Table 1 Characteristics of major osteobiologic alternatives to iliac crest bone graft.
HCT/P, human cell or tissue product; PLF, posterolateral fusion; PMA, premarket approval; BMP, bone morphogenetic protein; PDGF, platelet-derived growth factor
* Some Class II devices are 510(k) exempt, which is defined by the FDA.
† Human safety and efficacy have not been required to bring 510(k) orthopaedic bone grafts to market. However, human testing may be required to support a 510(k).
^ HCT/Ps are eligible for regulation exemption under Section 361 as minimally manipulated products where the mechanism of action is not “dependent on the metabolic activity of living cells,” otherwise they would be regulated as Class III medical devices.
+++ Definitely observed from studies
++ Somewhat observed from studies
+ Suggested by studies, perhaps some controversy or minimal effect
+/– Debate status
– None/no effect
Source: Abjornson C, Brecevich A, Callanan T, et al: ISASS Recommendations and coverage criteria for bone graft substitutes used in spinal surgery. Int J Spine Surg 2018;12(6):757-71.

AAOS Now

Published 12/20/2023
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John Cherf, MD, MPH, MBA, FAAOS

An Explanation of the Categorization of Osteobiologics

Editor’s note: This article is part two in a three-part series on osteobiologics. Part one, published in the November issue, discussed regulatory pathways of osteobiologics. Part three, published in January, discussed how surgeons can assess the quality and the costs of these products.

Historically, the “gold standard” for bone regeneration has been autologous iliac crest bone graft (ICBG).

ICBG is commonly used in orthopaedic surgery, as it possesses the three critical properties required for optimal bone regeneration: osteoinduction, osteoconduction, and osteogenesis. However, ICBG is associated with significant donor-site morbidities, including pain and infection. Success of a bone graft is enhanced when the product contains at least two of the following: cells for osteogenesis, signal for osteoinduction, and matrix for osteoconduction. Surgeons often mix osteobiologics together and/or with autograft to improve regenerative potential or to provide additional volume (often referred to as “extenders”).

The International Society for the Advancement of Spinal Surgery (ISASS) classified alternatives to ICBG into six major categories: cellular-based allografts (CBAs), nonstructural allografts, autologous cellular grafts, synthetic bone grafts, demineralized bone grafts (or demineralized bone matrices [DBMs]), and Class III drug-device combination products. Table 1 provides important characteristics for these six categories.

CBAs
CBAs contain a combination of osteoconductive carriers and cryopreserved allogeneic cells. Manufacturers often claim that these products are osteoconductive, osteoinductive, and osteogenic; however, the reproducibility of cell recovery, viability post-processing, and therapeutic dose have not been established. CBAs offer a promising bone-grafting technique; however, the regulatory pathway does not require clinical studies or FDA review of any data for market release. CBAs have very limited clinical or even preclinical data.

Nonstructural allografts
Nonstructural allografts are considered safe and are widely accepted in bone-healing procedures. Materials from human cadaver bones are processed, stored, and transplanted during surgery. Nonstructural allografts are available in bulk and can be fresh-frozen or freeze-dried in cancellous or cortical material. There is a significant body of literature and long-standing clinical experience with allografts. Most evidence describes allograft used as an extender combined with autograft or other osteobiologics. Risks of all allografts, including CBAs, include viral transmission and host rejection.

Autologous cellular grafts
Several different materials can make up autologous cellular grafts, including fresh autologous bone marrow aspirates. Platelets derived from peripheral blood and mesenchymal stem cells, obtained from bone marrow aspirate, are increasingly being used for various orthopaedic applications. Although the mechanism of action and precise biological composition are still poorly understood, these materials have had promising anecdotal clinical results for several orthopaedic applications, including bone regeneration. Autologous cellular grafts have mainly in vitro studies, with limited clinical studies available to support their safe and effective use.

Synthetic bone grafts
Currently available synthetic bone grafts are primarily tricalcium phosphate (TCP) and/or hydroxyapatite combinations. These osteoconductive compounds are attractive because they induce minimal immunologic reaction and have negligible systemic toxicity. Synthetics are available from many manufacturers in many forms with different chemical composition, porosity, and surface morphology, each of which influences biological activity. Synthetics have a long clinical history in orthopaedics, but the level of clinical evidence to support their safe and effective use is generally low and variable among products.

Demineralized bone matrices
DBMs are osteoconductive and potentially osteoinductive due to small amounts of retained bone morphogenetic proteins (BMPs) after removal of the mineral phase from cadaveric bone. DBMs have been used extensively in orthopaedic surgery alongside autogenous bone grafts in the repair of cysts, fractures, non-unions, and spine fusions. Evidence suggests a variation in DBM composition and concentration of BMPs associated with tissue processing. Although evidence exists for the use of DBMs with other osteobiologics, there is very limited evidence for standalone DBM use. DBM regulatory approval typically relies on animal studies, with limited clinical studies available to support their safe and effective use in humans.

Class III combinations
There are three Class III, drug-device combination products currently available: a BMP (Infuse, from Medtronic), platelet-derived growth factor (PDGF) (Augment, from Wright Medical), and peptide-based bone graft (i-FACTOR, from Cerapedics).

BMPs are known potent bone-forming agents. BMPs alone are considered osteoinductive and are usually added onto a collagen sponge or ceramic carrier. Evidence of the bone-forming potential of BMP-2 has been demonstrated in many preclinical and clinical investigations. Safety concerns, including wound complications and heterotopic ossification, have been reported, and it is believed that these issues may be due to high doses and lack of containment, leading to nonspecific action. Infuse (recombinant human bone morphogenetic protein-2 [rhBMP-2], Medtronic) is indicated in the United States for single-level anterior lumbar interbody fusion and for acute, open, stabilized tibial shaft fractures.

PDGF promotes wound healing and angiogenesis in humans, with preclinical studies demonstrating the stimulation of bone formation. Augment (Wright Medical) combines PDGF with B-TCP as an osteoconductive scaffold. Augment is supported by randomized, controlled trial data and is indicated in the United States for use as an alternative to autograft in arthrodesis of the ankle and/or hindfoot.

Peptides are short-chain amino acid sequences which are often copied from active sites in larger protein molecules or mimic cell binding or signalling domains. These products have a high degree of biological specificity to reduce the potential for unwanted clinical effects and provide predictable cellular responses. Numerous peptides for bone regeneration have been described in the literature. One peptide product has received premarket approval: i-FACTOR (Cerapedics), which is a 15 amino acid peptide that mimics the cell-binding domain of type I collagen. i-FACTOR is supported by randomized, controlled trial data and is indicated for use in single-level anterior cervical discectomy and fusion.

One of the limitations of the ISASS categorization of osteobiologics is the lack of a xenograft category. Both surgeons and patients need to be informed about biologics with xenograft materials to best understand the potential for disease transmission, immunologic rejection, as well as ethnic, cultural, and religious concerns. According to the ISASS categories, i-FACTOR is a Class III drug-device combination. The “drug” component is a synthetic peptide; however the “device” component is of bovine origin. This biologic might be better categorized as a xenograft or xenograft/synthetic combination.

There are significant variations in the regulatory pathways, mechanisms of action, compositions, clinical data documenting safety and efficacy, and costs within and between osteobiologics. The level of evidence available is often defined by classification and the associated FDA regulatory pathway. Class III drug-device products typically require FDA review of human clinical studies prior to approval, whereas other products generally do not and often have limited clinical and/or preclinical studies only. Additional information on osteobiologics can be found in the new AAOS textbook Orthobiologics, which is available at the AAOS Bookstore at aaos.org/store.

John Cherf, MD, MPH, MBA, FAAOS, is a member of the AAOS Board of Councilors, member of the AAOS Evidence-Based Quality and Value Committee, and vice chair of the Board of Councilors Committee on Economic Issues.

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