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Biologics include cells—such as stem cells, depicted here—as well as tissues and nonviable compounds such as growth factors.
Courtesy of Thinkstock

AAOS Now

Published 11/1/2016
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Adam I. Edelstein, MD

The ABCs of Biologics

The use of biologics is rapidly expanding in the treatment of orthopaedic pathology. Biologics are used to augment healing in various musculoskeletal tissues including bone, tendon, cartilage, and muscle. Biologics include cells, tissues, and nonviable compounds such as growth factors. Residents typically gain exposure to biologics during their surgical training but may have limited formal education on this topic.

In addition to mastering the procedural skills related to the use of biologics, residents must develop a knowledge base regarding their development, safety, and efficacy. This is especially true in light of the relative lack of regulatory oversight for certain biologics that reach the market without rigorous safety testing or evidence of efficacy. Although this article provides an overview, any surgeon considering the use of biologic augmentation should pursue an in-depth understanding of the points raised.

Biologic source
Biologics may be derived from the patient (autograft), transplanted from other human (allograft) or animal (xenograft) tissue, or synthetically derived. The age and sex of the allograft donor can influence the properties of the resulting biologic. For example, some studies have shown that donor age and sex influence characteristics of bone-patellar tendon-bone allografts used for anterior cruciate ligament reconstruction.

Use of allograft or xenograft tissues carries a potential risk of disease transmission. Donors are typically screened for medical history, and tissues undergo microbiologic and serologic testing. The American Association of Tissue Banks (AATB) provides standards for safe processing and handling of donor tissues, and the U.S. Food and Drug Administration (FDA) mandates the use of good tissue practices during manufacture. Risk of disease transmission is very low, although not zero, for most biologics derived from allograft and xenograft tissue.

It should be noted that not all manufacturers of biologic products use AATB-certified tissue banks. Additionally, many biologic products bypass rigorous safety testing by establishing substantial equivalence to products already on the market or by establishing that preparation of the biologic involved "minimal manipulation."

Method of collection
Various techniques are used to harvest autologous tissues or cells for use as biologic augmentation. These techniques include aspiration of bone marrow or peripheral blood, as well as surgical harvest of bone, soft tissue, or cartilage.

Some biologics, such as autologous bone graft, are used directly following harvest without further manipulation. Others require processing to isolate a desired component of the harvested tissue, as is done for platelet-rich plasma (PRP) from peripheral blood or the stromal vascular fraction from adipose tissue. Still others undergo more extensive processing, such as cells harvested for autologous chondrocyte implantation, in which harvested chondrocytes are isolated, expanded in culture, and subsequently reimplanted during a second surgery. The choice of harvest technique and subsequent processing steps affect the concentration, viability, and activity state of the cells and may impact the concentration of growth factors.

Carriers, reagents, diluents
Following collection and processing, biologics are often combined with biologically compatible carrier materials. These carriers can enhance handling properties to facilitate delivery to the target site, inducing a final product that may be a powder, gel, liquid, chips, or solid.

The type of carrier selected may affect the properties of the biologic or may alter the environment at the target site where the biologic is intended to function. In addition to carriers, other reagents or diluents may be added to the harvested biologic to alter its form or function. Conversely, a biologic may be concentrated or purified following collection, as with PRP.

Storage
Various storage techniques are used for biologics that are not harvested and used during the same procedure. Some biologics, such as demineralized bone matrix, can be stored in a lyophilized (freeze-dried) state and mixed with a carrier material immediately prior to use. Others are combined with the carrier at the time of packaging and are ready for use "off-the-shelf." The hydration status and temperature at which a biologic is stored may affect its activity at the time of use. The timing between biologic harvest and use may also affect the activation state and subsequent impact of the biologic.

Quantity and concentration
The quantity and concentration of the relevant biologically active components delivered to the target site may be highly variable, depending on the exact steps involved in the collection, processing, storage, and delivery of the biologic. For example, different preparations of PRP may contain differing concentrations of platelets, growth factors, and white blood cells and yield variable responses to treatment. Similarly, different lots of demineralized bone matrix, even from the same manufacturer, have been shown to contain highly variable amounts of growth factors.

Activation state
The potency of a biologic depends on its state of activation. The activation state of the biologic can be manipulated via the addition of reagents that trigger the desired biologic phenomenon.

When two biologics are mixed together, the result is a combination product. Such a product may have different properties than each constituent component in isolation, which makes combination products subject to more rigorous regulation by the FDA.

Standards of performance
Biologics are used with the intent of optimizing the local environment in which a healing process will occur. The extent to which the biologic is expected to affect the outcome of interest can be assayed in various ways, including the following: chemical or immunologic measures of biologic activity, in vitro assays to measure the impact of the biologic on cultured cells, or in vivo measures of biologic activity in animal models of the relevant disease process.

Clinical trials are the gold standard for demonstrating safety and efficacy of a biologic. To enable replication of the study and outcomes, reports of such trials must include details on the exact techniques used to harvest, process, and deliver the biologic because these steps significantly affect the outcome of biologic use. Many manufacturers consider that information proprietary. As a result, high-quality evidence is lacking for many biologics currently available. Familiarity with the latest evidence related to a specific product may help guide clinical use.

An abundance of biologic products are now available and are being used by orthopaedic surgeons with increasing frequency. Taking the time to learn about these products will be critical as surgeons seek to optimize safety and outcomes for patients seeking musculoskeletal care.

Adam I. Edelstein, MD, is a resident member of the AAOS Biological Implants Committee.

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