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Home , Bone grafting, Graft (surgery)

■ Review Article

cme ARTICLE Earn Category 1 credits Transplantation

AMY WILLIAMS, MD; ROBERT M. SZABO, MD, MPH

educational objectives

As a result of reading this article, physicians should be able to: recent work that has delineated the 1. Define the different types of . importance of osteoconductive scaffold- 2. Describe indications for use of autograft and allograft and the advantages ing, osteoinductive growth factors, and and drawbacks of each. osteogenic progenitor stem cells in bone healing. 3. Describe common complications of autograft and allograft techniques.

4. Explain the problems associated with vascularized allografts and com- AUTOGRAFT posite tissue transplantation. Autografting remains the gold stan- dard for replacing bone loss due to trau- ma, , tumor resection, revision fter blood, bone is the most fre- , or even whole limbs, can be trans- , and . Rapid quently transplanted human tis- planted from one person to another. incorporation and consolidation with the Asue. Basic science and clinical This article reviews the history of bone lack of immunologic considerations research completed in recent years sug- transplantation and current techniques, make bone harvested from the patient gests that bone autografting may eventual- and casts an eye toward the future. ideal. Autograft bone is osteoconductive ly become a thing of the past. Bone and contains osteoinductive proteins and replacement with synthetic materials and HISTORICAL PERSPECTIVE cells able to give rise to bone-forming growth factors are becoming common The first documented bone transplant cells. Although the viability of osteoin- procedures in the orthopedic operating was performed in 1668 by a Dutch sur- ductive proteins and osteogenic cells room. technology is geon, Job van Meekeren, when he used decreases following autografting, it is approaching the ability to synthesize bone dog cranium (xenograft) to repair a sol- generally agreed that autograft bone for a particular patient. For now, however, dier’s defect. Scottish surgeon (especially cancellous bone) and its traditional bone grafting remains impor- William Macewan performed the first lower risks make it preferable to allo- tant. bone allograft in 1880 when he replaced graft.4,5 Autograft bone, however, is limit- The demarcation between traditional the infected humerus of a 4-year-old boy ed in supply, particularly in children. procedures and the use of new bone graft with a tibia graft taken from a child with Classically harvested from the patient’s substitutes and growth factors is blurring, rickets.1 In his publication in 1914, as combination or composite techniques Phemister2 noted the importance of From the University of California, Davis, Sacramento, Calif. prove safe and appear effective. This “hemostasis, asepsis, and coaptation of Drs Williams and Szabo have not declared blurring of boundaries represents a stage parts” in successful bone grafting. any industry relationships. in the progression from autologous bone Phemister2 and Albee3 elucidated the Reprint requests: Robert M. Szabo, MD, transplantation to a time when replace- important factors in bone grafting in the MPH, University of California, Davis, School of Medicine, 4860 Y St, Ste 3800, Sacramento, CA ment bones can be synthesized and early 20th century, paving the way for the 95817.

488 ORTHOPEDICS | www.orthobluejournal.com BONE TRANSPLANTATION | WILLIAMS & SZABO cme ARTICLE Earn Category 1 credits iliac crest, autograft can be taken from the VASCULARIZED AUTOGRAFT distal radius, olecranon, proximal and dis- Vascularized cortical autografts are tal tibia, and ribs. effective structural grafts that heal quick- Complications associated with autolo- ly without the revascularization process gous bone graft harvesting have been well and consequent mechanical compromise documented.6 Common complications seen in avascular cortical auto- and allo- include increased blood loss, increased grafts. Typically, Ͼ90% of osteocytes pre- operative time, persistent pain at the donor sent in these grafts survive the transplant site, donor-site infection, herniation, and and bring their own blood supply, perhaps iatrogenic fracture. making the contribution of the recipient Cancellous autograft is useful in situa- bed tissues less important in healing.9,12 In tions where the bone void does not require other words, vascularized autografts bring significant structural support, as in the fill- all components for healing with them. One ing of cavities left by bone cysts and benign of the primary indications for this type of tumors. Similarly, it can be packed into 1A bone transplant is a recipient bed with sub- metaphyseal optimal vascularity of bone or soft tissues defects after the or large osseous defects. Common donor depressed surfaces have been elevated as in fractures of the tibial plateau, plafond, and dis- tal radius. Can- cellous bone can also be added to acute fractures and delayed or non-union sites to promote union 1B 1C in defects Ͻ6 cm.7 Spinal fusions are another scenario in Figure 1: Vascularized distal radius autograft. Avascular proximal pole of the scaphoid (A). Vascularized radial bone graft being transplanted to the scaphoid (B). Vascularized scaphoid autograft in which cancellous (and corticocancellous) place with screw fixation. Radiograph shows healing 8 weeks postoperatively (C). autograft is a mainstay. Cancellous bone grafts are revascularized and incorporate quickly, and although they provide no ini- tial structural support, after 12 months their defects between 6 and 12 cm is controver- sites of vascularized autografts are the ribs, strength is equivalent to that of a cortical sial.11 Defects Ͼ12 cm have been shown iliac wing, , distal radius, and scapula. graft.8,9 to have higher failure rates using nonvas- Vascularized distal radius grafts are Cortical autografts provide immediate cularized grafts compared to vascularized effective in treating osteonecrosis and structural support. Sources of nonvascu- cortical autografts.8 Nonvascularized cor- of the scaphoid,13 Kienböck’s larized cortical autografts include the iliac tical grafts may provide immediate struc- disease, and failed wrist arthrodesis14 crests, ribs, and fibula. Anterior cervical tural support but lose mechanical strength (Figure 1). The vascularized free fibula lends itself to the use of tri- over the first few months. This is due to graft has been used in numerous locations cortical graft from the iliac crest or dia- the revascularization process, which caus- for a variety of difficult problems.11 physeal, almost entirely cortical bone es osteoporosis and subsequent graft Potential situations in which a patient from the middle one third of the fibula. weakening. This process requires resorp- might benefit from vascularized autograft Both of these methods have generally tion of at least some graft bone to allow include osteonecrosis of the femoral resulted in higher fusion rates than allo- ingrowth of blood vessels and takes sig- head,15 reconstruction of tumor-related graft options.10 The use of nonvascular- nificantly longer in cortical bone than in defects in the proximal humerus and ized cortical autografts in segmental cancellous. lower extremity,16 treatment of congenital

MAY 2004 | Volume 27 • Number 5 489 ■ Review Article cme ARTICLE Earn Category 1 credits

2A 2B 2C

2D Figure 2: Free fibular vascularized autograft. Congenital pseudarthrosis of the left tibia (A). Preoperative radiograph (B). Harvesting of the vascularized fibula from the contralateral leg (C). Radiograph immediately postoperatively (D). Radiograph (E) and clinical appearance (F) 3.5 years postoperatively. 2E tibial pseudarthrosis,17 and nonunions of tional problems; Vail and Urbaniak21 the femur,18 tibia,19 and femoral neck20 reported having to use the contralateral (Figure 2). leg on one occasion and interposition Donor-site morbidity has been a con- grafting of the peroneal artery using 2F cern with vascularized fibula auto- reverse-saphenous vein graft in another grafts.21,22 In addition to persistent pain, situation. Until recently, all of their some of the problems with autogenous investigators have found motor weakness patients underwent preoperative arterio- bone grafting. The risk of infection trans- affecting primarily extensor hallucis graphy to rule out vascular anomalies. mission from donor to host, the immuno- longus and flexor hallucis longus, sensory They ended this practice as a cost-cutting genicity of foreign tissue, and ethical con- deficits, biomechanical alterations in the measure.21 cerns are relevant with allografting—the ankle, deep venous thrombosis, and latter increasingly so with the advent of delayed healing associated with ALLOGRAFT vascularized allografting and limb trans- the related devascularization of overlying Transplanting bone from one human to plant. soft tissues with peroneal artery ligation. another is an idea that has been with us Although considered by some to be a Vascular anatomic anomalies pose addi- for hundreds of years and circumvents “bone graft substitute,” demineralized

490 ORTHOPEDICS | www.orthobluejournal.com BONE TRANSPLANTATION | WILLIAMS & SZABO cme ARTICLE Earn Category 1 credits bone matrix (DBM) is bone harvested rather freeze-dried and vacuum-packed— from a single donor, crushed, and dem- conditions under which it can be stored ineralized with acid. The various manu- indefinitely—and a slightly increased dis- facturers of DMB add or modify steps in ease transmission risk. Freeze-drying sig- the processing, but the essential process is nificantly alters the biomechanical proper- the same. Treatment of allograft bone ties of bone, decreasing torsional strength with gamma irradiation or ethylene oxide by 50% and compressive strength by has been shown to inactivate pathogens. 10%.28 The risk of HIV transmission or Ethylene oxide is a gas that destroys bac- hepatitis viruses is small but present. teria, spores, and viruses in a dose-depen- Allograft suppliers screen donors for these dent fashion. However, use of ethylene viruses as well as other markers of sys- oxide has been complicated by host reac- temic disease.29 tion to treated tissues.23 Gamma irradia- A step higher on the disease transmis- tion has been shown to destroy human sion risk scale is the cortical allograft immunodeficiency virus (HIV), hepatitis (avascular). Cortical bone is of greater den- C, and other pathogens in allograft tissues sity than cancellous bone, and it is believed and is more commonly used today; how- that the density accounts for the slightly ever, this process weakens the structural higher risk of disease transmission, as integrity of the graft.24 Demineralized pathogens are less easily destroyed when 3A embedded in a more dense tissue bed. Two

3B bone has been widely used since Urist and uations. An interesting use of DBM com- Dowell25 first reported its clinical use in bines it with autologous , 3C 1968. Demineralized bone matrix is rec- which adds the osteoconductivity and - ognized as having a variable amount of inductivity of DBM to the osteoprogenitor Figure 3: Cortical allograft. Giant-cell tumor of the osteoinductive capacity and some osteo- cells of the recipient’s bone marrow—a distal radius (A). Fresh-frozen radial allograft (B). 26 Radiographs of a distal radius allograft with Sauve- conductive properties. The biologic true composite graft. Conveniently, this Kapandji procedure 15 years postoperative (C). activity varies with specific processing formulation can be applied percutaneous- and storage methods, in addition to varia- ly, avoiding more invasive techniques. tion among donors. Drawbacks of DBM include the risk of cases of HIV transmission resulting from Uses for DBM are numerous, although infection, although the demineralization cortical allografts have been reported.30 prospective, randomized, controlled stud- process has been proven to destroy HIV.27 Nonetheless, cortical allografts are used ies demonstrating its efficacy are not avail- Infection with HIV or hepatitis from DBM widely for bridging structural defects in able for all of its clinical applications. has not been reported. long bones, spinal arthrodesis, buttress or Currently, DBM is used to fill cavitary Cancellous allograft is used in the same strut grafts in limb salvage procedures, defects, facilitate spinal arthrodesis, and clinical scenarios as DBM and cancellous revision arthroplasty, and periprosthetic repair nonunions. It can also be used as a autograft. The differences are that cancel- fractures31 (Figure 3). Advantages include cancellous autograft extender in these sit- lous allograft is not demineralized, but vast supply and selection of bones to fit a

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but nailed to the host bone. Numerous stud- ies have shown that after 1 year, a signifi- cant amount of necrotic graft bone remains,

Figure 5: Proximal mixed with newly formed host bone, and humerus allograft- after many years, some graft bone remains. prosthesis composite This suggests that while meaningful clini- reconstruction. The cal healing does occur with cortical allo- prosthesis augments the proximal humerus grafts, the graft is never entirely replaced. allograft.

4 specific need, and machining to better Figure 4: Proximal serve a given function (eg, femoral ring humerus osteoarticular allograft with fracture; allografts used in anterior spinal arthrode- this is likely secondary sis). to the revascularization Cortical allografts usually are processed process. (, cleaning) and aseptically pre- served by freeze-drying or deep freezing. Freezing to Ϫ20°C allows preservation for approximately 1 year without substantial 5 compromise in strength; only thawing is required prior to implantation. Deep freez- allograft and fatigue failure of the supple- Osteoarticular and osteochondral allo- ing bone does not alter its immunogenici- mental fixation (with allograft fracture). grafts are used primarily in limb salvage ty.32 Freeze-drying, on the other hand, Unfortunately, fracture occurs with sig- and arthroplasty. Being able to replace decreases immunogenicity further, but nificant frequency as a result of graft large segments of bone that include the reduces the mechanical strength by 50% weakening associated with revasculariza- joint surface has been a significant advance when compared with fresh-frozen bone.33 tion or due to the inability to obey Wolff’s in preserving function and cosmesis in Reconstitution (rehydration) is required law (Figure 4). If a significant portion of limbs, which previously would have prior to implantation. A recent study in mice the graft is not revascularized, as it often required amputation. Malignant tumors of suggests that treating the grafts with is not in large allografts,35 a stress riser in the proximal humerus, for example, can be dimethyl sulfoxide further reduces necrotic bone can result in fracture effectively treated with resection and immunogenicity in deep-frozen speci- because the bone cannot respond to stress reconstruction using osteoarticular allo- mens.34 Although this has yet to be demon- concentrated at this site. Getty and graft attached to the shoulder through strated in humans, it could obviate the need Peabody36 reported a 25% fracture rate in repair of the soft tissues including joint for freeze-drying allografts with the con- proximal humeral osteoarticular allo- capsule and rotator cuff tendons (graft to comitant decrease in mechanical strength. grafts, and Gebhardt et al37 reported a host), and attached distally with plate and Cortical allografts are primarily osteo- 35% fracture rate in similar allografts. screw fixation or an intramedullary pros- conductive scaffolds, but cortical bone The healing process of cortical allograft thesis (Figure 5). In most cases, this offers immediate structural support as to host bone is prolonged, following the allows limb preservation, excellent hand well. This support diminishes as incorpo- steps of formation, inflammato- function, and reasonable shoulder func- ration proceeds until the revascularization ry process, resorption of graft bone and tion. process is complete and enough new bone revascularization, and finally replacement Osteoarticular grafts are usually deep- is laid down to restore strength. Often, it of graft with new host bone. Often the frozen for preservation and thawed prior is a race between incorporation of the majority of the bone graft is not replaced, to implantation. Fresh osteoarticular allo-

492 ORTHOPEDICS | www.orthobluejournal.com BONE TRANSPLANTATION | WILLIAMS & SZABO cme ARTICLE Earn Category 1 credits grafts are not commonly used due to their term immunosuppression to the equation recurrent or opportunistic , dia- immunogenicity; however, fresh osteo- seems inherently risky, it may be reason- betes mellitus, hypertension, Cushing’s chondral allografts have been used in joint able to attempt this procedure in these syndrome, neuropathy, nephropathy, resurfacing procedures. Osteochondral (previously infected) patients, as they myopathy (including cardiomyopathy), allografts are not frozen to preserve tissue stand to gain the most from successful pulmonary problems and malignancy, to viability. Chondrocytes, the key compo- new therapies for segmental bone or joint name a few—compare favorably against nent of osteochondral allografts, tolerate loss. the drawbacks of knee fusion or amputa- avascularity but not freezing. In contrast, Hoffman and Kirschner40 acknowl- tion? For now, both knee arthrodesis and bone cells usually do not survive avascu- edge that their immunosuppressive regi- above-knee amputation are widely per- lar transplantation but freezing helps keep men was inadequate, citing the more formed and accepted procedures, where- the bone structurally intact while reducing effective protocols used by investigators as vascularized bone allotransplants immunogenicity. Czitrom and Gross38 involved with composite tissue transplan- remain experimental and controversial. reported that the immune response to the tation, but also that life-long immunosup- With advances in transplant immunology graft in fresh osteochondral allografts and the ongoing development of new does not justify immunosuppression of drugs this may change. the host. Autografting remains the COMPOSITE TISSUE ALLOGRAFT VASCULARIZED ALLOGRAFTS gold standard for replacing In the past 3 years, nine unilateral and Transplanting (or implanting) allograft four bilateral human hand transplants bone requires dampening of the recipi- bone loss due to trauma, have been performed. As of January 2003, ent’s immune response, and this can be infection, tumor resection, only the first hand transplant performed accomplished in two ways: treat the graft with immunosuppressive therapy had to make it less immunogenic or treat the revision arthroplasty, and failed, and this has been attributed to the recipient to make the immune system less arthrodesis. patient’s lack of cooperation and noncom- “sensitive.” The advent of vascularized pliance with immunosuppressive medica- allograft has required a shift from manip- tions. The other three were evaluated ulating the grafts to manipulating the using the Carroll test, which assesses recipient’s immune system. pression is mandatory. In addition to the global upper extremity function, and were Hofmann et al39 and Kirschner40 complications associated with immuno- rated good (one patient) or fair (two reported their experience with transplan- suppression, possible complications of patients).41 tation of vascularized diaphyseal femora anticoagulation must be considered The most detailed reporting of experi- and vascularized knees. Using an because bone is a low-flow organ, and ence with has been immunosuppressive regimen consisting thrombosing of the graft vessels would provided by Margreiter et al,42 who of antithymocyte globulin, cyclosporine, defeat the purpose of using vascularized recently reported on the first 18 months azathioprine, and methylprednisolone, graft rather than avascular allograft bone. following a bilateral hand transplant per- which was tapered over 6 months to Two of these transplant patients were formed in Innsbruck, Austria. The patient cyclosporine monotherapy, three patients managed initially with postoperative was a healthy 47-year-old policeman who underwent transplantation of vascularized heparin and later switched to aspirin and lost his hands attempting to defuse a femoral diaphyses and five patients phenprocoumon. How long anticoagula- bomb 6 years prior to his transplant. The underwent transplantation of the entire tion is required is undetermined. immunosuppressive regimen used in his knee, including the extensor mechanism Although it appears this technique is case included antithymocyte globulin and joint capsule. According to their most potentially feasible, the indications induction therapy, methylprednisolone recent report, four of these eight patients remain elusive. Is it logical to attempt (later tapered to prednisone), tacrolimus, (two from each group) are currently transplanting allograft bone into a previ- and mycophenolate mofetil. Additionally, weight bearing on their transplants. The ously infected soft-tissue bed and then ganciclovir and cotrimoxazole prophylax- authors state that these vascularized bone immunosuppressing the patient? The is was required against cytomegalovirus transplants were “fraught with complica- investigators suggest that vascularized and Pneumocystis carinii, respectively. tions,” largely related to the immunosup- femoral or knee transplant is a “last line Postoperative rehabilitation was inten- pressive medications. Whereas transplant- of defense” for patients facing arthrode- sive, lasting 6 hours per day, 5 days per ing allograft bone into a previously infect- sis or above-knee amputation. Do the week for the first 12 months. Bone heal- ed soft-tissue bed and then adding long- risks of lifelong immunosuppression— ing was complete by clinical and radio-

MAY 2004 | Volume 27 • Number 5 493 ■ Review Article cme ARTICLE Earn Category 1 credits graphic criteria 7 months postoperatively. The risks of life-long immunosuppres- significant, which requires expensive The only wound complication was necro- sion do not outweigh the benefits of a life- medications and ongoing monitoring of sis of a split thickness graft per- saving or -extending procedure such as car- drug levels and possible toxicities. The formed at the initial operation, which diac, liver, and renal transplants. The indi- costs of rehabilitation, ongoing therapy, required debridement and regrafting of a cations for hand transplant are not clear; and the possible costs of treating compli- 3- to 4-cm area on the left forearm. Acute Margreiter et al42 state that only bilateral cations also must be considered. The issue rejection occurring on postoperative days hand loss is an indication for transplant, as regarding funding of this type of experi- 55 and 188 as characterized by diffuse the patient with unilateral hand loss is sure mental remains unresolved. erythema. The earlier episode was more to be disappointed when comparing the Ethical considerations have not been severe and required treatment with intra- transplanted hand to his or her own. an active area of until venous methylprednisolone and topical Perhaps the use of a prosthesis for a pre- recently. With the advent of vascularized steroids and tacrolimus. The second, scribed period of time should be required. bone and composite tissue allografting, milder episode was treated with topical ethical debates are already raging.44,45 In tacrolimus alone. addition to considering the usual issues Functional results at this time are Transplanting bone from surrounding , the ethics of described as 60% of normal hand func- who is a worthy recipient and who will tion, meaning active range of motion of one human to another is handle the costs will be an ongoing debate the fingers, wrist, and forearm average an idea that has been with among ethicists as it has been in the field 60% of normal. Full reinnervation us for hundreds of years of solid . Will it be occurred with sensation present through- more difficult to solicit donation of non- out (although decreased in the ulnar dis- and circumvents some of vital but cosmetically and psychological- tribution of one hand), normal skin tex- the problems with ly important body parts from donor fami- ture, sweat pattern, and hair growth. The ly members? patient has some weakness but is able to autogenous bone grafting. demonstrate grip and pinch strengths in THE FUTURE both hands and is able to perform activi- These are exciting times in orthopedic ties such as turning the pages of a news- Although the patient may feel strongly surgery. We are closing in on the ability to paper, writing with a pen, using a tele- that the potential benefits outweigh the replace bone with synthetic materials, phone and computer, eating, and caring definite risks and pass all the psychiatric which will spare our patients pain and for personal hygiene. He continues to evaluations, many variables remain. additional surgery while providing opti- have difficulty buttoning a shirt, but has Steroids, a component of every immuno- mal healing. We are also investigating returned to work and reports that the suppressive regimen and a potent weapon transplanting bones, , and limbs results have exceeded his expectations. against graft rejection, are known to cause using immunosuppressive drugs bor- He is able to perform activities that he psychosis. In steroid psychosis, the rowed from our transplant surgery col- was unable to do using the myoelectric patient could become disoriented, agitat- leagues as a means of repairing or replac- prostheses. ed and potentially damage or destroy the ing the most devastating bone loss. Who Composite tissue allografting is a com- graft. Will the patient be able to follow the will win the race between tissue engineer- plex subject. Although this policeman has rigorous postoperative rehabilitation pro- ing and transplantation technologies? avoided complications of immunosuppres- tocol? How long does the therapy last? Across the broad spectrum of bone loss sive therapy to date, he remains at high risk Margreiter et al42 initially recommended problems, both approaches are making for infections, drug toxicities, and malig- 12 months of therapy but notes that their valuable contributions. nancy. Steroids are known to cause healing patient is continuing with therapy after 18 problems; that this patient was able to heal months, perhaps with the hope of contin- REFERENCES bone, tendon, muscle, and skin with only ued improvement in hand function. Some 1. Macewan W. Observations concerning trans- initial loss of a small autologous skin graft amount of maintenance therapy must also plants of bone. Proc R Soc Lond. 1881; 32:232. is remarkable. Tacrolimus significantly be important. 2. Phemister DB. The fate of transplanted bone increases risk of lymphoma, but interest- The resources required for limb trans- and regenerative power of its various con- ingly, it also increases synthesis of axoto- plantation are enormous. In addition to the stituents. Surg Gynecol Obstet. 1914; 19:303. my-induced growth-associated protein cost of pretransplant evaluation and the 3. Albee F. Fundamentals in bone transplanta- (GAP-43), which may speed regener- surgery and immediate postoperative care, tion: experiences in three thousand bone graft operations. JAMA. 1923; 81:1429-1432. ation.43 the cost of immunosuppressive therapy is

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4. Sandhu HS, Grewal HS, Parvataneni H. 19. Amr SM, El-Mofty AO, Amin SN. Anterior 33. Pelker RR, Friedlaender GE, Markham TC. Bone grafting for spinal fusion. Orthop Clin versus posterior approach in reconstruction Biomechanical properties of bone allografts. North Am. 1999; 30:685-698. of infected nonunion of the tibia using the Clin Orthop. 1983; 174:54-57. 5. Burwell R. Studies in the transplantation of vascularized fibular graft: potentialities and 34. Wingenfeld C, Egli R, Hempfing A, Ganz R, bone, VII: the fresh composite homograft-auto- limitations. Microsurgery. 2002; 22:91-107. Leunig M. Cryopreservation of osteochon- graft of cancellous bone. An analysis of factors 20. LeCroy CM, Rizzo M, Gunneson EE, dral allografts: dimethyl sulfoxide promotes leading to osteogenesis in marrow transplants Urbaniak JR. Free vascularized fibular bone angiogenesis and immune tolerance in mice. and in marrow-containing bone grafts. J Bone grafting in the management of femoral neck J Bone Joint Surg Am. 2002; 84:1420-1429. Joint Surg Br. 1964; 46:110-140. nonunion in patients younger than fifty years. 35. Enneking WF, Campanacci DA. Retrieved 6. Younger EM, Chapman MW. Morbidity at J Orthop Trauma. 2002; 16:464-472. human allografts: a clinicopathological study. bone graft donor sites. J Orthop Trauma. 21. Vail TP, Urbaniak JR. Donor-site morbidity J Bone Joint Surg Am. 2001; 83:971-986. 1989; 3:192-195. with use of vascularized autogenous fibular 36. Getty PJ, Peabody TD. Complications and 7. Finkemeier CG. Bone-grafting and bone- grafts. J Bone Joint Surg Am. 1996; 78:204- functional outcomes of reconstruction with graft substitutes. J Bone Joint Surg Am. 211. an osteoarticular allograft after intra-articular 2002; 84:454-464. 22. Tang CL, Mahoney JL, McKee MD, resection of the proximal aspect of the 8. Gazdag AR, Lane JM, Glaser D, Forster RA. Richards RR, Waddell JP, Louie B. Donor humerus. J Bone Joint Surg Am. 1999; Alternatives to autogenous bone graft: effica- site morbidity following vascularized fibular 81:1138-1146. cy and indications. J Am Acad Orthop Surg. grafting. Microsurgery. 1998; 18:383-386. 37. Gebhardt MC, Roth YF, Mankin HJ. 1995; 3:1-8. 23. Fideler B, Vangsness C, Moore T, Li Z, Osteoarticular allografts for reconstruction in 9. Stevenson S. Biology of bone grafts. Orthop Rasheed S. Effects of gamma irradiation on the proximal part of the humerus after exci- Clin North Am. 1998; 30:543-552. the human immunodeficiency virus. A study sion of a musculoskeletal tumor. J Bone Joint in frozen human bone-patellar ligament-bone Surg Am. 1990; 72:334-345. 10. Malloy KM, Hilibrand AS. Autograft versus grafts obtained from infected cadavera. J 38. Czitrom AA, Gross AE. Allografts in allograft in degenerative cervical disease. Bone Joint Surg Am. 1994; 76:1032-1035. Clin Orthop. 2002; 394:27-38. Orthopaedic Practice. Philadelphia, Pa: 24. Campbell DG, Li P. Sterilization of HIV with Williams and Wilkins; 1992. 11. Weiland AJ. Current concepts review: vascu- irradiation: relevance to infected bone allo- 39. Hofmann GO, Kirschner MH, Wagner FD, larized free bone transplants. J Bone Joint grafts. Aust N Z J Surg. 1999; 69:517-521. Surg Am. 1981; 63:166-169. Brauns L, Gonschorek O, Buhren V. Allo- 25. Urist MR, Dowell T. Inductive substratum geneic vascularized grafting of human knee 12. Stevenson S. Enhancement of fracture heal- for osteogenesis in pellets of particulate bone joints under postoperative immunosuppres- ing with autogenous and allogeneic bone matrix. Clin Orthop. 1968; 61:61-78. sion of the recipient. World J Surg. 1998; grafts. Clin Orthop. 1988; 355:S239-S246. 26. Connolly JF. Injectable bone marrow prepa- 22:818-823. 13. Zaidemberg C, Siebert J, Angrigiani C. A new rations to stimulate osteogenic repair. Clin 40. Hofmann GO, Kirschner MH. Clinical expe- vascularized bone graft for scaphoid non- Orthop. 1995; 313:8-18. rience in allogeneic vascularized bone and union. J Hand Surg Am. 1991; 16:474-478. 27. Prewett AB, Moyer MP, O’Leary RK, joint allografting. Microsurgery. 2000; 14. Shin AY, Bishop AT. Pedicled vascularized Mellonig JT. Decalcification process inacti- 20:375-383. bone grafts for disorders of the carpus: vates HIV in spiked and infected bone. 41. Petit F, Minns AB, Dubernard J, Hettiaratchy scaphoid nonunion and Kienbock’s disease. J Transactions of the Orthopaedic Research S, Lee WP. Composite tissue allotransplanta- Am Acad Orthop Surg. 2002; 10:210-216. Society. 1992; 17:436. tion and reconstructive surgery: first clinical 15. Urbaniak JR, Coogan PG, Gunneson EB, 28. Pelker RR, Friedlaender GE, Markham TC, applications. Ann Surg. 2003; 237:19-25. Nunley JA. Treatment of osteonecrosis of the Panjabi M, Moen C. Effects of freezing and 42. Margreiter R, Brandacher G, Ninkovic M, femoral head with free vascularized fibular freeze-drying on the biomechanical proper- Steurer W, Kreczy A, Schneeberger S. A dou- grafting. A long-term follow-up study of one ties of rat bone. J Orthop Res. 1984; 1:405- ble-hand transplant can be worth the effort! hundred and three hips. J Bone Joint Surg 411. Transplantation. 2002; 74:85-90. Am. 1995; 77:681-694. 29. Musculoskeletal Transplant Foundation. 43. Gold BG, Yew JY, Zeleny-Pooley M. The 16. El-Gammal TA, El-Sayed A, Kotb MM. Available at http://www.mtf.org. Accessed immunosuppressant FK506 increases GAP- Hypertrophy after free vascularized fibular December 20, 2002. 43 mRNA levels in axotomized sensory neu- transfer to the lower limb. Microsurgery. rons. Neurosci Lett. 1998; 241:25-28. 2002; 22:367-370. 30. AATB Information Alert. McLean, Va: American Association of Tissue Banks; 44. Jones N. Concerns about human hand trans- 17. Weiland AJ, Weiss AP, Moore JR, Tolo VT. 1993. plantation in the 21st century. J Hand Surg Vascularized fibular grafts in the treatment of Am. 2002; 27:771-787. congenital pseudarthrosis of the tibia. J Bone 31. Szabo RM, Thorson EP, Raskind JR. Joint Surg Am. 1990; 72:654-662. Allograft replacement with distal radioulnar 45. Breidenbach WC III, Tobin GR II, Gorantla joint fusion and ulnar for treat- VS, Gonzalez RN, Granger DK. A position 18. Tu YK, Yen CY, Yeh WL, Wang IC, Wang ment of giant cell tumors of the distal radius. statement in support of hand transplantation. KC, Ueng WN. Reconstruction of posttrau- J Hand Surg Am. 1990; 15:929-933. J Hand Surg Am. 2002; 27:760-770. matic long bone defect with free vascularized bone graft: good outcome in 48 patients with 32. Langer F, Czitrom AA, Pritzker KP, Gross 6 years’ follow-up. Acta Orthop Scand AE. The immunogenicity of fresh and frozen Suppl. 2001; 72:359-364. allogeneic bone. J Bone Joint Surg Am. 1975; 57:216-220.

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