Replacement Bones, Grown to Order in the Lab

Researchers at Columbia use a bioreactor, left, to house and help cultivate material, right, that evolves into a bone.

By ANNE EISENBERG , NY Times

IF a lover breaks your heart, tissue engineers can’t fix it. But if sticks and stones break your bones, scientists may be able to grow custom-size replacements.

Gordana Vunjak-Novakovic, a professor of biomedical engineering at Columbia University, has solved one of many problems on the way to successful bone implants: how to grow new bones in the anatomical shape of the original.

Dr. Vunjak-Novakovic and her research team have created and nourished two small bones from scratch in their laboratory. The new bones, part of a joint at the back of the jaw, were created with human stem cells. The shape is based on digital images of undamaged bones.

Tissue-engineered bones have many implications, according to a leading figure in the field, Dr. Charles A. Vacanti, director of the laboratories for tissue engineering and regenerative medicine at the Brigham and Women’s Hospital in Boston. He has no connection to the Columbia work. “If your imaging equipment has sufficient high resolution, you can construct virtually any intricate shape you want — for example, the middle ear bone, creating an exact duplicate,” he said. “It’s a splendid example of tissue engineering at its best.”

Engineered bones are being tested in animals and in a few people, and may be common in operating rooms within a decade, said Rosemarie Hunziker, a program officer at the National Institute of Biomedical Imaging and Bioengineering, which sponsors research in the field, including that at Columbia.

Many businesses, including Osiris Therapeutics and Pervasis Therapeutics are forming around tissue engineering techniques. (Pervasis, for instance, is creating blood vessel linings.)

“It’s a field that is attracting much interest from venture capitalists,” said Robert Langer, a professor at M.I.T. Dr. Langer has more than 750 patents issued or pending in tissue engineering and drug delivery systems, and is an adviser to many companies that have started businesses based on his work.

Scott Hollister, a professor at the University of Michigan, Ann Arbor, is a co-founder of Tissue Regeneration Systems, a company that is commercializing technology his group is developing for skeletal reconstruction in the face, spine and extremities.

Dr. Vunjak-Novakovic, who has filed a patent application through Columbia, said that her lab’s work had attracted considerable interest from investors, but that it was too soon to talk about commercial applications. “We are starting studies with large animals that will establish safety and feasibility before commercialization, “she said.

Dr. Vunjak-Novakovic, Dr. Warren L. Grayson and other members of the team used digital images of the joint to guide a machine that carved a three-dimensional replica, called a scaffold, from cleansed bone material. The team turned the bare scaffold into living tissue by putting it into a chamber molded to its exact shape, and adding human cells, typically isolated from bone marrow or liposuctioned fat. A steady source of oxygen, growth hormones, sugar and other nutrients was piped into the chamber, or bioreactor, so the bone would flourish.

“The cells grow rapidly,” Dr. Vunjak-Novakovic said. “They don’t know whether they are in the body or in a culture. They only sense the signals.”

Traditional bone grafts are typically harvested from other parts of the body, often a traumatic step, or made of materials like titanium that aren’t always compatible with host bones or cause inflammation, said Dr. Francis Y. Lee, a professor of clinical orthopedic surgery at Columbia’s College of Physicians and Surgeons. Dr. Lee also has no connection to Dr. Vunjak-Novakovic’s work.

“If we have an anatomically matching scaffold that can host bone cells,” Dr. Lee said, “this will provide a new way of reconstructing bone and cartilage defects.”

The design of the bioreactor is ingenious, said Dr. Vacanti of Boston, because it allows sources of nourishment and other fluids to permeate the pores of the scaffold as new bone grows within the pores. Often, cells make tissue mainly on the outside of a scaffold, while cells inside tend to die. But Dr. Vunjak-Novakovic’s bioreactor permits close observation and control of additives by the research team. “They can direct the flow and monitor the effect on the development of tissue,” Dr. Vacanti said.

PROFESSOR Hollister at Michigan is also working on creating bones of a jaw joint. But instead of using a bioreactor to grow them, he plans to use the human body as the incubator. The scaffold for the new bone, designed from a CT scan and printed directly using a laser system, is filled with cells from bone marrow or fat that are taken from the patient to prevent immune-system reactions. “Then we will let the patient’s body naturally heal and reconstruct the tissue as the implant is resorbed by the body,” he said.

Many of the components to generate good bones are in place, said David L. Kaplan, professor and chairman of the department of biomedical engineering at Tufts University. “The technology is here,” he said, “to control the size, shape and functional features of human tissue in the lab.”

The complex problems of keeping tissue alive and integrated when implanted in the body are also well on their way to being solved, Dr. Hunziker said. “We are starting to put the pieces of the puzzle together in various combinations to generate good bone,” she said, “and it’s all going to come together in a reasonable amount of time.”

First commercial 3-D bio-printer makes human tissue and organs

rdmag.com
Thursday, December 10, 2009

Invetech, an innovator in new product development and custom automation for the biomedical, industrial and consumer markets, today announced that it has delivered the world’s first production model 3D bio-printer to Organovo, developers of the proprietary NovoGen bioprinting technology. Organovo will supply the units to research institutions investigating human tissue repair and organ replacement.

Dr. Fred Davis, president of Invetech, which has offices in San Diego and Melbourne, said, “Building human organs cell-by-cell was considered science fiction not that long ago. Through this clever combination of technology and science we have helped Organovo develop an instrument that will improve people’s lives, making the regenerative medicine that Organovo provides accessible to people around the world.”

Keith Murphy, CEO of Organovo, based in San Diego, said the units represent a breakthrough because they provide for the first time a flexible technology platform for organizations working on many different types of tissue construction and organ replacement.

”Scientists and engineers can use the 3-D bio printers to enable placing cells of almost any type into a desired pattern in 3-D,” said Murphy. “Researchers can place liver cells on a preformed scaffold, support kidney cells with a co-printed scaffold, or form adjacent layers of epithelial and stromal soft tissue that grow into a mature tooth. Ultimately the idea would be for surgeons to have tissue on demand for various uses, and the best way to do that is get a number of bio-printers into the hands of researchers and give them the ability to make three dimensional tissues on demand.”

The 3-D bio-printers include an intuitive software interface that allows engineers to build a model of the tissue construct before the printer commences the physical constructions of the organs cell-by-cell using automated, laser-calibrated print heads.

To help them develop the 3D bio-printers, Organovo selected Invetech in May 2009 as their technology development partner. “We selected Invetech because of their capabilities for sophisticated engineering and automation, cultural fit as a long term partner and their consideration towards protecting Organovo’s bioprinting IP and maximizing our commercial return on the program. They have good processes for product development and project management, and it was apparent that project execution would be handled very well. Invetech really offered the best overall package.” said Mr. Murphy.

Invetech was asked to design and develop a highly integrated, extremely reliable and simple to use 3D bio-printer system which could then be transferred to manufacture and commercial sale. Because of its history with precision design, robotics and manufacturing products, Invetech was able to combine prior art with new ideas to come up with a development plan that met Organovo’s budget and design goals. The process advanced smoothly and on schedule with Invetech teams in Melbourne and its San Diego office, not far from the Organovo office.

The printer, developed by Invetech, fits inside a standard biosafety cabinet for sterile use. It includes two print heads, one for placing human cells, and the other for placing a hydrogel, scaffold, or support matrix. One of the most complex challenges in the development of the printer was being able to repeatedly position the capillary tip, attached to the print head, to within microns. This was essential to ensure that the cells are placed in exactly the right position. Invetech developed a computer controlled, laser-based calibration system to achieve the required repeatability.

Invetech plan to ship a number of 3D bio-printers to Organovo during 2010 and 2011 as a part of the instrument development program. Organovo will be placing the printers globally with researchers in centers of excellence for medical research

Invetech

Organovo