Orthobiologics are biological substances that allow injured muscles, tendons, ligaments, and bone to heal more quickly. They are found naturally in the body; at higher concentrations they can aid in the healing process. These substances include autograft bone, allograft bone, demineralized bone matrix, bone morphogenic proteins, growth factors, stem cells, plasma-rich protein, and ceramic grafts. Their use in sports medicine has exploded in efforts to increase graft incorporation, stimulate healing, and get athletes back to sport with problems including anterior cruciate ligament ruptures, tendon ruptures, cartilage injuries, and fractures. This article reviews orthobiologics and their applications in pediatric sports medicine.
Key points
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Orthobiologics are biological substances that allow injured muscles, tendons, ligaments and bone to heal more quickly.Orthobiologics stimulate healing with a variety of osteoconductive, osteoinductive, and/or osteogenic properties.
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There is a paucity of literature involving pediatric patients; however, studies are underway with potentially transferrable results indicating their use in children.
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Autograft is the primary graft choice in most pediatric cases, including ligament reconstructions and osteochondral defects.
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Plasma-rich protein has shown promise in treating tendonopathies in adults and is used as an adjunct in other sports procedures. No specific pediatric studies have been conducted.
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The future of orthobiologics in pediatric sports medicine is promising, but more investigation must be done before its routine use in pediatric sports medicine.
Introduction
Orthobiologics are biological substances that allow injured muscles, tendons, ligaments, and bones to heal more quickly. These substances occur naturally in the body and, at higher concentrations, can aid in the healing process. Autograft bone, allograft bone, demineralized bone matrix, autologous bone marrow aspirate, bone morphogenic protein (BMP), platelet-rich plasma (PRP), and ceramic grafts are all types of orthobiologics. Over the last 2 decades, both surgeon interest and industry development have substantially increased. A PubMed search on “orthobiologics” resulted in 66 articles dating back to 2004. In 2013, the global orthobiologics market was estimated to be $3.7 billion dollars. It is expected to increase to $5.8 billion dollars by 2018. Much of the market interest is distributed throughout the subspecialties in orthopedic surgery, including trauma, foot and ankle, spine, sports medicine, and pediatrics. Their use in sports medicine has exploded in efforts to increase graft incorporation, stimulate healing, and get athletes with problems such as anterior cruciate ligament (ACL) ruptures, tendinopathies, and cartilage injuries back to sport. Because of the healing and regenerative potential in pediatric patients, there is a paucity of studies involving the use of orthobiologics in children with sports injuries. Much of their use in children has involved spinal surgery, tibial pseudarthrosis, and benign bone lesions. The purpose of this article is to review orthobiologics and their applications in pediatric sports medicine.
Introduction
Orthobiologics are biological substances that allow injured muscles, tendons, ligaments, and bones to heal more quickly. These substances occur naturally in the body and, at higher concentrations, can aid in the healing process. Autograft bone, allograft bone, demineralized bone matrix, autologous bone marrow aspirate, bone morphogenic protein (BMP), platelet-rich plasma (PRP), and ceramic grafts are all types of orthobiologics. Over the last 2 decades, both surgeon interest and industry development have substantially increased. A PubMed search on “orthobiologics” resulted in 66 articles dating back to 2004. In 2013, the global orthobiologics market was estimated to be $3.7 billion dollars. It is expected to increase to $5.8 billion dollars by 2018. Much of the market interest is distributed throughout the subspecialties in orthopedic surgery, including trauma, foot and ankle, spine, sports medicine, and pediatrics. Their use in sports medicine has exploded in efforts to increase graft incorporation, stimulate healing, and get athletes with problems such as anterior cruciate ligament (ACL) ruptures, tendinopathies, and cartilage injuries back to sport. Because of the healing and regenerative potential in pediatric patients, there is a paucity of studies involving the use of orthobiologics in children with sports injuries. Much of their use in children has involved spinal surgery, tibial pseudarthrosis, and benign bone lesions. The purpose of this article is to review orthobiologics and their applications in pediatric sports medicine.
Properties of orthobiologics
Three fundamental principles frequently are cited in describing the biology of bone grafting. All options provide unique combinations of osteoconductive, osteoinductive, and osteogenic properties ( Table 1 ).
| Osteoconductive | Osteoinductive | Osteogenic | |
|---|---|---|---|
| Cortical autograft | + | + | + |
| Cancellous autograft | +++ | +++ | +++ |
| Cortical allograft | + | +/− | − |
| Cancellous allograft | + | +/− | − |
| Demineralized bone matrix | + | ++ | − |
| Bone marrow aspirate | − | ++ | +++ |
| Bone morphogenic protein | − | + | + |
| Plasma rich protein | − | +++ | + |
| Ceramics | + | − | − |
Osteoconduction is the passive process by which a scaffold or trellis is implanted, allowing ingrowth of host capillaries, perivascular tissue, and mesenchymal stem cells (MSCs) to support ingrowth of new bone. These osteoconductive scaffolds have structures similar to cancellous bone. Bone autograft and allograft, demineralized bone matrix, calcium sulfate, and calcium phosphate are primary examples of osteoconductive grafts.
Osteoinduction is the process by which substances within the graft recruit pluripotent MSCs, which differentiate into osteoblasts and chondroblasts to form new bone through endosteal ossification. Growth factors such as BMP, platelet-derived growth factor, interleukins, fibroblast growth factor, and vascular endothelial growth factor play a role in mediating this process. Examples of orthobiologics with osteoinductive properties include bone autograft, BMP, bone marrow aspirate, and PRP.
Osteogenesis is the synthesis of new bone from graft containing viable donor osteoblasts or their precursors. This process then promotes primary bone formation in the proper environment using MSCs, osteoblasts, and osteocytes. Fresh autologous grafts and bone marrow aspirate are orthobiologics with osteogenic properties.
Autografts
Autologous grafting is the process by which bone and tissue are harvested from 1 site on the host and transplanted to another site in the same patient. It confers osteoconductive, osteoinductive, and osteogenic properties and is completely histocompatible. For these reasons, it is considered the “gold standard” to which all other orthobiologics are compared. Autologous grafts, however, do have limitations. Donor site pain, increased blood loss, increased operative time, and the potential for donor site infection are all drawbacks. Furthermore, there is a limited supply from the host, particularly in pediatric patients. Autologous grafts can be cortical, cancellous, or osteochondral, and include soft tissue components. Each graft varies in their biologic properties and rates and methods of incorporation. This is the predominant graft choice for most pediatric patients undergoing sports related procedures ( Fig. 1 ).
Allografts
Allograft is a graft that is harvested from human cadavers, sterilely processed, and transplanted to a recipient. It can be cortical, cancellous, osteochondral, or formed into a highly processed derivative, such as demineralized bone matrix. It is primarily osteoconductive, but, depending on the processing, may retain some osteoinductive properties. To prepare allograft, the soft tissues and cells are removed with ethanol and the graft is gamma irradiated for sterilization. This sterilization process adversely effects the biologic properties of the graft and limits its osteogenic and osteoinductive potential. Cancellous allografts are in the form of chips or croutons that can be used as bone-void fillers, and cortical allografts can provide rigid structural support; both require incorporation similar to their autogenous counterparts.
More than 200,000 allografts are used in the United States each year, making them one of the most common orthobiologics used. Advantages include the lack of donor site morbidity, decreased operative time, and decreased blood loss. They do, however, have higher costs than other alternatives and have the risk of viral and bacterial transmission. These rates are exceedingly low, but still should be mentioned. Recent studies have shown a higher rate of rerupture in ACL reconstruction with the use of allografts in the pediatric population (MOON study [Multicenter Orthopedic Outcomes Network]). Subsequently, allografts are used much more sparingly in children and are more common in adult patients.
Autologous bone marrow aspirate
Autologous bone marrow is another source of orthobiologic material with osteogenic and osteoinductive properties with potential applications in sports medicine. Bone marrow aspirate has a high concentration of MSCs that can be injected into the recipient site. It is easily obtainable from the iliac crest. One of the proposed theories for its effectiveness is that it also contains endothelial cell progenitor cells that can stimulate angiogenesis and restoration of blood flow at fracture sites. Bone marrow aspirate offers the advantages of being easy to obtain with much lower morbidity and fewer complications than other autologous grafts; however, it does not confer any structural support and can seep away from the intended target site because it is a liquid. For this reason, it often is combined with other osteoconductive scaffolds such as DBX or ceramics.
Bone morphogenic protein
BMP was initially discovered almost 50 years ago. Since that time, more than 20 different proteins have been discovered. They are members of the transforming growth factor-β superfamily. Their osteoinductive properties function as part of complex signaling pathways involved in osteoblastic differentiation and osteogenesis. They have various functions, including osteoinductive activity, promoting cartilage formation, and promoting angiogenesis. Two of the BMPs (BMP-2 and BMP-7) have proven to be effective in type I clinical studies of tibial fractures and nonunions and have been marketed for orthopedic use. Although their osteoinductive properties are inarguable, a number of complications have been reported, including renal or hepatic failure, heterotopic bone formation, wound complications, compartment syndrome, and carcinogenesis. Furthermore, they are soluble proteins and have a tendency to dissipate from their graft sites, diluting their concentrations and potential effectiveness. Despite this, the promising clinical outcomes of BMP have made it an intense research subject and major investment for industry. The use of recombinant BMP in pediatric patients is currently off label, although the Food and Drug Administration has acknowledged that its use may be acceptable if the parents are fully informed.
Platelet-rich plasma
PRP is an autologous suspension of platelets derived from a patient’s whole blood with double centrifuge techniques. It confers both osteogenic and osteoinductive properties. Once centrifuged, the platelets separate out into the layer above the erythrocytes. The platelets are rich in key growth factors stored in the α-granule, including platelet-derived growth factor, transforming growth factor-β1, vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor, and insulin-like growth factor-1. This extraction is then combined with calcium chloride to activate the platelets. It can be injected into the host at that point to enhance stem cell recruitment, angiogenesis, and extracellular matrix production. PRP has had some success in treating lateral epicondylitis and Achilles tendinopathy in adults. Its potential applications in sports medicine are still being studied extensively; however, no trials are specifically studying pediatric patients.
Ceramic grafts
Ceramic grafts are synthetic calcium salt–based substitutes that are alternatives to autologous and allogenic bone grafts. They are strictly osteoconductive, but can be combined with other orthobiologics. Ceramics are widely available at a relatively low cost and do not have the same risks with donor site morbidity and viral transmission risks as other types of graft. Calcium sulfate, calcium phosphate, tricalcium phosphate, and coralline hydroxyapatite are all examples with slightly different resorption rates and characteristics. Several different forms are available, including powders, pellets, putty, blocks, and injectable forms. Ceramics are primarily marketed as bone void fillers and have been recommended for the treatment of unicameral bone cysts in the pediatric population.
Applications in pediatric sports medicine
Orthobiologics have been widely used in sports medicine. ACL ruptures, cartilage damage, tendinopathies, and fractures are common musculoskeletal injuries affecting the young athletic population. Although much of the research involving orthobiologics and sports medicine has been done in adults, there are some studies that are pediatric specific or have transferrable results that can be applied to younger athletes.
Ligament injuries
Ligamentous injuries and reconstructions in children and adolescents are increasing in numbers. ACL reconstructions alone have increased at a rate of 924% from 1994 to 2006. Year-round sports participation, the increasing number of athletes participating in sports, and more focus on a single sport are all theories of why this may be occurring. Major ligamentous injuries in the pediatric population include the ACL, the medial patellofemoral ligament, and the ulnar collateral ligament (UCL).
Pediatric ACL injuries are typically seen in several forms: tibial spine avulsion fractures, partial ACL tears, and full-thickness ligament tears. The role for orthobiologics in these injuries is primarily for reconstruction of the ACL or augmentation of the repair, but some have advocated for their use in primary repair as well. Murray is currently working on a bridge enhanced ACL repair (BEAR [ Bridge-Enhanced ACL Repair]) trial, where stitches and a bridging scaffold are used to stimulate healing in a torn ACL. These investigators have currently performed the surgery in 10 patients and preliminary results are promising, but still not definitive enough to recommend its routine use over reconstructive techniques.
Graft choice has been studied extensively in the literature. Recent studies have shown that younger patients have an increased risk of ACL graft rupture and that the risk of rupture with allograft reconstruction is considerably higher than with autograft reconstruction. The MOON cohort had a four times higher incidence of rerupture with allograft reconstruction compared with autograft reconstruction in 10- to 19-year-old patients (MOON). The type of autograft used for ACL construction also varies. Choices include bone–patellar tendon–bone, quadriceps tendon, and hamstring autograft. Current recommendations from the academy show similar results in outcomes and strength of the grafts with bone–patellar tendon–bone and hamstring (American Academy of Orthopaedic Surgeons guidelines). Owing to concerns for placing bone across an open physis, soft tissue autografting has become the graft of choice in immature patients. In older adolescents, both hamstring and bone–patellar tendon–bone autografts can be used. Additionally, the MOON looked at autograft size and the risk of revision and determined that larger soft tissue grafts (>8 mm) had less of a risk of rerupture.
Other roles for orthobiologics in ACL reconstruction have focused on augmentation with osteoinductive substances such as PRP. One study by Vavken and colleagues evaluated a biomaterial used in several large animal models of primary repair of partial and complete ACL transections. Researchers developed a collagen–platelet composite, which was placed into the wound site to enhance cellular proliferation and biosynthesis. Their findings showed promising functional outcomes when combined with primary repair.
Recent studies regarding the use of orthobiologics in ACL surgery in adults have reported mixed results. Figueroa and colleagues, in a systematic review of PRP use in ACL surgery, found that although ACL graft maturity occurred more quickly with the use of PRP, there was no proof that the clinical outcomes of ACL surgery were enhanced by the use of PRP. Two other studies looked at graft incorporation via MRI signal after intraoperative use of PRP. Silva and colleagues showed no difference at 3 months, whereas 6 months after hamstring autograft reconstruction Ventura and colleagues noted differences in MRI signal density in grafts augmented with growth factors intraoperatively. Another cohort study by the MOON group evaluated augmentation of allograft ACL reconstructions with PRP at the end of the procedure ( Fig. 2 ). They found that, although effusions were decreased at 10 days in the PRP group, this difference disappeared by 8 weeks; there were no differences in patient-reported outcomes or number of additional surgeries at 2 years. This currently is an intense focus in research, but no definitive conclusions on the use of PRP in pediatric patients can be made at this time.
