Regeneration in medicine: A plastic surgeons “tail” of disease,stem cells,and a possible future

Regeneration in medicine is a concept that has roots dating back to the earliest known records of medical interventions. Unfortunately, its elusive promise has still yet to become a reality. In the field of plastic surgery, we use the common tools of the surgeon grounded in basic operative principles to achieve the present day equivalent of regenerative medicine. These reconstructive efforts involve a broad range of clinical deformities, both congenital and acquired. Outlined in this review are comments on clinical conditions and the current limitations to reconstruct these clinical entities in the effort to practice regenerative medicine. Cleft lip, microtia, breast reconstruction, and burn reconstruction have been selected as examples to demonstrate the incredible spectrum and diverse challenges that plastic surgeons attempt to reconstruct. However, on a molecular level, these vastly different clinical scenarios can be unified with basic understanding of development, alloplastic integration, wound healing, cell–cell, and cell‐matrix interactions. The themes of current and future molecular efforts involve coalescing approaches to recapitulate normal development in clinical scenarios when reconstruction is needed. It will be a better understanding of stem cells, scaffolding, and signaling with extracellular matrix interactions that will make this future possible. Eventually, reconstructive challenge will utilize more than the current instruments of surgical steel but engage complex interventions at the molecular level to sculpt true regeneration. Immense amounts of research are still needed but there is promise in the exploding fields of tissue engineering and stem cell biology that hint at great opportunities to improve the lives of our patients. Birth Defects Research (Part C) 84:322–334, 2008. © 2008 Wiley‐Liss, Inc.     

Factors affecting outcome in free-tissue transfer in the elderly

Free-tissue transfers have become the preferred surgical technique to treat complex reconstructive defects. Because these procedures typically require longer operative times and recovery periods, the applicability of free-flap reconstruction in the elderly continues to require ongoing review. The authors performed a retrospective analysis of 100 patients aged 65 years and older who underwent free-tissue transfers to determine preoperative and intraoperative predictors of surgical complications, medical complications, and reconstructive failures. The parameters studied included patient demographics, past medical history, American Society of Anesthesiology (ASA) status, site and cause of the defect, the free tissue transferred, operative time, and postoperative complications, including free-flap success or failure. The mean age of the patients was 72 years. A total of 46 patients underwent free-tissue transfer after head and neck ablation, 27 underwent lower extremity reconstruction in the setting of peripheral vascular disease, 10 had lower extremity traumatic wounds, nine had breast reconstructions, four had infected wounds, two had chronic wounds, and two underwent transfer for lower extremity tumor ablation. Two patients had an ASA status of 1, 49 patients had a status of 2, 45 patients had a status of 3, and four had a status of 4. A total of 104 flaps were transferred in these 100 patients. There were 49 radial forearm flaps, 34 rectus abdominis flaps, seven latissimus dorsi flaps, seven fibular osteocutaneous flaps, three omental flaps, three jejunal flaps, and one lateral arm flap. Four patients had planned double free flaps for their reconstruction. Mean operative time was 7.8 hours (range, 3.5 to 16.5 hours). The overall flap success rate was 97 percent, and the overall reconstructive success rate was 92 percent. There were six additional reconstructive failures related to flap loss, all of which occurred more than 1 month after surgery. Patients with a higher ASA designation experienced more medical complications (p = 0.03) but not surgical complications. Increased operative time resulted in more surgical complications (p = 0.019). All eight cases of reconstructive failure occurred in patients undergoing limb salvage surgery in the setting of peripheral vascular disease. Free-tissue transfer in the elderly population demonstrates similar success rates to those of the general population. Age alone should not be considered a contraindication or an independent risk factor for free-tissue transfer. ASA status and length of operative time are significant predictors of postoperative medical and surgical morbidity. The higher rate of reconstructive failure in the elderly peripheral vascular disease population compares favorably with other treatment modalities for this disease process.     

Free omental tissue transfer for extremity coverage and revascularization

Microvascular transfer of the omentum has several unique advantages for the reconstruction and revascularization of extremity wounds. The omentum provides well-vascularized, malleable tissue for reconstruction of extensive soft-tissue defects and has a long vascular pedicle (35 to 40 cm) with sizable vessels, which reduces some of the potential technical challenges of microsurgery. It can also be used for flow-through revascularization of ischemic distal extremities. The unique properties of the omentum make it an ideal tissue for the reconstruction of difficult extremity defects, allowing simultaneous reconstruction and revascularization. Experience with six free omental tissue transfers for upper-extremity and lower-extremity reconstruction is described. Three of the cases involved distal anastomoses to take advantage of the flow-through characteristics of the flap, providing distal arterial augmentation. All flaps accomplished the reconstructive goals of wound coverage and extremity revascularization. The omentum is a valuable, often overlooked tissue for the treatment of difficult extremity wounds.     

Total mandibular and lower lip reconstruction with a prefabricated osteocutaneous free flap.

Large, complex bony defects can be a vexing problem for the reconstructive surgeon, especially when standard donor sites are not available or do not provide sufficient tissue. Using the concept of flap prefabrication, we demonstrated in a single patient that (1) iliac crest bone chips and bone morphogenic protein in an alloplastic mandibular tray can ossify in a heterotopic location and (2) neovascularization sufficient to support a large, custom-designed bone graft occurs within a convenient "carrier" flap. Ultimately, the fields of angiogenesis and osteogenesis research could significantly contribute to the ability of the plastic surgeon to construct the "ideal" composite prefabricated flap for complicated reconstruction.     

Hyperbaric oxygen therapy in plastic surgery: a review article

The most important effects of hyperbaric oxygen (HBO), for the surgeon, are the stimulation of leukocyte microbial killing, the enhancement of fibroblast replication, and increased collagen formation and neovascularization of ischemic tissue. Preoperative hyperbaric oxygen induces neovascularization in tissue with radionecrosis. Refractory osteomyelitis and necrotizing fasciitis appear to respond to adjunctive hyperbaric oxygen. Crush injury and compartment syndrome appear to benefit through preservation of ATP in cell membranes, which limits edema. Hyperbaric oxygen in burn injury permits shorter hospital stays, a reduced number of surgeries, and less fluid replacement. Skin grafts and flaps are reported to take more completely and more rapidly. The same mechanisms may apply in ischemic problem wounds such as infected diabetic extremities. Contraindications and side effects are described. Hyperbaric oxygen will not heal normal wounds more rapidly but may, under certain circumstances, induce problem wounds to heal more like normal ones.     

Salvage of functional elbow range of motion in complex open injuries using a sensate transposition lateral arm flap

Complex open posterior elbow injuries pose three principal challenges to the reconstructive surgeon. First, the surgeon must provide stable soft-tissue closure over the joint/skeletal reconstruction. Second, the coverage must be thin and supple and promote the free gliding of the underlying structures. Finally, secondary and tertiary procedures must be anticipated beneath the flap, because a stiff, scarred, and adherent flap will only compromise these procedures. The results of 10 consecutive fasciocutaneous transposition lateral arm flaps for coverage of posterior elbow wounds are reported. This flap provides coverage that is thin and supple and that allows subsequent elevation for secondary procedures. Functionally, these flaps allowed for the development of an average arc of motion of 20 to 114 degrees and an average pronation-supination motion of 119 degrees.     

Tissue engineering of bone: the reconstructive surgeon's point of view

Bone defects represent a medical and socioeconomic challenge. Different types of biomaterials are applied for reconstructive indications and receive rising interest. However, autologous bone grafts are still considered as the gold standard for reconstruction of extended bone defects. The generation of bioartificial bone tissues may help to overcome the problems related to donor site morbidity and size limitations. Tissue engineering is, according to its historic definition, an "interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function". It is based on the understanding of tissue formation and regeneration and aims to rather grow new functional tissues than to build new spare parts. While reconstruction of small to moderate sized bone defects using engineered bone tissues is technically feasible, and some of the currently developed concepts may represent alternatives to autologous bone grafts for certain clinical conditions, the reconstruction of large-volume defects remains challenging. Therefore vascularization concepts gain on interest and the combination of tissue engineering approaches with flap prefabrication techniques may eventually allow application of bone-tissue substitutes grown in vivo with the advantage of minimal donor site morbidity as compared to conventional vascularized bone grafts. The scope of this review is the introduction of basic principles and different components of engineered bioartificial bone tissues with a strong focus on clinical applications in reconstructive surgery. Concepts for the induction of axial vascularization in engineered bone tissues as well as potential clinical applications are discussed in detail.     

The posterior calf fascial free flap

Six posterior calf fascial free flaps were employed to reconstruct defects of the upper and lower extremities. One flap failed due to a constricting dressing. Two flaps sustained partial loss secondary to bleeding and hematoma formation. One flap dehisced at the distal suture line due to mobility of an underlying fracture. All surviving flaps eventually healed and resulted in stable, thin coverage. Donor-site morbidity has been minimal. Shortcomings of this flap model have been defined in the peculiarities of its thinness, diffuse vascular oozing, the extent of the vascular territory, and in postoperative monitoring. These problems are analyzed and recommendations for their resolution are presented. Fascia represents a unique tissue which offers an exciting new dimension in the reconstruction of certain defects--particularly those in which thinness is a desirable option. In the posterior calf model, the inclusion of fat represents an alternative modification that allows the surgeon to tailor the design to a variety of problems where fascia alone is too thin and a cutaneous flap is too thick. This concept may find its greatest application in wounds involving the hand or foot. We believe that this and other fascial flap prototypes may offer an ideal solution for reconstruction of major wounds of the extremities.     

Chest-wall deformity following soft-tissue expansion for breast reconstruction

We have presented a case in which the presumed pressure effects of tissue expansion caused multiple nondisplaced rib fractures of the anterior thorax in a patient undergoing breast reconstruction. Although the deformity was severe, a satisfactory cosmetic result was obtained and there have been no clinically significant sequelae during a 1-year follow-up period. The degree of bony deformation was most likely enhanced by the combination of this patient's severe osteoporosis, chronic steroid use, and peripheral vascular disease. The fragility and ease of fracture in the bones of osteoporotic postmenopausal females and the long-term effects of steroids on tissues is well known. We believe this observation to be important, since many reconstructed patients are postmenopausal and have variable degrees of osteoporosis. Many undergo adjuvant chemotherapy with steroids and antihormonal agents, and this group of women may therefore be at a greater risk for the occurrence of pressure deformities. The incidence and long-term significance of such deformities are not known. The reconstructive surgeon should be alert to the possibility of this phenomenon occurring as a result of tissue expansion in the patient with severe osteoporosis, peripheral vascular disease, or chronic steroid use.     

Alternatives to thumb replantation

LEARNING OBJECTIVES: After studying this article, the participant should: 1. Have a variety of options for thumb reconstruction. 2. Know the advantages and disadvantages of the nonmicrosurgical and microsurgical techniques for thumb reconstruction. 3. Understand the decision making from the variety of thumb reconstruction techniques based on patient needs. 4. Have a basic understanding of the various thumb reconstruction techniques discussed. The traumatic amputation of the thumb is an absolute indication for attempted replantation. The profound disability of the hand resulting from absence of the thumb, with loss of pinch and grasp, obliges the surgeon to make every attempt to replant the amputated thumb and preserve hand function. However, not all attempts at replantation result in survival of the amputated portion, and unreconstructable damage to or complete loss of the amputated part may preclude attempted replantation. In such situations, the surgeon must have alternative methods of dealing with the sequelae of thumb loss. This article will discuss nonmicrosurgical and microsurgical techniques for thumb reconstruction.     

The integrated approach to suppurative mediastinitis: rewiring the sternum over transposed omentum

Acute mediastinitis after cardiopulmonary procedures remains a devastating complication and a challenge to the reconstructive surgeon. A review of the literature and our own experience confirm the need for early aggressive drainage followed by timely reconstruction. In carefully selected patients, the sternum may be reclosed, provided that omental tissue has been transposed into the defect between the myocardium and the posterior cortex of the sternum. The technique is outlined and the results are analyzed and compared with three additional patient subgroups: (1) sternal wounds rewired over drains, (2) sternal wounds rewired with drains and irrigation catheters, and (3) wounds closed by sternal excision and muscle-flap transposition. To date, nine omental transfers have been performed with complete success. Mediastinal drainage routinely ceases after 3 to 5 days, and hospitalization has averaged 10 to 14 days. Early open debridement allows establishment of drainage and permits close evaluation of the character of the bony sternum. Muscle flaps may then be used in those patients with multiply fractured or frankly necrotic sternal tissue, while sternal closure over omental flaps may be used in all other patients. Adherence to this protocol has allowed for bacteriologic control of the wound, minimal morbidity, and no mortality.     

Expanding the horizons in treatment of severe peripheral vascular disease using microsurgical techniques

The use of microvascular tissue transfer as an adjunct to arterial reconstruction has begun to have a positive impact on limb salvage in patients with advanced arteriosclerosis and nonhealing ischemic wounds. However, many patients with severe peripheral vascular insufficiency not amenable to conventional arterial reconstructive procedures eventually require limb amputation. We have treated 12 patients with advanced peripheral vascular disease and nonhealing ischemic wounds by three different methods. These included distal bypass alone, distal bypass done in conjunction with free-tissue transfer, and free-tissue transfer alone. All bypass grafts were done to vessels at or below the ankle using a reversed saphenous vein. In each case, the distal anastomosis was performed, using the operating microscope and standard microvascular technique. Mean follow-up for these patients is 18 months. Distal bypass alone resulted in limb salvage in three of five patients. In the combined bypass and free-flap group, three of five patients had salvage of their threatened extremity at a 1-year follow-up. Two patients with ischemic ulcers, rest pain, and unsuitable distal vessels for bypass were treated with free-tissue transfer alone. This resulted in healed wounds, limb salvage, and complete resolution of the rest pain symptoms in both patients. When advanced ischemia is complicated by large areas of tissue loss, combined bypass and microvascular free-issue transfer, performed in stages or simultaneously, is safe and can often result in limb salvage. In the rare instance of a completely obliterated distal runoff bed, free-tissue transfer alone may provide not only a healed wound, but also a means of "indirect" revascularization of the extremity and limb salvage.     

Prefabrication of 3D Cartilage Contructs: Towards a Tissue Engineered Auricle – A Model Tested in Rabbits

The reconstruction of an auricle for congenital deformity or following trauma remains one of the greatest challenges in reconstructive surgery. Tissue-engineered (TE) three-dimensional (3D) cartilage constructs have proven to be a promising option, but problems remain with regard to cell vitality in large cell constructs. The supply of nutrients and oxygen is limited because cultured cartilage is not vascular integrated due to missing perichondrium. The consequence is necrosis and thus a loss of form stability. The micro-surgical implantation of an arteriovenous loop represents a reliable technology for neovascularization, and thus vascular integration, of three-dimensional (3D) cultivated cell constructs. Auricular cartilage biopsies were obtained from 15 rabbits and seeded in 3D scaffolds made from polycaprolactone-based polyurethane in the shape and size of a human auricle. These cartilage cell constructs were implanted subcutaneously into a skin flap (15×8 cm) and neovascularized by means of vascular loops implanted micro-surgically. They were then totally enhanced as 3D tissue and freely re-implanted in-situ through microsurgery. Neovascularization in the prefabricated flap and cultured cartilage construct was analyzed by microangiography. After explantation, the specimens were examined by histological and immunohistochemical methods. Cultivated 3D cartilage cell constructs with implanted vascular pedicle promoted the formation of engineered cartilaginous tissue within the scaffold in vivo. The auricles contained cartilage-specific extracellular matrix (ECM) components, such as GAGs and collagen even in the center oft the constructs. In contrast, in cultivated 3D cartilage cell constructs without vascular pedicle, ECM distribution was only detectable on the surface compared to constructs with vascular pedicle. We demonstrated, that the 3D flaps could be freely transplanted. On a microangiographic level it was evident that all the skin flaps and the implanted cultivated constructs were well neovascularized. The presented method is suggested as a promising alternative towards clinical application of engineered cartilaginous tissue for plastic and reconstructive surgery.     

Lower extremity microsurgical reconstruction

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the indications for the use of free-tissue transfer in lower extremity reconstruction. 2. Understand modalities to enhance the healing and care of soft tissue and bone before free-tissue transfer. 3. Understand the lower extremity reconstructive ladder and the place of free-tissue transfer on the ladder. 4. Understand the specific principles of leg, foot, and ankle reconstruction. 5. Understand the factors that influence the decision to perform an immediate versus a delayed reconstruction. Free-tissue transfer using microsurgical techniques is now routine for the salvage of traumatized lower extremities. Indications for microvascular tissue transplantation for lower extremity reconstruction include high-energy injuries, most middle and distal-third tibial wounds, radiation wounds, osteomyelitis, nonunions, and tumor reconstruction. The authors discuss the techniques and indications for lower extremity reconstruction.     

Vascular delay revisited

The technique of vascular delay has been used by plastic surgeons for nearly 500 years and has proven useful for reliably transferring tissue and allowing for a greater volume of tissue to be reliably harvested. Delay procedures are an essential plastic surgical tool for a variety of aesthetic and reconstructive procedures. Despite the widespread use of vascular delay procedures, the mechanism by which this phenomenon occurs remains unclear. A number of groups have exhaustively examined microvascular changes that occur during vascular delay. Theories have been proposed ranging from the dilation of choke vessels to changes in metabolism and new blood vessel formation. Inherent in these theories is the concept that ischemia is able to act as the primary stimulus for vascular changes. The purpose of this review is to revisit the theories proposed to underlie the delay phenomenon in light of recent advances in vascular biology. In particular, the participation of bone marrow-derived endothelial progenitor cells in the delay phenomenon is explored. Greater understanding of the role these cells play in new blood vessel formation will be of considerable clinical benefit to high-risk patients in future applications of delay procedures.     

Principals of neovascularization for tissue engineering

The goals in tissue engineering include the replacement of damaged, injured or missing body tissues with biological compatible substitutes such as bioengineered tissues. However, due to an initial mass loss after implantation, improved vascularization of the regenerated tissue is essential. Recent advances in understanding the process of blood vessel growth has offered significant tools for therapeutic neovascularization. Several angiogenic growth factors including vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) were used for vascularization of ischemic tissues. Three approaches have been used for vascularization of bioengineered tissue: incorporation of angiogenic factors in the bioengineered tissue, seeding endothelial cells with other cell types and prevascularization of matrices prior to cell seeding. This paper reviews the process of blood vessel growth and tissue vascularization, and discuss strategies for efficient vascularization of engineered tissues.     

Soft-tissue expansion: concepts and complications

Soft-tissue expansion complements existing reconstructive techniques and provides new vistas for the plastic surgeon. The technique finds use for overcoming a shortage of tissue, for obtaining skin with special desirable qualities, for creation of flaps otherwise not possible because of the resultant donor site or limited vascularity, for creation of flaps with functioning muscle and overlying soft tissue, and for minimizing flap donor-site problems. Careful planning should include patient counseling, optimum incision placement, and time for a leisurely, complete expansion. The surgery can often be performed under local anesthesia and expansion is tolerated well. Patients should be counseled that the incidence of major complications in an unselected series is 1 in 4 patients. Major complications, however, typically result in a delay in reconstruction and not tissue loss.     

组织工程的突破与挑战——组织工程国家工程中心科研进展

组织工程技术已被普遍认为是解决组织、器官缺损修复与功能重建的有效手段,它的飞速发展依赖于细胞学、材料学、工程学、临床医学等多学科的交叉渗透.作为组织工程的三大核心,种子细胞、生物材料、组织构建各方面的突破,为组织工程技术的发展奠定了基础.组织工程国家工程中心近年来围绕上述核心开展了系列研究,通过研究胚胎干细胞、成体干细胞、同种异体干细胞、以及发育同源细胞替代的探索,为解决种子细胞来源问题提供了多种选择;生物支架材料的开发,为细胞增殖分化、组织再生提供理想的支持与空间,而生物反应器的开发与应用,进一步提高了组织构建技术,为促进组织的体外形成、重塑和功能成熟创造了条件.在此基础上,开展了大动物体内组织构建和缺损修复的研究,形成了以应用为目标的研究特色,并成功将部分技术应用于临床治疗.本文将对组织工程国家工程中心已有进展做简单介绍并对面临的挑战进行分析.     

Endothelial development taking shape

Blood vessel development is a vital process during embryonic development, during tissue growth, regeneration and disease processes in the adult. In the past decade researchers have begun to unravel basic molecular mechanisms that regulate the formation of vascular lumen, sprouting angiogenesis, fusion of vessels, and pruning of the vascular plexus. The understanding of the biology of these angiogenic processes is increasingly driven through studies on vascular development at the cellular resolution. Single cell analysis in vivo, advanced genetic tools and the widespread use of powerful animal models combined with improved imaging possibilities are delivering new insights into endothelial cell form, function and behavior angiogenesis. Moreover, the combination of in silico modeling and experimentation including dynamic imaging promotes insights into higher level cooperative behavior leading to functional patterning of vascular networks. Here we summarize recent concepts and advances in the field of vascular development, focusing in detail on the endothelial cell.