell death. Combining this approach with small-molecule drugs could offer a new potential approach for cancer treatment.<\/p>\n \u201cThe wave of the future is doing in situ tissue engineering using administered gene therapy and immunotherapy to promote healing and regeneration of tissues within the body,\u201d Green says. \u201cWe\u2019re going to see these technologies more and more.\u201d<\/p>\n <\/p>\n People who have lost soft tissue, whether as the result of a congenital disease or due to trauma or cancer surgery, present a challenge to surgeons. Doctors can transplant fat tissue harvested from elsewhere in the body, but without supporting blood vessel networks, the transplanted fat tends to die over time. Some patients don\u2019t have enough soft tissue to spare for the transplant, and synthetic materials, such as silicon gels used in breast implants, can induce foreign-body reactions by the immune system.<\/p>\n Ideally, says Hai-Quan Mao<\/a>, professor of materials science and engineering and of biomedical engineering, \u201cYou want the material to be porous enough to allow host tissue to grow into it but also retain its shape and the integrity of the repair site, and not lead to scarring and fibrosis by host immune cells. This concept is easy to understand, but it was difficult to come up with a material design to meet all of those requirements simultaneously.\u201d<\/p>\n Mao\u2019s team, working with Johns Hopkins plastic and reconstructive surgeons Sashank Reddy and Justin Sacks (now at Washington University in St. Louis), has invented a new type of synthetic soft tissue substitute that is well-tolerated and encourages the growth of soft tissue and blood vessels.<\/p>\n As a model, researchers observed the microscopic structure of fat, consisting of large cells clustered around an extracellular matrix that provides shape and stability. To devise a new biomaterial, they used a hydrogel made of hyaluronic acid \u2014 a naturally occurring component of the body\u2019s extracellular matrix and an ingredient found in more than 90% of cosmetic dermal fillers used in this country. Then, they incorporated nanofibers of polycaprolactone, the same material used in some resorbable sutures, to help the material retain its shape. They broke the fibers into short segments before making the composite gel to ensure easy injection through a needle. The resulting composite gel performed well in several animal studies, repairing deformities while encouraging growth of new blood vessels.<\/p>\n Mao and his co-investigators founded a company called LifeSprout that is conducting phase 1 clinical trials of small amounts (1 to 3 cubic centimeters) of the soft tissue substitute in the face for removing wrinkles or adding volume to a facial structure, before developing a strategy for larger-volume repairs.<\/p>\n They have been awarded a Maryland Stem Cell Research Fund grant to test this material for larger-volume repair, to see if they can speed and enhance regeneration by adding fat tissue-derived stem cells.<\/p>\n <\/p>\n The work made news headlines in March 2020, when Kim and colleagues sent some of their miniaturized heart tissues with SpaceX to the International Space Station for a month to study how space travel and weightlessness \u2014 which has been known to simulate accelerated aging \u2014 affects the heart\u2019s structure and function. Kim\u2019s team observed that contractile force and heart function declined compared to similar tissues studied on Earth.<\/p>\n Sponsored by the National Institutes of Health and NASA, the team now is gearing up for a second space launch in fall 2022. This time, the engineered heart tissue chips will be treated with some type of drug compound or mechanical stimulation (muscle conditioning) to see if diminishing function can be prevented or lessened. The lab has been testing various interventions using a desktop-sized random positioning machine that simulates microgravity. A companion project funded by NASA is focused on monitoring how radiation from the sun and other elements in space impacts changes in human cardiac tissues.<\/p>\n In other work, Kim, David Kass (professor of medicine and biomedical engineering), and their colleagues are validating 3D engineered muscular tissues as a \u201cclinical trial on a chip\u201d platform to study cardiac and skeletal muscle deficiencies in human Duchenne and Becker muscular dystrophies, inherited conditions marked by progressive muscle weakness. By placing these patients\u2019 induced pluripotent stem cell-derived muscular tissues in multiwell plates in the lab, investigators will simulate clinical trials of a novel drug for muscular dystrophy, assessing toxicity profiles, helping determine appropriate doses, and potentially personalizing therapy for patients. This avoids typical problems experienced with clinical trials, such as patient recruitment, patient dropout, and harmful side effects.<\/p>\n A platform of heart and skeletal muscle tissues to test new drugs already is commercially available through Curi Bio, a company Kim co-founded in 2015.<\/p>\n In separate studies, Leslie Tung<\/a>, professor of biomedical engineering, is using engineered heart slices to study electrophysiological conditions related to heart disease, such as arrhythmogenic cardiomyopathy, a cause of sudden cardiac death. His team seeds human induced pluripotent stem cells from patients onto a scaffold of slices of heart tissue from rats or pigs that have been stripped of their native cells. This serves as a model system to study heart arrhythmias and their potential treatments in the lab.<\/p>\n <\/p>\n Tuffaha is an expert on targeted muscle reinnervation, a peripheral nerve repair procedure for amputees during which each severed nerve at the amputation site is sutured to a smaller motor nerve in a neighboring muscle. This helps prevent the disorganized growth of nerve stumps into painful tumors called neuromas. However, the size difference between the two nerve stumps being connected creates additional technical challenges and still leads to neuroma development in some 30% of patients.<\/p>\n Three engineering undergraduate students stepped up to find a solution. Under Mao\u2019s direction, Michael Lan \u201921 (BME), Bruce Enzmann (MatSci) and Anson Zhou (BME) devised a flexible, cone-shaped device as a conduit to guide proper nerve growth over the different-sized nerves.<\/p>\n Similar to a simple funnel, the biodegradable device has an outer porous, extendable, cone-shaped synthetic polymeric conduit filled with a biodegradable gel. The team created the conduit by spinning a polymer solution into a nanofiber mesh under a high-voltage electrical field. The mesh was then molded into a cone shape. The ends of the conduit can easily be sutured to the two nerve stumps. The students filled the inside of the conduit with a biodegradable hydrogel that included a nerve inhibitor to reduce nerve growth and shrink nerve size as it grows through the conduit. Together, these components guide and regulate proper connections between the two nerve stumps.<\/p>\n The COVID-19 pandemic didn\u2019t slow down this team. With a new member, third-year student Juan Diego Carrizo (MatSci), they continued to work together via Zoom and prepared the prototype devices in a temporary space set up by the team. In pilot studies in rats \u2014 conducted by medical student Erica Lee in the Tuffaha group \u2014 the team observed the device achieved a tapered shape of regrown nerve within the device. It also prevented neuroma formation and generated fewer pain fibers compared to the TMR procedure itself.<\/p>\n The team has filed a provisional patent on its work under a spinoff company named Innerva. With a few funding sources \u2014 including $10,000 from the 2021 national Lemelson-MIT Student Prize competition for collegiate inventors and $85,000 from the Johns Hopkins University Cohen Translational Engineering Fund<\/a> \u2014 the team is continuing to refine the device.<\/p>\n <\/p>\n \u201cIf we didn\u2019t have blood, we\u2019d be 1 millimeter in size,\u201d says Mac Gabhann, associate professor of biomedical engineering. \u201cThe only reason we can be large, multiorgan organisms is because we have some sort of system that can move oxygen around the body to communicate among different organs.\u201d<\/p>\n Most people are familiar with the blood vessels they can see in their arms or their feet, he says. These vessels, like interstate highways, carry blood to smaller and smaller branches supporting all tissues in the body. Any given piece of tissue is packed with networks of tiny blood vessels, 1,000 times thinner than those we can observe.<\/p>\n Currently, some larger vessels that become injured or diseased, such as in the leg or heart, can be surgically repaired or bolstered, or replaced with synthetic materials. Patches of damaged skin can be repaired through skin grafts. Growing large amounts of tissue or thicker tissues, however, would be \u201ca major next step,\u201d Mac Gabhann says, and requires creating the right environment to encourage blood vessel growth.<\/p>\n Mac Gabhann\u2019s lab has been using computational modeling \u2014 the application of computers to simulate and study complex systems \u2014 to study vascular endothelial growth factor, a protein family heavily involved in blood vessel growth and development. The lab’s members want to know why and how these proteins direct the growth of varying blood vessel networks supporting different areas of the body. \u201cIf we can understand that,\u201d he says, \u201cwe can turn it into a forward engineering problem and design the signals we need to get the kind of networks we want.\u201d<\/p>\n He\u2019s looking primarily at two areas. One is skeletal muscle, working to develop a medical intervention that could help people with peripheral artery disease, a form of blockages of blood vessels in the leg that make it painful to exercise. The other is developmental biology, attempting to understand how blood vessel networks behave in growing tissues.<\/p>\n <\/p>\n Implanting devices can create a one-two punch for the immune system, Doloff notes. Doctors want to deliver grafts correctly to restore function, but if they\u2019re implanted in the midst of a chaotic autoimmune disorder, two immune challenges emerge: preventing graft rejection and modulating the immune system to prevent further damage. He\u2019s also pursuing immunoengineering studies to help prevent rejection of grafts.<\/p>\n In recent work, Doloff\u2019s team has demonstrated that loading implantable devices with a crystallized immunosuppressant drug that is slowly released at the local area can inhibit the immune response against those devices. The research team (not the lab) is also working on ways to encapsulate islet cells and transplant them into patients with diabetes, potentially to replace nonfunctioning pancreatic cells and eliminate the necessity for insulin injections or long-term immunosuppressant drugs needed with implanted devices and organ transplants.<\/p>\n \u201cOver the past few years, we\u2019ve gotten a lot of insights into foreign-body response,\u201d he says. \u201cWe can actually block biomaterial-specific responses quite effectively. And I\u2019m confident that we can do that now for not just biomaterials but even multicomponent devices, such as glucose monitors.\u201d<\/p>\n <\/p>\n The launch of the Translational Tissue Engineering Center<\/a> at Johns Hopkins in 2010 laid the foundation for many of today’s advances. Directed by biomedical engineering professor Jennifer Elisseeff<\/a>, a pioneer in regenerative immunology, the center was founded as a joint venture between the Wilmer Eye Institute and the Department of Biomedical Engineering. In 2019, the university created the Johns Hopkins Translational ImmunoEngineering Biotechnology Research Center<\/a> with a $6.7 million grant from the National Institutes of Health.<\/p>\n","protected":false},"excerpt":{"rendered":" Through advances in biomaterials, stem cell science, and more, researchers are moving tantalizingly close to regenerating damaged body parts, creating new organs, and equipping our existing tissues to fight off debilitating diseases.<\/p>\n","protected":false},"author":4,"featured_media":15818,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[28],"tags":[],"class_list":["post-15816","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-features","issue-winter-2022"],"acf":[],"yoast_head":"\n\n
\nBone and Facial Reconstruction<\/h2>\n
![\"\"](\"https:\/\/engineering.jhu.edu\/magazine-archive\/wp-content\/uploads\/2022\/01\/JHUE_SPOT_Bone_Face-300x202.jpg\")
Patients experiencing craniofacial bone loss resulting from trauma or cancer removal surgeries have a few options today for reconstructive surgeries. But they all have limitations. Autografts, a process that involves taking a piece of bone from another body part to transplant to the face, create a second defect. Allografts (which use donor tissue) hold the potential for disease transfer or rejection. Surgeons also can employ materials like metals to serve as an implant; these, too, are subject to possible rejection and don\u2019t move like native tissue.<\/p>\n\n
\nCellular-Level Technologies<\/h2>\n
![\"\"](\"https:\/\/engineering.jhu.edu\/magazine-archive\/wp-content\/uploads\/2022\/01\/JHUE_Tissue-Engineering_SPOT_Cell_Tissue-300x229.jpg\")
The human body holds trillions of cells that function like tiny computers, processing inputs that direct them to grow, divide, specialize, or self-destruct, explains Jordan Green<\/a>, professor of biomedical engineering.<\/p>\n\n
\nSoft Tissue<\/h2>\n
\n
\nHeart<\/h2>\n
![\"\"](\"https:\/\/engineering.jhu.edu\/magazine-archive\/wp-content\/uploads\/2022\/01\/JHUE_Mag_Winter-2022_SPOT_Heart-300x200.jpg\")
Deok-Ho Kim<\/a>\u2019s research in cardiac tissue engineering is out of this world. Kim, an associate professor of biomedical engineering, has developed 3D engineered cardiac tissues that mimic the microarchitecture and function of human heart tissue on a microchip.<\/p>\n\n
\nPeripheral Nerves<\/h2>\n
![\"\"](\"https:\/\/engineering.jhu.edu\/magazine-archive\/wp-content\/uploads\/2022\/01\/JHUE_Mag_Winter-2022_SPOT_Nerve-300x202.jpg\")
A couple of years ago, Johns Hopkins plastic and reconstructive surgeon Sami Tuffaha approached Hai-Quan Mao with a vexing problem.<\/p>\n\n
\nVasculature<\/h2>\n
![\"\"](\"https:\/\/engineering.jhu.edu\/magazine-archive\/wp-content\/uploads\/2022\/01\/JHUE_Mag_Winter-2022_SPOT_Blood-300x278.jpg\")
Feilim Mac Gabhann<\/a> likes to ask his students to name the human body’s most important organ. The usual suspects emerge: heart, brain, occasionally skin. But it\u2019s a trick question. In Mac Gabhann\u2019s eyes, it\u2019s blood.<\/p>\n\n
\nPancreas<\/h2>\n
![\"\"](\"https:\/\/engineering.jhu.edu\/magazine-archive\/wp-content\/uploads\/2022\/01\/JHUE_Tissue-Engineering_SPOT_Pancreas-300x290.jpg\")
Joshua Doloff\u2019s lab explores the intersection between therapeutics and living systems, with a goal of understanding what happens when new materials are introduced into the body and how the host immune system behaves and perceives them. An implanted glucose monitor functioning as an artificial pancreas for those with diabetes, for example, can be attacked by the body as foreign. This can lead to the development of scar tissue around the device, diminishing its function.<\/p>\n\n
\nHarnessing the Immune System<\/h2>\n