Abstract
Vascularized composite allotransplantation (VCA) represents one of the most complex frontiers in reconstructive surgery, requiring simultaneous transfer of multiple tissue types, including skin, muscle, bone, and nerves. Success depends on the multidisciplinary integration of immunology, surgery, rehabilitation, and psychology. Chang Gung Memorial Hospital has established itself as a pioneer in clinical VCA in Taiwan, contributing significantly through innovative basic research and successful clinical outcomes. This review explores our institutional experience, highlighting clinical cases and groundbreaking preclinical research within our comprehensive VCA program.
Keywords: vascularized composite allotransplantation, immunosuppression, tolerance induction, hand transplantation
Vascularized composite allotransplantation (VCA) encompasses the coordinated transplantation of anatomically and functionally integrated tissue complexes, including skin, muscle, neural components, bone, and vascular structures as unified grafts. These reconstructive procedures primarily address upper extremity, facial, and complex anatomical defects, restoring both morphological continuity and functional capacity in patients with severe composite tissue loss from trauma, malignancy, or congenital abnormalities. 1
Globally, more than 40 facial and over 210 hands/upper extremity VCAs have been performed with encouraging short-term to intermediate-term functional outcomes. Currently, graft rejection prevention follows solid organ transplantation (SOT) strategies. However, unlike SOT, VCA requires immunosuppression for non-life-threatening conditions, presenting unique ethical and clinical challenges ( Table 1 ).
Table 1. The difference between vascularized composite allotransplantation and solid organ transplantation.
| Aspect | VCA | SOT |
|---|---|---|
| Tissue complexity | Multiple tissue types within a single graft | Primarily one organ/tissue type |
| Immunogenicity | Higher (especially due to skin) | Lower (organs such as liver or heart demonstrate greater tolerogenicity) |
| Life-saving versus life-enhancing | Primarily life-enhancing (e.g., limb or face) | Typically life-saving (e.g., heart, liver, kidney) |
| Immunosuppression | Long-term with intensive maintenance protocols; may incorporate topical therapeutic regimens | Long-term with standardized maintenance protocols |
| Ethical concerns | Higher, often addresses quality of life rather than survival | More accepted, often essential for survival |
| Recipient evaluation | More comprehensive, extensive psychological and social assessment parameters | Primarily medical |
| Rejection monitoring | Often involves direct visual inspection and biopsy | Relies on laboratory tests and imaging |
| Histocompatibility matching | Must consider skin tone, limb size, etc. | Mainly blood type, HLA, organ size |
Abbreviations: HLA, human leukocyte antigen; SOT, solid organ transplantation; VCA, vascularized composite allotransplantation.
VCA centers worldwide have evolved significantly since the first successful hand transplantation in 1998. 2 Major institutions across Europe, North America, and Asia have established comprehensive programs combining surgical expertise, immunological research, and multidisciplinary patient care. The Center for VCA at Chang Gung Memorial Hospital, established in 2011, has demonstrated a strong commitment to advancing the field through successful clinical outcomes built on solid basic research foundations. Guided by the “bedside-to-bench-to-bedside” concept ( Fig. 1 ), our center emphasizes integration of clinical observations into fundamental research to drive scientific advancements. Through systematic analysis of real-world patient experiences—encompassing immune responses, graft rejection patterns, and functional recovery trajectories—our research teams develop targeted preclinical models, explore innovative therapeutic approaches, and optimize surgical techniques. This bidirectional exchange between clinical practice and experimental investigation ensures that scientific discoveries maintain clinical relevance and translational potential, ultimately advancing patient care through evidence-based innovations. The following review synthesizes our comprehensive research portfolio, spanning both preclinical investigations and clinical outcomes accumulated over more than a decade of institutional experience.
Fig. 1.
The concept of “bedside-to-bench-to-bedside” approach implemented at Chang Gung VCA Center. Clinical observations from VCA patients inform preclinical research including animal models, mechanistic studies, molecular analysis, and drug delivery studies, which then translate back to improved clinical protocols and patient care. VCA, vascularized composite allotransplantation.
Experimental Models and Preclinical Research
Animal Model Development
Osteomyocutaneous Flap Model
Our center has extensive experience studying VCA using rodent models. While rats provide valuable insights, mice offer superior advantages for immunological research. To overcome the technical challenges of small vessel anastomosis in mice, we developed a non-suture cuff technique. 3 The neck was selected as the preferred recipient site for mouse osteomyocutaneous grafts ( Fig. 2A ), offering improved accessibility and monitoring capabilities. 4 Similarly, in rat studies, neck placement instead of groin positioning provides advantages due to Brown-Norway recipients' active behavior. 5
Fig. 2.
VCA animal models developed at Chang Gung VCA Center. ( A ) Osteomyocutaneous flap model positioned at the neck for improved accessibility and monitoring; and ( B ) mystacial pad model for functional assessment studies. The mystacial pad model demonstrates vascular supply via external carotid artery (red arrow) and external jugular vein (blue arrow), with innervation from buccal and mandibular branches of the facial nerve (white arrow) and sensory supply via the infraorbital nerve (yellow arrow). VCA, vascularized composite allotransplantation.
Mystacial Pad Model
Adapted from Landin et al., 6 the mystacial pad allograft model receives motor innervation from buccal and mandibular branches of the facial nerve and sensory innervation via the infraorbital nerve ( Fig. 2B ). This less destructive model enables functional assessment studies, as the “whisking” behavior depends on intact afferent and efferent signal orchestration, similar to human hand function. Successful sequential transplantation and nerve regeneration have been demonstrated in this VCA model. 7 8
Face Model
Our center also contributed to the facial VCA model development through collaboration with international partners. In 2012, we first described orthotopic hemiface allotransplantation in mice, incorporating skin, muscle, and ear components with a 78% success rate. 9 However, this model was not permissive for the study of donor-specific stem cells due to the lack of a bone component, but may be beneficial for ischemia–reperfusion injury or nerve regeneration studies. Later, we established a heterotopic partial face transplantation model containing skin, mandible, teeth, and oral mucosa. 10 This comprehensive model enables investigation of bone marrow immunomodulatory properties, dental stem cell functions, and mucosal immune responses, critical components reflecting the tissue complexity encountered in clinical facial transplantation scenarios.
Transplant Immunology Research
Tolerance Induction Strategies
Collaborating with researchers at the University of Pittsburgh and Johns Hopkins University, 11 we explored costimulation blockade effectiveness in VCA containing vascularized bone marrow (VBM). Recipients receiving anti-CD154, CTLA4Ig, and short-term rapamycin achieved long-term graft survival (>120 days) with donor-specific tolerance confirmed via skin grafting. 12 This provided the first evidence supporting costimulation blockade with rapamycin facilitating VBM-induced tolerance in stringent murine VCA models.
Compared with conventional bone marrow transplantation, VBM demonstrates superior efficacy in inducing long-term donor-specific tolerance, 13 though VCA outcomes are affected by donor–recipient strain combinations. 5 The tolerance mechanism involves central tolerance, evidenced by thymic chimerism in tolerant VCA models. 12 13 14
Secondary Tolerance and Regulatory Mechanisms
VBM's ability to induce secondary allograft tolerance is evident in mystacial pad allografts transplanted 1 month after VBM, showing higher survival rates compared with controls without VBM transplantation (median survival time [MST] >90 vs. 70 days, p < 0.05). 7 We demonstrated that regulatory T cell (Treg) migration to donor VCA and lymph nodes contributes to donor-specific tolerance maintenance. 15 16
Extended studies examined narrow-band narrow-band ultraviolet B (NB-UVB) irradiation impacts on VBM and graft tolerance promotion. Preliminary findings suggest NB-UVB may reduce graft survival in VCA rat models, though further research is needed to clarify underlying mechanisms. 17 Comprehensive molecular analyses continue to uncover mechanisms for innovative therapy development ( Fig. 3A–C ).
Fig. 3.
Comprehensive molecular analysis and functional assessment techniques employed in VCA research at Chang Gung. ( A ) In vivo bioluminescence imaging (IVIS) for real-time assessment of donor bone marrow viability within transplanted grafts. ( B ) Flow cytometry analysis demonstrating donor cell identification in circulating blood. ( C ) RNA sequencing-based differentially expressed gene (DEG) analysis revealing significantly up- or downregulated genes (log 2 FC ≥2, p _adj <0.05) associated with graft rejection mechanisms. ( D ) Functional magnetic resonance imaging (fMRI) evaluation for capturing blood oxygen level-dependent (BOLD) activation during whisker pad stimulation in the transplanted mystacial pad. ( E ) Toluidine blue histological analysis performed on nerve specimens harvested from distal anastomotic regions to quantify myelinated axon density and assess morphological characteristics of nerve regeneration. VCA, vascularized composite allotransplantation.
Functional Assessment and Neuroplasticity
Functional assessments are vital components of post-VCA rehabilitation. Using our mystacial pad model, we found blood oxygen level-dependent (BOLD) responses to mystacial stimulation disappeared immediately postsurgery and reemerged at 4 weeks, plateauing at 2 months postoperatively. Preoperative BOLD responses localized primarily in the contralateral primary somatosensory cortex barrel field (S1BF). Postoperative BOLD responses were distributed across three locations: S1BF, secondary somatosensory cortex, and upper lip region of the primary somatosensory cortex.
Ultrasound biomicroscopy showed no vascular wall thickening or fibrosis. Microscopic findings revealed myelinated axon reductions of 11% and 37% at coaptation sites and distal locations, respectively. These data demonstrate functional recovery involving neuroplasticity within distributed networks in the primary somatosensory cortex ( Fig. 3D, E ).
Drug Delivery and Regenerative Medicine
Biomaterial-Based Immunosuppression
Current research focuses on bioengineering and regenerative medicine, specifically applying biomaterials for localized immunosuppression. Collaborating with researchers at National Tsing Hua University, we tested thermosensitive hydrogels to encapsulate tacrolimus. These hydrogels provide sustained tacrolimus release with high biocompatibility and biodegradability. A single dose improved both skin and VCA allograft outcomes by prolonging survival and promoting nerve regeneration. 8 18 19 20
Cell Therapy Applications
Cell therapy represents a potential strategy for immune system modulation and tolerance development. 21 Studies have examined adipose-derived stem cells, induced pluripotent stem cells, and Tregs applications. 22 23 24 25 Tregs therapy, currently in clinical trials for SOT, shows VCA potential. We demonstrated that Tregs from tolerant mice exhibited potent immunosuppressive potential, rescued allografts, and delayed rejection. 16 24
In another approach, interleukin (IL)-10 modified messenger ribonucleic acid (modRNA)-based protein replacement provides efficient, safe direct in vivo protein production. This method successfully prolonged survival after composite facial allografting through mixed chimerism induction. 26
Clinical Experience with Upper Extremity Vascularized Composite Allotransplantation
Patient Selection and Preoperative Evaluation
Our VCA program utilizes rigorous selection criteria for upper extremity transplantation candidates. Based on our extensive experience in upper extremity replantation and reconstruction, as well as a comprehensive attitude assessment of Taiwanese hand surgeons and patients, 27 we have established specific indications for upper extremity VCA at Chang Gung: (1) Bilateral hand amputation and (2) above-elbow amputation. These indications reflect both clinical evidence and sociocultural considerations within the Taiwanese health care context.
For above-elbow transplantation, while acknowledging certain limitations, including the absence of intrinsic recovery and substantially reduced extrinsic motor recovery with only protective sensation return, functional improvement remains very encouraging. 28 29 This approach is justified by the greater functional disability and higher prosthesis rejection rates observed in transhumeral amputees compared with transradial amputees, making VCA a valuable reconstructive option for this challenging patient population.
Recipients must have experienced upper limb loss for at least 6 months, with amputation above the wrist level. The screening process begins with clinical consultations where patients receive comprehensive information about alternative reconstructive options, surgical procedures, risks, and requirements for lifelong immunosuppression and rehabilitation.
Since 2016, 24 upper extremity amputees have been screened, with 7 placed on the waiting list after completing multidisciplinary evaluation. The preoperative assessment protocol includes medical, surgical, and psychiatric evaluations. Laboratory screening encompasses complete blood count, liver and renal function tests, blood typing, human leukocyte antigen (HLA) typing, infectious disease screening (HIV, hepatitis B/C, syphilis, cytomegalovirus, Epstein–Barr virus), and tumor markers.
Imaging studies include chest radiography, angiography, functional MRI, and upper extremity vascular ultrasound. Panel reactive antibody (PRA) testing establishes a 30% threshold for VCA eligibility. All candidates undergo crossmatch testing to confirm immunological compatibility prior to transplantation.
Clinical Cases and Surgical Outcomes
Our program has performed two upper extremity transplantations to date. Immunological screening showed that our first patient had PRA-I of 28.0% and PRA-II of 2.9%, while our second patient demonstrated PRA-I of 3.9% and PRA-II of 2.9%. Both patients had negative crossmatch results, confirming transplantation eligibility. Both procedures followed identical immunosuppression induction protocols with intraoperative antithymocyte globulin, tacrolimus, mycophenolate mofetil, and methylprednisolone administration.
Case 1: Bilateral Forearm Transplantation
Our first case, performed in March 2017, involved bilateral forearm transplantation in a 45-year-old male quadruple amputee—1 of only 16 such cases reported worldwide. The patient received grafts with a single HLA match and demonstrated stable tacrolimus levels after initial adjustment ( Fig. 4 ).
Fig. 4.
Clinical outcomes of bilateral forearm transplantation. ( A ) Pretransplantation status showing bilateral forearm amputation. ( B ) Intraoperative appearance of bilateral forearm allografts. ( C ) Functional recovery demonstration with ceremonial first pitch at 6.5 years posttransplantation, illustrating excellent long-term graft integration and motor function. ( D ) Long-term immunological monitoring showing stable tacrolimus therapeutic levels and preserved renal function (creatinine) following initial postoperative adjustment period.
The bilateral procedure required four surgical teams working concurrently, coordinating donor limb procurement and recipient stump preparation. Following microsurgical techniques, reconstruction sequence involved bone fixation at forearm level, arterial and venous anastomoses, muscle and tendon repairs, and nerve repairs, with attention to hemostasis and skin closure using Z-plasty techniques. Forearm flexors and extensors were preserved with intact bony attachments rather than muscle detachment, allowing bone-to-bone fixation for secure connection compared with periosteal reattachment.
Case 2: Above-Elbow Transplantation
The second case, performed in March 2018, was Taiwan's first above-elbow transplantation in a 43-year-old male. The donor limb was procured from Chiayi Chang Gung Memorial Hospital, located 240 km from Linkou Chang Gung Memorial Hospital. The limb was preserved with Histidine-Tryptophan-Ketoglutarate solution during the 2.5-hour transport, involving more proximal level transplantation compared with the previous forearm procedure ( Fig. 5 ).
Fig. 5.
Clinical outcomes of above-elbow transplantation. ( A, B ) Preoperative appearance and radiographic evaluation showing left elbow disarticulation. ( C ) Intraoperative appearance of the above-elbow upper extremity allograft. ( D ) Postoperative radiograph at 1 year demonstrating excellent bone union and osseointegration. ( E ) Patient's ability to grip steering wheel during driving at 2 years and 3 months posttransplantation.
Postoperative Rehabilitation and Functional Recovery
Both patients followed standardized rehabilitation protocols beginning posttransplantation. Passive range-of-motion exercises started on postoperative day 2, progressing to active movements at 3 weeks, neuromuscular electrical stimulation at 4 weeks, and light functional training at 8 weeks. By 3 months, patients were engaged in activities of daily living. Sensory reeducation commenced at 4 to 6 months posttransplantation, followed by vocational training once independent daily function was achieved.
Functional outcomes were assessed using the Hand Transplant Score System, disabilities of the arm, shoulder and hand (DASH) questionnaire, and motor and sensory recovery measurements. The first patient achieved a Hand Transplant Score of 80/100 (good) for both limbs, with S3 sensory recovery in median and ulnar nerve distributions, and motor recovery sufficient for daily activities. Functional MRI studies have demonstrated neuroplasticity in the somatosensory cortex since 4 months posttransplantation.
The second patient achieved a Hand Transplant Score of 77/100 with S3 sensory recovery and motor recovery of biceps and triceps, enabling elbow motion.
Psychosocial Impacts and Quality of Life
Psychosocial dimensions were comprehensively assessed through psychological evaluation before transplantation and ongoing support throughout recovery. Assessments were conducted weekly during the first postoperative month, biweekly for months 2 to 3, monthly for months 4 to 6, every 2 months for months 7 to 12, and every 6 months thereafter, using the Psychiatric Evaluation for Organ Transplantation and Health Questionnaire.
The first patient, having experienced quadruple amputation, demonstrated excellent adaptation to bilateral hand transplantation. The procedure improved hand function and enhanced overall mobility and gait. His psychological and social acceptance scores reached 14/15 on the Hand Transplant Score System, with patient satisfaction and well-being scores of 11/15.
The second patient faced psychological challenges corresponding to his immunological course. He maintained psychological and social acceptance scores of 14/15, with satisfaction scores of 10/15. This patient experienced a non-ST-elevation myocardial infarction requiring coronary intervention during recovery. His DASH score of 8.3 indicates minimal disability in daily function.
Immunological Monitoring and Rejection Episodes
Immunological surveillance was conducted through scheduled skin biopsies and vascular ultrasound monitoring. The first patient experienced two acute rejection episodes (Banff grade II) within the first 6 months posttransplantation, resolving within 2 weeks following high-dose steroid administration and topical immunosuppressant application. After 8 years of follow-up, the patient maintains graft function without further rejection episodes and has been weaned to minimal immunosuppression.
The second patient experienced over 10 cellular rejection episodes (Banff grade III) and three antibody-mediated rejection episodes, requiring treatment with antithymocyte globulin, rituximab, plasmapheresis, and intravenous immunoglobulin. Donor-specific antibodies were detected, with higher levels in the transplanted limb compared with native tissues (11% vs. 2%). Cytokine profile analysis revealed elevated proinflammatory cytokines and chemokines (interferon gamma-induced protein, macrophage inflammatory proteins, regulated on activation, and normal T-cell expressed and secreted) in the transplanted limb during rejection episodes. The patient's immunological stability was affected following COVID-19 infection in 2022, with multiple additional rejection episodes occurring subsequently.
Future Directions and Conclusions
The VCA program at Chang Gung Memorial Hospital continues advancing reconstructive transplantation through excellence, innovation, and patient-centered care. Success depends on close collaboration among medical, civic, and governmental organizations, along with lifelong dedication from patients and health care providers. Our landmark hand allotransplantations highlight interdisciplinary coordination strength, bolstered by robust familial and institutional support.
The program has made significant contributions through groundbreaking research and technological advancements, particularly in tolerance induction, novel drug delivery systems, and cell biology. Current research directions include the development of bioengineered tolerance induction protocols, advanced biomaterial applications for localized immunosuppression, and a comprehensive understanding of neuroplasticity mechanisms in VCA recovery.
Future investigations will focus on minimizing immunosuppression requirements through tolerance induction strategies, developing personalized immunosuppression protocols based on individual patient characteristics, and advancing regenerative medicine applications to enhance functional recovery. The integration of precision medicine approaches with advanced imaging modalities and molecular diagnostics promises to revolutionize VCA outcomes.
With its ambitious approach combining clinical excellence and innovative research, Chang Gung VCA Center will continue driving clinical and preclinical advancements, paving the way for future breakthroughs in reconstructive transplantation.
Acknowledgment
The authors thank Miss Ingrid Kuo and the Center for Big Data Analytics and Statistics at Chang Gung Memorial Hospital for creating Figure 1 illustration. We also acknowledge Zi-Chun Hsu, Zhi-Lin Peng, and staffs at Laboratory Animal Center, Genomic Medicine Core Laboratory, and Microscopy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan, for molecular imaging and technical assistance.
Funding Statement
Funding This work was supported by grants from the National Science and Technology Council of Taiwan (grant nos.: NSTC 112-2314-B-182A-038-MY3, 112-2326-B-182A-002-MY2, and 113-2811-B-182A-013) and Chang Gung Medical Foundation (grant no.: CPRPG3M0021-3).
Conflict of Interest None declared.
These authors contributed equally to this work.
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