New techniques emerge amid the evolution of cartilage repair
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Although cartilage repair and restoration still pose clinical challenges in orthopedics, the knowledge of cartilage repair and healing gained in the last decade has resulted in advanced surgical techniques and improved outcomes.
Many cartilage repair technologies available today look similar to those from 10 to 15 years ago, Kai Mithoefer, MD, of the Boston Sports and Shoulder Center and co-director of joint preservation at New England Baptist Hospital, said, noting these technologies have evolved into different techniques that provide better outcomes.
Source: K. Mithoefer
“The individual cartilage repair techniques have advanced to the next-generation technologies by reducing technical shortcoming of earlier generation technologies and with resultant improvement of clinical outcomes,” Mithoefer told Healio/Orthopedics Today.
As one of the most frequently used technologies for cartilage repair, microfracture has shown reasonable midterm to long-term results as long as it has been used for chondral defects with lesions less than 2 cm2 and with healthy surrounding cartilage, Mithoefer said. The quantity and quality of the repair tissue has been a factor in the durability of microfracture, with published literature showing decreased function 2 years after microfracture due to the limited amount and quality of repair tissue fillers, he said.
Improvements in microfracture
Mithoefer said recent discussions about the microfracture technique have focused on the awl or pick used to create small holes in the bone and its effect on the subchondral bone.
“Recent studies have shown that overgrowth of the subchondral bone can occur in up to 63% of the cases and the presence of overgrowth has been associated with an eight-times increased failure rate after microfracture,” Mithoefer said.
These findings have led to the development of new tools, such as nanofracture, which can be gentler on the subchondral bone, he said.
“They do not completely avoid the subchondral changes, but they have been shown in clinical studies to improve outcomes in comparison to the first-generation microfracture,” Mithoefer said.
Small drills have also been introduced in place of microfracture picks to reduce the occurrence of subchondral cysts and stiffening, according to Kenneth R. Zaslav, MD, FAAOS, director of the Center for Regenerative Orthopedic Medicine (CROM) at Lenox Hill Hospital, Northwell Health.
“The hope is that with a less stiff or more resilient or shock absorbent bone beneath, the new cartilage will last longer,” Zaslav said.
Daniel A. Grande, PhD, associate director of research at the CROM at Northwell Health, said products like scaffolds or ones that are combined with adipose or lipoaspirate stem cells with bone marrow aspirate (BMAC), are being used to augment and improve microfracture outcomes.
“[Microfracture is] still used widely, but it has suboptimal results and so there is also a proliferation of products out there to help improve that, whether it is a proprietary marrow augmentation method or some other thing,” Grande said.
Chondrocyte implantation
Another cartilage repair technique, autologous chondrocyte implantation (ACI), which has an 85% to 90% success rate at 20 years, has evolved into matrix-induced autologous chondrocyte implantation (MACI, Vericel), according to Zaslav.
Although MACI was approved by the FDA in 2016, Mithoefer said the technology has been used in Europe for more than 15 years.
“Long-term studies are available from Europe on the MACI technology that have shown excellent durability of the cartilage repair tissue and associated functional improvements 15 years after implantation, both in terms of pain and function, but also in terms of athletic ability, which is a key objective of what we are trying to achieve with these procedures,” he said.
One of the most significant improvements between ACI and MACI is related to the simplified surgical implantation technique, according to Mithoefer. ACI involves stitching a membrane scaffold from the patient over the defect and injecting chondrocytes beneath it, whereas MACI involves fixing a chondrocyte-coated membrane with fibrin glue to treated cartilage area.
“This significantly reduces the surgical time and additional technical improvements, such as the introduction of custom cutting templates, allow for a technically simplified and more perfectly fitted implantation of the graft into the area of the cartilage defect and have made a significant difference for technical ease and surgical time without compromising the effectiveness of the procedure,” Mithoefer said of the MACI procedure.
Unlike earlier generations of ACI, MACI has been approved for use in the patella, according to Brian J. Cole, MD, MBA, section head of the Cartilage Restoration Center at Rush University Medical Center.
Osteochondral allografts
Jason L. Dragoo, MD, professor and endowed chair of Regenerative Medicine at the University of Colorado School of Medicine and UCHealth, said if there is injury to the bone below the cartilage, the subchondral bone, osteochondral allograft transplantation (OCA) will be the principal procedure used going forward, because it provides a more structural solution from the beginning.
Over time, use of less bone in the allografting procedure led to better bone-to-bone healing, according to Zaslav.
Mithoefer said the addition of BMAC to the allografts facilitated bony ingrowth and healing.
Dragoo said the future of OCA research will involve learning how to resurface larger areas of the joint with larger and custom-shaped grafts instead of the current small- to medium-sized circle-shaped grafts.
“There are many limitations to our current technique, but the bottom line is this will require better transplantation matching,” he said. “Improved computer software matching of joint surfaces is being developed now; new instruments will be required to custom-cut cartilage for larger surface areas.”
Latest FDA cartilage approval
The Agili-C implant (Bioventus) is the newest product for cartilage repair to receive approval from the FDA, according to Cole.
Zaslav said the Agili-C product is a biphasic aragonite plug with drill holes that draw mesenchymal stem cells from the bone marrow to help form new cartilage cells.
“We get a unique chondral repair with these plugs, and we get perfect subchondral bone beneath and good-looking articular cartilage above,” Zaslav said.
According to results from a clinical trial used to obtain FDA approval, patients who received the Agili-C implant reported a 21-point improvement in KOOS pain and function scores compared with patients who underwent current standard-of-care arthroscopic procedures. Results also showed 88.5% of patients treated with the Agili-C implant had at least 75% of their cartilage defect filled with new tissue at 24-month follow-up.
The study included patients with chondral defects alone, as well as patients with chondral defects and mild to moderate arthritis, according to Zaslav.
“This is the first new technology for cartilage repair, and it is approved for all surface lesions of cartilage in the knee, including those with mild arthritis, just excluding severe arthritis,” he said. “This is a major breakthrough.”
Creating a good joint environment
Dragoo said outcomes of a cartilage procedure depend not only on the type of repair performed, but on the patient’s joint being a good environment for the maintenance of the transplanted tissue.
“There are new techniques that change the joint environment along with cartilage resurface,” Dragoo said. “That is in contrast to before, where all of the talks on the podium were just describing the cartilage repair techniques. These cannot be performed in their own silo. There has to be more focus on changing the forces within the joint to obtain results over time.”
Malalignment also should be addressed in patients with cartilage defects, Zaslav said.
“If the patient has a cartilage defect, but they are also malaligned and you do not address the malalignment, then whatever you do is bound to fail because, just like the cartilage that you were born with failed with that malaligned joint, the new cartilage will, too,” Zaslav said.
He said surgeons must consider meniscus integrity, as well as the option of a meniscus transplant if most of the patient’s meniscus is gone. Patients should also have good ACL and PCL stability, Zaslav said.
“If you put these good technologies into a healthy environment, or a complete organ, ie, you align the knee, make sure it is stable, you have a good meniscus and you perform the transplant, the results have a lot of longevity,” Zaslav said. “If you put any of these technologies in a poorly aligned joint and do not realign, it or an unstable joint and do not put a new ligament in, you are going to fail.”
Future research
As research on cartilage repair and restoration continues to evolve, one area that needs more understanding is how bone pathology contributes to pain and how that pain can be addressed, according to Cole. He said more research is needed on “the use of orthobiologics as an augmentation or adjunct to existing treatments for cartilage repair.”
Similarly, Dragoo said future research should examine whether the best resources to restore cartilage are within our bodies — our own progenitor cells — or if we need to rely on transplantation of cells and tissue from a donor who is healthier or has a more intact cartilage surface.
“Our hope is we could do a better job of stimulating our body to heal using our own body’s resources,” Dragoo said.
He said the next generation of nonstructural cartilage restoration will not involve the use of chondrocytes, which have limited growth potential. Instead, it will use less mature cells, such as adult progenitor cells, which may have more restoration potential.
One ongoing multicenter study is focused on whether certain aspects of platelet-rich plasma have a positive correlative effect on patients who may not be responders and whether a genetic sequence analysis and profile of the PRP can be corroborated, according to Grande.
“What we are looking for in outcomes is the ability to provide evidence-based medicine for what PRP should be used for, what should it not be used for, what works in PRP, etc.,” Grande said. From the study, “we will be able to provide information to support that, which I think is important for how surgeons should deliver PRP.”
Grande said he hopes the information gained by identifying the morphologically active constituents of PRP that benefit patients can be used to gain FDA approval for future cartilage repair treatments or provide more precise treatment for osteoarthritis.
Data on next-generation approaches
Grande said there has been extensive research on synovial fluid stem cells that have promising chondrogenic capabilities. These cells could be used as a next-generation drug for treating cartilage injuries and OA. Research is also being done on minced cartilage from non-weight-bearing sites used for cartilage repair, he said.
“Other things that I think are ‘hot’ are some of the work done by Farshid Guilak, PhD, at Washington University, in which he has been able to use CRISPR-Cas9 to have cells that can be implanted in the joint, but also be regulated like a rheostat or thermostat where they can be programmed to put out interleukin-1 [IL-1] receptor antagonists,” Grande said. “It can be turned on and off by a switch, like a rheostat, when it detects IL-1 beta in the synovial fluid, for promoting an anti-inflammatory, as well as a regenerative, property in the joint.”
Most importantly, more data are needed about the next generation of cartilage repair procedures, according to Dragoo.
“We have some basic science data, we have some biomechanics, but we do not have clinical trials,” Dragoo said. “We just do not have the clinical evidence for the new generation approaches to cartilage restoration, so we need to spend money and time to perform clinical trials that will supply the proof that these new generation products work better than the previous generation.”
Challenges with the FDA
Although results of the basic science and animal studies on these materials have been promising, Mithoefer said it is hard to translate these studies into higher clinical studies due to the rigorous requirements of the FDA.
Although necessary, the “combination of innovation that is challenged by the burden of the regulatory process” has led to difficulties enrolling patients in clinical trials, according to Cole.
“Over the last 10-plus years, we have seen two or three phase 3 studies die on the vine because of lack of enrollment,” Cole, who is an Orthopedics Today Editorial Board Member, said. “The requirements of the FDA have made it particularly difficult to enroll patients in a meaningful way. I think the market is, in some ways, poorly differentiated and reimbursement challenges have also created some difficulties, as well.”
However, Dragoo said, as part of the 21st Century Cures Act, the FDA has committed to changing and making new pathways for biologic product development to help bring new products to the market.
“There are many new companies that currently have FDA pathway products that employ autologous cells and cartilage tissue,” Dragoo said. “So, they are in development. They just have not made it across the finish line.”
- Reference:
- Agili-C – P210034. https://www.fda.gov/medical-devices/recently-approved-devices/agili-c-p210034. Published April 29, 2022. Accessed August 3, 2022.
- Brittberg M. Ann Jt. 2018;doi:10.21037/aoj.2018.11.09.
- Brittberg M. Journal of Cartilage and Joint Preservation. 2022;doi:10.1016/j.jcjp.2022.100060.
- Carey JL, et al. Orthop J Sports Med. 2020;doi:10.1177/2325967120941816.
- Hulme CH, et al. Emerg Top Life Sci. 2021;doi:10.1042/ETLS20210015.
- Krych AJ, et al. J Am Acad Orthop Surg. 2020;doi:10.5435/JAAOS-D-20-00266.
- Lyman S, et al. J Bone Joint Surg Am. 2016;doi:10.2106/JBJS.15.00573.
- Martin AR, et al. NPJ Regen Med. 2019;doi:10.1038/s41536-019-0074-7.
- McGowan KB, et al. Cartilage. 2013;doi:101177/1947603512460756.
- Medvedeva EV, et al. Int J Mol Sci. 2018;doi:10.3390/ijms19082366.
- Vaishya R. J Clin Orthop Trauma. 2016;doi:10.1016/j.jcot.2016.06.001.
- For more information:
- Brian J. Cole, MD, MBA, can be reached at 1611 W. Harrison St., Chicago, IL 60612; email: brian.cole@rushortho.com.
- Jason L. Dragoo, MD, can be reached at 175 Inverness Drive West, Suite 200, Englewood, CO 80112; email: alli.friedman@uchealth.org.
- Daniel A. Grande, PhD, can be reached at 350 Community Drive, Manhasset, NY 11030; email: dgrande@northwell.edu.
- Kai Mithoefer, MD, can be reached at 125 Parker Hill Ave., Boston, MA 02120; email: kmithoefer1@gmail.com.
- Kenneth R. Zaslav, MD, FAAOS, can be reached at 100 E. 77th St., New York, NY 10075; email: kzaslav@gmail.com.
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