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Science Highlight: March 5, 2013

New Cartilage Grows, Helps Repair Damaged Joints Thanks to Novel Engineering

Patients with cartilage damage were successful in regenerating new cartilage tissue, thanks to an innovative technique developed by an NIBIB grantee. The technique creates a scaffold by combining the use of a biogel that solidifies when exposed to light and a strong biological adhesive. It was recently tested in a small clinical trial in patients undergoing microfracture surgery a first-line therapy for cartilage repair. Patients who received the gel and adhesive experienced enhanced cartilage regeneration and decreased pain at six months post-surgery. The technique has the potential to transform the field of cartilage repair, which is notorious for poor clinical outcomes.

Current Approaches to Cartilage Repair

Hyaline cartilage is the name of the tough, flexible tissue that serves as a cushion for bones at joints, preventing them from rubbing against each other during physical activity. When hyaline cartilage is damaged as a result of trauma or gradual wear and tear normal movement of the joint can become limited and patients can experience severe pain as bones begin to grind against each other. Both can lead to disability over time.

Unfortunately, damage to cartilage is not readily repaired by the body. That’s because cartilage unlike most tissues in the body doesn’t have its own blood supply to bathe damaged tissue and provide factors promoting regeneration. Consequently, surgeons currently employ a technique called microfracture surgery to facilitate new cartilage growth. The surgery is generally performed in young adults who have a tear in the cartilage that surrounds the knee as a result of sports injury and is not effective in patients with widespread cartilage degeneration, or osteoarthritis.

During microfracture surgery, tiny holes are drilled into the bone located directly below missing cartilage in order to release blood and stem cells into the damaged space. The resulting “super clot” provides an enriched environment that promotes the production of new cartilage.

However, only 50% of microfracture surgeries are deemed successful in the long-term[1]. A main issue is that the resulting clot produces a new type of cartilage called fibrocartilage a mixture of smooth hyaline cartilage and fibrous scar-like tissue. This fibrocartilage is tough and dense and doesn’t function as well as hyaline cartilage as a cushion between joints. Additionally, microfractures can stimulate the production of bone tissue which can infiltrate regenerating cartilage and similarly disrupt its function.

Lighting the Way Towards Cartilage Regeneration

Though cartilage does a poor job of regenerating inside the body, researchers have been successfully building human cartilage outside of the body for decades. The process involves planting cartilage-producing cells or chondrocytes into a biological scaffold and then incubating them in conditions similar to those found in the human body.

Jennifer Elisseeff, Ph.D. director of the Cell and Tissue Engineering Program at Johns Hopkins University and inventor of the novel biogel and adhesive says scaffolds are key influencers of cartilage production. In her lab, she uses a specific type of scaffold called a hydrogel.

“As we’ve been learning more about biomaterials and how cells respond to them, we’ve learned that chondrocytes prefer to be in a softer material,” Elisseeff said. “The hydrogel environment provides a better mimic of the soft environment that is present when a tissue initially develops in a fetus.”

Not only do hydrogels encourage the production of cartilage, but they also deter the development of unwanted tissue. “We want to reduce scar formation and bone formation and these types of hydrogel scaffolds do that,” Elisseeff said.

(A) A mini-incision approach was created to expose the cartilage defect. (B) The adhesive was applied to the base and walls of the defect followed by surgical microfracture. (C) Last, the hydrogel solution was injected into the defect and solidified with light. (D) Bleeding from the microfracture holes was trapped in and around the hydrogel.

After several years of growing high-quality cartilage in the lab, Elisseeff predicted that if she could introduce a hydrogel scaffold into a patient following microfracture surgery, she might be able to influence the quality of the cartilage regenerated. Perhaps she could deter stem cells from producing fibrous and bony tissue, and, instead encourage them to produce smoother, hyaline-like cartilage.

But implanting a scaffold into a cartilage defect, which is an irregular space where cartilage has broken off or deteriorated, is no easy task. That’s because cartilage is slippery and any attempt to adhere a smooth gel scaffold to the walls of a cartilage defect is a losing battle. Adherence, however, is crucial. Without it, new tissue won’t integrate into a patient’s existing tissue, and thus won’t become functional.

It was with these barriers in mind that Elisseeff began to develop two novel technologies. The first was a gel made up of special molecules that polymerize or form chains when exposed to light, causing the gel to harden, forming a scaffold. The second was a biological adhesive that could bond to both her gel and to specific proteins found on the surface of cartilage tissue. Not only does the adhesive help to secure the hydrogel in place, but the type of material used chondroitin sulfate also promotes tissue growth at the interface of the hydrogel and tissue.

Elisseeff’s end goal was for a surgeon to be able to inject her gel into a cartilage defect directly following microfracture surgery whereupon it could mix with blood and stem cells released from the underlying bone↲and then make it harden with exposure to light. The biological adhesive would be applied to the cartilage walls surrounding the defect as well as the underlying bone prior to the surgery to ensure integration of the new tissue.

Clinical Trial Results

Elisseeff’s photoreactive gel and biological adhesive were recently tested in a pilot clinical trial involving eighteen patients with a tear in the cartilage surrounding their knee. Fifteen patients received microfracture surgery with the gel/adhesive combo while three patients received microfracture surgery alone.

New cartilage growth was assessed at sequential time points post-surgery using an innovative MRI technique developed by Garry Gold, M.D., of Stanford University. Through research supported by NIBIB, Gold developed a way to use MRI to distinguish between fibrous and smooth cartilage. This allowed the quality of cartilage to be assessed as it regenerated without taking a biopsy, a procedure that can be detrimental even when removing just a small amount of tissue.

Published in Science Translational Medicine, January 13, 2013, results from the trial showed that repaired cartilage filled more of the cartilage defect (86%) in patients who received the gel/adhesive than those who didn’t (64%). Additionally, there was no sign of bone overgrowth in patients who received the gel/adhesive, whereas one of the three patients who received only microfracture surgery showed signs of bone ingrowth. Lastly, cartilage formed in patients who received the gel/adhesive more closely resembled patient’s native cartilage at six months than patients who did not as verified by MRI.

Patients who received microfracture surgery alone reported an initial decrease in pain at three months that returned to base-line levels at six months post-surgery; those who received the gel/adhesive continued to report a decrease in pain at six months.

Rosemarie Hunziker, Ph.D., Program Director of the Division of Discovery Science and Technology at NIBIB said the study is exciting because it combines advancements in the fields of bioengineering and bioimaging to solve a long-standing problem in the field of cartilage repair.

“Tissue engineers have been making beautiful cartilage in the lab for years, but integration of new tissue into a cartilage defect has been the elusive “holy grail” that Dr. Ellisseff and her team may have found,” said Hunziker. “Still, without a way to evaluate new cartilage non-invasively, we wouldn’t have an objective method for determining whether this highly complex strategy really worked. The interplay of the sophisticated bioengineering based on key insights in the biology of cartilage, together with the novel MRI monitoring is a beautiful example of what the NIBIB does best… combining the life and the physical sciences to solve challenging and important problems in medicine.”

A larger clinical trial testing the gel and adhesive for cartilage repair is currently underway.

-- Margot Kern


1 Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR, Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am. J. Sports Med. 37, 2053-63 (2009).

 

Program Area: 
Health Terms: 
Biomaterials,
Injury,
Pain Conditions - Chronic,
Tissue Engineering/Regenerative Medicine