News Article

Reconnecting the ACL
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Featured firm in this article: Connective Orthopaedics Inc of Waltham, MA

As an orthopedic surgeon and researcher at Children's Hospital Boston, Dr. Martha Murray, MD, treats many young athletes who have torn their Anterior Cruciate Ligament (ACL). Her passion is developing ways to stimulate the healing of a patient's own ACL, rather than removing and replacing it. Her interest was piqued in graduate school when a friend tore his ACL and she wondered why it couldn't be stitched back together. Dr. Murray, who has a background in engineering, began by studying the underlying science of ACL regeneration. Over the years, she discovered a material that could facilitate ACL healing, tested it in animals, and developed surgical devices for the repair procedure. However she knew that bringing her innovations to the clinic would require a company partner. Today her technologies are in the hands of a startup company, Connective Orthopaedics, which is developing these products for clinical use. "Without translation, all the basic science in the world can't fix the ACL," said Dr. Murray. "Taking the steps toward clinical use--for anything from a drug or device or a completely new platform technology--requires interfacing with industry. The more clinicians can be involved in that translation, the better it will be for patients."

In the 1970's, surgeons tried sewing the ligament's ends back together, but the surgery failed 90 percent of the time within five years. Today, nearly 300,000 Americans tear their anterior cruciate ligament (ACL). The current technique for treating ACL tears is surgical reconstruction, which involves removing the torn ligament and replacing it with a graft of a tendon from elsewhere in the body or from a cadaver. While this allows patients to return to sports in the short term, many will develop early arthritis of the knee.

In her laboratory studies, Dr. Murray and colleagues found that the ligament tries to heal itself--cells migrate to the wound, growth factors are secreted and blood vessels appear to nourish the new tissue--but the ligament ends never join. What was missing was something to bridge the gap. Dr. Murray found a solution--a gel made of collagen and platelet-rich blood plasma. In animal studies, her team implanted the resulting gel into a torn ACL. Cells soon migrated into it, regenerated ligament tissue and made a permanent bridge, mending the tear. Murray published her findings (J Orthop Res. 2006 Apr;24(4):820-30) that show good healing, appropriate biomechanical function and a 40 percent return in strength six weeks after ACL injury.

Because she is a surgeon, Dr. Murray was always thinking about the end product that she would hold in her hands during a procedure. Her goal was to perform the ACL fix arthroscopically--via two small incisions, a camera to view the tear and a prototype device to deliver the end product (gel) clinically. With initial funding from CIMIT (Center for Integration of Medicine and Innovative Technology), she developed the device prototype in collaboration with students at MIT. With the benefit of an innovative prototype, ongoing facilitation by CIMIT and additional funding from the Massachusetts Technology Transfer Center (MTTC), she successfully engaged a local medical manufacturing company, Symmetry Medical Inc. (formally TNCO) to refine the device. Dr. Murray further advanced the technology by conducting a number of large animal studies in both pigs and dogs with funding support from the NIH, the Orthopaedic Research and Education Foundation and the National Football League. In a paper to be published within the next several months, the team has extended its results, with data in a pig model of ACL injury showing that the fix is effective for at least three months after surgery.

At this point in the technology's development, a company partner was needed to provide additional resources to translate her technology into clinical use. A company offers the necessary expertise to generate and maintain the IP portfolio, perform pre-clinical studies in a GMP/GLP manner, prepare for clinical studies, and integrate input from design and biologic experts.

After exploring various partnering options, the Technology and Innovation Office (TIDO) at Children's and Dr. Murray determined that a small startup company would be the best development partner. "We wanted the flexibility and nimbleness of a small company and also wanted to have some say in directing the path of research within the company," said Dr. Murray. TIDO of Children's agreed. "We knew that a startup would focus all of its efforts on development of the technology with the goal of getting it to market as quickly as possible," said Nurjana Bachman, PhD, manager of Business Development at TIDO. "This is aligned with our mission of facilitating the utilization of our patents for the benefit of patients and Dr. Murray's goal to develop a technology that she could use in clinic that would solve a problem that she observed and experienced as a surgeon."

Before deciding on a startup company, TIDO marketed the technology to a number of potential partners of various types--including large medical device companies, large companies with a focus on tissue engineering and regeneration, and medium sized companies with their own ground-breaking technologies. Each company was intrigued by the work, but since ACL repair had been declared a failure since the 1970s, the hurdle was particularly high to convince companies that Dr. Murray's innovation would be a viable solution. Further, the technology is disruptive in nature, with the potential to change the standard of care for ACL injuries. It represented an opportunity, but also a threat to large companies that currently have product lines that serve the current standard of care, ACL reconstruction.

Aaron Sandoski, Managing Director at Norwich Ventures, a Venture Capital Firm, saw these features as strengths of the technology, particularly in the hands of a startup company, rather than drawbacks. Throughout 2008, Sandoski had been looking into tissue engineering opportunities. When he reviewed Dr. Murray's technology, he felt it had all of the components of a successful product. It had a "game changing" technology, a large market and unmet medical need, and a passionate and cutting-edge research leader in the field. "Of all the technologies I reviewed in the tissue engineering arena, Dr. Murray's had the best odds to succeed," said Sandoski.

After ongoing talks with TIDO and Dr. Murray, the worldwide exclusive license agreement with a startup called Connective Orthopaedics, which received its initial funding from Norwich Ventures, was signed in 2008. At the time of the deal, 28 patent applications had been filed by TIDO. The patent portfolio includes the coverage of materials used to heal the native ACL, as well as the methods, the delivery devices, and the surgical kits that could be used in the ACL repair procedure.

While negotiating with TIDO, Norwich was able to conduct due diligence in conjunction with the startup formation. Norwich also brought in Dean Banks as the CEO, a venture capitalist who had previous experience in company operations, to run the newly formed company.

Thanks to Children's allowing Connective Orthopaedics to learn the ins and outs of the technology while the negotiation was taking place, the company was able to hit the ground running. A research lab was up and in operation in two months. A month later, they were able to reproduce the first generation material. "Connective benefitted from the strong relationship with Children's," said Banks.

The CEO was also impressed with the development Dr. Murray had done in five to ten years with public funding. "If you take a historical look at blockbuster medical technologies, you often see an inventive scientist/surgeon with a breakthrough hypothesis early, like Martha had in 2000, and they lay down a lot of patents well in advance of everyone in their field," said Banks. "Martha has all of the components of a healthcare innovator. With her training as an engineer, scientist and surgeon, she not only sees problems with the standard of care, but has the training and experience to fix them. On top of this, her determination and compassion drive her to move the technology forward and someday improve the lives of her patients."

Connective Orthopaedics is located in the Boston area and has positioned itself as a medical device company specializing in soft tissue repair in sports medicine applications, with the ultimate goal of healing the torn, native ACL. The company currently has seven employees, four of which are on the biomaterials team. Its scientific advisors include co-founder Dr. Kurt Spindler, MD from Vanderbilt University, and a Scientific Advisory Board (SAB) comprised of world renowned clinicians and researchers in orthopaedics, biomaterials and regenerative medicine.

Dr. Murray's role at Connective is to answer questions when they arise as a consultant, and she sits on the SAB and Board of Directors as a scientific resource. Sandoski believes the company will succeed behind the team it has built. "The combination of Dr. Murray's scientific and clinical expertise, the broad knowledge of the SAB, and the product development experience of Connective's phenomenal biomaterials team is a winning formula to change the way surgeons treat patients with ACL injuries." "Every day there is a celebration, a hurdle and someone new who steps up to get past that hurdle," said Banks.

The future looks bright for Connective Orthopaedics. "Connective has already achieved more than I ever could have hoped in getting this technology closer to being available for patients. Whatever else it accomplishes will be icing on the cake," said Dr. Murray.