Advances in Arthroplasty From the Harris Orthopaedics Lab: Maximizing Safety and Effectiveness

Research at Massachusetts General Hospital is improving joint implant materials to maximize their durability, minimize post-surgical pain and potentially eliminate infection-related complications associated with arthroplasty procedures.

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"During my 20 years in this field, I have seen the average age of those undergoing replacement surgery decrease from a little over 60, to now closer to the mid-fifties," says Ebru Oral, PhD, associate director of the Harris Orthopaedics Laboratory (HOL) at Massachusetts General Hospital. "An older population with longer active lives suggests that these procedures will be needed more often and in larger numbers. The successes in our lab and others have increased the safety and longevity of implants to address these issues."

Optimizing Materials for Long-term Use in Joint Implants

Orthopedists perform over one million total hip and knee arthroplasties annually in the United States, with a 103.7% increase in shoulder arthroplasties also reported from 2011 to 2017 (J Shoulder Elbow Surg). Further increases are expected as both the number of procedures performed in younger patients and the proportion of older adults in the general population grow (J Bone Joint Surg Am).

Total joint arthroplasty replaces damaged or dysfunctional joints with metal or ceramic bearings against counterfaces, most often made of ultra-high-molecular-weight polyethylene (UHMWPE). Because the friction in this system far exceeds that associated with natural cartilage, early challenges involved identifying surfaces able to withstand it. The primary goal of this surface is to avoid gradual disintegration and the generation of wear debris that might cause an inflammatory response and/or osteolysis.

Surfaces made of ultra-high-molecular-weight polyethylene (UHMWPE) have been used for biomedical applications related to joint replacements since the 1960s. However, the processes used to cross-link and sterilize UHMWPE require irradiation, which induces structural alterations that decrease its long-term stability.

As part of her postdoctoral research in the HOL, Dr. Oral developed a method incorporating an antioxidant in UHMWPE. "The technique involves the heat-mediated diffusion of liquid vitamin E in a homogenous distribution throughout the material and at a consistent concentration," describes Dr. Oral.

Studies showed that high-temperature melting of vitamin E-containing UHMWPE further increased its toughness and wear resistance (J Orthop Res). "Our work and that of others revolutionized UHMWPE's use in implants and largely eliminated issues with implant-related osteolysis," she says.

Developing Nonsurgical Approaches to Fighting Implant-related Infection

Prosthetic joint infection is among the most common reasons for revision surgery following total joint replacement. Systemic administration of antibiotics is an ineffective treatment due to limited penetration to the implant site.

The current gold-standard approach to treating infection is multistage surgery to remove all implanted components and replace them with an antibiotic-eluting compound, such as bone cement, which acts as a spacer within the joint for a 6- to 8-week period. Depending on the eradication of the infection, this is followed by another surgery to place a new implant.

This process presents potential complications:

• Weight-bearing activity with the spacer can result in dislocation or fracture
• Sub-optimal delivery of antibiotics (both concentration and duration) within the joint space
• Possible development of antibiotic resistance at the site due to delivery-related shortcomings
• The need for multiple surgeries to either address continued infection or replace the implants

To address these issues, the HOL has focused on developing load-bearing joint implant materials capable of efficiently releasing antibiotics over time to address in vivo infection effectively. Dr. Oral directed proof-of-concept research in an animal model resulting in a UHMWPE implant that both contained an antibiotic and demonstrated its sustained release over an extended period to alleviate infection at the implant site (Nat Biomed Eng).

"We were confident that this could be accomplished, but also understood that it differed significantly from previous UHMWPE formulations, as this constitutes an in vivo combination therapy," Dr. Oral notes. "Host conditions make it difficult to control for an immune response to the antibiotic, as well as variations in the bacterial strain associated with the infection and the possibility of acquired resistance."

Dr. Oral's current research now involves in vitro and preclinical studies to address how to prevent infections prophylactically and to tailor implants to patients according to their clinical profile.

Identifying Non-Opioid Solutions to Postsurgical Pain Management

Evidence suggests poorly managed postoperative pain after joint replacement is predictive of prolonged recovery, impaired function, and decreased patient satisfaction. Pain management following implant procedures generally involves the injection of a cocktail of medications at the implant site, resulting in 24 to 48 hours of relief. However, studies report variable outcomes of such injections following total knee and hip arthroplasties, and their ability to limit subsequent opioid consumption remains unproven.

The Harris Lab team is preparing to publish findings from a recent Department of Defense-funded study evaluating the possible delivery of analgesics via UHMWPE. Findings in an animal model demonstrated that a drug-eluting implant is at least as effective as synthetic opioids—and in some cases better—at providing pain relief following joint replacement. "Our results have confirmed the capability for sustained release of analgesics from UHMWPE over weeks. Targeting that relief to the implant site would be more effective and prevent the need for systemic administration of secondary drugs," Dr. Oral stresses.

Although questions remain concerning appropriate drug combinations and concentrations, the potential impact is particularly exciting. "We currently have two different formulations with translational potential in terms of their ability to be manufactured and processed using UHMWPE for clinical applications," Dr. Oral says. "This is definitely a new application for these drugs and will require navigating a very involved regulatory pathway for approval. However, I think the benefit is quite clear."

Ground Zero for Innovative Research to Optimize Implant Performance

Established in 1969 by Dr. William H. Harris, the HOL is a true innovation incubator, with lab investigators like Lab Director Dr. Orhun Murtatoglu and Dr. Oral authoring over 75 patents that have revolutionized arthroplasty. The lab is unique in its broad focus on basic and translational research, animal studies, and the active development and clinical application of better-performing implants.

Keeping with that mission, the HOL developed a technique—recently approved by the Food and Drug Administration—that allows chemical cross-linking of UHMWPE to eliminate gamma radiation use. And the lab's studies of infection control and pain management revealed novel insights about how the two therapies can potentially work together. "We have found that some analgesics can work synergistically with some antibiotics," Dr. Oral describes. "We are currently evaluating whether their combined delivery can address pain at the implant site and reduce the risk of acquired resistance to the antibiotic, thereby increasing its effectiveness."

Dr. Oral emphasizes that working in a clinical setting consistently reinforces the importance and potential impact of their work on people's lives. "Despite the fact that we are engineers and scientists, the environment engenders a motivation to consider problems in terms of their clinical translation constantly," she says. "Dr. Harris championed the concept of being both a clinician and researcher, as well as the importance of the lab as an engine capable of driving clinically relevant discoveries."

Learn more about the Harris Orthopaedics Laboratory

Learn more about research in the Department of Orthopaedic Surgery at Mass General