Although skeletal muscle and bone have robust regenerative potential, volumetric tissue loss overwhelms this innate regenerative capacity. Tendons, ligaments, and cartilage have limited regenerative potential, and the repair of these tissues following injury can be challenging.¹ The United States Bone and Joint Initiative estimates that for nearly one in two Americans older than 18 years, movement is restricted by a musculoskeletal disorder such as arthritis, back pain, fracture, osteoporosis, sports trauma, and other ailments that affect function and mobility. Regardless of the cause, musculoskeletal injuries represent a major cause of disability and burden to the health care system.² Strategies that can improve the restoration of functional tissue beyond that possible with current treatment methods are welcome and needed.

In the broadest sense, orthobiologics can be defined as those available naturally occurring products that have the potential to influence the behavior of cells and tissues. The targeted purpose of orthobiologic products is the repair of injured musculoskeletal tissues beyond a functional outcome that would otherwise be possible without their presence or influence. Orthobiologic products may include cells such as mesenchymal stromal cells (MSCs), isolated signaling molecules including bone morphogenetic protein, platelet products such as platelet-rich plasma, bioscaffold materials such as XenMatrix (porcine dermal surgical mesh), and demineralized bone matrix.

Autografts and allografts have not generally been considered as an orthobiologic and have generally been regulated as a human cells, tissues, and cellular and tissue-based product (HCT/P), but if the aforementioned definition is accepted, then such harvested tissues should also be considered as orthobiologics. It is recognized that these definitions and labels represent arbitrary semantics; however, these semantics are important in the discussion of autografts, allografts, and xenografts.

The use of tissue grafts in knee surgery, including the repair of cruciate and collateral ligament and meniscal injuries, is commonplace. Therefore, a brief historical review of such grafts at this anatomic site is relevant to the concept of orthobiologics. The use of autologous or allogeneic tissue to facilitate musculotendinous tissue repair has more than a century of reported use. Similarly, Lexer reported articular cartilage transplant during a span of almost 2 decades beginning in 1908.³ In 1913, Giertz⁴ described the use of autologous fascia lata for medial collateral ligament repair, and another study reported the use of fascia lata for anterior cruciate ligament (ACL) repair in 1917.⁵ The use of hamstring grafts for ACL repair was first reported by Galeazzi in 1924,⁶ and Franke⁷ was the first to describe the use of free bone-patellar tendon-bone grafts in 1969 for the same application. The use of allografts became more commonplace in the early 1980s when Curtis et al⁸ described the use of freeze-dried fascia lata for ACL repair. The process is referred to as fibrovascular creeping substitution, that is, the cellular, vascular, and connective tissue changes that occurred within the graft over time. The very concept of graft remodeling at the cellular level provided the stimulus for interventional strategies that could promote desirable tissue remodeling events and inhibit undesirable events.

In 1987, Jackson et al⁹ presented disappointing findings of ACL freeze-dried bone-patellar tendon-bone allografts in an experimental study in goats, but in 1991, more favorable findings were reported when a more thorough freeze/thaw process was used to remove cellular elements, that is, decellularization. In retrospect, the likely explanation between these disparate outcomes involves the fate of the cells in non-decellularized tissue grafts.

Free graft tissue is, by definition, devascularized and injured. As with all injured tissue, the initial response
of the recipient to such a graft involves activation of the innate immune system by cell debris and the associated damage-associated molecular patterns.¹⁰ An infiltration of neutrophils is quickly followed by mononuclear macrophages, the secretome of which largely determines downstream remodeling events. These downstream events include neovascularization, graft matrix degradation, fibroblast infiltration, and the formation of scar tissue. The cellular and extracellular components of every tissue and organ are repeatedly replaced (ie, turnover), albeit at different rates, as part of normal, healthy homeostatic processes. It is not surprising, therefore, that the same phenomenon occurs following surgical placement of decellularized autologous, allogeneic, and xenogeneic tissue and that it may occur at an accelerated rate compared with native healthy tissue. In the absence of cellular debris and other proinflammatory stimuli (eg, bacteria), the proinflammatory response is mitigated and the constructive replacement of native tissue occurs.

In contrast to default wound healing that typically results in scar tissue formation and absence of new functional tissue, the presence of an (acellular) extracellular matrix (ECM)-based bioscaffold provides not only a structural template but also biologically relevant signaling molecules that contribute to a functional, three-dimensional tissue replacement structure. It should be noted that the early stages of bioscaffold remodeling involve many of the same biologic processes that characterize inflammation, that is, cell infiltration and neovascularization that manifest as swelling, redness, and heat. The relevance of these events is the potential effect on the clinical evaluation and interpretation of normal graft remodeling versus an adverse inflammatory response or the presence of an infectious process. Both processes will manifest as swelling with possible redness in the early phase, but the downstream outcome will differ. An understanding of the biology of autografts, allografts, and xenografts will avoid misinterpretation of otherwise desirable events.

Xenotransplantation, or transplantation of organs or tissues across species boundaries, marked the earliest attempt at functional organ transplantation in the early 1900s. Although the clinical outcome was unsuccessful, these initial attempts identified the presence of a humoral substance that mediated rejection.¹¹,¹² Owen¹³ suggested a genetic component to allogeneic and xenograft rejection when a kidney from one calf was successfully transplanted into its identical twin. Although transplantation of xenogeneic organs is still not feasible, the use of decellularized tissue (ie, the remaining ECM) products is commonplace.

Acellular xenogeneic and allogeneic ECM scaffold materials do not elicit an adverse immune response; rather, these materials activate the immune system toward a prohealing, restorative immune response.¹⁴,¹⁵,¹⁶,¹⁷,¹⁸ Such materials are available as surgical meshes,¹⁹,²⁰,²¹ topical powders and hydrogels, and hybrid forms as inductive scaffolds for wound healing.²²,²³ The reservoir of cytokines, chemokines, and matrix-bound nanovesicles released from ECM bioscaffolds facilitate events that promote not only the development but also the maintenance and repair of tissues when such bioscaffolds are placed at the site of injury. These processes facilitate the inherent restorative capacity of the human body to the extent possible in adult mammals.¹⁶,²⁴,²⁵,²⁶,²⁷,²⁸

The use of biologic materials to support and promote tissue healing, specifically allogeneic and xenogeneic tissues, has become commonplace in a variety of surgical applications, including orthopaedic surgery. Although autologous and allogeneic donor tissue has been used to replace damaged or missing tissue/organs for at least 80 years, the value of removing cells from these donor tissues and using the remaining ECM was not fully recognized until the 1990s.²⁹ Just as the antigenic epitopes of allogeneic and xenogeneic cells elicit an acute rejection response, the effect of cytoplasmic and nuclear cell debris present within poorly decellularized tissue products elicits an inflammatory response that typically leads to scar tissue formation. In contrast, the thorough removal of cells and cell debris from harvested donor tissues tends to promote a constructive and functional tissue remodeling response. The message here is that not all bioscaffolds are created equal, and a working knowledge of their manufacturing considerations and the biology of graft remodeling will markedly improve the chances for a favorable clinical outcome.