Bone Grafts, Bone Substitutes, and Orthobiologics: Applications in Plastic Surgery

Abstract

As reconstructive needs often extend past the soft tissue alone, a plastic surgeon must also be well versed in the methods of bony reconstruction. Understanding of the basic science of fracture healing and the biochemical mechanisms of the different bone grafts, bone substitutes, and orthobiologics is essential to selecting among the many different options available to the modern plastic surgeon. This review provides a broad overview of these different options and the specific applications for plastic surgeons based on anatomic location.

The human skeleton possesses a unique restorative capacity, and bone adaptability allows for efficient repair to prevent fractures. However, the dynamic equilibrium of bone can be overwhelmed by the sudden emergence of load exceeding bone strength or gradually accumulated damage under conditions of cyclic loading, resulting in bone fracture. ¹ Fracture healing and bone repair mirror the events that take place during the embryonic development of the skeleton, remarkably permitting bones to heal in a manner consistent with preinjury composition, structure, and function. ² Given the complex interlay of geometric, mechanical, and biologic factors affecting the repair process, not all fractures heal spontaneously. Suboptimal conditions such as infection, poor vascular supply, malnutrition, and significant bone or soft-tissue loss can impair effective osteosynthesis. ³ As a result, the goal of surgical fracture care is to facilitate the natural regenerative process of bone and restore function. Fracture care is accomplished by usage of modern bone grafts, bone substitutes, and orthobiologics that can augment healing via their osteoinductive, osteoconductive, and/or osteogenic mechanisms. ⁴ This review provides a comprehensive overview of the basic science, clinical utility, and future promise afforded by bone grafts, bone substitutes, and orthobiologics in promoting osseous union.

Fracture healing is understood as both a local and systemic process. While cellular signaling pathways and molecules function locally at the fracture site, there is systemic recruitment of mesenchymal stem cells (MSCs) from surrounding tissues. ⁵ Successful bone regeneration relies on the presence of progenitor cells, osteoinductive growth factors, and proper osteoconductive stimuli. ⁴ Consequently, delayed fracture repair or nonunion can result from an impairment of any or all of these factors. Fracture nonunion is commonly identified on radiography as either hypertrophic or atrophic. Hypertrophic nonunion is attributed to mechanical instability and repair is performed with skeletal fixation to restore stability. Atrophic nonunion is a result of biologic causes, such as poor vascularization and is treated by restoration of osteogenic potential by resecting impeding fibrous tissue and applying bone graft or another osteoinductive surface. ⁴

Bone grafts and substitutes possess osteoconductive, osteoinductive, and osteogenic properties to provide mechanical support and foster bone healing. Osteoconduction describes the attachment of osteoblast and osteoprogenitor cells, allowing the migration and ingrowth of host capillaries, perivascular tissue, and MSCs. Osteoinduction permits the differentiation of recruited MSCs into cells of the bone-forming lineage, such as chondroblasts and osteoblasts. ⁶ Osteogenesis refers to the final product of differentiation and subsequent formation of new bone by donor cells derived from either host or grafted materials.

Enhanced understanding of fracture healing has permitted the application of a wide variety of grafting materials, including natural bone grafts, synthetic bone graft substitutes, growth factors, and bioinorganic ions. Growth factors mediate the osteoinductive process and include bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), and platelet-rich plasma (PRP). ⁷ Bioinorganic ions, such as copper, silicon, magnesium, strontium, zinc, and silicon, are recognized as essential cofactors of human enzymes and coenzymes. The role of these ions in fracture repair is influenced by host site nutritional deficiency or excess as well as the ions' capacity to promote secondary signaling in the healing process. ⁷ The osteoinductive, osteoconductive, and osteogenic properties of bone graft substrates has been described in the literature and validated in plastic and reconstructive, orthopedic, and neurosurgical practice. The following sections provide an overview of the grafting materials in the surgeon's arsenal and the varied and ever-evolving applicability of these materials in reconstructive procedures.

Natural Bone Grafts

Autologous bone grafting is often considered the gold standard and describes the harvesting of osseous matter and subsequent transplantation to a different site within the same patient. ⁸ With osteoconductive, osteoinductive, and osteogenic properties, autologous bone grafts integrate well into the host bone. Furthermore, autologous bone grafting permits complete histocompatibility between the donor and recipient grafting sites. The commonly employed forms include cancellous bone graft, cortical bone graft, and vascularized bone graft.

Cancellous bone graft is rich in MSCs and therefore possesses significant osteogenic potential and the ability to regenerate new bone from graft. Cancellous autograft additionally has a large trabecular surface area for revascularization and site incorporation. ⁸ Following transplantation of this autologous bone graft, a local hematoma of inflammatory cells and chemotactic mitogens forms and promotes recruitment of MSCs to lay down fibrous granulation tissue. ⁹ Macrophages eliminate necrotic graft tissue while neovascularization commences. ⁷ Subsequent incorporation of the autograft leads to osteoblastic production of osteoid seams, which are mineralized over the following 6 to 12 months to form new bone. ⁹

Whereas cancellous bone is characterized by low density, cortical bone is highly dense and possesses superior structural integrity. The creeping substitution of cortical autograft is mediated primarily by osteoclasts, and following osteoclast resorption, there is appositional bone growth over a necrotic core. ⁷ This dense architecture does, however, limit the supply of osteoblasts, osteocytes, and other cellular progenitors in cortical bone. The process of revascularization and incorporation following transplantation can take several years, particularly when the graft and implantation site sizes are large. ³

Vascularized bone graft preserves nutrient, metaphyseal, and perforating vessels for anastomosis to arteries and veins at the recipient site. ³ Common vascularized grafts employed include free iliac crest, distal radius, and free fibula strut grafts. The vascularized graft is incorporated into the recipient site by primary or secondary bone healing, which can serve to increase the graft's osteogenic potential and prevent an initial loss of graft strength that is encountered in nonvascularized cortical grafts. ^{10 11} The grafting of viable vascularized autograft promotes primary bone healing at the host–graft interface, reducing the amount of time needed for healing and improving overall biomechanical stability as this type of graft does not undergo substitution. ¹²

Allogeneic bone grafting is performed via harvesting bony tissue from one individual and subsequently transplanting to a genetically different individual of the same species. ³ Allografts include cortical bone, cancellous bone, and demineralized bone matrix (DBM). Though lacking in osteogenic potential, allografts exhibit both osteoconductive and osteoinductive properties. ¹¹ Advantages of this form of grafting include decreased operative time and donor site morbidity. As allograft preparation involves irradiation for bacterial, fungal, and viral sterilization to appropriately reduce infectious risk, a negative consequence of this process is diminished structural integrity. ^{13 14} As allografts are immunogenic and activate major histocompatibility antigens, they have a higher graft failure rate when compared with autografts. ¹⁵ Nonetheless, bone allograft is considered the best alternative to autograft in patients with poor healing potential, extensive comminution after fractures, and established nonunion. ¹⁶

Cancellous allografts are the most common type of commercial allogeneic graft material and due to their poor independent ability to promote bone healing, they are often used as adjuncts in spinal fusion augmentation and as filler material for cavitary skeletal defects. ⁸ Following an initial inflammatory process during incorporation, cancellous autografts become encased in a layer of fibrous tissue that can delay osteointegration for months to years. The fibrous tissue impairs host deposition of osteoid and bone, and cancellous autografts offer little mechanical strength as predominantly osteoconductive grafts. ¹³

Cortical allografts, much like cortical autografts, provide excellent structural support and can fill large skeletal defects necessitating immediate loading-bearing resistance. ³ Their resistance to compressive strength permits application in spinal and periprosthetic hip fracture procedures. ³ The incorporation of cortical allografts relies on an initial inflammatory cascade that facilitates subsequent healing through the process of creeping substitution. ⁸ Much like their autograft counterparts, cortical allografts are incorporated after osteoclast resorption and the formation of new appositional bone.

Demineralized bone matrix is employed more frequently than both cortical and cancellous autografts ¹⁷ and is an adjunct to spinal fusion procedures, nonunion grafting, and filling of bony defects. A highly processed allograft derivative, DBM consists of collagen, noncollagenous proteins, and other growth factors. ¹⁸ DBM can be used for filling bone defects, and many modern DBM preparations involve mixing with cortical and cancellous bone chips to confer additional osteoconductive properties. ⁸ The osteoinductive capacity of DBM is determined by growth factors that remain after preparation. DBM is incorporated much like autografts; growth factors trigger an endochondral cascade and the final result is new bone formation at the implantation site. ⁸

Synthetic Bone Graft Substitutes

A purely osteoconductive alternative to autografts and allografts, synthetic bone grafts have limited biologic role in fracture healing but do come in a variety of forms, including powders, putty, pellets, and implant coatings. Loading these biomaterials with antibiotics enables their usage in the setting of infectious osseous defects. ³ Commonly employed synthetic bone grafts include calcium sulfate, calcium phosphate substitutes, and bioactive glass. Calcium sulfate, also referred to as plaster of Paris, is relatively inexpensive and can be used percutaneously to fill bone voids as a liquid graft. ³ Calcium sulfate has a rapid resorption rate but weak internal strength, limiting its use to small bone defects with rigid internal fixation. ¹⁹

With a composition similar to the mineral phase of calcified tissue, calcium phosphate ceramics are synthetic mineral salts available commercially as porous implants, nonporous dense implants, and granular particles with pores. ⁷ Calcium phosphate compounds are generally prepared as mixed calcium salts with varying mineral compositions. ²⁰ Calcium phosphate cements, unlike ceramics, contain an aqueous curing agent that enables their use in filling defects with various shapes and subsequent solidification via an isothermal reaction with aqueous phase mixing. As a whole, calcium phosphate substitutes are notable for their strength in compression, capacity for osteointegration, and slow biodegradation.

Bioactive glass, or bioglass, describes a group of synthetic silicate-based ceramics. Since the 1970s, bioactive glass formulations have been refined for stability and strong physical bonding through incorporation of oxide agents. ²¹ Upon implantation, bioactive glass accumulates silicon ions and develops a hydroxyapatite coating on the surface. This coating serves to attract osteoprogenitor cells and is partially replaced by bone through a creeping substitution process. ²² As its mechanical properties are brittle and weak, bioglass is primarily applied, in conjunction with growth factors, for the reconstruction of facial defects. ²³

Growth Factors

As bone graft substitutes do not possess osteoinductive capacity, they rely on osteoconduction to facilitate the migration and attachment of osteoprogenitor cells, which can secrete growth factors to promote bone formation. ¹⁶ Given their requirement in bone healing, growth factors can be directly applied and BMPs, FGFs, VEGFs, parathyroid hormone (PTH), and PRP. The direct application of growth factors can be used to prevent delayed or nonunion. ²⁴

Bone morphogenetic proteins are members of the TGF-β family and function to promote osteoblastic differentiation and osteogenesis (with the exception of BMP-1, which is a metalloproteinase). ¹³ BMP-2, -4, -6, -7, -9, and -14 are primarily osteogenic, and BMP-2 and -7 are notable for their ability to promote local neovascularization. ^{13 25 26} BMP-2 is uniquely known for its ability to induce MSC differentiation into osteoblasts, ²⁷ and recombinant human BMP-2 has been approved for use in acute, open fractures. ¹³ BMP-7–infused collagen carriers have been found to be as effective as autologous bone grafting in treating bony nonunion, and BMP-7 is an alternative to autograft settings of long bone nonunion in revision posterior lumbar fusion procedures. ^{13 28} Challenges of using BMPs include their particular solubility and consequent dissipation from intended sites, leading to ectopic bone formation and painful nerve compression, ejaculatory dysfunction, and life-threatening inflammatory reactions. ²⁹ For appropriate carriage and delivery at intended osseous sites, BMPs require molecular carriers such as synthetic polymers, calcium ceramics, or nonstructural carriers. Synthetic polymers and calcium ceramics allow for future bone growth around the site, while nonstructural carriers function well for use inside or around additional implants. ³

Fibroblast growth factors and VEGF both promote angiogenesis at the fracture site, with the former increasing cellular division and collagen deposition and the latter promoting vasculogenesis. ³ FGFs additionally have potent mitogenic effects on mesenchymal progenitor cells. ⁷ VEGF has an extensively described role in normal physiology and pathophysiology and in fracture healing, the growth factor enables vascular invasion of the forming hypertrophic cartilage and initiates endochondral ossification. ¹³ In the process of bone healing, VEGF is released from the hematoma and promotes the development of endothelial cells to induce vascular invasion in a hypoxic environment. ³ Though useful in angiogenesis, VEGF is limited by its unstable and short-lived in vivo capacity, necessitating a gene delivery vehicle. ⁷ Caution must additionally be taken to prevent hemangiomas and VEGF-stimulated tumor development.

Utilizing the cascade of growth factors released by the aggregation and degranulation of platelets in a native fracture hematoma, PRP has been shown to enhance cellular proliferation, chondrogenesis, and callus strength in animal models. ¹³ Key mitogenic and chemotactic growth factors in PRP include platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), transforming growth factor-β (TGF-β), FGFs, and VEGF. However, evidence supporting PRP application in treating human fractures is thus far inconclusive.

Surgical Application

Craniomaxillofacial

The reconstruction of cranial and maxillofacial defects has traditionally been approached with bone grafting as these defects have complex structural needs. Cranial vault defects mandate protection of the underlying cerebrum, jaw defects need restoration of joint function and mechanical integrity, and facial aesthetics can neither be neglected nor underemphasized in the restoration process. ³⁰ Bone grafts can stimulate bone formation within a defect, augment cheek prominence and/or restore facial contour, and provide support and protection of vital structures, such as during reconstruction of the orbital floor or calvarium. ³⁰ The most frequently utilized grafts in craniomaxillofacial reconstruction are cancellous and vascularized bone grafts, as these autografts are believed to promote cell survival. ^{31 32} Calvarial and cortical bone have a slow rate of resorption and are ideal for grafting over facial bone surfaces for augmentation or contouring purposes. If bone formation must be augmented at the recipient site, osteoconductive graft materials with interconnected internal spaces offer a larger surface area for osteoclasts to attach and dissolve the graft, initiating graft incorporation. ^{30 31}

Autograft sources for craniofacial reconstruction include free nonvascularized bone grafts, regional pedicle bone grafts, and vascularized bone grafts. Among these, free nonvascularized bone grafts have been the most extensively explored. Large segments of cortical, corticocancellous, or cancellous nonvascularized or vascularized iliac crest can be readily harvested. A full-thickness iliac crest graft can closely approximate the structure of mandibular bone, and the grafting is further complemented by rehabilitation with osseointegrated dental implants. ^{30 33 34} Mandibular defects ≤6 cm can be treated with graft implantation as either corticocancellous blocks or particulate cancellous bone delivered within a titanium mesh or crib of alloplastic rib bone support. ^{35 36} Furthermore, posterior iliac crest graft can be used for craniofacial reconstruction and offers a lower donor site morbidity rate than anterior iliac crest grafting, sparing the patient postoperative pain, persistent hematoma, abdominal content herniation, vascular or lateral femoral cutaneous nerve injury, and aesthetically unfavorable iliac crest contour defects. ^{37 38 39 40 41}

Calvarial graft is frequently employed in craniofacial reconstruction for facial augmentation, orbital floor and roof reconstruction, and the covering of cranial defects. ³⁰ Given that the skull is thickest at the parietal region, an area of 8 cm × 10 cm can be safely harvested from this area. ⁴² Though calvarial thickness is variable, preoperative radiographic assessment of bone thickness can facilitate identification of optimal donor bone. Anatomic consideration should be given to the tightly adherent dura with inner cortex harvesting, identification and preservation of vascular structures such as the superior sagittal sinus, the thinning of bone inferolateral to the temporal line, and nearby temporalis muscle attachment. Proximal structures, such as the transcortical emissary veins, subcortical vessels, and arachnoid plexuses must be protected and preserved during dissection. ^{30 42} Orbital and malar reconstruction can be performed with curved bone from the temporoparietal region that can be harvested in strips 6 cm long × 2 cm wide to prevent fracture during harvest. ⁴³ Calvarial bone can be harvested as full-thickness outer cortex, partial-thickness outer cortex, or bicortical, with partial-thickness outer cortex demonstrating particular utility in filling small defects in the pediatric population. ⁴² Calvarial graft complications include graft fracture during harvest, surface deformities at the donor and/or recipient sites, dural exposure or tear, and rarely, intracranial hemorrhage. ⁴²

Similarly located within the craniomaxillofacial region, chin and retromolar grafts offer two approaches to fill small defects. Through an intraoral approach, up to 3 cm of cortical and corticocancellous bone can be obtained from the chin and used to cover cleft palate and orthognathic defects. Additionally, as chin graft is slow to resorb, it functions well as an onlay graft for facial augmentation. ³⁰ Retromolar graft is used similarly to chin graft, albeit with a smaller amount of available bone. Retromolar graft can be obtained as a block of cortical or corticocancellous bone from the area behind the third molar. ⁴⁴

Larger defects can be treated with tibial and rib grafts, with each approach offering unique advantages in craniomaxillofacial reconstruction. Tibial cortex is mechanically stiff and can be used to augment facial bone and atrophic alveolar ridge for implant placement. The anterior surface of the tibial plateau provides both cortical and corticocancellous bone for grafting, and the tibial cortex can additionally be used to bridge osteotomy defects. ³⁰ Mandibular segmental defects can be treated with nonvascularized rib in either osseous or osseochondral segments. ⁴⁴ Ascending mandibular ramus and condylar defects are frequently treated with costochondral grafts. ^{45 46 47} Costochondral graft complications include postoperative chest wall pain, pleuritis, hemo/pneumothorax as a result of pleural injury, and facial asymmetry caused by graft overgrowth. ^{46 48 49}

Pedicle rib, clavicle, and temporal bone grafts offer limited but specific utility in reconstruction. Pedicled rib is able to reach the lower third of the face and can therefore be used to perform soft-tissue reconstruction in mandibular defects. ⁴⁴ Pedicled clavicular periosteum transfer or clavicular bony segment that is either full or partial thickness can be used to reconstruct small mandibular bone defects. ^{50 51} Both techniques preserve the neurovascular supply of the sternocleidomastoid muscle (SCM), which can aid in restoration of facial musculature, the lower lip, and performance of mastication and/or tongue movements. ⁵² However, pedicled clavicle complications include aesthetically unfavorable contour at the donor site and possibility for oncologic activity with cervical lymph node involvement. ⁵² Lastly, pedicled temporal bone can be obtained as either full or partial thickness and used to reconstruct maxillary, palatal, orbital rim, orbital floor, or ascending mandibular ramus defects. ³⁰

While there are several techniques for mandibular reconstruction, the gold standard is often considered to be vascularized bone grafting because the blood supply is independent of the recipient site condition, making this graft resistant to site scarring, poor vascularity, and prior site radiotherapy. ⁴⁴ Unlike free grafts, which can have a high primary reconstruction failure rate, vascularized grafts are suited for primary reconstruction and permit simultaneous bone and soft-tissue reconstruction with a composite flap. As harvesting vascular grafts and performing their anastomoses demand greater surgical technique, this form of grafting does have increased operative time and possibly higher postoperative morbidity and mortality. Nonetheless, fibula, iliac crest, scapula, and radius vascularized grafts are optimal for microvascular reconstruction of mandibular defects. ³⁰

Demineralized bone matrix graft has been identified as a useful adjunct in craniofacial reconstructive procedures, given the osteoconductive and osteoinductive properties of the allograft, as well as its mechanical stiffness. Sheets of cortical DBM can be molded into defects, and this approach has shown particular promise in reconstruction of large cranial vault defects after cranioplasty. ⁵³ Though the mechanical stiffness of DBM offers some protection to the underlying brain, the natural incorporation of this allograft into recipient sites is slow and inconsistent, necessitating acceleration with bone augmenting factors, such as bone morphogenetic proteins (BMP). ^{54 55}

Synthetic bone substitutes and bone augmenting factors have been incorporated in craniomaxillofacial reconstruction to promote both fixation and cellular differentiation, respectively. Calcium phosphate and sulfate preparations have been used to reconstruct cranial contour defects. ^{56 57} Calcium phosphate hydroxyapatite cement has additionally shown utility in blocking cerebrospinal fluid leaks and obliterating the frontal sinus. ⁵⁸ During the regenerative process, growth factors, such as those in the TGF-β family and vascular endothelial growth factor (VEGF), promote the differentiation of angiogenic and bone-forming cells. With concomitant BMP induction of osteogenesis, TGF-β and VEGF have shown clinical use in facilitating bone healing and growth in irradiated osseous defects and calvarial defects. ^{59 60}

Surgical reconstruction of craniomaxillofacial defects is most frequently performed with autogenous bone grafting. However, newer developments in biologic technology and tissue engineering will continue to expand the scope of these reconstructive procedures. As defects in this part of the skeleton vary from the millimetric periodontal defects to the much larger traumatic or surgically excised segmental defects, craniomaxillofacial reconstruction is a challenging task and requires a nuanced application of bone graft, substitutes, and augmentation factors that is sustained by evidence from multiple randomized controlled human studies.

Upper Extremity

Bone grafting in the upper extremity is used to treat fractures with acute bone loss, nonunion or malunion of fractures, bony lesions, and infection-induced bone loss. ⁶¹ As with grafting in other areas of the skeleton, options for repair include autografts, allografts, and bone graft substitutes.

The spectrum of autologous bone grafts most commonly used includes iliac crest and distal radius, as well as proximal ulna, toe phalanx, metacarpal, distal femur, scapula, and fibula. ⁶¹ When immediate mechanical stability is desired, cortical bone grafts are used because of their dense mineralization and consequent slow revascularization and incorporation. ³¹ For arthrodesis and treatment of nonunion, cancellous bone graft is ideal with its active recruitment of mesenchymal stem cells. ⁶² Corticocancellous bone graft combines the structural support of cortical grafts and the osteointegrative properties of cancellous bone grafts. Iliac crest corticocancellous bone graft can be applied for larger upper extremity defects while smaller defects can be treated with a distal radius corticocancellous graft. ⁶³ Larger bone defects, and particularly those with established avascular necrosis, can be treated with vascularized cortical or corticocancellous autografts from the fibula (peroneal artery branches), iliac crest (deep circumflex iliac artery branches), distal radius (supraretinacular artery), rib (posterior intercostal artery branches), and/or medial femoral condyle (descending geniculate artery branches). ⁶⁴

Vascularized grafts are notably helpful in treating nonunion in the setting of previously failed surgery, unfused growth plates, and avascular necrosis. ⁶¹ This type of graft is most frequently employed for scaphoid nonunion. ⁶⁵ Scaphoid nonunion can be treated with vascularized dorsal distal radius or vascularized medial femoral condyle, with the latter showing utility in treating clavicle nonunion as well. ⁶¹ Vascularized medial femoral condyle autograft has an attached viable articular surface that functions well within the intra-articular relationship between the scaphoid and the lunate bones, attributing to its high successful union rate. Complications of this autograft include donor site pain, saphenous nerve paresthesia, and seroma. ⁶⁶ Diaphyseal pseudarthrosis, radical bone resection, and upper extremity injuries with extensive bone loss can be treated with vascularized fibular bone graft harvested from the peroneal artery. ⁶¹ Vascularized fibular bone graft is structurally similar to diaphyseal long bone and provides variable functional outcomes depending on the pre-existing bone loss pathology. Associated complications include injury to the peroneal nerve and donor site stress fractures. ⁶⁷

Bypassing the harvesting and limited quantity problems often associated with autografts, allografts can be applied in upper extremity reconstruction as well. DBM complements autologous bone graft and demonstrates fusion rates similar to those achieved with iliac crest and without the morbidity of autograft harvest in the context of humeral shaft fractures. ⁶⁸ Bone graft substitutes, such as calcium phosphate supplement, have shown promise in fixation of distal radius fractures when used in conjunction with traditional fixation techniques. ⁶⁹ Hydroxyapatite cement, in conjunction with autologous cancellous bone graft, has shown higher success rates in open reduction internal fixation of acute fractures of the humerus, radius, and ulna when compared with autograft alone. ⁷⁰ Lastly, BMPs, such as BMP-7, can be used along with allograft or autograft in treatment of scaphoid nonunion, producing improved functional outcomes. ⁷¹

Of note, large osseous defects or contaminated wounds in the upper extremity can be treated with an induced membrane technique to facilitate bone healing. ⁷² Contaminated wounds are a contraindication for acute bone grafting. The induced membrane technique consists of a primary stage involving bony fixation through external fixation with plate and screw contracts or intramedullary nailing and insertion of a cement spacer. Over the course of the subsequent 6 to 8 weeks, an induced membrane forms around the cement spacer. Following this time period, the cement spacer can be explanted and autograft can be inserted and encased in the induced membrane. ⁷²

Graft structural integrity and osteointegrative ability are important considerations in upper extremity reconstruction. Autografts are the most popular modality in these procedures but are increasingly combined with allografts and bone substitutes to achieve more durable and improved functional outcomes. Optimal patient outcomes hinge on minimizing donor site morbidity and treating the recipient site with the appropriate combination of grafting materials.

Spinal Fusion

Cervical and lumbar spinal disease, whether degenerative or neoplastic, is often best treated with spinal fusion procedures. The ideal bone grafts for this application combine healing with restoration of segment mobility. Vascularized bone grafting has shown promise in augmenting fusion in the setting of a variety of skeletal pathologies, with its applicability explored in cervical arthrodesis, ¹² occipitocervical and cervicothoracic fusion, ⁷³ lumbar fusion, ⁷⁴ lumbar osteodiscitis, ⁷⁵ and lumbosacral fusion. ⁷⁶ In patients who require long-segment ventral cervical reconstruction, arthrodesis can be achieved with a pedicled clavicular graft that provides the benefits of a vascularized free fibula without the added morbidity of a free tissue transfer. ¹² Cadaveric specimens have demonstrated that the posterior occipitocervicothoracic spine is amenable to reconstruction with pedicled vascularized bone grafting. Split and full-thickness occipital vascularized bone grafts can be mobilized on a semispinalis pedicle from the occiput to T1, spanning up to four levels. ⁷³ Scapular vascularized bone grafts can be mobilized from the occiput to T7, spanning up to eight levels, and rib vascularized bone grafts can be mobilized from C6 to T12. ⁷³ In contrast to the traditional posterior open approach for lumbar spine reconstruction, rotation of a vascularized spinous process graft to augment posterolateral arthrodesis adds mere minutes to total operative time, while limiting morbidity and providing for improved spinal fusion in as little as 3 months postoperatively. ⁷⁴ It has been well established that recurrent infection contributes to failed spinal fusion, and in patients with this susceptibility as well as other risk factors for pseudarthrosis, vascularized autograft can be used to accommodate posterior, anterior, and lateral surgical approaches for lumbar debridement, fixation, and fusion. ⁷⁵ Cadaveric studies have additionally shown that lumbosacral fusion can be achieved with pedicled posterior element and iliac crest vascularized bone grafts that successfully incorporate into high risk recipient sites. The broad scope and applicability of vascularized bone grafting in spinal fusion procedures, particularly for patients who are inherently at higher risk for nonunion, encourage the use of this graft in spite of added distant donor site morbidity and surgical challenge associated with microvascular anastomoses.

Iliac crest bone graft most strongly confers osteointegrative properties (the ability of an implant to anchor within the surrounding bony tissue and prevent the formation of fibrous tissue), thus continues to be considered the gold standard in spinal fusion procedures as the cortical component provides mechanical stability and the cancellous component provides both osteoinductive and osteoconductive properties. ⁷⁷ However, due to the potential morbidity associated with harvesting, limited availability of iliac crest bone graft, and increased operative time associated with harvesting, interest has increased in the development of synthetic biological materials that retain the low immunogenicity of iliac crest bone graft. ⁷⁸

These alternatives materials include DBM, and ceramics. ⁷⁷ Ceramics have notable biocompatibility and structure similar to normal bone. ⁷⁹ Approximately 60% of the commercially available bone graft substitutes for spinal reconstruction procedures are ceramics and include calcium sulfate, bioactive glass, and calcium phosphate. ⁸⁰ Silicate-substituted calcium phosphate has great ease and versatility of use, yielding fusion rates of 90% throughout the cervical, thoracic, and lumbar spines. ⁷⁷ Two bone substitutes, biomimetic magnesium hydroxyapatite (MgHA) and human DBM dispersed in biomimetic MgHA (HDBM-MgHA), have shown promise in animal models as alternatives to autografts for spinal fusion. MgHA formulations permit the development of new bone tissue that is morphologically similar to both preexisting host bone and bone that is formed through autograft treatment. HDBM-MgHA functions similarly and forms new bone with thin and irregular trabeculae from a cartilaginous zone, mimicking the slow endochondral ossification model of bone growth. ⁸¹

Given the larger defect area in spinal reconstructive procedures, supplementing traditional autograft techniques with adjunctive biomaterials has shown to promote successful spinal fusion. Further clinical data are needed to assess the safety and performance of bone graft substitutes in facilitating spinal fusion throughout the cervical, thoracic, and lumbar regions.

Pelvic

Pelvic resection, though an uncommon procedure, can be performed in the setting of tumors, trauma, or severe infection. Consequent reconstruction is complicated by a high implant failure rate due to demanding mechanical loading conditions, as well as adverse outcomes of poor wound healing and deep infection. ⁸² As a result, the decision to perform reconstruction is made with careful consideration of both functional and quality-of-life benefits. Nonetheless, reconstruction of defects of the iliac wing and sacrum can be helpful to prevent pseudarthrosis and is traditionally performed with bridging techniques. ⁸³ Allograft or autograft is most frequently used and fixed to the remaining ilium or sacrum with internal fixation techniques. Autologous fibular grafts and allogeneic bone grafts can be secured with polyaxial screws and titanium rods, ⁸⁴ but there has been no demonstrable benefit to incorporating bone cement in this fixation process. ^{85 86} The ideal implant for pelvic ring reconstruction needs good primary and torsional stability, introduces the least amount of foreign material, and possesses antimicrobial properties. ⁸²

Given the complexity of pelvic anatomy, there has been no one established ideal method for pelvic reconstruction. ⁸⁷ The nature of the reconstruction depends on the type of preceding pelvic resection. Enneking and Dunham proposed a classification scheme for these subtypes of pelvic resection in 1978, ⁸⁸ and this scheme continues to be applied today. Type I resections involve all or part of the ilium, while sparing the acetabulum. Type IA resection involve resection of the ilium with removal of the gluteal muscles, while type IS resections involve partial resection of the sacrum as well and are referred to as “extended hemipelvectomies.” Type II resections involve the periacetabular region of the pelvis and are frequently the most debilitating as the acetabulum, and frequently the femoral head (type IIA resection), are resected. Type III resections involve the ischiopubic region of the pelvis, an area that completes the pelvic ring and adds intrinsic structural stability. As the obturator nerve is frequently sacrificed in this type of resection, there is subsequent dysfunction of the adductor muscles. However, the acetabulum remain continuous with the axial skeleton so type III resections yield good structural outcomes. ⁸⁹ Pelvic reconstruction is performed when there is loss of pelvic bony continuity between the acetabulum and the sacrum or there has been resection of the acetabulum. Thus, partial type I pelvic resections and complete type III resections do not typically require reconstruction. ⁸⁹

Complete type I, IA, or IS pelvic resections are approached with bony reconstruction to reconstitute continuity of the sacrum and acetabulum. ⁸⁹ With gaps that are too large to be closed with direct apposition, nonvascularized or vascularized autologous fibular strut grafting has shown success in facilitating bony healing. This type of autograft works well in the setting of unfavorable biologic conditions, such as smoking, diabetes, infection, and radiated recipient sites. ⁸⁹ For younger patients who have favorable soft-tissue envelopes, fibular allograft has shown both good recipient site incorporation and avoidance of donor site morbidity. ⁹⁰ Type II resections can be approached with iliofemoral or ischiofemoral arthrodesis, as well as arthroplasty with allograft-prosthetic composite. Reconstitution of the bone defect is performed with size-matched pelvic allograft or autograft and subsequent fixation with screws and plates. ⁸⁹ Lastly, though type III resections generally do not necessitate reconstruction when acetabular stability can be maintained, careful closure with sheet graft material or local tissue flaps can be performed for prevention of visceral or bladder hernias in the created defect. ⁸⁹

Pelvic reconstruction techniques are informed by the extent of preceding resection and with the intent to restore or maintain stability. Allogenic bone transplant is technically demanding and requires high-quality allogenic bone. ⁸⁷ If the functional benefits outweigh potential complications of increased operating time, blood loss, and infection risk, reconstruction is performed as a feasible method of improving patient functional outcomes.

Lower Extremity

Lower-extremity reconstruction is frequently performed due to traumatic injury and aims to achieve a healed wound with minimal donor site morbidity as well as optimized long-term functional status and aesthetic appearance for the patient. ⁹¹ Tibial wounds induced by trauma are frequently accompanied by bony injury, and successful reconstruction hinges on achieving both bone stability and soft-tissue coverage. Similarly, ankle wounds are frequently associated with long bone fractures. As with other anatomic regions aforementioned, autologous and bone grafting alternatives can be considered for application in lower extremity reconstruction.

Defects in the tibial region lend themselves to bone grafting and vascularized bone transfer, with the former approach used for bony defects < 6 cm and the latter for defects larger than 6 cm. ^{92 93} The vascularized fibula graft, obtained from the contralateral leg, has reliable supply from the perforators of the peroneal artery and can be adapted to suit a range of bony and soft-tissue defects. For larger defects, the vascularized fibula bone graft can be combined with thin wire external fixators to achieve osteosynthesis. ⁹¹ The postoperative phase of extremity reconstruction involves assessing the patient's return to ambulation through dependent training and gradual increase in external compressive support.

Given its widespread application in reconstruction, the iliac crest is a popular source of autologous bone for lower-extremity grafting, but other autograft sources, such as the proximal and distal tibia, distal fibula, and calcaneus have also been applied. Distal tibia bone graft has demonstrated a high union rate and consequent utility in triple arthrodesis, ankle fractures, and midfoot fusions. ⁹⁴ Potential complications from harvesting bone from the distal tibia include chronic swelling, pain, poor wound healing, and infection. ³⁸ Furthermore, relative contraindications to distal tibia bone grafting include osteopenia and peripheral neuropathy. ⁹⁴ The distal tibia can, however, complement other cortical bone graft sources to provide structural support. Distal fibula grafting can be used to perform ankle and tibiotalocalcaneal arthrodesis. ³⁸ Proximal tibia bone graft has additionally shown promise in augmenting treatment of acute fractures and nonunion with limited postoperative complications and good weight-bearing ability after surgery. ⁹⁵ Calcaneal grafts have a larger complication profile than other forms of grafting applied in lower extremity reconstruction, and in particular, they necessitate non–weight-bearing ambulation for several weeks postoperatively to decrease the risk of calcaneal fracture. ⁹⁶

As harvesting autologous bone presents potential morbidity to the patient, bone grafting alternatives such as allograft and ceramics should be considered as well. The primary concern in allograft usage focuses on preventing transmission of infectious disease to the patient, and as such, the tissue is appropriately processed by combinations of physical irrigation and debridement, chemical treatments, freezing or freeze-drying, and terminal sterilization. ⁹⁷ Furthermore, larger allografts are generally used in more complicated procedures with compounding longer operating times, larger dissections, increased blood loss, and introduction of larger portions of avascular organic material into wounds. As such, infection can likely occur as a complication of the surgical procedure and not the allograft itself. ³⁸ Nonunion of the allograft to the host bone is a potential complication and success can be better ensured by including the presence of a stable construct and maintaining appropriate contact between the host bone and allograft. ⁹⁷ As a type of allograft, DBM can complement iliac crest autograft in hindfoot arthrodesis. ⁹⁸ DBM can also be utilized in performing arthroscopic subtalar arthrodesis. ⁹⁹

Crystalline materials such as ceramics are synthetic bone grafting alternatives and are advantageous in that they have no risk of infectious disease transmission, do not require a donor site, and are available in large quantity. ³⁸ Hydroxyapatite has compressive strength akin to cancellous bone and can be used to fill bony cavities in metaphyseal fracture defects. ³⁸ Calcium phosphate cements, developed to enhance fracture stabilization, augment calcaneal fracture internal fixation and recipient sites show improved compressive strength. ^{100 101}

Nonautogenous materials enable decreased operating times and patient morbidity, but their successful incorporation in lower-extremity reconstruction involves understanding the biology of bone grafting and considering their prior usage in cases similar to the current patient's needs. More recently, autologous bone marrow aspirate (BMA) has shown to augment bone grafting in the lower extremity with a 96% radiographic union rate and limited postoperative complications. ¹⁰² However, further prospective trials are needed to determine the full potential of this technique, as well as the scope of allografts and ceramics in complementing autografting.

Conclusion and Future Applications

In conclusion, the use of bone grafts, bone substitutes, and orthobiologics has immense potential in transforming the lives of patients and permitting complex joint reconstructions. The advantageous properties of bone graft can be complemented with additives such as antibiotics to mitigate infection risk, BMPs to expedite and facilitate the process of remodeling and bony incorporation, and tissue engineering to seed allograft with stem cells to increase graft shear strength and ability to withstand compaction forces. ¹⁰³ The outlook on these augmentation techniques is promising for more widespread incorporation of bone and synthetic grafting.

A novel combination of osteogenic cells, osteoinductive growth factors, and osteoconductive matrix, “composite graft” is an emerging surgical option. This category of grafts includes bone marrow and synthetic composites, osteoinductive growth factors and synthetic composites, ultraporous composites, BMP, and polyglycolic acid polymer composites. Notably, composite synthetic grafts combine the three favorable bone-forming properties in controlled combinations while eliminating some of the disadvantages associated with autografting. ¹⁰⁴ The osteoconductive matrix assists in delivering bioactive agents, and the direct infusion of osteoprogenitor cells provides for more rapid and consistent bone recovery outcomes. ^{7 104}

Furthermore, preliminary work in the development of nanocomposites that can be combined with osteoconductive and osteoinductive factors, as well as osteogenic cells, is gaining recognition as a prospect of introducing a new class of biomaterial with many of the previously established benefits of autologous bone grafts. Future tissue engineering research aims to identify optimal nanocomposite processing conditions, optimize biomaterial strength to achieve that of natural bone, promote graft resorption, elucidate the molecular mechanisms by which cells and nanocomposite matrix can interact in vivo to promote bone regeneration, and improve angiogenesis within the nanocomposite graft to promote graft survival. ¹⁰⁵ Though autografts and allografts have been the most extensively explored and used in reconstructive procedures, donor shortage and infection risk compel incorporation of newer synthetic biomaterials and nanocomposites that can both widen the scope of and enhance patient outcomes in reconstructive grafting procedures.